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Method for preparing pharmaceutical pure quetiapine fumarate

A technology for preparing quetiapine fumarate and drugs, applied in organic chemistry and other fields, can solve problems such as environmental pollution, achieve the effects of reducing costs, shortening the reaction cycle, and improving quality

Active Publication Date: 2008-06-04
HUNAN DONGTING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved in the present invention is: provide the production method of pharmaceutical pure quetiapine fumarate, the relevant impurity content of the quetiapine fumarate produced by this method is controlled below 0.1%, good in quality and high in yield , reduce the consumption of raw materials, and at the same time solve the problem of recycling phosphorus oxychloride and the problem of environmental pollution

Method used

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  • Method for preparing pharmaceutical pure quetiapine fumarate
  • Method for preparing pharmaceutical pure quetiapine fumarate
  • Method for preparing pharmaceutical pure quetiapine fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] ① Chlorination: Add 20Kg of dibenzo[b.f][1.4]thiazepine-11-[10H]ketone, 128Kg of toluene, 6.5Kg of N-N-dimethylaniline, and 28Kg of phosphorus oxychloride to the reaction In the tank, through N 2 , stir and heat up to reflux, time the reaction for 6.5 hours, when the reaction is over, cool down to 17°C, add ice (slowly) 100Kg, stir for 30 minutes, filter, extract by layer, wash with water until neutral, dehydrate under reduced pressure, decolorize, and get chlorine compound in toluene.

[0029] ② Addition into salt: put the toluene liquid of the above chloride into the reaction tank according to 20Kg ring compound, N-[2-(2-hydroxyethoxy) ethyl]piperazine 10Kg, and anhydrous sodium carbonate 12Kg , stir and heat up to reflux, time the reaction for 6.5 hours, when the reaction is over, filter, add 5% hydrochloric acid 40Kg layered extraction, then add solid Na 2 CO 3 Adjust the pH to 10-11, add 55Kg of toluene to dissolve, wash with water until neutral, and dehydrate u...

Embodiment 2

[0033] 1. Chlorination: the process steps are the same as in Example 1, except that some technical parameters are different: add 120Kg of toluene, 7.2Kg of N-N-dimethylaniline, 40Kg of thionyl chloride, timed reaction for 7 hours, cool to 20°C, stir for 20 minute.

[0034] 2. Addition into salt: process step is the same as embodiment 1, but some technical parameters are different: add N-[2-(2-hydroxyethoxy) ethyl] piperazine 13Kg, anhydrous sodium carbonate 11Kg, timed reaction 6 hours , add 7% hydrochloric acid, adjust pH9-10, get quetiapine 24Kg, add 4Kg of fumaric acid to get quetiapine fumarate 24.0Kg, addition salt yield 67%, relevant impurity content 0.085%. Its spectrum is as figure 2 As shown, the peak area table is as follows:

[0035]

[0036] Total: 10056.302

Embodiment 3

[0038] 1. Chlorination: the process steps are the same as in Example 1, except that some technical parameters are different: add 130Kg of toluene, 7Kg of N-N-dimethylaniline, 39Kg of phosphorus oxychloride, timed reaction for 7 hours, cool to 20°C, and stir for 30 minutes .

[0039] 2. Addition into salt: process step is the same as embodiment 1, but some technical parameters are different: add N-[2-(2-hydroxyethoxy) ethyl] piperazine 14Kg, anhydrous sodium carbonate 13Kg, timed reaction 6.5 hours , add 7% hydrochloric acid, adjust PH10-11, get quetiapine 24.0Kg, add 3.8Kg fumaric acid, get quetiapine fumarate 24.3Kg, one-way yield 67.8%, relevant impurity content 0.075%. Its spectrum is as image 3 As shown, the peak area table is as follows:

[0040]

[0041] Total: 6444.376

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Abstract

The invention relates to a preparation method of pure quetiapine fumarate and the steps of the process thereof are that: (1)chlorination: four materials of dibenzo(b,f)(1,4)thiazepine-11-(10H)-ketone, chlorinated oxidant, N,N-Dimethylaniline and toluol react to obtain toluol solution of chloride; (2) addition and salification: the toluol solution of chloride reacts to obtain quetiapine according to the ratio of 1:0.5-1:0.5-0.8 of cyclic product (kg) to N-(2-(2-Hydroxyethoxy)ethyl)piperazine (kg) to anhydrous sodium carbonate; the mixture of the quetiapine (kg) and fumaric acid (kg) and ethanol (kg) is then salified to obtain the quetiapine fumarate according to the respective ratio 1:0.1-0.3:2-4. The invention effectively controls the impurity content of the quetiapine fumarate below 0.1 percent, improves the quality of products and achieves the standard of pharmaceutical purity and causes little side effects to patients. In addition, the invention also solves the problems of recovery of phosphorus oxychloride and environment pollution, shortens the cycle of reaction, improves the yield and reduces the cost.

Description

technical field [0001] The invention relates to the production of a chemical drug for treating schizophrenia, that is, a production method for preparing pure quetiapine fumarate. Background technique [0002] Quetiapine fumarate has been developed and produced for many years, and its production steps and process conditions are as follows: [0003] 1. chlorination reaction, batching ratio: dibenzo [b.f] [1.4] thiazepine-11- [10H] ketone (kg): phosphorus oxychloride (kg): N-N-dimethylaniline (kg)= 1:9:0.33 [0004] Put the above three raw materials into the reaction tank, stir and heat up to reflux, and time the reaction for 6.5 hours. When the reaction is over, recover phosphorus oxychloride, add toluene while it is hot to dissolve, cool down to 20°C, add ice water, stir for 30 minutes, and filter , layered, washed with water until neutral, dried over anhydrous magnesium sulfate for more than 20 hours, filtered, and recovered toluene under reduced pressure to obtain chlorid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/16
Inventor 吴南林唐焕宇
Owner HUNAN DONGTING PHARMA
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