A kind of synthetic method of selinexor crude drug

A synthetic method and raw material drug technology, which is applied in the field of synthesis of Selinexor raw material drug, can solve problems such as affecting the yield and difficult to remove, and achieve the effect of reducing synthesis steps and increasing yield

Inactive Publication Date: 2019-11-08
广州市闻皓生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 remove and affect the yield; when intermediate 3 and intermediate 4 synthesize raw material drug 5, it is necessary to Ultra-low temperature, and the product needs to be purified by column, the yield is only 20%

Method used

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  • A kind of synthetic method of selinexor crude drug
  • A kind of synthetic method of selinexor crude drug
  • A kind of synthetic method of selinexor crude drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0025] A. Synthesis of compound 7

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

[0027] B. Synthesis of Compound 8

[0028] In a 50ml three-necked flask, add compound 7 obtained in the previous step, 40ml of glacial acetic acid and 1.38g of sodium iodide, heat up to 115°C, and react for 3h; after the reaction, the system is lowered to room temperature, the system is transferred to a 500ml bottle, and 50ml of Water and 100 ml of dichloromet...

Embodiment 2

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

[0033] A. Synthesis of compound 7

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

[0035] B. Synthesis of Compound 8

[0036] In a 50ml three-necked flask, add compound 7 obtained in the previous step, 40ml of glacial acetic acid and 1.38g of sodium iodide, heat up to 120 ° C, and react for 2.5h; 60ml of water and 120ml of dichloromethane, stirred for 15min, left to separate layers, the organic phase was washed with saturated s...

Embodiment 3

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

[0041] A. 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, and after stirring to dissolve, add 0.3g of compound 4 and 3g of T at 2°C 3 P, 0.75g DIPEA; the system was stirred at 0°C for 25min to react, after the reaction was completed, 40ml of dichloromethane and 35ml of water were added, the layers were separated, the organic phase was evaporated to dryness to obtain a crude product of compound 7, and the crude product was directly dropped without purification;

[0043] B. Synthesis of Compound 8

[0044] In a 50ml three-necked flask, add compound 7 obtained in the previous step, 35ml of glacial acetic acid and 1.38g of sodium iodide, heat up to 110 ° C, and react for 3.5h; 50 ml of water and 100 ml of dichloromethane were stirred for 8 min, and then left to separate layers. The organic phase was washed w...

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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 method for synthesizing 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 orphan drug designation to Selinexor for the treatment of acute myeloid leukemia and diffuse large B-cell lymphoma, and in June 2014, the EMA also granted orphan drug designation to Selinexor for the treatment of these two diseases. In January 2015, it received FDA orphan drug designation for the tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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