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Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib

A technology for carfilzomib and intermediates, applied in the field of preparation of carfilzomib, carfilzomib intermediates and its preparation, can solve the problem of low final product yield, multiple starting materials, low reaction yield, etc. problem, to achieve the effect of improving yield and purity, mild and controllable reaction conditions, and simple preparation process

Active Publication Date: 2015-02-18
重庆兴泰濠制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method can finally synthesize carfilzomib, but there are still some problems when it is applied to large-scale production, such as the low yield of sodium iodide chlorine substitution reaction, which not only consumes more starting materials, but also leads to the loss of final product. The yield is low; moreover, there are many types of reactions in this synthetic method, the reaction conditions are complicated and varied, and the controllability is poor, so it is not suitable for large-scale industrial production

Method used

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  • Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib
  • Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib
  • Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib

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preparation example Construction

[0045] The preparation process of the intermediate is simple, only involves condensation and deprotection reactions between amino acids, and the reaction conditions are mild and controllable. To prepare carfilzomib using the intermediate as a raw material, only the epoxidation reaction can be carried out, and the epoxidation reaction conditions adopted have higher selectivity, which improves the yield and purity of carfilzomib, and prepares The yield of carfilzomib is more than 35%, and the purity is more than 99%, which provides an economical and environment-friendly synthesis process for the preparation of carfilzomib.

[0046] A carfilzomib intermediate provided by the present invention has a structure represented by formula (XIII).

[0047] The present invention also provides a method for preparing the above-mentioned carfilzomib intermediate, comprising:

[0048] Under the action of a condensing agent and an organic base, the compound shown in the formula (XI) is condens...

Embodiment 1

[0103] Preparation of compound shown in embodiment 1 formula (XII)

[0104] Add 23.1g (0.10mol) of N-Boc-L-leucine with the structure shown in formula (1) into a 1000mL three-necked flask, add 400mL of dichloromethane, stir and dissolve; cool the solution to -10°C under stirring, and pour 78.1 g (0.15 mol) of PyBOP was added thereto, and a dichloromethane (100 mL) solution of 10.7 g (0.11 mol) of N,O-dimethylhydroxylamine hydrochloride was slowly added dropwise to the mixture. The resulting solution was stirred at room temperature for 10 h, then diluted with water, extracted twice with dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered to remove anhydrous magnesium sulfate. The solvent was evaporated to dryness under reduced pressure to obtain 23.6 g of the compound represented by formula (2).

[0105] Under the protection of nitrogen, add 13.7g (0.05mol) of the compound represented by the formula (2) in...

Embodiment 2

[0107] Preparation of compound shown in embodiment 2 formula (V-a)

[0108] Under nitrogen protection, add 27.9g (0.10mol) of N-Boc-L-homophenylalanine and 26.0g (0.105mol) of L-leucine methyl ester trifluoroacetate into a 1000mL three-necked flask, and add 500mL Tetrahydrofuran, and 51.7 g (0.4 mol) of DIEA were added thereto, and the mixture was cooled to 0° C. with stirring. To this mixture was added HOBT 14.9 g (0.11 mol). The reactant was placed under nitrogen, stirred for 2 h, distilled under reduced pressure, the residue was dissolved in 300 mL of dichloromethane, and washed twice with saturated sodium bicarbonate, water and saturated saline, each time 150 mL , the organic layer was evaporated to dryness under reduced pressure to obtain 36.5 g of the compound represented by formula (IV), and then 120 mL of a mixed solution of trifluoroacetic acid:dichloromethane=4:1 was added thereto, stirred and reacted at 15° C. for 7 h, and concentrated to obtain off-white Solid 29...

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Abstract

The invention provides a carfilzomib intermediate with a structure shown as the formula (XIII). The preparation process of the intermediate is simple, only amino acid condensation and deprotection reactions are related, and the reaction condition is mild and controllable. The intermediate is taken as a raw material to prepare carfilzomib, only an epoxidation reaction is needed, the epoxidation reaction condition has higher selectivity, yield and purity of carfilzomib are improved, the yield of the prepared carfilzomib is higher than 35%, the purity is higher than 99%, and an economical and environment-friendly synthetic process is provided for preparation of carfilzomib.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical compounds, in particular to a carfilzomib intermediate and a preparation method thereof, and a carfilzomib preparation method. Background technique [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 base)-4-methylpentanamide, trade name is Kyprolis, and molecular formula is C40H57N5O7, has the structure shown in formula (I): [0003] [0004] In the past three decades, the incidence of cancer in the world has been increasing at an average annual rate of 3% to 5%, and cancer has become the number one cause of death for human beings. How to effectively prevent and treat cancer has always been a key topic in medical research. Among them, multiple myeloma is a malignant clonal disease of plasma cells. The incidence rate is increasing ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06
CPCY02P20/55
Inventor 姚全兴李靖纳特·芬妮翠茜·伯尔吴进喻威艾威
Owner 重庆兴泰濠制药有限公司
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