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Preparation method of intermediate compounds of carfilzomib and intermediate compounds

A technology for compounds and intermediates, applied in the field of compound preparation, can solve problems such as difficulties in industrialization, and achieve the effects of excellent yield, reduced cost, and improved stereoselectivity

Inactive Publication Date: 2014-12-24
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses a chiral complex of metal manganese as a catalyst to induce asymmetric epoxidation to increase the selectivity to 7:1, but because the chiral complex is not commercialized, the industrialization of this method is still difficult

Method used

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  • Preparation method of intermediate compounds of carfilzomib and intermediate compounds
  • Preparation method of intermediate compounds of carfilzomib and intermediate compounds
  • Preparation method of intermediate compounds of carfilzomib and intermediate compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Preparation of N, N-di-tert-butoxycarbonyl-L-leucine

[0054]

[0055] 200g (0.152mol) of L-leucine was dissolved in 500mL of acetonitrile solvent, followed by the addition of 80mL (0.76mol) of diisopropylethylamine, 18.4g (0.152mol) of 4-dimethylaminopyridine and 100g ( 0.456mol) of tert-butoxyformic anhydride, stirred and heated to reflux for 12 hours, TLC detected that the raw material spots disappeared, cooled to room temperature and added water to quench the reaction, added dichloromethane for extraction, the organic phase was washed with saturated brine, anhydrous sulfuric acid After sodium drying, filtration and concentration, 45.2 g of brown solid compound N,N-di-tert-butoxycarbonyl-L-leucine was obtained, with a yield of 90%. The purity is 98.4%.

[0056] 1H NMR (500MHz, DMSO-d6) δppm 12.36[br, 1H,], 3.91-3.87[m, 1H], 1.64-1.61[m, 2H], 1.51-1.47[m, 1H], 1.36[s, 18H] ], 0.87-0.83 [m, 6H].ESI / MS: m / z=332.20(M+H)+.

Embodiment 2

[0057] Example 2: Preparation of (N, N-(di-tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-formamide

[0058]

[0059] Dissolve N, N-di-tert-butoxycarbonyl-L-leucine (45.2 g, 0.137 mol) in 300 mL of DCM, and add N, O-dimethylhydroxylamine hydrochloride (26.7 g, 0.274 mol), Triethylamine (27.7g, 0.274mol), DMAP (1.7g, 0.014mol), stirred at room temperature for 10 minutes after adding, added EDCl (52.5g, 0.137mmol), stirred at room temperature for 3 hours, and TLC detected that the raw material spots disappeared, and added water The reaction was quenched, extracted with dichloromethane, the organic phase was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 47.7g of yellow oily compound (N,N-(di-tert-butoxycarbonyl)-L -Leucine-N'-methoxy-N'-formamide, the yield is 93%. The purity is 96.5%.

[0060] 1H NMR (CDCl3, 500MHz): δppm 4.70 (m, 1H), 3.76, (s, 3H), 3.17, (s, 3H), 1.69, (m, 1H), 1.45-1.37 (m, 2H)...

Embodiment 3

[0061] Example 3: Preparation of (S)-4,4-(di-tert-butoxycarbonylamino)-2,6-dimethyl-1-hepten-3-one

[0062]

[0063] Preparation of 2-propenylmagnesium bromide Grignard reagent: Add magnesium chips (6.7g, 0.279mol) and iodine particles (20mg catalytic amount) to 200mLTHF, heat to reflux, and slowly add 2-bromopropene dropwise after reflux for 1 hour (0.254mol), and then add dropwise about 10mL of iodine, the color disappears, and the reaction is initiated. After the addition of 2-bromopropene is completed, the reaction is refluxed for 2 hours and then cooled to 0-5°C.

[0064] Add (N-(di-tert-butoxycarbonyl)-L-leucine-N′-methoxy-N′-formamide) THF solution (47.7 g in 150 mL THF) dropwise to the prepared Grignard reagent Medium, 0.127mol), after reacting at room temperature for 12 hours, TLC detects that the raw material spots disappear, adding saturated ammonium chloride to quench the reaction, extracting with ethyl acetate, washing the organic phase with saturated brine, dr...

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Abstract

The invention discloses a preparation method of an intermediate compound I of carfilzomib. The method is characterized by comprising the following steps: by using L-leucine as an initial raw material, protecting two active hydrogens on the amino group, carrying out Weinreb amidation, reacting with magnesium 2-propenylbromide, and carrying out epoxidation and amino protection removal to obtain the compound disclosed as Formula I. The invention also discloses intermediate compounds II, III, VI and V of carfilzomib. The preparation method is simple and efficient, has the advantages of low cost and high selectivity, and is beneficial to industrial production.

Description

technical field [0001] The present invention relates to a preparation method of a compound, in particular to a key intermediate (2S)-2-amino-4-methyl-1- The preparation method of [(2R)-2-methyloxiranyl]-1-pentanone trifluoroacetate. Background technique [0002] Carfilzomib (Carfilzomib) is a protease inhibitor applied by the Onyx Pharmaceuticals Inc pharmaceutical company in the United States, and its trade name is Kyprolis, which is used for the treatment of multiple myeloma. The drug is an injection, which was approved by the US FDA in July 2012 for the treatment of patients with multiple myeloma who have failed other drug treatments. And (2S)-2-amino-4-methyl-1-[(2R)-2-methyloxiranyl]-1-pentanone trifluoroacetate I is a preparation carfilzomib key intermediates. (WO 2005105827) [0003] [0004] For the synthesis of this key intermediate, the methods reported at present have the following several kinds: [0005] WO2009045497 discloses the following route, using L...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/36C07D301/03C07C269/06C07C271/22
CPCC07D303/36C07C271/18C07C271/22C07D301/03
Inventor 郑保富高强张宪恕丁福斗杨旭慧
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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