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Method for synthesizing N-benzylhydroxylamine hydrochloride

A technology of benzyl hydroxylamine hydrochloride and benzyl nitrone, which is applied in the field of industrially synthesized preparation of N-benzyl hydroxylamine hydrochloride, can solve the problems of high price and low yield, and achieve simple operation and high reaction efficiency. The effect of high efficiency and product purity and stable conditions

Inactive Publication Date: 2015-04-22
SHANGHAI TWISUN BIO PHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] (1) Directly use the benzylation reaction of hydroxylamine to synthesize, and the main product of the reaction is N, N-dibenzylhydroxylamine, resulting in a very low yield of this method
[0006] (2) N-benzyl hydroxylamine hydrochloride is prepared by the reduction of benzyl oxime, but this method needs to use expensive sodium cyanoborohydride or borane as a reducing agent

Method used

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  • Method for synthesizing N-benzylhydroxylamine hydrochloride
  • Method for synthesizing N-benzylhydroxylamine hydrochloride
  • Method for synthesizing N-benzylhydroxylamine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Add 100 g of dibenzylamine, 500 mL of methanol and 3.0 g of sodium tungstate dihydrate into a 1.0 L four-necked reaction flask. While stirring, cool down to 0°C with an ice-salt bath. Slowly add 115mL of hydrogen peroxide dropwise into the reaction flask, and control the temperature <5°C during the dropwise addition. After the addition was complete, the mixture was incubated in an ice-water bath for 2 hours. The temperature was raised naturally, and the reaction was stirred overnight at room temperature. The reaction solution was slowly added to ice water. After suction filtration, the filter cake was dried at 45°C to obtain 91.4 g of C-phenyl-N-benzylnitrone, with a yield of 85.3%.

[0027] ESI: m / z=212[M+H]; 1 H NMR (400MHz, DMSO) δ8.28–8.19 (m, 2H), 8.10 (s, 1H), 7.50 (dd, J=7.7, 1.5Hz, 2H), 7.46–7.32 (m, 6H), 5.07 ( s,2H).

Embodiment 2

[0029] Add 91.4 g of C-phenyl-N-benzylnitrone and 455 mL of MTBE to a 2.0 L one-necked bottle. A solution of 29.8 g of hydroxylamine hydrochloride in methanol (320 mL) was added dropwise with stirring. After the addition, the reaction was stirred for 5h. The reaction solution was concentrated with a rotary evaporator. Add 455 mL of MTBE to the concentrated solid, stir and filter to obtain a white solid.

[0030] The white solid was dissolved in 66 mL of methanol under heating, and 330 mL of MTBE was added dropwise thereto. After cooling down to room temperature, a large amount of white solid was precipitated, which was filtered and dried to obtain 50 g of N-benzylhydroxylamine with a yield of 72.4%.

[0031] ESI: m / z=124[M+H]; 1 H NMR (400MHz, DMSO) δ11.77(br,2H), 10.98(br,1H), 7.60–7.46(m,2H), 7.46–7.35(m,3H), 4.30(s,2H).

Embodiment 3

[0033] Put 4.0kg of dibenzylamine, 20kg of methanol, and 120g of sodium tungstate dihydrate into the 50L reaction kettle in sequence. Start stirring, and cool down the temperature of the materials in the reactor to 0°C. Slowly add 4.6L of 30% hydrogen peroxide dropwise into the reactor, and control the temperature <5°C during the dropwise addition. After the addition was complete, the mixture was incubated in an ice-water bath for 2 hours. Take the reaction solution and detect the content of dibenzylamine therein by HPLC, when the content of dibenzylamine is less than 5%. The temperature was raised naturally, and stirred overnight at room temperature. The reaction solution was slowly added to 70 L of ice water. Stirring was continued for 1 h. After centrifugation, the filter cake was washed with 2L of water each time until the centrifuged liquid was detected to be free of peroxide with starch potassium iodide test paper. The filter cake was dried at 45°C to obtain 3.97kg ...

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Abstract

The invention provides a method for synthesizing N-benzylhydroxylamine hydrochloride in industrial production. The method comprises the following steps: mixing an oxidant, diphenylamine and an organic solvent under the action of tungstate, so as to obtain C-phenyl-N-benzyl nitrone; mixing the C-phenyl-N-benzyl nitrone, MTBE and hydroxylamine hydrochloride methyl alcohol, so as to obtain a product, namely N-benzylhydroxylamine hydrochloride. The overall synthesis process disclosed by the invention is simple and convenient to operate, and stable in condition, the reaction yield is high and the product purity is high. According to the technique disclosed by the invention, the effectiveness of the method is confirmed by multiple batches of kilo-scale verification; and the large-scale production of N-benzyl hydroxylamine is smoothly achieved.

Description

technical field [0001] The invention relates to an organic synthesis intermediate, in particular to a preparation method for industrially synthesizing N-benzyl hydroxylamine hydrochloride. Background technique [0002] As an important intermediate in organic synthesis, N-benzylhydroxylamine hydrochloride has played an important role in nitrone chemistry. It condenses with aldehydes and ketones or reacts with C-C triple bonds to generate N-benzyl nitrone. The 1,3-cycloaddition reaction of the obtained nitrones is an effective method for constructing isoxazolines. This method is often used to synthesize biologically active compounds and plays a unique role in drug synthesis. For example, this efficient synthetic method was used in a synthetic method of the new antiplatelet drug ticagrelor to construct its key intermediate. [0003] But the synthesis method of N-benzylhydroxylamine hydrochloride reported at present all has various defects. For example: [0004] (1) Directl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C239/10
Inventor 叶方国徐佳发叶敏
Owner SHANGHAI TWISUN BIO PHARM
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