CN106045843A - Production process of calcium (+/-)-3-methyl-2-oxovalerate - Google Patents
Production process of calcium (+/-)-3-methyl-2-oxovalerate Download PDFInfo
- Publication number
- CN106045843A CN106045843A CN201610430679.7A CN201610430679A CN106045843A CN 106045843 A CN106045843 A CN 106045843A CN 201610430679 A CN201610430679 A CN 201610430679A CN 106045843 A CN106045843 A CN 106045843A
- Authority
- CN
- China
- Prior art keywords
- calcium
- racemic ketoprofen
- glycolylurea
- ketoprofen isoleucine
- butylidene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to production process of calcium (+/-)-3-methyl-2-oxovalerate and belongs to the technical field of medicine synthesizing. The production process includes: preparing 2-butylidene hydantoin, preparing crude calcium (+/-)-3-methyl-2-oxovalerate and refining the crude calcium (+/-)-3-methyl-2-oxovalerate, to be more specific, allowing hydantoin to react with butanone to generate the 2-butylidene hydantoin, subjecting the 2-butylidene hydantoin to sodium hydroxide hydrolysis, then allowing the 2-butylidene hydantoin to react with a calcium chloride aqueous solution to generate salt, and recrystallizing to obtain the calcium (+/-)-3-methyl-2-oxovalerate. The production process is simple, easy to operate, low in production cost and high in yield, and the calcium (+/-)-3-methyl-2-oxovalerate produced by the method is high in purity.
Description
Technical field
The invention belongs to the technical field of pharmaceutical synthesis, relate to forming of racemic ketoprofen isoleucine calcium, be specifically related to racemization
The production technology of ketone isoleucine calcium.
Background technology
Racemic ketoprofen isoleucine calcium is one of main component of α keto acid compound (opening same).2-ketoacid and derivant thereof exist
The aspects such as food, daily use chemicals and medicine show the most wide application prospect.In food applications, can drink as sport nutrition
The composition of material；In functional type skin protection cosmetics, good moisturizing, wrinkle resistant, shrinkproof, aging resistance and anti-allergic effects can be played.
In medical applications, α keto acid compound can treat the infringement caused because of chronic renal insufficiency, and can be as treatment uremic
The specific drug of disease.Patients with renal failure takes α keto acid compound, and coordinates low protein diet, can alleviate the high filter of glomerule
Cross, protect nephron, to light, Moderate Chronic Renal Failure patient, can mitigation symptoms, delay disease progression；To severe chronic
Patients with renal failure, then can improve its malnutrition situation, is corresponding amino acid whose succedaneum.
The synthesis of racemic ketoprofen isoleucine calcium mainly has following several method: route 1 uses grignard reagent and oxalic acid diethyl
Ester reacts, and then ester becomes calcium salt, and the method yield is higher, but severe reaction conditions, need anhydrous, high-purity nitrogen (argon) atmosphere and
Cryogenic conditions, the most relatively low low temperature, the most difficult control.Route 2 is with ILE as raw material, uses uncle
Butanol chlorine and catalyst DBU reaction, generate imines, then after imines is hydrolyzed into carbonyl, hydrolysis generates keto acid in the basic conditions.
This route also faces the problem that cost is higher.Route 3 uses 2-Methyl Butyric Acid to be that raw material result two-step reaction generates 3-first
Base-2-oxopentanoic, ester can directly become calcium salt.It is the most that the shortcoming of this route lies also in reaction raw materials, is unfavorable for
Atom economy, it is impossible to effectively utilize raw material, high expensive, environment is negatively affected bigger.
Summary of the invention
The present invention solves that in prior art, synthesising racemation ketone isoleucine calcium is difficult to control to, cost is high, bears environment
Face rings big problem, it is provided that the production production technology of a kind of racemic ketoprofen isoleucine calcium, and production technology of the present invention is simple, easily
Operation, low cost, yield is good.
The present invention the technical scheme is that for realizing its purpose
The production technology of racemic ketoprofen isoleucine calcium, preparation, racemic ketoprofen isoleucine calcium including 2-butylidene glycolylurea are thick
The preparation of product and refining of racemic ketoprofen isoleucine calcium crude product, comprise the following steps:
The preparation of A, 2-butylidene glycolylurea: by glycolylurea, water, butanone mixing, heat temperature raising, by realizing what monoethanolamine was carried
Amino preferably possesses whole character of primary amine, and the hydroxyl carried makes it play preferable affine energy with the aldehyde radical in reactant
Power, thus promote condensation reaction to be easier to occur, it being heated to 50-70 DEG C, add monoethanolamine, monoethanolamine reaches preferably to urge
Change effect, excessively violent in order to prevent from reacting, use dropping mode to add monoethanolamine, continue to be heated to backflow, question response liquid
After clarification, stop heating, be cooled to room temperature, separate out solid, filter, be dried, obtain 2-butylidene glycolylurea；
B, the preparation of racemic ketoprofen isoleucine calcium crude product: mixed with sodium hydroxide solution by 2-butylidene glycolylurea, backflow is anti-
Should, after 2-butylidene glycolylurea is completely dissolved, stopping heating, be cooled to room temperature, adjust pH value to 0.5-1.5, regulation pH value is extremely
The purpose of 0.5-1.5 is to remove the sodium hydroxide of excess, makes solid separate out completely from reactant liquor, adds ethyl acetate extraction, adds
Activated carbon decolorizing, filters, dropping anhydrous calcium chloride aqueous solution in filtrate, precipitation solid, 30-35 DEG C of isothermal holding 4-5h, by
In calcium precipitation speed quickly, if dropping calcium chloride excessive velocities, generate precipitation particles diameter the least, be difficult to filter, thus
Affect product yield.The present invention uses 30-35 DEG C of isothermal holding 4-5h, the available preferable white solid of particle granules size,
Ensure that racemic ketoprofen isoleucine calcium separates out as far as possible from solution.Too high or too low for temperature all can affect product yield；Reaction
To 4-5h, racemic ketoprofen isoleucine calcium separates out the most completely, and it is little that time lengthening separates out benefit to calcium salt.Be then passed through filter,
Wash, be dried, obtain racemic ketoprofen isoleucine calcium crude product；
C, racemic ketoprofen isoleucine calcium crude product refined: 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, the mol ratio of monoethanolamine are 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.The present invention controls reflux temperature and is 75-80 DEG C, makes a second
Hydramine reaches optimal catalysis active reaction speed to be increased, and the response time shortens.
In step B, sodium hydroxide solution in terms of sodium hydrate solid, 2-butylidene glycolylurea and sodium hydrate solid mole
Ratio is 1:(2.5-3.5).
In step B, the temperature of back flow reaction is 95-105 DEG C, and the response time is 5-7h.
In step B, anhydrous calcium chloride aqueous solution is in terms of anhydrous calcium chloride solid, and 2-butylidene glycolylurea is solid with anhydrous calcium chloride
The mol ratio of body is 1:(0.2-0.4), for making keto acid sodium salt completely by CaCl2Displacement generates calcium picrolonate, anhydrous calcium chloride consumption
Very few, affect reaction yield, consumption is too much, causes the waste of anhydrous calcium chloride, the most finally uses 2-butylidene glycolylurea and nothing
The mol ratio of water calcium chloride solid is 1:(0.2-0.4) it is optimum response thing mol ratio, become salt effect best.
In step B, during washing, methanol is used to wash.
In step C, water being heated to 60-75 DEG C, add racemic ketoprofen isoleucine calcium crude product, insulated and stirred is to entirely
Molten, add activated carbon decolorizing, filtered while hot, filtrate adds acetone or alcohol, stirs and be cooled to 5-10 DEG C, stands crystallize 8-
10h, filtration, primary drying, sieve, redrying, obtain racemic ketoprofen isoleucine calcium.After deliberation, the change of redrying is used
Learn the sedimentation method, select suitable digestion time, dry temperature, it is ensured that the racemization structure of racemic ketoprofen isoleucine calcium, obtain height
The quality product of density, production suitable for industrialized.
The baking temperature of primary drying and redrying is 30-50 DEG C, and the time of primary drying is 10-12h, and secondary is done
The dry time is 20-24h.
The invention has the beneficial effects as follows:
1, the purity of racemic ketoprofen isoleucine calcium of the present invention reaches more than 99.5%, and calcium content reaches 13.22-13.7%,
Total recovery reaches more than 50%.
2, the production technology reaction condition of the present invention is gentle, and device simple is simple to operate, and productivity ratio is high, and purity is good, cost
Low, environmental hazard is low, is suitable for industrialized production.The most miscellaneous≤0.1%, the most miscellaneous≤0.5%, residual solvent≤0.1%, heavy metal≤
7ppm, meets State Food and Drug Administration's standard YBH03302011.The racemic ketoprofen isoleucine produced than existing technique
Calcium quality control is tightened up, and quality is more stable.
3, the present invention is by by glycolylurea: butanone: monoethanolamine mol ratio controls as 1:(1.4-1.6): (0.9-1.1), can
Improving the yield of 2-butylidene glycolylurea, the consumption of butanone is improved by the present invention, reduces the consumption of monoethanolamine so that reach simultaneously
The control ratio of the present invention, not only improves productivity but also can be cost-effective.
4, the present invention is in the preparation process of racemic ketoprofen isoleucine calcium crude product, is additionally arranged 30-35 DEG C of insulated and stirred 4h
Process, due to calcium precipitation speed quickly, if dropping calcium chloride excessive velocities, generate precipitation particles diameter the least, be difficult to
Filter, thus affect product yield.The present invention uses 30-35 DEG C of isothermal holding 4h, and available particle granules size is the whitest
Solid, it is ensured that racemic ketoprofen isoleucine calcium separates out as far as possible from solution.Too high or too low for temperature all can affect product yield；
Reaction is to 4h, and racemic ketoprofen isoleucine calcium separates out the most completely, and it is little that time lengthening separates out benefit to calcium salt.
5, in subtractive process, the temperature of primary drying of the present invention and redrying the most only needs 30-50 DEG C, baking temperature
It is far smaller than existing baking temperature, after deliberation, uses the chemical precipitation method of redrying, be dried for twice by strict control
Time, dry temperature, the change of product crystal structure and density can be affected.The present invention uses 5-10 DEG C to stand crystallize 8h, mistake
Filter, primary drying, sieve, redrying, the baking temperature of primary drying and redrying is 30-50 DEG C, can obtain crystalline substance
Body structural integrity, highdensity quality product.Can ensure that the racemization structure of racemic ketoprofen isoleucine calcium simultaneously, suitable for industrialized
Produce.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1
The preparation of A, Zhong Ding fork glycolylurea (2-butylidene glycolylurea)
Glycolylurea 9.6kg (96mol), 19.2kg water are added in reactor with butanone 10.4kg (144.4mol), stirring, in
White casse liquid.It is heated to 50-70 DEG C (preferably 55-65 DEG C), adds monoethanolamine 5.86kg (96mol).Slowly it is heated to back
Stream, in reactant liquor, white solid is gradually dissolved to clarification.In 75-80 DEG C of back flow reaction 5-7h (preferably 78 DEG C back flow reaction 6h),
(GF is detected through thin layer chromatography254Thin-layer silicon offset plate: RfZhong Ding pitches=0.62；RfGlycolylureaAt=0.32, iodine is smoked almost without point；Developing solvent:
CHCl3: MeOH=5:1), glycolylurea raw material disappears, and stops heating.It is cooled to room temperature, separates out solid.Filter, by filter cake 16kg
Purified water is stirred and is washed, and is filtered dry, 60 DEG C of vacuum drying 8h, obtains off-white color solid 11.14kg, yield 75.4%.Through analyzing detection, Zhong Ding
HPLC purity >=95% of fork glycolylurea.
B, the preparation of racemic ketoprofen isoleucine calcium (α-one base-Beta-methyl valeric acid calcium) crude product
Weigh 8.64kg sodium hydroxide (216mol) and add in reactor with 34.56kg purified water, stirring and dissolving.Add secondary
Fourth fork glycolylurea (2-butylidene glycolylurea) 11.1kg (72mol), steam gives heat, in 95-105 DEG C of back flow reaction 5-7h (preferably 100 DEG C
Back flow reaction 6h), increase the return time of intermediate 2-butylidene glycolylurea and sodium hydroxide, glycolylurea intermediate can be made to hydrolyze more
Completely, product yield is improved.Treat Zhong Ding fork glycolylurea raw material hydrolysis completely, stop heating, detect (GF through thin layer chromatography254Silica gel
Plate: RfProduct=0.22；RfZhong Ding pitchesAlmost without point at=0.66；Developing solvent: CHCl3: MeOH=5:1).It is cooled to room temperature, under cooling
Adjust pH value to 1 with concentrated hydrochloric acid, add the extraction of 50kg ethyl acetate, add 280g activated carbon decolorizing 15min, filter.By anhydrous for 2.4kg chlorine
Change the solution of calcium (21.6mol)/6kg water, slowly instill under room temperature in above-mentioned filtrate, separate out solid, be incubated in 30-35 DEG C of stirring
4-5h (preferably 4.2-4.7h).Filter, wash twice with 12L × 2 methanol.In 60 DEG C of forced air drying about 6h after filtration, obtain micro-Huang
Color solid 5.5kg, crude yield 85.4%.(GF is detected through thin layer chromatography254Silica gel plate: RfProduct=0.23；Developing solvent: CHCl3:
MeOH=5:1).
C, racemic ketoprofen isoleucine calcium refined
66kg purified water is added in dissolution kettle, stirs and be heated to 60-75 DEG C (preferably 68-72 DEG C).Add
5.5kg racemic ketoprofen isoleucine calcium crude product, insulated and stirred, to the most molten, adds 400g activated carbon, and decolour 30min.Fine straining while hot
(0.45μm).Filtrate enters in crystallization kettle, adds acetone 170kg recrystallization, stirs and cool down, and 5-10 DEG C stands crystallize 8-10h
(preferably 6-9 DEG C stands crystallize 8.5-9.5h).Filter, be vacuum dried 10-12h (preferably 40 DEG C vacuum drying through 30-50 DEG C
10h), cross 20 mesh sieves, continue vacuum drying 20h and obtain racemic ketoprofen isoleucine calcium 4.3kg, yield: 78.2%, detect through analyzing,
HPLC purity 99.6% (Rezex ROA-Organic Acid 300 × 7.80mm, flow phase: 0.0025mol/L sulfuric acid solution,
λ=205nm, column temperature 30 DEG C), every quality index meets medicinal standard.
Total recovery is, 75.4% × 85.4% × 78.2%=50.35%
Embodiment 2
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol ratio of monoethanolamine is 1:1.4:0.9, yield 74.3%.
In step B, 2-Aden glycolylurea is 1:3.5,2-Aden glycolylurea and anhydrous chlorine with the mol ratio of sodium hydrate solid
The mol ratio changing calcium solid is 1:0.2, obtains slightly yellow solid, yield 85.1%.
In step C, water is heated to 60 DEG C, yield: 77.8%, through analyzing detection, HPLC purity 99.7%.
Total recovery is, 74.3% × 85.1% × 77.8%=49.19%.
Embodiment 3
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol ratio of monoethanolamine is 1:1.5:0.9, yield 75.3%.
In step B, 2-Aden glycolylurea is 1:2.5,2-Aden glycolylurea and anhydrous chlorine with the mol ratio of sodium hydrate solid
The mol ratio changing calcium solid is 1:0.2, obtains slightly yellow solid, yield 84.2%.
In step C, water is heated to 75 DEG C, yield: 78.7%, through analyzing detection, HPLC purity 99.6%.
Total recovery is, 75.3% × 84.2% × 78.7%=49.90%.
Embodiment 4
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol ratio of monoethanolamine is 1:1.6:0.9, yield 75.9%.
In step B, 2-Aden glycolylurea is 1:3.5,2-Aden glycolylurea and anhydrous chlorine with the mol ratio of sodium hydrate solid
The mol ratio changing calcium solid is 1:0.4, obtains slightly yellow solid, yield 85.7%.
In step C, water being heated to 60 DEG C, add 95% ethanol 66kg recrystallization, yield: 77.1%, through dividing
Analysis detection, HPLC purity 99.7%.
Total recovery is, 75.9% × 85.7% × 77.1%=50.15%.
Embodiment 5
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol ratio of monoethanolamine is 1:1.4:1.1, yield 74.3%.
In step B, 2-Aden glycolylurea is 1:2.5,2-Aden glycolylurea and anhydrous chlorine with the mol ratio of sodium hydrate solid
The mol ratio changing calcium solid is 1:0.4, obtains slightly yellow solid, yield 84.8%.In step C, water is heated to 60 DEG C,
Adding 95% ethanol 66kg recrystallization, yield: 78.0%, through analyzing detection, HPLC purity 99.6%.
Total recovery is, 74.3% × 84.8% × 78.0%=49.14%.
Embodiment 6
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol ratio of monoethanolamine is 1:1.5:1.1, yield 75.5%.
In step C, water being heated to 75 DEG C, add 95% ethanol 66kg recrystallization, yield: 85.1%, through dividing
Analysis detection, HPLC purity 99.7%.
Total recovery is, 75.5% × 85.4% × 85.1%=50.42%.
Embodiment 7
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol 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
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol ratio of monoethanolamine is 1:1.4:1, yield 75.2%.
Total recovery is, 75.2% × 85.4% × 78.2%=50.22%.
Embodiment 9
Substantially the same manner as Example 1, but there is following change:
In step A, glycolylurea: butanone: the mol 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) adds 12ml water and is heated with stirring to 60 DEG C of additions butanone 9.37g (0.13mol), drips second
Hydramine 4.8g (0.08mol), drips and finishes in 80 DEG C of stirring reaction 4h, and reaction cools down after terminating, adjusts pH=4 with concentrated hydrochloric acid, separates out solid
Body, filters, and with distilled water wash and be dried, obtains 9.4g, and yield 61%, elementary analysis is qualified.
(2) synthesis of α-one base-Beta-methyl valeric acid calcium salt
Take intermediate 15.4g (0.1mol) with 20% mass than NaOH solution 100g, be heated to reflux 2h, 110 DEG C, reaction knot
Shu Houyong concentrated hydrochloric acid adjusts pH=5, and cold filtration removes solid, and filtrate reduced in volume, to dry, add 150ml absolute methanol and heats back
Stream 1h, filtered while hot, filtrate reduced in volume, to dry, adds 20ml distilled water, by 5.6g (0.05mol) calcium chloride and 10ml water group
The solution become slowly instills under cooling, separates out white solid, filters, 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 after ethyl alcohol recrystallization, put into vacuum drying oven, 75-80 DEG C of drying, obtain α-one base-Beta-methyl
Valeric acid calcium salt finished product 4.5g.Yield 30.2%, elementary analysis is qualified.
The total recovery of comparative example 1 is 61% × 30.2%=18.422%, and total recovery is the lowest, through analyzing detection,
HPLC purity 90.2-93%.
Comparative example 2
The preparation method of a kind of racemic ketoprofen isoleucine calcium, is characterised by comprising the following steps:
A. in the alcoholic solution of metal alkoxide, add dialkyl oxalate, drip off and be incubated half an hour；
B. it is incubated complete, adds 2 methyl butyraldehyde, drip off and be incubated half an hour；
C. at not higher than 25 DEG C, add alkali liquor, add insulation 0.5-10 hour；
D. after insulation terminates, add acid, adjust pH to 1.0-4.0, add organic solvent extraction；
E. merge organic facies, add water, add dilute adjusting PH with base and add water tune pH to 5-7 to 5-7, layering, organic facies, merge water
Phase.Aqueous phase adds dilute adjusting PH with base and becomes calcium salt to 8-9, addition calcium chloride water, be incubated 1-3 hour, and cooling is centrifugal, 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 drips 0-0.8 times of purified water
The organic solvent of weight, refined, obtain racemic ketoprofen isoleucine calcium highly finished product, purity 99.5%.
Comparative example 2 uses dialkyl oxalate to react, and this method total recovery is higher, but cost of material is high, and condition is severe
Carve, need low temperature, anhydrous, oxygen free condition, be solvent with ether, be not suitable for commercial production.
Claims (9)
1. the production technology of racemic ketoprofen isoleucine calcium, including preparation, the racemic ketoprofen isoleucine calcium crude product of 2-butylidene glycolylurea
Preparation and racemic ketoprofen isoleucine calcium crude product refined, it is characterised in that comprise the following steps:
The preparation of A, 2-butylidene glycolylurea: by glycolylurea, water, butanone mixing, be heated to 50-70 DEG C, add monoethanolamine, continue to add
Heat, to backflow, after the clarification of question response liquid, stops heating, is cooled to room temperature, separate out solid, filters, is dried, and obtains 2-butylidene sea
Cause；
B, the preparation of racemic ketoprofen isoleucine calcium crude product: 2-butylidene glycolylurea is mixed with sodium hydroxide solution, back flow reaction, treat
After 2-butylidene glycolylurea is completely dissolved, stop heating, be cooled to room temperature, adjust pH value to 0.5-1.5, add ethyl acetate extraction, add
Activated carbon decolorizing, filters, and drips anhydrous calcium chloride aqueous solution, separate out solid in filtrate, is then passed through filtering, washing, 30-35
DEG C isothermal holding 4-5h, obtains racemic ketoprofen isoleucine calcium crude product；
C, racemic ketoprofen isoleucine calcium crude product refined: racemic ketoprofen isoleucine calcium crude product is dissolved in water, through acetone or alcohol weight
Crystallization, obtains racemic ketoprofen isoleucine calcium.
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 1, it is characterised in that: in step A, glycolylurea,
Butanone, the mol ratio of monoethanolamine are 1:(1.4-1.6): (0.9-1.1).
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 1, it is characterised in that: in step A, it is heated to
75-80 DEG C of back flow reaction 5-7h.
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 1, it is characterised in that: in step B, hydroxide
Sodium solution is in terms of sodium hydrate solid, and 2-butylidene glycolylurea is 1:(2.5-3.5 with the mol ratio of sodium hydrate solid).
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 1, it is characterised in that: in step B, backflow is anti-
The temperature answered is 95-105 DEG C, and the response time is 5-7h.
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 1, it is characterised in that: in step B, anhydrous chlorine
Change calcium aqueous solution is in terms of anhydrous calcium chloride solid, and 2-butylidene glycolylurea is 1:(0.2-with the mol ratio of anhydrous calcium chloride solid
0.4)。
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 1, it is characterised in that: in step B, washing
Time, use methanol to wash.
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 1, it is characterised in that: in step C, water is added
Heat is warming up to 60-75 DEG C, adds racemic ketoprofen isoleucine calcium crude product, and insulated and stirred, to the most molten, adds activated carbon decolorizing, while hot mistake
Filter, filtrate add acetone or alcohol, stir and be cooled to 5-10 DEG C, stand crystallize 8-10h, filtration, primary drying, sieve, two
Secondary dry, obtain racemic ketoprofen isoleucine calcium.
The production technology of racemic ketoprofen isoleucine calcium the most according to claim 8, it is characterised in that: primary drying and secondary
The baking temperature being dried is 30-50 DEG C, and the time of primary drying is 10-12h, and the time of redrying is 20-24h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610430679.7A CN106045843B (en) | 2016-06-16 | 2016-06-16 | The production technology of racemic ketoprofen isoleucine calcium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610430679.7A CN106045843B (en) | 2016-06-16 | 2016-06-16 | The production technology of racemic ketoprofen isoleucine calcium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106045843A true CN106045843A (en) | 2016-10-26 |
| CN106045843B CN106045843B (en) | 2019-04-02 |
Family
ID=57169037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610430679.7A Active CN106045843B (en) | 2016-06-16 | 2016-06-16 | The production technology of racemic ketoprofen isoleucine calcium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106045843B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627637A (en) * | 2019-09-25 | 2019-12-31 | 福安药业集团重庆博圣制药有限公司 | One-step method for preparing racemic ketone isoleucine calcium |
| CN113735727A (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 racemic ketone isoleucine 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 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603516A (en) * | 2012-01-30 | 2012-07-25 | 浙江新和成股份有限公司 | D,L-alpha-ketoisovaline calcium dihydrate crystals and preparation method thereof |
| CN102701954A (en) * | 2011-06-13 | 2012-10-03 | 浙江昂利康制药有限公司 | Preparation method of alpha-ketovaline calcium |
| 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 |
| 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 |
| CN104058954A (en) * | 2014-07-07 | 2014-09-24 | 绍兴民生医药有限公司 | Environment-friendly technology for preparing ketoleucine calcium in aqueous phase |
-
2016
- 2016-06-16 CN CN201610430679.7A patent/CN106045843B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102701954A (en) * | 2011-06-13 | 2012-10-03 | 浙江昂利康制药有限公司 | Preparation method of alpha-ketovaline calcium |
| CN102603516A (en) * | 2012-01-30 | 2012-07-25 | 浙江新和成股份有限公司 | D,L-alpha-ketoisovaline calcium dihydrate crystals and preparation method thereof |
| 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 |
| 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 |
| CN104058954A (en) * | 2014-07-07 | 2014-09-24 | 绍兴民生医药有限公司 | Environment-friendly technology for preparing ketoleucine calcium in aqueous phase |
Non-Patent Citations (1)
| Title |
|---|
| 陆晓等: "α-酮缬氨酸钙的合成", 《药学进展》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627637A (en) * | 2019-09-25 | 2019-12-31 | 福安药业集团重庆博圣制药有限公司 | One-step method for preparing racemic ketone isoleucine calcium |
| CN110627637B (en) * | 2019-09-25 | 2022-05-27 | 福安药业集团重庆博圣制药有限公司 | One-step method for preparing racemic ketone isoleucine calcium |
| CN113735727A (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 racemic ketone isoleucine 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 |
| 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 |
| CN113735727B (en) * | 2020-05-30 | 2024-05-24 | 北京福元医药股份有限公司沧州分公司 | Preparation method of raceme ketoisoleucine calcium and intermediate thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106045843B (en) | 2019-04-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102992957B (en) | Solvent-out crystallization method of erythritol | |
| CN104387320B (en) | A kind of preparation method of high-purity milrinone | |
| CN103420881B (en) | A kind of preparation method of medicinal racemization hydroxyl Methionine calcium salt newly | |
| CN106045843A (en) | Production process of calcium (+/-)-3-methyl-2-oxovalerate | |
| CN105968032A (en) | Synthetic method of metformin hydrochloride | |
| CN104058954B (en) | A kind of friendly process preparing keto-leucine calcium in aqueous phase | |
| CN104326984A (en) | Synthesis method of high-purity pharmaceutical injection-grade edaravone raw material | |
| CN102718829B (en) | The preparation method of TUDCANa | |
| CN103087017B (en) | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product | |
| CN113461580B (en) | N-acetyl-L-cysteine synthesis method | |
| CN105085312A (en) | Preparation method of oxytetracycline hydrochloride | |
| WO2021212535A1 (en) | Method for refining benzhexol hydrochloride | |
| CN102924311A (en) | L-ornithine-L-aspartate preparation method | |
| CN110105235B (en) | Preparation method of high-purity sodium pantothenate | |
| CN108164530A (en) | A kind of environmentally friendly process for purification of theobromine | |
| CN104628564A (en) | Fenofibric acid choline salt crystal form and preparation method thereof | |
| CN105218390A (en) | A kind of Propacetamol Hydrochloride preparation technology of improvement | |
| CN105461691B (en) | A kind of preparation method of Azelnidipine | |
| CN107698596A (en) | A kind of synthetic method of Allopurinol | |
| CN105061327B (en) | A kind of synthetic method of sulfamethoxyplridazine | |
| CN110330447B (en) | Preparation method and application of nafamostat mesylate intermediate | |
| CN106749216A (en) | A kind of process for purification of crystal formation A Azilsartans | |
| CN109060473B (en) | Preparation method of ambroxol hydrochloride impurity reference substance | |
| CN105017029A (en) | Preparation method of p-bromoaniline | |
| CN103172532B (en) | A kind of preparation method of ethylenediaminetetraacidic acidic calcium disodium salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |