Process for preparing formoterol and related compounds

• US 5,434,304 A
• Filed: 09/20/1994
• Issued: 07/18/1995
• Est. Priority Date: 09/26/1990
• Status: Expired due to Term

• Current Assignee: ABet Astra
• Original Assignee: ABet Astra
• Inventors: Mansson, Katarina L., Jakupovic, Edib, Trofast, Jan W.
• Primary Examiner(s): PRESCOTT, ARTHUR
• Application Number:
  US08/309,167
• Time in Patent Office: 301 Days
• Field of Search: 564/221, 564/219, 564/220, 560/21, 560/37, 560/38, 568/583, 568/584, 568/585
• US Class Current: 564/221
• CPC Class Codes: C07C 231/14 by formation of carboxamide groups together with reactions not involving the carboxamide groups
• CPC Class Codes: C07C 233/43 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton

Abstract

The present invention is directed to a process for preparing formoterol and related compounds and derivatives thereof and their pharmacologically and pharmaceutically acceptable fumarate salts and/or solvates. The present invention is also directed to certain formoterol related compounds per se.

Claims

1. A process for preparing a compound of the formula I ##STR17## wherein R¹ is H or a straight or branched alkyl group having 1-5 carbon atoms, A is either ##STR18## wherein R is a straight or branched alkyl group having 1-5 carbon atoms and R² is H or a straight or branched alkyl group having 1-5 carbon atoms;

or ##STR19## wherein R is as defined above, in the form of a pure racemate, which comprises the steps of

a) reacting ##STR20## to give compound IV ##STR21## b) reducing and formylating compound IV to give compound V ##STR22## c) forming the fumarate of compound V and separating the racemates by crystallization,

d) extracting the base of the desired racemate of compound V,

e) hydrogenolyzing of the protecting benzyl groups of said base of compound V and

f) alkylating the compound obtained.

4. The process of claim 1, which further comprises, prior to step f), the step of forming a pharmaceutically acceptable fumarate and/or solvate of the compound resulting from step e).

6. The process according to claim 1, 3, 4 or 5, wherein step a) is carried out in the presence of a solvent, such as a lower alcohol, at reflux temperature or in the absence of a solvent at a temperature in the range of 80°

-120°

C.

7. The process according to any one of claims 1, 3, 4 and 5, wherein step b) is a one-step reaction with Raney-nickel/formic acid or a two-step reaction comprising catalytic reduction of the nitro group followed by formulation in an excess of formic acid.

8. The process according to any one of claims 1, 3, 4, and 5, wherein the separating of the racemates by crystallization in step c) is carried out in a solvent system comprising ethyl acetate, isopropyl acetate and/or methyl isobutylketone.

9. The process according to claim 8, wherein the solvent system further comprises small amounts of solvents more polar than the solvents defined in claim 8, such as dimethylformamide, dimethylsulfoxide and/or methanol.

10. The process according to claim 9, wherein the amount of the more polar solvent is less than 15%.

11. The process according to claims 1 or 4, wherein R² is a straight or branched alkyl group having 1-5 carbon atoms.

2. A compound of the formula I ##STR23## or a pharmaceutically acceptable fumarate and/or solvate thereof, in the form of the pure racemates or a mixture of the four isomers, wherein R¹ is H or a straight or branched alkyl group having 1-5 carbon atoms, A is either ##STR24## wherein R is a straight or branched alkyl group having 1-5 carbon atoms and R² is H or a straight or branched alkyl group having 1-5 carbon atoms;

or ##STR25## wherein R is as defined above.

3. A process for preparing a compound of the formula I ##STR26## wherein A is ##STR27## and R¹ is H, in the form of a pure racemate, which comprises the steps of

a) reacting ##STR28## to give compound IV ##STR29## b) reducing and formylating compound IV to give compound V ##STR30## c) forming the fumarate of compound V and separating the racemates by crystallization,

d) extracting the base of the desired racemate of compound V, and

e) hydrogenolyzing the protecting benzyl groups of said base of compound V.

5. The process of claim 3, which further comprises the step of forming a pharmaceutically acceptable fumarate and/or solvate of the compound resulting from step e).