Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate

A technology of methyl oxirane and carbamic acid, applied in the direction of organic chemistry and the like, can solve the problems of poor crystalline properties, difficult control and poor selectivity of compound compounds, and achieve the effects of low cost, simple operation and high yield

Active Publication Date: 2015-06-03
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Obtain the mixture of formula (I) and formula (II) with 76% yield in this route, compound (I): the weight ratio of compound (II) is 1.7:1, and this reaction is difficult to control, and selectivity is poor, and Compound (I) and compound (II) have poor crystallization properties, and the two are difficult to separate

Method used

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  • Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate
  • Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate
  • Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add compound III (102g, 0.4mol), asymmetric chiral catalyst (R)-La-BINOL (3.24g, 2mol%), triphenylphosphine (14.8g, 20mol%), 500mL toluene into a 1L reaction flask , Stir at room temperature. Then, tert-butanol (108g, 1.2mol) was slowly added dropwise. After 0.5h of reaction, TLC monitoring was performed. After the reaction was complete, the reaction solution was filtered and the filtrate was collected. The filtrate was quenched with 300 mL of saturated sodium sulfite solution, tetrahydrofuran was rotary evaporated under reduced pressure, and 400 mL of ethyl acetate was added for extraction. The organic phase was washed with 100 mL of water, 100 mL of saturated brine, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure. 92 g of light yellow oily substance is compound I, the yield is 85.0%, and the ee value is 93%.

[0026] Compound I 1 H NMR(400MHz,DMSO)δ7.11(d,J=7.6Hz,1H), 4.08(dd,J=14.1,7.3Hz,1H), 3.16(d,J=5.2Hz,1H), 2.99(d ,J=5.2Hz,1H),1.75–1.58...

Embodiment 2

[0028] The reaction solvent was changed from toluene to tetrahydrofuran, and the rest was the same as in Example 1. The compound I was finally obtained with a yield of 84.1% and an ee value of 91%.

Embodiment 3

[0030] The reaction solvent was changed from toluene to dichloromethane, and the rest were the same as in Example 1. Finally, compound I was obtained with a yield of 80.0% and an ee value of 85%.

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Abstract

The invention relates to a preparation method of a carfilzomib intermediate: [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate. The preparation method comprises the following step: adding triphenylphosphine and tert-butyl alcohol hydroperoxide to a compound (III) to carry out catalytic reaction in the presence of an asymmetric chiral catalyst (R)-La-BINOL. The compound (III) is shown in a formula in the specification. The carfilzomib intermediate (I) can be synthesized with a starting material (III) by adopting the preparation method. The preparation method is accessible in used raw materials and simple in reaction conditions, is simple and convenient to operate, is simple in aftertreatment, has good selectivity, is good in yield and is suitable for industrial production.

Description

Technical field [0001] The present invention relates to an intermediate of Carfilzomib: [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]carbamic acid tert-butyl ester Preparation. Background technique [0002] Carfilzomib, the chemical name is (S)-2-((S)-2-(2-(2H-1,4-oxazine-4(3H)-yl)acetamido)-4- Phenylbutanamide)-4-methyl-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl) -1-oxopentane-2-ylamino)-1-oxo-3-phenylpropan-2-yl)pentanamide is a proteasome inhibitor developed by Proteolix for the treatment of relapse and refractory Of multiple myeloma. It was approved by the U.S. Food and Drug Administration (FDA) on July 20, 2012 for the treatment of multiple myeloma (MM) patients who had previously received at least 2 drugs (including bortezomib and immunomodulator therapy). Its chemical structure As follows: [0003] [0004] The compound represented by formula (I) is an intermediate for the synthesis of carfilzomib, and its chemical name is [(1S)-3-methyl-1-[[(2R)-2-m...

Claims

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Application Information

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IPC IPC(8): C07D303/36C07D301/19
CPCC07D301/19C07D303/36
Inventor 叶天健刘涛马苏旺张绩生何思陈尧
Owner ZHEJIANG YONGNING PHARMA
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