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Preparing method of blonanserin intermediate

A technology of blonanserin and intermediate, which is applied in the field of medicinal chemistry to achieve the effect of improving yield

Active Publication Date: 2010-06-23
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] According to literature reports, in the preparation method provided by this synthetic route, the yield of the compound of formula I is 60%, but the inventor prepared 4-(4-fluorophenyl)-5,6,7,8 , 9,10-hexahydrocyclooctanopyridin-2(1H)-one, the yield is only about 17%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The preparation of 3-(4-fluorophenyl)-3 oxopropionamide (II):

[0027] In a 250mL reaction flask, add 26g of polyphosphoric acid solution to 2g of 3-(4-fluorophenyl)-3-oxopropionitrile. React at 75°C for 2 hours, TLC shows that the reaction is almost complete, add 60ml of ice water, stir for 1 hour, add KOH to adjust the pH value, extract, dry, concentrate and dry to obtain 2g of white solid (II). Yield 90%. (MS: m / z 180.04 (M-H+))

[0028] Preparation of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one (I):

[0029] Add (II) 0.5g, p-toluenesulfonic acid 1.0g, cyclooctanone 0.4g and toluene 50ml into a 250ml reaction flask, heat to 110°C for 3 hours, then concentrate the reaction solution to dryness, add dichloromethane 50ml was stirred for 10 minutes, and washed with water until neutral. Drying, concentration and drying gave 0.7 g of white solid (I), with a yield of 93%.

[0030] (Anal. Calcd. C, 75.25; H, 6.69; N, 5.16. Found: C, 70.52; H, 6....

Embodiment 2

[0032] Example 2: Preparation of 3-(4-fluorophenyl)-3 oxopropionamide (II):

[0033] In a 250mL reaction flask, add 80g of polyphosphoric acid solution to 5g of 3-(4-fluorophenyl)-3-oxopropionitrile. Reacted at 75°C for 5 hours, TLC showed that the reaction was almost complete, added 150ml of ice water, stirred for 1 hour, extracted with ethyl acetate, washed with saturated sodium bicarbonate, dried, concentrated and dried to obtain 4.8g of white solid (II). Yield 86.4%.

[0034] Preparation of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one (I):

[0035] Add 2g of (II), 5g of p-toluenesulfonic acid, 1.6g of cyclooctanone and 200ml of toluene into a 500mL reaction flask, heat to 110°C and react for 3.5 hours, then concentrate the reaction solution to dryness, add 300ml of dichloromethane and stir 10 minutes, add water to wash until neutral. Drying, concentration and drying gave 2.5 g of white solid (I). Yield: 83.0%.

[0036] Two-step total yield: 71...

Embodiment 3

[0038] The preparation of 3-(4-fluorophenyl)-3 oxopropionamide (II):

[0039] In a 1L reaction flask, 308 g of polyphosphoric acid solution was added to 29.5 g of 3-(4-fluorophenyl)-3-oxopropionitrile. Reacted at 75°C for 5 hours, TLC showed that the reaction was almost complete, added 600ml of ice water, stirred for 1 hour, extracted with ethyl acetate, washed with saturated sodium bicarbonate, dried, concentrated and dried to obtain 27.4g of white solid (II). Yield 83.6%.

[0040] Preparation of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one (I):

[0041] Add (II) 18.5g, p-toluenesulfonic acid 35g, cyclooctanone 12.9g and toluene 500ml into a 1L reaction flask, heat to 110°C for 5 hours, then concentrate the reaction solution to dryness, add 300ml of dichloromethane Stir for 10 minutes, add water to wash until neutral. Drying, concentration and drying gave 14 g of white solid (I). Yield: 76%.

[0042] Two-step total yield: 63.5%.

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Abstract

The invention discloses a preparing method of blonanserin intermediate. The method is processed according to the following two steps of: (a) producing 3-(4-fluorophenyl)-3 oxo-propanamide through the reaction of 3-(4-fluorophenyl)-3 oxypropionitrile; and (b) obtaining 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane pyridine-2-(1H)-ketone through the reaction between the 3-(4-fluorophenyl)-3 oxo-propanamide and cyclooctanone. The yield coefficient of the 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane pyridine-2-(1H)-ketone prepared by using the method is increased to about 80 percent from 17 percent.

Description

technical field [0001] The present 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)- Method for the preparation of ketones. Background technique [0002] The blonanserin intermediate described in this specification refers to 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one, which The compound is an important intermediate in the synthesis process of the new atypical antipsychotic drug Blonanserin, and its structure is shown in the following formula (1). [0003] [0004] JP4099768A and EP0385237 have reported the synthetic method of formula I compound, and this method is with 3-(4-fluorophenyl)-3 oxopropionitrile and cyclooctanone as raw material, reacts in polyphosphoric acid to obtain 4-(4-fluoro Phenyl)-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:...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/04
Inventor 王俊芳王小妹王哲烽时惠麟王小梅隋强
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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