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A kind of method for efficiently preparing blonanserin intermediate

A technology for blonanserin and intermediates, which is applied in the field of medicinal chemistry, can solve the problems of difficult product quality control, unachieved effects, complex products, etc., and achieves the effects of convenient post-processing, avoiding the impact on the environment, and simple reaction steps.

Active Publication Date: 2021-12-03
HUNAN XIANGZHONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the process of realizing the present invention, the inventor finds that the prior art has at least the following problems: we use HPLC to follow up when we study by the method of JP4099758A, and find that the reaction process goes through 3-(4-fluorophenyl)-3 oxopropionamide intermediate, which is then converted to the product 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one (BN-03), but When the reaction is terminated, the product is complex, difficult to separate, the yield is extremely low, and the product quality is difficult to control
Obviously did not achieve the effect provided by the patent

Method used

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  • A kind of method for efficiently preparing blonanserin intermediate
  • A kind of method for efficiently preparing blonanserin intermediate
  • A kind of method for efficiently preparing blonanserin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Using ammonium phosphotungstate-tetrabutylammonium bisulfate as a catalyst to prepare 3-(4-fluorophenyl)-3-oxopropionamide.

[0048] In a 500ml clean reaction bottle, add 25.0g (0.15mol) of p-fluorobenzoylacetonitrile and 55ml of dichloromethane. Add 70ml of 30% hydrogen peroxide, 8g of ammonium phosphotungstate-silica gel, 2.5g of tetrabutylammonium bisulfate and 56ml of 20% sodium hydroxide solution under ice cooling. After the addition was complete, the reaction mixture was warmed to room temperature. Temperature controlled reaction for 1-3 hours. The progress of the reaction was monitored by HPLC. After the reaction was complete, 100ml of 20% sodium bisulfite solution was added and stirred for 1 hour. Filter, wash with dichloromethane, and drain. 100ml of dichloromethane was added to the filtrate, the layers were separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain 26.96g of a...

Embodiment 2

[0052] Using ammonium phosphotungstate-tetrabutylammonium bisulfate as a catalyst to prepare 3-(4-fluorophenyl)-3-oxopropionamide.

[0053] In a 5-liter clean reactor, add 250.0g (1.5mol) p-fluorobenzoylacetonitrile and 550ml dichloromethane. Add 700ml 30% hydrogen peroxide, 80g ammonium phosphotungstate-silica gel, 25g tetrabutylammonium bisulfate and 560ml 20% sodium hydroxide solution under ice cooling. After the addition was complete, the reaction mixture was warmed to room temperature. Temperature controlled reaction for 1-3 hours. The progress of the reaction was monitored by HPLC. After the reaction was complete, 1000ml of 20% sodium bisulfite solution was added and stirred for 1 hour. Filter, wash with dichloromethane, and drain. 1000ml of dichloromethane was added to the filtrate, the layers were separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain 258.6g of a light yellow solid...

Embodiment 3

[0057] Using ammonium phosphomolybdate-tetrabutylammonium bisulfate as a catalyst to prepare 3-(4-fluorophenyl)-3-oxopropionamide.

[0058] In a 500ml clean reaction bottle, add 25.0g (0.15mol) of p-fluorobenzoylacetonitrile and 55ml of dichloromethane. Add 70ml of 30% hydrogen peroxide, 8g of ammonium phosphomolybdate-silica gel, 2.5g of tetrabutylammonium bisulfate and 56ml of 20% sodium hydroxide solution under ice cooling. After the addition was complete, the reaction mixture was warmed to room temperature. Temperature controlled reaction for 1-3 hours. The progress of the reaction was monitored by HPLC. After the reaction was complete, 100ml of 20% sodium bisulfite solution was added and stirred for 1 hour. Filter, wash with dichloromethane, and drain. 100ml of dichloromethane was added to the filtrate, the layers were separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain 25.87g of a...

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Abstract

The invention discloses a preparation method of a high-efficiency blonanserin intermediate (BN-03), which is carried out according to the following two steps: (1) p-fluorobenzoylacetonitrile is composed of a heteropolyacid (salt) and a phase transfer catalyst In the presence of a composite catalyst, under alkaline conditions and in an organic solvent, hydrolyze with 30% hydrogen peroxide to generate 3‑(4‑fluorophenyl)‑3 oxopropionamide; (2) 3‑(4‑fluorophenyl)‑3 Reaction of oxopropanamide with cyclooctanone under the catalysis of an acid and in at least one organic solvent to give 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane The total yield of pyridin-2(1H)-one increased from 63.5% to about 85%.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to blonanserin intermediate 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine-2(1H)- Efficient preparation of ketones. Background technique [0002] The blonanserin intermediate refers to 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one, which is a new SARS It is an important intermediate in the synthesis of antipsychotic drug blonanserin, and its structure is shown in the following formula. [0003] [0004] JP4099758A and EP0385237 have reported the synthetic method of BN-03 compound, and this method is raw material with p-fluorobenzoylacetonitrile and cyclooctanone, reacts in polyphosphoric acid to obtain 4-(4-fluorophenyl)-5,6, 7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one, the reaction is carried out at 120°C, as shown in the following reaction formula. [0005] [0006] According to literature reports, in the preparation method provi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/04
CPCC07D221/04
Inventor 段世辉杨贞皓尹文乐蒋敏
Owner HUNAN XIANGZHONG PHARM CO LTD