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A kind of preparation method of blonanserin intermediate

A technology of blonanserin and intermediates, applied in the field of medicinal chemistry, can solve the problems of ineffectiveness, long reaction time to the end point, complex products, etc., and achieve increased uniformity, stable effective conversion rate, and simple reaction steps Effect

Active Publication Date: 2022-04-01
湖南省湘中制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] According to the method provided by this patent, the present inventor has carried out relevant experimental research, and according to the HPLC intermediate monitoring result, it is found that the reaction takes a long time to the end point, and when it reaches the end point, the product is more complicated, and not only the impurity 3-(4-fluorobenzene Base)-3 oxopropionic acid, also produced more BN-02 bisketals, especially after amplification, it was more obvious, obviously did not achieve the effect provided by the patent

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  • A kind of preparation method of blonanserin intermediate
  • A kind of preparation method of blonanserin intermediate
  • A kind of preparation method of blonanserin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 1. Use sodium bisulfate as a catalyst to prepare 3-(4-fluorophenyl)-3-oxopropionamide

[0039] In a 250ml clean reaction bottle, add 25.0g (0.15mol) of p-fluorobenzoylacetonitrile, 36ml of water, and 36g of sodium bisulfate (0.3mol) (analytically pure). After the addition was complete, the temperature of the reaction mixture was raised to 60° C. under rapid stirring, and the reaction was carried out under temperature control for 3 hours. HPLC monitors the reaction process, and when the residual amount of p-fluorobenzoylacetonitrile in the system is less than 1%, it is considered that the reaction is complete, and the reaction is completed, and the temperature is lowered to below 30°C, and the dripping of mass concentration is 12% ammoniacal liquor, and the pH is adjusted to 9. Stir and crystallize at a temperature of 15°C for 1 hour, filter, wash, filter and dry at 80°C to obtain 25.5 g of 3-(4-fluorophenyl)-3-oxopropionamide, yield 92%, HPLC 98.5%.

[0040] 2. Cataly...

Embodiment 2

[0043] 1. Use zirconium sulfate as a catalyst to prepare 3-(4-fluorophenyl)-3-oxopropionamide

[0044] In a 250ml clean reaction flask, add 25.0g (0.15mol) of p-fluorobenzoylacetonitrile, 36ml of water, and 85g of zirconium sulfate (0.3mol) (analytically pure). Others were the same as Step 1 of Example 1. After drying at 80°C, 26.3 g of 3-(4-fluorophenyl)-3-oxopropionamide was obtained, with a yield of 95%, and HPLC 99.2%.

[0045] 2. Catalytic preparation of BN-03 (4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one) by pyridine

[0046] In a 250ml clean reaction bottle, add 125g of polyphosphoric acid, 25g of 3-(4-fluorophenyl)-3-oxopropionamide obtained in step 1, 20.0g of cyclooctanone, and 2ml of pyridine in sequence. Others were the same as step 2 of Example 1 to obtain 34 g of white crystalline solid. Yield: 91.07%, purity (HPLC): 99.3%, melting point: 235.0-236.0°C.

Embodiment 3

[0048] 1. Use zirconium sulfate as a catalyst to prepare 3-(4-fluorophenyl)-3 oxopropionamide, the steps are the same as step 1 in Example 2.

[0049] 2. Preparation of BN-03(4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine) using DMAP (N,N-dimethylaminopyridine) as a catalyst -2(1H)-one)

[0050] In a 250ml clean reaction bottle, 125g of polyphosphoric acid, 25g of 3-(4-fluorophenyl)-3 oxopropionamide, 20.0g of cyclooctanone, and 1.85g (0.02mol) of DMAP were sequentially added. After the addition was completed, the temperature was raised to 115° C., and the reaction was carried out under temperature control for 4 hours. HPLC monitors the reaction process, and when the residual amount of 3-(4-fluorophenyl)-3-oxopropanamide in the system is less than 3%, the reaction is considered complete. Cool down to 80°C, add 120ml of ethanol, stir well, then drop the material liquid into 1200ml of dilute alkaline water, stir and crystallize for 1 hour, filter to obtain off-wh...

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Abstract

The invention relates to a preparation method of a blonanserin intermediate, comprising the following steps: p-fluorobenzoylacetonitrile is hydrolyzed in an aqueous solution in the presence of acid sulfate, and then neutralized with ammonia water until the pH is 8-9 , filter, and dry to obtain 3-(4-fluorophenyl)-3 oxopropionamide; 3-(4-fluorophenyl)-3 oxopropionamide and cyclooctanone react in the presence of polyphosphoric acid and a catalyst, The catalyst is pyridine or a pyridine derivative, which is then crystallized in alkaline water and beaten with methyl-tert ether to obtain a blonanserin intermediate; the product of the present invention has high yield and few impurities, and it also has a high yield during enlarged production. Advantages, suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a blonanserin intermediate. 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 synthetic process of type antipsychotic drug blonanserin (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 provided by this synthetic route, the yiel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/04
CPCC07D221/04
Inventor 段世辉杨贞皓曾乐乐
Owner 湖南省湘中制药有限公司
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