CN110105362B - Safe and green folic acid synthesis method catalyzed by heteropoly acid - Google Patents
Safe and green folic acid synthesis method catalyzed by heteropoly acid Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a safe and green folic acid synthesis method catalyzed by heteropoly acid. The synthesis method of folic acid comprises the following steps: (1) adding acrolein, heteropoly acid, 2, 5, 6-triamino-4-hydroxypyrimidine, p-aminobenzoate and an alcohol solvent into a reactor, stirring and heating, reacting, cooling the materials after the reaction is finished, performing suction filtration, washing a filter cake with the solvent, combining the filtrate with a washing solution, decoloring with activated carbon, and evaporating the solvent after the suction filtration to obtain a light yellow solid intermediate 6. (2) Dissolving L-sodium glutamate and the intermediate 6 in an alcohol-water mixed solution, stirring and heating for reaction, cooling and cooling the materials after the reaction is finished, preserving heat for growing crystals, performing suction filtration, washing filter cakes with water to obtain a crude folic acid product, and refining to obtain the folic acid. The synthesis method uses acrolein which is relatively easy to obtain and cheap as a raw material, has complete and rapid reaction and no residue, ensures that the system is tasteless, and obviously improves the yield and the purity.
Description
The technical field is as follows:
the invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a safe and green folic acid synthesis method catalyzed by heteropoly acid.
Background art:
folic acid, also called vitamin B9, vitamin M, is a water-soluble vitamin that is essential for the growth and reproduction of body cells. The chemical name is N- [4- [ (2-amino-4-oxo-1, 4-dihydro-6-pteridine) methylamino]Benzoyl radical]-L-glutamic acid. Molecular formula C19H19N7O6Molecular weight of 441.40, structural formula:
the heteropoly acid (HPA) is oxygen-containing polyacid which is bridged by heteroatoms and polyatomic atoms through oxygen atom coordination according to a certain structure, and is a bifunctional green catalyst with both acid-base property and oxidation-reduction property. It is a kind of green catalyst with no environmental pollution, and may be used in alkylation and dealkylation of aromatic hydrocarbon, esterification, dewatering, redox reaction, ring opening, condensation, addition and etherification, etc. Because of the unique acidity, quasi-liquid phase behavior, and multiple functions (acid, oxidation, photoelectrocatalysis) of heteropoly acid, they are widely regarded by researchers in the field of catalytic research.
The prior art processes for the synthesis of folic acid have many drawbacks:
1. in the large-scale production process, the intermediate 1 is cyclized and then is butted with the intermediate 2:
and (3) synthesizing an intermediate 1, namely trichloroacetone:
the intermediate 2 is synthesized by N-p-aminobenzoyl-L-glutamic acid fragment:
the method has the following defects:
first, for the synthesis of intermediate 1:
the safety is that the synthesis of the trichloroacetone needs to use chlorine, and the chlorination reaction using the chlorine is one of the key monitoring dangerous chemical process types, wherein the chlorination reaction is an exothermic process, particularly the chlorination is carried out at a higher temperature, the reaction is more violent, the speed is high, and the heat release is larger; the chloridizing agent chlorine is a highly toxic chemical, has strong oxidability and higher storage pressure, most of the chlorination processes adopt liquid chlorine production, namely vaporization and chlorination, and once leakage occurs, the risk is higher; the generated hydrogen chloride gas has strong corrosivity after meeting water; the chlorination reaction off-gas may form an explosive mixture.
Secondly, the method is environment-friendly, and the waste water obtained after the hydrogen chloride tail gas generated by the reaction is absorbed is high-salinity waste water, so that the treatment is complex and the cost is increased.
Limitations of production plants: the chlorine is a highly toxic chemical, has strong oxidability and high storage pressure, and has potential safety hazards in transportation and storage, and in addition, although the chlorine is low in price, the transportation cost is high, so that the production of the traditional folic acid process can only be produced by a company with chlorine capacity or the surrounding chlorine capacity, and the industrialization upgrading of the folic acid is not facilitated.
Fourthly, the process route is limited: in the production process of trichloroacetone, the trichloroacetone is difficult to be prepared into pure. After the chlorine gas is introduced into the acetone, 2 methyl groups exist in the structure, the number of the reaction sites is large, dichloroacetone cannot be avoided in the trichloroacetone production process, and tetrachloroacetone is generated, so that the acetone utilization rate is low, the purification cost is high, and the folic acid production cost is increased.
In the synthesis of the intermediate 2, namely the N-p-aminobenzoyl-L-glutamic acid fragment, in order to reduce the production cost, the starting material used in the large-scale production process of the intermediate 2 is p-nitrobenzoyl chloride, so that the nitro reduction reaction cannot be avoided, the catalytic hydrogenation cannot be avoided, certain potential safety hazards exist, and the method is one of the key dangerous chemical process types.
And in the butt joint of the intermediate 1 and the intermediate 2 after cyclization, the purity of the synthesized folic acid is influenced because the high-purity trichloroacetone is difficult to obtain, and the synthesis cost of the high-purity folic acid is high. In addition, the yield of the cyclic compound 3 (chlorochiridine) is low, and the yield of the product is also seriously affected.
In combination, although the reaction has the characteristics of low requirements on production conditions and low material availability and price, the process route is long (5 steps), the total yield is low (about 50%), the product quality is difficult to control, and the process safety and environmental protection are poor.
2. Dibromoacrolein process route:
although the method for synthesizing folic acid by substituting 2, 3-dibromopropionaldehyde for 1, 2-dichloroacetone can obtain high-purity folic acid, the activity of cyclized bromomethyl pyridine is poor, the reaction steps and the operation are as complicated, the total yield is only 36.9 percent, and the cost is greatly increased; in addition, the use of bromine also affects the economy, safety and environmental protection of the process.
3.1,1,3, 3-tetramethoxy-2-propanol route:
the total yield of a route for synthesizing folic acid from 1,1,3, 3-tetramethoxy-2-propanol can reach 65%, in the process, although the total yield of the process route is improved, the production process has the advantages of large total yield of the process route, high raw material cost for preparing 1,1,3, 3-tetramethoxy-2-propanol, difficult preparation, more side reactions and low yield, so the cost is high, in addition, 280 tons of wastewater generated by producing one ton of folic acid is generated, ammonia nitrogen and inorganic salt in the wastewater seriously pollute the environment, and industrial production cannot be realized.
In conclusion, two classical synthesis routes and one large-scale production process route both have certain limitations, so that the development of the folic acid synthesis method which is simple and convenient to operate, safe and environment-friendly and has ideal yield is significant.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a synthesis method of folic acid catalyzed by heteropoly acid.
The synthesis method of folic acid comprises the following steps:
(1) adding acrolein, heteropoly acid, 2, 5, 6-triamino-4-hydroxypyrimidine, p-aminobenzoate and an alcohol solvent into a reactor, stirring and heating, reacting, cooling the materials after the reaction is finished, performing suction filtration, washing a filter cake with the solvent, combining the filtrate with a washing solution, decoloring with activated carbon, and evaporating the solvent after the suction filtration to obtain a light yellow solid intermediate 6.
(2) Dissolving L-sodium glutamate and the intermediate 6 in an alcohol-water mixed solution, stirring and heating for reaction, cooling and cooling the materials after the reaction is finished, preserving heat for growing crystals, performing suction filtration, washing filter cakes with water to obtain a crude folic acid product, and refining to obtain the folic acid.
Wherein R is C1-C6 alkyl; preferably, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In the above-mentioned method, the first step is,
in the step (1), the reaction temperature is 30-60 ℃, the cooling temperature after the reaction is finished is 0-15 ℃, and the reaction time is 0.5-5 hours.
The molar ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine to the p-aminobenzoate, the acrolein and the heteropoly acid is (1-2): (1-2): (1-3): (0.01-0.3);
the mass ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine to the alcohol solvent is 1 (1-10), the mass ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine to the activated carbon is 1 (0.03-0.2), and the mass ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine to the washing solvent is 1 (0.5-5).
The p-aminobenzoic acid ester is one or a combination of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl p-aminobenzoate.
The alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
Acrolein is a cyclization reagent;
the heteropoly acid is a phosphorus-containing heteropoly acid. The general formula of the structure is H3+n-xCsx﹝PMo12-nVnO40(2 ≦ X ≦ 3,0 ≦ n ≦ 2) selected from one or more of heteropolyacids of the above general structural formula, said heteropolyacids being H4Cs2﹝PMo11V1O40﹞、H5Cs2﹝PMo10V2O40﹞、H3Cs3﹝PMo11VO40One or more of (a) such (b).
In the step (2), the reaction temperature is 60-120 ℃, and the reaction time is 6-20 hours; cooling temperature is-20-20 deg.C after reaction, and crystal growth time is 0.5-8 hr.
The molar ratio of the L-sodium glutamate to the intermediate 6 is 1: (0.1-1), preferably 1: 0.25, wherein the alcohol-water mass ratio of the used alcohol-water solvent is 1: (1-2.5), the mass ratio of the intermediate 6 to the alcohol-water solvent is 1 (0.5-10).
In the alcohol-water solvent, the alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
The refining method comprises the following steps: adding the folic acid crude product into one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, wherein the mass ratio of the folic acid crude product to the alcohol solvent is 1: (1-30), stirring, keeping the system at a certain temperature within the range of-20 ℃ to 120 ℃ until the system is dissolved, adding activated carbon, keeping the mass ratio of the folic acid crude product to the activated carbon at 1 (0.03-0.2), keeping the temperature, stirring, keeping the temperature for 0.1 hour to 1 hour, cooling, crystallizing, keeping the temperature within the range of-50 ℃ to 50 ℃, and filtering to obtain the folic acid.
The synthesis method uses a structure of one-step synthesis of a connection structure of a pyridine parent nucleus and p-aminobenzoic acid by heteropoly acid catalytic oxidation reaction. A safe green catalytic oxidation system is used, trichloroacetone and other materials which are difficult to prepare, difficult to prepare and pure or have high pollution are abandoned, acrolein which is relatively cheap and easy to obtain is used as a raw material, the reaction is completely and quickly carried out, no residue is left, the odorless system is ensured, the yield and the purity are obviously improved, the purity of a crude product reaches 99.1-99.3%, and the yield is 95.9-98.2%.
The specific implementation mode is as follows:
the following examples are merely some specific embodiments of the present invention, and the present invention is not limited to the following embodiments, but may be modified in many ways. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
The process screening process comprises the following steps:
1. intermediate 6 for the preparation of different heteropolyacids:
following the procedure of step (1), different heteropoly acids were selected to prepare intermediate 6, the results of which are shown in Table 1:
| heteropolyacids | Yield of | Purity of |
| H4Cs2﹝PMo11V1O40﹞ | 93.5％ | 98.4％ |
| H5Cs2﹝PMo10V2O40﹞ | 95.1％ | 98.4％ |
| H3Cs3﹝PMo11VO40﹞ | 95.4％ | 98.3％ |
The results show that the reaction is carried out with H4Cs2﹝PMo11V1O40﹞、H5Cs2﹝PMo10V2O40﹞、H3Cs3﹝PMo11VO40When the heteropoly acid is used, the purity of the prepared intermediate 6 can reach more than 98 percent, and H is used5Cs2﹝PMo10V2O40Or H3Cs3﹝PMo11VO40When the ester is taken as heteropoly acid, the yield of the intermediate 6 can reach more than 95 percent.
Effect of the molar ratio of 2, 5, 6-triamino-4-hydroxypyrimidine, p-aminobenzoate, acrolein to heteropolyacid on yield and purity of intermediate 6:
effect of the molar ratio of sodium L-glutamate to intermediate 6 on the yield and purity of Folic acid
| Sodium L-glutamate: intermediate 6 (example where R is methyl) | Yield of | Purity of |
| 1：1 | 93.5％ | 99.5％ |
| 1：3 | 28.5％ | 83.3％ |
| 1：0.5 | 93.7％ | 99.7％ |
| 1：0.25 | 95.1％ | 99.7％ |
| 1：0.1 | 93.3％ | 99.6％ |
The molar ratio of the L-sodium glutamate to the intermediate 6 is 1: (0.1-1), preferably 1: 0.25, wherein the alcohol-water mass ratio of the used alcohol-water solvent is 1: (1-2.5), the mass ratio of the intermediate 6 to the alcohol-water solvent is 1 (0.5-10).
The method comprises the following steps:
example 1:
acrolein (5.60 kg) (100mol), heteropoly acid H4Cs2﹝PMo11V1O403mol of free 2, 5, 6-triamino-4-hydroxypyrimidine 14.11kg (100mol), methyl p-aminobenzoate 15.11kg (100mol) and methanol 35kg are added into a 200L reaction kettle, the mixture is stirred and heated to 60 ℃ for reaction for 2 hours, after the reaction is finished, the material is cooled to 0 ℃, suction filtration is carried out, a filter cake is washed by 8kg of methanol, a filtrate is combined with a washing solution, 0.42kg of activated carbon is added for decoloration, a solvent is evaporated after the suction filtration, a light yellow solid intermediate 6 is obtained, the yield is 92.8-95.5%, and the purity is 98.1-98.4% by HPLC detection.
Example 2:
acrolein (5.60 kg) (100mol), heteropoly acid H4Cs2﹝PMo11V1O403.3mol of free 2, 5, 6-triamino-4-hydroxypyrimidine, 15.52kg (110mol) of free 2, 5, 6-triamino-4-hydroxypyrimidine and 16.62kg (110mol) of methyl p-aminobenzoate and 35kg of methanol are added into a 200L reaction kettle, the mixture is stirred and heated to 60 ℃ for reaction for 2 hours, materials are cooled to 0 ℃ after the reaction is finished, suction filtration is carried out, a filter cake is washed by 8kg of methanol, filtrate and washing liquid are combined, 0.42kg of activated carbon is added for decoloration, the solvent is evaporated after the suction filtration, a light yellow solid intermediate 6 is obtained, the yield is 94.1-96.2% (calculated by acrolein), and the purity is 96.0-97.
Example 3:
acrolein (5.60 kg) (100mol), heteropoly acid H4Cs2﹝PMo11V1O403.3mol of free 2, 5, 6-triamino-4-hydroxypyrimidine, 14.11kg (100mol) of free 2, 5, 6-triamino-4-hydroxypyrimidine, 16.51kg (100mol) of ethyl p-aminobenzoate and 38kg of ethanol are added into a 200L reaction kettle, the mixture is stirred and heated to 55 ℃ for reaction for 2 hours, after the reaction is finished, the material is cooled to 0 ℃, suction filtration is carried out, a filter cake is washed by 5kg of ethanol, a filtrate is combined with a washing solution, 0.42kg of activated carbon is added for decoloration, a solvent is evaporated after suction filtration, a light yellow solid intermediate 6 is obtained, the yield is 93.8-95.9% (calculated by acrolein), and the purity is 96..
Example 4:
acrolein (5.60 kg) (100mol), heteropoly acid H4Cs2﹝PMo11V1O401.2mol of free 2, 5, 6-triamino-4-hydroxypyrimidine, 14.11kg (100mol) of free 2, 5, 6-triamino-4-hydroxypyrimidine, 17.91kg (100mol) of isopropyl p-aminobenzoate and 38kg of ethanol are added into a 200L reaction kettle, the mixture is stirred and heated to 55 ℃ for reaction for 2 hours, after the reaction is finished, the material is cooled to 0 ℃, suction filtration is carried out, a filter cake is washed by 5kg of ethanol, a filtrate and a washing solution are combined, 0.42kg of activated carbon is added for decoloration, a solvent is evaporated after suction filtration, a light yellow solid intermediate 6 is obtained, the yield is 92.9-95.0% (calculated by acrolein), and the purity is 89.
Step two:
example 5:
dissolving 8.46kg (50mol) of L-sodium glutamate and 16.31kg (50mol) of intermediate 6(R is methyl) in a solution consisting of 20kg of water and 60kg of ethanol, stirring, heating to 70 ℃ for reaction for 20h, cooling to 0 ℃, standing, keeping warm, growing crystals for 3h, carrying out suction filtration, washing a filter cake with water to obtain a crude product of folic acid, refining and drying to obtain the folic acid, wherein the yield is 83.1-86.2%, and the purity is 99.5-99.8% by HPLC detection.
Example 6:
dissolving 12.69kg (75mol) of L-sodium glutamate and 16.31kg (50mol) of intermediate 6(R is methyl) in a solution composed of 30kg of water and 70kg of n-butyl alcohol, stirring, heating to 110 ℃ for reacting for 18h, cooling to 0 ℃, standing, keeping warm, growing crystals for 3h, carrying out suction filtration, washing a filter cake with water to obtain a crude product of folic acid, refining and drying to obtain folic acid, wherein the yield is 92.3-95.1%, and the purity is 99.5-99.8% by HPLC detection.
Example 7:
dissolving 12.69kg (75mol) of L-sodium glutamate and 16.31kg (50mol) of intermediate 6(R is methyl) in a solution consisting of 25kg of water and 60kg of isopropanol, stirring, heating to 80 ℃ for reacting for 18h, cooling to-20 ℃, standing, keeping warm, growing crystals for 7h, carrying out suction filtration, washing a filter cake with water to obtain a crude product of folic acid, refining and drying to obtain the folic acid, wherein the yield is 90.2-93.8%, and the purity is 99.3-99.7% by HPLC detection.
Example 8:
dissolving 16.92kg (100mol) of L-sodium glutamate and 16.31kg (50mol) of intermediate 6(R is methyl) in a solution consisting of 30kg of water and 70kg of n-butyl alcohol, stirring, heating to 110 ℃ for reacting for 18h, cooling to 0 ℃, standing, keeping warm, growing crystals for 3h, carrying out suction filtration, washing a filter cake with water to obtain a crude product of folic acid, refining and drying to obtain folic acid, wherein the yield is 92.5-94.9%, and the purity is 99.5-99.8% by HPLC detection.
Claims (8)
1. A synthesis method of folic acid catalyzed by heteropoly acid is characterized by comprising the following steps:
(1) adding acrolein, heteropoly acid, 2, 5, 6-triamino-4-hydroxypyrimidine, p-aminobenzoate and an alcohol solvent into a reactor, stirring and heating to react to obtain a light yellow solid intermediate 6;
(2) dissolving L-sodium glutamate and the intermediate 6 in an alcohol-water mixed solution, stirring and heating for reaction to obtain a crude product of folic acid, and refining to obtain folic acid;
the structural formula of the intermediate 6 is as follows:
r is C1-C6 alkyl;
in the step (1), the molar ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine, the p-aminobenzoate, the acrolein and the heteropolyacid is (1-2): (1-2): (1-3): 0.01-0.03;
in the step (1), the heteropoly acid is H4Cs2﹝PMo11V1O40﹞、H5Cs2﹝PMo10V2O40﹞、H3Cs3﹝PMo11VO40One of the (l);
in the step (2), the mol ratio of the L-sodium glutamate to the intermediate 6 is 1: (0.1-1).
2. The method of synthesis according to claim 1,
in the step (1), the p-aminobenzoate is one or more of methyl p-aminobenzoate, ethyl p-aminobenzoate, n-propyl p-aminobenzoate, isopropyl p-aminobenzoate, n-butyl p-aminobenzoate, isobutyl p-aminobenzoate and tert-butyl p-aminobenzoate.
3. The method of synthesis according to claim 1,
in the step (1), the mass ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine to the activated carbon is 1 (0.03-0.2), and the mass ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine to the washing solvent is 1: 0.57;
4. the method of synthesis according to claim 1,
in the step (1), the alcohol solvent is one or a combination of more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, and the mass ratio of the 2, 5, 6-triamino-4-hydroxypyrimidine to the alcohol solvent is 1 (1-10).
5. The method of synthesis according to claim 1,
in the step (1), the reaction temperature is 30-60 ℃, the cooling temperature after the reaction is finished is 0-15 ℃, and the reaction time is 0.5-5 hours.
6. The method of synthesis according to claim 1,
in the step (2), the reaction temperature is 60-120 ℃, and the reaction time is 6-20 hours; cooling temperature is-20-20 deg.C after reaction, and crystal growth time is 0.5-8 hr.
7. The method of synthesis according to claim 1,
in the step (2), the mol ratio of the L-sodium glutamate to the intermediate 6 is 1: 0.25, wherein the alcohol-water mass ratio of the used alcohol-water solvent is 1: 2.4, the mass ratio of the intermediate 6 to the alcohol-water solvent is 1: 5.2.
8. The synthesis method according to claim 1, wherein the refining method comprises the following steps: adding the folic acid crude product into one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, wherein the mass ratio of the folic acid crude product to the alcohol solvent is 1: (1-30), stirring, keeping the system at a certain temperature within the range of-20 ℃ to 120 ℃ until the system is dissolved, adding activated carbon, keeping the mass ratio of the folic acid crude product to the activated carbon at 1 (0.03-0.2), keeping the temperature, stirring, keeping the temperature for 0.1 hour to 1 hour, cooling, crystallizing, keeping the temperature within the range of-50 ℃ to 50 ℃, and filtering to obtain the folic acid.
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