* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With palladium 10% on activated carbon; ammonium formate In methanol at 20℃; for 0.5 h;
Reaction vessel was added N- Nitrobenzoylhydrazone -L- glutamic acid 27.23g (0.1mol), methanol 118g, turn on stirring, was added 10percent Pd / C0.59g, then slowly added ammonium formate 18.92g (0.3mol), stirred at room temperature for 30 minutes, filtered, recovered Pd / C next applied, the filtrate was adjusted with hydrochloric acid in methanol PH = 3, the precipitated crystals were filtered after 30 minutes resting, a small amount of methanol, washed, dried, to give N - amino-benzoyl -L- glutamic acid 25.75g, HPLC purity of 99.88percent, a yield of 96.58percent, the total yield of 95.64percent (with on-nitro benzoic acid).
25.7 g
With iron(III) chloride hexahydrate; hydrazine hydrate In methanol at 20℃;
3 Add 29.3 g of N-p-nitrobenzoyl-L-glutamic acid obtained in Step 2, 118 g of methanol, and 0.81 g of ferric chloride hexahydrate (0.003 mol) to the reaction apparatus, and slowly drip with stirring. 15.0 g of hydrazine hydrate (0.3 mol) was added, and the reaction was stirred to completion at room temperature. After completion of the reaction, the pH was adjusted to 3.5 with hydrochloric acid, crystallized, filtered, and the filter cake was washed with methanol, and then dried under reduced pressure to give 25.7 g of N-p-aminobenzoyl-L-glutamic acid with a purity of 99.95percent (HPLC) The three-step yield based on p-nitrobenzoic acid was 96.6percent.
Reference：
[1] Patent: CN105439895, 2016, A, . Location in patent: Paragraph 0029; 0030
[2] Chirality, 2010, vol. 22, # 2, p. 252 - 257
[3] Journal of the Chemical Society, 1949, p. 1401,1404
[4] Yakugaku Zasshi, 1949, vol. 69, p. 457[5] Chem.Abstr., 1950, p. 3442
[6] Chemische Berichte, 1951, vol. 84, p. 485,488[7] Zeitschrift fuer Naturforschung, 1950, vol. 5b, p. 132,135
[8] Patent: US2560616, 1948, ,
[9] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 738,741
[10] J. Immunol., 1935, vol. 29, p. 371,373
[11] Pharmaceutical Chemistry Journal, 1985, vol. 19, # 4, p. 273 - 275[12] Khimiko-Farmatsevticheskii Zhurnal, 1985, vol. 19, # 4, p. 448 - 450
[13] Patent: CN108147977, 2018, A, . Location in patent: Paragraph 0015; 0019; 0020; 0021; 0022; 0024
2
[ 233600-78-7 ]
[ 4271-30-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 10, p. 1311 - 1323
3
[ 56-86-0 ]
[ 4271-30-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 10, p. 1311 - 1323
[2] Journal of the Chemical Society, 1949, p. 1401,1404
4
[ 62-23-7 ]
[ 4271-30-1 ]
Reference：
[1] Patent: CN105439895, 2016, A,
[2] Patent: CN108147977, 2018, A,
5
[ 13726-52-8 ]
[ 4271-30-1 ]
Reference：
[1] Nature (London, United Kingdom), 1948, vol. 162, p. 153
6
[ 404-26-2 ]
[ 4271-30-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 10, p. 1311 - 1323
7
[ 126063-08-9 ]
[ 4271-30-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 10, p. 1311 - 1323
8
[ 23150-65-4 ]
[ 4271-30-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 10, p. 1311 - 1323
9
[ 122-04-3 ]
[ 4271-30-1 ]
Reference：
[1] Journal of the Chemical Society, 1949, p. 1401,1404
[2] Yakugaku Zasshi, 1949, vol. 69, p. 457[3] Chem.Abstr., 1950, p. 3442
10
[ 59-30-3 ]
[ 4271-30-1 ]
[ 948-60-7 ]
[ 712-30-1 ]
Reference：
[1] Photochemistry and Photobiology, 2006, vol. 82, # 3, p. 817 - 822
11
[ 7148-24-5 ]
[ 4271-30-1 ]
Reference：
[1] Journal of the Chemical Society, 1949, p. 1401,1404
12
[ 59-30-3 ]
[ 4271-30-1 ]
Reference：
[1] Journal of Photochemistry and Photobiology B: Biology, 2018, vol. 181, p. 157 - 163
13
[ 59-30-3 ]
[ 712-30-1 ]
[ 4271-30-1 ]
Reference：
[1] Photochemistry and Photobiology, 2007, vol. 83, # 3, p. 526 - 534
14
[ 59-30-3 ]
[ 4271-30-1 ]
[ 150-13-0 ]
[ 948-60-7 ]
[ 712-30-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 1, p. 67 - 71
15
[ 3475-39-6 ]
[ 4271-30-1 ]
[ 35011-47-3 ]
[ 59-30-3 ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium carbonate In ethanol; water at 40℃;
(1) 20.63 g of 1,1,3-tribromoacetone was added to 600 mL of ethanol solution,Stirring and heating to 40 ;(2) until 1,1,3-tribromo acetone completely dissolved, continue to add 5.33g p-aminobenzoyl-L-glutamineAcid stirring until all dissolved, the first reaction solution;(3) Add 144 g of water to a separate reaction flask, weigh 14.23 g of 2,4,5-triamino-6-hydroxypyrimidine sulfate into the reaction flask in portions, and adjust the pH to 7.5 with saturated sodium carbonate.To 2,4,5-triamino-6-Hydroxypyrimidine sulfate completely dissolved to obtain a second reaction solution;(4) the second reaction solution is added to the first reaction solution in batches,Incubated for 8h;(5) After the reaction is completed, suction filtration to obtain crude folic acid;(6) The folic acid crude added to the reaction flask, and the volume ratio of 1: 1 was added to a mixture of water and ethanol 100g,Slowly added to a concentration of 98percent H2SO4 solution 17.3g, stirring 35min;(7) The above material was transferred to a large reaction flask,Adding a volume ratio of 1: 1 water and ethanol mixture 400g, crystal precipitation;(8) temperature control 55 ° C, stirring 50min, suction filtered acid-soluble folic acid crude solid;(9) at room temperature, the above-obtained solid was suction filtered into the reaction flask, and add water 530g,Heated to 95 , adding 20percent mass concentration of sodium hydroxide solution to adjust the pH to 9,Until the solid is completely dissolved;(10) After all the dissolved activated carbon was added 1.2g, stirred for 30min, suction filtration,The filtrate obtained by suction filtration was transferred to another reaction flask and incubated at 60 ° C.,The pH was adjusted to 2.5 with concentrated hydrochloric acid;(11) the reaction flask temperature was continued to cool to 50 , pressure filtration, the filter cake was washed with 700mL of purified water,5.3g folic acid dried to get fine.The yield of the above folic acid boutique is 60percent.
Reference：
[1] Patent: CN107163051, 2017, A, . Location in patent: Paragraph 0025; 0026; 0027; 0028; 0029; 0030; 0031-0069
16
[ 921-03-9 ]
[ 4271-30-1 ]
[ 35011-47-3 ]
[ 59-30-3 ]
Yield
Reaction Conditions
Operation in experiment
83.2%
at 20 - 30℃; for 2 h; Ionic liquid
The reaction flask was charged with 100 g of N-p-aminobenzoylglutamic acid,120 g 2,4,5-triamino-6-hydroxypyrimidine sulfate,160 g of 1,1,3-trichloroacetone,140 g of sodium metabisulfite,100 g of 1-ethyl-3-methylimidazolium tetrafluoroborate ([emim] BF4)Stirring temperature 20 ~ 30 stirring reaction 2h,During the reaction with sodium hydroxide to adjust the system pH 3.0 ~ 3.5,After the reaction is stopped, the mixture is stirred, filtered and the crude acid is obtained.The resulting crude folic acid and 4.5 L of purified water were added to the reaction flask and heated to 80 to 90 ° C with stirring. Then,Sodium chloride solution (2N) to adjust the system pH to 8 ~ 9, add 15g activated carbon stirring stirring for 30 minutes, hot filter. filtrateTemperature control 80 ~ 90 , adding dilute hydrochloric acid (2N) adjusted to pH 3.0 ~ 3.5, slowly cool to room temperature, filter, filter cake placed in the bakeBox temperature control 60 ~ 65 vacuum drying 5h, folic acid pure 138g, yield 83.2percent, HPLC purity 99.7percent, which miscellaneousQuality butterfly content of 0.09percent.
46.2%
at 45℃; for 3 h;
Was added to the reaction vessel 500L 350L of water was stirred, heated to system 45 deg C. Followed by sodium acetate 2.1kg, sodium metabisulfite 7.0kg, 2,4,5-triamino-6-hydroxy-pyrimidine sulfate 3.0kg, N- amino-benzoyl glutamate 3.5kg were also added, then was slowly added trichloroacetone 4.5kg, 3h After the addition reaction, the reaction was added with 40percent sodium hydroxide aqueous solution adjusted PH = 3.3. After the reaction was cooled to room temperature, 40percent aqueous sodium hydroxide solution with PH = 3.3. Rejection filter folic acid crude. The crude product was 40L at room temperature and 10percent hydrochloric acid solution beating 0.5h, filter cloth, the water 0.6kg of magnesium oxide was added to 25L of 80 deg.] C, and then added to the filter cake acid was stirred 0.5 hours, activated carbon was added 0.15kg, 80 stirring was continued for 0.5 hours . Hot filtered and the filtrate cooled to 25 crystallization, filtration. The solid was added to 10L of purified water, heated to dissolve 70 , with 10percent hydrochloric acid solution to adjust pH = 1, cool to 25 . Filtration, the filter cake was added to 1L purified water beating 10min, filtered, the filter cake is folic acid refined products. Purity 99.8percent, yield 46.2percent.
Reference：
[1] Patent: CN106432241, 2017, A, . Location in patent: Paragraph 0023; 0024; 0025; 0026; 0027; 0028; 0029-0046
[2] Patent: CN105440035, 2016, A, . Location in patent: Paragraph 0029; 0030; 0031
With palladium 10% on activated carbon; ammonium formate; In methanol; at 20℃; for 0.5h;
Reaction vessel was added N- Nitrobenzoylhydrazone -L- glutamic acid 27.23g (0.1mol), methanol 118g, turn on stirring, was added 10% Pd / C0.59g, then slowly added ammonium formate 18.92g (0.3mol), stirred at room temperature for 30 minutes, filtered, recovered Pd / C next applied, the filtrate was adjusted with hydrochloric acid in methanol PH = 3, the precipitated crystals were filtered after 30 minutes resting, a small amount of methanol, washed, dried, to give N - amino-benzoyl -L- glutamic acid 25.75g, HPLC purity of 99.88%, a yield of 96.58%, the total yield of 95.64% (with on-nitro benzoic acid).
25.7 g
With iron(III) chloride hexahydrate; hydrazine hydrate; In methanol; at 20℃;
3 Add 29.3 g of N-p-nitrobenzoyl-L-glutamic acid obtained in Step 2, 118 g of methanol, and 0.81 g of ferric chloride hexahydrate (0.003 mol) to the reaction apparatus, and slowly drip with stirring. 15.0 g of hydrazine hydrate (0.3 mol) was added, and the reaction was stirred to completion at room temperature. After completion of the reaction, the pH was adjusted to 3.5 with hydrochloric acid, crystallized, filtered, and the filter cake was washed with methanol, and then dried under reduced pressure to give 25.7 g of N-p-aminobenzoyl-L-glutamic acid with a purity of 99.95% (HPLC) The three-step yield based on p-nitrobenzoic acid was 96.6%.
Yield of folic acid=68% of theory based on 2-hydroxymalondialdehyde used. For the isolation of the folic acid from this solution the pH value is adjusted to 3.0 with acetic acid. The folic acid precipitates and can be filtered off. There are obtained 3.08 g of folic acid crude product having a content of 91% of pure L-folic acid=63.5% of theory. The unreacted p-aminobenzoyl-L-glutamic acid is recovered from the filtrate by exhaustively extracting with methyl acetate at pH=3.0. There are obtained 3.23 g of p-aminobenzoyl-L-glutamic acid crude product having a content of 90% of pure p-aminobenzoyl-L-glutamic acid. The content of pure p-aminobenzoyl-L-glutamic acid is determined by HPLC.
With sodium metabisulfite; at 20 - 30℃; for 2h;Ionic liquid;
The reaction flask was charged with 100 g of N-p-aminobenzoylglutamic acid,120 g 2,4,5-triamino-6-hydroxypyrimidine sulfate,160 g of 1,1,3-trichloroacetone,140 g of sodium metabisulfite,100 g of 1-ethyl-3-methylimidazolium tetrafluoroborate ([emim] BF4)Stirring temperature 20 ~ 30 stirring reaction 2h,During the reaction with sodium hydroxide to adjust the system pH 3.0 ~ 3.5,After the reaction is stopped, the mixture is stirred, filtered and the crude acid is obtained.The resulting crude folic acid and 4.5 L of purified water were added to the reaction flask and heated to 80 to 90 C with stirring. Then,Sodium chloride solution (2N) to adjust the system pH to 8 ~ 9, add 15g activated carbon stirring stirring for 30 minutes, hot filter. filtrateTemperature control 80 ~ 90 , adding dilute hydrochloric acid (2N) adjusted to pH 3.0 ~ 3.5, slowly cool to room temperature, filter, filter cake placed in the bakeBox temperature control 60 ~ 65 vacuum drying 5h, folic acid pure 138g, yield 83.2%, HPLC purity 99.7%, which miscellaneousQuality butterfly content of 0.09%.
46.2%
With sodium metabisulfite; sodium acetate; at 45℃; for 3h;
Was added to the reaction vessel 500L 350L of water was stirred, heated to system 45 deg C. Followed by sodium acetate 2.1kg, sodium metabisulfite 7.0kg, 2,4,5-triamino-6-hydroxy-pyrimidine sulfate 3.0kg, N- amino-benzoyl glutamate 3.5kg were also added, then was slowly added trichloroacetone 4.5kg, 3h After the addition reaction, the reaction was added with 40% sodium hydroxide aqueous solution adjusted PH = 3.3. After the reaction was cooled to room temperature, 40% aqueous sodium hydroxide solution with PH = 3.3. Rejection filter folic acid crude. The crude product was 40L at room temperature and 10% hydrochloric acid solution beating 0.5h, filter cloth, the water 0.6kg of magnesium oxide was added to 25L of 80 deg.] C, and then added to the filter cake acid was stirred 0.5 hours, activated carbon was added 0.15kg, 80 stirring was continued for 0.5 hours . Hot filtered and the filtrate cooled to 25 crystallization, filtration. The solid was added to 10L of purified water, heated to dissolve 70 , with 10% hydrochloric acid solution to adjust pH = 1, cool to 25 . Filtration, the filter cake was added to 1L purified water beating 10min, filtered, the filter cake is folic acid refined products. Purity 99.8%, yield 46.2%.
In N,N-dimethyl acetamide; at 45℃; for 4h;Industrial scale;
The reaction flask was charged with 12.75 g (50 mmol) of 2-amino-4-hydroxy-6-bromomethylpteridine and 200 ml of N, N-dimethylamide, and 19.97 g (75 mmol) of N- Aminobenzoyl) -L-glutamic acid in 200 ml of N, N-dimethylacetamide was added and the mixture was heated to 45 C for 4 hours. Then, 330 ml of N, N-dimethylacetamide was distilled off under reduced pressure And the residue was stirred with 300 ml of water. The pH value was adjusted to 3.0-3.5 with 10% sodium carbonate aqueous solution. The resulting solid was filtered through acetone and stirred at 40 C for 30 minutes. After cooling, Dried to give 19.64 g, 89% yield, HPLC purity 97.6%.
2-amino-4-hydroxy-6-chloromethylpteridine[ No CAS ]
[ 59-30-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
In methanol; at 45℃; for 5h;Industrial scale;
The reaction flask was charged with 10.53 g (50 mmol) of 2-amino-4-hydroxy-6-chloromethylpteridine and 120 ml of methanol,After the addition, 26.62 g (100 mmol) of N- (4-aminobenzoyl) -L-glutamic acid in 220 ml of methanol was added dropwise. The mixture was heated to 45 C for 5 hours, and 290 ml of methanol was distilled off under reduced pressure And the residue was stirred with 300 ml of water. The pH value was adjusted to 3.0-3.5 with 10% sodium carbonate aqueous solution. The resulting solid was filtered and stirred at 40 C for 45 minutes. After cooling, the mixture was vacuum dried to give 18.76 g, 85% yield, HPLC purity 97.5%.
Step 1. Preparation of crude product,A four-necked flask was charged with 2,4,5-triamino-6-hydroxypyrimidine sulfate, p-aminobenzoylglutamic acid and trichloroacetone in a molar ratio of 1: 1: 1, , The raw materials in the flask are stirred, and when the three components are mixed uniformly, an alkaline sodium hydroxide liquid is added, and the basic sodium hydroxide is added in an amount of 10% of the total weight of the raw materials, wherein the basic sodium hydroxide is And the reaction temperature was 55C, the pH value was 3.0, and the reaction time was 9 hours. The crude product was prepared by the reaction under the basic condition. Step 2, adding sodium metabisulfite to the crude product, adding sodium metabisulfite 10% by weight of the crude product, stirring at 38 C for 0.5h, dropping 10% sodium carbonate solution to maintain the pH value at 3.5 for 2h; , The reaction solution was cooled to 25C, filtered, the filtrate and solid, the filtrate recycling; Step 3, acid extraction, The solid was put into a three-necked flask and dissolved in 35% sulfuric acid at 30 C. After stirring for 10 min, a pale yellow solid was precipitated, stirred at 35C for 1 h, poured into water at 30C (600 ml) 34~35C stirring 0.5h, suction filtration, filter cake washed with water after drying, in acid extract; Step 4: alkali refining, Add water to the reaction bottle two, and heated to 70~80C, the acid extract added to the reaction bottle II, followed by adding 10% sodium hydroxide solution to adjust the pH 8 ~ 8.5, to be completely soluble acid extract after adding activated carbon , Decolorization temperature 0.5h, add the right amount of hydrochloric acid, and adjust the pH of 2.5 to 3 for pickling (pickling temperature of 30 C), filtration, in pure folic acid. The folic acid prepared in this Example was 80% in yield and 97% in purity.
69.7%
350 kg of methanol and 420 kg of water were pumped into a 1500 liter reactor, and stirring was started, and then 35 kg (146 mol) of 2,4,5-triamino-6-hydroxypyrimidine sulfate, 283 kg of a 10% aqueous solution of trichloroacetone (175 mol) and 26 kg of sodium metabisulfite were sequentially introduced. After reacting for half an hour, 40.9 kg of <strong>[4271-30-1]N-p-aminobenzoyl-L-glutamic acid</strong> (154 mol) was charged, and the reaction vessel was heated to 40-45 C. Adjusting the pH of the system with aqueous sodium hydroxide solution to control the pH between 3 and 3.5 continuous reaction for 6 hours. Plate and frame pressure filtration to obtain crude folic acidIn a 2000 liter reactor, the crude folic acid was dissolved in about 7 times the mass ratio of methanol, and about 3 times by mass of thionyl chloride was slowly added dropwise, and the dropping temperature was completely dissolved at 10 C, and then distilled off under reduced pressure. After 80% methanol, folic acid crystals were precipitated, and 45 kg of pure folic acid was obtained by pressure filtration. The purity was 97.5%, and the yield (calculated as 2,4,5-triamino-6-hydroxypyrimidine sulfate) was 69.7%.
Under nitrogen protection,The 4.42 g (0.020 mol) of 2,4,5-triamino-6-hydroxypyrimidine sulfate,3.46 g (0.013 mol) of <strong>[4271-30-1]N-p-aminobenzoyl-L-glutamic acid</strong>,40 ml of deionized water and 0.27 g of phase transfer catalyst tetrabutylammonium chloride into a three-necked flask with a thermometer and stirring,The mixture was stirred at 40 C for 30 minutes.then,Was slowly added dropwise 5.4 g (0.025 mol) of 1,1,2,2,3-pentachloropropane and a mixed solution of 20 ml of anhydrous ethanol, thepH during the addition of sodium hydroxide solution so that the material is maintained at 8.0,Reaction at 40 C for 6 hours;After the reaction,The material was cooled to 20 C,After standing for 8 hours and filtering,The filter cake was washed with 20 ml of absolute ethanol,Dry folic acid crude,The yield was 79.3%;Liquid chromatography monitoring,The crude folic acid purity was 72.6%.
With sodium metabisulfite; sodium carbonate; In water; at 32 - 35℃;pH 3 - 3.5;
The first batch of 13.3kg N- (4-aminobenzoyl) -L-glutamic acid was added to 700L of water, stirred for 15 minutes and then added to the first batch of 2,4,5-triamino-6-hydroxy Pyrimidine sulfate 11.95kg,Stirring for 15 minutes to join the first batch of sodium metabisulfite 4.75kg, stirring the material evenly distributed before adding the first batch of trichloroacetone crystals 12.8kg and stir and mix,When adding the material to maintain the system temperature at 32-35 C ,The above feeding process took about 45min;Then adjusting the pH value between 3.0-3.5 with 10wt% sodium carbonate solution and controlling the pH of the reaction system between 3.0-3.5 during the reaction, the above system is detected by LC-MS,When the concentration of N- (4-aminobenzoyl) -L-glutamic acid was reduced to 1/4 of the initial concentration, it took 40 minutes. Then, the remaining N- (4 -aminobenzoyl) -L-glutamic acid, 11.95 kg of 2,4,5-triamino-6-hydroxypyrimidine sulfate and 1.9 kg of sodium metabisulfite,Stir well and then add 12.8kg residual trichloroacetone crystals, stir with 10wt% sodium carbonate solution was continued to adjust the pH to 3.5, which lasted 45min, and then at 35 C and the reaction system to ensure the pH of 3.5 to continue the reaction 6 hour,The conversion of N- (4-aminobenzoyl) -L-glutamic acid by LC-MS was 92%. Then turn on the cooling water valve to cool the reaction solution to 20-25 C and filter press through the plate frame. The filter cake is the crude folic acid (wet product 120kg), which is used for acid dissolving in the next section.After the filter press generated waste can be decolorization adsorption treatment,For subsequent recycling; can also be discharged into the sewage treatment system, using the above method of synthesis of 1 ton of crude folic acid,Only produce 7-8 tons of waste water.
With sodium carbonate; In ethanol; water; at 40℃;pH 7.5;
(1) 20.63 g of 1,1,3-tribromoacetone was added to 600 mL of ethanol solution,Stirring and heating to 40 ;(2) until 1,1,3-tribromo acetone completely dissolved, continue to add 5.33g p-aminobenzoyl-L-glutamineAcid stirring until all dissolved, the first reaction solution;(3) Add 144 g of water to a separate reaction flask, weigh 14.23 g of 2,4,5-triamino-6-hydroxypyrimidine sulfate into the reaction flask in portions, and adjust the pH to 7.5 with saturated sodium carbonate.To 2,4,5-triamino-6-Hydroxypyrimidine sulfate completely dissolved to obtain a second reaction solution;(4) the second reaction solution is added to the first reaction solution in batches,Incubated for 8h;(5) After the reaction is completed, suction filtration to obtain crude folic acid;(6) The folic acid crude added to the reaction flask, and the volume ratio of 1: 1 was added to a mixture of water and ethanol 100g,Slowly added to a concentration of 98% H2SO4 solution 17.3g, stirring 35min;(7) The above material was transferred to a large reaction flask,Adding a volume ratio of 1: 1 water and ethanol mixture 400g, crystal precipitation;(8) temperature control 55 C, stirring 50min, suction filtered acid-soluble folic acid crude solid;(9) at room temperature, the above-obtained solid was suction filtered into the reaction flask, and add water 530g,Heated to 95 , adding 20% mass concentration of sodium hydroxide solution to adjust the pH to 9,Until the solid is completely dissolved;(10) After all the dissolved activated carbon was added 1.2g, stirred for 30min, suction filtration,The filtrate obtained by suction filtration was transferred to another reaction flask and incubated at 60 C.,The pH was adjusted to 2.5 with concentrated hydrochloric acid;(11) the reaction flask temperature was continued to cool to 50 , pressure filtration, the filter cake was washed with 700mL of purified water,5.3g folic acid dried to get fine.The yield of the above folic acid boutique is 60%.
To a 500 ml three-mouth flask is added in 200 ml PH=2.0 acetic acid/sodium acetate buffer solution and N - (4 - [...]) - L - glutamic acid (2.66 g, 0 . 01 muM), heating 43 C dissolved, to embrace the mixes the sulfurous acid accepts [...] (i. the 9 g, 0.01 muM), dissolved, then adding trichloroacetone (2.42 g, 0 . 15 muM) and Rr/Meso - Fe 0.7 - 0.3 cu - ZSM - 5 (1 g) to embrace the [...] reaction 0.5 h, then adding 2, 4, 5 - c amino -6 - hydroxy pyrimidine sulfate (2.39 g, 0 . 01 muM) 38 C lower reaction 5 h after, cooling to room temperature the reaction, machines for filtering, the filtrate can be after treatment can be recycled, the filter cake is water (10 ml) wash-coating, and a ground line, folic acid crude product is obtained.The crude product weighing (wet weight) of folic acid, adding to its mass ratio of 1:1 of 35% sulfuric acid aqueous solution to stir until dissolved, about 10 min after the yellow solid precipitated, continuing to stir 1 h, adds volume is about sulfuric acid volume 10 times 35 C in water, in the 35 C next to embrace the mixes approximately 30 min, crystallization completely, standing, filtered, the filter cake washing washing and beautiful, and a ground line to obtain the acid refined product. The acid refining product add weight is about acid refining product wet weight 10 times of distilling water, heating to 80 C, adding acid refining product, accumulates mixes evenly, for 10% of sodium hydroxide solution to adjust solution PH in 9 - 9.5, stirring to dissolve all, adding activated carbon (0.2%, with an acid extract the ratio of wet weight), thermal insulation decoloring, to take advantage of the heat filter, the filtrate is 78 - 80 C under, for 1:1 of the hydrochloric acid to regulate pH2.5 - 3, thermal insulation 10 min, filtered while hot, the filter cake is washed to neutral and cold water, is put into the 40 C oven drying, be folic acid pure product 3.40 g, yield is 75.5%. By the HPLC detection, folic acid purity is 98.3%, in accordance with the Pharmacopoeia USP32 version of the requirement.
(2S)-2-[4-[(4S)-4-[4-[[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino]benzoylamino]-4-carboxybutyrylamino]benzoylamino]glutaric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 30℃; for 24h;
Folic acid, p-aminobenzoylglutamic acid, EDCI, HOBT, catalyst DMAP were dissolved in 500 mL DMF, and TEA was added, wherein, based on the ratio of the amount of the substance, folic acid: p-aminobenzoylglutamic acid: TEA: EDCI :HOBT:DMAP=1:1.5:1.5:2:2:0.05. The reaction temperature of the water bath was controlled at 30 C, and the reaction stirring time was 24 h. After the reaction, the reaction mixture was concentrated under reduced pressure, and the temperature of the steaming water bath was controlled at 60 C. The concentrated solid was cooled, 300 mL of purified water was added, and the mixture was stirred at room temperature for 4 hours, filtered, and the filter cake was washed with pure water (each time). 100 mL washing 3 times), drying to obtain crude N-p-aminobenzoyl glutamyl folate, purity 14.0%. The freeze-drying temperature is ? -30 C, the degree of vacuum is ? -10 Pa, and the time is 36 hours.(2) Purification of folic acid impurity HThe crude folic acid impurity H is dissolved in ammonia water, filtered, and the filtrate is separated into semi-preparative chromatographic separations, 10 ml each time, and the effluent is collected, combined, and concentrated under reduced pressure. The concentrated solution is diluted twice with pure water, and then subjected to semi-preparative chromatography with mass fraction. 10% methanol was washed out, and the effluent was collected, concentrated, and dried to obtain folic acid impurity H. The concentration is concentrated in a vacuum, the concentration temperature is 45 C, the degree of vacuum is ? -0.09 MPa, the freeze-drying temperature is ? -30 C, the degree of vacuum is ? -10 Pa, and the time is 12 hours.The purity of the obtained folic acid impurity H was 98.5%.
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