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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

A tert-butoxycarbonyl and oxa technology, which is applied to N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2, can solve the problem of inability to realize large-scale industrial production and environmental Serious pollution, difficult to remove by-products and other problems, to achieve the effect of shortening production time, high overall yield and saving production cost

Inactive Publication Date: 2007-06-27
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

[0012] (b) The by-product of chromium trioxide is serious to environmental pollution;
[0013] (c) The raw materials used are more expensive and the cost is high, for example, dicyclohexylcarbodiimide (DCC) is finally used,
[0014] (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

[0027] Synthesis of N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane

[0028] The first step: Synthesis of N-tert-butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0029] L-hydroxyproline (300g, 2.29mol) was dissolved in anhydrous methanol (2.0L), and thionyl chloride (335g, 2.8mol) was added dropwise at room temperature, and the reaction solution was refluxed and stirred for 1 hour, concentrated to dryness directly, and then Tetrahydrofuran (6.0 L), pyridine (727 g, 9.2 mol) and BOC anhydride (520 g, 2.4 mol) were added at room temperature. After 1 hour of reaction, p-toluenesulfonyl chloride (437 g, 2.3 mol) was added, and the reaction was continued for 2 hours at room temperature. Add saturated aqueous sodium bicarbonate solution (6L), separate layers, extract the aqueous phase with ethyl acetate (3L), combine the organic phases, and concentrate to dryness to obtain a crude product, which is recrystallized from methyl tert-butyl ether (2.5...

Embodiment 2

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

[0034] The first step: Synthesis of N-tert-butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0035] L-Hydroxyproline (60g, 0.46mol) was dissolved in anhydrous methanol (0.4L), sulfuric acid (55g, 0.56mol) was added dropwise at room temperature, and the reaction solution was refluxed and stirred for 1 hour, concentrated to zero, and then dissolved in Add dichloromethane (1.2L), add pyridine (108g, 1.4mol) and BOC anhydride (104g, 0.48mol), react for 1 hour, add p-toluenesulfonyl chloride (88g, 0.46mol), continue to react for 2 hours, add saturated Aqueous sodium bicarbonate solution (1L), separated layers, washed the organic phase with water (1L), concentrated to dryness to obtain the crude product, recrystallized from methyl tert-butyl ether (0.6L) to obtain the pure product N-tert-butoxycarbonyl-O - p-toluenesulfonyl-L-hydroxyproline methyl ester (152 g, 0.38 mol), yield...

Embodiment 3

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

[0040] The first step: Synthesis of N-tert-butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0041] 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 stirred at reflux for 1 hour, concentrated to dryness, and then 1 , 4-dioxane (60mL), pyridine (g, 63mmol) and BOC anhydride (5.2g, 24mmol) were added at room temperature, after reacting for 1 hour, p-toluenesulfonyl chloride (4.4g, 23mmol) was added, and the reaction was continued for 2 hour, add saturated aqueous sodium bicarbonate (30mL), separate the layers, wash the organic phase with water (30mL), and concentrate to dryness to obtain a crude product, which is recrystallized from methyl tert-butyl ether (25mL) to obtain pure N-tert-butoxy Carbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester (8...

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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 an N-protected 5-aza-2-oxa-3-ketone-bicyclo-[2,2,1]heptane drug intermediate, in particular to an N-tert-butyl An industrial preparation method for one-pot synthesis 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 relatively important drug intermediate, but so far there is no effective preparation of this product industrial synthesis method. Two preparation methods have been reported in the literature. Method 1 uses L-hydroxyproline as a raw material, which is first protected by a commonly used protecting group, and then N-protected 5-aza-2-oxa is obtained by Mitsunobu reaction. -3-keto-bicyclo-[2,2,1]heptane (Heterocycles 1983, 817-828); method 2, also protect L-hydroxyproline first, then use Jones's reagent to oxidize the secondary alcohol to ketone, and then use Sodium borohydride obtains the reductio...

Claims

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Application Information

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Patent Type & Authority Applications(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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