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Novel preparation method of 5-aminomethyl nicotinic acid

A technology of aminomethylnicotinic acid and methylnicotinic acid is applied in the field of preparation of 5-aminomethylnicotinic acid, which can solve the problems of hidden danger of explosion, high corrosiveness, intense reaction and the like, and achieves safe operation and high yield , mild conditions

Active Publication Date: 2014-02-26
RENNOTECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The existing 5-aminomethylnicotinic acid is usually obtained by reducing 5-cyanomethylnicotinic acid, and 5-cyanomethylnicotinic 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 the 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 Synthesis544,2001, all disclose the technology of using sodium hypochlorite and osmium tetroxide as oxidizing agent respectively

Method used

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  • Novel preparation method of 5-aminomethyl nicotinic acid

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Embodiment 15

[0023] The preparation of embodiment 15-aminomethyl nicotinic acid

[0024] The preparation of 5-aminomethyl nicotinic acid comprises the following steps:

[0025] (1) Preparation of methyl 5-(phthalamido)methylnicotinate

[0026] 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 1.11g of diethyl azodicarboxylate in tetrahydrofuran (8mL) dropwise, stir at room temperature for 12 hours, and complete reaction of methyl 5-hydroxymethylnicotinate to obtain methyl 5-(phthalamido)methylnicotinate .

[0027] (2) Preparation of 5-(phthalamido)methylnicotinic acid

[0028] 5-(phthalamido) methyl nicotinic acid aqueous solution, slowly dropwise add 1.0 M sodium hydroxide aqueous solution to adjust the pH of the reaction system to 14, stir for 1 h, and the hydrolysis is complete by HPLC detection. Ethyl acetate was added for extraction. Concentr...

Embodiment 25

[0031] The preparation of embodiment 25-aminomethyl nicotinic acid

[0032] The preparation of 5-aminomethyl nicotinic acid comprises the following steps:

[0033] (1) Preparation of methyl 5-(phthalamido)methylnicotinate

[0034] 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 them in 20mL of tetrahydrofuran, add dropwise 0.6mol azo The ethyl acetate solution of diethyl diformate was refluxed for 3 hours, and the 5-hydroxymethyl nicotinic acid methyl ester was completely reacted to obtain 5-(phthalamide) methyl nicotinic acid methyl ester.

[0035] (2) Preparation of 5-(phthalamido)methylnicotinic acid

[0036] 5-(phthalamido) methyl nicotinic acid methanol solution, slowly dropwise add 1.0 M sodium hydroxide aqueous solution to adjust the pH of the reaction system to 12, stir for 24 hours, and the hydrolysis is complete by HPLC detection. Ethyl acetate was added for ex...

Embodiment 35

[0039] The preparation of embodiment 35-aminomethyl nicotinic acid

[0040] The preparation of 5-aminomethyl nicotinic acid comprises the following steps:

[0041] (1) Preparation of methyl 5-(phthalamido)methylnicotinate

[0042] 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 them in 20mL of tetrahydrofuran, add dropwise 0.6mol azo The toluene solution of diethyl diformate was stirred at room temperature for 24 hours, and the 5-hydroxymethyl nicotinic acid methyl ester was completely reacted to obtain 5-(phthalamide) methyl nicotinic acid methyl ester.

[0043] (2) Preparation of 5-(phthalamido)methylnicotinic acid

[0044] 5-(phthalamido) methyl nicotinic acid 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 acetate was...

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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-aminomethylnicotinic acid is usually obtained by reducing 5-cyanomethylnicotinic acid, and 5-cyanomethylnicotinic 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 nicotin...

Claims

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Application Information

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IPC IPC(8): C07D213/803C07D213/80
CPCC07D213/80C07D213/803
Inventor 邹正才宋明辉
Owner RENNOTECH
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