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Method for synthesizing Blonanserin

A synthesis method, the technology of blonanserin, applied in the direction of organic chemistry, etc., can solve the problems of many side reactions, high pollution, strong irritation of chlorinated reagents, etc., and achieves simple and easy-to-control operation, low reaction temperature, and product purity. Good results

Active Publication Date: 2014-05-28
HEBEI GUOLONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main defects of these methods are: (1) the chlorinated reagent is highly irritating and highly polluting; (2) the chlorination reaction time of phosphorus oxychloride is long and the side reactions are many; (3) the selectivity of the intermediate B condensation reaction is poor
Intermediate B contains two aromatic molecular structures of chloropyridine and fluorobenzene, and fluorine and chlorine are atoms of the same family. N - During the reaction of ethylpiperazine, fluorine may also participate in the condensation reaction to produce impurity A (see the reaction formula below), which is formed in the last step of blonanserin and is difficult to remove, which affects the preparation of high-purity blonanserin

Method used

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  • Method for synthesizing Blonanserin
  • Method for synthesizing Blonanserin
  • Method for synthesizing Blonanserin

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Example 1 2-p-Toluenesulfonic acid-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydroaryloctano[b]pyridine ester (Intermediate II-1 ) preparation

[0034] Under stirring, 2.71 g (10.0 mmol) of Intermediate I was dissolved in 40 mL of chloroform, 5 mL of chloroform containing 1.93 g (10.2 mmol) of p-toluenesulfonyl chloride was added, 1.4 mL of pyridine was added dropwise, and the mixture was stirred at 40 °C. The reaction was monitored by TLC. The reaction was poured into 100 mL of water with stirring, and the pH was adjusted to neutrality. Methyl tert-butyl ether was added for extraction, the liquid was separated, the extract was washed with water, and the extract was removed by rotary evaporation to obtain Intermediate II-1. White solid, the crude product was recrystallized to obtain 3.18g of intermediate II-1, yield 75.3%, m.p.: 117~118 ℃.

[0035]

[0036] The structure of intermediate II-1 is:

[0037] MS: m / e 426, [M+H]

[0038] IR absorption peak (cm -1 ): 2958.5, ...

Embodiment 2

[0040] Example 2 2-p-Toluenesulfonic acid-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydroaryloctano[b]pyridine ester (Intermediate II-1 ) preparation

[0041] According to the method of Example 1, the mole number of p-toluenesulfonyl chloride was adjusted to be twice that of the reactant intermediate I, and the yield of intermediate II-1 was 83.5%.

Embodiment 3

[0042] Example 3 2-p-Toluenesulfonic acid-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydroaryloctano[b]pyridine ester (Intermediate II-1 ) preparation

[0043] According to the method of Example 1, the mole number of p-toluenesulfonyl chloride was adjusted to be 5 times, 10 times and 20 times that of the reactant intermediate I, and the yield of intermediate II-1 was all lower than 75%. Processing losses are large.

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Abstract

The invention discloses a method for synthesizing Blonanserin, wherein the method comprises the following steps of taking 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(1H)-one (which is named as an intermediate I) as an initial raw material, enabling the initial raw material to react with a substituted sulfonyl chloride to obtain 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-substituted sulphonate (which is named as an intermediate II-(1-n)), condensing the intermediate II-(1-n) with N-ethyl piperazine to obtain the Blonanserin, refining the obtained Blonanserin to obtain the Blonanserin with purity of 99.8%. The method provided by the invention prepares the Blonanserin raw material that has high purity and accords with the medicinal use by using a sulfonylation process; the method prepared by the invention has the advantages of high reaction selectivity, high product purity, low solvent toxicity, simple operation and easiness in control; the method provided by the invention is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing blonanserin, and belongs to the technical field of chemical drug preparation. technical background [0002] Blonanserin (English name: Blonanserin) chemical name is 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10- Hexahydroaryloctino[b]pyridine is a new generation of atypical antischizophrenic drugs, which has a dopamine D2 receptor blocking effect equivalent to haloperidol, and also has a strong blocking effect on 5-HT2A. The selectivity of the two receptors is stronger than other antipsychotic drugs, the safety and tolerance are significantly better than traditional antipsychotic drugs, and the side effects are small. [0003] [0004] The CAS number of blonanserin is 132810-10-7, and the molecular structure is as follows: [0005] At present, the disclosed synthetic methods of blonanserin are mainly composed of halogenated pyridone and N - Prepared by condensation of ethyl piperazine...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/04
Inventor 孙京国冯玉玲邢杰浩王泾丹王晓婷孟庆秘
Owner HEBEI GUOLONG PHARMA CO LTD
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