WO2006032970A3 - PROCESS FOR PREPARING 7α-ALKOXYCARBONYL SUBSTITUTED STEROIDS - Google Patents

PROCESS FOR PREPARING 7α-ALKOXYCARBONYL SUBSTITUTED STEROIDS Download PDF

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Publication number
WO2006032970A3
WO2006032970A3 PCT/IB2005/002757 IB2005002757W WO2006032970A3 WO 2006032970 A3 WO2006032970 A3 WO 2006032970A3 IB 2005002757 W IB2005002757 W IB 2005002757W WO 2006032970 A3 WO2006032970 A3 WO 2006032970A3
Authority
WO
WIPO (PCT)
Prior art keywords
alkoxycarbonyl
substrate
reaction
enester
product
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/IB2005/002757
Other languages
French (fr)
Other versions
WO2006032970A2 (en
Inventor
S Zaheer Abbas
Michael Bauer
Marlon V Carlos
Paul David
Thaddeus Franczyk
Chung C Kim
Jon P Lawson
Keith D Maisto
David Mckenzie
Mark Pozzo
Joseph Wieczorek
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 LLC
Original Assignee
Pharmacia LLC
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 LLC filed Critical Pharmacia LLC
Priority to BRPI0515106-6A priority Critical patent/BRPI0515106A/en
Priority to EP05805074A priority patent/EP1794177A2/en
Priority to CA002579954A priority patent/CA2579954A1/en
Priority to JP2007530794A priority patent/JP2008512439A/en
Priority to MX2007002846A priority patent/MX2007002846A/en
Publication of WO2006032970A2 publication Critical patent/WO2006032970A2/en
Publication of WO2006032970A3 publication Critical patent/WO2006032970A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/001—Lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • 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
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Processes are described for the conversion of a steroid substrate having a 4,7-carbonyl bridge to a structure comprising a 7α-alkoxycarbonyl substituent by reaction of the substrate with an alkoxy group source, preferably in the presence of a base. Several optional process modifications are described. The reaction may be conducted at a temperature greater than about 70°C, with substantially shorter residence times than are required at lower temperatures. A saponification target may be incorporated into the reaction medium to consume free hydroxide compounds. The product 7α-alkoxycarbonyl compound may be recovered by crystallization, residual steroid values may be recovered from the crystallization mother liquor by extraction, and the extract may be processed to produce a repulp solution wherein the steroids may be re-equilibrated to produce additional 7α-alkoxycarbonyl substituted steroid product. Alternatively, the repulp solution may be recycled to a primary reactor wherein 4,7-carbonyl bridge substrate is converted to 7α-alkoxycarbonyl product. The process is particularly useful in the preparation of eplerenone, wherein a diketone intermediate comprising a 4,7-carbonyl bridge is reacted with an alkali metal methoxide to yield an 11α-hydroxy-7α-methoxycarbonyl compound (hydroxyester), the 11α-hydroxy group is converted to a leaving group which is then abstracted to produce a Δ-9,11 enester, and the enester is epoxidized to eplerenone. Also disclosed is an epoxidation reaction conducted at relatively low hydrogen peroxide to enester substrate ratio.
PCT/IB2005/002757 2004-09-09 2005-08-25 PROCESS FOR PREPARING 7α-ALKOXYCARBONYL SUBSTITUTED STEROIDS Ceased WO2006032970A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BRPI0515106-6A BRPI0515106A (en) 2004-09-09 2005-08-25 process for preparing substituted 7 (alpha) -alkoxycarbonyl steroids
EP05805074A EP1794177A2 (en) 2004-09-09 2005-08-25 Process for preparing 7 -alkoxycarbonyl substituted steroids
CA002579954A CA2579954A1 (en) 2004-09-09 2005-08-25 Process for preparing 7.alpha.-alkoxycarbonyl substituted steroids
JP2007530794A JP2008512439A (en) 2004-09-09 2005-08-25 Process for preparing 7α-alkoxycarbonyl substituted steroids
MX2007002846A MX2007002846A (en) 2004-09-09 2005-08-25 Process for preparing 7 -alkoxycarbonyl substituted steroids.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US60842504P 2004-09-09 2004-09-09
US60/608,425 2004-09-09
US61213304P 2004-09-22 2004-09-22
US60/612,133 2004-09-22

Publications (2)

Publication Number Publication Date
WO2006032970A2 WO2006032970A2 (en) 2006-03-30
WO2006032970A3 true WO2006032970A3 (en) 2006-08-17

Family

ID=35519906

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/002757 Ceased WO2006032970A2 (en) 2004-09-09 2005-08-25 PROCESS FOR PREPARING 7α-ALKOXYCARBONYL SUBSTITUTED STEROIDS

Country Status (8)

Country Link
EP (1) EP1794177A2 (en)
JP (1) JP2008512439A (en)
AR (1) AR050632A1 (en)
BR (1) BRPI0515106A (en)
CA (1) CA2579954A1 (en)
MX (1) MX2007002846A (en)
TW (1) TW200617020A (en)
WO (1) WO2006032970A2 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262450A (en) * 2014-09-19 2015-01-07 江苏嘉逸医药有限公司 Method for preparing and refining eplerenone
CN104725461B (en) * 2015-04-02 2016-08-17 山东新华制药股份有限公司 The preparation method of eplerenone
CN108129536A (en) * 2017-12-25 2018-06-08 江西赣亮医药原料有限公司 A kind of preparation method of Dexamethasone Intermediate

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2241680A1 (en) * 1971-08-25 1973-03-01 Searle & Co 17-HYDROXY-7- (LOWER ALCOXY) CARBONYL3-OXO-17ALPHA-PREGN-4-EN-21-CARBONIC ACID GAMMA-LACTONES, THE ACIDS AND THEIR SALTS UNDER THEM
US3787396A (en) * 1972-08-24 1974-01-22 Searle & Co 17-hydroxy-7-(lower alkoxy)carbonyl-3-oxo-17alpha-pregn-4-ene-21-carboxylic acid ypsilon-lactones and congeners
DE2443746A1 (en) * 1973-09-14 1975-03-20 Searle & Co 4 ', 5-DIHYDRO-7ALPHA-ALKOXYCARBONYLSPIRO SQUARE CLAMP ON ANDROST-4-EN17.2' (3'H) -FURAN SQUARE BRACKET TO -3-ONE AND CORRESPONDING DELTA HIGH 1.4 CONNECTIONS
DE2609695A1 (en) * 1976-03-05 1977-09-15 Schering Ag (17-Alpha)-(3)-hydroxypropyl-(17-beta)-hydroxy androstenones - aldosterone antagonist type diuretics and intermediates for spironolactone
DE2627186A1 (en) * 1976-03-05 1977-12-29 Schering Ag (17-Alpha)-(3)-hydroxypropyl-(17-beta)-hydroxy androstenones - aldosterone antagonist type diuretics and intermediates for spironolactone
EP1148061A2 (en) * 1996-12-11 2001-10-24 G.D. Searle & Co. Process for preparation of 9, 11- epoxy steroids and intermediates useful therein

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2241680A1 (en) * 1971-08-25 1973-03-01 Searle & Co 17-HYDROXY-7- (LOWER ALCOXY) CARBONYL3-OXO-17ALPHA-PREGN-4-EN-21-CARBONIC ACID GAMMA-LACTONES, THE ACIDS AND THEIR SALTS UNDER THEM
US3787396A (en) * 1972-08-24 1974-01-22 Searle & Co 17-hydroxy-7-(lower alkoxy)carbonyl-3-oxo-17alpha-pregn-4-ene-21-carboxylic acid ypsilon-lactones and congeners
DE2443746A1 (en) * 1973-09-14 1975-03-20 Searle & Co 4 ', 5-DIHYDRO-7ALPHA-ALKOXYCARBONYLSPIRO SQUARE CLAMP ON ANDROST-4-EN17.2' (3'H) -FURAN SQUARE BRACKET TO -3-ONE AND CORRESPONDING DELTA HIGH 1.4 CONNECTIONS
DE2609695A1 (en) * 1976-03-05 1977-09-15 Schering Ag (17-Alpha)-(3)-hydroxypropyl-(17-beta)-hydroxy androstenones - aldosterone antagonist type diuretics and intermediates for spironolactone
DE2627186A1 (en) * 1976-03-05 1977-12-29 Schering Ag (17-Alpha)-(3)-hydroxypropyl-(17-beta)-hydroxy androstenones - aldosterone antagonist type diuretics and intermediates for spironolactone
EP1148061A2 (en) * 1996-12-11 2001-10-24 G.D. Searle & Co. Process for preparation of 9, 11- epoxy steroids and intermediates useful therein

Also Published As

Publication number Publication date
CA2579954A1 (en) 2006-03-30
AR050632A1 (en) 2006-11-08
MX2007002846A (en) 2007-04-30
BRPI0515106A (en) 2008-07-08
WO2006032970A2 (en) 2006-03-30
JP2008512439A (en) 2008-04-24
EP1794177A2 (en) 2007-06-13
TW200617020A (en) 2006-06-01

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