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Preparation method and intermediate of brexpiprazole and preparation method of intermediate

A kind of technology of epizole and compound, applied in the field of pharmaceutical chemical synthesis

Active Publication Date: 2016-05-04
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses column chromatographic purification many times and is not suitable for mass production industrial processes

Method used

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  • Preparation method and intermediate of brexpiprazole and preparation method of intermediate
  • Preparation method and intermediate of brexpiprazole and preparation method of intermediate
  • Preparation method and intermediate of brexpiprazole and preparation method of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Embodiment 1: the preparation of compound 8a

[0083]

[0084] At room temperature, in a 100ml three-necked flask, add compound 9a (40.6g, 0.20mol), bis(2-chloroethyl)amine (34.1g, 0.24mol), potassium carbonate (55.3g, 0.40mol), toluene (400ml), Heat up to 110°C and reflux, react for 4 hours, TLC observes that the reaction is complete; the system is cooled to room temperature, add 400ml of water, separate the layers, extract the aqueous layer with 400ml of toluene, combine the organic layers, concentrate to obtain 64.2g of solid, and use 200ml of n-heptane Make a slurry, filter, and remove the solvent from the filtrate to obtain 57.9 g of solid. The yield is 89.1%.

[0085] 1 HNMR (300MHz, CDCl 3 ): δ10.22(s,1H),7.17(t,J=14.8Hz,1H),7.07(dd,J=15.0,3.3Hz,1H),6.86(dd,J=14.7,3.4Hz,1H) ,3.85-3.53(m,8H).

Embodiment 2

[0086] Embodiment 2: the preparation of compound 7a

[0087]

[0088] At room temperature, a 500ml three-necked flask was mechanically stirred, and compound 8a (48.8g, 0.15mol), ethyl thioglycolate (21.6g, 0.18mol), N,N-dimethylformamide (675ml), potassium carbonate (45.6 g, 0.33mol), heated to 100°C, stirred and reacted for 4 hours, observed by TLC, the reaction of the raw materials was complete; cooled to room temperature, added 750ml of water, 750ml of ethyl acetate, separated, added 750ml of ethyl acetate to the water layer for extraction, and combined the organic layer, washed with 900ml of water, washed with 600ml of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed from the organic layer to obtain 51.8g of a brown solid. Add 225ml of methyl tert-butyl ether and raise the temperature to 40°C and stir for 1 hour, then lower it to room temperature and stir for 2 Filtrate for 1 hour, remove the solvent from the filtrate, and dry to obtain ...

Embodiment 3

[0090] Embodiment 3: the preparation of compound 6a

[0091]

[0092] At room temperature, in a 250ml three-necked flask, add compound 7a (41.5g, 0.12mol), methanol 200ml, and water 40ml, cool down to 0°C, add lithium hydroxide monohydrate (10.1g, 0.24mol) in three batches, and stir for 5 minutes. Raise the temperature to 50°C and react for 3 hours. TLC observed that the reaction of the raw materials was complete. Concentrate the reaction solution under reduced pressure in a water bath at 40°C until it stopped dripping. Add 2000ml of water and adjust the pH to 2-3 with 1mol / L hydrochloric acid, and extract twice with 1200ml of ethyl acetate. , combined the organic layers, washed with 800ml of saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain off-white solid, then added 800ml of methyl tert-butyl ether for beating and filtered, the filtrate was desolventized, dried to obtain 32.5g of off-white solid, and collected The rate is 85.1%.

[0093] 1 HN...

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Abstract

The invention relates to the technical field of medicinal chemical synthesis and in particular relates to a preparation method and an intermediate of brexpiprazole and a preparation method of the intermediate. The preparation method of the brexpiprazole is shown in the following flow chart (described in the specification), wherein X1 and X2 are halogen, X1 is bromine preferably, and X2 is chlorine preferably. The invention provides a preparation method of a new compound 1 by providing new compounds 2 and 3. The preparation method of the new compound 1 mainly comprises two-step reaction, namely substitution and cyclization. Byproducts produced in the preparation method of the new compound 1 are less and are easy to separate, and column chromatography treatment does not need to be carried out. Meanwhile, the invention also provides a preparation method of the compound 2. The preparation method of the compound 2 has the advantages that generation of byproducts is greatly reduced, overall yield of reaction is improved, column chromatography treatment does not need to be carried out and production time is shortened while production cost is reduced, so that the preparation method of the compound 2 is applicable to industrial production.

Description

technical field [0001] The present invention relates to the field of chemical synthesis of medicines, in particular to a preparation method of epizole and its intermediate and the preparation method of the intermediate Background technique [0002] As an adjuvant drug for the treatment of major depressive disorder (MDD) in adults and a drug for treating schizophrenia in adults, Ipizopa was discovered by Otsuka Pharmaceutical Co., Ltd. and jointly developed with Lundbeck Pharmaceuticals. The product was approved by the US FDA on July 11, 2015, and the trade name is Rexulti. [0003] Patent CN200680011923.0 specifically discloses a synthetic method of epizole, first using 7-hydroxyl-1H-quinolin-2-one (a) and 1-bromo-4-chlorobutane (b) to synthesize 7 -(4-Chlorobutoxy)-1H-quinolin-2-one (c), then compound c and benzothiophene (d) are docked to synthesize epirazole (e). The specific process is as follows: [0004] [0005] In the process of synthesizing compound c, a large...

Claims

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Application Information

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IPC IPC(8): C07D409/12C07D215/22C07D333/54C07D333/70C07C223/06C07C221/00
CPCC07C221/00C07C223/06C07D215/22C07D333/54C07D333/70C07D409/12
Inventor 叶天健陆修伟郁光亮陈尧石松安
Owner ZHEJIANG YONGNING PHARMA
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