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WO2001004342A1 - Procede de preparation d'exemestane - Google Patents

Procede de preparation d'exemestane Download PDF

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Publication number
WO2001004342A1
WO2001004342A1 PCT/US2000/016298 US0016298W WO0104342A1 WO 2001004342 A1 WO2001004342 A1 WO 2001004342A1 US 0016298 W US0016298 W US 0016298W WO 0104342 A1 WO0104342 A1 WO 0104342A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
dione
present
electron carrier
methyleneandrost
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/US2000/016298
Other languages
English (en)
Inventor
Mark A. Krook
Bradley D. Hewitt
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.)
Pharmacia and Upjohn Co
Original Assignee
Pharmacia and Upjohn Co
Upjohn Co
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 Pharmacia and Upjohn Co, Upjohn Co filed Critical Pharmacia and Upjohn Co
Priority to AU58733/00A priority Critical patent/AU5873300A/en
Publication of WO2001004342A1 publication Critical patent/WO2001004342A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P33/00—Preparation of steroids
    • C12P33/02—Dehydrogenating; Dehydroxylating

Definitions

  • PROCESS TO PREPARE EXEMESTANE BACKGROUND OF THE INVENTION 1.
  • Field of the Invention The present invention is an enzymatic ⁇ '-dehydrogenation of a 6-methylene steroid. 2. Description of the Related Art
  • Biotechnology and Bioengineering, 37, 97-102 (1991) discloses the ⁇ '- dehydrogenation of 6 ⁇ -methylhydrocortisone 21 -acetate by A. simplex in an organic solvent.
  • the steroid of the present invention is not a 6 ⁇ -methyl steroid.
  • US Patent 4,684,610 claims a process for converting 1,2-saturated steroids to 1,2- dehydro steroids by contacting the 1,2-saturated steroid with A. simplex or B. cyclooxydans in the presence of exogenous electron carrier and a water-immiscible aromatic hydrocarbon solvent. No 6-methylene steroids were exemplified.
  • US Patent 4,808,616 discloses the transformation of 6- methyleneandrost-4-ene-3,17-dione to 6-methyleneandrosta-l,4-diene-3,17-dione by nonmicrobial chemical means, using DDQ.
  • the present invention uses biotransformation to accomplish the ⁇ '-dehydrogenation.
  • US Patent 4,990,635 discloses the transformation of 6- methyleneandrost-4-ene-3,17-dione to 6-methyleneandrosta-l,4-diene-3,17-dione by nonmicrobial chemical means.
  • the 2-bromo intermediate is formed followed by debromination.
  • the present invention does not form any 2-bromo intermediates but rather uses biotransformation to accomplish the ⁇ '-dehydrogenation.
  • US Patent 4,876,045 discloses the transformation of 6- methyleneandrost-4-ene-3,17-dione to 6-methyleneandrosta-l,4-diene-3,17-dione by use of Jones reagent.
  • the present invention does not use a chemical process but rather uses a biotransformation to accomplish the ⁇ '-dehydrogenation.
  • US Patent 4,749,649 discloses the use to scavengers of toxic oxygen species in the microbial ⁇ '-dehydrogenation of steroids.
  • SUMMARY OF INVENTION Disclosed is a process for the preparation of 6-methyleneandrosta-l,4-diene-3,17- dione (UT) which comprises contacting 6-methyleneandrost-4-ene-3,17-dione (H) with ⁇ 1 - dehydrogenating enzymes of A. simplex in the presence of a water-immisible organic solvent and an exogenous electron carrier.
  • the conversion of 6-methyleneandrost-4-ene-3,l 7-dione (H) to 6- methyleneandrosta- 1 ,4-diene-3 , 17-dione (in) with A. simplex can be performed using whole cells or cell free preparations. It is preferred to use whole cells using a two phase system.
  • the non-aqueous phase contains the 6-methyleneandrost-4-en-3,l 7-dione (H), an exogenous electron carrier and a water-immiscible organic solvent.
  • the 6-methyleneandrost-4-en-3,l 7-dione (H) be present in a concentration of from about 10 g/L to about 125 g/L; it is more preferred that the 6-methyleneandrost-4-ene-3,l 7-dione (H) is present in a concentration from about 50 g/L to about 125 g/L.
  • Operable exogenous electron carriers are selected from the group consisting of menadione, menadione bisulfite, 1,4-naphthoquinone, phenazine methosulfate, phenazine ethosulfate and vitamin K-type compounds.
  • the exogenous electron carrier is selected from the group consisting of menadione and 1,4-naphthoquinone; it is more preferred that the exogenous electron carrier is menadione. It is preferred to add the exogenous electron carrier in catalytic amounts, for example, in an amount of from about 3 to about 5% (wt exogenous electron carrier/wt of 6-methyleneandrost-4-ene-3,l 7-dione (IT)). It is more preferred that the exogenous electron carrier is present in an amount of about 4%.
  • Operable water-immiscible organic solvents are selected from the group consisting of toluene, xylene, benzene, heptane, methylene chloride, n-octanol or mixtures thereof and the alike. It is preferred that the water-immiscible organic solvent be toluene. It is preferred that the water-immiscible organic solvent be present in a range of from about 1 to about 99% it is more preferred that the water-immiscible organic solvent is present in a range of from about 60 to about 95%.
  • the aqueous phase contain both catalase and a buffer.
  • a buffer Virtually any buffer which will maintain the pH in the range of from about a low end of pH range 8 to about high end of pH range 9 is operable and these buffers are well known to those skilled in the art.
  • the buffer be phosphate.
  • the aqueous phase is prepared by mixing catalase, the buffer, and a cell concentrate of A. simplex and water.
  • the aqueous phase is preferably added to the briskly agitated non-aqueous phase to begin the bioconversion.
  • the temperature is controlled at about 30° and the pH is controlled between 8.7 and 8.9 by the addition of base, preferably hydroxide, and more preferably sodium hydroxide.
  • the reaction mixture is preferably sparged with both air (about 0.10 SCHF) flow and nitrogen (0.30 SCHF) flow and permitted to react until less than about 0.1% residual 6-methyleneandrost-4-ene-3,l 7-dione (H) remains. If necessary, additional source of enzyme is added to assure completion. When the reaction is complete, the pH control, the air and nitrogen feeds and agitation are turned off and the reaction mixture permitted to settle.
  • the aqueous phase is drawn off from the bottom of the reactor and then the non-aqueous phase is removed. Additional water-immiscible organic solvent is added to the bioconversion vessel, the agitator is again started and the aqueous phase is added. Again the agitation is stopped and the aqueous phase is permitted to settle. The spent aqueous cell layer is discarded and the water-immiscible organic solvent phase is drained from the reactor. The water-immiscible organic solvent phase is filtered to assure cell removal. The clarified filtrate is then concentrated and the desired 6-methyleneandrosta-l,4-diene-3,l 7-dione (in) obtained by means well known to those skilled in the art.
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone.
  • Chromatography column and flash chromatography refers to purification separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • the ratios of solvents used are volume/volume (v/v).
  • the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight volume (wt/v).
  • SCFH refers to standard cubic feet hr.
  • the aqueous phase is prepared as a mixture of catalase (0.015 g), potassium dibasic phosphate (2.2 g), A. simplex cell concentrate (obtained by fermentation, concentrated to contain about 20% dried solids, 50 mL) and water (50 mL).
  • the aqueous phase is added to the briskly agitated toluene mixture (500 RPM) to begin the bioconversion.
  • the temperature is controlled at 30° using a water bath and the pH is controlled between 8.7 and 8.9 using sodium hydroxide (2N) additions.
  • the reaction mixture is sparged with a regulated flow air (0.10 SCFH) and nitrogen (0.30 SCFH) flow, respectively.
  • the mixture is allowed to react until less than 0.1 % residual 6-methyleneandrost-4- ene-3, 17-dione remains. If necessary, more A. simplex cells are added during the reaction to assure completion.
  • the pH control, air feed, nitrogen feed, and agitation are turned off and the aqueous phase is permitted to settle.
  • the aqueous layer is drawn from the bottom of the reactor and then the toluene mixture is removed.
  • toluene 600 mL is added to the bioconversion vessel.
  • the agitator is started and the aqueous cell layer is added.
  • the agitation is stopped and the aqueous phase is allowed to settle.
  • the spent aqueous cell layer is discarded and the toluene extract is drained from the reactor.
  • the two toluene extracts are filtered.
  • the clarified filtrate is then concentrated to about 100 mL.
  • Octane 250 mL is then added over a 30 - 45 minute period at 20-25°.
  • the crystal slurry is cooled to -5 to -10 ° and held for 1 hr.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

La présente invention concerne une Δ1-déshydrogénation de 6-méthylèneandrost-4-ène-3,17-dione (II) destinée à produire un 6-méthylèneandrosta-1,4-diène-3,17-dione (III) utile comme agent pharmaceutique.
PCT/US2000/016298 1999-07-07 2000-06-27 Procede de preparation d'exemestane Ceased WO2001004342A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58733/00A AU5873300A (en) 1999-07-07 2000-06-27 Process to prepare exemestane

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14255499P 1999-07-07 1999-07-07
US60/142,554 1999-07-07

Publications (1)

Publication Number Publication Date
WO2001004342A1 true WO2001004342A1 (fr) 2001-01-18

Family

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Application Number Title Priority Date Filing Date
PCT/US2000/016298 Ceased WO2001004342A1 (fr) 1999-07-07 2000-06-27 Procede de preparation d'exemestane

Country Status (2)

Country Link
AU (1) AU5873300A (fr)
WO (1) WO2001004342A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009034398A1 (fr) * 2007-09-11 2009-03-19 Richter Gedeon Nyrt. Procédé de synthèse de 6-hydroxyméthyl-l,4-androstadiène-3,17-dione
WO2009002510A3 (fr) * 2007-06-25 2009-03-19 Scinopharm Taiwan Ltd Polymorphe cristallin d'exemestane
EP2142561A4 (fr) * 2007-05-04 2010-04-21 Scinopharm Taiwan Ltd Procédé servant à préparer des inhibiteurs de l'aromatase
RU2425052C1 (ru) * 2010-03-04 2011-07-27 Татьяна Степановна Савинова Способ получения 6-метиленандрост-4-ен-3,17-диона из андрост-4-ен-3,17-диона, способ получения 6-метиленандроста-1,4-диен-3,17-диона (эксеместана) с использованием полученного 6-метиленандрост-4-ен-3,17-диона
US8138343B2 (en) 2007-06-25 2012-03-20 Scinopharm Taiwan Ltd. Crystalline polymorph of 7-ethyl-10-hydroxycamptothecin
CN106520890A (zh) * 2016-11-01 2017-03-22 河南甾体生物科技有限公司 11α‑羟基‑16α,17α‑环氧黄体酮脱氢物的制备方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4202841A (en) * 1977-08-25 1980-05-13 Hoffmann-La Roche Inc. D-Homopregnanes
US4272630A (en) * 1979-01-24 1981-06-09 Alig L D-Homosteroids
EP0054810A2 (fr) * 1980-12-23 1982-06-30 Schering Aktiengesellschaft Procédé de préparation de 3-oxo-delta-1,4-stéroides
EP0127294A1 (fr) * 1983-05-16 1984-12-05 The Upjohn Company Deshydrogénation de stéroides
US4524134A (en) * 1982-07-30 1985-06-18 The Upjohn Company Process for preparing 1,2-dehydro steroids
WO1986005813A1 (fr) * 1985-04-03 1986-10-09 Schering Aktiengesellschaft Berlin Und Bergkamen Procede de production de 1-methyle-1,4-androstadiene-3,17-dione
WO1988007092A1 (fr) * 1987-03-12 1988-09-22 The Upjohn Company DESHYDROGENATON-1,2 D'ESTERS STEROIDES 21 A l'AIDE D'A. SIMPLEX
US4808616A (en) * 1985-07-09 1989-02-28 Farmitalia Carlo Erba S.R.L. 6-substituted androsta-1,4-diene-3,17-diones
EP0307134A1 (fr) * 1987-09-11 1989-03-15 FARMITALIA CARLO ERBA S.r.l. Procédé de préparation de dérivés d'androsta-1,4-diène 3,17-dions substitués par un méthylène
WO1996012034A1 (fr) * 1994-10-13 1996-04-25 Poli Industria Chimica S.P.A. Procede microbiologique de preparation de 17 beta-carboxy substitues 3-oxo-4-azasteroides et l'utilisation de tels produits en tant qu'inhibiteurs de l'enzyme 5 alpha-reductase

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4202841A (en) * 1977-08-25 1980-05-13 Hoffmann-La Roche Inc. D-Homopregnanes
US4272630A (en) * 1979-01-24 1981-06-09 Alig L D-Homosteroids
EP0054810A2 (fr) * 1980-12-23 1982-06-30 Schering Aktiengesellschaft Procédé de préparation de 3-oxo-delta-1,4-stéroides
US4524134A (en) * 1982-07-30 1985-06-18 The Upjohn Company Process for preparing 1,2-dehydro steroids
EP0127294A1 (fr) * 1983-05-16 1984-12-05 The Upjohn Company Deshydrogénation de stéroides
WO1986005813A1 (fr) * 1985-04-03 1986-10-09 Schering Aktiengesellschaft Berlin Und Bergkamen Procede de production de 1-methyle-1,4-androstadiene-3,17-dione
US4808616A (en) * 1985-07-09 1989-02-28 Farmitalia Carlo Erba S.R.L. 6-substituted androsta-1,4-diene-3,17-diones
WO1988007092A1 (fr) * 1987-03-12 1988-09-22 The Upjohn Company DESHYDROGENATON-1,2 D'ESTERS STEROIDES 21 A l'AIDE D'A. SIMPLEX
EP0307134A1 (fr) * 1987-09-11 1989-03-15 FARMITALIA CARLO ERBA S.r.l. Procédé de préparation de dérivés d'androsta-1,4-diène 3,17-dions substitués par un méthylène
WO1996012034A1 (fr) * 1994-10-13 1996-04-25 Poli Industria Chimica S.P.A. Procede microbiologique de preparation de 17 beta-carboxy substitues 3-oxo-4-azasteroides et l'utilisation de tels produits en tant qu'inhibiteurs de l'enzyme 5 alpha-reductase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PINHEIRO H M ET AL: "EFFECTS OF SOLVENT MOLECULAR TOXICITY AND MICROENVIRONMENT COMPOSITION ON THE DELTA-1 DEHYDROGENATION ACTIVITY OF ARTHROBACTER-SIMPLEX CELLS", BIOTECHNOLOGY AND BIOENGINEERING, vol. 37, no. 2, 1991, pages 97 - 102, XP002150354, ISSN: 0006-3592 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2142561A4 (fr) * 2007-05-04 2010-04-21 Scinopharm Taiwan Ltd Procédé servant à préparer des inhibiteurs de l'aromatase
JP2010526141A (ja) * 2007-05-04 2010-07-29 シノファーム タイワン，リミテッド アロマタアーゼ阻害剤の製造方法
AU2008248222B2 (en) * 2007-05-04 2013-03-28 Scinopharm Taiwan, Ltd. Process for preparing aromatase inhibitors
WO2009002510A3 (fr) * 2007-06-25 2009-03-19 Scinopharm Taiwan Ltd Polymorphe cristallin d'exemestane
US8138343B2 (en) 2007-06-25 2012-03-20 Scinopharm Taiwan Ltd. Crystalline polymorph of 7-ethyl-10-hydroxycamptothecin
WO2009034398A1 (fr) * 2007-09-11 2009-03-19 Richter Gedeon Nyrt. Procédé de synthèse de 6-hydroxyméthyl-l,4-androstadiène-3,17-dione
RU2425052C1 (ru) * 2010-03-04 2011-07-27 Татьяна Степановна Савинова Способ получения 6-метиленандрост-4-ен-3,17-диона из андрост-4-ен-3,17-диона, способ получения 6-метиленандроста-1,4-диен-3,17-диона (эксеместана) с использованием полученного 6-метиленандрост-4-ен-3,17-диона
CN106520890A (zh) * 2016-11-01 2017-03-22 河南甾体生物科技有限公司 11α‑羟基‑16α,17α‑环氧黄体酮脱氢物的制备方法

Also Published As

Publication number Publication date
AU5873300A (en) 2001-01-30

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