CN106316828A - Preparation method of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate - Google Patents
Preparation method of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate Download PDFInfo
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Abstract
The invention discloses a preparation method of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate. Some existing methods are complex in operation, low in yield, long in reaction time and harsh in condition. Sec-butyl hydantoin or isopropylidene hydantoin as the raw material and alkali liquor containing a buffer solution conduct micro-negative pressure ring-opening reaction to obtain corresponding alpha-keto acid salt; obtained alpha-keto acid salt is subjected to impurity extraction through hydrocarbon, halogenated hydrocarbon, ketone or ether solvent, subjected to acidification to obtain a corresponding alpha-keto acid crude product, then subjected to impurity extraction through hydrocarbon, halogenated hydrocarbon, ketone or ether solvent and subjected to adsorption refining through activated carbon, hargil or resin to obtain alpha-keto acid; the obtained alpha-keto acid is prepared into calcium salt, and calcium salt is crystallized to obtain alpha-keto acid calcium dihydrate. The yield of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate is remarkably improved.
Description
Technical field
The present invention relates to the preparation of medical material, specifically a kind of high-purity alpha-one isoleucine calcium dihydrate and
The preparation method of α-one valine calcium dihydrate.
Background technology
α-one isoleucine calcium and α-one valine calcium are the main components of α keto acid compound.α keto acid compound is used for
Uremia therapy, provides essential amino acids for nephrotic and reduces the absorption of amino nitrogen as far as possible.Ketone group or hydroxyamino acid itself
Not containing amino, it utilizes the nitrogen transformation of non essential amino acid to be aminoacid, therefore can reduce urea synthesis, and uremia's toxicity is produced
The accumulation of thing is also reduced.
One, the structural formula of α-one isoleucine calcium is as follows:
The structural formula of α-one isoleucine calcium dihydrate is as follows:
At present α-one isoleucine calcium mainly has following several synthetic method:
(1) Minoru Igarashi et al. is at J.Org.Chem.1963, and 28 (11): 3088-3092 with ethyl cyanoacetate
It is initiation material with isobutylaldehyde, reacts through Knoevenagel-Cope, prepare 2-Asia sec-butyl ethyl cyanoacetate, be then passed through oxygen
The processes such as change, hydrolysis generate corresponding α-one isoleucine.The initiation material ethyl cyanoacetate that this route uses, toxicity is relatively big,
And reactions steps longer (6 step altogether), operation complexity, yield is low；Oxidizing process uses hydrogen peroxide, is unfavorable for safety in production.
(2) Hua Jinxiu et al. proposes with glycolylurea and butanone as initiation material at " during chemical industry print " 2007,21 (12): 5-8,
Condensation reaction, prepares 5-Asia sec-butyl glycolylurea, is then passed through hydrolyze, is acidified, becomes the process generation different bright ammonia of corresponding α-one such as calcium salt
Acid calcium.
(3) Roger Robert Gaudette at GB155099355 with sub-sec-butyl glycolylurea as raw material, through hydrolysis, acid
Change, become the processes such as calcium salt to generate corresponding α-one isoleucine calcium.This synthetic route is relatively easy, and reactions steps is shorter, but 5-is sub-
The hydrolysis difficulty of sec-butyl glycolylurea is big, it is generally required to the alkali liquor ability normal reaction of 4-12 times of mole, and the response time is long,
Condition is harsh, and hydrolysis yield is low.At longer reaction times, the impurity of production is more, and reactant liquor detects, general maximum contaminant
Peak about 1.5%, total impurities peak about 3.5%；The crude product maximum contaminant peak about 1% typically resulted in, total impurities peak 2.5% is left
Right；After refining crystallization, product maximum contaminant peak 0.5%, total impurities peak 1.0%；End product quality is low, relevant content of material
Higher.
Two, the structural formula of α-one valine calcium is as follows:
The structural formula of α-one valine calcium dihydrate is as follows:
At present α-one valine calcium mainly has following several synthetic method:
(1) Minoru Igarashi et al. is at J.Org.Chem.1963, and 28 (11): 3088-3092 with ethyl cyanoacetate
It is initiation material with acetone, reacts through Knoevenagel-Cope, prepare 2-isopropylidene ethyl cyanoacetate, be then passed through oxygen
The processes such as change, hydrolysis generate corresponding α-one valine.The initiation material ethyl cyanoacetate that this route uses, toxicity is relatively big, and
Reactions steps longer (6 step altogether), operation complexity, yield is low；Oxidizing process uses hydrogen peroxide, is unfavorable for safety in production.
(2) Hua Jinxiu et al. proposes with glycolylurea and acetone as initiation material at " during chemical industry print " 2007,21 (12): 5-8,
Condensation reaction, prepares 5-isopropylidene glycolylurea, is then passed through hydrolyze, is acidified, becomes the process corresponding α-one valines of generation such as calcium salt
Calcium.
(3) Roger Robert Gaudette at GB15509935 with isopropylidene glycolylurea as raw material, through hydrolysis, acid
Change, become the processes such as calcium salt to generate corresponding α-one valine calcium.This synthetic route is relatively easy, and reactions steps is shorter, but 5-Asia is different
The hydrolysis difficulty of propyl group glycolylurea is big, it is generally required to the alkali liquor ability normal reaction of 4-12 times of mole, and the response time is long, bar
Part is harsh, and hydrolysis yield is low.As preparation with α-one isoleucine calcium, at longer reaction times, the impurity of production is relatively
Many, reactant liquor detects, general maximum contaminant peak about 1.5%, total impurities peak about 3.5%；The crude product maximum typically resulted in is miscellaneous
Mass peak about 1.0%, total impurities peak about 2.5%；After refining crystallization, product maximum contaminant peak 0.5%, total impurities peak
1.0%；End product quality is low, and relevant content of material is higher.
Summary of the invention
The technical problem to be solved is the defect overcoming above-mentioned prior art to exist, it is provided that a kind of raw material is easy
Obtain, side reaction is few, yield is high, environmentally friendly, reaction condition is gentle easily-controllable and applicable large-scale production, uses under tiny structure anti-
Technology is answered to produce high-purity alpha-one isoleucine calcium and the preparation method of α-one valine calcium.
To this end, the technical solution used in the present invention is as follows: a kind of α-one isoleucine calcium dihydrate and α-one valine
The preparation method of calcium dihydrate, comprises the steps:
1) with sub-sec-butyl glycolylurea or isopropylidene glycolylurea as raw material, to carry out tiny structure open loop anti-with the alkali liquor containing buffer
Should, obtain corresponding 2-ketoacid salt；
2) by step 1) the 2-ketoacid salt that obtains is first with hydro carbons, halogenated hydrocarbon, ketone or ether solvent abstraction impurity removal, then acid
Change and obtain corresponding 2-ketoacid crude product, and with hydro carbons, halogenated hydrocarbon, ketone or ether solvent abstraction impurity removal, then with living
Property charcoal, the refined 2-ketoacid that obtains of hargil or resin absorption, described 2-ketoacid is α-one isoleucine or α-one valine；
3) by step 2) 2-ketoacid that obtains makes calcium salt, and crystallization obtains alpha-calcium picrolonate dihydrate, described 2-ketoacid
Calcium dihydrate is α-one isoleucine calcium dihydrate or α-one valine calcium dihydrate；α-one isoleucine dihydrate
Corresponding raw material is sub-sec-butyl glycolylurea, and the raw material that α-one valine dihydrate is corresponding is isopropylidene glycolylurea.
Under tiny structure reactive state, can in time the gas of generation be removed in time, short to the time to rupture of product, impurity
Relatively fewer.Use buffer, can effectively alleviate high alkalinity and raw material and the destruction of product, minimizing impurity are generated,
Reactant liquor detects, maximum contaminant peak about 1.0%, total impurities peak about 2.5%.Step 2) in, through primary abstraction impurity removal
After, reactant liquor maximum contaminant peak about 0.8%, total impurities peak about 2.0%；After secondary abstraction impurity removal (i.e. after acidifying
Remove impurity), 2-ketoacid solution maximum contaminant peak about about 0.7%, total impurities peak about about 1.8%.After absorption, obtain high-purity
The 2-ketoacid solution maximum contaminant peak 0.1～0.3% of degree, total impurities peak 0.5～1.0%.
The synthetic route of α-one isoleucine calcium:
The synthetic route of α-one valine calcium
During with sub-sec-butyl glycolylurea for raw material, the yield of α-one isoleucine calcium dihydrate is: 75.0～82.0%.With
When isopropylidene glycolylurea is raw material, the yield of α-one valine calcium dihydrate is: 71.0～79.0%.
Further, step 1) described in be sodium hydroxide or potassium hydroxide and sodium carbonate, carbonic acid containing the alkali liquor of buffer
One in potassium, sodium phosphate, potassium phosphate, dibastic sodium phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Borax, glycine
Or two or more mixed solutions.
Further, in the described alkali liquor containing buffer, buffer mole is sodium hydroxide or potassium hydroxide mole
0.01～0.50 times, preferably 0.02～0.10 times.
Further, the mole of described sodium hydroxide or potassium hydroxide is sub-sec-butyl glycolylurea or isopropylidene glycolylurea rubs
2.0～4.0 times of that amount, preferably 2.5～3.5 times.
Further, step 1) in, reaction temperature is 90～102 DEG C, preferably 90～95 DEG C；Vacuum is-0.030
～-0.001MPa, it is preferably-0.03～-0.015MPa.
Further, step 2) in, described varsol is normal hexane, hexamethylene or toluene；Halogenated hydrocarbon solvent is
Dichloromethane, dichloroethanes or trichloro ethylene；Ketones solvent is butanone, methyl propyl ketone, methyl isopropyl Ketone, methyl butyl
Ketone, methyl iso-butyl ketone (MIBK), metacetone, Ketohexamethylene or 1-Phenylethanone.；Ether solvent is ether, diisopropyl ether, n-butyl ether, methyl-tert
Butyl ether or methyl phenyl ethers anisole.
Further, step 2) in, described acidifying uses mineral acid to carry out, described mineral acid be sulphuric acid, hydrochloric acid or
Phosphoric acid.
Further, step 3) in, described 2-ketoacid uses calcium hydroxide or calcium chloride to add alkali and make calcium salt, described
Alkali is sodium hydroxide or potassium hydroxide.α-one isoleucine calcium, the maximum contaminant peak of α-one valine calcium crude product (i.e. calcium salt)
0.05～0.2%, total impurities peak 0.3～0.7%.
Further, step 3) use alcohols solvent or alcohols solvent aqueous solution to crystallize, maximum contaminant peak 0.02～
0.1%, total impurities peak 0.1～0.5%；Described alcohols solvent is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutyl
One or more mixed solution in alcohol, the tert-butyl alcohol.
The method have the advantages that
1., by alkali liquor adds buffer, make the alkalescence of alkali liquor during reaction that the destruction of raw material, intermediate and product to be subtracted
Weak；Tiny structure deviates from the gas (such as ammonia) that reaction generates in time, decreases the destruction to raw material, intermediate and product.Instead
Answer liquid total impurities from conventional about 4%, be reduced to about 2.5%；Maximum contaminant peak, from conventional about 2%, is reduced to 1%
Left and right.
2. on the basis of above-mentioned reaction, by abstraction impurity removal, the adsorption refining of acid, one-tenth calcium salt and calcium salt process for refining
Integrated use, makes the maximum contaminant peak of product control to 0.02～0.1%, and total impurities peak controls to 0.1～0.5%；Than routine
The maximum contaminant peak 0.5% of technology, total impurities peak 1.5% substantially reduces, it is thus achieved that high-quality α-one isoleucine calcium two water
Compound and α-one valine calcium dihydrate.
3. the yield of α-one isoleucine calcium dihydrate and α-one valine calcium dihydrate is improved significantly, α-one
The yield of isoleucine calcium dihydrate can reach 75.0～82.0%, and routine techniques is about 63%；α-one valine
The yield of calcium dihydrate can reach 71.0～79.0%, and routine techniques is about 62%.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1: the preparation of high-purity alpha-one isoleucine calcium dihydrate
In carrying churned mechanically 2000mL four-hole bottle, sub-sec-butyl glycolylurea 308g (2.0mol) of input under room temperature, 30%
Sodium hydroxide 800g (6.0mol), sodium phosphate 98.4g (0.6mol) control reaction vacuum-0.005MPa, reaction temperature 99～
Reacting at 100 DEG C, the gas vacuum of generation is extracted out, controls response time 180～270 minutes the most sub-sec-butyl glycolylurea content and is less than
1.0% (HPLC)；Reactant liquor detects, maximum contaminant peak 1.0%, total impurities peak 2.3%.Reactant liquor is cooled to room temperature, adds ring
Hexane 300mL extracts 1 time, layering.Water layer detection maximum contaminant peak 0.8%, total impurities peak 1.8%.Above water layer 545mL
35% hydrochloric acid (6.02mol) adjusts pH value=6.5, obtains extracting 1 with 300mL toluene under α-one isoleucine crude product solution room temperature
Secondary, obtain α-one isoleucine solution maximum contaminant peak about 0.7%, total impurities peak about 1.5%.Above α-one isoleucine solution
Add activated carbon 5g, stir 15 minutes under room temperature, be filtered to remove activated carbon, obtain high-purity alpha-one isoleucine solution maximum contaminant
Peak 0.15%, total impurities peak 0.6%.Above high-purity alpha-one isoleucine solution quickly stirs down and drips 40%CaCl2Solution
490g (1.76mol), separates out a large amount of white α-one isoleucine calcium, filters, and (moisture content is about to obtain α-one isoleucine calcium crude product
30%), maximum contaminant peak 0.10%, total impurities peak 0.50%.Above α-one isoleucine calcium crude product adds 2500mL methanol crystallization,
Filter, dry, obtain 261g high-purity alpha-one isoleucine calcium dihydrate, external standard content 99.4%, maximum contaminant peak
0.05%, total impurities peak 0.43%, yield 78.0%.
Embodiment 10: the preparation of high-purity alpha-one isoleucine calcium dihydrate
In carrying churned mechanically 2000mL four-hole bottle, sub-sec-butyl glycolylurea 308g (2.0mol) of input under room temperature, 40%
Potassium hydroxide 1120g (8.0mol), potassium phosphate 84.8g (0.4mol) control reaction vacuum-0.030MPa, reaction temperature 90～
Reacting at 91 DEG C, the gas vacuum of generation is extracted out, controls response time 360～540 minutes sub-sec-butyl glycolylurea content and is less than
1.0% (HPLC)；Reactant liquor detects, general maximum contaminant peak 0.90%, total impurities peak 2.3%.Reactant liquor is cooled to room temperature, adds
Enter 300mL diisopropyl ether to extract 1 time, layering.Water layer detection maximum contaminant peak 0.80%, total impurities peak 2.0%.
Above water layer 730mL 35% hydrochloric acid (8.05mol) adjusts pH value=6.5, obtains α-one isoleucine crude product solution
Extracting 1 time with 300mL toluene under room temperature, obtain α-one isoleucine solution maximum contaminant peak about 0.80%, total impurities peak is about
1.8%.
Above α-one isoleucine solution adds active hargil 5g, stirs 15 minutes, be filtered to remove active hargil under room temperature,
To high-purity alpha-one isoleucine solution maximum contaminant peak 0.31%, total impurities peak 0.9%.
Above high-purity alpha-one isoleucine solution quickly stirs down and drips 40%CaCl2Solution 490g (1.76mol), analysis
Go out a large amount of white α-one isoleucine calcium, filter, obtain α-one isoleucine calcium crude product (moisture content about 30%), maximum contaminant peak
0.20%, total impurities peak 0.63%.
Above α-one isoleucine calcium crude product adds 2500mL alcohol crystal, filters, dries, obtains 272g high-purity alpha-one different
Leucine-calcium dihydrate, external standard content 99.4%, maximum contaminant peak 0.08%, total impurities peak 0.48%, yield 81.3%.
Embodiment 19: the preparation of high-purity alpha-one valine calcium dihydrate
In carrying churned mechanically 2000mL four-hole bottle, input isopropylidene glycolylurea 280g (2.0mol) under room temperature, 30%
Sodium hydroxide 800g (6.0mol), glycine 90g (1.2mol) control reaction vacuum-0.01MPa, reaction temperature 98～99 DEG C
Lower reaction, the gas vacuum of generation is extracted out, controls response time 180～240 minutes isopropylidene glycolylurea content less than 1.0%
(HPLC)；Reactant liquor detects, general maximum contaminant peak 1.0%, total impurities peak 2.5%.Reactant liquor is cooled to room temperature, adds
300mL toluene extracts 1 time, layering.Water layer detection maximum contaminant peak 0.8%, total impurities peak 2.1%.Above water layer is used
545mL35% hydrochloric acid (6.02mol) adjusts pH value=6.5, obtains using 300mL dichloromethane under α-one valine crude product solution room temperature
Extract 1 time, obtain α-one valine solution maximum contaminant peak about 0.7%, total impurities peak about 1.8%.Above α-one valine is molten
Liquid adds activated carbon 5g, stirs 15 minutes, be filtered to remove activated carbon, obtain high-purity alpha-one valine solution maximum contaminant under room temperature
Peak 0.2%, total impurities peak 0.8%.Above high-purity alpha-one valine solution quickly stirs down and drips 40%CaCl2Solution 490g
(1.76mol), separate out a large amount of white α-one valine calcium, filter, obtain α-one valine calcium crude product (moisture content about 30%),
Big impurity peaks 0.10%, total impurities peak 0.62%.Above α-one valine calcium crude product adds 2500mL methanol crystallization, filters, dries,
Obtain 232g high-purity alpha-one valine calcium dihydrate, external standard content 99.4%, maximum contaminant peak 0.06%, total impurities peak
0.51%, yield 75.7%.
Embodiment 28: the preparation of high-purity alpha-one valine calcium dihydrate
In carrying churned mechanically 2000mL four-hole bottle, input isopropylidene glycolylurea 280g (2.0mol) under room temperature, 40%
Potassium hydroxide 1120g (8.0mol), Borax 152.5g (0.4mol) control reaction vacuum-0.02MPa, reaction temperature 94～95
Reacting at DEG C, the gas vacuum of generation is extracted out, controls response time 270～360 minutes isopropylidene content less than 1.0%
(HPLC)；Reactant liquor detects, general maximum contaminant peak 0.90%, total impurities peak 2.3%.Reactant liquor is cooled to room temperature, adds
300mL toluene extracts 1 time, layering.Water layer detection maximum contaminant peak 0.80%, total impurities peak 2.0%.Above water layer 730mL
35% hydrochloric acid (8.05mol) adjusts pH value=6.5, obtains extracting 1 with 300mL diisopropyl ether under α-one valine crude product solution room temperature
Secondary, obtain α-one valine solution maximum contaminant peak about 0.70%, total impurities peak about 1.6%.Above α-one valine solution adds
Active hargil 5g, stirs 15 minutes under room temperature, is filtered to remove active hargil, obtains high-purity alpha-one valine solution maximum contaminant
Peak 0.11%, total impurities peak 0.70%.Above high-purity alpha-one valine solution quickly stirs down and drips 40%CaCl2Solution
490g (1.76mol), separates out a large amount of white α-one valine calcium, filters, and (moisture content is about to obtain α-one valine calcium crude product
30%), maximum contaminant peak 0.09%, total impurities peak 0.56%.Above α-one valine calcium crude product adds 2500mL alcohol crystal, mistake
Filter, dry, obtain 241g high-purity alpha-one valine calcium dihydrate, external standard content 99.5%, maximum contaminant peak 0.07%, always
Impurity peaks 0.48%, yield 78.8%.
Comparative example 1: the preparation of high-purity alpha-one isoleucine calcium dihydrate
With in churned mechanically 2000mL there-necked flask, under room temperature, put into sub-sec-butyl glycolylurea 308g (2.0mol),
30% sodium hydroxide 800g (6.0mol), reacts 5 hours at reaction temperature 100～102 DEG C；Reactant liquor detects, maximum contaminant peak
1.7%, total impurities peak 3.7%.Reactant liquor is cooled to room temperature, adjusts pH value=6.5 with 545mL 35% hydrochloric acid (6.02mol),
40%CaCl is dripped under the alpha-keto-leucine solution stirring arrived2Solution 490g (1.76mol), separates out a large amount of white different bright ammonia of α-one
Acid calcium, filters, obtains α-one isoleucine calcium crude product (moisture content about 30%), maximum contaminant peak 1.3%, total impurities peak 2.5%.
Above α-one isoleucine calcium crude product adds 2500mL methanol crystallization, filters, dries, and obtains 206g α-one isoleucine calcium two hydration
Thing, external standard content 98.0%, maximum contaminant peak 0.63%, total impurities peak 1.56%, yield 63.7%.
Comparative example 2: the preparation of high-purity alpha-one valine calcium monohydrate
With in churned mechanically 2000mL there-necked flask, under room temperature, put into isopropylidene glycolylurea 308g (2.0mol),
30% sodium hydroxide 800g (6.0mol), reacts 4.0 hours at reaction temperature 100～102 DEG C.Reactant liquor detects, maximum contaminant
Peak 1.9%, total impurities peak 3.5%.Reactant liquor is cooled to room temperature, adjusts pH value=6.5 with 545mL 35% hydrochloric acid (6.02mol),
40%CaCl is dripped under the α-one valine solution stirring obtained2Solution 490g (1.76mol), separates out a large amount of white α-one figured silk fabrics ammonia
Acid calcium, filters, obtains α-one valine calcium crude product (moisture content about 30%), maximum contaminant peak 1.3%, total impurities peak 2.7%.With
Upper α-one valine calcium crude product adds 2500mL methanol crystallization, filters, dries, and obtains 259.5g α-one valine calcium monohydrate,
External standard content 98.2%, maximum contaminant peak 0.53%, total impurities peak 1.19%, yield 61.7%.
Claims (10)
1. α-one isoleucine calcium dihydrate and a preparation method for α-one valine calcium dihydrate, including walking as follows
Rapid:
1) with sub-sec-butyl glycolylurea or isopropylidene glycolylurea as raw material, tiny structure ring-opening reaction is carried out with the alkali liquor containing buffer,
Obtain corresponding 2-ketoacid salt；
2) by step 1) the 2-ketoacid salt that obtains is first with hydro carbons, halogenated hydrocarbon, ketone or ether solvent abstraction impurity removal, then be acidified
To corresponding 2-ketoacid crude product, and with hydro carbons, halogenated hydrocarbon, ketone or ether solvent abstraction impurity removal, then with activated carbon,
Hargil or resin absorption refined acquisition 2-ketoacid, described 2-ketoacid is α-one isoleucine or α-one valine；
3) by step 2) 2-ketoacid that obtains makes calcium salt, and crystallization obtains alpha-calcium picrolonate dihydrate, described alpha-calcium picrolonate two
Hydrate is α-one isoleucine calcium dihydrate or α-one valine calcium dihydrate；α-one isoleucine dihydrate is corresponding
Raw material be sub-sec-butyl glycolylurea, the raw material that α-one valine dihydrate is corresponding is isopropylidene glycolylurea.
Preparation method the most according to claim 1, it is characterised in that step 1) described in be hydrogen-oxygen containing the alkali liquor of buffer
Change sodium or potassium hydroxide and sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, dibastic sodium phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid
One or more mixed solution in potassium dihydrogen, Borax, glycine.
Preparation method the most according to claim 2, it is characterised in that in the described alkali liquor containing buffer, buffer mole
Amount is 0.01～0.50 times of sodium hydroxide or potassium hydroxide mole.
Preparation method the most according to claim 2, it is characterised in that the mole of described sodium hydroxide or potassium hydroxide is
Sub-sec-butyl glycolylurea or 2.0～4.0 times of isopropylidene glycolylurea mole.
Preparation method the most according to claim 1, it is characterised in that step 1) in, reaction temperature is 90～102 DEG C, very
Reciprocal of duty cycle is-0.030～-0.001MPa.
Preparation method the most according to claim 5, it is characterised in that step 1) in, reaction temperature is 90～95 DEG C, vacuum
Degree is for-0.03～-0.015MPa.
Preparation method the most according to claim 1, it is characterised in that step 2) in, described varsol be normal hexane,
Hexamethylene or toluene；Halogenated hydrocarbon solvent is dichloromethane, dichloroethanes or trichloro ethylene；Ketones solvent is butanone, methyl-prop
Base ketone, methyl isopropyl Ketone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), metacetone, Ketohexamethylene or 1-Phenylethanone.；Ether solvent is
Ether, diisopropyl ether, n-butyl ether, methyl tertiary butyl ether(MTBE) or methyl phenyl ethers anisole.
Preparation method the most according to claim 1, it is characterised in that step 2) in, described acidifying uses mineral acid to enter
OK, described mineral acid is sulphuric acid, hydrochloric acid or phosphoric acid.
Preparation method the most according to claim 1, it is characterised in that step 3) in, described 2-ketoacid uses hydroxide
Calcium or calcium chloride add alkali and make calcium salt, and described alkali is sodium hydroxide or potassium hydroxide.
Preparation method the most according to claim 1, it is characterised in that step 3) use alcohols solvent or alcohols solvent water
Solution crystallizes；Described alcohols solvent is in methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol
One or more mixed solution.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735775A (en) * | 2020-05-30 | 2021-12-03 | 北京福元医药股份有限公司沧州分公司 | Preparation method of alpha-ketovaline calcium and intermediate thereof |
| CN113735776A (en) * | 2020-05-30 | 2021-12-03 | 北京福元医药股份有限公司沧州分公司 | Preparation method of alpha-ketoleucine calcium and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113735775A (en) * | 2020-05-30 | 2021-12-03 | 北京福元医药股份有限公司沧州分公司 | Preparation method of alpha-ketovaline calcium and intermediate thereof |
| CN113735776A (en) * | 2020-05-30 | 2021-12-03 | 北京福元医药股份有限公司沧州分公司 | Preparation method of alpha-ketoleucine calcium and intermediate thereof |
| CN113735775B (en) * | 2020-05-30 | 2023-08-08 | 北京福元医药股份有限公司沧州分公司 | Preparation method of alpha-ketovaline calcium and intermediate thereof |
| CN113735776B (en) * | 2020-05-30 | 2023-09-15 | 北京福元医药股份有限公司沧州分公司 | Preparation method of alpha-ketoleucine calcium and intermediate thereof |
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