Deuterated aripiprazole as well as preparation method and application thereof

A technology of aripiprazole and deuterium, which is applied in the field of deuterated aripiprazole and its preparation, can solve the problems of waste of reaction raw materials, high price, and limited wide use, and achieve saving of deuterium reagents, reasonable process design, highly operable effect

Inactive Publication Date: 2018-06-29
QINZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, deuterium is still the best internal standard. For a long time, the deuterium internal standard used in my country has been dependent on imports. Due to its extremely high price, it has severely limited the wide use of this type of standard in China.
[0005] Currently, deuterated d 8 There are very few preparation methods for deuterated aripiprazole, and the process has not been optimized. The raw material used in the reaction is 1,4-bromodeuterobutane, which has a strong activity in halogenation reactions , it is easy to react with two molecules of raw materials (I) simultaneously to generate a by-product intermediate; when preparing an important intermediate (II), an excess of 1,4-bromodeuterobutane more than 2.0 equivalents is required to participate in the reaction to obtain a higher yield High-efficiency intermediate (II), 1,4-bromodeuterobutane is expensive, the waste of reaction raw materials is serious, and the cost is too high, which seriously limits deuterium d 8 Widespread use of deuterated aripiprazole

Method used

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  • Deuterated aripiprazole as well as preparation method and application thereof
  • Deuterated aripiprazole as well as preparation method and application thereof
  • Deuterated aripiprazole as well as preparation method and application thereof

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preparation example Construction

[0033] A kind of preparation method of deuterated d8 aripiprazole, it comprises the following steps:

[0034] Step 1. Dissolve the raw material 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (I) in a polar solvent, add a base to react for about 5 minutes, and then add 1,4-dichlorobutane Alkane-d8 (CAS: 83547-96-0), heating reaction to obtain compound (II);

[0035]

[0036] Step 2, dissolving N-Boc-piperazine (III) and 1-bromo-2,3-dichlorobenzene (IV) in a polar solvent, adding a base, and reacting by Buchwald under the catalysis of a palladium catalyst and a phosphorus catalyst Compound (IV) is obtained;

[0037]

[0038] Step 3, reacting the intermediate compound (IV) prepared in step 2 with a polar organic solvent solution of hydrochloric acid or trifluoroacetic acid to obtain the hydrochloride or trifluoroacetic acid salt of compound (V);

[0039]

[0040]Step 4, dissolving compound (V) in a polar solvent, adding base to react for 5 minutes, and then adding compound (I...

Embodiment 1

[0054] Step 1, the preparation of compound (II):

[0055]

[0056] Add (1.63g, 10mmol) 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, (2.48g, 18mmol) potassium carbonate, 80mL anhydrous acetonitrile into a 1000mL three-necked flask, and protect it under nitrogen The reaction was carried out for 5 minutes, and then (22.6g, 150mmol) 1,4-dichlorobutane-d8 was added, replaced by nitrogen three times, under the protection of nitrogen, the reaction was carried out at 80°C for 3 hours, TLC and LCMS monitored 3,4-dihydro- 7-Hydroxy-2(1H)-quinolinone did not remain, the reaction was basically completed, cooled to room temperature, added 30mL of water, extracted with dichloromethane (50mL×3), combined the organic phases, concentrated, and the crude product was subjected to column chromatography[ Silica gel (200-300 mesh), eluent: V (ethyl acetate): V (petroleum ether) = 6: 1] to obtain 2.40 g of light yellow solid compound (II), yield: 92.0%, LCMS [M+ H] + = 262.2.

[0057] Step 2, the ...

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Abstract

The invention belongs to the fields of organic and medicine synthesis, and discloses deuterated d8 aripiprazole as well as a preparation method and application thereof. According to the preparation method, 1,4-dichlorobutane-d8 serving as a raw material is subjected to four-step reaction synthesis to obtain deuterated mark d8-aripiprazole. According to the preparation method provided by the invention, the whole process is reasonable in design, high in operability and simple in operation, a deuterated reagent is low in cost, the product is easy to separate and purify, the obtained target product is stable in chemical property, the isotopic abundance is high, the yield is high and the purity can reach to 100 percent. The preparation method provided by the invention can be used for producinga deuterated internal standard substance which is used during analysis and detection of the deuterated aripiprazole, and a test sample can be provided for research on aripiprazole metabolic mechanism,so that the metabolic process and the action mechanism of the aripiprazole in a human body can be known more accurately and conveniently; and the deuterated d8 aripiprazole can be used for preparinga pharmaceutical composition, is applied to a dopamine system stabilizer for treating schizophrenia, schizoaffective psychosis and other psychotic disorders, and has important application value.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the technical field of organic drug synthesis, in particular to a deuterated aripiprazole and a preparation method and application thereof. Background technique [0002] Aripiprazole, the trade name is Anlufan, the chemical name is 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy}-3, 4-Dihydro-2(1H)-quinolinone is a quinolinone derivative. It was invented by Japan's Otsuka Company in 1988, and later jointly developed with Bristol-Myers-Squibb Company of the United States. It was approved by FICA in the United States on November 15, 2002. It is clinically used to treat various acute and chronic schizophrenia and emotional obstacle. Deuterated aripiprazole is the first and only FICA-approved dopamine system stabilizer (DSS). Different from other antipsychotic drugs that antagonize dopamine receptors, it can not only partially activate dopamine D2 receptors, so that the dopamin...

Claims

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Application Information

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IPC IPC(8): C07D215/22A61P25/18A61P25/08A61P25/14A61P25/00
CPCC07D215/22
Inventor 范和良孔亚芬黄海方尹艳镇庞庭才
Owner QINZHOU UNIV
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