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US4435579A Expired / Lapsed US ⏱️ 0.0 years remaining

Resolution of substituted dibenzo[b,f]thiepin-3-carboxylic acid-5-oxides with ephedrine

Assignee: Merck Frosst Canada and Co
•
Filing: 1982-07-12
•
Granted: 1984-03-06
•
Expires: 2002-07-12
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Abstract

Abstract The present invention is concerned with an improved process for the production of highly active optical isomers of (-) 7 or 8 fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide having the structural formula ##STR1## in which the fluoro substituent replaces a hydrogen in the 7 or 8 position. The two active isomers represented by formula II are S(-)7-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide and R(-)8-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide. It is especially concerned with the resolution of the racemic 7 or 8 fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide by first forming and separating diastereomers of said racemic carboxylic acids by salt formation with ephedrine followed by crystallization and regeneration of the desired (-) isomers and recycling of the (+) isomer by racemization of the regenerated isomer. The compounds obtained in high yield by this process are highly active prostaglandin antagonists which are useful in treating a variety of conditions such as allergic asthma.

Inventors

  • 👤 Patrice C. Belanger
  • 👤 Haydn W. R. Williams
  • 👤 Joshua Rokach

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-10-25 16:53
CPC Classifications
C; C07; C07D; C07D337/00; C07D337/02; C07D337/06; C07D337/10; C07D337/14

Claims Analysis

Total Claims: 9
Claim 1
Independent Claim 117 words
An improved process for the preparation of (-)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide of the Formula I: ##STR4## which comprises: (1) Heating a solution of equimolar amounts of racemic (7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide and (d or l)-ephedrine in a lower alcohol to form a diastereoisomeric mixture of (d or l)-ephedrine salts of (-)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide and (+)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide; (2) Recovering the crystalline (d or l)-ephedrine (-) acid salt; (3) Recycling the (d or l)-ephedrine (+) acid salt by first hydrolysis with aqueous acid followed by racemization with trifluoroacetic anhydride to regenerate the racemic (7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide; and (4) Acidifying said (d or l)-ephedrine (-) acid salt with aqueous acid to produce (-)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide.
Claim 2
Dependent Claim 117 words
An improved process for the preparation of (-)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide of the Formula I: ##STR4## which comprises: (1) Heating a solution of equimolar amounts of racemic (7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide and (d or l)-ephedrine in a lower alcohol to form a diastereoisomeric mixture of (d or l)-ephedrine salts of (-)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide and (+)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide; (2) Recovering the crystalline (d or l)-ephedrine (-) acid salt; (3) Recycling the (d or l)-ephedrine (+) acid salt by first hydrolysis with aqueous acid followed by racemization with trifluoroacetic anhydride to regenerate the racemic (7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide; and (4) Acidifying said (d or l)-ephedrine (-) acid salt with aqueous acid to produce (-)(7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide.
Claim 3
Dependent Claim 37 words
The process of claim 1 wherein the formation of the diasterioisomeric mixture of ephedrine salts is carried out in the presence of acetonitrile or a lower aliphatic alcohol selected from methanol, ethanol, propanol, i-propanol or mixture thereof.
Claim 4
Dependent Claim 11 words
The d- or l-ephedrine salt of racemic (7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide.
Claim 5
Dependent Claim 11 words
The d- or l-ephedrine salt of racemic (7 or 8)-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide.
Claim 6
Dependent Claim 11 words
The d- or l-ephedrine salt of R(-)8-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide of claim 3.
Claim 7
Dependent Claim 11 words
The d- or l-ephedrine salt of S(+)8-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide of claim 3.
Claim 8
Dependent Claim 11 words
The d- or l-ephedrine salt of S(-)7-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide of claim 3.
Claim 9
Dependent Claim 11 words
The d- or l-ephedrine salt of R(+)7-fluorodibenzo[b,f]-thiepin-3-carboxylic acid-5-oxide of claim 3.

References Cited (Backward Citations)

US3509154A Cited
US4104280A Cited
US4237160A Cited
US4334077A Cited

USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1987-03-06 1987-09-05 1988-03-06 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1991-03-06 1991-09-05 1992-03-06 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 1995-03-06 1995-09-05 1996-03-06 $7700.00 Window Closed / Lapsed

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