CN101182323A - Method for preparing folic acid - Google Patents
Method for preparing folic acid Download PDFInfo
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- CN101182323A CN101182323A CNA2007101856461A CN200710185646A CN101182323A CN 101182323 A CN101182323 A CN 101182323A CN A2007101856461 A CNA2007101856461 A CN A2007101856461A CN 200710185646 A CN200710185646 A CN 200710185646A CN 101182323 A CN101182323 A CN 101182323A
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Abstract
The present invention relates to a preparation method of folic acid, the technical steps of which are as follows: firstly, p-nitrobenzoyl chloride and sodium glutamate are used to prepare for a medium product N-p-amino-benzoyl glutamic acid; then, methyl cyanoacetate, guanidine nitrate and sodium methoxide are used to prepare for the medium product 6-hydroxyl-2, 4, 5-triamino pyrimidine sulfate; finally, the two kinds of medium products are used to prepare for a crude product of the folic acid which is refined to obtain the pure product of the folic acid. The present invention has the beneficial effects of reducing the production cost greatly, improving the product efficiency and reducing the pollution to the environment.
Description
Technical field
The present invention relates to a kind of preparation method of folic acid.
Background technology
Folic acid belongs to the basic kind of VITAMIN, is anti-anemic, is applied to fields such as feed, medicine and food.In foodstuffs industry,, in fodder industry, be used as anti-anemic thing additive as accessory substance; Folic acid is usually used in treating diseases such as cell anemia, large bowel cancer in pharmaceutical industries.
Useful amino substance, α, beta-2-dibrom propionic aldehyde, triamino thing are reacted in acetate-sodium acetate buffer solution of the prior synthesizing method of folic acid obtains thick folic acid, through the refining folic acid that obtains containing 2 molecular crystal water.This synthetic method craft complexity, conditional request harshness, shortcoming such as reaction time is long, yield is low, cost is high, raw material is difficult to obtain.Also useful 2-replaces mda and p-benzoyl base-L-L-glutamic acid reaction obtains corresponding diimine; then in the presence of sulphite; in pH value is that the phonetic pyrrone reaction of 3-8 and triamino makes folic acid, though this method yield increases, production cost is very high.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method with folic acid that cost is low, yield is high.
The technical solution adopted for the present invention to solve the technical problems:
A kind of preparation method of folic acid is characterized in that its processing step is as follows:
(1) at first produce intermediate product N-NSC 71042:
A, take by weighing each raw material according to the following portions by weight ratio:
Paranitrobenzoyl chloride: 1
Sodium Glutamate: 1-2;
B, carry out condensation reaction, reduction reaction successively again:
To meet paranitrobenzoyl chloride that said ratio requires and Sodium Glutamate and under temperature 5-30 ℃, the condition of PH7～11, carry out 1～5 hour condensation reaction; Adding hydrochloric acid again, to transfer its pH value be 4.0～7.0, carries out reduction reaction in temperature 30-100 ℃ with hydrogen under the effect of catalyzer then, and PH1.0～5.0 are transferred with hydrochloric acid in the reaction back that finishes, intermediate product N-NSC 71042;
(2) produce intermediate product 6-hydroxyl-2,4 again, 5-Triaminopyrimidine vitriol:
A, take by weighing each raw material according to the following portions by weight ratio:
Methyl cyanoacetate: 1
Guanidinium nitrate: 1-2
Sodium methylate: 2-5
Sodium Nitrite: 0.6-1;
B, encircle and reaction, duct type nitrosification instantaneous reaction, reduction reaction successively:
Methyl cyanoacetate, sodium methylate, Guanidinium nitrate are mixed by the said ratio requirement, under 30～100 ℃ of temperature, reflux state, carried out ring-closure reaction 1-5 hour, at temperature 3-30 ℃, carry out duct type nitrosification instantaneous reaction with Sodium Nitrite under PH1.0～5.0 conditions, carry out reduction reaction with hydrogen pressurising 8～12Mpa under catalyst action again, add the sulfuric acid salify at last and get intermediate product 6-hydroxyl-2,4,5-Triaminopyrimidine vitriol;
(3) utilize above-mentioned two kinds of intermediate products to produce the folic acid crude product, re-refine pure product:
A, take by weighing above-mentioned intermediate product according to the following portions by weight ratio:
N-NSC 71042: 1
6-hydroxyl-2,4,5-Triaminopyrimidine vitriol: 1-2
Trichloroacetone: 1-2.5;
B, encircle and react the folic acid crude product, through refining pure product:
N-NSC 71042, trichloroacetone and the 6-hydroxyl-2 that will meet said ratio, 4,5-Triaminopyrimidine vitriol is in the presence of sodium carbonate and pyrosulphite are received, keep PH1.0～5.0, under temperature 20-50 ℃ the condition, ring and reaction 3-6 hour, the folic acid crude product, through refining pure product.
At the catalyzer described in above-mentioned (1), (2) step is Ni-Al alloy catalyst or palladium-carbon catalyst, and catalyst consumption is:
Catalyst consumption is the 1/15-1/5 that is reduced thing weight in step (1);
Catalyst consumption is the 1/20-1/10 that is reduced thing weight in step (2).
Described duct type nitrosification instantaneous reaction is meant that reactant is in and carries out instantaneous reaction under the flow state that the flow of control reactant is: 600-1500L/h in pipeline; The pH value of its moment is 1.0-3.0.
Beneficial effect of the present invention is as follows:
(1) the present invention is a main raw material with paranitrobenzoyl chloride and methyl cyanoacetate, has reduced the cost of raw material.
(2) the present invention is synthesizing 6-hydroxyl-2,4 by methyl cyanoacetate and Guanidinium nitrate, and in the 5-Triaminopyrimidine vitriol process, the canalization production method has been adopted in nitrosification, has improved product yield, has strengthened quality product.
(3) all reduction reactions of the present invention all adopt the hydrogen reducing method, have not only improved quality product, and have reduced the pollution to environment.
Embodiment
Embodiment 1:
(1) at first produce intermediate product N-NSC 71042:
A, take by weighing raw material:
Paranitrobenzoyl chloride: 100Kg
Sodium Glutamate: 100Kg
B, carry out condensation reaction, reduction reaction successively again:
To meet paranitrobenzoyl chloride that said ratio requires and Sodium Glutamate and under temperature 5-15 ℃, the condition of PH7～9, carry out 1～2.5 hour condensation reaction; Adding hydrochloric acid again, to transfer its pH value be 4.0～6.5, carries out reduction reaction in temperature 30-70 ℃ with hydrogen under the effect of Ni-Al alloy catalyst then, and the consumption of Ni-Al alloy catalyst is to be reduced 1/15 of thing weight; Reaction finishes the back with hydrochloric acid accent PH1.0～3.0, gets intermediate product N-NSC 71042;
(2) produce intermediate product 6-hydroxyl-2,4 again, 5-Triaminopyrimidine vitriol:
A, take by weighing raw material:
Methyl cyanoacetate: 100Kg
Guanidinium nitrate: 100Kg
Sodium methylate: 200Kg
Sodium Nitrite: 60Kg
B, encircle and reaction, duct type nitrosification instantaneous reaction, reduction reaction successively:
Methyl cyanoacetate, sodium methylate, Guanidinium nitrate are mixed by the said ratio requirement, under 30～77 ℃ of temperature, reflux state, carried out ring-closure reaction 1-3 hour, at temperature 3-18 ℃, (flow of control reactant is 600L/h to carry out duct type nitrosification instantaneous reaction with Sodium Nitrite under PH1.0～2.0 conditions, the PH of its moment is 1.0), carry out reduction reaction with hydrogen pressurising 8Mpa under the Ni-Al alloy catalyst effect again, the consumption of Ni-Al alloy catalyst is to be reduced 1/20 of thing weight; Add the sulfuric acid salify at last and get intermediate product 6-hydroxyl-2,4,5-Triaminopyrimidine vitriol;
(3) utilize above-mentioned two kinds of intermediate products to produce the folic acid crude product, re-refine pure product:
A, take by weighing intermediate product:
N-NSC 71042: 100Kg
6-hydroxyl-2,4,5-Triaminopyrimidine vitriol: 100Kg
Trichloroacetone: 100Kg
B, encircle and react the folic acid crude product, through refining pure product:
N-NSC 71042, trichloroacetone and the 6-hydroxyl-2 that will meet said ratio, 4,5-Triaminopyrimidine vitriol is in the presence of sodium carbonate and pyrosulphite are received, keep PH1.0～3.0, under temperature 20-38 ℃ the condition, ring and reaction 3-4 hour, the folic acid crude product, through refining pure product.
C, with the pure product liquid-phase chromatographic analysis of folic acid, purity is more than 94%, yield is 70%.
Embodiment 2:
(1) at first produce intermediate product N-NSC 71042:
A, take by weighing raw material:
Paranitrobenzoyl chloride: 100Kg
Sodium Glutamate: 110Kg
B, carry out condensation reaction, reduction reaction successively again:
To meet paranitrobenzoyl chloride that said ratio requires and Sodium Glutamate and under temperature 10-15 ℃, the condition of PH9～10, carry out 2.5～3.5 hours condensation reaction; Adding hydrochloric acid again, to transfer its pH value be 6.5～7.0, carries out reduction reaction in temperature 70-90 ℃ with hydrogen under the effect of Ni-Al alloy catalyst then, and the consumption of Ni-Al alloy catalyst is to be reduced 1/10 of thing weight; Reaction finishes the back with hydrochloric acid accent PH 3.0～3.5, gets intermediate product N-NSC 71042;
(2) produce intermediate product 6-hydroxyl-2,4 again, 5-Triaminopyrimidine vitriol:
A, take by weighing raw material:
Methyl cyanoacetate: 100Kg
Guanidinium nitrate: 130Kg
Sodium methylate: 400Kg
Sodium Nitrite: 80Kg
B, encircle and reaction, canalization nitrosification instantaneous reaction, reduction reaction successively:
Methyl cyanoacetate, sodium methylate, Guanidinium nitrate are mixed by the said ratio requirement, under 65～77 ℃ of temperature, reflux state, carried out ring-closure reaction 1-3 hour, at temperature 8-18 ℃, (flow of control reactant is 1000L/h to carry out duct type nitrosification instantaneous reaction with Sodium Nitrite under PH2.0～2.5 conditions, the PH of its moment is 2.0), carry out reduction reaction with hydrogen pressurising 10Mpa under the Ni-Al alloy catalyst effect again, the consumption of Ni-Al alloy catalyst is to be reduced 1/15 of thing weight; Add the sulfuric acid salify at last and get intermediate product 6-hydroxyl-2,4,5-Triaminopyrimidine vitriol;
(3) utilize above-mentioned two kinds of intermediate products to produce the folic acid crude product, re-refine pure product:
A, take by weighing intermediate product:
N-NSC 71042: 100Kg
6-hydroxyl-2,4,5-Triaminopyrimidine vitriol: 120Kg
Trichloroacetone: 150Kg
B, encircle and react the folic acid crude product, through refining pure product:
N-NSC 71042, trichloroacetone and the 6-hydroxyl-2,4 that will meet said ratio, 5-Triaminopyrimidine vitriol is in the presence of sodium carbonate and pyrosulphite are received, keep PH3.0～3.5, under temperature 38-42 ℃ the condition, encircle and reacted 5 hours, the folic acid crude product, through refining pure product.
C, with the pure product liquid-phase chromatographic analysis of folic acid, purity is more than 98%, yield is 85%.
Embodiment 3:
(1) at first produce intermediate product N-NSC 71042:
A, take by weighing raw material:
Paranitrobenzoyl chloride: 100Kg
Sodium Glutamate: 200Kg
B, carry out condensation reaction, reduction reaction successively again:
To meet paranitrobenzoyl chloride that said ratio requires and Sodium Glutamate and under temperature 15-30 ℃, the condition of PH9～11, carry out 3～5 hours condensation reaction; Adding hydrochloric acid again, to transfer its pH value be 6.0～7.0, carries out reduction reaction in temperature 80-100 ℃ with hydrogen under the effect of palladium-carbon catalyst then, and the consumption of palladium-carbon catalyst is to be reduced 1/15 of thing weight; Reaction finishes the back with hydrochloric acid accent PH 4.0～5.0, gets intermediate product N-NSC 71042;
(2) produce intermediate product 6-hydroxyl-2,4 again, 5-Triaminopyrimidine vitriol:
A, take by weighing raw material:
Methyl cyanoacetate: 100Kg
Guanidinium nitrate: 200Kg
Sodium methylate: 500Kg
Sodium Nitrite: 100Kg
B, encircle and reaction, duct type nitrosification instantaneous reaction, reduction reaction successively:
Methyl cyanoacetate, sodium methylate, Guanidinium nitrate are mixed by the said ratio requirement, under 80～100 ℃ of temperature, reflux state, carried out ring-closure reaction 4-5 hour, at temperature 20-30 ℃, (flow of control reactant is 1500L/h to carry out duct type nitrosification instantaneous reaction with Sodium Nitrite under PH1.0～5.0 conditions, the PH of its moment is 3.0), carry out reduction reaction with hydrogen pressurising 12Mpa under the palladium-carbon catalyst effect again, the consumption of palladium-carbon catalyst is to be reduced 1/10 of thing weight; Add the sulfuric acid salify at last and get intermediate product 6-hydroxyl-2,4,5-Triaminopyrimidine vitriol;
(3) utilize above-mentioned two kinds of intermediate products to produce the folic acid crude product, re-refine pure product:
A, take by weighing intermediate product:
N-NSC 71042: 100Kg
6-hydroxyl-2,4,5-Triaminopyrimidine vitriol: 200Kg
Trichloroacetone: 250Kg
B, encircle and react the folic acid crude product, through refining pure product:
N-NSC 71042, trichloroacetone and the 6-hydroxyl-2,4 that will meet said ratio, 5-Triaminopyrimidine vitriol is in the presence of sodium carbonate and pyrosulphite are received, keep PH4.0～5.0, under temperature 30-50 ℃ the condition, encircle and reacted 5 hours, the folic acid crude product, through refining pure product.
C, with the pure product liquid-phase chromatographic analysis of folic acid, purity is more than 96%, yield is 80%.
Claims (3)
1. the preparation method of a folic acid is characterized in that its processing step is as follows:
(1) at first produce intermediate product N-NSC 71042:
A, take by weighing each raw material according to the following portions by weight ratio:
Paranitrobenzoyl chloride: 1
Sodium Glutamate: 1-2;
B, carry out condensation reaction, reduction reaction successively again:
To meet paranitrobenzoyl chloride that said ratio requires and Sodium Glutamate and under temperature 5-30 ℃, the condition of PH7～11, carry out 1～5 hour condensation reaction; Adding hydrochloric acid again, to transfer its pH value be 4.0～7.0, carries out reduction reaction in temperature 30-100 ℃ with hydrogen under the effect of catalyzer then, and PH1.0～5.0 are transferred with hydrochloric acid in the reaction back that finishes, intermediate product N-NSC 71042;
(2) produce intermediate product 6-hydroxyl-2,4 again, 5-Triaminopyrimidine vitriol:
A, take by weighing each raw material according to the following portions by weight ratio:
Methyl cyanoacetate: 1
Guanidinium nitrate: 1-2
Sodium methylate: 2-5
Sodium Nitrite: 0.6-1;
B, encircle and reaction, duct type nitrosification instantaneous reaction, reduction reaction successively:
Methyl cyanoacetate, sodium methylate, Guanidinium nitrate are mixed by the said ratio requirement, under 30～100 ℃ of temperature, reflux state, carried out ring-closure reaction 1-5 hour, at temperature 3-30 ℃, carry out duct type nitrosification instantaneous reaction with Sodium Nitrite under PH1.0～5.0 conditions, carry out reduction reaction with hydrogen pressurising 8～12Mpa under catalyst action again, add the sulfuric acid salify at last and get intermediate product 6-hydroxyl-2,4,5-Triaminopyrimidine vitriol;
(3) utilize above-mentioned two kinds of intermediate products to produce the folic acid crude product, re-refine pure product:
A, take by weighing above-mentioned intermediate product according to the following portions by weight ratio:
N-NSC 71042: 1
6-hydroxyl-2,4,5-Triaminopyrimidine vitriol: 1-2
Trichloroacetone: 1-2.5;
B, encircle and react the folic acid crude product, through refining pure product:
N-NSC 71042, trichloroacetone and the 6-hydroxyl-2 that will meet said ratio, 4,5-Triaminopyrimidine vitriol is in the presence of sodium carbonate and pyrosulphite are received, keep PH1.0～5.0, under temperature 20-50 ℃ the condition, ring and reaction 3-6 hour, the folic acid crude product, through refining pure product.
2. the preparation method of a kind of folic acid according to claim 1 it is characterized in that at the catalyzer described in above-mentioned (1), (2) step be Ni-Al alloy catalyst or palladium-carbon catalyst, and catalyst consumption is:
Catalyst consumption is the 1/15-1/5 that is reduced thing weight in step (1);
Catalyst consumption is the 1/20-1/10 that is reduced thing weight in step (2).
3. the preparation method of a kind of folic acid according to claim 2 is characterized in that described duct type nitrosification instantaneous reaction is meant that reactant is in and carries out instantaneous reaction under the flow state in pipeline, and the flow of control reactant is: 600-1500L/h; The pH value of its moment is 1.0-3.0.
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| CN2007101856461A CN101182323B (en) | 2007-12-26 | 2007-12-26 | Method for preparing folic acid |
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| CN2007101856461A CN101182323B (en) | 2007-12-26 | 2007-12-26 | Method for preparing folic acid |
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| CN102141562A (en) * | 2010-09-28 | 2011-08-03 | 上海师范大学 | Method for analyzing purity of 2,4,5-triamino-6-hydroxy pyrimidine sulfate sample by utilizing titration |
| CN102558180A (en) * | 2011-05-13 | 2012-07-11 | 河北冀衡（集团）药业有限公司 | Preparation method for folic acid |
| CN103755706A (en) * | 2014-02-11 | 2014-04-30 | 新发药业有限公司 | Environment-friendly preparation method of synthetic folic acid |
| CN103896945A (en) * | 2014-03-11 | 2014-07-02 | 新发药业有限公司 | Simple and convenient folic acid environment-friendly production method |
| CN104478751A (en) * | 2014-12-13 | 2015-04-01 | 常熟华港制药有限公司 | Preparation method of p-amino benzamide glutamic acid |
| CN105439895A (en) * | 2015-12-30 | 2016-03-30 | 浙江汇能生物股份有限公司 | Preparation method of N (4-aminobenzoyl)-L-glutamic acid |
| CN105541729A (en) * | 2015-12-31 | 2016-05-04 | 南昌大学 | Method for separating and purifying salt in 2,4,5-triamino-6-hydroxy pyrimidine sulfate production process |
| CN106432241A (en) * | 2015-08-04 | 2017-02-22 | 常州制药厂有限公司 | New folic acid preparation method |
| CN106496231A (en) * | 2016-09-30 | 2017-03-15 | 河北科技大学 | A kind of environment-friendly type preparation method of synthesis Folic Acid |
| CN107365311A (en) * | 2017-08-16 | 2017-11-21 | 浙江圣达生物药业股份有限公司 | A kind of preparation method and applications of trans folic acid |
| CN108774231A (en) * | 2018-07-06 | 2018-11-09 | 南通市常海食品添加剂有限公司 | A kind of environment-protection production method of folic acid |
| CN113651712A (en) * | 2021-08-17 | 2021-11-16 | 北京斯利安药业有限公司 | Method for preparing N-p-aminobenzoyl-L-glutamic acid |
| CN113816961A (en) * | 2021-08-17 | 2021-12-21 | 北京斯利安药业有限公司 | Folic acid synthesis method |
| CN114524771A (en) * | 2020-11-23 | 2022-05-24 | 江苏八巨药业有限公司 | Preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate |
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| US5410056A (en) * | 1993-01-26 | 1995-04-25 | Hoffman-La Roche Inc. | Method for the production of folic acid |
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| CN102141562B (en) * | 2010-09-28 | 2012-11-07 | 上海师范大学 | Method for analyzing purity of 2,4,5-triamino-6-hydroxy pyrimidine sulfate sample by utilizing titration |
| CN102558180A (en) * | 2011-05-13 | 2012-07-11 | 河北冀衡（集团）药业有限公司 | Preparation method for folic acid |
| CN103755706A (en) * | 2014-02-11 | 2014-04-30 | 新发药业有限公司 | Environment-friendly preparation method of synthetic folic acid |
| CN103755706B (en) * | 2014-02-11 | 2015-08-12 | 新发药业有限公司 | A kind of environment-friendly preparation method synthesizing folic acid |
| CN103896945A (en) * | 2014-03-11 | 2014-07-02 | 新发药业有限公司 | Simple and convenient folic acid environment-friendly production method |
| CN103896945B (en) * | 2014-03-11 | 2015-07-01 | 新发药业有限公司 | Simple and convenient folic acid environment-friendly production method |
| CN104478751A (en) * | 2014-12-13 | 2015-04-01 | 常熟华港制药有限公司 | Preparation method of p-amino benzamide glutamic acid |
| CN106432241A (en) * | 2015-08-04 | 2017-02-22 | 常州制药厂有限公司 | New folic acid preparation method |
| CN106432241B (en) * | 2015-08-04 | 2019-07-12 | 常州制药厂有限公司 | A method of preparing folic acid |
| CN105439895A (en) * | 2015-12-30 | 2016-03-30 | 浙江汇能生物股份有限公司 | Preparation method of N (4-aminobenzoyl)-L-glutamic acid |
| CN105439895B (en) * | 2015-12-30 | 2018-02-27 | 浙江汇能生物股份有限公司 | A kind of preparation method of N- p-benzoyls-Pidolidone |
| CN105541729A (en) * | 2015-12-31 | 2016-05-04 | 南昌大学 | Method for separating and purifying salt in 2,4,5-triamino-6-hydroxy pyrimidine sulfate production process |
| CN105541729B (en) * | 2015-12-31 | 2019-04-16 | 南昌大学 | The process for separation and purification of salt in 2,4,5- triamido -6- hydroxy pyrimidine sulfate production process |
| CN106496231A (en) * | 2016-09-30 | 2017-03-15 | 河北科技大学 | A kind of environment-friendly type preparation method of synthesis Folic Acid |
| CN106496231B (en) * | 2016-09-30 | 2017-12-08 | 河北科技大学 | A kind of environment-friendly type preparation method for synthesizing folic acid |
| CN107365311A (en) * | 2017-08-16 | 2017-11-21 | 浙江圣达生物药业股份有限公司 | A kind of preparation method and applications of trans folic acid |
| CN108774231A (en) * | 2018-07-06 | 2018-11-09 | 南通市常海食品添加剂有限公司 | A kind of environment-protection production method of folic acid |
| CN114524771A (en) * | 2020-11-23 | 2022-05-24 | 江苏八巨药业有限公司 | Preparation method of 6-hydroxy-2,4,5-triaminopyrimidine sulfate |
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| CN113816961A (en) * | 2021-08-17 | 2021-12-21 | 北京斯利安药业有限公司 | Folic acid synthesis method |
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