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Synthesis process for Rucaparib intermediate of ovarian cancer treating medicine

A synthesis process and intermediate technology, which is applied in the field of synthesis technology of ovarian cancer drug intermediates, can solve the problems of few reaction steps, many reaction steps, long reaction time and the like, and achieves few reaction steps, short reaction time and low production cost. Effect

Inactive Publication Date: 2017-06-13
THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to overcome the existence of the synthetic technique of existing Rucaparib intermediate 8-fluoro-1,3,4,5-tetrahydro-azepine[5,4,3-cd]indol-6-one Harsh conditions, many reaction steps, too long reaction time and low yield etc. defects, provide a kind of less reaction steps, high yield and more suitable for the preparation of Rucaparib intermediate for industrial production

Method used

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  • Synthesis process for Rucaparib intermediate of ovarian cancer treating medicine
  • Synthesis process for Rucaparib intermediate of ovarian cancer treating medicine
  • Synthesis process for Rucaparib intermediate of ovarian cancer treating medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of 3-(2-bromoethyl)-7-fluoro-indole-5-carboxylic acid methyl ester

[0026] Under nitrogen protection, 19.3g (100mmol) of methyl 7-fluoro-indole-5-carboxylate, 0.97g of palladium tetrakistriphenylphosphine, 41.4g (300mmol) of potassium carbonate and 20.7g of 1,2-dibromoethane (110mmol) was refluxed in 150ml of acetonitrile for 2 hours to monitor the end of the reaction. The reaction solution was cooled to room temperature, filtered, the filtrate was washed with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the Crystallization gave 27.5 g of methyl 3-(2-bromoethyl)-7-fluoro-indole-5-carboxylate, with a yield of 91.7%.

[0027] 1 H NMR (400MHz, CDCl 3 )δ: 2.40 (t, 2H) 3.51 (t, 2H) 3.64 (s, 3H) 7.11 ~ 7.18 (m, 2H) 7.44 (m, 1H) 11.22 (s, 1H).

Embodiment 2

[0029] Synthesis of 3-(2-bromoethyl)-7-fluoro-indole-5-carboxylic acid methyl ester

[0030] Under nitrogen protection, 38.6g (200mmol) of methyl 7-fluoro-indole-5-carboxylate, 3.8g (10%) of palladium tetrakistriphenylphosphine, 130.3g (400mmol) of cesium carbonate and 1,2-dibromo 22.6g (120mmol) of ethane was refluxed in 200ml of acetonitrile for 2 hours. After monitoring the end of the reaction, the reaction liquid was cooled to room temperature, filtered, the filtrate was washed with water, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. , recrystallized from petroleum ether to obtain 56.2 g of methyl 3-(2-bromoethyl)-7-fluoro-indole-5-carboxylate, with a yield of 93.6%.

Embodiment 3

[0034] The synthesis of the compound shown in formula II:

[0035]Under nitrogen protection, 6 g (20 mmol) of 3-(2-bromoethyl)-7-fluoro-indole-5-carboxylic acid methyl ester obtained in step 1), 0.2 g iodine and 0.5 g (21 mmol) of dry magnesium chips were added Stir in 120ml of absolute diethyl ether for 1.5 hours until 3-(2-ethylmagnesium bromide)-7-fluoro-indole-5-carboxylic acid methyl ester is generated, then adjust the temperature of the resulting reaction solution to 45°C and stir for 3 hours , monitored until the end of the reaction, cooled in an ice bath and poured into saturated ammonium chloride, extracted with dichloromethane, washed, concentrated and dried to obtain 8-fluoro-cyclohexyl[5,4,3-cd]indol-6-one 3.44 g.

[0036] 3.78g (20mmol) of 8-fluoro-cyclohexyl[5,4,3-cd]indol-6-one, 21.7g (24mmol) of hydroxylamine hydrochloride and 0.73g (4mmol) of copper acetate were added to ethanol, and then Aqueous ammonia was added dropwise under stirring to adjust the pH to ...

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Abstract

The invention discloses a synthesis process for a Rucaparib intermediate of an ovarian cancer treating medicine. The synthesis process for the Rucaparib intermediate of the ovarian cancer treating medicine is characterized by comprising the following step that a compound as shown in the formula II is reacted under acidic conditions to obtain the Rucaparib intermediate as shown in the formula I; the synthesis process for the Rucaparib intermediate provided by the invention has fewer reaction steps, and is low in production cost, short in reaction time, high in production efficiency and more suitable for industrialized production. The intermediate prepared through the process disclosed by the invention is high in yield and purity.

Description

technical field [0001] The present invention relates to a synthesis process of ovarian cancer drug intermediates, in particular to 8-fluoro-1,3,4,5-tetrahydro-azepine[5,4,3-cd]indene, an intermediate of Rucaparib Synthetic process 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 studies have shown t...

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 THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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