CN104987287B - A kind of preparation method of spherical Lysine m-benzoylhydratropate - Google Patents
A kind of preparation method of spherical Lysine m-benzoylhydratropate Download PDFInfo
- Publication number
- CN104987287B CN104987287B CN201510311676.7A CN201510311676A CN104987287B CN 104987287 B CN104987287 B CN 104987287B CN 201510311676 A CN201510311676 A CN 201510311676A CN 104987287 B CN104987287 B CN 104987287B
- Authority
- CN
- China
- Prior art keywords
- benzoylhydratropate
- lysine
- preparation
- solvent
- acetonitrile
- 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.)
- Active
Links
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 title claims abstract description 64
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 239000004472 Lysine Substances 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000012046 mixed solvent Substances 0.000 claims abstract description 21
- 229960000991 ketoprofen Drugs 0.000 claims abstract description 18
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 239000012296 anti-solvent Substances 0.000 claims abstract description 14
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 13
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 238000009413 insulation Methods 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000006185 dispersion Substances 0.000 abstract description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 13
- 238000005352 clarification Methods 0.000 description 12
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000001514 detection method Methods 0.000 description 10
- 239000002245 particle Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- 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
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of preparation method of spherical Lysine m-benzoylhydratropate, comprise the following steps：1) by Ketoprofen dissolving in methyl alcohol, heating is completely dissolved it, adds the lysine of identical molar equivalent, and the reaction solution that must be clarified is filtered in room temperature reaction；2) under low temperature, uniform into reaction solution that anti-solvent is added dropwise, anti-solvent is acetonitrile, ethyl acetate, the mixed solvent or acetonitrile of isopropyl acetate and the mixed solvent or acetonitrile of ethyl acetate and the mixed solvent of isopropyl acetate；3) under low temperature, insulation crystallization 1 ~ 10 hour；4) filter, dry, spherical Lysine m-benzoylhydratropate is made.It is harsh to equipment requirement that this method efficiently solves current industrialized production, product stability difference and the more low problem of yield, and obtained product, which has, to be stablized, good fluidity, the features such as good dispersion, and strong guarantee is provided for the steady production of preparation；Meanwhile, technological operation is simple, is adapted to industrialized production, with very strong practical value.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, specifically a kind of spherical Lysine m-benzoylhydratropate preparation method.
Background technology
Ketoprofen has anti-inflammatory, analgesia, and antipyretic, toxicity is low, the features such as Small side effects, and its antiinflammation is better than Bu Luo
Sweet smell, is mainly used in the diseases such as treatment rheumatoid arthritis, rheumatic arthritis and gout.But Ketoprofen water solubility is poor, sternly
Ghost image rings its bioavilability.
Lysine m-benzoylhydratropate, also known as lysine Ketoprofen, are lysine and Ketoprofen formation
Double salt.Lysine m-benzoylhydratropate has very strong water solubility, can not only ensure the drug effect of Ketoprofen, and can be with
It is greatly enhanced the water solubility of Ketoprofen.The chemical structural formula of Lysine m-benzoylhydratropate is as follows：
。
Chinese CN1939893A reports a kind of Lysine m-benzoylhydratropate preparation method, is that lysine is dissolved in into water
In, Ketoprofen is added, after clarification, by freeze-drying, Lysine m-benzoylhydratropate is prepared.The deficiency of this method
It is in one side refrigerating process temperature is too low, and general equipment is unable to reach；Another aspect cooling time is long, reduces work
Make efficiency, improve production cost, be unfavorable for large-scale production；Meanwhile, product stability as obtained by refrigerating process compared with
Difference, especially hygroscopicity can be stronger, not easy to maintain.
Chinese CN 103524365 reports a kind of preparation method of lysine-ketoprofen, and this method dissolves lysine
In water, after reaction terminates, dilution crystallization is carried out by the way that ethanol is added dropwise into salt for the rear Ketoprofen that adds.According to this method institute
The product yield prepared is relatively low, and the less stable of products obtained therefrom, in atmosphere easily moisture absorption, can not be protected under normal temperature
Deposit.
The content of the invention
In order to solve the above technical problems, the present invention, which provides one kind, prepares spherical Lysine m-benzoylhydratropate preparation method,
This method is simple to operate, it is easy to which industrialization is controlled, and the stabilization of obtained product is higher.
The present invention is adopted the following technical scheme that：A kind of preparation method of spherical Lysine m-benzoylhydratropate, including it is as follows
Step：
1) by Ketoprofen dissolving in methyl alcohol, heating is completely dissolved it, adds the bad ammonia of identical molar equivalent
Acid, is reacted at room temperature 1.5-4 hours；Filter the reaction solution that must be clarified；
2) under -20 °C ~ 10 °C, to step 1）Uniform in obtained reaction solution that anti-solvent is added dropwise, the anti-solvent is second
Nitrile, ethyl acetate, the mixed solvent or acetonitrile of isopropyl acetate and the mixed solvent or acetonitrile of ethyl acetate and acetic acid are different
The mixed solvent of propyl ester；
3) in step 2）At a temperature of, insulation crystallization 1 ~ 10 hour, preferably 2 hours；
4) filter, dry, spherical Lysine m-benzoylhydratropate is made.
Wherein, step 1）The ratio between middle Ketoprofen and methanol are 1:2~1:10, preferably 1：4.
It is preferred that, step 1）Middle anti-solvent is the body of acetonitrile and isopropyl acetate mixed solvent, acetonitrile and isopropyl acetate
The ratio between product is 1:10~10:1, it is furthermore preferred that the ratio between volume of acetonitrile and isopropyl acetate is 1: 1.
Step 1）HPLC >=95% of the Ketoprofen raw material of middle addition, content >=95% of lysine raw material.
Preferably, step 2）Dropping temperature be -5 °C ~ 5 °C.
Step 2）The ratio between volume and inventory of middle anti-solvent 2:1~20:1, preferably the ratio between anti-solvent and inventory is 8:
1.Inventory refers to Ketoprofen and lysine quality sum.
Step 2）The time for adding of middle anti-solvent is 1 ~ 5 hour, it is preferable that time for adding is 2 ~ 3 hours.
Step 1）With step 2）The middle methanol used, acetonitrile, ethyl acetate, isopropyl acetate are technical grade.
The invention has the advantages that：
1. it is the spherical Lysine m-benzoylhydratropate particle of purpose of 20 mesh ~ 150, this particle that can prepare particle diameter by this method
There is preferably mobility and preferably dispersiveness relative to sheet-like particle.
2. the solid prepared by this method has stronger stability, can deposit in atmosphere will not inhale for a period of time
It is wet, can be drying, packaging, storage and the stable offer of preparation are more efficiently ensured.
3. the temperature conditionss of this method reaction are easier to reach, simple to operate, relatively low to equipment requirement, it is adapted to extensive chemical industry
Factory's amplification production, and preparation time is shorter, it is easy to and industrialization is controlled, and the quality of products obtained therefrom is higher, meets GMP and country
It is required that.
Brief description of the drawings
Fig. 1 is the microscope figure of spherical Lysine m-benzoylhydratropate made from embodiment 1；
Fig. 2 is Fig. 1 partial enlarged drawing；
Fig. 3 is the size distribution spectrogram of spherical Lysine m-benzoylhydratropate made from embodiment 1；
Fig. 4 is the DSC spectrograms of spherical Lysine m-benzoylhydratropate made from embodiment 1；
Fig. 5 is spherical Lysine m-benzoylhydratropate TGA spectrograms made from embodiment 1；
Fig. 6 is the XRPD spectrograms of spherical Lysine m-benzoylhydratropate made from embodiment 1.
Embodiment
Technical scheme is further described with reference to specific embodiment, but protection scope of the present invention
Not limited to this.
Embodiment 1
50 g Ketoprofens raw materials are added in 200 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 2 hours.5 °C are cooled to, is added dropwise what is be made up of 350mL acetonitriles and 350mL isopropyl acetates to reaction solution
Mixed solvent, time for adding is 2 hours, crystallization, 2 hours of growing the grain, filters, dries, can obtain 68.32 g products, molar yield
For 85.4%；HPLC=99.75%, singly miscellaneous≤0.05%, always miscellaneous≤0.25%.
The microscope figure for the spherical Lysine m-benzoylhydratropate solid that the present embodiment that Fig. 1 is shown is obtained.From microscope
It is the spherical of about 20 μm of radius that data in enlarged drawing, which can be seen that the Lysine m-benzoylhydratropate solid prepared with the method,
Solid.
The particle size distribution figure of the spherical Lysine m-benzoylhydratropate of the present embodiment acquisition is shown in Fig. 3.From sample
From the point of view of results of grain size analysis, the Lysine m-benzoylhydratropate even particle size distribution prepared with the method is presented preferably just
State is distributed.
Understood with reference to Fig. 4, Fig. 5 and Fig. 6：Spherical Lysine m-benzoylhydratropate manufactured in the present embodiment is unformed, no
It is crystal.
Embodiment 2
50 g Ketoprofens raw materials are added in 400 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 1.5 hours.- 5 °C are cooled to, is added dropwise to reaction solution by 400mL acetonitriles and 600mL isopropyl acetate groups
Into mixed solvent, time for adding be 2 hours, crystallization, 3 hours of growing the grain, filter, dry, 67.04 g products, quality can be obtained
Yield is 83.8%；HPLC=99.65%, singly miscellaneous≤0.10%, always miscellaneous≤0.35%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 3
50 g Ketoprofens raw materials are added in 500 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 3.5 hours.- 10 °C are cooled to, is added dropwise to reaction solution by 400mL acetonitriles and 600mL isopropyl acetate groups
Into mixed solvent, time for adding be 3 hours, crystallization, 3 hours of growing the grain, filter, dry, 67.92 g products, quality can be obtained
Yield is 84.9%；HPLC=99.6%, singly miscellaneous≤0.05%, always miscellaneous≤0.40%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 4
50 g Ketoprofens raw materials are added in 150 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 3.5 hours.- 10 °C are cooled to, is added dropwise and is made up of 600mL acetonitriles and 400mL ethyl acetate to reaction solution
Mixed solvent, time for adding is 3 hours, and crystallization 5 hours of growing the grain, filters, dries, can obtain 68.24 g products, quality is received
Rate is 85.3%；HPLC=99.70%, singly miscellaneous≤0.10%, always miscellaneous≤0.30%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 5
50 g Ketoprofens raw materials are added in 200 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 4 hours.- 15 °C are cooled to, is added dropwise what is be made up of 400mL acetonitriles and 600mL ethyl acetate to reaction solution
Mixed solvent, time for adding is 5 hours, crystallization, 3 hours of growing the grain, filters, dries, can obtain 68.52 g products, mass yield
For 85.7%；HPLC=99.6%, singly miscellaneous≤0.05%, always miscellaneous≤0.40%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 6
50 g Ketoprofens raw materials are added in 200 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 2.5 hours.- 20 °C are cooled to, is added dropwise and is made up of 600mL acetonitriles and 800mL ethyl acetate to reaction solution
Mixed solvent, time for adding is 2 hours, and crystallization 3 hours of growing the grain, filters, dries, can obtain 67.44 g products, quality is received
Rate is 84.3%；HPLC=99.7%, singly miscellaneous≤0.05%, always miscellaneous≤0.30%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 7
50 g Ketoprofens raw materials are added in 100 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 2.5 hours.0 °C is cooled to, is added dropwise and is made up of 100mL acetonitriles and 1000mL ethyl acetate to reaction solution
Mixed solvent, time for adding is 5 hours, and crystallization 1 hour of growing the grain, filters, dries, can obtain 63.63 g products, quality is received
Rate is 79.5%；HPLC=99.7%, singly miscellaneous≤0.10%, always miscellaneous≤0.30%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 8
50 g Ketoprofens raw materials are added in 100 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 2.5 hours.0 °C is cooled to, is added dropwise and is made up of 1000 mL acetonitriles and 10 mL ethyl acetate to reaction solution
Mixed solvent, time for adding be 2 hours, crystallization, 10 hours of growing the grain, filter, dry, 68.48 g products, quality can be obtained
Yield is 85.6%；HPLC=99.7%, singly miscellaneous≤0.10%, always miscellaneous≤0.30%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 9
50 g Ketoprofens raw materials are added in 100 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 2.5 hours.0 °C is cooled to, is added dropwise what is be made up of 80 mL acetonitriles and 80 mL ethyl acetate to reaction solution
Mixed solvent, time for adding is 1 hour, crystallization, 2 hours of growing the grain, filters, dries, can obtain 60.19 g products, mass yield
For 75.2%；HPLC=99.7%, singly miscellaneous≤0.10%, always miscellaneous≤0.30%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 10
50 g Ketoprofens raw materials are added in 100 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 2.5 hours.0 °C is cooled to, is added dropwise to reaction solution by 1000 mL acetonitriles and 600 mL ethyl acetate groups
Into mixed solvent, time for adding be 2 hours, crystallization, 10 hours of growing the grain, filter, dry, 71.48 g products, matter can be obtained
It is 89.4% to measure yield；HPLC=99.1%, singly miscellaneous≤0.20%, always miscellaneous≤0.90%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Embodiment 11
50 g Ketoprofens raw materials are added in 200 mL methanol, dissolved clarification is heated with stirring to, relying for equivalent is added
Propylhomoserin, reacts at room temperature 2 hours.10 °C are cooled to, is added dropwise and is made up of 350mL acetonitriles and 350mL isopropyl acetates to reaction solution
Mixed solvent, time for adding be 2 hours, crystallization, 2 hours of growing the grain, filter, dry, 66.5 g products can be obtained, mole receive
Rate is 83.1%；HPLC=99.70%, singly miscellaneous≤0.10%, always miscellaneous≤0.30%.
It can be obtained by XRPD tests and microscope detection：The Lysine m-benzoylhydratropate that the present embodiment is obtained is also for ball
Shape outward appearance, and XRPD spectrograms and Fig. 4 are consistent.
Spherical Lysine m-benzoylhydratropate prepared by this method has a good fluidity, good dispersion, and stability is preferably etc.
Feature, it is substantially non-hygroscopic after long period placement, it is that the quality stability of Lysine m-benzoylhydratropate provides safeguard, is preparation
Steady production provide strong guarantee；Meanwhile, technological operation is simple, is adapted to industrialized production, with very strong practical value.
Claims (10)
1. a kind of preparation method of spherical Lysine m-benzoylhydratropate, it is characterised in that comprise the following steps：
1) by Ketoprofen dissolving in methyl alcohol, heating is completely dissolved it, adds the lysine of identical molar equivalent, room temperature
Reaction 1.5-4 hours；Filter the reaction solution that must be clarified；
2) under -20 °C ~ 10 °C, to step 1）Uniform in obtained reaction solution that anti-solvent is added dropwise, the anti-solvent is acetonitrile, acetic acid
Ethyl ester, the mixed solvent or acetonitrile of isopropyl acetate and the mixed solvent or acetonitrile of ethyl acetate and isopropyl acetate it is mixed
Bonding solvent；
3) in step 2）At a temperature of, insulation crystallization 1 ~ 10 hour；
4) filter, dry, spherical Lysine m-benzoylhydratropate is made.
2. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 1, it is characterised in that step
1）The ratio between quality and volume of middle Ketoprofen and methanol are 1:2~1:10, unit is g/mL.
3. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 1, it is characterised in that step
1）Middle anti-solvent is acetonitrile and isopropyl acetate mixed solvent, and the ratio between volume of acetonitrile and isopropyl acetate is 1:10~10:1.
4. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 3, it is characterised in that acetonitrile
It is 1 with the ratio between the volume of isopropyl acetate: 1.
5. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 1, it is characterised in that step
1）HPLC >=95% of the Ketoprofen raw material of middle addition, content >=95% of lysine raw material.
6. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 1, it is characterised in that step
2）Dropping temperature be -5 °C ~ 5 °C.
7. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 1, it is characterised in that step
2）The ratio between volume and inventory of middle anti-solvent 2:1~20:1, inventory refers to Ketoprofen and lysine quality sum.
8. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 1, it is characterised in that step
2）The time for adding of middle anti-solvent is 1 ~ 5 hour.
9. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 8, it is characterised in that step
2）The time for adding of middle anti-solvent is 2 ~ 3 hours.
10. a kind of preparation method of spherical Lysine m-benzoylhydratropate according to claim 1, it is characterised in that step
Rapid 1）With step 2）The middle methanol used, acetonitrile, ethyl acetate, isopropyl acetate are technical grade.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510311676.7A CN104987287B (en) | 2015-06-10 | 2015-06-10 | A kind of preparation method of spherical Lysine m-benzoylhydratropate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510311676.7A CN104987287B (en) | 2015-06-10 | 2015-06-10 | A kind of preparation method of spherical Lysine m-benzoylhydratropate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104987287A CN104987287A (en) | 2015-10-21 |
| CN104987287B true CN104987287B (en) | 2017-07-18 |
Family
ID=54299210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510311676.7A Active CN104987287B (en) | 2015-06-10 | 2015-06-10 | A kind of preparation method of spherical Lysine m-benzoylhydratropate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104987287B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3508199A1 (en) * | 2018-01-05 | 2019-07-10 | Dompé farmaceutici S.p.A. | Immediate-release pharmaceutical compositions containing ketoprofen lysine salt |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748584B (en) * | 2016-11-29 | 2019-03-19 | 西南科技大学 | The method that emulsion method prepares spheroidization small organic molecule compound |
| EP3842408A1 (en) * | 2019-12-23 | 2021-06-30 | Dompé farmaceutici S.p.A. | Co-crystal of ketoprofen and its preparation, pharmaceutical compositions comprising the same and uses thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923798A (en) * | 2005-08-30 | 2007-03-07 | 陈亦林 | Preparation method of dexibuprofen amino acid salt and application |
| CN103524365A (en) * | 2013-09-03 | 2014-01-22 | 蚌埠丰原医药科技发展有限公司 | Method for preparing lysine ketoprofen |
-
2015
- 2015-06-10 CN CN201510311676.7A patent/CN104987287B/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3508199A1 (en) * | 2018-01-05 | 2019-07-10 | Dompé farmaceutici S.p.A. | Immediate-release pharmaceutical compositions containing ketoprofen lysine salt |
| WO2019134940A1 (en) * | 2018-01-05 | 2019-07-11 | Dompe' Farmaceutici S.P.A. | Immediate-release pharmaceutical compositions containing ketoprofen lysine salt |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104987287A (en) | 2015-10-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104987287B (en) | A kind of preparation method of spherical Lysine m-benzoylhydratropate | |
| CN103319502B (en) | Sulbenicillin sodium preparation method | |
| CN104844625A (en) | Cefamandole nafate new crystal form and crystallization preparing method thereof | |
| CN103709139A (en) | Preparation method of anhydrous dexilant | |
| CN103554203A (en) | Amorphous crystal of tylonolide, and preparation method thereof | |
| WO2023019839A1 (en) | Preparation and post-treatment method for 5-aminolevulinate | |
| CN103833755A (en) | Crystal form B of Apixaban and preparation method thereof | |
| CN114957236A (en) | Preparation method of 2-acylaminothiazole compound | |
| CN104744464B (en) | Istradefylline crystal formation | |
| CN102718676B (en) | Agomelatine sulfate and preparation method thereof | |
| CN103980166B (en) | A kind of novel crystal forms of florfenicol and preparation method thereof | |
| CN105884644A (en) | Advantage forms and preparation method of neutral endopeptidase inhibitor salt | |
| CN102464639A (en) | Novel crystal forms of mycophenolate sodium and preparation method thereof | |
| CN105237617A (en) | Monohydrate of N(2)-L-alanyl-L-glutamine and preparation method of monohydrate | |
| CN103374052B (en) | Capecitabine crystal formation and preparation method thereof | |
| CN107827911A (en) | A kind of 7 phenylacetylamino cephalosporanic acid composite crystals and preparation method thereof | |
| CN105960393A (en) | lithium styrene sulfonate | |
| WO2017152858A1 (en) | Crystal form of ceritinib and preparation method thereof | |
| CN107188820A (en) | One planting sand storehouse is than novel crystal forms of bent sodium salt and preparation method thereof | |
| CN106977413A (en) | A kind of preparation method of DL L-aminobutanedioic acids DL ornithines | |
| CN107337708A (en) | Pidotimod novel crystal forms and preparation method thereof | |
| CN102060804A (en) | Method for preparing 1,3,4-thiadiazole derivatives | |
| CN107245041A (en) | A kind of preparation method of arginine Ibuprofen | |
| WO2015123801A1 (en) | Preparation method for polymorphic 6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine and use thereof | |
| JP2011178739A (en) | Carnitine fumarate and method for producing the same |
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 | ||
| CP03 | Change of name, title or address |
Address after: 226100 No.1, Linjiang Avenue, Linjiang Town, Haimen District, Nantong City, Jiangsu Province Patentee after: Jiangsu Weiqida Pharmaceutical Co., Ltd Patentee after: SHANGSHAI SHYNDEC PHARMACEUTICAL Co.,Ltd. Address before: 226100 No.3 Inner 2, Lingdian Industrial Centralized East District, Haimen City, Nantong City, Jiangsu Province Patentee before: SHANGHAI SHYNDEC PHARMACEUTICAL Co.,Ltd. Patentee before: SHANGSHAI SHYNDEC PHARMACEUTICAL Co.,Ltd. |
|
| CP03 | Change of name, title or address |