Process for preparing an anticholinergic

• US 6,486,321 B2
• Filed: 12/19/2001
• Issued: 11/26/2002
• Est. Priority Date: 12/22/2000
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Meissner, Helmut, Banholzer, Rolf, Broeder, Wolfgang, Mathes, Andreas, Specht, Peter, Luettke, Sven, Graulich, Manfred
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): Murphy, Jennifer C.
• Application Number:
  US10/025,425
• Publication Number:
  US 20020133010A1
• Time in Patent Office: 342 Days
• Field of Search: 546/89, 546/125
• US Class Current: 546/89
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 451/10 acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Abstract

The invention relates to a new process for preparing (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^2,4] nonane-bromide.

Claims

1. A process for preparing tiotropium bromide of formula (I):

said process comprising epoxidizing the tropenol ester of formula (VII);

to form the scopine ester of formula (IV);

which is then quaternized with methyl bromide to form tiotropium bromide of formula (I).

2. A process according to claim 1, wherein a mixture of vanadium pentoxide with hydrogen peroxide is used as the epoxidising agent for epoxidising (VII) to form (IV).

3. A process according to claim 1, wherein the epoxidation of (VII) to form (IV) is carried out in a solvent which is selected from among water, dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone.

4. A process according to claim 1, wherein the quaternization of (IV) to form (I) is carried out using methylbromide in a solvent which is selected from among water, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone and dichloromethane.

5. A process according to any one of claims 1 to 4, wherein the compound of formula (VII)

is obtained by reacting tropenol of formula (V),

optionally in the form of an acid addition salt thereof, with an ester of formula (VI)

wherein R is a group which is selected from among hydroxy, methoxy, ethoxy, O— N-succinimide, O—

N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, —

S-methyl, —

S-ethyl and —

S-phenyl.

6. A process according to claim 5, wherein the tropenol (V) is used in the form of an acid addition salt thereof which is selected from among the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate salts.

7. A process according to claim 5, wherein the reaction of (V) with (VI) to form (VII) is carried out in a suitable organic solvent.

8. A process according to claim 5, wherein the reaction of (V) with (VI) to form (VII) is carried out in an organic solvent selected from among toluene, benzene, n-butylacetate, dichloromethane, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidinone.

9. A process according to claim 5, wherein the reaction of (V) with (VI) to form (VII) is carried out in the presence of an organic or inorganic base.

10. A process according to claim 5, wherein the reaction of (V) with (VI) to form (VII) is carried out in the presence of a base selected from among the organic amines.

11. A process according to claim 5, wherein the reaction of (V) with (VI) to form (VII) is carried out in the presence of diisopropylethylamine, triethylamine, DBU or pyridine.

12. A process according to claim 5, wherein the reaction of (V) with (VI) to form (VII) is carried out in the presence an inorganic base.

13. A process according to claim 5, wherein the reaction of (V) with (VI) to form (VII) is carried out in the presence of an alkali metal or alkaline earth metal carbonate, alkoxide or hydride of lithium, sodium, potassium or calcium.

14. A process according to claim 5, wherein if R denotes hydroxy in the compound of formula (VI), the reaction of (V) with (VI) to form (VII) is carried out in the presence of coupling reagents.

15. A process according to claim 14, wherein the coupling reagents are selected from among carbonyldiimidazole, carbonyldi-1,2,4-triazole, dicyclohexylcarbodiimide and ethyl-dimethylaminopropylcarbodiimide.