CN102766165A

CN102766165A - Methods for synthesizing molybdopterin precursor z derivatives

Info

Publication number: CN102766165A
Application number: CN201210169347XA
Authority: CN
Inventors: 龙翔天; 代丹梅; A·布伦纳; D·K·瓦特; K·克林奇; S·M·巴亚斯; R·A·迪克森; G·M·里特尔; C·A·S·兰德雷; N·G·R·普罗伊塞
Original assignee: Alexion Pharmaceuticals Inc
Current assignee: Alexion Pharmaceuticals Inc
Priority date: 2011-02-18
Filing date: 2012-02-20
Publication date: 2012-11-07

Abstract

Provided herein are synthetic methods for preparing a compound of formula (I): Also provided herein are synthetic methods for preparing a compound of formula (XIII): The disclosure also provides useful intermediates, derivatives, prodrugs, and pharmaceutically acceptable salts, solvates and hydrates of the formula (I) and formula (XIII) compounds. These compounds are useful for treating diseases associated with molybdenum cofactor deficiency.

Description

The method of synthetic molybdenum pterin precursor Z verivate

The cross reference of related application

The application requires to enjoy the U.S. Provisional Application of submitting on February 18th, 2,011 61/444; 389,61/498 of submission on June 20th, 2011; 801,61/498 of submission on June 20th, 2011; 61/599,314 the right of priority of submitting on February 15th, 808 and 2012, its full content mode is by reference incorporated the application into.

Technical field

The application provides the new synthetic intermediate that is used to prepare the compound method of molybdenum pterin (molybdopterin) verivate precursor Z and is used for synthesizing it.The application also provides useful as intermediates, verivate, prodrug and pharmaceutical salts, solvolyte and the hydrate of precursor Z.These compounds are particularly useful for treatment and lack (molybdenum cofactor deficiency) relevant disease with the molybdenum coenzyme.

Background technology

It is a kind of polyphenic genetic block that molybdenum coenzyme (Moco) lacks.Moco is made up of the molybdenum of covalently bound two thiolate that partly are connected to one or two and unique three cycloptern, is referred to as molybdenum pterin (MPT) usually.Moco is synthetic through biosynthetic pathway; Said biosynthetic pathway can according to biosynthesizing midbody precursor Z (ring pyrans and pterin monophosphate (cyclic pyranopterin monophosphate), cPMP), MPT and adenosine acidifying MPT be divided into four steps.The sudden change of Moco biosynthetic enzyme genes causes molybdenum to rely on the loss that enzyme sulphite-oxydase, xanthine oxidoreductase enzyme and aldehyde oxidase produce.All impaired because coenzyme lacks in view of the activity of all these the three kinds enzymes that contain coenzyme, the destructive result of said disease is tracked to sulphite-oxidase activity impaired.But it is a kind of rare serious disease with serious nervous symptoms that people Moco lacks, and said nervous symptoms comprises brain decay growth, the outbreak that can not treat, the lens (ocular lense) and the mental retardation of displacement.Up to date, also do not have the efficacious therapy means, and suffer from the ailing patient that Moco lacks and just die in early days in childhood.

Have now found that administration molybdenum pterin derivatives precursor Z (metastable midbody in a kind of Moco biosynthetic pathway) is a kind of effective treat-ment (referring to USP 7,504,095) that lacks and relate to change Moco synthetic relative disease to people Moco.Yet the same as most of disease alternative medicine, this therapy is subject to the degree capable of using of therapeutic activity agent.

Summary of the invention

Before used fermentation process to prepare precursor Z (formula (I) and (XIII) compound).Yet these methods exist the cost of stability problem, low yield and scale operation to hinder.The alternative techniques of following compound method as these fermentation process proposed.

The application provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

Make the compound of formula (II) compound and formula (III) compound reaction with preparation formula (IV), said formula (II) compound is:

Said formula (III) compound is:

The compound of said formula (IV) is:

Each R wherein ₁Be H or protection base independently;

Selective protection formula (IV) compound is to prepare the compound of formula V:

Make formula V compound phosphorylation with preparation formula (VI) compound:

And make formula (VII) compound deprotection with preparation formula (I) compound.

In some embodiments, said pharmaceutical salts is a hydrochloride.

In some embodiments, said formula (II) compound is:

In some embodiments, said formula (III) compound is shielded or unprotected semi-lactosi, seminose, glucose or gulose.For example, formula (III) compound can be:

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether or Ben Yajiaji ethylidene ether part.

In some embodiments, step (a) is included in and makes formula (II) compound and the reaction of formula (III) compound under the existence of hydrazine.For example, said hydrazine can be selected from phenyl hydrazine and alkyl hydrazine.In some embodiments, said hydrazine is a phenyl hydrazine.

In some embodiments, the phosphorylation of step (c) comprises and makes the reaction of formula V compound and P (V) phosphorylation agent.For example, P (V) phosphorylation agent can be selected from: POCl ₃, H ₃PO ₄, PO (OBn) xCl ₃-x, Cl ₃CCH ₂OP (O) Cl ₂And (BnO) ₂P (O) OP (O) (OBn) ₂In some embodiments, P (V) phosphorylation agent is POCl ₃In some embodiments, the phosphorylation of step (c) comprises and makes formula V compound and P (III) phosphitylation reagent react.For example, P (III) phosphitylation reagent can be selected from: P (OCH ₂CH ₂CN) ₂Cl, P (OCH ₂CH ₂CN) (NPr ₂-i) Cl and cyano ethyl-O-P [N (i-Pr) ₂)].In some embodiments, step (c) further comprises the SULPHOSUCCINIC ACID ESTER of the phosphorous acid ester of oxidation gained with preparation compound (VI).

In some embodiments, step (d) comprises and makes formula (VI) compound and be selected from following oxidant reaction: RuO ₄, Dai Si-Martin's reagent (Dess-Martin), DMSO/ trifluoromethanesulfanhydride anhydride and PDC.

In some embodiments, the deprotection of said formula (VII) compound under anaerobic carries out.

In some embodiments, said formula (IV) compound is:

In some embodiments, said formula V compound is:

In some embodiments, said formula (VI) compound is:

In some embodiments, said formula (VII) compound is:

In some embodiments, this method further comprises formula (I) is formulated as pharmaceutical composition.

The application also provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, and this method comprises: in the presence of hydrazine, make the reaction of formula (II-A) compound and formula (III-A) compound with preparation formula (IV-A) compound, said formula (II-A) compound is:

Said formula (III-A) compound is:

Said formula (IV-A) compound is:

Optionally protection (IV-A) compound is with preparation formula (V-A) compound:

R wherein ₁It is the protection base;

Make formula (V-A) compound phosphorylation with preparation formula (VI-A) compound:

Oxidation-type (VI-A) compound is with preparation formula (VII-A) compound:

Make formula (VII-A) compound deprotection with preparation formula (I) compound.

The application further provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, and this method comprises: in the presence of hydrazine, make the reaction of formula (II-A) compound and formula (III-A) compound with preparation formula (IV-A) compound; Optionally protection (IV-A) compound is with preparation formula (V-B) compound:

Each R wherein ₁Be the protection base independently;

Make formula (V-B) compound phosphorylation with preparation formula (VI-B) compound:

Oxidation-type (VI-B) compound is with preparation formula (VII-B) compound:

Make formula (VII-B) compound deprotection with preparation formula (I) compound.

The application also provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, comprising: make the reaction of formula (II) compound and formula (VIII) compound with preparation formula (IX) compound, said formula (VIII) compound is:

R wherein ₂Said is H or protection base;

Said formula (IX) compound is:

Optionally protection (IX) compound is with preparation formula (X) compound:

R wherein ₃For protecting base;

Oxidation-type (X) compound is with preparation formula (XI) compound:

And make formula (XI) compound deprotection with preparation formula (I) compound.

The application further provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, and this method comprises makes formula (II) compound and the reaction of formula (III) compound with preparation formula (IV) compound; Optionally protection (IV) compound is with preparation formula V compound; Oxidation formula V compound is with preparation formula (XII) compound:

Make formula (XII) compound phosphorylation with preparation formula (VII) compound; And

Make formula (VII) compound deprotection with preparation formula (I) compound.

The application provides formula (IV) compound or pharmaceutically acceptable salt thereof form:

Each R wherein ₁Be H or protection base independently.For example, formula (IV) compound or pharmaceutically acceptable salt thereof form can for:

The application also provides formula V compound or pharmaceutically acceptable salt thereof form:

Each R wherein ₁Be H or protection base independently.For example, formula V compound or pharmaceutically acceptable salt thereof form can be selected from:

In some embodiments, the formula V compound or pharmaceutically acceptable salt thereof is selected from

:

The application further provides formula (VI) compound or pharmaceutically acceptable salt thereof form:

Each R wherein ₁Be H or protection base independently.For example, formula (VI) compound or pharmaceutically acceptable salt thereof form can be selected from:

in some embodiments, formula (VI) compound or pharmaceutically acceptable salt thereof is selected from:

The application provides formula (VII) compound or pharmaceutically acceptable salt thereof form:

Each R wherein ₁Be H or protection base independently.For example, formula (VII) compound or pharmaceutically acceptable salt thereof form is selected from:

in some embodiments, formula (VII) compound or pharmaceutically acceptable salt thereof form is selected from:

The application also provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, and this method comprises:

Make the reaction of formula (II) compound and formula (XXII) compound with preparation formula (IV) compound, said formula (XXII) compound is:

Optionally protection (IV) compound is with preparation formula V compound; Make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation (VII) compound; And make formula (VII) compound deprotection with preparation formula (I) compound.

In some embodiments, said formula (II) compound is:

In some embodiments, said formula (XXII) compound is:

In some embodiments, the phosphorylation of said step (c) comprises and makes the reaction of formula V compound and P (V) phosphorylation agent.For example, P (V) phosphorylation agent can be selected from: POCl ₃, H ₃PO ₄, PO (OBn) xCl ₃-x, Cl ₃CCH ₂OP (O) Cl ₃And (BnO) ₂P (O) OP (O) (OBn) ₂In some embodiments, P (V) phosphorylation agent is Cl ₂PO (OCH ₃).

In some embodiments, step (d) comprises and makes formula (VI) compound and be selected from following oxidant reaction: RuO ₄, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride and PDC.

In some embodiments, said formula (IV) compound is:

In some embodiments, said formula V compound is:

In some embodiments, said formula (VI) compound is:

In some embodiments, said formula (VII) compound is:

The application also provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises: in the presence of hydrazine, make the reaction of formula (II-A) compound and formula (XXII-A) compound with preparation formula (IV-A) compound, said formula (II-A) compound is:

Said formula (XXII-A) compound is:

Said formula (IV-A) compound is:

Optionally protection (IV-A) compound is with preparation formula (V-C) compound:

Make formula (V-A) compound phosphorylation with preparation formula (VI-C) compound:

Oxidation-type (VI-C) compound is with preparation formula (VII-C) compound:

Make formula (VII-C) compound deprotection with preparation formula (I) compound.

Make the reaction of formula (XXIII) compound with preparation formula (XXIV) compound, said formula (XXIII) compound is:

Each R wherein ₁Be H or protection base and R independently ₄Be H or leavings group;

Said formula (XXIV) compound is:

Formula (XXIV) compound and formula (II) compound are reacted with preparation formula (XXV) compound:

Annulation to formula (XXV) compound carries out catalysis with preparation formula (IV) compound; Optionally protection (IV) compound is with preparation formula V compound; Make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation (VII) compound; And make formula (VII) compound deprotection with preparation formula (I) compound.

In some embodiments, formula (XXIII) compound is selected from:

For example, formula (XXIV) compound can for:

In some embodiments, formula (II) compound is:

In some embodiments, formula (XXV) compound is:

In some embodiments, the phosphorylation of step (c) comprises and makes the reaction of formula V compound and P (V) phosphorylation agent.For example, P (V) phosphorylation agent can be selected from: POCl ₃, H ₃PO ₄, PO (OBn) xCl ₃-x, Cl ₃CCH ₂OP (O) Cl ₃And (BnO) ₂P (O) OP (O) (OBn) ₂In some embodiments, P (V) phosphorylation agent is Cl ₂PO (OCH ₃).

In some embodiments, the deprotection of formula (VII) compound under anaerobic carries out.

In some embodiments, formula (XXIII) compound is:

In some embodiments, formula (XXIV) compound is:

In some embodiments, formula (XXV) compound is:

In some embodiments, leavings group is selected from: tosylate, brosylate, m-nitrobenzene sulfonic acid ester, methanesulfonates, oxygen, triflate, perfluoro butyl sulphonate and trifluoroethyl sulphonate.

The application also provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, and this method comprises: make the reaction of formula (XXIII-A) compound with preparation formula (XXIV) compound, said formula (XXIII-A) compound is:

Said formula (XXIV) compound is:

Make the reaction of formula (XXIV) compound and formula (II-A) compound with preparation formula (XXV-A) compound, said formula (II-A) compound is:

Said formula (XXV-A) compound is:

The annulation of formula (XXV) compound is carried out catalysis with preparation formula (IV-D) compound:

Optionally protection (IV-D) compound is with preparation formula (V-D) compound:

Make formula (V-D) compound phosphorylation with preparation formula (VI-D) compound:

Oxidation-type (VI-D) compound is to prepare (VII-D) compound:

And make formula (VII-D) compound deprotection with preparation formula (I) compound.

The application also provides a kind of method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form:

This method comprises:

Make the reaction of formula (II) compound and formula (III) compound with preparation formula (IV) compound, said formula (II) compound is:

Said formula (III) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

Optionally protection (IV) compound is to prepare the formula V compound:

Make formula V compound phosphorylation with preparation formula (VI) compound:

Oxidation-type (VI) compound is with preparation formula (XIV) compound:

And make formula (XIV) compound deprotection with preparation formula (XIII) compound.

The application also provides a kind of preparation formula (XIII) compound or pharmaceutically acceptable salt thereof, and this method comprises:

Make the reaction of formula (II) compound and formula (VIII) compound with preparation formula (IX) compound, said formula (VIII) compound is:

Wherein:

R ₂Be H or protection base,

Said formula (IX) compound:

Optionally protection (IX) compound is with preparation formula (X) compound:

R wherein ₃It is the protection base;

Oxidation-type (X) compound is with preparation formula (XV) compound:

Make formula (XV) compound deprotection with preparation formula (XIII) compound.

The application further provides a kind of method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof, and this method comprises: make the reaction of formula (II) compound and formula (III) compound with preparation formula (IV) compound; Optionally protection (IV) compound is with preparation formula V compound; Make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation formula (XIV) compound:

Make formula (XIV) compound deprotection with preparation formula (XIII) compound.

The application also provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, and this method comprises: oxidation-type (VI) compound is with preparation formula (VII) compound; And make formula (VII) compound deprotection with preparation formula (I) compound.

In some embodiments, formula (I) compound or pharmaceutically acceptable salt thereof can through as the preparation of getting off: make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation formula (VII) compound; And make formula (VII) compound deprotection with preparation formula (I) compound.

The application also provides a kind of method for preparing formula (I) compound or pharmaceutically acceptable salt thereof, and this method comprises: optionally protection (IV) compound is with preparation formula V compound; Make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation formula (VII) compound; Make formula (VII) compound deprotection with preparation formula (I) compound.

The application also provides a kind of method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form, and this method comprises: oxidation-type (VI) compound is with preparation formula (XIV) compound; And make formula (XIV) compound deprotection with preparation formula (XIII) compound.

In some embodiments, formula (XIII) compound or pharmaceutically acceptable salt thereof through as the preparation of getting off: make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation formula (XIV) compound; And make formula (XIV) compound deprotection with preparation formula (XIII) compound.

The application also provides a kind of method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form, and this method comprises: optionally protection (IV) compound is with preparation formula V compound; Make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation formula (XIV) compound; And make formula (XIV) compound deprotection with preparation formula (XIII) compound.

The application also provides a kind of method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof, and this method comprises: make the reaction of formula (II) compound and formula (XXII) compound with preparation formula (IV) compound; Optionally protection (IV) compound is with preparation formula V compound; Make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation formula (XIV) compound; And make formula (XIV) compound deprotection with preparation formula (XIII) compound.

The application also provides a kind of method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof, and this method comprises: make the reaction of formula (XXIIII) compound with preparation formula (XXIV) compound; Make the reaction of formula (XXIV) compound and formula (II) compound with preparation formula (XXV) compound; Annulation to formula (XXV) compound carries out catalysis with preparation formula (IV) compound; Optionally protection (IV) compound is with preparation formula V compound; Make formula V compound phosphorylation with preparation formula (VI) compound; Oxidation-type (VI) compound is with preparation formula (XIV) compound; And make formula (XIV) compound deprotection with preparation formula (XIII) compound.

The application further provides formula (I) compound or pharmaceutically acceptable salt thereof through above-mentioned any means preparation.In some embodiments, pharmaceutical composition is provided, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through above-mentioned any means preparation, and pharmaceutical excipient.The application also provides formula (XIII) compound through above-mentioned any means preparation.In some embodiments, pharmaceutical composition is provided, it comprises formula (XIII) compound or pharmaceutically acceptable salt thereof through above-mentioned any means preparation, and pharmaceutical excipient.

The application also provides a kind of method for preparing formula (XXIV) compound or pharmaceutically acceptable salt thereof:

Wherein:

Each R ₁Be H or protection base, this method comprises makes formula (XXIII) compound and alkali reaction with preparation formula (XXIV) compound, and said formula (XXIII) compound is:

Wherein:

R ₄Be H or leavings group.

Description of drawings

Fig. 1 shows that the example description use is synthesized and the external synthetic histogram of the Moco of the precursor Z (cPMP) of purifying.

Fig. 2 provides three the multiple data of the external synthetic of MPT from synthetic precursor Z (cPMP).

Fig. 3 provides three the multiple data of the external synthetic of MPT from the precursor Z (cPMP) of the purifying that uses the E.coli. preparation.

Embodiment

It is understandable that, for the sake of clarity, also can in single embodiment, merge and provide in some characteristic of the present invention described in the context of the embodiment of separating.On the contrary, for the sake of brevity, also can provide separately or with the Asia combination of any appropriate in the of the present invention a plurality of characteristics described in the context of single embodiment.

Except as otherwise noted, all technical and scientific terms of the application's use have the identical meanings of being understood by disclosure those skilled in the art usually.Incorporate all patents, application, open application and other disclosed full content mode by reference that the application quotes into the application.Have under the multidefined situation at the term that the application quotes, unless otherwise mentioned, being defined as at first of this part used.

For term " for example " with " such as " with and grammer equivalence term, phrase " unrestrictedly " is interpreted as following implication, unless expressly stated otherwise.Use like the application, term " about " is intended to explain because the variation that testing error causes.All measurements of the application's report are interpreted as being revised by term " about ", and no matter whether term clearly uses, only if offer some clarification in addition.Use like the application, singulative " a ", " an " and " the " comprise the referent of plural form, only if context offers some clarification in addition.

Term " salt " comprises compound and one or more counter ion (positively charged ion and/or negatively charged ion) of any ionic species.Salt also comprises zwitterionic compound (promptly containing one or more positively charged ion and anionic molecule, for example zwitterionic amino acid).The counter ion that appear in the salt can comprise positively charged ion, negatively charged ion or zwitter-ion arbitrarily.Exemplary negatively charged ion includes but not limited to: cl ions; Bromide anion; Iodide ion; Nitrate ion; Sulfate ion; Hydrogen sulfate ion; Sulfite ion; Sulfurous acid hydrogen radical ion; Phosphate anion; The acid phosphatase radical ion; Perchlorate; Chloranion; Chlorition; The hypochlorite ion; The periodate ion; Iodate ion; The iodous acid radical ion; The hypoiodous acid radical ion; Carbanion; Bicarbonate ion; The Yi Yansuan radical ion; Acetate ion; Trichloroacetic acid ion; The trifluoroacetic acid radical ion; Lactate ion; The salicylate ion; The citric acid radical ion; The tartrate anion ion; The pantothenate ion; The hydrogen tartrate radical ion; The xitix radical ion; Succinate ion; The maleate ion; The gentisinic acid radical ion; Fumarate ion; The glyconic acid radical ion; The saccharic acid radical ion; The saccharic acid radical ion; Formate ion; The benzoate anion ion; The glutamate ion; The methanesulfonate ion; The trifluoromethanesulfonic acid radical ion; The ethyl sulfonic acid radical ion; The Phenylsulfonic acid radical ion; The tosic acid radical ion; To the trifluoromethylbenzene sulfonate ion; Hydroxide ion; Aluminate ion and borate ion.The exemplary male ion includes but not limited to: monovalent base metallic cation such as lithium, sodium, potassium and cesium ion, and divalent alkaline-earth metal positively charged ion such as beryllium, magnesium, calcium, strontium and barium ion.The present invention also comprises transition-metal cation such as gold and silver, copper and zine ion, and non-metal cations is such as ammonium salt.

Compound the term " prodrug " that uses like the application is meant, it carries out chemical conversion to produce the for example described compound of the application and/or its salt and/or its solvolyte through metabolism or chemical process after to experimenter's administration.Term " prodrug " can comprise the ester and the carbonic ether of formation; For example, through using one or more hydroxyl that method known to those skilled in the art makes the described compound of the application and the substituted acylation reaction of alkyl, alkoxyl group or aryl for example to produce acetic ester, pivalate, methyl carbonic and benzoic ether accordingly.For example, the compound that contains carboxyl can form the hydrolyzable ester of physiology, its through hydrolysis in vivo to produce The compounds of this invention as prodrug.Said prodrug Orally-administrable, this be since in many cases hydrolysis under the influence of digestive ferment, take place.Also can use administered parenterally, for example under the situation that hydrolysis takes place in blood.

The term " solvolyte " that the application uses is intended to describe molecular complex (molecular complex), and it comprises one or more medicinal solvent molecules of compound of the present invention and chemistry amount, for example, and ethanol.When solvent use a technical term during for water " hydrate ".The typical method that is used to prepare and differentiates hydrate and solvolyte is at K.J.Guillory, " Generation of Polymorphs, Hydrates, Solvates; and Amorphous Solids, " in:Polymorphism in Pharmaceutical Solids, ed.Harry G.Brittan; Vol.95, Marcel Dekker, Inc.; New York describes in the 1999 202-209 pages or leaves, incorporates its full content method by reference into the application.

Use like the application, it is chemical that the chemical structure that contains one or more three-dimensional center that with dashed lines and thick line

describe is intended to the absolute stereo at one or more the three-dimensional center in the present chemical structure of indicating.Use like the application, the chemical bond of representing through single line can not show three-dimensional select (stereo-preference).Only if do opposite explanation in addition, the comprising one or more three-dimensional center of the application's example description and do not show absolute or stereochemical relatively chemical structure contains stereoisomeric forms in any ratio (for example diastereomer, enantiomer) of all possible compound and composition thereof.Has the single enantiomerism series that single thick line or dotted line and at least one extra single-step structure contain all possible diastereomer.

The fractionation of the racemic mixture of compound can be carried out through in numerous methods known in the art any one.Illustrative methods comprises uses chiral separation acid, the salt formation organic acid fractional recrystallization with optically-active.For the suitable resolving agent of fractional recrystallization method for for example; Have acid such as the D of optically-active and tartrate, diacetylated tartrates, dibenzoyl tartaric acid, racemic melic acid, oxysuccinic acid, the lactic acid of L shaped formula, perhaps various camphorsulfonic acid classes with optically-active are such as camphorsulfonic acid.Other resolving agent that is suitable for the fractional recrystallization method comprises methyl-benzyl amine (for example its S and R form or the pure form of non-stereoisomerism), 2-phenyl glycinol (glycinol), norephedrine, ephedrine, N-methylephedrine, the cyclohexylethylamine, 1 of the form that stereoisomerism is pure, 2-diamino-cyclohexane etc.

The fractionation of racemic mixture also can be carried out through wash-out on the post of filling with the resolving agent (for example dinitrobenzene formylphenyl glycocoll) with optically-active.Suitable eluting solvent combination can be confirmed by those skilled in the art.

Mixture of the present invention also can comprise all isotropic substances that appear at atom in midbody or the final compound.Isotropic substance comprises having the same atoms number but the atom of different mass number.For example, the isotropic substance of hydrogen comprises tritium and deuterium.

The term " compound " that the application uses is intended to comprise all steric isomers, geometrical isomer, tautomer and the isotropic substance of said structure.The compound that is accredited as the application of a kind of concrete tautomeric form through name or structure is intended to comprise other tautomeric form, unless otherwise mentioned.

All compounds and pharmaceutical salts thereof can exist with other material such as water and solvent (for example hydrate and solvolyte).

In some embodiments, compound of the present invention or its salt are essentially isolating." isolating basically " is meant that said compound at least partly or is basically formed or detected residing environment separation by it.Part is separated and for example can be comprised, is rich in the compsn of The compounds of this invention.Basically separate can comprise contain by weight at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% the The compounds of this invention or the compsn of its salt.The method that is used for separating compound and salt thereof is conventional in the art.

The phrase " medicinal " that the application uses is meant such compound, material, compsn and/or formulation; It is in the scope that rational medicine is judged; Be applicable to human and animal's tissue and contact; Its no excessive toxicity, stimulation, anaphylaxis or other problem or complication, and have reasonably benefited/risk ratio.

Statement " envrionment temperature " and " room temperature " used like the application they are intelligible in the art, and typically refer to such temperature, temperature of reaction for example, and it is about the indoor temperature that reaction belongs to, for example, about 20 ℃ of about 30 ℃ temperature extremely.

The application also provides the pharmaceutical salts of the said compound of the application." pharmaceutical salts " used like the application is meant the verivate of disclosed compound, wherein parent compound through the acid that will exist perhaps alkali partly be converted into its salt form and modify.The instance of pharmaceutical salts includes but not limited to the inorganic or organic acid salt of alkaline residue such as amine; The alkali salt of acidic residues such as carboxylic acid or organic salt; Deng.The pharmaceutical salts of the compound that the application provides comprises the conventional non-toxic salt of the parent compound of formation, for example, and from nontoxic inorganic or organic acid salt.The pharmaceutical salts of the compound that the application provides can be synthetic through the conventional chemical method by the parent compound that contains alkalescence or acidic moiety.Usually, said salt can prepare with chemical suitable alkali of measuring or sour in water or organic solvent or both mixtures, the reaction through free acid or the alkali form that makes these compounds; In some embodiments, can use non-aqueous media such as ether, ETHYLE ACETATE, alcohol (for example methyl alcohol, ethanol, Virahol or butanols) or acetonitrile (ACN).Suitably the list of salt appears at Remington ' s Pharmaceutical Sciences, 17th ed., Mack Publishing Company; Easton, Pa., 1985; P.1418 with Journal of Pharmaceutical Science; In 66,2 (1977), incorporate its full content separately mode by reference into the application.The ordinary method that is used to prepare salt form is at for example Handbook of Pharmaceutical Salts: Properties, Selection, and and Use, Wiley-VCH describes in 2002.

Synthetic

The compound that the application provides comprises that its salt can use the preparation of known organic synthesis technology and can synthesize according in numerous possible route of synthesis any one.

The reaction that is used for preparing the compound that the application provides can be carried out at appropriate solvent, and said solvent can easily be selected by the technician in organic synthesis field.Appropriate solvent can be not basically be reacted in temperature that reaction is carried out (for example scope can in the temperature in solvent freezing temp to the solvent boils temperature) with starting substance (reactant), midbody or product.Given reaction can be carried out at a kind of solvent or in more than a kind of mixture of solvent.Depend on concrete reactions step, the technician can select the appropriate solvent for concrete reactions step.

The preparation of the compound that the application provides can comprise the protection and the deprotection of various chemical groups.Those skilled in the art can easily confirm the needs for protection and deprotection and selection due care group.The chemical of blocking group can appear at for example Protecting Group Chemistry, 1 ^StEd., Oxford University Press, 2000; March ' s Advanced Organic chemistry:Reactions, Mechanisms, and Structure, 5 ^ThEd., Wiley-Interscience Publication, 2001; And Peturssion, S.et al., " Protecting Groups in Carbohydrate Chemistry, " J.Chem.Educ. in 74 (11), 1297 (1997), incorporates its full content separately mode by reference into the application.

Reaction can be monitored according to any suitable currently known methods in this area.For example, product forms and can (such as nuclear magnetic resonance spectrometry (for example pass through the spectroscope method ¹H perhaps ¹³C), infrared spectroscopy, spectrophotometry (for example UV-visible light), mass spectroscopy) or chromatographic process (such as HPLC (HPLC), LC/MS (LCMS) or tlc (TLC)) monitor.Compound can (comprise HPLC (HPLC) (" Preparative LC-MS Purification:Improved Compound Specific Method Optimization " K.F.Blom through the whole bag of tricks by those skilled in the art; Et al.; J.Combi.Chem.6 (6) (2004) incorporates its full content mode by reference into the application) and the normal phase silica gel chromatography method) carry out purifying.

Formula (I) compound and other useful compound and midbody can be according to forming shown in the scheme 1.For example, the di-amino-pyrimidine ketone compound of formula (II) can react to obtain the compound of formula (IV) with the hexose of shielded or unprotected formula (III).The theheterocyclic nitrogen atom of the piperazine ring of formula (IV) can use standard conditions by optionally protection, to obtain the formula V verivate then.The phosphorylation of formula V compound can obtain the SULPHOSUCCINIC ACID ESTER midbody of formula (VI).The SULPHOSUCCINIC ACID ESTER of formula (VI) can be converted into the glycol of formula (VII) under suitable oxidizing condition.At last, formula (VII) compound can deprotection to obtain formula (I) compound.

Scheme 1

Formula (II) compound:

In some embodiments, being prepared as of formula (II) compound:

Each R wherein ₁Be H or protection base independently.

Formula (II) can comprise, for example, compound 2,5,6-Triaminopyrimidine-4 (3H)-ketone and salt and verivate:

in some embodiments, formula (II) compound can be hydrochloride form:

As described, the functional group of some formula (II) structure (for example, the 2-position of aminopyrimidine ring, and the theheterocyclic nitrogen atom of 3-position) can use R ₁The protection of protection base.For this purpose, R ₁The amino protecting group that can comprise any appropriate includes, but are not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.R ₁The protection base can be identical or different.

Particularly; Carbamate protection base can comprise; For example; Carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc), carboxylamine carboxyl benzyl ester (cbz), Urethylane, urethanum, carboxylamine 9-(2-sulfo group) fluorenyl methyl esters, carboxylamine 9-(2; The 7-dibromo) fluorenyl methyl esters, carboxylamine 17-four benzo [a; C; G, i] fluorenyl methyl esters (Tbfmoc), carboxylamine 2-chloro-3-indenyl methyl esters (Climoc), carboxylamine 2, [9-(10 for 7-two-tertiary butyl; 10-dioxo-10; 10,10,10-tetrahydrochysene thioxanthene base)] methyl esters (DBD-Tmoc), carboxylamine 1; 1-dioxo benzo [b] thiophene-2-base methyl esters (Bsmoc), carboxylamine 2; 2,2-trichloro ethyl ester (Troc), carboxylamine 2-trimethyl silyl ethyl ester (Teoc), carboxylamine 2-phenyl chlorocarbonate (hZ), carboxylamine 1,1-dimethyl--2-halo ethyl ester, carboxylamine 1; 1-dimethyl--2; 2-dibromo ethyl ester (DB-t-boc), carboxylamine 1,1-dimethyl--2,2; 2-trichloro ethyl ester (TCBoc), carboxylamine 1-methyl isophthalic acid-(4-xenyl) ethyl ester (Bpoc), carboxylamine 1-(3; 5-two-tert-butyl-phenyl)-1-methyl ethyl ester (t-Bumeoc), carboxylamine N-(the 2-pivaloyl group is amino)-1,1-dimethyl-ethyl ester, carboxylamine 2-[(2-nitrophenyl) disulfide group]-1-phenyl chlorocarbonate (NpSSPeoc), carboxylamine 2-(N, N-dicyclohexyl formamido group) ethyl ester, carboxylamine 1-diamantane ester (1-Adoc), carboxylamine ethene ester (Voc), carboxylamine 1-sec.-propyl allyl ester (Ipaoc), carboxylamine 4-nitro cinnyl ester (Noc), carboxylamine 3-(3 ' pyridyl) third-2-alkene ester (Paloc), carboxylamine 8-quinoline ester, carboxylamine alkyl dithioesters, carboxylamine to methoxy benzyl ester (Moz), carboxylamine to nitrobenzyl ester (Pnz), carboxylamine to bromobenzyl ester, carboxylamine to benzyl chloride ester, carboxylamine 2; 4-benzyl dichloride ester, carboxylamine 4-methyl sulfinyl benzyl ester (Msz), carboxylamine phenylbenzene methyl esters, carboxylamine 2-methyl sulfenyl ethyl ester, carboxylamine 2-methyl sulphonyl ethyl ester, carboxylamine 2-(p-toluenesulfonyl) ethyl ester, [2-(1 for carboxylamine; 3-dithia cyclohexyl)] methyl esters (Dmoc), carboxylamine 4-methyl sulfenyl phenyl ester (Mtpc), carboxylamine 2,4-dimethyl-sulfenyl phenyl ester (Bmpc), carboxylamine 2-phosphono ethyl ester (Peoc), carboxylamine 1, chloro-is to acyloxy benzyl ester between 1-dimethyl--2-cyanic acid ethyl ester, carboxylamine 2-(4-nitrophenyl) ethyl ester, carboxylamine 4-phenyl acetoxyl group benzyl ester (PhAcOZ) and carboxylamine.In some embodiments, carbamate protection base is selected from carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc) and carboxylamine carboxyl benzyl ester (cbz).

Acid amides protection base can comprise; For example, ethanamide, phenyl-acetamides, 3-Phenylpropionamide, penta-4-alkene acid amides, picolinamide, 3-pyridyl methane amide, BM, to phenylbenzamaide, 2-methyl-2-(adjacent phenylazo phenoxy) propionic acid amide), 4-neoprene acid amides, aceto-acetamide, 3-(p-hydroxybenzene) propionic acid amide) and (N '-disulfide group benzyl oxygen base carbonylamino) ethanamide.

Formula (II) compound can use the currently known methods preparation; Such as at Sharma et al., Indian Journal of Chemistry, Section B:Organic Chemistry Including Medicinal Chemistry; 43B, the method described in 385 (2004).For example, 2,5,6-Triaminopyrimidine-4 (3H)-ketone prepares shown in scheme 2.

Scheme 2

Formula (II) compound or pharmaceutically acceptable salt thereof also can comprise tautomeric structure:

Formula (III) compound:

Other embodiment of the application provides the preparation of formula (III) compound:

Each R wherein ₁Be H or protection base independently.

Formula (III) can comprise, for example, and shielded or unprotected hexose.Especially, glucose, seminose, semi-lactosi, allose, altrose, gulose, idose, talose and verivate thereof.Hexose can be D or L configuration.For example, following hexose all is included in formula (III) scope:

In some embodiments, hexose is shielded or unprotected glucose or semi-lactosi.For example, formula (III) compound can be shielded or unprotected semi-lactosi (for example, D-semi-lactosi).In some embodiments, hexose is shielded or unprotected gulose or semi-lactosi.

As described, formula (III) compound can be the form (that is unprotected sugar) of free sugar.Alternatively, the available R of the hydroxyl of some formula (III) structure (for example, the hydroxyl of hexose 3,4 and 5-position) ₁The protection of protection base.For this purpose, R ₁The hydroxy functional group that can comprise any appropriate includes, but are not limited to ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

Especially; Ether protection base can comprise methyl, methoxymethyl (MOM), benzyl oxygen ylmethyl (BOM), methoxy ethoxy methyl (MEM), 2-(trimethyl silyl) ethoxyl methyl (SEM), methyl sulfenyl methyl (MTM), phenyl sulfenyl methyl (PTM), azido methyl, cyano methyl, 2; 2-two chloro-1; 1-two fluoro ethyls, 2-chloroethyl, 2-bromotrifluoromethane, THP trtrahydropyranyl (THP), 1-ethoxyethyl group (EE), phenacyl-, 4-bromobenzene formyl methyl, cyclopropyl methyl, allyl group, propargyl, sec.-propyl, cyclohexyl, the tertiary butyl, benzyl, 2; 6-dimethyl benzyl, 4-methoxy-benzyl (MPM-OAr), adjacent nitrobenzyl, 2; 6-dichloro benzyl, 3,4-dichloro benzyl, 4-(dimethylamino) carbonyl benzyl, 4-methyl sulfinyl benzyl (Msib), 9-anthryl methyl, 4-picolyl, seven fluoro-p-methylphenyls, tetrafluoro-4-pyridyl, trimethyl silyl (TMS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) and triisopropyl silyl (TIPS) protection base.

Ester protection base can comprise acetoxyl group (OAc), formic acid aryl ester, acetate aryl ester, levulinic acid aryl ester, PIVALIC ACID CRUDE (25) aryl ester, phenylformic acid aryl ester and 9-fluorenes aryl ester carboxylic acid.In one embodiment, ester protection base is an acetoxyl group.

Carbonic ether protection base can comprise aryl carbonate ester methyl ester, carbonic acid 1-diamantane ester (Adoc-OAr), the carbonic acid tert-butyl ester (BOC-OAr), carbonic acid 4-methyl sulfinyl benzyl ester (Msz-OAr), carbonic acid 2; 4-dimethyl-penten-3-ester (Doc-OAr), aryl carbonates 2; 2,2-trichloro ethyl ester, aryl carbonates vinyl acetate, aryl carbonates benzyl ester and aryl carbonates.

Sulphonate protection base can comprise methylsulfonic acid aryl ester, toluenesulphonic acids aryl ester and 2-formyl Phenylsulfonic acid aryl ester.

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, hexose 4 with the R of 5-position ₁Group can merge with form one or more below shielded hexose:

Formula (III) compound can prepare according to glucide synthetic currently known methods.The method of protection glucide also is known, as at The Organic Chemistry of Sugars, and Taylor & Francis, 2006, p.181; And Peturssion, S.et al., J.Chem.Educ. states in 74 (11), 1297 (1997), incorporates its full content separately mode by reference into the application.

When cognitive by those skilled in the art and when discussing hereinafter, the stereochemistry of formula (III) structure can be controlled in the stereochemistry of midbody follow-up in formula (I) synthetic.In addition, can improve the stereospecificity of the solubleness and the adjustment successive reaction step of formula (III) compound to the protection of some hydroxyls.

Formula (IV) compound:

Another embodiment that the application provides relates to the preparation of formula (IV) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.

As described, the amino and the hydroxyl of formula (IV) compound can be shielded or unprotected form.For example, can comprise that with formula (IV) compound or pharmaceutically acceptable salt thereof of unprotected form compound 2-is amino-6,7-dihydroxyl-8-(hydroxymethyl)-5a, 6,7,8,9a, 10-six hydrogen-3H-pyrans is [3,2-g] pteridine-4 (5H)-ketone also:

The amino and/or the hydroxyl of some formula (IV) structure can be used R ₁The protection of protection base.For this purpose, R ₁The suitable amino or the hydroxy functional group that can comprise technician's selection of chemical field arbitrarily.For example, the amino protecting group in the open scope of the application includes, but are not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.The instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

Particularly; Carbamate protection base can comprise; For example; Carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc), carboxylamine carboxyl benzyl ester (cbz), Urethylane, urethanum, carboxylamine 9-(2-sulfo group) fluorenyl methyl esters, carboxylamine 9-(2; The 7-dibromo) fluorenyl methyl esters, carboxylamine 17-four benzo [a; C; G, i] fluorenyl methyl esters (Tbfmoc), carboxylamine 2-chloro-3-indenyl methyl esters (Climoc), carboxylamine 2, [9-(10 for 7-two-tertiary butyl; 10-dioxo-10; 10,10,10-tetrahydrochysene thioxanthene base)] methyl esters (DBD-Tmoc), carboxylamine 1; 1-dioxo benzo [b] thiophene-2-base methyl esters (Bsmoc), carboxylamine 2; 2,2-trichloro ethyl ester (Troc), carboxylamine 2-trimethyl silyl ethyl ester (Teoc), carboxylamine 2-phenyl chlorocarbonate (hZ), carboxylamine 1,1-dimethyl--2-halo ethyl ester, carboxylamine 1; 1-dimethyl--2; 2-dibromo ethyl ester (DB-t-boc), carboxylamine 1,1-dimethyl--2,2; 2-trichloro ethyl ester (TCBoc), carboxylamine 1-methyl isophthalic acid-(4-xenyl) ethyl ester (Bpoc), carboxylamine 1-(3; 5-two-tert-butyl-phenyl)-1-methyl ethyl ester (t-Bumeoc), carboxylamine N-(the 2-pivaloyl group is amino)-1,1-dimethyl-ethyl ester, carboxylamine 2-[(2-nitrophenyl) disulfide group]-1-phenyl chlorocarbonate (NpSSPeoc), carboxylamine 2-(N, N-two is the hexyl formamyl not) ethyl ester, carboxylamine 1-diamantane ester (1-Adoc), carboxylamine ethene ester (Voc), carboxylamine 1-sec.-propyl allyl ester (Ipaoc), carboxylamine 4-nitro cinnyl ester (Noc), carboxylamine 3-(3 ' pyridyl) third-2-alkene ester (Paloc), carboxylamine 8-quinoline ester, carboxylamine alkyl dithioesters, carboxylamine to methoxy benzyl ester (Moz), carboxylamine to nitrobenzyl ester (Pnz), carboxylamine to bromobenzyl ester, carboxylamine to benzyl chloride ester, carboxylamine 2; 4-benzyl dichloride ester, carboxylamine 4-methyl sulfinyl benzyl ester (Msz), carboxylamine phenylbenzene methyl esters, carboxylamine 2-methyl sulfenyl ethyl ester, carboxylamine 2-methyl sulphonyl ethyl ester, carboxylamine 2-(p-toluenesulfonyl) ethyl ester, [2-(1 for carboxylamine; 3-dithia cyclohexyl)] methyl esters (Dmoc), carboxylamine 4-methyl sulfenyl phenyl ester (Mtpc), carboxylamine 2,4-dimethyl-sulfenyl phenyl ester (Bmpc), carboxylamine 2-phosphono ethyl ester (Peoc), carboxylamine 1, chloro-is to acyloxy benzyl ester between 1-dimethyl--2-cyanic acid ethyl ester, carboxylamine 2-(4-nitrophenyl) ethyl ester, carboxylamine 4-phenyl acetoxyl group benzyl ester (PhAcOZ) and carboxylamine.In some embodiments, carbamate protection base is selected from carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc) and carboxylamine carboxyl benzyl ester (cbz).

Ether protection base can comprise methyl, methoxymethyl (MOM), benzyl oxygen ylmethyl (BOM), methoxy ethoxy methyl (MEM), 2-(trimethyl silyl) ethoxyl methyl (SEM), methyl sulfenyl methyl (MTM), phenyl sulfenyl methyl (PTM), azido methyl, cyano methyl, 2; 2-two chloro-1; 1-two fluoro ethyls, 2-chloroethyl, 2-bromotrifluoromethane, THP trtrahydropyranyl (THP), 1-ethoxyethyl group (EE), phenacyl-, 4-bromobenzene formyl methyl, cyclopropyl methyl, allyl group, propargyl, sec.-propyl, cyclohexyl, the tertiary butyl, benzyl, 2; 6-dimethyl benzyl, 4-methoxy-benzyl (MPM-OAr), adjacent nitrobenzyl, 2; 6-dichloro benzyl, 3,4-dichloro benzyl, 4-(dimethylamino) carbonyl benzyl, 4-methyl sulfinyl benzyl (Msib), 9-anthryl methyl, 4-picolyl, seven fluoro-p-methylphenyls, tetrafluoro-4-pyridyl, trimethyl silyl (TMS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) and triisopropyl silyl (TIPS) protection base.

Carbonic ether protection base can comprise aryl carbonate ester methyl ester, carbonic acid 1-diamantane ester (Adoc-OAr), the carbonic acid tert-butyl ester (BOC-OAr), t-butyl carbamate (Boc), carbonic acid 4-methyl sulfinyl benzyl ester (Msz-OAr), carbonic acid 2; 4-dimethyl-penten-3-ester (Doc-OAr), aryl carbonates 2; 2,2-trichloro ethyl ester, aryl carbonates vinyl acetate, aryl carbonates benzyl ester and aryl carbonates.

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, 4 of the hexose ring composition of formula (IV) with the R of 5-position ₁Group can merge to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.

Protect some amino and hydroxyl can improve the solubleness of formula (IV) compound.For example the preparation of formula (IV) acetyl derivative can improve solubleness and increase the product separation yield.

Formula (IV) compound can be through making the reaction of formula (II) compound and formula (III) compound with preparation formula (IV) compound, and said formula (II) compound is:

Said formula (III) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently, as stated.

Particularly, formula (IV) but compound through type (II) compound and formula (III) compound react in the presence of the reagent that can realize cyclisation arbitrarily and prepare.Said reagent can easily be confirmed and for example can comprise by the technician, through substituted or without substituted hydrazine.Suitably the limiting examples of hydrazine reagent comprises phenyl hydrazine and alkyl hydrazine, for example, and phenyl hydrazine and p-nitrophenyl hydrazine.

Also it is understandable that the stereospecificity of the subsequent reactions step of the isomeric forms adjustable synthesis type (I) of formula (IV) structure.Therefore, specific isomer can this synthesis step separate or, alternatively, the isomer mixture of formula (IV) can be accomplished than latter stage and separates at synthetic.

In some embodiments, formula (IV) compound or pharmaceutically acceptable salt thereof or hydrate comprise isomer:

In building-up process, the stereochemistry of formula (IV) product can be chosen wantonly through the C-3 of the hexose of processing formula (III) and the stereochemistry on the C-4 position and control.For example, derived from the different isomer mixture of verivates different aspect the reactant of the formula (III) of glucose, seminose, semi-lactosi, allose, altrose, gulose, idose and talose and the stereochemistry on the C-3 of sugar and C-4 position with the product of production (IV).

Formula (IV) synthetic stereoselectivity also can be controlled through on some positions of the compound of formula (III), incorporating a large amount of protection bases into.For example, introduce the stereoselectivity that the isopropylidene ethylidene ether can be adjusted reaction on any position in C-3, C-4 or the C-5 position of formula (III) sugar.

The formula V compound:

Another embodiment that the application provides relates to the preparation of formula V compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.For example, the formula V compound comprises compound (V-A) or its pharmaceutical salts:

R wherein ₁Be H or protection base.The formula V compound also comprises, for example, compound 2-is amino-6,7-dihydroxyl-8-(hydroxymethyl)-4-oxo-5a, and 6,7,8,9a, 10-six hydrogen-3H-pyrans be [3,2-g] pteridine-5 (4H)-carboxylic acid (9H-fluorenes-9-yl) methyl esters or its pharmaceutical salts also:

In some embodiments, the formula V compound can comprise, for example, and one or more following compound:

In some embodiments; One or more above compounds can be separated through several different methods by those skilled in the art; Comprise performance liquid chromatography (HPLC) (" Preparative LC-MS Purification:Improved Compound Specific Method Optimization " K.F.Blom, et al., J Combi.Chem.6 (6); 874 (2004), its full content is incorporated this paper into as a reference) and normal phase silica gel chromatography.

As described, the amino of some formula V structure and/or hydroxyl can be used R ₁The protection of protection base.For this purpose, R ₁The suitable amino or the hydroxy functional group that can comprise technician's selection of chemical field arbitrarily.For example, the amino protecting group in the open scope of the application includes but not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.The instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

Particularly; Carbamate protection base can comprise; For example; Carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc), carboxylamine carboxyl benzyl ester (cbz), Urethylane, urethanum, carboxylamine 9-(2-sulfo group) fluorenyl methyl esters, carboxylamine 9-(2; The 7-dibromo) fluorenyl methyl esters, carboxylamine 17-four benzo [a; C; G, i] fluorenyl methyl esters (Tbfmoc), carboxylamine 2-chloro-3-indenyl methyl esters (Climoc), carboxylamine 2, [9-(10 for 7-two-tertiary butyl; 10-dioxo-10; 10,10,10-tetrahydrochysene thioxanthene base)] methyl esters (DBD-Tmoc), carboxylamine 1; 1-dioxo benzo [b] thiophene-2-base methyl esters (Bsmoc), carboxylamine 2; 2,2-trichloro ethyl ester (Troc), carboxylamine 2-trimethyl silyl ethyl ester (Teoc), carboxylamine 2-phenyl chlorocarbonate (hZ), carboxylamine 1,1-dimethyl--2-halo ethyl ester, carboxylamine 1; 1-dimethyl--2; 2-dibromo ethyl ester (DB-t-boc), carboxylamine 1,1-dimethyl--2,2; 2-trichloro ethyl ester (TCBoc), carboxylamine 1-methyl isophthalic acid-(4-xenyl) ethyl ester (Bpoc), carboxylamine 1-(3; 5-two-tert-butyl-phenyl)-1-methyl ethyl ester (t-Bumeoc), carboxylamine N-(the 2-pivaloyl group is amino)-1,1-dimethyl-ethyl ester, carboxylamine 2-[(2-nitrophenyl) disulfide group]-1-phenyl chlorocarbonate (NpSSPeoc), carboxylamine 2-(N, N-dicyclohexyl formamyl) ethyl ester, carboxylamine 1-diamantane ester (1-Adoc), carboxylamine ethene ester (Voc), carboxylamine 1-sec.-propyl allyl ester (Ipaoc), carboxylamine 4-nitro cinnyl ester (Noc), carboxylamine 3-(3 ' pyridyl) third-2-alkene ester (Paloc), carboxylamine 8-quinoline ester, carboxylamine alkyl dithioesters, carboxylamine to methoxy benzyl ester (Moz), carboxylamine to nitrobenzyl ester (Pnz), carboxylamine to bromobenzyl ester, carboxylamine to benzyl chloride ester, carboxylamine 2; 4-benzyl dichloride ester, carboxylamine 4-methyl sulfinyl benzyl ester (Msz), carboxylamine phenylbenzene methyl esters, carboxylamine 2-methyl sulfenyl ethyl ester, carboxylamine 2-methyl sulphonyl ethyl ester, carboxylamine 2-(p-toluenesulfonyl) ethyl ester, [2-(1 for carboxylamine; 3-dithia cyclohexyl)] methyl esters (Dmoc), carboxylamine 4-methyl sulfenyl phenyl ester (Mtpc), carboxylamine 2,4-dimethyl-sulfenyl phenyl ester (Bmpc), carboxylamine 2-phosphono ethyl ester (Peoc), carboxylamine 1, chloro-is to acyloxy benzyl ester between 1-dimethyl--2-cyanic acid ethyl ester, carboxylamine 2-(4-nitrophenyl) ethyl ester, carboxylamine 4-phenyl acetoxyl group benzyl ester (PhAcOZ) and carboxylamine.In some embodiments, carbamate protection base is selected from carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc) and carboxylamine carboxyl benzyl ester (cbz) protection base.

Ester class protection base can comprise acetoxyl group (OAc), formic acid aryl ester, acetate aryl ester, levulinic acid aryl ester, PIVALIC ACID CRUDE (25) aryl ester, phenylformic acid aryl ester and 9-fluorenes aryl ester carboxylic acid.In one embodiment, ester protection base is an acetoxyl group.

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, 4 of the hexose ring composition of formula V with the R of 5-position ₁Group can merge to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.

Protect some amino and hydroxyl can improve the solubleness of formula V compound.For example, the preparation of the acetyl derivative of formula V can improve solubleness and increase the product separation yield.The formula V compound can be through optionally protection (IV) compound be with preparation formula V compound, and said formula (IV) compound is:

Said formula V compound is:

Wherein:

Each R ₁Be H or protection base independently, as stated.

Particularly, but formula V compound through type (IV) compound and any agent reaction and using is implemented in N5 goes up selectivity and settle R ₁The condition of protection base prepares.For settling R ₁The suitable reagent of protection base and condition can easily be confirmed by those skilled in the art.For example, can use the reactive chlorine compound derivative to settle carboxylamine 9-fluorenyl methyl esters (Fmoc), as at E.Atherton et al.; " The Fluorenylmethoxycarbonyl Amino Protecting Group, " in The Peptides, S.Udenfriend and J.Meienhofer; Eds., Academic Press, New York; 1987, Vol.9, report among the page 1.The protection of use t-butyl carbamate (Boc) can be through the compound and for example (Boc) that makes formula (IV) ₂O reacts in aqueous NaOH and realizes, as at D.Tarbell et al., and Proc.Natl.Acad.Sci., USA is described in 69,730 (1972).Urethylane and urethanum can easily be introduced, and as at E.J.Corey et al., Tetrahedron Lett. is described in 1051 (1978).

It is understandable that also the isomeric form of formula V structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (I).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula V can be accomplished and separation than latter stage at synthetic.

In some embodiments, the formula V compound comprises isomer:

In addition, as stated, the formula V compound also comprises tautomeric structure:

Formula (VI) compound:

In another embodiment, preparation formula (VI) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.For example, formula (VI) compound comprises compound (VI-A) or its pharmaceutical salts:

R wherein ₁Be H or protection base.Formula (VI) chemical combination also comprises, for example, and compound or pharmaceutically acceptable salt thereof:

In some embodiments, formula (VI) compound comprises, for example, and compound (VI-B) or its pharmaceutical salts:

for example, formula (VI) compound or pharmaceutically acceptable salt thereof can comprise one or more:

in some embodiments; One or more above compounds can be separated through several different methods by those skilled in the art; Comprise performance liquid chromatography (HPLC) (" Preparative LC-MS Purification:Improved Compound Specific Method Optimization " K.F.Blom; Et al.; J.Combi.Chem.6 (6) (2004), its full content mode is by reference incorporated the application into) and normal phase silica gel chromatography.

As described, the amino and/or the hydroxyl of some formula (VI) structure can be used R ₁The protection of protection base.For this purpose, R ₁The suitable amino or the hydroxy functional group that can comprise technician's selection of chemical field arbitrarily.For example, the amino protecting group in the open scope of the application includes but not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.The instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

Particularly; Carbamate protection base can comprise; For example; Carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc), carboxylamine carboxyl benzyl ester (cbz), Urethylane, urethanum, carboxylamine 9-(2-sulfo group) fluorenyl methyl esters, carboxylamine 9-(2; The 7-dibromo) fluorenyl methyl esters, carboxylamine 17-four benzo [a; C; G, i] fluorenyl methyl esters (Tbfmoc), carboxylamine 2-chloro-3-indenyl methyl esters (Climoc), carboxylamine 2, [9-(10 for 7-two-tertiary butyl; 10-dioxo-10; 10,10,10-tetrahydrochysene thioxanthene base)] methyl esters (DBD-Tmoc), carboxylamine 1; 1-dioxo benzo [b] thiophene-2-base methyl esters (Bsmoc), carboxylamine 2; 2,2-trichloro ethyl ester (Troc), carboxylamine 2-trimethyl silyl ethyl ester (Teoc), carboxylamine 2-phenyl chlorocarbonate (hZ), carboxylamine 1,1-dimethyl--2-halo ethyl ester, carboxylamine 1; 1-dimethyl--2; 2-dibromo ethyl ester (DB-t-boc), carboxylamine 1,1-dimethyl--2,2; 2-trichloro ethyl ester (TCBoc), carboxylamine 1-methyl isophthalic acid-(4-xenyl) ethyl ester (Bpoc), carboxylamine 1-(3; 5-two-tert-butyl-phenyl)-1-methyl ethyl ester (t-Bumeoc), carboxylamine N-(the 2-pivaloyl group is amino)-1,1-dimethyl-ethyl ester, carboxylamine 2-[(2-nitrophenyl) disulfide group]-1-phenyl chlorocarbonate (NpSSPeoc), carboxylamine 2-(N, N-dicyclohexyl formamyl) ethyl ester, carboxylamine 1-diamantane ester (1-Adoc), carboxylamine ethene ester (Voc), carboxylamine 1-sec.-propyl allyl ester (Ipaoc), carboxylamine 4-nitro cinnyl ester (Noc), carboxylamine 3-(3 ' pyridyl) third-2-alkene ester (Paloc), carboxylamine 8-quinoline ester, carboxylamine alkyl dithioesters, carboxylamine to methoxy benzyl ester (Moz), carboxylamine to nitrobenzyl ester (Pnz), carboxylamine to bromobenzyl ester, carboxylamine to benzyl chloride ester, carboxylamine 2; 4-benzyl dichloride ester, carboxylamine 4-methyl sulfinyl benzyl ester (Msz), carboxylamine phenylbenzene methyl esters, carboxylamine 2-methyl sulfenyl ethyl ester, carboxylamine 2-methyl sulphonyl ethyl ester, carboxylamine 2-(p-toluenesulfonyl) ethyl ester, [2-(1 for carboxylamine; 3-dithia cyclohexyl)] methyl esters (Dmoc), carboxylamine 4-methyl sulfenyl phenyl ester (Mtpc), carboxylamine 2,4-dimethyl-sulfenyl phenyl ester (Bmpc), carboxylamine 2-phosphono ethyl ester (Peoc), carboxylamine 1, chloro-is to acyloxy benzyl ester between 1-dimethyl--2-cyanic acid ethyl ester, carboxylamine 2-(4-nitrophenyl) ethyl ester, carboxylamine 4-phenyl acetoxyl group benzyl ester (PhAcOZ) and carboxylamine.In some embodiments, carbamate protection base can be selected from basic formic acid 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc) and carboxylamine carboxyl benzyl ester (cbz) protection base.

Ester class protection base can comprise acetoxyl group (OAc), formic acid aryl ester, acetate aryl ester, levulinic acid aryl ester, PIVALIC ACID CRUDE (25) aryl ester, phenylformic acid aryl ester and 9-fluorenes aryl ester carboxylic acid.In one embodiment, ester protecting group is an acetoxyl group.

Protect some amino and hydroxyl can improve the solubleness of formula (VI) compound.For example the preparation of the acetyl derivative of formula (VI) can improve solubleness and increase the product separation yield.

Formula (Vl) compound can be through phosphorylation formula V compound with preparation formula (VI) compound or pharmaceutically acceptable salt thereof form, and said formula V compound is:

Said formula (VI) compound is:

Wherein each R1 is H or protection base independently, as stated.

Particularly, formula (VI) compound can prepare through the formula V compound is reacted with the phosphorylation agent that is suitable for the formula that forms (VI) compound arbitrarily.Suitable phosphorylation agent and condition can easily be confirmed by those skilled in the art.For example, formula (VI) compound can obtain through the formula V compound is handled with P (V) phosphorylation agent.Suitable substance P (V) phosphorylation agent includes but not limited to POCl ₃, H ₃PO ₄, PO (OBn) _xCl _3-x, Cl ₃CCH ₂OP (O) Cl ₂, PO (OCH ₃) _xCl _3-x, PO (OCH ₃) Cl ₂, PO (OCH ₃) _xCl _3-x, PO (OCH ₃) Cl ₂(BnO) ₂P (O) OP (O) (OBn) ₂In some embodiments, P (V) phosphorylation agent is POCl ₃

In one embodiment, phosphorylation reaction can be through using POCl with the formula V compound ₃Carry out to obtain formula (VI) compound in the envrionment temperature processing.In another embodiment, formula (VI) compound is through using POCl with the formula V compound ₃Form 60 ℃ of processing.

Phosphorylation reaction also can comprise the formula V compound with P (III) phosphitylation agent treated to form the phosphorous acid ester midbody.Suitable substance P (III) phosphitylation reagent for example comprises P (OCH ₂CH ₂CN) ₂Cl; P (OCH ₂CH ₂CN) (NPr ₂-i) Cl; And cyano ethyl-O-P [N (i-Pr) ₂)] ₂When P (III) phosphitylation reagent was used for phosphorylation, follow-up oxidizing reaction can be used for obtaining corresponding SULPHOSUCCINIC ACID ESTER.When P (III) reagent was used for synthesis type (VI) compound, Boc or Cbz group can be used for the R on the N5 of formula (IV) compound ₁Protection, this is owing to be used for the alkaline environment of phosphitylation.

Also it is understandable that, the isomeric form of formula (VI) structure can be controlled in consecutive steps in formula (I) synthetic stereospecificity.Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (VI) can be accomplished and separation than latter stage at synthetic.

In some embodiments, formula (VI) compound comprises isomer:

As stated, formula (VI) compound also can comprise tautomeric structure.

Formula (VII) compound:

In another embodiment, preparation formula (VII) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.For example, formula (VII) compound comprises compound (VII-A) or its pharmaceutical salts:

R wherein ₁Be H or protection base.

Formula (VII) compound also comprises, for example, and compound or pharmaceutically acceptable salt thereof:

In some embodiments, formula (VII) compound comprises compound (VII-B) or its pharmaceutical salts:

for example, formula (VII) compound can comprise one or more following compounds:

or its pharmaceutical salts.In some embodiments; One or more above compounds can be separated through several different methods by those skilled in the art; Comprise performance liquid chromatography (HPLC) (" Preparative LC-MS Purification:Improved Compound Specific Method Optimization " K.F.Blom; Et al., J.Combi.Chem.6 (6) (2004), its full content mode is by reference incorporated the application into) and normal phase silica gel chromatography.

As described, the amino and/or the hydroxyl of some formula (VII) structure can be used R ₁The protection of protection base.For this purpose, R ₁The suitable amino or the hydroxy functional group that can comprise technician's selection of chemical field arbitrarily.For example, the amino protecting group in the open scope of the application includes but not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.The instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

Ester class protection base can comprise acetic ester, formic acid aryl ester, acetate aryl ester, levulinic acid aryl ester, PIVALIC ACID CRUDE (25) aryl ester, phenylformic acid aryl ester and 9-fluorenes aryl ester carboxylic acid.

Protect some amino and hydroxyl can improve the solubleness of formula (VII) compound.For example the preparation of the acetyl derivative of formula (VII) compound can improve solubleness and increase the product separation yield.

Formula (VII) compound can pass through oxidation-type (VI) compound with preparation formula (VII) compound, and said formula (VI) compound is:

Said formula (VII) compound is:

Wherein:

Each R ₁Be H or protection base independently, as stated.

In this was synthetic, formula (VII) compound can be through making formula (VI) compound and being suitable for the oxidant reaction that selectivity forms the glycol of formula (VII) arbitrarily and preparing.Suitable oxygenant and condition can easily be confirmed by those skilled in the art.For example, formula (VII) compound can through with formula (VI) compound with ruthenium compound such as RuO ₄ ^-/ NMO handles and forms.Also can use other oxygenant; Such as Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride, TFAA/DMSO, PDC, hydrogen peroxide, inorganic peroxide, nitric acid, nitrate salt, chlorite, oxymuriate, perchlorate, hypochlorite, superoxide, iodine, ozone, Nitrous Oxide, silver suboxide, permanganate, hexavalent chromium compound, chromic acid, dichromic acid, chromium trioxide, PCC, persulfuric acid, sulfoxide, sulfuric acid, Tollens reagent, 2,2 '-pyridyl disulfide (DPS) and perosmic anhydride.In one embodiment, the pyrazine ring of compound (VI) is not oxidized thus to use certain oxidizing condition.In some embodiments, oxygenant is selected from RuO ₄ ^-/ NMO, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride and PDC.

For example, oxidizing reaction can be through using RuO with formula (VI) compound _- ⁴/ NMO handles in envrionment temperature and carries out to obtain formula (VII) compound.In another embodiment, formula (VII) compound is through using RuO with formula (VI) compound ^- ₄/ NMO forms in the Temperature Treatment of 20-60 ℃ or 20,25,30,35,40,45,50 or 55 ℃.

It is understandable that also the isomeric form of formula (VII) structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (I).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (VII) can be accomplished and separation than latter stage at synthetic.

In some embodiments, formula (VII) compound comprises isomer or its pharmaceutical salts:

shows that as above formula (VII) compound also can comprise tautomeric structure or its pharmaceutical salts:

Formula (I) compound:

In some embodiments, preparation formula (I) compound and pharmaceutical salts and hydrate:

formula (I) compound or pharmaceutically acceptable salt thereof also comprises tautomeric structure:

Preferably carry out the synthetic of formula (I) compound thus to realize required stereochemistry and to avoid oxidation that this is because the open loop of pyranoid ring in the chemosynthesis process.

Formula (I) compound can be for example through making formula (VII) compound deprotection with preparation formula (I) compound, and said formula (VII) compound is:

Each R wherein ₁Be H or protection base independently, as stated.

In this was synthetic, deprotection for example can comprise that some amino on formula (VII) compound and the continuous deprotection of hydroxyl protecting group or one kettle way deprotection are to obtain formula (I) compound.Suitable reagent and condition for formula (VII) compound deprotection can easily be confirmed by those skilled in the art.For example, compound (I) can form through formula (VII) compound is handled under certain condition, and said condition makes hydroxyl protecting group such as acetic ester, isopropylidene and Ben Yajiaji protection base left away by formula (VII) structure.For example, can use catalyst n aOMe in methyl alcohol, to make the acetate group fracture through Zempl é n condition as alkali.Ben Yajiaji and isopropylidene can or use acidic hydrolysis fracture through hydrogenization, as at R.M.Hann et al., and J.Am.Chem.Soc., report in 72,561 (1950).In another example, can carry out deprotection, amino protecting group such as carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc) and carboxylamine carboxyl benzyl ester (cbz) protection base are ruptured by formula (VII) compound thus.Can under mild conditions, remove carboxylamine 9-fluorenyl methyl esters (Fmoc) to obtain unhindered amina and diphenylene-oxide with amine alkali (for example piperidines), as at E.Atherton et al., " The Fluorenylmethoxycarbonyl Amino Protecting Group; " In The Peptides; S.Udenfriend and J.Meienhofer, Academic Press, New York; 1987, p.1 described in.Can under acidic conditions (the for example solution of 3M HCl in EtOAc), remove t-butyl carbamate (Boc), as at G.L.Stahl et al., J.Org.Chem., report in 43,2285 (1978).Hydrogenization can be used for making carboxylamine carboxyl benzyl ester (cbz) protection base fracture, and as at J.Meienhofer et al., Tetrahedron Lett. is described in 29,2983 (1988).

In order to prevent the oxidation at reaction process Chinese style (I), deprotection can carry out under anoxia condition.Deprotection also can carry out in the temperature of envrionment temperature or about 20-60 ℃ (for example 25,30,35,40,45,50 or 55 ℃).

Formula (I) compound can pharmaceutical salts isolated in form.For example, formula (I) compound can be in crystallization in the presence of the HCl to form the HCl salt form of compound.Formula (I) compound also can be separated, for example is precipitated as sodium salt through handling with NaOH.Formula (I) compound is unsettled under some reactions and storage requirement.In some embodiments, the final solution that comprises formula (I) compound can pass through the methods known in the art acidifying.For example, if in solution, store, formula (I) compound can be stored in acidic solution.

Replacedly, the compound of formula (I) can be prepared as follows, for example:

Reaction makes formula (II-A) compound and formula (III-A) compound with preparation formula (IV-A) compound in the presence of hydrazine, and said formula (II-A) compound is:

Said formula (III-A) compound is:

Said formula (IV-A) compound is:

R wherein ₁Be the protection base, as stated;

Oxidation-type (VI-A) compound is with preparation formula (VII-A) compound:

Make formula (VII-A) compound deprotection with preparation formula (I) compound.For example, formula (I) compound can be according to preparation shown in the scheme 3.Scheme 3.

In another embodiment, formula (I) compound can be through being prepared as follows:

Said formula (III-A) compound is:

Said formula (IV-A) compound is:

Optionally protection (IV-A) compound is with preparation formula (V-B) compound:

Each R wherein ₁Be the protection base independently, as stated;

Each R wherein ₁Be the protection base independently, as stated;

Oxidation-type (VI-B) compound is with preparation formula (VII-B) compound:

And make formula (VII-B) compound deprotection with preparation formula (I) compound.For example, formula (I) compound can be according to preparation shown in the scheme 4.

Scheme 4.

Alternatively, formula (I) compound can form shown in scheme 5.The di-amino-pyrimidine ketone compound of formula (II) can with the phosphorylation hexose coupling of formula (VIII) to obtain formula (IX) compound.The theheterocyclic nitrogen atom of piperazine ring can be obtained formula (X) compound by protection, and it can oxidation obtains the glycol of formula (XI).The glycol of formula (XI) can and transform at deprotection under the appropriate condition and obtain formula (I) compound then.

Scheme 5.

In this embodiment, the SULPHOSUCCINIC ACID ESTER pyrans that can occur when avoiding not expecting in synthetic initial introducing and the balance of furans isomer at synthetic subsequent step.For example, formula (I) compound can be as preparing shown in the scheme 6.

Scheme 6.

Formula I compound also can be according to forming shown in the scheme 7.The di-amino-pyrimidine ketone compound of formula (II) can with the coupling of formula (III) compound to obtain the bridged piperazine derivatives of formula (IV).The piperazine ring nitrogen-atoms of formula (IV) compound can be protected to obtain the verivate of formula V under standard conditions.The formula V structure can be oxidized to obtain formula (XII) compound.Make formula (XII) compound phosphorylation obtain formula (VII) compound.The whole deprotection of formula (VII) compound is to obtain formula (I) compound.

Scheme 7.

For example, formula (I) compound can prepare shown in scheme 8.

Scheme 8.

In an optional embodiment, formula (I) compound can form shown in scheme 9.The di-amino-pyrimidine ketone compound of formula (II) can have the optionally imines of formula (XX) of good area with preparation with the 2-carbonyl hexose standard analysis condensation of formula (XVIII).Further use Lewis acid (LA) (for example, TMSOTf) activation end group position functional group (such as acetic ester) with the compound of the cyclisation that obtains formula (XXI).Can be at the newly-generated glycosidic link of equatorial position.Hydrogenation of formula (XXI) compound can prepare formula (IV) compound.Selective protection formula (IV) compound obtains the formula V compound, and it is oxidized to obtain formula (XII) compound.Formula (XII) compound can obtain formula (I) compound like the said processing of the application then.

Scheme 9.

For example, formula (I) compound can prepare shown in scheme 10.

Scheme 10.

Alternatively, formula (I) compound can form shown in scheme 11.In this was synthetic, the di-amino-pyrimidine ketone of formula (II) and the cyclisation of hexose standard analysis can be carried out in the presence of alkali.Obtain cyclisation product with Lewis acid (LA) activation, it can be by deprotection to form unprotected ketone.This ketone can be obtained formula (I) compound or formula (XIII) compound by phosphorylation and/or whole deprotection as the application is said.Scheme 11.

For example, formula (I) compound can prepare shown in scheme 12.

Scheme 12.

In an optional embodiment, formula (I) compound can be made by the cyclization of compound Z, shown in scheme 13.

Scheme 13.

Alternatively, formula (I) compound can prepare shown in scheme 14.The di-amino-pyrimidine ketone compound of formula (II) can obtain the bridged piperazine derivatives suc as formula (IV) with the coupling of formula (XXII) compound.The piperazine ring nitrogen-atoms of formula (IV) compound can be protected to obtain the verivate of formula V under standard conditions.In some embodiments, the formula V compound can experience optionally deprotection before phosphorylation.For example, one or more hydroxylic moieties can be before phosphorylation deprotection.Make formula V compound phosphorylation to obtain formula (VI) compound.Formula (VI) structure can be oxidized so that formula (VII) compound to be provided.The whole deprotection of formula (VII) compound can obtain formula (I) compound.

Scheme 14.

For example, formula (I) compound or pharmaceutically acceptable salt thereof can through as the preparation of getting off:

In the presence of hydrazine, make the reaction of formula (II-A) compound and formula (XXII-A) compound with preparation formula (IV-A) compound, said formula (II-A) compound is:

Said formula (XXII-A) compound is:

Said formula (IV-A) compound is:

Each R wherein ₁Be H or protection base, of the application.Can make compound (V-C) phosphorylation to obtain formula (VI-C) compound then:

Oxidable then formula (VI-C) compound is with preparation formula (VII-C) compound:

At last, make formula (VII-C) compound deprotection with preparation formula (I) compound.

Alternatively, formula (I) compound can prepare shown in scheme 15.Formula (XXIII) compound can experience epoxidation to obtain formula (XXIV) compound.Formula (XXIV) compound can with the coupling of formula (II) compound with preparation formula (XXV) compound.Formula (XXV) compound can experience ring-closure reaction to obtain the bridged piperazine derivatives of formula (IV).The piperazine ring nitrogen-atoms of formula (IV) compound can be protected to obtain the verivate of formula V under standard conditions.Make formula V compound phosphorylation obtain formula (VI) compound.Formula (VI) structure can be oxidized so that formula (VII) compound to be provided.Can make the whole deprotection of formula (VII) compound to obtain formula (I) compound.

Scheme 15.

Make the reaction of formula (XXIII-A) compound with preparation formula (XXIV) compound, said formula (XXIII-A) compound is:

Each R wherein ₁Be H or protection base and R independently ₄Be H or leavings group, said formula (XXIV) compound is:

Make the reaction of formula (XXIV) compound (II-A) compound with preparation formula (XXV-A) compound, said formula (II-A) compound is:

Said formula (XXV-A) compound is:

The annulation of formula (XXV-A) compound is carried out catalysis with preparation formula (IV-D) compound:

Selective protection formula (IV-D) compound is with preparation formula (V-D) compound:

Each R wherein ₁Be H or protection base.

Oxidation-type (VI-D) compound is with preparation formula (VII-D) compound:

At last, make formula (VII-D) compound deprotection with preparation formula (I) compound.Formula (XII) compound:

In another embodiment, preparation formula (XII) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.

As described, the amino and/or the hydroxyl of some formula (XII) structure can be used R ₁The protection of protection base.For this purpose, R ₁The suitable amino or the hydroxy functional group that can comprise technician's selection of chemical field arbitrarily.For example, the amino protecting group in the open scope of the application includes but not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.The instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

Ester class protection base can comprise acetoxyl group (OAc), formic acid aryl ester, acetate aryl ester, levulinic acid aryl ester, PIVALIC ACID CRUDE (25) aryl ester, phenylformic acid aryl ester and 9-fluorenes aryl ester carboxylic acid.In one embodiment, ester class protection base is an acetoxyl group.

Protect some amino and hydroxyl can improve the solubleness of formula (XII) compound.For example the preparation of the acetyl derivative of formula (XII) compound can improve solubleness and increase the product separation yield.

Formula (XII) compound can be through oxidation formula V compound with preparation formula (XII) compound, and said formula V compound is:

Said formula (XII) compound is:

Wherein:

Each R ₁Be H or protection base independently, as stated.

In this was synthetic, formula (XII) compound can be through making the formula V compound and being suitable for the oxidant reaction that selectivity forms the glycol of formula (XII) arbitrarily and preparing.Suitable oxygenant and condition can easily be confirmed by those skilled in the art.For example, formula (XII) compound can through with the formula V compound with ruthenium compound such as RuO ₄ ^-/ NMO handles and forms.Also can use other oxygenant; Such as Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride, TFAA/DMSO, PDC, hydrogen peroxide, inorganic peroxide, nitric acid, nitrate salt, chlorite, oxymuriate, perchlorate, hypochlorite, superoxide, iodine, ozone, Nitrous Oxide, silver suboxide, permanganate, hexavalent chromium compound, chromic acid, dichromic acid, chromium trioxide, PCC, persulfuric acid, sulfoxide, sulfuric acid, Tollens reagent, 2,2 '-pyridyl disulfide (DPS) and perosmic anhydride.In one embodiment, the pyrazine ring of compound (XII) is not oxidized thus to use certain oxidizing condition.In some embodiments, oxygenant is selected from RuO ₄ ^-/ NMO, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride, TFAA/DMSO and PDC.

For example, oxidizing reaction can be through using RuO with the formula V compound ^- ₄/ NMO handles in envrionment temperature and carries out to obtain formula (XII) compound.In another embodiment, formula (XII) compound is through using RuO with the formula V compound ^- ₄/ NMO forms in the Temperature Treatment of 20-60 ℃ (for example about 20,25,30,35,40,45,50 or 55 ℃).

It is understandable that also the isomeric form of formula (XII) structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (I).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (XII) can be accomplished and separation than latter stage at synthetic.

Formula (XIII) compound:

In another embodiment, preparation formula (XIII) compound or pharmaceutically acceptable salt thereof or hydrate:

Formula (XIII) compound or pharmaceutically acceptable salt thereof or hydrate also comprise tautomeric structure:

Formula (I) compound is the reaction product of formula (XIII) compound and water.Because equilibrium establishment between these two products, these two types of materials possibly be present in the aqueous solution under some pH and condition.Those skilled in the art's may command synthesis condition (for example, carrying out down anhydrous) is with the ketone material of the formula (XIII) of separation and purification form.

Formula (XIII) compound can be through making formula (XIV) compound deprotection with preparation formula (XIII) compound, and said formula (XIV) compound is:

Wherein:

Each R ₁Be H or protection base independently, as stated.

In this was synthetic, deprotection for example can comprise that some amino of formula (XIV) and the continuous deprotection of hydroxyl protecting group or one kettle way deprotection are to obtain formula (XIII) compound.Suitable reagent and condition for formula (XIV) compound deprotection can easily be confirmed by those skilled in the art.For example, compound (XIII) can form through formula (XIV) compound is handled under certain condition, and said condition makes hydroxyl protecting group such as acetic ester, isopropylidene and Ben Yajiaji protection base left away by formula (XIV) structure.For example, can use catalyst n aOMe in methyl alcohol, to make the acetate group fracture through Zempl é n condition as alkali.Ben Yajiaji and isopropylidene can or use acidic hydrolysis fracture through hydrogenization, as at R.M.Hann et al., and J.Am.Chem.Soc., report in 72,561 (1950).In another example, can carry out deprotection, amino protecting group such as carboxylamine 9-fluorenyl methyl esters (Fmoc), t-butyl carbamate (Boc) and carboxylamine carboxyl benzyl ester (cbz) protection base are ruptured by formula (XIV) compound thus.Can under mild conditions, remove carboxylamine 9-fluorenyl methyl esters (Fmoc) to obtain unhindered amina and diphenylene-oxide with amine alkali (for example piperidines), as at E.Atherton et al., " The Fluorenylmethoxycarbonyl Amino Protecting Group; " In The Peptides; S.Udenfriend and J.Meienhofer, Academic Press, New York; 1987, p.1 described in.Can under acidic conditions (the for example solution of 3M HCl in EtOAc), remove t-butyl carbamate (Boc), as at G.L.Stahl et al., J.Org.Chem., report in 43,2285 (1978).Hydrogenization can be used for making carboxylamine carboxyl benzyl ester (cbz) protection base fracture, and as at J.Meienhofer et al., Tetrahedron Lett. is described in 29,2983 (1988).

In order to prevent the oxidation at reaction process Chinese style (XIII), deprotection can carry out under anoxia condition.Deprotection also can carry out in the temperature of envrionment temperature or 20-60 ℃ (perhaps 25,30,35,40,45,50 or 55 ℃).

Alternatively, formula (XIII) compound can form shown in scheme 16.The di-amino-pyrimidine ketone compound of formula (II) can with the phosphorylation hexose coupling of formula (VIII) to obtain formula (IX) compound.The piperazine ring nitrogen-atoms can be by protection to obtain formula (X) compound, and it can be oxidized to obtain the glycol of formula (XV).The glycol of formula (XV) can and be converted into formula (XIII) compound at deprotection under the conditions suitable then.

Scheme 16.

In another embodiment, formula (XIII) compound can form shown in scheme 17.For example, the di-amino-pyrimidine ketone compound of formula (II) can react to obtain formula (IV) compound with the hexose of shielded or unprotected formula (III).The theheterocyclic nitrogen atom of formula (IV) piperazine ring can optionally be protected to obtain the formula V verivate under standard conditions then.Make formula V compound phosphorylation can obtain the SULPHOSUCCINIC ACID ESTER midbody of formula (VI).The SULPHOSUCCINIC ACID ESTER of formula (VI) can be converted into the glycol of formula (XIV) under suitable oxidizing condition.At last, formula (XIV) compound can deprotection to obtain formula (XIII) compound.

Scheme 17

Alternatively, formula (XIII) compound can be by preparation shown in the scheme 18.The di-amino-pyrimidine ketone compound of formula (II) can react to obtain formula (IV) compound with formula (XXII) compound.The piperazine ring nitrogen-atoms of formula (IV) compound can optionally be protected to obtain the formula V verivate under standard conditions.In some embodiments, the formula V compound can experience optionally deprotection before phosphorylation.For example, one or more hydroxylic moieties can be before phosphorylation deprotection.Make formula V compound phosphorylation to obtain formula (VI) compound.Formula (VI) structure can be oxidized so that formula (XIV) compound to be provided.The whole deprotection of formula (XIV) compound can obtain formula (XIII) compound.

Scheme 18

Alternatively, formula (I) compound can prepare shown in scheme 19.Formula (XXIII) compound can experience epoxidation to obtain formula (XXIV) compound.Formula (XXIV) compound can with the coupling of formula (II) compound with preparation formula (XXV) compound.Formula (XXV) compound can experience ring-closure reaction to obtain formula (IV) bridged piperazine derivatives.The piperazine ring nitrogen-atoms of formula (IV) compound can be protected to obtain the formula V verivate under standard conditions.The phosphorylation of formula V compound obtains formula (VI) compound.Formula (VI) structure can be oxidized so that formula (XIV) compound to be provided.The whole deprotection of formula (XIV) compound can obtain formula (I) compound.

Scheme 19

Formula (XIII) compound can be separated into the form of pharmaceutical salts.For example, formula (XIII) compound can be in crystallization in the presence of the HCl to form the hydrochloride form of compound.Formula (XIII) compound also can be separated, for example, is precipitated as sodium salt through handling with NaOH.Formula (XIII) compound is unsettled under some reaction and storage condition.In some embodiments, the final solution means known in the art capable of using that comprise formula (XIII) compound are carried out acidifying.For example, if be stored in the solution, formula (XIII) compound can be stored in the acidic solution.

Formula (XIV) compound

In another embodiment, preparation formula (XIV) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.

As described, some amino and/or the hydroxyl of formula (XIV) structure can be used R ₁The protection of protection base.For this purpose, R ₁The suitable amino or the hydroxy functional group that can comprise technician's selection of chemical field arbitrarily.For example, the amino protecting group in the open scope of the application includes but not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.The instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

Protect some amino and hydroxyl can improve the solubleness of formula (XIV) compound.For example the preparation of the acetyl derivative of formula (XIV) compound can improve solubleness and increase the product separation yield.

Formula (XIV) compound can pass through oxidation-type (VI) compound with preparation formula (XIV) compound, and said formula (VI) compound is:

Said formula (XIV) compound is:

Wherein:

Each R ₁Be H or protection base independently, as stated.

In this was synthetic, formula (XIV) compound can be through making formula (VI) compound and being suitable for the oxidant reaction that selectivity forms the ketone of formula (XIV) arbitrarily and preparing.Suitable oxygenant and condition can easily be confirmed by those skilled in the art.For example, formula (XIV) compound can through with formula (VI) compound with ruthenium compound such as RuO ₄ ^-/ NMO handles and forms.Also can use other oxygenant; Such as Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride, TFAA/DMSO, PDC, hydrogen peroxide, inorganic peroxide, nitric acid, nitrate salt, chlorite, oxymuriate, perchlorate, hypochlorite, superoxide, iodine, ozone, Nitrous Oxide, silver suboxide, permanganate, hexavalent chromium compound, chromic acid, dichromic acid, chromium trioxide, PCC, persulfuric acid, sulfoxide, sulfuric acid, Tollens reagent, 2,2 '-pyridyl disulfide (DPS) and perosmic anhydride.In one embodiment, the pyrazine ring of compound (XIV) is not oxidized thus to use certain oxidizing condition.In some embodiments, oxygenant is selected from RuO ₄ ^-/ NMO, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride and PDC.

For example, oxidizing reaction can be through using RuO with formula (VI) compound ^- ₄/ NMO handles in envrionment temperature and carries out to obtain formula (XIV) compound.In another embodiment, formula (XIV) compound is through using RuO with formula (VI) compound ^- ₄/ NMO forms in the Temperature Treatment of 20-60 ℃ or 20,25,30,35,40,45,50 or 55 ℃.

It is understandable that also the isomeric form of formula (XIV) structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (XIII).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (XIV) can be accomplished and separation than latter stage at synthetic.

In one embodiment, formula (XIV) compound comprises isomer:

Formula (XIV) compound also comprises tautomeric structure:

Formula (XXII) compound

Another embodiment relates to formula (XXII) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.

As described, the hydroxyl of formula (XXII) compound can be shielded or unprotected form.For example, the formula of unprotected form (XXII) compound can comprise compound (XXII-A) or its pharmaceutical salts:

Some hydroxyl of formula (XXII) structure can be used R ₁The protection of protection base.For this purpose, R ₁Can comprise the suitable hydroxy functional group of technician's selection of chemical field arbitrarily.For example, the instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, 4 of the hexose ring composition of formula (XXII) with the R of 5-position ₁Group can merge to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.

Protect some amino and hydroxyl can improve the solubleness of formula (XXII) compound.For example the preparation of the acetyl derivative of formula (XXII) compound can improve solubleness and increase the product separation yield.

Formula (XXII) compound can according to currently known methods (referring to for example, Goswami, S.; Adak, A.K.Tetrahedron Lett. (2005), 46,221-224) preparation or can commercial buy.

It is understandable that also the isomeric form of formula (XXII) structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (I).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (XXII) can be accomplished and separation than latter stage at synthetic.

In some embodiments, formula (XXII) compound or pharmaceutically acceptable salt thereof or hydrate comprise isomer:

Formula (XXIII) compound

Another embodiment relates to formula (XXIII) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base and R independently ₄Be H or leavings group.

As described, the hydroxyl of formula (XXIII) compound can be shielded or unprotected form.For example, the formula of unprotected form (XXIII) compound can comprise compound 2-(allyl group oxygen base)-6-(hydroxymethyl) tetrahydrochysene-2H-pyrans-3,4,5-triol or its pharmaceutical salts:

Some hydroxyl of formula (XXIII) structure can be used R ₁The protection of protection base.For this purpose, R ₁Can comprise the suitable hydroxy functional group of technician's selection of chemical field arbitrarily.For example, the instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, 4 of the hexose ring composition of formula (XXIII) with the R of 5-position ₁Group can merge to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, formula (XXIII) compound can be formula (XXIII-A) compound or pharmaceutically acceptable salt thereof:

for example, compound (XXIII) can comprise compound or pharmaceutically acceptable salt thereof:

Protect some amino and hydroxyl can improve the solubleness of formula (XXIII) compound.For example the preparation of the acetyl derivative of formula (XXIII) compound can improve solubleness and increase the product separation yield.

As described, R ₄Can be leavings group.To this purpose, R ₄Can comprise the suitable hydroxyl leavings group of technician's selection of chemical field arbitrarily.For example, the instance of unrestriced hydroxyl protecting group can comprise tosylate, brosylate, m-nitrobenzene sulfonic acid ester, methanesulfonates, oxygen, triflate, perfluoro butyl sulphonate and trifluoroethyl sulphonate.

Formula (XXIII) compound can or can commercially be bought according to the currently known methods preparation.

It is understandable that also the isomeric form of formula (XXIII) structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (I).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (XXIII) can be accomplished and separation than latter stage at synthetic.

In one embodiment, formula (XXII) compound or pharmaceutically acceptable salt thereof or hydrate comprise isomer:

Formula (XXIV) compound

Another embodiment relates to formula (XXIV) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.

As described, the hydroxyl of formula (XXIV) compound can be shielded or unprotected form.For example, the formula of unprotected form (XXIV) compound can comprise 2-(allyl group oxygen base)-4-(hydroxymethyl)-3,7-dioxa two ring [4.1.0] heptane-5-alcohol or its pharmaceutical salts:

Some hydroxyl of formula (XXIV) structure can be used R ₁The protection of protection base.For this purpose, R ₁Can comprise the suitable hydroxy functional group of technician's selection of chemical field arbitrarily.For example, the instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, 4 of the hexose ring composition of formula (XXIV) with the R of 5-position ₁Group can merge to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, formula (XXIV) compound comprises compound or pharmaceutically acceptable salt thereof:

Protect some amino and hydroxyl can improve the solubleness of formula (XXIV) compound.For example the preparation of the acetyl derivative of formula (XXIV) compound can improve solubleness and increase the product separation yield.

Formula (XXIV) compound can be through making formula (XXIII) compound and alkali reaction with preparation formula (XXIV) compound, and said formula (XXIII) compound is:

Said formula (XXIV) compound is:

R wherein ₁Be H or protection base independently, and R ₄Be H or leavings group, as stated.

In this was synthetic, formula (XXIV) compound can be through making formula (XXIII) compound and being suitable for the alkali reaction that selectivity forms the epoxide of formula (XXIV) arbitrarily and preparing.Suitable alkali and condition can easily be confirmed by those skilled in the art.For example, formula (XXIV) compound can form with highly basic formula (XXIII) compound after such as sodium-hydroxide treatment.Also can use other alkali such as Pottasium Hydroxide, hydrated barta, cesium hydroxide, strontium hydroxide, calcium hydroxide, Marinco H, Lithium Hydroxide MonoHydrate, rubidium hydroxide, butyllithium, lithium diisopropylamine, diethylamino lithium, sodium amide, sodium hydride and two (trimethyl silyl) Lithamide.

For example, reaction can be through carrying out in about 0 ℃ (being warmed to ambient temperature overnight) processing formula (XXIII) compound in organic solvent with sodium hydroxide to obtain formula (XXIV) compound.

It is understandable that also the isomeric form of formula (XXIV) structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (I).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (XXIV) can be accomplished and separation than latter stage at synthetic.

In one embodiment, formula (XXIV) compound or pharmaceutically acceptable salt thereof or hydrate comprise isomer:

Formula (XXV) compound

Another embodiment relates to formula (XXV) compound or pharmaceutically acceptable salt thereof or hydrate:

Each R wherein ₁Be H or protection base independently.

As described, the hydroxyl of formula (XXV) compound can be shielded or unprotected form.For example, the formula of unprotected form (XXV) compound can comprise 6-(allyl group oxygen base)-5-((2,4-diamino--6-hydroxy pyrimidine-5-yl) amino)-2-(hydroxymethyl) tetrahydrochysene-2H-pyrans-3,4-glycol or its pharmaceutical salts:

Alternatively, one or more hydroxyls can be protected.For example, formula (XXV) compound can comprise compound 6-(allyl group oxygen base)-7-((2,4-diamino--6-(benzyl oxygen base) pyrimidine-5-yl) amino)-2-phenyl six hydrogen pyrans also [3,2-d] [1,3] dioxin-8-alcohol or its pharmaceutical salts:

As described, some amino and/or the hydroxyl of formula (XXV) structure can be used R ₁The protection of protection base.For this purpose, R ₁The suitable amino or the hydroxy functional group that can comprise technician's selection of chemical field arbitrarily.For example, the amino protecting group in the open scope of the application includes but not limited to carbamate, acid amides, N-alkyl or N-aryl deriveding protection base.The instance of unrestriced hydroxyl protecting group can comprise ether, ester, carbonic ether or sulphonate protection base.R ₁The protection base can be identical or different.

In some embodiments, two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, 4 of the hexose ring composition of formula (XXV) with the R of 5-position ₁Group can merge to form isopropylidene ethylidene ether, Ben Yajiaji ethylidene ether, 1; 5-dioxo spiro [5.5] undecane (cyclohexylene ethylidene ether), 6; 10-dioxo spiro [4.5] decane (ring pentylidene ethylidene ether) or 2-isobutyl--2-methyl isophthalic acid, 3-diox part.For example, formula (XXV) compound can comprise compound or pharmaceutically acceptable salt thereof:

Protect some amino and hydroxyl can improve the solubleness of formula (XXV) compound.For example the preparation of the acetyl derivative of formula (XXV) compound can improve solubleness and increase the product separation yield.

Formula (XXV) compound can prepare to obtain formula (XXV) compound through making the reaction of formula (XXIV) compound and formula (II) compound, and said formula (XXIV) compound is:

Said formula (II) compound is:

Said formula (XXV) compound is:

R wherein ₁Be H or protection base independently, as stated.In this was synthetic, formula (XXV) compound can prepare to form formula (XXV) compound through making formula (XXIV) compound and the coupling of formula (II) compound.Appropriate reaction conditions can easily be confirmed by those skilled in the art.For example, formula (XXV) compound can through with formula (XXIV) and (II) compound in the presence of oxygenant such as lithium perchlorate, handle and form.Also can use other oxygenant, such as RuO ₄ ^-/ NMO, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride, TFAA/DMSO, PDC, hydrogen peroxide, inorganic peroxide, nitric acid, nitrate salt, chlorite, oxymuriate, perchlorate, hypochlorite, superoxide, iodine, ozone, Nitrous Oxide, silver suboxide, permanganate, hexavalent chromium compound, chromic acid, dichromic acid, chromium trioxide, PCC, persulfuric acid, sulfoxide, sulfuric acid, Tollens reagent, 2,2 '-pyridyl disulfide (DPS) and perosmic anhydride.

For example, oxidizing reaction can through with formula (XXIV) and (II) mixture of compound in organic solvent, handle simultaneously heating (for example at about 90 ℃) with lithium perchlorate and carry out to obtain formula (XXV) compound.

It is understandable that also the isomeric form of formula (XXV) structure can be controlled in the stereospecificity of the synthetic middle consecutive steps of formula (I).Therefore, specific isomer can separate in this step of synthetic, and perhaps replacedly, the isomer mixture of formula (XXV) can be accomplished and separation than latter stage at synthetic.

In one embodiment, formula (XXV) compound or pharmaceutically acceptable salt thereof or hydrate comprise isomer:

Formula (XXV) compound can be used for preparation formula (IV) compound then.Formula (IV) compound can be through making formula (XXV) compound and 1, and the reaction of 3-dimethyl barbituric acid prepares to obtain formula (IV) compound, and said formula (XXV) compound is:

Said formula (IV) compound is R wherein ₁H or protection are basic independently, as stated.

In this was synthetic, formula (IV) compound can be through making formula (XXV) compound and 1, and the 3-dimethyl barbituric acid reacts in the presence of catalyzer to form formula (IV) compound and prepares.Appropriate catalyst and reaction conditions can easily determine for those skilled in the art.For example, formula (XXV) compound can form through formula (XXIV) compound and formula (II) compound are handled in the presence of catalyzer such as tetrakis triphenylphosphine palladium (0).Also can use other catalyzer.

Pharmaceutical prepn and formulation

When the medicine, the form administration that the compound that the application provides can pharmaceutical composition.These compsns can known mode prepare in pharmaceutical field, but and administered by various routes, its depend on topical therapeutic or whole body therapeutic whether be expection and depend on zone to be treated.Administration can be topical (comprise through skin, epidermis, eye drops with in mucous membrane comprises nose, intravaginal and rectum send), pulmonary administration, and (the for example suction through powder agent or aerosol or be blown into comprises atomizer; Interior or the intranasal administration of tracheae), oral administration or administered parenterally.Administered parenterally comprises intravenously, intra-arterial, subcutaneous, intraperitoneal, intramuscular administration or injection or infusion administration; Perhaps for example sheath is interior or the interior administration of ventricle in the encephalic administration.Administered parenterally can be single form of injecting administration, for example perhaps can be continous pouring pump form.The pharmaceutical composition and the preparation that are used for topical can comprise transdermal patch, ointment, lotion, ointment, gelifying agent, drops, suppository, sprays, liquid preparation and powder agent.Conventional pharmaceutical carrier, moisture, powder or contain oil base, thickening material etc. and can be necessary or ideal.

The present invention also provides pharmaceutical composition, and it contains the compound or pharmaceutically acceptable salt thereof that the application as activeconstituents provides and the combination of one or more pharmaceutical carriers (vehicle).In some embodiments, said compsn is suitable for topical.In the process of the compsn that preparation the application provides; Typically with activeconstituents and mixed with excipients; With vehicle dilution or in said carrier, wrap up, said carrier be the perhaps form of other inclusion agents (container) of capsule, wafer, charta for example.When said vehicle was used as thinner, it can be solid, semi-solid or fluent material, and it is used as vehicle, carrier or medium for activeconstituents.Therefore, compsn can be tablet, pill, powder agent, lozenge, wafer, cachet, elixir, suspensoid, emulsion, solution, syrup, aerosol (as solid or in liquid medium), contains the form of the powder agent of the ointment, soft hard gelatin capsule, suppository, aseptic injectable solution agent and the sterile packed that for example reach 10% active compound by weight.

In the process of preparation preparation, active compound grinds to obtain suitable granularity, afterwards it is mixed with other composition.If it is insoluble that active compound is essentially, then it can grind and be the granularity less than 200 mesh sieves.If it is water miscible that active compound is essentially, then granularity can be through grinding adjustment to reach in preparation uniform distribution basically, for example about 40 mesh sieves.

The compound that the application provides can use known Ginding process to grind, such as wet-milling to obtain being suitable for the granularity of tablet and other preparation type.The fine dispersion of the compound that the application provides (nanoparticle) preparation can be through the means known in the art preparation, for example referring to International Application No. WO 2002/000196.

Some instances of appropriate excipients comprise lactose, Vadex, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, gum arabic, calcium phosphate, alginate, tragakanta, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, PVP K120, Mierocrystalline cellulose, water, syrup and methylcellulose gum.Preparation can extraly comprise: lubricant such as talcum, Magnesium Stearate and MO; Wetting agent; Emulsifying agent and suspending agent; Sanitas such as methyl-and propyl hydroxy-benzoic ether; Sweeting agent; And seasonings.Can prepare compsn that the application provides so that through provide after adopting means known in the art to patient's administration activeconstituents fast, continue or delay to discharge.

Compsn can be formulated as unit dosage, and each dosage contains 5 activeconstituentss to about 1000mg (1g) of having an appointment, more commonly about activeconstituents of 100 to about 500mg.Term " unit dosage " be meant with suitable pharmaceutical vehicle associating suitably as unit independently physically for human experimenter and other mammiferous integral dose, each unit contains and obtains expecting the true in advance quantitative active substance of calculating of therapeutic action.

In some embodiments, the compsn that provides of the application contains 5 to about 50mg the activeconstituents of having an appointment.The compsn that those skilled in the art will recognize that this enforcement contains has an appointment 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45 or about activeconstituents of 45 to about 50mg.

In some embodiments, the compsn that provides of the application contains 50 to about 500mg the activeconstituents of having an appointment.The compsn that those skilled in the art will recognize that this enforcement contains has an appointment 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400 or about activeconstituents of 450 to about 500mg.

In some embodiments, the compsn that provides of the application contains 500 to about 1000mg the activeconstituents of having an appointment.The compsn that those skilled in the art will recognize that this enforcement contains has an appointment 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950 or about activeconstituents of 950 to about 1000mg.

Similarly dosage can be used for the described compound of the application in method that the application provides and purposes.

Active compound in wide dosage range for effectively and usually carrying out administration with medicinal significant quantity.Yet the amount that will be understood that the compound of actual administration is confirmed according to correlated condition by the doctor that usually said condition comprises the compound of illness to be treated, selected route of administration, actual administration, age, body weight and the reaction of individual patient, the seriousness of patient's symptom etc.

, main activeconstituents is mixed the solid that contains the uniform mixture of the compound that the application provides with formation write out a prescription and design (preformulation) compsn with drug excipient such as tablet for the preparation solids compsn.When these prescription design team compounds are identified as when even, typically with activeconstituents homodisperse in whole compsn, said thus compsn can easily be subdivided into EU Equivalent Unit formulation such as tablet, pill and capsule.Then this solid prescription design preparation is subdivided into the unit dosage of type as stated, it contains the activeconstituents that for example about the application of 0.1 to about 1000mg provides.

Tablet that the application provides or pill can be by dressings or are cooperated in addition to obtain to provide the formulation of long-acting advantage.For example, said tablet or pill can comprise internal dose and outside dose components, and said outside dose components is the encapsulated form outside the internal dose composition.Can be through enteric layer with two kinds of component separating, said enteric layer is used in stomach, preventing disintegration and allows complete the entering into of internal component perhaps to delay in the duodenum to discharge.Multiple material can be used for said enteric layer or coatings, and said material comprises the mixture of multiple polymeric acid and polymeric acid and said material such as shellac, hexadecanol and rhodia.

Comprise the aqueous solution, suitably rectify syrup, the moisture or oleaginous suspension of flavor and have the emulsion of edible oil such as oleum gossypii seminis, sesame oil, Oleum Cocois or peanut oil with the liquid form that is used for oral or drug administration by injection in compound that can the application be provided and compsn are blended in, and elixir and similar drug media thing.

In some embodiments, the compound that provides of preparation the application is to be used for intravenous administration.The pharmaceutical composition that is applicable to injection can comprise aseptic aqueous solution (water soluble) or dispersion liquid and the sterilized powder that is used for temporarily preparing aseptic injectable solution or dispersion liquid.For intravenous administration, suitable carriers comprises saline water, bacteriostatic water, Cremophor EL ^TM(BASF, Parsippany, NJ) or phosphate buffered saline (PBS) (PBS).In all cases, said composition is necessary for aseptic and should be to reach and has the fluid that is easy to the syringeability degree.It should be stable under preparation and storage environment, and must be able to prevent the pollution of mikrobe such as bacterium and fungi.This carrier can be solvent or dispersion medium, and it for example comprises, water, ethanol, polyvalent alcohol (for example, glycerine, Ucar 35 and liquid macrogol etc.), and suitable mixture.Suitable flowability can be for example through using dressing such as Yelkin TTS, under the dispersive situation, keep required granularity and using tensio-active agent to keep.Stop microbial process to realize through multiple antiseptic-germicide and anti-mycotic agent, for example, p-Hydroxybenzoate, butylene-chlorohydrin, phenol, xitix, Thiomersalate etc.Under many situations, preferably in compsn, comprise isotonic agent, for example, carbohydrate, polyvalent alcohol such as N.F,USP MANNITOL, sorbyl alcohol, sodium-chlor.Through in compsn, comprising for example aluminum monostearate and the gelatin absorption that can prolong injectable composition of the reagent that prolong to absorb.

Aseptic injectable solution can through the active compound of aequum is merged with the combination of more than one compositions of enumerating or this composition in suitable solvent as required, then filtration sterilization prepares.Usually, dispersion liquid prepares through active compound and aseptic vehicle are merged, and said aseptic vehicle contains basic dispersion medium and above other required composition of enumerating.Under the situation of the sterilized powder that is used to prepare aseptic injectable solution, preferred manufacturing procedure is vacuum-drying and freeze-drying, the powder of the other required composition of sterile filtration solution before it obtains activeconstituents and comes from arbitrarily.

The compsn that is used for sucking or be blown into is included in the solution and the suspensoid of medicinal moisture or organic solvent or their mixture, and powder agent.Said liquid or solids compsn can contain suitable aforesaid pharmaceutical excipient.In some embodiments, the interior inhalation route administration of said compsn administered through oral or nose is to reach local or general action.Compsn can be sprayed through using rare gas element.Spray solution can or can directly suck with the spraying plant that face shield, curtain cover (tent) or intermittent positive pressure breathing machine are connected by spraying plant.Solution, suspension or powder composition can carry out oral administration or carry out nasal administration by the device according to suitable mode delivery formulation.

Local administration preparation can contain one or more conventional carriers.In some embodiments, ointment can contain water and one or more hydrophobic carriers, and said carrier is selected from for example Liquid Paraffin, Voranol EP 2001, Ucar 35, white vaseline etc.The carrier compositions of ointment can be the basis with glycerine and one or more other components (for example glyceryl monostearate, PEG-glyceryl monostearate and cetyl stearyl alcohol) blended water.Can use and suitable blended Virahol of other component (for example, glycerine, hydroxy ethyl cellulose etc.) and water preparation gelifying agent.In some embodiments, local administration preparation contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2 or the compound that provides at least about the application of 5wt%.Local administration preparation can be suitably in for example 100g (it is optional relevant with the treatment that is used for selected indication) pipe internal packing.

In one embodiment, the compound that the application provides avoids the preparing carriers eliminated fast in the body with the protection compound, such as the sustained release preparation, comprises and implanting and the micro-capsule delivery system.Can use biodegradable, biocompatible polymer, such as ethylene vinyl acetate, polyanhydride, Sodium bromoacetate homopolymer, SRU, collagen, poe and POLYACTIC ACID.Said preparation can use the standard technique preparation or be available commercially, and for example, from Alza Corporation and Nova Pharmaceuticals, Inc obtains.Liposome suspension (comprising the selected liposome with cell of the antigenic monoclonal antibody of pair cell of target) also can be used as pharmaceutical carrier.These can be according to the preparation of those skilled in the art's currently known methods, and for example, like USP 4,522,811 is said.

Amount to the compound of patient's administration or compsn will be according to changes such as the material of treating administration, administration purpose (such as prevention or treatment), patient's states, administering modes.In treatment is used, can with compsn with enough healings or at least part suppress disease symptoms and complication thereof amount to suffering from patient's administration of disease.Effective dose depends on morbid state to be treated and clinicist's judgement, and multiple factor such as severity of disease, patient's age, body weight and general state etc. are depended in said judgement.

The compsn of patient's administration can be the form of aforesaid pharmaceutical composition.These compsns can be sterilized through conventional sterilising technology, perhaps can carry out aseptic filtration.Can pack aqs soln so that its as original uses, perhaps with its lyophilized, said lyophilized preparation mixes with aseptic aqueous carrier before administration.The pH of compound formulation is typically between 3 and 11, more preferably between 5 to 9, and most preferably between 7 to 8.The purposes that will be appreciated that some aforementioned excipients, carrier or stablizer will cause the formation of drug salts.

The therapeutic dose of the compound that the application provides can change according to concrete purposes, the administering mode of compound, patient's health and state and the doctor's that prescribes the judgement of for example adopting treatment.The ratio of the compound that the application in pharmaceutical composition provides or concentration can change according to numerous factors, and said factor comprises dosage, chemical feature (for example hydrophobicity) and route of administration.For example, the compound that provides of the application can provide to be used for administered parenterally in the moisture physiology buffered soln that contains 0.1 to about 10%w/v the compound of having an appointment.Some typical dosage ranges are every kg body weight 1g extremely about every day of about every day of every kg body weight 1mg.In some embodiments, dosage range is every kg body weight 100mg extremely about every day of about every day of every kg body weight 0.01mg.Dosage possibly depend on holistic health state, the RBE of selected compounds, the preparation of vehicle and the variable of route of administration thereof such as the type of disease or illness and progress degree, concrete patient.But the effective dose origin comes from dose-response curve external or the animal model test macro and extrapolates.

Embodiment

Embodiment 1. preparation precursor Z (cPMP)

Scheme 20

Test

Air-sensitive is reflected under the argon gas carries out.Organic solution is through anhydrous MgSO ₄Drying, and with solvent removed under reduced pressure.Anhydrous and the commercially available acquisition of chromatographic solvent (anhydrous level solvent is available from Sigma-Aldrich Fine Chemicals) and need not any being further purified and to use.Thin-layer chromatography (t.l.c.) is being coated with 60F ₂₅₄Carry out on the on glass or aluminium flake of silica gel.As follows organic cpds is carried out video picture: under UV-light or use ammonium molybdate (5wt%) and cerous sulfate (IV) 4H ₂O (0.2wt%) is at H ₂SO ₄(2M) solution in the aqueous solution, I ₂(0.2%) one of and among the KI (7%) at H ₂SO ₄The dip-dye of solution (1M) or the solution of 0.1% triketohydrindene hydrate in EtOH.Chromatogram (post fast) is carried out on silica gel (40-63 μ m), or on the automatic system with continuous gradient device, carries out.Specific rotation is with the path length record of 1dm, and unit is 10 ^-1deg cm ²g ^-1Concentration unit is g/100mL. ¹H NMR spectrum is at CDCl ₃, CD ₃OD (interior mark Me ₄Si, δ 0ppm) or D ₂Measure among the O (HOD, δ 4.79ppm), and ¹³C NMR spectrum is at CDCl ₃(medullary ray, δ 77.0ppm), CD ₃OD (medullary ray, δ 49.0ppm) or DMSO d ₆(medullary ray, δ 39.7ppm), D ₂O (mark reference or interior mark CH in not having ₃CN, δ 1.47ppm) the middle measurement. ¹H and ¹³The appointment of C resonance based on 2D ( ¹H- ¹H DQF-COSY, ¹H- ¹³C HSQC, HMBC) and DEPT experiment. ³¹P NMR is in 202.3MHz operation and need not be with reference to reporting.High resolving power electrospray ionization mass spectrum (ESI-HRMS) is record on Q-TOF Tandem mass spectrograph.CampbeU Microanalytical Department is passed through in trace analysis, University of Otago, and Dunedin, New Zealand carries out.A. preparation (5aS, 6R, 7R, 8R, 9aR)-and 2-amino-6,7-dihydroxyl-8-(hydroxymethyl)-3H, 4H, 5H, 5aH, 6H, 7H, 8H, 9aH, 10H-pyrans be [3,2-g] pteridine-4-ketone monohydrate (1) also

With 2,5,6-triamino-3,4-dihydro-pyrimidin-4-ketone dihydrochloride (Pfieiderer, W.; Chem.Ber.1957,90,2272; Org.Synth.1952,32,45; Org Synth.1963, Coll.Vol.4,245,10.0g, 46.7mmol), D-semi-lactosi phenyl hydrazones (Goswami, S.; Adak, A.K.Tetrahedron Lett.2005,46,221-224,15.78g, 58.4mmol) and 2 mercapto ethanol (1mL) at MeOH-H ₂Stir and be heated to backflows (bathing warm 110 ℃) in 1: 1 mixture (400mL) of O and kept two hours.After being cooled to envrionment temperature, add ether (500mL), jolting flask and ether layer inclined to and discard.Divide two parts of ether (500mL) further to repeat this operation, then the volatile matter of evaporation of residual.Add methyl alcohol (40mL), H successively ₂O (40mL) and triethylamine (39.4mL, 280mmol) and to mix species with 1 couple of several milligrams brilliant.After 5 minutes, leach yellow solid, obtain 1 with a small amount of MeOH washing and drying, it is monohydrate (5.05g, 36%), and it has the suitable purity that is used for further application.With analysis part by the DMSO-EtOH or the H that boils ₂Recrystallization among the O.MPt?226?dec.

(c1.13，DMSO)。 ¹H NMR (DMSO d ₆): δ 10.19 (bs, the D of exchange ₂O, 1H), 7.29 (d, J=5.0Hz, the slowly D of exchange ₂O, 1H), 5.90 (s, the D of exchange ₂O, 2H), 5.33 (d, J=5.4Hz, the D of exchange ₂O, 1H), 4.66 (ddd, J～5.0 ,～1.3 ,～1.3Hz, 1H), 4.59 (t, J=5.6Hz, the D of exchange ₂O, 1H), 4.39 (d, J=10.3Hz, the D of exchange ₂O, 1H), 3.80 (bt, J～1.8Hz, the D of exchange ₂O, 1H), 3.70 (m, 1H), 3.58 (dd, J=10.3,3.0Hz, 1H), 3.53 (dt, J=10.7,6.4Hz, 1H), 3.43 (ddd, J=11.2,5.9,5.9Hz, 1H), 3.35 (t, J=6.4Hz, 1H), 3.04 (wide multiplet, 1H). ¹³C NMR (DMSO d ₆Medullary ray δ 39.7): δ 156.3 (C), 150.4 (C), 148.4 (C), 99.0 (C), 79.4 (CH), 76.5 (CH), 68.9 (CH), 68.6 (CH), 60.6 (CH ₂), 53.9 (CH).C ₁₀H ₁₅N ₅O ₅H ₂The analytical calculation value of O is 39.60C, 5.65H, and 23.09N, measured value are 39.64C, 5.71H, 22.83N.

B. prepare compound 2 (a or b) and 3 (a, b or c)

With one contract tert-Butyl dicarbonate (10.33g, 47.3mmol) and DMAP (0.321g, (1.5g is 5.26mmol) in the suspension of the stirring in anhydrous THF (90mL) 2.63mmol) under argon gas, to join 1 at 50 ℃.After 20 hours, obtaining settled solution. evaporating solvent also obtains two kinds of product cuts with residue at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel purifying (gradient is 0 to 40%EtOAc solution in hexane).The first product wash-out is yellow foam (1.46g).Product is used ¹H NMR is observed the mixture of two kinds of compounds, and it mainly comprises the product (2a or 2b) with seven Boc groups.Sample is obtained 2a or 2b by the crystallization of EtOAc-hexane, and it is good crystalline solid.MPt?189-191℃.

(c?0.99，MeOH)。 ¹H NMR (500MHz, CDCl ₃): δ 5.71 (t, J=1.7Hz, 1H), 5.15 (dt, J=3.5 ,～1.0,1H), 4.97 (t, J=3.8; 1H), 4.35 (wide triplet, J=～1.7,1H), 4.09-3.97 (m, 3H), 3.91 (m, 1H); 1.55,1.52,1.51,1.50,1.45 (5s, 45H), 1.40 (s, 18H). ¹³C?NMR(125.7MHz，CDCl ₃)：δ152.84(C)，152.78(C)，151.5(C)，150.9(C)，150.7(2×C)，150.3(C)，149.1(C)，144.8(C)，144.7(C)，118.0(C)，84.6(C)，83.6(C)，83.5(C)，82.7(3×C)，82.6(C)，76.3(CH)，73.0(CH)，71.4(CH)，67.2(CH)，64.0(CH ₂)，51.4(CH)，28.1(CH ₃)，27.8(2x?CH ₃)，27.7(CH ₃)，27.6(3×CH ₃)。MS-ESI+:C ₄₅H ₇₂N ₅O ₁₉ ⁺, (M+H) ⁺, calculated value is 986.4817, measured value is 986.4818.C ₄₅H ₇₁N ₅O ₁₉H ₂The calculated value of O is 54.39C, 7.39H, 6.34N; Measured value is 54.66C, 7.17H, 7.05N.Obtain second cut, it is yellow foam (2.68g), through ¹H NMR finds that this product has six Boc groups and has (3a, 3b or 3c).A spot of sample is obtained clear crystal by the crystallization of EtOAc-hexane.

(c，1.17，CHCl ₃)。 ¹H NMR (500MHz, CDCl ₃): δ 11.10 (wide unimodal, the D of exchange ₂O, 1H), 5.58 (t, J=1.8Hz, 1H), 5.17 (d, J=3.4Hz, 1H), 4.97 (t, J=3.9Hz, 1H), 4.62 (s, the D of exchange ₂O, 1H), 4.16 (dd, J=11.3,5.9Hz, 1H), 4.12 (dd, J=11.3,6.4Hz, 1H), 3.95 (dt, J=6.1,1.1Hz, 1H), 3.76 (m, 1H), 1.51,1.50,1.49,1.48,1.46 (5s, 54H). ¹³C?NMR(125.7MHz，CDCl ₃)：δ156.6(C)，153.0(C)，152.9(C)，151.9(C)，150.6(C)，149.4(2×C)，136.2(C)，131.8(C)，116.9(C)，85.0(2×C)，83.3(C)，82.8(C)，82.49(C)，82.46(C)，73.3(CH)，71.5(CH)，67.2(CH)，64.5(CH ₂)，51.3(CH)，28.0，27.72，27.68，27.6(4×CH ₃)。MS-ESI+:C ₄₀H ₆₄N ₅O ₁₇ ⁺, (M+H) ⁺Calculated value is 886.4287, and measured value is 886.4289.

C. prepare compound 4a, 4b or 4c.

Step 1Will from the main inclusion compound 2a of above-mentioned B or first cut of 2b (1.46g 1.481mmol) is dissolved among the MeOH (29mL), and add the solution of sodium methylate in MeOH (1M, 8.14mL, 8.14mmol).Placing envrionment temperature after 20 hours, with solution with Dowex 50WX8 (H ⁺) the resin neutralization, then solid is leached evaporating solvent.

Step 2Will from second cut that mainly comprises 3a, 3b or 3c of above-mentioned B (2.68g 3.02mmol) is dissolved among the MeOH (54mL), add the solution of sodium methylate in MeOH (1M, 12.10mL, 12.10mmol).Placing envrionment temperature after 20 hours, with solution with Dowex 50WX8 (H ⁺) the resin neutralization, then solid is leached evaporating solvent.

Will be from above-mentioned Step 1With Step 2Product merge, and (gradient is 0 to 15%MeOH at CHCl at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel purifying ₃In solution) obtain 4a, 4b or 4c, it is beige solid (1.97g). ¹H NMR (500MHz, DMSO d ₆): δ 12.67 (wide unimodal, the D of exchange ₂O, 1H), 5.48 (d, J=5.2Hz, the D of exchange ₂O, 1H), 5.43 (t, J=～1.9Hz, D ₂Become d after the O exchange, J=1.9Hz, 1H), 5.00 (wide unimodal, the D of exchange ₂O, 1H), 4.62 (d, J=5.7Hz, the D of exchange ₂O, 1H), 4.27 (d, J=6.0Hz, the D of exchange ₂O, 1H), 3.89 (dt, J=5.2,3.8Hz, D ₂Become t after the O exchange, J=3.9Hz, 1H), 3.62 (dd, J=6.0,3.7Hz, D ₂Become d after the O exchange, J=3.7Hz, 1H), 3.52-3.39 (m, 4H), 1.42 (s, 9H), 1.41 (s, 18H). ¹³C?NMR(125.7MHz，DMSO?d ₆)：δ157.9(C)，151.1，(C)，149.8(2×C)，134.6(C)，131.4(C)，118.8(C)，83.5(2×C)，81.3(C)，78.2(CH)，76.5(CH)，68.1(CH)，66.8(CH)，60.6(CH ₂)，54.4(CH)，27.9(CH ₃)，27.6(2×CH ₃)。MS-ESI+:C ₂₅H ₄₀N ₅O ₁₁ ⁺, (M+H) ⁺Calculated value is 586.2719, and measured value is 586.2717.

D. prepare compound 5a, 5b or 5c

(992mg 1.69mmol) is dissolved in the anhydrous pyridine and concentrates with compound 4a, 4b or 4c.Under nitrogen atmosphere, residue is dissolved in anhydrous CH ₂Cl ₂(10mL) and in the pyridine (5mL), solution is cooled to-42 ℃ in acetonitrile/the dry ice bath.(187 μ L 1.86mmol), and stir mixture 2 hours 20 minutes dropwise to add the dichloro methyl orthophosphoric acid.(10mL) is added in the cooling solution with water, from cryostat, takes out then, with ETHYLE ACETATE (50mL) and saturated NaCl solution (30mL) dilution.Separate organic moiety also with saturated NaCl solution washing.The water that merges is further used ethyl acetate extraction twice, and the organic layer that merges is used MgSO ₄Dry and concentrated.Obtain ring-type methyl orthophosphoric acid 5a, 5b or 5c (731mg, 65%) through silica gel flash column chromatography purifying (with the eluant solution of 2-20% methyl alcohol in ETHYLE ACETATE). ¹H?NMR(500MHz，CDCl ₃)：δ11.75(1H)，5.59(t，J＝1.8Hz，1H)，5.30(s，1H)，4.89(d，J＝3.8Hz，1H)，4.68(dt，J＝12.6，2.0Hz，1H)，4.44(m，1H)，4.11(m，1H)，4.12(m，1H)，3.78(s，1H)3.70(s，1H)，3.60(d，J＝11.6Hz，3H)，1.58(s，9H)，1.49(s，18H)。 ¹³C?NMR(500MHz，CDCl ₃)：δ157.7(C)，151.4(C)，149.7(2C)，134.3(C)，132.1(C)，117.8(C)，84.5(2C)，82.8(C)，75.1(CH)，69.8(CH ₂)，68.8(CH)，68.4(CH)，56.0(CH)，55.9(CH ₃)，28.2(3CH ₃)，27.8(6CH ₃)。 ³¹P?NMR(500MHz，CDCl ₃)：δ-5.7ppm。MS-ESI+:C ₂₆H ₄₀N ₅NaO ₁₃P ⁺(M+Na) ⁺Calculated value is 684.2252, and measured value is 684.2251.

E. prepare compound 6a, 6b or 6c

(223mg 0.34mmol) is dissolved in anhydrous CH with compound 5a, 5b or 5c under nitrogen atmosphere ₂Cl ₂(7mL).(104 μ L 1.46mmol), are cooled to solution-78 ℃ to add anhydrous DMSO.(104 μ L 0.74mmol), and stir mixture 40 minutes dropwise to add trifluoroacetic anhydride.Add N, (513 μ L 2.94mmol), and continue to stir 50 minutes at-78 ℃ the N-diisopropyl ethyl amine.Add saturated NaCl solution (20mL), from cryostat, take out then, use CH ₂Cl ₂(30mL) dilution.(170 μ L 8.75mmol), and stirred the mixture 10 minutes to add Glacial acetic acid min. 99.5.Separate each layer, water is used CH ₂Cl ₂(10mL) washing.With the organic phase that merges with 5% aqueous hydrochloric acid, 3: 1 saturated NaCl solution: 10%NaHCO ₃Solution and saturated NaCl solution continuous washing are used MgSO ₄Dry and concentrated compound 6a, 6b or the 6c (228mg, equivalent) of obtaining, it has the suitable purity that is used for further application. ¹H?NMR(500MHz，CDCl ₃)：δ5.86(m，1H)，5.07(m，1H)，4.70-4.64(m，2H)，4.49-4.40(m，1H)，4.27(m，1H)，3.56，m，4H)，1.49(s，9H)，1.46(s，18H)ppm。 ¹³C?NMR(500MHz，CDCl ₃)：δ157.5(C)，151.1(C)，150.6(2C)，134.6(C)，132.7(C)，116.6(C)，92.0(C)，84.6(2C)，83.6(C)，78.0(CH)，76.0(CH)，70.4(CH ₂)，67.9(CH)，56.2(CH ₃)56.0(CH)，28.2(3CH ₃)，26.8(6CH ₃)ppm。 ³¹P?NMR(500MHz，CDCl ₃)：δ-6.3ppm。

F. prepare compound 7: (4aR, 5aR, 11aR, 12aS)-1,3,2-dioxa phosphino-[4 ', 5 ': 5,6] pyrans [3,2-g] pteridine-10 (4H)-ketone also, 8-amino-4a, 5a, 6,9,11,11a, 12,12a-octahydro-2,12,12-trihydroxy--2-oxide compound

Compound 6a, 6b or 6c (10mg, 14.8 μ mol) are dissolved in the anhydrous acetonitrile (0.2mL) and are cooled to 00 ℃.Dropwise add bromo trimethyl silyl (19.2 μ l, 148 μ mol), and mixture be warmed to envrionment temperature, stirred 5 hours, during form throw out.Add HCl _(aq)(10 μ l, 37%) further stirs mixture 15 minutes.With centrifugal 15 minutes of mixture (3000g), collect the throw out of gained.Add acetonitrile (0.5mL), and with mixture further centrifugal 15 minutes.With acetonitrile washing and further repetition twice of centrifugation step, the solid of gained is obtained compound 7 (4mg, 75%) in high vacuum dry. ¹H NMR (500MHz, D ₂O): δ 5.22 (d, J=1.6Hz, 1H), 4.34 (dt, J=13,1.6Hz, 1H), 4.29-4.27 (m, 1H), 4.24-4.18 (m, 1H), 3.94 (wide multiplet, 1H), 3.44 (t, J=1.4Hz, 1H). ³¹P?NMR(500MHz，D ₂O)：δ-4.8。MS-ESI+:C ₁₀H ₁₅N ₅O ₈P ⁺, (M+H) ⁺Calculated value is 364.0653, and measured value is 364.0652.

Embodiment 2. passes through the comparison of precursor Z (cPMP) with the precursor Z (cPMP) that is prepared by intestinal bacteria of synthetic preparation in external the synthesizing of Moco

Use synthetic precursor Z (cPMP) and by the sample of the cPMP of intestinal bacteria purifying external synthetic comparing to Moco.Moco uses purifying composition intestinal bacteria MPT synthase, bridging albumen, molybdate, ATP and apo-sulfite oxidase synthetic also comprising.Referring to USP 7,504,095; And " Biosynthesis and molecular biology of the molybdenum cofactor (Moco) " in Metal Ions in Biological Systems; Mendel, Ralf R.and Schwarz, G ü nter; Informa Plc; 2002, Vol.39, pages 317-68.This is measured based on cPMP to the conversion of MPT, use reorganization bridging albumen and the molybdate insertion of ATP and the reconstruction of final people's apo-sulfite oxidase subsequently.

As shown in Figure 1, confirm from synthetic the obtaining of the Moco of synthetic cPMP, and compare the difference of not finding that Moco transforms with the cPMP of intestinal bacteria purifying.

Embodiment 3. passes through the comparison of precursor Z (cPMP) with the precursor Z (cPMP) that is prepared by intestinal bacteria of synthetic preparation in external the synthesizing of MPT

Use synthetic precursor Z (cPMP) and by the sample of the cPMP of intestinal bacteria purifying external synthetic comparing to MPT.The synthetic MPT synthase of use that also comprise of MPT from colibacillary assembled in vitro.Referring to USP 7,504,095; And " Biosynthesis and molecular biology of the molybdenum cofactor (Moco) " in Metal Ions in Biological Systems; Mendel, Ralf R.and Schwarz, G ü nter; Informa Plc; 2002, Vol.39, pages 317-68.Each experiment repeats three times, and is shown in Fig. 2 and 3.

Shown in Fig. 2 and 3, confirm from synthetic the obtaining of the MPT of synthetic cPMP, and compare the notable difference of not finding that MPT transforms with the cPMP of intestinal bacteria purifying.All observe cPMP in all samples and transform to the linearity of MPT, this has proved the identity (referring to Fig. 2) of synthetic cPMP.Think that the technicality between each time repetition is because coarse concentration of synthetic cPMP is confirmed (hindering the existence of chromophore).

Embodiment 4. preparation precursor Z (cPMP)

A. prepare starting substance

Scheme 21.

B. introduce the SULPHOSUCCINIC ACID ESTER of protection

Scheme 22.

Use midbody [10] (630mg) to form annular phosphate and obtain required product [11], it is 1: 1 mixture (494mg, 69%) of diastereomer.

Scheme 23.

C. the oxidation of molecule is with whole deprotection

Oxidation obtains successfully having proved midbody [12] together with glycol to secondary alcohol, but oxidation products [13] has shown significant unstable and can not be by purifying.For this reason, attempt before oxidation, SULPHOSUCCINIC ACID ESTER being carried out deprotection.Yet the reaction of midbody [11] and TMSBr causes accomplishing the deprotection of molecule, obtains midbody [14].Use Dai Si-Martin's reagent oxidation agent to attempt alcohol is oxidized to together with glycol, obtain aromatize pteridine [15].

Use Dai Si-Martin's reagent oxidation agent oxidation intermediates [11] to obtain the mixture of starting substance, oxidation products and a plurality of by products.Use the method oxidation intermediates of describing among the embodiment 1 [11] at last.Only observe partially oxidation after the processing, obtain [11]/2: 1 mixtures of [16].Crude mixture carries out last deprotection.Obtain pale solid and usefulness ¹H-NMR and HPLC-MS analyze.These are analyzed and show that cPMP produces together with the precursor [11] of deprotection.

Because analytical HPLC condition causes cPMP by the good separation of major impurity, this method can be repeated on preparation property HPLC to separate final material.

Claims

1. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) make the reaction of formula (II) compound and formula (III) compound with preparation formula (IV) compound, said formula (II) compound is:

Said formula (III) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

(b) optionally protection (IV) compound is with preparation formula V compound, and said formula V compound is:

(c) make formula V compound phosphorylation with preparation formula (VI) compound, said formula (VI) compound is:

(d) oxidation-type (VI) compound is with preparation formula (VII) compound, and said formula (VII) compound is:

(e) make formula (VII) compound deprotection with preparation formula (I) compound.

2. the process of claim 1 wherein that said pharmaceutical salts is a hydrochloride.

3. each method among the claim 1-2, wherein said formula (II) compound is:

4. each method among the claim 1-3, wherein said formula (III) compound is shielded or unprotected semi-lactosi, seminose, glucose or gulose.

5. each method among the claim 1-4, wherein said formula (III) compound is:

6. each method among the claim 1-5, wherein two adjacent R ₁Group is joined together to form isopropylidene ethylidene ether or Ben Yajiaji ethylidene ether part.

7. each method among the claim 1-6, wherein said step (a) are included under the existence of hydrazine and make formula (II) compound and the reaction of formula (III) compound.

8. the method for claim 7, wherein said hydrazine is selected from phenyl hydrazine and alkyl hydrazine.

9. the method for claim 8, wherein said hydrazine is a phenyl hydrazine.

10. each method among the claim 1-9, the phosphorylation of wherein said step (c) comprise makes formula V compound and the reaction of P (V) phosphorylation agent.

11. the method for claim 10, wherein said P (V) phosphorylation agent is selected from: POCl ₃, H ₃PO ₄, PO (OBn) xCl ₃-x, Cl ₃CCH ₂OP (O) Cl ₂(BnO) ₂P (O) OP (O) (OBn) ₂

12. the method for claim 10, wherein said P (V) phosphorylation agent is POCl ₃

13. comprising, each method among the claim 1-9, the phosphorylation of wherein said step (c) make formula V compound and P (III) phosphitylation reagent react.

14. the method for claim 13, wherein said P (III) phosphitylation reagent is selected from: P (OCH ₂CH ₂CN) ₂Cl, P (OCH ₂CH ₂CN) (NPr ₂-i) Cl and cyano ethyl-O-P [N (i-Pr) ₂)].

15. the method for claim 13, wherein said step (c) further comprise the SULPHOSUCCINIC ACID ESTER of the phosphorous acid ester of oxidation gained with preparation compound (VI).

16. each method among the claim 1-15, wherein step (d) comprises and makes formula (VI) compound and be selected from following oxidant reaction: RuO ₄, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride and PDC.

17. each method among the claim 1-16, the deprotection of wherein said formula (VII) compound under anaerobic carries out.

18. each method among the claim 1-17, wherein said formula (IV) compound is:

19. each method among the claim 1-18, wherein said formula V compound is:

20. each method among the claim 1-19, wherein said formula (VI) compound is:

21. each method among the claim 1-20, wherein said formula (VII) compound is:

22. each method among the claim 1-21, wherein this method further comprises formula (I) compound is formulated as pharmaceutical composition.

23. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) formula (II-A) compound and formula (III-A) compound are reacted with preparation formula (IV-A) compound in the presence of hydrazine, said formula (II-A) compound is:

Said formula (III-A) compound is:

Said formula (IV-A) compound is:

(b) optionally protection (IV-A) compound with preparation formula (V-A) compound:

R wherein ₁It is the protection base;

(c) make formula (V-A) compound phosphorylation with preparation formula (VI-A) compound:

(d) oxidation-type (VI-A) compound is with preparation formula (VII-A) compound:

(e) make formula (VII-A) compound deprotection with preparation formula (I) compound.

24. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

Said formula (III-A) compound is:

Said formula (IV-A) compound is:

(b) optionally protection (IV-A) compound with preparation formula (V-B) compound:

Each R wherein ₁Be the protection base independently;

(c) make formula (V-B) compound phosphorylation with preparation formula (VI-B) compound:

(d) oxidation-type (VI-B) compound is with preparation formula (VII-B) compound:

(e) make formula (VII-B) compound deprotection with preparation formula (I) compound.

25. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) make the reaction of formula (II) compound and formula (VIII) compound with preparation formula (IX) compound, said formula (II) compound is:

Each R wherein ₁Be H or protection base independently;

Said formula (VIII) compound is:

R wherein ₂Be H or protection base;

Said formula (IX) compound is:

(b) optionally protection (IX) compound with preparation formula (X) compound:

R wherein ₃For protecting base;

(c) oxidation-type (X) compound is with preparation formula (XI) compound:

(d) make formula (XI) compound deprotection with preparation formula (I) compound.

26. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

Said formula (III) compound is:

Said formula (IV) compound is:

Each R wherein ₁Be H or protection base independently;

(b) optionally protection (IV) compound with preparation formula V compound:

(c) oxidation formula V compound is with preparation formula (XII) compound:

(d) make formula (XII) compound phosphorylation with preparation formula (VII) compound:

Make formula (VII) compound deprotection with preparation formula (I) compound.

27. formula (IV) compound:

Or its pharmaceutical salts form, wherein each R ₁Be H or protection base independently.

28. the compound of claim 27, wherein said formula (IV) compound is:

Or its pharmaceutical salts form.

29. formula V compound:

30. the compound of claim 29, wherein said formula V compound is selected from:

or its pharmaceutical salts form.

31. the compound of claim 29, wherein said formula V compound is selected from:

or its pharmaceutical salts.

32. formula (VI) compound:

33. the compound of claim 32, wherein said formula (VI) compound is selected from:

or its pharmaceutical salts form.

34. the compound of claim 32, wherein said formula (VI) compound is selected from:

or its pharmaceutical salts.

35. formula (VII) compound:

36. the compound of claim 35, wherein said formula (VII) compound is selected from:

or its pharmaceutical salts form.

37. the compound of claim 35, wherein said formula (VII) compound is selected from:

or its pharmaceutical salts form.

38. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form:

This method comprises:

Said formula (III) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

(b) optionally protection (IV) compound with preparation formula V compound:

(c) make formula V compound phosphorylation with preparation formula (VI) compound:

(d) oxidation-type (VI) compound is with preparation formula (XIV) compound:

(e) make formula (XIV) compound deprotection with preparation formula (XIII) compound.

39. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form:

This method comprises:

Each R wherein ₁Be H or protection base independently,

Said formula (VIII) compound is:

Wherein:

R ₂Be H or protection base,

Said formula (IX) compound is:

(b) optionally protection (IX) compound with preparation formula (X) compound:

R wherein ₃It is the protection base;

(c) oxidation-type (X) compound is with preparation formula (XV) compound:

(d) make formula (XV) compound deprotection with preparation formula (XIII) compound.

40. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof:

This method comprises:

Said formula (III) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

(b) optionally protection (IV) compound with preparation formula V compound:

(d) oxidation-type (VI) compound is with preparation formula (XIV) compound:

41. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) oxidation-type (VI) compound is with preparation formula (VII) compound, and said formula (VI) compound is:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (VII) compound is:

(b) make formula (VII) compound deprotection with preparation formula (I) compound.

42. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) make formula V compound phosphorylation with preparation formula (VI) compound, said formula V compound is:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (VI) compound is:

(b) oxidation-type (VI) compound is with preparation formula (VII) compound:

(c) make formula (VII) compound deprotection with preparation formula (I) compound.

43. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) optionally protection (IV) compound is with preparation formula V compound, and said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

Said formula V compound is:

(b) make formula V compound phosphorylation with preparation formula (VI) compound:

(c) oxidation-type (VI) compound is with preparation formula (VII) compound:

(d) make formula (VII) compound deprotection with preparation formula (I) compound.

44. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form:

This method comprises:

(a) oxidation-type (VI) compound is with preparation formula (XIV) compound, and said formula (VI) compound is:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (XIV) compound is:

(b) make formula (XIV) compound deprotection with preparation formula (XIII) compound.

45. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form:

This method comprises:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (VI) compound is:

(b) oxidation-type (VI) compound is with preparation formula (XIV) compound:

(c) make formula (XIV) compound deprotection with preparation formula (XIII) compound.

46. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof form:

This method comprises:

Wherein:

Each R ₁Be H or protection base independently;

Said formula V compound is:

(c) oxidation-type (VI) compound is with preparation formula (XIV) compound:

(d) make formula (XIV) compound deprotection with preparation formula (XIII) compound.

47. formula (I) compound or pharmaceutically acceptable salt thereof:

It prepares through following method, and said method comprises:

Said formula (III) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

(b) optionally protection (IV) compound with preparation formula V compound:

(d) oxidation-type (VI) compound is with preparation formula (VII) compound:

48. formula (I) compound or pharmaceutically acceptable salt thereof:

It prepares through following method, and said method comprises:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (VII) compound is:

49. formula (I) compound or pharmaceutically acceptable salt thereof:

It prepares through following method, and said method comprises:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (VI) compound is:

(b) oxidation-type (VI) compound is with preparation formula (VII) compound:

50. formula (I) compound or pharmaceutically acceptable salt thereof:

It prepares through following method, and said method comprises:

Wherein:

Each R ₁Be H or protection base independently;

Said formula V compound is:

(c) oxidation-type (VI) compound is with preparation formula (VII) compound:

51. formula (XIII) compound or pharmaceutically acceptable salt thereof:

It prepares through following method, and said method comprises:

Said formula (VIII) compound is:

Wherein:

R ₂Be H or protection base,

Said formula (IX) compound is:

Each R ₁Be H or protection base independently;

(b) optionally protection (IX) compound with preparation formula (X) compound:

R wherein ₃It is the protection base;

(c) oxidation-type (X) compound is with preparation formula (XV) compound:

52. formula (XIII) compound:

Or its pharmaceutical salts form, said compound prepares through following method, and said method comprises:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (XIV) compound is:

53. formula (XIII) compound:

Wherein:

Each R ₁Be H or protection base independently;

Said formula (VI) compound is:

(b) oxidation-type (VI) compound is with preparation formula (XIV) compound:

54. formula (XIII) compound:

Wherein:

Each R ₁Be H or protection base independently;

Said formula V compound is:

(c) oxidation-type (VI) compound is with preparation formula (XIV) compound:

55. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) make the reaction of formula (II) compound and formula (XXII) compound with preparation formula (IV) compound, said formula (II) compound is:

Said formula (XXII) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

(b) optionally protection (IV) compound with preparation formula V compound:

(d) oxidation-type (VI) compound is with preparation formula (VII) compound:

56. the method for claim 55, wherein said formula (II) compound is:

57. each method among the claim 55-56, wherein said formula (XXII) compound is:

58. comprising, each method among the claim 55-57, the phosphorylation of wherein said step (c) make formula V compound and the reaction of P (V) phosphorylation agent.

59. the method for claim 58, wherein said P (V) phosphorylation agent is selected from: POCl ₃, PO (OCH3) xCl ₃-x, H ₃PO ₄, PO (OBn) xCl ₃-x, Cl ₃CCH ₂OP (O) Cl ₂And (BnO) ₂P (O) OP (O) (OBn) ₂

60. the method for claim 58, wherein said P (V) phosphorylation agent is ChPO (OCH ₃).

Make formula (VI) compound and be selected from following oxidant reaction: TFAA/DMSO, RuO 61. each method among the claim 55-60, wherein said step (d) comprise ₄, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride and PDC.

62. each method among the claim 55-61, the deprotection of wherein said formula (VII) compound under anaerobic carries out.

63. each method among the claim 55-62, wherein said formula (IV) compound is:

64. each method among the claim 55-63, wherein said formula V compound is:

65. each method among the claim 55-64, wherein said formula (VI) compound is:

66. each method among the claim 55-65, wherein said formula (VII) compound is:

67. each method among the claim 55-66, wherein said method further comprise formula (I) is formulated as pharmaceutical composition.

68. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) formula (II-A) compound and formula (XXII-A) compound are reacted with preparation formula (IV-A) compound in the presence of hydrazine, said formula (II-A) compound is:

Said formula (XXII-A) compound is:

Said formula (IV-A) compound is:

(b) optionally protection (IV-A) compound with preparation formula (V-C) compound:

(c) make formula (V-A) compound phosphorylation with preparation formula (VI-C) compound:

(d) oxidation-type (VI-C) compound is with preparation formula (VII-C) compound:

(e) make formula (VII-C) compound deprotection with preparation formula (I) compound.

69. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) make the reaction of formula (XXIII) compound with preparation formula (XXIV) compound, said formula (XXIII) compound is:

Said formula (XXIV) compound is:

(b) make the reaction of formula (XXIV) compound and formula (II) compound with preparation formula (XXV) compound, said formula (II) compound is:

Said formula (XXV) compound is:

(c) annulation of formula (XXV) compound is carried out catalysis with preparation formula (IV) compound:

(d) optionally protection (IV) compound with preparation formula V compound:

(e) make formula V compound phosphorylation with preparation formula (VI) compound:

(f) oxidation-type (VI) compound is with preparation formula (VII) compound:

(g) make formula (VII) compound deprotection with preparation formula (I) compound.

70. the method for claim 69, wherein said formula (XXIII) compound is selected from:

71. each method among the claim 69-70, wherein said formula (XXIV) compound is:

72. each method among the claim 69-71, wherein said formula (II) compound is:

73. each method among the claim 69-72, wherein said formula (XXV) compound is:

74. comprising, each method among the claim 69-73, the phosphorylation of wherein said step (e) make formula V compound and the reaction of P (V) phosphorylation agent.

75. the method for claim 74, wherein said P (V) phosphorylation agent is selected from: POCl ₃, PO (OCH3) xCl ₃-x, H ₃PO ₄, PO (OBn) xCl ₃-x, Cl ₃CCH ₂OP (O) Cl ₂And (BnO) ₂P (O) OP (O) (OBn) ₂

76. the method for claim 74, wherein said P (V) phosphorylation agent is Cl ₂PO (OCH ₃).

Make formula (VI) compound and be selected from following oxidant reaction: TFAA/DMSO, RuO 77. each method among the claim 69-76, wherein said step (f) comprise ₄, Dai Si-Martin's reagent, DMSO/ trifluoromethanesulfanhydride anhydride and PDC.

78. each method among the claim 69-77, the deprotection of wherein said formula (VII) compound under anaerobic carries out.

79. each method among the claim 69-78, wherein said formula (XXIII) compound is:

80. each method among the claim 69-79, wherein said formula (XXIV) compound is:

81. each method among the claim 69-80, wherein said formula (XXV) compound is:

82. each method among the claim 69-81, wherein said formula (IV) compound is:

83. each method among the claim 69-82, wherein said formula V compound is:

84. each method among the claim 69-83, wherein said formula (VI) compound is:

85. each method among the claim 69-84, wherein said formula (VII) compound is:

86. each method among the claim 69-85, wherein said method further comprise formula (I) is formulated as pharmaceutical composition.

87. each method among the claim 69-86, wherein leavings group is selected from: tosylate, brosylate, m-nitrobenzene sulfonic acid ester, methanesulfonates, oxygen, triflate, perfluoro butyl sulphonate and trifluoroethyl sulphonate.

88. method for preparing formula (I) compound or pharmaceutically acceptable salt thereof:

This method comprises:

(a) make the reaction of formula (XXIII-A) compound with preparation formula (XXIV) compound, said formula (XXIII-A) compound is:

Each R wherein ₁Be H or protection base and R independently ₄Be H or leavings group; Said formula (XXIV) compound is:

(b) make the reaction of formula (XXIV) compound and formula (II-A) compound with preparation formula (XXV-A) compound, said formula (II-A) compound is:

Said formula (XXV-A) compound is:

(c) annulation of formula (XXV-A) compound is carried out catalysis with preparation formula (IV-D) compound:

(d) optionally protection (IV-D) compound with preparation formula (V-D) compound:

(e) make formula (V-D) compound phosphorylation with preparation formula (VI-D) compound:

(f) oxidation-type (VI-D) compound is to prepare (VII-D) compound:

(g) make formula (VII-D) compound deprotection with preparation formula (I) compound.

89. formula (I) compound or pharmaceutically acceptable salt thereof:

It prepares through following method, and said method comprises:

Said formula (XXII) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

(b) optionally protection (IV) compound with preparation formula V compound:

(d) oxidation-type (VI) compound is with preparation formula (VII) compound:

90. formula (I) compound or pharmaceutically acceptable salt thereof:

It prepares through following method, and said method comprises:

Said formula (XXIV) compound is:

Said formula (XXV) compound is:

(d) optionally protection (IV) compound with preparation formula V compound:

(f) oxidation-type (VI) compound is with preparation formula (VII) compound:

91. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof:

This method comprises:

Said formula (XXII) compound is:

Said formula (IV) compound is:

Wherein:

Each R ₁Be H or protection base independently;

(b) optionally protection (IV) compound with preparation formula V compound:

(d) oxidation-type (VI) compound is with preparation formula (XIV) compound:

92. method for preparing formula (XIII) compound or pharmaceutically acceptable salt thereof:

This method comprises:

Said formula (XXIV) compound is:

Said formula (XXV) compound is:

(d) optionally protection (IV) compound with preparation formula V compound:

(f) oxidation-type (VI) compound is with preparation formula (XIV) compound:

(g) make formula (XIV) compound deprotection with preparation formula (XIII) compound.

93. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 1, and pharmaceutical excipient.

94. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 23, and pharmaceutical excipient.

95. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 24, and pharmaceutical excipient.

96. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 25, and pharmaceutical excipient.

97. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 26, and pharmaceutical excipient.

98. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 55, and pharmaceutical excipient.

99. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 68, and pharmaceutical excipient.

100. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 69, and pharmaceutical excipient.

101. pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 88, and pharmaceutical excipient.

102. pharmaceutical composition, it comprises formula (XIII) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 39, and pharmaceutical excipient.

103. pharmaceutical composition, it comprises formula (XIII) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 40, and pharmaceutical excipient.

104. pharmaceutical composition, it comprises formula (XIII) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 91, and pharmaceutical excipient.

105. pharmaceutical composition, it comprises formula (XIII) compound or pharmaceutically acceptable salt thereof through the method preparation of claim 92, and pharmaceutical excipient.

106. method for preparing formula (XXIV) compound or pharmaceutically acceptable salt thereof:

Wherein:

Wherein:

R ₄Be H or leavings group.