KR910002510B1 - Preparation method of n-phosphone methyl glycine - Google Patents

Abstract

A process for preparing N-phosphonomethyl glycine (I) comprises (a) reacting glycine with para-formaldehyde in C1-4 alkanol soln. in the presence of tertiary base to obtain methylolglycine (hydroxymethylglycine), (b) reacting the methylolglycine with a mixture of trialkyl (or aryl) phosphite (II) and dialkyl (or aryl) hydrogen phosphite obtd. by mixing (II) with H2O at 20- -10deg.C., and (c) treating the resulting material with a strong inorganic acid or alkali. The cpd. (I) is useful as an intermediate for the manufacture of herbicides.

Description

Method for preparing N-phosphonomethylglycine

Figure 1 shows the results of the NMR measurement of the present invention, (a)-(f) is a chart showing the results of ¹ H NMR measurement. (g)-(l) is a chart showing the results of C ¹³ NMR measurement.

2 is a table (a)-(g) showing the results of measuring the present invention by IR.

The present invention relates to a novel process for producing a kind of N-phosphonomethylglycine.

N-phosphonomethylglycine has been widely used as an intermediate for producing effective herbicides, and various synthetic methods have been studied in the past, but most of them were iminodiacetic acid as a starting material.

The method of the present invention uses glycine, which is cheaper than iminodiacetic acid and has a lower molecular weight as a starting material. The basic reaction of glycine as starting material is first reacting glycine with paraformaldehyde in an alkanol solution in the presence of a tertiary base. The NH ₂ group of glycine is mono or dimethylrolled and then reacted with dialkylhydrogenphosphite (hereinafter abbreviated as DALHP) to form N, N-dialkylphosphonomethylglycinate to produce an acid or N-phosphonomethylglycine as a target is obtained by dealkylation reaction or demethylol reaction with alkali (Japanese Patent Laid-Open No. 56-68688, U.S. Patent No. 4,237,065, 1980.12.2).

The reaction is as follows.

(Wherein R is C ₁ to C ₄ alkyl)

3HCL is used for the dealkylation reaction of 2HCL, and the remaining 1 molecule of HCL is used as a catalyst for the demethylol reaction. In the past, these methods, which eventually resulted in HCL salts of N-phosphonomethylglycine, used relatively expensive DALHP as organophosphorus. The basic theory of this reaction is esterification by condensation of the acid of DALHP with the alcohol of methylolglycine.

The process of the present invention is to esterify by reaction with methylolglycine using inexpensive trialkylphosphite without using DALHP.

In the present invention, studies and experiments on the above possibilities were carried out to obtain N-phosphonomethylglycine, which is a target of high yield and high purity, by the method of the present invention, thereby completing the novel method of the present invention. It has also been found that this novel method can be used not only for trialkyl phosphites but also triaryl phosphites. In this case, the trialkyl phosphite is C ₁ to C ₄ trialkyl phosphite, the triaryl phosphite is a phenyl or phenyl derivative compound, for example, methoxyphenyl, ethoxyphenyl, propoxyphenyl, appendecphenyl, chlorophenyl, methylphenyl , Ethylphenyl, propylphenyl and the like, and produce the same effect. A known method of obtaining N-phosphonomethylglycine using trialkyl (or aryl) phosphite, a method of reacting chloromethylglycine with trialkyl (or aryl) phosphite, is trialkyl by CL of chloromethylglycine. It is by dealkylation reaction of (or aryl) phosphite, and is fundamentally different from the esterification reaction of this invention in basic technical philosophy. In addition, the dealkylation reaction by CL, which is the conventional method, has a drawback that the yield is only 30 to 40% and there is no economic value.

In addition, chloromethylglycine has the trouble of chlorinating the OH group of the methylol compound of glycine with SOCL ₂ or the like. Since the reaction stage is increased, an expensive hydrochloric acid facility is required, thus increasing the production cost. There is a drawback.

The gist of the present invention is trialkyl (or aryl) phosphite by monoalkylation (or monodearylation) by simple operation such as stirring the trialkyl (or aryl) phosphite as it is or mixing H ₂ O and a part thereof and A simple method of making a mixture of dialkyl (or aryl) hydrogen phosphites and reacting it with methylrolllycin was completed the esterification reaction of methylrolllycine with organophosphorus at a high reaction rate to obtain the desired product.

The most characteristic theoretical basis of the process according to the invention breaks the theory that conventional trialkyl (or aryl) phosphites and methylolglycine are unreacted so that the simplest method, simple apparatus and high reaction rates of both materials in a short time under suitable conditions It is demonstrated that the target product is obtained with purity of 96% or more without recrystallization.

First, the structural formula of the methylol glycine described above for the first time is as follows.

HO, H ₂ C, NH, CH ₂ COOH

The compound was obtained by reacting glycine with HCHO, but when tested by Karlfisher, water was detected, and the amount was equivalent to the molecular equivalent of methylglycine. In this analysis, the water was judged to be H ₂ O generated by intramolecular dehydration of methylolglycine.

That is, the following dehydration reaction occurred in the molecule.

HO, CH _2, NH, CH ₂ COOH → H ₂ C: NH, CH ₂ COOH + H ₂ O

Thus the H ₂ O will act as free H ₂ O. Next, after the decomposition of trialkyl (or aryl) by H ₂ O, when the alkyl group is C ₁ to C ₄ , for example, when 50 ° C. or less is present in excess of H ₂ O, a short time (about 4 In time), only monodialkyl was produced (the same is the case with an aryl group), and in the case of 50 degreeC or more, the dealkylation rate with respect to a 2nd alkyl group increased with the temperature rise.

[Examples 1 to 4]

In other words, in the reaction scheme,

1) For temperature below 50 ℃:

2) Temperature over 50 ℃:

The reaction was confirmed by GLC.

Therefore, when trialkyl (or aryl) phosphite is added to methylol glycine at 50 ° C. or lower, first of the trialkyl (or aryl) phosphite is formed by H ₂ O generated by intramolecular dehydration of methylol glycine. One alkyl (or aryl) group leaves to produce dialkylhydrogenphosphite (or diarylhydrogenphosphite) and ROH.

Next, the dialkylhydrogen phosphite and glycine methine produced by intramolecular dehydration of methylglycine react to produce dialkylphosphonomethylglycine.

The same applies to the triaryl phosphite.

That is, the following reaction is considered.

1) and HO C H ₂ and NH and _{CH 2 COOH → H 2 C:} NH and CH ₂ COOH + H ₂ O

The H ₂ O produced here reacts with the trialkyl (or aryl) phosphite (Scheme below) to produce a dialkyl (or aryl) hydrogen phosphite.

The dialkyl (or aryl) hydrogen phosphite is reacted with the glycine methine compound (Scheme) to be the target.

When trialkyl (or aryl) phosphite is added at a theoretical equivalent weight to dimethylol glycine having two methylol groups bound to glycine, N-methyloldialkyl (or aryl) phosphono is reacted only with the first methylol of glycine under appropriate conditions. When methylglycinate is produced and a strong acid is added thereto, dealkylation (or dearylation) reaction and methylol reaction take place, and the desired product N-phosphonomethylglycine is obtained. Instead of using the trialkyl (or aryl) phosphite itself, the trialkyl phosphite is first reacted with H ₂ O first to form a dialkyl (or aryl) harddrogen phosphite, and then the mixture is added to methylolglycine The same desired product is obtained in high yield.

If the reaction is represented by the following scheme,

H ₂ O generated in the above reaction reacts with (RO) ₃ P to repeat the reaction shown in formula (1), followed by the reaction shown in formula (2). That is, when a part of trialkyl (or aryl) phosphite is first reacted with H ₂ O and then used, the reaction of the reaction formula (1) and the reaction formula (2) above is repeated to obtain trialkyl (or aryl) phosphite. All of them become spontaneously dialkyl (or aryl) (hydrogen phosphites in the reaction system and react with methylolglycine to produce intermediates of the desired product, with trialkyl (or aryl) phosphites and H ₂ O The reaction is carried out under any temperature.

In other words, in the case of monotalalkylation (or monotalarylation) reaction, the reaction proceeds at a constant rate of O to 50 ° C, and the reaction occurs even at 0 ° C or less.

The monodealkylation reaction (or dearylation) of the trialkyl (or aryl) phosphite is satisfactorily at least partly but not all, and the test results show that it is 1/4 equivalent to the trialkyl (or aryl) phosphite, or The object is also achieved by the following H ₂ O addition.

The monotalalkyl (or aryl) reaction of trialkyl (or aryl) phosphite is optionally carried out by the action of H ₂ O at temperatures of up to 50 ° C., and the reaction with methylol glycine (mono, dimethylol glycine) It may also optionally react with the first methylol group at a temperature below 50 ° C. to give the desired product in high yield. If the temperature is above 50 ° C., in particular reflux at the boiling point of the alkanol (eg, 64 to 65 ° C. for CH ₃ OH, 81 to 82 ° C. for C ₂ H ₅ OH), the yield is higher than the reaction below 50 ° C. Lowers. Even at 50 degreeC or more, for example, 55 degreeC-60 degreeC etc., a yield will become low with an increase of temperature. This is because the monoalkyl (or aryl) dihydrogen phosphite produced by decomposition of the dialkyl (or aryl) hydrogen phosphite at high temperature reacts with methylolglycine to produce various substances (Comparative Example 12 ). Although the trialkyl phosphites used as starting materials are mainly alkyl of C ₁ to C _4, for triaryl phosphite example, it can be used also aryl group is phenyl, tolyl, ethylphenyl, butylphenyl, methoxyphenyl, ethoxyphenyl.

Alkanols (C ₁ to C ₄ ) are suitable as the solvent for performing the reaction. In other words, alkanol is a polar solvent having high solubility in the reaction product, and can be easily distilled and recovered after completion of the reaction and reused.

Although tertiary bases such as triethylamine are selected as catalysts for promoting the reaction and improving the yield, various amines such as triethylamine, tripropylamine, tributylamine and the like can be used, and these are organic The binding of phosphorus and methylolglycine is facilitated. In addition, the reaction proceeds without the presence of a catalyst, but the yield of the reaction is lowered.

The amount of tertiary base used is theoretical equivalent.

When alkanol is used as the solvent, the dilution drainage is 1 to 5 times as appropriate for the total amount of the raw materials used, and when it is 1 times or less, the reaction worsens, and when it is 5 times or more, there is no effect of improving the yield and the reaction equipment is increased. The recovery time is long and economical. It is preferable to use only the theoretical equivalent amount of trialkyl (or aryl) phosphite relative to methylol glycine, and the use of the raw material is excessive in N, N-bis methylol glycine in which a methylol group is bound to two molecules. The phosphite of reacts with the second methylol group to produce bis- (phosphonomethyl) glycinetetraalkyl (or aryl) ester, which has the disadvantage of lowering the yield and purity of the target product. As described above, the reaction between the trialkyl (or aryl) phosphite and H ₂ O is preferably 50 ° C. or lower, and the reaction with methylol glycine (whether mono or dimethylol) is as described above. Above 50 ° C, various complex reactions occur in the dealkyl (or aryl) reaction of the phosphite by H ₂ O to the second alkyl (or aryl) group. Therefore, it is preferable not to react above 50 ° C.

The reaction time is preferably as short as possible, and should not be longer than 4 hours even if it is long.

This is to avoid excessive reaction with H ₂ O by prolonged heating of the trialkyl (or aryl) phosphite. Within 4 hours, 50 degrees C or less is suitable. The dialkyl (or aryl) phosphonomethyl glycinate or N-hydroxymethyldialkyl (or aryl) phosphonomethyl glycinate produced by the reaction as described above is desorbed at 100 to 120 ° C. with a strong inorganic acid. The alkylation and dehydroxymethylation reactions sometimes cause the desired N-phosphomethylglycine to precipitate as white crystals within a pH of 0.6 to 3.0, which is dried to produce 96.0 to 98.07 in purity. Yield is around 80% (for glycine).

The characteristics of the theoretical basis for synthesizing N-phosphonomethylglycine using trialkyl (or aryl) phosphite instead of dialkyl (or aryl) hydrogen phosphite have been described, and examples are provided to demonstrate this. However, this embodiment is representative and the scope of the present invention is not limited to the embodiment only.

Example 1

63 g (0.5 mol) of trimethyl phosphite are placed in a three-necked flask (equipped with a reflux-capacitor, thermometer) and placed in an ice bath to place the whole on a magnetic stirrer. 4.5 g (0.25 mol) of water was added thereto, stirred at 0 ° C. for 10 minutes, and tested by GLC. CH ₃ OH trimethyl phosphite (hereinafter abbreviated as TMP) and dimethylhydrogen phosphite (hereinafter referred to as DMP) Abbreviation) is as follows.

RT 0.413 CH ₃ 0H 15.7065%

R.T 1.580 TMP 49.3989%

R.T 2.335 DMP 34.8949%

After stirring for 4 hours again, there was no change.

Example 2

DMP 63g (0.5 mol), H ₂ O 4.5g (0.25 mol) was stirred for 10 hours at 10, 20, 30, 40 and 50 ° C for another 4 hours, and the test was performed by GLC. The same result was obtained.

Example 3

DMP 63 g (0.5 mol), H ₂ O 13.5 g (0.75 mol, 0.25 mol excess) was stirred for 4 hours at 50 ℃ in the same apparatus as Example 1 (except ice bath), and tested by GLC, the methyl radical of TMP 2 No peak of the released monomethyldihydrogenphosphite was found.

Example 4

Triethyl phosphite, tripropyl phosphite, and tributyl phosphite were tested in the same manner as in Example 3, and no peak of monoalkyldihydrogen phosphite was found.

Example 5

32 g of paraformaldehyde, 200 CC of methanol, and 50 g of triethylamine are dissolved at room temperature to dissolve, and then 38 g of glycine is added to react at 30 to 40 ° C. 63 g of trimethyl phosphite (consisting of a mixture of CH ₃ OH, TMP, DMHP) treated with the reaction method of Example 1 was added thereto, the temperature was raised to 50 ° C., heated at this temperature for 2 hours, and then concentrated. After hydrochloric acid was added and subjected to demethyl group and demethylol group reaction at 100 to 120 ° C., the desired N-phosphonomethylglycine was obtained as white crystals at pH 0.6 to 3.0. Yield: 68.6, UV analysis: purity 96.5%, HPLC analysis: purity 96.3%, melting point: 228.5 ° C to 229 ° C, yield: 78.3% (UV analysis based on glycine)

Example 6

UV analysis was carried out in the same manner as in Example 1, except that 500CC of methanol was used. Purity: 97.5%. HPLC: Analytical Purity 97.2%, Melting Point: 229 ° C, Yield: 70.1 g, Yield: 80.8% (for glycine)

Example 7

The test was carried out in the same manner as in Example 1 except that 83 g of triethyl phosphite and ethanol 500CC were used.

UV Analysis Value: Purity 97.0%

HPLC: Analytical Values: Purity 96.8%

Melting Point: 228.8 to 229 ° C

Yield: 69.0 g, yield: 79.2% (for glycine)

Example 8

After dissolving 33 g of paraformaldehyde, 500 cc of propyl alcohol, and 50 g of triethylamine at room temperature, 38 g of glycine was added thereto, followed by stirring at 30 to 40 ° C. for reaction. It raises to ° C and reacts for 3 hours. Thereafter, concentrated hydrochloric acid was added for treatment, heated to 100 to 120 ° C., and then cooled to obtain white crystals of N-phosphonomethylglycine having a pH in the range of 0.6 to 3.0.

UV analysis value: purity 96.3%

HPLC analysis value: purity 96.2%

Melting Point: 228.5 ~ 229 ℃

Yield: 69.9 g

Yield: 79.6% (for glycine)

Example 9

25.5 g of paraformaldehyde, 500 CC of butanol and 50 g of triethylamine were dissolved at room temperature, and then dissolved, and 38 g of glycine was added to react at 30 to 40 ° C. After the reaction was carried out for 3 hours and the solution was added with 30% NaOH solution, it was maintained at 60 to 80 ° C for 1 hour to distill the butanol to precipitate crystals of light yellow N-phosphonomethylglycine in the pH range of 1.0 to 3.0. It was made.

UV analysis value: Purity 93.0%

HPLC analysis value: purity 92.7%

Melting Point: 224 ~ 225 ℃

Yield: 55.2 g

Yield: 60.7%

Example 10

After dissolving 32 g of paraformaldehyde, 500 ethanol and 50 g of triethylamine at room temperature, 38 g of glycine was added and stirred at 30 to 40 ° C. for reaction, and 155 g of triphenylphosphite was added at 40 ° C. or lower, followed by 50 ° C. Reaction at 3 hours. After treatment with concentrated hydrochloric acid, ethanol was distilled off and the temperature was raised to 100-120 ° C. to dealkylation by adding hydrochloric acid, followed by cooling to obtain N-phosphonomethylglycine, a white crystalline phase ranging from pH 1.0 to 3.0, as a precipitate. It was.

UV Analysis Value: Purity 97.2%

HPLC analysis value: purity 97.0%

Melting Point: 228.5 ~ 229 ℃

Yield: 71.5 g

Yield: 82.2% (for glycine)

Example 11

33 g of paraformaldehyde, 500 g of CH ₃ OH, and 50 g of triethylamine were stirred at room temperature to dissolve, and then 38 g of glycine was added to react at 30 to 40 ° C. After the entire solution became transparent, trimethyl phosphite was added and reacted at 0 ° C. for 4 hours to 5 hours. After confirming that the peak of trimethyl phosphite disappeared by GLC, the mixture was treated with HCL at a temperature of 40 ° C. or lower, and then removed. Methylolation reaction and methanol is distilled off.

HCl is added again at 100 to 120 ° C. to dealkylate, and then cooled to obtain a white crystal precipitate in the range of pH 0.6 to 3.0.

UV Analysis Value: Purity 97.7%

HPLC analysis value: purity 97.5%

Melting Point: 229-229.2 ℃

Example 12

33g of paraformaldehyde, 500CC of methanol and 50g of triethylamine were placed in a three-necked flask (1000CC), and equipped with a reflux-condenser and a thermometer. After reacting at 占 폚 to make the whole transparent, 63 g of trimethyl phosphite was treated with 4.5 g of H ₂ O according to the method of Example 2 in advance, and reacted at a temperature of 65 to 67 占 폚 (reflux) for 2 hours, followed by cooling. After the reaction with demethylol with concentrated hydrochloric acid, methanol is distilled off. After treatment with hydrochloric acid at 100-120 ° C. for dealkylation and cooling, white crystal precipitate N-phosphonomethylglycine in the pH range of 0.6-3.0 is obtained. Obtained.

UV analysis value: purity 96.2%

HPLC analysis value: purity 96.1%

Melting Point: 228-228.5 ℃

Yield: 62.0 g

Yield: 70.5% (for glycine)

In the description of the present invention, the reactants of Examples 5,8,10,11 and 99.9% standard glyphosate acid (N-phosphonomethylglycine) were measured by elemental analysis, NMR and IR, and the following values were obtained. .

(Ⅰ) Elemental Analysis Results

Target Reactant: N-phosphonomethylglycine (glyphosate)

Molecular Formula: C ₃ H ₈ NO ₅ P

Molecular Weight: 169.8

Analysis

TABLE 1

The 99.9% standard is the purity calculated by comparing the mixture of Examples 5,8,10,11 with the standard glyphosate acid by recrystallization UV, HPLC, and melting point measurement. The samples of Examples _{5, 8} , 10, and 11 were all close to the theoretical values by the above analysis results, and were found to be molecular formula C ₃ H ₈ NO ₅ P.

Analysis

TABLE 2

Sample: white powder, 5 points

(Note) The sample was then dried under reduced pressure to provide the analysis under 50~60 ℃, P ₂ O ₅ coexist. As an example, when the chemical formula of No. 1 is calculated, that is, C _2.99 H _8.08 N _1.00 P _1.04 O _{5.04 ≒} C ₃ H ₈ NO ₅ P, it is assumed that the compound is expected.

(II) NMR measurement result (refer to FIG. 1 (a)-(l)

NMR ( ¹ HNMR, C ¹³ NMR) was measured on the reaction product of 99.9% standard and Examples 5,8,10,11 to obtain the following results.

a) ¹ HNMR (see Figures 1 (a)-(f))

NMR measurement with 1% D ₂ O solution gave the following results.

1,000 times of accumulation times

b) C ¹³ NMR (see Figure 1 (g)-(l))

0.9 g of isopropyl amine and 0.8 g of D ₂ O were added to 0.3 g of the sample (glyphosate), followed by stirring and dissolving, and measured by C ¹³ NMR δ (ppm)

¹ H NMR and C ¹³ NMR measurement results The same results were obtained for all 99.9% standard products and Examples 5, ⁸ , ¹⁰ , and ¹¹ .

3) IR measurement result (refer to Figure 2 (a)-(g))

Claims (5)

The mixture of the trialkyl (or aryl) phosphite as it is or in part thereof with dealkyl (or dearyl) in water is lower than the boiling point of the alkanol used in the presence of tertiary amine in C ₁ to C ₄ alkanol. A method for producing N-phosphonomethylglycine, which is reacted with methylolglycine (hydroxymethylglycine) produced by the reaction of glycine with paraformaldehyde at a temperature of and then treated with concentrated inorganic acid or alkali. The method of claim 1, wherein after trialkyl (or aryl) phosphite is added to methylolglycine, water is added at an amount of not more than 1/4 equivalent to trialkyl (or aryl) phosphite at 50 ° C or lower. Method for producing N-phosphonomethylglycine, characterized in that. The compound of claim 1, wherein the alkyl of the trialkyl phosphite is a C ₁ to C ₄ alkyl group, and the aryl of the triaryl phosphite is methylphenyl, ethylphenyl, propylphenyl, butylphenyl, methoxyphenyl, ethoxyphenyl, propoxy Phenyl, butoxy-phenyl or chlorophenyl. A process for producing N-phosphonomethylglycine. The method of claim 1, wherein trialkyl (or aryl) phosphite is added to methylolglycine (hydroxymethylglycine) produced by the reaction of glycine and paraformaldehyde at 20 to 10 DEG C, and immediately treated with an inorganic acid or an alkali. Method for producing N-phosphonomethylglycine, characterized in that. The method for preparing N-phosphonomethylglycine according to claim 1, which is performed at a temperature of 50 ° C or less.

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