MXPA06006263A - Methods of preparing compounds useful as protease inhibitors - Google Patents

Abstract

The invention relates to methods of preparing compounds of formula (I), useful as inhibitors of the HIV protease enzyme. The present invention also relates to intermediate compounds useful in the preparation of compounds of formula (I).

Description

METHODS FOR THE PREPARATION OF USEFUL COMPOUNDS AS PROTEASE INHIBITORS This application claims the priority of the Provisional Application of E.U.A. No. 60 / 527,477, filed December 4, 2003, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION The present invention relates to methods of preparing, and to intermediates useful in the preparation of, human immunodeficiency virus (HIV) protease inhibitors. The acquired immunodeficiency syndrome (AIDS) causes a gradual degradation of the body's immune system, as well as a progressive deterioration of the central and peripheral nervous systems. Since its initial discovery in the early 1980s, AIDS has spread rapidly and has now reached epidemic proportions in a relatively limited segment of the population. Intense research has led to the discovery of the agent responsible, human retrovirus III T lymphotropic (HTLV-III), now more commonly called HIV. HIV is a member of the class of viruses known as retroviruses and is the etiological agent of AIDS. The genome of the retrovirus is composed of RNA that is converted to DNA by reverse transcription. Then, this retroviral DNA is stably integrated into the chromosome of the host cell and, using the replication procedures of the host cells, produces new retroviral particles and the infection progresses to other cells. HIV seems to have a particular affinity for human T4 lymphocytes, which play a vital role in the body's immune system. The HIV infection of these white blood cells depletes this population of leukocytes. Ultimately, the immune system becomes ineffective and ineffective against various opportunistic diseases such as, among others, pneumonia due to pneumocystis carini, Kaposi's sarcoma and cancer of the lymphatic system. Although the exact mechanism of the formation and functioning of the HIV virus is not known, the identification of the virus has led to some progress in the control of the disease. For example, it has been found that the drug azidothymidine (AZT) is effective in inhibiting the reverse transcription of the retrovirus genome of the HIV virus, which provides a measure of control, although not a cure, for patients affected by AIDS. The search continues to find drugs that can cure or at least provide an improved control measure of the deadly HIV virus and, therefore, the treatment of AIDS and related diseases. Retroviral replication routinely performs the post-translational processing of polyproteins. This processing is carried out by protease enzymes encoded by the HIV virus. This provides mature polypeptides that will subsequently contribute to the formation and function of infectious viruses. If this molecular processing is repressed, the normal production of HIV ends. Thus, HIV protease inhibitors can function as viral anti-HIV agents. The HIV protease is one of the products of the translation of the pol 25 gene of the structural protein of HIV. This retroviral protease specifically cleaves other structural polypeptides at separate sites to release these structural proteins and newly activated enzymes, rendering replication of the virion competent. As such, inhibition of HIV protease by potent compounds can prevent the proviral integration of infected T cells during the early phases of the HIV-1 life cycle, as well as inhibit viral proteolytic processing during the latter stages. In addition, protease inhibitors may have the advantages of these more readily available, of having a longer life in the virus and of being less toxic than the drugs currently available., possibly due to its specificity for retroviral protease. In, for example, the patent of E.U.A. No. 5,962,640, the US patent. No. 5,932,550, the US patent. No. 6,222,043, the patent of E.U.A. No. 5,644,028, WO 02/100844, Australian Patent No. 705193, Canadian Patent Application No. 2,179,935, European Patent Application No. 0 751 145, Japanese Patent Application No. 100867489, Y. Hayahsi et al., J. Org. Chem., 66, 5537-5544 (2001), K.

Yoshimura et al., Proc. Nati Acad. Sci. USA, 96, 8675-8680 (1999) and T. Mimoto et al., J. Med. Chem., 42, 1789-1802 (1999) methods for preparing compounds useful as inhibitors of HIV protease have been described. . Therefore, methods for preparing compounds useful as protease inhibitors were previously known. However, these methods were linear and, therefore, ineffective. The improved methods of the invention provide convergent synthetic pathways with maximized efficiency.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to methods for preparing compounds of formula (I), or a salt or solvate thereof: wherein: R 1 is phenyl optionally substituted with at least one substituent selected independently from C 6 alkyl hydroxyl, C 1 C 6 alkylcarbonyloxy, C 1 -C 4 arylcarbonyloxy and heteroarylcarbonyloxy; R2 is C2-C6 alkenyl, C6-C6 alkyl optionally substituted with at least one halogen or - (CR4R5) nR8; n is an integer from 0 to 5; R2 is H or C4 alkyl; Z is S, O, SO, S02, CH2 or CFH; R3 is hydrogen or a hydroxyl protecting group; Each R4, R5, R6 and R7 are selected independently from H, C? -C6 alkyl; and R8 is C6-C-? aryl or optionally substituted with at least one substituent selected from C6 alkyl, hydroxyl and halogen; which comprise: inducing the reaction of a compound of formula (II), wherein Y 1 is hydroxyl or a leaving group and R 1 is as described for formula (I), with a compound of formula (III), or a salt or solvate thereof: (ll) (Hl) The present invention further comprises deprotecting the compound of formula (I) when R3 is a hydroxyl protecting group, to give a compound of formula (I) wherein R3 is hydrogen. The present invention also provides intermediates that are useful for the preparation of compounds of formula (I).

Additional embodiments of the present invention are described below. In another aspect of the present invention there are provided methods for preparing compounds of formula (I), wherein: R is phenyl optionally substituted with at least one substituent selected independently from C 1 -C 6 alkyl, hydroxyl, C 1 C 6 alkylcarbonyloxy, C 6 -C 6 arylcarbonyloxy and heteroarylcarbonyloxy; R2 is C2-C6 alkenyl, C6-C6 alkyl optionally substituted with at least one halogen or - (CH2) nR8; n is an integer from 0 to 5; R 2 is H or C 1 -C 4 alkyl; Z is S, O, SO, S02l CH2 or CFH; R3 is hydrogen or a hydroxyl protecting group; each R4, R5, R6 and R7 are independently selected from H, C? -C6 alkyl; and R 8 is C 6 -C 0 aryl optionally substituted with at least one substituent selected from C 6 alkyl, hydroxyl and halogen; which comprise: inducing the reaction of a compound of formula (II), wherein Y1 is hydroxyl or a leaving group with a compound of formula (III), or a salt or solvate thereof: (II) (III) In another aspect of the present invention there are provided methods for the preparation of compounds of formula (I), which comprise: (i) the reaction of a compound of formula (IV), wherein Y 1 is hydroxy or -OP1, wherein P1 is a suitable protecting group, and R3 is hydrogen, C4 alkyl or a suitable hydroxyl protecting group, with a compound of formula (V), wherein Y2 is a leaving group, give a compound of formula (II); (IV) (V) (ll) (ii) reacting the compound of formula (II) with a compound of formula (III), or a salt or solvate thereof, to give a compound of formula (I); Y (») (Hl) (iii) the optional deprotection of those compounds of formula (I), wherein R 3 is a hydroxyl protecting group, to give a compound of formula (I) wherein R 3 is hydrogen. In another aspect of the present invention any of the methods described herein are provided for preparing the compounds of the formula (I) wherein in the compound of (II) Y1 is hydroxyl. In still another aspect of the present invention any of the methods described herein are provided for the preparation of compounds of formula (I), wherein: R1 is phenyl optionally substituted with at least one substituent selected independently from C-Cß alkyl, hydroxyl, C ?C6 alkylcarbonyloxy, C6-C ar ar arylcarbonyloxy, and heteroarylcarbonyloxy; R2 is C2-C6 alkenyl, C6-C6 alkyl optionally substituted with at least one halogen or - (CH2) nR8; n is 0, 1, 2 0 3; R2 'is H; - Z is S, O, CH2 or CFH; R3 is hydrogen or a hydroxyl protecting group; R4 and R5 are hydrogen; and R6 and R7 are CrC6 alkyl; and R8 is C6-C? or optionally substituted with at least one substituent selected from C6 alkyl, hydroxyl and halogen. Yet another aspect of the present invention provides any of the methods described herein for the preparation of compounds of formula (I), wherein: R 1 is phenyl optionally substituted with at least one substituent selected independently from "C" alkyl C6, hydroxyl, CiC β alkylcarbonyloxy, C 6 -C 0 arylcarbonyloxy and heteroarylcarbonyloxy, R 2 is C 2 -C 6 alkenyl, CrC 6 alkyl optionally substituted with at least one halogen or - (CH 2) n R 8; n is 0, 1, 2 or 3; R2 is H; Z is S; R3 is hydrogen; R4 and R5 are hydrogen; R6 and R7 are methyl; and R8 is phenyl optionally substituted with at least one substituent selected from C6 alkyl, hydroxyl and halogen. In still another aspect of the present invention, any of the methods described herein for the preparation of compounds of formula (I) is provided, wherein: R 1 is phenyl optionally substituted with at least one substituent selected independently from alkyl of CrC6, hydroxyl, C6C6alkylcarbonyloxyC6-C6alkylcarbonyloxy and heteroarylcarbonyloxy; R2 is C2-C6 alkenyl, C6-C6 alkyl optionally substituted with at least one halogen or - (CH2) nR8; n is 0, 1, 2 or 3; R2 'is H; Z is S; R3 is a hydroxyl protecting group; R4 and R5 are hydrogen; R6 and R7 are methyl; and R8 is phenyl optionally substituted with at least one substituent selected from CrC6 alkyl, hydroxyl and halogen. Yet another aspect of the present invention provides any of the methods described herein for the preparation of compounds of formula (I), wherein: R 1 is phenyl optionally substituted with at least one substituent selected independently from methyl, hydroxyl and methylcarbonyloxy; R2 is C2-C6 alkenyl, d-C6 alkyl optionally substituted with at least one halogen or -CH2R8; R2 'is H; Z is S; R3 is hydrogen or a hydroxyl protecting group; R4 and R5 are hydrogen; R6 and R7 are methyl; Y; - - R8 is phenyl substituted with at least one methyl. The present invention also provides any of the methods described herein for the preparation of compounds of formula (I), wherein: R1 is phenyl optionally substituted with at least one substituent selected independently from methyl, hydroxyl and methylcarbonyloxy; R2 is C2-C6 alkenyl; R2 'is H; Z is S; R3 is hydrogen or a hydroxyl protecting group; R4 and R5 are hydrogen; and R6 and R7 are methyl. Also provided in the present invention are any of the methods described herein for the preparation of compounds of formula (I), wherein: R 1 is phenyl substituted with methyl and hydroxyl; R2 is allyl; R2 'is H; Z is S; R3 is hydrogen or methylcarbonyl; R4 and R5 are hydrogen; and R6 and R7 are methyl. The present invention also provides any of the methods described herein for the preparation of compounds of formula (I), wherein: R 1 is phenyl substituted with methyl and methylcarbonyloxy; R2 is allyl; R2 'is H; Z is S; R3 is methylcarbonyl; R and R are each hydrogen; and R6 and R7 are methyl. Also provided in the present invention are any of the methods described herein for the preparation of compounds of formula (i), wherein the compound of formula n (I) is: Yet another aspect of the present invention provides methods for the preparation of compounds of formula (I-A), comprising: the reaction of a compound of formula (Il-A) with a compound of formula (III-A), or a salt or solvate thereof. (ll-A) (III-A) In still another aspect of the present invention are provided " methods for the preparation of compounds of formula (I-A), who understand (i) the reaction of a compound of formula (IV-A) with a compound of formula (V-A), (1V-A) (V-A) (ll-B) to give a compound of formula (II-B); (I) treating the compound of formula (II-B) with an acylating agent to give a compound of formula (ll-A); Y P CH3 O S O Ac0? ANY oH K ^ H OAc (ll-A) (iii) the reaction of the compound of formula (ll-A) with a compound of formula (III-A). (li-A) (III-A) In still another aspect of the present invention there are provided methods for the preparation of compounds of formula (I-B), which comprise: (i) the reaction of a compound of formula (11-A) with a compound of formula (III-A), or a salt or solvate thereof (ll-A) (lll-A) d-A) to give a compound of formula (I-A); and (ii) deprotecting the compound of formula (1-A). Another aspect of the present invention provides a method for the preparation of a compound of formula (I-B) comprising: (i) the reaction of a compound of formula (IV-A) with a compound of formula (V-A), (IV-A) (V-A) (ll-B) to give a compound of formula (II-B); (ii) treating the compound of formula (11-B) with an acylating agent to give a compound of formula (11-A); Y (ll-A) (iii) the reaction of the compound of formula (11-A) with a compound of formula (III-A). (ll-A) (lll-A) (l-A) to give a compound of formula (I-A); and (iv) deprotection of the compound of formula (1-A). In another aspect of the present invention any of the methods described herein are provided for the preparation of compounds of formula (I), wherein: R 1 is phenyl optionally substituted with at least one substituent selected independently from methyl, hydroxy and methylcarbonyloxy; R2 is -CH2R8; R2 'is H; Z is S; R3 is hydrogen or a hydroxyl protecting group; R4 and R5 are hydrogen; R6 and R7 are methyl; and R8 is phenyl substituted with at least one methyl. In another aspect of the present invention any of the methods described herein are provided for the preparation of compounds of formula (I), wherein: R 1 is phenyl substituted with methyl and methylcarbonyloxy; R2 is -CH2R8; R2 'is H; Z is S; R3 is methylcarbonyl; R4 and R5 are hydrogen; R6 and R7 are methyl; and R8 is phenyl substituted with at least one methyl. In still another aspect of the present invention any of the methods described herein is provided for the preparation of compounds of formula (I), wherein: R 1 is phenyl substituted with methyl and hydroxyl; R2 is -CH2R8; R2 'is H; Z is S; R3 is hydrogen; R4 and R5 are hydrogen; R6 and R7 are methyl; and R8 is phenyl substituted with at least one methyl. Also provided in the present invention are any of the methods described herein for the preparation of compounds of formula (I), wherein the compound of formula (I): Still another aspect of the present invention provides methods for the preparation of compounds of formula (lC), comprising: the reaction of a compound of formula (11-A) with a compound of formula (III-B), or a salt or solvate thereof. (ll-A) (III-B) In still another aspect of the present invention there are provided methods for the preparation of compounds of formula (I C), which comprise: (i) the reaction of a compound of formula (IV-A) with a compound of formula (VA), (IV-A) (V-A) (ll-B) to give a compound of formula (II-B); (ii) treating the compound of formula (11-B) with an acylating agent to give a compound of formula (11-A); Y (ll-A) (iii) the reaction of the compound of the formula (11-A) with a compound of the formula (III-B), (II-A) (III-B) In still another aspect of the present invention are provided methods for the preparation of compounds of formula (Id), comprising: (i) the reaction of a compound of formula (11-A) with a compound of formula (III-B), or a salt or solvate thereof, (ll-A) (lll-B) (l-C) to give a compound of formula (I-C); and (ii) deprotection of the compound of formula (I C) Yet another aspect of the present invention provides a method for the preparation of a compound of formula (Id), which comprises (i) the reaction of a compound of formula (IV) A) with a compound of formula (VA), (IV-A) (V-A) (ll-B) to give a compound of formula (II-B); (ii) treating the compound of formula (11-B) with an acetylating agent to give a compound of formula (11-A); Y (ll-A) (iii) the reaction of the compound of formula (11-A) with a compound of formula (111-B), and (il-A) (III-B) (I C) to give a compound of formula (lC); and (iv) deprotecting the compound of formula (I-C) to give the compound of formula (I-D). Another aspect of the present invention provides compounds of formulas (I-A), (I-B), (II-A), (III-A), (III-B), (I-C) and (I-D): (Hl-A) (III-B) all of which are intermediates useful in the preparation of compounds of formula (I). Another aspect of the present invention provides the preparation of compounds of formula (ll-A), (ll-A) which comprises treating a compound of formula (11-B) with an acetylating agent. In another aspect of the present invention, said acetylating agent is selected from acetic anhydride and acetyl chloride. (ll-B) DETAILED DESCRIPTION OF THE INVENTION In accordance with a convention used in the art,? ^ Is used in structural formulas herein to represent the bond that is the point of attachment of the moiety or substituent to the core or structure. When the phrase "substituted with at least one substituent" is used herein, it is meant that the group in question may be substituted with at least one of the selected substituents. The number of substituents a group can have in the compounds of the invention depends on the number of positions available for substitution. For example, an aryl ring in the compounds of the invention may contain from 1 to 5 additional substituents, depending on the degree of substitution present in the ring. Those skilled in the art can determine the maximum number of substituents a group can have in the compounds of the invention. The term "reaction, react", as used herein, refers to one or more chemical processes, in which contact between two or more reagents is allowed to effect a chemical change or transformation. For example, when reagent A and reagent B are allowed to come into contact to give one or more chemical compounds C, it is said that A has "reacted" with B to produce C. The term "protection, protect", as is used herein, refers to a process in which a functional group in a chemical compound is selectively masked with a non-reactive functional group to allow one or more selective reactions to occur elsewhere in said chemical compound . In the present such non-reactive functional groups are referred to as "protecting groups". For example, the term "hydroxyl protecting group", as used herein, refers to groups that are capable of selectively masking the reactivity of a hydroxyl group (-OH). The term "suitable protecting group", as used herein, refers to protecting groups that are useful in the preparation of the compounds of the present invention. Generally, such groups can be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds. Those skilled in the art are aware of protecting groups that are suitable for use in the methods and methods of the present invention. The chemical properties of such protecting groups, methods for their introduction and removal can be found in, for example, T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & amp;; Sons, NY (1999). With the terms "deprotection", "deprotected" or "deprotect", as used herein, it is intended to refer to the process of removing a protecting group from a compound. The term "leaving group" as used herein, refers to a functional chemical group that generally allows a nucleophilic substitution reaction to occur at the atom to which it is attached. For example, in the acid chlorides of the formula CI-C (O) R, wherein R is alkyl, aryl or heterocycle, the -Cl group is generally referred to as leaving group because it allows nucleophilic substitution reactions to be carried out in the carbonyl carbon. Suitable leaving groups are known to those skilled in the art and can include halides, aromatic heterocycles, cyano, amino groups (usually under acidic conditions), ammonium groups, alkoxide groups, carbonate groups, formates and hydroxy groups that have been activated by the reaction with compounds such as carbodiimides. For example, suitable leaving groups include, but are not limited to, chlorine, bromine, iodine, cyano, imidazole and hydroxy groups which have been allowed to react with a carbodiimide such as dicylohexylcarbodiimide (optionally in the presence of an additive such as hydroxybenzotriazole) or a carbodiimide derivative The term "acetylating agent", as used herein, refers to chemical compounds that are useful for the introduction of an acetyl group, -C (0) CH3 > in a hydroxyl group in the compounds of the invention. With the symbol "Ac-", as used in the chemical structures of the present, it is intended to represent an acyl group in the compounds of the invention. Useful acetylating agents include, but are not limited to, acetic anhydride, acetyl chloride, acetyl bromide, and acetyl iodide. In addition, such acetylating agents can be presented in situ by the reaction of acetyl chloride with sodium iodide in acetone, to give an intermediate agent of acetyl iodide. By the term "acetic anhydride", as used herein, is meant a compound with the chemical formula CH3C (0) OC (0) CH3. In addition, the term "-OAc", as used in the chemical structures herein, represents the group -OC (0) CH3. As used herein, the term "aliphatic" means a saturated or unsaturated hydrocarbon, straight or branched chain, containing 1 to 10 carbon atoms which may be unsubstituted or substituted with one or more of the substituents described later. The term "aliphatic" is intended to encompass alkyl, alkenyl and alkynyl groups. As used herein, the terms "C6 alkyl" and "C6-C6 alkyl", which may be used interchangeably, represent a straight or branched chain saturated hydrocarbon, containing from 1 to 6. carbon atoms which may be unsubstituted or substituted with one or more of the substituents described below. Likewise, the terms "C1.4 alkyl" and "C1-C4 alkyl", which may be used interchangeably, represent a straight or branched chain saturated hydrocarbon, containing from 1 to 4 carbon atoms which it may be unsubstituted or substituted with one or more of the substituents described below. Examples of alkyl substituents include, but are not limited to, methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, and the like. The terms "C2-6 alkenyl" and "C2-C6 alkenyl", which may be used interchangeably, represent a straight or branched chain hydrocarbon, containing one or more double bonds and having from 2 to 6 atoms carbon that may be unsubstituted or substituted with one or more of the substituents described below. Examples of alkenyl substituents include, but are not limited to, ethenyl, propenyl, butenyl, allyl pentenyl, and the like. The terms "aryl of C6-? 4" and "aryl of C6-C? 4", which can be used interchangeably, as used herein, means a group derived from an aromatic hydrocarbon containing from 6 to 14 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl. The terms "Ph" and "phenyl", as used herein, mean a group -C6H5. The term "benzyl", as used herein, means a group -CH2C6H5. The term "phenyl" ran is used herein, refers to a 6-member completely unsaturated carbocyclic group. With the symbol "Ph", as they are used in the chemical structures of the present, we want to represent a phenyl group or The term "heteroaryl", as used herein, refers to a group comprising an aromatic monovalent monocyclic, monocyclic or bicyclic group, contending from 5 to 18 ring atoms, including from 1 to 5 heteroatoms selected from nitrogen, Oxygen and sulfur, which may be unsubstituted or substituted with one or more of the substituents-described below. As used herein, the term "heteroaryl" is intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that an N-oxide derivative can be formed) of the nitrogen-containing heteroaryl groups described herein. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo [b] thienyl. , naphtho [2,3-b] tiantrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinolinyl, pteridinyl , carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazilyl, isothiazolyl, phenothiazinyl and phenoxazinyl. Illustrative examples of N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, N-oxide triazinyl, isoquinolyl N-oxide and quinolyl N-oxide. Other examples of heteroaryl groups include the following moieties: wherein R is H, alkyl, hydroxyl or represents a compound according to formula I. The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. The terms "alkylcarbonyloxy of G? -6" and "C5 alkylcarbonyloxy", which may be used interchangeably, and as used herein, refer to groups of the formula -OC (0) R, in which that R is an alkyl group comprising from 1 to 6 carbon atoms. The terms "C6-arylcarbonyloxy" or "and" C6-C "arylcarbonyloxy or, which may be used interchangeably, and as used herein, refer to groups of the formula -OC (0) R, wherein R is an aryl group comprising from 6 to 10 carbon atoms.

The term "heteroarylcarbonyloxy" as used herein, refers to a group of the formula -OC (0) R, wherein R is a heteroaromatic group as defined above. If a compound of the invention or an intermediate product in the present invention is a base, a desired salt can be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alphahydroxy acid, such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as acid p-toluenesulfonic or ethanesulfonic acid, or the like. If a compound of the invention or an intermediate product in the present invention is an acid, a desired salt can be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base, such as an amine. (primary, secondary or tertiary); an alkali metal or alkaline earth metal hydroxide; or similar. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary and tertiary amines; and cyclic amines such as piperidine, morpholine and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. The compounds of the present invention contain at least one chiral center and can exist as simple stereoisomers (e.g., single enantiomers or single diastereomers), any mixture of stereoisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. Specifically, it is contemplated that, unless otherwise indicated, all stereoisomers, mixtures and racemates of the present compounds are within the scope of the present invention. It is intended that the compounds identified herein describe compounds that are present in a form that contains at least from at least 90% to at least 99% of a simple stereoisomer of each chiral center present in the compounds. When the stereochemistry of the chiral carbons present in the chemical structures illustrated herein is not specified, it is specifically contemplated that all possible stereoisomers are encompassed therein. The compounds of the present invention can be prepared and used in stereoisomerically pure form or "in substantially stereoisomerically pure form." As used herein, the term "stereoisomeric" purity refers to "enantiomeric" purity and / or "diastereomeric" purity. "of a compound The term" stereoisomerically pure form ", as used herein, is intended to encompass compounds containing from at least about 95% to at least about 99%, and all values therebetween, of a simple stereoisomer The term "substantially enantiomerically pure", as used herein, is intended to encompass compounds containing from at least about 90% to at least about 95%, and all values therebetween, of a simple stereoisomer The term "diastereomerically pure", as used herein, is intended to encompass compounds containing at least approximately 95% to at least about 99%, and all values between them, of a single diastereoisomer. The term "substantially diastereomerically pure", as used herein, is intended to encompass compounds containing from at least about 90% to at least about 95%, and all values therebetween, of a single diastereomer. The terms "racemic" or "racemic mixture," as used herein, refer to a mixture containing equal amounts of opposite configurations. For example, a racemic mixture of a compound containing a stereoisomeric center would comprise an equal amount of that compound in which the stereoisomeric center is of the (S) and (R) configurations. By the term "enantiomerically enriched", as used herein, it is intended to refer to compositions in which a stereoisomer of a compound is present in an amount greater than the opposite stereoisomer. Likewise, the term "diastereomerically enriched", as used herein, refers to compositions in which a diastereomer of a compound is present in an amount greater than the other diastereomer (s). The compounds of the present invention can be obtained in stereoisomerically pure form (i.e., enantiomerically and / or diastereomerically pure) or substantially stereoisomerically pure (i.e., substantially enantiomeric and / or diastereomerically pure). Such compounds can be obtained synthetically, according to the methods described herein, using stereoisomerically pure or substantially stereoisomerically pure materials. Alternatively, these compounds can be obtained by resolution / separation of mixtures of stereoisomers, including racemic and diastereomeric mixtures, using methods known to those skilled in the art. Examples of methods that may be useful for resolution / separation of stereoisomeric mixtures include derivatization with stereochemically pure reagents to form diastereomeric mixtures, chromatographic separation of diastereomeric mixtures, chromatographic separation of enantiomeric mixtures using chiral stationary phases, enzymatic resolution of covalent derivatives - and crystallization / recrystallization. Other useful methods can be found in Enantiomers, Racemates and Resolutions, J. Jacques et al., 1981, John Wiley and Sons, New York, NY, the disclosure of which is incorporated herein by reference. Preferred stereoisomers of the compounds of the present invention are described herein.

If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent can be protected-with a suitable protecting group that is stable under the reaction conditions used in these methods. The protecting group can be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or a target compound. Those skilled in the art are well aware of suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups; examples of which can be found in T. Greene- and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley- & Sons, New York (1999), which is incorporated herein in its entirety as a reference. In some cases a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is useful as an intermediate in the methods of this invention or that is a desired substituent on a target compound. In the compounds of this invention, R2 and R2, independently or together, can be a suitable nitrogen protecting group. As indicated above, suitable nitrogen protecting groups are known to those skilled in the art and any nitrogen protecting group that is useful in the methods for preparing the compounds of this invention or which may be useful in the inhibitory compounds of the invention can be used. the HIV protease of this invention. Examples of nitrogen protecting groups include alkyl, alkyl substituted, carbamate, urea, amide, melamine, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide, phosphinyl, phosphoryl, silyl, organometallic, borinic acid and boronic acid groups . In T. Green and P. Wuts, supra, examples of each of these groups are described, methods for protecting the nitrogen residues using these groups and methods for removing these groups from the nitrogen moieties. Preferably, when R 2 and / or R 2 are independently suitable nitrogen protecting groups, suitable substituents R 2 and R 2 include, but are not limited to, carbamate protecting groups such as alkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl) and aryloxycarbonyl (for example, Cbz: benzyloxycarbonyl or FMOC: fluorene-9-methyloxycarbonyl), alkyloxycarbonyls (for example, methyloxycarbonyl, alkyl or arylcarbonyl, substituted alkyl, especially arylalkyl (for example, trityl (triphenylmethyl), benzyl and substituted benzyl), and When R2 and R2 together are a suitable nitrogen protecting group, the substituents R2 / R2 include phthalimido and a base (1,2-bis (dialkylsilyl)) ethylene). The following procedures illustrate the preparation of HIV protease inhibitors according to the methods of the present invention. These compounds, prepared by the methods of the present invention, are potent inhibitors of HIV protease and, therefore, are useful in the prevention and treatment of acquired immune deficiency syndrome (AIDS) and the AIDS-related complex ("CRS"). ").

Unless otherwise indicated, the variables according to the following procedures are as defined above. The starting materials, the synthesis of which is not specifically described herein or is provided in connection with published references, are commercially available or can be prepared using methods known to those skilled in the art. Certain synthetic modifications can be carried out according to methods familiar to those skilled in the art. The compounds of formula (I), wherein R 1 is phenyl substituted with at least one hydroxyl group, and Z, R 2, R 2, R 3, R 4, R 5, R 6 and R 7, are as defined above in the present, can be prepared from compounds of formula I, wherein R1 is phenyl substituted with at least one group selected from C? -6 alkylcarbonyloxy, C6-? oarylcarbonyloxy and heteroarylcarbonyloxy. Alkylcarbonyloxy groups of C? -6, C6-10 arylcarbonyloxy and heteroarylcarbonyloxy can be cleaved under conditions that directly provide the desired hydroxyl substituted compounds of the invention. In general, the alkylcarbonyloxy groups of C6-6, C6-6alkylcarbonyloxy and heteroarylcarbonyloxy can be cleaved under basic conditions, in a solvent that does not interfere with the desired transformation, and at a temperature that is compatible with the other parameters of the reaction. , all of which are known to the person skilled in the art. For example, suitable bases include, but are not limited to, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a sodium alkoxide such as sodium methoxide or sodium ethoxide, a potassium alkoxide such as potassium methoxide or potassium ethoxide, or a base formed in situ using a suitable combination of reagents, such as a combination of trialkyl or aryl amine in combination with an alkanol such as methanol. Or such a transformation can be carried out using an acid known to those skilled in the art which is suitable to cleave such a group without interfering with the desired transformation. Such acids include, but are not limited to, hydrogen halides such as hydrochloric acid or hydroiodic acid, an alkyl sulfonic acid such as methanesulfonic acid, an aryl sulfonic acid such as benzenesulfonic acid, nitric acid, sulfuric acid, perchloric acid or Doric acid. In addition, suitable solvents include those known to the person skilled in the art to be compatible with the reaction conditions and include alkyl esters and aryl esters, alkyl, heterocyclic and aryl ethers, hydrocarbons, alkyl and alkyl alcohols. aryl, halogenated alkyl and aryl compounds, alkyl and aryl nitriles, alkyl and aryl ketones, and aprotic heterocyclic solvents. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. Finally, these transformations can be carried out at temperatures of -20 ° C to 100 ° C, depending on the specific reagents and solvents and are within the capacity of a person skilled in the art. In Green et al., Protective Groups in Orqanic Svnthesis; John Wiley and Sons, New York, (1999) can find other suitable reaction conditions. Compounds of formulas (I) and (X), in which R3 is hydrogen and Z, R1, R2, R2 ', R4, R5, R6, R7, R8 and R9 are as defined hereinabove, can be prepare from compounds of formulas (I) and (X) wherein R3 is a hydroxyl protecting group. The choice of a suitable hydroxy protecting group is well within the knowledge of one skilled in the art. Suitable hydroxyl protecting groups that are useful in the present invention include, but are not limited to, alkyl or aryl esters, alkyl silanes, aryl silanes or alkylaryl silanes, alkyl or aryl carbonates, benzyl groups, substituted benzyl groups, substituted ethers or ethers. The various hydroxy protecting groups can be cleaved suitably using a series of reaction conditions known to the person skilled in the art. The particular conditions used will depend on the particular protecting group as well as the other functional groups contained in the subject compound. The choice of suitable conditions is within the knowledge of those skilled in the art. For example, if the hydroxy protecting group is an alkyl or aryl ester, the cleavage of the protecting group can be carried out using a suitable base, such as a carbonate, a bicarbonate, a hydroxide, an alkoxide or a base formed in situ from an appropriate combination of agents. In addition, such reactions can be carried out in a solvent that is compatible with the reaction conditions and does not interfere with the desired transformation. For example, suitable solvents may include alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl ethers, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, nitriles of aryl, alkyl ketones, aryl ketones, alkylaryl ketones or aprotic heterocyclic compounds. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. Finally, such reactions can be carried out at a suitable temperature of -20 ° C to 100 ° C, depending on the specific reagents used. The choice of a suitable temperature is within the ability of one skilled in the art In Green et al., Protective Groups in Orqanic Synthesis; John Wiley and Sons, New York, (1999) can find other suitable reaction conditions. In addition, if R3 is an alkyl silane, aryl silane or alkylaryl silane, such groups can be cleaved under conditions known to the person skilled in the art. For example, such silane protecting groups can be cleaved by exposing the subject compound to a source of fluoride ions, such as the use of an organic fluoride salt such as the tetraalkylammonium fluoride salt, or an inorganic fluoride salt. Suitable fluoride ion sources include, but are not limited to, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, sodium fluoride, and potassium fluoride. Alternative Gomo, such silane protecting groups can be cleaved under acidic conditions using mineral or organic acids, with or without the use of a pH regulating agent. For example, suitable acids include, but are not limited to, hydrofluoric acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid and methanesulfonic acid. Such silane protecting groups can also be cleaved using suitable Lewis acids. For example, suitable Lewis acids include, but are not limited to, borane dimethylbromo, triphenylmethyl tetrafluoroborate and certain Pd (II) salts. Such silane protecting groups can also be cleaved under basic conditions employing suitable organic or inorganic basic compounds. For example, such basic compounds include, but are not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. The cleavage of a silane protecting group can be carried out in a suitable solvent compatible with the specific reaction conditions and which will not interfere with the desired transformation. Among such suitable solvents are, for example, alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl ethers, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, nitriles of aryl, alkyl ketones, aryl ketones, alkylaryl ketones or aprotic heterocyclic compounds. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. Finally, such reactions can be carried out at a suitable temperature of -20 ° C to 100 ° C, depending on the specific reagents used. The choice of a suitable temperature is within the ability of one skilled in the art. In Green et al., Protective Groups in Qrganic Synthesis; John Wiley and Sons, New York, (1999) can find other suitable reaction conditions. When R3 is a benzyl or substituted benzyl ether, the cleavage of the protecting group can be carried out by treating the subject compound with hydrogen in the presence of a suitable catalyst, "oxidation with suitable compounds, exposure to light of specific wavelengths. , electrolysis, protic acid treatment or treatment with Lewis acids The choice of particular reagents to effect such transformation will depend on the specific subject compound used and is within the ability of one skilled in the art. , such benzyl or substituted benzyl esters can be cleaved using hydrogen gas in the presence of a suitable catalyst Suitable catalysts include, but are not limited to, 5% palladium on carbon, 10% palladium on carbon, platinum at 5% on carbon, 10% platinum on carbon, the choice of a particular catalyst and the amounts of catalyst, the The amount of hydrogen gas and the pressure of hydrogen gas used to effect the desired transformation will depend on the specific subject compound and the specific reaction conditions used. Such choices are within the ability of one skilled in the art. In addition, such benzyl and substituted benzyl ethers can be cleaved under oxidative conditions in which a suitable amount of an oxidant is used. Suitable such oxidants include, but are not limited to, dichlorodicyanoquinone (DDQ), ceric ammonium nitrate (CAN), ruthenium oxide in combination with sodium periodate, iron (III) chloride or ozone. In addition, such ethers can be cleaved using a suitable Lewis acid. Such suitable Lewis acids include, but are not limited to, dimethylbromo borane, triphenylmethyl tetrafluoroborate, sodium iodide combined with trifluoroborane-etherate, trichloroborane or tin (IV) chloride. The cleavage of a benzyl ether or substituted benzyl protecting group can be carried out in a suitable solvent which is compatible with the specific reaction conditions selected and which does not interfere with the desired transformation. Among such suitable solvents are, for example, alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl ethers, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, nitriles of aryl, alkyl ketones, aryl ketones, alkylaryl ketones or aprotic heterocyclic compounds. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether methyl phenyl ether, tetrahydrofuran, 2-methylethylhydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol , 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine , or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. Finally, such reactions can be carried out at a suitable temperature of -20 ° C to 100 ° C, depending on the specific reagents used. The choice of a suitable temperature is within the ability of one skilled in the art. In Green et al., Protective Groups in Organic Synthesis; John Wiley and Sons, New York, (1999) Other suitable reaction conditions can be found When R3 is a methyl ether, the cleavage of the protecting group can be carried out by treating the subject compound with organic or inorganic acids or Lewis acids. The choice of a particular reagent will depend on the type of methyl ether present as well as the other reaction conditions. The choice of a suitable reagent to cleave a methyl ether is within the ability of one skilled in the art. Suitable reagents include, but not limited to, hydrochloric acid, sulfuric acid, nitric acid, para-toluenesulfonic acid or Lewis acids such as boron trifluoride etherate. These reactions can be carried out in solvents compatible with the specific reaction conditions chosen and will not interfere with the desired transformation. Among such suitable solvents are, for example, alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl ethers, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, nitriles of aryl, alkyl ketones, aryl ketones, alkylaryl ketones or aprotic heterocyclic compounds. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or "any mixture of the above solvents." Furthermore, if necessary in this transformation water can be used as a cosolvent Finally, such reactions can be carried out at a suitable temperature of -20 ° C to 100 ° C, in function of the specific reagents u The choice of a suitable temperature is within the capacity of a person skilled in the art. In Green et al., Protective Groups in Organic Synthesis; John Wiley and Sons, New York, (1999) can find other suitable reaction conditions.

When R3 is a carbonate, the cleavage of the protecting group can be carried out by treating the subject compound with suitable basic compounds. Such suitable basic compounds may include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. The choice of a specific reagent will depend on the type of carbonate present as well as the other reaction conditions. These reactions can be carried out in solvents compatible with the specific reaction conditions chosen and will not interfere with the desired transformation. Among such suitable solvents are, for example, alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl ethers, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, nitriles of aryl, alkyl ketones, aryl ketones, alkylaryl ketones or aprotic heterocyclic compounds. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. Finally, - such reactions can be carried out at a suitable temperature of -20 ° C to 100 ° C, depending on the specific reagents used. The choice of a suitable temperature is within the ability of one skilled in the art. In Green et al., Protective Groups in Organic Synthesis; John Wiley and Sons, New York, (1999) can find other suitable reaction conditions. In addition, the compounds of formula (I) wherein R 1 is phenyl substituted with the least one hydroxy group and R 3 is hydrogen, can be prepared from compounds of formula (I) wherein R 1 is phenyl optionally substituted with at least one substituent independently selected from C6-6alkylcarbonyloxycarboxyloxy; and heteroarylcarbonyloxy; and R3 is a hydroxyl protecting group. In these compounds, the R 1 alkylcarbonyloxy group of C β, C 6 - α arylcarbonyloxy or V heteroarylcarbonyloxy and the hydroxyl protecting group R 3 can be removed using reaction conditions in which both groups are eliminated concomitantly or can be phased out. For example, when R 1 is phenyl substituted with alkylcarbonyloxy and R 3 is an alkyl ester, both groups can be cleaved by reacting the subject compound with a base in a suitable solvent and at a suitable temperature. The choice of a suitable base, solvent and temperature will depend on the particular subject compound and the particular protecting groups that are being used. These choices are within the capacity of a person skilled in the art. For example, in the compound (1), in which R1 is phenyl substituted with methylcarbonyloxy and methyl and R3 is acetoxy, the methylcarbonyl and acetoxy protecting groups were concomitantly cleaved after the reaction of the compound (1) with potassium hydroxide in a mixture of methanol and acetonitrile to give the desired compound, as shown below. d) Alternatively, in compounds of formula (I) in which R1 is phenyl substituted with at least one group selected from C-? 6 alkylcarbonyloxy, C6-? Oarylcarbonyloxy and heteroarylcarbonyloxy; and R3 is a hydroxyl protecting group, the C6 alkylcarbonyloxy group, C6- [alpha] o and heteroarylcarbonyloxy arylcarbonyloxy and the hydroxyl protecting group R3 can be cleaved stepwise to give a compound of formula (I) wherein R1 is phenyl substituted with hydroxy and R3 is hydrogen. The choice of the hydroxyl protecting group R3 and the conditions that affect its cleavage will depend on the specific subject compound selected and are within the knowledge of one skilled in the art. For example, in the compounds of formula (I) in which R 1 is phenyl substituted with C 1 -C 6 alkylcarbonyloxy and R 3 is a silane protecting group, the silane protecting group R 3 can be cleaved, first, by treatment of the subject compound with a fluoride source such as tetrabutylammonium fluoride in acetonitrile at room temperature, followed by cleavage of the C 1 -C 6 alkylcarbonyloxy group in R 1 by treatment with a base such as potassium hydroxide in a mixture of methanol and acetonitrile at room temperature. Compounds of formula (I), wherein Z, R 1, R 2, R 2 ', R 3, R 4, R 5, R 5 and R 7, are as defined hereinabove, can be prepared by the reaction of a compound of formula (II), wherein Y1 is a leaving group and R1 and R3 are as defined hereinabove, with a compound of formula (III) or a salt or solvate thereof.

The present invention specifically contemplates that the compounds of formula (I) can be prepared by the reaction of compounds of formula (III) with compounds of formula (11), wherein R3 is hydrogen, an alkyl group of C? -4 optionally substituted or a suitable protecting group, such as an alkylcarbonyl group of C? -6, arylcarbonyl of C6-? oo or heteroarylcarbonyl. For example, as shown below, compound (2), wherein R3 is methylcarboxy, was treated with thionyl chloride in a mixture of pyridine and acetonitrile and then allowed to react with compound (3) to give the compound desired (4), as shown below. (2. 3. 4) Alternatively, as shown below, the compound (5), wherein R5 is hydrogen, was allowed to react with the compound (3) to give the desired product, compound (6). (5) (3) (6) That R 3 in the compounds of formula (II) is hydrogen, an optionally substituted C 1-4 alkyl group or a suitable protecting group depends on the desired specific product compounds and / or the conditions of specific reactions used. Such choices are within the knowledge of one skilled in the art. For example, as shown below, compound (5) was allowed to react with acetic anhydride in ethyl acetate and methanesulfonic acid at about 70 ° C to give compound (2). (5) (2) The compounds of formula (II), wherein Y 1 is hydroxy and R 1 and R are as defined hereinbefore, can be prepared by reaction of compounds of formula (IV), wherein Y1 and R3 are as defined hereinabove, with compounds of formula (V), wherein R1 is as defined hereinbefore and Y2 is hydroxy or a suitable leaving group, as shown below.

= In general, these reactions can be carried out in a solvent which does not interfere with the reaction, for example alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, non-competitive alcohols, halogenated solvents, nitriles of alkyl or aryl, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol , ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C, depending on the reagents, solvents and other specific optional additives used. Such reactions can also be stimulated with the addition of optional additives. Examples of such additives include, but are not limited to, hydroxybenzotriazole (HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornerio-endo-2,3-dicarboxylamide. (HONB) and 4-dimethylaminopyridine (DMAP).

Whether these additives are necessary depends on the identity of the reagents, the solvent and the temperature. Such choices are within the knowledge of the person skilled in the art. In general, the leaving group Y2 in the compounds of formula (V) should be such as to provide sufficient reactivity with the amine in the compounds of formula (IV). The compounds of formula (V) which contain such suitable leaving groups can be prepared, isolated and / or purified and, subsequently, can react with the compounds of formula (IV). Alternatively, compounds of formula (V) with suitable leaving groups can be prepared and then reacted without isolation or subsequent purification with the compounds of formula (IV) to give compounds of formula (II). Suitable leaving groups in the compounds of formula (V) are halides, aromatic heterocycles, sulfonic acid esters, phosphoric acid esters, anhydrides, or groups derived from the reaction of compounds of formula (V) in which Y 2 is hydroxy, with reagents such as carbodiimides or carbodiimide species. Examples of suitable leaving groups include, but are not limited to, chloride, iodide, imidazole, -OC (0) alky, -OC (0) aryl, OC (O) O-alkyl, OC (0) Oaryl, OS (02) alkyl, OS (02) aryl, OPO (Oaryl) 2, OPO (Oa! Quilo) 2 and the reaction derivatives of the compounds of formula (V) wherein Y 2 is -OH with carbodiimides. Other suitable leaving groups are known to those skilled in the art and can be found in, for example, Humphrey, J.M.; Chamberlin, A. R. Chem. Rev., 1997, 97, 2243; Comprehensive Organic Synthesis; Trost, B. M., Ed; Pergamon: New York, (1991); vol. 6, pages 301-434; and Comprehensive Organic Transformations; Larock, R. C; VCH: New York, (1989), chapter 9.. "- Compounds of formula (V) in which Y 2 is a halogen can be prepared from compounds of formula (V) in which Y 2 is hydroxy by reaction with a suitable agent For example, compounds of formula can be prepared (V) wherein Y2 is chloro from compounds of formula (V) in which Y2 is hydroxy by reaction with agents such as thionyl chloride or oxalyl chloride These reactions can be carried out in the presence of a Suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine The resulting compounds can be isolated and then reacted with the compounds of formula (IV) or can be formed in situ and react with the compounds of formula (IV) without isolation or subsequent purification.These reactions can be carried out in a solvent which does not interfere with the desired transformation. Suitable solvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. Suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the previous solvents. Also, if necessary in this transformation water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. For example, as shown below, the compound (7) was allowed to react with the compound (8) in a mixture of tetrahydrofuran and water, in the presence of triethylamine, at room temperature, to give the desired compound (5). (7) (5) The compounds of formula (IV), wherein Y 1 is hydroxy and R 3 is as defined above, they are commercially available or can be prepared by methods known to those skilled in the art.

(IV) For example, the compounds of formula (IV) can be prepared as shown in the following scheme. In general, an N-protected amino acid derivative is reduced to an aldehyde using reducing agents that are suitable for such a transformation. For example, suitable reducing agents are dialkyl aluminum hydride agents, such as, for example, diisobutyl aluminum hydride. Another method for preparing the compounds of formula (IV) is to reduce a suitable carboxylic acid to an alcohol with a suitable reducing agent such as, for example, LiAIH4 or BH3 or NaBH, followed by oxidation of the alcohol in the corresponding aldehyde with PCC, in Swem conditions or using, for example, pyr * S03 / DMSO / NET3. Another method for preparing the compounds of formula (IV) is to reduce a suitable carboxylic acid derivative, such as a Weinreb amide or an acyl imidazole, using a suitable reducing agent such as, for example, LiAIH4 or diisobutyl aluminum hydride. Alternatively, the compounds of formula (IV) can be prepared by the preparation of a suitable aldehyde by reduction of the corresponding acid chloride. A compound is then added to the aldehyde which is the equivalent of adding a C02 carboxylate anion. For example, cyanide can be added to the aldehyde to give a cyanohydrin which can be hydrolyzed under acidic or basic conditions to give the desired compound, (d). As an alternative to the aldehyde it can be added to nitromethane under basic conditions to give an intermediate product which is then converted to the desired compound. These compounds can be prepared according to the following procedures. In those compounds, where Y3 is -CN, R. Pedrosa et al., Tetrahedron Asym. 2001, 1_2, 347. For the compounds in which Y3 is -CH2N02, M. Shibasaki et al., Tetrahedron Lett. 1994, 35, 6123. ? 3 = -CN or -CH2N02 Pg = protecting group The compounds of formula (V), wherein Y2 is hydroxy and R is as defined hereinabove, are commercially available or can be prepared by known methods for experts in the art. For example, such compounds can be prepared from the corresponding alcohols by oxidation with suitable reagents. Such oxidizing agents include, but are not limited to, Kmn04j pyridinium dichromate (PDC), H2Cr207 (Jones reagent) and 2,2,6,6-tetramethylpiperidinyl-2-oxyl (TE PO) / NaCl02. The compounds of formula (III), wherein Z is S, O, SO, S02, CH2 or CFH, and R2, R2, R4, R5, R6 and R7 are as defined hereinabove, are commercially available or they can be prepared by methods known to those skilled in the art. For example, see Mimote, T. et al., J. Med. Chem., 1999, 42, 1789.; EP 0751145; the patents of E.U.A. Nos. 5,644,028, 5,932,550, 5,962,640, 5,932,550 and 6,222,043, H. Hayashi et al., J. Med. Chem., 1999, 42, 1789 and PCT publication No. WO 01/05230 A1, which are incorporated herein by reference. Alternatively, the compounds of formula (I), wherein R1 is phenyl optionally substituted with at least one substituent independently selected from C6-6 alkyl, hydroxyl, Ci-alkylcarbonyloxy. e, C6- [alpha] o and heteroarylcarbonyloxy arylcarbonyloxy, and Z, R2, R2 ', R3, R4, R5, R6 and R7 are as defined hereinabove, can be prepared by reaction of compounds of formula (VI), where Z, R2, R2, R3, R4, R5, R6 and R7 are as defined hereinabove with compounds of formula (V), wherein R1 and Y2 are as defined hereinabove. In general, these reactions can be carried out in a solvent that does not interfere with the reaction, for example alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, non-competitive alcohols, halogenated solvents, alkyl nitriles or of aryl, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide. , dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents.In addition, if necessary in this transformation water can be used as a co-solvent.In addition, such reactions can be carried out at temperatures from -20 ° C to 100 ° C, depending on the reactants , solvents and other additives or specific policies used. Such reactions can also be stimulated with the addition of optional additives. Examples of such additives include, but are not limited to, hydroxybenzotriazole (HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-endo-2,3-dicarboxyimide (HONBJ). and 4-dimethylaminopyridine (DMAP): Whether these additives are necessary depends on the identity of the reagents, the solvent and the temperature, such choices are well within the skill of the person skilled in the art.

In general, the leaving group Y2 in the compounds of formula (V) must be such as to provide sufficient reactivity with the amino group in the compounds of formula (VI). Compounds of formula (V) containing such suitable leaving groups can be prepared, isolated and / or purified and subsequently reacted with the compounds of formula (VI). Alternatively, compounds of formula (V) can be prepared with suitable leaving groups and then reacted without isolation or subsequent purification with the compounds of formula (VI) to give compounds of formula (I). Suitable leaving groups in the compounds of formula (V) are halides, aromatic heterocycles, sulfonic acid esters, phosphoric acid esters, anhydrides, or groups derived from the reaction of compounds of formula (V) in which Y 2 is hydroxy, with reagents such as carbodiimides or carbodiimide species. Examples of suitable leaving groups include, but are not limited to, chloride, iodide, midazole, -OC (0) alkyl, -OC (0) aryl, -OC (0) O-alkyl, OC (0) -aryl , OS (02) alkyl, OS (02) aryl, OPO (Oaryl) 2, OPO (Oalkyl) 2 and the derivatives of the reaction of the compounds of formula (V) in which Y 2 is -OH with carbodiimides. Compounds of formula (V) wherein Y 2 is a halogen can be prepared from compounds of formula (V) wherein Y 2 is hydroxy by reaction with a suitable agent. For example, compounds of formula (V) wherein Y 2 is chloro can be prepared from compounds of formula (V) wherein Y 2 is hydroxy by reaction with agents such as thionyl chloride or oxalyl chloride. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide., a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (VI) or they can be formed in situ and reacted with the compounds of formula (VI) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylene and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Compounds of formula (VI), wherein Z, R2, R2 ', R3, R4, R5, R6 and R7, are as defined hereinabove, can be prepared from compounds of formula (VII), wherein Pg1 is a suitable nitrogen protecting group, Y4 is hydroxy or a suitable leaving group, and R3 is as defined hereinabove, with a compound of formula (III), wherein Z, R2, R2 ', R3, R4, R5, R6 and R7, are as defined hereinabove, or a salt or solvate thereof.

A suitable protecting group Pg1 in the compounds of formula (VII) is one which is stable to the following reaction conditions in which the compounds of formula (VII) are allowed to react with the compounds of formula (III). In addition, such a protecting group should be selected so that it can be removed after the compounds of formula (VII) have been allowed to react with the compounds of formula (III), to give an intermediate compound which is subsequently deprotected to a compound of formula (VI). Suitable protecting groups include, but are not limited to, carbamates such as t-butyloxycarbonyl and benzyloxycarbonyl, imides such as phthaloyl, or suitable benzyl groups. Such protecting groups can be introduced into the compounds of formula (VII) and subsequently removed to provide compounds of formula (VI) according to methods known to those skilled in the art and as found in, for example, Greene et al., Protective. Groups in Organic Svnthesis; John Wiley & Sons: New York, (1999). In general, the leaving group Y4 in the compounds of formula (VII) must be such as to provide sufficient reactivity with the amino group in the compounds of formula (III). The compounds of formula (VII) containing such suitable leaving groups can be prepared, isolated and / or purified and subsequently reacted with the compounds of formula (III) Alternatively compounds of formula (VII) with suitable leaving groups can be prepared and then react without isolation or subsequent purification with the compounds of formula (III) to give compounds of formula (VI). Suitable leaving groups in the compounds of formula (VII) are halides, aromatic heterocycles, sulfonic acid esters, esters of phosphoric acid, anhydrides, or groups derived from the reaction of compounds of formula (VII) in which Y4 is hydroxy, with reagents such as carbodiimides or carbodiimide species Examples of suitable leaving groups include, but are not limited to to them, chloride, iodide, imidazole, -OC (0) alkyl, -OC (0) aryl, -OC (0) O-alkyl, OC (0) aryl, OS (02) alkyl, OS (02) aryl, OPO ( Oari lo) 2, OPO (Oalkyl) 2 and the derivatives of the reaction of the compounds of formula (VII) in which Y 4 is -OH with carbodiimides. Compounds of formula (VII) can be prepared in which Y4- is a halogen from compounds of formula (VII) in which Y4 is hydroxy by reaction with a suitable agent. For example, compounds of formula (VII) in which Y4 is chloro can be prepared from compounds of formula (VII) in which Y4 is hydroxy by reaction with agents such as thionyl chloride or oxalyl chloride. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (III) or they can be formed in situ and reacted with the compounds of formula (III) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisoi, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Compounds of formula (VII) in which Y4 is an aromatic heterocycle can be prepared from compounds of formula (VII) in which Y4 is hydroxy by reaction with a suitable agent such as carbonyl diimidazole. These compounds can be isolated and then reacted with the compounds of formula (III) or can be formed in situ and reacted with the compounds of formula (III) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol , ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the ability of one skilled in the art.

Compounds of formula (VII) in which Y4 is a -OC (0) alkyl or -OC (0) aryl can be prepared from compounds of formula (VII) in which Y4 is hydroxy by reaction with suitable reagents such as acyl halides, acyl imidazoles or carboxylic acid under dehydration conditions. Suitable reagents include, but are not limited to, pivaloyl chloride, acetyl chloride, acetyl iodide formed in situ from acetyl chloride and sodium iodide, acetyl imidazole or acetic acid under dehydration conditions. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (III) or they can be formed in situ and reacted with the compounds of formula (III) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. " Suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butironitrile. , t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1 - propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyrite dina, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Compounds of formula (VII) in which Y4 is a -OC (0) alkyl or -OC (0) aryl can be prepared from compounds of formula (VII) in which Y4 is hydroxy by reaction with suitable reagents such as chloroformates of the formula CI-C (0) Oalkyl or CI-C (0) Oaryl. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (III) or they can be formed in situ and reacted with the compounds of formula (III) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. Suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. Also, if it is necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Compounds of formula (VII) in which Y4 is a -OS (02) alkyl or -OS (02) aryl can be prepared from compounds of formula (VII) in which Y4 is hydroxy by reaction with a suitable agent as an alkyl or aryl sulfonyl chloride. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (III) or they can be formed in situ and reacted with the compounds of formula (III) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Alternatively compounds of formula (VI) can be prepared by reaction of compounds of formula (VII), wherein Y4 is -OH, with compounds of formula (III) under dehydration conditions using agents such as carbodiimides or carbodiimide-derived species . Such suitable agents include, but are not limited to, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC), 2-chloro-4,6-dimethoxy-1,3, 5-triazine (CDMT), cyanuric chloride, 4- (4,6-dimethoxy-1, 3,5-triazin-2-yl) -4-methylmorpholine chloride, 0- (7-azabenzotriazol-1-yl) hexafluorophosphate ) -N, N, N ', N'-tetramethyluronium (HATU), carbonyldiimidazole (CDI), benzotriazo! -1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), 2-ethoxy-1 - ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate (HBTU), 2- (1 H-beñzotriazol-1-yl) tetrafluoroborate -1, 1, 3,3, -tetramethyluronium (TBTU) and 3- (diethoxyphosphoryloxy) -1, 2,3-benzotriazin-4 (3H) -one (DEPBT). These reactions can be carried out in the presence of optional additives. Suitable additives include, but are not limited to, hydroxybenzotriazole (HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbomeno-endo-2,3-dicarboxiimide (HONB) and 4-dimethyaminopyridine (DMAP). Whether these additives are necessary depends on the identity of the reagents, the solvent and the temperature. Such choices are within the knowledge of the person skilled in the art. Alternatively, the compounds of formula (I) can be prepared by reaction of a compound of formula (VIII) wherein Y5 is hydroxy or a suitable leaving group and Z, R1, R3, R4, R5, R6 and R7 are as defined hereinabove, with a compound of formula (IX), wherein R2 and R2 are as defined hereinabove, or a salt or solvate thereof. In general, the leaving group Y5 in the compounds of formula (VIII) must be such as to provide sufficient reactivity with the amino group in the compounds of formula (IX). Compounds of formula (Viil) containing such suitable leaving groups can be prepared, isolated and / or purified and subsequently reacted with the compounds of formula (IX). Alternatively, compounds of formula (HIV) with suitable leaving groups can be prepared and then reacted without isolation or subsequent purification with the compounds of formula (IX) to give compounds of formula (I). Suitable leaving groups in the compounds of formula (VIII) are halides, aromatic heterocycles, sulfonic acid esters, anhydrides, or groups derived from the reaction of compounds of formula (VIII) in which Y 5 is hydroxy, with such reagents as carbodiimides or carbodiimide species. Examples of suitable leaving groups include, but are not limited to, chloride, iodide, imidazole, -OC (0) alkyl, -OC (0) aryl, OC (0) O-alkyl, OC (0) Oaryl, OS (02) alkyl, OS (02) aryl, OPO (Oalkyl) 2, OPO (Oaryl) 2, and the derivatives of the reaction of the compounds of formula (VIII) wherein Y 5 is -OH with carbodiimides. Compounds of formula (VIII) wherein Y5 is a halogen can be prepared from compounds of formula (VIII) wherein Y5 is hydroxy by reaction with a suitable agent. For example, compounds of formula (VIII) wherein Y5 is chlorine can be prepared from compounds of formula (VIII) wherein Y5 is hydroxy by reaction with agents such as thionyl chloride or oxaliium chloride. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, - for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (IX) or can be formed in situ and reacted with the compounds of formula (IX) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. Suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methylisobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, -propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, "such reactions can be carried out at temperatures from -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen." Such choices are well within the knowledge of an expert in the technique. preparing compounds of formula (VIII) wherein Y5 is an aromatic heterocycle from compounds of formula (VIII) wherein Y5 is hydroxy by reaction with a suitable agent such as carbonyl diimidazole. These compounds can be isolated and then reacted with the compounds of formula (IX) or can be formed in situ and reacted with the compounds of formula (IX) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such - Reactions can be carried out at temperatures from -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the ability of one skilled in the art. Compounds of formula (VIII) wherein Y 5 is a -OC (0) alkyl or -OC (0) aryl can be prepared from compounds of formula (VIII) in which Y 5 is hydroxy by reaction with suitable reagents such as acyl halides, acyl imidazoles or carboxylic acid under dehydration conditions. Suitable reagents may include, but are not limited to, pivaloyl chloride, acetyl chloride, acetyl iodide formed in situ from acetyl chloride and sodium iodide, acetyl imidazole or acetic acid under dehydration conditions. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (IX) or can be formed in situ and reacted with the compounds of formula (IX) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide. , dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Compounds of formula (VIII) in which Y5 is a -OC (0) Oalkyl, -OC (O) Oaryl can be prepared from compounds of formula (VIII) wherein Y5 is hydroxy by reaction with suitable agents such as chloroformates of the formula CI-C (0) Oalkyl or CI-C (0) OariIo. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (IX) or can be formed in situ and reacted with the compounds of formula (IX) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones., aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide. , propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Compounds of formula (VIII) in which Y5 is a -OS (02) alkyl or -OS (02) aryl can be prepared from compounds of formula (VIII) in which Y5 is hydroxy by reaction with a suitable agent such as an alkyl or aryl sulfonyl chloride. These reactions can be carried out in the presence of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine, for example triethylamine, or a heteroaromatic base, for example pyridine. The resulting compounds can be isolated and then reacted with the compounds of formula (IX) or can be formed in situ and reacted with the compounds of formula (IX) without isolation or subsequent purification. These reactions can be carried out in a solvent that does not interfere with the desired transformation. Suitable solvents include alkyl or aryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones, aromatic hydrocarbons or heteroaromatic hydrocarbons. For example, suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethylacetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane, methanol , ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanoi, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, anisole, xylenes and pyridine, or any mixture of the above solvents. In addition, if necessary in this transformation, water can be used as a cosolvent. In addition, such reactions can be carried out at temperatures of -20 ° C to 100 ° C. The specific reaction conditions chosen will depend on the subject compound and the specific reagents chosen. Such choices are within the knowledge of one skilled in the art. Alternatively compounds of formula (I) can be prepared by reaction of compounds of formula (VIII), in which Y5 is -OH, with compounds of formula (IX) under dehydration conditions using agents such as carbodiimides or carbodiimide-derived species . Such suitable agents include, but are not limited to, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC), 2-chloro-4,6-dimethoxy-1,3, 5-triazine (CDMT), cyanuric chloride, 4- (4,6-dimethoxy-1, 3,5-triazin-2-yl) -4-methylmorpholine chloride, 0- (7-azabenzotriazol-1-yl) -N, N hexafluorophosphate, N ', N'-tetramethyluronium (HATU), carbonyldiimidazole (CDl), benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), 2-ethoxy-1-ethoxycarbonyl-1, 2- dihydroquinoline (EEDQ), 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate (HBTU), 2- (1 H-benzotriazol-1-yl) -1-tetrafluoroborate, 1, 3,3, -tetramethyluronium (TBTU) and 3- (diethoxyphosphoryloxy) -1, 2,3-benzotriazin-4 (3H) -one (DEPBT). These reactions can be carried out in the presence of optional additives. Suitable additives include, but are not limited to, hydroxybenzotriazole (HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-endo-2,3-dicarboxyimide (HONB). ) and 4-dimethylaminopyridine (DMAP). Whether these additives are necessary depends on the identity of the reagents, the solvent and the temperature. Such choices are within the knowledge of the person skilled in the art. The compounds of formula (IX) are commercially available or can be prepared by methods described herein or known to those skilled in the art. These examples and preparations given below illustrate more and are examples of the methods of the present invention. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples. In the following examples, compounds with one or more stereoisomeric centers, unless otherwise indicated, have a stereochemical purity of at least 95%.

EXAMPLES In the examples described below, unless otherwise indicated, all temperatures in the following description are expressed in degrees centigrade (° C) and all parts and percentages are by weight, unless otherwise indicated thing. Various starting materials and other reagents were obtained from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and are used without further purification, unless otherwise indicated. The reactions set forth below were carried out under positive pressure of nitrogen, argon or with a drying tube, at room temperature (unless otherwise indicated) in anhydrous solvents. Thin-layer chromatography analysis was performed on 254 15.5 ° C glass silica gel plates (Analtech (0.25 mm)) and eluted with the appropriate proportions of solvent (v / v). The reactions were analyzed by high pressure liquid chromatography (HPLC) or thin layer chromatography (TLC) and stopped according to the consumption of starting material. The plates of the TLC were visualized by UV, phosphomolybdic acid staining or iodine staining. The 1 H NMR spectra were recorded on a Bruker instrument operating at 300 MHz and the 13 C NMR spectra were recorded at 75 Mz. The NMR spectra are obtained as solutions of DMSO-d6 or CDCI (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or DMSO-d6 ((2.50 ppm and 39.52 ppm)). Other NMR solvents were used as needed. When communicating peak multiplicities the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, a = width, dd = doublet of doublets, dt = doublet of triplets. The coupling constants, when provided, communicate in Herztios. The infrared spectra were recorded on a Perkin Elmer FT-IR spectrometer as net oils, as KBr sediments or as CDCI3 solutions and, when communicated, expressed in wave numbers (crrf1). The mass spectra were obtained using LC / EM or APCI. All melting points are uncorrected. All final products had a purity greater than 95% (by HPLC at wavelengths of 220 nm and 254 nm). In the following examples and preparations, "Et" means ethyl, "Ac" means acetyl, "Me" means methyl, "Ph" means phenyl, (Ph02) POCI means chlorodiphenyl phosphate, "HCl" means hydrochloric acid, "EtOAc" means ethyl acetate, "Na2C03" means sodium carbonate, "NaOH" means sodium hydroxide, "NaCl" means sodium chloride, "Net3" means triethylamine, "THF" means tetrahydrofuran, "DIC" means diisopropylcarbodiimide, "HOBt" means hydroxy benzotriazole, "H20" means water, "NaHC03" means sodium hydrogen carbonate, "K2C03" means potassium carbonate, "MeOH" means methanol, "i-PrOAc" means isopropyl acetate, "MgSO4" means magnesium sulfate, "DMSO" means dimethylsulfoxide, "AcCl" means acetyl chloride, "CH2Cl2" means chloride. methylene, "MTBE" means methyl butyl ether, "DMF" means dimethylformamide, "SOCl2" means thionyl chloride, "H3P0" means phosphoric acid, "CH3SO3H" means methanesulfonic acid, "Ac20" means acetic anhydride , "CH3CN" means acetonitrile and "KOH" means potassium hydroxide.

EXAMPLE 1 Preparation of (4R) -4-alHcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tere-butyl ester The compound tere-butyl ester of (4R) -5,5-dimethyl-thiazolidine-3,4-dicarboxylic acid (which can be prepared according to the methods of Ikunaka, M. et al., Tetrahedron Asym., 2002, 13, 1201; Mimoto, T. et al., J. Med. Chem., 1999, 42, 1789 and Mimoto, T. et al., European Patent Application 0574135A1 (1993), 250 g, 0.957 moles) was added to a I purged with argon and dissolved in EtOAc (1.25 I). The solution was cooled to 2 ° C and then (PhO) 2POCI (208 ml, 1.00 moles) was added in one portion. Drop by drop was added Net3 (280 mi; 2.01 moles) through an addition funnel and then the resulting suspension was stirred at 0 ° C. Seven minutes later allylamine (75.4 ml, 1.00 moles) was added dropwise. The ice bath was removed and the suspension allowed to warm to room temperature. Half an hour later, 1 N HCl (750 mL, 0.750 mol) was added. The mixture was transferred to a 4 I separatory funnel using EtOAc (50 mL) to rinse. The layers were separated. The organic fraction was washed with 7.2% aqueous Na 2 CO 3 (2 x 1.25 I) and then transferred to a 3 I distillation flask and diluted with EtOAc (400 mL). The solution was dried azeotropically and concentrated to a volume of 800 ml by distillation of EtOAc at 1 atmosphere. After cooling to 25 ° C, the clear yellow solution of EtOAc of tere-butyl ester of (4R) -4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid was taken directly to the next step . An aliquot was removed and concentrated to give (4R) -4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tere-butyl ester as a crystalline solid; mp = 94-98 ° C, 1 H NMR (300 MHz, CDCl 3) d 6.12 (br s, 1 H), 5.88 (app ddt, J = . 2 17.1, 5.6 Hz, 1 H), 5.28 (app, J = 17.1, 1.5 Hz, 1 H), 5.18 (app dd, J = 1.2, 10.2 Hz, 1 H), 4.68 (s, 2H) , 4.14 (br s, 1 H), 3.95 (br t, J = 5.4 Hz, 2 H), 1.62 (s, 3 H), 1.49 (s, 9 H), 1.46 (s, 3 H); 13 C NMR (75 MHz, CDCl 3) d 170.0, 154.0, 134.4, 116.9; 82.0, 73.3, 54.0, 48.7, 42.0, 30.6, 28.6, 24.6; MS (LC) m / z 301.1599 (301.1586 caled, for C 14 H 25 N 203 S, M + H +); elemental analysis calculated for C 4H2 N203S: C, 55.97; H, 8.05; N, 9.32; found: C, 56.11; H, 8.01; N, 9.11.

EXAMPLE 2 Preparation of (4R) -5,5-dimethyl-thiazole-4-carboxylic acid allylamide The methanesulfonic acid compound (155 ml, 2.39 moles) was added dropwise to the EtOAc solution of (4R) -4-allylcarbamoyl-5,5-d.methyl-thiazolidine-3-carboxylic acid tere-butyl ester. in a 3-liter flask. After stirring at room temperature overnight, the solution was cooled to 7 ° C and H20 (400 ml) was poured. The mixture was transferred to a 4 I separation funnel [using H20 (30 mL) to rinse]. And the layers separated. The organic fraction was extracted with H20 (190 ml). The extracts combined with H20 were transferred to a 5 liter flask and cooled to 8 ° C. The pH was adjusted from 0.4 to 9.3 using 3N NaOH (-1.05 I). 2-Methyltetrahydrofuran (1.55 I) was poured in, followed by the addition of NaCl (150 g). The ice bath was removed and the mixture allowed to warm to room temperature. The pH was readjusted to 9.0 using 3N NaOH (~1 mL). The mixture was transferred to a 4 I separatory funnel using 2-methyl tetrahydrofuran (50 ml) to rinse and the layers were separated. The aqueous phase was extracted with 2-methytetrahydrofuran (950 ml). The organic extracts were vacuum filtered through celite directly in a 5 liter distillation flask, using 2-methyltetrahydrofuran (200 ml) to rinse. The solution was dried azeotropically and concentrated to a volume of 1.2 I by distillation of 2-methyltetrahydrofuran at 1 atmosphere. An aliquot was concentrated and weighed, which showed that 161 g of (4R) -5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide [84% of 3-tert-butyl acid ester] was present in the solution. (4R) -5,5-Dimetii-thiazolidine-3,4-dicarboxylic acid. This solution was taken directly to the next stage. The above concentrated aliquot afforded (4R) -5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide as a crystalline solid: mp = 45-47 ° C, 1 H NMR (300 MHz, CDCl 3) d 6.73 (br s, 1 H), 5.87 (app ddt7 J = 10.2 17.1, 5.7 Hz, 1 H), 5.17-5.27 (m, 2H), 4.27 (Ab q, JAB = 9.7 Hz,? = 22.5 Hz, 2H), 2.94 (app tt, J = 1.5, 5.8 Hz, 2H), 3.51 (s, 1 H), 1.74 (s, 3H), 1.38 (s, 3H); 13 C NMR (75 MHz, CDCl 3) d 169.7, 134.4, 116.9, 74.8, 57.2, 51.6, 41.9, 29.1, 27.3; EM (CL) m / z 201.1063 (201.1062 caled, for C9H? 7N2OS, M + H +); elemental analysis calculated for C9H? 6N2OS: C, 53.97; H, 8.05; N, 13.99; found: C, 56.93; H, 8.09; N, 14.07.

EXAMPLE 3 Preparation of (2S, 3S) -3- (3-Acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-butyric acid The (2S, 3S) -3-amino-2-hydroxy-4-phenyl-butyric acid compound (which can be prepared according to the method of Pedrosa et al., Tetrahedron Asym, 2001, 12, 347; M. Shibasaki et al. Tetrahedron Lett, 1994, 35, 6123 and Ikunaka, M. et al., Tetrahedron Asym, 2002, 13, 1201; (185 g, 948 mmol) was added to a 5 I flask and suspended in THF (695 mi) H20 (695 mL) was added, followed by Net.3 (277 mL, 1990 mmol) After stirring for 45 minutes, the solution was cooled to 6 ° C. A solution was then added dropwise. of acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester (201 g, 948 mmol) in THF (350 mL). Half an hour later the pH was adjusted from 8.7 to 2.5 with 6N HCl (-170 mL). Solid NaCl (46 g), then the ice bath was removed and the mixture was stirred vigorously while warming to room temperature The mixture was transferred to a 4 I separatory funnel using 1: 1 THF / H20 (50 ml). ) for the transfer and then the lower aqueous phase was removed. The organic fraction was transferred to a 5 liter distillation flask and then diluted with fresh THF (2.5 L). The solution was dried azeotropically and concentrated to a volume of 1.3 I by distillation of THF at 1 atmosphere. To complete the azeotropic drying, fresh THF (2.0 L) was added and the solution was concentrated to 1.85 I by distillation at 1 atmosphere and maintained at 55 ° C. Dropwise n-heptane (230 ml) was added through an addition funnel and then the solution was seeded immediately. After the crystallization was initiated, additional n-heptane (95 ml) was added dropwise. The resulting crystalline suspension was stirred vigorously for 7 minutes. Then more n-heptane (1.52 I) was added as a slow stream. The crystalline suspension was then allowed to cool slowly to room temperature and stirred overnight. The suspension was filtered under vacuum and the filtrate was washed with 1: 1 THF / n-heptane (700 ml). After drying in a vacuum oven at 45-50 ° C, 324 g (92%) of (2S, 3S) -3- (3-acetoxy-2-methyl-benzoylamino) -2-hydroxy-4 acid was obtained. phenyl-butyric in the form of a crystalline solid contaminated with ~ 7 mol% Et3N »HCl: mp = 189-191 ° C, 1 H NMR (300 MHz, DMSO-d6) d 12.65 (br s, 1 H), 3.80 ( d, J = 9.7 Hz, 1 H), 7.16-7.30 (m, 6H), 7.07 (dd, J = 1.1, 8.0 Hz, 1 H), 7.00 (dd, J = 1.1, 7.5 Hz), 4.40-4.52 (m, 1 H) ), 4.09 (d, J = 6.0 Hz, 1 H), 2.92 (app dd, J = 2.9, 13.9 Hz, 1 H), 2.76 (app dd, J = 11.4, 13.9 Hz, 1 H), 2.29 (s) , 3H), 1.80 (s, 3H); 13 C NMR (75 MHz, DMSO-d 5) d 174.4, 169.3, 168.1, 149.5, 139.7, 139.4, 129.5, 128.3, 127.9, 126.5, 126.3, 124.8, 123.3, 73.2, 53: 5, 35.4, 20.8, 12.6; MS (LC) m / z 372.1464 (372.1447 caled, for C20H22NO6, M + H +); elemental analysis calculated for C20H2? NO6S: «0.07 Et3N« HCI: C, 64.34; H, 5.86, N, 3.95; Cl, 0.70; found: C, 64.7; H, 5.9; N, 3.6; Cl; 0.6.

EXAMPLE 4 Preparation of acetic acid ester 3-. { (1S, 2S) -3-l 4R) -4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-n-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl} -2- methyl-phenyl The (2S, 3S) -3- (3-acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-butyric acid compound (271 g, 731 mmol) was added to a 5 I flask with a solution of (4R) -5,5-dimethyl-thiazolidin-4-carboxylic acid allylamide (161 g, 804 mmol) in 2-methyltetrahydrofuran (1.20 I of total solution), while using 2-methyltetrahydrofuran (500 ml) to rinse . HOBt »H20 (32.6 g, 241 mmol) was added using 2-methyltetrahydrofuran (50 mL) to rinse. The white suspension was allowed to stir at room temperature for 10 minutes. Diisopropylcarbodiimide (119 ml, 760 mmol) was added in three portions (40 ml + 40 ml + 39 ml) at 30 minute intervals. One hour after the last addition of DIC, Celite (100 g) was added and the suspension allowed to stir at room temperature for 3 hours. The mixture was filtered under vacuum, while 2-methyltetrahydrofuran (400 ml) was used to rinse the solids and wash the resulting filtrate. The filtrate was transferred to a 4 I separatory funnel, using 2-methyltetrahydrofuran (50 mL) to rinse. The solution was washed with 1N HCl (1.25 I) and then with an aqueous solution of NaHCO3 (27 g), NaCl (134 g) and H20 (1.25 I). The resulting organic phase was transferred to a 3 I distillation flask and then the solution was reduced to a volume of 1.12 I by distillation of 2-methyltetrahydrofuran at one atmosphere. Then the solution was diluted with 2-methyltetrahydrofuran (230 ml) to bring the total volume to 1.35 I. After cooling the solution to 23 ° C, the solution of crude acetic acid ester 3-. { (1S, 2S) -3 - [(4R) -4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl] -1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl} -2-methyl-phenyl was used directly in the next step.

EXAMPLE 5 Preparation of (4R) -3- | "2S.3S) -2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyrin-5,5-dimethyl-thiazolidine-allylamide 4-carboxylic To a solution of 2-methyltetrahydrofuran of acetic acid ester 3-. { (1S, 2S) -3 - [(4R) -4-Aliicarbamoyl-5,5-dimethy-thiazolidin-3-yl] -1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl} Crude -2-methyl phenyl (theoretical amount: 405 g, 731 mmol) sequentially MeOH (330 ml) and K 2 C 3 (66.9 g; 484 mmoles) in a 3 I flask at room temperature. Two and a half hours later more K2C03 (20 g, 144 mmol) was added. Three hours later the reaction mixture was vacuum filtered on a sheet of Celite using a 4: 1 ratio of 2-methyltetrahydrofuran / MeOH (330 ml) to rinse over the solids and wash the filtrate. The filtrate was transferred to a separating funnel of 6 μl using 4: 1 of 2-methyltetrahydrofuran / MeOH (80 ml) to rinse. The solution was diluted with i-PrOAc (1.66 I) and then washed with a solution of NaCl (83.0) and water (1.60 ml). The organic fraction was washed with 0.5 N HCl (1.66 I) and then with a saturated NaCl solution (400 ml). The resulting organic fraction was transferred to a 4 L Erlenmeyer flask and MgSO (120 g) was added. After stirring for 10 minutes, the mixture was vacuum filtered directly into a 5 L distillation flask using a 2: 1 ratio of i-ProAc / 2-methyltetrahydrofuran (600 ml to rinse the separatory funnel and the Erlenmeyer-type flask and washing the MgSO4 The 2-methyltetrahydrofuran was displaced by distillation to one atmosphere with the simultaneous addition of i-PrOAc in five portions (a total of 3.60 I was used)., maintaining a minimum volume in the container of -2.50 I. The resulting crystallization mixture was cooled to 75 ° C and kept at this temperature for 30 minutes. The suspension was then allowed to slowly cool to room temperature overnight. The suspension was filtered under vacuum, using i-PrOAc (600 ml) to transfer and wash the crystals. After drying in a vacuum oven at 40 ° C, 204 g of (54% of (2S, 3S) -3- (3-acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenylbutyric acid were obtained. ) of (4R) -3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyryl-5,5-dimethyl-thiazolidin-allylamide Crystalline 4-carboxylic acid This material was recrystallized as described below.

EXAMPLE 6 Recrystallization of (4R) -3-f (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyryl] -5,5-dimethyl acid allylamide -thiazolidin-4-carboxylic acid To a 5 liter flask was added (4R) -3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl- (4R) acid allylamide. butyrium] -5,5-dimethyl-thiazolidin-4-carboxylic acid (193 g, 378 mmol) and then suspended in EtOAc (1.28 I). After heating the suspension to 76 ° C, -MeOH (68 ml) was added and then the internal temperature was reduced to 70 ° C. To the solution was added, dropwise, n-heptane (810 ml), maintaining the internal temperature at 70 ° C. After the addition of n-heptane was complete, the resulting crystal suspension was maintained at 70 ° C for 30 minutes and then allowed to cool slowly to room temperature overnight. The suspension was filtered under vacuum using a 1.6: 1 ratio of EtOAc / n-heptane (500 ml) to transfer and wash the crystals. Then, the crystals were dried in a vacuum oven at 45 ° C to give 162 g (84% recovery) of (4R) -3 - [(2S, 3S) -2-hydroxy-3- (3) allylamide. purified -hydroxy-2-methyl-benzoylamino) -4-phenyl-butyryl] -5,5-dimethyl-thiazolidin-4-carboxylic acid ester - in the form of a white crystalline solid: mp = 173-175 ° C, 1 H NMR (300 MHz, DMSO-d6) exhibited a -10: 1 mixture of rotamers, resonances of the major rotamer d 9.35 (s, 1 H), 8.04-8.15 (m, 2H), 7.13-7.38 (m, 5H), 6.96 (t, J = 7.7 Hz, 1 H), 6.79 (d, J = 7.2 Hz, 1 H), 6.55 (d, J = 7.5 Hz, 1 H), 5.71-5.87 (m, 1 H), 5.45 ( br d, J = 6.2 Hz, 1 H), 4.98-5.27 (m, 4H), 4.38-4.52 (m, 3H), 3.58-3.86 (m, 2H), 2.68-2.90 (m, 2H), 1.84 ( s, 3H), 1.52 (s, 3H), 1.37 (s, 3H) [characteristic resonances of the minor rotamer d 9.36 (s), 8.21 (d, J = 10.5 Hz), 7.82 (5, J = 5.8 Hz), 4.89 (s), 4.78 (Ab q, JAB = 9.8 Hz,? = 27.1 Hz), 4.17-4.24 (m), 2.93-3.01 (m), 1.87 (s), 1.41 (s)]; '3C NMR (75 MHz, DMSO-d6) exhibited a -10: 1 mixture of rotamers, resonances of the major rotamer d 170.4, 169.5, 168.2, 155.7, 139.6, 139.4, 135.5, 135.4, 129.9, 128.2, 126.2, 126.1, 121.9, 117.8, 115.6, 72.4, 72.1, 53.1, 51.4, 48.2, 41.3, 34.2, 30.5, 25.0, 12.6 [characteristic resonances of the minor rotamer d 171.4. 169.7. 168.6. 139.0. 129.5. 128.4. 70.6. 54.2. 49.1. 41.5. 31.4. 24.8]; MS (Cl) m / z 512.2224 (512.2219 caled, for C27H34N305S, M + H +); elemental analysis calculated for C27H33N305S: C, 63.38; H, 6.50; N, 8.22; found: C, 63.19; H, 6.52; N, 8.10.

EXAMPLE 7 Preparation of (R) -5,5-dimetH-thiazolidin-4-carboxylic acid allylamide; Hydrochloride A solution of 3-tert-butyl ester of (R) -5,5-dimethyl-thiazolidin-3,4-dicarboxylic acid (105 kg, 402 moles) and ethyl acetate (690 l) was treated with diphenylchlorophosphate (113 kg, 422 moles) and then cooled to 0 ° C. Maintaining the temperature at 5 ° C, Net3 (85.5 kg, 844 moles) was added and then the mixture was kept at this temperature for 2 hours. The mixture was cooled to 0 ° C and then allylamine (24.1 kg, 422 moles) was added maintaining the temperature at 5 ° C. The mixture was heated to 20 ° C and then quenched with 10% by weight aqueous HCl (310 I). After separation of the layers, the organic fraction was washed with 8.6% by weight of aqueous Na 2 CO 3 (710 I). After separation of the layers, the aqueous fraction was extracted with ethyl acetate (315 I). The combined ethyl acetate extracts containing AG-074278 were dried by azeotropic distillation at one atmosphere keeping a minimum volume in the vessel of approximately 315 I. The resulting suspension of tere-butyl ester of (R) -4-allylcarbamoyl 5,5-dimethyl-thiazolidin-3-carboxylic acid was cooled to 5 ° C. A 13% by weight solution of anhydrous HCl (36.8 kg, 1008 moles) in ethyl acetate (263 I) was cooled to 5 ° C and then added to the suspension of tere-butyl ester of (R) -acid. 4-Allylcarbamoyl-5,5-dimethyl-thiazolidin-3-carboxylic maintaining the temperature at 15 ° C. The resulting suspension was kept at 20 ° C for 19 hours and then cooled and kept at 5 ° C for 2 hours. Then the suspension was leaked, using cold ethyl acetate to rinse. The wet filtrate was dried under vacuum at 45 ° C to give 90.5 kg (95.2%) of (R) -5,5-dimethythiazolidin-4-carboxylic acid allylamide hydrochloride as a white solid: NMR 1H (300 MHz, DMSO-d6) d 8.94 (app t, J = 5.5 Hz, 1 H), 5.82 (ddt, J = 10.4, 17.2, 5.2 Hz, 1 H), 5.19-5.25 (m, 1 H) , 5.10-5.14 (m, 1H), 4.38 (Ab q, JAB = 9.8 Hz,? = 14.5 Hz, 2H), 4.08 (s, 1 H), 3.72-3.91 (m, 2H), 1.58 (s, 3H) ), 1.32 (s, 3H); 13 C NMR (75 MHz, DMSO-d 6) d 161.7. 132.2. 114.0. 67.9. 51.4. 43.5. 39.3. 25.3. 24.3; MS (Cl) m / z 201.1070 (201.1062 caled, for C9H? 7N2OS, M + H +); elemental analysis calculated for C9H? 7ClN2OS: C, 45.65; H, 7.24; N, 11.83; Cl, 14.97; found: C, 45.41; H, 7.33; N, 11.69; Cl, 15.22.

EXAMPLE 8 Preparation of (2S, 3S) -2-Acetoxy-3- (3-acetoxy-2-methyl-benzoylamino) -4-phenyl-butyric acid A mixture of (2S, 3S) -3-amino-2-hydroxy-4-phenyl-butyric acid (110 kg, 563 moles), NaCl (195 kg) and THF (413 I) was charged with Net3 (120 kg, 1183 moles) and H20 (414 I) at room temperature. The resulting mixture was cooled to 0 ° C. To a different reactor was added 3-chlorocarbonyl-2-methyl-phenyl acetic acid ester (120 kg, 563 mol) and then dissolved in THF (185 I). The resulting solution of 3-chlorocarbonyl-2-methyl-phenyl acetic acid ester was cooled to 10 ° C and then added to the mixture of (2S, 3S) -3-amino-2-hydroxy-4-phenyl- Butyric keeping the temperature at < 10 ° C during the addition. The resulting biphasic mixture was stirred at 5 ° C for 1 hour and then adjusted to a pH of 2.5-3.0 with concentrated HCl (62 kg). Then, the mixture was heated to 25 ° C and the layers were separated. The resulting THF fraction, containing (2S, 3S) -3- (3-aGethoxy-2-methy-benzoylamino) -2-hydroxy-4-phenyl-butyric acid was partially concentrated by distillation at one atmosphere. The THF was then replaced with ethyl acetate by distillation at one atmosphere maintaining a minimum vessel volume of 1500 I. The resulting solution was cooled to 25 ° C and then charged with acetic anhydride (74.8 kg, 733 moles) and methanesulfonic acid. (10.8 kg, 112 moles). The mixture was heated at 70 ° C for about 3 hours. The mixture was cooled to 25 ° C and then quenched with H20 (1320 I) maintaining the temperature at 20 ° C. After removal of the aqueous layer, the organic fraction was charged with ethyl acetate (658 I) and H20 (563 I). After stirring, the aqueous phase was removed. The organic fraction was washed twice with 13% by weight of aqueous NaCl (2 x 650 I). The organic fraction was partially concentrated and dried by vacuum distillation (70-140 mm Hg) to a volume of about 1500 I. The resulting solution was heated to 40 ° C and then charged with n-heptane (1042 I) maintaining The temperature at 40 ° C. The solution was seeded with (2S, 3S) -2-acetoxy-3- (3-acetoxy-2-methyl-2-benzoylamino) -4-phenyl-butyric acid (0.1 kg) and then additional n-heptane was slowly added. (437 I). The crystallization mixture was maintained at 40 ° C for 1 hour. Maintaining the temperature at 40 ° C, additional n-heptane (175 I) was added. The crystalline suspension was cooled and kept at 25 ° C for 1 hour, then at 0 ° C for 2 hours. The suspension was filtered using n-heptane to rinse. The wet filtrate was dried under vacuum at 55 ° C to give 174 kg (74.5%) of (2S, 3S) -2-acetoxy-3- (3-acetoxy-2-methyl-2-benzoylamino) -4- fenii-butyric in the form of a white solid: mp = 152-154 ° C; 1 H NMR (300 MHz, CDCl 3) d 7.21-7.35 (m, 5H), 7.13 (app t, J = 7.9 Hz, 1 H), 7.01 (app d, J = 8.1 Hz, 1 H), 6.94 (m , 1 H) (app d, J = 7.2 Hz, 1 H), 5.99 (d, J = 9.0 Hz, 1 H), 5.33 (d, J = 4.1 Hz, 1 H), 4.96-5.07 (m, 1 H), 3.07 (dd, J = 5.5, 14.6 Hz, 1 H), 2.90 (dd, J = 10.0, 14.5 Hz, 1 H), 2.30 (s, 3H), 2.18 (s, 3H), 1.96 (s) , 3H); 13 C NMR (125 MHz, CDCl 3) d 170.4, 170.2, 169.6, 169.5, 149.5, 137.81, 136.5, 129.2, 128.6, 128.4, 127.0, 126.6, 124.5, 123.7, 73.1, 50.9, 35, 9, 20.6, 20.5, 12.4; elemental analysis calculated for C22H23N07: C, 63.92; H, 5.61; N, 3.39; found: C, 64.22; H, 5.68; N, 3.33; MS (Cl) m / z 414.1572 (414.1553 caled, for C22H24N07, M + H +).

EXAMPLE 9 Preparation of (4R) -3-r (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyryl] -5,5-allylamide -dimethyl-thiazolidin-4-carboxylic acid 1. KOH MeOH, CH3CN 2. Crystallize A solution of (2S, 3S) -2-acetoxy-3- (3-acetoxy-2-methyl-benzoylamino) -4-phenyl-butyric acid (140 kg, 339 moles), CH3CN (560 I) and pyridine (64.3) kg, 813 moles) was cooled to 15 ° C. SOCI2 (44.3 kg, 373 moles) was charged maintaining the temperature at 15 ° C. The mixture was maintained at 15 ° C for 1 hour. A different reactor was charged with allylamide hydrochloride of (R) -5 acid, 5-dimethyl-thiazolidin-4-carboxylic acid (96.6 kg, 408 mol), CH3CN (254 I) and pyridine (29.5 kg, 373 mol) and then cooled to 15 ° C. The solution of (2S, 3S) -2-acetoxy-3- (3-acetoxy-2-methyl-benzoylamino) -4-phenyl-butyric acid chloride was added to the solution of allylamide of (R) -5 acid, 5-dimethyl-thiazolidin-4-carboxylic maintaining the temperature at 15 ° C. The mixture was maintained at 15 ° C for 6 hours. A separate reactor was charged with KOH (167 kg, 2709 moles) and methanol (280 I) using a cooling cylinder at 0 ° C. The resulting KOH / methanol solution was cooled to 5 ° C. To the KOH / methanol solution was added a crude mixture of 3- acetic acid ester. { (1S, 2S) -2-acetoxy-3 - [(R) -4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl] -1-benzyl-3-oxo-propylcarbamoyl} -2-methyl-phenyl keeping the temperature at 10 ° C. After completing the addition, the mixture was kept at 25 ° C for 3 hours. The mixture was charged with H20 (840 ml) and ethyl acetate (840 ml), followed by acidification to a pH of 5-6.5 with concentrated HCl (85 kg) maintaining the temperature at 20 ° C. The resulting layers were separated. The organic fraction was washed sequentially with 6.8% by weight of aqueous NaHC 3 (770 I), an aqueous solution of HCl / NaCl (H20, 875 I; HCi conc .: 207 kg; NaCl: 56 kg), 8.5% by weight of aqueous NaHCO 3 (322 I) and then with 3.8% by weight of aqueous NaCl (728 I). The resulting organic fraction was partially concentrated by distillation to an atmosphere. The solvent was exchanged with ethyl acetate by continuous distillation and keeping the temperature of the vessel at > 70 ° C. Ethyl acetate was added in such a way that the volume of the vessel remained at about 840 I. The solution was then cooled to 20 ° C and maintained at that temperature until crystallization was observed. N-Heptane (280 I) was added and the suspension was stirred at 15 ° C for 4 hours. The crystals were rinsed using a ratio of 2.4: 1 (v / v) ethyl acetate / cold n-heptane. The wet filtrate was dried under vacuum at 45 ° C to provide (R) -3 - [(2S, 3S) -2-hydroxy-3- (hydroxy-2-methyl-benzoylamino) -4-phenylbutyryl acid allylamide. ] -5,5-dimethyl-thiazolidin-4-carboxylic acid crude. The decolorization and recrystallization was carried out in the following manner: a mixture of (R) -3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4- acid crude phenyl-butyryl] -5,5-dimethyl-thiazolidin-4-carboxylic acid, carbon ADP (21 kg), Supercel (3 kg) and ethyl acetate (780 I) was heated to 70 ° C. To the mixture was added CH3OH (40 I). The mixture was filtered and the resulting clear filtrate was heated to reflux to an atmosphere to begin distillation. The CH3OH was displaced as follows: ethyl acetate (388 I) was charged maintaining the volume of the vessel at approximately 840 I and at 70 ° C. The solution was slowly charged with n-heptane (316 I) maintaining a temperature of 70 ° C. The mixture was then cooled to 20 ° C and maintained at this temperature for 4 hours. The crystals were filtered using 2.1: 1 (v / v) ethyl acetate / cold n-heptane to rinse. The wet filtrate was dried under vacuum at 45 ° C to give 103 kg (59.6%) of (4R) -3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-met) allylamide L-benzoylamino) -4-phenyl-butyryl] -5,5-dimethyl-thiazolidin-4-carboxylic acid in the form of a white crystalline solid: mp: 173-175 ° C, 1 H NMR (300 MHz, DMSO-d6) exhibited a -10: 1 mixture of rotamers, resonances of the major rotamer d 9.35 (s, 1 H), 8.04-8.15 (m, 2H), 7.13-7.38 (m, 5H), 6.96 (t, J = 7.7 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1 H), 6.55 (d, J = 7.5Hz, 1H), 5.71 -5.87 (m, 1H), 5.45 (da, J = 6.2 Hz, 1H), 4.98-5.27 (m, 4H), 4.38-4.52 (m, 3H), 3.58-3.86 (m, 2H), 2.68-2.90 (m, 2H), 1.84 (s, 3H), 1. 52 (s, 3H), 1.37 (s, 3H) [characteristic resonances of the minor rotamer d 9.36 (s), 8.21 (d, J = 10.5 Hz), 7.82 (5, J = 5.8 Hz), 4.89 (s), 4.78 (Ab q, JAB = 9. 8 Hz,? = 27.1 Hz), 4.17-4.24 (m), 2.93-3.01 (m), 1.87 (s), 1.41 (s)]; 13 C NMR (75 MHz, DMSO-d6) exhibited a -10: 1 mixture of rotamers, resonances of the major rotamer d 170.4, 169.5, 168.2, 155.7, 139. 6, 139.4, 135.5, 135.4, 129.9, 128.2, 126.2, 126.1, 121.9, 117.8, 115.6, 72. 4, 72.1, 53.1, 51.4, 48.2, 41.3, 34.2, 30.5, 25.0, 12.6 [characteristic resonances of the minor rotamer d 171.4, 169.7, 168.6, 139.0, 129.5, 128.4, 70.6, 54.2, 49.1, 41.5, 31.4, 24.8]; MS (Cl) m / z 512.2224 (512.2219 caled, for C27H34N305S, M + H +); elemental analysis calculated for C27H33N305S: C, 63.38; H, 6.50; N, 8.22; found: C, 63.19; H, 6.52; N, 8.10.

EXAMPLE 10 Preparation of (2S, 3S) -3-amino-2-hydroxy-4-phenyl-butyric acid hydrochloride In a suspension of (2S, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyric acid (163 g, 551 mmol) is and CH 2 Cl 2 (2.0 l) was introduced HCl gas (51 g, 1.4 moles) ) by bubbles. The resulting whitish suspension was allowed to warm to room temperature and was stirred overnight. The 1 H NMR analysis of a concentrated aliquot showed a conversion of approximately 95% in the product. The suspension was cooled to 0 ° C and additional bubbles of HCl gas (46 g, 1.3 moles) were introduced into the suspension. After warming to room temperature, the suspension was stirred overnight. The suspension was filtered under vacuum, the solid was rinsed with CH2CI2 (200 ml) and then the solid was dried in a vacuum oven at 45 ° C for 24 hours, to give 129 g (100%) of acid hydrochloride (2S). , 3S) -3-amino-2-hydroxy-4-phenyl-butyric acid as a white solid: 1H-NMR (300 MHz, DMSO-d6) d 13.05 (br s, 1 H), 8.25 (br s) , 3H), 7. 22-7.34 (m, 5H), 4.41 (d, J = 2.6 Hz, 1 H), 3.66 (br s, 1 H), 2.84 (AB portion of ABX, JAX = 11.0 Hz, JB? = 2.8 Hz,? = 19.6 Hz, 2H); 13 C NMR (75 MHz, DMSO-d 6) d 172.4, 136.6, 129.8, 128.7, 127.1, 69.6, 55.0, 33.6; MS (Cl) m / z 196.0979 (196.0974 caled, for C10H NO3, M -Cl ").

EXAMPLE 11 Preparation of (2S, 3S) -3- (3-Acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-1-butyric acid: To a suspension of (2S, 3S) -3-amin? R2-hydroxy-4-phenyl-butyric acid hydrochloride (100 g, 432 mmol), H20 (320 mL) and tetrahydrofuran (320 mL) was added NEt3 (186 me, 1.34 moles). The suspension was cooled to 4 ° C and dropwise a solution of 3-chlorocarbonyl-2-methyl-phenyl acetic acid ester (93.6 g, 440 mmol) and THF (160 ml) was added dropwise. The resulting solution was warmed to room temperature and stirred for 1 hour. The solution was cooled to 10 ° C and the pH was adjusted to 2.0 using 6N HCl (87 ml). NaCl (25 g) and tetrahydrofuran (200 ml) were added and the mixture was warmed to room temperature. The phases were separated and the tetrahydrofuran fraction was dried over MgSO4 and filtered. The filtrate was concentrated to a volume of 330 ml using a rotary evaporator and then diluted with tetrahydrofuran (230 ml). Slowly n-heptane (1.2 L) was added and the resulting white suspension of solid was stirred at room temperature overnight. The suspension was filtered under vacuum, the solid was rinsed with n-heptane (2 x 500 ml) and the solid was dried in a vacuum oven at 45 ° C for 24 hours to give 150 g (93.6%) of acid (2S). , 3S) -3- (3-Acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-butyric acid in the form of a white solid contaminated with -7.7 mol% of Et3N »HCl: mp = 189-191 ° C, 1 H NMR (300 MHz, DMSO-d 6) d 12.65 (br s, 1 H), 3.80 (d, J = 9.7 Hz, 1H), 7.16-7.30 (m, 6H), 7.07 (dd, J = 1.1, 8.0 Hz, 1 H), 7.00 (dd, J = 1.1, 7.5 Hz), 4.40-4.52 (m, 1H), 4.09 (d, J = 6.0 Hz, 1 H), 2.92 (app dd, J = 2.9, 13.9 Hz, 1 H), 2.76 (app dd, J = 11.4, 13.9 Hz), 2.76 (app dd, J = 11.4, 13.9 Hz, 1H), 2.29 (s, 3H), 1.80 (s, 3H); 13 C NMR (75 MHz, DMSO-d 6) d 174.4, 169.3, 168.1, 149.5, 139.7, 139.4, 129.5, 128.3, 127.9, 126.5, 126.3, 124.8, 123.3, 73.2, 53.5, 35.4, 20.8, 12.6; MS (Cl) m / z 372.1464 (372.1447 caled, for C20H22NO6, M + H +).

EXAMPLE 12 Preparation of 2-methyl-benzylamide of (4R) -3-r (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butirill-5, 5-dimethyl-thiazolid-4-carboxylic acid NaOMß / ßOH A solution of dicyclohexylcarbodiimide (3.05 g, 14.08 mmol) was added dropwise to a suspension of (2S, 3S) -3- (3-acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-butyric acid. (5.00 g, 13.5 mmol), (4R) -5,5-dimethyl-thiazolidin-4-carboxylic acid 2-methyl-benzylamide (3.74 g, 14.1 mmol), HOBt «H20 (1.82 g, 13.5 mmol) and acetate of ethyl (100 ml) at room temperature. After stirring at room temperature overnight, the suspension was filtered under vacuum. The filtrate was washed sequentially with 5% aqueous Na 2 CO 3 (50 mL), 1N HCl (50 mL) and half-saturated aqueous NaCl (50 mL). After drying over Na 2 SO, the ethyl acetate solution of 3- acetic acid ester. { (1S, 2S) -1-benzyl-3 - [(4R) -5,5-dimethyl-4- (2-methyl-benzylcarbamoyl) - (thiazolidin-3-yl] -2-hydroxy-3-oxo- propylcarbamoyl.) -2-methyl-phenyl was concentrated to a volume of about 15 ml using a rotary evaporator, methanol (11 ml) was added and then the solution was cooled to 0 ° C. NaOMe (3.1) was added drop by drop. mi of a 25% by weight solution in methanol, 13.5 mmol) and the resulting mixture was stirred at 0 ° C for 1 hour, ethyl acetate (108 ml) was added and then 0.15N HCl (108 ml) was added slowly. The mixture was warmed to room temperature and the layers were separated The organic fraction was washed with 2.5% aqueous Na 2 CO 3 (30 mL) and then with a solution of NaCl (6.6 g) and 0.1 N HCl (30 mL). The resulting organic fraction was dried over Na 2 SO 4, filtered and then concentrated to a volume of about 21 ml using a rotary evaporator, ethyl acetate (15 ml) was added, followed by the slow addition of n-heptane. (75 ml.) The resulting suspension was stirred overnight and filtered under vacuum. The solid was rinsed with n-heptane (2 x 25 ml) and then dried in a vacuum oven at 45 ° C for 24 hours, to give 7.41 g (95.4%) of 2-methy-benzylamide acid (4R). ) -3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyryl] -5,5-dimethyl-thiazolidin-4-carboxylic acid: 1H-NMR (300 MHz, DMSO-d6) exhibited a -7: 1 mixture of rotamers, resonances of the major rotamer d 9.37 (s, 1 H), 8.32 (t, J = 5.6 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.10-7.34 (m, 9H), 6.95 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1 H), 6.56 (d, J = 7.1 Hz, 1 H ), 5.46 (brs, 1 H), 5.08 (AB q, JAB = 9.1 Hz, 2H), 4.38-4.50 (m, 3H), 4.11 (dd, J = 4.7, 15.1 Hz, 1 H), 2.85 ( app dd, J = 2.8, 13.6 Hz, 1H), 2.73 (app dd, J = 10.5, 13.5 Hz, 1 H), 2.27 (s, 3H), 1.84 (s, 3H), 1.50 (s, 3H), 1.36 (s, 3H) [main characteristics of the minor rotamer d 8.19 (d, J = 8.5 Hz), 8.07 (t, J = 5.7 Hz), 6.49 (d, J = 7.5 Hz), 4.93 (s), 4.80 ( Ab q, JAB = 9.7 Hz), 1.82 (s), 1.40 (s)]; 13 C NMR (75 MHz, DMSO-d6) exhibited a -7: 1 mixture of rotamers, resonances of the major rotamer d 170.5, 169.5, 168.3, 155.7, 139. 7, 139.4, 137.1, 136.0, 130.2, 129.9, 128.3, 128.2, 127.2, 126.2, 126.1, 126.0, 121.8, 117.8, 115.6, 72.4, 71.9, 53.2, 51.5, 48.1, 40.8, 34.2, 30.6, 25.0, 19.1, 12.6 [main characteristics of the minor rotamer d 171.4, 169.6, 168. 8, 139.0, 137.0, 135.8, 129.5, 128.4, 71.9, 54.3, 31.5, 24.8]; MS (Cl) m / z 576.2552 (576.2532 caled, for C32H38N305S, M + H +).

EXAMPLE 13 Preparation of (2S, 3S) -3-amino-2-hydroxy-4-phenyl-butyric acid ethyl ester hydrochloride; To absolute ethanol (500 ml), which had been cooled to 2 ° C with an ice bath, SOCI2 (49.4 ml, 677 mmol) was added dropwise. After stirring the resulting solution for 0.5 hour, (2S, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyric acid (50.0 g) was added.; 169 mmol) as a solid. After stirring the resulting suspension for 20 minutes, the ice bath was removed and the mixture was warmed to room temperature. Two hours later the flask was immersed in an oil bath and the yellowish solution was heated to reflux overnight. The flask was then equipped with a distillation head, the temperature of the oil bath was increased to 85-90 ° C and 375 ml of distillate (ethanol) was collected (b.p. = 76-82 ° C, 1 atm ) and they were discarded. The yellowish solution remaining in the boiling vessel was allowed to cool to 35 ° C. Methyl t-butyl ether (400 ml) was added slowly, followed by the addition of n-heptane (100 ml). The resulting suspension was allowed to stir overnight and then filtered under vacuum. The solid was rinsed with n-heptane (3 x 150 ml) and then dried in a vacuum oven at 45 ° C overnight to give 40.2 g (91.3%) of ethyl ester hydrochloride (2S, 3S) ) -3-amino-2-hydroxy-4-phenyl-butyric as an off-white solid: mp = 129.5-131.5 ° C 1 H NMR (300 MHz, DMSO-d6) d 8.46 (br s, 3H), 7.19- 7.33 (m, 5H), 6.37 (d, J = 5.2 Hz, 1H), 4.48 (dd, J = 2.4, 5.0 Hz, 1H), 3.68-3.82 (m, 2H), 3.56 (app dd, J = 10.7 7.1 Hz, 1H), 2.82-2.95 (m, 2H), 1.00 (t, J = 7.1 Hz, 3H); 1 H NMR (300 MHz, D20) d 7.19-7.33 (m, 5H), 4.51 (d, J = 2.8 Hz, 1 H), 4.06 (dt, J = 2.8, 7.5 Hz, 1 H), 3.85 (app, J = 10.6, 7.2 Hz, 1H), 3.68 (app, J = 10.6, 7.2 Hz, 1 H), 2.83-2.97 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H); 13 C NMR (75 MHz, DMSO-d 6) d 170.7, 136.5, 129.9, 128.5, 127.1, 69.0, 60.8, 54.8, 33.3, 14.0; MS (Cl) m / z 224.1297 (224.1287 caled, for C? 2H18N03, M-CI ").

EXAMPLE 14 Preparation of (2S, 3S) -3- (3-Acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-butyric acid ethyl ester: To a room temperature suspension of (2S, 3S) -3-amino-2-hydroxy-4-phenyl-butyric acid ethyl ester hydrochloride (38.9 g, 150 mmol) and CH2Cl2 (800 mL) was added NEt3 ( 63.0 ml, 450 mmol) and the resulting solution was cooled to 1 ° C. Slowly a solution of 3-chlorocarbonyl-2-methyl-phenyl acetic acid ester (35.0 g, 165 mmol) and CH2Cl2 (150 ml) was added and the resulting white suspension was allowed to warm to room temperature and stir during cooling. night. 0.5N HCl (400 mL) was added and the resulting layers were separated. The organic fraction was washed with H20 (400 mL) and then with a quarter of saturated aqueous NaHCO3. To the organic fraction was added methanol (40 ml), which was then dried over MgSO 4 and filtered. The filtrate was concentrated to a solid with a rotary evaporator and then dried in a vacuum oven at 45 ° C overnight to give 60.0 g (101%) of ethyl ester of (2S, 3S) -3- acid. (3-Acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-butyric in the form of an off-white solid: 1 H NMR (300 MHz, CDCl 3) d 6.93 (m, 8H), 6.02 (d, J = 9.0 Hz, 1 H), 4.78-4.87 (m, 1 H), 4.37 (d, J = 3.0 Hz, 1 H), 4.13 (app, J = 10.7, 7.2 Hz, 1 H), 4.04 (app of , J = 10.7, 7.1 Hz, 1 H), 2.79 (d, J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.95 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13 C NMR (75 MHz, DMSO-d6) d 172.7, 169.3, 168.1, 149.6, 139.5, 139.2, 129.5, 128.3, 128.0, 126.6, 126.4, 124.8, 123.4, 73.4, 60.7, 53.5, 35.5, 20.8, 14.5, 12.6; MS (Cl) m / z 400.1751 (400.1760 caled, for C22H26N06, M + H +); elemental analysis calculated for C22H25N06: C, 66.15; H, 6.31; N, 3.51; found: C, 65.90; H, 6.28; N, 3.39.

EXAMPLE 15 Preparation of (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyric acid To a suspension of (2S, 3S) -3- (3-acetoxy-2-methyl-benzoylamino) -2-hydroxy-4-phenyl-butyric acid ethyl ester (58.9 g, 147 mmol) and tetrahydrofuran (300 ml) ) at room temperature NaOH (-108 ml of a 3N aqueous solution, 324 mmol) was added. The resulting warm biphasic solution was stirred at room temperature overnight. The matrix was equipped with a distillation head and immersed in an oil bath. A total of 340 ml of distillate was collected at one atmosphere with the variable oil bath temperature of 75-125 ° C. The resulting light yellow solution remaining in the boiling vessel was diluted with H20 (100 mL) and then cooled to 0 ° C. Slowly 6N HCl (60 mL) was added, followed by ethyl acetate (250 mL) and the resulting mixture was warmed to room temperature with vigorous stirring. The resulting layers were separated. The organic fraction was washed with one third of saturated aqueous NaCl and then dried over MgSO4, filtered and then concentrated to about 220 ml using a rotary evaporator. The resulting solution was allowed to stir at room temperature overnight. The resulting suspension of solid was filtered under vacuum and the solid was rinsed with n-heptane (2 x 200 mL). After drying in a vacuum oven at 45 ° C for 48 hours, 45.1 g (92.8%) of (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) acid were obtained - 4-phenyl-butyric in the form of a white solid: 1 H NMR (300 MHz, DMSO-d 6) d 12.6 (br s, 1 H), 9.35 (s, 1 H), 8. 05 (d, J = 9.0 Hz, 1H), 7.16-7.30 (m, 5H), 6.95 (t, J = 7.8 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1 H), 6.53 (d, J = 6.7 Hz, 1 H), 5.63 (br s, 1 H), 4.38-4.49 (m, 1 H), 4.07 (d, J = 5.9 Hz, 1 H), 2.87 (app dd, J = 3.0, 13.8 Hz, 1 H), 2.74 (app dd, J = 11.2, 13.9 Hz, 1 H), 1.80 (s, 3H); 13 C NMR (75 MHz, DMSO-d6) d 174.2, 168.9, 155.4, 139.3, 139. 2, 129.3, 128.1, 126.0, 125.8, 121.5, 117.6, 115.2, 73.0, 53.1, 35.1, 12.3; MS (Cl) m / z 330.1348 (330.1341 caled, for C? 8H20NO5, M + H +); EXAMPLE 16 Preparation of 2-methyl-benzylamide of (4R) -3-f (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyropic acid 5,5-dimethyl-thiazolidin-4-carboxylic acid To a solution of (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyric acid (5.00 g, 15.2 mmoies) (which can be prepared according to the procedure is found in H. Hayashi et al., J. Med. Chem. 1999, 42, 1789, R. Kato et al., U.S. Patent No. 5,932,550 and JR Tata et al., PCT Publication No. WO 01 / 05230 A1) HOBt «H20 (2.05 g, 15.2 mmol) and tetrahydrofuran (50 mL) at room temperature was added slowly a solution of dicyclohexylcarbodiimide (3.29 g, 15.9 mmol) and tetrahydrofuran (15 mL). The resulting suspension was stirred at room temperature overnight. Ethyl acetate (35 ml) was added and then the suspension was filtered under vacuum, using ethyl acetate (20 ml) to rinse. The filtrate was washed sequentially with 5% aqueous Na 2 CO 3 (50 mL), 0.5 N HCl (50 mL) and one quarter saturated aqueous NaCl (50 mL). The resulting organic fraction was dried over MgSO4, filtered and then concentrated to a volume of 45 ml using a rotary evaporator. The solution was allowed to stir at room temperature overnight. The resulting suspension was filtered under vacuum and the solid discarded. The filtrate was concentrated with a rotary evaporator to give (4R) -3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4- methyl-benzylamide. phenyl-butyryl] -5,5-dimethyl-thiazolidin-4-carboxylic acid in the form of a yellowish solid. This solid was dissolved in isopropyl acetate (62 ml) and the mixture in crystallization was stirred at room temperature overnight. The suspension was filtered under vacuum. The solid was rinsed with isopropyl acetate (2 x 20 ml) and then dried in a vacuum oven at 45 ° C for 24 hours to give 5.60 g (64.1%) of 2-methyl-benzylamide of (4R) - 3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyryl] -5,5-dimethyl-thiazolidin-4-carboxylic acid in the form of a white solid: 1 H-NMR (300 MHz, DMSO-d6) exhibited a -7: 1 mixture of rotamers, resonances of the major rotamer d 9.37 (s, 1 H), 8.32 (t, J = 5.6 Hz, 1 H ), 8.14 (d, J = 8.3 Hz, 1 H), 7.10-7.34 (m, 9H), 6.95 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.56 ( d, J = 7.1 Hz, 1 H), 5.46 (br s, 1 H), 5.08 (AB q, JAB = 9.1 Hz, 2H), 4.38-4.50 (m, 3H), 4.11 (dd, J = 4.7, 15.1 Hz, 1 H), 2.85 (app dd, J = 2.8, 13.6 Hz, 1 H), 2.73 (app dd, J = 10.5, 13.5 Hz, 1H), 2.27 (s, 3H), 1.84 (s, 3H) ), 1.50 (s, 3H), 1.36 (s, 3H) [characteristic resonances of the minor rotamer d 8.19 (d, J = 8.5 Hz), 8.07 (t, J = 5.7 Hz), 6.49 (d, J = 7.5 Hz) ), 4.93 (s), 4.80 (Ab q, JAB = 9.7 Hz), 1 .82 (s), 1. 0 (s) l; 13 C NMR (75 MHz, DMSO-d6) exhibited a -7: 1 mixture of rotamers, resonances of the major rotamer d 170.5, 169.5, 168.3, 155.7, 139.7, 139.4, 137.1, 136.0, 130.2, 129.9, 128.3, 128.2, 127.2 , 126.2, 126.1, 126.0, 121.8, 117.8, 115.6, 72.4, 71.29, 53.2, 51.5, 48.1, 40.8, 34.2, 30.6, 25.0, 19.1, 12.6 [characteristic resonances of the minor rotamer d 17-1.4, 169.6, 168.8, 139.0 , 137.0, 135.8, 129.5, 128.4, 71.9, 54.3, 31.5, 24.8] MS (Cl) m / z 576.2552 (576.2532 caled, for C32H38N305S, M + H +).

EXAMPLE 17 Preparation of 2-methyl-benzylamide of (4R) -3-r (2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenyl-butyrin-5, 5-dimethyl-thiazoHdin-4-carboxylic acid: A solution of (2S, 3S) -2-acetoxy-3- (3-acetoxy-2-methyl-benzoylamino) -4-phenyl-butyric acid (140 kg, 229 moles), CH3CN (560 I) and pyridine (64.3) kg, 813 moles) is cooled to 15 ° C. SOCI2 (44.3 kg, 373 moles) is charged maintaining the temperature at 15 ° C. The mixture is maintained at 15 ° C for 1 hour. A separate reactor is charged with (4R) -5,5-dimethyl-thiazolidin-4-carboxylic acid 2-methyl-benzylamide (89.7 kg, 339 moles), CH3CN (254 I) and pyridine (29.5 kg), 373 moles) and then cooled to 15 ° C. The solution of (2S, 3S) -2-acetoxy-3- (3-acetoxy-2-methyl-benzoylamino) -4-phenyl-butyric acid chloride is added to the solution of 2-methyl benzylamide of acid (4R) -5,5-dimethyl-thiazolidin-4-carboxylic acid maintaining the temperature at 15 ° C. The mixture is maintained at 15 ° C for 6 hours. A separate reactor is charged with KOH (167 kg, 2709 moles) and methanol (280 I) using a cooling cylinder at 0 ° C. The resulting KOH / methanol solution is cooled to 5 ° C. To the KOH / methanol solution is added the crude acetic acid mixture maintaining the temperature at 10 ° C. When the addition is complete, the mixture is maintained at 25 ° C for 3 hours. The mixture is charged with H20 (840 I) and ethyl acetate (840 I) and then followed by acidification to a pH of 5-6.5 with concentrated HCl (85 kg) maintaining the temperature at 20 ° C. The resulting layers are separated. The organic fraction is washed sequentially with 6.8% by weight aqueous NaHC03, a solution of aqueous HCl / NaCl (H20: 875 I; HCl conc .: 207 kg; NaCl: 56 kg), 8.5% by weight aqueous NaHC03 (322 I) and then with 3.8% by weight aqueous NaCl (728 I). The resulting organic fraction is partially concentrated by distillation at one atmosphere. The solvent is exchanged with ethyl acetate by continuous distillation and keeping the temperature of the vessel at > 70 ° C. Ethyl acetate is added so that the volume of the vessel remains at approximately 840 I. Afterwards, the solution is cooled to 20 ° C and maintained at this temperature until crystallization is observed. N-Heptane (280 I) is added and the suspension is stirred at 15 ° C for 4 hours. The crystals are rinsed using 2.4: 1 (v / v) ethyl acetate / cold n-heptane to rinse. The dried filtrate is dried under vacuum at 45 ° C to provide (4R) -3 - [(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-methyl-benzoyl) amino acid 2-methyl-benzylamide) 4-phenyl-butyryl] -5,5-dimethyl-thiazolidin-4-carboxylic acid.

Claims (15)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A method for preparing a compound of formula (I), or a salt or solvate thereof: wherein: R1 is phenyl optionally substituted with a! minus one substituent independently selected from C? -C6 alkyl, hydroxyl, C? C6 alkylcarbonyloxy, C6-C6 arylcarbonyloxy and heteroarylcarbonyloxy; R2 is C2-C6 alkenyl, C6-C6 alkyl optionally substituted with at least one halogen or - (CR4R5) nR8; n is an integer from 0 to 5; R2 is H or C4 alkyl; Z is S, O, SO, S02, CH2 or CFH; R3 is hydrogen or a hydroxyl protecting group; each R 4, R 5, R 6 and R 7 are independently selected from H, C 6 C alkyl; and R8 is C6-C10 aryl optionally substituted with at least one substituent selected from C? -C6 alkyl) hydroxyl and halogen; comprising: inducing the reaction of a compound of formula (II), wherein Y1 is hydroxyl or a leaving group and R1 is as described for formula (I), with a compound of formula (III), or a salt or solvate thereof: (ll) (Hi) 2. - The method according to claim 1, further characterized in that the compound of formula (II), Y1 is hydroxyl. 3. The method according to claim 1, further characterized in that in the compound of formula (I): n is 0, 1, 2 or 3; R2 'is H; Z is S, O, CH2 or CFH; R4 and R5 are hydrogen; and R6 and R7 are alkyl 4. - The method according to claim 3, further characterized in that in the compound of formula (I): Z is S; R3 is hydrogen; and R6 and R7 are methyl. 5. The method according to claim 3, further characterized in that in the compound of formula (I): Z is S; R3 is a hydroxyl protecting group; R4 and R5 are hydrogen; R6 and R7 are methyl; and R8 is phenyl optionally substituted with at least one substituent selected from CrC6 alkyl, hydroxy, and halogen. 6. The method according to claim 3, further characterized in that in the compound of formula (I): R1 is phenyl optionally substituted with at least one substituent selected independently from methyl, hydroxyl and methylcarbonyloxy; R2 is C2-C6 alkenyl, CrC6 alkyl optionally substituted with at least one halogen or -CH2R8; Z is S; R6 and R7 are methyl; and R8 is phenyl optionally substituted with at least one methyl. 7. The method according to claim 6, further characterized in that in the compound of formula (I) R2 is C2-C6 alkenyl. 8. The method according to claim 7, further characterized in that in the compound of formula (I): R1 is phenyl substituted with methyl and hydroxy; R2 is allyl; and R3 is hydrogen or methylcarbonyl. 9. The method according to claim 7, further characterized in that in the compound of formula (I): R1 is phenyl substituted with methyl and methylcarbonyloxy; R2 is allyl; and R3 is methylcarbonyl. 10. The method according to claim 8, further characterized in that the compound of formula (I) is: 11. - A method for preparing a compound of formula (I-A), which comprises: the reaction of a compound of formula (11-A) with a compound of formula (III-A), or a salt or solvate thereof, (II-A) (III-A) 12.- A method for preparing a compound of formula (I-A), comprising: (i) the reaction of a compound of formula (IV-A) with a compound of formula (V-A), (IV-A) (V-A) (ll-B) to give a compound of formula (II-B); (ii) treating the compound of formula (II-B) with an acylating agent to give a compound of formula (H-A); and (ll-A) (iii) the reaction of the compound of formula (11-A) with a compound of formula (III-A). (H-A) (lll-A) 13. - A method for preparing a compound of formula (I-B), comprising: (i) the reaction of a compound of formula (11-A) with a compound of formula (III-A), or a salt or solvate thereof, (ll-A) (lll-A) (l-A) to give a compound of formula (I-A); and (ii) deprotection of the compound of formula (1-A). 14. A method for preparing a compound of formula (I-B), comprising: (i) the reaction of a compound of formula (IV-A) with a compound of formula (V-A), (1V-A) (V-A) (H-B) to give a compound of formula (II-B); (ii) treating the compound of formula (II-B) with an acylating agent to give a compound of formula (11-A); Y (ll-A) (iii) the reaction of the compound of formula (11-A) with a compound of formula (III-A). to give a compound of formula (I-A); and (iv) deprotection of the compound of formula (1-A). 15. A compound of formula (I-A),