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Preparation method of intermediate of drug Rucaparib treating ovarian cancer

An intermediate and ovarian cancer technology, applied in the field of preparation of ovarian cancer drug Rucaparib intermediates, can solve the problems of long reaction time, complicated process, harsh conditions, etc., and achieve the effect of short reaction time, high reaction efficiency and mild conditions

Active Publication Date: 2017-05-31
NANJING IMMUNOPHAGE BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] For the preparation method of Rucaparib intermediate 8-fluoro-1,3,4,5-tetrahydro-azepine[5,4,3-cd]indol-6-one in the prior art, there are still harsh conditions, Due to the defects of complex process, long reaction time and low yield, the present invention is specially proposed

Method used

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  • Preparation method of intermediate of drug Rucaparib treating ovarian cancer
  • Preparation method of intermediate of drug Rucaparib treating ovarian cancer
  • Preparation method of intermediate of drug Rucaparib treating ovarian cancer

Examples

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Effect test

preparation example 1

[0032] Preparation of Dimethyl (1-diazo-2-oxo-3-cyanopropyl)phosphonate

[0033] Under ice-cooling, drop 220ml LiHMDS (1mol / L in THF) into 13.6g (110mmol) of dimethyl methylphosphonate for mixing, then add 9.9g (100mmol) of methyl 2-cyanoacetate to the above mixture , kept stirring in an ice bath for 2 hours, and monitored the completion of the reaction. Add 100ml of saturated ammonium chloride to quench the reaction, add ethyl acetate to extract three times (80mlx3), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and concentrate to obtain (2-oxo-3-cyanopropyl) The crude dimethyl phosphonate was used in the next step without further purification.

[0034] The obtained (2-oxo-3-cyanopropyl) dimethyl phosphonate crude product, p-toluenesulfonyl azide 23.7g (TsN 3 120mmol) was dissolved in acetonitrile, then 20.7g (150mmol) of potassium carbonate was added, stirred at room temperature for 8 hours, filtered, the filtrate was concentr...

preparation example 2

[0037] Preparation of Dimethyl (1-diazo-2-oxo-3-cyanopropyl)phosphonate

[0038] Under ice-cooling, drop 200ml LiHMDS (1mol / L in THF) into dimethyl methylphosphonate 14.8 (120mmol) for mixing, then add 9.9g (100mmol) of methyl 2-cyanoacetate to the above mixture, The reaction was kept stirring in an ice bath for 2 hours, and the completion of the reaction was monitored. Add 100ml of saturated ammonium chloride to quench the reaction, add ethyl acetate to extract three times (80mlx3), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and concentrate to obtain (2-oxo-3-cyanopropyl) The crude dimethyl phosphonate was used in the next step without further purification.

[0039] The obtained (2-oxo-3-cyanopropyl) dimethyl phosphonate crude product, p-toluenesulfonyl azide 21.7g (TsN 3 110mmol) was dissolved in acetonitrile, then 22.1g (160mmol) of potassium carbonate was added, the reaction was stirred at room temperature for 7 hours, fi...

Embodiment 1

[0041] Preparation of 3-cyanoethyl-6-fluoro-1H-indole-4-carboxylic acid methyl ester

[0042] 1) Under the protection of nitrogen, first mix 33.2g (110mmol) of methyl 3-fluoro-5-trifluoromethanesulfonylbenzoate and 130.3g (400mmol) of cesium carbonate in 180ml tetrahydrofuran for 5-10min, then add ( 21.7 g (100 mmol) of dimethyl 1-diazo-2-oxo-3-cyanopropyl)phosphonate was stirred and reacted at room temperature for 1.5 hours. After the stirring reaction was completed, the reaction solution was concentrated under reduced pressure and washed with water to obtain a mixture M;

[0043] 2) Mix the mixture M obtained in step 1) with 50ml of hydrochloric acid (6mol / L,) in 150ml of tetrahydrofuran, heat up to 55°C and stir for reaction. After the reaction is completed for 2 hours, adjust the pH to 7-8 with sodium bicarbonate, ethyl acetate Extraction and concentration under reduced pressure gave 20.8 g of methyl 3-cyanoethyl-6-fluoro-1H-indole-4-carboxylate, with a yield of 89.6%. HR...

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Abstract

The invention discloses a preparation method of an intermediate of drug Rucaparib treating ovarian cancer. The preparation method comprises the following steps: 1) in the presence of protective gas and inorganic alkali, stirring 3-fluoro-5-trifylmethyl benzoate with (1-diazo-2-oxo--cyan propyl) dimethylphosphonate to react to obtain a mixture M; 2) stirring the mixture M obtained I the step 1) in an acidic condition to react to obtain 3-cyanoethyl-6-fluoro-1H-indole-4-methyl formate; and 3) performing palladium -carbon catalytic hydrogenation on the product obtained in the step 2) in the acidic condition to obtain the intermediate 8-fluoro-1,3,4,5-tetrahydro[5,4,3-cd] indoe-6-one. According to the method disclosed by the invention, a target compound is high in yield and purity; the method is mild in condition, relatively few in step, short in reaction time and more suitable for industrial production.

Description

technical field [0001] The present invention relates to a method for preparing an intermediate of Rucaparib, a drug for treating ovarian cancer, in particular to the intermediate 8-fluoro-1,3,4,5-tetrahydro-azepine[5,4,3-cd ] The preparation method of indol-6-one. Background technique [0002] In recent years, statistics have found that the incidence of ovarian cancer has increased year by year, and it has become a major killer threatening women's health. Regrettably, there is still a lack of effective drugs clinically. Rucaparib (trade name Rubraca) is a polyadenosine diphosphate-ribose polymerase inhibitor developed by Clovis Oncology. Its chemical name is: 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepine[5,4,3- cd] indol-6-one phosphate, molecular formula C 19 h 18 FN 3 O·H 3 PO 4 , CAS: 459868-92-9, its structural formula is as follows. [0003] [0004] Rucaparib is the first PARP inhibitor used in human cancer therapy. Preclinical st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/06
CPCC07D487/06
Inventor 陈令浩
Owner NANJING IMMUNOPHAGE BIOTECH CO LTD
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