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Preparation method of carfilzomib key intermediate and derivatives thereof

A carfilzomib and intermediate technology, applied in the direction of organic chemistry and the like, can solve the problems of poor stereoselectivity, low yield and high cost, and achieve the effects of mild operating conditions, high yield and low cost

Inactive Publication Date: 2017-10-10
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0028] In order to solve the above problems of poor stereoselectivity, low yield and high cost, the present invention provides a card with high stereoselectivity of the main product, high yield, low production cost, little environmental pollution, and suitable for industrial production through experimental research. The preparation method of Fezomib key intermediate and its derivative F, the specific content is as follows:

Method used

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  • Preparation method of carfilzomib key intermediate and derivatives thereof
  • Preparation method of carfilzomib key intermediate and derivatives thereof
  • Preparation method of carfilzomib key intermediate and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The following specific examples are used to further illustrate the present invention, but they are not meant to limit the scope of the present invention in any way. Example 1: Synthesis of [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-carbamic acid tert-butyl ester (6)

[0053]

[0054] Add 0.12mol[(1S,2S)-1-hydroxy-4-methyl-1-[[(2R)-2-methyloxiranyl]pent-2-yl]carbamate (5 ) Dissolve in 100ml dimethyl sulfoxide, add 0.24mol diisopropylethylamine, add 0.24mol pyridine sulfur trioxide in batches under ice bath, warm to room temperature to react, TLC detects the reaction to completion, add appropriate amount of water and use acetic acid The ethyl ester was extracted and washed with 1N dilute hydrochloric acid and saturated brine once, and the organic phase was dried and concentrated to obtain 0.10 mol of the epoxidized product (6) with a yield of 83.3%.

[0055] 1 H NMR(400MHz, CDCl 3 )δ4.86(d,J=8.0Hz,1H), 4.30(t,J=9.6Hz,1H), 3.27(d,J=4.8Hz,1H), 2.87(d,J=4.8Hz,1H) ...

Embodiment 2

[0057] Example 2: Synthesis of [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-carbamic acid tert-butyl ester (6)

[0058] Using the same method as in Example 1, but changing the amount of diisopropylethylamine and pyridine sulfur trioxide to 0.12 mol, 0.08 mol of epoxidized product (6) was finally obtained, with a yield of 75.5%.

Embodiment 3

[0059] Example 3: [(1S,2S)-1-hydroxy-4-methyl-1-[[(2R)-2-methyloxiranyl]pent-2-yl] t-butyl carbamate ( 5) Synthesis

[0060]

[0061] Weigh 0.2mol [(3R,4S)-3-hydroxy-2,6-dimethyl-1-en-4-yl]carbamic acid tert-butyl ester (4), add 200ml of dichloromethane to dissolve, then add 0.04 mol vanadium acetylacetonate, under the protection of nitrogen, cool to 0℃ in an ice bath, slowly add tert-butanol peroxygen dropwise, double vigorous stirring overnight, TLC detects the disappearance of the raw materials, add appropriate amount of water and extract with dichloromethane, respectively with saturated thio After washing with sodium sulfate and saturated brine once, the organic phase was dried, concentrated and purified to obtain 0.12 mol of hydroxyl epoxidized product (5), with a yield of 60.8%.

[0062] 1 H NMR(600MHz, CDCl 3 )δ4.88(d,J=9.6Hz,1H),3.95-3.85(m,1H), 3.82(d,J=3.0Hz,1H), 2.97(d,J=4.8Hz,1H), 2.61( d,J=4.8Hz,1H),2.44(s,1H),1.69-1.57(m,1H),1.48-1.44(m,1H),1.43(s,9H),1.36(s,3H),1.1...

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Abstract

The invention belongs to the technical field of compound preparation, and more specifically relates to a carfilzomib key intermediate [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-carbamate and a preparation method of its derivative. The method takes a compound E as a raw material, the compound E is dissolved by a solvent and is reacted with diisopropylethylaine and pyridine, after complete reaction, a reaction product is purified to obtain a product F; the concrete reaction processes are shown in a following specification: wherein, R1 is selected from C1-6 alkyl or C6-10 aryl C1-6 alkyl; R2 is tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz). According to the invention, operation condition for all the steps is mild, the used reagents are conventional reagents which have the advantages of low cost, high yield, and little environmental pollution, and the key intermediate is adapted to large scale industrial production.

Description

Technical field [0001] The invention belongs to the technical field of compound preparation, and specifically relates to a key intermediate of carfilzomib [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl Yl]-carbamate and its derivatives. Background technique [0002] Carfilzomib (carfilzomib) is used to treat multiple myeloma (MM) that has previously received at least two drugs (including bortezomib and immunomodulator therapy). It is a new generation of highly selective irreversible proteasome blockers. Among them, in the preparation process of carfilzomib, [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-carbamate ( 6) Its key intermediate. [0003] [0004] Further in-depth research found that the compound with the general formula F can be used for drugs with similar structure to carfilzomib and certain proteases [0005] Synthesis of body inhibitor, where R 1 Is C 1-6 Alkyl or C 6-10 Aryl C 1-6 alkyl: [0006] [0007] By analyzing and summarizing the prior art,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D303/36C07D301/00C07D301/19
CPCC07D301/00C07D301/19C07D303/36
Inventor 朱永强杜晓雷萌
Owner NANJING NORMAL UNIVERSITY
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