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Preparation method of quetiapine fumarate

A technology of quetiapine fumarate and fumaric acid, which is applied in the field of synthesis and purification of quetiapine fumarate, can solve the problems of incomplete reaction of raw materials, low product purity, low yield, etc., and achieve the reduction of impurities , the effect of shortening the reaction time

Active Publication Date: 2010-03-24
HAINAN SHENGKE LIFE SCI RES INST
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Problems solved by technology

[0005] EP240228 discloses that by 11-piperazine-dibenzo[B, F][1,4]thiazepine dihydrochloride, and 2-(2-chloroethoxy)ethanol reaction obtains free base and fumar It is obtained by acid salt formation, but the raw material reaction is incomplete and the product purity is low
The refinement of quetiapine fumarate adopts ethanol recrystallization, and the product obtained has more impurities, and the method of column chromatography is also disclosed to purify the free base, which has a low yield and is unfavorable for industrialization

Method used

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  • Preparation method of quetiapine fumarate
  • Preparation method of quetiapine fumarate
  • Preparation method of quetiapine fumarate

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Embodiment 1

[0024] In a 2L three-necked flask, sequentially add 676g of n-propanol, 248g of N-methylpyrrolidone, 56g of polyethylene glycol 400, 11-piperazine-dibenzo[B,F][1,4]thiazepine disalt Salt 140g, anhydrous sodium carbonate 160g, potassium iodide 5g and 2-(2-chloroethoxy)ethanol 70g, reflux for 6h. Add 30 g of anhydrous sodium carbonate and 25 g of 2-(2-chloroethoxy)ethanol, and reflux for 4 hours. Add 20 g of anhydrous sodium carbonate and 15 g of 2-(2-chloroethoxy)ethanol, and reflux for 4 hours. The reaction solution is poured into 1.8 kg of ethyl acetate and washed with 2.5 kg of water. Dilute hydrochloric acid was added, and the reaction was stirred at room temperature for 1h. The aqueous phase was washed with 3.5 kg of dichloromethane and 2.2 kg of ethyl acetate, respectively. The water phase was adjusted to a pH value of 10-11 with saturated sodium carbonate aqueous solution, 2.7 kg of ethyl acetate was added to the water phase for extraction, the organic phase was washed...

Embodiment 2

[0026] Add 400g of ethyl acetate and 139g of crude quetiapine fumarate into a 1L three-neck flask, stir at room temperature for 2h, filter with suction, rinse with 200g of ethyl acetate, dry the filter cake at 50°C (blast oven) to constant weight, and obtain a white solid 131 g, yield: 94.2%.

[0027] Purity: 99.74%, see attached data figure 1 ,2.

Embodiment 3

[0029] In a 5L reactor, sequentially add 1.69kg of n-propanol, 0.62kg of N-methylpyrrolidone, 140g of polyethylene glycol, 11-piperazine-dibenzo[B,F][1,4]thiazepine Hydrochloride 350g, anhydrous sodium carbonate 400g, potassium iodide 12.5g and 2-(2-chloroethoxy)ethanol 175g, reflux for 6h. Add 75g of anhydrous sodium carbonate and 62.5g of 2-(2-chloroethoxy)ethanol, and reflux for 4h. Add 50 g of anhydrous sodium carbonate and 32.5 g of 2-(2-chloroethoxy)ethanol, and reflux for 4 hours. The reaction solution is poured into 4.5 kg of ethyl acetate and washed with 6.25 kg of water. Dilute hydrochloric acid was added, and the reaction was stirred at room temperature for 1h. The aqueous phase was washed with 8.75 kg of dichloromethane and 5.5 kg of ethyl acetate, respectively. Adjust the pH value of the aqueous phase to 10-11 with saturated sodium carbonate aqueous solution, add 6.25kg of ethyl acetate to the aqueous phase for extraction, wash the organic phase with 2×5kg of wa...

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Abstract

The invention discloses a preparation method of quetiapine fumarate with high purity, which is suitable for industrialization and includes: taking 11-piperazine-dibenzo[B, F][1, 4]thiazepine dihydrochloride as the initial raw material, N-substituting and salt-forming to generate quetiapine fumarate. The highly finished product obtained by the method has high purity, the operating method is simple, the production cost is low, the yield is high, the preparation method is more suitable for industrialization, and the reaction time is shortened by adding a phase-transfer catalyst.

Description

technical field [0001] The invention relates to a process for synthesizing and refining quetiapine fumarate. Background technique [0002] Quetiapine Fumarate (Quetiapine Fumarate) is 2-[2-(4-dibenzo[b, f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol, hemifumarate, 2-[ 2-(-Dibenzo[b,f][1,4]thiazepine-11-yl-1-piperazinyl)ethoxy]-ethanol 1 / 2 fumarate has the following structure : [0003] [0004] Quetiapine fumarate is an atypical antipsychotic drug and a new type of thiaphenazine antipsychotic drug, which can block various neurotransmitter receptors such as dopamine (DA) and 5-hydroxytryptamine (5-AT) in the brain . [0005] EP240228 discloses that by 11-piperazine-dibenzo[B, F][1,4]thiazepine dihydrochloride, and 2-(2-chloroethoxy)ethanol reaction obtains free base and fumar Acid salt formation is obtained, but the raw material reaction is incomplete and the product purity is low. The refinement of quetiapine fumarate adopts ethanol recrystallization, and the o...

Claims

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Application Information

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IPC IPC(8): C07D281/16
Inventor 陈拥军谌伦华贺永宁焦育红
Owner HAINAN SHENGKE LIFE SCI RES INST
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