CN113461508B - Preparation method of alpha-ketophenylalanine calcium - Google Patents
Preparation method of alpha-ketophenylalanine calcium Download PDFInfo
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- CN113461508B CN113461508B CN202010243145.XA CN202010243145A CN113461508B CN 113461508 B CN113461508 B CN 113461508B CN 202010243145 A CN202010243145 A CN 202010243145A CN 113461508 B CN113461508 B CN 113461508B
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
Abstract
The invention relates to a preparation method of alpha-ketophenylalanine calcium and a purification method of alpha-ketophenylalanine calcium. The method comprises the steps of reacting hydantoin, benzaldehyde and calcium hydroxide in water to obtain a reaction system containing benzylidene hydantoin; heating the reaction system for hydrolysis reaction to obtain an alpha-ketophenylalanine calcium solution; adjusting the pH value of the alpha-ketophenylalanine calcium solution to 5-8, and crystallizing to obtain the alpha-ketophenylalanine calcium. The method is green and environment-friendly, generates less three wastes, has less operation steps and is simple and easy to implement; meanwhile, the alpha-ketophenylalanine calcium prepared by the method has higher yield and purity.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of alpha-ketophenylalanine calcium and a further purification method of the alpha-ketophenylalanine calcium.
Background
Alpha-ketophenylalanine is a precursor for biosynthesis of phenylalanine, which is an essential amino acid in human bodies, and is an important raw material of compound alpha-ketonic acid tablets. Alpha-ketophenylalanine and its salts are also important ingredients in functional beverages. The compound alpha-ketonic acid tablet can increase glomerular filtration and urinary albumin excretion, is matched with low-protein diet to relieve the symptoms of uremia patients, and has good effect on slowing down renal function deterioration.
According to the literature reports, the synthesis of the alpha-ketophenylalanine calcium mainly comprises the following three methods: the route 1 takes 1-phenyl-2-acetone as a raw material and generates alpha-ketophenylalanine calcium through oxidation and salt-forming reaction, and the route 2 takes phenylacetic acid as a raw material and reacts with cyanogen diethyl phosphate, and then the alpha-ketophenylalanine calcium is obtained through hydrolysis, oxidation and salt-forming reaction; in the route 3, benzaldehyde and hydantoin are used as raw materials, the raw materials react under the action of organic alkali to generate 5-benzylidene hydantoin, then alpha-ketophenylalanine is obtained through hydrolysis, acidification, extraction and concentration under the alkaline condition, and calcium salt is generated with calcium chloride to obtain alpha-ketophenylalanine calcium. Comparing the three methods to find: the raw materials of the synthetic routes 1 and 2 are not easy to obtain, the operation is complex, the reaction conditions are harsh, the cost is high, potential safety hazards exist, and meanwhile, the method is large in environmental pollution and not suitable for industrial production. The raw materials of the synthetic route 3 are simple and easy to obtain, the operation is simple, the synthetic route is suitable for industrial production, the alpha-ketophenylalanine is obtained by concentration, the temperature at the later stage of concentration is high, the alpha-ketophenylalanine is easy to decompose, the product is yellow, the impurities are more, the qualified product can be obtained by repeated recrystallization, meanwhile, the route 3 is a two-step reaction, the alpha-ketophenylalanine is obtained by preparation firstly, the calcium source is added to obtain the alpha-ketophenylalanine calcium, the utilization rate of equipment is low, the occupied equipment is more, the working hours are taken, and the yield is low.
In the prior art, methods for producing alpha-ketophenylalanine calcium by using benzaldehyde and hydantoin as raw materials exist, but all have certain defects. CN103193628A discloses that hydantoin is prepared from hydantoin and benzaldehyde through reaction under the action of organic base, hydrolysis, acidification and extraction under strong alkaline condition, organic base is added to form salt, extraction is carried out to obtain water phase, and then the water phase is reacted with calcium chloride to obtain alpha-ketophenylalanine calcium. In the method, alkali needs to be added into a reaction system for multiple times, a large amount of acid is added for adjusting the pH value, a large amount of inorganic salt is generated, the impurity removal effect in the extraction process is poor, a large amount of extraction solvent needs to be consumed, and multiple tests are carried out. CN107033089B discloses that hydantoin and benzaldehyde are used as raw materials, glycine, strong base and organic alcohol are used as catalysts, the benzalhydantoin is obtained by catalytic cyclization reaction of the organic base and the organic alcohol, the benzalhydantoin is hydrolyzed in sodium hydroxide alkali liquor to obtain alpha-ketophenyl sodium propionate, and then the alpha-ketophenyl calcium alanine is obtained by reaction of the alpha-ketophenyl sodium propionate and calcium acetate. In the preparation method, modes and equipment such as decoloration filtration, freeze crystallization, a clapboard and diaphragm filter press are adopted, the operation is complex, the equipment utilization rate is low, and the early investment cost is high.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the preparation method of the alpha-ketophenylalanine calcium, which is environment-friendly, generates less three wastes, has less operation steps and is simple and easy to implement; meanwhile, the alpha-ketophenylalanine calcium prepared by the method has higher yield and purity.
In order to realize the purpose, the invention adopts the following scheme:
the invention provides a preparation method of alpha-ketophenylalanine calcium, which comprises the following steps:
(1) Reacting hydantoin, benzaldehyde and calcium hydroxide in water to obtain a reaction system containing benzylidene hydantoin;
(2) Heating the reaction system for hydrolysis reaction to obtain an alpha-ketophenylalanine calcium solution;
(3) Adjusting the pH value of the alpha-ketophenylalanine calcium solution to 5-8, and crystallizing to obtain the alpha-ketophenylalanine calcium.
The inventor researches a preparation method of alpha-ketophenylalanine calcium, and develops a method for preparing the alpha-ketophenylalanine calcium by a one-pot method in order to realize the purposes of simple and feasible production process, controllable operation steps and high yield and purity of a generated product. In particular, the calcium hydroxide added at the beginning of the reaction has several effects: in the step (1), calcium hydroxide is used as a catalyst for condensation reaction of hydantoin and benzaldehyde; in the step (2), calcium hydroxide is used as alkali and participates in hydrolysis reaction; in step (3), calcium hydroxide provides a source of calcium for the formation of calcium α -ketophenylalanine. The invention can avoid adding reaction reagent for many times in the reaction process, and really realizes the one-pot reaction.
In the chemical reaction, the calcium hydroxide has low solubility, so the effect of participating in the chemical reaction is not ideal, the reaction is incomplete or the reaction time is overlong, and the final product has low yield and low purity. Thus, although synthetic routes require a step to increase calcium ion, calcium hydroxide is still rarely the choice of reactant by those skilled in the art. For example, in the technical scheme disclosed in CN107033089B, sodium hydroxide is selected as a reaction reagent to participate in the reaction, the reaction generates α -ketophenylalanine, and then calcium chloride is added to α -ketophenylalanine to react, and finally α -ketophenylalanine calcium is generated. Despite the increased number of process steps, there is a better yield of the final product, up to 94.8%. In the invention, researches of researchers find that calcium hydroxide can be selected as a reaction reagent to participate in the reaction, and calcium source is provided for the formation of alpha-ketophenylalanine calcium while the calcium hydroxide participates in the hydrolysis reaction, so that the operation steps are reduced, the reaction efficiency is improved, and the yield and the purity of a final product are not reduced. Therefore, the technical scheme of the one-pot method overcomes the problem of low solubility of calcium hydroxide, promotes hydrolysis reaction and salt forming reaction of alpha-ketophenylalanine calcium, promotes complete reaction, shortens reaction time, and overcomes the technical bias that calcium hydroxide is easy to cause incomplete chemical reaction by technical personnel in the field.
In the step (1), the molar ratio of the hydantoin, the benzaldehyde and the calcium hydroxide is 1 to 1.3.
In the step (1), the reaction temperature is 20 to 40 ℃, and the preferable reaction temperature is 20 to 30 ℃. Under such conditions, although the calcium hydroxide added is not necessarily completely dissolved, it does not affect the progress of the reaction, and the calcium hydroxide only acts as a catalyst for the condensation reaction in step (1) and does not directly participate in the reaction.
In the step (1), the low-temperature reaction can not only reduce the energy consumption, but also stabilize the material properties in the reaction system, the condensation reaction adopted in other documents reacts under the high-temperature condition, and the high-temperature condition can promote the hydrolysis and ring opening of the hydantoin, so that the problems of low yield and low quality purity are caused, and the low-temperature reaction can avoid the production of impurities caused by the hydrolysis of the hydantoin.
In the step (2), the temperature of the hydrolysis reaction is 95-105 ℃, and the system is in a reflux state to generate the alpha-ketophenylalanine calcium.
In the step (3), preferably, the pH value of the alpha-ketophenylalanine calcium-containing solution is adjusted to be 6.5 to 7.5; the acid for adjusting the pH is hydrochloric acid; when the pH value is adjusted, the temperature of the reaction liquid is below 50 ℃; the crystallization temperature is 10 to 20 ℃.
The method only uses a single solvent (water) in the process of synthesizing the alpha-ketophenylalanine calcium, and is convenient to recycle; after partial products are recovered from the centrifugal mother liquor of alpha-ketophenylalanine calcium prepared by condensation hydrolysis reaction, calcium chloride can be recovered as a byproduct, and the concentrated effluent can be applied to the condensation step.
Through the three steps, the yield of the alpha-ketophenylalanine calcium ranges from 90 to 95 percent, and the purity is more than or equal to 98.0 percent.
In another aspect, the present invention also discloses a method for purifying alpha-ketophenylalanine calcium, which comprises the following steps: and adding the alpha-ketophenylalanine calcium obtained in the reaction into a solvent, adding hydrochloric acid for dissolving, adding alkali, cooling to 10-20 ℃, and crystallizing to obtain a refined alpha-ketophenylalanine calcium product.
The solvent comprises one or more of methanol, ethanol, isopropanol and DMF; preferably, the solvent is methanol.
The base includes an amine organic base such as triethylamine, diethylamine, ethylamine, ethanolamine, aqueous ammonia or diisopropylethylamine. The molar ratio of the amine organic base to the hydrochloric acid is 1.
The alkali may be inorganic alkali such as sodium hydroxide and potassium hydroxide.
The yield of the alpha-ketophenylalanine calcium obtained by the purification method is 90 to 95 percent, and HPLC (high performance liquid chromatography) is more than or equal to 99.9 percent. Meanwhile, the centrifugal mother liquor is used as a solvent for recycling through simple rectification, so that the centrifugal mother liquor is green and environment-friendly, and the production cost is reduced.
The method for purifying the alpha-ketophenylalanine calcium can be used for purifying any crude alpha-ketophenylalanine calcium product, particularly the alpha-ketophenylalanine calcium which is generated by taking hydantoin and benzaldehyde as raw materials through a benzylidene hydantoin hydrolysis path, and the purity and the yield of the obtained product are improved.
The preparation method of the alpha-ketophenylalanine calcium disclosed by the invention has the beneficial effects that:
(1) The preparation method adopts a one-pot method, does not need to purify the intermediate benzylidene hydantoin, and simplifies the operation steps;
(2) Calcium hydroxide is used as a catalyst, a hydrolysis reagent and a calcium source in the reaction steps (1), (2) and (3), and is added in the step (1) at one time, so that repeated reagent addition is avoided, and the operation steps are reduced;
(3) Water in the preparation process can be used indiscriminately, calcium chloride can be recovered as a byproduct, waste water and solid discharged are little, and the environment is protected;
(4) The process equipment of the invention is less in use and convenient for large-scale production.
The purification method of alpha-ketophenylalanine calcium disclosed by the invention has the beneficial effects that:
(1) The alpha-ketophenylalanine calcium is dissolved in the solvent by the formation acid in the solvent, and then the alkali is added into the system for crystallization and refining, so that the problem that the traditional alpha-ketophenylalanine calcium refining is difficult to dissolve is solved, and meanwhile, a high-purity alpha-ketophenylalanine calcium refined product is obtained;
(2) Reaction water is used as a solvent, so that the safety coefficient is high; rectifying the refined centrifugal mother liquor to recover methanol or other solvents, wherein the yield is 75-80%, the purity gas phase detection is more than or equal to 99.85%, and the refined centrifugal mother liquor can be used as a refined solvent for mechanical application, so that the environmental protection pressure is reduced;
(3) The API of the alpha-ketophenylalanine calcium obtained by the process has uniform granularity and meets the requirement of raw material medicaments for preparation of the preparation.
Detailed Description
The following examples are provided to further illustrate the technical solutions of the present invention, but not to limit the present invention.
Example 1:
(1) Preparation of alpha-ketophenylalanine calcium
a) Adding 1750g of water and 350g (3.47 mol) of hydantoin into a 10L four-mouth bottle, sequentially adding 393g (3.70 mol) of benzaldehyde and 194g (2.62 mol) of calcium hydroxide into a reaction bottle, heating to 20 ℃, and carrying out heat preservation reaction for 2h to obtain a reaction solution (containing undissolved calcium hydroxide solid) containing benzylidene hydantoin;
b) Heating the reaction solution (containing undissolved calcium hydroxide solid) to 100 ℃, heating and refluxing, and reacting for 5 hours to obtain a solution containing alpha-ketophenylalanine calcium;
c) And (3) cooling the solution containing the alpha-ketophenylalanine calcium to 40 ℃, controlling the temperature to be 40 ℃, slowly and dropwise adding 31% hydrochloric acid to adjust the pH value to 6.5, controlling the temperature to be 40 ℃, keeping the temperature for 2 hours, cooling to 20 ℃, keeping the temperature for crystallization for 2 hours, performing suction filtration, and leaching a filter cake by using 350g of water to obtain 604g of alpha-ketophenylalanine calcium. The yield of the alpha-ketophenylalanine calcium is 95 percent, and the purity is 98.4 percent.
(2) Purification of alpha-ketophenylalanine calcium
1500g of ethanol and the alpha-ketophenylalanine calcium are added into a 10L four-mouth bottle, the temperature is controlled at 25 ℃, and about 390g of 31 percent hydrochloric acid is added for dissolution under stirring. And slowly adding about 335g of triethylamine dropwise, starting slow cooling, keeping the temperature for 2h when the reaction solution becomes turbid, continuously cooling to 15 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, leaching a filter cake with 250g of methanol, and drying to constant weight to obtain 572g of a refined product of the alpha-ketophenylalanine calcium, wherein the yield of the purification step is 95%, and the HPLC (high performance liquid chromatography) is more than or equal to 99.9%.
Example 2:
(1) Preparation of alpha-ketophenylalanine calcium
a) Adding 1750g of water and 350g (3.47 mol) of hydantoin into a 10L four-mouth bottle, sequentially adding 423g (4.00 mol) of benzaldehyde and 257g (2.47 mol) of calcium hydroxide into a reaction bottle, heating to 30 ℃, and carrying out heat preservation reaction for 2h to obtain a reaction solution (containing undissolved calcium hydroxide solid) containing benzylidene hydantoin;
b) Heating the reaction solution (containing undissolved calcium hydroxide solid) to 100 ℃, heating and refluxing, and reacting for 4 hours to obtain a solution containing alpha-ketophenylalanine calcium;
c) And (3) cooling the solution containing the alpha-ketophenylalanine calcium to 45 ℃, controlling the temperature to be 45 ℃, slowly dropwise adding 31% hydrochloric acid to adjust the pH value to 7, controlling the temperature to be 45 ℃, keeping the temperature for 2h, cooling to 10 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, and leaching a filter cake with 350g of water to obtain 598g of alpha-ketophenylalanine calcium. The yield of the alpha-ketophenylalanine calcium is 94 percent, and the purity is 98.2 percent.
(2) Purification of alpha-ketophenylalanine calcium
1500g of ethanol and the alpha-ketophenylalanine calcium are added into a 10L four-mouth bottle, the temperature is controlled at 25 ℃, and about 390g of 31 percent hydrochloric acid is added for dissolution under stirring. Slowly adding 242g of diethylamine dropwise, beginning to slowly cool, keeping the temperature for 2h when the reaction solution begins to become turbid, continuing to cool to 15 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, leaching the filter cake with 300g of ethanol, and drying to constant weight to obtain 559g of refined alpha-ketophenylalanine calcium product, wherein the yield of the purification step is 94%, and the HPLC (high performance liquid chromatography) is more than or equal to 99.9%.
Example 3:
(1) Preparation of alpha-ketophenylalanine calcium
a) Adding 1750g of water and 350g (3.47 mol) of hydantoin into a 10L four-mouth bottle, sequentially adding 405g (3.82 mol) of benzaldehyde and 180g (2.43 mol) of calcium hydroxide into a reaction bottle, heating to 25 ℃, and carrying out heat preservation reaction for 2h to obtain a reaction liquid (containing undissolved calcium hydroxide solid) containing benzylidene hydantoin;
b) Heating the reaction solution (containing undissolved calcium hydroxide solid) to 95 ℃, heating and refluxing, and reacting for 4 hours to obtain a solution containing alpha-ketophenylalanine calcium;
c) And (3) cooling the solution containing the alpha-ketophenylalanine calcium to 40 ℃, controlling the temperature to be 40 ℃, slowly and dropwise adding 31% hydrochloric acid to adjust the pH value to 7.5, controlling the temperature to be 40 ℃, keeping the temperature for 2 hours, cooling to 10 ℃, keeping the temperature for crystallization for 2 hours, performing suction filtration, and leaching a filter cake by using 350g of water to obtain 591g of alpha-ketophenylalanine calcium. The yield of alpha-ketophenylalanine calcium is 93%, and the purity is 98.5%.
(2) Purification of alpha-ketophenylalanine calcium
1500g of methanol and the alpha-ketophenylalanine calcium are added into a 10L four-mouth bottle, the temperature is controlled at 20 ℃, and about 390g of 31 percent hydrochloric acid is added for dissolution under stirring. Slowly adding 428g of diisopropylethylamine dropwise, starting slow cooling, keeping the temperature for 2h when the reaction solution becomes turbid, continuously cooling to 10 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, leaching the filter cake with 250g of methanol, and drying to constant weight to obtain 559g of a refined product of the alpha-ketophenylalanine calcium, wherein the yield of the purification step is 95%, and the HPLC (high performance liquid chromatography) is more than or equal to 99.9%.
Example 4:
(1) Preparation of alpha-ketophenylalanine calcium
a) Adding 1750g of water and 350g (3.47 mol) of hydantoin into a 10L four-mouth bottle, sequentially adding 368g (3.47 mol) of benzaldehyde and 154g (2.08 mol) of calcium hydroxide into a reaction bottle, heating to 40 ℃, and carrying out heat preservation reaction for 2h to obtain a reaction solution (containing undissolved calcium hydroxide solid) containing benzylidene hydantoin;
b) Heating the reaction solution (containing undissolved calcium hydroxide solid) to 105 ℃, heating and refluxing, and reacting for 4 hours to obtain a solution containing alpha-ketophenylalanine calcium;
c) And (3) cooling the solution containing the alpha-ketophenylalanine calcium to 45 ℃, controlling the temperature to be 45 ℃, slowly and dropwise adding 31% hydrochloric acid to adjust the pH value to 8, controlling the temperature to be 45 ℃, keeping the temperature for 2 hours, cooling to 10 ℃, keeping the temperature for crystallization for 2 hours, performing suction filtration, and leaching a filter cake by using 350g of water to obtain 585g of alpha-ketophenylalanine calcium. The yield of the alpha-ketophenylalanine calcium is 92 percent, and the purity is 98.5 percent.
(2) Purification of alpha-ketophenylalanine calcium
1500g of isopropanol and the alpha-ketophenylalanine calcium are added into a 10L four-mouth bottle, the temperature is controlled at 2 ℃, and about 387g of 31% hydrochloric acid is added to dissolve under stirring. And slowly adding about 149g of ethylamine dropwise, starting slow cooling, keeping the temperature for 2h when the reaction solution becomes turbid, continuously cooling to 20 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, leaching a filter cake by using 300g of isopropanol, and drying to constant weight to obtain 534g of a refined product of the alpha-ketophenylalanine calcium, wherein the yield of the purification step is 91%, and the HPLC (high performance liquid chromatography) is more than or equal to 99.9%.
Example 5:
(1) Preparation of alpha-ketophenylalanine calcium
a) Adding 1750g of water and 350g (3.47 mol) of hydantoin into a 10L four-mouth bottle, sequentially adding 479g (4.51 mol) of benzaldehyde and 257g (3.47 mol) of calcium hydroxide into a reaction bottle, heating to 30 ℃, and carrying out heat preservation reaction for 2h to obtain a reaction liquid (containing undissolved calcium hydroxide solid) containing benzylidene hydantoin;
b) Heating the reaction solution (containing undissolved calcium hydroxide solid) to 95 ℃, heating and refluxing, and reacting for 4 hours to obtain a solution containing alpha-ketophenylalanine calcium;
c) And (3) cooling the solution containing the alpha-ketophenylalanine calcium to 50 ℃, controlling the temperature to be 50 ℃, slowly dropwise adding 31% hydrochloric acid to adjust the pH value to 5, controlling the temperature to be 50 ℃, keeping the temperature for 2h, cooling to 20 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, and leaching a filter cake with 350g of water to obtain 591g of alpha-ketophenylalanine calcium. The yield of alpha-ketophenylalanine calcium is 93%, and the purity is 98.0%.
(2) Purification of alpha-ketophenylalanine calcium
In a 10L four-necked flask, 1500g of DMF and the above alpha-ketophenylalanine calcium were added, the temperature was controlled at 30 ℃, and about 387g of 31% hydrochloric acid was added with stirring to dissolve the mixture. And slowly adding 202g of ethanolamine dropwise, starting slow cooling, keeping the temperature for 2h when the reaction solution becomes turbid, continuously cooling to 10 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, leaching a filter cake by using 250g of methanol, and drying to constant weight to obtain 547g of a refined alpha-ketophenylalanine calcium product, wherein the yield of the purification step is 92%, and the HPLC (high performance liquid chromatography) is more than or equal to 99.9%.
Example 6:
(1) Preparation of alpha-ketophenylalanine calcium
a) Adding 1750g of water and 350g (3.47 mol) of hydantoin into a 10L four-mouth bottle, sequentially adding 393g (3.70 mol) of benzaldehyde and 194g (2.62 mol) of calcium hydroxide into a reaction bottle, heating to 40 ℃, and carrying out heat preservation reaction for 2h to obtain a reaction liquid (containing undissolved calcium hydroxide solid) containing benzylidene hydantoin;
b) Heating the reaction solution (containing undissolved calcium hydroxide solid) to 100 ℃, heating and refluxing, and reacting for 4 hours to obtain a solution containing alpha-ketophenylalanine calcium;
c) And (3) cooling the solution containing the alpha-ketophenylalanine calcium to 45 ℃, controlling the temperature to be 45 ℃, slowly dropwise adding 31% hydrochloric acid to adjust the pH value to 6.5, controlling the temperature to be 40 ℃, keeping the temperature for 2h, cooling to 20 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, and leaching a filter cake with 350g of water to obtain 578g of the alpha-ketophenylalanine calcium. The yield of the alpha-ketophenylalanine calcium is 91 percent, and the purity is 98.2 percent.
(2) Purification of alpha-ketophenylalanine calcium
1000g of methanol, 500g of ethanol and the alpha-ketophenylalanine calcium are added into a 10L four-mouth bottle, the temperature is controlled to be 25 ℃, and about 387g of 31 percent hydrochloric acid is added to dissolve the alpha-ketophenylalanine calcium under stirring. Then slowly dripping about 116g of ammonia water, beginning to slowly cool, keeping the temperature for 2h when the reaction solution begins to become turbid, continuing to cool to 15 ℃, keeping the temperature for crystallization for 2h, carrying out suction filtration, leaching a filter cake by using 250g of methanol, and drying to constant weight to obtain 540g of refined alpha-ketophenylalanine calcium product, wherein the yield in the purification step is 93%, and the HPLC (high performance liquid chromatography) is more than or equal to 99.9%.
Example 7:
(1) Preparation of alpha-ketophenylalanine calcium
a) Adding 1750g of water and 350g (3.47 mol) of hydantoin into a 10L four-mouth bottle, sequentially adding 442g (4.16 mol) of benzaldehyde and 231g (3.12 mol) of calcium hydroxide into a reaction bottle, heating to 40 ℃, and carrying out heat preservation reaction for 2h to obtain a reaction liquid (containing undissolved calcium hydroxide solid) containing benzylidene hydantoin;
b) Heating the reaction solution (containing undissolved calcium hydroxide solid) to 100 ℃, heating and refluxing, and reacting for 4 hours to obtain a solution containing alpha-ketophenylalanine calcium;
c) And (3) cooling the solution containing the alpha-ketophenylalanine calcium to 40 ℃, controlling the temperature to be 40 ℃, slowly dropwise adding 31% hydrochloric acid to adjust the pH value to 6.5, controlling the temperature to be 45 ℃, keeping the temperature for 2 hours, cooling to 20 ℃, keeping the temperature for crystallization for 2 hours, carrying out suction filtration, and leaching a filter cake with 350g of water to obtain 585g of alpha-ketophenylalanine calcium. The yield of the alpha-ketophenylalanine calcium is 92 percent, and the purity is 98.5 percent.
(2) Purification of alpha-ketophenylalanine calcium
1000g of methanol, 500g of ethanol and the alpha-ketophenylalanine calcium are added into a 10L four-mouth bottle, the temperature is controlled at 25 ℃, and about 387g of 31 percent hydrochloric acid is added to dissolve the alpha-ketophenylalanine calcium under stirring. And slowly adding about 335g of triethylamine, slowly cooling, keeping the temperature for 2h when the reaction solution becomes turbid, continuously cooling to 15 ℃, keeping the temperature for crystallization for 2h, performing suction filtration, leaching the filter cake with 250g of methanol, and drying to constant weight to obtain 540g of a refined product of the alpha-ketophenylalanine calcium, wherein the yield of the purification step is 94%, and the HPLC (high performance liquid chromatography) is more than or equal to 99.9%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.
Claims (11)
1. The preparation method of the alpha-ketophenylalanine calcium is characterized by comprising the following steps:
(1) Reacting hydantoin, benzaldehyde and calcium hydroxide in water to obtain a reaction system containing benzylidene hydantoin;
(2) Heating the reaction system for hydrolysis reaction to obtain an alpha-ketophenylalanine calcium solution;
(3) Adjusting the pH value of the alpha-ketophenylalanine calcium solution to 5-8, and crystallizing to obtain the alpha-ketophenylalanine calcium.
2. The method for preparing calcium α -ketophenylalanine according to claim 1, wherein the molar ratio of hydantoin to benzaldehyde to calcium hydroxide is 1 to 1.3.
3. The method for preparing calcium α -ketophenylalanine according to claim 1, wherein the reaction temperature in the step (1) is 20 to 40 ℃.
4. The method for preparing calcium α -ketophenylalanine according to claim 3, wherein the reaction temperature in the step (1) is 20 to 30 ℃.
5. The method for preparing alpha-ketophenylalanine calcium according to claim 1, wherein the reaction temperature in the step (2) is 95 to 105 ℃.
6. The method for producing alpha-ketophenylalanine calcium according to claim 1, wherein the pH in the step (3) is adjusted to 6.5 to 7.5.
7. A purification method of alpha-ketophenylalanine calcium is characterized in that the alpha-ketophenylalanine calcium according to any one of claims 1 to 6 is added into a solvent, then hydrochloric acid is added for dissolution, then alkali is added, the temperature is reduced to 10 to 20 ℃, and crystallization is carried out to obtain a refined alpha-ketophenylalanine calcium product.
8. The method for purifying calcium α -ketophenylalanine according to claim 7, wherein said solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol and DMF.
9. The method of purifying α -ketophenylalanine calcium according to claim 7, wherein said base is an amine-based organic base.
10. The method of claim 9, wherein said amine-based organic base is triethylamine, diethylamine, ethylamine, ethanolamine, or diisopropylethylamine.
11. The method of purifying α -ketophenylalanine calcium according to claim 7, wherein said base is aqueous ammonia.
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| CN103193628A (en) * | 2013-04-26 | 2013-07-10 | 河北九派制药股份有限公司 | Alpha-ketophenylalanine calcium preparation method |
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| CN102050725A (en) * | 2010-12-03 | 2011-05-11 | 浙江新和成股份有限公司 | Method for preparing Alpha-keto-phenylalanine calcium |
| CN103193628A (en) * | 2013-04-26 | 2013-07-10 | 河北九派制药股份有限公司 | Alpha-ketophenylalanine calcium preparation method |
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