Synthetic method of methoxamine hydrochloride

A technology of methoxamine hydrochloride and its synthesis method, which is applied in the field of chemistry, can solve problems such as difficult industrial production, high requirements for synthesis conditions, unstable oximation products, etc., and achieve short preparation cycle, high purity, and less environmental pollution Effect

Active Publication Date: 2014-08-27
SHANDONG JINHE DRUG RES DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Methoxamine hydrochloride was recorded in the 2000 edition of the Chinese Pharmacopoeia, and it was also recorded in the 2010 edition of the Chinese Pharmacopoeia, but there are few domestic reports on its synthesis method
Chinese patent CN101417956B has reported the synthetic method of methoxamine hydrochloride: this patent adopts nitrogen to protect methylation, after oximation reaction, then reduction, salt formation obtains target product; Stable, large variables in production, uncontrollable, difficult to achieve industrial production

Method used

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  • Synthetic method of methoxamine hydrochloride

Examples

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Effect test

Embodiment 1

[0036] Embodiment 1, the preparation of N-trifluoroacetyl-DL-α-alanine

[0037] Add 100g of DL-α-alanine and 500ml of anhydrous methanol to a 1000ml three-necked reaction flask, stir at room temperature, add 160ml of triethylamine dropwise at room temperature, add 160g of ethyl trifluoroacetate dropwise, control the temperature at 25°C, and stir the reaction 8h, during the reaction process, the solution gradually turned into a light yellow clear liquid, and the HPLC monitored the completion of the reaction; the methanol solvent was evaporated under reduced pressure, and a white solid appeared, which was dissolved in 500ml purified water, and the pH value was adjusted to 1 with 36% (g / g) concentrated hydrochloric acid. -2 or so, extracted three times with ethyl acetate, 200ml each time, combined the organic phases, washed with 200ml purified water, separated into layers, kept the organic layer, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressur...

Embodiment 2

[0038] Example 2, Preparation of 2-trifluoroacetyl-1-(2,5-dimethoxyphenyl)-1-propanone

[0039] Add 185g of N-trifluoroacetyl-DL-α-alanine alanine and 500ml of dichloromethane to a 1000ml reaction bottle, stir and cool down to 15°C, add 121g of oxalyl chloride dropwise, and control the temperature at 15°C; 1.5h After dropping, react for 1 hour; rise to room temperature, react for 3 hours, weigh 118g of p-xylylene dimethyl ether and dissolve in 200ml of dichloromethane, drop the mixture into the reaction bottle, drop it within 20 minutes, react for 1 hour at 15°C, and react for 8 hours at room temperature. After the reaction is complete, pour the reaction solution into 500ml of ice water, stir while adding, separate the liquids, wash the organic phase twice with water, and dry with anhydrous sodium sulfate; After drying, 213g of Intermediate II was obtained, with a yield of 83.1%, and HPLC of 99.3%.

Embodiment 3

[0040] Example 3, 2-amino-1-(2,5-dimethoxyphenyl)-1-propanone hydrochloride

[0041] Add 180 g of 2-trifluoroacetyl-1-(2,5-dimethoxyphenyl)-1-propanone, 108 g of 36% (g / g) concentrated hydrochloric acid, and 250 ml of ethanol into a 1000 ml single-port reaction flask, and heat to Reflux, the reaction solution is gradually light yellow and clear, reflux reaction for 4h, the reaction is completed, the reaction solution is concentrated under reduced pressure at 70°C, and the liquid is evaporated to dryness to obtain a reddish-brown oily liquid. Add 100ml of n-hexane and 100ml of dichloromethane to the residue, and wash for 2h , filtered and dried to obtain 136 g of light yellow solid, yield 82.5%.

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Abstract

The invention discloses a synthetic method of methoxamine hydrochloride, and the synthetic method comprises the following steps of: adopting DL-alpha-alanine as a raw material and adopting methanol as a solvent, and obtaining N-trifluoroacetyl-DL-alpha-alanine under the action of triethylamine; reacting the N-trifluoroacetyl-DL-alpha-alanine with hydroquinone dimethyl; obtaining 2-trifluoroacetyl-1-(2,5-dimethoxyphenyl)-1-acetone by adopting methylene dichloride as a solvent and adopting oxalyl chloride as an acylating agent; obtaining 2-amino-1-(2,5-dimethoxyphenyl)-1-acetone hydrochloride after the removal of a protective group by adopting alcohol as a solvent under the action of hydrochloric acid; and finally, obtaining a course product of the methoxamine hydrochloride after a reduction reaction under the action of potassium borohydride and obtaining a refined product of the methoxamine hydrochloride by adopting alcohol as a refined solvent, wherein the purity of the refined product of the methoxamine hydrochloride is 99.9%, the content of an individual impurity of the refined product of the methoxamine hydrochloride is less than 0.05%, and the content of the total impurities of the refined product of the methoxamine hydrochloride is less than 0.1%. The preparation method disclosed by the invention has the advantages of easiness for the acquisition of raw materials and convenience for operation; and the prepared product has the advantages of high purity, high yield and lower cost and is very suitable for large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing methoxamine hydrochloride, belonging to the technical field of chemistry. Background technique [0002] Methoxamine Hydrochloride (Methoxamine Hydrochloride) is an α-adrenergic receptor agonist, which has obvious vasoconstriction effect. It can increase both systolic blood pressure and diastolic blood pressure by increasing peripheral resistance, but has no exciting effect on the heart. It is suitable for hypotension caused by massive bleeding, trauma, and surgery, as well as the prevention of hypotension and supraventricular paroxysmal tachycardia before spinal anesthesia. It can also be used for postoperative circulatory failure and hypotensive shock caused by peripheral circulatory failure. [0003] The chemical name of methoxamine is: 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol, the molecular formula is C 11 h 17 NO 3 , Its hydrochloride is mainly used clinically. Methoxamine hyd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/70C07C213/00
CPCY02P20/55
Inventor 常建晖王振彭坤
Owner SHANDONG JINHE DRUG RES DEV
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