CN113735775B - Preparation method of alpha-ketovaline calcium and intermediate thereof - Google Patents
Preparation method of alpha-ketovaline calcium and intermediate thereof Download PDFInfo
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- CN113735775B CN113735775B CN202010480008.8A CN202010480008A CN113735775B CN 113735775 B CN113735775 B CN 113735775B CN 202010480008 A CN202010480008 A CN 202010480008A CN 113735775 B CN113735775 B CN 113735775B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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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
- C07C51/41—Preparation of salts of carboxylic acids
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a preparation method of alpha-ketovaline calcium and an intermediate thereof, which adopts hydantoin and acetone to obtain the alpha-ketovaline calcium intermediate isopropylidene hydantoin under the catalysis of ammonia water. And then the alpha-ketovaline calcium is prepared from isopropylidene hydantoin, so that the alpha-ketoleucine calcium with high yield and high purity can be obtained, and the method is suitable for industrial mass production.
Description
Technical Field
The invention relates to a preparation method of an alpha-ketovaline calcium intermediate and a method for preparing alpha-ketovaline calcium by using the intermediate, belonging to the technical field of medicines.
Background
In recent years, chronic Kidney Disease (CKD) has a high incidence and tends to be younger, and is increasingly receiving attention. CKD has a hidden progression and once advanced, the cost of both therapeutic and care will increase. The compound alpha-keto acid tablet is matched with low protein diet, can delay the progress of renal failure, has important value in the treatment of CKD, and has become a core means of the treatment of CKD.
The alpha-ketovaline calcium is one of the main components of the compound alpha-ketoacid tablet, the compound alpha-ketoacid tablet is marketed in Germany for the first time by Fei Senyou Sikabi corporation in Germany in 1996, the trade names are the same, and the medicine is a compound preparation containing 1 kind of calcium hydroxyamino acid, 4 kinds of calcium ketoamino acid and 5 kinds of amino acid. The components synthesize corresponding essential amino acids through the transamination of enzymes, urea nitrogen is degraded, and the accumulation of uremic toxins is reduced by recycling nitrogenous metabolites, so that uremic symptoms are improved; by high glomerular filtration, blood phosphorus and PTH levels are reduced to delay progression of chronic renal failure, thereby deferring the time to begin dialysis; the essential amino acid is supplemented to achieve the effects of correcting amino acid metabolic disorder and improving nutritional status.
The chemical name of the alpha-ketovaline calcium is calcium bis (3-methyl-2-oxo-butyrate), and the structural formula is as follows:
。
known synthesis methods of alpha-ketovaline calcium are:
patent CN201110156569.3 discloses a preparation method of alpha-ketovaline calcium, which comprises heating hydantoin and acetone to 70-80 ℃ for reflux reaction under the action of borax-sodium hydroxide buffer solution (ph=9.8±0.2) or sodium carbonate decahydrate-sodium bicarbonate buffer solution (ph=9.9±0.2), and reducing the temperature after reduced pressure distillation to obtain 5-isopropylidene hydantoin; heating and refluxing 5-isopropylidene hydantoin and sodium hydroxide for reaction, adjusting the pH value to be 1-2 by acid, extracting twice by methyl tertiary butyl ether, and distilling the organic phase under reduced pressure to obtain oily alpha-ketovaline; and then adjusting the alpha-ketovaline aqueous solution to pH 6-8 by using a sodium hydroxide aqueous solution, and reacting the decolored activated carbon with a calcium salt to obtain the alpha-ketovaline calcium.
Patent CN201210171694.6 discloses a preparation method of alpha-ketovaline calcium, which comprises the steps of dripping dialkyl oxalate into an alcohol solution of metal alkoxide, dripping isobutyraldehyde, carrying out heat preservation and stirring, adding an alkali solution, adjusting acid after the reaction is finished, extracting with an organic solvent, adjusting the pH of an organic phase, adjusting the pH of an obtained water phase again, adding a calcium chloride aqueous solution into the water phase to form salt, obtaining a crude ketovaline calcium product, and then refining in a mixed solvent of purified water and the organic solvent to obtain a refined ketovaline calcium product. The reaction route has high cost and high safety risk, the post-treatment steps are complex, and the post-treatment steps of multiple extraction and refining such as organic solvent extraction, pH adjustment, mixed solvent refining and the like are needed, so that the method is not beneficial to large-scale production.
Patent CN201410457101.1 discloses a novel preparation process of alpha-ketovaline calcium, which comprises the steps of sequentially adding N-heterocyclic imidazole salt, potassium carbonate, a reaction solvent and alpha-valine into a reaction kettle, introducing compressed air, and carrying out heating reflux reaction; after the reaction is finished, cooling to room temperature, distilling to remove the solvent, adding distilled water, extracting the water phase for 3 times by using an extraction solvent, merging the organic phases, drying, filtering at normal pressure, and evaporating to remove the solvent to obtain an oily crude product alpha-ketovaline; dissolving alpha-ketovaline in distilled water, stirring, heating and refluxing for reaction, adding strong alkali, regulating the pH value of the solution to be 7, adding active carbon for decolorization, reacting with an aqueous solution containing calcium chloride, filtering and drying to obtain the alpha-ketovaline calcium. The method has complicated process operation steps and complex post-treatment, and is not beneficial to large-scale production.
In summary, the method for preparing alpha-ketovaline calcium disclosed at present has the problems of excessive impurities, difficult refining, complicated post-treatment steps, high cost and the like, and is not suitable for industrial mass production.
Disclosure of Invention
The invention provides a preparation method of an alpha-ketovaline calcium intermediate, which adopts hydantoin and acetone to obtain the alpha-ketovaline calcium intermediate isopropylidene hydantoin under the catalysis of ammonia water, and the isopropylidene hydantoin prepared by the method can obtain the isopropylidene hydantoin with high yield and high purity without a post-treatment step of impurity removal. The alpha-ketovaline calcium prepared by the isopropylidene hydantoin prepared by the method can also be obtained with high yield and high purity, and is suitable for industrial mass production.
The invention provides a preparation method of alpha-ketovaline calcium intermediate isopropylidene hydantoin, which is characterized in that hydantoin and acetone react under the catalysis of ammonia water to obtain the alpha-ketovaline calcium intermediate isopropylidene hydantoin.
In the prior art, in order to control the generation of impurities, the inventor researches the types of catalysts used in the prior art, and discovers that the commonly used alkaline catalysts such as ethanolamine and the like cannot effectively control the generation of impurities. The inventors have conducted intensive studies on how high-yield and high-purity isopropylidene hydantoin can be obtained and how the post-treatment step can be achieved simply and easily. The method selects ammonia water as a catalyst, and uses the ammonia water to catalyze the reaction of hydantoin and acetone, the reaction condition is mild, the reaction speed can be effectively controlled, the alkaline hydrolysis of hydantoin is inhibited, the generation of impurities is controlled, the yield and purity of isopropylidene hydantoin are improved, the yield of the isopropylidene hydantoin is up to more than 90%, the purification steps such as further purification and filtration are not needed, and the purity can be up to more than 99%.
The reaction solvent is one or more of water, methanol, ethanol and isopropanol.
In the reaction, the dosage of ammonia water in the reaction is calculated by the dosage of ammonia contained in the reaction, and the molar ratio of the hydantoin to the dosage of the acetone to the dosage of the ammonia is 1:1-6:0.3-2.
In the reaction, the mass fraction of ammonia in the ammonia water is 10-28%.
The catalytic reaction temperature is 40-60 ℃.
In the reaction, after the reaction of the hydantoin and the acetone is finished, the pH value is adjusted to 6-7, and isopropylidene hydantoin with higher purity can be obtained, specifically, the hydantoin and the acetone react under the catalysis of ammonia water, the pH value is adjusted to 6-7, and the alpha-ketovaline calcium intermediate isopropylidene hydantoin is obtained.
Another embodiment of the invention provides a preparation method of alpha-ketovaline calcium, which comprises the following specific steps:
(1) Reacting isopropylidene hydantoin prepared by the preparation method of the alpha-ketovaline calcium intermediate with alkali to obtain alpha-ketovaline salt;
(2) And (3) reacting the alpha-ketovaline salt with a calcium salt to obtain the alpha-ketovaline calcium.
In the reaction, the isopropylidene hydantoin and the alkali in the step (1) can be selectively reacted under the condition of micro negative pressure; when isopropylidene hydantoin reacts with alkali under the condition of micro negative pressure, ammonia generated by the reaction overflows from the reaction liquid rapidly in the environment of micro negative pressure, so that the reaction is promoted to be carried out in the forward reaction direction, the reaction speed of isopropylidene hydantoin and alkali is accelerated, and the reaction time is saved by more than 25%. Meanwhile, the invention can collect the generated ammonia gas by another container with water, the prepared ammonia water can be used in the catalysis of the reaction of hydantoin and acetone, the reaction byproducts are efficiently utilized, the purpose of circular economy is realized, meanwhile, the ammonia gas is collected, the exhaust of waste gas generated by the reaction can be strictly controlled, and the pollution to the environment is reduced.
In the step (1), isopropylidene hydantoin and alkali are reacted under the pressure of-0.1 to-0.05 MPa.
In the step (1), when isopropylidene hydantoin reacts with alkali, the step of absorbing with water to generate ammonia is further included.
In the step (1), the reaction solvent of isopropylidene hydantoin and alkali may be one or more of water, ethanol and butanol.
The alkali in the step (1) is selected from one or more of potassium tert-butoxide, sodium ethoxide, potassium ethoxide and potassium hydroxide.
In the step (1), the molar ratio of the isopropylidene hydantoin to the alkali is 1:2-6.
The reaction temperature of isopropylidene hydantoin and alkali in the step (1) is 40-50 ℃.
The calcium salt in the step (2) is one of calcium chloride, calcium acetate and calcium citrate.
The reaction solvent of the alpha-ketovaline salt and the calcium salt in the step (2) can be one or more of methanol, ethanol, isopropanol and water.
The alpha-ketovaline calcium prepared by the method does not need further post-treatment and refining steps, and the product with the HPLC purity of more than or equal to 99.9 percent can be obtained, which accords with the pharmaceutical standard.
Detailed Description
Example 1
(1) Preparation of isopropylidene hydantoin
To 20mL of water were added 6.4g of ammonia water (25% by mass) (0.094 mol), 9.4g of hydantoin (0.094 mol) and 5.5g of acetone (0.095 mol) in this order; heating to 40 ℃ for reaction for 5 hours, cooling to 25 ℃ after the reaction is finished, preserving heat for 1 hour, filtering, and drying to obtain 12.00g isopropylidene hydantoin. The yield thereof was found to be 91.18% and the purity thereof was found to be 99.91%.
(2) Preparation of alpha-ketovaline salt
To 50mL of ethanol was added 7.67g KOH (0.137 mol), 9.60g (0.0686 mol) isopropylidene hydantoin; heating to 40 ℃ under slight negative pressure (the pressure is-0.05 MPa), and reacting for 2 hours; and a container for holding water for collecting the generated ammonia gas and preparing ammonia water. Cooling after the reaction is finished, controlling the temperature of the reaction solution to be 25 ℃, preserving the heat for 1 hour, filtering and drying to obtain 9.62g of ketovaline potassium. Yield 91.06%, purity 99.94%.
(3) Preparation of alpha-ketovaline calcium
9g of valine potassium ketol is dissolved in 30mL of water and 15mL of ethanol, the temperature is raised to 50 ℃, calcium chloride aqueous solution (5 g of calcium chloride is dissolved in 15mL of water) is added, the temperature is kept for 1 hour, the temperature is reduced to 10 ℃, the reaction is carried out for 2 hours, filtration and drying are carried out, and 7.30g of alpha-valine calcium ketol is obtained, the yield is 93.23%, and the purity is 99.95%.
Example 2
(1) Preparation of isopropylidene hydantoin
To 20mL of methanol were added 2.0g of ammonia water (25% by mass) (0.029 mol), 9.4g of hydantoin (0.094 mol) and 10. 10 g of acetone (0.172 mol) in this order; heating to 45 ℃ for reaction for 6 hours, cooling to 20 ℃ after the reaction is finished, preserving heat for 1 hour, filtering, and drying to obtain 12.04g of isopropylidene hydantoin. The yield thereof was found to be 91.49% and the purity thereof was found to be 99.92%.
(2) Preparation of alpha-ketovaline salt
To 50mL of water was added 23.0g of potassium t-butoxide (0.205 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 50 ℃ and reacting for 3 hours; cooling after the reaction is finished, controlling the temperature of the reaction solution to be 20 ℃, preserving the heat for 1 hour, filtering and drying to obtain 9.70g of ketovaline potassium. Yield 91.82% and purity 99.90%.
(3) Preparation of alpha-ketovaline calcium
9g of potassium valine ketone was dissolved in 30mL of water and 15mL of methanol, the temperature was raised to 55℃and an aqueous solution of calcium chloride (6 g of calcium chloride was dissolved in 18mL of water) was added; the temperature is kept for reaction for 1 hour, the temperature is reduced to 10 ℃, the reaction is carried out for 3 hours, and 7.34g of alpha-ketovaline calcium is obtained after filtration and drying. The yield thereof was found to be 93.74% and the purity thereof was found to be 99.95%.
Example 3
(1) Preparation of isopropylidene hydantoin
To 20mL of water and 10mL of ethanol, 5.7g of ammonia water (28% by mass) (0.094 mol), 9.4g of hydantoin (0.094 mol) and 10.8g of acetone (0.186 mol) were added in this order; heating to 60 ℃ for reaction for 5 hours, cooling to 20 ℃ after the reaction is finished, preserving heat for 0.5 hour, filtering, and drying to obtain 11.86g isopropylidene hydantoin. The yield was 90.12% and the purity was 99.93%.
(2) Preparation of alpha-ketovaline salt
To 50mL of ethanol was added 14.4g of potassium ethoxide (0.171 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 45 ℃ under slight negative pressure (the pressure is minus 0.06 MPa), and reacting for 2 hours; the other container is used for containing water and collecting the generated ammonia gas to prepare ammonia water; cooling after the reaction is finished, controlling the temperature of the reaction solution to be 20 ℃, preserving the heat for 1 hour, filtering and drying to obtain 9.72g of ketovaline potassium. The yield is 92.01 percent and the purity is more than 99.94 percent.
(3) Preparation of alpha-ketovaline calcium
9g of potassium valine ketone is dissolved in 30mL of water and 20mL of isopropanol, the temperature is raised to 60 ℃, and an aqueous solution of calcium chloride (5 g of calcium chloride is dissolved in 18mL of water) is added; the temperature is kept for reaction for 1 hour, the temperature is reduced to 20 ℃, the reaction is carried out for 2 hours, and 7.29g of alpha-ketovaline calcium is obtained after filtration and drying. Yield 93.10% and purity 99.97%.
Example 4
(1) Preparation of isopropylidene hydantoin
To 20mL of isopropanol, 12.8g of ammonia water (25% by mass) (0.188 mol), 9.4g of hydantoin (0.094 mol), and 32.7g of acetone (0.564 mol) were sequentially added; heating to 50 ℃ for reaction for 7 hours, cooling to 25 ℃ after the reaction is finished, adjusting the pH to 6 by using a proper amount of hydrochloric acid, preserving the heat for 1 hour, filtering, and drying to obtain 12.25g of isopropylidene hydantoin. The yield thereof was found to be 93.09% and the purity thereof was found to be 99.96%.
(2) Preparation of alpha-ketovaline salt
To 50mL of butanol was added 27.9g of sodium ethoxide (0.410 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 40 ℃ under slight negative pressure (the pressure is minus 0.08 MPa), and reacting for 2 hours; the other container is used for containing water and collecting the generated ammonia gas to prepare ammonia water; cooling after the reaction is finished, controlling the temperature of the reaction solution to be 10 ℃, preserving the heat for 2 hours, filtering and drying to obtain 8.79g of sodium valine ketone. The yield is 92.85 percent and the purity is more than 99.91 percent.
(3) Preparation of alpha-ketovaline calcium
8g of sodium valine ketone is dissolved in 30mL of water and 15mL of ethanol, the temperature is raised to 50 ℃, and an aqueous solution of calcium chloride (5 g of calcium chloride is dissolved in 10mL of water) is added; the temperature is kept for reaction for 1 hour, the temperature is reduced to 15 ℃, the reaction is carried out for 2 hours, and 7.24g of alpha-ketovaline calcium is obtained after filtration and drying. The yield thereof was found to be 92.46% and the purity thereof was found to be 99.96%.
Example 5
(1) Preparation of isopropylidene hydantoin
To 20mL of water were added 3.9g of ammonia water (mass fraction: 22%) (0.05 mol), 9.4g of hydantoin (0.094 mol), and 13.54g of acetone (0.233 mol) in this order; heating to 45 ℃ for reaction for 5 hours, cooling to 25 ℃ after the reaction is finished, adjusting the pH to 7 by using a proper amount of hydrochloric acid, preserving the heat for 1 hour, filtering, and drying to obtain 12.27g of isopropylidene hydantoin. The yield thereof was found to be 93.24% and the purity thereof was found to be 99.92%.
(2) Preparation of alpha-ketovaline salt
To 30mL of ethanol and 20mL of water was added 19.7g of sodium t-butoxide (0.205 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 50 ℃ under slight negative pressure (the pressure is minus 0.1 MPa), and reacting for 2 hours; the other container is used for containing water and collecting the generated ammonia gas to prepare ammonia water; cooling after the reaction is finished, controlling the temperature of the reaction solution to be 30 ℃, preserving the heat for 1 hour, filtering and drying to obtain 8.64g of sodium valine ketone. The yield is 91.27 percent and the purity is more than 99.92 percent.
(3) Preparation of alpha-ketovaline calcium
8g of sodium valine ketone is dissolved in 30mL of water and 15mL of ethanol, the temperature is raised to 55 ℃, and an aqueous solution of calcium citrate (25 g of calcium citrate is dissolved in 50mL of water) is added; the temperature is kept for reaction for 1 hour, the temperature is reduced to 30 ℃, the reaction is carried out for 1 hour, and 7.26g of alpha-ketovaline calcium is obtained after filtration and drying. The yield thereof was found to be 92.72% and the purity thereof was found to be 99.96%.
Example 6
(1) Preparation of isopropylidene hydantoin
To 20mL of water, 22.3g of ammonia water (mass fraction: 10%) (0.131 mol), 9.4g of hydantoin (0.094 mol), and 18.5g of acetone (0.319 mol) were sequentially added; heating to 45 ℃ for reaction for 5 hours, cooling to 30 ℃ after the reaction is finished, adjusting the pH to 6.5 by using a proper amount of hydrochloric acid, preserving heat for 1 hour, filtering, and drying to obtain 12.40g of isopropylidene hydantoin. The yield thereof was found to be 94.22% and the purity thereof was found to be 99.91%.
(2) Preparation of alpha-ketovaline salt
To 50mL of ethanol was added 11.5g of potassium ethoxide (0.137 mol), 7.6g of potassium hydroxide (0.136 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 40 ℃ under slight negative pressure (the pressure is-0.05 MPa), and reacting for 2 hours; the other container is used for containing water and collecting the generated ammonia gas to prepare ammonia water; cooling after the reaction is finished, controlling the temperature of the reaction solution to be 20 ℃, preserving the heat for 1.5 hours, filtering and drying to obtain 9.75g of ketovaline potassium. The yield is 92.29 percent and the purity is more than 99.95 percent.
(3) Preparation of alpha-ketovaline calcium
9g of potassium valine ketone is dissolved in 30mL of water and 15mL of ethanol, the temperature is raised to 50 ℃, and an aqueous solution of calcium acetate (7 g of calcium acetate is dissolved in 25mL of water) is added; the temperature is kept for 2 hours, the temperature is reduced to 10 ℃, the reaction is carried out for 3 hours, the filtration and the drying are carried out, and 7.30g of alpha-ketovaline calcium is obtained. The yield thereof was found to be 93.23% and the purity thereof was found to be 99.95%.
Comparative example 1
Preparation of isopropylidene hydantoin
To 20mL of water were added, in order, 5.8g of ethanolamine (0.095 mol), 9.4g of hydantoin (0.094 mol), and 5.5g of acetone (0.095 mol); heating to 40 ℃ for reaction for 5 hours, cooling to 25 ℃ after the reaction is finished, preserving heat for 1 hour, filtering, and drying to obtain 11.17g isopropylidene hydantoin. The yield thereof was found to be 84.9% and the purity thereof was found to be 98.46%.
Comparative example 2
Preparation of isopropylidene hydantoin
To 20mL of water were added, in order, 3.8g of sodium hydroxide (0.095 mol), 9.4g of hydantoin (0.094 mol), and 5.5g of acetone (0.095 mol); heating to 40 ℃ for reaction for 5 hours, cooling to 25 ℃ after the reaction is finished, preserving heat for 1 hour, filtering, and drying to obtain 10.31g isopropylidene hydantoin. Yield 78.3% and purity 97.97%.
Comparative example 3
Preparation of isopropylidene hydantoin (prepared according to CN102701954A example 1)
9.54kg of borax, 1.84kg of sodium hydroxide and 120kg of water were thoroughly stirred and dissolved to prepare a borax-sodium hydroxide buffer solution (ph=9.8±0.2). Adding 20kg of hydantoin and 20kg of acetone, heating to 70-80 ℃ for reflux reaction for 5 hours, controlling vacuum to be reduced in pressure and distilled for 30 minutes under the condition of minus 0.09MPa, cooling to 10-15 ℃ and stirring for 1 hour, wherein a large amount of 5-isopropylidene hydantoin white solid is precipitated; filtering and drying to obtain 22.53kg of isopropylidene hydantoin. The yield was 80.5% and the purity was 96.87%.
Claims (12)
1. A preparation method of an alpha-ketovaline calcium intermediate is characterized in that hydantoin and acetone react under the catalysis of ammonia water to obtain the alpha-ketovaline calcium intermediate isopropylidene hydantoin; wherein the mass fraction of ammonia in the ammonia water is 10-28%.
2. The method for preparing the alpha-ketovaline calcium intermediate according to claim 1, wherein the reaction solvent is one or more of water, methanol, ethanol and isopropanol.
3. The method for preparing the alpha-ketovaline calcium intermediate according to claim 1, wherein the molar ratio of hydantoin, acetone and ammonia is 1:1-6:0.3-2.
4. The method for preparing alpha-ketovaline calcium intermediate according to claim 1, wherein the catalytic reaction temperature is 40 to 60 ℃.
5. The method for preparing the alpha-ketovaline calcium intermediate according to claim 1, wherein the hydantoin and the acetone react under the catalysis of ammonia water, and the pH is regulated to 6-7, so that the alpha-ketovaline calcium intermediate isopropylidene hydantoin is obtained.
6. The preparation method of the alpha-ketovaline calcium is characterized by comprising the following steps of:
(1) The isopropylidene hydantoin is prepared according to the preparation method of any one of the alpha-ketovaline calcium intermediates of claims 1 to 5; reacting the isopropylidene hydantoin with alkali to obtain alpha-ketovaline salt;
(2) Adding calcium salt into alpha-ketovaline salt to react to obtain alpha-ketovaline calcium;
wherein the alkali in the step (1) is selected from one or more of potassium tert-butoxide, sodium ethoxide, potassium ethoxide and potassium hydroxide.
7. The method for producing alpha-ketovaline calcium according to claim 6, wherein the isopropylidene hydantoin and the base in the step (1) are reacted under a slightly negative pressure.
8. The method for producing alpha-ketovaline calcium according to claim 7, wherein the isopropylidene hydantoin in step (1) is reacted with a base under a pressure of-0.1 to-0.05 MPa.
9. The method according to claim 6, wherein the isopropylidene hydantoin in step (1) is further absorbed by water to produce ammonia gas when reacted with a base.
10. The method for preparing alpha-ketovaline calcium according to claim 6, wherein the reaction solvent is one or more of water, ethanol and butanol.
11. The method for producing alpha-ketovaline calcium according to claim 6, wherein the molar ratio of isopropylidene hydantoin to base in the step (1) is 1:2 to 6.
12. The method for preparing alpha-ketovaline calcium according to claim 6, wherein the calcium salt is one of calcium chloride, calcium acetate and calcium citrate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102701954A (en) * | 2011-06-13 | 2012-10-03 | 浙江昂利康制药有限公司 | Preparation method of alpha-ketovaline calcium |
| CN106316828A (en) * | 2016-08-16 | 2017-01-11 | 浙江新和成股份有限公司 | Preparation method of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102701954A (en) * | 2011-06-13 | 2012-10-03 | 浙江昂利康制药有限公司 | Preparation method of alpha-ketovaline calcium |
| CN106316828A (en) * | 2016-08-16 | 2017-01-11 | 浙江新和成股份有限公司 | Preparation method of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate |
Non-Patent Citations (1)
| Title |
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| 海因法合成几种α-酮酸盐;花锦秀等;《化工时刊》;第21卷(第12期);5-8 * |
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