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A kind of synthetic method of 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid

A technology of tert-butoxycarbonyl and azabicycle, applied in the synthesis field of 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid, It can solve the problems such as no suitable industrial synthesis method, and achieve the effects of reasonable reaction process design, convenient operation and easy reaction.

Active Publication Date: 2018-03-27
CHANGZHOU HEQUAN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mainly solve the technical problem that there is no suitable industrial synthesis method at present

Method used

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  • A kind of synthetic method of 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid
  • A kind of synthetic method of 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0012] Compound 1 (50 g, 0.382 mol) was dissolved in tetrahydrofuran (500 mL), then sodium hydroxide aqueous solution (33.6 g, 0.84 mol, 1M) was added dropwise at 0°C, and BOC anhydride (82.4 g, 0.382 mol) was added dropwise . After the addition is complete, stir overnight at room temperature. TLC (dichloromethane / methanol volume ratio=10 / 1, R f = 0.3) shows that the reaction is complete. The reaction solution was concentrated to remove THF, and then acidified to pH = 2 with 1N hydrochloric acid solution. The aqueous phase was extracted several times with dichloromethane, and the organic phase was dried and spin-dried to obtain compound 2 (66.3 g), yield: 71%.

[0013] Dissolve compound 2 (110g, 0.476 mol) in dichloromethane (2.0 L), add trichloroisocyanuric acid (110 g, 0.476 mol) while stirring, and then add 2,2,6,6-tetramethyl Piperidine oxide (3.7 g, 0.0238 mol), reacted at room temperature for 1 h, then quenched with water, filtered out the insoluble matter, extracted...

Embodiment 2

[0020] Compound 1 (200 g, 1.53 mol) was dissolved in tetrahydrofuran (1.5 L), then sodium hydroxide aqueous solution (128.5 g, 3.21 mol, 1M), BOC anhydride (400.7 g, 1.84 mol) were added dropwise at 0°C. After completion, stir overnight at room temperature. TLC (dichloromethane / methanol volume ratio=10 / 1, R f = 0.3) shows that the reaction is complete. The reaction solution was concentrated to remove THF, and then acidified to pH = 2 with 1N hydrochloric acid solution. The aqueous phase was extracted several times with dichloromethane, and the organic phase was dried and spin-dried to obtain compound 2 (237.8 g), yield: 67.2%.

[0021] Dissolve compound 2 (178 g, 0.77 mol) in dichloromethane (2.0 L), add trichloroisocyanuric acid (178.89 g, 0.77 mol) while stirring, and then add 2,2,6,6-tetramethyl Piperidine oxide (6.05 g, 0.0385 mol), reacted at room temperature for 1 h, then quenched with water, filtered out the insoluble matter, extracted the aqueous phase with dichlor...

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Abstract

The invention relates to a synthesis method of 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid, which mainly solves the technical problem that there is no suitable industrial synthesis method at present . The present invention is divided into six steps, at first by reaction of compound 1 and Boc anhydride under alkaline conditions, obtain compound 2, then use 2,2,6,6-tetramethyl piperidine oxide oxidation to generate compound 3, then compound 3 and Grignard reagent reaction to obtain compound 4, reduction of carboxylic acid 4 with tetrahydrolithium aluminum to obtain compound 5, compound 5 was reacted with n-butyllithium and p-toluenesulfonyl chloride in two stages to obtain compound 6, and finally compound 6 was treated with sodium periodate Oxidation affords the final compound 7. The reaction formula is as follows: .

Description

technical field [0001] A method for synthesizing the compound 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid involved in the present invention. Background technique [0002] The compound 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid (CAS: 1330763-18-2) and related derivatives in medicinal chemistry and organic Widely used in synthesis. Although the substance 5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid has been reported at present, no synthetic method suitable for industrialization has been found. Therefore, it is necessary to develop a synthetic method that is easy to obtain raw materials, easy to operate, easy to control the reaction, suitable for overall yield, and suitable for industrial production. Contents of the invention [0003] The purpose of this invention is to develop a kind of raw material that is easy to get, easy to operate, easy to control the reaction, and a higher yield of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/08
Inventor 刘洋张金保邱继平于涵邢少廷赵东靳爱杰哈维杰柴艳萍周乐乐袁晓斌于凌波何振民马汝建陈民章
Owner CHANGZHOU HEQUAN PHARMA CO LTD