Novel method for preparing penehyclidine hydrochloride

A technology of penehyclidine hydrochloride and penehyclidine, which is applied in the field of preparation of penehyclidine hydrochloride, can solve the problems of high cost, harsh conditions, and difficult purification of penehyclidine hydrochloride, and achieve the elimination of distillation Crystallization, low production cost, cheap and easy-to-obtain raw materials

Pending Publication Date: 2022-07-29
南京亿华药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the existing synthesis process, there are steps such as using sulfur-containing compounds to carry out epoxidation and using sodium hydride to open the ring. The reagents are expensive, the conditions are harsh, the product separation and purification are difficult, and the yield is limited, which makes the cost of penhyclidine hydrochloride It is very high, so it is necessary to further reduce its cost by developing new synthetic routes

Method used

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  • Novel method for preparing penehyclidine hydrochloride
  • Novel method for preparing penehyclidine hydrochloride
  • Novel method for preparing penehyclidine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of Intermediate 1: Add quinuclidin-3-ol (50g, 0.39mol), paraformaldehyde (39.0g, 0.43mol), and 250ml dimethyl sulfoxide into a 2000ml three-necked flask in turn, stir rapidly, and pass through to dry Hydrogen chloride gas (produced by mixing concentrated sulfuric acid and sodium chloride), the temperature of the reaction solution was controlled by an ice-water bath not to exceed 40 °C, and the hydrogen chloride was passed in for 5 hours, then stopped, and nitrogen was passed into the reaction solution to purge the hydrogen chloride gas, and 750ml of water was added. , Slowly add saturated sodium bicarbonate solution dropwise to adjust pH to 8-9, extract twice with 100 ml of ethyl acetate each time, combine the organic layers, wash with 150 ml of saturated brine, dry over anhydrous magnesium sulfate, filter, and distill the filtrate under reduced pressure to dry to obtain 41.0 g of pale yellow liquid.

Embodiment 2

[0030] Preparation of intermediate 2: Dissolve 38 g of intermediate 1 in 80 ml of anhydrous tetrahydrofuran, stir evenly, add 10 ml to a 250 ml three-necked flask, add magnesium chips (6.3 g, 0.26 mol), and 2 elemental iodine, stir evenly, and react The liquid turned yellow, heated to about 45 ℃ of the reaction liquid, and began to generate bubbles, the color of the reaction liquid gradually subsided, and the reaction was initiated. The reaction was continued to be stirred for 2 h to reflux to obtain a solution of Intermediate 2, which was directly used in the next reaction.

Embodiment 3

[0032] Preparation of intermediate 3: N-methoxy-N-methylcyclopentanecarboxamide (31.4 g, 0.20 mol) and 125 ml of anhydrous tetrahydrofuran were added to a 500 ml three-necked reaction flask, respectively, and the intermediate obtained in Example 2 was added 2 The solution was added dropwise to the above solution through a constant pressure dropping funnel. During the dropwise addition, the temperature of the reaction solution was controlled not to exceed 30°C by means of an ice-water bath and the drop rate. The reaction was quenched. After the dropwise addition, saturated potassium carbonate aqueous solution was added in batches to adjust the pH to 8-9, the solution was separated, dried over anhydrous magnesium sulfate, and filtered to obtain the tetrahydrofuran solution of intermediate 3, which was directly used in the next reaction.

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Abstract

The invention discloses a novel method for preparing penehyclidine hydrochloride, which comprises the following steps: taking quinuclidin-3-ol as a raw material, carrying out chloromethylation on the quinuclidin-3-ol, trioxymethylene and hydrochloric acid to obtain an intermediate 1, preparing the intermediate 1 into a Grignard reagent to obtain an intermediate 2, carrying out addition reaction on the intermediate 2 and N-methoxyl-N-methylcyclopentanecarboxamide to obtain an intermediate 3, and preparing the intermediate 3 into the penehyclidine hydrochloride. And reacting the intermediate 3 with a phenylmagnesium bromide Grignard reagent to obtain penehyclidine, and salifying the penehyclidine through hydrochloric acid to obtain the penehyclidine hydrochloride. According to the method, the reaction conditions are simple, the steps 2-4 are a one-pot shrinkage reaction, the operation is simple and easy to implement, a large amount of operations such as distillation and crystallization are omitted, and the emission of volatile organic gases (VOCs) and organic waste liquid is greatly reduced; the preparation raw materials are cheap and easy to obtain, the production cost is low, and industrial production prospects are achieved.

Description

technical field [0001] The invention relates to a new preparation method of penehyclidine hydrochloride, and belongs to the field of pharmaceutical synthesis. Background technique [0002] The main purpose of pre-anesthetic medication is to relieve anxiety, sedation, increase pain threshold, reduce airway secretions, prevent autonomic adverse reflexes, reduce gastric juice volume and increase pH value, prevent vomiting, reduce the dosage of anesthetics and adverse reactions. Anticholinergic drugs are used as premedication for anesthesia. They can block the cholinergic receptors on the effectors innervated by the postganglionic cholinergic nerves, inhibit the action of various smooth muscles and the secretion of glands, and inhibit the vagus nerve reflex, thereby balancing the autonomic function. function of the nervous system. The application of anticholinergic drugs can reduce anesthesia and surgical complications and reduce the risk of surgery. Especially for children, g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 杨鹏辉袁和亮刘武
Owner 南京亿华药业有限公司
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