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Brexpiprazole impurity compound and preparation method thereof

A technology of ebiprazole and compounds, applied in the field of medicinal chemistry

Inactive Publication Date: 2017-06-27
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are few reports on its related process impurities and degradation impurities, and the present invention is aimed at the impurities produced during the synthesis process, storage and use of ebiprazole, and will affect the product quality, which is of great importance to the control of product quality. the meaning of

Method used

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  • Brexpiprazole impurity compound and preparation method thereof
  • Brexpiprazole impurity compound and preparation method thereof
  • Brexpiprazole impurity compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 7-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-oxyl)butoxy)-3,4-dihydroquinolin-2(1H)-one ( Compound 3) Preparation

[0043] Add 2.09g of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one and 485mg of lithium hydroxide monohydrate to a mixed solvent of 40ml of N-methylpyrrolidone and 4ml of water at 40°C and stir for 2 hours After cooling down to room temperature, add 4.0g of 7-(4-iodobutoxy)-3,4-dihydroquinolin-2(1H)-one and stir until the reaction is basically completed, add 50ml of methanol to crystallize, and filter with suction. Drying yielded 3.2 g of product.

Embodiment 2

[0045] Preparation of 7-(4-(2-oxo-1,2-dihydroquinolin-7-oxyl)butoxy)quinolin-2(1H)-one (compound I)

[0046] Add 5.9g DDQ to 40ml dimethyl sulfoxide and stir at 40°C, and take the 7-(4-(2-oxo-1,2,3,4-tetrahydroquinoline- 2.0g of 7-oxyl)butoxy)-3,4-dihydroquinolin-2(1H)-one, dissolved in 150ml dimethyl sulfoxide by heating, then added dropwise to the dimethyl sulfoxide solution of DDQ, kept warm Reacted for 4 hours. After the reaction was completed, the temperature was lowered, and a total of 80 ml of sodium sulfite and sodium bicarbonate aqueous solution was added dropwise. A solid precipitated, which was suction filtered, washed with water, and dried to obtain 1.3 g of the title compound.

[0047] 1 H-NMR (DMSO-d 6 ) δ ppm:

[0048] 1.197 (4H, brs),4.084 (4H, brs), 6.275~6.299 (2H, d), 6.784~6.803 (4H,m), 7.538~ 7.561 (2H, d), 7.785~7.808 (2H,d), 11.565 (1H, s).

Embodiment 3

[0050] Preparation of 5-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (compound II)

[0051]5.0 g of 5-(4-chlorobutoxy)-quinolin-2(1H)-one and 5.5 g of 4-bromobenzo[b]thiophene hydrochloride, 3.55 g of potassium carbonate and 2.04 g of sodium bromide were added Put it into 40ml of N-methylpyrrolidone, raise the temperature to 70-80°C and react for 3-5 hours, after the reaction is completed, cool down to room temperature, add 120ml of water, a white solid precipitates, filter with suction, wash the filter cake twice with water, and dry under reduced pressure 7.52 g of the title compound were obtained.

[0052] 1 H-NMR (DMSO-d 6 ) δ ppm:

[0053] 1.653~1.726 (2H, qunt), 1.767~1.863 (2H, qunt), 2.446~2.482 (2H,t), 2.624(4H, brs), 3.064 (4H, brs), 4.124~4.155 (2H, t) , 6.426~6.450 (1H, d), 6.727~6.747 (1H, d), 6.862~6.881 (1H, d), 6.881~6.899 (1H, d), 7.253~7.292 (1H, t), 7.388~7.402 (1H , d), 7.382~7.423 (1H, t), 7.600~7.620 (1H, d), 7.680~7.694(1H, d...

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Abstract

The invention discloses a brexpiprazole impurity compound and a preparation method thereof. The impurity compound can be one or more of a compound I, a compound II, a compound III and a compound IV. The invention also discloses a use of the impurity compound in the control of the quality of brexpiprazole.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an ebiprazole impurity compound and a preparation method thereof. [0002] technical background [0003] Brexpiprazole (brexpiprazole), chemical structural formula as formula 6, chemical name is 7-(4-(4-(benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1H - Quinolin-2-one. [0004] [0005] Ebiprazole is a serotonin-dopamine activity modulator (SDAM) with dopamine D 2 Receptor partial agonism and 5-HT1A partial receptor agonism, in addition to 5-HT2A receptor antagonism, jointly developed by Otsuka Pharmaceutical Co., Ltd. and Lundbeck. On July 11, 2015, the U.S. FDA approved Rexulti (brexpiprazole trade name) as an adjuvant drug for the treatment of major depressive disorder (MDD) in adults, as well as a drug for the treatment of schizophrenia in adults. [0006] Impurity research is an important part of the drug development process, which is directly re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12C07D409/14C07D215/22G01N30/02
CPCC07D215/22C07D409/12C07D409/14G01N30/02G01N2030/027
Inventor 罗绪付廷印张耀春张华骄左小勇雷皇书邓杰
Owner CHONGQING PHARMA RES INST
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