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Synthesis method of rucaparib camsylate

A technology of camphorsulfonate and synthesis method, which is applied to the preparation of sulfonic acid, chemical instruments and methods, and the preparation of organic compounds, etc., which can solve the problems of not being able to meet the requirements of medicine, unqualified refined products, and low utilization rate of raw materials. Achieve the effect of improving synthesis efficiency, high utilization rate and short reaction cycle

Inactive Publication Date: 2020-04-14
CHONGQING BEISHENG PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this synthesis method produces many impurities, and the product is not suitable for refined and qualified products. The single impurity cannot reach 0.1%, which cannot meet the requirements of medicine, and its total yield is only 42.14%, which has a low utilization rate of raw materials.

Method used

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  • Synthesis method of rucaparib camsylate
  • Synthesis method of rucaparib camsylate
  • Synthesis method of rucaparib camsylate

Examples

Experimental program
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Embodiment 1

[0036] Step 1: Take compound M-1 (80g, 0.392mol) and add it to 600mL tetrahydrofuran, then add pyridinium tribromide (150.36g, 0.468mol), react at 10°C for 1h and filter with suction, add the filter cake to After stirring in 5% aqueous sodium bicarbonate solution (400 mL) for 1 h, suction filtration, the filter cake was washed with water (200 mL), and air-dried to obtain pale yellow compound M-2 (100.54 g), with a yield of 90.65%.

[0037] Step 2: Take compound M-2 (90g, 0.318mol), add it to a mixed solution of 900mL N,N-dimethylacetamide and 135mL water, add p-formylphenylboronic acid (57.20g, 0.382mol), sodium carbonate (84.24g, 0.795mol) and Pd(dppf)Cl 2 (6.98g, 9.54mmol), heated up to 90-100°C and reacted for 2h (this process was carried out under nitrogen protection), after the reaction, add water (1800mL) and crystallize at 10°C for 1h, then suction filter, and wash the filter cake with water to neutral properties, dried, added to absolute ethanol (720mL), stirred at 7...

Embodiment 2

[0042]Step 1: Take compound M-1 (80g, 0.39mol) and add it to 600mL tetrahydrofuran, then add pyridinium tribromide (150.36g, 0.468mol), react at 20°C for 1h and filter with suction, add the filter cake to After stirring in 5% aqueous sodium bicarbonate solution for 1 h, suction filtration, the filter cake was washed with water until neutral, and air-dried to obtain light yellow compound M-2 (101.29 g), with a yield of 91.23%.

[0043] Step 2: Take compound M-2 (90g, 0.318mol), add it to a mixed solution of 900mL N,N-dimethylacetamide and 135mL water, add p-formylphenylboronic acid (57.20g, 0.382mol), sodium carbonate (84.24g, 0.795mol) and Pd(dppf)Cl 2 (6.98g, 9.54mmol), heated to 90-100°C and reacted for 2h (this process was carried out under the protection of nitrogen), after the reaction, add water (1800mL), crystallize at 10°C for 1h and suction filter, the filter cake was washed with water until Neutral, dry, add absolute ethanol (720mL), stir at 75-80°C for 1h, drop to...

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Abstract

The invention relates to a synthesis method of rucaparib camsylate. The method comprises the following steps: 1) carrying out a reaction on a compound M-1 and pyridinium tribromide by using tetrahydrofuran and / or dichloromethane as a solvent to obtain a compound M-2; 2) carrying out a reaction on the compound M-2 and p-formyl phenylboronic acid under the catalytic action of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride by using N,N-dimethylacetamide as a solvent to obtain a compound M-3, wherein the reaction temperature is higher than or equal to 90 DEG C; 3) carrying out a reaction on the compound M-3 and methylamine under the catalytic action of p-toluenesulfonic acid by using methanol and / or ethanol as a solvent, adding sodium borohydride, and reducing to obtain a compound M-4; 4) carrying out a reaction on the compound M-4 and an alkali by taking water as a solvent to obtain a compound M-5; and 5) carrying out a reaction on the compound M-5 and camphorsulfonic acid by taking methanol and / or ethanol as a solvent to obtain the rucaparib camsylate. According to the invention, the compounds M-1, M-3 and M-4 react at room temperature, the conditions are mild and controllable, the reaction period is short, the synthesis efficiency can be effectively improved, the production cost is reduced, and the purity of the obtained product reaches 99.95-99.98%.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a method for synthesizing recaprabib camphorsulfonate. Background technique [0002] Polyadenosine diphosphate-ribose polymerase (PARP) is a family of ribozymes responsible for ADP-ribosylation, in which poly ADP-ribosyltransferase converts the ADP-ribose moiety from NAD + Transfer to specific amino acid side chains in nuclear target protein repair enzymes or to previously attached ADP-ribose units. The PARP family in humans includes 17 enzymes, of which PARP-1 is best characterized. [0003] As a phosphoribose polymerase (PARP) inhibitor, Rucaparib Camsylate can selectively kill tumor cells with defective homologous recombination function, while causing less harm to normal cells. [0004] In December 2016, Rucaparib received accelerated approval from the FDA for the treatment of patients with advanced ovarian cancer who have undergone two or more chemotherapy treatments and whose tumo...

Claims

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Application Information

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IPC IPC(8): C07D487/06C07C303/22C07C303/44C07C309/19
CPCC07C303/22C07C303/44C07D487/06C07C2602/42C07C309/19
Inventor 潘敬坤庞云
Owner CHONGQING BEISHENG PHARMA TECH CO LTD
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