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WO1993022321A1 - Derives d'alkynyle contenant du phosphore - Google Patents

Derives d'alkynyle contenant du phosphore Download PDF

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Publication number
WO1993022321A1
WO1993022321A1 PCT/GB1993/000837 GB9300837W WO9322321A1 WO 1993022321 A1 WO1993022321 A1 WO 1993022321A1 GB 9300837 W GB9300837 W GB 9300837W WO 9322321 A1 WO9322321 A1 WO 9322321A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
group
general formula
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1993/000837
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English (en)
Inventor
Richard Simon Todd
Maxwell Reeve
Alan Hornsby Davidson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vernalis R&D Ltd
Original Assignee
British Bio Technology Ltd
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Filing date
Publication date
Application filed by British Bio Technology Ltd filed Critical British Bio Technology Ltd
Publication of WO1993022321A1 publication Critical patent/WO1993022321A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4015—Esters of acyclic unsaturated acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel compounds which are useful intermediates in the synthesis of a range of mevinic acids and other HMGCoA reductase inhibitors, to a process for the synthesis of these compounds and to their use in the synthesis of mevinic acids.
  • a number of mevinic acids have been reported to be potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • EP-A-0251625 discloses compounds of structure:
  • R1 is a group of formula CH 2 OH, CH 2 OCOR3 , CO 2 R4 or CONR6R7 wherein R3, R4, R6, and R7 can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.
  • ketophosphonate reagent that is the precursor to the substituted ethyl tetrahydropyran moiety:
  • WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids.
  • the document describes the synthesis of (1S, 2S,4aR,6S,8S,8aS,4'R,6aR')-6'- ⁇ 2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]-6-[(E)-prop-1-enyl]-1-napthalenyl)ethyl ⁇ -tetrahydro-4'-hydroxy-2H-pyran-2'-one which has the structure:
  • both of these syntheses involve a large number of steps, for example, nine steps are involved in the process of US 4950075, and this makes the procedures unsuitable for the production of ketophosphonates on a large scale since the overall yield of the process is low and the product may be contaminated with one or more of the intermediates. Therefore, it would be particularly advantageous to develop a process for the synthesis of ketophosphonates in which fewer steps are used.
  • n is 0 or 1;
  • R 1 and R 2 each independently represents a group R, OR, NHR or NR 2 in which the two R groups may be the same or different and wherein:
  • R is -C 1-8 alkyl optionally substituted with one or more halogen atoms, -C 2-8 alkenyl, -C 3-8 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, -C 1-8 alkyl (C 3-8 cycloalkyl), phenyl, -C 1 -C 6 alkylphenyl, -C 2 -C 6 alkenylphenyl, or R 1 and R 2 together form a C 2 -C 6 alkyl bridge which may optionally be substituted at any position with a C 1-4 alkyl group;
  • the compounds of general formula I When Y is CHOH or CHOQ, the compounds of general formula I have a chiral centre and can therefore adopt either the R or the S stereoisomeric configuration. Compounds having the S configuration are preferred.
  • C 1 -C 8 alkyl refers to straight chain or branched chain hydrocarbon groups having from one to eight carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • hydroxy C 1 -C 8 alkyl refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group.
  • alkoxy groups are hydroxyethyl and hydroxy-n-propyl.
  • C 3 -C 8 cycloalkyl refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 4 -C 8 cycloalkenyl refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds. Illustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • halogen or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
  • substituted alkyl refers to a straight or branched chain hydrocarbon group of one to three carbon atoms substituted with one or more aryl groups. Illustrative of such groups are benzyl and diphenyl methyl.
  • suitable protecting group refers to a group temporarily attached to a reactive centre in a multi-functional molecule. Such protecting groups are well known to those skilled in the art. The protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites. For a good review of protecting groups, see “Protective Groups in Organic Synthesis", Greene, T W Ed., John Wiley and Sons, 1981.
  • X represents C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, any of which may be substituted with one or more halogen atoms, optionally protected hydroxy, C 1-6 alkoxy, C 1-6 alkyl-OH, a nitrile, C 1-6 alkyl nitrile, a halogen, a CO 2 R 3 , CONR 3 2 , -C(OR 4 ) 3 , C 1-6 alkyl CO 2 R 3 , C 1-6 alkyl CONR 3 2 , C 1-8 alkyl-C(OR 4 ) 3 , or optionally protected CHO or C 1-6 alkyl CHO;
  • R 3 is H, C 1-6 alkyl or a suitable acid protecting group
  • R 4 is C 1-8 alkyl, or the three R 4 groups together with the carbon atom and the oxygen atoms to which they are attached form a tricyclic ortho-ester.
  • protecting groups for the hydroxy functions are alkylsiloxy groups such as trimethylsiloxy, triisopropylsiloxy and t-butyldimethylsiloxy.
  • Preferred protecting groups for the aldehyde functions are acetals.
  • R 1 and R 2 each represent a group OR
  • R represents a C 1-6 alkyl group
  • R 3 is C 1-6 alkyl.
  • n 1
  • X is more preferably optionally protected hydroxy, C 1-6 alkoxy, a nitrile, halogen, CO 2 R 3 CONR 3 2 or -C(OR 4 ) 3 group and in the most preferred compounds of general formula I, X is CO 2 R 3 .
  • a particularly preferred compound is methyl 6- (diethylphosphono)-3(S)-hydroxyhex-5-ynoate.
  • n, R 1 and R 2 are as defined in general formula I;
  • R 5 is hydrogen or a protecting group which can easily be removed in situ to expose the acetylene carbanion
  • Y and X are as defined for general formula I; A is a leaving group; or
  • Y and A together form a -CH-O- or -CH-O-SO 2 -O- bridge in which the CH moiety is at the Y group end of the bridge; under basic conditions; (b) optionally after step (a), converting a compound of general formula I to another compound of general formula I.
  • the protecting group R 5 in general formula II is a tri(C 1-6 )alkylsilyl group, for example a trimethylsilyl group.
  • the group A in general formula III may be a halogen atom, a C 1-6 alkyl sulphonate or an aryl sulphonate.
  • the reaction is preferably carried out in a polar aprotic solvent such as tetrahydrofuran, dimethylsulphoxide or dimethylformamide.
  • the base is a strong base which is preferably derived from lithium. n-Butyl lithium has been found to be particularly suitable but lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LHMDS) may also be used. It is also possible to use potassium t-butoxide but a base which is weaker than this will usually not be effective.
  • a Lewis acid such as boron trifluoride etherate may also be present, especially in cases when, in general formula III, Y and A form a -CH-O- or -CH-O-SO 2 -O- bridge.
  • a compound of general formula I in which n is 0 can readily be converted into a compound of general formula I in which n is 1 by oxidation.
  • Compounds of general formula II are available in the art or may be prepared by methods known to those skilled in the art, for example, see Burt et al, J. Chem. Soc., 2, 2273-76 (1969).
  • Compounds of general formula III are also available in the art or may be prepared by methods analogous to those described in the art, for example, by Larcheveque et al, Tetrahedron. 46, (12), 4277-4282 (1990) and Seiki et al, Chem. Letters, 8, 1389-1392 (1984).
  • R 1 , R 2 , n, Y and X are as defined for general formula I; the process comprising reacting a compound of general formula I with an aqueous acid under catalytic conditions in an alcoholic solvent.
  • the acid will preferably be a strong non-oxidising acid, with sulphuric acid being the most preferred.
  • the alcoholic solvent should preferably be at least partially miscible with water and methanol is a particularly, suitable solvent.
  • Mercury (II) salts are the most preferred catalysts for the reaction.
  • the compounds of general formula I are useful intermediates in the synthesis of a wide variety of compounds, particularly intermediates of various active mevinic acid derivatives.
  • Z is a bulky organic substituent.
  • This reaction is particularly suitable for the production of mevinic acid precursors in which Z is a group of general formula VII
  • R 7 represents a hydrogen atom, COC 1-8 alkyl, COC 3-8 cycloalkyl, COC 3-8 cycloalkylC 1-8 alkyl, COC 2-8 alkenyl, COO 1- 6 alkyl substituted phenyl group, or a suitable protecting group;
  • R 8 represents a hydrogen atom, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, or a C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C 1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;
  • R 9 represents a hydrogen atom or a C 1-8 alkyl group;
  • R 10 represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond. From these compounds of formula VI, a range of mevinic acid derivatives can be prepared which are active as HMG-CoA reductase inhibitors.
  • R 3 , R 7 , R 8 , R 9 , R 10 , a, b and c are as defined above and d is a single or a double bond; the process comprising converting a compound of general formula I in which X is CO 2 R 3 to a compound of general formula IV in which X is CO 2 R 3 and subsequently converting the compound of general formula IV to a compound of general formula VIII or IX by any suitable process.
  • the compound of general formula IV may be reacted with a compound of general formula V wherein Z is a group of general formula VII as described above to form a compound of general formula VI.
  • This compound may then be converted to compounds of general formulae VIII and IX by the process described in WO-A-9100280.
  • Example 1 gives a method for the preparation of a compound of general formula I
  • Example 2 gives a method for the conversion of a compound of general formula I to a compound of general formula IV.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne les composés de la formule (I), dans laquelle n est égal à 0 ou 1; R1 et R2 représentent chacun d'une manière indépendante un groupe R, OR, NHR ou NR¿2?, où les deux groupes R peuvent être les mêmes ou différents, et où: R est un (C1-C8)alkyle, le cas échéant substitué avec un ou plusieurs atomes d'halogène, un (C2-C8)alcényle, un (C3-C8)cycloalkyle, un (C1-C6)allkyl-O-(C1-C6)alkyle, un (C1-C8)alkyl(C3-C8)cycloalkyle, un phényle, un (C1-C6)alkylphényle, un (C2-C6)alcénylphényle, ou R?1 et R2¿ forment ensemble un pont (C¿2?-C6)alkylène qui peut être, le cas échéant, substitué dans une position quelconque avec un groupe (C1-C4)alkyle, Y est CHOH, CHOQ, où Q est un groupe protecteur approprié ou un groupe C=O; X représente un groupe quelconque, mais sans interaction chimique ou stérique avec le groupe Y. Ces composés sont des intermédiaires utiles dans la préparation de cétophosphonates et de leurs dérivés. Ceux-ci sont des intermédiaires utiles à la synthèse d'une variété de composés, par exemple de dérivés de l'acide mévinique.
PCT/GB1993/000837 1992-04-23 1993-04-22 Derives d'alkynyle contenant du phosphore Ceased WO1993022321A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929208790A GB9208790D0 (en) 1992-04-23 1992-04-23 Compounds
GB9208790.7 1992-04-23

Publications (1)

Publication Number Publication Date
WO1993022321A1 true WO1993022321A1 (fr) 1993-11-11

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4950775A (en) * 1985-10-11 1990-08-21 University Of California Antihypercholesterolemic compounds and synthesis thereof
WO1991000280A1 (fr) * 1989-07-04 1991-01-10 British Bio-Technology Limited 6-(hydronaphtyl-1-ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones et les hydroxy acides correspondants
WO1993002089A1 (fr) * 1991-07-22 1993-02-04 British Bio-Technology Limited Procede de couplage de cetophosphanate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4950775A (en) * 1985-10-11 1990-08-21 University Of California Antihypercholesterolemic compounds and synthesis thereof
WO1991000280A1 (fr) * 1989-07-04 1991-01-10 British Bio-Technology Limited 6-(hydronaphtyl-1-ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones et les hydroxy acides correspondants
WO1993002089A1 (fr) * 1991-07-22 1993-02-04 British Bio-Technology Limited Procede de couplage de cetophosphanate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE no. 5, 1966, PARIS FR pages 1707 - 1713 G. STURTZ 'Action de bromo-1 acétyléniques sur les phosphites dialcoyliques sodés. Préparations de beta-cétophosphonates à longue chaine.' *

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AU4265593A (en) 1993-11-29
GB9208790D0 (en) 1992-06-10

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