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

A technology of tert-butoxycarbonyl and oxa, applied to the industrialization of continuous synthesis of N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane In the field of preparation, it can solve the problems of inability to scale production and achieve the effects of easy reaction, low preparation cost and reasonable choice of reaction 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

[0022] The technical problem to be solved in the present invention is: solve the need for column Chromatographic purification, the problem of being unable to produce on a large scale; providing a kind of N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2 with higher overall yield and lower preparation cost , 2,1] the industrialized preparation method of continuous synthesis of heptane

Method used

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

Examples

Experimental program
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Embodiment 1

[0034] Synthesis of N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane

[0035] The first step: Synthesis of N-tert-butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0036] 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, and concentrated to dryness to obtain a crude product L-hydroxyproline methyl ester hydrochloride is directly dissolved in methanol (6.0L), and triethylamine (680g, 6.3mol) and BOC anhydride (520g, 2.4mol) are added at room temperature, and after 1 hour of reaction, Concentrate to dryness to obtain the crude product N-tert-butoxycarbonyl-L-hydroxyproline methyl ester, which is dissolved in dichloromethane (3L), and anhydrous pyridine (237g, 3.0mol) and p-toluenesulfonyl chloride are added at room temperature (437g, 2.3mol), reacted for 2 hours, added saturated a...

Embodiment 2

[0040] Synthesis of N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane

[0041] The first step: Synthesis of N-tert-butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0042]L-hydroxyproline (72g, 0.55mol) was dissolved in anhydrous methanol (0.48L), concentrated sulfuric acid (60g, 0.6mol) was added dropwise at room temperature, the reaction solution was stirred at room temperature for 5 hours, and concentrated to dryness to obtain the crude product L- Hydroxyproline methyl ester hydrochloride, directly dissolve it in methanol (1.44L), add triethylamine (163g, 1.5mol) and BOC anhydride (1245g, 0.58mol) at room temperature, react for 1 hour, and concentrate to dryness , to obtain the crude product N-tert-butoxycarbonyl-L-hydroxyproline methyl ester, which was dissolved in toluene (0.72L), and anhydrous pyridine (56.9g, 0.72mol) and p-toluenesulfonyl chloride (104g , 0.55mol), reacted for 2 hours, added saturated aqueous sodium bicarbonate (0.72L...

Embodiment 3

[0046] Synthesis of N-tert-butoxycarbonyl-5-aza-2-oxa-3-one-bicyclo-[2,2,1]heptane

[0047] The first step: Synthesis of N-tert-butoxycarbonyl-O-p-toluenesulfonyl-L-hydroxyproline methyl ester

[0048] 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, and concentrated to dryness to obtain the crude product L-hydroxyproline Proline methyl ester hydrochloride, directly dissolve it in 1,4-dioxane (60mL), add triethylamine (6.8g, 63mmol) and BOC anhydride (5.2g, 24mmol) at room temperature, reaction 1 After one hour, it was concentrated to dryness to obtain the crude product N-tert-butoxycarbonyl-L-hydroxyproline methyl ester, which was dissolved in tetrahydrofuran (30mL), and anhydrous triethylamine (3.0g, 30mol) was added at room temperature and p- Toluenesulfonyl chloride (4.4g, 23mmol), reacted for 2 hours, added saturate...

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Abstract

The present invention relates to continuous industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane. 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-one-bicyclo-[2,2,1]heptane drug intermediate, in particular to an N-tert-butyl An industrial preparation method for the continuous 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 gives the reduct...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/08
Inventor 周盛峰吴岳林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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