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A kind of preparation method of 5-aminomethylnicotinic acid

A technology based on aminomethylnicotinic acid and phthaloamide, which is applied in the field of preparation of 5-aminomethylnicotinic acid, can solve the problems of hidden dangers of explosion, rapid and intense reaction, etc., and achieve safe operation and good conditions. Gentle, easy-to-process effect

Active Publication Date: 2015-10-28
RENNOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The existing 5-aminomethyl nicotinic acid is usually obtained by reduction of 5-cyanomethyl nicotinic acid, and 5--cyanomethyl nicotinic acid is usually obtained by the following methods: (1) Elimination method: in three Under the action of chlorinated dehydrating agents such as phosphorus chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, etc., the acyl or oxime group in 5-carbamoyl nicotinic acid is dehydrated to obtain 5-cyanomethyl nicotinic acid; The reaction is more intense, faster, and highly corrosive. For example, the patent WO2006 / 589A1 and the document J.Med.Chem, 52(10), 3381, 2009, both disclose that the acyl group is dehydrated by phosphorus trichloride to prepare 5 -aminomethyl nicotinic acid; (2) oxidation method: under the action of oxidant sodium hypochlorite, osmium tetroxide or nickel peroxide, the amino group is oxidized to 5-cyanonicotinic acid; potential explosion safety hazard; such as documents Synth.Commun.27,3559,1997 and Synthesis 544,2001, all disclose the technology of using sodium hypochlorite and osmium tetroxide as oxidizing agent respectively

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  • A kind of preparation method of 5-aminomethylnicotinic acid

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Embodiment 15

[0026] The preparation of embodiment 15-aminomethyl nicotinic acid

[0027] The preparation of 5-aminomethyl nicotinic acid comprises the following steps:

[0028] (1) Preparation of 5-(phthalamido) methylnicotinate

[0029] Add 1.00g of methyl 5-hydroxymethylnicotinate, 1.56g of triphenylphosphine and 0.88g of phthalamide into a clean and dry three-necked flask, and dissolve them in 6ml of tetrahydrofuran. Add 1.11 g of diethyl azodicarboxylate in tetrahydrofuran (8 mL) dropwise, and stir at room temperature for 12 hours to complete the reaction of 5-hydroxymethyl nicotinic acid methyl ester to obtain 5-(phthalamido) methyl nicotinic acid methyl ester .

[0030] (2) Preparation of 5-(phthalamido) methyl nicotinic acid

[0031] 5-(phthalamido)methyl nicotinic acid aqueous solution was slowly added dropwise with 1.0 M sodium hydroxide aqueous solution to adjust the pH of the reaction system to 14, stirred for 1 h, and the hydrolysis was complete by HPLC detection. Ethyl ace...

Embodiment 25

[0034] The preparation of embodiment 25-aminomethyl nicotinic acid

[0035] The preparation of 5-aminomethyl nicotinic acid comprises the following steps:

[0036] (1) Preparation of 5-(phthalamido) methylnicotinate

[0037] Add 0.1mol 5-hydroxymethyl nicotinic acid methyl ester, 0.6mol triphenylphosphine and 0.1mol phthalamide to a clean and dry three-necked flask, dissolve in 20mL tetrahydrofuran, dropwise add 0.6mol The ethyl acetate solution of diethyl nitrogen dicarboxylate was refluxed for 3 hours, and the 5-hydroxymethyl nicotinic acid methyl ester was completely reacted to obtain 5-(phthalamido) methyl nicotinic acid methyl ester.

[0038] (2) Preparation of 5-(phthalamido) methyl nicotinic acid

[0039] 5-(phthalamido) methyl nicotinic acid methanol solution, slowly dropwise added 1.0M aqueous sodium hydroxide solution to adjust the pH of the reaction system to 12, stirred for 24 hours, and HPLC detected that the hydrolysis was complete. Ethyl acetate was added for...

Embodiment 35

[0042] The preparation of embodiment 35-aminomethyl nicotinic acid

[0043] The preparation of 5-aminomethyl nicotinic acid comprises the following steps:

[0044] (1) Preparation of 5-(phthalamido) methylnicotinate

[0045] Add 0.1mol 5-hydroxymethyl nicotinic acid methyl ester, 0.5mol triphenylphosphine and 0.12mol phthalamide to a clean and dry three-necked flask, dissolve in 20mL tetrahydrofuran, add dropwise 0.6mol The toluene solution of diethyl nitrogen dicarboxylate was stirred at room temperature for 24 hours, and the 5-hydroxymethyl nicotinic acid methyl ester was completely reacted to obtain 5-(phthalamido) methyl nicotinic acid methyl ester.

[0046] (2) Preparation of 5-(phthalamido) methyl nicotinic acid

[0047] 5-(phthalamido)methyl nicotinic acid methyl ester ethanol solution, slowly dropwise add 1.0M sodium hydroxide aqueous solution to adjust the pH of the reaction system to 14, stir for 12 hours, and the hydrolysis is complete by HPLC detection. Ethyl ac...

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Abstract

The invention provides a novel preparation method of 5-aminomethyl nicotinic acid. The method comprises steps of: reacting 5-(hydroxymethyl)nicotinate with a nitrogen source reagent under existence of a dehydrating agent to obtain 5-(phthalic diamide) methylnicotinate; hydrolyzing the 5-(phthalic diamide) methylnicotinate under acid or alkaline conditions to obtain 5-(phthalic diamide) methyl nicotinic acid; and reacting the 5-(phthalic diamide) methyl nicotinic acid with a deprotection reagent to obtain the 5-aminomethyl nicotinic acid. The method is simple in technology, mild in condition, safe in operation, and high in yield.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a novel preparation method of 5-aminomethylnicotinic acid. Background technique [0002] 5-Aminomethylnicotinic acid is an important pharmaceutical intermediate. The existing 5-aminomethyl nicotinic acid is usually obtained by reduction of 5-cyanomethyl nicotinic acid, and 5--cyanomethyl nicotinic acid is usually obtained by the following methods: (1) Elimination method: in three Under the action of chlorinated dehydrating agents such as phosphorus chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, etc., the acyl or oxime group in 5-carbamoyl nicotinic acid is dehydrated to obtain 5-cyanomethyl nicotinic acid; The reaction is more intense, faster, and highly corrosive. For example, the patent WO2006 / 589A1 and the document J.Med.Chem, 52(10), 3381, 2009, both disclose that the acyl group is dehydrated by phosphorus trichloride to prepare 5 -aminomethyl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/803C07D213/80
CPCC07D213/80C07D213/803
Inventor 邹正才宋明辉
Owner RENNOTECH
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