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Method of synthesizing 1, 2-morpholine hydrochloride

A technology of morpholine hydrochloride and hydroxylamine hydrochloride is applied in the field of synthesis of 1,2-morpholine hydrochloride, can solve the problems of high synthesis cost, complicated operation, expensive synthesis raw materials, etc. Easy to scale up, cost-effective effects

Inactive Publication Date: 2013-06-05
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the problems of expensive synthesis raw materials, complicated operation and high synthesis cost

Method used

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  • Method of synthesizing 1, 2-morpholine hydrochloride
  • Method of synthesizing 1, 2-morpholine hydrochloride
  • Method of synthesizing 1, 2-morpholine hydrochloride

Examples

Experimental program
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Embodiment 1

[0012] Example 1: Dissolve 10 g (75 mmol, 1.0 eq) of N-tert-butoxycarbonyl-hydroxylamine in 200 mL of THF, then add 150 mmol (2.0 eq) of potassium tert-butoxide, and stir at room temperature for 1 hour . Then, a THF solution (50 mL) of 1,4-dibromobutane (17.8 g, 82.5 mmol, 1.1 eq) was added dropwise to the reaction solution, heated to reflux and stirred for 12 hours. Then the reaction solution was cooled, and saturated ammonium chloride solution was added, extracted with ethyl acetate (200 ml*3), the organic phase was washed twice with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure 13.5 g of crude N-tert-butoxycarbonyl-1,2-cyclobutanolamine were obtained.

[0013] Dissolve 13.5 g of crude N-tert-butoxycarbonyl-1,2-cyclobutanolamine in 100 mL methyl tert-butyl ether, and add 20 mL methyl tert-butyl ether hydrogen chloride gas-saturated solution dropwise. Stir at room temp...

Embodiment 2

[0014] Example 2: Dissolve 10 g (75 mmol) N-tert-butoxycarbonyl-hydroxylamine in 200 mL of THF, then add 188 mmol (2.5 eq ) potassium tert-butoxide, and stir at room temperature for 1 hour. Then, a THF solution (50 mL) of 1,4-dibromobutane (17.8 g, 82.5 mmol, 1.1 eq) was added dropwise to the reaction solution, and heated to reflux with stirring for 12 hours. Then the reaction solution was cooled, a saturated solution of ammonium chloride was added, extracted with ethyl acetate (200 ml*3), the organic phase was washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 14.5 g of crude N-tert-butoxycarbonyl-1,2-cyclobutanolamine.

[0015] Dissolve 14.5 g of crude N-tert-butoxycarbonyl-1,2-cyclobutanolamine in 100 mL methyl tert-butyl ether, and add 20 mL methyl tert-butyl ether hydrogen chloride gas-saturated solution dropwise. Stir at room temperature for 3 ho...

Embodiment 3

[0016] Example 3: Example 2: Dissolve 10 g (75 mmol) N-tert-butoxycarbonyl-hydroxylamine in 200 mL of THF, then add 225 mmol (3.0 eq ) potassium tert-butoxide, and stir at room temperature for 1 hour. Then, a THF solution (50 mL) of 1,4-dibromobutane (17.8 g, 82.5 mmol, 1.1 eq) was added dropwise to the reaction liquid, and heated to reflux with stirring for 14 hours. Then the reaction solution was cooled, a saturated solution of ammonium chloride was added, extracted with ethyl acetate (200 ml*3), the organic phase was washed with saturated brine, the combined organic phases were filtered over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 14.8 g of Crude N-tert-butoxycarbonyl-1,2-cyclobutanolamine.

[0017] Dissolve 14.8 g of crude N-tert-butoxycarbonyl-1,2-cyclobutanolamine in 100 mL of methyl tert-butyl ether, and add 20 mL of methyl tert-butyl ether hydrogen chloride gas-saturated solution dropwise. Stir at room temperature f...

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Abstract

The invention relates to a preparation method of 1, 2-ring ding hydroxylamine and mainly solves the technical problems existing in an existing synthetic process that the path is long, the yield coefficient is low, the reaction is not easy to control, the experimental operation is inconvenient to conduct and the like. According to the preparation method of the 1, 2-ring ding hydroxylamine, N- tertiary-butoxyocarbonyl- hydroxylamine hydrochloride and 1, 4- dibromobutane are used as raw materials, potassium tert-butoxide is used as alkali, tetrahydrofuran is used as solvent, and the 1, 2-ring ding hydroxylamine is prepared under the condition of heating reflux for 12 hours. The equation is as follows: the 1, 2-ring ding hydroxylamine obtained by the preparation method of the 1, 2-ring ding hydroxylamine is a useful intermediate body or a product synthesized by a lot of drugs.

Description

technical field [0001] The invention relates to a synthesis method of 1,2-morpholine hydrochloride. Background technique [0002] 1,2-Morpholine hydrochloride and related derivatives are widely used in medicinal chemistry and organic synthesis. The present synthetic method of 1,2-morpholine hydrochloride 【.King, H. J. Chem. SOC. 1942,432.] Mainly through the reaction of ethyl 1-aminocarboxylate with 1,4-dibromobutane and then removing the ethoxycarbonyl group to obtain 1,2-morpholine hydrochloride. This synthetic method mainly has the following problems: (1) The starting materials are expensive and (2) The reaction process is complicated to operate. The specific reaction formula is as follows. [0003] [0004] Therefore, it is more necessary to develop a synthetic method with low raw material price, convenient operation and easy control of reaction. Contents of the invention [0005] The purpose of the invention is to develop a method for synthesizing 1,2-morpholin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/02
Inventor 耿春梅孙继奎郭爱新马建义姜鲁勇马汝建
Owner 上海药明康德新药开发有限公司
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