Preparation method of brexpiprazole

A compound, room temperature technology, applied in organic chemistry and other directions, can solve the problems of complex post-processing, high cost, and affecting the quality of brexpiprazole

Active Publication Date: 2016-04-06
SHENZHEN FONCOO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route uses heavy metal palladium to catalyze the reaction, which is expensive, complicated post-treatment, and is prone to produce the following two impurities (patent WO2013015456): and Affect the quality of brexpiprazole

Method used

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  • Preparation method of brexpiprazole
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  • Preparation method of brexpiprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 3 preparations of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride compound

[0022] Add 14.92g (100mmol) of 4-aminobenzo[b]thiophene and 17.85g (100mmol) of bis(2-chloroethyl)amine hydrochloride into the reaction flask, then add 0.86g (5mmol) of p-toluenesulfonamide ) and xylene 225mL, stirred and reacted at 120-150°C for 16 hours. Then it was naturally lowered to room temperature, and then lowered to 0°C for 2 hours, and 21.66 g of off-white solid crystals were obtained by suction filtration, with a yield of 85.0% and a purity of 98%.

[0023] 1 H-NMR (DMSO-d 6 )δppm: 3.24-3.35 (8H, m), 6.94 (1H, d, J = 7.6Hz), 7.31 (1H, dd, J = 7.8Hz, 7.8Hz), 7.50 (1H, d, J = 5.5Hz) , 7.68 (1H, d, J=8.1Hz), 7.73 (1H, d, J=5.5Hz), 9.36 (2H, brs).

Embodiment 2

[0025] Preparation of 7-[4-(4-benzo[b]thiophen-4yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one compound 1

[0026] Add 14.01g (55mmol) of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride, 15.90g (150mmol) of sodium carbonate, 140mL of water and 70mL of methanol into the reaction flask, heat up to 50°C and stir for 30min After the solid was dissolved, 12.58 g (50 mmol) of 7-(4-chlorobutoxy)-1H-quinolin-2-one was added, then the temperature was raised to 70° C., and the reaction was stirred for about 16 hours, then naturally cooled to room temperature, and then lowered to Heat it at 0°C for 2 hours, and filter with suction to obtain 20.70 g of off-white solid crystals, with a yield of 95.5% and a purity of 98%.

[0027] 1 H-NMR (DMSO-d 6 )δppm: 1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.45 (2H, t, J=7Hz), 2.5-2.8 (4H, m), 2.9-3.2 (4H, m), 4.06 (2H, t, J = 6.5Hz), 6.31 (1H, d, J = 9.5Hz), 6.75-6.85 (2H, m), 6.89 (1H, d, J = 7.5Hz), 7.28 (1H, dd , J=8Hz, 8Hz), 7.40(1H, d, J=5.5Hz), 7....

Embodiment 3

[0029] 4 Preparation of 7-(4-chlorobutoxy)-1H-quinolin-2-one compound

[0030] Add 16.12g (100mmol) of 7-hydroxy-2(1H)-quinoline copper into the reaction flask, then add 160mL of methanol, then add 7.01g (125mmol) of potassium hydroxide, raise the temperature to 50°C and stir for 30min, after the solid dissolves Add 51.44 g (300 mmol) of 1-bromo-4-chlorobutane, then raise the temperature to reflux, stir and react for 16 hours, then cool down to room temperature naturally, then lower to 0-5°C and keep warm for 2 hours. g, yield 81.2%, purity 95%.

[0031] 1 H-NMR (DMSO-d 6 )δppm: 1.95-2.15 (4H, m), 3.60-3.70 (2H, m), 4.10 (2H, t, J = 5.6Hz), 6.56 (1H, dd, J = 9.0Hz, 3.8Hz), 6.82 ( 1H, dd, J=8.7Hz, 2.4Hz), 6.86 (1H, d, J=2.3Hz), 7.45 (1H, d, J=8.7Hz), 7.75 (1H, d, J=9.4Hz), 12.55 (1H, brs).

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Abstract

The invention discloses a preparation method of a compound brexpiprazole represented by formula (1). The preparation method adopts 4-aminobenzo[b]thiophene as an initial raw material to synthesize a piperazine ring, avoids a heavy metal palladium catalyzed reaction, reduces the synthesis steps and impurities, and reduces the cost.

Description

technical field [0001] The present invention relates to the preparation method of the compound brexpiprazole shown in formula (1), especially use 4-aminobenzo[b]thiophene as starting material to synthesize piperazine ring, avoid heavy metal palladium catalyzed reaction, reduce synthesis steps, reduce The preparation method of the invention belongs to the technical field of raw material drug synthesis. technical background [0002] Brexpiprazole is the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound developed by Otsuka Pharmaceutical Company for the adjuvant treatment of schizophrenia and major depression. The best-selling drug - another blockbuster after aripiprazole. [0003] Brexpiprazole has a wide range of activities in multiple monoamine systems, the partial agonist activity of dopamine D2 receptors is reduced, and the affinity for specific 5-HT receptors (such as 5-HT1A, 5-HT2A, 5-HT7) is increased, It has better efficacy and t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12
Inventor 彭锦安周革文
Owner SHENZHEN FONCOO PHARMACEUTICAL CO LTD
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