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Process for the preparation of tiotropium bromide

a technology of tiotropium bromide and process, applied in the field of improvement, can solve the problems of more complex synthesis methods and unsuitable methods for industrial scale preparation

Inactive Publication Date: 2008-02-28
SICOR SOC ITAL CORTICOSTEROIDI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because of the dangerous reaction conditions, this method is not suitable for industrial scale preparation.
However, these methods of synthesis are more complex procedures involving a number of synthetic steps.” Therefore a different synthetic approach was developed, where the coupling is carried out using scopine methobromide rather than scopine, but details, including the yield, of this coupling reaction are not reported.

Method used

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  • Process for the preparation of tiotropium bromide
  • Process for the preparation of tiotropium bromide
  • Process for the preparation of tiotropium bromide

Examples

Experimental program
Comparison scheme
Effect test

example 1

Comparative Example: Preparation of Scopine Hydrochloride According to GB '781

[0063] 10.0 g (22.84 mmol) of scopolamine hydrobromide trihydrate was suspended in 100 mL of absolute ethanol, and cooled to about 0° C. Sodium borohydride (4.0 g, 105.7 mmol) was then added portion-wise while maintaining the temperature at a maximum of 30° C. 4.8 mL of water was then added to the reaction mixture. After 3.5 hours, the reaction was completed and 50 mL of diethyl ether was then added. The reaction was then cooled to 0° C., and acidified with 2M hydrochloric acid in diethyl ether to a pH of about 2. The suspension was stirred at room temperature for 30 minutes and then filtered on GochP3. The white solid was dried at 45° C. under vacuum for 4 hours, yielding 9 g of product containing 79% of salts determined by sulphuric ashes.

example 2

Preparation of Methyl di-(2-thienyl)glycolate

[0064] 1050 mL of tetrahydrofuran was loaded in a 2 L round bottomed flask. 22.6 g (0.93 mol) of magnesium turnings were then added, and the mixture was kept at 35° C., while catalytic bromoethane (200 mg, 1.84 mmol) was loaded. 150 g (0.92 mol) of 2-bromothiophene was added dropwise, and after about 15% (13 ml) of reagent was exothermicity was observed. The temperature was maintained at a maximum of 50-55° C., and the remaining 2-bromothiophene was then added. At the end of the addition, the reaction mixture was heated to 65° C. for 1.5 hours to 2 hours, and then cooled to 25° C.

[0065] The Grignard solution thus formed was added drop-wise, in about 2.5 hours to 3 hours, into a solution of dimethyl oxalate (54.3 g, 0.46 mol) dissolved in 300 mL of tetrahydrofuran, while maintaining the temperature at maximum 5-10° C. via cooling bath.

[0066] The solution was kept under stirring for 0.5 hours to 1.0 hours at 5-10° C., and then saturated ...

example 3

Crystallization of Methyl di-(2-thienyl)glycolate in Ethanol 96% / n-heptane

[0072] Crude methyl di-(2-thienyl)glycolate (2.0 g) was dissolved in ethanol 96% (8.0 ml) at 45° C. 16.0 mL of n-heptane were then added drop-wise at 45° C. in 20 minutes. The solution was maintained at 45° C. for hour, and then it was cooled to 0° C. in 1 hour, and left at this temperature for another hour. The solid was filtered on a sintered glass funnel and it was washed once with n-heptane (2 mL). Drying for 6 hours at 50° C. under vacuum yielded 1.4 g of methyl di-(2-thienyl)glycolate (70%)

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Abstract

The invention is directed to improved processes for preparing Tiotropium bromide.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 60 / 830,231 filed Jul. 10, 2006; U.S. Provisional Patent Application No. 60 / 835,201, filed Aug. 3, 2006; U.S. Provisional Application No. 60 / 835,200, filed Aug. 3, 2006; and U.S. Provisional Application No. 60 / 836,037, filed Aug. 7, 2006, the disclosures of which are hereby incorporated herein by reference. This application is also related to U.S. patent application Ser. No. 11 / 643,013, filed Dec. 19, 2006.FIELD OF THE INVENTION [0002] The invention is directed to improved processes for preparing Tiotropium bromide. BACKGROUND [0003] Tiotropium bromide, (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]nonane bromide or 6β,7β-epoxy-3β-hydroxy-8-methyl-1αH,5αH-tropanium bromide, di-2-thienylglycolate, has the following chemical structure: It is an anticholinergic drug with specificity for muscar...

Claims

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Application Information

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IPC IPC(8): C07D491/044
CPCC07D491/18
Inventor BUSOLLI, JONATHANDIULGHEROFF, NICOLASCARPITTA, FRANCESCAVOLONTE, ROBERTAPONTIROLI, ALESSANDRO
Owner SICOR SOC ITAL CORTICOSTEROIDI SPA
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