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An industrially applicable process for preparing high purity aclidinium bromide

A kind of aclidinium bromide, high-purity technology, applied in the field of preparing aclidinium bromide of formula I, can solve problems such as long reaction time or chlorinated solvent, inconvenient use

Inactive Publication Date: 2016-06-15
ZENTIVA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conversely, with the exception of process patent EP2044067, for the alkylation of quinuclidinyl ester V, it is inconvenient to use high excess of alkylating agent, long reaction times or chlorinated solvents

Method used

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  • An industrially applicable process for preparing high purity aclidinium bromide
  • An industrially applicable process for preparing high purity aclidinium bromide
  • An industrially applicable process for preparing high purity aclidinium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1 (reference examples; program according to the method of patent EP2130830)

[0126] Fresh sodium ethoxide (43 mg, 1.2 equiv) and methyl bis(2-thienyl)glycolate VI (200 mg, 1.2 equiv) were added to R-(-)-3-quinuclidine under an inert argon atmosphere Alcohol III (63mg, 0.5mmol) was suspended in anhydrous toluene (5ml). The reaction mixture was heated for 2.5 hours (1 hour at 70°C to 80°C and 1.5 hours at 80°C to 95°C). At the same time, an azeotropic mixture consisting of toluene and methanol, a by-product of the reaction, was partially removed by distillation (1.5 ml). When the internal temperature reached 110°C to 115°C, an additional 2ml was removed by distillation. Add 4 ml of anhydrous toluene and continue distillation. Heating was stopped after 3 ml of the azeotrope had been removed by distillation. The reaction mixture was cooled in an ice bath, and 2 ml diethyl ether and 2 ml water were added. The resulting two layers were separated, and the aqueo...

Embodiment 2

[0127] Example 2 (Preparation method of quinuclidinyl ester V, experiments 1 to 4 of Table 1)

[0128] 1.5 g of bis(2-thienyl) methyl glycolate VI (5.9 mmol) and 0.86 g of R-(-)-3-quinuclidinol III (1.15 equivalents) were weighed into a flask, and placed in an inert argon atmosphere Add 20mlMeTHF to it. The reaction mixture was heated to 35 °C and a 1 M solution of tert-butoxide (sodium tert-butoxide or potassium tert-butoxide according to Table 1) in MeTHF was added dropwise to the reaction mixture under an inert argon atmosphere over 20 min (0.5 equivalent). After adding the base, a distillation apparatus was fitted to the flask, and the reaction mixture was gradually heated to 80° C. (the internal temperature of the reaction mixture was 70° C.) and stirred further at this temperature for the time mentioned in Table 1. During this period, the azeotrope consisting of MeTHF and methanol, a by-product of the reaction, was simultaneously removed by distillation under reduced...

Embodiment 3

[0129] Example 3 (Preparation method of quinuclidinyl ester V, experiments 5 to 7 of Table 1)

[0130] 1.5 g of bis(2-thienyl) methyl glycolate VI (5.9 mmol) and 0.86 g of R-(-)-3-quinuclidinol III (1.15 equivalents) were weighed into a flask, and placed in an inert argon atmosphere Add 20mlMeTHF to it. The reaction mixture was heated to 35 °C and a 1 M solution of sodium tert-butoxide in MeTHF (amount of base specified in Table 1) was added dropwise to the reaction mixture under an inert argon atmosphere over 20 min. After adding the base, a distillation apparatus was fitted to the flask, and the reaction mixture was gradually heated to 80° C. (the internal temperature of the reaction mixture was 70° C.) and stirred further at this temperature for the time mentioned in Table 1. During this period, the azeotrope consisting of MeTHF and methanol, a by-product of the reaction, was simultaneously removed by distillation under reduced pressure. The total amount of azeotrope re...

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Abstract

The invention relates to an efficient and industrially applicable process for preparing aclidinium bromide of formula I, comprising the following steps a) preparation of the quinuclidinyl ester by transestenfication of methyl di(2-thienly)giycolate with R-(-)-3-quinuclidinol in the presence of a sterically hindered base in an inert solvent; b) isolation of the quinuclidinyl ester; and c) quaternization of the quinuclidinyl ester by 3-phenoxypropyl bromide in a suitable solvent.

Description

technical field [0001] The present invention relates to an efficient and industrially applicable process for the preparation of aclidinium bromide of formula I. The focus of the new method is the applicability of the method in industrial scale synthesis. In addition, the newly developed method eliminates the formation of impurities, thereby preparing API with high purity to meet the high requirements for purity in pharmaceutical production. [0002] [0003] Aclidinium bromide Background technique [0004] Aclidinium bromide of structure I is (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azinium bicyclo [2.2.2] Names of acetate bromides. Aclidinium bromide was first described in document WO0104118 by Almirall, it is a selective antagonist of cholinergic receptors, for M 3 Receptors have long-term effects. It has a pronounced bronchodilation effect. It is used to treat chronic obstructive pulmonary disease (COPD). The therapeutic dose of active sub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor I·塞尔纳约瑟夫·哈吉塞克
Owner ZENTIVA AS
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