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Method for preparing epoxybutane compounds and intermediates thereof

A compound and cyclization reaction technology, applied in the field of butylene oxide compounds and heterocyclic compounds, can solve the problems of irritating odor, high cost and high processing cost of sulfonyl halide compounds, and achieve high industrial application and Effects of economic value, moderation of reaction conditions, simple reaction type

Active Publication Date: 2015-06-10
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] This method can utilize halomethyl alcohol compounds of 2S, 3S configuration, which has made great progress, but it also has some disadvantages at the same time. Sulfonyl halide compounds have pungent odor, and most of them are insoluble in water. Difficulty is big; Sodium trichloroacetate, sodium trifluoroacetate strong base are irritating, need the reagent of benzene class or halogenation as solvent when synthesizing formula (2-3) compound by formula (2-2) compound, and they all It is very toxic; considering the whole route, the cost is very high, resulting in poor process feasibility
[0019] In view of the good drug prospects of atazanavir, the low utilization rate of existing resources in the prior art, the high toxicity of the reagents used, serious environmental pollution, and high process costs, it is necessary to develop a 2R, 3S configuration with more medical value The synthesis method of epoxy compounds, in particular, to develop a kind of halomethyl alcohol compounds with 2S and 3S configurations that are not fully utilized in existing resources as raw materials, and convert them into 2R, 3S configurations Efficient Synthesis of Epoxy Compounds

Method used

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  • Method for preparing epoxybutane compounds and intermediates thereof
  • Method for preparing epoxybutane compounds and intermediates thereof
  • Method for preparing epoxybutane compounds and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of (4S, 5R)-4-benzyl-5-chloromethyl-2-oxazolidinone

[0056] Add (2S, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (10.0 g, 33.4 mmol) into 100 mL of anhydrous methyl tert-butyl ether, at 10 Slowly add SOCl dropwise at ℃ 2 (12.1 mL, 167.0 mmol), after the dropwise addition was completed, the reaction mixture was then heated to 50° C. and reacted at this reaction temperature for 8 hours. After the reaction was completed, cool to 0°C and wash with saturated NaHCO 3 The solution was quenched, separated, and the organic phase was concentrated to 100 mL to obtain a solution of (4S, 5R)-4-benzyl-5-chloromethyl-2-oxazolidinone in methyl tert-butyl ether with a concentration of 33.4 mol / L, used directly in the next reaction.

Embodiment 2

[0057] Example 2: Preparation of (4S, 5R)-4-benzyl-5-chloromethyl-3-tert-butoxycarbonyl-2-oxazolidinone

[0058] Take 50 mL of (4S, 5R)-4-benzyl-5-chloromethyl-2-oxazolidinone in methyl tert-butyl ether solution (50ml, 16.7mmol) obtained in the previous step reaction, add triethylamine (2.6mL, 18.0mmol), di-tert-butyl dicarbonate (3.64g, 16.7mmol) and 4-Dimethylaminopyridine (1.95g, 1.6mmol), the reaction mixture was stirred at 15°C for 8 hours. After the reaction was completed, 5.28 g of solid (4S,5R)-4-benzyl-5-chloromethyl-3-tert-butoxycarbonyl-2-oxazolidinone was obtained by filtration, with a yield of 97.1%.

[0059] 1 H NMR (500 MHz, CDCl 3 ( dd, J=11.9, 5.8 Hz, 1H), 3.35 (dd, J=13.5, 3.5 Hz, 1H), 3.29 (dd, J=11.9, 3.7 Hz, 1H), 2.84 (dd, J=13.5, 9.3 Hz , 1H), 1.60 (s, 9H). MS-ESI: 348.1 (M+Na + )

Embodiment 3

[0060] Example 3: Preparation of (2R, 3S)-3-tert-butoxycarbonylamino-1,2-epoxy-benzenebutane

[0061] (4S, 5R)-4-benzyl-5-chloromethyl-3-tert-butoxycarbonyl-2-oxazolidinone (2.0 g, 6.2 mmol) was added to 5 mL of ethanol, and potassium hydroxide ( 0.70g, 12.4mmol) was dissolved in 5mL ethanol, and this potassium hydroxide ethanol solution was slowly added dropwise to (4S, 5R)-4-benzyl-5-chloromethyl-3-tert-butoxycarbonyl-2- In the oxazolidinone ethanol solution system, after the dropwise addition, the reaction mixture continued to react at 20°C for 5 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in 20 mL of ethyl acetate, extracted, and the organic phase was concentrated to obtain Color oily liquid (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-benzenebutane 1.56g, yield 95.2%, HPLC purity 99.3%, this oily liquid can be solidified at -20°C A white solid was obtained.

[0062] 1 H NMR (500 MHz, CDCl 3 ( ...

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Abstract

The invention relates to the technical field of heterocyclic compounds, in particular to the preparation of epoxybutane compounds. The preparation method comprises the following steps of: performing a cyclization reaction of halomethyl alcohol compounds with 2S, 3S or 2R, 3R configuration and a chlorination reagent to obtain oxazolidinone derivatives with 4S, 5R or 4R, 5S configuration; protecting amino groups of the obtained oxazolidinone derivatives under alkaline conditions to obtain N-substituted oxazolidinone derivatives with 4S, 5R or 4R, 5S configuration; and performing an epoxidation reaction on the obtained N-substituted oxazolidinone derivatives under alkaline conditions to obtain the epoxybutane compounds with 2R, 3S or 2S, 3R configuration.

Description

technical field [0001] The invention relates to the technical field of heterocyclic compounds, in particular to the technical field of butylene oxide compounds. Background technique [0002] Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), and Atazanavir is an effective drug used to treat AIDS. At present, atazanavir can be synthesized from 2R, 3S-configured butylene oxide compounds as raw materials. The synthesis of atazanavir can refer to the method in patent WO2008065490. The specific route is as follows: [0003] [0004] The method is to use butylene oxide compound (2R, 3S)-3-tert-butoxycarbonylamino-4-phenyl-1,2-epoxybutane as raw material, and carry out epoxidation with the compound of formula (9) Ring-opening reaction obtains formula (6) compound, formula (6) compound and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutyric acid in 1-hydroxybenzotriazole (DCC), In the presence of 1,3-dicyclohexylcarbodiimide (HO...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/22C07D263/20C07D263/26C07D303/36C07D301/02
CPCY02P20/55
Inventor 李涛高红军车大庆
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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