CN105294507A - Method for synthesizing 4-guanidino-butyric acid - Google Patents

Abstract

The invention discloses a method for synthesizing 4-guanidino-butyric acid and belongs to the field of preparation of substituted guanidine acyclic compounds. The method specifically comprises the following steps: (i) synthesizing sodium 4-aminobutyrate; and (ii) synthesizing 4-guanidino-butyric acid and (iii) refining 4-guanidino-butyric acid. According to the method, the raw materials are readily available, the reaction conditions are simple, and no byproduct difficult to treat is produced, so that the method is applicable to large-scale industrial application.

Description

The synthetic method of 4-guanidine radicals butyric acid

Technical field

The invention belongs to the acyclic compound field of the guanidine that preparation replaces, be specifically related to a kind of synthetic method of 4-guanidine radicals butyric acid.

Background technology

4-guanidine radicals butyric acid, English name 4-guanidino-butyricacid, molecular formula: C ₅h ₁₁n ₃o ₂, relative molecular mass: 145.16, CAS:463-00-3, fusing point: 280 ~ 282 DEG C.4-guanidine radicals butyric acid exists in the brain of rodent and people.One of functional moiety wherein 4-Aminobutanoicacid is natural to be present in multiple animal and plant body, and be one of the composition of Chinese medicine Motherwort Herb etc., 4-Aminobutanoicacid is a kind of important inhibitory neurotransmitter, and it participates in multiple Metabolic activity, has very high physiologically active.

Guanidine radicals compounds, has important physiological function in human body, and current guanidine radicals compounds can be used for mankind's health protection and foodstuff additive, and what be widely used has creatine and derivative, guanidoacetic acid, guanidinopropionic acid etc.The application of the guanidine radicals compounds of these 2 ~ 3 carbon atoms is more and more extensive, and the consumption as creatine reaches thousands of tons of every year.The guanidine compound developing 4 and above carbon atom has certain realistic meaning.Exploitation 4-guanidine radicals butyric acid can utilize 4-Aminobutanoicacid to do raw material, the synthesis industrialization of domestic 4-Aminobutanoicacid, the low decades of times of price of cost ratio plant milk extract product, so exploitation 4-guanidine radicals butyric acid has favourable condition.

The operational path synthesizing 4-guanidine radicals butyric acid in prior art mainly contains following several:

1.S-ethyl thiourea hydrobromide method:

React to obtain S-ethyl thiourea hydrobromate with thiocarbamide, monobromethane, then react with 4-Aminobutanoicacid hot solution, through crystallisation by cooling, refine to obtain the crystallization of guanidine radicals butyric acid.

2.S-methyl-isourea method:

4-Aminobutanoicacid first makes 4-Aminobutanoicacid salt with sodium hydroxide, then with S-methyl-isourea Reactive Synthesis 4-guanidine radicals butyric acid in the basic conditions.

3. guanidine hydrochloride method:

First with Guanidinium hydrochloride and the obtained free guanidine of sodium hydrate solid reaction, then free guanidine and 4-chloro-butyric acid react obtained 4-guanidine radicals butyric acid.

4. cyanamide method:

Cyanamide is the comparatively effective guanidinated reagent of one.First can obtain aminobutyric acid sodium, then cyanamide and aminobutyric acid sodium obtain 4-guanidine radicals Sodium propanecarboxylate in the basic conditions, then obtain 4-guanidine radicals butyric acid with hcl acidifying.

Comprehensive above several technique, method one: S-ethyl thiourea hydrobromide method, at present because bromine price is up to more than 20,000 yuan per ton, monobromethane price is high and do not have an economy, and by-product sulfur alcohol needs process; Method two: S-methyl-isourea method, relative molecular weight is large, and Atom economy is bad, and by-product thiomethyl alcohol has taste, and process comparatively bothers; Method three: guanidine hydrochloride method, Atom economy is best, but 4-chloro-butyric acid industrialization product is difficult to obtain; Method four: cyanamide method, because it is easily condensed into Dyhard RU 100, so in the aqueous solution of commodity containing have an appointment 5% Dyhard RU 100, and commodity cyanamide not for shelf-stable, particularly at high temperature, more can produce more Dyhard RU 100 in storage, in simultaneous reactions process, also have multiple competition side reaction, as poly, generate uric acid etc.Therefore, in the product produced with any one operational path with cyanamide, the impurity such as impurity Dyhard RU 100 can be there is, because Dyhard RU 100 has obvious bitter taste, affect quality and the mouthfeel of product.

Summary of the invention

The present invention proposes to overcome the shortcoming existed in prior art, its objective is the synthetic method providing a kind of 4-guanidine radicals butyric acid.

Reaction principle of the present invention and chemical equation:

4-Aminobutanoicacid first makes 4-Aminobutanoicacid salt with sodium hydroxide, then with oxygen Methyl Isourea Sulfate Reactive Synthesis 4-guanidine radicals butyric acid in the basic conditions.

This reaction is N-alkylated reaction, compares easily and exothermic heat of reaction, so reaction should be carried out at lesser temps.Basic group guanidine radicals [-NH (C=NH) NH ₂] be the organic bases that known alkalescence is the strongest, pKa value is 12.48, completely protonated under physiological condition.And the alkyl carboxylic acid pKa below general 5 carbon is between 4 ~ 5, if butyric acid pKa is 4.8.Because the basic group of 4-guanidine radicals butyric acid is away from carboxyl, so inducing action greatly weakens.Therefore the isoelectric pH of 4-guanidine radicals butyric acid is greater than 7, reaction should be carried out at alkaline condition, is conducive to the precipitation of product.

Technical scheme of the present invention is:

A synthetic method for 4-guanidine radicals butyric acid, comprises the steps:

The synthesis of (I) 4-Aminobutanoicacid sodium:

A. in reaction vessel, add 4-Aminobutanoicacid and water, stirring and dissolving, be cooled to less than 10 DEG C;

B. drip sodium hydroxide solution under Keep agitation, control temperature of reaction below 50 DEG C;

C. dropwise, regulator solution pH is between 11 ~ 13; Namely 4-Aminobutanoicacid sodium solution is obtained;

The synthesis of (II) 4-guanidine radicals butyric acid:

D. oxygen Methyl Isourea Sulfate is added water to whole dissolving, obtain oxygen Methyl Isourea Sulfate solution;

E. in oxygen Methyl Isourea Sulfate solution, drip the 4-Aminobutanoicacid sodium solution that above-mentioned steps obtains, temperature of reaction controls at 30 DEG C ~ 35 DEG C;

F. dropwise, regulator solution pH, between 11 ~ 13, continues isothermal reaction 5 ~ 6 hours;

G. react end, cooling reaction solution to 4 DEG C ~ 5 DEG C, separates out crude product, filters;

H. the dissolving that Recycling Mother Solution is used for oxygen Methyl Isourea Sulfate is remained;

Refining of (III) 4-guanidine radicals butyric acid:

I. with deionized water by gained dissolving crude product, be heated to crude product and all dissolve, heating and temperature control is below 80 DEG C;

J. slow cooling crystallize out, is incubated 1 hour when being cooled to 0 DEG C ~ 2 DEG C;

K. gained crystal rinses surface with frozen water, and 50 DEG C ~ 60 DEG C oven dry, to obtain final product.

In described step a, the mol ratio of 4-Aminobutanoicacid and water is 1:3.

In described step b, the mass concentration of sodium hydroxide solution is 30%.

The sodium hydroxide solution dripped in described step b and the mol ratio of 4-Aminobutanoicacid are 1:1.

The oxygen Methyl Isourea Sulfate added in described steps d and the mol ratio of 4-Aminobutanoicacid are 1:1.4.

In described step I, the add-on of deionized water is 3 times of crude product quality.

The invention has the beneficial effects as follows:

Raw material of the present invention is easy to get, and reaction conditions is simple, is not difficult to the by product processed, is suitable for large-scale industrial application.

Embodiment

Be described in detail below in conjunction with the synthetic method of specific embodiment to 4-guanidine radicals butyric acid of the present invention:

A synthetic method for 4-guanidine radicals butyric acid, comprises the steps:

The synthesis of (I) 4-Aminobutanoicacid sodium:

A. in reaction vessel, add 4-Aminobutanoicacid and water, stirring and dissolving, be cooled to less than 10 DEG C;

B. drip sodium hydroxide solution under Keep agitation, control temperature of reaction below 50 DEG C;

C. dropwise, regulator solution pH is between 11 ~ 13; Namely 4-Aminobutanoicacid sodium solution is obtained;

The synthesis of (II) 4-guanidine radicals butyric acid:

D. oxygen Methyl Isourea Sulfate is added water to whole dissolving, obtain oxygen Methyl Isourea Sulfate solution;

E. in oxygen Methyl Isourea Sulfate solution, drip the 4-Aminobutanoicacid sodium solution that above-mentioned steps obtains, temperature of reaction controls at 30 DEG C ~ 35 DEG C;

F. dropwise, regulator solution pH, between 11 ~ 13, continues isothermal reaction 5 ~ 6 hours;

G. react end, cooling reaction solution to 4 DEG C ~ 5 DEG C, separates out crude product, filters;

H. the dissolving that Recycling Mother Solution is used for oxygen Methyl Isourea Sulfate is remained;

Refining of (III) 4-guanidine radicals butyric acid:

I. with deionized water by gained dissolving crude product, be heated to crude product and all dissolve, heating and temperature control is below 80 DEG C;

J. slow cooling crystallize out, is incubated 1 hour when being cooled to 0 DEG C ~ 2 DEG C;

K. gained crystal rinses surface with frozen water, and 50 DEG C ~ 60 DEG C oven dry, to obtain final product.

In described step a, the mol ratio of 4-Aminobutanoicacid and water is 1:3.

In described step b, the mass concentration of sodium hydroxide solution is 30%.

The sodium hydroxide solution dripped in described step b and the mol ratio of 4-Aminobutanoicacid are 1:1.

The oxygen Methyl Isourea Sulfate added in described steps d and the mol ratio of 4-Aminobutanoicacid are 1:1.4.

In described step I, the add-on of deionized water is 3 times of crude product quality.

Embodiment 1

A synthetic method for 4-guanidine radicals butyric acid, comprises the steps:

The synthesis of (I) 4-Aminobutanoicacid sodium:

A. in reaction vessel, 51.5g(0.5mol is added) 4-Aminobutanoicacid and 30g water, stirring and dissolving, is cooled to less than 10 DEG C;

B. dripping mass concentration under Keep agitation is 30% sodium hydroxide solution, controls temperature of reaction below 50 DEG C;

C. dropwise, regulator solution pH is 11; Namely 4-Aminobutanoicacid sodium solution is obtained;

The synthesis of (II) 4-guanidine radicals butyric acid:

D. 53.5g oxygen Methyl Isourea Sulfate is added water to whole dissolving, obtain oxygen Methyl Isourea Sulfate solution;

E. in oxygen Methyl Isourea Sulfate solution, drip the 4-Aminobutanoicacid sodium solution that above-mentioned steps obtains, temperature of reaction controls at 30 DEG C;

F. dropwise, regulator solution pH is 11, continues isothermal reaction 5 hours;

G. react end, cooling reaction solution to 4 DEG C, separates out crude product, filters;

H. the dissolving that Recycling Mother Solution is used for oxygen Methyl Isourea Sulfate is remained;

Refining of (III) 4-guanidine radicals butyric acid:

I. use the deionized water of crude product quality 3 times by gained dissolving crude product, be heated to crude product and all dissolve, heating and temperature control is below 80 DEG C;

J. slow cooling crystallize out, is incubated 1 hour when to be cooled to DEG C;

K. gained crystal rinses surface with frozen water, and 50 DEG C of oven dry, to obtain final product.

Claims (6)

1. a synthetic method for 4-guanidine radicals butyric acid, is characterized in that: comprise the steps:

The synthesis of (I) 4-Aminobutanoicacid sodium:

A. in reaction vessel, add 4-Aminobutanoicacid and water, stirring and dissolving, be cooled to less than 10 DEG C;

B. drip sodium hydroxide solution under Keep agitation, control temperature of reaction below 50 DEG C;

C. dropwise, regulator solution pH is between 11 ~ 13; Namely 4-Aminobutanoicacid sodium solution is obtained;

The synthesis of (II) 4-guanidine radicals butyric acid:

D. oxygen Methyl Isourea Sulfate is added water to whole dissolving, obtain oxygen Methyl Isourea Sulfate solution;

E. in oxygen Methyl Isourea Sulfate solution, drip the 4-Aminobutanoicacid sodium solution that above-mentioned steps obtains, temperature of reaction controls at 30 DEG C ~ 35 DEG C;

F. dropwise, regulator solution pH, between 11 ~ 13, continues isothermal reaction 5 ~ 6 hours;

G. react end, cooling reaction solution to 4 DEG C ~ 5 DEG C, separates out crude product, filters;

H. the dissolving that Recycling Mother Solution is used for oxygen Methyl Isourea Sulfate is remained;

Refining of (III) 4-guanidine radicals butyric acid:

I. with deionized water by gained dissolving crude product, be heated to crude product and all dissolve, heating and temperature control is below 80 DEG C;

J. slow cooling crystallize out, is incubated 1 hour when being cooled to 0 DEG C ~ 2 DEG C;

K. gained crystal rinses surface with frozen water, and 50 DEG C ~ 60 DEG C oven dry, to obtain final product.

2. the synthetic method of a kind of 4-guanidine radicals butyric acid according to claim 1, is characterized in that: in described step a, the mol ratio of 4-Aminobutanoicacid and water is 1:3.

3. the synthetic method of a kind of 4-guanidine radicals butyric acid according to claim 1, is characterized in that: in described step b, the mass concentration of sodium hydroxide solution is 30%.

4. the synthetic method of a kind of 4-guanidine radicals butyric acid according to claim 1, is characterized in that: the sodium hydroxide solution dripped in described step b and the mol ratio of 4-Aminobutanoicacid are 1:1.

5. the synthetic method of a kind of 4-guanidine radicals butyric acid according to claim 1, is characterized in that: the oxygen Methyl Isourea Sulfate added in described steps d and the mol ratio of 4-Aminobutanoicacid are 1:1.4.

6. the synthetic method of a kind of 4-guanidine radicals butyric acid according to claim 1, is characterized in that: in described step I, the add-on of deionized water is 3 times of crude product quality.