PROCESS FOR THE MANUFACTURING OF BETAMIMETICS

• US 20070088160A1
• Filed: 08/10/2006
• Published: 04/19/2007
• Est. Priority Date: 08/15/2005
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Rall, Werner, KRUEGER, Thomas, Ries, Uwe, Soyka, Rainer, Duran, Adil, Schnaubelt, Juergen, Leuter, Zeno
• Application Number:
  US11/463,703
• Publication Number:
  US 20070088160A1
• Time in Patent Office: Days
• US Class Current: 544/105
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 201/08 by substitution of hydrogen atoms by nitro groups
• CPC Class Codes: C07C 205/45 the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• CPC Class Codes: C07C 221/00 Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 225/22 having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 233/13 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 45/71 being hydroxy groups
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 265/36 condensed with one six-membered ring
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a process for preparing betamimetics of formula 1, wherein n denotes 1 or 2;

• R¹ denotes hydrogen, halogen, C_1-4-alkyl or O—C_1-4-alkyl;
• R² denotes hydrogen, halogen, C_1-4-alkyl or O—C_1-4-alkyl;
• R³ denotes hydrogen, C_1-4-alkyl, OH, halogen, O—C_1-4-alkyl, O—C_1-4-alkylene-COOH, O—C_1-4-alkylene-COO—C_1-4-alkyl.

Claims

1. A process for preparing a compound of formula 1,

wherein

n denotes 1 or 2;

R¹ denotes hydrogen, halogen, C_1-4-alkyl or O—

C_1-4-alkyl;

R² denotes hydrogen, halogen, C_1-4-alkyl or O—

C_1-4-alkyl;

R³ denotes hydrogen, C_1-4-alkyl, OH, halogen, O—

C_1-4-alkyl, O—

C_1-4-alkylene-COOH, O—

C_1-4-alkylene-COO—

C_1-4-alkyl;

said process comprising reacting a compound of formula 1a,

wherein PG represents a protective group, with a compound of formula 1b,

wherein R¹, R², R³ and n have the meanings given above, in an organic solvent to obtain a compound of formula 1c,

wherein R¹, R², R³, n and PG have the meanings given above, and cleaving the protective group PG to obtain the compound of formula 1.

2. A process for preparing a compound of formula 1 according to claim 1, wherein

n denotes 1 or 2;

R¹ denotes hydrogen, halogen or C_1-4-alkyl;

R² denotes hydrogen, halogen or C_1-4-alkyl; and

R³ denotes hydrogen, C_1-4-alkyl, OH, halogen, O—

C_1-4-alkyl, O—

C_1-4-alkylene-COOH or O—

C_1-4-alkylene-COO—

C_1-4-alkyl.

3. A process for preparing a compound of formula 1 according to claim 1, wherein

n denotes 1 or 2;

R¹ denotes hydrogen, fluorine, chlorine, methyl or ethyl;

R² denotes hydrogen, fluorine, chlorine, methyl or ethyl; and

R³ denotes hydrogen, C_1-4-alkyl, OH, fluorine, chlorine, bromine, O—

C_1-4-alkyl, O—

C_1-4-alkylene-COOH, O—

C_1-4-alkylene-COO—

C_1-4-alkyl.

4. A process for preparing a compound of formula 1 according to claim 1, wherein

n denotes 1 or 2;

R¹ denotes hydrogen, methyl or ethyl;

R² denotes hydrogen, methyl or ethyl; and

R³ denotes hydrogen, methyl, ethyl, OH, methoxy, ethoxy, O—

CH₂—

COOH, O—

CH₂—

COO-methyl or O—

CH₂—

COO-ethyl.

5. A process for preparing a compound of formula 1 according to claim 1, wherein

n denotes 1 or 2;

R¹ denotes hydrogen or methyl;

R² denotes hydrogen or methyl; and

R³ denotes hydrogen, methyl, OH, methoxy, O—

CH₂—

COOH or O—

CH₂—

COO-ethyl.

6. A process according to claim 1, wherein the compound of formula 1a is prepared by reacting a compound of formula 2a,

wherein PG is as defined in claim 1 and R⁴ denotes halogen with DIP chloride in a suitable solvent.

7. A process according to claim 6 wherein the compound of formula 2a is prepared by reacting a compound of formula 3a,

wherein PG has the meaning given in claim 6, with a halogenating reagent in a suitable solvent.

8. A process according to claim 7 wherein the compound of formula 3a is prepared by hydrogenating a compound of formula 4a in a suitable solvent,

wherein PG has the meaning given in claim 7.

9. A process according to claim 8 wherein the compound of formula 4a is prepared by reacting a compound of formula 5a,

wherein PG has the meaning given in claim 8, with a nitrogenating reagent in a suitable solvent.

10. A process according to claim 9 wherein the compound of formula 5a is prepared by reacting a compound of formula 6a in a suitable solvent with a compound PG-A, wherein PG is a protective group and A is a leaving group,

11. A process according to claim 1, wherein the compound of formula 1b is prepared by reacting a compound of formula 2b with a strong base in a suitable solvent,

wherein R¹, R², R³ and n have are as defined in claim 1 and

R⁵ denotes Me.

12. A process according to claim 11 wherein the compound of formula 2b is prepared by reacting a compound of formula 3b with acetonitrile in the presence of an acid in a suitable solvent,

wherein R¹, R², R³ and n are as defined in claim 11.

13. A process according to claim 12 wherein the compound of formula 3b is prepared by reacting in a suitable solvent a compound of formula 4b with methylmagnesium bromide or methylmagnesium chloride,

wherein R¹, R², R³ and n are as defined in claim 12.

14. A compound of formula 3a,

wherein PG is as defined in claim 1.

15. A compound of formula 4a,

wherein PG is as defined in claim 1.

16. A compound of formula 4a^#,

wherein PG is as defined in claim 1.

17. A compound of formula 2b,

wherein R¹, R², R³ and n are as defined in claim 1, and

R⁵ denotes Me.

18. A process for preparing a compound of formula 2a,

wherein PG is as defined in claim 1 and R⁴ denotes halogen, said process comprising reacting a compound of formula 3a,

wherein PG is as defined in claim 1, with a halogenating reagent selected from tetrabutylammonium tribromide, benzyltrimethyl ammonium dichloriodide, N-bromo-succinimide, N-chloro-succinimide, sulphuryl chloride and bromine/dioxane.

19. A process for preparing a compound of formula 3a,

wherein PG is as defined in claim 1, said process comprising subjecting a compound of formula 4a to catalytic hydrogenation and then reaction with chloroacetyl chloride,

wherein PG is as defined in claim 1.

20. A process according to claim 19, wherein a compound of formula 4a^#,

wherein PG is as defined in claim 19, is formed as an intermediate product of the hydrogenation.

21. A process for preparing a compound of formula 4a,

wherein PG is as defined in claim 1, said process comprising reacting a compound of formula 5a,

wherein PG is as defined in claim 1, with a nitrogenating reagent selected from 65% nitric acid, potassium nitrate/sulphuric acid and nitronium tetrafluoroborate.

22. A process for preparing a compound of formula 1b,

wherein R¹, R², R³ and n are as defined in claim 1, said process comprising reacting a compound of formula 2b,

wherein R¹, R², R³ and n are as defined in claim 1 and

R⁵ denotes Me,

with a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide and caesium hydroxide.

23. A process for preparing a compound of formula 2b,

wherein R¹, R², R³ and n are as defined in claim 1 and

R⁵ denotes Me,

said process comprising reacting a compound of formula 3b,

wherein R¹, R², R³ and n are as defined in claim 1, with a compound of formula

wherein R⁵ has the meaning given above, in the presence of a hygroscopic reagent selected from sulphuric acid, formic acid, p-toluenesulphonic acid, methanesulphonic acid, perchloric acid and polyphosphoric acid and then with a base selected from aqueous solutions of ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.