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Preparation method of cyclopentolate hydrochloride intermediate

A technology for cyclopentolate and intermediates, which is applied in the field of preparation of cyclopentatropate hydrochloride intermediates, can solve the problems of high labor protection requirements for workers, high humidity requirements, unfavorable safety production and the like, and achieves reduction of production risks and a The requirements of labor protection for workers, the reduction of crystallization and impurity removal procedures, and the effect of environmental protection

Inactive Publication Date: 2019-11-22
SHANDONG SHEN LIAN BIOLOGY TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Because 2-(dimethylamino)ethylphenylacetate has multiple active sites, the selectivity is poor, and the post-treatment of thionyl chloride requires distillation operation, which requires high equipment, and is relatively corrosive to reaction equipment and distillation equipment. Powerful, not conducive to industrial production
[0015] After searching, it is found that 2-(1-hydroxycyclopentyl)-phenylacetic acid is the key intermediate for the preparation of cyclopentolate. Method 1 requires self-made formatting reagents, requires anhydrous raw materials and reagents, and requires relatively high humidity in the working environment. High, cumbersome operation, harsh response regulations
The second is to use anhydrous ether as a solvent, which has a low boiling point, is flammable and explosive, and has strong anesthetic properties, which is not conducive to safe production.
Third, the purity of the product obtained after quenching is low, and multi-step refining is required to meet the purity requirement, and the yield is low
Because organic alkalis are highly corrosive, they require high labor protection for workers, which is not conducive to safe production in the workshop.

Method used

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  • Preparation method of cyclopentolate hydrochloride intermediate
  • Preparation method of cyclopentolate hydrochloride intermediate
  • Preparation method of cyclopentolate hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 1. Preparation of Phenylacetic Acid

[0041] Add 300ml of purified water and 8.4g (0.21mol) of sodium hydroxide to the reaction flask, stir, dissolve, add 30.0g (0.20mol) of methyl phenylacetate, heat up to 50°C, stir for 2h, cool down to T=10°C , 18.4ml (0.23mol) of hydrochloric acid was added dropwise, stirred for 1h, filtered, and dried to obtain 25.9g of phenylacetic acid (95.1% yield), with a purity of 99.9% (HPLC area purity method).

[0042] 2. Preparation of 2-(1-hydroxycyclopentyl)-phenylacetic acid

[0043] Add 300ml of 1M phenylmagnesium chloride tetrahydrofuran solvent into the reaction flask, raise the temperature to 40°C, add dropwise 50ml of tetrahydrofuran containing 17.7g (0.13mol) of phenylacetic acid, after the dropwise completion, keep stirring for 2h, then add 12.0g (0.14mol) of cyclopentanone dropwise. mol), the temperature was lowered to 0°C for 2 hours after dropping, and the reaction liquid was quenched by adding 500 ml of 5% hydrochloric acid ...

Embodiment 2

[0045] 1. Preparation of Phenylacetic Acid

[0046] Add 300ml of purified water and 15.2g (0.11mol) of potassium carbonate to the reaction flask, stir, dissolve, add 30.0g (0.20mol) of methyl phenylacetate, raise the temperature to 60°C, stir for 3h, cool down to T=0°C, 18.4ml (0.23mol) of hydrochloric acid was added dropwise, stirred for 2h, filtered, and dried to obtain 25.9g of phenylacetic acid (93.6% yield) with a purity of 99.8% (HPLC area purity method).

[0047] 2. Preparation of 2-(1-hydroxycyclopentyl)-phenylacetic acid

[0048] Add 300ml of 1M isopropylmagnesium chloride tetrahydrofuran solvent into the reaction flask, heat up to 30°C, add dropwise 50ml of tetrahydrofuran containing 17.7g (0.13mol) of phenylacetic acid, after the dropwise completion, keep stirring for 1h, then add dropwise 12.0g of cyclopentanone ( 0.14mol), after dropping, keep it warm for 1 hour, cool down to 0°C, quench the reaction solution by adding 500ml of 10% hydrochloric acid aqueous solut...

Embodiment 3

[0050] The phenylacetic acid obtained in Example 1 was used as a raw material to prepare 2-(1-hydroxycyclopentyl)-phenylacetic acid.

[0051] Add 150ml of 2M m-toluene magnesium chloride tetrahydrofuran solvent into the reaction flask, add 50ml of tetrahydrofuran containing 17.7g (0.13mol) of phenylacetic acid dropwise at room temperature, after the dropwise completion, stir for 2h, add dropwise 12.0g (0.14mol) of cyclopentanone, dropwise After that, the temperature was raised to 35°C for 1 hour, and the temperature was lowered to 0°C. The reaction solution was quenched by adding 300ml of 15% aqueous hydrochloric acid solution prepared in advance, and extracted by adding 100ml of ethyl acetate. Evaporate to dryness under reduced pressure to obtain an oil, add cyclohexane to beat at room temperature for 8 hours, filter, and dry to obtain 24.5 g of 2-(1-hydroxycyclopentyl)-phenylacetic acid (yield 85.6%) with a purity of 95.2% (HPLC area normalization one method).

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and relates to a preparation method of a cyclopentolate hydrochloride intermediate. Methyl phenylacetate is used as a raw material, the price is low, the methyl phenylacetate is commercially produced, the goods source is sufficient, and the quality is stable. The commercially available Grignard reagent is adopted, so that the risk that flammable and explosive reagents are used and are not controlled when the Grignard reagent is self-made is avoided. Commercially available Grignard reagents have been industrially produced and are convenient and easy to obtain. And the intermediate is purified by adopting a crystallization solvent, so that the purity of the intermediate is ensured, the preparation yield of the cyclopentolate hydrochloride is increased, and subsequent crystallization and impurity removal processes are reduced. And the production risk and the labor protection requirement of workers are reduced, environmental protection is facilitated, and the economic benefit is improved. The yield of phenylacetic acid can reach 95% or above, the purity of phenylacetic acid can reach 99.9% or above, the production requirements of the cyclopentolate hydrochloride intermediate are completely met, and the yield and purity of the product 2-(1-hydroxycyclopentyl)-phenylacetic acid are much higher than those of 2-(1-hydroxycyclopentyl)-phenylacetic acid produced by a common method.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and relates to a preparation method of a cyclopentolate hydrochloride intermediate. Background technique [0002] The chemical name of cyclopentolate hydrochloride is: α-(1-hydroxycyclopentyl)phenylacetic acid-2-dimethylaminoethyl ester hydrochloride, which is a synthetic anticholinergic drug developed by Alcon Company, which has the functions of dilating mydriasis and regulating paralysis role. Alcon launched cyclopentolate hydrochloride eye drops in 1975 for clinical use in mydriasis and cycloplegia. Its structural formula is as follows: [0003] [0004] According to existing literature reports, there are the following three synthetic routes: [0005] Synthetic Route 1: Patent US2554511 [0006] [0007] This patent reports the synthetic method of cyclopentolate hydrochloride for the first time, prepares isopropyl magnesium bromide with isopropyl bromide, magne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/367C07C51/43C07C59/54
CPCC07C51/02C07C51/09C07C51/367C07C51/43C07C2601/08C07C59/54C07C57/32
Inventor 高云兵苗元旭张兆元李立甄爱华刘建洋
Owner SHANDONG SHEN LIAN BIOLOGY TECH CO LTD
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