A kind of preparation method of low-cost 3-hydroxypyridine

A hydroxypyridine and benzyl technology, applied in the field of preparation of 3-hydroxypyridine, can solve the problems of unsuitability for industrial production, difficult operation, large amount of waste water, etc., and achieves easy implementation and control, reduced raw material cost, and good reaction selectivity. Effect

Active Publication Date: 2020-08-04
XINFA PHARMA
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  • Abstract
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Problems solved by technology

Chinese patent CN103664760A discloses a preparation method of 3-hydroxypyridine, which uses pyridine, mercuric sulfate and fuming sulfuric acid at 210-220°C for 8-10 hours to prepare pyridine-3-sulfonic acid, and then pyridine-3-sulfonic acid Acid and basic substances are heated and melted to obtain 3-hydroxypyridine, no specific yield given
[0004] The raw material 3-chloropyridine or 3-aminopyridine used in the above method is expensive, the temperature of sulfonation reaction or hydrolysis reaction is high, it is difficult to operate, the post-treatment is cumbersome, and the amount of waste water is large, so it is not suitable for industrial production.

Method used

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  • A kind of preparation method of low-cost 3-hydroxypyridine
  • A kind of preparation method of low-cost 3-hydroxypyridine

Examples

Experimental program
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Effect test

Embodiment 1

[0051] Example 1: Preparation of N-benzyl-3-aza-1,7-pimelic acid dimethyl ester

[0052] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser, add 250 grams of methanol, 24.4 grams (0.1 moles) of methyl 4-benzylamino butyrate hydrochloride, 11.5 grams (0.105 moles) of 2- Methyl chloroacetate, 30.3 grams (0.22 moles) of potassium carbonate, stirred and reacted between 60-65°C for 6 hours, then cooled to 30°C, filtered, the filter cake was washed once with 40 grams of methanol, the filtrates were combined, and methanol was recovered by distillation , Distilled under reduced pressure (105-120° C. / 3 mmHg) to obtain 25.8 g of N-benzyl-3-aza-1,7-pimelic acid dimethyl ester with a yield of 92.6% and a gas phase purity of 99.5%.

Embodiment 2

[0053] Example 2: Preparation of N-benzyl-3-aza-1,7-pimelic acid dimethyl ester

[0054] In the 1000 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser, add 400 gram tetrahydrofuran, 49.0 gram (0.2 mol) methyl 4-benzylamino butyrate hydrochloride, 32.1 gram (0.21 mol) 2- Methyl bromoacetate, 58.0 g (0.42 moles) of potassium carbonate, stirred and reacted at 60-65°C for 6 hours, then cooled to 30°C, filtered, the filter cake was washed once with 40 g of tetrahydrofuran, the filtrates were combined, and tetrahydrofuran was recovered by distillation , Distilled under reduced pressure (105-120° C. / 3 mmHg) to obtain 52.6 g of N-benzyl-3-aza-1,7-pimelic acid dimethyl ester with a yield of 94.3% and a gas phase purity of 99.7%.

Embodiment 3

[0055] Example 3: Preparation of N-benzyl-3-aza-1,7-pimelic acid diethyl ester

[0056] In the 500 milliliter four-neck flask that is connected with stirring, thermometer, reflux condenser, add 200 grams of ethanol, 25.8 grams (0.1 moles) of ethyl 4-benzylaminobutyrate hydrochloride, 18.5 grams (0.11 moles) of 2- Ethyl bromoacetate, 26.5 grams (0.25 moles) of sodium carbonate, stirred and reacted between 70-75°C for 4 hours, then cooled to 30°C, filtered, the filter cake was washed with 40 grams of ethanol, the filtrates were combined, and the ethanol was recovered by distillation. Pressure distillation (105-125° C. / 3 mmHg) yielded 28.2 g of N-benzyl-3-aza-1,7-pimelic acid diethyl ester with a yield of 91.7% and a gas phase purity of 99.6%.

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Abstract

The invention relates to a preparation method of low-cost 3-hydroxypyridine. The method comprises the steps of enabling 4-benzylaminobutyrate hydrochloride and 2-haloacetate to be subjected to a substitution reaction so as to obtain N-benzyl-3-aza-1, 7-pimelate diester; then, enabling the N-benzyl-3-aza-1, 7-pimelate diester to be subjected to an intramolecular condensation reaction, and carrying out hydrolytic decarboxylation to obtain N-benzylpiperidin-3-one; then, carrying out catalytic hydrogenolysis to remove benzyl so as to obtain piperidin-3-one; enabling the piperidin-3-one and halogen to be subjected to a halogenating reaction so as to obtain 2, 4-dihalogenated piperidine-3-one; then, enabling the 2, 4-dihalogenated piperidine-3-one and an acid-binding agent to be subjected to an elimination reaction to obtain 3-hydroxypyridine. The raw materials used in the preparation method are low in price and easy to obtain, the operation conditions are mild, simple and convenient, and less wastewater is produced; the method is high in operation safety, environmental protection property, product yield and purity, and low in cost.

Description

technical field [0001] The invention relates to a low-cost preparation method of 3-hydroxypyridine, which belongs to the technical field of medicinal chemistry. Background technique [0002] 3-Hydroxypyridine, the English name is 3-Hydroxypyridine, CAS number is 109-00-2, 3-Hydroxypyridine is a white needle crystal, widely used in the preparation of organic synthetic medicine and dyes, and can be used as a pharmaceutical intermediate And specific catalysts, can prepare 3-methoxy-2-pyridinecarbaldehyde, 3-(N,N-dimethylcarbamoyloxy)pyridine, penicillin and other pharmaceutical intermediates. [0003] The preparation methods of 3-hydroxypyridine mainly include 3-chloropyridine direct or indirect hydrolysis method, 3-aminopyridine diazotization-hydrolysis method, pyridine sulfonation-hydrolysis method. Chinese patent CN103664760A discloses a preparation method of 3-hydroxypyridine, which uses pyridine, mercuric sulfate and fuming sulfuric acid at 210-220°C for 8-10 hours to pre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/65
CPCC07D213/65
Inventor 戚聿新鞠立柱张明峰吕强三王涛
Owner XINFA PHARMA
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