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Synthetic method of carfilzomib intermediate and carfilzomib intermediate

A synthesis method and carfilzomib technology are applied in chemical instruments and methods, preparation of organic compounds, preparation of carbamate derivatives, etc., and can solve the problems of long reaction route, complicated process, low overall yield, etc. The effect of high production cost, high reaction yield and concise process route

Active Publication Date: 2015-04-29
苏州中科新药篮生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although the reagents used in this route are relatively cheap, the reaction route is long, the process is cumbersome, the overall yield is not high, and purification is difficult

Method used

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  • Synthetic method of carfilzomib intermediate and carfilzomib intermediate
  • Synthetic method of carfilzomib intermediate and carfilzomib intermediate
  • Synthetic method of carfilzomib intermediate and carfilzomib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Synthesis of compound 5a

[0064]

[0065] Dissolve 231g (1.0mol, 1eq) of 6a in 2L of dichloromethane, add 195g (1.2mol, 1.2eq) of carbonyldiimidazole in batches within half an hour at room temperature, stir at room temperature for 1 hour, add 138g (3.0 mol, 3.0eq) ethanol, continued to stir at room temperature for 4 hours, sampling TLC showed that the reaction was complete. Add 500ml of water, stir and separate the layers, and the organic phase is successively washed with 500ml of saturated sodium bicarbonate, 500ml of 1N aqueous hydrochloric acid, 500ml of water, and 200ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 246.4g of a light yellow oily liquid. Yield 95.0%, HPLC purity 99.9%.

Embodiment 2

[0067] Synthesis of compound 5b

[0068]

[0069] Dissolve 265.3g (1.0mol, 1eq) of 6b in 2L of dichloromethane, add 195g (1.2mol, 1.2eq) of carbonyldiimidazole in batches within half an hour at room temperature, after the addition is complete, stir at room temperature for 1 hour, then add 138g ( 3.0mol, 3.0eq) ethanol, continued to stir at room temperature for 4 hours, sampling TLC showed that the reaction was complete. Add 500ml of water, stir and separate the layers, and the organic phase is washed successively with 500ml of saturated sodium bicarbonate, 500ml of 1N aqueous hydrochloric acid, 500ml of water, and 200ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 287.3g of light buttery liquid. Yield 98.0%, HPLC purity 99.7%.

Embodiment 3

[0071] Synthesis of compound 5c

[0072]

[0073] Dissolve 231g (1.0mol, 1eq) of 6a in 2L of dichloromethane, add 195g (1.2mol, 1.2eq) of carbonyldiimidazole in batches within half an hour at room temperature, after the addition is complete, stir at room temperature for 1 hour, then add 324.4g ( 3.0mol, 3.0eq) benzyl alcohol, continued to stir at room temperature for 4 hours, sampling TLC showed that the reaction was complete. Add 500ml of water, stir and separate the layers, and the organic phase is successively washed with 500ml of saturated sodium bicarbonate, 500ml of 1N aqueous hydrochloric acid, 500ml of water, and 200ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 311.8g of light buttery liquid. Yield 97.0%, HPLC purity 99.8%.

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Abstract

The invention relates to the field of chemical synthesis of medicines, and in particular relates to a synthetic method of a carfilzomib intermediate 1. The synthetic method of the carfilzomib intermediate 1 comprises the steps of ring opening, ring closing, deprotection and the like. The method is simple in routes, high in yield of each reaction step and suitable for industrial production. The invention also provides a new compound which is a key intermediate required for synthesizing the compound 1, and the key intermediate is shown in a formula 4 in the specification. The method also provides a synthetic method of the compound 4; in the method, an expensive reagent 2-bromopropylene is not used, so that the production cost is reduced.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for synthesizing a carfilzomib intermediate and an intermediate thereof. Background technique [0002] Carfilzomib, chemical name is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxirane-2-yl )1-oxopentane-2-ylcarbamoyl)-2-phenethyl)-2-((S)-2-(2-morpholineacetamido)-4-phenylbutanylamino) -4-methylpentanamide, the foreign name or common name is Carfilzomib, the trade name is Kyprolis, the molecular formula is C19H25BN4)4, and the specific structural formula is as follows: [0003] [0004] On July 20, 2012, the U.S. Food and Drug Administration (FDA) approved the marketing of ONYX PHARMS INC’s product carfilzomib (carfilzomib) freeze-dried powder for injection. Carfilzomib can be used for treatment of patients who have received at least 2 drugs before (including bortezomib and immunomodulators) treated multiple myeloma patients. Multiple myeloma is a ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/36C07D301/12C07C271/16C07C269/06C07C271/48
CPCC07C269/06C07C271/16C07C2601/02C07D301/00C07D303/36C07C271/22
Inventor 不公告发明人
Owner 苏州中科新药篮生物医药科技有限公司
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