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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 problems such as low yield of target product, and achieve the effects of high yield, mild reaction and reduced reaction time

Active Publication Date: 2017-05-31
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The deficiency of this method is: target product yield is lower

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0016] The synthetic method of metaraminol tartrate of the present embodiment has the following steps:

[0017] ① Weigh 1.5g of m-hydroxybenzaldehyde, add 4.61g of nitroethane and 30mL of absolute ethanol and dissolve it under stirring, cool down to 0°C, add 0.06g of DIPEA, 0.07g of copper acetate monohydrate and 0.07g of cinchonine, Stir the reaction at 5±2°C for 5h until m-hydroxybenzaldehyde no longer decreases.

[0018] ② Adjust the pH to 7 with glacial acetic acid while stirring, and evaporate the solvent to dryness under reduced pressure at 55°C; add 15mL of water to dissolve, extract three times with 3×15mL ethyl acetate, combine the ethyl acetate phase, and evaporate the solvent to dryness under reduced pressure at 50°C , 1.36g of the addition reaction product was obtained, in which (R, S) configuration and (S, R) configuration were in excess of 82%.

[0019] ③Dissolve the product in 13.6mL of methanol, add 15mg of 5wt%Pt / C catalyst, replace the air in the reactor wit...

Embodiment 2～ Embodiment 5）

[0026] Each embodiment is basically the same as Embodiment 1, and the differences are shown in Table 1.

[0027] Table 1

[0028] Example 1 Example 2 Example 3 Example 4 Example 5 m-Hydroxybenzaldehyde 1.5g 1.5g 0.5g 5g 25g Nitroethane 4.61g 4.61g 1.54g 15.37g 76.84g Absolute ethanol 30mL 30mL 10mL 100mL 500mL Adding catalyst system temperature 0℃ 5℃ 5℃ 0℃ 0℃ DIPEA 0.06g 0.06g 0.02g 0.1g 1.0g Copper acetate monohydrate 0.07g 0.07g 0.022g 0.2g 0.8g cinchoning 0.07g 0.07g 0.02g 0.2g 0.8g Addition reaction temperature and time 5±2℃，5h 5±2℃，5h 5±2℃，6h 5±2℃，4h 5±2℃，5h Glacial acetic acid to adjust pH 7 6 6.5 6.5 6 water 15mL 15mL 5mL 50mL 250mL ethyl acetate 3×15mL 3×15mL 3×5mL 3×50mL 3×250mL Addition product 1.36g 1.32g 0.46g 4.50g 22.2g (R,S) configuration and (S,R) configuration in excess 82% 75% 80% 83% 79% Methan...

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PUM

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Abstract

The invention discloses a synthesis method of metaraminol bitartrate, which comprises the following steps of: (1) additive reaction of nitroethane and hydroxybenzaldehyde, (2) additive reaction post-treatment and purification, (3) catalytic hydrogenation and (4) salification, wherein a catalysis system adopted by the additive reaction is copper acetate monohydrate, amine and chiral alkali; the amine in the catalysis system is N,N-diisopropylethylamine and / or triethylamine; the temperature and time of the additive reaction are 0-10 DEG C and 4-6h respectively; pH (potential of hydrogen) of a reaction system is adjusted to 6-7 by acetic acid in the additive reaction post-treatment and purification. On the one hand, N,N-diisopropylethylaine and the like are used to substitute imidazole to form the catalysis system with chiral alkali and copper acetate monohydrate, on the other hand, the pH of the system after the additive reaction is adjusted to 6-7, so that a higher-yield target product can be obtained.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of metaraminol bitartrate. Background technique [0002] Metaraminol Bitartrate is the bitartrate of Metaraminol Bitartrate. It is an α-adrenoceptor agonist developed by Fresenius Kabi Company in the United States. It mainly acts on α-receptors. It is suitable for early treatment of shock and prevention of spinal Acute hypotension during internal block anesthesia. [0003] Due to the presence of two chiral carbon atoms in metaraminolamine, there are four configurations (R, S), (S, R), (R, R), and (S, S), where (R, S) is Effective configurations, (S, R) are its enantiomers, and (R, R) and (S, S) are its diastereomers. [0004] Chinese patent document CN103739504A discloses a kind of synthetic method of m-hydroxylamine bitartrate, and this method comprises: (1) addition reaction: with nitroethane and m-hydroxybenzaldehyde, take copper ace...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C215/52C07C51/41C07C59/255
CPCC07C51/412C07C201/12C07C213/00C07C213/02C07C215/52C07C205/17C07C59/255
Inventor 胡国宜胡锦平王永成奚小金
Owner CHANGZHOU SUNLIGHT PHARMA
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