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

A technology of methyloxiranyl and carbamic acid, which is applied in the direction of organic chemistry, can solve the problems of poor crystallization properties, difficult separation, and difficult control of compounds, and achieve the effects of good yield, easy operation, and simple reaction conditions

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] In the 1L reaction flask, add phase transfer catalyst 8.85g PTC A (0.015mol, 3mol%) successively, 56g potassium hydroxide (1.0mol, 2.0eq), 500mL n-butyl ether, under stirring at room temperature, add 127g compound III (0.5mol, 1.0eq). Cool down to 0°C, slowly add 113.3g of 30% hydrogen peroxide (1.0mol, 2.0eq) dropwise, and keep the temperature not higher than 4°C. After adding heat preservation, the temperature was higher than 0°C and lower than 4°C for 36h.

[0033] TLC monitoring, after the reaction is complete, filter, the filtrate is quenched with 300mL saturated sodium sulfite solution, the upper organic phase is separated, concentrated to dryness under reduced pressure, the residue is dissolved in 600mL ethyl acetate, washed with 150mL saturated brine, and dried over anhydrous sodium sulfate. After spin-drying under reduced pressure, 131 g of a light yellow oily substance was obtained, namely compound I, with a yield of 97.0% and an ee value of 84%.

[0034] Co...

Embodiment 2

[0037] PTC B was used to replace PCT A to participate in the reaction, and the rest was the same as in Example 1. The final yield was 94.1%, and the ee value was 80%.

Embodiment 3

[0039] PTC C was used instead of PCT A to participate in the reaction, and the rest was the same as in Example 1, and the final yield was 95.2%, and the ee value was 76%.

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Abstract

The invention relates to a chiral preparation method of a carfilzomib intermediate: [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate. The preparation method comprises the step that a compound (III) carries out catalytic reaction with a phase transfer catalyst (PTC) and hydrogen peroxide under alkaline conditions. 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 available 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 a carfilzomib intermediate: [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl] carbonyl] butyl] tert-butyl carbamate Chiral preparation method. Background technique [0002] Carfilzomib (Carfilzomib), the chemical name is (S)-2-((S)-2-(2-(2H-1,4-oxazin-4(3H)-yl)acetamido)-4- Phenylbutyramide)-4-methyl-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxirane-2-yl) -1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)pentanamide, a class of proteasome inhibitors developed by Proteolix for the treatment of relapsed and refractory of multiple myeloma. Approved by the U.S. Food and Drug Administration (FDA) on July 20, 2012 for the treatment of patients with multiple myeloma (MM) who had previously received at least 2 drugs, including bortezomib and an immunomodulator, the chemical structure of As follows: [0003] [0004] The compound shown in formula (I) is an intermediate for the synthesis of carfilzomib, and its chemical name is [(1S)...

Claims

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Application Information

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IPC IPC(8): C07D303/36C07D301/12
CPCC07D301/12C07D303/36
Inventor 叶天健刘涛马苏旺张绩生何思
Owner ZHEJIANG YONGNING PHARMA
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