* 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 sodium tetrahydroborate; acetic acid In tetrahydrofuran at 30 - 60℃; for 3 h;
500 ml with stirring,150 ml of tetrahydrofuran was added to the three-necked flask of the thermometer and the condenser.25.3g (0.1mol)Ethyl 2-methyl-3-hydroxypyridine-4,5-dicarboxylate,9.49 g (0.25 mol) of sodium borohydride,Then, 7.5 g (0.125 mol) of glacial acetic acid was slowly added dropwise with stirring, and when glacial acetic acid was added dropwise,Control the temperature of the melt solution system to 30 ° C,After the completion of the dropwise addition, slowly heat up to 60 ° C,Reflux reaction 3 hours;After the reaction is completed, the solution system is cooled to 5 ° C, and 20percent dilute hydrochloric acid solution is added to the solution system.The pH of the solution system is adjusted to 2, and 20percent sodium hydroxide is added dropwise to the solution system.Adjust the pH to 14, when adding dilute hydrochloric acid and sodium hydroxide to the solution system,Control the temperature of the solution system below 10 ° C to prevent the addition of hydrochloric acid solution,The temperature in the solution system is too high; the system is filtered again, and the filter residue is washed twice with tetrahydrofuran.The washings and the filtrate were combined, and tetrahydrofuran was distilled off, and 150 ml of ethyl acetate was added to the residue, and the mixture was extracted three times.The extract phases were combined, and then ethyl acetate was evaporated under reduced pressure, and then 20 ml of anhydrous ethanol was added to the residue after concentration.And pass hydrogen chloride gas to saturation, then stand at room temperature for 3 hours, filter,After washing and drying, 19.3 g of vitamin B6 having a purity of 98.8percent was obtained, and the yield of vitamin B6 of the present example was 94percent
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[ 5442-82-0 ]
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[ 98590-00-2 ]
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[ 100313-76-6 ]
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17
[ 99069-01-9 ]
[ 65-23-6 ]
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18
[ 90110-24-0 ]
[ 65-23-6 ]
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With sulfuric acid; In dichloromethane; at 45℃; for 6h;Inert atmosphere;
To a mixture of pyridoxine (3.5 g, 20.7 mmol) in CH2Cl2 (70 mL) dimethoxypropane (21.1 mL, 172 mmol) and 96% H2SO4 (1.25 mL, 23.5 mmol) were added under argon atmosphere. The mixture was refluxed at 45 C for 6 h, resulting in a deep brownish/red color. The solution was then diluted with CH2Cl2, washed with sodium bicarbonate, and extracted with CH2Cl2. The combined organic fractions were dried over sodium sulfate, and concentrated in vacuo. The crude compound was re-dissolved in a mixture of Et2O/pentane (2:1) and refluxed at 40 C for 30 min. During this time, the desired product began crystallizing. The solution was then tempered to room temperature and kept at -25 C for 30 h. The precipitate was collected via suction filtration and washed with cold (-25 C) pentane to afford 5 as a fluffy, white, crystalline solid (3.72 g, 86%): mp 106-107 C; 1H NMR (400 MHz, CDCl3) delta 1.55 (s, 6H), 2.39 (s, 3H), 2.79 (s-broad, 1H), 4.56 (s, 2H), 4.94 (s, 2H), 7.86 (s, 1H).
65.7%
With toluene-4-sulfonic acid; at 20℃; for 0.5h;
1-2. Preparation of 2,2,8-Trimethyl-4H-[1,3]dioxino[4,5-d]pyridin-5-yl)methanol (7) intermediate[0116]90 g (0.4 mol) of para-toluene sulfonic acid was added to the mixture of 20 g (0.1 mol) of pyridoxine and 244 mL (1.9 mol) of 2,2-dimethoxy-propane in flame-dried 3-necked round flask (1 L). The mixture was allowed to stir for 30 min at room temperature, neutralized with NaHCO3 and concentrated under reduced pressure. After extraction with dichloromethane, the combinated organic layer was washed with water, dried with MgSO4, filtrated, concentrated, followed by purifying column chromatography (solvent: dichloromethane/methanol=20:1) to obtain 2,2,8-Trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanol (7) as the target substance (yield: 65.7%).[0117]1H NMR (CDCl3): delta 1.52 (6H, s, 2×CH3), 2.34 (3H, s, CH3), 4.52 (2H, s, CH2), 4.91 (2H, s, CH2), 7.78 (1H, s, H-6);[0118]MS (ESI): m/z=210.2 (M++1).
65.7%
With toluene-4-sulfonic acid; at 20℃; for 30h;
4.1.1 2,2,8-Trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanol (7) To a mixture of 20 g (0.1 mol) of pyridoxine and 244 mL (1.9 mol) of 2,2-dimethoxypropane was added 90 g (0.4 mol) of para-toluenesulfonic acid in flame-dried 1 L three-neck flask. This mixture was stirred for 30 h at room temperature and neutralized with NaHCO3 and concentrated in evaporation. After extraction with dichloromethane, the combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and purified by column chromatography with dichloromethane/methanol = 20:1. Yield 65.7% 1H NMR (CDCl3) delta 1.52 (6H, s, 2 * CH3), 2.34 (3H, s, CH3), 4.52 (2H, s, CH2), 4.91 (2H, s, CH2), 7.78 (1H, s, H-6). MS (ESI): m/z = 210.2 (M++1).
With sodium tetrahydroborate; acetic acid In tetrahydrofuran at 30 - 60℃; for 3h;
1; 4 Example 4:
500 ml with stirring,150 ml of tetrahydrofuran was added to the three-necked flask of the thermometer and the condenser.25.3g (0.1mol)Ethyl 2-methyl-3-hydroxypyridine-4,5-dicarboxylate,9.49 g (0.25 mol) of sodium borohydride,Then, 7.5 g (0.125 mol) of glacial acetic acid was slowly added dropwise with stirring, and when glacial acetic acid was added dropwise,Control the temperature of the melt solution system to 30 ° C,After the completion of the dropwise addition, slowly heat up to 60 ° C,Reflux reaction 3 hours;After the reaction is completed, the solution system is cooled to 5 ° C, and 20% dilute hydrochloric acid solution is added to the solution system.The pH of the solution system is adjusted to 2, and 20% sodium hydroxide is added dropwise to the solution system.Adjust the pH to 14, when adding dilute hydrochloric acid and sodium hydroxide to the solution system,Control the temperature of the solution system below 10 ° C to prevent the addition of hydrochloric acid solution,The temperature in the solution system is too high; the system is filtered again, and the filter residue is washed twice with tetrahydrofuran.The washings and the filtrate were combined, and tetrahydrofuran was distilled off, and 150 ml of ethyl acetate was added to the residue, and the mixture was extracted three times.The extract phases were combined, and then ethyl acetate was evaporated under reduced pressure, and then 20 ml of anhydrous ethanol was added to the residue after concentration.And pass hydrogen chloride gas to saturation, then stand at room temperature for 3 hours, filter,After washing and drying, 19.3 g of vitamin B6 having a purity of 98.8% was obtained, and the yield of vitamin B6 of the present example was 94%
With Me3SiH(OEt)2; tetrabutyl ammonium fluoride In 1,4-dioxane at 100℃; for 24h;
With triethylamine In dichloromethane at 25℃; for 12h;
99 Example 99: [5-acetoxy-4-(acetoxymethyl)-6-methyl-3-pyridyl] methyl acetate
To a solution of 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol (1 g) in CH2CI2 (20 mL) was added acetic anhydride (1.81 g) and triethylamine (1.79 g) at 25°C. Then the mixture was stirred at 25 00 for 12 h. The reaction mixture was diluted with H20 (30 mL), extracted three times with EtOAc (30 mL) and thecombined organic phase were concentrated under reduced pressure. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate, 10:1 to 5:1) to give [5-acetoxy-4-(acetoxymethyl)-6- methyl-3-pyridyl] methyl acetate (1.2 g, 68% yield) as a colorless oil. LCMS: 296.0 (M÷H) 1H NMR (400 MHz, CDCI3): O 8.441 (s, 1H), 5.258(s, 1H), 5.133 (s, 1H), 2.412 (s, 3H), 2.376 (s, 3H), 2.073 (s, 3H), 2.026 (s, 3H) ppm
In toluene byproducts: NH3; mixt. of pyridoxine and NH4BPh4 (1:1 molar ratio) refluxed with toluene until evolution of NH3 ceased (about 10 h); filtered; dried at 120°C; recrystallized in 1-propanol; elem. anal.;
Example 3Preparation of pyridoxine, (S)-oxo-2-piperidine carboxylate (Salt IIId)169.2 mg of pyridoxine free base (1 mmol) and 143.1 mg of (S)-oxo-2-piperidine carboxylic acid (1 mmol) (Aldrich) were weighed into a vial and mixed with about 0.2 mL of a solution of isopropyl alcohol containing 4.4percent water.The mixture was heated in the closed vial to a temperature of about 35° C.The mixture was gradually cooled to room temperature overnight.Then, about 2.5 mL of isopropyl alcohol was added under boiling to give a clear solution, and the solution was left to cool to room temperature.Diethyl ether was added and the mixture was maintained at a temperature of about -18° C. to afford crystallization.The crystals were obtained by filtration, washed with cold isopropyl alcohol and dried to yield 270 mg of Salt IIId in 86percent yield.1H NMR (D2O), delta ppm: 1.1 (m, 2H), 1.7 (m, 1H), 2.0 (m, 1H), 2.3 (t, 2H), 2.5 (s, 3H), 3.9 (m 1H), 4.7 (s, 2H), 4.9 (s, 2H), 8.0 (s, 1H).
Example 5 Preparation of pyridoxine, N-methyl-L-2-pyrrolidone-5-carboxylate (Salt IIb) L-pyroglutamic acid ethyl ester (10 g, 0.07 mole) is dissolved in tetrahydrofuran (100 mL) and cooled to 0 C. Sodium hydride (2 g, in a 60% suspension in oil, 0.084 mole) is added to the mixture, followed by addition of methyl iodide (5.2 mL, 0.084 mole) under constant mixing. The mixture is allowed to warm up to ambient temperature and mixed for an additional hour. The solvent is evaporated under reduced pressure and water is added (10 mL). The aqueous layer is extracted with dichloromethane, which is evaporated to yield the crude 1-methyl-L-pyroglutamic acid ethyl ester.The obtained crude 1-methyl-L-pyroglutamic acid ethyl ester is dissolved in methanol (100 mL) and a solution of 2N sodium hydroxide (35 mL) is added. The mixture is heated at reflux for 3 hours then cooled and the methanol is evaporated. The resulting aqueous solution is acidified to pH 2 using HCl 1M, washed with dichloromethane and evaporated to yield 1-methyl-L-pyroglutamic acid.2.86 g of 1-methyl-L-pyroglutamic acid and 3.38 g of pyridoxine base are thoroughly sieved and mixed for half an hour. A solution containing 20 mL isopropanol and 1 mL deionized water is added to mixture and the resulting solution is stirred for half an hour at 35 C. during which time a thick solid is obtained. The thus formed solid is filtered off and vacuum dried at 38 C. for 24 hours. The resulting solid is dissolved in about 60 mL of boiling isopropanol and the mixture is allowed to reach 38 C. to enable crystallization. The thus formed crystals are filtered off and vacuum dried at 38 C. for additional 24 hours to obtain Salt IIb.
With fluorosilicic acid In methanol; water at 20℃;
4.2. Synthesis of bis[4,5-bis(hydroxymethyl)-2-methylpyridinium-3-ol] hexafluorosilicate (II)
4,5-Bis(hydroxymethyl)-2-methylpyridine-3-ol (L2; 1.69g, 0.01mol) was dissolved in boiling methanol (70mL) and to the obtained solution the fluorosilicic acid (FSA, 45%, 9mL, molar ratio L2:FSA=1:3) was added. A reaction mixture stored at ambient conditions prior to the beginning of crystallization of the reaction product, which was obtained in an approximately qualitative yield. Colorless transparent crystals of the composition (L2H)2[SiF6] (II) with m.p.>175°C (with decomposition). Anal. found, %: Si 5.59, N 5.88, F 22.14. Calcd. for C16H24F6N2O6Si: Si 5.82, N 5.81, F 23.63. Mass spectrum: [ML2]+ (m/z=169, I=53%), [ML2-H2O]+ (m/z=151, I=50%), [ML2-H2O-CHO2]+ (m/z=106, I=52%), [ML2-H2O-CO-HCO]+ (m/z=94, I=100%), [SiF3]+ (m/z=85, I=67%). IR-spectrum: 3350, 3277, 3094 (ν(OH), ν(NH+)), 721 (ν(SiF)), 482 (δ(SiF2)). 19F NMR (188.14MHz, D2O): δ=-130.59ppm (s, J(SiF)=100.2Hz, SiF62-).
Stage #1: 5-hydroxy-6-methyl-3,4-pyridinedimethanol With acetic acid; zinc for 3h; Reflux;
Stage #2: With hydrogenchloride In methanol; diethyl ether for 1h; Reflux;
In neat (no solvent) at 105℃; for 96h; regioselective reaction;
II. General Procedure for the Synthesis of 4’-O-Substituted Pyridoxine Derivatives (2, 5a-5l).
General procedure: Pyridoxine was added to the appropriate alcohol (0.2 M) and the solution was heated to 105 °C for 96 hours. The solution was then cooled to room temperature and concentrated in vacuo. The crude mixture was purified by flash chromatography [EtOAc-methanol (98:2)] to afford the desired 4’-O-substituted pyridoxine derivatives.
With sodium tetrahydroborate; benzoic acid In tetrahydrofuran at 40 - 60℃; for 2h;
3; 5 Example 5:
500 ml with stirring,150 ml of tetrahydrofuran was added to the three-necked flask of the thermometer and the condenser.25.3g (0.1mol)2-methyl-3-hydroxypyridine-4,5-dicarboxylic acid butyl ester,9.49 g (0.25 mol) of sodium borohydride, and then slowly add 7.5 g (0.125 mol) of benzoic acid with stirring.When the benzoic acid is added dropwise, the temperature of the controlled melt solution system does not exceed 40 ° C. After the completion of the dropwise addition, the temperature is slowly raised to 60 ° C, and the reflux reaction is carried out for 2 hours; after the reaction is completed, the solution system is cooled to 8 ° C.Adding 20% dilute hydrochloric acid solution to the solution system, and setting the pH of the solution system to 2,Then add 30% sodium hydroxide to the solution system to adjust the pH to 14. When the diluted hydrochloric acid and sodium hydroxide are added dropwise to the solution system, the temperature of the solution system is controlled to be below 10 ° C to prevent the addition of the hydrochloric acid solution. ,The temperature in the solution system is too high. The system was filtered, the residue was washed twice with tetrahydrofuran, the washings and the filtrate were combined, and tetrahydrofuran was distilled off. To the residue, 150 ml of ethyl acetate was added and extracted three times, and the extract phases were combined.Then, ethyl acetate in the extract phase was distilled off under reduced pressure, and then 20 ml of absolute ethanol was added to the residue.And pass hydrogen chloride gas to saturation, then stand at room temperature for 3 hours, filter,After washing and drying, 19.71 g of vitamin B6 having a purity of 98.8% was obtained, and the yield of vitamin B6 of the present example was 95%.
With sodium tetrahydroborate; oxalic acid In 2-methyltetrahydrofuran at 30 - 70℃; for 4h;
2 Example 2:
500 ml with stirring,150 ml of 2-methyltetrahydrofuran was added to a three-necked flask of a thermometer and a condenser.25.3g (0.1mol)2-methyl-3-hydroxypyridine-4,5-dicarboxylate,11.34 g (0.3 mol) of sodium borohydride,Then under the action of stirring,9 g (0.15 mol) of oxalic acid was slowly added to the solution system in batches.In the process of adding oxalic acid dropwise, the temperature of the control solution system is controlled at 30 ° C, after the addition is completed,Slowly raise the temperature of the solution system to 70 ° C, after refluxing for 4 hours,Cool the solution system to 5 ° C,Adding 17% dilute hydrochloric acid solution to the solution system, adjusting the pH of the solution system to 2,Then add 25% sodium hydroxide solution to the solution system to adjust the pH of the solution system to 14,When dilute hydrochloric acid and sodium hydroxide are added dropwise to the solution system, the temperature of the control solution system is below 10 ° C.Preventing the temperature in the solution system from being too high when the hydrochloric acid solution is added; then filtering and separating the solution system,The filtrate was extracted twice with 150 ml of 2-methyltetrahydrofuran;Then, 2-methyltetrahydrofuran (about 90% by volume) in the filtrate was distilled off under reduced pressure.Then, hydrogen chloride gas is introduced into the residue to saturate the solution.Then, the solution system was allowed to stand for 3 hours at room temperature, and the crystals were filtered and washed.Drying gives a vitamin B6 with a purity of 98.5%, 17.52 g, and the yield of vitamin B6 in this example is 90%.
With potassium carbonate In acetonitrile at 25 - 50℃; for 12h;
100 Example 100: [5-butanoyloxy-4-(butanoyloxymethyl)-6-methyl-3-pyridyl]methyl butanoate
To a solution of 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol (1 g) in acetonitrile (50 mL) was added butanoyl chloride (1.89 g) and K2003 (3.27 g) at 25°C. Then the mixture was stirred at 50 00 for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate, 10:1 to 5:1) to give [5-butanoyloxy-4-(butanoyloxymethyl)-6-methyl-3-pyridyl]methyl butanoate (1 .2 g, 50%) as a colorless oil. LCMS: 380.2(M÷H÷) 1H NMR (400 MHz, methanol-d4): O 8.391 (s, 1H), 5.326(s, 1H), 5.173 (s, 1H), 2.683 (m, 2H),2.366 (s, 3H), 2.327-2.253 (m, 4H), 1.75 (m, 2H), 1.596 (m, 4H), 1.088 (t, 3H), 0.924 (t, 3H), 0.918 (t,3H) ppm
With triethylamine In dichloromethane at 25℃; for 12h;
80 Example 80: [4-(acetoxymethyl)-5-hydroxy-6-methyl-3-pyridyl] methyl acetate
To a solution of 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol (0.5 g) in 0H2012 (10 mL) was added triethylamine (0.63 g) and acetic anhydride (0.63 g) at 25°C. Then the mixture was stirred at 25 00 for 12h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prepHPLC to give [4-(acetoxymethyl)-5-hydroxy-6-methyl-3-pyridyl] methyl acetate (0.036 g, 69%) as a white solid. LOMS: 254.1 (M÷H) 1H NMR (400 MHz, 0D013): O 8.224(s, 1H), 8.122 (s, 1H), 5.222 (s, 2H), 5.194 (s, 2H), 2.529 (s, 3H), 2.141 (s, 3H), 2.108 (s, 3H) ppm
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 12h;
102 Example 102: [5-[2-(1 H-indol-3-yl)acetyl]oxy-4-[[2-(1 H-indol-3-yl)acetyl]oxymethyl]-6-methyl-3-pyridyl]methyl 2-(1 H-indol-3-yl)acetate
To a mixture of 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol (0.5 g) and 2-(1 H-indol-3-yl)acetic acid (1 .55 g) in CH2CI2 (50 mL) was added N,Ndicyclohexylcarbodiimide (1 .83 g) and 4- dimethylaminopyridine (0.036 g) at 25°C .Then the mixture was stirred at 25 00 for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase prep-HPLC (018, water (0.05%HCI)-acetonitrile gradient) to give [5-[2-(1 H-indol-3-yl)acetyl]oxy-4- [[2-(1 H-indol-3-yl)acetyl]oxymethyl]-6-methyl-3-pyridyl]methyl 2-(1 H-i ndol-3-yl)acetate (1 .6 g, 46%) as awhite solid. 1H NMR (400 MHz, 0D013): O 8.339 (s, 1 H), 8.0 -7.9 (br 2H), 7.681 (m, 1 H), 7.503 - 7.011 (m, 15H), 5.143 (s, 2H), 4.850 (s, 2H), 3.998 (s, 2H), 3.714 (s, 2H), 3.576 (s, 2H), 2.272 (s, 3H) ppm
6 Example 6: Preparation of Vitamin B6
To a 500 ml four-necked flask was added 180 g of ethanol, 26.5 g (0.1 mol) of 1,5-dihydro-3-n-propyl-8-Methyl-9-methylcarbonyloxypyrido[3,4-e]-1,3-dioxoheptacyclocycle (Compound V1 prepared from Example 1),30.0 g of 30% concentrated hydrochloric acid (0.25 mol),The reaction was refluxed for 5 hours while distilling out the n-butyraldehyde formed by deprotection (collection, which can be used for the preparation of raw materials),After the deprotection reaction is completed, it is slightly cooled.Distilled to dryness under reduced pressure below 40 °C,The n-butyraldehyde was completely distilled off. To the residue was added 40 g of ethanol, 0.1 g of activated carbon, and decolorized at 70 ° C for 30 minutes.Filtration, the filtrate was cooled to 17-18 ° C,After suction filtration, the filter cake was dried to obtain 19.7 g of vitamin B6 product, the yield was 95.9%, and the HPLC purity was 99.9%.The content of the external standard method was determined to be 99.8%.
7 Example 7: Preparation of Vitamin B6
To a 500 ml four-necked flask was added 180 g of ethanol, 26.5 g (0.1 mol) of 1,5-dihydro-3-isopropyl-8-Methyl-9-methylcarbonyloxypyrido[3,4-e]-1,3-dioxopyran (V2 prepared by Example 4),30.0 g of 25% concentrated hydrochloric acid (0.2 mol),The reaction was refluxed for 6 hours while distilling off the isobutyraldehyde formed by deprotection (collection, which can be used for the preparation of raw materials),After the deprotection reaction is completed, it is slightly cooled.Distilled to dryness under reduced pressure below 40 °C,The isobutyraldehyde was completely distilled off. To the residue was added 40 g of ethanol, 0.1 g of activated carbon, and decolorized at 70 ° C for 30 minutes.Filtration, the filtrate was cooled to 15-16 ° C, and filtered, and the filter cake was dried to obtain 19.9 g of vitamin B6 product.The yield was 96.8%, and the HPLC purity was 99.9%.The content of the external standard method was determined to be 99.9%.
With hydrogenchloride In lithium hydroxide monohydrate at 50℃; for 4h; Green chemistry;
7 Example 7: Preparation of Vitamin B6
200 g of methanol was added to 500 ml four-necked flask, 30.5 g (0.22 mol) of 2-aminopropionic acid methyl ester hydrochloride and 100 g of 27% sodium methoxide in methanol solution were added, stirred, maintained at 30-35 deg. C, 39.0 g (0.2 mol) of 2-n-propyl-5-cyano-6-formyl-1,3-dioxo heptacyclo (from Example 4 embodiment) was added dropwise, and the reaction was stirred for 5 hours at 50 °C. 80 g of 35% concentrated hydrochloric acid (hydrogen cyanide gas from this process) was added below 50 deg. C, refluxed for 4 hours, hot-filtered, the filtrate was distilled under reduced pressure to recover the solvent and n-butyraldehyde, 40 g of ethanol and 0.2 g of activated carbon were added, decolorized at 70 deg. C for 30 minutes, filtered, the filtrate was cooled, crystallized, suction-filtered, and the filter cake was dried to obtain 38.5 g of vitamin B6, purity 99.8% (HPLC), yield 93.7%.
90%
With hydrogenchloride In dichloromethane; lithium hydroxide monohydrate at 40℃; for 3h;
2-3; 11-15; 18; 3-6 Embodiment 2: the preparation of vitamin B6 crude product (hydrolysis reaction)
Add 800ml of dichloromethane and 229g of compound 4 prepared in Example 1 into the reaction flask, add 130ml of 32wt% concentrated hydrochloric acid, under stirring conditions, reflux under normal pressure at about 40°C for 3h, add a water separator to the reflux device, and water is discharged from the reaction system, The organic phase was returned to the reaction flask, and the water was refluxed until the reaction was completed; the temperature was lowered to 5°C, the crystals were grown for 1 h, filtered, the filter cake was washed with 95wt% ethanol aqueous solution, and vacuum dried at 40-70°C to obtain crude vitamin B6, 207g. The molar yield of the hydrolysis reaction was 98%.Fig. 1 is the purity and content of the crude product of vitamin B6 obtained in the present embodiment, the content of impurity A, and HPLC diagram; %.Example 3: Preparation of vitamin B6 finished product (refining)Add 300g of purified water and 150g of crude product B6 into the reaction flask, heat up to dissolve the clear, add 7.5g of activated carbon, stir and decolorize at 70°C for 60min, filter while hot, wash the activated carbon filter cake with 75g of 80°C hot water, distill the filtrate under reduced pressure, and distill until The residual weight of the system is 285-300g, slowly cooled to room temperature, cooled to 5°C, crystallized for 1 hour, suction filtered, washed with 150ml of 95wt% ethanol aqueous solution, and vacuum-dried at 40-70°C to obtain refined vitamin B6, 135g. The molar yield of the purification step was 90%.
With hydrogenchloride In lithium hydroxide monohydrate at 45℃; for 4h; Green chemistry;
8 Example 8: Preparation of Vitamin B6
To a 500 ml four-necked flask was added 200 g of methanol, 22.5 g (0.22 mol) of methyl 2-aminopropionate, and 50 g of 27% sodium methoxide in methanol, stirred, kept between 30-35 ° C, 39.0 g ( 0.2 mol of 2-isopropyl-5-cyano-6-formyl-1,3-dioxopentidine (prepared from Example 5) was added dropwise, and the reaction was stirred at 45 ° C for 5 hours. Then 60 g of 35% concentrated hydrochloric acid was added below 45 ° C (this process produces hydrogen cyanide gas), reflux for 4 hours, hot-filtered, the solvent and isobutyraldehyde were recovered under reduced pressure, then 40 g of ethanol and 0.2 g activated carbon were added and decolorized at 70 ° C for 30 minutes, filtered, the filtrate was cooled and crystallized, suction filtered, and the filter cake was dried to obtain 38.9 g of vitamin B6. The product had a purity of 99.9% (HPLC) and a yield of 94.7%.
With hydrogenchloride In dichloromethane; lithium hydroxide monohydrate at 40℃; for 3h;
17 Example 17 Hydrolysis reaction
800ml of dichloromethane and 229g of the compound of formula II prepared in Example 16 (R2 is isopropyl) were added to the reaction flask, 130ml of 32% concentrated hydrochloric acid was added, and under stirring conditions, reflux at about 40°C for 3h at normal pressure, and the reflux device was added. Water tank, water is discharged from the reaction system, the organic phase is returned to the reaction flask, and the water is separated by refluxing until the reaction is completed; the temperature is lowered to 5 °C, the crystal is grown for 1 h, filtered, the filter cake is washed with 95wt% ethanol aqueous solution, and vacuum-dried at 40-70 °C to obtain Crude vitamin B6, 189g. The molar yield of the hydrolysis reaction was 96%.
With hydrogenchloride In water at 55℃; for 4h; Green chemistry;
9 Example 9: Preparation of Vitamin B6
200 g ethanol was added to a 500 ml four-necked flask, 25.8 g (0.22 mol) of ethyl 2-aminopropionate and 35.0 g of potassium carbonate were added. stirred, and kept at 50 ° C. 39.0 g (0.2 mol) of 2-methyl-2-ethyl-5-cyano-6-formyl-1,3-dioxepane (prepared from Example 6) was added dropwise, and the reaction was stirred at 55 ° C for 6 hours. Then 80 g of 30% concentrated hydrochloric acid was added below 55 ° C (this process produces hydrogen cyanide gas), reflux for 4 hours, hot-filtered, the solvent and 2-butanone were recovered under reduced pressure, and then 40 g of ethanol and 0.2 activated carbon were added, decolorized at 70 ° C for 30 minutes, filtered, the filtrate was cooled and crystallized, suction filtered, and the filter cake was dried to obtain 35.5 g of vitamin B.6. The product had a purity of 99.7% (HPLC) and a yield of 86.4%.
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