Synthesis method of metaraminol bitartrate

A technology of meta-hydroxylamine bitartrate and a synthesis method is applied in the synthesis field of meta-hydroxylamine bitartrate, can solve the problems of limited industrial application, high technical difficulty, many key technologies and the like, and achieves easy purchase, high enantioselectivity and high efficiency Effect

Active Publication Date: 2014-04-23
广州普星药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The first synthetic method has 4-step reactions, the starting material m-hydroxypropiophenone needs to be custom synthesized, and the second reduction reaction involves chiral reduction, which limits industrial application
[0014] The second synthesis method actually has 3 steps of reaction, which requires the use of enzymes as catalysts. There are many key technologies involved in the acquisition, activity, and catalytic ability of enzymes, which are technically difficult; the second reduction reaction still faces the problem of chiral reduction. question

Method used

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  • Synthesis method of metaraminol bitartrate
  • Synthesis method of metaraminol bitartrate
  • Synthesis method of metaraminol bitartrate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Weigh 0.15 g of m-hydroxybenzaldehyde, add 1.5 ml of nitroethane and 5 ml of absolute ethanol and dissolve under stirring, cool to -20°C, add 0.01 g of imidazole, 0.012 g of copper acetate monohydrate and 0.01 g of cinchonine, and Stir and react at -20∽-25°C for 35 hours until the reactant m-hydroxybenzaldehyde no longer decreases; adjust the pH value of the reaction solution to 3 with 20% hydrochloric acid under stirring, and spin evaporate the solvent under reduced pressure at 80°C After adding 10ml of water to dissolve the product, extract it three times with 3×10ml ethyl acetate, combine the ethyl acetate phases, and evaporate the solvent to dryness under reduced pressure at 50°C to obtain the crude product; after dissolving the crude product with 9ml dichloromethane, the After standing, the precipitated crystals were dried at 60°C to obtain 0.11 g ((R,S), (S,R) enantiomeric excess 75%) of the addition reaction product. Dissolve the crystals in 15ml of absolute etha...

Embodiment 2

[0043]Weigh 1.22g of m-hydroxybenzaldehyde, add 3ml of nitroethane and 40ml of absolute ethanol and dissolve it under stirring, cool down to -23°C, add 0.1g of imidazole, 0.07g of copper acetate monohydrate and 0.07g of cinchonine, in - Stir and react at 20∽-25°C for about 40 hours until the reactant m-hydroxybenzaldehyde is nearly complete; adjust the pH value of the reaction solution to 2 with 20% hydrochloric acid under stirring, and spin evaporate the solvent under reduced pressure at 80°C After adding 10ml of water to dissolve the product, use 4 × 25ml of ethyl acetate to extract 4 times, combine the ethyl acetate phases, and filter out after drying with anhydrous sodium sulfate overnight, and the solvent is evaporated to dryness under reduced pressure at 50°C to obtain the crude product; After the crude product was dissolved in 15ml of chloroform, it was placed at room temperature, and the precipitated crystals were dried at 60°C to obtain 0.76 g ((R,S), (S,R) enantiomeri...

Embodiment 3

[0046] Weigh 6.0 grams of m-hydroxybenzaldehyde, add 10 ml of nitroethane and 90 ml of absolute ethanol and dissolve it under stirring, cool to -20 ° C, add 0.5 grams of imidazole, 0.4 grams of copper acetate monohydrate and 0.4 grams of cinchonine, in - Stir and react at 15∽-20°C for 40 hours until the reactant m-hydroxybenzaldehyde no longer decreases; adjust the pH value of the reaction solution to 3 with 20% hydrochloric acid under stirring, and spin evaporate the solvent under reduced pressure at 80°C; After adding 50ml of water to dissolve the product, extract 3 times with 3×50ml of ethyl acetate, combine the ethyl acetate phases, and evaporate the solvent under reduced pressure at 50°C to obtain a crude product; after dissolving the crude product with 30ml of dichloroethane, After standing at room temperature, the precipitated crystals were dried at 60°C to obtain 4.3 g ((R,S), (S,R) enantiomeric excess 80%) of the addition reaction product. Dissolve the crystals in 60m...

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Abstract

The invention discloses a synthesis method of metaraminol bitartrate, and in particular provides a method for synthesizing metaraminol bitartrate by using a chiral catalysis method. The synthesis method comprises the steps: catalyzing a chiral addition reaction of hydroxybenzaldehyde and nitroethane by using a chiral catalyst system consisting of cinchona alkaloid, copper acetate hydrate and less imidazole to obtain an addition product with a dominant required spatial configuration, and then reducing nitro by using hydrogen in the presence of Pd-C to obtain amine to obtain aramine, and salifying the aramine with L(+)-tartaric acid to obtain a final product metaraminol bitartrate. According to the synthesis method, an enzyme catalyst is prevented from being used, a raw material of the synthesis reaction is easily available, the chiral catalyst is easily purchased or prepared self, the synthesis steps are relatively less, the chiral control efficiency is higher, the enantioselectivity is high, the yield is good, the reaction operation is easily controlled, and is safe and reliable, and the foundation is laid for the later industrialized amplification production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a synthesis method of metaraminol bitartrate. Background technique [0002] Metaraminol bitartrate, Chinese alias: Alamin, English alias: Metaraminal bitartrate, CAS number: 33402-03-8, molecular formula C 9 h 13 NO 2 ·C 4 h 6 o 6 , molecular weight 317.29) is the bitartrate of metaraminolamine. [0003] At present, the common synthetic methods of metaraminol are as follows: [0004] 1. Use m-hydroxypropiophenone as raw material to obtain the target product after hydroxyl protection, nitrosation, Raney nickel hydrogenation reductive amination, and then deprotection. The reaction formula is shown in formula 1: [0005] [0006] Formula 1 [0007] 2. Take m-hydroxybenzaldehyde as a raw material to obtain 1-acetyl-m-hydroxybenzyl alcohol through enzyme catalysis in the presence of D-glucose, and obtain the target product by reduction and deprotection in the presence of ammon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/60C07C213/00C07C213/02C07C59/255C07C51/41
Inventor 蒲含林朱义波相东方
Owner 广州普星药业有限公司
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