Novel synthesis method of Selinexor active pharmaceutical ingredient

A synthesis method and a technology for an API, which are applied in the new synthesis field of Selinexor API, can solve the problems of affecting the yield and being difficult to remove, and achieve the effect of reducing the synthesis steps and improving the yield.

Inactive Publication Date: 2017-06-13
广州市闻皓生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in this method, the double bond from intermediate 1 to 2 is easy to reverse, and trans impurities are likely to be produced during synthesis and production, which are difficult to remov...

Method used

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  • Novel synthesis method of Selinexor active pharmaceutical ingredient
  • Novel synthesis method of Selinexor active pharmaceutical ingredient
  • Novel synthesis method of Selinexor active pharmaceutical ingredient

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] A novel synthetic method of Selinexor bulk drug, comprising the following steps:

[0025] A, the synthesis of compound 7

[0026] In a 50ml three-neck flask, add 0.2g of compound 6, 15ml of dichloromethane and 15ml of ethyl acetate, stir and dissolve, then add 0.3g of compound 4 and 3g of T 3 P, 0.75g DIPEA; the system was stirred at 0°C for 30 minutes to react, after the reaction was completed, 50ml of dichloromethane and 30ml of water were added, the liquid was separated, and the organic phase was evaporated to dryness to obtain the crude compound 7, which was directly cast down without purification;

[0027] B, the synthesis of compound 8

[0028] Add compound 7, 40ml glacial acetic acid and 1.38g sodium iodide obtained in the previous step to a 50ml three-necked flask, raise the temperature to 115°C, and react for 3h; Water and 100ml of dichloromethane were stirred for 10min, and the layers were allowed to stand. The organic phase was washed with saturated sodium ...

Embodiment 2

[0032] A novel synthetic method of Selinexor bulk drug, comprising the following steps:

[0033] A, the synthesis of compound 7

[0034] In a 50ml three-neck flask, add 0.2g of compound 6, 15ml of dichloromethane and 15ml of ethyl acetate, stir and dissolve, then add 0.3g of compound 4 and 3g of T 3 P, 0.75g DIPEA; the system was stirred at 1°C for 35 minutes to react, after the reaction was completed, 50ml of dichloromethane and 30ml of water were added, the liquid was separated, and the organic phase was evaporated to dryness to obtain the crude compound 7, which was directly cast down without purification;

[0035] B, the synthesis of compound 8

[0036] Add compound 7, 40ml glacial acetic acid and 1.38g sodium iodide obtained in the previous step to a 50ml three-necked flask, raise the temperature to 120°C, and react for 2.5h; 60ml of water and 120ml of dichloromethane, after stirring for 15min, let stand to separate layers, the organic phase was washed with saturated so...

Embodiment 3

[0040] A novel synthetic method of Selinexor bulk drug, comprising the following steps:

[0041] A, the synthesis of compound 7

[0042] In a 50ml three-necked flask, add 0.2g of compound 6, 15ml of dichloromethane and 15ml of ethyl acetate, stir and dissolve, then add 0.3g of compound 4 and 3g of T 3 P, 0.75g DIPEA; the system was stirred at 0°C for 25 minutes to react, after the reaction was completed, 40ml of dichloromethane and 35ml of water were added, the liquid was separated, and the organic phase was evaporated to dryness to obtain the crude compound 7, which was directly cast down without purification;

[0043] B, the synthesis of compound 8

[0044] Add compound 7, 35ml glacial acetic acid and 1.38g sodium iodide obtained in the previous step to a 50ml three-necked flask, raise the temperature to 110°C, and react for 3.5h; 50ml of water and 100ml of dichloromethane were stirred for 8min, and the layers were separated. The organic phase was washed with saturated sod...

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Abstract

The invention provides a novel synthesis method of a Selinexor active pharmaceutical ingredient. The method comprises the following steps: mixing a compound 6, dichloromethane and ethyl acetate, adding a compound 4, T3P and DIPEA (diisopropylethylamine) at low temperature, reacting, adding water and ethyl acetate, skimming, and drying up the organic phase by distillation to obtain a compound 7 crude product; mixing the compound 7, glacial acetic acid and sodium iodide, heating and reacting; after the reaction finishes, cooling, adding water and dichloromethane, standing to stratify, washing the organic phase, drying, and distilling to obtain a compound 8; mixing the compound 1, DBACO and DMF (N,N-dimethylformamide), dropwisely adding a compound 8 DMF solution, and reacting; and after the reaction finishes, adding water and ethyl acetate, drying up the organic phase by distillation, and recrystallizing to obtain the compound 5. The synthesis method solves the problem that the traditional synthesis technique can easily generate trans impurities, reduces the synthesis steps, enhances the yield, and provides a new technique for synthesizing the Selinexor active pharmaceutical ingredient.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a novel synthesis method of a Selinexor bulk drug. Background technique [0002] Selinexor is an oral biologically effective selective nuclear export protein inhibitor. It entered the clinic for the first time in 2012. So far, a total of 21 clinical trials have been carried out. The indications include chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, Prostate cancer, melanoma, non-small cell lung cancer, glioma, neuroblastoma, gynecological tumor, diffuse large B-cell lymphoma, squamous cell carcinoma, rectal cancer, etc. In May 2014, the FDA granted Selinexor the orphan drug title for the treatment of acute myeloid leukemia and diffuse large B-cell lymphoma. In June 2014, EMA also awarded Selinexor the orphan drug title for the treatment of these two diseases. In January 2015, it was approved as an orphan drug by the FDA for the treatment of m...

Claims

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Application Information

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IPC IPC(8): C07D403/12
CPCC07D403/12
Inventor 陈新颖徐亮刘文忠
Owner 广州市闻皓生物科技有限公司
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