WO1994007888A1 - Composes chiraux et leur utilisation - Google Patents

Composes chiraux et leur utilisation Download PDF

Info

Publication number
WO1994007888A1
WO1994007888A1 PCT/GB1993/002008 GB9302008W WO9407888A1 WO 1994007888 A1 WO1994007888 A1 WO 1994007888A1 GB 9302008 W GB9302008 W GB 9302008W WO 9407888 A1 WO9407888 A1 WO 9407888A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
hydroxy
preparation
lactone
Prior art date
Application number
PCT/GB1993/002008
Other languages
English (en)
Inventor
Stanley Michael Roberts
Horacio F. Olivo
Raymond Mccague
Original Assignee
Chiroscience Limited
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
Priority claimed from GB929220253A external-priority patent/GB9220253D0/en
Priority claimed from GB939308239A external-priority patent/GB9308239D0/en
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to AU48291/93A priority Critical patent/AU4829193A/en
Publication of WO1994007888A1 publication Critical patent/WO1994007888A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/707—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a three- to five-membered ring

Definitions

  • This invention relates to chiral compounds and their use, specifically as synthons in the preparation of therapeutic agents.
  • Mevinic acids such as co pactin and mevinolin have been shown to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. Structure-activity relationships have revealed that the hydroxy-lactone moiety of such compounds is essential for biological activity. Consequently, a great amount of effort has been directed toward the synthesis of the enantiomerically pure hydroxy- lactone moiety and simple derivatives.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • the starting material shown in the Reaction Scheme i.e. the compound of formula I, is the (+)-enantiomer of an adduct disclosed as a racemate by Lubineau et aJL, Tet.
  • the mixture of diastereoiso ers is obtained bywater-promoted hetero-Diels-Alder cycloaddition of glyoxylic acid with cyclopentadiene, and rearrangement of the bicyclic olefinic adduct, yielding endo-( ⁇ )-i and exo-hydroxylactones in a 4:1 ratio.
  • the major compound may be purified by column chromatography or by recrystallisation from extraction liquors. This racemic hydroxylactone has been used as a synthon in the synthesis of sesbanimides; see Grieco et aJL, J. C. S. Chem. Comm. (1992) 368.
  • MacKeith et a_l J. Chem. Soc. Perkin Trans. 1 (1993) 313, disclose resolution of the hydroxylactone by biotransfor ation and the use of one enantiomer to prepare the anti-HIV agent Carbovir via an enantiomer of the versatile synthon 2-hydroxy-3-(hydroxymethyl)cyclopentene (see formula-' III) .
  • the resolution and use of the hydroxylactones are also the subject of International Patent Application No. PCT/GB93/00826.
  • the compound of formula III shown in the Reaction Scheme is also disclosed, but as a minor product, difficult to separate from other enantiomers, of the Prins reaction between cyclopentene and paraformaldehyde. Se Saville- Stones et al , J. Chem. Soc. Perkin Trans. I (1991) 2603-4 and also WO-A-9218444.
  • the bicyclic hydroxylactone can be used as a synthon in the preparation of optically-pure hypocholestemic agents, e.g. via the key hydroxylactone described above. Synthetic routes by which this may be achieved are shown in the Reaction Scheme.
  • the intermediates of formulae V and VI at least are novel.
  • the Reaction Scheme I shows stereochemistry appropriate to the preparation of HMG-CoA reductase inhibition.
  • Z provides this activity or comprises one or more carbon atoms such that this activity can be introduced by subsequent synthetic steps, but the nature of Z is not critical to the chemistry that is involved. Accordingly, Z may be any organic group, but usually contains at least one bond other than C-C or C-H. Description of the Invention
  • Z is a functionalised single C atom: more specific examples are CH 2 OR, R being H or alkyl, such as CH 2 OH (as in the particular Example herein and in the known hydroxylactone) , CH 2 Hal such as CH 2 Br, CHO or an ethylenically-unsaturated group such as vinyl or ⁇ -alkenyl.
  • Known blceking groups may be used, as necessary or desired.
  • steps a,, a 2 and a 3 each involve introduction of a hydroxyl function by electrophilic or nucleophilic addition onto a double bond with the desired stereochemistry. This may be carried out following hydroboration, or by halohydrin formation followed by reductive removal of the halogen. Alternatively, and as illustrated in the Example, the double bond may be converted to the epoxide which is then reduced.
  • Steps b, and b 2 are also parallel. They may be conducted by lactone cleavage (hydrolysis or reduction) then oxidation of the allylic hydroxyl group, e.g. with pyridinium chlorochromate or tetrapropylammonium per- ruthenate/N-methylmorpholine N-oxide.
  • Step c. is described by MacKeith et a and is the subject of International Patent Application No. PCT/GB93/00826. Step c 2 is parallel to step c r
  • Steps d- j and d 2 each involve selective oxidation of a secondary hydroxyl function.
  • activated manganese dioxide is a known reagent selective for the allylic hydroxyl.
  • suitable protecting groups are trialkylsilyl and acyl. Protecting groups may be introduced as necessary in other steps, and then removed, if desired, each by conventional means.
  • step e involves Baeyer-Villiger oxidation. Again, this may be conducted by generally known procedures.
  • the present invention provides processes for converting a single enantiomer bicyclic hydroxylactone into a (S-lactone that is useful as a synthetic intermediate for cholesterol-lowering agents that are inhibitors of HMG-CoA reductase.
  • the group Z may be introduced such that this activity is obtained directly, e.g. into formula V or VI, as described above, or at any other stage illustrated herein. Note that, for these purposes, the enantiomer used is opposite to that appropriate for the synthesis of carbocyclic nucleosides corresponding to the natural configuration.
  • Example illustrates the invention and, in particular, compounds V and VI and steps c,, d- , a 3 and e.
  • Diol (III) is selectively monoprotected with TBDMSC1 in CH 2 C1 2 , using DMAP and triethylamine (70%) , as described by Chaudhury et a ⁇ l, Tet. Lett. (1979) 99.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des 4-hydroxy-δ-lactones sont utiles comme intermédiaires dans la préparation d'inhibiteurs de l'enzyme (HMG-CoA réductase) limitant le taux dans la biosynthèse du cholestérol. Ces composés sont préparés à partir de synthons de la formule (A) dans laquelle soit Y représente H et -^_-^_-^_ est une liaison double ou époxyde, soit Y représente OH éventuellement bloqué (au dessus de l'anneau, opposé à Z) et -^_-^_-^_ est une liaison simple; et Z représente un groupe organique.
PCT/GB1993/002008 1992-09-25 1993-09-27 Composes chiraux et leur utilisation WO1994007888A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48291/93A AU4829193A (en) 1992-09-25 1993-09-27 Chiral compounds and their use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB929220253A GB9220253D0 (en) 1992-09-25 1992-09-25 Cyclopentenes
GB9220253.0 1992-09-25
GB9308239.4 1993-04-21
GB939308239A GB9308239D0 (en) 1993-04-21 1993-04-21 Chiral compounds and their use

Publications (1)

Publication Number Publication Date
WO1994007888A1 true WO1994007888A1 (fr) 1994-04-14

Family

ID=26301685

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/002008 WO1994007888A1 (fr) 1992-09-25 1993-09-27 Composes chiraux et leur utilisation

Country Status (2)

Country Link
AU (1) AU4829193A (fr)
WO (1) WO1994007888A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8404461B2 (en) 2009-10-15 2013-03-26 SK Biopharmaceutical Co. Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester
US8501436B2 (en) 2009-06-22 2013-08-06 Sk Biopharmaceuticals Co. Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4474971A (en) * 1982-09-29 1984-10-02 Sandoz, Inc. (Tetrahydropyran-2-yl)-aldehydes
EP0469480A2 (fr) * 1990-08-01 1992-02-05 Hoechst Aktiengesellschaft Procédé pour la préparation stéréosélective des delta lactones substituées à 5 et leur utilisation
FR2669031A1 (fr) * 1990-11-09 1992-05-15 Rhone Poulenc Sante Procede de preparation de derives du tetrahydropyranne.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4474971A (en) * 1982-09-29 1984-10-02 Sandoz, Inc. (Tetrahydropyran-2-yl)-aldehydes
EP0469480A2 (fr) * 1990-08-01 1992-02-05 Hoechst Aktiengesellschaft Procédé pour la préparation stéréosélective des delta lactones substituées à 5 et leur utilisation
FR2669031A1 (fr) * 1990-11-09 1992-05-15 Rhone Poulenc Sante Procede de preparation de derives du tetrahydropyranne.

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
CHEM. PHARM. BULL., vol. 39, no. 10, 1991, pages 2702 - 2705 *
CHEMICAL ABSTRACTS, vol. 114, no. 1, 7 January 1991, Columbus, Ohio, US; abstract no. 6104f, page 601; column R; *
CHEMICAL ABSTRACTS, vol. 116, no. 13, 30 March 1992, Columbus, Ohio, US; abstract no. 129459z, page 948; column L; *
HANS PAULSEN ET.AL., CHEMISCHE BERICHTE, vol. 114, 1981, WEINHEIM, pages 346 - 358 *
J. CHEM. SOC., CHEM . COMMUN., vol. 17, 1990, pages 1178 - 1179 *
KEITH BIGGADIKE ET. AL., JOURNAL OF THE CHEMICAL SOCIETY. CHEMICAL COMMUNICATIONS, no. 4, 15 February 1987 (1987-02-15), pages 251 - 254 *
KEITH BIGGADIKE ET. AL., JOURNAL OF THE CHEMICAL SOCIETY. PERKIN TRANSACTIONS 1, no. 3, March 1988 (1988-03-01), pages 549 - 554 *
LISE-LOTTE GUNDERSEN ET. AL., ACTA CHIMICA SCANDINAVICA, vol. 46, no. 8, August 1992 (1992-08-01), pages 761 - 771 *
SEIICHI TAKANO ET.AL., JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY. SYNTHESIS., no. 7, 1989, STUTTGART, pages 539 - 541 *
SEONG JIN KIM ET. AL., TETRAHEDRON LETTERS, vol. 29, no. 44, 1988, OXFORD, pages 5613 - 5616 *
SERAFIN VALVERDE ET. AL., THE JOURNAL OF ORGANIC CHEMISTRY, vol. 57, no. 5, 28 February 1992 (1992-02-28), WASHINGTON, pages 1613 - 1615 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501436B2 (en) 2009-06-22 2013-08-06 Sk Biopharmaceuticals Co. Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester
US8404461B2 (en) 2009-10-15 2013-03-26 SK Biopharmaceutical Co. Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester
US9068207B2 (en) 2009-10-15 2015-06-30 Sk Biopharmaceuticals Co. Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester
US9434970B2 (en) 2009-10-15 2016-09-06 Sk Biopharmaceuticals Co., Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester

Also Published As

Publication number Publication date
AU4829193A (en) 1994-04-26

Similar Documents

Publication Publication Date Title
KR100511533B1 (ko) 키랄 중간체, 그의 제조방법 및 그를 이용한 HMG-CoA환원저해제의 제조방법
Danishefsky et al. Chelation-controlled facially selective cyclocondensation reactions of chiral alkoxy aldehydes: Syntheses of a mouse androgen and of a carbon-linked disaccharide
Hoffmann et al. Stereoselective synthesis of alcohols, XXXI: Stereoselective C C bond formation using chiral Z‐pentenylboronates
Tanis et al. Furans in synthesis. 8. Formal total syntheses of (.+-.)-and (+)-aphidicolin
Miller et al. Synthesis of optically active butenolides via chromium alkoxycarbene complexes: total synthesis of (+)-tetrahydrocerulenin and two butenolides from the marine sponge Plakortis lita
Mulzer et al. Stereoselective additions to carboxylic acid dianions and β-lactone substituted ester enolates
US5430171A (en) T-butyl (R)-(-)-4-cyano-3-hydroxybutyrate and process for preparing the same
Srinivas et al. Stereoselective total synthesis of (+)-varitriol
US6278001B1 (en) Method for preparing (+) compactin and (+) mevinolin analog compounds having a β-hydroxy-δ-lactone grouping
Katagiri et al. Facile synthesis of the carbocyclic analogue of β-ribofuranosyl-malonate, new synthon for carbocyclic C-nucleoside formation by retrograde aldol CC bond fission
EP0044158A1 (fr) Dérivés de l'imidazolidin-2-one optiquement actifs et leur préparation
WO1994007888A1 (fr) Composes chiraux et leur utilisation
GB2030144A (en) Keto-bicyclooctanes
EP0373949B1 (fr) Mono-esters d'acides dicarboxyliques, leur préparation et leur utilisation
Kumar et al. Synthesis of intermediates for the lactone moiety of mevinic acids via tellurium chemistry
EP0164049B1 (fr) Procédé de préparation d'inhibiteurs de la HMG-CoA réductase contenant un élément 3,5-dihydroxypentanoique
Hill et al. Stereochemistry of valine and isoleucine biosynthesis II. Absolute configuration of (−) α, β-dihydroxyisovaleric acid and (−) α, β-dihydroxy-β-methylvaleric acid
EP0585104B1 (fr) Méthode de préparation d'un composé hydrocarboné monocyclique saturé et un intermédiaire pour celle-ci
EP1048643B1 (fr) Procédé de préparation d'époxydes chiraux
Garcia-Valverde et al. Lithium derivatives from enantiomerically pure 2-(2′-haloethyl) dioxolanes: Formation and use as chiral propanal homoenolate synthons
US4739082A (en) Enantiomerically pure mono acetal-protected diols, their preparation and use
JPS6393742A (ja) ビシクロ〔４．２．０〕オクタ−２−エン−７−オンの鏡像異性体、その誘導体類およびビシクロ〔４．２．０〕オクタン誘導体類の新規合成方法ならびにその中間体
EP0515142A1 (fr) Epoxydes optiquement actifs et procédé pour leur préparation
US5840923A (en) Chiral cyclopentene derivatives and their preparation
EP0627396B1 (fr) Dérivés du cyclohexanediol

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR BY CA CZ FI GB HU JP KP KR KZ LK LV MG MN MW NO NZ PL RO RU SD SK UA US VN

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 PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA