Synthesis method of 2-mercaptonicotinoyl glycine

Abstract

The invention provides a synthesis method of 2-mercapto nicotinoyl glycine, and belongs to the technical field of chemical synthesis. The synthesis method of 2-mercapto nicotinoyl glycine provided by the invention comprises the following steps: mixing 2-mercapto nicotinic acid, alcohol and a first catalyst, and carrying out methyl esterification reaction to obtain synthetic ester; and mixing glycine, a basic catalyst and an organic solvent, then adding the synthetic ester, and carrying out amine-ester exchange to obtain the 2-mercaptonicotinoyl glycine. 2-mercaptonicotinic acid is adopted as a raw material, methyl esterification is firstly performed to obtain synthetic ester, then glycine is dissolved under the condition of a basic catalyst to prepare sodium glycinate, the situation that 2-mercaptonicotinoyl glycine cannot be prepared from glycine through amine ester exchange into a diad is avoided, then the sodium glycinate and the synthetic ester are subjected to amine ester exchange, and the 2-mercaptonicotinoyl glycine is obtained. The process flow is short, so that the yield is increased, the pollution is reduced, and the generation of odor is avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing 2-mercaptonicotinoylglycine. Background Art

[0002] 2-Mercaptonicotinylglycine (2-MNG) is a whitening ingredient that addresses topical pigmentation issues such as age spots and post-acne marks.

[0003] At present, the synthetic route of 2-mercaptonicotinylglycine is:

[0004]

[0005] However, the synthetic route uses highly polluting raw material thionyl chloride, which is highly corrosive and polluting. In addition, an excessive amount of sodium thiosulfate is used, which produces a strong odor during the production process and is difficult to avoid. The long production process leads to a low yield. Therefore, how to solve the problems of high pollution, low yield and odor in the existing synthetic method has become a technical problem that needs to be solved urgently in this field. Summary of the invention

[0006] The purpose of the present invention is to provide a method for synthesizing 2-mercaptonicotinoylglycine. The method provided by the present invention has low pollution, high yield and avoids the generation of odor during production.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a method for synthesizing 2-mercaptonicotinoylglycine, comprising the following steps:

[0009] (1) mixing 2-mercaptonicotinic acid, alcohol and a catalyst, and performing a methyl esterification reaction to obtain a synthetic ester;

[0010] (2) Glycine, an alkaline catalyst and an organic solvent are mixed, and then the synthetic ester obtained in step (1) is added to carry out amine ester exchange to obtain 2-mercaptonicotinoylglycine.

[0011] Preferably, the alcohol in step (1) is at least one of methanol, ethanol and isopropanol.

[0012] Preferably, in step (1), the mass ratio of 2-mercaptonicotinic acid to alcohol is 1:(2-5).

[0013] Preferably, the catalyst in step (1) is SOCl2 or p-toluenesulfonic acid.

[0014] Preferably, the mass of the p-toluenesulfonic acid is 1-10% of the mass of 2-mercaptonicotinic acid; the molar ratio of the SOCl2 to 2-mercaptonicotinic acid is (1.1-1.3):1.

[0015] Preferably, when the catalyst is SOCl2, the temperature of the methyl esterification reaction in step (1) is room temperature; when the catalyst is p-toluenesulfonic acid, the temperature of the methyl esterification reaction in step (1) is 50-70°C.

[0016] Preferably, the organic solvent in step (2) is at least one of DMSO and sulfolane.

[0017] Preferably, the alkaline catalyst in step (2) is at least one of sodium methoxide and sodium ethoxide.

[0018] Preferably, the temperature of the amine ester exchange in step (2) is 100-140°C.

[0019] Preferably, in step (2), the molar ratio of glycine, alkaline catalyst and synthetic ester is (0.9-1.1):(1.1-1.3):1.

[0020] The present invention provides a method for synthesizing 2-mercaptonicotinic acid, comprising the following steps: mixing 2-mercaptonicotinic acid, alcohol and a first catalyst, performing a methyl esterification reaction to obtain a synthetic ester; mixing glycine, an alkaline catalyst and an organic solvent, and then adding the synthetic ester to perform an amine ester exchange to obtain 2-mercaptonicotinic acid. The present invention uses 2-mercaptonicotinic acid as a raw material, first performs a methyl esterification to obtain a synthetic ester, then dissolves glycine under alkaline catalyst conditions to prepare sodium glycinate, thereby avoiding the amine ester exchange of glycine itself into a dimer and failing to prepare 2-mercaptonicotinic acid, and then performs an amine ester exchange with the synthetic ester to obtain 2-mercaptonicotinic acid. The process flow is short, thereby improving the yield, and the use of highly polluting raw materials such as thionyl chloride and sodium thiosulfate is avoided in the production process, thereby reducing pollution and avoiding the generation of odor. Experimental results show that the synthesis method provided by the present invention has low pollution, no odorous gas that is difficult to absorb is generated, and the industrial feasibility is strong, and the overall yield reaches 70%. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the HNMR spectrum of 2-mercaptonicotinic acid in Example 1;

[0022] Figure 2 This is the HNMR spectrum of 2-mercaptonicotinoylglycine prepared in Example 1;

[0023] Figure 3 is the HNMR spectrum of 2-mercaptonicotinic acid methyl ester in Example 2;

[0024] Figure 4 This is the HPLC spectrum of 2-mercaptonicotinoylglycine prepared in Example 3;

[0025] Figure 5 This is the HNMR spectrum of the impurity prepared in Comparative Example 1. DETAILED DESCRIPTION

[0026] The present invention provides a method for synthesizing 2-mercaptonicotinoylglycine, comprising the following steps:

[0027] (1) mixing 2-mercaptonicotinic acid, alcohol and a catalyst, and performing a methyl esterification reaction to obtain a synthetic ester;

[0028] (2) Glycine, an alkaline catalyst and an organic solvent are mixed, and then the synthetic ester obtained in step (1) is added to carry out amine ester exchange to obtain 2-mercaptonicotinoylglycine.

[0029] The present invention has no particular limitation on the sources of the raw materials, and commercially available products known to those skilled in the art may be used.

[0030] The invention mixes 2-mercaptonicotinic acid, alcohol and a catalyst, and performs a methyl esterification reaction to obtain a synthetic ester.

[0031] The present invention has no particular limitation on the preparation method of the 2-mercaptonicotinic acid, and the 2-mercaptonicotinic acid can be prepared by a preparation method well known to those skilled in the art.

[0032] In the present invention, the method for preparing 2-mercaptonicotinic acid is preferably to mix 2-chloronicotinic acid, a thiolation agent, an acid and a solvent, and perform a thiolation reaction to obtain 2-mercaptonicotinic acid.

[0033] In the present invention, the thiolation agent is preferably thiourea; the acid is preferably concentrated hydrochloric acid; the solvent is preferably ethanol and water; the molar ratio of the 2-chloronicotinic acid to the thiolation agent is preferably 1:(1.1-1.3), more preferably 1:1.2.

[0034] The present invention has no particular limitation on the amount of the acid used, and operations familiar to those skilled in the art may be used.

[0035] The present invention has no particular limitation on the concentration of the concentrated hydrochloric acid, and concentrated hydrochloric acid well known to those skilled in the art may be used.

[0036] The present invention has no particular limitation on the amount of the solvent, as long as the raw material is dissolved. The present invention has no particular limitation on the ratio of the ethanol to water, as long as the raw material is completely dissolved.

[0037] The present invention has no special limitation on the operation of mixing the 2-chloronicotinic acid, the thio reagent, the acid and the solvent, and the technical scheme for preparing the mixed material well known to those skilled in the art can be adopted.

[0038] In the present invention, the temperature of the thiolation reaction is preferably 60 to 80° C. The present invention has no particular limitation on the time of the thiolation reaction, and the reaction can be monitored by TLC.

[0039] After the thiolation reaction is completed, the present invention preferably performs post-treatment on the product obtained by the thiolation reaction to obtain 2-mercaptonicotinic acid.

[0040] In the present invention, the post-treatment preferably includes cooling, adding alkali solution, first stirring, first filtration, adjusting pH value, second stirring, second filtration, beating, third filtration and drying performed in sequence.

[0041] The present invention has no particular limitation on the cooling operation, and the temperature may be reduced to 10° C. using an operation well known to those skilled in the art.

[0042] In the present invention, the alkali solution is preferably a strong alkali solution; the mass concentration of the strong alkali solution is preferably 20-30%, more preferably 25%; the strong alkali solution is preferably a sodium hydroxide solution. The present invention has no particular limitation on the amount of the alkali solution, as long as the solid in the product obtained by the thiolation reaction is completely dissolved.

[0043] In the present invention, the alkali solution is preferably added in a dropwise manner. The present invention has no particular limitation on the rate of the dropwise addition, and the operation well known to those skilled in the art can be used.

[0044] The present invention has no particular limitation on the first stirring operation, and any operation well known to those skilled in the art may be used.

[0045] The present invention has no particular limitation on the first filtering operation, and a small amount of insoluble matter can be removed by filtering using an operation well known to those skilled in the art.

[0046] In the present invention, the pH value is preferably 2 to 3. The present invention has no particular limitation on the operation of adjusting the pH value, as long as the pH value of the filtrate is adjusted to 2 to 3.

[0047] The present invention has no particular limitation on the second stirring operation, and any operation well known to those skilled in the art may be used.

[0048] The present invention has no particular limitation on the second filtration operation, and the filtrate can be removed by an operation well known to those skilled in the art.

[0049] The present invention has no particular limitation on the beating operation, and the residual inorganic salts can be removed by using operations well known to those skilled in the art.

[0050] The present invention has no special limitation on the operation of the third filtration, and the filtrate can be removed by an operation well known to those skilled in the art.

[0051] The present invention has no special limitation on the drying operation, and the drying operation can be performed until constant weight.

[0052] In the present invention, the alcohol is preferably at least one of methanol, ethanol and isopropanol, more preferably methanol; the mass ratio of 2-mercaptonicotinic acid to alcohol is preferably 1:(2-5). As an embodiment, the mass ratio of 2-mercaptonicotinic acid to alcohol can be 1:(3.5-4.5), or 1:4.

[0053] In the present invention, the catalyst is preferably SOCl2 or p-toluenesulfonic acid, more preferably p-toluenesulfonic acid.

[0054] In the present invention, when the catalyst is SOCl2, the molar ratio of SOCl2 to 2-mercaptonicotinic acid is preferably (1.1-1.3):1, more preferably 1.2:1; when the catalyst is p-toluenesulfonic acid, the mass of p-toluenesulfonic acid is preferably 1-10% of the mass of 2-mercaptonicotinic acid.

[0055] As an embodiment, the mass of the p-toluenesulfonic acid may be 2-9% of the mass of 2-mercaptonicotinic acid, or may be 3%, 4%, 5%, 6%, 7% or 8%.

[0056] The present invention has no special limitation on the operation of mixing the 2-mercaptonicotinic acid, alcohol and catalyst, and the technical scheme for preparing the mixed material well known to those skilled in the art can be adopted.

[0057] In the present invention, when the catalyst is SOCl2, the temperature of the methyl esterification reaction is preferably room temperature; when the catalyst is p-toluenesulfonic acid, the temperature of the methyl esterification reaction is preferably 50-70°C. As an embodiment, the temperature of the methyl esterification reaction can be 55-65°C, and can also be 60°C. The present invention does not specifically limit the time of the methyl esterification reaction, and the reaction can be completed by monitoring by TLC. The present invention limits the temperature of the methyl esterification reaction within the above range to increase the degree of the methyl esterification reaction, thereby increasing the yield.

[0058] In the present invention, when the catalyst is SOCl2, the methyl esterification reaction is preferably carried out under stirring. The present invention has no particular limitation on the stirring operation, and the operation well known to those skilled in the art can be used.

[0059] After the methyl esterification reaction is completed, the product obtained by the methyl esterification reaction is preferably post-treated to obtain a synthetic ester.

[0060] In the present invention, the post-treatment preferably includes cooling, filtering and washing in sequence or cooling, concentration under reduced pressure, beating, filtering and washing in sequence.

[0061] The present invention has no particular limitation on the cooling operation, and any operation well known to those skilled in the art may be used.

[0062] The present invention has no particular limitation on the operation of vacuum concentration, and vacuum concentration to dryness may be performed using an operation well known to those skilled in the art.

[0063] The present invention has no particular limitation on the operations of beating, filtering and washing, and operations well known to those skilled in the art may be adopted.

[0064] After obtaining the synthetic ester, the present invention mixes glycine, a basic catalyst and an organic solvent, then adds the synthetic ester to carry out amine ester exchange to obtain 2-mercaptonicotinoylglycine.

[0065] In the present invention, the alkaline catalyst is preferably at least one of sodium methoxide and sodium ethoxide, more preferably sodium methoxide.

[0066] In the present invention, the organic solvent is preferably at least one of DMSO and sulfolane, more preferably DMSO. The present invention has no particular limitation on the amount of the organic solvent, as long as the raw materials are completely dissolved.

[0067] In the present invention, the molar ratio of glycine, alkaline catalyst and synthetic ester is preferably (0.9-1.1): (1.1-1.3): 1, and more preferably (1.05-1.08): (1.22-1.25): 1. In the present invention, limiting the molar ratio of glycine, alkaline catalyst and synthetic ester to the above range can increase the degree of amine transesterification, thereby increasing the yield.

[0068] In the present invention, the alkaline catalyst is preferably added in batches; the temperature of the batch addition is preferably ≤5°C. The present invention has no special limitation on the amount of each batch when adding in batches, as long as it is added in batches. In the present invention, the alkaline catalyst releases heat when it dissolves, and the reaction of glycine to generate sodium glycinate is also an exothermic reaction. Adding at ≤5°C can avoid the high temperature during the exothermic reaction, resulting in the self-condensation of glycine without forming sodium glycinate to form a dimer, thereby avoiding the generation of subsequent dimer impurities.

[0069] In the present invention, the temperature for mixing the glycine, the alkaline catalyst and the organic solvent is preferably 50 to 60°C; the mixing time is preferably 0.5 to 3 hours, more preferably 1 to 1.5 hours; and the mixing is preferably carried out under stirring conditions. The present invention has no particular limitation on the stirring operation, and the operation well known to those skilled in the art can be used.

[0070] In the present invention, glycine is first dissolved under alkaline conditions to prepare sodium glycinate, otherwise glycine itself will undergo amine ester exchange to form a dimer, the structural formula of the dimer is shown in Formula I:

[0071]

[0072] The present invention has no particular limitation on the operation of adding the synthetic ester, and any operation well known to those skilled in the art may be used.

[0073] In the present invention, the temperature of the amine transesterification is preferably 100 to 140° C. As an embodiment, the temperature of the amine transesterification can be 110 to 130° C., or 115 to 125° C. The present invention has no particular limitation on the time of the amine transesterification, and the reaction can be completed by monitoring the reaction by TLC. The present invention limits the temperature of the amine transesterification to the above range, which can increase the degree of amine transesterification and thus increase the yield.

[0074] After the amine transesterification is completed, the present invention preferably performs post-treatment on the product obtained by the amine transesterification to obtain 2-mercaptonicotinoylglycine.

[0075] In the present invention, the post-processing preferably comprises the following steps:

[0076] 1) cooling the product obtained by the amine ester exchange, first adding water, first adjusting the pH value, first stirring and first filtering in sequence to obtain a crude product;

[0077] 2) The crude product obtained in step 1) is sequentially subjected to a second step of adding water, adding alkali solution, a second step of stirring, a second step of filtering, a second step of adjusting the pH value, a third step of filtering, washing with water and drying to obtain 2-mercaptonicotinoylglycine.

[0078] In the present invention, the product obtained by the amine ester exchange is preferably subjected to sequential cooling, water addition, a first pH adjustment, a first stirring and a first filtration to obtain a crude product.

[0079] The present invention has no particular limitation on the cooling operation, and the temperature can be lowered to below 20° C. using an operation well known to those skilled in the art.

[0080] The present invention has no particular limitation on the first water-adding operation, and any operation well known to those skilled in the art may be used.

[0081] In the present invention, the pH value is preferably 2 to 3. The present invention has no special limitation on the first operation of adjusting the pH value, as long as the pH value of the solution is ensured to be 2 to 3.

[0082] The present invention has no particular limitation on the first stirring operation, and any operation well known to those skilled in the art may be used.

[0083] The present invention has no special limitation on the first filtering operation, and any filtering operation well known to those skilled in the art may be used.

[0084] After obtaining the crude product, the present invention preferably sequentially performs a second step of adding water, adding alkali solution, a second step of stirring, a second step of filtering, a second step of adjusting the pH value, a third step of filtering, washing with water and drying the crude product to obtain 2-mercaptonicotinoylglycine.

[0085] The present invention has no particular limitation on the second water-adding operation, and any operation well known to those skilled in the art may be used.

[0086] In the present invention, the alkali solution is preferably a strong alkali solution; the mass concentration of the strong alkali solution is preferably 15-25%, more preferably 20%; the strong alkali solution is preferably a sodium hydroxide solution. The present invention has no special limitation on the amount of the alkali solution, as long as the solid in the crude product is completely dissolved.

[0087] In the present invention, the alkali solution is preferably added in a dropwise manner. The present invention has no particular limitation on the rate of the dropwise addition, and the operation well known to those skilled in the art can be used.

[0088] The present invention has no particular limitation on the second stirring operation, and any operation well known to those skilled in the art may be used.

[0089] The present invention has no particular limitation on the second filtering operation, and a filtering operation well known to those skilled in the art may be used to remove a very small amount of turbidity.

[0090] In the present invention, the pH value is preferably 2 to 3. The present invention has no special limitation on the second operation of adjusting the pH value, as long as the pH value of the solution is ensured to be 2 to 3.

[0091] The present invention has no special limitation on the third filtering operation, and any filtering operation well known to those skilled in the art may be used.

[0092] The present invention has no particular limitation on the water washing operation, and water washing until neutrality is sufficient.

[0093] The present invention has no special limitation on the drying operation, and the drying operation can be performed until constant weight.

[0094] The synthesis method provided by the invention has high yield, low pollution, no generation of odorous gas that is difficult to absorb, strong industrial feasibility, and an overall yield of 70%.

[0095] The process flow route of the synthesis method provided by the present invention is:

[0096]

[0097] The synthesis method provided by the present invention is generally simple, has no odor, has little environmental pollution, and has a high yield, with the overall yield reaching 70%.

[0098] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0099] Example 1

[0100] The synthesis method of 2-mercaptonicotinoylglycine is as follows:

[0101] (1) In a dry 1L three-necked flask, 100g of 2-chloronicotinic acid, 58g of thiourea, 100mL of ethanol, 300mL of water and 50mL of 30wt% concentrated hydrochloric acid were added, and the temperature was raised to 60°C with stirring to carry out thiolation reaction for 5h. The reaction was completed by TLC monitoring, and a yellow solid was precipitated. The temperature was then lowered to 10°C, and 190g of 25wt% sodium hydroxide solution was slowly added dropwise, and the solid gradually dissolved. After the addition was completed, stirring was continued for 3h, and a small amount of insoluble matter was removed by filtration. The filtrate was adjusted to pH 3 with 250g of 10wt% dilute hydrochloric acid, and stirring was continued for 1h. The filter cake was then beaten with warm water to remove residual inorganic salts, filtered, and dried to obtain 83g of 2-mercaptonicotinic acid, with a yield of about 84%, wherein the molar ratio of the 2-chloronicotinic acid to thiourea was 1:1.2;

[0102] (2) In a dry 500 mL three-necked flask, add 77.5 g of 2-mercaptonicotinic acid obtained in step (1) and 200 mL of methanol, stir and cool to below 0° C., slowly dropwise add 71.5 g of SOCl2, and then stir at room temperature to carry out methyl esterification reaction overnight. After the reaction is completed by TLC monitoring, slowly pour into 1 L of cold water to precipitate a light yellow solid, which is then filtered and washed with water in turn to obtain 67.6 g of light yellow solid 2-mercaptonicotinic acid methyl ester, with a yield of about 80%; wherein the molar ratio of SOCl2 to 2-mercaptonicotinic acid is 1.2:1;

[0103] (3) In a dry 250mL three-necked flask, 15g of glycine and 48mL of DMSO were added, and then the temperature was lowered to below 5°C, 12.5g of sodium methoxide was added in batches, and then the temperature was slowly raised to 50°C and stirred for 1h to completely dissolve the glycine, and then 32g of 2-mercaptonicotinic acid methyl ester obtained in step (2) was added, and the temperature was further raised to 125°C for amine ester exchange for 7h. The reaction was monitored by HPLC to complete, and the temperature was lowered to below 20°C, 100mL of water was slowly added, and then the pH value was adjusted to 3 with 85g of 10wt% dilute hydrochloric acid to precipitate a large amount of yellow solid, and then the mixture was stirred at room temperature for 2h, filtered, and a crude product was obtained; wherein the molar ratio of glycine, sodium methoxide and 2-mercaptonicotinic acid methyl ester was 1.05:1.22:1;

[0104] (4) The crude product obtained in step (3) was added to 100 g of water, the temperature was controlled below 30° C., 38 g of 20 wt % sodium hydroxide solution was slowly added dropwise until it was completely dissolved, and stirring was continued for 1 h. A very small amount of turbidity was removed by filtration, and the filtrate was adjusted to pH 3 with 70 g of 10 wt % dilute hydrochloric acid, filtered, and the filter cake was washed with water until neutral, and dried to obtain 34 g of 2-mercaptonicotinoylglycine, with a yield of about 85%, a melting point of 241.6-241.9° C. (capillary measurement), and an HPLC purity of 99.2%.

[0105] The HNMR spectrum of 2-mercaptonicotinic acid in Example 1 is as follows: Figure 1 shown.

[0106] from Figure 1 It can be seen that the present invention prepares 2-mercaptonicotinic acid.

[0107] The HNMR spectrum of 2-mercaptonicotinoylglycine prepared in Example 1 is as follows: Figure 2 shown.

[0108] from Figure 2 It can be seen that the present invention prepares 2-mercaptonicotinoylglycine.

[0109] Example 2

[0110] The synthesis method of 2-mercaptonicotinoylglycine is as follows:

[0111] (1) In a dry 1L three-necked flask, 155g of 2-mercaptonicotinic acid, 500mL of methanol and 7.75g of p-toluenesulfonic acid were added, and the temperature was raised to 65°C for methyl esterification reaction for 6h. The reaction was completed by TLC monitoring, and the mixture was concentrated to dryness under reduced pressure, and water was added for pulping, filtered, and washed with water to obtain 160g of light yellow solid 2-mercaptonicotinic acid methyl ester, with a yield of about 95%; wherein p-toluenesulfonic acid was 5% of the mass of 2-mercaptonicotinic acid;

[0112] (2) In a dry 1L three-necked flask, add 75g of glycine and 240mL of DMSO, then cool to below 5°C, add 63g of sodium methoxide in batches, then slowly heat to 55°C and stir for 1h to dissolve the glycine completely, then add 160g of 2-mercaptonicotinic acid methyl ester obtained in step (1), and continue to heat to 125°C for amine ester exchange for 7h. After the reaction is completed by HPLC monitoring, cool to below 20°C, slowly add 100mL of water, and then adjust the pH value to 2 with 435g of 10wt% dilute hydrochloric acid to precipitate a large amount of yellow solid, then continue to stir at room temperature for 1h, filter, and obtain a crude product; wherein the molar ratio of glycine, sodium methoxide and 2-mercaptonicotinic acid methyl ester is 1.05:1.22:1;

[0113] (3) The crude product obtained in step (2) is added to 500 g of water, the temperature is controlled below 30° C., 195 g of 20 wt % sodium hydroxide solution is slowly added dropwise until it is completely dissolved, stirring is continued for 1 hour, and then a very small amount of turbidity is removed by filtration. The filtrate is adjusted to pH 3 with 350 g of 10 wt % dilute hydrochloric acid, filtered, and the filter cake is washed with water until it is neutral and dried to obtain 170 g of 2-mercaptonicotinoylglycine, with a yield of about 85%, a melting point of 241.6-241.9° C. (capillary measurement), and an HPLC purity of 99.3%.

[0114] The HNMR spectrum of 2-mercaptonicotinate methyl ester in Example 2 is as follows: Figure 3 shown.

[0115] from Figure 3 It can be seen that the present invention prepares methyl 2-mercaptonicotinate.

[0116] Example 3

[0117] (1) In a dry 200L enamel kettle, 25kg 2-chloronicotinic acid, 14.5kg thiourea, 25L ethanol, 75L water and 12.5L 30wt% concentrated hydrochloric acid were added, and the temperature was raised to 80°C with stirring to carry out thiolation reaction for 6h. The reaction was completed by TLC monitoring, and a yellow solid was precipitated. The temperature was then lowered to 10°C, and 48kg 25wt% sodium hydroxide solution was slowly added dropwise, and the solid gradually dissolved. After the addition was completed, stirring was continued for 3h, and a small amount of insoluble matter was removed by filtration. The filtrate was adjusted to pH 3 with 62kg 10wt% dilute hydrochloric acid, and stirring was continued for 3h. The filter cake was centrifuged and slurried with 30°C warm water to remove residual inorganic salts, and then centrifuged and dried to obtain 20.5kg 2-mercaptonicotinic acid with a yield of about 83%, wherein the molar ratio of the 2-chloronicotinic acid to thiourea was 1:1.2;

[0118] (2) In a dry 100L glass kettle, 15.5kg of 2-mercaptonicotinic acid obtained in step (1), 50L of methanol and 0.78kg of p-toluenesulfonic acid were added, and the temperature was raised to 65°C for methyl esterification reaction for 8h. The reaction was monitored by TLC to complete, and the mixture was concentrated under reduced pressure until a large amount of solid precipitated. 60L of water was added for pulping, centrifugal filtration was performed, and the mixture was washed with water to obtain 15.5kg of light yellow solid 2-mercaptonicotinic acid methyl ester, with a yield of about 92%; wherein p-toluenesulfonic acid was 5% of the mass of 2-mercaptonicotinic acid;

[0119] (3) In a dry 100L glass reactor, 6kg of glycine and 21kg of DMSO were added, the temperature was lowered to below 5°C, 5kg of sodium methoxide was added in batches, the temperature was slowly raised to 50°C and stirred for 3h to completely dissolve the glycine, 12.5kg of 2-mercaptonicotinic acid methyl ester obtained in step (2) was added, the temperature was further raised to 130°C and kept for 7h to carry out amine ester exchange, and the reaction was completed by HPLC monitoring, the temperature was lowered to below 20°C, 40kg of water was slowly added, and the pH value was adjusted to 3 with 33kg of 10wt% dilute hydrochloric acid to precipitate a large amount of yellow solid, and the mixture was stirred for 2h at room temperature, and centrifuged to obtain a yellow crude product; wherein the molar ratio of glycine, sodium methoxide and 2-mercaptonicotinic acid methyl ester was 1.08:1.25:1;

[0120] (4) The crude product obtained in step (3) and 50 kg of water are placed in a 100 L kettle, the temperature is controlled below 30° C., 15 kg of 20 wt % sodium hydroxide solution is slowly added dropwise under stirring until it is completely dissolved, stirring is continued for 1 hour, and then a very small amount of turbidity is removed by filtration. The filtrate is adjusted to pH 3 with 28 kg of 10 wt % dilute hydrochloric acid, centrifuged and dried, the solid is washed with water until it is neutral, and dried to obtain 14 kg of 2-mercaptonicotinoylglycine, with a yield of about 89.3%, a melting point of 241.1-241.4° C. (capillary measurement), and an HPLC purity of 99.4%.

[0121] The HPLC spectrum of 2-mercaptonicotinoylglycine prepared in Example 3 is as follows: Figure 4 shown.

[0122] from Figure 4 It can be seen that the purity of 2-mercaptonicotinoylglycine is 99.4%.

[0123] Comparative Example 1

[0124] The operation of step (3) was changed on the basis of Example 1, and other conditions remained unchanged;

[0125] (3) In a dry 250 mL three-necked flask, 15 g of glycine and 48 mL of DMSO were added, and 32 g of 2-mercaptonicotinic acid methyl ester obtained in step (2) was heated to 125° C. for 16 h for amine ester exchange. The reaction purity was not high according to HPLC monitoring, and the main impurity accounted for 35%. The temperature was then lowered to below 20° C., 100 mL of water was slowly added, and the solid was precipitated. The solid was filtered and 2 g of the solid was taken to obtain the impurity by preparative separation;

[0126] The HNMR spectrum of the impurity prepared in Comparative Example 1 is as follows Figure 5 shown.

[0127] It can be seen from the above examples that the synthesis method provided by the present invention has low pollution and high yield, and at the same time avoids the generation of odor during the production process.

[0128] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-mercaptonicotinoylglycine, comprising the following steps: (1) mixing 2-mercaptonicotinic acid, alcohol and a catalyst, and performing a methyl esterification reaction to obtain a synthetic ester; (2) Glycine, an alkaline catalyst and an organic solvent are mixed, and then the synthetic ester obtained in step (1) is added to carry out amine ester exchange to obtain 2-mercaptonicotinoylglycine.

2. The synthesis method according to claim 1, characterized in that In step (1), the alcohol is at least one of methanol, ethanol and isopropanol.

3. The synthesis method according to claim 1 or 2, characterized in that In the step (1), the mass ratio of 2-mercaptonicotinic acid to alcohol is 1:(2-5).

4. The synthesis method according to claim 1, characterized in that In the step (1), the catalyst is SOCl2 or p-toluenesulfonic acid.

5. The synthesis method according to claim 4, characterized in that The mass of the p-toluenesulfonic acid is 1-10% of the mass of 2-mercaptonicotinic acid; the molar ratio of the SOCl2 to 2-mercaptonicotinic acid is (1.1-1.3):

1.

6. The synthesis method according to claim 4, characterized in that When the catalyst is SOCl2, the temperature of the methyl esterification reaction in step (1) is room temperature; when the catalyst is p-toluenesulfonic acid, the temperature of the methyl esterification reaction in step (1) is 50-70°C.

7. The synthesis method according to claim 1, characterized in that The organic solvent in step (2) is at least one of DMSO and sulfolane.

8. The synthesis method according to claim 1, characterized in that The alkaline catalyst in step (2) is at least one of sodium methoxide and sodium ethoxide.

9. The synthesis method according to claim 1, characterized in that The temperature of the amine transesterification in step (2) is 100-140°C.

10. The synthesis method according to claim 1, characterized in that In the step (2), the molar ratio of glycine, alkaline catalyst and synthetic ester is (0.9-1.1):(1.1-1.3):1.

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