CN102617455B - Preparation method of pyridoxal or pyridoxal hydrochloride - Google Patents

Abstract

The invention discloses a preparation method of pyridoxal or pyridoxal hydrochloride. The preparation method comprises: using pyridoxine or pyridoxine hydrochloride represented by formula (III) as the initial raw material, using water as the reaction solvent, The pyridoxine or pyridoxine hydrochloride are selectively oxidized in water under the action of a catalytic oxidation system to prepare pyridoxal or pyridoxal hydrochloride shown in formula (I); the catalytic oxidation system includes an oxygen source , catalysts, inorganic salts and amine ligands. The preparation method of the invention has high conversion rate, good selectivity, mild reaction conditions, convenient operation, low cost, environmental friendliness and good industrial application value.

Description

A kind of preparation method of pyridoxal or pyridoxal hydrochloride

(1) Technical field

The invention relates to a method for preparing pyridoxal or pyridoxal hydrochloride, in particular to a method for selectively oxidizing pyridoxine or pyridoxine hydrochloride to prepare pyridoxal or pyridoxal hydrochloride.

(2) Background technology

Pyridoxal hydrochloride is a derivative of vitamin _B6 , as shown in formula (I), it is a key intermediate for the synthesis of pyridoxal 5-phosphate. The chemical name of pyridoxal 5-phosphate is 2-methyl-3-hydroxy-4-formaldehyde-5-hydroxymethylpyridinium phosphate, referred to as PLP, which is a kind of vitamin _B6 formed under the action of adenosine triphosphate kinase in cells. The active ingredient has a structural formula such as formula (II):

As a coenzyme, pyridoxal 5-phosphate can interact with more than 100 different enzymes in the body to jointly affect the biochemical activities and metabolism of cells in the body. It is an essential substance to maintain the normal immune system of the human body; it is an essential substance for the growth, development and maintenance of balance of the human body; it is a coenzyme for the phosphorylation of animal starch. In addition, pyridoxal 5-phosphate, as a coenzyme, can also assist the synthesis of neuroamine in brain cells, accelerate the recovery of damaged brains; assist the myelin formation of nerve fibers in the nervous system; assist cell folic acid metabolism, etc.

Bibliography reports following several methods synthetic pyridoxal:

Method 1, Ahens H; Korytnyk W. (J.Heterocycl.Chem.Vol.4, 1967:625-626) reported that pyridoxine hydrochloride was used as a starting material, and pyridoxal was obtained by selective oxidation with manganese dioxide, Yield 77%. Method 2, More Ashok. (Spectrochimica Acta Part A.Vol.72, 2009: 204-208) reported the selective oxidation of pyrimidine with H ₂ O ₂ as oxidant and dichlorotris(triphenylphosphine) ruthenium complex as catalyst Pyridoxine is pyridoxal, and the yield is 96.66%.

The above two methods have disadvantages. The first method uses manganese dioxide as an oxidant, which produces a large amount of manganese-containing wastewater, which is difficult to handle and is not environmentally friendly; the second method uses transition metal Ru, which is expensive and currently There is no industrial application value yet, and researchers need to further develop it.

(3) Contents of the invention

In order to overcome the disadvantages of large reaction pollution and complicated process in the prior art, the purpose of the present invention is to provide a method with high conversion rate, good selectivity, mild reaction conditions, convenient operation, low cost, environmental friendliness and good industrial application The method for the selective oxidation of pyridoxine or pyridoxine hydrochloride to prepare pyridoxal or pyridoxal hydrochloride of value.

In order to realize the above-mentioned purpose of the invention, the present invention adopts following technical scheme:

A kind of preparation method of pyridoxal or pyridoxal hydrochloride, described preparation method comprises: take pyridoxine or pyridoxine hydrochloride shown in formula (III) as initial raw material, take water as reaction solvent, described pyridoxine Pyridoxine or pyridoxine hydrochloride are selectively oxidized in water under the effect of a catalytic oxidation system to prepare pyridoxal or pyridoxal hydrochloride shown in formula (I);

The catalytic oxidation system includes an oxygen source, a catalyst, an inorganic salt and an amine ligand;

The oxygen source is selected from one of the following: air, oxygen, hydrogen peroxide;

The catalyst is selected from one or any combination of the following: 2,2,6,6-tetramethylpiperidine-nitrogen-oxygen free radical, 4-hydroxyl-2,2,6,6-tetramethyl Piperidine-1-oxyl radical, 4-acetamido-2,2,6,6-tetramethylpiperidin-1-nitroxyl radical, 4-amino-2,2,6,6-tetramethyl Piperidin-1-oxyl radical;

The inorganic salt is selected from one or any combination of the following: copper nitrate, copper sulfate, copper trifluoromethanesulfonate, copper sulfide, copper acetate, copper bromide, cuprous bromide, copper iodide, iodine Cuprous chloride, cupric chloride, cuprous chloride;

The amine ligand is selected from one or any combination of the following: 1,2-ethylenediamine, tert-butylamine, diethylamine, triethylamine, tri-tert-butylamine, tri-n-butylamine, 1, 4-diazabicyclo[2.2.2]octane, morpholine, pyridine, 2-aminopyridine, 4-dimethylaminopyridine, 4,6-dimethyl-2-pyridinamine, ammonia water, ammonium chloride , ammonium sulfate, ammonium carbonate, ammonium bicarbonate, 2,2'-bipyridine, 4-isopropylpyridine, 4-hydroxypyridine.

In the reaction process of the present invention, pyridoxal and pyridoxal hydrochloride are in chemical equilibrium, so preparing pyridoxal hydrochloride is actually preparing pyridoxal.

In the present invention, the selective oxidation is carried out under the action of a catalytic oxidation system, and the catalytic oxidation system is preferably composed of an oxygen source, a catalyst, an inorganic salt and an amine ligand.

In the present invention, when the oxygen source is air or oxygen, the pressure of the air or oxygen is 1-5 atmospheres, preferably 1-2 atmospheres. When the oxygen source is hydrogen peroxide, the amount of hydrogen peroxide used is 0.5 to 8 times, preferably 1 to 2 times, the moles of pyridoxine or pyridoxine hydrochloride based on the moles of H ₂ O ₂ .

The catalyst described in the present invention is a nitroxide free radical, and the amount of the catalyst used is 0.01-5 times, preferably 0.05-3 times, the mole number of pyridoxine or pyridoxine hydrochloride in terms of moles.

The inorganic salt described in the present invention is copper salt or cuprous salt, preferably the inorganic salt is one of the following: copper bromide, copper iodide, copper chloride, copper nitrate. In the present invention, the molar amount of the inorganic salt is 0.01-3 times, preferably 0.01-1 times, more preferably 0.01-0.5 times the moles of pyridoxine or pyridoxine hydrochloride.

The amine ligands described in the present invention are preferably selected from one of the following: 4-dimethylaminopyridine, 4-hydroxypyridine, ammonia water, ammonium chloride, and triethylamine. In the present invention, the molar amount of the amine ligand used is 0.01-5 times, preferably 0.01-1 times, the molar number of pyridoxine or pyridoxine hydrochloride.

In the present invention, the selective oxidation is carried out at a temperature of 0-55°C. Preferably, the selective oxidation is carried out at a temperature of 10-30°C.

In the present invention, conventional methods (such as liquid chromatography) can be used to monitor the reaction end point, and the general reaction time is 1-2 hours.

In the present invention, after the selective oxidation is completed, pyridoxal or pyridoxal hydrochloride can be obtained by column chromatography. But because pyridoxal and pyridoxal hydrochloride are unstable and difficult to separate, so in practical applications, the reaction solution obtained after the selective oxidation is completed is not separated and added to p-ethoxyaniline for reaction to obtain the corresponding Schiff base (IX) , the Schiff base is stable in nature and can be used for subsequent reactions. For specific operations, please refer to the paper ANew Synthesis of Pyridoxal-5-phosphate, Vol.41, 1968: 161-165 published by Masaru Iwanami.

Compared with the prior art, the method for preparing pyridoxal or pyridoxal hydrochloride of the present invention has the following advantages: high conversion rate, good selectivity, mild reaction conditions, convenient operation, low cost, environmental friendliness, and Good industrial application value.

(4) Specific implementation methods

The technical scheme of the present invention is described below with specific examples, but protection scope of the present invention is not limited thereto:

Example 1

In a 25mL reaction flask with a stirrer and a thermometer, add 0.085g (0.5mmol) 2,2,6,6-tetramethylpiperidine-nitrogen-oxygen radical, 0.29g (2mmol) copper bromide successively, 0.40g (5mmol) pyridine and 2.06g (10mmol) pyridoxine hydrochloride. Add 5 mL of water, control the temperature at 30°C, and start stirring. Then 2.0 g (18 mmol) of 30% hydrogen peroxide was added dropwise while controlling the reaction temperature at 30-35° C. After the dropwise addition, keep stirring at 30-35° C. for 1-2 hours, and the obtained reaction solution has a pyridoxine conversion rate of 99% through liquid phase detection (liquid phase conditions: chromatographic column is XDB-G8 250×4.6mm 5um. The mobile phase is methanol: buffer=15:85; buffer: 0.04% sodium pentanesulfonate and adjust the pH to 3 with glacial acetic acid; the detection wavelength is 284nm), and the reaction selectivity is 98%.

In addition, take about 5mL of the reaction solution and put it directly on the silica gel column, the eluent is dichloromethane:methanol=20:1, the final eluent is obtained by gradient elution, and concentrated to dryness to obtain pyridoxal hydrochloride as a white solid, melting point 164.1-164.8°C, NMR characteristics are as follows: ¹ HNMR (400MHz, DMSO), δ: 8.27 (s, 1H, CHO), 6.63 (d, 1H, CH), 5.00-5.16 (m, 2H, CH ₂ ), 2.62 (s, 3H, _CH3 ).

Since pyridoxal hydrochloride is unstable and difficult to separate, in practical applications, check the paper published by Masaru Iwanami [A NewSynthesis of Pyridoxal-5-phosphate, Vol.41, 1968: 161-165], the reaction solution is not separated and then added to the 1.37 g (10 mmol) of ethoxyaniline was treated to obtain 2.10 g of yellow Schiff base (IX). The overall yield of the two-step reaction was 88%.

Example 2

The oxygen source was changed to 1 atmosphere of oxygen, the inorganic salt was changed to 1.5g (10mmol) copper nitrate, the amine ligand was changed to 1.0g (10mmol) triethylamine, and other operations were the same as in Example 1 to obtain 2.21g of a yellow solid. The conversion rate of pyridoxine is up to 99% and the reaction selectivity is 97% according to liquid phase detection. The overall yield of the two-step reaction was 89%.

Example 3

The oxygen source is changed into oxygen at 2 atmospheric pressures, the inorganic salt is changed into 0.29g (2mmol) cuprous bromide, and the amine ligand is changed into 0.24g (4mmol) 1,2-ethylenediamine, and other operations are the same as in Example 1, 1.90 g of a yellow solid was obtained. The conversion rate of pyridoxine is up to 87% and the reaction selectivity is 95% according to liquid phase detection. The overall yield of the two-step reaction was 74%.

Example 4

Catalyst is changed into 0.17g (1mmol) 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl free radical, 30% hydrogen peroxide is changed into 0.55g (5mmol), and inorganic salt is changed into 0.095g ( 0.5mmol) copper iodide, the amine ligand was replaced with 0.24g (5mmol) 35% ammonia water, and other operations were the same as in Example 1 to obtain 2.07g of a yellow solid. The conversion rate of pyridoxine was detected by liquid phase to reach 91%, and the reaction selectivity was 95%. The overall yield of the two-step reaction was 80%.

Example 5

The catalyst is changed to 0.09g (0.5mmol) 4-amino-2,2,6,6-tetramethylpiperidine-1-oxygen free radical, 30% hydrogen peroxide is changed to 2.8g (25mmol), and the inorganic salt is changed to 0.20g (2mmol) cupric chloride, the amine ligand is changed into 1.4g (16mmol) morpholine, other operation is the same as embodiment 1, obtains yellow solid 2.29g. The conversion rate of pyridoxine is up to 98% and the reaction selectivity is 96% according to liquid phase detection. The overall yield of the two-step reaction was 86%.

Example 6

The catalyst is changed to 0.086g (0.5mmol) 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl radical, the oxygen source is changed to air at an atmospheric pressure, and the inorganic salt is changed to 1.0 (5mmol) Copper acetate, the amine ligand was replaced by 1.3g (7mmol) tri-n-butylamine, the reaction temperature was changed to 0-5°C, and other operations were the same as in Example 1 to obtain 1.93g of a yellow solid. The conversion rate of pyridoxine is up to 85% and the reaction selectivity is 95% according to liquid phase detection. The overall yield of the two-step reaction was 72%.

Example 7

Catalyst is changed into 0.86g (5mmol) 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl radical, 30% hydrogen peroxide is changed into 1.4g (12mmol), 0.15g (1mmol) brominated Copper, the amine ligand was changed to 0.095 (1 mmol) 4-hydroxypyridine, the reaction temperature was changed to 30-35° C., and other operations were the same as in Example 1 to obtain 2.05 g of a yellow solid. The conversion rate of pyridoxine was detected by liquid phase to reach 92%, and the reaction selectivity was 96%. The overall yield of the two-step reaction was 81%.

Example 8

The catalyst was changed to 0.16g (0.8mmol) 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-nitrogen radical, the oxygen source was changed to 1 atmospheric pressure of oxygen, and the inorganic salt was changed to 0.29 g (2mmol) copper nitrate, the amine ligand was replaced with 1.2g (12mmol) triethylamine, and other operations were the same as in Example 1 to obtain 2.10g of a yellow solid. The conversion rate of pyridoxine is up to 99% and the reaction selectivity is 92% according to liquid phase detection. The overall yield of the two-step reaction was 84%.

Example 9

The catalyst is changed to 3.0g (15mmol) 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-nitrogen free radical, 30% hydrogen peroxide is changed to 1.4g (12mmol), and the inorganic salt is changed to 2.6 g (18 mmol) of cuprous bromide, the amine ligand was replaced with 0.98 (8 mmol) of 4-dimethylaminopyridine, and other operations were the same as in Example 1 to obtain 1.95 g of a yellow solid. The conversion rate of pyridoxine is up to 86% and the reaction selectivity is 97% according to liquid phase detection. The overall yield of the two-step reaction was 75%.

Example 10

Catalyst is changed into 4.3g (25mmol) 2,2,6,6-tetramethylpiperidine-nitrogen-oxygen free radical, 30% hydrogen peroxide is changed into 2.3g (20mmol), inorganic salt is changed into 0.38g (2mmol) iodide Copper, amine ligands were replaced by 0.009g (0.1mmol) morpholine, and other operations were the same as in Example 1 to obtain 2.05g of a yellow solid. The conversion rate of pyridoxine is up to 93% and the reaction selectivity is 99% according to liquid phase detection. The overall yield of the two-step reaction was 85%.

Example 11

Catalyst is changed into 4.7g (30mmol) 2,2,6,6-tetramethylpiperidine-nitrogen-oxygen free radical, inorganic salt is changed into 0.20g (2mmol) cupric chloride, and amine ligand is changed into 1.9g ( 10mmol) tri-n-butylamine, and other operations were the same as in Example 1 to obtain 2.02g of a yellow solid. The conversion rate of pyridoxine is up to 90% and the reaction selectivity is 95% according to liquid phase detection. The overall yield of the two-step reaction was 76%.

Claims (9)

1. a preparation method of pyridoxal or pyridoxal hydrochloride, said preparation method comprising: taking pyridoxine or pyridoxine hydrochloride shown in formula (Ⅲ) as initial raw material, taking water as reaction solvent, said Pyridoxine or pyridoxine hydrochloride are selectively oxidized in water under the action of a catalytic oxidation system to prepare pyridoxal or pyridoxal hydrochloride shown in formula (I); the selective oxidation is performed at 0-55°C under temperature conditions; The catalytic oxidation system includes an oxygen source, a catalyst, an inorganic salt and an amine ligand; The oxygen source is selected from one of the following: air, oxygen, hydrogen peroxide; The catalyst is selected from one or any combination of the following: 2,2,6,6-tetramethylpiperidine-nitrogen-oxygen free radical, 4-hydroxyl-2,2,6,6-tetramethyl Piperidin-1-oxyl radical, 4-acetamido-2,2,6,6-tetramethylpiperidin-1-nitroxyl radical, 4-amino-2,2,6,6-tetramethyl Piperidin-1-oxyl radical; The inorganic salt is selected from one or any combination of the following: copper nitrate, copper sulfate, copper acetate, copper bromide, cuprous bromide, copper iodide, cuprous iodide, cupric chloride, chlorinated Cuprous; The amine ligand is selected from one or any combination of the following: 1,2-ethylenediamine, tert-butylamine, diethylamine, triethylamine, tri-tert-butylamine, tri-n-butylamine, 1, 4-diazabicyclo[2.2.2]octane, morpholine, pyridine, 2-aminopyridine, 4-dimethylaminopyridine, 4,6-dimethyl-2-pyridinamine, ammonia, 2,2 '-bipyridine, 4-isopropylpyridine, 4-hydroxypyridine. 2. the preparation method of pyridoxal or pyridoxal hydrochloride as claimed in claim 1 is characterized in that: described selective oxidation is carried out under the temperature condition of 10～30 ℃. 3. the preparation method of pyridoxal or pyridoxal hydrochloride as claimed in claim 1 is characterized in that: described catalytic oxidation system is made up of oxygen source, catalyzer, inorganic salt and amine ligand. 4. the preparation method of pyridoxal or pyridoxal hydrochloride as described in one of claim 1～3, it is characterized in that: described pyridoxine or pyridoxine hydrochloride and catalyzer, inorganic salt, amine ligand The molar ratio is 1:0.01～5:0.01～3:0.01～5; and the oxygen source is air or oxygen, and the pressure of the air or oxygen is 1 to 5 atmospheres, or the oxygen source is hydrogen peroxide , the molar ratio of pyridoxine or pyridoxine hydrochloride to H2O2 is 1:0.5-8. 5. the preparation method of pyridoxal as claimed in claim 4 or pyridoxal hydrochloride is characterized in that: the mol ratio of described pyridoxine or pyridoxine hydrochloride and catalyzer, inorganic salt, amine ligand is 1 : 0.05～3: 0.01～1: 0.01～1; and the oxygen source is air or oxygen, and the pressure of the air or oxygen is 1 to 2 atmospheres, or the oxygen source is hydrogen peroxide, and the pyridine The molar ratio of pyridoxine or pyridoxine hydrochloride to H2O2 is 1:1~2. 6. the preparation method of pyridoxal as claimed in claim 4 or pyridoxal hydrochloride is characterized in that: described inorganic salt is selected from following one: copper bromide, copper iodide, cupric chloride, cupric nitrate. 7. the preparation method of pyridoxal as claimed in claim 5 or pyridoxal hydrochloride is characterized in that: described inorganic salt is selected from following one: copper bromide, copper iodide, cupric chloride, cupric nitrate. 8. The preparation method of pyridoxal or pyridoxal hydrochloride as claimed in claim 6 or 7, is characterized in that: described amine ligand is selected from one of following: 4-dimethylaminopyridine, 4-hydroxyl Pyridine, ammonia, triethylamine. 9. the preparation method of pyridoxal as claimed in claim 1 or pyridoxal hydrochloride is characterized in that: described preparation method also comprises the steps: after selective oxidation is finished, gained reaction solution directly adds to Ethoxyaniline, reaction obtains the Schiff base shown in formula (IX), and described pyridoxal or pyridoxal hydrochloride are preserved with the form of Schiff base,