Preparation method of blonanserin intermediate

A technology of blonanserin and intermediates, which is applied in the field of medicinal chemistry, can solve the problems of complex products, long reaction time to the end point, and no effect is achieved, and achieves simple reaction steps, stable effective conversion rate, and increased uniformity. Effect

Active Publication Date: 2021-10-22
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

Method used

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  • Preparation method of blonanserin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] 1. Preparation 3- (4-fluorophenyl) -3 oxypropamide with sodium hydrogen sulfate

[0039] In a 250 ml of clean reaction flask, 25.0 g (0.15 mol) was added to fluorobenzoyl acetonitrile, 36 ml of water, 36 g sodium hydrogen sulfate (0.3 mol). The reaction mixture was warmed to 60 ° C with rapid stirring, and the temperature was controlled for 3 hours. HPLC monitors the reaction process, when the residual amount of fluorobenzoyloy in the system is less than 1%, it is considered to be complete, reactive, cooling to 30 ° C, dropping the mass concentration of 12%, tonifying pH 9. The controlled temperature was stirred at 15 ° C for 1 hour, filtered, washed, filtered, dried 80 ° C to give 3- (4-fluorophenyl) -3 oxpropanamide 25.5 g, yield 92%, HPLC 98.5%.

[0040] 2. Preparation of BN-03 (4- (4-fluorophenyl) -5, 6, 7, 8, 9, 10-hexahydrocycloalkane-2 (1H)-ketone) by pyridine catalysis

[0041]In a 250 ml of clean reaction flask, 125 g of polyphosphoric acid was sequentially added t...

Embodiment 2

[0043] 1. Preparation of 3- (4-fluorophenyl) -3 oxpropanamide using a catalyst using a catalyst using a zirconium sulfate

[0044] In a 250 ml of clean reaction flask, 25.0 g (0.15 mol) was added to fluorobenzoyloy, 36 ml of water, 85 g of zirconium sulfate (0.3 mol). Other and the step 1 of Example 1 were the same, after drying at 80 ° C, 3- (4-fluorophenyl) -3 oxpropanamide 26.3 g, yield 95%, HPLC 99.2%.

[0045] 2. Preparation of BN-03 (4- (4-fluorophenyl) -5, 6, 7, 8, 9, 10-hexahydrocycloalkane-2 (1H)-ketone) by pyridine catalysis

[0046] In a 250 ml clean reaction bottle, 125 g of polyphosphoric acid was sequentially added, and 3- (4-fluorophenyl) -3 oxypropanamide obtained by step 1, 20.0 g of cyclophily of cyclophily, 2 ml of pyridine. Other and the step 2 of Example 1 were the same, and the white crystalline solid 34 g was obtained. The yield was 91.07%, purity (HPLC): 99.3%, melting point 235.0-236.0 ° C.

Embodiment 3

[0048] 1, 3- (4-fluorophenyl) -3 oxypropanamide was prepared using a catalyst using a catalyst of zirconium sulfate, and step 1 of the second embodiment.

[0049] 2, use DMAP (N, N-dimethylaminopyridine) to prepare BN-03 (4- (4-fluorophenyl) -5,6,7,8,9,10-hex hydrogen octanepyridine -2 (1H) - ketone)

[0050] In a 250 ml of clean reaction flask, 125 g of polyphosphoric acid was sequentially added, 3- (4-fluorophenyl) -3 oxypropanamide 25g, cyclophily of cyclophily, 0.0 g, DMAP 1.85 g (0.02 mol). The increased, heated to 115 ° C, and the temperature was controlled for 4 hours. HPLC monitors the reaction process, which is considered to be completed when the residual amount of 3- (4-fluorophenyl) -3 oxpropanamide is less than 3% in the system. Cooling to 80 ° C, add 120 ml of ethanol, thoroughly stirred, and then droplets into 1200 mL of dilute alkali, stirred alcohol, filtrate, derived white solid, mixed with 200 ml of tert-butyl methyl ether, white crystalline solid 35.5g. The yiel...

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Abstract

The invention relates to a preparation method of a blonanserin intermediate, which comprises the following steps: hydrolyzing p-fluorobenzoyl acetonitrile in an aqueous solution in the presence of acid sulfate, then neutralizing with ammonia water until the pH value is 8-9, filtering and drying to obtain 3-(4-fluorophenyl)-3-oxopropanamide; and reacting 3-(4-fluorophenyl)-3-oxopropanamide with cyclooctanone in the presence of polyphosphoric acid and a catalyst, which is pyridine or a pyridine derivative, crystallizing in alkaline water, and pulping with methyl tert-butyl ether to obtain the blonanserin intermediate. The preparation method has the advantages of high product yield and few impurities, also has the advantage of high yield during large-scale production, and is suitable for industrial production.

Description

Technical field [0001] The present invention belongs to the field of medical chemistry, and in particular to a method of preparation of a neutral lumin intermediate. Background technique [0002] Bronal forest intermediate refers to 4- (4-fluorophenyl) -5, 6, 7, 8, 9, 10-hexahydrocycloalkane-2 (1H)-ketone, the compound is a new SARS. Important intermediates in the BLONAnserin synthesis process, as shown in the following formula: [0003] [0004] JP4099758A and EP0385237 reported a synthetic method of BN-03 compounds which were reacted in polyphosphoric acid to obtain 4- (4-fluorophenyl) -5, 6 in polyphosphoric acid in polyphosphate. 7, 8, 9, 10-hexahydrocycloalkane and pyridine-2 (1H) - ketone, reaction at 120 ° C, as follows: [0005] [0006] According to the literature, in the preparation method provided by the synthesis route, the yield of the compound of formula BN-03 is 60%, but the inventors have prepared 4- (4-fluorophenyl) -5, 6, 7 according to the above document. 8...

Claims

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Application Information

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Patent Type & Authority Applications(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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