CN106045843B - The production technology of racemic ketoprofen isoleucine calcium - Google Patents
The production technology of racemic ketoprofen isoleucine calcium Download PDFInfo
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- CN106045843B CN106045843B CN201610430679.7A CN201610430679A CN106045843B CN 106045843 B CN106045843 B CN 106045843B CN 201610430679 A CN201610430679 A CN 201610430679A CN 106045843 B CN106045843 B CN 106045843B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
Abstract
The production technology of racemic ketoprofen isoleucine calcium, belong to the technical field of pharmaceutical synthesis, the preparation of preparation, racemic ketoprofen isoleucine calcium crude product including 2- butylidene glycolylurea and the purification of racemic ketoprofen isoleucine calcium crude product, it is reacted using glycolylurea with butanone and generates 2- butylidene glycolylurea, 2- butylidene glycolylurea, at salt, then is recrystallized to give racemic ketoprofen isoleucine calcium using sodium hydroxide hydrolysis and calcium chloride water.This simple production process, easy to operate, production cost is low, high income, the racemic ketoprofen isoleucine calcium purity is high of production.
Description
Technical field
The invention belongs to the technical fields of pharmaceutical synthesis, are related to forming for racemic ketoprofen isoleucine calcium, and in particular to racemization
The production technology of ketone isoleucine calcium.
Background technique
Racemic ketoprofen isoleucine calcium is one of the main component of α keto acid compound (opening same).2-ketoacid and its derivative exist
Food, daily use chemicals and medicine etc. show increasingly wide application prospect.In food applications, sport nutrition drink can be used as
The ingredient of material；In functional form skin protection cosmetics, good moisturizing, wrinkle resistant, shrinkproof, anti-aging and anti-allergic effects can be played.
In medical applications, α keto acid compound can treat damage caused by due to chronic renal insufficiency, and can be used as treatment uremic
The specific drug of disease.Patients with renal failure takes α keto acid compound, and cooperates low protein diet, can reduce the high filter of glomerulus
It crosses, the protection nephron can reduce symptom, delay disease progression to light, Moderate Chronic Renal Failure patient；To severe chronic
Patients with renal failure can then improve its malnutritive situation, be the substitute of corresponding amino acid.
The synthesis of racemic ketoprofen isoleucine calcium is mainly the following method: route 1 is using grignard reagent and oxalic acid diethyl
Ester reaction, then by ester at calcium salt, this method yield is higher, but severe reaction conditions, need anhydrous, high-purity nitrogen (argon) atmosphere and
Cryogenic conditions, especially lower low temperature are more difficult to control in industrial conditions.Route 2 is to use uncle using l-Isoleucine as raw material
Butanol chlorine and catalyst DBU reaction, generate imines, then after imines is hydrolyzed into carbonyl, hydrolysis generates ketone acid under alkaline condition.
This route also faces the relatively high problem of cost.Route 3 uses 2-Methyl Butyric Acid to generate 3- first for raw material result two-step reaction
Base -2- oxopentanoic, ester can be directly at calcium salts.It is relatively more that the shortcomings that this route, lies also in reaction raw materials, is unfavorable for
Atom economy, cannot efficiently use raw material, and high expensive negatively affects environment larger.
Summary of the invention
The present invention is to solve synthesising racemation ketone isoleucine calcium in the prior art to be difficult to control, at high cost, is born to environment
Face rings big problem, provides a kind of production production technology of racemic ketoprofen isoleucine calcium, simple production process of the present invention, easily
Operation, at low cost, yield is good.
The present invention be realize its purpose the technical solution adopted is that:
The production technology of racemic ketoprofen isoleucine calcium, preparation, racemic ketoprofen isoleucine calcium including 2- butylidene glycolylurea are thick
The preparation of product and the purification of racemic ketoprofen isoleucine calcium crude product, comprising the following steps:
A, the preparation of 2- butylidene glycolylurea: glycolylurea, water, butanone being mixed, heat temperature raising, to realize monoethanolamine institute band
Amino preferably has whole properties of primary amine, and the hydroxyl of institute's band makes it play preferable affine energy with the aldehyde radical in reactant
Power is heated to 50-70 DEG C so that condensation reaction be promoted to be easier to occur, and monoethanolamine is added, monoethanolamine, which reaches, preferably urges
Change effect, reacts in order to prevent excessively acutely, monoethanolamine is added using dropwise addition mode, continues to be heated to flowing back, to reaction solution
After clarification, stop heating, be cooled to room temperature, solid is precipitated, filtering, drying obtain 2- butylidene glycolylurea；
B, the preparation of racemic ketoprofen isoleucine calcium crude product: 2- butylidene glycolylurea is mixed with sodium hydroxide solution, and reflux is anti-
Answer, after 2- butylidene glycolylurea is completely dissolved, stops heating, be cooled to room temperature, adjust pH value to 0.5-1.5, adjust pH value to
The purpose of 0.5-1.5 is to remove excessive sodium hydroxide, and solid is precipitated completely from reaction solution, ethyl acetate is added to extract, adds
Active carbon decoloring, filtering, the dropwise addition anhydrous calcium chloride aqueous solution into filtrate, precipitation solid, 30-35 DEG C of isothermal holding 4-5h, by
Quickly in calcium precipitation speed, if calcium chloride excessive velocities are added dropwise, generation precipitation particles diameter is too small, is not easy to filter, thus
Influence product yield.The present invention uses 30-35 DEG C of isothermal holding 4-5h, and the ideal white solid of particle granules size can be obtained,
Guarantee that racemic ketoprofen isoleucine calcium is precipitated from solution as far as possible.It is too high or too low for temperature all to influence product yield；Reaction
To 4-5h, racemic ketoprofen isoleucine calcium is almost precipitated, and the time extends little to calcium salt precipitation benefit.Then by filtering,
Washing, drying, obtain racemic ketoprofen isoleucine calcium crude product；
C, the purification of racemic ketoprofen isoleucine calcium crude product: racemic ketoprofen isoleucine calcium crude product is dissolved in water, through acetone or second
Alcohol recrystallization, obtains racemic ketoprofen isoleucine calcium.
In step A, glycolylurea, butanone, monoethanolamine molar ratio be 1:(1.4-1.6): (0.9-1.1).
In step A, it is heated to 75-80 DEG C of back flow reaction 5-7h.It is 75-80 DEG C that the present invention, which controls reflux temperature, makes a second
Hydramine reaches optimal catalytic activity reaction rate and increases, and the reaction time shortens.
In step B, sodium hydroxide solution is in terms of sodium hydrate solid, mole of 2- butylidene glycolylurea and sodium hydrate solid
Than for 1:(2.5-3.5).
In step B, the temperature of back flow reaction is 95-105 DEG C, reaction time 5-7h.
In step B, for anhydrous calcium chloride aqueous solution in terms of anhydrous calcium chloride solid, 2- butylidene glycolylurea and anhydrous calcium chloride are solid
The molar ratio of body is 1:(0.2-0.4), to make ketone acid sodium salt completely by CaCl2Displacement generates calcium picrolonate, anhydrous calcium chloride dosage
It is very few, reaction yield is influenced, dosage is excessive, causes the waste of anhydrous calcium chloride, therefore finally use 2- butylidene glycolylurea and nothing
The molar ratio of water calcium chloride solid is 1:(0.2-0.4) it is optimum response object molar ratio, it is best at salt effect.
In step B, when washing, washed using methanol.
In step C, water is heated to 60-75 DEG C, is added racemic ketoprofen isoleucine calcium crude product, insulated and stirred is to complete
It is molten, active carbon decoloring is added, filters while hot, acetone or alcohol is added in filtrate, and it stirs and is cooled to 5-10 DEG C, standing crystallization 8-
10h, filtering, primary drying, sieving, redrying obtain racemic ketoprofen isoleucine calcium.Through studying, using the change of redrying
The precipitation method are learned, select suitable digestion time, drying temperature, it is ensured that the racemization structure of racemic ketoprofen isoleucine calcium obtains height
The quality product of density is suitable for industrialized production.
Primary drying and the drying temperature of redrying are 30-50 DEG C, and the time of primary drying is 10-12h, secondary dry
The dry time is 20-24h.
The beneficial effects of the present invention are:
1, the purity of racemic ketoprofen isoleucine calcium of the present invention reaches 99.5% or more, and calcium content reaches 13.22-13.7%,
Total recovery reaches 50% or more.
2, production technology reaction condition of the invention is mild, and device simple is easy to operate, and productivity is high, and purity is good, cost
Low, environmental hazard is low, is suitble to industrialized production.Singly miscellaneous≤0.1%, always miscellaneous≤0.5%, residual solvent≤0.1%, heavy metal≤
7ppm meets State Food and Drug Administration standard YBH03302011.Than the racemic ketoprofen isoleucine of prior art production
Calcareous amount control is tightened up, and quality is more stable.
3, the present invention is by by glycolylurea: butanone: monoethanolamine molar ratio controls as 1:(1.4-1.6): (0.9-1.1), it can
The yield of 2- butylidene glycolylurea is improved, the present invention improves the dosage of butanone, while reducing the dosage of monoethanolamine, so that reaching
Control ratio of the invention had not only improved yield but also energy save the cost.
4, the present invention is additionally arranged 30-35 DEG C of insulated and stirred 4h's in the preparation process of racemic ketoprofen isoleucine calcium crude product
Processing, quickly due to calcium precipitation speed, if calcium chloride excessive velocities are added dropwise, generation precipitation particles diameter is too small, is not easy
Filter, to influence product yield.The present invention uses 30-35 DEG C of isothermal holding 4h, and it is preferably white that particle granules size can be obtained
Solid guarantees that racemic ketoprofen isoleucine calcium is precipitated from solution as far as possible.It is too high or too low for temperature all to influence product yield；
To 4h, racemic ketoprofen isoleucine calcium is almost precipitated for reaction, and the time extends little to calcium salt precipitation benefit.
5, in subtractive process, the temperature of primary drying of the present invention and redrying only needs 30-50 DEG C, drying temperature
Far smaller than existing drying temperature, through studying, using the chemical precipitation method of redrying, dry twice by strict control
Time, drying temperature can influence the variation of product crystal structure and density.The present invention uses 5-10 DEG C of standing crystallization 8h, mistake
The drying temperature of filter, primary drying, sieving, redrying, primary drying and redrying is 30-50 DEG C, available crystalline substance
Body structural integrity, highdensity quality product.It can guarantee the racemization structure of racemic ketoprofen isoleucine calcium simultaneously, be suitable for industrialization
Production.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below.
Embodiment 1
A, Zhong Ding pitches the preparation of glycolylurea (2- butylidene glycolylurea)
Glycolylurea 9.6kg (96mol), 19.2kg water and butanone 10.4kg (144.4mol) are added in reaction kettle, stirs, is in
White casse liquid.It is heated to 50-70 DEG C (preferably 55-65 DEG C), is added monoethanolamine 5.86kg (96mol).Slowly it is heated to back
It flows, white solid is gradually dissolved to clarification in reaction solution.In 75-80 DEG C of back flow reaction 5-7h (preferably 78 DEG C of back flow reaction 6h),
(GF is detected through thin-layer chromatography254Thin layer silica gel plate: RfZhong Ding fork=0.62；RfGlycolylureaIodine is smoked almost without point at=0.32；Solvent:
CHCl3: MeOH=5:1), glycolylurea raw material disappears, and stops heating.It is cooled to room temperature, solid is precipitated.Filtering, by filter cake 16kg
Purified water, which is stirred, washes, and is filtered dry, and 60 DEG C of vacuum drying 8h obtain off-white powder 11.14kg, yield 75.4%.Through analysis detection, Zhong Ding
Pitch HPLC purity >=95% of glycolylurea.
B, the preparation of racemic ketoprofen isoleucine calcium (α -one base-Beta-methyl valeric acid calcium) crude product
It weighs 8.64kg sodium hydroxide (216mol) and 34.56kg purified water adds in reaction kettle, stirring and dissolving.It is added secondary
Fourth pitches glycolylurea (2- butylidene glycolylurea) 11.1kg (72mol), and steam is to warm, in (preferably 100 DEG C of 95-105 DEG C of back flow reaction 5-7h
Back flow reaction 6h), increase the return time of intermediate 2- butylidene glycolylurea and sodium hydroxide, the hydrolysis of glycolylurea intermediate can be made more
Completely, product yield is improved.Completely to the hydrolysis of Zhong Ding fork glycolylurea raw material, stop heating, detect (GF through thin-layer chromatography254Silica gel
Plate: RfProduct=0.22；RfZhong Ding forkAlmost without point at=0.66；Solvent: CHCl3: MeOH=5:1).It is cooled to room temperature, under cooling
With concentrated hydrochloric acid tune pH value to 1, add 50kg ethyl acetate to extract, add 280g activity carbon decoloring 15min, filters.By the anhydrous chlorine of 2.4kg
The solution for changing calcium (21.6mol)/6kg water, slowly instills in above-mentioned filtrate at room temperature, and solid is precipitated, and heat preservation is stirred in 30-35 DEG C
4-5h (preferably 4.2-4.7h).Filtering, is washed twice with the methanol of 12L × 2.In 60 DEG C of forced air drying about 6h after filtering, micro- Huang is obtained
Color solid 5.5kg, crude yield 85.4%.(GF is detected through thin-layer chromatography254Silica gel plate: RfProduct=0.23；Solvent: CHCl3:
MeOH=5:1).
C, the purification of racemic ketoprofen isoleucine calcium
66kg purified water is added in dissolution kettle, stirs and is heated to 60-75 DEG C (preferably 68-72 DEG C).It is added
400g active carbon is added in 5.5kg racemic ketoprofen isoleucine calcium crude product, insulated and stirred to Quan Rong, and decolourize 30min.Refined filtration while hot
(0.45μm).Filtrate enters in crystallization kettle, and acetone 170kg recrystallization is added, and stirs and cooling, 5-10 DEG C of standing crystallization 8-10h
(preferably 6-9 DEG C standing crystallization 8.5-9.5h).Filtering, through 30-50 DEG C of vacuum drying 10-12h (preferably 40 DEG C vacuum drying
10h), 20 meshes are crossed, continue to be dried in vacuo 20h obtaining racemic ketoprofen isoleucine calcium 4.3kg, yield: 78.2%, through analysis detection,
HPLC purity 99.6% (Rezex ROA-Organic 300 × 7.80mm of Acid, mobile phase: 0.0025mol/L sulfuric acid solution,
λ=205nm, 30 DEG C of column temperature), every quality index meets medicinal standard.
Total recovery is 75.4% × 85.4% × 78.2%=50.35%
Embodiment 2
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.4:0.9, yield 74.3%.
In step B, the molar ratio of 2- Aden glycolylurea and sodium hydrate solid is 1:3.5,2- Aden glycolylurea and anhydrous chlorine
The molar ratio for changing calcium solid is 1:0.2, obtains yellowish solid, yield 85.1%.
In step C, water is heated to 60 DEG C, yield: 77.8%, through analysis detection, HPLC purity 99.7%.
Total recovery is 74.3% × 85.1% × 77.8%=49.19%.
Embodiment 3
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.5:0.9, yield 75.3%.
In step B, the molar ratio of 2- Aden glycolylurea and sodium hydrate solid is 1:2.5,2- Aden glycolylurea and anhydrous chlorine
The molar ratio for changing calcium solid is 1:0.2, obtains yellowish solid, yield 84.2%.
In step C, water is heated to 75 DEG C, yield: 78.7%, through analysis detection, HPLC purity 99.6%.
Total recovery is 75.3% × 84.2% × 78.7%=49.90%.
Embodiment 4
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.6:0.9, yield 75.9%.
In step B, the molar ratio of 2- Aden glycolylurea and sodium hydrate solid is 1:3.5,2- Aden glycolylurea and anhydrous chlorine
The molar ratio for changing calcium solid is 1:0.4, obtains yellowish solid, yield 85.7%.
In step C, water is heated to 60 DEG C, 95% ethyl alcohol 66kg recrystallization is added, yield: 77.1%, through dividing
Analysis detection, HPLC purity 99.7%.
Total recovery is 75.9% × 85.7% × 77.1%=50.15%.
Embodiment 5
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.4:1.1, yield 74.3%.
In step B, the molar ratio of 2- Aden glycolylurea and sodium hydrate solid is 1:2.5,2- Aden glycolylurea and anhydrous chlorine
The molar ratio for changing calcium solid is 1:0.4, obtains yellowish solid, yield 84.8%.In step C, water is heated to 60 DEG C,
95% ethyl alcohol 66kg recrystallization is added, yield: 78.0%, through analysis detection, HPLC purity 99.6%.
Total recovery is 74.3% × 84.8% × 78.0%=49.14%.
Embodiment 6
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.5:1.1, yield 75.5%.
In step C, water is heated to 75 DEG C, 95% ethyl alcohol 66kg recrystallization is added, yield: 85.1%, through dividing
Analysis detection, HPLC purity 99.7%.
Total recovery is 75.5% × 85.4% × 85.1%=50.42%.
Embodiment 7
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.6:1.1, yield 76.4%.
Total recovery is 76.4% × 85.4% × 78.2%=51.02%.
Embodiment 8
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.4:1, yield 75.2%.
Total recovery is 75.2% × 85.4% × 78.2%=50.22%.
Embodiment 9
It is substantially the same manner as Example 1, but have following change:
In step A, glycolylurea: butanone: the molar ratio of monoethanolamine is 1:1.6:1, yield 76.2%.
Total recovery is 76.2% × 85.4% × 78.2%=50.89%.
Comparative example 1
(1) synthesis of isobutyl group glycolylurea intermediate
Glycolylurea 10g (0.1mol) is added 12ml water and is heated with stirring to 60 DEG C of addition butanone 9.37g (0.13mol), and second is added dropwise
Hydramine 4.8g (0.08mol), drop, which finishes, is stirred to react 4h in 80 DEG C, cools down after reaction, with concentrated hydrochloric acid tune pH=4, is precipitated solid
Body, filtering, is washed with distilled water and dries, and obtains 9.4g, yield 61%, elemental analysis qualification.
(2) α -one base-Beta-methyl valeric acid calcium salt synthesis
It takes intermediate 15.4g (0.1mol) and 20% mass than NaOH solution 100g, is heated to reflux 2h, 110 DEG C, reaction is tied
Shu Houyong concentrated hydrochloric acid tune pH=5, cold filtration remove solid, and filtrate decompression is concentrated to dryness, and 150ml anhydrous methanol is added and heats back
1h is flowed, is filtered while hot, filtrate decompression is concentrated to dryness, and 20ml distilled water is added, by 5.6g (0.05mol) calcium chloride and 10ml water group
At solution slowly instilled under cooling, white solid is precipitated, filtering and is washed with a small amount, is dried to obtain α -one base-β-first
Base valeric acid calcium salt crude product 5.3g, then vacuum drying oven is put into after ethyl alcohol recrystallization, 75-80 DEG C of drying obtains α -one base-Beta-methyl
Valeric acid calcium salt finished product 4.5g.Yield 30.2%, elemental analysis are qualified.
The total recovery of comparative example 1 is 61% × 30.2%=18.422%, and total recovery is very low, through analysis detection,
HPLC purity 90.2-93%.
Comparative example 2
A kind of preparation method of racemic ketoprofen isoleucine calcium, be characterized in that the following steps are included:
A. in the alcoholic solution of metal alkoxide, dialkyl oxalate is added, drips off heat preservation half an hour；
B. heat preservation finishes, and 2 methyl butyraldehyde is added, and drips off heat preservation half an hour；
C. lye is added at not higher than 25 DEG C, adds heat preservation 0.5-10 hours；
D. after keeping the temperature, acid is added, adjusts pH to 1.0-4.0, organic solvent extraction is added；
E. merge organic phase, add water, dilute adjusting PH with base is added to 5-7, layering, organic phase, which adds water, adjusts pH to 5-7, merges water
Phase.Dilute adjusting PH with base is added to 8-9 in water phase, and calcium chloride water is added into calcium salt, keeps the temperature 1-3 hours, cooling centrifugation obtains racemic ketoprofen
Isoleucine calcium；
F. racemic ketoprofen isoleucine calcium crude product is dissolved in the purified water of 7-15 times of weight, then 0-0.8 times of purified water is added dropwise
The organic solvent of weight, purification, obtains racemic ketoprofen isoleucine calcium highly finished product, purity 99.5%.
Comparative example 2 is reacted using dialkyl oxalate, this method total recovery is higher, but cost of material is high, and condition is severe
It carves, needs low temperature, anhydrous, oxygen free condition, be solvent with ether, be not suitable for industrial production.
Claims (7)
1. the production technology of racemic ketoprofen isoleucine calcium, preparation, racemic ketoprofen isoleucine calcium crude product including 2- butylidene glycolylurea
Preparation and racemic ketoprofen isoleucine calcium crude product purification, which comprises the following steps:
A, the preparation of 2- butylidene glycolylurea: glycolylurea, water, butanone are mixed, 50-70 DEG C is heated to, is added one using dropwise addition mode
Ethanol amine continues to be heated to flowing back, and after reaction solution clarification, stops heating, is cooled to room temperature, solid is precipitated, and filters, is dry,
Obtain 2- butylidene glycolylurea；
B, the preparation of racemic ketoprofen isoleucine calcium crude product: 2- butylidene glycolylurea being mixed with sodium hydroxide solution, back flow reaction, to
After 2- butylidene glycolylurea is completely dissolved, stops heating, be cooled to room temperature, adjusts pH value to 0.5-1.5, add ethyl acetate to extract, add
Anhydrous calcium chloride aqueous solution is added dropwise into filtrate for active carbon decoloring, filtering, and solid is precipitated, is then filtered, washed, 30-35
DEG C isothermal holding 4-5h, obtains racemic ketoprofen isoleucine calcium crude product；
C, the purification of racemic ketoprofen isoleucine calcium crude product: racemic ketoprofen isoleucine calcium crude product is dissolved in water, through acetone or alcohol weight
Crystallization, obtains racemic ketoprofen isoleucine calcium；
In step C, water is heated to 60-75 DEG C, racemic ketoprofen isoleucine calcium crude product is added, insulated and stirred to Quan Rong adds
Entering active carbon decoloring, filters while hot, acetone or alcohol is added in filtrate, and it stirs and is cooled to 5-10 DEG C, standing crystallization 8-10h, mistake
Filter, primary drying, sieving, redrying obtain racemic ketoprofen isoleucine calcium；Primary drying and the drying temperature of redrying are equal
It is 30-50 DEG C, the time of primary drying is 10-12h, and the time of redrying is 20-24h.
2. the production technology of racemic ketoprofen isoleucine calcium according to claim 1, it is characterised in that: in step A, glycolylurea,
Butanone, monoethanolamine molar ratio be 1:(1.4-1.6): (0.9-1.1).
3. the production technology of racemic ketoprofen isoleucine calcium according to claim 1, it is characterised in that: in step A, be heated to
75-80 DEG C of back flow reaction 5-7h.
4. the production technology of racemic ketoprofen isoleucine calcium according to claim 1, it is characterised in that: in step B, hydroxide
For sodium solution in terms of sodium hydrate solid, the molar ratio of 2- butylidene glycolylurea and sodium hydrate solid is 1:(2.5-3.5).
5. the production technology of racemic ketoprofen isoleucine calcium according to claim 1, it is characterised in that: in step B, reflux is anti-
The temperature answered is 95-105 DEG C, reaction time 5-7h.
6. the production technology of racemic ketoprofen isoleucine calcium according to claim 1, it is characterised in that: in step B, anhydrous chlorine
Change calcium aqueous solution in terms of anhydrous calcium chloride solid, the molar ratio of 2- butylidene glycolylurea and anhydrous calcium chloride solid is 1:(0.2-
0.4)。
7. the production technology of racemic ketoprofen isoleucine calcium according to claim 1, it is characterised in that: in step B, washing
When, it is washed using methanol.
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| 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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| CN103044238A (en) * | 2012-11-26 | 2013-04-17 | 绍兴民生医药有限公司 | Method for preparing calcium 3-methyl-2-oxovalerate |
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