New synthesis method of aripiprazole

Abstract

A preparation method of aripiprazole comprises the following steps: reacting a raw material tetrahydrofuran with paratoluensulfonyl chloride under the catalysis of zinc chloride to obtain 4-chlorobutyl paratoluenesulfonate in a rapid mild high-output manner; reacting 4-chlorobutyl paratoluenesulfonate with 7-hydroxyquinolinone under the action of a solvent and an alkali to generate 4-chlorobutoxyquinolinone; and reacting chlorobutoxyquinolinone with piperazine hydrochloride in the certain solvent and the alkali to generate aripiprazole. Each of the intermediate 4-chlorobutoxyquinolinone and the finally obtained product aripiprazole contains a low content of dimer, so the tedious low-efficiency time-consuming removal process of the dimer can be avoided. The method has the advantages of simple process, high output, safety and low cost.

Description

Technical field:

[0001] The invention belongs to the technical field of medicine and relates to a preparation method of an antipsychotic drug aripiprazole. technical background:

[0002] Aripiprazole (aripiprazole, formula I), the chemical name is 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro -2(1H)-quinolinone, developed by Otsuka Corporation in 1988, was approved by the US FDA on November 15, 2002, for the treatment of schizophrenia, and is the first third-generation atypical antipsychotic new drug. The mechanism of action of aripiprazole is completely different from the typical and atypical antipsychotic drugs that are currently on the market. It is a partial agonist of dopamine D3 receptors, a partial agonist of 5-HT1A receptors and an antagonist of 5-HT2A receptors. Studies have shown that the drug is a dopamine-serotonin system stabilizer; compared with typical and atypical antipsychotics that have been marketed, it has better efficacy on negative sym...

Examples

Embodiment 1

[0028] Preparation of 4-chlorobutyl p-toluenesulfonate

[0029] Add 4 g of anhydrous zinc chloride, 76 g of p-toluenesulfonyl chloride, and 20 mL of toluene into a 250 ml three-necked flask, stir and heat to 80°C, add 37.5 g of tetrahydrofuran dropwise, keep warm for 2 hours after the dripping, and pour the reaction solution into ice water. Add toluene to make the organic reverse phase to the upper layer, separate the water layer, wash the organic phase with sodium bicarbonate solution to neutrality, then wash with saturated brine, dry over anhydrous magnesium sulfate, recover toluene by distillation under reduced pressure, and decompress the oil pump Distilled to obtain 77 grams of 4-chlorobutyl p-toluenesulfonate, yield 73%, purity 98%

Embodiment 2

[0031] 4-Bromobutoxyquinolinone

[0032] Add dehydrated ethanol 30ml, potassium carbonate 2.5 grams (18mmol), 7-hydroxyquinolinone 2.45 grams (15mmol), 1,4-dibromobutane 9.7 grams (45mmol) respectively in the there-necked flask, heating reaction for a period of time, TLC Or HPLC monitoring to the end of the reaction. After the reaction was completed, after concentrating under reduced pressure to recover most of the ethanol, 30ml of water was added to the reaction flask, and after stirring for a period of time, a solid was precipitated, filtered by suction, and washed to obtain 4.08 grams of crude product of 4-bromobutoxyquinolinone, dimer Content 17%, HPLC purity 78.6%.

Embodiment 3

[0034] 4-Chlorobutoxyquinolinone

[0035] 1. Add 30ml of absolute ethanol, 2.5 grams (18mmol) of potassium carbonate, 2.45 grams (15mmol) of 7-hydroxyquinolinone, and 11.8 grams (45mmol) of 4-chlorobutyl p-toluenesulfonate to the three-necked flask, and heat to react 2 Hours, TLC or HPLC monitoring to the end of the reaction. After the reaction was completed, after concentrating under reduced pressure to recover most of the ethanol, 30ml of water was added to the reaction flask, and after stirring for a period of time, a solid was precipitated, filtered by suction, and washed to obtain 3.21 grams of crude product of 4-chlorobutoxyquinolinone, dimer Content 0.7%, HPLC purity 97.3%.

[0036] 2. Add 30ml of absolute ethanol, 0.72 grams (18mmol) of sodium hydroxide, 2.45 grams (15mmol) of 7-hydroxyquinolinone, and 11.8 grams (45mmol) of 4-chlorobutyl p-toluenesulfonate to the three-necked flask, and heat the reaction After 1.5 hours, TLC or HPLC monitored to the end of the react...

Technical field:

[0001] The invention belongs to the technical field of medicine and relates to a preparation method of an antipsychotic drug aripiprazole. technical background:

[0002] Aripiprazole (aripiprazole, formula I), the chemical name is 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro -2(1H)-quinolinone, developed by Otsuka Corporation in 1988, was approved by the US FDA on November 15, 2002, for the treatment of schizophrenia, and is the first third-generation atypical antipsychotic new drug. The mechanism of action of aripiprazole is completely different from the typical and atypical antipsychotic drugs that are currently on the market. It is a partial agonist of dopamine D3 receptors, a partial agonist of 5-HT1A receptors and an antagonist of 5-HT2A receptors. Studies have shown that the drug is a dopamine-serotonin system stabilizer; compared with typical and atypical antipsychotics that have been marketed, it has better efficacy on negative sym...

Examples

Embodiment 1

[0028] Preparation of 4-chlorobutyl p-toluenesulfonate

[0029] Add 4 g of anhydrous zinc chloride, 76 g of p-toluenesulfonyl chloride, and 20 mL of toluene into a 250 ml three-necked flask, stir and heat to 80°C, add 37.5 g of tetrahydrofuran dropwise, keep warm for 2 hours after the dripping, and pour the reaction solution into ice water. Add toluene to make the organic reverse phase to the upper layer, separate the water layer, wash the organic phase with sodium bicarbonate solution to neutrality, then wash with saturated brine, dry over anhydrous magnesium sulfate, recover toluene by distillation under reduced pressure, and decompress the oil pump Distilled to obtain 77 grams of 4-chlorobutyl p-toluenesulfonate, yield 73%, purity 98%

Embodiment 2

[0031] 4-Bromobutoxyquinolinone

[0032] Add dehydrated ethanol 30ml, potassium carbonate 2.5 grams (18mmol), 7-hydroxyquinolinone 2.45 grams (15mmol), 1,4-dibromobutane 9.7 grams (45mmol) respectively in the there-necked flask, heating reaction for a period of time, TLC Or HPLC monitoring to the end of the reaction. After the reaction was completed, after concentrating under reduced pressure to recover most of the ethanol, 30ml of water was added to the reaction flask, and after stirring for a period of time, a solid was precipitated, filtered by suction, and washed to obtain 4.08 grams of crude product of 4-bromobutoxyquinolinone, dimer Content 17%, HPLC purity 78.6%.

Embodiment 3

[0034] 4-Chlorobutoxyquinolinone

[0035] 1. Add 30ml of absolute ethanol, 2.5 grams (18mmol) of potassium carbonate, 2.45 grams (15mmol) of 7-hydroxyquinolinone, and 11.8 grams (45mmol) of 4-chlorobutyl p-toluenesulfonate to the three-necked flask, and heat to react 2 Hours, TLC or HPLC monitoring to the end of the reaction. After the reaction was completed, after concentrating under reduced pressure to recover most of the ethanol, 30ml of water was added to the reaction flask, and after stirring for a period of time, a solid was precipitated, filtered by suction, and washed to obtain 3.21 grams of crude product of 4-chlorobutoxyquinolinone, dimer Content 0.7%, HPLC purity 97.3%.

[0036] 2. Add 30ml of absolute ethanol, 0.72 grams (18mmol) of sodium hydroxide, 2.45 grams (15mmol) of 7-hydroxyquinolinone, and 11.8 grams (45mmol) of 4-chlorobutyl p-toluenesulfonate to the three-necked flask, and heat the reaction After 1.5 hours, TLC or HPLC monitored to the end of the react...

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