A kind of preparation method of cyclopentolate hydrochloride

A technology of cyclopentolate hydrochloride and hydrochloric acid, which is applied in the field of preparation of cyclopentolate hydrochloride, can solve the problems of high labor protection requirements for workers, poor reproducibility of the preparation process, unfavorable large-scale preparation, etc., to achieve environmental protection and The effect of safe production in the workshop, avoiding the use of flammable, explosive and toxic reagents, and reducing labor protection requirements for workers

Active Publication Date: 2019-03-08
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This method has the following deficiencies: a. The synthesis of compound 3 needs to go through a griddle reaction, and the reaction process is guaranteed to be absolutely anhydrous and oxygen-free. At the same time, various raw materials and reagents need to be dried and dewatered, so the operation is cumbersome and the reaction conditions are harsh; b. Organic solvents such as anhydrous ether and isopropyl bromide are used in the reaction process, which has high labor protection requirements for workers and is not conducive to safe operation in the workshop
[0010] This method has the following disadvantages: a. It involves vacuum distillation operation and requires high equipment requirements; b. Thionyl chloride, anhydrous ether and metal sodium are used in the reaction process, the equipment is corroded, and the labor protection of workers is high, which is not conducive to the safe operation of the workshop ; c. The preparation process has poor reproducibility
Since 2-(dimethylamino)ethylphenylacetate has multiple reactive sites, the reaction selectivity is low, the resulting 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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  • A kind of preparation method of cyclopentolate hydrochloride
  • A kind of preparation method of cyclopentolate hydrochloride
  • A kind of preparation method of cyclopentolate hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0035] (1) Synthesis of intermediate 3

[0036] N 2 Under protection, phenylacetic acid (7.0 g) and acetonitrile (250 mL) were sequentially added into a 500 mL reaction flask, stirred to dissolve, cooled to 0° C., potassium tert-butoxide (15.0 g) was added in batches, and reacted at room temperature for 1 h. Then, the temperature of the system was lowered to 0° C., and an acetonitrile solution (140 mL) of cyclopentanone (9.0 mL) was slowly added dropwise. After dropping, slowly rise to room temperature and continue to react for 5h. After the reaction was detected by TLC, 200 mL of saturated ammonium chloride solution was added to the system, stirred for 20 min, and ethyl acetate (30 mL×2) was added to the residual liquid for extraction. The aqueous layer was slowly adjusted to pH 2 with 0.1 mol / L hydrochloric acid, added dichloromethane (50 mL×2) for extraction, the organic layer was washed with water, dried, and concentrated under reduced pressure to obtain intermediate 3 (...

Embodiment 2

[0042] (1) Synthesis of intermediate 3

[0043] N 2Under protection, phenylacetic acid (3.5g) and dioxane (120mL) were sequentially added into a 250mL reaction flask, stirred to dissolve, cooled to 0°C, sodium hydride (3.0g) was added in batches, and reacted at room temperature for 1h. The system was cooled down to -20°C, and a solution of cyclopentanone (5.5 mL) in dioxane (90 mL) was slowly added dropwise. After dropping, slowly rise to room temperature and continue to react for 5h. After the reaction was detected by TLC, 100 mL of saturated ammonium chloride solution was added to the system, stirred for 20 min, and ethyl acetate (20 mL×2) was added to the residual liquid for extraction. The aqueous layer was slowly adjusted to pH 6 with 10mol / L dilute sulfuric acid, extracted with dichloromethane (30mL×2), the organic layer was washed with water, dried, and concentrated under reduced pressure to obtain intermediate 3 (3.6g, yield 63%), purity 93.80% (HPLC normalization m...

Embodiment 3

[0049] (1) Synthesis of intermediate 3

[0050] Phenylacetic acid (7.0 g) and tetrahydrofuran (250 mL) were sequentially added into a 500 mL reaction flask, stirred to dissolve, and cooled to 0°C. N 2 Under replacement conditions, 2 mol / L lithium diisopropylamide tetrahydrofuran solution (36 mL) was added in batches and reacted at room temperature for 1 h. The system was cooled down to -60°C, and a tetrahydrofuran solution (140 mL) of cyclopentanone (5.5 mL) was slowly added dropwise. After dropping, slowly rise to room temperature and continue to react for 10h. After the reaction was detected by TLC, 200 mL of saturated ammonium chloride solution was added to the system, stirred for 20 min, and ethyl acetate (30 mL×2) was added to the residual liquid for extraction. The aqueous layer was slowly adjusted to pH 5 with 6mol / L acetic acid, extracted with dichloromethane (50mL×2), the organic layer was washed with water, dried, and concentrated under reduced pressure to obtain ...

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PUM

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Abstract

The invention relates to a preparation method of an M-type cholinoceptor blocker cyclopentolate hydrochloride. The preparation method comprises that phenylacetic acid as an initial raw material and cyclopentanone undergoes a reaction to produce 2-(1-hydroxycyclopentyl)-phenylacetic acid (as intermediate 3), the 2-(1-hydroxycyclopentyl)-phenylacetic acid undergoes a replacement reaction and the reaction product undergoes a salification reaction to produce cyclopentolate hydrochloride. The preparation method can be operated simply, is safe and controllable, has low labor protection demands and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a preparation method of cyclopentolate hydrochloride. Background technique [0002] Cyclopentolate hydrochloride, whose chemical name is α-(1-hydroxycyclopentanone)-2-dimethylaminoethyl phenylacetate hydrochloride, is a white crystalline powder, easily soluble in water. The common name in English is Cyclopentolate Hydrochloride, the foreign trade names include: Cyclogyl, Cyclopen, Ciclolux, etc., and the domestic trade name is Saifeijie. Its structural formula is as follows: [0003] [0004] Cyclopentolate hydrochloride is a synthetic M-type cholinergic receptor antagonist, the mechanism of action is similar to that of tropicamide, it competitively antagonizes the cholinergic neurotransmitter acetylcholine (in the iris ciliary body and pupillary sphincter) Stimulation of M-choline receptors, resulting in cycloplegia and mydriasis. Studies have shown t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/08C07C219/10
CPCC07C51/367C07C213/06C07C213/08C07C219/10C07C59/54
Inventor 刘文涛杨传伟李新志段崇刚郑德强杨海霞龚艳艳边玲
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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