[go: up one dir, main page]

WO1993010129A1 - Intermediaires et procede de preparation d'acides meviniques - Google Patents

Intermediaires et procede de preparation d'acides meviniques Download PDF

Info

Publication number
WO1993010129A1
WO1993010129A1 PCT/GB1992/002004 GB9202004W WO9310129A1 WO 1993010129 A1 WO1993010129 A1 WO 1993010129A1 GB 9202004 W GB9202004 W GB 9202004W WO 9310129 A1 WO9310129 A1 WO 9310129A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
compound
general formula
coc
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/GB1992/002004
Other languages
English (en)
Inventor
Christopher Norman Lewis
Richard Simon Todd
Christopher Mark Blackwell
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by British Bio Technology Ltd filed Critical British Bio Technology Ltd
Publication of WO1993010129A1 publication Critical patent/WO1993010129A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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 primarily to novel compounds which are useful intermediates in the synthesis of a range of mevinic acids and novel synthetic procedures relating thereto.
  • EP-A-0251625 discloses compounds of structure
  • R 1 is a group of formula CH 2 OH, CH 2 OCOR 3 , CO 2 R 4 or CONR 6 R 7 wherein R 3 , R 4 , R 6 , and R 7 can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.
  • the compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations.
  • a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.
  • 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,6'R)-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 (4)
  • WO-A-9100280 discloses the synthesis of a precursor of (4) via a reagent (5) containing chiral centre (a) thus
  • WO-A-9100280 further describes a procedure for the introduction of the second chiral centre, b, via chiral reduction of the keto function in the introduced side chain to give (9) thus
  • US-A-4950775 discloses that (5) is prepared with a purity of approximately 98%, with 2% comprising the undesired enantiomer.
  • the chiral reduction step of (8) to (9) described in WO-A-9100280 also produces undesired isomers as impurities, with up to 5% of the thus introduced hydroxy function being of the undesired configuration.
  • the dihydroxy compound (9) produced by the procedures disclosed and described in WO-A-9100280 is thus contaminated with up 10% impurities consisting of undesired diastereoisomers.
  • R 1 represents a hydrogen atom, or a COC 1-8 alkyl, COC 3-8 cycloalkyl, COC 3-8 cycloalkyl (C 1-8 alkyl), COC 2-8 alkenyl, COC 1-6 alkylphenyl, COC 1-6 alkyl (substituted phenyl), an Si(R 6 R 7 R 8 ) group or a suitable protecting group;
  • R 2 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 or C 2-5 alkynyl group substituted with a phenyl or substituted phenyl group, or an osi(R 6 R 7 R 8 ) group, C 1-8 alkyl-OSi(R 6 R 7 R 8 ), hydroxy group protected by a suitable protecting group or a hydroxy (C 1-8 alkyl) group protected by a suitable protecting group;
  • R 3 represents a hydrogen atom or a C 1-8 alkyl group
  • R 4 represents a hydrogen atom, or a methyl or ethyl group
  • R 5 represents a C 1-5 alkyl group
  • R 6 , R 7 , and R 8 each independently represents a C 1-8 alkyl group or a phenyl 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.
  • C 1-8 alkyl refers to straight chain or branched chain hydrocarbon groups having from one to eight carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • C 1-5 alkyl and C 1- 6 alkyl refer to similar groups having from one to five and one to six carbon atoms respectively.
  • C 2-8 alkenyl refers to straight chain or branched chain hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable.
  • C 2-5 alkenyl refers to similar groups having from two to five atoms.
  • C 2-8 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, propynyl, butynyl and pentynyl.
  • C 2-5 alkynyl refers to similar groups having from two to five carbon atoms.
  • hydroxy C 1-8 alkyl refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group. Illustrative of such alkoxy groups are hydroxyethyl and hydroxy-propyl.
  • C 3 -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.
  • halogen or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
  • substituted phenyl means a phenyl group substituted with up to four substituents, each of which may be C 1-6 alkyl, C 1-6 alkoxy, hydroxy, thiol, amino, halo, trifluoromethyl or nitro.
  • suitable protecting group refers to a group temporarily attached to a reactive centre in a multifunctional molecule. 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.
  • R 1 represents a COC 1-8 alkyl, an Si(R 6 R 7 R 8 ) group, or a suitable protecting group
  • R 2 represents a hydrogen atom , C 1-8 alkyl , C 2 -8 alkenyl, an OSi(R 6 R 7 R 8 ) group, a C 1-8 alkyl-OSi(R 6 R 7 R 8 ) group, a hydroxy group protected by a suitable protecting group or a hydroxy (C 1-8 ) alkyl group protected by a suitable protecting group
  • R 3 represents a hydrogen atom or a methyl group
  • R 4 represents a methyl group
  • R 5 represents a methyl group
  • R 6 represents a methyl group
  • R 7 represents a methyl group
  • R 8 represents a t-butyl group
  • a is optionally a single
  • Particularly preferred compounds include: 1. Methyl(1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7 , - ⁇ 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))- 3',5'-bis(t-butyldimethylsiloxy)heptanoate. 2.
  • R 3 , R 4 and R 5 are as defined as in general formula I;
  • R 9 represents a hydrogen atom, a COC 1-8 alkyl, COC 3-8 cycloalkyl, COC 3-8 cycloalkylC 1-8 alkyl, COC 2-8 alkenyl, COC 1-6 alkylphenyl, COC 1-6 alkyl (substituted phenyl) group or a suitable protecting group;
  • R 10 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 or C 2-5 alkynyl group substituted with a phenyl or substituted phenyl group, a hydroxy group, a hydroxy (C 1-8 alkyl) group, or a hydroxy group protected by a suitable protecting group or a hydroxy (C 1-8 alkyl) group protected by a suitable protecting group; (a) with
  • Suitable nitrogenous bases for use in step (a) are hexamethyldisilazane , imidazole or pyridine and suitable solvents are polar solvents such as dichlorome thane, acetonitrile or dimethyl formamide. It may also be advantageous to employ a catalyst such as dimethylaminopyridine.
  • a suitable base for use in step (b) is 2,6-lutidine although other bases could be used and a suitable solvent is a polar solvent such as dichloromethane or chloroform. The reaction takes place at a temperature of -10 to 40°C, preferably 0 to 25°C.
  • diastereoisomers of compounds of general formula II have very similar mobilities in a variety of chromatographic systems and consequently it has proved very difficult to prepare compounds of general formula II in high purity. Multiple recrystallisation steps have had to be employed with concomitant loss of material .
  • diastereoisomers of compounds of general formula I have marked differences in mobility in a range of chromatographic systems and can therefore be separated easily. It is therefore possible to use compounds of formula I in place of compounds of formula II in syntheses where separate isomers are required.
  • An additional valuable property of compounds of general formula I is that treatment with a desilylating agent leads to desilylation followed by rapid lactonisation to the corresponding mevinic acid.
  • R 3 , R 4 , R 9 , R 10 , a, b and c are as defined above the process comprising treating a compound of general formula I as defined above with an acidic desilylating agent.
  • An acidic solution of fluoride ions will act as a desilylating agent and a suitable reagent for use in this case is a solution of hydrofluoric acid in acetonitrile.
  • the reaction should preferably be carried out at a temperature between 0°C and 50°C.
  • a process for the conversion of a mixture of isomers of general formula II to a selected isomer of general formula V comprising converting the mixture of isomers of general formula II to a mixture of isomers of general formula I; separating out the required isomer of general formula I and converting that isomer to a compound of general formula V.
  • the following examples which are for the purposes of illustration only, show the synthesis of a compound of general formula I from a compound of general formula II and a compound of general formula III, the separation of diastereoisomers of a compound of general formula I, and the preparation of an diastereoisomerically pure compound of general formula V.
  • the (3'S, 5'S) isomer (8.3 mg; 0.012 mmol) produced above was stirred in a mixture of 48% hydrofluoric acid and acetonitrile (1:9) at room temperature for 90 minutes. Solid sodium hydrogen carbonate was added carefully, then the reaction diluted with water and extracted with ethyl acetate (3 x). The organic layers were dried and evaporated to give the lactone as a white solid.
  • the (3'R, 5'R) isomer (6.35 g; 9.0. mmol) produced in a manner similar to that described above was stirred in a mixture of 48% hydrofluoric acid and acetonitrile (1:19, 120 mL) at room temperature for 90 minutes. Saturated aqueous sodium hydrogen carbonate solution was added carefully until effervescence ceased, then the reaction mixture extracted with ethyl acetate (4 ⁇ 50 mL). The organic layers were washed with brine (50 mL), dried and evaporated to give a white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

L'invention concerne des composés de la formule (I) dans laquelle R1 représente un atome d'hydrogène, ou un alkyle COC¿1-8?, un cycloalkyle COC3-8, un cycloalkyle COC3-8(C1-8alkyle), un alcényle COC2-8, un alkylphényle COC1-6, un alkyle COC1-6(phényle substitué), un groupe Si(R?6R7R8¿) ou un groupe protecteur approprié. R2 représente un atome d'hydrogène, alkyle C¿1-8?, alcényle C2-8, un groupe alkynyle C2-8, ou un alkyle C1-5, alcényle C2-5 ou un groupe alkynyle C2-5 substitué à un phényle ou un groupe phényle substitué, ou un groupe OSi(R?6R7R8¿), C¿1-8?alkyl OSi(R?6R7R8¿), un groupe hydroxy protégé par un groupe protecteur approprié ou un groupe hydroxy(C¿1-8?)alkyle protégé par un groupe protecteur approprié; R?3¿ représente un atome d'hydrogène ou un groupe alkyle C¿1-8; R?4 représente un atome d'hydrogène, ou un groupe méthyle ou éthyle; R5 représente un groupe alkyle C¿1-5?; R?6, R7 et R8¿ représentent indépendamment l'un de l'autre un groupe alkyle C¿1-8? ou un groupe phényle; a, b, c sont chacun indépendamment une liaison simple ou double sauf si a et c sont des liaisons doubles, b est alors une liaison simple. Ces composés sont utilisés comme intermédiaires dans la préparation d'inhibiteurs de réductase HMG-CoA dérivés de l'acide mévinique.
PCT/GB1992/002004 1991-11-11 1992-11-02 Intermediaires et procede de preparation d'acides meviniques Ceased WO1993010129A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9123933.5 1991-11-11
GB919123933A GB9123933D0 (en) 1991-11-11 1991-11-11 Compounds

Publications (1)

Publication Number Publication Date
WO1993010129A1 true WO1993010129A1 (fr) 1993-05-27

Family

ID=10704434

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1992/002004 Ceased WO1993010129A1 (fr) 1991-11-11 1992-11-02 Intermediaires et procede de preparation d'acides meviniques

Country Status (4)

Country Link
AU (1) AU2883792A (fr)
GB (1) GB9123933D0 (fr)
WO (1) WO1993010129A1 (fr)
ZA (1) ZA928451B (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0299656A1 (fr) * 1987-07-10 1989-01-18 Merck & Co. Inc. Procédé pour l'alkylation de l'alpha-C du groupe 8-acyle de mévinoline et de ses analogues
EP0331240A2 (fr) * 1988-02-29 1989-09-06 Merck & Co. Inc. Intermédiaires et procédés pour inhibiteurs de bêta 6-hydroxyméthyl HMG-COA réductase
US4950775A (en) * 1985-10-11 1990-08-21 University Of California Antihypercholesterolemic compounds and synthesis thereof

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
EP0299656A1 (fr) * 1987-07-10 1989-01-18 Merck & Co. Inc. Procédé pour l'alkylation de l'alpha-C du groupe 8-acyle de mévinoline et de ses analogues
EP0331240A2 (fr) * 1988-02-29 1989-09-06 Merck & Co. Inc. Intermédiaires et procédés pour inhibiteurs de bêta 6-hydroxyméthyl HMG-COA réductase

Also Published As

Publication number Publication date
AU2883792A (en) 1993-06-15
ZA928451B (en) 1993-09-27
GB9123933D0 (en) 1992-01-02

Similar Documents

Publication Publication Date Title
EP0216785B1 (fr) Analogues indenes de mevalonolactones et leurs derives
EP0785205B1 (fr) 2-silyloxytetrahydrothienopyridine, son sel, et son procede de production
US4611067A (en) Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein
EP1340752B1 (fr) Procédé de production de statines semi-synthétiques via de nouveaux intermédiaires
EP0331524B1 (fr) Synthèse de trichostatines
CA2713009C (fr) Carboxylate de ((2s,4r)-4,6-dihydroxytetrahydro-2h-pyran-2-yl)methyle et son procede de fabrication
KR20010040760A (ko) 심바스타틴의 제조 방법
US4677211A (en) Preparation of lactones
US5874595A (en) Method for the preparation of baccatin III and derivatives thereof from 10-deacetylbaccatin III
KR20010074856A (ko) 선택적인 락톤화 방법
US4571428A (en) 6-Substituted-4-hydroxy-tetrahydropyran-2-ones
EP0349063B1 (fr) Inhibiteurs d'HMG-Co-A réductase oxygénés en position 5
US4645854A (en) Process for preparing HMG-CoA reductase inhibitors with a 3,5-dihydroxypentanoate subunit
EP0296810B1 (fr) Produits intermédiaires et procédés pour la préparation des inhibiteurs de HMG-COA-réductase
US4625039A (en) 4-trisubstituted silyl protected hydroxy-6-oxo-tetrahydropyran-2-yl-aldehyde intermediates
US4539153A (en) Method of preparing 1 α-hydroxyvitamin D and 1 α-hydroxyprevitamin D compounds, and adducts of a previtamin D or tachysterol compound with a suitable dienophile
EP0164049B1 (fr) Procédé de préparation d'inhibiteurs de la HMG-CoA réductase contenant un élément 3,5-dihydroxypentanoique
WO1993010129A1 (fr) Intermediaires et procede de preparation d'acides meviniques
US4940797A (en) Process for synthesis of FK-506 C10-C18 intermediates
EP0609058A2 (fr) Dérivés d'esters du hexahydronaphthalène, leur préparation et leurs applications thérapeutiques
US5650523A (en) Process for the desilylation of a 4-silyloxy-tetrahydro-pyran-2-one
EP0287340B1 (fr) Procédé d'acylation pour la synthèse d'inhibiteurs de HMG-COA réductase
US4866186A (en) Process for the formation of 6-desmethyl-6-exo-methylene derivatives of lovastatin and analogs thereof
EP0306263B1 (fr) Inhibiteurs d'HMG-COA réductase
EP1650211B1 (fr) Procédé de préparation de dérivés d' imidazopyrane

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA