CN109761801A - A kind of novel preparation method of keto-valine calcium - Google Patents
A kind of novel preparation method of keto-valine calcium Download PDFInfo
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- CN109761801A CN109761801A CN201910136710.XA CN201910136710A CN109761801A CN 109761801 A CN109761801 A CN 109761801A CN 201910136710 A CN201910136710 A CN 201910136710A CN 109761801 A CN109761801 A CN 109761801A
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Abstract
The invention belongs to technical field of medicine synthesis, and in particular to a kind of novel preparation method of keto-valine calcium and isopropyl -4 5-, the application of 4 '-dimethyl dihydrofuran -2,3- diketone.The new method prepares keto-valine calcium using 5- isopropyl -4,4 '-dimethyl dihydrofuran -2,3- diketone and calcium hydroxide as raw material reaction.The new method is at low cost, preparation method is simple, synthetic route is short and environmentally friendly；The purity is high (99.9%) of gained keto-valine calcium highly finished product, molar yield is up to 87.8%, is suitable for industrialized production, is conducive to the extensive use of keto-valine calcium industrially.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of novel preparation method and 5- isopropyl of keto-valine calcium
The application of base -4,4 '-dimethyl dihydrofuran -2,3- diketone.
Background technique
The present invention relates to a kind of synthesis of ALPHA-Ketovaline Calcium (keto-valine calcium).The molecular formula of keto-valine calcium
For C10H14CaO6, English name is α-Ketovaline Calcium, CAS:51828-94-5, and structural formula is as follows:
Keto-valine calcium is one of the main component of α keto acid compound (opening same).2-ketoacid and its derivative food,
Daily use chemicals and medicine etc. show increasingly wide application prospect.In food applications, sport nutrition beverage can be used as
Ingredient；In functional form skin protection cosmetics, good moisturizing, wrinkle resistant, shrinkproof, anti-aging and anti-allergic effects can be played.It is curing
Treatment application is upper, and α keto acid compound can treat damage caused by due to chronic renal insufficiency, and it is uremic to can be used as treatment
Specific drug.Patients with renal failure takes α keto acid compound, and cooperates low protein diet, can reduce the high filtration of glomerulus,
The protection nephron can reduce symptom, delay disease progression to light, Moderate Chronic Renal Failure patient；To severe chronic renal function
Energy failure patients can then improve its malnutritive situation, be the substitutes of corresponding amino acid.
According to the literature, the synthesis of keto-valine calcium is mainly the following method: (the He lvetica of route 1
Chimica Acta, 1982,65 (7): 2024-2028.) it is reacted using grignard reagent with diethy-aceto oxalate, then by ester at calcium
Salt, this method molar yield is higher, but severe reaction conditions, needs anhydrous, high-purity nitrogen (argon) atmosphere and cryogenic conditions, especially
Lower temperature, it is more difficult to control in industrial conditions.Route 2 (JP54103824A and CN101514154) uses glycolylurea and acetone
Reaction generates isopropylidene glycolylurea, and isopropylidene glycolylurea obtains product using hydrolysis, at salt, which uses glycolylurea, acetone,
Calcium chloride etc. is raw material, and raw material is simply relatively suitble to industrialization, but should consider to decompose a large amount of ammonias and carbon generated when hydrolysis
Environmental pollution caused by acid group.3 nitrile alcohol of route is raw material (Synthesis, 1 971, (10): 538-539.), by reaction, is turned
Alpha-hydroxy-N- tert-butylamides are turned to, ketoamine is reoxidised into, then hydrolyzes, finally obtain target product at salt.Route 4
(Tetra hedron Letters, 1978,48:4809-4810.) carries out addition-cancellation with corresponding ketone and organolithium reagent
Reaction generates corresponding keto ester, then obtains target product at salt through one soap of hydrolysis.Route 3,4 expensive starting materials of route, toxicity
Greatly, seriously polluted, reaction step is more, at high cost, therefore be not suitable for industrialized production.
Patent of invention CN201210171694.6 discloses a kind of method for preparing α-one valine calcium, reaction mechanism
Are as follows: in methanol solution of sodium methylate, diethy-aceto oxalate occurs rapidly transesterification and generates dimethyl oxalate, after isobutylaldehyde instills,
Aldol condensation occurs in itself under the action of sodium methoxide, then under sodium methoxide catalyzed effect, and ester occurs with dimethyl oxalate and hands over
It changes, generates cyclic lactone after sloughing a methyl formate rapidly, then open loop under the action of buck, generate α-one valine sodium
Then salt is acidified, extract, and washing adjusts pH to be refining to obtain α-one valine calcium at salt.The preparation method is the disadvantage is that, using closing It is still more at raw material, production cost is increased, synthetic route is more complex, and the molar yield of product is relatively low (can not to be surpassed It crosses 80%).
Therefore compared with the method for preparation α-one valine calcium disclosed above, the present invention provides one kindPreparation method letter The new method for preparing keto-valine calcium of the high molar yield of low cost single, process route is shorter。
Summary of the invention
In view of this, the purpose of the present invention is to provide a kind of novel preparation method of keto-valine calcium, the new method technique
Simply, synthetic route is short and product molar high income.
To achieve the goals above, the present invention uses following scheme:
A kind of novel preparation method of keto-valine calcium, using isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone
Keto-valine calcium is prepared with calcium hydroxide reaction, reaction equation is as follows:
Further, by isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone are dissolved in organic solvent, temperature control after dissolution
The glycerin solution of calcium hydroxide is added, after dissolution temperature control be added calcium hydroxide glycerin solution or aqueous solution or glycerine with
For water arbitrarily than mixed solution reaction 4-10 hours, decrease temperature crystalline filters to obtain keto-valine calcium crude product；Isopropyl -4 5-,
The weight ratio 1.5-3.5:1 of 4 '-dimethyl dihydrofuran -2,3- diketone and calcium hydroxide.
Further, the temperature of the temperature control is 0-100 DEG C, 0-55 DEG C of preferred temperature.
It is furthermore preferred that the temperature of the temperature control is 55 DEG C.
Further, the organic solvent includes but is not limited to methanol, ethyl alcohol, isopropanol, acetone, DMF, preferably methanol.
Further, the mixing time is 4-10 hours.
Preferred mixing time is 8 hours.
Preferably the weight ratio of the 5- isopropyl -4,4 '-dimethyl dihydrofuran -2,3- diketone and calcium hydroxide is
2.3:1。
The weight ratio of isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone and methanol is 1:7-15, preferably:
1:8.8:.
Further, the ratio of the calcium hydroxide and glycerine is 1:20.
Preferably, the ratio of the calcium hydroxide and glycerine is 1:10
Further, methanol, ethyl alcohol, acetone, DMF, water and above-mentioned solvent and water is added in the keto-valine calcium crude product
It is any than decrease temperature crystalline after mixed solvent rising temperature for dissolving, after filtering keto-valine calcium highly finished product, preferably 20% methanol-water
Solution.
The weight ratio of the keto-valine calcium crude product and 20% methanol aqueous solution is 1:2~5, preferably 1:3.
Further, the temperature of the heating is 55 DEG C to 100 DEG C.
Preferably, the temperature of the heating is 55 DEG C.
Further, the cooling temperature is 0 to 50 DEG C, preferably 0 DEG C
Further, the time of the decrease temperature crystalline is 1-10 hours, preferably 2 hours.
The keto-valine calcium highly finished product calculate its molar yield and detect its purity by HPLC.
The second object of the present invention is to provide a kind of answering for 5- isopropyl -4,4 '-dimethyl dihydrofuran -2,3- diketone
With specially isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone are preparing the application in keto-valine calcium.
The beneficial effects of the present invention are:
1) the present invention provides a kind of new method for preparing keto-valine calcium, the method use isopropyl -4 5-, 4 '-two
Methyl dihydrofuran -2,3- diketone and calcium hydroxide are primary raw material preparation, and the new method is at low cost, preparation method is simple, closes
It is short and environmentally friendly at route；
2) using the purity is high (99.9%) of the keto-valine calcium highly finished product of the new method, molar yield is up to 87.8%,
Suitable for industrialized production, be conducive to the extensive use of keto-valine calcium industrially.
Specific embodiment
Illustrated embodiment is in order to which preferably the present invention will be described, but is not that the contents of the present invention are limited only to institute
For embodiment.So those skilled in the art according to foregoing invention content to embodiment carry out it is nonessential improvement and
Adjustment, still falls within protection scope of the present invention.
Embodiment 1 prepares keto-valine calcium
By isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone 170.21g (1mol) are dissolved in methanol 1500g,
Dissolution is sufficiently stirred, 0 DEG C to 55 DEG C of temperature control, the 740.9g glycerin solution of calcium hydroxide 74.09g is added, it is small to be stirred to react 8
When, cool down 0 DEG C and crystallize 2 hours, filters, obtain keto-valine calcium crude product 140g, molar yield 90%.
Keto-valine calcium crude product 140g is added in 20% methanol aqueous solution, 55 DEG C of dissolutions is warming up to, cools down 0 DEG C and crystallize 2
Hour, filtering obtains keto-valine calcium crude product 123g, molar yield 87.8%.HPLC purity 99.9%.
Embodiment 2 prepares keto-valine calcium
By isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone 170.21g (1mol) are dissolved in methanol 1500g,
Dissolution is sufficiently stirred, 20 DEG C to 55 DEG C of temperature control, the glycerin solution of calcium hydroxide 56.67g is added, is stirred to react 4 hours, cool down
0 DEG C crystallizes 4 hours, and filtering obtains keto-valine calcium crude product 130g, molar yield 86%.
Keto-valine calcium crude product 130g is added in 20% methanol aqueous solution, 55 degrees Celsius of dissolutions is warming up to, cools down 0 DEG C and tie
4 hours brilliant, filtering obtains keto-valine calcium crude product 113g, molar yield 86.9%.HPLC purity 99.9%.
Embodiment 3 prepares keto-valine calcium
By isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone 300g are dissolved in methanol 2400g, are sufficiently stirred molten
Solution, is added the glycerin solution of calcium hydroxide 100g, is stirred to react 10 hours, cooling down 0 DEG C, it is small to crystallize 4 by 10 DEG C to 35 DEG C of temperature control
When, filtering obtains keto-valine calcium crude product 275g, molar yield 92%.
Keto-valine calcium crude product 275g is added in methanol aqueous solution, 55 degrees Celsius of dissolutions is warming up to, cools down 0 DEG C and crystallize 6
Hour, filtering obtains keto-valine calcium crude product 244.03g, molar yield 89.1%.HPLC purity 99.9%.
4 5- isopropyl -4,4 ' of embodiment-dimethyl dihydrofuran -2,3- diketone is preparing the application in keto-valine calcium
A) by isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3- diketone 340.42g are dissolved in methanol 3000g, sufficiently
Stirring and dissolving；
B) 40 DEG C to 50 DEG C of temperature control are added the glycerin solution of calcium hydroxide 148.18g, are stirred to react 6 hours, cooling 0
DEG C crystallization 6 hours, filtering, obtain keto-valine calcium crude product 290g, molar yield 92%；
C) keto-valine calcium crude product 290g is added in methanol aqueous solution, is warming up to 55 degrees Celsius of dissolutions, cools down 0 DEG C and crystallize
8 hours, filtering obtained keto-valine calcium crude product 266.32g, molar yield 91.83%, HPLC purity 99.9%.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (10)
1. a kind of novel preparation method of keto-valine calcium, which is characterized in that isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,3-
Diketone and calcium hydroxide reaction prepare keto-valine calcium, and reaction equation is as follows:
2. new method according to claim 1, which is characterized in that by isopropyl -4 5-, 4 '-dimethyl dihydrofuran -2,
3- diketone is dissolved in organic solvent, and the glycerin solution of temperature control addition calcium hydroxide or aqueous solution or glycerine and water are any after dissolution
Than mixed solution reaction 4-10 hours, decrease temperature crystalline filtered to obtain keto-valine calcium crude product；5- isopropyl-the 4,4 '-diformazan
The weight ratio 1.5-3.5:1 of base dihydrofuran -2,3- diketone and calcium hydroxide.
3. new method according to claim 2, which is characterized in that methanol aqueous solution is added in the keto-valine calcium crude product
Decrease temperature crystalline after rising temperature for dissolving obtains keto-valine calcium highly finished product after filtering.
4. new method according to claim 2, which is characterized in that the temperature of the temperature control is 0-55 DEG C.
5. new method according to claim 2, which is characterized in that the temperature of the decrease temperature crystalline is 0 DEG C -50 DEG C；It is described
The time of decrease temperature crystalline is 1-10 hours.
6. new method according to claim 3, which is characterized in that the temperature of the heating is 55 DEG C to 100 DEG C.
7. new method according to claim 2, which is characterized in that the time being stirred to react is 4-10 hours.
8. new method according to claim 2, which is characterized in that isopropyl -4 5-, 4 '-dimethyl dihydrofuran -
2,3- diketone also dissolves in ethyl alcohol, isopropanol, acetone and DMF solvent.
9. new method according to claim 2, which is characterized in that the ratio of the calcium hydroxide and glycerine is 1:20.
10.5- isopropyl -4,4 '-dimethyl dihydrofuran -2,3- diketone is preparing the application in keto-valine calcium.
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| CN201910136710.XA CN109761801B (en) | 2019-02-25 | 2019-02-25 | Novel method for preparing ketovaline calcium |
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Non-Patent Citations (1)
| Title |
|---|
| HIROYUKI HATA等: "Synthesis of Dihydro-2,3-furandiones from Diethyl Oxalate and Aldehydes Through the Action of Sodium Methoxide", 《SYNTHESIS》 * |
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