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Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole

A technology of aripiprazole and hydrate, which is applied in the field of synthesis and preparation of hydrate particles, which can solve the problems of many impurities, refractory aluminum chloride, high pollution, etc.

Pending Publication Date: 2021-08-06
北京逸诚医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In this patent route, the utilization rate of 7-hydroxy-3,4-dihydro-2(1H)quinolinone is relatively high, but the use of p-tert-butylbenzenesulfonyl chloride may also introduce genotoxic impurities, aluminum trichloride Difficult to handle and highly polluted, more impurities may be produced, so the advantage of this route is not obvious
[0016] In the patent CN03132278.6, the one-pot method is directly used, and the operation seems very simple, but the yield is very low, and there are many impurities in theory, so it is difficult to guarantee the quality of the final raw material medicine
[0017] There are many patents and documents about the synthesis of aripiprazole and the preparation of various crystal forms. Most of the patents have independent steps and need to be purified separately, especially the first step 7-(4-bromobutoxy)- The synthesis and purification of 3,4-dihydro-2(1H)-quinolinone is very cumbersome, so its market price is almost close to that of aripiprazole

Method used

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  • Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole
  • Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole
  • Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole

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Experimental program
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Effect test

Embodiment

[0117] Embodiment 1---7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (HARA2) synthesis

[0118] 7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (155.08g, 0.95mol), 1,4-dibromobutane (821.05g, 3.80mol), anhydrous potassium carbonate (196.97g , 1.43mol), acetone (700ml) were added to a 2L reaction flask, refluxed and stirred for 10h, cooled, and the acetone was evaporated under reduced pressure, water (800ml) was added to the residue, filtered, and the filter cake was washed with water (500ml). Slurry and filter twice with n-hexane (400m1), and air-dry at 60°C for 2 hours to obtain intermediate 2 (201.60g, 88.00%), in which the dimer accounted for 11.76% (see the attached figure 1 ), the yield is 62.47% according to the calculation of pure intermediate 2. It was directly used in the next step of synthesis without further purification.

[0119] Embodiment 2---7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (HARA2) synthesis

[0120] 7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (8.16g, 0.0...

Embodiment 3

[0121] Embodiment 3---7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (HARA2) synthesis

[0122] 7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (8.16g, 0.05mol), 1,4-dibromobutane (5.39g, 0.025mol), anhydrous potassium carbonate (7.60g , 0.055mol), DMF (100m1) were added to a 250ml reaction bottle, stirred at room temperature for 20h, added to 100ml of water, filtered to obtain 4.50g of solid (dimer accounted for 77.07%, HPLC spectrum see attached image 3 )). 4.40 grams of solids were refluxed with 100 ml of ethyl acetate for beating, cooled and filtered to obtain 3.55 grams of solids (dimers accounted for 91.67%, and the HPLC spectrum was shown in the attached Figure 4 ), see attached Figure 5 , This example shows that the equivalent of 1,4-dibromobutane will directly affect the proportion of dimer impurities. The solubility of dimer is relatively small, and most of dimer can be removed by beating with ethyl acetate.

Embodiment 4

[0123] Embodiment 4---7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (HARA2) synthesis

[0124] 7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (8.16g, 0.05mol), 1,4-dibromobutane (12.95g, 0.06mol), anhydrous potassium carbonate (8.29g , 0.06mol), DMF (50m1) were added to a 250ml reaction bottle, stirred at room temperature for 20h, cooled, added to 200ml of water, filtered to obtain 12.31g of solid (dimer accounted for 35.35%), and 10.43g of solid was taken with n-hexane Alkane (100ml) was beaten and filtered, and the filter cake was then beaten and filtered with 80ml of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain intermediate 2 (6.15g, 95.12%), of which the dimer accounted for 2.57%. Yield 46.26%.

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Abstract

The invention discloses a synthesis method of high-purity aripiprazole and a preparation method of hydrate particles of aripiprazole. The method comprises the following steps: step (1), carrying out Williamson etherification on 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-dibromobutane under the action of potassium carbonate to obtain 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone; step (2), synthesizing 2,3-dichlorophenyl piperazine hydrochloride from 2,3-dichloroaniline and bis(2-chloroethyl) amine hydrochloride; step (3), carrying out an alkylation coupling reaction of nitrogen on 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone and 1-(2,3-dichlorophenyl) piperazine hydrochloride, so as to prepare aripiprazole; (4) refining: recrystallizing aripiprazole by using ethyl acetate to obtain high-purity anhydrous aripiprazole; and (5) preparation of aripiprazole hydrate particles: refluxing and dissolving anhydrous aripiprazole in an ethanol-water system, and controlling the stirring rate and the cooling rate to obtain the aripiprazole hydrate particles.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the synthesis of aripiprazole and the preparation method of hydrate particles thereof. Background technique [0002] Aripiprazole (Aripiprazole), chemical name: 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 (1H)-quinolinone, abbreviated as HARA in this patent, has the following structural formula: [0003] [0004] Aripiprazole is a quinolinone derivative, which is the first third-generation atypical antipsychotic new drug, invented by Otsuka Company of Japan in 1988, and later cooperated with Bristo-Myeres Squibb Company of the United States Jointly developed and approved by the US FDA on November 15, 2002, it is currently clinically used to treat schizophrenia. Its chemical structure is as follows: figure 1 shown. Studies have shown that compared with typical and atypical antipsychotics that have been marketed, this drug has better curative...

Claims

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Application Information

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IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 丁坚英韩斌吴恩龙
Owner 北京逸诚医药科技有限公司