CN102675087B - Preparation method of novel alpha-ketovaline calcium - Google Patents
Preparation method of novel alpha-ketovaline calcium Download PDFInfo
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Abstract
The invention discloses a preparation method of novel alpha-ketovaline calcium, which comprises the steps of: dropping diethyl oxalate into alcoholic solution of metal alkoxide, then dropping isobutyraldehyde, preserving heat and agitating, adding alkali solution, regulating pH after heat preservation, extracting, adding a certain amount of water into the extract, adding alkali liquor for regulating the pH, dropping calcium chloride water solution for salification to obtain crude alpha-ketovaline calcium and then refining the crude alpha-ketovaline calcium in mixed solvent of purified water and organic solvent to obtain refined alpha-ketovaline calcium. The preparation method has the advantages that the reaction conditions are moderate, the operation is simple to conduct, the steps are fewer, the yield is high, the quality is high, the price of the used raw materials is low, no pollution is caused, waste gas and a great quantity of waste residues are not produced and the method is suitable for industrial mass production.
Description
Technical field
The present invention relates to the synthetic technical field of medicine, be specifically related to the chemical synthesis and preparation method of α-one α-amino-isovaleric acid calcium.
Background technology
α-one α-amino-isovaleric acid calcium, English name: α-Ketovaline Calcium, chemical name: ALPHA-Ketovaline Calcium, CAS:51828-94-5.α-one α-amino-isovaleric acid calcium is one of main component of α keto acid compound (opening same).Alpha-ketoacid and derivative thereof have demonstrated day by day wide application prospect at aspects such as food, daily use chemicals and medicine.In food applications, can be used as the composition of sports nutrition beverage; In functional type skin protection cosmetics, can play good moisturizing, wrinkle resistant, shrinkproof, anti-aging and anti-allergic effects.In medical applications, α keto acid compound can be treated the infringement causing because of chronic renal insufficiency, and can be used as the uremic specifics for the treatment of.Patients with renal failure is taken α keto acid compound, and coordinates low protein diet, and the height that can alleviate renal glomerulus filters, the protection nephron, and to light, Moderate Chronic Renal Failure patient, can mitigation symptoms, delay disease progression; To severe patients of chronic renal failure, can improve its malnutritive situation, be corresponding amino acid whose substitute.
According to the literature, α-one α-amino-isovaleric acid calcium synthetic mainly contains following several method: route 1(Helvetica Chimica Acta, 1982,65 (7): 2024-2028.) adopt grignard reagent to react with oxalic acid diethyl ester, then ester is become to calcium salt, the method yield is higher, but severe reaction conditions, need anhydrous, high-purity nitrogen (argon) atmosphere and cold condition, particularly lower temperature, more difficult control under industrial condition.Route 2(JP54103824A and CN101514154) adopt glycolylurea to react generation isopropylidene glycolylurea with acetone, isopropylidene glycolylurea obtains product through hydrolysis, salify again, this route adopts glycolylurea, acetone, calcium chloride etc. are raw material, raw material is simply relatively applicable to industrialization, but decomposes the environmental pollution that a large amount of ammonias of producing and carbonate cause should consider to be hydrolyzed time.Route 3 nitrile alcohol are raw material (Synthesis, 1971, (10): 538-539.), through reaction, be converted into Alpha-hydroxy-N-tert-butylamides, be reoxidised into ketoamine, be then hydrolyzed, last salify obtains target product.Route 4(Tetrahedron Letters, 1978,48:4809-4810.) with corresponding ketone and organolithium reagent, carry out addition-elimination reaction, generate corresponding keto ester, then obtain target product through being hydrolyzed a soap salify.Route 3, route 4 raw materials are expensive, toxicity is large, seriously polluted, reactions steps is many, cost is high, so are not suitable for suitability for industrialized production.The present invention is with reference to existing document (Agricultural Biology and Chemistry, 1987,51 (1): 289-290. and Synthesis, 1991:289-291. theory of correlation and JP59164749) is addressed the description of mechanism, invent a kind of higher yield, prepared more cheaply the method for α-one α-amino-isovaleric acid calcium.Reaction mechanism of the present invention is: in methanol solution of sodium methylate, transesterify oxalic dimethyl ester occurs rapidly oxalic acid diethyl ester, after isobutyric aldehyde splashes into, there is aldol condensation in self under the effect of sodium methylate, then under sodium methylate katalysis, again with dimethyl oxalate generation transesterify, after sloughing rapidly a methyl-formiate, generate cyclic lactone, then open loop under the effect of buck, generates α-one α-amino-isovaleric acid sodium salt, then acidifying, extraction, washing, adjusts pH, salify, refines to obtain α-one α-amino-isovaleric acid calcium.
Summary of the invention
The invention provides a kind of new method of preparing α-one α-amino-isovaleric acid calcium, can solve the deficiency that prior art exists.
For realizing object of the present invention, the preparation method of this α-one α-amino-isovaleric acid calcium, is characterized in that it comprises the following steps:
A. in the alcoholic solution of metal alkoxide, add dialkyl oxalate, control temperature at-10 ~ 50 degree, be incubated 0.2 ~ 2.0 hour;
B. be incubated completely, add isobutyric aldehyde, control temperature at-20 ~ 40 degree, be incubated 0.2 ~ 2.0 hour;
C. be incubated completely, add alkali lye, control temperature at-20 ~ 60 degree, be incubated 0.5 ~ 10 hour;
D. after insulation finishes, add acid, add organic solvent extraction;
E. merge organic phase, add adjusting PH with base 4 ~ 8, layering, organic phase adds water again and adjusts pH4 ~ 8, merges water.Water adds adjusting PH with base 6 ~ 10, adds calcium chloride water to become calcium salt, is incubated 1 ~ 3 hour, lowers the temperature centrifugal, obtains α-one α-amino-isovaleric acid calcium crude product;
F. α-one α-amino-isovaleric acid calcium crude product is dissolved in the purified water of 5 ~ 15 times of weight, then adds the organic solvent of 0 ~ 1.8 times of purified water weight, refining, obtain α-one α-amino-isovaleric acid calcium highly finished product.
Metal alkoxide in described a step adopts sodium methylate, sodium ethylate, and sodium isopropylate, sodium tert-butoxide, isoamyl sodium alkoxide, potassium methylate, potassium ethylate, potassium isopropoxide, potassium tert.-butoxide, isoamyl potassium alcoholate, chooses wherein any one.
Alcoholic solution in described step a is selected from: methyl alcohol, ethanol, Virahol.Choose wherein any one.
Dialkyl oxalate in described step a is selected from: oxalic acid diethyl ester, dimethyl oxalate.Choose wherein any one.
Metal alkoxide in described step a and the mol ratio of dialkyl oxalate are: 0.7 ~ 1.6.
Isobutyric aldehyde in described step b and the mol ratio of oxalic acid diethyl ester are: 0.6 ~ 1.6.
Alkali lye in described step c is sodium hydroxide solution, potassium hydroxide solution.Choose wherein any one.The mol ratio of alkali lye and oxalic acid diethyl ester: 0.2 ~ 2.0.
Organic solvent in described steps d is selected from: esters solvent, and as ethyl acetate, methyl acetate, propyl acetate; Ketones solvent: mibk, pimelinketone; Ether solvent is as methyl tertiary butyl ether, ether, propylene oxide, isopropyl ether; Halohydrocarbon: methylene dichloride, chloroform, tetracol phenixin.Choose wherein any one; Acid in steps d is hydrochloric acid, sulfuric acid, acetic acid, formic acid, chooses wherein any one.
Alkali in described step e is selected from: triethylamine, diethanolamine, pyridine, ammoniacal liquor, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate.Choose wherein any one.Calcium chloride in step e and the mol ratio of oxalic acid diethyl ester: 0.2 ~ 1.2.
The refining weight ratio with purified water and α-one α-amino-isovaleric acid calcium crude product described in described step f is 5.0 ~ 15 times.
Refining in described step f is selected from organic solvent: methyl alcohol, ethanol, Virahol, n-propyl alcohol, acetone, tetrahydrofuran (THF).Choose wherein any one.
The refining weight ratio by organic solvent and purified water in described step f is 0 ~ 1.8 times.
Reaction mechanism of the present invention: in methanol solution of sodium methylate, transesterify oxalic dimethyl ester occurs rapidly oxalic acid diethyl ester, after isobutyric aldehyde splashes into, there is aldol condensation in self under the effect of sodium methylate, then under sodium methylate katalysis, again with dimethyl oxalate generation transesterify, after sloughing rapidly a methyl-formiate, generate cyclic lactone, then open loop under the effect of buck, generates α-one α-amino-isovaleric acid sodium salt, then acidifying, extraction, washing, adjusts pH, salify, refines to obtain α-one α-amino-isovaleric acid calcium.
Its chemical equation is
Beneficial effect of the present invention: the present invention is due to its unique reaction mechanism, adopt the preparation method of one kettle way, consider again the strict demand of quality product, therefore, after finishing, reaction adopt a series of aftertreatment means to carry out purified product, remove unnecessary impurity, obtain α-α-amino-isovaleric acid calcium of 99.5% above liquid phase purity, total recovery is more than 60%.With route 1 relatively, condition is more gentle, operates also easylier, toxicity is also less.Compare with route 2, saved this step of isopropylidene glycolylurea intermediate, not only on producing, saved a step, for analyzing a lot of work of having saved, such as formulating control standard in hydrolysis, formulate intermediate quality standard etc. again.The technical superiority that the present invention is larger is, the ammonia, the environmental pollutions such as carbonate and the detrimentally affect to quality product that while having avoided the hydrolysis of isopropylidene glycolylurea intermediate, have produced.With route 3, route 4 is compared, and no matter, in toxicity, on to the detrimentally affect of environment, or in the step of the control of cost and reaction, all reduces greatly.Therefore, the present invention has obvious beneficial effect, is applicable to industrialized production.
Embodiment
Embodiment 1
25
ounder C, by oxalic acid diethyl ester 300kg, splash in 390kg methanol solution of sodium methylate, drip off insulated and stirred half an hour, add isobutyric aldehyde 180kg, add insulation half an hour, be not more than 25
ounder the condition of C, add 30% aqueous sodium hydroxide solution 500kg, drip off insulation 5 hours, drip 400kg hydrochloric acid, stir half an hour, add methyl iso-butyl ketone (MIBK) 600kg extraction three times, organic phase adds 100kg purified water, adds sodium hydroxide to regulate pH value to 7.8, layering, organic phase adds sodium hydroxide to regulate pH value to 4.2 again, and layering merges water.Water adds sodium hydroxide to regulate pH value to 8.8, is being not less than 20
oc adds 300kg calcium chloride water, drips off insulated and stirred 2 hours, slow cooling to 5
oc, is incubated 1 hour, and centrifuge dripping obtains α-α-amino-isovaleric acid calcium crude product 358kg, and HPLC purity assay is 99.6%.
α-α-amino-isovaleric acid calcium crude product 358kg drops in 3000kg purified water, is heated to reflux also molten clear, drips 500kg methyl alcohol, molten clear, adds gac 1.0kg decolouring.Press filtration while hot, is cooled to room temperature naturally, is then cooled to 2 ~ 5
oc, is incubated 2 hours, and centrifuge dripping, dries to obtain 200kg white crystalline powder, and HPLC analyzes, and purity is 99.8%, and total recovery is 72.1%.
Embodiment 2
25
ounder C, dimethyl oxalate 236kg is splashed in 486kg alcohol sodium alcohol solution, drip off insulated and stirred half an hour, add isobutyric aldehyde 173kg, add insulation half an hour, be not more than 25
ounder the condition of C, add 30% aqueous sodium hydroxide solution 260kg, drip off insulation 5 hours, drip 400kg hydrochloric acid, stir half an hour, add methyl iso-butyl ketone (MIBK) 600kg extraction three times, organic phase adds 100kg purified water, add potassium hydroxide that the aqueous solution is regulated to pH value to 4.5, layering, organic phase adds potassium hydroxide to regulate pH value to 6.5 again, layering, merge water, add potassium hydroxide to regulate pH value to 8.8, be not less than 20
oc adds 290kg calcium chloride water, drips off insulated and stirred 2 hours, slow cooling to 5
oc, is incubated 1 hour, and centrifuge dripping obtains α-α-amino-isovaleric acid calcium crude product 366kg, and HPLC purity assay is 99.7%.
α-α-amino-isovaleric acid calcium crude product 366kg drops in 3000kg purified water, adds thermosol clear, drips 500kg methyl alcohol, molten clear, adds gac 1.0kg decolouring.Press filtration while hot, is cooled to room temperature naturally, is then cooled to 2 ~ 5
oc, is incubated 2 hours, and centrifuge dripping, dries to obtain 205kg white crystalline powder, and HPLC analyzes, and purity is 99.9%, and total recovery is 76.0%.
Embodiment 3:
The present embodiment difference from Example 1 is only, with aqueous ammonia to replace sodium hydroxide, carrys out adjust pH, obtains the refining dry product of 193kg, and total recovery is 69.6%.
Embodiment 4:
The present embodiment difference from Example 1 is only, with 600kg ethyl acetate, replaces methyl iso-butyl ketone (MIBK) to do solvent extraction, obtains the refining dry product of 185kg, and total recovery is 66.7%.
Embodiment 5:
The present embodiment difference from Example 1 is only, with 600kg methyl tertiary butyl ether, replaces methyl iso-butyl ketone (MIBK) to do solvent extraction, obtains the refining dry product of 190kg, and total recovery is 68.5%.
Embodiment 6:
The present embodiment difference from Example 2 is only, with 625kg ethanol, replaces methyl alcohol, obtains the refining dry product of 205kg, and total recovery is 73.9%.
Embodiment 7:
The present embodiment difference from Example 2 is only, with 625kg acetone, replaces methyl alcohol, obtains the refining dry product of 183kg, and total recovery is 66.0%.
Embodiment 8:
The present embodiment difference from Example 2 is only, with 625kg Virahol, replaces methyl alcohol, obtains the refining dry product of 199kg, and total recovery is 71.8%.
Claims (10)
1. a preparation method for α-one α-amino-isovaleric acid calcium, is characterized in that, comprises the following steps:
A. in the alcoholic solution of metal alkoxide, add dialkyl oxalate, control temperature at-10～50 ℃, be incubated 0.2～2.0 hour;
B. add isobutyric aldehyde, control temperature at-20～40 ℃, be incubated 0.2～2.0 hour;
C. add alkali lye, control temperature at-20～60 ℃, be incubated 0.5～10 hour;
D. add acid, add organic solvent extraction;
E. merge organic phase, add adjusting PH with base 4～8, layering, organic phase adds water again and adjusts pH4～8, merge water, water adds adjusting PH with base 6～10, adds calcium chloride water being not less than 20oC, drips off insulated and stirred 1～3 hour, slow cooling is to 5oC, be incubated 1 hour, centrifuge dripping, obtains α-one α-amino-isovaleric acid calcium crude product;
F. α-one α-amino-isovaleric acid calcium crude product is dissolved in the purified water of 5～15 times of weight, the organic solvent that adds again 0～1.8 times of purified water weight, add thermosol clear, add activated carbon decolorizing, while hot press filtration, naturally be cooled to room temperature, then be cooled to 2～5oC, be incubated 2 hours, centrifuge dripping, dry, obtain α-one α-amino-isovaleric acid calcium highly finished product.
2. preparation method according to claim 1, is characterized in that, the metal alkoxide in described a step adopts sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, isoamyl sodium alkoxide, potassium methylate, potassium ethylate, potassium isopropoxide, potassium tert.-butoxide, isoamyl potassium alcoholate, chooses wherein any one.
3. preparation method according to claim 1, is characterized in that, the alcoholic solution in described step a is selected from: methyl alcohol, and ethanol, Virahol, chooses wherein any one.
4. preparation method according to claim 1, is characterized in that, the dialkyl oxalate in described step a is selected from: oxalic acid diethyl ester, dimethyl oxalate, chooses wherein any one.
5. preparation method according to claim 1, is characterized in that, the metal alkoxide in described step a and the mol ratio of dialkyl oxalate are: 0.7～1.6.
6. preparation method according to claim 1, is characterized in that, the isobutyric aldehyde in described step b and the mol ratio of oxalic acid diethyl ester are: 0.6～1.6.
7. preparation method according to claim 1, is characterized in that, the alkali lye in described step c is sodium hydroxide solution, and potassium hydroxide solution is chosen wherein any one; The mol ratio of alkali lye and oxalic acid diethyl ester: 0.2～2.0.
8. preparation method according to claim 1, is characterized in that, the organic solvent in described steps d is selected from: esters solvent: ethyl acetate, methyl acetate, propyl acetate; Ketones solvent: mibk, pimelinketone; Ether solvent: methyl tertiary butyl ether, ether, propylene oxide, isopropyl ether; Halohydrocarbon: methylene dichloride, chloroform, tetracol phenixin, chooses wherein any one; Acid in steps d is hydrochloric acid, sulfuric acid, acetic acid, formic acid, chooses wherein any one.
9. preparation method according to claim 1, is characterized in that, the alkali in described step e is selected from: triethylamine, diethanolamine, pyridine, weak ammonia, aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, sodium bicarbonate aqueous solution, aqueous sodium carbonate, chooses wherein any one; Calcium chloride in step e and the mol ratio of oxalic acid diethyl ester: 0.2～1.2.
10. preparation method according to claim 1, is characterized in that, refining in described step f is selected from organic solvent: methyl alcohol, and ethanol, Virahol, n-propyl alcohol, acetone, tetrahydrofuran (THF), chooses wherein any one.
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Address after: 312071 Zhejiang province Shaoxing Paojiang Industrial Zone Tang Road No. 315 Patentee after: SHAOXING MINSHENG PHARMACEUTICAL CO., LTD. Address before: 312071 Zhejiang province Shaoxing Paojiang Industrial Zone Tang Road No. 315 Patentee before: Shaoxing Minsheng Pharmaceutical Co.,Ltd. |