WO2004113314A1 - Nouveaux esters de boronate - Google Patents

Nouveaux esters de boronate Download PDF

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Publication number
WO2004113314A1
WO2004113314A1 PCT/IN2004/000175 IN2004000175W WO2004113314A1 WO 2004113314 A1 WO2004113314 A1 WO 2004113314A1 IN 2004000175 W IN2004000175 W IN 2004000175W WO 2004113314 A1 WO2004113314 A1 WO 2004113314A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
aryl
alkyl
carbons
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
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PCT/IN2004/000175
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English (en)
Inventor
Ramakrishan Melarkode
Sanjay Tiwari
Shrikumar Suryanarayan
Anand Khedkar
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Biocon Ltd
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Biocon Ltd
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Filing date
Publication date
Application filed by Biocon Ltd filed Critical Biocon Ltd
Publication of WO2004113314A1 publication Critical patent/WO2004113314A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila and more particularly to compounds of formula II which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin. BACKGROUND OF THE INVENTION
  • Ri and R 2 are independently chosen alkyl of one to three carbons and R 3 is alkyl of from 1 to 8 carbon atoms, alternatively compounds of formula la,
  • ⁇ and R 2 are independently chosen from alkyl of one to three carbons, phenyl or Ri and R 2 taken together as - (CH2)n- wherein n is 4 or 5 and R 3 is alkyl of from 1 to 8 carbon atoms and also compounds of Formula lb
  • R x and R 2 are alkyl of from 1-5 carbons and R 3 is as defined above is a valuable structural element for synthesizing compounds, which are known as ant hypercholesterolemic agents having an inhibitory effect on HMG-CoA reductase.
  • EP 0 319 847 describes a process for the preparation of compounds of formula 1 starting from L-Malic acid. This process, however, suffers from the fact that the process is not industrially scalable and also possesses purification problems due to the non- crystalline nature of the intermediates.
  • US 5,998,633 describes a process for the preparation of protected esters of 3,4-dihydroxy butyric acid from a carbohydrate moiety which is transformed into the desired 3,4-dihydroxy butanoic acid derivatives in about 4 steps.
  • the 3,4-dihydroxy butanoic acid derivative is then functionalized into compounds of formula I involving a multiple number of steps.
  • Ar ' unsubstituted or substituted aryl or heteroaryl
  • R 3 alkyl from 1 to 8 carbons, aryl or aralkyl
  • the present invention also provides for a process for the manufacture of compounds of formula II
  • Ar unsubstituted or substituted aryl or heteroaryl
  • R 3 alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of:
  • the compound of formula II is oxidized to a compound of formula VIII, where R 3 is alkyl from 1 to 8 carbons, aryl or aralkyl and Ar is unsubstituted or substituted aryl or heteroaryl using pyridinium chloro chromate or DMSO/oxalyl chloride.
  • Formula IX The compound of formula IX is further converted to a compound of formula VII, where R 3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl.
  • Compound of formula II serves as a good intermediate for the synthesis of important substrates, which are useful in the synthesis of statins.
  • Compound of formula II can be converted into a facile leaving group by treating with tosyl chloride, methane sulfonyl chloride and the resulting intermediate can be displaced with cyanide to give compounds of formula VII.
  • Compound of formula II can be converted to formula IX by reacting with aqueous HBr solution or by reaction with triphenyl phosphine and CBr 4 which is then converted to compound of formula VII.
  • Compound of formula II can be oxidized using standard procedures to give a compound of formula VIII.
  • the present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin.
  • Example 4 Synthesis of tert-Butyl 6-triphenylmethyIoxy- 3,5-phenylboranatohexanoate (Formula VI)
  • the crude product from example-3 was dissolved in 100ml of toluene and 5.6g of phenyl boronic acid was added. Water was removed by azeotropic distillation over a period of 3h.
  • the reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give lOg of the title product.
  • Example 5 Synthesis of tert-butyl 6-hydroxy-3,5- (phenylboranato)hexanoate (Formula II)
  • Rl and R2 are alkyl 1 to 3 carbons
  • R3 is alkyl from 1 to 8 carbons
  • Rl and R2 are alkyl from 1 to 5 carbons
  • R 3 is alkyl from 1 to 8 carbons

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

Abstract

La présente invention porte sur des dérivés de dihydroxy hexanoate optiquement actifs, sur des esters de boronate de formule (IIa) qui sont utiles comme intermédiaires dans la synthèse des inhibiteurs de l'enzyme HMG-CoA tels que l'atorvastatine, la cérivastatine, la rosuvastatine, la pitavastatine, la fluvastatine. Ar = aryle ou hétéroaryle non substitué ou substitué, R3 = alkyle contenant de 1 à 8 atomes de carbone, aryle ou aralkyle, R4 = O, OH, CN ou un halogène et a = une liaison unique ou une double liaison.
PCT/IN2004/000175 2003-06-23 2004-06-18 Nouveaux esters de boronate Ceased WO2004113314A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN508MA2003 2003-06-23
IN508/MAS/2003 2003-06-23

Publications (1)

Publication Number Publication Date
WO2004113314A1 true WO2004113314A1 (fr) 2004-12-29

Family

ID=33524014

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2004/000175 Ceased WO2004113314A1 (fr) 2003-06-23 2004-06-18 Nouveaux esters de boronate

Country Status (1)

Country Link
WO (1) WO2004113314A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7416865B2 (en) 2000-05-09 2008-08-26 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7442811B2 (en) 2002-06-17 2008-10-28 Astrazeneca Uk Limited Process for the preparation of dioxane acetic acid esters
KR100933172B1 (ko) 2007-11-30 2009-12-21 씨제이제일제당 (주) 아토르바스타틴 칼슘염의 개선된 제조방법
US7642363B2 (en) 2000-07-19 2010-01-05 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
US7718812B2 (en) 2001-12-27 2010-05-18 Astrazeneca Uk Limited Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates
US7879585B2 (en) 2006-10-02 2011-02-01 Codexis, Inc. Ketoreductase enzymes and uses thereof
JP2015513556A (ja) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． 新規なスタチン中間体、並びにこれを用いたピタバスタチン、ロスバスタチン、セリバスタチン及びフルバスタチンの製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4598089A (en) * 1983-06-22 1986-07-01 Hoffmann-La Roche Inc. Leucine derivatives
US4983746A (en) * 1984-12-21 1991-01-08 Hoffmann-La Roche Inc. Oxetanones and process for their production

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4598089A (en) * 1983-06-22 1986-07-01 Hoffmann-La Roche Inc. Leucine derivatives
US4983746A (en) * 1984-12-21 1991-01-08 Hoffmann-La Roche Inc. Oxetanones and process for their production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EISENREICH ET AL.: "tracer studies with crude U-13C-lipid mixtures: biosynthesis of the lipase inhibitor lipstatin", J. BIOL. CHEM., vol. 272, no. 2, January 1997 (1997-01-01), pages 867 - 874 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7416865B2 (en) 2000-05-09 2008-08-26 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7732171B2 (en) 2000-05-09 2010-06-08 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7888083B2 (en) 2000-05-09 2011-02-15 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7642363B2 (en) 2000-07-19 2010-01-05 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
US7989643B2 (en) 2000-07-19 2011-08-02 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US7718812B2 (en) 2001-12-27 2010-05-18 Astrazeneca Uk Limited Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates
US7442811B2 (en) 2002-06-17 2008-10-28 Astrazeneca Uk Limited Process for the preparation of dioxane acetic acid esters
US7879585B2 (en) 2006-10-02 2011-02-01 Codexis, Inc. Ketoreductase enzymes and uses thereof
US8273547B2 (en) 2006-10-02 2012-09-25 Codexis, Inc. Engineered ketoreductases and methods for producing stereoisomerically pure statins
US8617864B2 (en) 2006-10-02 2013-12-31 Codexis, Inc. Polynucleotides encoding ketoreductases for producing stereoisomerically pure statins and synthetic intermediates therefor
KR100933172B1 (ko) 2007-11-30 2009-12-21 씨제이제일제당 (주) 아토르바스타틴 칼슘염의 개선된 제조방법
JP2015513556A (ja) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． 新規なスタチン中間体、並びにこれを用いたピタバスタチン、ロスバスタチン、セリバスタチン及びフルバスタチンの製造方法

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