Preparation method of ipratropium bromide

A technology of ipratropium bromide and ipropyltropine alcohol, applied in the direction of organic chemistry, can solve the problems of poor reproducibility of the preparation process, unfavorable large-scale preparation, and great harm to experimenters, so as to avoid flammable and explosive and the use of toxic reagents, reducing workers' labor protection requirements, and reducing the effect of workshop equipment requirements

Inactive Publication Date: 2017-01-25
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This method has the following deficiencies: a. Isopropyl atropine is less soluble in toluene, and the reaction solution needs to be heated to 60° C. for dissolution, while the boiling point of methyl bromide is 3.6° C., causing a large amount of volatilization of methyl bromide in the reaction process, and methyl bromide is a highly toxic chemical reagent , which is harmful to the experimenters and is likely to cause environmental pollution
[0011] This method has following deficiencies: a. involves vacuum distillation operation, and equipment requirement is high; b. reaction process uses hydrochloric acid, metal sodium, and equipment corrosion is big, and worker's labor protection is high, is unfavorable for safe operation of workshop; c. this preparation process is heavy poor performance
Since isopropyltropinone has multiple reactive sites, the reaction selectivity is low, the product yield is low, the purity is poor, and it is difficult to separate, which is not conducive to large-scale preparation

Method used

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  • Preparation method of ipratropium bromide
  • Preparation method of ipratropium bromide
  • Preparation method of ipratropium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] (1) Synthesis of Intermediate 4

[0040] In the 250mL reaction flask, add isopropyltropine alcohol (5g), ethyl phenylacetate (7.3g), tetrahydrofuran (30mL) successively, stir to dissolve clear, cool to 0 ℃, add sodium hydride (0.78g), T= 10 ~ 20 ℃ reaction 3h. After the TLC detection reaction was complete, dilute hydrochloric acid (1.5mol / L, 30mL) was added to the system, dichloromethane (60mL) was extracted, and the organic layer was washed with 5% aqueous sodium carbonate solution (30ml), washed with water (30ml), dried, and reduced Concentrated under reduced pressure to obtain intermediate 4 (5.6 g, yield 66.0%) with a purity of 95.90% (HPLC normalization method). ESI-MS (C 18 h 25 NO 2 ,m / z) measured value (calculated value): 287.12 (287.40) [M-H] - .

[0041] (2) Synthesis of intermediate 3

[0042] Add intermediate 3 (5.0 g), methyl formate (50 mL), and potassium (1.02 g) to the reaction flask in sequence, and react at T=10-20° C. for 6 h. After the reacti...

Embodiment 2

[0048] (1) Synthesis of Intermediate 4

[0049] Add isopropyltropine alcohol (10g), ethyl phenylacetate (14.6g), and benzene (60mL) successively into a 250mL reaction flask, stir to dissolve, cool to -10°C, add sodium ethoxide (0.78g), T = 0 ~ 10 ℃ reaction 5h. After the TLC detection reaction was complete, dilute hydrochloric acid (0.5mol / L, 60mL) was added to the system, dichloromethane (60mL) was extracted, and the organic layer was washed with 5% potassium hydroxide aqueous solution (60ml), washed with water (60ml), and dried. Concentration under reduced pressure gave intermediate 4 (13.7 g, yield 80.7%) with a purity of 96.31% (HPLC normalization method). ESI-MS (C 18 h 25 NO 2 ,m / z) measured value (calculated value): 287.51 (287.40) [M-H] - .

[0050] (2) Synthesis of intermediate 3

[0051] Intermediate 3 (13.0 g), ethyl formate (130 mL), and lithium (0.47 g) were sequentially added to the reaction flask, and reacted at T=15-25° C. for 4 h. After the reaction wa...

Embodiment 3

[0057] (1) Synthesis of Intermediate 4

[0058] In the 250mL reaction flask, add isopropyltropine alcohol (5g), ethyl phenylacetate (7.3g), toluene (50mL) successively, stir to dissolve clear, cool to 0 ℃, add sodium methylate (1.8g), T= 20 ~ 30 ℃ reaction 2h. After TLC detection reaction is complete, add dilute hydrochloric acid (2mol / L, 50mL) in the system, extract, add dichloromethane (50mL) in the aqueous phase, extract, organic layer 5% sodium hydroxide aqueous solution (30ml) washes, washes with water (30ml), dried, and concentrated under reduced pressure to obtain intermediate 4 (8.0g, yield 94.4%) with a purity of 97.60% (HPLC normalization method). ESI-MS (C 18 h 25 NO 2 ,m / z) measured value (calculated value): 287.30 (287.40) [M-H] - .

[0059] (2) Synthesis of Intermediate 3

[0060] Intermediate 3 (5.0 g), ethyl formate (25 mL), and sodium (0.60 g) were sequentially added to the reaction flask, and reacted at T=20-30° C. for 4 h. After the reaction was dete...

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Abstract

The invention relates to a preparation method of an M-choline receptor blocking agent of ipratropium bromide 1. The preparation method comprises the following steps of using ethyl phenylacetate as starting raw materials; performing reaction with isopropyl tropanol; generating phenylacetate isopropyl tropeine; then, performing substitution, reduction and addition reaction to obtain the ipratropium bromide. The method has the advantages that the operation is simple; safety and controllability are realized; the work protection is low; the preparation method is suitable for industrial production. The formula is shown as the accompanying drawing, and the molecular weight is 412.36.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a preparation method of ipratropium bromide. Background technique [0002] Ipratropium bromide, chemical name (1R,3r,5s,8r)-3-[[(2RS)-3-hydroxy-2-phenylpropoxy]oxo]-8-methyl-8- (1-Methylethyl)-8-azabicyclo(3.2.1)octane bromide, white or off-white crystalline powder, soluble in water, easily soluble in methanol, slightly soluble in ethanol. The common name in English is Ipratropium Bromide, the foreign trade names are: ATROVENT Nasal Spray, and the domestic trade names are Aiquanle, Kebite, etc. Its structural formula is as follows: [0003] [0004] Ipratropium bromide is a potent anticholinergic drug with high selectivity to bronchial smooth muscle M receptors. It has a strong effect on relaxing bronchial smooth muscle and a weak effect on respiratory glands and cardiovascular system. The dose for dilating the bronchi is only 1 / 20-1 / 10 of the dose for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/10
CPCC07D451/10
Inventor 李帅郑德强索栋李树英耿志鹏张利剑李东岳刘文涛何淑旺
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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