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Synthetic method of kyprolis

A synthetic method, the technology of carfilzomib, which is applied in the field of carfilzomib synthesis, can solve the problems of multiple reaction types, consumption, complex and diverse reaction conditions, etc.

Active Publication Date: 2014-03-19
重庆兴泰濠制药有限公司
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  • Summary
  • 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 reaction yield of the linear synthesis method, and the used sodium iodide chlorine substitution reaction yield is not high, so it consumes more Starting raw materials; and in this synthetic method, due to the use of chloroacetyl chloride, the pollution is relatively large; in addition, in this synthetic method, there are many reaction types, complex and diverse reaction conditions, and poor controllability, so it is not suitable for large-scale industrial production

Method used

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  • Synthetic method of kyprolis
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  • Synthetic method of kyprolis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] The preparation of embodiment 1 compound V

[0128] Under nitrogen protection, add 14.6g (0.10mol) of morpholin-4-ylacetic acid and 20.3g (0.105mol) of L-homophenylalanine methyl ester into a 1000mL three-necked flask, add 500mL of acetonitrile, and then add DIEA51 .7 g (0.4 mol), the mixture was cooled to 0°C with stirring. To this mixture was added HOBT 14.9 g (0.11 mol) followed by three additions of PyBOP totaling 57.3 g (0.11 mol) over five minutes. The reactant was placed under nitrogen, stirred and reacted for 8 hours, distilled under reduced pressure, the residue was dissolved in 300mL ethyl acetate, washed twice with saturated sodium bicarbonate, water and saturated saline respectively, each dosage was 150mL, organic The layer was evaporated to dryness under reduced pressure to obtain 19.5g of the compound, which was dissolved in a mixed solution of methanol:water=3:1, cooled to 0°C, and 12.1g (0.5mol) of lithium hydroxide was added to react for 12h, and then ...

Embodiment 2

[0132] The preparation of embodiment 2 compound V

[0133] Under the protection of argon, add 14.6g (0.10mol) of morpholin-4-ylacetic acid and 48.3g (0.25mol) of L-homophenylalanine ethyl ester into a 2000mL three-necked flask, add 1200mL tetrahydrofuran, and then add 158.2 g (2.0 mol) of pyridine, and the mixture was cooled to -20°C with stirring. Add HATU380.2g (1.0mol) to this mixture, place the reactant under nitrogen, stir the reaction for 24h, distill under reduced pressure, dissolve the residue in 300mL ethyl acetate, wash with saturated sodium bicarbonate, water and saturated saline successively Wash twice respectively, each time the amount is 150mL, the organic layer is evaporated to dryness under reduced pressure to obtain 21.6g of the compound, which is dissolved in a mixed solution of methanol: water = 9:1, cooled to 0°C, and 24.2g of lithium hydroxide is added (1.0mol) reacted for 8 hours, terminated the reaction with 200mL saturated ammonium chloride, adjusted t...

Embodiment 3

[0138] Embodiment 3 Preparation of Compound V

[0139] Add 14.6g (0.10mol) of morpholin-4-ylacetic acid and 114.8g (0.50mol) of L-homophenylalanine methyl ester hydrochloride into a 2000mL three-necked flask, add 600mL of DMF, and then add 50.6 g (0.50mol), the mixture was stirred at 20°C, TBTU64.2g (0.2mol) was added to the mixture, the reactant was placed under nitrogen, stirred for 24h, distilled under reduced pressure, and the residue was dissolved in 300mL of dichloro Methane was washed twice with saturated sodium bicarbonate, water and saturated brine successively, each time the dosage was 150mL, and the organic layer was evaporated to dryness under reduced pressure to obtain 20.4g of the compound, which was dissolved in methanol:water=5:1 mixed In the solution, cool to 0°C, add 19.4g (0.8mol) of lithium hydroxide to react for 8 hours, stop the reaction with 200mL saturated ammonium chloride, adjust the pH value to about 3 with 1N hydrochloric acid, extract twice with 10...

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Abstract

The invention relates to the technical field of drug synthesis, and particularly relates to a synthetic method of kyprolis. The synthetic method comprises the following steps: carrying out condensation reaction on morpholine-4-base acetic acid, L-homophenylalanine ester and salt, and then carrying out decarboxylation protection to generate a compound V; carrying out the condensation reaction on the decarboxylation, the salt and N-Boc-L-leucine, and then carrying out deamination protection to generate a compound VI; carrying out the condensation reaction on the compound V and the compound VI, and then carrying out decarboxylation protection to generate a compound VII; carrying out the condensation reaction on the compound VII and a compound VIII to obtain the kyprolis. The method disclosed by the invention can be used for enhancing the reaction yield by adopting a converging synthetic method; the used reagent is easy, convenient, easy to obtain and less in pollution. The process disclosed by the invention only relates to the condensation and deprotection between amino acids and is simple and controllable in reaction and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of carfilzomib. Background technique [0002] Carfilzomib, chemical name (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxirane-2-yl )-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholineacetamido)-4-phenylbutanylamino )-4-methylpentanamide, the foreign name or common name is Carfilzomib, the trade name is Kyprolis, and the molecular formula is C 19 h 25 BN 4 o 4 , has the structure shown in formula IX. [0003] [0004] On July 20, 2012, the U.S. Food and Drug Administration (FDA) approved the listing of ONYXPHARMSINC’s product carfilzomib (carfilzomib) freeze-dried powder for injection. Carfilzomib can be used for the treatment of at least 2 drugs (including Bortezomib and immunomodulators) in patients with multiple myeloma. Multiple myeloma is a malignant clonal disease of plasma cells. The incidence rate is increasing year by year, ...

Claims

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Application Information

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IPC IPC(8): C07K7/06
CPCY02P20/55
Inventor 姚全兴李靖李娅喻威
Owner 重庆兴泰濠制药有限公司
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