A kind of preparation method of key intermediate of anti-ovarian cancer drug rucaparib

An intermediate and ovarian cancer technology, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as potential safety hazards and environmental pollution, unfavorable safety production, and scarce raw material costs, so as to ensure safe production, facilitate industrial production, and avoid explosion risks. Effect

Active Publication Date: 2018-06-26
石家庄久正生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The first step of the above three routes requires the use of nitrification reaction, which is an exothermic reaction with a fast reaction rate, and it is very easy to cause an explosion due to an out-of-control reaction. Industrial production has great safety hazards and environmental pollution, which is not conducive to safe production; route one and The raw materials used in the technical route of route 2 are scarce and costly, and it is difficult to purchase domestically
The reaction route of route 1 and route 3 is longer, the reaction cycle is too long, and the reaction efficiency is low

Method used

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  • A kind of preparation method of key intermediate of anti-ovarian cancer drug rucaparib
  • A kind of preparation method of key intermediate of anti-ovarian cancer drug rucaparib
  • A kind of preparation method of key intermediate of anti-ovarian cancer drug rucaparib

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Step 1: Dissolve compound S-1 (18.5g, 0.1mol) in 150ml of N,N-dimethylformamide, add NCS (N-chlorosuccinimide) (13.3g, 0.1mol) , the reaction solution was reacted at 35°C for 4 hours, and then the insoluble matter was filtered, extracted with ethyl acetate, and washed with water. The organic solvent was dried with anhydrous sodium sulfate, and spin-dried to obtain 20 g of compound S-2, which was directly used in the next reaction.

[0040] Step 2: Dissolve compound S-2 (20g, 0.09mol) in tetrahydrofuran, add vinylmagnesium bromide (1M, 360mL) dropwise at -30°C, continue to react for 1 hour after the dropwise addition, and chlorinate with saturated The reaction was quenched with ammonium, extracted with ethyl acetate, and the organic layer was separated. The organic phase was spin-dried and recrystallized from ethyl acetate to obtain 8 g of pure compound S-3.

[0041] Step 3: Dissolve compound S-3 (16g, 0.083mol) in 150ml of methanol, add thionyl chloride (4.8mL, 0.066m...

Embodiment 2

[0046] Step 1: Dissolve compound S-1 (18.5g, 0.1mol) in 150ml of N,N-dimethylformamide, add NCS (N-chlorosuccinimide) (19.9g, 0.15mol) , the reaction solution was reacted at 45°C for 10 hours, and then the insoluble matter was filtered, extracted with ethyl acetate, and washed with water. The organic solvent was dried with anhydrous sodium sulfate, and spin-dried to obtain 20.6 g of compound S-2, which was directly used in the next reaction.

[0047] Step 2: Dissolve compound S-2 (20g, 0.09mol) in tetrahydrofuran, add vinylmagnesium bromide (1M, 180mL) dropwise at -45°C, continue the reaction for 1.5 hours after the dropwise addition, and then dissolve the mixture with saturated ammonium chloride The reaction was quenched, extracted with ethyl acetate, and the organic layer was separated. The organic phase was spin-dried and recrystallized from ethyl acetate to obtain 9.5 g of pure compound S-3.

[0048]Step 3: Compound S-3 (16 g, 0.083 mol) was dissolved in 150 ml of methan...

Embodiment 3

[0053] Step 1: Dissolve compound S-1 (18.5g, 0.1mol) in 150ml of N,N-dimethylformamide, add NCS (N-chlorosuccinimide) (16g, 0.12mol), The reaction solution was reacted at 50°C for 24 hours, and then the insoluble matter was filtered, extracted with ethyl acetate, and washed with water. The organic solvent was dried with anhydrous sodium sulfate, and spin-dried to obtain 18.5 g of compound S-2, which was directly used in the next reaction.

[0054] Step 2: Dissolve compound S-2 (20g, 0.09mol) in tetrahydrofuran, add vinylmagnesium bromide (1M, 270mL) dropwise at -10°C, continue to react for 2 hours after the dropwise addition, and dissolve with saturated ammonium chloride The reaction was quenched, extracted with ethyl acetate, and the organic layer was separated. The organic phase was spin-dried and recrystallized from ethyl acetate to obtain 10 g of pure compound S-3.

[0055] Step 3: Compound S-3 (16 g, 0.083 mol) was dissolved in 150 ml of methanol, and thionyl chloride (...

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Abstract

The invention discloses a method for preparing a key intermediate of an ovarian cancer-resistant medicine Rucaparib. The method is characterized by comprising the following steps: a compound S-1 reacts with NCS to obtain a compound S-2; the compound S-2 reacts with vinylmagnesium bromide to obtain a compound S-3; the compound S-3 reacts with thionyl chloride to obtain a compound S-4; the compound S-4 is dissolved in DMF and then reacts with phosphorus oxychloride to obtain a compound S-5; nitromethane and ammonium acetate are added into the compound S-5 to react to obtain a compound S-6; and the compound S-6 reacts with hydrogen at normal temperature to obtain the key intermediate of the ovarian cancer-resistant medicine Rucaparib. According to the method, nitration is avoided, the safety risk in the production process is reduced, and the method is safe and environmentally friendly; raw materials are easy to obtain and low in cost, and the production cost is effectively reduced; reaction routes are effectively reduced, and the method saves time and labor and greatly improves reaction efficiency.

Description

technical field [0001] The invention relates to the preparation of pharmaceutical intermediates, in particular to the technical field of the preparation method of a key intermediate of Rucaparib, an anti-ovarian cancer drug. Background technique [0002] Rucaparib was granted "Breakthrough Therapy" qualification in the United States in 2015 as a monotherapy for advanced ovarian cancer with BRCA (breast cancer susceptibility gene mutation) and is the first polyadenosine diphosphate-ribose polymerase ( PARP) inhibitors. [0003] Polyadenosine diphosphate-ribose polymerase (PARP) is a kind of DNA damage detection enzyme, which plays a key role in DNA damage repair and cell apoptosis. Multiple studies have shown that PARP is a good target for tumor treatment. [0004] And rucaparib starts from its key intermediate and can synthesize the final product through four steps, as follows: [0005] [0006] And its key intermediate 8-fluoro-3,4,5,6-tetrahydro-1H-benzazepine[5,4,3-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/06
CPCC07D487/06
Inventor 王振华李胜斌刘春辉胡丽英
Owner 石家庄久正生物科技有限公司
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