CN1080633A - The improvement synthetic method of glycine - Google Patents

Abstract

A kind of acetic acid chlorine the 4th ammonium by following formula (I) is provided:

Cl(R ₃N·CH ₂COOH) (I)

(in the formula, R ₃Represent C ₁-C ₄Alkyl) with the thanomin of following formula (II):

(in the formula, R ₁Represent H or CH ₂The OH yl) in the reaction medium of water, depresses reaction to adding, to make the improvement synthetic method of glycine at normal pressure as solvent.

Description

The improvement synthetic method of glycine

The present invention relates to the improvement synthetic method of glycine, relate in particular to, the acetic acid chlorine tetramine that order is generated by monochloroacetic acid (hereinafter to be referred as MCA) and triamine, react with water-soluble aqueous itself and the carbinolamine (amino methanol) that generates by ammonia and formaldehyde reaction of making, synthesize the modification method of the glycine of purpose by general reaction at short notice.

As everyone knows, glycine, claim an amido acetic acid again, be to be employed widely as foodstuff additive improving taste and to increase between preservation period, and be used as agriculture synthesis material, medical synthesis material, decomposition that he plants the synthesis material of Amino acid and xitix (vitamin C) and prevent agent and be employed.

Up to now, the synthetic method of glycine makes its hydrolysis the Strecker method of glycine then nearly all by the aminolysis of methyl alcohol nitrile and synthetic amido first vinegar nitrile.With the method for MCA as starting raw material, be only limited to laboratory method, be not feasible economically.Its reason (can be with reference to Org.synthesis, Vol.I, P300) as follows:

(1) when reaction, except glycine, secondary imines two acetic acid (iminodiacetic acid), nitrogen base three acetic acid of giving birth to, yield is lower;

(2) need a large amount of ammonia that use;

(3) long reaction time (needing a couple of days usually);

In order to improve above-mentioned shortcoming, existing multiple achievement in research is disclosed in the patent documentation.For example United States Patent (USP) the 3rd, 190, and No. 914 is to make MCA react with ammonia and formaldehyde (36.% solution) in the aqueous solution, makes glycine with the 80-90% yield.But the shortcoming of this method is, during reaction with same mole, very long and yield of reaction times only 70.% increases to more than 90.% in order to make yield, then must use the ammonia more than 3 moles.With this understanding, the hydrochloric acid that generates when MCA changes into glycine can combine with ammonia and generate ammonium chloride, causes the glycine separation difficulty.For this reason, need to implement to utilize both its condensing crystal operation beginning amounts of dissolubility difference to reach the separation purpose repeatedly, historical facts or anecdotes border yield can be quite low for several times.

In addition by Japanese Patent Publication 58-22055 number, for preventing to generate secondary biology, be used as catalyst and use volatile salt or ammonium chloride in a large number, but in reaction, still can generate imines two acetic acid unavoidably, and used ammonia vol is for generating more than 10 times of glycine, therefore reactor unit volume productivity is quite low, will become complexity by the operation of reclaiming the purpose product in the reaction solution, increases cost.

The precedent of not using ammonia and using the ring hexamethylenetetramine instead is also arranged in addition, but the coreaction rate is on the low side, promptly about 70-80%, the low ring hexamethylenetetramine of solubleness can harm separation when separated the reaction back simultaneously.

At present preferably separation method for answering spent ion exchange resin, but this method need be fully such as extraction, expansion, developping solution concentrate, fairly large operating equipment such as crystallization, and regeneration of ion-exchange resin and/or replacement charge also become and increase one of cost reason.

The present invention is for improving the shortcoming of above-mentioned currently known methods, and providing a kind of is starting raw material with MCA, and by a kind of method of reacting high yield and high purity manufacturing glycine.

Main idea of the present invention as mentioned above, in the aqueous solution, earlier MCA and triamine are generated acetic acid chlorine tetramine, the Cl ionization that makes MCA to be promoting activity, with season its with a carbinolamine reaction that generates by ammonia or ammoniacal liquor and formaldehyde solution reaction, with selection generation glycine.Then, C is added in this dry back of resultant distillation ₁-C ₄Alkyl alcohol, state is dissolved in the hot alkyl alcohol carbinolamine while hot, and precipitate and separate is dissolved in the glycine of hot alkyl alcohol hardly, promptly can light operation obtain the sweet amido of purity more than 98%.

The inventor will be at C ₁-C ₄The glycine method for making of implementing above-mentioned main idea reaction in the alkyl alcohol proposes patent application (No. 79106637) and has checked and approved and announced in the 395th page of the patent gazette of bulletin on February 1st, 1991 to Patent Office.It is a kind of with C that this case provides ₁-C ₄Alkyl alcohol still has the shortcoming of using and using the inflammableness solvent as formalin with the paraformaldehyde (paraformaldehyde) than high price as the method for solvent with series reaction manufacturing glycine yet the inventor found that this method more after deliberation.

The present invention provides a kind of to use inexpensive formaldehyde solution to substitute paraformaldehyde for eliminating above-mentioned shortcoming, makes the water consumption substitution alkyl alcohol simultaneously and obtains the glycine improved preparation of same reaction result.

By formalin and ammoniacal liquor reaction synthesizing methanol amine, the typical example that makes itself and MCA react with the currently known methods that makes glycine again is a United States Patent (USP) the 3rd, 190, No. 914.According to said method directly use, therefore under comparatively high temps, react, and yield is also not high for promoting reactive the need for MCA not being given in advance sensitization.So commercial value is not high and generation ammonium chloride is arranged, and causes the isolating difficulty of glycine.

According to the inventive method, headed by shilling MCA and triamine to generate acetic acid chlorine tetramine, make chlorine (Cl) sensitization, make itself and carbinolamine react, theoretical reaction yield is advanced in acquisition then.

And acetic acid chlorine the 4th ammonium and carbinolamine reaction can generate the methylol glycine in theory, and the methylol glycine can be decomposed into glycine and formaldehyde because of the catalysis of the 3rd its hydrochloric acid of amine hydrochlorate, obtains the glycine of estimating.

A kind of improvement synthetic method of glycine is the acetic acid chlorine tetramine with following formula I

(in the formula, R ₃Represent C ₁-C ₄Alkyl) with the thanomin of following formula II:

(in the formula, R ₁Represent H or CH ₂The OH yl) in the reaction medium of water, depresses reaction up to adding at normal pressure as solvent.Wherein acetic acid chlorine the 4th ammonium of formula I is to react generation by monochloroacetic acid and triamine in water or inert organic solvents.Wherein the thanomin of formula II is by ammonia gas or ammoniacal liquor and formalin suspension reaction generation.

The inventive method can be described in detail as follows:

(A) reaction mechanism

The inventive method mainly comprises following three reactions:

(1) MCA and triamine form the acetic acid oronain;

(2) ammonia (or ammoniacal liquor) and formaldehyde reaction synthesizing methanol amine;

(3) above-mentioned two kinds of resultants reaction generates glycine.

MCA and triamine are that MCA is dissolved in the water, and slowly add triamine and make its reaction, obtain water-soluble aqueous resultant.Because of this reaction is an exothermic reaction,, triamine can sharply rise to boiling point so once being added fashionable temperature.Preferable temperature of reaction is below 70 ℃.Especially the triamine addition is preferably and slightly surpasses theoretical amount, makes the MCA complete reaction.In addition, also can be after benzene,toluene,xylene etc. be modulated into the chlorination tetramine in the strong solvent in advance, use soluble in water.

Carbinolamine is by making an addition to ammoniacal liquor (for example 28% ammoniacal liquor) under being lower than 20 ℃ of temperature or will making in the gas shape ammonia importing formaldehyde solution (37% for example commercially available formaldehyde solution).Reaction end can be determined according to HPLC.Can obtain a carbinolamine resultant as ammonia being added into pH9.0 when above, can avoid generating simultaneously two or trimethanolamine.When temperature of reaction surpasses 30 ℃, cause side reactions such as unwanted dehydration reaction because of meeting, so should avoid.

Again, this carbinolamine aqueous solution once or is in batches added in the reactant solution of MCA and triamine, then react, can in 3 hours and even 10 several branches, transform into glycine 40-70 ℃ of following reaction because of heating.70 ℃ down can moment reactions, but reaction times when long, carbinolamine can play Deamination and become dimethanolamine or trimethanolamine, and then at high temperature dehydration becomes (CH ₂) m in the mNn(formula, n is an integer) and sneak in the glycine as impurity, so should under lower temperature, react as far as possible.Level of response can be followed the trail of by HPLC.When the crest (peak) of MCA reaches 0.5% stopped reaction when following.

This reaction can be carried out smoothly at normal pressure; And pressurize, reaction is also carried out equally, can not shorten the reaction times though yield is not promoted.

(B) solvent

Present method solvent for use is a water, because reaction is the moment reaction, can obtain highly purified resultant so can finish at short notice also.The solvent that uses is as long as allow the above-mentioned reaction amount of carrying out promptly enough.When the reaction of MCA and triamine, use solvent (being water) to get final product for the 0.5 times of amount that is not less than MCA.Formaldehyde can directly use 37% commercially available solution, ammoniacal liquor also can directly use 28% solution.Should improve in the diluted state reactivity, fail equally to promote but obtain the result, increase equipment is so there is no real benefit in vain.

(C) temperature of reaction and reaction times

The main stage of the inventive method is the reaction of acetic acid chlorine the 4th ammonium and carbinolamine, obtains the purpose product though can carry out under the arbitrary temp that uses below the solvent boiling point, and temperature of reaction is suitable for room temperature to 70 ℃ scope, carries out under preferable 40-60 ℃.Almost but moment is finished reaction in the time of 60-70 ℃, so this temperature range is comparatively desirable during successive reaction.Reaction times and temperature of reaction are inversely proportional, can shorten the reaction times when promptly temperature is high, but temperature are low, and for example during the following temperature of room temperature, sluggish need about 7-8 hour in the time of 30 ℃, and in the time of 40 ℃ about 3 hours, in the time of 50 ℃ about 1.5 hours.Thereby the reaction times can significantly shorten, this is the characteristic of the application's method.

(D) mol ratio

The use mol ratio of the necessary raw material of the synthetic institute of glycine is preferably 1.0-2.0mol for MCAl mol is used more than the carbinolamine 1.0mol usually, and the best is 1.5mol, and the use more than the 2.0mol is unnecessary.

When making carbinolamine, the consumption of ammonia is preferably excessive slightly, promptly preferably is added into more than the pH9.0.Can obtain the high purity crystalline substance by high yield in the case, and can avoid side reaction products such as unwanted imines two acetic acid and nitrotrimethylolmethane acetic acid.

(E) triamine

The triamine of Shi Yonging is to be selected from the triamine with alkyl in the method, but wherein taker for having C ₁-C ₄The alkyl person, for example Trimethylamine, triethylamine, tripropylamine, tributylamine preferably are to select a kind of in triethylamine, tripropylamine and the tributylamine for use.

Though also can select for use the triamine of pyridine and pyridines, ring hexamethylenetetramine etc. to use as triamine, after pyridine and pyridines and the MCA reaction, be higher than under 60 ℃ of temperature, the COOH base of MCA can decompose generation CO ₂And become N-methyl chloride pyridine in fact, and do not become the acetic acid chloropyridine.And encircle hexamethylenetetramine and can carry out the following formula reaction with MCA, and glycine is generated 3 times of mole ammonium chlorides, so need increase equipment, complicated operation does not conform to economy.

(F) glycine building-up reactions aftertreatment

After the reaction of acetic acid chlorine the 4th ammonium and carbinolamine reaction generation glycine ends, reaction solution is all evaporated the universe dry up, add C then ₁-C ₄Alkyl alcohol, stir down at 50-60 ℃, the secondary biology except that glycine all is dissolved in the alkyl alcohol.Because of glycine is insoluble in the hot alkyl alcohol, so will obtain after its filtration, with hot alkyl alcohol washing for several times, refilter, then can be close to theoretical yield and obtain the thick glycine of purity 98% above crystallinity powdery.Used C ₁-C ₄Alkyl alcohol can be selected for use such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the 3rd butanols etc.This elementary reaction is outside the claim, is therefore only narrated, and erectile problem is shown embodiment.

(G) successive reaction is suitable for

This reaction along with the increase in temperature speed of response is accelerated, almost can be finished reaction in time more than 60 ℃ applicable to room temperature and even with the boiling temperature scope of solvent usually within moment and even 1-2 minute.As the mol ratio PARA FORMALDEHYDE PRILLS(91,95) with ammonia is that superfluous state more than 0.5 uses, and then can suppress imines two acetic acid and generate.

The used reactor of successive reaction can be known tubular reactor, in order to promote the contact of reactant between mutually, is preferably in and wherein sets the distribution tool, impels charges and reactant to disperse.In several minutes, to finish reaction fast in order making again, to need to use high-temperature, preferably 70-80 ℃.As be intermittent type, long-time pyroreaction will be become in this temperature, and the impurity generation can be increased.But the occasion of continous way does not then have this problem.According to continous way, can reach almost 100% transformation efficiency to MCA.

Now specify method of the present invention in down according to embodiment, only the present invention be suitable for be not limited to for embodiment.

Embodiment 1

With monochloroacetic acid (MCA) 47.25g(0.5mol) be dissolved in the 50cc water, contain in there-necked flask (volume 500cc, reflux exchanger is housed, temperature is taken into account separating funnel), and this container placed on the magnetic stirring apparatus, with 52g(0.52mol) triethylamine drips through separating funnel, at room temperature stirs then can generate heat automatically and temperature is risen slowly.And remain on 60 ℃ on one side with water-bath, end to dripping Yi Bian drip triethylamine.Be warming up to 70 ℃ then, stir and finished the reaction that changes into acetic acid chlorine tetramine in 30 minutes; This is as A liquid.

In addition, with 28% ammoniacal liquor 60.7g(NH ₃17g 1mol) is positioned in another container same as described above, drips 37% formalin 61.6g(HCHO22.5g with separating funnel, 0.75mol), and temperature is remained in 20 ℃ or following stirring.Determine to have generated a carbinolamine (mono-amino methanol) according to HPLC; With this as B liquid.

B liquid is splashed in the A liquid in room temperature, and this moment, temperature rose one by one, and water-bath holds it in 40 ℃, waited to drip to close still to remain on 40 ℃ and continue to stir, then can be in about 3 hours end reaction.Determine the crest completely dissolve of MCA according to HPLC, this moment is at the crest of the dehydration methylene imines class that also occurs a carbinolamine, dimethanolamine and three methyl alcohol and this three on the HPLC chart except the crest that glycine occurs.But, there is no the crest that imines two acetic acid, nitrogen base acetic acid occur.

With the standard agent of glycine relatively quantitatively and calculation result, the inversion quantity of glycine is 36.6g; Transformation efficiency is 97.6%.

Embodiment 2-4

Except the temperature of reaction with A liquid, B liquid changes into 50 ℃, 60 ℃ and 70 ℃, all the other are all according to embodiment 1 described operation, and the glycine that the result obtains and the growing amount of imines two acetic acid are as shown in the table:

Reaction times in reaction times glycine glycine transformation efficiency imines two vinegar

Embodiment (℃) (branch) (g) (%) acid (g)

2????50????120????36.2????96.53????0.6

3????60????60????35.4????94.40????1.2

4????70????30????34.7????92.00????2.0

Embodiment 5 and 6

Except replacing triethylamine among the embodiment 1 with 0.52mol tripropyl amine and Tributylamine respectively, and temperature changes into outside 40 ℃ (embodiment 5) and 50 ℃ (embodiment 1), and all the other are all according to embodiment 1 operation.Shown in the reaction result following table:

Reaction times in reaction times glycine glycine transformation efficiency imines two vinegar

The embodiment triamine (℃) (branch) (g) (%) acid (g)

5 tripropyl amines 40 180 36.5 97.3-

6 Tributylamines 50 90 36.0 96.0 0.5

Embodiment 7 and 8

MCA, triethylamine and the water yield are identical with embodiment 1 in the A liquid;

Ammonia vol in the B liquid/formaldehyde liquid measure changes 0.75mol/0.6mol and 1.25mol/1.0mol respectively into, and A liquid and B liquid are remained on more than 50 ℃, and all the other know 1 operation according to embodiment.Reaction result is as shown in the table:

Embodiment 9 and 10

A liquid: MCA47.25g(0.5mol), triethylamine 52g(0.52mol), water 50cc 60 ℃ of reactions to make acetic acid chlorine the 4th ammonium solution.

B liquid: 28% ammoniacal liquor/formalin proportioning 0.75mol)/0.6mol(is the weight ratio of 45.58g/75.89g).

The reaction of A liquid and B liquid is respectively 70 ℃ and 80 ℃ of enforcements (according to embodiment 1); The result is as shown in the table:

Embodiment 11

According to the operation of embodiment 1, use the proportioning raw materials (A liquid/B liquid) of embodiment 1,40 ℃ of temperature feed N ₂Gas makes to press in the container and keeps 5kg/cm ², in 1.5 hours reaction times, obtain glycine amount 36.5g, transformation efficiency 97.3%.

Embodiment 12

With MCA47.25g(0.5mol), water 70g, tripropyl amine 52g(0.12mol) heating produces acetic acid chlorine the 4th ammonium (A liquid);

With formaldehyde 38% solution 39.47g(0.5mol) produce carbinolamine (B liquid) with 28% ammoniacal liquor 50g 20 ℃ of reactions.Ear is not put into three-necked flask than A liquid/B liquid of 0.5/0.77 remain on 50 ℃, 10 minutes after drip 28% ammoniacal liquor 20g by separating funnel with 10 fens clock times, kept 30 minutes down and finish reaction at 50 ℃ then.Keep pH9.0-10.0 in the reaction.Check and calculation result that according to HPLC glycine is 36.8g, transformation efficiency 98.13% and imines two acetic acid can't be determined according to HPLC.

Embodiment 13

At formaldehyde 22.5g(0.75mol), in the aqueous suspensions of water 36.7cc, drip 28% ammoniacal liquor 71.0g(NH down at 20 ℃ ₃19.88g, 1.17mol), the carbinolamine solution that reaction generates is as A liquid.

MCA47.25g is dissolved among the water 55cc, drips triethylamine 52g reaction solution as B liquid.

Synthetic equipment therefor of above A liquid and B liquid and method are described identical with embodiment 1.Press embodiment 1 and operate equally, A liquid and B liquid 50 ℃ of reactions, were finished reaction in about 2 hours.Glycine inversion quantity 36.5g as a result, transformation efficiency 97.3%, the generation of imines two acetic acid fails to determine.

Embodiment 14(successive reaction mode)

At internal diameter 22mm(external diameter 25mm) the inner 100 sieve mesh stainless steels of filling rolling-in of 2 meters of stainless steel bodys, the pipe outside is then with nickel-chromium line well heater coating of asbestos lagging and install a thermoswitch.The top of body sets the distribution tool that offers 40 sieve meshes footpath pore fifty-fifty.Other modulates following solution:

A liquid: with MCA472.5g(5mol) water-soluble 700cc is with itself and triethylamine 520g(5.2mol) reaction, obtain acetic acid oronain aqueous solution 1420cc;

B liquid: by 28% ammoniacal liquor 455.4g(NH ₃127.5g, 7mol) and 37% formalin 486.5g(180gHCHO, 6mol) reaction, obtain carbinolamine liquid, volume transfers to 942cc.

Reaction tubes is heated to 80 ℃ in advance, treat that temperature is stable after, with A liquid with the 71cc/ branch, B liquid with 47.1/ minute flow velocity by distributing tool to disperse in the ingress pipe, by the effusive required time of the net of 100 sieve meshes about 6 minutes.

Check effluent liquid according to HPLC, glycine content is 15.45%(w/v), total glycine amount is 365g, is 97.33% to the MCA transformation efficiency, fails to confirm the generation of imines two acetic acid.One carbinolamine almost completely is converted into dimethanolamine, also determines a spot of trimethanolamine.

Claims (5)

1, a kind of improvement synthetic method of glycine is characterized in that: described reaction is acetic acid chlorine the 4th ammonium with following formula I:

(in the formula, R ₃Represent C ₁-C ₄Alkyl) with the thanomin of following formula II:

(in the formula, R ₁Represent H or CH ₂The OH yl) in the reaction medium of water, depresses reaction up to adding at normal pressure as solvent.

2, the method for claim 1 is characterized in that wherein acetic acid chlorine the 4th ammonium of formula I is to react generation by monochloroacetic acid and triamine in water or inert organic solvents.

3, the method for claim 1 is characterized in that, wherein the thanomin of formula II is by ammonia gas or ammoniacal liquor and formalin suspension reaction generation.

4, the method for claim 1 is characterized in that wherein this reaction is to use following temperature of solvent boiling point and normal pressure to carry out up to adding to depress.

5, method as claimed in claim 2 is characterized in that wherein this triamine has C ₁-C ₄The amine of alkyl.