Synthesis process of (2R)-(1,4-dioxane-2-yl)-N-methyl-methanamine hydrochloride

A technology of methyl methylamine hydrochloride and synthesis process, applied in directions such as organic chemistry, can solve problems such as high cost of chiral column, bringing in by-products, difficulty in industrialization, etc., avoiding chiral splitting, simple raw materials, The effect of easy availability of raw materials

Inactive Publication Date: 2011-03-16
江西远邦药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Using chiral column for resolution, high cost of chiral column, easy to pollute, and chiral derivatization often brings in by-products and other disadvantages, industrialization is difficult, and further research is still needed

Method used

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  • Synthesis process of (2R)-(1,4-dioxane-2-yl)-N-methyl-methanamine hydrochloride
  • Synthesis process of (2R)-(1,4-dioxane-2-yl)-N-methyl-methanamine hydrochloride
  • Synthesis process of (2R)-(1,4-dioxane-2-yl)-N-methyl-methanamine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] 1) Add 0.05 grams of [(R, R)-N, N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexanediamine cobalt in a four-necked flask 2 ·SnCl 2 100 grams of epichlorohydrin and 50 grams of 2-chloroethanol were reacted at 0°C for 12 hours, cooled to 10°C, added 500 grams of dichloromethane, neutralized to pH= 7.0-8.0, standing to separate layers, drying the organic layer with anhydrous sodium sulfate, distilling off dichloromethane to obtain crude product 81.3 of (S)-3-(2-chloroethoxy)-1-chloropropan-2-ol gram, gas chromatography analysis, content 93.7%, directly used in next step reaction;

[0020] 2) Add 250 grams of acetone in a four-necked flask, 50 grams of (S)-3-(2-chloroethoxy)-1-chloropropan-2-alcohol and 50 grams of sodium carbonate reflux reaction for 3 hours, cooled to 0 ℃, filter, remove insoluble matter, distill off acetone, obtain (2R)-2-[(2-chloroethoxy) methyl] oxirane crude product 28.9 grams, gas chromatography analysis, content 91.6%, directly for the next re...

Embodiment 2

[0024] 1) Add 0.05 grams of [(R, R)-N, N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexanediamine cobalt in a four-necked flask 2 ·SnCl 4 100 grams of epichlorohydrin and 100 grams of 2-chloroethanol were reacted at 20°C for 24 hours, cooled to 20°C, added 500 grams of dichloromethane, neutralized to pH= 7.0-8.0, standing to separate layers, the organic layer was dried with anhydrous sodium sulfate, dichloromethane was evaporated to obtain (S)-3-(2-chloroethoxy)-1-chloropropan-2-ol crude product 70.5 gram, gas chromatography analysis, content 93.5%, directly used in next step reaction;

[0025] 2) Add 250 grams of acetone in a four-necked flask, 50 grams of (S)-3-(2-chloroethoxy)-1-chloropropane-2-alcohol and 150 grams of sodium carbonate reflux reaction for 5 hours, cooled to 10 DEG C, filter, remove insoluble matter, evaporate acetone, obtain (2R)-2-[(2-chloroethoxy) methyl] oxirane crude product 28.1 grams, gas chromatography analysis, content 91.6%, directly for the ...

Embodiment 3

[0029] 1) Add 0.05 grams of [(R, R)-N, N'-bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexanediamine cobalt in a four-necked flask 2 ·FeCl 3 100 grams of epichlorohydrin and 75 grams of 2-chloroethanol were reacted at 15°C for 20 hours, cooled to 15°C, added 500 grams of dichloromethane, neutralized to pH= 7.0-8.0, standing to separate layers, drying the organic layer with anhydrous sodium sulfate, evaporating dichloromethane to obtain (S)-3-(2-chloroethoxy)-1-chloropropan-2-ol crude product 80.0 gram, gas chromatography analysis, content 93.7%, directly used in next step reaction;

[0030] 2) Add 250 grams of acetone in a four-necked flask, 50 grams of (S)-3-(2-chloroethoxy)-1-chloropropan-2-alcohol and 75 grams of potassium carbonate reflux reaction for 4 hours, cooled to 0 ℃, filter, remove insoluble matter, evaporate acetone, obtain (2R)-2-[(2-chloroethoxy) methyl] oxirane crude product 29.1 grams, gas chromatography analysis, content 91.5%, directly for the next reacti...

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Abstract

The invention discloses a synthesis process of (2R)-(1,4-dioxane-2-yl)-N-methyl-methanamine hydrochloride. The synthesis process comprises the following steps: epoxy chloropropane and 2-chlorohydrin react to obtain (S)-3-(2-chlorooxethyl)-1-chloropropane-2-alcohol under the action of an salen catalyst; the (S)-3-(2-chlorooxethyl)-1-chloropropane-2-alcohol is subject to closed loop to obtain (2R)-2-[(2-chlorooxethyl) methyl]ethylene oxide under the action of carbonate; the (2R)-2-[(2-chlorooxethyl) methyl]ethylene oxide and hydroxide are subject to backflow reaction; toluenesulfonyl is added to the reaction product to obtain (2S)-1,4-dioxin-2-methyl-4-methyl p-toluenesulfonate ester; and the (2S)-1,4-dioxin-2-methyl-4-methyl p-toluenesulfonate ester and methylamine react in a high-pressure autoclave and hydrochloric acid is added to obtain the (2R)-(1,4-dioxane-2-methyl)-N-methyl-methanamine hydrochloride. In the synthesis process, a kinetic resolution technique is adopted so as to directly synthesize chiral compounds, raw materials can be obtained simply and easily, the reaction condition is mild, chiral separation is omitted, the cost is low and the synthesis process can be used for industrialized production.

Description

technical field [0001] The invention relates to a synthesis process of compounds, in particular to a synthesis process of (2R)-(1,4-dioxane-2-yl)-N-methylmethylammonium hydrochloride. Background technique [0002] Tyrosinase inhibitors are the main rate-limiting enzymes in the process of melanin production, and their activity is positively correlated with the amount of melanin synthesis (Li Na, Lu Xiaoxiang. Food Industry Science and Technology, 2010, 31(07), 407-409). [0003] (2R)-(1,4-dioxane-2-yl)-N-methylmethylammonium hydrochloride is an important intermediate for the synthesis of a tyrosinase inhibitor (Dinsmore, Christopher J.; Jewell , James P.; Katz, Jason D.; Machacek, Michelle R.; Otte, Ryan D.; Young, Jonathan R. WO 2007002258). [0004] (Avalle P, Foley J R, Wang Y L, Yehl P.US, 2009 / 0182002A1 (2009) derivatize the amino group of (1,4-dioxane-2-yl)-N-methylmethylamine with The chiral AD column was resolved, and finally the deprotecting agent was removed to ob...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/12
Inventor 何广泉宋亲京蒋行海
Owner 江西远邦药业有限公司
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