CN106518660A - Preparation method of alpha-ketoleucine calcium dihydrate or alpha-ketophenylalanine calcium monohydrate - Google Patents
Preparation method of alpha-ketoleucine calcium dihydrate or alpha-ketophenylalanine calcium monohydrate Download PDFInfo
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Abstract
The invention discloses a preparation method of alpha-ketoleucine calcium dihydrate or alpha-ketophenylalanine calcium monohydrate. In an existing method, the quality of a final product is low, and the content of related substances is high. The method comprises the steps that isobutylidene hydantoin or benzal hydantoin is taken as a raw material and generates a pipeline continuous flow ring-opening reaction with an alcohol-water solution of alkali, and then corresponding alpha-ketoacid salt is obtained, wherein the pipeline continuous flow ring-opening reaction is a continuous ring-opening reaction conducted in a pipeline reactor; the obtained alpha-ketoacid salt is firstly extracted with a hydrocarbon solvent or a halohydrocarbon solvent or a ketone solvent or an ether solvent for impurity removal and then acidized to obtain a corresponding crude alpha-ketonic acid product, the crude alpha-ketonic acid product is extracted with the hydrocarbon solvent or the halohydrocarbon solvent or the ketone solvent or the ether solvent for impurity removal, and then a fine alpha-ketonic acid product is obtained; the obtained alpha-ketonic acid is prepared into calcium salt, crystallization is conducted, and the alpha-ketoacid calcium hydrate is obtained. Accordingly, the high-quality and high-purity alpha-ketoleucine calcium dihydrate and alpha-ketophenylalanine calcium monohydrate are obtained.
Description
Technical field
The present invention relates to the preparation of medical material, specifically a kind of high-purity alpha-keto-leucine-calcium dihydrate or α-
The preparation method of α-Ketophenylalanine Calcium monohydrate.
Background technology
Alpha-keto-leucine-calcium and α-Ketophenylalanine 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 intake of amino nitrogen as far as possible.Ketone group or hydroxyamino acid itself
Amino is not contained, it is aminoacid which utilizes the nitrogen transformation of non essential amino acid, therefore can reduce urea synthesiss, and uremia's toxicity is produced
The accumulation of thing is also reduced.
First, the structural formula of alpha-keto-leucine-calcium is as follows：
The structural formula of alpha-keto-leucine calcium dihydrate is as follows：
Alpha-keto-leucine-calcium mainly has following several synthetic methods at present：
(1) Minoru Igarashi et al. are in J.Org.Chem.1963, and 28 (11)：3088-3092 is proposed with cyanogen second
Acetoacetic ester and isobutylaldehyde are initiation material, and Jing Knoevenagel-Cope reactions are obtained 2- isobutylidene ethyl cyanoacetates, then
Corresponding alpha-keto-leucine is generated through processes such as oxidation, hydrolysis.The initiation material that this route is used be ethyl cyanoacetate, toxicity
It is larger, and reactions steps longer (6 step altogether), complex operation, yield are low；Oxidizing process uses hydrogen peroxide, is unfavorable for safe life
Produce.
(2) Hua Jinxiu et al. exists《Print during chemical industry》2007,21(12)：5-8 is proposed with glycolylurea and isobutylaldehyde as initial former
Material, condensation reaction are obtained 5- isobutylidene glycolylureas, then through hydrolyzing, being acidified, generate the bright ammonia of corresponding α -one into processes such as calcium salts
Sour calcium.Roger Robert Gaudette adopt 5- isobutylidenes glycolylurea for raw material in GB1550993, then through hydrolysis, acid
Change, corresponding alpha-keto-leucine-calcium is generated into processes such as calcium salts.This synthetic route is relatively easy, and reactions steps are shorter, but 5- Asias are different
The hydrolysis difficulty of butyl glycolylurea is big, generally requires 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.At longer reaction times, the impurity of production is more, reacted liquid detection, general maximum contaminant
Peak 1.5% or so, total impurities peak 3.5% or so；The crude product maximum contaminant peak 1% or so for typically resulting in, total impurities peak 2.5% is left
It is right；Jing after refining crystallization, product maximum contaminant peak 0.5%, total impurities peak 1.0%；End product quality is low, and relevant material (has
Close the term that material is crude drug：It is the impurity contained in product) content is higher.
2nd, the structural formula of α-Ketophenylalanine Calcium is as follows：
The structural formula of α-Ketophenylalanine Calcium monohydrate is as follows：
α-Ketophenylalanine Calcium mainly has following several synthetic methods at present：
(1) Minoru Igarashi et al. are in J.Org.Chem.1963, and 28 (11)：3088-3092 is with ethyl cyanoacetate
It is initiation material with benzaldehyde, Jing Knoevenagel-Cope reactions are obtained 2- benzal ethyl cyanoacetates, then through oxygen
The processes such as change, hydrolysis generate corresponding α -one Phenylalanine.The initiation material that this route is used be ethyl cyanoacetate, toxicity compared with
Greatly, and reactions steps longer (6 step altogether), complex operation, yield are low；Oxidizing process uses hydrogen peroxide, is unfavorable for safety in production.
(2) Peng Tao et al. exists《Aminoacid and living resources》2004,26 (1)：39-40 is proposed and with glycolylurea and benzaldehyde is
Initiation material, condensation reaction are obtained 5- benzal glycolylureas, then through hydrolyzing, being acidified, generate corresponding α -one into processes such as sodium salts
L-Phenylalanine sodium.This synthetic route is relatively easy, and reactions steps are shorter, but the hydrolysis difficulty of 5- benzal glycolylureas is big, typically needs
The alkali liquor ability normal reaction of 4-12 times of mole is wanted, and the response time is long, condition is harsh, and hydrolysis yield is low.It is bright with α -one
Propylhomoserin calcium is the same, and at longer reaction times, the impurity of production is more, reacted liquid detection, general maximum contaminant peak 1.5%
Left and right, total impurities peak 3.5% or so；The crude product maximum contaminant peak 1.0% or so for typically resulting in, total impurities peak 2.5% or so；Jing
After refining crystallization, product maximum contaminant peak 0.5%, total impurities peak 1.0%；End product quality is low, relevant material (relevant material
It is the term of crude drug：It is the impurity contained in product) content is higher.
The content of the invention
The technical problem to be solved is the defect for overcoming above-mentioned prior art to exist, there is provided a kind of raw material is easy
, few side reaction, high income, the preparation method of the gentle easily-controllable and suitable large-scale production of environmentally friendly, reaction condition, which makes
With the alcohol-water solution reaction production high-purity alpha -one of pipeline continuous stream reaction technology, isobutylidene glycolylurea or benzal glycolylurea and alkali
Leucine-calcium dihydrate or α-Ketophenylalanine Calcium monohydrate.
For this purpose, the technical solution used in the present invention is as follows：A kind of alpha-keto-leucine calcium dihydrate or α -one Phenylalanine
The preparation method of calcium monohydrate, comprises the steps：
1) with isobutylidene glycolylurea or benzal glycolylurea as raw material, pipeline continuous stream open loop is carried out with the alcohol-water solution of alkali anti-
Should, obtain corresponding 2-ketoacid salt；Described pipeline continuous stream ring-opening reaction refers to that what is carried out in pipeline reactor continuously opens
Ring reacts；
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 obtains corresponding 2-ketoacid crude product, then uses hydro carbons, halogenated hydrocarbon, ketone or ether solvent abstraction impurity removal again, obtains α -one
Sour fine work；
3) by step 2) 2-ketoacid that obtains makes calcium salt, and crystallization obtains alpha-calcium picrolonate hydrate；Described 2-ketoacid is
Alpha-keto-leucine or α -one Phenylalanine；Described alpha-calcium picrolonate hydrate is alpha-keto-leucine calcium dihydrate or α -one phenylpropyl alcohols
Propylhomoserin calcium monohydrate, the wherein corresponding raw material of alpha-keto-leucine calcium dihydrate be isobutylidene glycolylurea, α -one Phenylalanine
The corresponding raw material of calcium monohydrate is benzal glycolylurea.
Further, step 1) in, the alcohol-water solution of the alkali is the alcohol of the alcohol-water solution or potassium hydroxide of sodium hydroxide
Aqueous solution, described alcohol be methanol, ethanol, isopropanol, one or more in normal propyl alcohol.
Further, the alcohol-water solution mass concentration of the alkali is 5～30%, preferably 10～20%；Alkali and sub- isobutyl
The mol ratio of base glycolylurea or benzal glycolylurea is 1：1.0～2.5, preferably 1:1.5～2.0；The reaction temperature that ring-opening reaction is adopted
Spend for 100～160 DEG C, preferably 110～140 DEG C；Gauge is 0～0.8MPa, preferably 0.1～0.5MPa.
Further, described pipeline continuous stream ring-opening reaction is carried out in pipeline reactor, and pipeline reactor is micro- logical
Road reactor or normal size pipeline reactor；The diameter of normal size pipeline reactor is generally 1～100mm；It is preferred to manage
Road reactor diameter be 2～10mm, pipeline reactor by internal structure split, material circulation latus rectum be 1～3mm, pipeline
Reactor changes sectional area shape by multiple feed using mixing, shunting, and fluid eddy flow installs the means such as static mixer additional
Course of reaction reinforcing is carried out, the effect of micro passage reaction is obtained；The reaction pressure of pipeline reactor is gone out by pipeline reactor
The counterbalance valve control of mouth.Pipeline reactor is contacted material selection rustless steel, Hastelloy, nickel, nickel alloy, titanium, titanium and is closed with material
Gold, Yin Kaonaier alloys, impermeable graphite, carborundum etc.；Reactor provides heat, leading portion using steam, conduction oil, electrical heating
For preheating section, rear end is conversion zone, and the reaction temperature of open loop refers to conversion zone temperature.
Further, described isobutylidene glycolylurea or benzal glycolylurea can be pre-mixed with the alcohol-water solution of alkali and be added again
Enter pipeline reactor, it is also possible to which isobutylidene glycolylurea or benzal glycolylurea are separately added into into pipe reaction with the alcohol-water solution of alkali
Device；The alcohol-water solution of isobutylidene glycolylurea or benzal glycolylurea and alkali time of staying in pipeline reactor is 1～60 minute, excellent
The time of staying of choosing is 5～15 minutes.
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 is carried out using mineral acid, described mineral acid be sulphuric acid, hydrochloric acid or
Phosphoric acid.
Further, step 3) in, described 2-ketoacid adds alkali to make calcium salt using calcium hydroxide or calcium chloride, described
Alkali is sodium hydroxide or potassium hydroxide.
Further, step 3) in, described crystallization is using alcohols solvent or the mixed solution of alcohols solvent and water, described
Alcohols solvent be methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, one or more in the tert-butyl alcohol.
Isobutylidene glycolylurea or benzal glycolylurea carry out pipeline continuous stream ring-opening reaction with alkali liquor, obtain corresponding α -one bright
Propylhomoserin sodium or potassium, α -one L-Phenylalanine sodium or nak response liquid.As the response time is short, product departs from reaction system in time,
The destruction of product is little, and impurity content is low.Reactant liquor detection, general maximum contaminant peak 1.0% or so, total impurities peak 2.0% or so.
Alpha-keto-leucine sodium or potassium, α -one L-Phenylalanine sodium or nak response liquid is obtained, and partial impurities is removed with solvent extraction,
After extraction is finished, reactant liquor maximum contaminant peak 0.8% or so, total impurities peak 1.7% or so.
The impurity for extracting removing under above sodium salt and potassium salt state is as follows：
Alpha-keto-leucine sodium or nak response liquid mainly have：
α -one L-Phenylalanine sodium or nak response liquid mainly have：
Above-mentioned impurity poor solubility in water, can be removed with solvent extraction in advance according to different solubility.
It is miscellaneous that the alpha-keto-leucine for obtaining, α -one Phenylalanine crude product solution after acidifying removes part with solvent extraction again
Matter, after the extraction of α -one Phenylalanine crude product solution is finished, maximum contaminant peak 0.1～0.3%, total impurities peak 0.5～1.0%.
The impurity that extracted products are removed under above acid condition：
Alpha-keto-leucine mainly has：
α -one Phenylalanine mainly has：
Above-mentioned impurity dissolubility in water is bigger than product acid, can use solvent extraction product acid according to different solubility, miscellaneous
Matter is stayed in water, so that impurity is removed.
After obtaining highly purified alpha-keto-leucine, α -one Phenylalanine, add alkali into calcium salt, alkali with calcium hydroxide or calcium chloride
Generally sodium hydroxide or potassium hydroxide, filter, obtain alpha-keto-leucine-calcium, α-Ketophenylalanine Calcium crude product, maximum contaminant peak
0.05～0.2%, total impurities peak 0.3～0.7%.
Alcohols solvent or alcohols solvent aqueous crystallization are used after obtaining alpha-keto-leucine-calcium, α-Ketophenylalanine Calcium crude product,
Drying obtains high-purity alpha-keto-leucine-calcium dihydrate, α-Ketophenylalanine Calcium monohydrate, and maximum contaminant peak 0.02～
0.1%, total impurities peak 0.1～0.5%.
The yield of alpha-keto-leucine calcium dihydrate is：73.0～79.5%.
The yield of α-Ketophenylalanine Calcium monohydrate is：85.5～90.5%.
The synthetic route of alpha-keto-leucine-calcium is as follows：
The synthetic route of α-Ketophenylalanine Calcium is as follows：
The invention has the advantages that：
1. by the synergism of alcohol-water solution, alkali consumption is reduced to 1.0-2.5 times of substrate, the alcohol water of alkali when making reaction
Destruction of the alkalescence of solution to raw material, intermediate and product weakens；Promote with reference to the good mixing of micro passage reaction and reaction,
Reaction time is short, the gas (such as ammonia) that abjection reaction in time is generated, and decreases and raw material, intermediate and product are broken
It is bad.Reactant liquor total impurities is reduced to 2.0% or so from conventional 4% or so；Maximum contaminant peak reduces from conventional 2% or so
For 1% or so.
2. after ring-opening reaction terminates, by abstraction impurity removal, the adsorption refining of acid, into the collection of the technique such as calcium salt and calcium salt be refined
Into use, the maximum contaminant peak of product is made to control 0.02～0.1%, total impurities peak control to 0.1～0.5%；Than conventional skill
The maximum contaminant peak 0.5% of art, total impurities peak 1.0% or so are substantially reduced, and obtain high-quality, highly purified alpha-keto-leucine
Calcium dihydrate and α-Ketophenylalanine Calcium monohydrate.
3. the yield of alpha-keto-leucine calcium dihydrate and α-Ketophenylalanine Calcium monohydrate is improved significantly, α -one
The yield of leucine-calcium dihydrate can reach 73.0～79.5%, and routine techniquess are 62% or so；α -one Phenylalanine
The yield of calcium monohydrate can reach 85.5～90.5%, and routine techniquess are 67% or so.
Specific embodiment
Embodiment 1：The preparation of high-purity alpha-keto-leucine-calcium dihydrate
In with churned mechanically 2000mL there-necked flasks, isobutylidene glycolylurea 308g (2.0mol) under room temperature, is put into,
20% sodium hydroxide 800g (4.0mol, water 400g, methanol 240g), first stirs uniformly pulpous state；In the micro- of model MR260
(material in channel reactor：Carborundum；Producer：Dutch Chemtrix BV；With 1 piece of preheating table, 3 pieces of Sptting plate is quenched plate 1
Block, microchannel aperture：2 × 2mm), reactor is noted to the micro passage reaction of MR260 with constant-flux pump with 200 DEG C of heat-conducting oil heatings
Enter the mixing slurry of above-mentioned isobutylidene glycolylurea and 20% sodium hydroxide, control reaction pressure 0.2MPa (gauge pressure), reaction
React at 120～125 DEG C of temperature, feed time about 20 minutes, charging is finished, in plate, material is extruded with nitrogen, during control reaction
Between 12～15 minutes；Reactant liquor detection, maximum contaminant peak 0.9%, total impurities peak 2.1%.Reactant liquor is cooled to room temperature, adds
300mL toluene is extracted 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 under alpha-keto-leucine crude product solution room temperature with 300mL hexamethylene extraction 1
It is secondary, obtain high-purity alpha -one leucine solution maximum contaminant peak 0.2%, total impurities peak 0.6%.Above high-purity alpha-keto-leucine
Solution quickly stirs lower Deca 40%CaCl2Solution 490g (1.76mol), separates out a large amount of white alpha-keto-leucine-calciums, filters, obtain
To alpha-keto-leucine-calcium crude product (moisture content about 30%), maximum contaminant peak 0.15%, total impurities peak 0.45%.The bright ammonia of above α -one
Sour calcium crude product adds 2500mL methanol crystallizations, filters, dries, obtains 255g high-purity alpha-keto-leucine-calcium dihydrates, and external standard contains
Amount 99.4%, maximum contaminant peak 0.08%, total impurities peak 0.41%, yield 76.2%.
Embodiment 10：The preparation of high-purity alpha-keto-leucine-calcium dihydrate
In with churned mechanically 2000mL there-necked flasks, isobutylidene glycolylurea 308g (2.0mol) under room temperature, is put into,
20% potassium hydroxide 1400g (5.0mol, water 1000g, ethanol 120g), first stirs uniformly pulpous state；In model MR260
(material in micro passage reaction：Carborundum；Producer：Dutch Chemtrix BV；With 1 piece of preheating table, 3 pieces of Sptting plate is quenched plate 1
Block, microchannel aperture：2 × 2mm), reactor is noted to the micro passage reaction of MR260 with constant-flux pump with 200 DEG C of heat-conducting oil heatings
Enter the mixing slurry of above-mentioned isobutylidene glycolylurea and 20% potassium hydroxide, control reaction pressure 0.25MPa (gauge pressure), reaction
React at 123～128 DEG C of temperature, feed time about 20 minutes, charging is finished, in plate, material is extruded with nitrogen, during control reaction
Between 10～15 minutes；Reactant liquor detection, maximum contaminant peak 0.85%, total impurities peak 2.0%.Reactant liquor is cooled to room temperature, adds
300mL hexamethylene is extracted 1 time, layering.Water layer detection maximum contaminant peak 0.55%, total impurities peak 1.7%.Above water layer is used
35% hydrochloric acid of 730mL (8.05mol) adjusts pH value=6.5, obtains using 300mL diisopropyl ethers under alpha-keto-leucine crude product solution room temperature
Extraction 1 time, obtains high-purity alpha -one leucine solution maximum contaminant peak 0.18%, total impurities peak 0.5%.Above high-purity alpha -one
Leucine solution adds Ca (OH)2Pressed powder 124.5g (1.68mol) is stirred, and separates out a large amount of white alpha-keto-leucine-calciums, mistake
Filter, obtains alpha-keto-leucine-calcium crude product (moisture content about 30%), maximum contaminant peak 0.12%, total impurities peak 0.43%.Above α-
α-Ketoleucine Calcium crude product adds 2500mL alcohol crystals, filters, dries, obtains 262g high-purity alpha-keto-leucine-calcium dihydrates,
External standard content 99.4%, maximum contaminant peak 0.05%, total impurities peak 0.40%, yield 78.3%.
Embodiment 19：The preparation of high-purity α-Ketophenylalanine Calcium monohydrate
In with churned mechanically 2000mL there-necked flasks, input benzal glycolylurea 308g (2.0mol) under room temperature, 20%
Sodium hydroxide 600g (3.0mol, water 430g, isopropanol 50g), first stirs uniformly pulpous state；In the micro- logical of model MR260
(material in road reactor：Carborundum；Producer：Dutch Chemtrix BV；With 1 piece of preheating table, 3 pieces of Sptting plate is quenched 1 piece of plate,
Microchannel aperture：2 × 2mm), reactor is injected to the micro passage reaction of MR260 with constant-flux pump with 200 DEG C of heat-conducting oil heatings
The mixing slurry of above-mentioned benzal glycolylurea and 20% sodium hydroxide, control reaction pressure 0.2MPa (gauge pressure), reaction temperature
React at 120～125 DEG C, feed time about 20 minutes, charging is finished, material is extruded with nitrogen in plate, control the response time 12
～15 minutes；Reactant liquor detection, maximum contaminant peak 0.8%, total impurities peak 2.0%.Reactant liquor is cooled to room temperature, adds 300mL
Hexamethylene is extracted 1 time, layering.Water layer detection maximum contaminant peak 0.7%, total impurities peak 1.6%.Above water layer 545mL 35%
Hydrochloric acid (6.02mol) adjusts pH value=6.5, obtains being extracted 1 time with 300mL toluene under α -one Phenylalanine crude product solution room temperatures, obtains
To high-purity alpha -one Phe solution maximum contaminant peak 0.3%, total impurities peak 0.7%.Above high-purity alpha -one Phenylalanine
Solution quickly stirs lower Deca 40%CaCl2Solution 516g (1.86mol), separates out a large amount of white α-Ketophenylalanine Calciums, filters,
Obtain α-Ketophenylalanine Calcium crude product (moisture content about 30%), maximum contaminant peak 0.20%, total impurities peak 0.55%.Above α -one
Phenylalanine calcium salt. crude product adds 2500mL methanol crystallizations, filters, dries, obtains one hydration of 328.5g high-purities α-Ketophenylalanine Calcium
Thing, external standard content 99.4%, maximum contaminant peak 0.07%, total impurities peak 0.35%, yield 85.5%.
Embodiment 28：The preparation of high-purity α-Ketophenylalanine Calcium monohydrate
In with churned mechanically 2000mL there-necked flasks, input benzal glycolylurea 308g (2.0mol) under room temperature, 10%
Potassium hydroxide 1400g (2.5mol, water 1110g, normal propyl alcohol 150g), first stirs uniformly pulpous state；In the micro- of model MR260
(material in channel reactor：Carborundum；Producer：Dutch Chemtrix BV；With 1 piece of preheating table, 3 pieces of Sptting plate is quenched plate 1
Block, microchannel aperture：2 × 2mm), reactor is noted to the micro passage reaction of MR260 with constant-flux pump with 200 DEG C of heat-conducting oil heatings
Enter the mixing slurry of above-mentioned benzal glycolylurea and 10% potassium hydroxide, control reaction pressure 0.25MPa (gauge pressure), reaction temperature
React at 123～128 DEG C of degree, feed time about 20 minutes, charging is finished, material is extruded with nitrogen in plate, control the response time
13～18 minutes；Reactant liquor detection, maximum contaminant peak 0.80%, total impurities peak 2.2%.Reactant liquor is cooled to room temperature, adds
300mL hexamethylene is extracted 1 time, layering.Water layer detection maximum contaminant peak 0.65%, total impurities peak 1.8%.Above water layer is used
35% hydrochloric acid of 730mL (8.05mol) adjusts pH value=6.5, obtains using 300mL isopropyls under α -one Phenylalanine crude product solution room temperatures
Ether is extracted 1 time, obtains high-purity alpha -one Phe solution maximum contaminant peak 0.20%, total impurities peak 0.7%.Above high-purity
α -one Phe solution adds Ca (OH)2Pressed powder 138g (1.865mol), stirring is lower to separate out a large amount of white α -one phenylpropyl alcohols
Propylhomoserin calcium, filters, obtains α-Ketophenylalanine Calcium crude product (moisture content about 30%), maximum contaminant peak 0.11%, total impurities peak
0.47%.Above α-Ketophenylalanine Calcium crude product adds 2500mL alcohol crystals, filters, dries, obtains 340.5g high-purity alpha -one
Phenylalanine calcium salt. monohydrate, external standard content 99.3%, maximum contaminant peak 0.06%, total impurities peak 0.39%, yield 88.6%.
Comparative example 1：The preparation of high-purity alpha-keto-leucine-calcium dihydrate
In with churned mechanically 2000mL there-necked flasks, isobutylidene glycolylurea 308g (2.0mol) under room temperature, is put into,
30% sodium hydroxide 800g (6.0mol), reacts 3 hours at 100～102 DEG C of reaction temperature；Reactant liquor detection, maximum contaminant peak
1.6%, total impurities peak 3.7%.Reactant liquor is cooled to room temperature, adjusts pH value=6.5 with 35% hydrochloric acid of 545mL (6.02mol), obtains
Deca 40%CaCl under the alpha-keto-leucine solution stirring for arriving2Solution 490g (1.76mol), separates out a large amount of white alpha-keto-leucines
Calcium, filters, obtains alpha-keto-leucine-calcium crude product (moisture content about 30%), maximum contaminant peak 1.2%, total impurities peak 2.6%.More than
Alpha-keto-leucine-calcium crude product adds 2500mL methanol crystallizations, filters, dries, obtains 206g alpha-keto-leucine calcium dihydrates, external standard
Content 98.5%, maximum contaminant peak 0.51%, total impurities peak 1.13%, yield 61.6%.
Comparative example 2：The preparation of high-purity α-Ketophenylalanine Calcium monohydrate
In with churned mechanically 2000mL there-necked flasks, input benzal glycolylurea 308g (2.0mol) under room temperature, 30%
Sodium hydroxide 800g (6.0mol), reacts 3.5 hours at 100～102 DEG C of reaction temperature.Reactant liquor detection, maximum contaminant peak
1.7%, total impurities peak 3.6%.Reactant liquor is cooled to room temperature, adjusts pH value=6.5 with 35% hydrochloric acid of 545mL (6.02mol), obtains
Lower Deca 40%CaCl of α -one Phe solution stirring for arriving2Solution 490g (1.76mol), separates out a large amount of white α -one phenylpropyl alcohols
Propylhomoserin calcium, filters, obtains α-Ketophenylalanine Calcium crude product (moisture content about 30%), maximum contaminant peak 1.2%, total impurities peak
2.6%.Above α-Ketophenylalanine Calcium crude product adds 2500mL methanol crystallizations, filters, dries, obtains 259.5g α -one Phenylalanine
Calcium monohydrate, external standard content 98.4%, maximum contaminant peak 0.50%, total impurities peak 1.09%, yield 67.5%.
Claims (10)
1. the preparation method of a kind of alpha-keto-leucine calcium dihydrate or α-Ketophenylalanine Calcium monohydrate, walks including following
Suddenly：
1) with isobutylidene glycolylurea or benzal glycolylurea as raw material, pipeline continuous stream ring-opening reaction is carried out with the alcohol-water solution of alkali,
Obtain corresponding 2-ketoacid salt；Described pipeline continuous stream ring-opening reaction refers to that the continuous open loop carried out in pipeline reactor is anti-
Should；
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, hydro carbons, halogenated hydrocarbon, ketone or ether solvent abstraction impurity removal is then used again, 2-ketoacid essence is obtained
Product；
3) by step 2) 2-ketoacid that obtains makes calcium salt, and crystallization obtains alpha-calcium picrolonate hydrate；Described 2-ketoacid is α -one
Leucine or α -one Phenylalanine；Described alpha-calcium picrolonate hydrate is alpha-keto-leucine calcium dihydrate or α -one Phenylalanine
Calcium monohydrate, the wherein corresponding raw material of alpha-keto-leucine calcium dihydrate be isobutylidene glycolylurea, α-Ketophenylalanine Calcium one
The corresponding raw material of hydrate is benzal glycolylurea.
2. preparation method according to claim 1, it is characterised in that step 1) in, the alcohol-water solution of the alkali is hydrogen-oxygen
Change the alcohol-water solution of the alcohol-water solution or potassium hydroxide of sodium, described alcohol is methanol, ethanol, isopropanol, the one kind in normal propyl alcohol
Or it is various.
3. preparation method according to claim 2, it is characterised in that step 1) in, the alcohol-water solution quality of the alkali is dense
Spend for 5～30%, alkali is 1 with the mol ratio of isobutylidene glycolylurea or benzal glycolylurea：1.0～2.5, it is anti-that ring-opening reaction is adopted
Temperature is answered for 100～160 DEG C, gauge is 0～0.8MPa.
4. preparation method according to claim 3, it is characterised in that the alcohol-water solution mass concentration of the alkali is 10～
20%, alkali is 1 with the mol ratio of isobutylidene glycolylurea or benzal glycolylurea:1.5～2.0, the reaction temperature that ring-opening reaction is adopted
For 110～140 DEG C；Gauge is 0.1～0.5MPa.
5. preparation method according to claim 1, it is characterised in that described pipeline continuous stream ring-opening reaction is anti-in pipeline
Carry out in answering device, pipeline reactor is micro passage reaction or normal size pipeline reactor；Normal size pipeline reactor
A diameter of 1～100mm, normal size pipeline reactor by internal structure split, material circulation latus rectum be 1～3mm, pipeline
Reactor changes sectional area shape by multiple feed using mixing, shunting, and fluid eddy flow installs static mixer means additional and enters
Row course of reaction is strengthened, and obtains the effect of micro passage reaction.
6. preparation method according to claim 1, it is characterised in that step 1) in, described isobutylidene glycolylurea or Asia
Benzyl glycolylurea is pre-mixed with the alcohol-water solution of alkali and adds pipeline reactor, or will be isobutylidene glycolylurea or benzal extra large
Because the alcohol-water solution with alkali is separately added into pipeline reactor；The alcohol-water solution of isobutylidene glycolylurea or benzal glycolylurea and alkali is in pipe
In road reactor, the time of staying is 1～60 minute.
7. preparation method 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.
8. preparation method according to claim 1, it is characterised in that step 2) in, described acidifying is entered using mineral acid
OK, described mineral acid is sulphuric acid, hydrochloric acid or phosphoric acid.
9. preparation method according to claim 1, it is characterised in that step 3) in, described 2-ketoacid uses hydroxide
Calcium or calcium chloride add alkali to make calcium salt, and described alkali is sodium hydroxide or potassium hydroxide.
10. preparation method according to claim 1, it is characterised in that step 3) adopt alcohols solvent or alcohols solvent with
The mixed solution of water is crystallized；Described alcohols solvent is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, uncle
One or more in butanol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824531A (en) * | 2019-04-02 | 2019-05-31 | 禄丰天宝磷化工有限公司 | A method of continuous quickly preparation DL- phenylglycine and the like |
| CN110627638A (en) * | 2019-09-25 | 2019-12-31 | 福安药业集团重庆博圣制药有限公司 | Method for preparing ketoleucine calcium hydrate by one-step method and application thereof |
| CN117229139A (en) * | 2023-09-12 | 2023-12-15 | 河北天成药业股份有限公司 | Preparation method of sodium ketophenylalanine and calcium ketophenylalanine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607888A (en) * | 2009-07-23 | 2009-12-23 | 河北九派制药有限公司 | The preparation method of alpha-keto-leucine-calcium |
| CN102030631A (en) * | 2010-12-03 | 2011-04-27 | 浙江新和成股份有限公司 | Method for synthesizing alpha-ketoleucine calcium |
| CN102584570A (en) * | 2012-01-30 | 2012-07-18 | 浙江新和成股份有限公司 | Alpha-ketone-benzol lactamine calcium- hydrate crystal and preparation method thereof |
| CN102617331A (en) * | 2012-01-30 | 2012-08-01 | 浙江新和成股份有限公司 | Alpha-ketoleucine calcium dihydrate crystal and preparation method thereof |
| CN103193628A (en) * | 2013-04-26 | 2013-07-10 | 河北九派制药股份有限公司 | Alpha-ketophenylalanine calcium preparation method |
-
2016
- 2016-09-28 CN CN201610859260.3A patent/CN106518660A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607888A (en) * | 2009-07-23 | 2009-12-23 | 河北九派制药有限公司 | The preparation method of alpha-keto-leucine-calcium |
| CN102030631A (en) * | 2010-12-03 | 2011-04-27 | 浙江新和成股份有限公司 | Method for synthesizing alpha-ketoleucine calcium |
| CN102584570A (en) * | 2012-01-30 | 2012-07-18 | 浙江新和成股份有限公司 | Alpha-ketone-benzol lactamine calcium- hydrate crystal and preparation method thereof |
| CN102617331A (en) * | 2012-01-30 | 2012-08-01 | 浙江新和成股份有限公司 | Alpha-ketoleucine calcium dihydrate crystal and preparation method thereof |
| CN103193628A (en) * | 2013-04-26 | 2013-07-10 | 河北九派制药股份有限公司 | Alpha-ketophenylalanine calcium preparation method |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824531A (en) * | 2019-04-02 | 2019-05-31 | 禄丰天宝磷化工有限公司 | A method of continuous quickly preparation DL- phenylglycine and the like |
| CN110627638A (en) * | 2019-09-25 | 2019-12-31 | 福安药业集团重庆博圣制药有限公司 | Method for preparing ketoleucine calcium hydrate by one-step method and application thereof |
| CN110627638B (en) * | 2019-09-25 | 2022-05-27 | 福安药业集团重庆博圣制药有限公司 | Method for preparing ketoleucine calcium hydrate by one-step method and application thereof |
| CN117229139A (en) * | 2023-09-12 | 2023-12-15 | 河北天成药业股份有限公司 | Preparation method of sodium ketophenylalanine and calcium ketophenylalanine |
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