CN113651712A - Method for preparing N-p-aminobenzoyl-L-glutamic acid - Google Patents
Method for preparing N-p-aminobenzoyl-L-glutamic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of N-p-aminobenzoyl-L-glutamic acid, which comprises the following steps: mixing a toluene solution of paranitrobenzoyl chloride and L-glutamic acid in water, carrying out condensation reaction under the condition that the pH value is 10-11, and separating a water phase in a product obtained by the condensation reaction; and (3) carrying out reduction reaction on the water phase, ammonium formate and palladium-carbon, removing the palladium-carbon, and then precipitating crystals.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a method for preparing N-p-aminobenzoyl-L-glutamic acid.
Background
The arylamine compounds are extremely important organic raw materials and are widely applied to the fields of medicines, pesticides, dyes, high polymer materials and the like. N-p-aminobenzoyl-L-glutamic acid is one of arylamines, and is an intermediate for synthesizing folic acid (also called vitamin M) which is an anti-anemia drug. The compound is an important organic raw material and an intermediate, and is widely applied to the field of medicines.
At present, p-nitrobenzoyl chloride and glutamic acid are condensed to obtain N-p-nitrobenzoyl-L-glutamic acid in China, and the obtained product is subjected to reduction reaction to obtain the N-p-aminobenzoyl-L-glutamic acid. The reduction of aromatic nitro compounds by chemical methods is the most important method for synthesizing aromatic amine compounds, and the chemical reduction methods can be roughly divided into dosage type reduction methods and catalytic type reduction methods.
The dosage type reduction method mainly comprises the following steps: a metal reduction method, a metal hydride reduction method, a metal sulfide reduction method, and the like. The method has the advantages of simple operation, cheap raw materials, large environmental pressure, difficult product separation and generally low reduction yield. The catalytic reduction method adopts CO and H under the action of a metal catalyst2O、H2And the gas is used as a reducing agent or a hydrogen-containing organic substance or inorganic salt is used as a hydrogen donor to reduce the nitro compound, and the method has high reduction efficiency and is environment-friendly. However, in the former, gas is directly used as a reducing agent, the reaction is usually carried out under a certain pressure and temperature, and the pressure resistance and heat resistance of equipment are high; the latter transfer hydrogenation reduction method adopts hydrogen-containing substances as hydrogen donors to provide proton hydrogen, the reaction is usually carried out at normal temperature and normal pressure, a plurality of problems caused by using gas can be effectively avoided, the reaction condition is mild, and the operation is safe and simple.
In view of the increasingly prominent advantages of catalytic transfer hydrogenation reduction methods in many reduction methods, there have been increasing reports of related documents in recent years, and catalytic hydrogenation reactions carried out in the presence of metal catalysts using organic compounds as hydrogen donors in the reactions instead of gaseous hydrogen are called Catalytic Transfer Hydrogenation (CTH). The ammonium formate-Pd/C system takes ammonium formate as a hydrogen donor in the reduction reaction, and is safe and easy to operate. However, there are problems in that a complicated post-treatment step is required and an intermediate product formed in the previous step needs to be separated and purified and then subjected to the next reaction.
Disclosure of Invention
Based on the above, it is necessary to provide a method for preparing N-p-aminobenzoyl-L-glutamic acid, aiming at the problem that the intermediate product needs to be separated and purified in the reaction process.
A preparation method of N-p-aminobenzoyl-L-glutamic acid comprises the following steps:
mixing a toluene solution of paranitrobenzoyl chloride and L-glutamic acid in water, carrying out condensation reaction under the condition that the pH value is 10-11, and separating a water phase in a product obtained by the condensation reaction;
and (3) carrying out reduction reaction on the water phase, ammonium formate and palladium-carbon, removing the palladium-carbon, and then precipitating crystals.
In one embodiment, the step of separating the aqueous phase from the product resulting from the condensation reaction is removing the organic phase from the product resulting from the condensation reaction.
In one embodiment, the addition amount of the reaction raw materials is, in terms of molar ratio, that of paranitrobenzoyl chloride and L-glutamic acid ═ 1: (1-1.1).
In one embodiment, the ratio of the paranitrobenzoyl chloride to the toluene in the toluene solution of the paranitrobenzoyl chloride is (18-22) g:80 ml.
In one embodiment, the addition amount of the reaction raw materials is that the ratio of the paranitrobenzoyl chloride, the ammonium formate and the palladium-carbon is 1: (2-6): (2-6).
In one embodiment, the addition amount of the reaction raw materials is that the ratio of the paranitrobenzoyl chloride, the ammonium formate and the palladium-carbon is 1: (3-4): (3-4).
In one embodiment, the step of mixing a toluene solution of paranitrobenzoyl chloride and L-glutamic acid in water is: mixing L-glutamic acid with water, dropwise adding a toluene solution of p-nitrobenzoyl chloride, and dropwise adding an acid-forming agent in the process to enable the pH of the reaction solution to be 10-11.
In one embodiment, the condensation reaction is carried out at a reaction temperature of 0-10 ℃ for 2-3 hours.
In one embodiment, the reaction temperature of the reduction reaction is 45-55 ℃, and the reaction time is 2-7 hours.
In one embodiment, the step of precipitating crystals comprises: and (3) dropwise adding hydrochloric acid into the filtrate after the palladium carbon is removed, and adjusting the pH of the filtrate to 3-3.5.
A method for synthesizing folic acid, comprising:
the method is used for preparing the N-p-aminobenzoyl-L-glutamic acid, and the folic acid is prepared by taking the N-p-aminobenzoyl-L-glutamic acid as a raw material.
In the condensation reaction, toluene is used as a reaction system of paranitrobenzoyl chloride, the pH value is strictly controlled to be 10-11, and research results show that in the pH value range, the probability of hydrolyzing paranitrobenzoyl chloride into nitrobenzoic acid is greatly reduced, the selectivity is good, side reactions are reduced, the conversion rate and the yield are increased, the conversion rate reaches over 90 percent, the purity is over 99 percent, the quality and the purity of N-paranitrobenzoyl-L-glutamic acid in a condensation reaction product are ensured, and the condensation reaction liquid is directly put into the next reaction after being separated from an organic phase, so that the step of separating out N-paranitrobenzoyl-L-glutamic acid into crystals by increasing hydrochloric acid in the step when the conventional paranitrobenzoyl chloride and L-glutamic acid are used as raw materials for preparing folic acid is avoided, the generation of waste liquid is reduced, and the environmental pollution is reduced, the cost for treating the waste liquid is reduced. In the reduction reaction, ammonium formate is used for providing a hydrogen source, palladium-carbon is used as a catalyst, the reaction temperature is mild, the requirement on reaction equipment is not high, the reaction operability is strong, and the production safety is ensured.
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FIG. 1 is a schematic diagram of a process for preparing N-p-aminobenzoyl-L-glutamic acid according to an embodiment of the present invention.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The embodiment of the invention provides a preparation method of N-p-aminobenzoyl-L-glutamic acid, which comprises the following steps:
mixing a toluene solution of paranitrobenzoyl chloride and L-glutamic acid in water, carrying out condensation reaction under the condition that the pH value is 10-11, and separating a water phase in a product obtained by the condensation reaction;
and (3) carrying out reduction reaction on the water phase, ammonium formate and palladium-carbon, removing the palladium-carbon, and then precipitating crystals.
In the condensation reaction, toluene is used as a reaction system of paranitrobenzoyl chloride, the pH value is strictly controlled to be 10-11, and research results show that in the pH value range, the probability of hydrolyzing paranitrobenzoyl chloride into nitrobenzoic acid is greatly reduced, the selectivity is good, side reactions are reduced, the conversion rate and the yield are increased, the conversion rate reaches over 90 percent, the purity is over 99 percent, the quality and the purity of N-paranitrobenzoyl-L-glutamic acid in a condensation reaction product are ensured, and the condensation reaction liquid is directly put into the next reaction after being separated from an organic phase, so that the step of separating out N-paranitrobenzoyl-L-glutamic acid into crystals by increasing hydrochloric acid in the step when the conventional paranitrobenzoyl chloride and L-glutamic acid are used as raw materials for preparing folic acid is avoided, the generation of waste liquid is reduced, and the environmental pollution is reduced, the cost for treating the waste liquid is reduced. In the reduction reaction, ammonium formate is used for providing a hydrogen source, palladium-carbon is used as a catalyst, the reaction temperature is mild, the requirement on reaction equipment is not high, the reaction operability is strong, and the production safety is ensured.
In some embodiments, the starting materials are added in a molar ratio of p-nitrobenzoyl chloride to L-glutamic acid ═ 1: (1-1.1).
In some embodiments, the ratio of paranitrobenzoyl chloride to toluene in the toluene solution of paranitrobenzoyl chloride is (18-22) g:80 ml. Specifically, 80ml of toluene may contain 18g, 18.5g, 19g, 19.5g, 20g, 20.5g, 21g, 21.5g or 22g of p-nitrobenzoyl chloride.
In some embodiments, the reaction feed is added in a molar ratio of p-nitrobenzoyl chloride to ammonium formate of 1: (2-6). Specifically, the molar ratio of nitrobenzoyl chloride to ammonium formate can be 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1: 6. Preferably 1 (3-4).
In some embodiments, the reaction feed is added in a molar ratio of p-nitrobenzoyl chloride to palladium on carbon 1: (2-6). Specifically, the molar ratio of nitrobenzoyl chloride to palladium carbon can be 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 and 1: 6. Preferably 1 (3-4).
The palladium-carbon is a catalyst for the reduction reaction, and the proportion of the palladium-carbon is selected, so that the reduction reaction has higher selectivity, fewer byproducts and higher reaction efficiency, therefore, compared with the traditional process, the condensation reaction of the invention does not need to obtain a solid intermediate, and the reaction solution is directly put into the reduction reaction after simple treatment.
In some embodiments, the step of mixing a toluene solution of paranitrobenzoyl chloride and L-glutamic acid in water is: mixing L-glutamic acid with water, dropwise adding a toluene solution of p-nitrobenzoyl chloride, and dropwise adding an acid-forming agent in the process to enable the pH of the reaction solution to be 10-11 so as to reduce the generation of impurities. The acid scavenger is selected from hydroxides. Examples of the hydroxide include sodium hydroxide and potassium hydroxide.
In some embodiments, the condensation reaction is carried out at a reaction temperature of 0 to 10 ℃ for 2 to 3 hours. Preferably, the condensation reaction temperature may be 1 ℃, 2 ℃,3 ℃,4 ℃,5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃ and 10 ℃. Alternatively, the condensation reaction time may be 2 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, 2.6 hours, 2.7 hours, 2.8 hours, 2.9 hours, 3 hours. The proportion of the corresponding condensation reactant is matched under the condensation condition, so that the reaction selectivity is higher, and the impurities are less.
In some embodiments, the reduction reaction is carried out at a reaction temperature of 45 ℃ to 55 ℃ for a reaction time of 2 hours to 7 hours. Alternatively, the reduction reaction temperature may be 45 deg.C, 46 deg.C, 47 deg.C, 48 deg.C, 49 deg.C, 50 deg.C, 51 deg.C, 52 deg.C, 53 deg.C, 54 deg.C, 55 deg.C. Alternatively, the reduction reaction time may be 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours. The reaction selectivity is higher and the impurities are less by matching with the proportion of the corresponding reduction reactant under the reduction condition.
In some embodiments, the method for removing palladium on carbon after the reduction reaction may be, for example, a common separation method such as filtration or dialysis.
In some embodiments, the step of precipitating crystals comprises: and (3) dropwise adding hydrochloric acid into the filtrate after the palladium carbon is removed, and adjusting the pH of the filtrate to 3-3.5. The hydrochloric acid is preferably concentrated hydrochloric acid. Preferably, the temperature of the crystallization reaction may be 45 to 55 ℃. The method can also comprise the steps of suction filtration and drying after crystallization. The drying temperature may be 55 ℃ to 65 ℃.
In some embodiments, the step of separating the aqueous phase from the product resulting from the condensation reaction is removing the organic phase from the product resulting from the condensation reaction. The aqueous phase is obtained by removing only the organic phase from the product obtained by the condensation reaction. In some embodiments, the reduction reaction is followed by direct crystallization to yield the product N-p-aminobenzoyl-L-glutamic acid by removal of only the palladium on carbon. The two-step reaction of the invention uses water as a reaction solvent, a solid intermediate is not required to be taken after the condensation reaction, the operation is simplified, the yield is improved, the temperature of the reduction reaction is mild, the requirement on reaction equipment is not high, the reaction operability is strong, Pd/C can be recycled and reused for many times, the production cost is reduced, the production safety is ensured, the total yield of the two-step reaction can reach more than 80%, the purity of N-p-aminobenzoyl-L-glutamic acid is more than 99.00%, and the quality is ensured while the yield is improved. The method reduces the generation of waste liquid in the reaction process, avoids the pollution to the environment to the maximum extent, saves the cost, improves the quality, and is a green and environment-friendly process suitable for industrial production.
Referring to fig. 1, in some embodiments, a method for preparing N-p-aminobenzoyl-L-glutamic acid includes the following steps, and does not include other steps, by which N-p-aminobenzoyl-L-glutamic acid with higher purity can be obtained, the steps including:
(1) mixing a toluene solution of paranitrobenzoyl chloride and L-glutamic acid in water, carrying out condensation reaction under the condition that the pH value is 10-11, and separating a water phase in a product obtained by the condensation reaction;
(2) and (3) carrying out reduction reaction on the water phase, ammonium formate and palladium-carbon, removing the palladium-carbon, and then precipitating crystals.
(1) In the condensation reaction, the pH value is strictly controlled to be 10-11, and research results show that, within the pH value range, the probability of hydrolyzing the paranitrobenzoyl chloride into nitrobenzoic acid is greatly reduced, the selectivity is good, the side reaction is reduced, the conversion rate and the yield are increased, the conversion rate reaches over 90 percent, the purity is over 99 percent, the quality and the purity of the N-paranitrobenzoyl-L-glutamic acid in a condensation reaction product are ensured, and the condensation reaction liquid is directly put into the next reaction after an organic phase is separated, so that the step that N-p-nitrobenzoyl-L-glutamic acid is separated out to be crystal due to the need of increasing a large amount of hydrochloric acid in the step when the folic acid is prepared by taking the conventional p-nitrobenzoyl chloride and the L-glutamic acid as raw materials is avoided, the generation of waste liquid is reduced, the pollution to the environment is reduced, and the cost for treating the waste liquid is reduced.
(2) In the reduction reaction, ammonium formate is used for providing a hydrogen source, palladium-carbon is used as a catalyst, the reaction temperature is mild, the requirement on reaction equipment is not high, the reaction operability is strong, the production safety is ensured, and the method is a route suitable for industrial production.
The N-p-aminobenzoyl-L-glutamic acid prepared by the invention can be used for the synthesis process of folic acid.
In some embodiments, the step of synthesizing folic acid can comprise: 2,4, 5-triamino-6-hydroxypyrimidine sulfate, 1, 3-trichloroacetone, pyrosulfurous acid and N-p-aminobenzoyl-L-glutamic acid prepared in any one of the above embodiments are subjected to a cyclization reaction under a condition that the pH value is 2-4.
In some embodiments, the temperature of the cyclization reaction is from 50 ℃ to 60 ℃ and the reaction time is from 5 hours to 10 hours. Alternatively, the temperature of the cyclization reaction may be 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃ and 60 ℃. Alternatively, the cyclization reaction time may be 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours. The reaction selectivity is higher and the impurities are less by matching the proportion of the corresponding cyclization reactant under the cyclization condition.
In some embodiments, carbonate is used as an acid-binding agent to reduce the generation of impurities by adjusting the pH of the cyclization reaction to 2-4. The carbonate may be, for example, potassium carbonate, sodium carbonate, or the like.
In some embodiments, the reaction starting materials are added in a molar ratio of p-nitrobenzoyl chloride: 2,4, 5-triamino-6-hydroxypyrimidine sulfate: 1,1, 3-trichloroacetone ═ 1: (1.0-1.3): (2.0-5). Specifically, paranitrobenzoyl chloride: 2,4, 5-triamino-6-hydroxypyrimidine sulfate: the 1,1, 3-trichloroacetone molar ratio may be 1: (2.0-5), 1: 1.1: (2.0-5), 1: 1.2: (2.0-5), 1: 1.3: (2.0-5) and (1.0-1.3): 2.1 (1.0-1.3): 4.1 (1.0-1.3): 4.1 (1.0-1.3): 5.
the following are specific examples.
Example 1
Adding 17.44g L-glutamic acid and 80mL of water into a 500mL reaction bottle, stirring and cooling to 5 ℃, dropwise adding a 15% sodium hydroxide solution until the reaction system is clear, dropwise adding a toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride is dissolved in 80mL of toluene), controlling the pH to be 10, finishing the reaction for 2 hours, standing and separating the reaction solution, separating an organic phase, and obtaining an aqueous phase HPLC intermediate 1 with the purity of 99.46%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3h, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3, crystallizing for 1h, performing suction filtration to obtain a white solid, and drying for 8h at 60 ℃ to obtain 24.61g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 85.79% and the purity of 99.41%.
Example 2
15.86g L-glutamic acid (0.11mol) and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 10 ℃ by stirring, 15% sodium hydroxide solution is dripped into the reaction system until the reaction system is clear, then toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride is dissolved in 80mL of toluene) is dripped at the same time, the pH value is controlled to be 11, the reaction is dripped for 2 hours, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of the HPLC intermediate 1 of the aqueous phase is 93.87%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3h, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3.5, crystallizing for 1h, performing suction filtration to obtain a white solid, drying for 8h at 60 ℃, and obtaining 22.35g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 77.91% and the purity of 93.21%.
Example 3
17.44g (0.12mol) of L-glutamic acid and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15% sodium hydroxide solution is dripped until the reaction system is clear, a toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride (0.11mol) is dripped into 80mL of toluene), the pH is controlled to be 9, the reaction is finished for 2h, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of an HPLC intermediate 1 of an aqueous phase is 93.87%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g (0.43mol) of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3 hours, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3.5, crystallizing for 1 hour, performing suction filtration to obtain a white solid, drying for 8 hours at 60 ℃, and obtaining 21.92g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 76.41 percent and the purity of 93.21 percent.
Example 4
17.44g (0.12mol) of L-glutamic acid and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15% sodium hydroxide solution is dripped until the reaction system is clear, a toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride (0.11mol) is dripped into 80mL of toluene), the pH value is controlled to be 12, the reaction is dripped for 2 hours, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of an HPLC intermediate 1 of an aqueous phase is 95.35%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g (0.43mol) of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3 hours, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3.5, crystallizing for 1 hour, performing suction filtration to obtain a white solid, drying for 8 hours at 60 ℃, and obtaining 22.15g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 77.22% and the purity of 95.10%.
Example 5
19.85g (0.135mol) of L-glutamic acid and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15% sodium hydroxide solution is dripped until the reaction system is clear, a toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride (0.11mol) is dripped into 80mL of toluene), the pH value is controlled to be 10, the reaction is dripped for 2 hours, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of an HPLC intermediate 1 of an aqueous phase is 99.66%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g (0.43mol) of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3 hours, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3.5, crystallizing for 1 hour, performing suction filtration to obtain a white solid, drying for 8 hours at 60 ℃, and obtaining 23.77g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 82.86% and the purity of 99.43%.
Example 6
14.71g (0.10mol) of L-glutamic acid and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15% sodium hydroxide solution is dripped until the reaction system is clear, toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride (0.11mol) is dripped into 80mL of toluene), the pH value is controlled to be 10, the reaction is dripped for 2 hours, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of HPLC intermediate 1 of an aqueous phase is 94.82%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g (0.43mol) of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3 hours, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3.5, crystallizing for 1 hour, performing suction filtration to obtain a white solid, drying for 8 hours at 60 ℃, and obtaining 22.94g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 79.97% and the purity of 94.17%.
Example 7
17.44g (0.12mol) of L-glutamic acid and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15% sodium hydroxide solution is dripped until the reaction system is clear, a toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride (0.11mol) is dripped into 80mL of toluene), the pH value is controlled to be 10, the reaction is dripped for 2 hours, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of an HPLC intermediate 1 of an aqueous phase is 99.47%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g (0.43mol) of ammonium formate and 1.28g of palladium carbon, stirring and heating to 30 +/-5 ℃, reacting for 3h, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3.5, crystallizing for 1h, performing suction filtration to obtain a white solid, drying for 8h at 60 ℃, and obtaining 23.15g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 80.70% and the purity of 99.02%.
Example 8
17.44g (0.12mol) of L-glutamic acid and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15% sodium hydroxide solution is dripped until the reaction system is clear, toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride (0.11mol) is dissolved in 80mL of toluene) is dripped simultaneously, the pH value is controlled to be 10, the reaction is dripped for 2 hours, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of the HPLC intermediate 1 of the aqueous phase is 99.50%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g (0.43mol) of ammonium formate and 1.28g of palladium carbon, stirring and heating to 65 +/-5 ℃, reacting for 3 hours, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3.5, crystallizing for 1 hour, performing suction filtration to obtain a white solid, drying for 8 hours at 60 ℃, and obtaining 23.66g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 82.48% and the purity of 99.49%.
Example 9
17.44g L-glutamic acid and 80mL of water are put into a 500mL reaction bottle, the temperature is reduced to 5 ℃ by stirring, 15% sodium hydroxide solution is dripped into the reaction system until the reaction system is clear, then dichloroethane solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride is dissolved in 80mL of dichloroethane) is dripped at the same time, the PH value is controlled to be 10, the reaction is dripped for 2 hours, the reaction solution is kept stand for liquid separation, an organic phase is separated, and the purity of the HPLC intermediate 1 of the aqueous phase is 99.46%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3h, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3, crystallizing for 1h, performing suction filtration to obtain a white solid, and drying for 8h at 60 ℃ to obtain 21.44g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 74.74% and the purity of 98.76%.
Example 10
Adding 17.44g L-glutamic acid and 80mL of water into a 500mL reaction bottle, stirring and cooling to 5 ℃, dropwise adding a 15% sodium hydroxide solution until the reaction system is clear, dropwise adding a toluene solution of p-nitrobenzoyl chloride (20.00g of p-nitrobenzoyl chloride is dissolved in 120mL of toluene), controlling the pH to be 10, finishing the reaction for 2 hours, standing and separating the reaction solution, separating an organic phase, and obtaining an aqueous phase HPLC intermediate 1 with the purity of 99.46%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3h, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3, crystallizing for 1h, performing suction filtration to obtain a white solid, and drying for 8h at 60 ℃ to obtain 24.11g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 84.05% and the purity of 99.02%.
Example 11
Adding 17.44g L-glutamic acid and 80mL of water into a 500mL reaction bottle, stirring and cooling to 5 ℃, dropwise adding a 15% sodium hydroxide solution until the reaction system is clear, dropwise adding a toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride is dissolved in 50mL of toluene), controlling the pH to be 10, finishing the reaction for 2 hours, standing and separating the reaction solution, separating an organic phase, and obtaining an aqueous phase HPLC intermediate 1 with the purity of 99.46%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3h, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3, crystallizing for 1h, performing suction filtration to obtain a white solid, and drying for 8h at 60 ℃ to obtain 22.77g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 79.38% and the purity of 96.45%.
Example 12 application for folate synthesis
Adding 17.44g L-glutamic acid and 80mL of water into a 500mL reaction bottle, stirring and cooling to 5 ℃, dropwise adding a 15% sodium hydroxide solution until the reaction system is clear, dropwise adding a toluene solution of paranitrobenzoyl chloride (20.00g of paranitrobenzoyl chloride is dissolved in 80mL of toluene), controlling the pH to be 10, finishing the reaction for 2 hours, standing and separating the reaction solution, separating an organic phase, and obtaining an aqueous phase HPLC intermediate 1 with the purity of 99.46%.
Putting the water phase into a 500ml reaction bottle, adding 27.20g of ammonium formate and 1.28g of palladium carbon, stirring and heating to 50 +/-5 ℃, reacting for 3h, filtering out the palladium carbon, dropwise adding concentrated hydrochloric acid into the filtrate at 10-20 ℃, adjusting the pH value to 3, crystallizing for 1h, performing suction filtration to obtain a white solid, and drying for 8h at 60 ℃ to obtain 24.61g of N-p-aminobenzoyl-L-glutamic acid with the molar yield of 85.79% and the purity of 99.41%.
Putting N-p-aminobenzoyl-L-glutamic acid into a 1000ml reaction bottle, adding 600ml of water, adjusting the pH value to 3 +/-0.5 by using concentrated hydrochloric acid under stirring, adding 30.94g of 2,4, 5-triamino-6-hydroxypyrimidine sulfate (0.13mol), 79.53g of 1,1, 3-trichloroacetone and 15.58g of sodium metabisulfite, controlling the internal temperature to be 50 ℃, reacting for 7 hours, performing suction filtration to obtain a tawny folic acid crude product, and drying to obtain 38.92g of folic acid, wherein the total yield is 81.82% and the HPLC purity is 83.02%.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the patent protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the patent of the invention is subject to the appended claims, and the description can be used for explaining the contents of the claims.
Claims (10)
1. A preparation method of N-p-aminobenzoyl-L-glutamic acid is characterized by comprising the following steps:
mixing a toluene solution of paranitrobenzoyl chloride and L-glutamic acid in water, carrying out condensation reaction under the condition that the pH value is 10-11, and separating a water phase in a product obtained by the condensation reaction;
and (3) carrying out reduction reaction on the water phase, ammonium formate and palladium-carbon, removing the palladium-carbon, and then precipitating crystals.
2. The method for producing N-p-aminobenzoyl-L-glutamic acid according to claim 1, wherein the reaction raw materials are added in an amount of p-nitrobenzoyl chloride to L-glutamic acid ═ 1: (1-1.1).
3. The method for preparing N-p-aminobenzoyl-L-glutamic acid according to claim 1, wherein the ratio of p-nitrobenzoyl chloride to toluene in the toluene solution of p-nitrobenzoyl chloride is (18-22) g:80 ml.
4. The method for producing N-p-aminobenzoyl-L-glutamic acid according to claim 1, wherein the reaction raw materials are added in such an amount that the ratio of p-nitrobenzoyl chloride, ammonium formate and palladium on carbon is 1: (2-6): (2-6).
5. The process according to claim 4, wherein the starting materials are added in a molar ratio of nitrobenzoyl chloride to ammonium formate to palladium on carbon of 1: (3-4): (3-4).
6. The method for producing N-p-aminobenzoyl-L-glutamic acid according to any one of claims 1 to 5, wherein the step of mixing a toluene solution of p-nitrobenzoyl chloride and L-glutamic acid in water comprises: mixing L-glutamic acid with water, dropwise adding a toluene solution of p-nitrobenzoyl chloride, and dropwise adding an acid-forming agent in the process to enable the pH of the reaction solution to be 10-11.
7. The method for producing N-p-aminobenzoyl-L-glutamic acid according to any one of claims 1 to 5, wherein the condensation reaction is carried out at a reaction temperature of 0 to 10 ℃ for 2 to 3 hours.
8. The method for producing N-p-aminobenzoyl-L-glutamic acid according to any one of claims 1 to 5, wherein the reduction reaction is carried out at a reaction temperature of 45 ℃ to 55 ℃ for 2 hours to 7 hours.
9. The method for producing N-p-aminobenzoyl-L-glutamic acid according to any one of claims 1 to 5, wherein the step of precipitating a crystal comprises: and (3) dropwise adding hydrochloric acid into the filtrate after the palladium carbon is removed, and adjusting the pH of the filtrate to 3-3.5.
10. A method for synthesizing folic acid, which is characterized by comprising the following steps:
use of the method according to any one of claims 1 to 9 for the production of N-p-aminobenzoyl-L-glutamic acid and for the production of folic acid using it as a starting material.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101182323A (en) * | 2007-12-26 | 2008-05-21 | 潘福星 | Method for preparing folic acid |
| CN105439895A (en) * | 2015-12-30 | 2016-03-30 | 浙江汇能生物股份有限公司 | Preparation method of N (4-aminobenzoyl)-L-glutamic acid |
| CN108147977A (en) * | 2017-12-27 | 2018-06-12 | 江苏尚莱特医药化工材料有限公司 | The preparation method of N- p-benzoyls-Pidolidone |
| CN110668968A (en) * | 2019-09-24 | 2020-01-10 | 涉县津东经贸有限责任公司 | Preparation method of p-aminobenzoyl glutamic acid |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101182323A (en) * | 2007-12-26 | 2008-05-21 | 潘福星 | Method for preparing folic acid |
| CN105439895A (en) * | 2015-12-30 | 2016-03-30 | 浙江汇能生物股份有限公司 | Preparation method of N (4-aminobenzoyl)-L-glutamic acid |
| CN108147977A (en) * | 2017-12-27 | 2018-06-12 | 江苏尚莱特医药化工材料有限公司 | The preparation method of N- p-benzoyls-Pidolidone |
| CN110668968A (en) * | 2019-09-24 | 2020-01-10 | 涉县津东经贸有限责任公司 | Preparation method of p-aminobenzoyl glutamic acid |
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