CN113735775A - 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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- CN113735775A CN113735775A CN202010480008.8A CN202010480008A CN113735775A CN 113735775 A CN113735775 A CN 113735775A CN 202010480008 A CN202010480008 A CN 202010480008A CN 113735775 A CN113735775 A CN 113735775A
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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 an alpha-ketovaline calcium intermediate isopropylidene hydantoin under the catalysis of ammonia water. And the isopropylidene hydantoin is used for preparing the alpha-ketovaline calcium, and the alpha-ketoleucine calcium with high yield and high purity can be obtained, so that the method is suitable for industrial large-scale 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 been receiving increasing attention in a situation of high incidence and a trend toward youthful condition. CKD progression is insidious and once advanced, the cost of treatment and care is dramatically increased. The compound alpha-ketonic acid tablet can delay the progression of renal failure by matching with low-protein diet, has important value in CKD treatment, and gradually becomes a core means of CKD treatment.
The alpha-ketovaline calcium is one of the main components of the compound alpha-ketoacid tablet, the compound alpha-ketoacid tablet is firstly marketed in Germany by the German Feedes Youscabi company in 1996, the trade name is the same, and the medicine is a compound preparation containing 1 type of calcium hydroxylamino acid, 4 types of calcium ketoamino acid and 5 types of amino acid. The above components are subjected to transaminase to synthesize corresponding essential amino acids, urea nitrogen is degraded, and nitrogen-containing metabolites are reused to reduce accumulation of uremic toxins, thereby improving uremic symptoms; by hyperfiltration of the glomeruli, the blood phosphorus and PTH levels are reduced to delay the progression of chronic renal failure, thereby delaying the time to begin dialysis; essential amino acid is supplemented to correct amino acid metabolism disorder and improve nutritional status.
The chemical name of the alpha-ketovaline calcium is calcium bis (3-methyl-2-oxobutyrate), and the structural formula is as follows:
the known synthesis methods of alpha-ketovaline calcium are as follows:
patent CN201110156569.3 discloses a method for preparing 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), distilling under reduced pressure, and cooling to obtain 5-isopropylidene hydantoin; heating and refluxing 5-isopropylidene hydantoin and sodium hydroxide for reaction, adjusting the pH value to 1-2 by acid, extracting twice by methyl tert-butyl ether, and distilling an organic phase under reduced pressure to obtain oily alpha-ketovaline; and adjusting the pH value of the alpha-ketovaline aqueous solution to 6-8 by using a sodium hydroxide aqueous solution, decoloring the alpha-ketovaline aqueous solution by using activated carbon, and reacting the decolored activated carbon with a calcium salt to obtain 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, keeping the temperature and stirring, adding an alkali solution, adjusting the 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, adding a calcium chloride aqueous solution into the water phase to form salt, obtaining a crude product of the ketovaline calcium, and refining in a mixed solvent of purified water and the organic solvent to obtain a refined product of the ketovaline calcium. The reaction route has high cost, high safety risk and complex post-treatment steps, and needs multiple post-treatment steps of organic solvent extraction, pH adjustment, mixed solvent refining and the like, thereby being not beneficial to large-scale production.
The patent CN201410457101.1 discloses a new 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 heating for 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, combining 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 base, adjusting the pH of the solution to 7, adding activated carbon for decolorization, reacting with an aqueous solution containing calcium chloride, filtering, and drying to obtain the calcium alpha-ketovaline. The method has complex process operation steps and complex post-treatment, and is not beneficial to large-scale production.
In conclusion, the currently disclosed methods for preparing alpha-ketovaline calcium have the problems of excessive product impurities, difficulty in refining, complicated post-treatment steps, high cost and the like, and are not suitable for industrial large-scale 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. The isopropylidene hydantoin prepared by the method is used for preparing the alpha-ketovaline calcium, also can obtain the alpha-ketovaline calcium with high yield and high purity, and is suitable for industrial large-scale production.
The invention provides a preparation method of an alpha-ketovaline calcium intermediate isopropylidene hydantoin, which is characterized in that hydantoin and acetone react under the catalytic action of ammonia water to obtain the alpha-ketovaline calcium intermediate isopropylidene hydantoin.
In the existing preparation method, hydantoin is easy to hydrolyze during the catalytic reaction of hydantoin and acetone, and in order to control the generation of impurities, the inventor researches the types of catalysts used in the prior art and finds that the generation of impurities cannot be effectively controlled by common alkaline catalysts such as ethanolamine and the like. The inventors have made intensive studies on how to obtain isopropylidene hydantoin in high yield and high purity and how to realize easy implementation of the post-treatment step. The invention selects ammonia water as a catalyst, catalyzes the reaction of hydantoin and acetone by the ammonia water, has mild reaction conditions, can effectively control the reaction speed, inhibit the alkaline hydrolysis of hydantoin, control the generation of impurities, and improve the yield and the purity of isopropylidene hydantoin, the yield of the prepared isopropylidene hydantoin reaches more than 90 percent, and the purity can reach more than 99 percent without further purification, filtration and other refining steps.
The reaction solvent is one or more of water, methanol, ethanol and isopropanol.
In the reaction, the dosage of the ammonia water in the reaction is calculated by the dosage of the ammonia, and the molar ratio of the dosage of the hydantoin, the acetone and the ammonia is 1: 1-6: 0.3-2.
In the above reaction, the mass fraction of ammonia in the ammonia water is 10 to 28%.
The temperature of the catalytic reaction is 40-60 ℃.
In the reaction, after the reaction of the hydantoin and acetone is finished, the pH is adjusted to 6-7, isopropylidene hydantoin with higher purity can be obtained, specifically, the hydantoin and acetone react under the catalysis of ammonia water, and the pH is adjusted to 6-7, so that the isopropylidene hydantoin serving as the alpha-ketovaline calcium intermediate is obtained.
The invention also provides a preparation method of the alpha-ketovaline calcium, which comprises the following specific steps:
(1) reacting isopropylidene hydantoin prepared according to the preparation method of the alpha-ketovaline calcium intermediate with alkali to obtain alpha-ketovaline salt;
(2) reacting the alpha-ketovaline salt with a calcium salt to obtain the alpha-ketovaline calcium.
In the reaction, the isopropylidene hydantoin in the step (1) and the alkali can be selectively reacted under the condition of slight negative pressure; when the isopropylidene hydantoin reacts with the alkali under the condition of slight negative pressure, the ammonia gas generated by the reaction overflows from the reaction liquid quickly in the environment of slight negative pressure, so that the reaction is promoted to be carried out in the positive reaction direction, the reaction speed of the isopropylidene hydantoin and the alkali is accelerated, and the reaction time is saved by more than 25%. Meanwhile, the invention can also use another container filled with water to collect the generated ammonia gas, the prepared ammonia water can also be used in the reaction catalysis of the hydantoin and the acetone, the reaction by-product is efficiently utilized, the aim of circular economy is realized, and meanwhile, the collection of the ammonia gas can also strictly control the emission of waste gas generated by the reaction, thereby reducing the pollution to the environment.
In the step (1), isopropylidene hydantoin and alkali are reacted under the pressure of-0.1 to-0.05 MPa.
In the step (1), the reaction of isopropylidene hydantoin with alkali also includes a step of absorbing ammonia gas with water.
In the step (1), the reaction solvent of isopropylidene hydantoin and alkali may be one or more of water, ethanol and butanol.
In the step (1), the alkali 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.
In the step (1), the reaction temperature of the isopropylidene hydantoin and the alkali is 40-50 ℃.
In the step (2), the calcium salt is selected from 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 HPLC purity more than or equal to 99.9 percent can be obtained and meets the medicinal standard.
Detailed Description
Example 1
(1) Preparation of isopropylidene hydantoin
6.4g of ammonia (25% by mass) (0.094 mol), 9.4g of hydantoin (0.094 mol) and 5.5g of acetone (0.095 mol) were sequentially added to 20mL of water; heating to 40 deg.C for 5 hr, cooling to 25 deg.C after reaction, keeping the temperature for 1 hr, filtering, and drying to obtain 12.00g isopropylidene hydantoin. The yield was 91.18% and the purity was 99.91%.
(2) Preparation of alpha-ketovaline salts
To 50mL of ethanol were added 7.67g of KOH (0.137 mol), 9.60g (0.0686 mol) of isopropylidene hydantoin; heating to 40 ℃ under micro negative pressure (the pressure is-0.05 MPa), and reacting for 2 hours; and the other container is used for containing water and collecting the generated ammonia gas to prepare ammonia water. After the reaction, the temperature was reduced, the temperature of the reaction solution was controlled at 25 ℃, and the reaction solution was kept at the temperature for 1 hour, filtered, and dried to obtain 9.62g of potassium ketovalinate. The yield is 91.06 percent and the purity is 99.94 percent.
(3) Preparation of alpha-ketovaline calcium
Dissolving 9g of potassium ketovalinate in 30mL of water and 15mL of ethanol, heating to 50 ℃, adding a calcium chloride aqueous solution (5 g of calcium chloride is dissolved in 15mL of water), keeping the temperature for reaction for 1 hour, cooling to 10 ℃, reacting for 2 hours, filtering, and drying to obtain 7.30g of alpha-calcium ketovalinate, wherein 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 (25% by mass) (0.029 mol), 9.4g of hydantoin (0.094 mol), and 10 g of acetone (0.172 mol) in this order; heating to 45 deg.C for 6 hr, cooling to 20 deg.C after reaction, holding for 1 hr, filtering, and drying to obtain 12.04g isopropylidene hydantoin. The yield was 91.49%, and the purity was 99.92%.
(2) Preparation of alpha-ketovaline salts
To 50mL of water were added 23.0g of potassium tert-butoxide (0.205 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 50 ℃, and reacting for 3 hours; after the reaction, the temperature is reduced, the temperature of the reaction liquid is controlled to be 20 ℃, the temperature is kept for 1 hour, and 9.70g of potassium ketovalinate is obtained after filtration and drying. The yield was 91.82%, and the purity was 99.90%.
(3) Preparation of alpha-ketovaline calcium
Dissolving 9g of potassium ketovalinate in 30mL of water and 15mL of methanol, heating to 55 ℃, and adding an aqueous solution of calcium chloride (6 g of calcium chloride dissolved in 18mL of water); keeping the temperature for reaction for 1 hour, cooling to 10 ℃, reacting for 3 hours, filtering and drying to obtain 7.34g of alpha-ketovaline calcium. The yield was 93.74% and the purity was 99.95%.
Example 3
(1) Preparation of isopropylidene hydantoin
To 20mL of water and 10mL of ethanol were added 5.7g of ammonia (28 mass%) (0.094 mol), 9.4g of hydantoin (0.094 mol), and 10.8g of acetone (0.186 mol) in this order; heating to 60 deg.C for 5 hr, cooling to 20 deg.C after reaction, maintaining for 0.5 hr, 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 salts
To 50mL of ethanol were added 14.4g of potassium ethoxide (0.171 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 45 ℃ under micro negative pressure (the pressure is-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; after the reaction, the temperature is reduced, the temperature of the reaction liquid is controlled to be 20 ℃, the temperature is kept for 1 hour, and 9.72g of potassium ketovalinate is obtained after filtration and drying. The yield is 92.01 percent, and the purity is more than 99.94 percent.
(3) Preparation of alpha-ketovaline calcium
Dissolving 9g of potassium ketovalinate in 30mL of water and 20mL of isopropanol, heating to 60 ℃, and adding an aqueous calcium chloride solution (5 g of calcium chloride dissolved in 18mL of water); keeping the temperature for reaction for 1 hour, cooling to 20 ℃, reacting for 2 hours, filtering and drying to obtain 7.29g of alpha-ketovaline calcium. The yield was 93.10%, and the purity was 99.97%.
Example 4
(1) Preparation of isopropylidene hydantoin
To 20mL of isopropyl alcohol were added 12.8g of aqueous ammonia (25% by mass) (0.188 mol), 9.4g of hydantoin (0.094 mol), and 32.7g of acetone (0.564 mol) in this order; heating to 50 deg.C for 7 hr, cooling to 25 deg.C, adjusting pH to 6 with appropriate amount of hydrochloric acid, maintaining for 1 hr, filtering, and drying to obtain 12.25g isopropylidene hydantoin. The yield was 93.09% and the purity was 99.96%.
(2) Preparation of alpha-ketovaline salts
To 50mL of butanol were added 27.9g of sodium ethoxide (0.410 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 40 ℃ under micro negative pressure (the pressure is-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; after the reaction is finished, the temperature is reduced, the temperature of the reaction liquid is controlled to be 10 ℃, the temperature is kept for 2 hours, and the reaction liquid is filtered and dried to obtain 8.79g of ketovaline sodium. The yield is 92.85%, and the purity is more than 99.91%.
(3) Preparation of alpha-ketovaline calcium
Dissolving 8g of ketovaline sodium in 30mL of water and 15mL of ethanol, heating to 50 ℃, and adding a calcium chloride aqueous solution (5 g of calcium chloride dissolved in 10mL of water); keeping the temperature for reaction for 1 hour, cooling to 15 ℃, reacting for 2 hours, filtering and drying to obtain 7.24g of alpha-ketovaline calcium. The yield was 92.46%, and the purity was 99.96%.
Example 5
(1) Preparation of isopropylidene hydantoin
3.9g of ammonia (22% by mass) (0.05 mol), 9.4g of hydantoin (0.094 mol) and 13.54g of acetone (0.233 mol) are added to 20mL of water in this order; heating to 45 deg.C for 5 hr, cooling to 25 deg.C, adjusting pH to 7 with appropriate amount of hydrochloric acid, maintaining for 1 hr, filtering, and drying to obtain 12.27g isopropylidene hydantoin. The yield was 93.24% and the purity was 99.92%.
(2) Preparation of alpha-ketovaline salts
To 30mL of ethanol and 20mL of water were added 19.7g of sodium tert-butoxide (0.205 mol), 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 50 ℃ under micro negative pressure (the pressure is-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; after the reaction, the temperature is reduced, the temperature of the reaction liquid is controlled at 30 ℃, the temperature is kept for 1 hour, and the reaction liquid is filtered and dried to obtain 8.64g of ketovaline sodium. The yield is 91.27%, and the purity is more than 99.92%.
(3) Preparation of alpha-ketovaline calcium
Dissolving 8g of ketovaline sodium in 30mL of water and 15mL of ethanol, heating to 55 ℃, and adding a calcium citrate aqueous solution (25 g of calcium citrate is dissolved in 50mL of water); keeping the temperature for reaction for 1 hour, cooling to 30 ℃, reacting for 1 hour, filtering and drying to obtain 7.26g of alpha-ketovaline calcium. The yield was 92.72%, and the purity was 99.96%.
Example 6
(1) Preparation of isopropylidene hydantoin
22.3g of ammonia (10% by mass) (0.131 mol), 9.4g of hydantoin (0.094 mol) and 18.5g of acetone (0.319 mol) are added to 20mL of water in this order; heating to 45 deg.C for 5 hr, cooling to 30 deg.C after reaction, adjusting pH to 6.5 with appropriate amount of hydrochloric acid, maintaining for 1 hr, filtering, and drying to obtain 12.40g isopropylidene hydantoin. The yield was 94.22% and the purity was 99.91%.
(2) Preparation of alpha-ketovaline salts
To 50mL of ethanol were added 11.5g of potassium ethoxide (0.137 mol), 7.6g of potassium hydroxide (0.136 mol), and 9.60g of isopropylidene hydantoin (0.0686 mol); heating to 40 ℃ under micro 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; after the reaction, the temperature is reduced, the temperature of the reaction liquid is controlled to be 20 ℃, the temperature is kept for 1.5 hours, and 9.75g of ketovaline potassium is obtained after filtration and drying. The yield is 92.29%, and the purity is more than 99.95%.
(3) Preparation of alpha-ketovaline calcium
Dissolving 9g of potassium ketovalinate in 30mL of water and 15mL of ethanol, heating to 50 ℃, and adding an aqueous solution of calcium acetate (7 g of calcium acetate in 25mL of water); keeping the temperature for reaction for 2 hours, reducing the temperature to 10 ℃, reacting for 3 hours, filtering and drying to obtain 7.30g of alpha-ketovaline calcium. The yield was 93.23%, and the purity was 99.95%.
Comparative example 1
Preparation of isopropylidene hydantoin
5.8g of ethanolamine (0.095 mol), 9.4g of hydantoin (0.094 mol) and 5.5g of acetone (0.095 mol) were added to 20mL of water in this order; heating to 40 deg.C for 5 hr, cooling to 25 deg.C after reaction, maintaining for 1 hr, filtering, and drying to obtain 11.17g isopropylidene hydantoin. The yield was 84.9%, and the purity was 98.46%.
Comparative example 2
Preparation of isopropylidene hydantoin
To 20mL of water were added 3.8g of sodium hydroxide (0.095 mol), 9.4g of hydantoin (0.094 mol), and 5.5g of acetone (0.095 mol) in this order; heating to 40 deg.C for 5 hr, cooling to 25 deg.C after reaction, maintaining for 1 hr, filtering, and drying to obtain 10.31g isopropylidene hydantoin. The yield was 78.3% and the purity was 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 are fully stirred and dissolved to prepare a borax-sodium hydroxide buffer solution (pH is 9.8 +/-0.2). Then adding 20kg of hydantoin and 20kg of acetone, heating to 70-80 ℃, carrying out reflux reaction for 5 hours, controlling vacuum, carrying out reduced pressure distillation for 30 minutes under the condition of-0.09 MPa, cooling to 10-15 ℃, and stirring for 1 hour, wherein a large amount of 5-isopropylidene hydantoin white solid is separated out; filtered and dried to obtain 22.53kg of isopropylidene hydantoin. The yield was 80.5% and the purity was 96.87%.
Claims (14)
1. The preparation method of the 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.
2. The method of claim 1, wherein the reaction solvent is one or more of water, methanol, ethanol, and isopropanol.
3. The method for producing an α -ketovaline calcium intermediate according to claim 1, wherein the molar ratio of hydantoin, acetone and ammonia is 1:1 to 6:0.3 to 2.
4. The method of claim 1, wherein the ammonia content of the aqueous ammonia is 10-28% by weight.
5. The method of claim 1, wherein the catalytic reaction temperature is 40-60 ℃.
6. The preparation method of the alpha-ketovaline calcium intermediate, according to claim 1, characterized in that the hydantoin is reacted with acetone under the catalysis of ammonia water, and the pH is adjusted to 6-7 to obtain the alpha-ketovaline calcium intermediate isopropylidene hydantoin.
7. The preparation method of alpha-ketovaline calcium is characterized by comprising the following steps:
(1) reacting isopropylidene hydantoin prepared by the preparation method of any one of the alpha-ketovaline calcium intermediates of claims 1 to 6 with alkali to obtain an alpha-ketovaline salt;
(2) adding calcium salt into the alpha-ketovaline salt to react to obtain the alpha-ketovaline calcium.
8. The method of claim 7, wherein the isopropylidene hydantoin is reacted with the base in step (1) under a slightly negative pressure.
9. The method of producing α -ketovaline calcium according to claim 8, wherein isopropylidene hydantoin is reacted with the base under a pressure of-0.1 to-0.05 MPa in the step (1).
10. The method of producing α -ketovaline calcium according to claim 7, wherein in the step (1), when isopropylidene hydantoin is reacted with a base, a step of generating ammonia gas by absorption with water is further provided.
11. The method of claim 7, wherein the reaction solvent is one or more of water, ethanol, and butanol.
12. The method for preparing alpha-ketovaline calcium according to claim 7, wherein the base is selected from one or more of potassium tert-butoxide, sodium ethoxide, potassium ethoxide and potassium hydroxide.
13. The method for producing alpha-ketovaline calcium according to claim 7, wherein the molar ratio of isopropylidene hydantoin to the base in step (1) is 1: 2-6.
14. The method of claim 7, wherein the calcium salt is selected from the group consisting 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 (2)
| Title |
|---|
| 花锦秀等: "海因法合成几种α-酮酸盐", 《化工时刊》 * |
| 郝宏山等: "α-酮缬氨酸钙合成工艺研究", 《精细化工中间体》 * |
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