An optimized process for synthesizing glyphosate using the glycine-dimethyl phosphite method and an in-situ nuclear magnetic resonance monitoring method for phosphine spectra

Abstract

The present invention discloses a method for preparing glyphosate and a method for monitoring glyphosate by in-situ nuclear magnetic resonance. The method for preparing glyphosate of the present invention comprises the following steps: (1) in an organic solvent, polyformaldehyde, methanol, an organic amine and a dehydrating agent are subjected to a depolymerization reaction; (2) the mixed system after the depolymerization reaction in step (1) is mixed with glycine to carry out an addition reaction; (3) the mixed system after the addition reaction in step (2) is mixed with dimethyl phosphite to carry out a condensation reaction; (4) the mixed system after the condensation reaction in step (3) is mixed with an acid to carry out a hydrolysis reaction to obtain glyphosate. The method of the present invention can increase the yield of glyphosate to 90%, and the purity can reach more than 99%. In addition, the phosphine spectrum detection method of glyphosate in the present invention can monitor the process of glyphosate in real time, and has the advantages of simplicity, intuition, high efficiency, etc.

Description

Technical Field

[0001] The invention relates to an optimized process for synthesizing glyphosate by a glycine-dimethyl phosphite method and an in-situ nuclear magnetic resonance monitoring method for phosphine spectrum. Background Art

[0002] Glyphosate, chemical name is N-(phosphonomethyl)glycine, common name is Glyphosate, chemical formula is C 3 H 8 NO 5 P is an organophosphine herbicide, referred to as PMG (the structural formula is shown below).

[0003]

[0004] Glyphosate is an amino acid derivative. As a highly efficient, low-toxic, systemic and broad-spectrum herbicide, it was screened and synthesized by Monsanto Chemical Company in the United States in the 1960s (Pr℃. North Cent. Weed Control Conf. 1971, 26, 64-68.). By the 1980s, glyphosate had become an important herbicide in the world, and in the following decades, it had a profound impact on the world pesticide industry (PNAS, 2001, 98, 2944-2946.). In recent years, with the promotion of glyphosate-resistant transgenic crops, the glyphosate industry has developed rapidly (Pesticides. 2009, 547-551.). Glyphosate has good conductivity and can effectively eradicate annual and perennial weeds, and will not accumulate in the bodies of aquatic organisms and animals. After entering the soil, it will form a complex with divalent metal ions and become inactive, and will be degraded by microorganisms, will not pollute groundwater and soil, and will not harm the environment, humans, aquatic organisms and animals, and is highly safe (Chemical Progress. 2013, 32, 1635-1640). At present, in the international herbicide market, glyphosate is the most widely used and largest-volume herbicide (Shanghai Chemical Industry, 2014, 39, 26-31.).

[0005] There are many methods for synthesizing glyphosate. The main synthetic routes include chloromethylphosphonic acid method, iminodiacetic acid method (IDA), dialkyl phosphite method, trialkyl phosphite method, ethyl bromoacetate method, iminodiacetonitrile method, benzyl chloride method, chloroacetic acid method, nitrilotriacetic acid method, etc. There are two main industrial production processes, namely glycine-dimethyl phosphite method and iminodiacetic acid method. The glycine-dimethyl phosphite process is widely used in China, while the iminodiacetic acid process is more widely used abroad (Pesticides, 2003, 42, 16-18.). At present, only a few manufacturers in my country use the IDA method to produce glyphosate, while most domestic companies represented by Zhejiang Xin'an Chemical Group Co., Ltd. still use the alkyl ester method to produce glyphosate. According to public data (data from the Internet), the development characteristics of China's glyphosate industry are: 1) Glyphosate ranks first in China's exported pesticides, with an average export value of US$542 million in 2018. 2) China's effective glyphosate production capacity is stable at 720,000 tons / year. There are many glyphosate companies in China, and the glycine method has the largest production capacity. Xin'an Chemical accounts for 11% of the production capacity, and there is a strong demand for process optimization. 4) Xingfa Group, a leading glyphosate company, has continued to grow its operating income, reaching 3.364 billion yuan in 2018. Developing a glyphosate synthesis process with higher yield, stronger practicality and higher product purity has important economic value and wide application value.

[0006] The preparation methods of glyphosate reported in the prior art have technical problems of low total yield and low product purity, which need to be solved urgently. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the technical problems of low yield and purity in the existing glyphosate preparation method, and provide a glyphosate preparation method or a phosphine spectrum detection method thereof. The preparation method of the present invention can increase the glyphosate synthesis yield from about 80% to 90%, and the purity of the glyphosate prepared by the preparation method of the present invention can reach 99%. In addition, the phosphine spectrum detection method of glyphosate in the present invention can monitor the process of glyphosate in real time, and has the advantages of simplicity, intuitiveness, high efficiency, etc.

[0008] The present invention provides a method for preparing glyphosate, which comprises the following steps:

[0009] (1) in an organic solvent, subjecting paraformaldehyde, methanol, an organic amine and a dehydrating agent to a depolymerization reaction; wherein the dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate, dimethoxypropane and diethoxypropane;

[0010] (2) mixing the mixed system after the depolymerization reaction in step (1) with glycine to carry out an addition reaction;

[0011] (3) mixing the mixed system after the addition reaction in step (2) with dimethyl phosphite to carry out a condensation reaction;

[0012] (4) mixing the mixed system after the condensation reaction in step (3) with an acid and performing a hydrolysis reaction to obtain glyphosate;

[0013]

[0014] In step (1), the dehydrating agent is preferably trimethyl orthoformate.

[0015] In step (1), the organic amine is a conventional organic amine in the art, preferably one or more of triethylamine, tetrahydropyrrole, and diethylamine, and more preferably triethylamine.

[0016] In step (1), the organic solvent may be a conventional organic solvent in the art, preferably an alcohol solvent, such as methanol or ethanol. When the organic solvent is methanol, methanol is both a reaction solvent and a reaction raw material.

[0017] In step (1), the reaction temperature of the depolymerization reaction can be a conventional temperature in the art, preferably 40-42°C, such as 42°C.

[0018] In step (1), the reaction time of the depolymerization reaction can be a conventional time in the art, preferably 0.5-2 hours, such as 1 hour.

[0019] In step (1), the molar ratio of the paraformaldehyde to the methanol can be a conventional molar ratio in the art, preferably 1:(3-10), more preferably 1:(4-7), for example 1:5.

[0020] In step (1), the molar ratio of the paraformaldehyde to the organic amine can be a conventional molar ratio in the art, preferably 1:(0.3-1), more preferably 1:(0.4-0.6), for example 1:0.5.

[0021] In step (1), the molar ratio of the paraformaldehyde to the dehydrating agent can be a conventional molar ratio in the art, preferably 1:(0.3-1), more preferably 1:(0.4-0.6), for example 1:0.5.

[0022] In step (2), glycine is preferably added to the mixed system after the depolymerization reaction in step (1). The temperature of the addition is preferably below 37°C, preferably 30-37°C.

[0023] In step (2), the molar ratio of the paraformaldehyde to the glycine can be a conventional molar ratio in the art, preferably 1:(0.3-1), more preferably 1:(0.4-0.6), for example 1:0.5.

[0024] In step (2), the reaction temperature of the addition reaction can be a conventional temperature in the art, preferably 38-40°C, such as 40°C.

[0025] In step (2), the reaction time of the addition reaction can be a conventional time in the art, preferably 1.5-2 hours, for example 1.5 hours.

[0026] In step (3), dimethyl phosphite is preferably added to the mixed system after the addition reaction in step (2). The temperature of the addition is preferably lower than 40°C, preferably 35-40°C.

[0027] In step (3), the molar ratio of the dimethyl phosphite to the glycine can be a conventional molar ratio in the art, preferably (1-1.3):1, more preferably (1-1.2):1, for example 1.18:1.

[0028] In step (3), the reaction temperature of the condensation reaction can be a conventional temperature in the art, preferably 50-54°C, such as 52°C.

[0029] In step (3), the reaction time of the condensation reaction can be a conventional time in the art, preferably 2-2.5 hours, such as 2 hours.

[0030] In step (4), the reaction temperature of the hydrolysis reaction can be a conventional temperature in the art, preferably 90-125°C.

[0031] In step (4), the reaction time of the hydrolysis reaction can be a conventional time in the art, preferably 4-12 hours, such as 6.5 hours.

[0032] In step (4), the amount of acid used in the hydrolysis reaction can be the amount conventionally used in the art, wherein the molar ratio of hydrogen ions in the acid to glycine in the addition reaction can be the molar ratio conventionally used in the art, preferably (2-5):1, for example 3.6:1.

[0033] In step (4), the acid in the hydrolysis reaction may be sulfuric acid and / or hydrochloric acid, preferably hydrochloric acid.

[0034] In step (4), when the acid in the hydrolysis reaction is hydrochloric acid, the mass fraction of the hydrochloric acid can be 10-37%, or 20-37%, for example 30%.

[0035] In step (4), it is preferred to add acid to the hydrolysis reaction. The temperature of the addition may be a conventional temperature in the art, preferably 0-10°C, such as 5°C.

[0036] In step (4), the method of adding acid to the hydrolysis reaction is preferably to add the acid to the reaction system in two portions, wherein:

[0037] After the first addition of acid, step heating is performed, the steps of which may be:

[0038] a. Heating at 90-100° C. (e.g., 95° C.) for 1-2 hours (e.g., 1.5 hours);

[0039] b. Heating at 100-110° C. for 1-2 hours (e.g., 1.5 hours);

[0040] c. Heating at 110-120° C. for 1-2 hours (e.g., 1.5 hours) until a white solid appears in the reaction system;

[0041] After the second addition of acid, step heating is performed, the steps of which may be:

[0042] d. Heating at 110-120° C. for 0.5-2 hours (e.g., 1 hour);

[0043] e. Heating at 120-125° C. for 0.5-2 hours (e.g., 1 hour);

[0044] f. When the temperature in the system reaches 125°C, the reaction is completed.

[0045] In step (4), when the acid is added for the first time, the amount of acid added is preferably the amount conventional in the art, and the molar ratio of the hydrogen ions in the acid to the glycine in the addition reaction can be the molar ratio conventional in the art, preferably (2-3):1, for example 2.4:1.

[0046] In step (4), when the acid is added for the second time, the amount of acid added is preferably an amount conventional in the art, and the molar ratio of the hydrogen ions in the acid to the glycine in the addition reaction can be a molar ratio conventional in the art, preferably (1-2):1, for example 1.2:1.

[0047] In step (4), the hydrolysis reaction can be carried out while heating and removing the solvent.

[0048] In the present invention, the preparation method of glyphosate may further include post-treatment, and the post-treatment method may adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may include the following steps: after the hydrolysis reaction is completed, stirring and crystallizing, solid-liquid separation, and solid drying.

[0049] In the post-treatment, the stirring crystallization time can be a conventional time in the art, preferably 0.1-2 hours, for example 2 hours;

[0050] In the post-treatment, when stirring and crystallizing, ice water may be added to achieve sufficient crystallization, and the amount of ice water added may be a conventional amount in the art.

[0051] In the post-treatment, the solid-liquid separation method can be a conventional method in the art, preferably a suction filtration method.

[0052] In the post-treatment, the separated solid can be washed with water to remove impurities. The number of water washings can be conventional in the art, preferably 1-4 times, for example 2 times.

[0053] In the post-treatment, the temperature for drying the solid can be a conventional temperature in the art, preferably 70-90°C, such as 80°C.

[0054] The present invention provides a method for preparing a compound C, which comprises the following steps: in a solvent, paraformaldehyde, methanol and triethylamine undergo a depolymerization reaction under the action of a dehydrating agent to obtain the compound C;

[0055]

[0056] Wherein, the dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate, dimethoxypropane and diethoxypropane.

[0057] Wherein, the conditions of the depolymerization reaction are the same as those described in the present invention.

[0058] The present invention provides a method for preparing a compound E', which comprises the following steps: in an organic solvent, compound C, glycine, triethylamine and a dehydrating agent undergo addition reaction to obtain compound E';

[0059]

[0060] Wherein, the dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate, dimethoxypropane and diethoxypropane.

[0061] In the addition reaction, the organic solvent is a conventional organic solvent in the art, preferably an alcohol solvent, such as methanol.

[0062] In the addition reaction, when glycine is added to the reaction system, the temperature of the reaction system is lower than 37°C.

[0063] In the addition reaction, the molar ratio of the compound 1 to the glycine can be a conventional molar ratio in the art, preferably 1:(0.3-1), more preferably 1:(0.4-0.6), for example 1:0.5.

[0064] In the addition reaction, the reaction temperature of the addition reaction can be a conventional temperature in the art, preferably 38-40°C, such as 40°C.

[0065] In the addition reaction, the reaction time of the addition reaction can be a conventional time in the art, preferably 1.5-2 hours, such as 1.5 hours.

[0066] The present invention provides a method for preparing a compound G', which comprises the following steps: in an organic solvent, a compound E' and dimethyl phosphite are subjected to a condensation reaction under the action of a dehydrating agent to obtain the compound G';

[0067]

[0068] Wherein, the dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate, dimethoxypropane and diethoxypropane.

[0069] In the condensation reaction, the organic solvent is a conventional organic solvent in the art, preferably an alcohol solvent, such as methanol.

[0070] In the condensation reaction, when dimethyl phosphite is added to the reaction system, the temperature of the reaction system is lower than 40°C.

[0071] In the condensation reaction, the molar ratio of the dimethyl phosphite to the compound 2 can be a conventional molar ratio in the art, preferably (1-1.3):1, more preferably (1-1.2):1, for example 1.18:1.

[0072] In the condensation reaction, the reaction temperature of the condensation reaction can be a conventional temperature in the art, preferably 50-54°C, such as 52°C.

[0073] In the condensation reaction, the reaction time of the condensation reaction can be a conventional time in the art, preferably 2-2.5 hours, such as 2 hours.

[0074] The present invention also relates to a 31 The method of P-NMR in-situ nuclear magnetic monitoring of glyphosate includes any of the following methods:

[0075] Method 1 includes the following steps (using the acid hydrolysis termination solution of the hydrolysis reaction as the detection object):

[0076] (1) Record the feeding amounts of glycine and dimethyl phosphite in the above-mentioned method for preparing glyphosate, record the glycine equivalent as 1, and the dimethyl phosphite equivalent as a; wherein a is 1-1.3; set the total integral of all products to 100×a;

[0077] (2) The acid hydrolysis termination solution of the hydrolysis reaction of the preparation method of glyphosate as described above is sampled while hot and mixed with a base (such as an organic amine, for example, triethylamine) to obtain a solution b;

[0078] (3) Solution b, a base (such as an organic amine, e.g. triethylamine) and D 2 O mixed, and the phosphine spectrum was measured; the integral of the corresponding glyphosate was its yield;

[0079] Method 2 includes the following steps (taking glyphosate in the recrystallization mother liquor as the detection object):

[0080] (1) Recrystallize the glyphosate mother liquor with a base (such as triethylamine) and D 2 O after mixing, shake well, and measure its phosphine spectrum;

[0081] (2) Taking glyphosate powder as the control, the total integral of all phosphine-containing compounds in the phosphine spectrum is set to 100, and the phosphine spectrum integral value of glyphosate is the glyphosate content in the crystallization mother liquor; the total equivalent number of dimethyl phosphite minus the equivalent number of dimethyl phosphite consumed by glyphosate powder, the total equivalent number of phosphine-containing compounds × the percentage of glyphosate in the mother liquor, is the glyphosate content in the mother liquor;

[0082] (3) Glyphosate yield = glyphosate dry powder yield + glyphosate content in mother liquor × residual phosphine equivalent;

[0083] Method 3 includes the following steps (taking glyphosate recrystallization mother liquor as the detection object):

[0084] (1) Configuration The concentration of the external standard solution is h, where h is 0.05-1mmol / mL;

[0085] (2) The external standard solution, glyphosate recrystallization mother liquor and D 2 O mixed, and the phosphine spectrum thereof was measured, wherein the volume of the external standard solution was the same as that of the mother liquor of glyphosate recrystallization;

[0086] (3) The integral value of the phosphine spectrum is set to 10, and the integral value of the phosphine spectrum of glyphosate is obtained; the integral value × h × the total volume of the recrystallization mother liquor / 10 = the mass of glyphosate in the mother liquor;

[0087] (4) Glyphosate yield = (mass of glyphosate dry powder + mass of glyphosate in mother liquor) / theoretical mass of glyphosate × 100%, where the theoretical mass of glyphosate = (mass of glycine × 169) / 75.

[0088] In step (1) of method 1, the base is preferably triethylamine.

[0089] In step (1) of method 1, a is preferably 1.18.

[0090] In step (2) of method 1, the base is preferably triethylamine.

[0091] In step (2) of method 1, the amount of the hot sample is the conventional amount in the analytical method in the art, preferably 0.1-1 mL, such as 0.5 mL.

[0092] In step (2) of method 1, the amount of triethylamine added is 1-5 times the amount of the sample;

[0093] In step (3) of method 1, solution b: triethylamine: D 2 The volume ratio of O is 1:1:3.

[0094] In step (3) of method 1, a preferred embodiment is to take 0.1 mL of solution b, 0.1 mL of triethylamine and D 2 O take 0.3mL.

[0095] In step (1) of method 2, the base is preferably triethylamine.

[0096] In step (1) of method 2, the amount of the glyphosate recrystallization mother liquor can be the amount conventionally used in analytical methods in the art, preferably 0.05-1 mL, such as 0.1 mL.

[0097] In step (1) of method 2, the amount of the base (such as triethylamine) can be the conventional amount in the analytical method in the art, preferably 1-5 times, for example 1 times, the volume of the glyphosate recrystallization mother liquor.

[0098] In step (1) of method 2, glyphosate recrystallization mother liquor: triethylamine: D 2 The volume ratio of O is 1:1:3.

[0099] In step (3) of method 2, a preferred embodiment is to take 0.1 mL of glyphosate recrystallization mother liquor, 0.1 mL of triethylamine and D 2 O take 0.3mL.

[0100] In step (1) of method three, the h is preferably 0.05-0.5 mmol / L, such as 0.1 mmol / L.

[0101] In step (2) of method three, the amount of the glyphosate recrystallization mother liquor can be the conventional amount in the analytical method in the art, preferably 0.05-1 mL, such as 0.1 mL.

[0102] In step (2) of method three, the amount of the external standard solution can be the conventional amount in the analytical method in the art, and is preferably the same as the volume of the glyphosate recrystallization mother liquor.

[0103] In step (2) of method 3, glyphosate recrystallization mother liquor: external standard solution: D 2 The volume ratio of O is 1:1:3.

[0104] In step (2) of method 3, a preferred embodiment is to take 0.1 mL of glyphosate recrystallization mother liquor, 0.1 mL of external standard solution and D 2 O take 0.3mL.

[0105] The present invention also provides a 31 The method of P-NMR in-situ nuclear magnetic monitoring of glyphosate key intermediates comprises the following steps:

[0106] (1) Record the feeding amounts of glycine and dimethyl phosphite in the above-mentioned method for preparing glyphosate, record the glycine equivalent as 1, and the dimethyl phosphite equivalent as a; wherein a is 1-1.3; set the total integral of all products to 100×a;

[0107] (2) In the hydrolysis reaction of the preparation method of glyphosate as described above, sampling and mixing with D 2 O and measure its phosphine spectrum, then the phosphine spectrum integral value of the key intermediate of glyphosate is its content.

[0108] In step (1), a is preferably 1.18.

[0109] In step (2), the amount of sampling is the conventional amount in the analytical method in the art, preferably 0.1-1 mL, such as 0.5 mL.

[0110] The reagents and raw materials used in the present invention are commercially available.

[0111] In any technical solution of the present invention, when calculating the specific amount of each material: the molecular weight of paraformaldehyde is 30.

[0112] Paraformaldehyde: Aladdin Biochemical | Product Number: C104188 | Purity: AR; 500G.

[0113] The positive progress of the present invention is that the optimized process can achieve the preparation of glyphosate on a scale of 50 grams (90% yield), and the purity is improved (>99%), and it is feasible for industrial pilot and production. The optimized process and detection method have an important guiding role in the glyphosate industry and have great application potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0114] Figure 1 In situ analysis of key intermediates in the acid hydrolyzate of glyphosate synthesis 31 P–NMR monitoring spectrum.

[0115] Figure 2 In situ reaction system of glyphosate final product in glyphosate synthesis process 31 P–NMR monitoring spectrum.

[0116] Figure 3 is the percentage content of glyphosate in the mother solution31 Example of a P-NMR spectrum.

[0117] Figure 4 Determination of glyphosate content in the final product mother liquor by external standard method 31 P-NMR spectrum. DETAILED DESCRIPTION

[0118] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0119] In any technical solution of the present invention, when calculating the specific amount of each material: the molecular weight of paraformaldehyde is 30.

[0120] Paraformaldehyde: Aladdin Biochemical | Product Number: C104188 | Purity: AR; 500G.

[0121] The present invention is described in detail below by way of examples. The following examples only list the optimized process and 31 It is necessary to point out here that the following embodiments are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by technicians in this field based on the above content of the present invention belong to the scope of protection of the present invention.

[0122] Example 1

[0123] Method for optimizing the process of synthesizing glyphosate by glycine-dimethyl phosphite method:

[0124]

[0125] Step (1), depolymerization reaction:

[0126]

[0127] At room temperature (25°C), add paraformaldehyde [(HCHO) n , 38 g, 1.27 mol, 2.0 equiv.], one port was connected with a thermometer and the other port was sealed with a stopper. After stirring, methanol (MeOH, 256 mL, 6.34 mol), trimethyl orthoformate [Me(OMe) 3 , 69 mL, 0.634 mol, 1.0 equiv.] and triethylamine (NEt 3, 88 mL, 0.634 mol, 1.0 equiv.), heated to 42°C (temperature of the reaction system measured by a thermometer), and stirred for 1 h until the reaction system became a clear system.

[0128] Step (2), addition reaction:

[0129]

[0130] When the thermometer shows <37°C (30-37°C), glycine (Gly, 47.6 g, 0.634 mol, 1.0 equiv.) is added to the mixed system of methoxymethanol obtained in step (1) with stirring, and the temperature is controlled to 40°C (the temperature of the reaction system measured by the thermometer). The reaction is carried out for 1.5 hours until the glycine is completely dissolved and the reaction system becomes a clear system.

[0131] Step (3), condensation reaction:

[0132]

[0133] When the thermometer shows <40°C (35-40°C), dimethyl phosphite [PHO(OMe) 2 , 68 ml, 0.748 mol, 1.18 equiv.], the temperature was controlled at 52°C (the temperature of the reaction system measured by a thermometer), the reaction was continued for 2.0 h, and the reaction system turned light yellow.

[0134] Step (4), hydrolysis reaction:

[0135]

[0136] Under ice bath conditions (0-10°C), 30% concentrated hydrochloric acid (160ml, 1.522mol, 2.4equiv.) was added dropwise to the mixed system of dimethylphosphite and methylglycine obtained in step (3) with stirring, and the mixture was ice bathed for 0.5h to obtain the initial acid solution of the hydrolysis reaction. The reaction solution was taken, D 2 O as deuterated solvent, in situ measurement 31 P-NMR (see attached Figure 1). Heat in stages and remove the solvent at the same time, <100℃, 1.5h, 100-110℃, 1.5h; 110-120℃, 1.5h, until white solid appears in the reaction system. Cool to ice bath conditions (0-10℃), continue to add 30% concentrated hydrochloric acid (80ml, 0.761mol, 1.2equiv.) dropwise while stirring, heat in stages and remove the solvent at the same time, 110-120℃, 1.0h; 120-125℃, 1.0h, until the temperature in the system reaches 125℃, stop heating, the reaction is over, and the acid hydrolysis termination solution of the hydrolysis reaction is obtained. Take a sample while hot at 125℃, and pre-treat with triethylamine, D 2 O completely dissolved, measured in situ 31 P-NMR, phosphine spectrum integration, quantitative glyphosate yield (85.6%). (See Appendix for details) Figure 2 ).

[0137] Recrystallization

[0138] After the hydrolysis reaction is completed, the system is cooled naturally, and a large amount of white solid is precipitated in the system, which is glyphosate crystals. Stir the crystals at room temperature for 0.5h, add 50ml of ice water, continue stirring, and fully crystallize. Filter by suction, wash the filter cake with water twice, and dry the filter cake in an oven at 80℃ to obtain glyphosate dry powder (85.8g, yield 80%, purity 99%). After the filtrate is distilled under reduced pressure to remove water, a small amount of methanol is added, and a large amount of white solid is precipitated, which is triethylamine hydrochloride (Cl - H + Nt 3 ), filtered, and triethylamine hydrochloride white solid (71.6g, yield 82%) and mother liquor were obtained. Glyphosate dry powder and mother liquor were respectively 31 The glyphosate content is detected by P-NMR. 31 P-NMR method analysis (see Appendix Figure 3 ).

[0139]

[0140] Example 2

[0141] The same operation as in Example 1 was performed, except that the amounts of all raw materials were halved.

[0142] After the hydrolysis reaction is completed, the in situ 31 P-NMR, phosphine spectrum integration, quantitative glyphosate yield (86.96%).

[0143] The dry powder of glyphosate in the recrystallization operation was 42.8 g (yield: 79.9%, purity: 99%).

[0144] Example 3

[0145] The same operation as in Example 2 was repeated, except that the amount of dimethyl phosphite was 1.2 equivalents. After the hydrolysis reaction was completed, the in situ 31 P-NMR, phosphine spectrum integration, quantitative glyphosate yield (89.7%).

[0146] The glyphosate dry powder in the recrystallization operation was 34.3 g (yield 64.1%, purity 99%). The mother liquor obtained after recrystallization was 438 ml.

[0147] Example 4

[0148] This embodiment uses 31 The invention is described in detail using the P-NMR nuclear magnetic technology to quickly monitor the reaction system and determine the glyphosate content in the glyphosate dry powder and mother solution. 31 P-NMR in-situ nuclear magnetic monitoring method:

[0149] Method 1: Taking the initial acid hydrolysis solution of the hydrolysis reaction in Example 1 as an example, the content of the key intermediate in the acid hydrolysis solution is detected. The key intermediate has a certain positive correlation with the total yield of glyphosate.

[0150] Analytical method: Acid hydrolysis stage, ice bath, add 2.4 equivalents of 30% HCl with a dropping funnel, 0℃, react for 30 minutes, take samples, D 2 O dilution, NMR phosphine spectrum 31 P-NMR. The reaction feed ratio is 1.00 for glycine and 1.18 for dimethyl phosphite. The total integral of the phosphine spectrum is set to 118, and the integral of the key intermediate in the acid hydrolysis solution is its corresponding content. Taking the NMR spectrum of the key intermediate (mixture) with a content of 101.3% as an example, the attribution is as follows: Figure 1 shown.

[0151] Taking the acid hydrolysis termination solution of the hydrolysis reaction in Example 1 as an example, the total content of glyphosate was detected. After the reaction was completed, a sample was taken while hot (e.g., 125° C.), and triethylamine (NEt 3 , promote glyphosate salt), the volume ratio of the added triethylamine to the sample volume is 1:1, which can greatly improve the sample in D 2 Solubility in O.

[0152] NMR sample preparation: Take about 0.1 ml of the acid hydrolysis termination solution of the hydrolysis reaction into the NMR tube, add triethylamine (0.1 ml), D 2 O (0.3 ml), shake well and measure the phosphine spectrum.

[0153] Analysis method: The reaction feed ratio is 1.00 for glycine and 1.18 for dimethyl phosphite. The total integral of the phosphine spectrum of all products is set to 118, and the integral of the corresponding glyphosate is its yield. The integral of the phosphine spectrum of glyphosate is 85.6%, so the yield of glyphosate is 85.6%, which is classified as follows: Figure 2 shown.

[0154] Method 2: Taking the mother liquor after two recrystallizations after the hydrolysis reaction in Example 2 as an example, the glyphosate content was detected and the total content was calculated.

[0155] NMR sample preparation: Take about 0.1 ml of the mother solution into the NMR tube, add triethylamine (0.1 ml), D 2 O (0.3 ml), shake well and measure the phosphine spectrum.

[0156] Analysis method: Using glyphosate powder as a control, measure the percentage (%) of glyphosate in the mother liquor. According to the equivalent number corresponding to the dry powder yield (%) and the law of conservation of mass, the total equivalent number of the remaining phosphine-containing compounds in the mother liquor is calculated as:

[0157] The total equivalent number of dimethyl phosphite minus the equivalent number of dimethyl phosphite consumed by glyphosate powder, the total equivalent number of phosphine-containing compounds multiplied by the percentage of glyphosate in the mother liquor, is the glyphosate content in the mother liquor, and finally the total yield is calculated. Specific characterization and attribution are as follows Figure 3 shown.

[0158] Using glyphosate powder as a control, it was confirmed that the glyphosate in the mother liquor was 20.5ppm, the main byproduct, glyphosate, was 12.9ppm, and hydroxymethylphosphite was 22.1ppm. All phosphine-containing compounds were integrated, and the total integral was 100, so the integral of glyphosate in the mother liquor was 17.6, so the glyphosate content in the mother liquor was calculated to be 17.6%.

[0159] The amount of glyphosate dry powder in this batch of products is: 42.8g, and the calculated dry powder yield is 79.9%, then the corresponding phosphine equivalent is 0.799equiv, and the remaining phosphine equivalent is: 1.20-0.799=0.401equiv, then the glyphosate content in the mother liquor is 0.401x17.6%=7.06%, therefore, the total glyphosate yield of this batch of products is: 79.9%+7.06%=86.96%.

[0160] Method 3: Taking the mother liquor after two recrystallizations in Example 3 as an example, the glyphosate content was detected by external standard method and the total content was calculated. As an external standard, the glyphosate content in the mother liquor was measured, and the total yield was finally calculated. Figure 4 shown.

[0161] External standard preparation: weigh the phosphine ligand chiral phenol (210 mg, 1 mmol), dilute to 10 ml of methanol, and prepare a 0.1 mmol / ml external standard solution. When measuring, add 0.1 ml of the external standard solution, and the external standard amount is 0.01 mmol.

[0162] NMR sample preparation: Take 0.1 ml of the mother solution into the NMR tube, add 0.1 ml of the external standard solution, D 2 O (0.3 ml), shake well and measure the phosphine spectrum.

[0163] Analysis method: Figure 4 As shown, the phosphine spectrum of chiral phenol is 78.3ppm, and the phosphine spectrum of glyphosate in the acidic mother liquor is 19.5ppm. We set the integral of chiral phenol to 10.0, and the integral of glyphosate in the mother liquor to 18.2, so the glyphosate content in 0.1ml mother liquor is calculated to be 0.0182mmol. The mother liquor is 438ml, so the glyphosate content of the mother liquor is: 438x10 x0.0182x0.1691=13.48g. The amount of glyphosate dry powder in this batch of products is 34.3g, and the total yield is 48.1g, and the calculated total yield is: 89.7%.

[0164] Comparative Example 1

[0165] According to the process conditions of the existing patent (CN105622666A), molecular sieves were added in the first step, and the other steps were completely the same, but recrystallization could not be successfully achieved, and the glyphosate content in the obtained dry powder was <60%.

[0166] Comparative Example 2

[0167] According to the process conditions of Example 1, trimethyl orthoformate was not added in the depolymerization reaction, and the other steps were completely the same. After the reaction was completed, the phosphine spectrum detection and analysis showed that the glyphosate yield was 80%. Recrystallization was possible, but the glyphosate content in the dry powder was 90%.

Claims

1. A method for preparing glyphosate, It is characterized in that It includes the following steps: (1) in an organic solvent, subjecting paraformaldehyde, methanol, an organic amine and a dehydrating agent to a depolymerization reaction; wherein the dehydrating agent is trimethyl orthoformate and / or triethyl orthoformate; (2) mixing the mixed system after the depolymerization reaction in step (1) with glycine to carry out an addition reaction; (3) mixing the mixed system after the addition reaction in step (2) with dimethyl phosphite to carry out a condensation reaction; (4) mixing the mixed system after the condensation reaction in step (3) with an acid and performing a hydrolysis reaction to obtain glyphosate; 2. The preparation method according to claim 1, It is characterized in that It meets one or more of the following conditions: (1) In step (1), the dehydrating agent is trimethyl orthoformate; (2) In step (1), the organic amine is one or more of triethylamine, tetrahydropyrrole and diethylamine; (3) In step (1), the organic solvent is an alcohol solvent; (4) In step (1), the reaction temperature of the depolymerization reaction is 40-42°C; (5) In step (1), the reaction time of the depolymerization reaction is 0.5-2 hours; (6) In step (1), the molar ratio of the paraformaldehyde to the methanol is 1:(3-10); (7) In step (1), the molar ratio of the paraformaldehyde to the organic amine is 1:(0.3-1); (8) In step (1), the molar ratio of the paraformaldehyde to the dehydrating agent is 1:(0.3-1); (9) In step (2), glycine is added to the mixed system after the depolymerization reaction in step (1); the temperature of the addition is lower than 37° C.; (10) In step (2), the molar ratio of the paraformaldehyde to the glycine is 1:(0.3-1); (11) In step (2), the reaction temperature of the addition reaction is 38-40°C; (12) In step (2), the reaction time of the addition reaction is 1.5-2 hours; (13) In step (3), dimethyl phosphite is added to the mixed system after the addition reaction in step (2); the temperature of the addition is lower than 40° C.; (14) In step (3), the molar ratio of the dimethyl phosphite to the glycine is (1-1.3):1; (15) In step (3), the reaction temperature of the condensation reaction is 50-54°C; (16) In step (3), the reaction time of the condensation reaction is 2-2.5 hours; (17) In step (4), the reaction temperature of the hydrolysis reaction is 90-125°C; (18) In step (4), the reaction time of the hydrolysis reaction is 4-12 hours; (19) In step (4), the molar ratio of hydrogen ions in the acid of the hydrolysis reaction to glycine in the addition reaction is (2-5):1; (20) In step (4), the acid in the hydrolysis reaction is sulfuric acid and / or hydrochloric acid; when the acid in the hydrolysis reaction is hydrochloric acid, the mass fraction of the hydrochloric acid is 10-37%; (21) In step (4), an acid is added to the hydrolysis reaction at a temperature of 0-10°C.

3. The preparation method according to claim 2, It is characterized in that One or more of the following conditions are met: (1) In step (1), the organic amine is triethylamine; (2) In step (1), the organic solvent is methanol or ethanol; when the organic solvent is methanol, methanol serves as both a reaction solvent and a reaction raw material; (3) In step (1), the reaction temperature of the depolymerization reaction is 42° C.; (4) In step (1), the reaction time of the depolymerization reaction is 1 hour; (5) In step (1), the molar ratio of the paraformaldehyde to the methanol is 1:(4-7); (6) In step (1), the molar ratio of the paraformaldehyde to the organic amine is 1:(0.4-0.6); (7) In step (1), the molar ratio of the paraformaldehyde to the dehydrating agent is 1:(0.4-0.6); (8) In step (2), the temperature for adding glycine is 30-37°C; (9) In step (2), the molar ratio of the paraformaldehyde to the glycine is 1:(0.4-0.6); (10) In step (2), the reaction temperature of the addition reaction is 40° C.; (11) In step (2), the reaction time of the addition reaction is 1.5 hours; (12) In step (3), the temperature of adding dimethyl phosphite is 35-40° C.; (13) In step (3), the molar ratio of the dimethyl phosphite to the glycine is (1-1.2):1; (14) In step (3), the reaction temperature of the condensation reaction is 52°C; (15) In step (3), the reaction time of the condensation reaction is 2 hours; (16) In step (4), the reaction time of the hydrolysis reaction is 6.5 hours; (17) In step (4), the molar ratio of hydrogen ions in the acid of the hydrolysis reaction to glycine in the addition reaction is 3.6:1; (18) In step (4), the acid in the hydrolysis reaction is hydrochloric acid; when the acid in the hydrolysis reaction is hydrochloric acid, the mass fraction of the hydrochloric acid is 20-37%; (19) In step (4), when the acid is added to the hydrolysis reaction, the temperature of the addition is 5°C; (20) The preparation method of glyphosate further comprises post-treatment, wherein the post-treatment comprises the following steps: after the hydrolysis reaction is completed, stirring for crystallization, solid-liquid separation, and solid drying.

4. The preparation method according to claim 3, It is characterized in that One or more of the following conditions are met: (1) In step (1), the molar ratio of the paraformaldehyde to the methanol is 1:(4.9-5.1); (2) In step (1), the molar ratio of the paraformaldehyde to the organic amine is (1.9-2.1):1; (3) In step (1), the molar ratio of the paraformaldehyde to the dehydrating agent is (1.9-2.1):1; (4) In step (2), the molar ratio of the paraformaldehyde to the glycine is (1.9-2.1):1; (5) In step (3), the molar ratio of dimethyl phosphite to glycine is 1.18:1; (6) In step (4), the acid in the hydrolysis reaction is hydrochloric acid, and the mass fraction of the hydrochloric acid is 30%; (7) During post-treatment, the stirring and crystallization time is 0.1-2 hours; (8) During post-treatment, ice water may be added during the stirring and crystallization to ensure sufficient crystallization; (9) In post-treatment, the method of solid-liquid separation is suction filtration; (10) In post-treatment, the separated solid is washed with water to remove impurities, and the number of water washings is 1-4 times; (11) In post-treatment, the solid is dried at a temperature of 70-90°C.

5. The preparation method according to claim 4, It is characterized in that One or more of the following conditions are met: (1) During post-treatment, the stirring and crystallization time was 2 hours; (2) In post-treatment, the separated solid is washed with water to remove impurities, and the number of water washings is 2 times; (3) In post-treatment, the solid is dried at a temperature of 80°C.

6. The preparation method according to claim 2, It is characterized in that In step (4), the method of adding acid to the hydrolysis reaction is to add the acid to the reaction system twice, wherein after the first addition of the acid, stepwise heating is performed, and the steps are as follows: a. Heat at 90-100°C for 1-2 hours; b. Heat at 100-110°C for 1-2 hours; c. Heat at 110-120°C for 1-2 hours until a white solid appears in the reaction system; After the second addition of acid, step heating is performed, the steps are: d. Heat at 110-120°C for 0.5-2 hours; e. Heat at 120-125°C for 0.5-2 hours; f. When the temperature in the system reaches 125°C, the reaction is completed.

7. The preparation method according to claim 6, It is characterized in that In step (4), the method of adding acid to the hydrolysis reaction is to add the acid to the reaction system twice, wherein after the first addition of the acid, stepwise heating is performed, and the steps are as follows: a. Heat at 95°C for 1.5 hours; b. Heat at 100-110°C for 1.5 hours; c. Heat at 110-120°C for 1.5 hours until a white solid appears in the reaction system; After the second addition of acid, step heating is performed, the steps are: d. Heat at 110-120°C for 1 hour; e. Heat at 120-125°C for 1 hour; f. When the temperature in the system reaches 125°C, the reaction is completed.

8. The preparation method according to claim 6, It is characterized in that It meets one or more of the following conditions: (1) In step (4), when the acid is added for the first time, the molar ratio of hydrogen ions in the acid to the glycine in the addition reaction is (2-3):1; (2) In step (4), when the acid is added for the second time, the molar ratio of hydrogen ions in the acid to the glycine in the addition reaction is (1-2):1; (3) In step (4), the hydrolysis reaction is carried out while removing the solvent while heating.

9. The preparation method according to claim 8, It is characterized in that It meets one or both of the following conditions: (1) In step (4), when the acid is added for the first time, the molar ratio of hydrogen ions in the acid to the glycine in the addition reaction is 2.4:1; (2) In step (4), when the acid is added for the second time, the molar ratio of hydrogen ions in the acid to the glycine in the addition reaction is 1.2:

1.

10. A method for preparing compound C, It is characterized in that It includes the following steps: In a solvent, paraformaldehyde, methanol and triethylamine undergo depolymerization reaction under the action of a dehydrating agent to obtain compound C, wherein the dehydrating agent is trimethyl orthoformate and / or triethyl orthoformate. Wherein, the conditions of the depolymerization reaction are the same as the conditions of the depolymerization reaction described in any one of claims 1-4.

11. A 31 P-NMR in situ nuclear magnetic monitoring method for glyphosate, It is characterized in that It includes the following methods: Method 1: The acid hydrolysis termination solution of the hydrolysis reaction is used as the detection object, including the following steps: (1) Record the feeding amounts of glycine and dimethyl phosphite in the preparation method according to any one of claims 1 to 4, with the glycine equivalent being recorded as 1 and the dimethyl phosphite equivalent being recorded as a; wherein a is 1 to 1.3; and set the total integral of all products to 100×a; (2) sampling the acid hydrolysis termination solution of the hydrolysis reaction of the preparation method according to any one of claims 1 to 4 while it is hot, and mixing it with a base to obtain a solution b, wherein the base is an organic amine; (3) mixing the solution b, the base and D 2 O is mixed, and its phosphine spectrum is measured; the integral of the corresponding glyphosate is its yield; and the base is an organic amine.

12. The method according to claim 11, It is characterized in that One or more of the following conditions are met: (1) In step (1) of method 1, the amount of the base is the same as the volume of the sample; (2) In step (1) of method 1, the base is triethylamine; (3) In step (1) of method 1, a is 1.18; (4) In step (2) of method 1, the base is triethylamine; (5) In step (2) of method 1, the amount of hot sample is 0.1-1 mL; (6) In step (2) of method 1, the amount of base added is 1-5 times the volume of the sample; (7) In step (3) of method 1, solution b: triethylamine: D 2 The volume ratio of O is 1:1:3; (8) In step (3) of method 1, 0.1 mL of solution b, 0.1 mL of triethylamine and 0.3 mL of D2O were taken.

13. The method according to claim 11, It is characterized in that In step (2) of method 1, the amount of hot sampling is 0.5 mL.

Images