CN109761801B - Novel method for preparing ketovaline calcium - Google Patents
Novel method for preparing ketovaline calcium Download PDFInfo
- Publication number
- CN109761801B CN109761801B CN201910136710.XA CN201910136710A CN109761801B CN 109761801 B CN109761801 B CN 109761801B CN 201910136710 A CN201910136710 A CN 201910136710A CN 109761801 B CN109761801 B CN 109761801B
- Authority
- CN
- China
- Prior art keywords
- calcium
- ketovaline
- temperature
- dimethyldihydrofuran
- isopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a novel preparation method of ketovaline calcium and application of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione. The new method takes 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-diketone and calcium hydroxide as raw materials to react to prepare the calcium ketovalinate. The novel method has low cost, simple preparation method, short synthetic route and environmental friendliness; the obtained refined ketovaline calcium product has high purity (99.9%) and high molar yield (87.8%), is suitable for industrial production, and is beneficial to wide application of ketovaline calcium in industry.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a novel preparation method of ketovaline calcium and application of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione.
Background
The invention relates to synthesis of calcium 3-methyl-2-oxo-butyrate (calcium ketovalinate). The molecular formula of the Ketovaline Calcium is C10H14CaO6, and the English name is alpha-Ketovaline Calcium, CAS: 51828-94-5, the structural formula is shown as follows:
ketovaline calcium is one of the main components of the compound alpha-ketonic acid tablet (Kaiki). The alpha-keto acid and the derivatives thereof show increasingly wide application prospects in the aspects of food, daily chemicals, medicines and the like. In food application, the product can be used as an ingredient of sports nutritional beverage; in functional skin care cosmetics, the skin care cream has good effects of moisturizing, preventing wrinkles, preventing shrinkage, resisting aging and resisting allergy. In medical application, the compound alpha-ketonic acid tablet can treat the damage caused by chronic renal insufficiency and can be used as a specific medicine for treating uremia. The compound alpha-ketonic acid tablet is taken by a patient with renal failure and is matched with low-protein diet, so that the high filtration of glomeruli can be relieved, nephrons can be protected, and symptoms can be relieved and the progress of the disease can be delayed for the patient with light and moderate chronic renal failure; for severe chronic renal failure patients, the nutritional deficiency can be improved, and the amino acid is a substitute for the corresponding amino acid.
The following methods are reported in the literature for synthesizing ketovaline calcium: route 1(He lvetica Chimica Acta,1982,65(7): 2024-. Route 2(JP54103824A and CN101514154) adopts hydantoin and acetone to react to generate isopropylidene hydantoin, which is hydrolyzed and salified to obtain the product, which adopts hydantoin, acetone, calcium chloride and the like as raw materials, which are simple and relatively suitable for industrialization, but should consider environmental pollution caused by a large amount of ammonia and carbonate generated during hydrolysis. Route 3 nitrile alcohols are used as raw materials (Synthesis, 1971, (10): 538) -539.) and are converted into alpha-hydroxy-N-tert-butylamides through reaction, then oxidized into ketoamines, then hydrolyzed and finally salified to obtain the target products. Route 4 (tetrahedron Letters,1978,48: 4809-. The raw materials of the route 3 and the route 4 are expensive, have high toxicity, serious pollution, multiple reaction steps and high cost, so the method is not suitable for industrial production.
The invention patent CN201210171694.6 discloses a method for preparing alpha-ketovaline calcium, which has a reaction mechanism as follows: in a sodium methoxide methanol solution, diethyl oxalate is quickly subjected to ester exchange to generate dimethyl oxalate, isobutyraldehyde is dripped into the solution and then subjected to aldol condensation under the action of sodium methoxide, then the solution is subjected to ester exchange with dimethyl oxalate under the catalytic action of sodium methoxide, a part of methyl formate is quickly removed to generate cyclic lactone, then the cyclic lactone is subjected to ring opening under the action of alkaline water to generate alpha-ketovaline sodium salt, and then the alpha-ketovaline calcium salt is acidified, extracted, washed, adjusted in pH value, salified and refined to obtain the alpha-ketovaline calcium.The preparation method has the disadvantages that The raw materials are still more, the production cost is increased, the synthesis route is more complicated, and the molar yield of the product is lower (no material can exceed the yield) Over 80%).
Thus, in contrast to the above disclosed method for preparing calcium alpha-ketovaline, the present invention provides a method for preparing calcium alpha-ketovalineThe preparation method is simple Novel method for preparing ketovaline calcium with short single process route, low cost and high molar yield。
Disclosure of Invention
In view of the above, the present invention aims to provide a novel method for preparing ketovaline calcium, which has the advantages of simple process, short synthetic route and high product molar yield.
In order to achieve the purpose, the invention adopts the following scheme:
a novel method for preparing ketovaline calcium adopts 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-diketone to react with calcium hydroxide to prepare the ketovaline calcium, and the reaction equation is as follows:
further, dissolving 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione in an organic solvent, adding a calcium hydroxide glycerol solution at a controlled temperature after dissolving, adding the calcium hydroxide glycerol solution or an aqueous solution or a mixed solution of glycerol and water at a controlled temperature after dissolving, reacting for 4-10 hours, cooling, crystallizing, and filtering to obtain a coarse ketovaline calcium product; the weight ratio of the 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione to the calcium hydroxide is 1.5-3.5: 1.
Further, the temperature of the temperature control is 0-100 ℃, and the preferred temperature is 0-55 ℃.
More preferably, the temperature controlled temperature is 55 ℃.
Further, the organic solvent includes, but is not limited to, methanol, ethanol, isopropanol, acetone, DMF, preferably methanol.
Further, the stirring time is 4 to 10 hours.
The preferred stirring time is 8 hours.
The preferred weight ratio of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione to calcium hydroxide is 2.3: 1.
The weight ratio of the 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione to the methanol is 1:7-15, preferably: 1: 8.8:.
Further, the ratio of the calcium hydroxide to the glycerol is 1: 20.
preferably, the ratio of the calcium hydroxide to the glycerol is 1: 10
Furthermore, the coarse product of the ketovaline calcium is added with methanol, ethanol, acetone, DMF, water and a mixed solvent of the solvent and the water in any ratio, and the mixture is heated, dissolved, cooled, crystallized and filtered to obtain a refined product of the ketovaline calcium, preferably 20 percent methanol water solution.
The weight ratio of the ketovaline calcium crude product to the 20% methanol aqueous solution is 1: 2-5, preferably 1: 3.
Further, the temperature of the temperature rise is 55 ℃ to 100 ℃.
Preferably, the temperature of the temperature rise is 55 ℃.
Further, the temperature of the cooling is 0 to 50 ℃, preferably 0 DEG C
Further, the time for cooling crystallization is 1-10 hours, preferably 2 hours.
The molar yield of the refined product of ketovaline calcium is calculated and the purity of the refined product is detected by HPLC.
The invention also aims to provide application of the 5-isopropyl-4, 4 '-dimethyldihydrofuran-2, 3-dione, in particular application of the 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione in preparation of ketovaline calcium.
The invention has the beneficial effects that:
1) the invention provides a novel method for preparing ketovaline calcium, which uses 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione and calcium hydroxide as main raw materials for preparation, and has the advantages of low cost, simple preparation method, short synthetic route and environmental friendliness;
2) the refined ketovaline calcium product prepared by the novel method has high purity (99.9%) and molar yield up to 87.8%, is suitable for industrial mass production, and is beneficial to wide industrial application of the ketovaline calcium.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
EXAMPLE 1 preparation of calcium ketovaline
Dissolving 170.21g (1mol) of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione in 1500g of methanol, fully stirring for dissolution, controlling the temperature to be 0-55 ℃, adding 740.9g of glycerol solution containing 74.09g of calcium hydroxide, stirring for reaction for 8 hours, cooling to be 0 ℃, crystallizing for 2 hours, and filtering to obtain 140g of crude ketovaline calcium product with the molar yield of 90%.
Adding 140g of the crude ketovaline calcium product into a 20% methanol water solution, heating to 55 ℃ for dissolution, cooling to 0 ℃ for crystallization for 2 hours, and filtering to obtain 123g of crude ketovaline calcium product with the molar yield of 87.8%. HPLC purity 99.9%.
EXAMPLE 2 preparation of calcium ketovalinate
Dissolving 170.21g (1mol) of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione in 1500g of methanol, fully stirring for dissolving, controlling the temperature to be between 20 and 55 ℃, adding 56.67g of calcium hydroxide glycerol solution, stirring for reacting for 4 hours, cooling to be 0 ℃, crystallizing for 4 hours, and filtering to obtain 130g of crude ketovaline calcium product with the molar yield of 86%.
Adding 130g of crude ketovaline calcium into 20% methanol water solution, heating to 55 ℃ for dissolution, cooling to 0 ℃ for crystallization for 4 hours, and filtering to obtain 113g of crude ketovaline calcium with a molar yield of 86.9%. HPLC purity 99.9%.
EXAMPLE 3 preparation of calcium ketovalinate
Dissolving 300g of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione in 2400g of methanol, fully stirring and dissolving, controlling the temperature to be between 10 and 35 ℃, adding 100g of calcium hydroxide glycerol solution, stirring and reacting for 10 hours, cooling to 0 ℃, crystallizing for 4 hours, and filtering to obtain 275g of crude ketovaline calcium product with the molar yield of 92%.
275g of crude ketovaline calcium product is added into methanol water solution, the temperature is raised to 55 ℃ for dissolution, the temperature is lowered to 0 ℃ for crystallization for 6 hours, and filtration is carried out to obtain 244.03g of crude ketovaline calcium product with the molar yield of 89.1%. HPLC purity 99.9%.
EXAMPLE 45 application of isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione to preparation of calcium ketovalinate
a) 340.42g of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione is dissolved in 3000g of methanol and fully stirred for dissolution;
b) controlling the temperature to be 40-50 ℃, adding 148.18g of calcium hydroxide glycerol solution, stirring for reaction for 6 hours, cooling to 0 ℃, crystallizing for 6 hours, and filtering to obtain 290g of crude ketovaline calcium product with the molar yield of 92%;
c) 290g of crude ketovaline calcium product is added into methanol water solution, the temperature is raised to 55 ℃ for dissolution, the temperature is lowered to 0 ℃ for crystallization for 8 hours, and filtration is carried out to obtain 266.32g of crude ketovaline calcium product, the molar yield is 91.83%, and the HPLC purity is 99.9%.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (9)
1. The preparation method of the ketovaline calcium is characterized in that 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione reacts with calcium hydroxide to prepare the ketovaline calcium, and the reaction equation is as follows:
2. the preparation method according to claim 1, wherein 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione is dissolved in an organic solvent, after dissolution, a glycerol solution or an aqueous solution of calcium hydroxide or a mixed solution of glycerol and water at any ratio is added at a controlled temperature for reaction for 4-10 hours, and the temperature is reduced for crystallization, and a coarse product of ketovaline calcium is obtained by filtration; the weight ratio of the 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione to the calcium hydroxide is 1.5-3.5: 1.
3. The preparation method according to claim 2, wherein the crude ketovaline calcium is dissolved in aqueous methanol at an elevated temperature, crystallized at a reduced temperature, and filtered to obtain a refined ketovaline calcium product.
4. The method of claim 2, wherein the controlled temperature is between 0 ℃ and 55 ℃.
5. The preparation method according to claim 2, wherein the temperature of the temperature-reducing crystallization is 0-50 ℃; the time for cooling and crystallizing is 1-10 hours.
6. The production method according to claim 3, wherein the temperature of the elevated temperature is 55 ℃ to 100 ℃.
7. The method according to claim 2, wherein the reaction time is 4 to 10 hours.
8. The method of claim 2, wherein the organic solvent is ethanol, isopropanol, acetone, or DMF.
9. The method according to claim 2, wherein the ratio of calcium hydroxide to glycerol is 1: 20.
application of 5-isopropyl-4, 4' -dimethyldihydrofuran-2, 3-dione in preparing ketovaline calcium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910136710.XA CN109761801B (en) | 2019-02-25 | 2019-02-25 | Novel method for preparing ketovaline calcium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910136710.XA CN109761801B (en) | 2019-02-25 | 2019-02-25 | Novel method for preparing ketovaline calcium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109761801A CN109761801A (en) | 2019-05-17 |
| CN109761801B true CN109761801B (en) | 2021-10-01 |
Family
ID=66457189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910136710.XA Active CN109761801B (en) | 2019-02-25 | 2019-02-25 | Novel method for preparing ketovaline calcium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109761801B (en) |
-
2019
- 2019-02-25 CN CN201910136710.XA patent/CN109761801B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN109761801A (en) | 2019-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5288902A (en) | Method of manufacturing ferulic acid | |
| CN112759566A (en) | Application of liquid sodium methoxide in synthesis of alpha-acetyl-gamma-butyrolactone and synthesis method of alpha-acetyl-gamma-butyrolactone | |
| CN108569975B (en) | Preparation method of bromfenac sodium sesquihydrate | |
| CN109553550B (en) | Method for synthesizing dihydrooat alkaloid | |
| CN109761801B (en) | Novel method for preparing ketovaline calcium | |
| CN105820042A (en) | Production technology of p-hydroxy benzaldehyde and production system thereof | |
| US20120095260A1 (en) | Process for preparation of L-Arginine alpha-ketoglutarate 1:1 and 2:1 | |
| EP0349432B1 (en) | Strontium salt, process for its preparation and pharmaceutical compositions containing same | |
| CN110627638B (en) | Method for preparing ketoleucine calcium hydrate by one-step method and application thereof | |
| CN107698471A (en) | It is a kind of to MSM benzaldehyde preparation method | |
| CN101492388A (en) | Method for synthesizing meldonium drug raw material | |
| EP3964514A1 (en) | Ginkgolide b derivative and salt thereof, preparation method therefor and use thereof | |
| CN110627637A (en) | One-step method for preparing racemic ketone isoleucine calcium | |
| CN110642722A (en) | Method for preparing N, N-tetramethyl decamethylene diamine | |
| CN115232138B (en) | Huperzine A intermediate and nontoxic synthesis process of raw materials thereof | |
| CN114195761B (en) | Preparation method of high-purity sitafloxacin hydrate 3/2 | |
| CN113214197B (en) | Preparation method of vitamin C ethyl ether | |
| CN112574020B (en) | Preparation method of high-quality 1, 3-cyclohexanedione product | |
| SU1447823A1 (en) | Salts of analogs 7-oxo-pg-12 with ephedrine exhibiting activity inhibiting blood coagulation and reducing blood tension | |
| CN117623903A (en) | Preparation method of D-calcium glucarate | |
| CN107721881A (en) | Preparation method of 2-guanidino phenylpropionic acid | |
| US1075581A (en) | Anhydrid of salicylic acid and process of preparing the same. | |
| KR100503267B1 (en) | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid | |
| DE2237361A1 (en) | (5-INDOLYLOXY) ACETIC ACID DERIVATIVES AND METHOD FOR MANUFACTURING THE SAME | |
| CN117486717A (en) | Preparation method of sodium stearyl fumarate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |