Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron

A technology of tert-butoxycarbonyl and oxa, which is applied in the field of industrialized preparation of N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane , can solve the problems of inability to realize large-scale industrial production, difficult to remove by-products, serious environmental pollution, etc., to achieve the effect of shortening production time, high overall yield, and simplifying operation process

Inactive Publication Date: 2010-05-26
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] (b) The by-product of chromium trioxide is serious to environmental pollution;
[0019] (c) The raw materials used are more expensive and the cost is high, for example, dicyclohexylcarbodiimide (DCC) is finally used,
[0020] (d) The by-products generated by the reaction are difficult to remove, and column chromatography is required to purify the product. The yield is only 50-60%, and large-scale industrial production cannot be realized.

Method used

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  • Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron
  • Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron
  • Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Synthesis of N-tert-Butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane

[0034] Step 1: Synthesis of N-tert-Butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0035] L-Hydroxyproline (300g, 2.29mol) was dissolved in anhydrous methanol (2.0L), thionyl chloride (335g, 2.8mol) was added dropwise at room temperature, the reaction solution was refluxed and stirred for 1 hour, then concentrated directly to then at room temperature Add tetrahydrofuran (6.0L), pyridine (727g, 9.2mol) and BOC anhydride (520g, 2.4mol), after 1 hour of reaction, add p-toluenesulfonyl chloride (437g, 2.3mol), continue the reaction at room temperature for 2 hours, add Saturated aqueous sodium bicarbonate solution (6L), separate the layers, extract the aqueous phase with ethyl acetate (3L), combine the organic phases, concentrate to dryness to obtain a crude product, and recrystallize methyl tert-butyl ether (2.5L) to obtain a pure product N-tert-Butoxycarbonyl-O-p-toluenesulfonyl-...

Embodiment 2

[0039] Synthesis of N-tert-Butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane

[0040] Step 1: Synthesis of N-tert-Butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0041] L-Hydroxyproline (60g, 0.46mol) was dissolved in anhydrous methanol (0.4L), sulfuric acid (55g, 0.56mol) was added dropwise at room temperature, the reaction solution was refluxed and stirred for 1 hour, concentrated to dryness, and then added to the solution at room temperature In dichloromethane (1.2L), add pyridine (108g, 1.4mol) and BOC anhydride (104g, 0.48mol), after reacting for 1 hour, add p-toluenesulfonyl chloride (88g, 0.46mol), continue the reaction for 2 hours, add Saturated aqueous sodium bicarbonate solution (1L), separate the layers, wash the organic phase with water (1L), concentrate to obtain a crude product, and recrystallize methyl tert-butyl ether (0.6L) to obtain pure N-tert-butoxycarbonyl-O -P-toluenesulfonyl-L-hydroxyproline methyl ester (152g, 0.38mol), yield: 83%...

Embodiment 3

[0045] Synthesis of N-tert-Butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane

[0046] Step 1: Synthesis of N-tert-Butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0047] L-Hydroxyproline (3g, 22.9mmol) was dissolved in anhydrous methanol (20mL), acetyl chloride (2.2g, 28mmol) was added dropwise at room temperature, the reaction solution was refluxed and stirred for 1 hour, concentrated to a temperature, and then added at room temperature 1. 4-Dioxane (60mL), add pyridine (g, 63mmol) and BOC anhydride (5.2g, 24mmol) at room temperature, after reacting for 1 hour, add p-toluenesulfonyl chloride (4.4g, 23mmol), continue the reaction for 2 hours Add saturated aqueous sodium bicarbonate solution (30mL), separate the layers, wash the organic phase with water (30mL), and concentrate to dryness to obtain a crude product. After recrystallization from methyl tert-butyl ether (25mL), pure N-tert-butoxycarbonyl is obtained. -O-p-toluenesulfonyl-L-hydroxyproline methy...

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Abstract

The present invention relates to industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane in one kettle. The present invention prepares N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane with facile L-hydroxy praline as material, and through methyl esterification, tert-butoxy carbonyl radical protection, paratoluene sulfonation, hydrolysis and lactonization. The present invention has lowered cost, raised yield, less environmental pollution and no need of column chromatographic purification, and may be used in industrial production.

Description

Technical field: [0001] The invention relates to a preparation method of N-protected 5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane drug intermediates, in particular to a kind of N-tert-butyl Industrialized preparation method of oxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane. Background technique: [0002] N-protected 5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane is a more important pharmaceutical intermediate, but so far there is no effective preparation for this product Industrial synthesis method. Two preparation methods have been reported in the literature. Method one, using L-hydroxyproline as a raw material, firstly protect it with a commonly used protecting group, and then obtain the N-protected 5-aza-2-oxa by Mitsunobu reaction. -3-keto-bicyclo-[2,2,1]heptane (Heterocycles 1983, 817-828); Method two, also protect L-hydroxyproline first, then use Jone's reagent to oxidize the secondary alcohol to ketone, and then use Sodium borohydride obtains the reduced product cis-hydroxy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/08
Inventor 周盛峰马汝建唐苏翰陈曙辉李革
Owner 上海药明康德新药开发有限公司
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