Method for preparing tiotropium bromide

A tiotropium bromide and thiophenol-based technology, applied in the field of preparation of tiotropium bromide, can solve problems such as harsh reaction conditions, unsuitability for large-scale production, etc., and achieve the effects of less environmental pollution, low cost and high yield

Inactive Publication Date: 2010-10-20
NANJING JINDANCHENG MEDICINETECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Chinese patent CN1861598 has reported the synthesis of tiotropium bromide anhydrate, and its key step also is to use scopolamine and two (2-thienyl) glycolic acid methyl ester (II), forms two (2) under the condition of metal sodium fusion - Thiophyl) scopolamine glycolate intermediate (Ⅲ), the specific yield of tiotropium bromide is not given in the patent, but the harsh reaction conditions are not suitable for large-scale production

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  • Method for preparing tiotropium bromide
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  • Method for preparing tiotropium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of scopolamine bis(2-thiophene) glycolate.

[0037] In a dry three-necked flask, add 6.2g scopolamine (40mmol), 11.2g methyl bis(2-thiophenol) glycolate (44mmol), 0.5g anhydrous potassium carbonate (3.6mmol) and 50mL normal heptane. The three-necked bottle is equipped with a water separator and a condenser. Under nitrogen protection, the system was heated to reflux in an oil bath (oil bath temperature 134° C.) for 3 hours. Naturally cooled, 20 mL of ethyl acetate was added, potassium carbonate was filtered off, and washed with ethyl acetate. The filtrate was collected, evaporated to dryness, washed with acetonitrile, and the remaining solvent was removed in vacuo to obtain 12.2 g of scopolamine bis(2-thiophene)glycolate (yield 81%).

[0038] 1 H NMR (500MHz, CDCl 3 ), (ppm): 7.32-7.30(m, 2H), 7.13-7.12(m, 2H), 7.00-6.98(m, 2H), 5.14-5.12(m, 1H), 4.81(s, 1H), 3.07 -3.06(m, 2H), 3.00(s, 2H), 2.47(s, 3H), 2.17-2.11(m, 2H), 1.62-1.58(m, 2H).

Embodiment 2

[0039] Example 2: Preparation of scopolamine bis(2-thiophene) glycolate.

[0040] In a dry three-necked flask, add 3.1g scopolamine (20mmol), 5.6g bis(2-thienyl)glycolic acid methyl ester (22mmol), 0.5g anhydrous potassium carbonate (3.6mmol) and 50mL n-hexane alkyl. The three-necked bottle is equipped with a water separator and a condenser. Under nitrogen protection, the system was heated to reflux in an oil bath (oil bath temperature 134° C.) for 3 hours. Naturally cooled, 20 mL of ethyl acetate was added, potassium carbonate was filtered off, and washed with ethyl acetate. The filtrate was collected, evaporated to dryness, washed with acetonitrile, and the remaining solvent was removed by vacuum to obtain 4.9 g of scopolamine bis(2-thienyl)glycolate (65% yield).

[0041] 1 H NMR (500MHz, CDCl 3 ), (ppm): 7.32-7.30(m, 2H), 7.13-7.12(m, 2H), 7.00-6.98(m, 2H), 5.14-5.12(m, 1H), 4.81(s, 1H), 3.07 -3.06(m, 2H), 3.00(s, 2H), 2.47(s, 3H), 2.17-2.11(m, 2H), 1.62-1.58(m, 2H). ...

Embodiment 3

[0042] Example 3: Preparation of scopolamine bis(2-thiophene) glycolate.

[0043]In a dry three-necked flask, add 3.1g scopolamine (20mmol), 5.6g methyl bis(2-thiophene) glycolate (22mmol), 0.5g anhydrous potassium carbonate (3.6mmol) and 50mL normal heptane. The three-necked bottle is equipped with a water separator and a condenser. Under nitrogen protection, the system was heated to reflux in an oil bath (oil bath temperature 134° C.) for 3 hours. After natural cooling, 20 mL of methyl tetrahydrofuran was added, potassium carbonate was filtered off, and washed with ethyl acetate. The filtrate was collected, evaporated to dryness, washed with acetonitrile, and the remaining solvent was removed in vacuo to obtain 5.9 g of scopolamine bis(2-thienyl)glycolate (yield 78%).

[0044] 1 H NMR (500MHz, CDCl 3 ), (ppm): 7.32-7.30(m, 2H), 7.13-7.12(m, 2H), 7.00-6.98(m, 2H), 5.14-5.12(m, 1H), 4.81(s, 1H), 3.07 -3.06(m, 2H), 3.00(s, 2H), 2.47(s, 3H), 2.17-2.11(m, 2H), 1.62-1.58(m, ...

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Abstract

The invention discloses a method for preparing tiotropium bromide, which comprises the following steps of: adding scopine, bis(2-thiophene) methylglycollate and potassium carbonate into an organic solvent, and heating and refluxing the mixture for 1 to 4 hours at the temperature of between 120 and 150 DEG C under inert atmosphere to prepare bis(2-thiophene) scopine glycolate; and adding the bis(2-thiophene) scopine glycolate and methyl bromide into the organic solvent, and reacting the mixture for 15 to 25 hours at the room temperature under the inert atmosphere with stirring to prepare the tiotropium bromide. Compared with the prior art, the method for preparing the tiotropium bromide has the advantages of high yield, easy operation, mild condition, low environmental pollution, low cost and large-scale production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of tiotropium bromide. Background technique [0002] Tiotropium Bromide was first reported in European Patent EP418716A1. Molecular formula is C 19 h 22 BrNO 4 S 2 , has the following structure: [0003] [0004] Tiotropium bromide is a long-acting and highly effective anticholinergic drug used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. [0005] U.S. Patent No. 5,610,163 reports that the synthesis of tiotropium bromide (Ⅳ) is obtained by the reaction of two (2-thiophene) glycolate scopolamine intermediates (Ⅲ) with methyl bromide, and two (2-thiophene) glycolate scopolamine The scopolamine intermediate (Ⅲ) is prepared from scopolamine (I) and bis(2-thienyl)glycolic acid methyl ester (II) and metal sodium or sodium methoxide under melting conditions, and the reaction yield is 44 ~70%, its harsh reaction co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/10
Inventor 侯本晶赵倩
Owner NANJING JINDANCHENG MEDICINETECH
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