A kind of preparation new method of drotaverine hydrochloride intermediate

A technology for drotaverine hydrochloride and intermediates, which is applied in the field of preparing drotaverine hydrochloride intermediates, can solve the problems of high equipment requirements, operator safety, environmental protection risks, potential safety hazards, and the like, and achieves safe and efficient solutions. Environmental concerns, avoidance of reaction steps, good practical effects

Active Publication Date: 2021-08-17
JIANGSU LIANHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Existing preparation 3, will use highly toxic reagent cyanide in the method for 4-diethoxyphenylacetonitrile, bring risk to operator's safety and environmental protection; From 3,4-diethoxyphenylacetonitrile The preparation process of 3,4-diethoxyphenethylamine requires pressurized hydrogenation, which requires high equipment and has potential safety hazards

Method used

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  • A kind of preparation new method of drotaverine hydrochloride intermediate
  • A kind of preparation new method of drotaverine hydrochloride intermediate
  • A kind of preparation new method of drotaverine hydrochloride intermediate

Examples

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Comparison scheme
Effect test

Embodiment 1

[0035] A kind of preparation new method of drotaverine hydrochloride intermediate 3,4-diethoxyphenylacetic acid (V), comprises the following steps:

[0036] 1) Synthesis of 1,2-diethoxy-4-bromobenzene (II)

[0037] Add 529 mmol of 4-bromocatechol (I) and 3 L of acetonitrile into the four-neck flask, add 2.113 mol of potassium carbonate and 1.693 mol of iodoethane under stirring conditions, raise the temperature to 70-80°C, and keep the temperature for 4-6 hours. After the reaction was completed, filter at room temperature, evaporate the filtrate to dryness under reduced pressure, add 600 mL of ethyl acetate to dissolve it, and wash with water 3 times, 100 mL each time. Dry over anhydrous sodium sulfate and evaporate to dryness under reduced pressure to obtain a yellow oily substance, namely 449 mmol of 1,2-diethoxy-4-bromobenzene (II), with a molar yield of 84.9%. Product 1,2-diethoxy-4-bromobenzene (II) is characterized, 1 H NMR (500MHz, MeOD): δ: 7.033~7.038(s, 1H, -ArH), ...

Embodiment 2

[0043] A kind of preparation new method of drotaverine hydrochloride intermediate 3,4-diethoxyphenethylamine (VII), comprises the following steps:

[0044] 1) Synthesis of 1,2-diethoxy-4-bromobenzene (II)

[0045] Add 529 mmol of 4-bromocatechol (I) and 3 L of acetonitrile into the four-neck flask, add 2.113 mol of potassium carbonate and 1.693 mol of iodoethane under stirring conditions, raise the temperature to 70-80°C, and keep the temperature for 4-6 hours. After the reaction was completed, filter at room temperature, evaporate the filtrate to dryness under reduced pressure, add 600 mL of ethyl acetate to dissolve it, and wash with water 3 times, 100 mL each time. Dry over anhydrous sodium sulfate and evaporate to dryness under reduced pressure to obtain a yellow oily substance, namely 449 mmol of 1,2-diethoxy-4-bromobenzene (II), with a molar yield of 84.9%. Product 1,2-diethoxy-4-bromobenzene (II) is characterized, 1 H NMR (500MHz, MeOD): δ: 7.033~7.038(s, 1H, -ArH), 6...

Embodiment 3

[0053] A kind of preparation new method of drotaverine hydrochloride intermediate 3,4-diethoxyphenylacetic acid (V), comprises the following steps:

[0054] 1) Synthesis of 1,2-diethoxy-4-bromobenzene (II)

[0055] Add 529 mmol of 4-bromocatechol (I) and 3 L of acetonitrile into a four-neck flask, add 2.138 mol of potassium hydroxide and 1.167 mol of diethyl sulfate under stirring conditions, raise the temperature to 70-80°C, and keep the temperature for 4-6 hours. After the reaction was completed, filter at room temperature, evaporate the filtrate to dryness under reduced pressure, add 600 mL of ethyl acetate to dissolve, wash with 5% sodium hydroxide solution 3 times, 100 mL each time, and wash 3 times with water, 100 mL each time. Dry over anhydrous sodium sulfate and evaporate to dryness under reduced pressure to obtain a yellow oily substance, namely 457 mmol of 1,2-diethoxy-4-bromobenzene (II), with a molar yield of 86.4%. Characterize the product 1,2-diethoxy-4-bromobe...

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Abstract

The invention discloses a new method for preparing a drotaverine hydrochloride intermediate. reaction to prepare 1,2-diethoxy-4-bromobenzene; 2) 1,2-diethoxy-4-bromobenzene via Suzuki-Miyaura coupling reaction with ethyl bromoacetate or methyl bromoacetate The reaction produces 3,4-diethoxyphenylacetic acid ester; 3) 3,4-diethoxyphenylacetic acid ester is hydrolyzed to obtain 3,4-diethoxyphenylacetic acid; 4) 3,4 ‑diethoxyphenylacetate and ammonia to obtain 3,4‑diethoxyphenylacetamide; 5) 3,4‑diethoxyphenylacetamide is reduced to obtain 3,4‑diethoxy Phenylethylamine. This application adopts the way of direct preparation, and the process of preparing 3,4-diethoxyphenylacetonitrile avoids using sodium cyanide, and adopts aluminum hydride lithium reduction when preparing 3,4-diethoxyphenylethylamine, and avoids In order to use the method of pressurized hydrogenation, the safety and environmental protection problems are effectively solved, the process is simple, easy to realize, and has good practicability.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a new method for preparing an intermediate of drotaverine hydrochloride. Background technique [0002] Drotaverine hydrochloride, chemical name: 1-{(3,4-diethoxyphenyl)methylene}-6,7-diethoxy-1,2,3,4 -Tetrahydroisoquinoline hydrochloride, trade name RNO-SPA (RNO-SPA), is a novel antispasmodic drug developed by the Chinoin pharmaceutical company, a joint venture company of the French company Sanofi in Hungary. The drug is an isoquinoline derivative, and compared with traditional anisodamine, atropine and other anticholinergic antispasmodics, it is characterized by comprehensive effects, long-lasting curative effect, and small adverse reactions. The drug's indications include coronary insufficiency, obliterative endarteritis, angina pectoris, gastrointestinal smooth muscle spasm, irritable bowel syndrome, biliary colic, renal colic and urinary tract spasm, uterine cramps, d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/02C07C217/60C07C51/09C07C59/64
Inventor 黄坤李威王冬军王道生褚青松秦雄剑
Owner JIANGSU LIANHUAN PHARMA
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