Preparation method of carfilzomib

A carfilzomib and compound technology, applied in the direction of peptides, etc., can solve the problems of difficult removal of by-products, harsh reaction conditions, high temperature control requirements, etc., and achieve the effects of easy removal, short reaction time and simple operation

Inactive Publication Date: 2016-03-30
KUNMING GUIYAN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the published preparation methods of carfilzomib, such as patents US2005245435, WO2010108172, WO2009045497, WO2005105827, and WO2011109355, etc. reported the synthesis method of carfilzomib, the condensing agent used for condensation is mostly PyBOP, HOBT, but PyBOP, HOBT Long reaction time, high requirements for temperature control, complex feeding operation, harsh reaction conditions, nitrogen protection is required, by-products are difficult to remove, and column chromatography is often required for purification, which is not convenient for industrial production

Method used

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  • Preparation method of carfilzomib
  • Preparation method of carfilzomib

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Experimental program
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Effect test

Embodiment 1

[0030] Compound Ⅱ (10.4g, 50mmol), compound Ⅲ (29.7g, 52.5mmol) and TBTU (19.3g, 60mmol) were dissolved in 200ml of dichloromethane, placed in an ice-water bath, and then N,N-diisopropyl Dichloromethane solution of ethylamine (13.0g, 100mmol), remove the ice-water bath after the addition, stir at room temperature for 2h to obtain a reaction solution, add 2% sodium bicarbonate solution (500ml×2) to wash, and then wash with saturated saline (500ml×2), dried with anhydrous sodium sulfate (10g), concentrated under reduced pressure to obtain a viscous crude product, and then beaten with a mixture of n-hexane and ethyl acetate (volume ratio 5:1) in a certain volume ratio After 12 hours, it was filtered and dried to obtain 32.0 g of the target product carfilzomib as a white solid with a yield of 89.0%.

Embodiment 2

[0032] Compound II (10.4g, 50mmol), compound III (29.7g, 52.5mmol) and TBTU (19.3g, 60mmol) were dissolved in 200ml of dichloromethane, placed in an ice-water bath, and then triethylamine (10.1g, 100mmol) of dichloromethane solution, remove the ice-water bath after the addition, and stir at room temperature for 2h to obtain a reaction solution, add 2% sodium bicarbonate solution (500ml×2) to wash, and then wash with saturated brine (500ml×2), Dry over anhydrous sodium sulfate (10g), concentrate under reduced pressure to obtain a viscous crude product, then use a certain volume ratio of n-hexane and ethyl acetate (volume ratio: 5:1) to beat for 12 hours, filter, and dry to obtain The target product, carfilzomib, was 30.6 g of white solid, and the yield was 86.0%.

Embodiment 3

[0034] Take 32.0 g of the crude carfilzomib obtained above, heat it to 70-80°C with ethanol (128ml), cool down to below 0°C after dissolving, and filter after crystallization for 3 hours. The filter cake is rinsed with a small amount of ethanol. Dry in a blast oven at 50°C to obtain 26.9 g, with a yield of 84%.

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Abstract

The invention discloses a preparation method of carfilzomib. According to the method, TBTU namely 2-(1H-benzotriazoleL-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate is taken as the condensing agent to carry out condensation. The method has the advantages that the reaction time is short, the nitrogen gas protection is not needed, the operation is convenient and feasible, the byproduct of condensing agent TBTU can be easily removed, the tedious steps such as column chromatography are not needed; a mixed solvent is cured in the post treatment to obtain the solid carfilzomib, the column chromatography is not needed, and the crude product is recrystallized by alcohol so as to obtain the refined product of carfilzomib. The preparation method can be applied to industrial production.

Description

technical field [0001] The invention relates to the technical field of organic drug synthesis, in particular to a preparation method of an antitumor drug carfilzomib. technical background [0002] Carfilzomib (Carfilzomib), the chemical name is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxirane- 2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenethyl)-2-((S)-2-(2-morpholineacetamido)-4-phenyl Butyramide)-4-methylpentanamide, the trade name is Kyprolis, and the molecular formula is C 40 h 57 N 5 o 7 , the structure is shown in formula (I): [0003] [0004] Carfilzomib (Carfilzomib) is a protease inhibitor developed by Onyx Pharmaceuticals Inc of the United States. The trade name is Kyprolis. The drug is an injection and was approved by the US FDA in July 2012. Treatment of patients with myeloma. Multiple myeloma is a malignant clonal disease of plasma cells. The incidence rate is increasing year by year, ranking second in hematological malignancies. With the improvement of tr...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/30C07K1/02
CPCC07K7/06
Inventor 王应飞丛艳伟普绍平彭娟李宗浩邱学翁张琪黄天俊
Owner KUNMING GUIYAN PHARMA
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