CN103524365A - Method for preparing lysine ketoprofen - Google Patents
Method for preparing lysine ketoprofen Download PDFInfo
- Publication number
- CN103524365A CN103524365A CN201310395437.5A CN201310395437A CN103524365A CN 103524365 A CN103524365 A CN 103524365A CN 201310395437 A CN201310395437 A CN 201310395437A CN 103524365 A CN103524365 A CN 103524365A
- Authority
- CN
- China
- Prior art keywords
- ketoprofen
- lysine
- reaction
- drying
- vacuum
- 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.)
- Pending
Links
Abstract
The invention discloses a method for preparing lysine ketoprofen. The method comprises the following steps: adding ketoprofen into a lysine solution, reacting at room temperature to form salts, adding absolute ethyl alcohol for crystallization after the reaction is ended, performing suction filtration, and performing vacuum drying on the filter cake to obtain the product of lysine ketoprofen. The preparation method has the advantages that the yield is high and can be over 95 percent, the product purity is high and can be over 99 percent, the reaction conditions are moderate, the reaction time is short, the drying temperature is proper, the production cost is greatly reduced, and the process is simple and suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, specifically, relate to a kind of preparation method of lysine-ketoprofen.
Background technology
Ketoprofen is a kind of NSAID (non-steroidal anti-inflammatory drug), and its main mechanism is reversible inhibition epoxidase and oxygenase of ester, thereby suppresses the biosynthesizing of Prostaglandins and Leukotrienes, brings into play analgesic, analgesia and antiinflammation.Yet Ketoprofen is aryl alkanoic acid compounds, water insoluble, after stomach and intestine administration in main distribution and stomach, small intestine and kidney, so larger to GI hormesis, side effect is clinically more, as stomachache, pyrosis sense, nausea,vomiting,diarrhea, poor appetite etc.
Lysine-ketoprofen, is called again ARTROSILENE, is the double salt of Methionin and Ketoprofen.This product is a kind of newtype drug combination of Ketoprofen, has potent anti-inflammatory, analgesic activity.Lysine-ketoprofen has not only kept original drug effect of Ketoprofen, and has changed its water-fast character.This has not only improved bioavailability, and has reduced untoward reaction, has expanded Ketoprofen use range clinically.The water-based patch that in July, 2012, Chinese patent CN101977598 contained Lysine m-benzoylhydratropate is authorized.
Chinese patent CN1939893 discloses lysine-ketoprofen and preparation method thereof, and it is mainly in lysine solution, to add Ketoprofen, stirs clarification, vacuum lyophilization.But there is following shortcoming in aforesaid method: product drying temperature is too low, and general device cannot withstand the low temperature of-45 ℃, and this has increased production cost undoubtedly; Complete whole product drying process and need altogether 21 hours, time of drying is long, and this has further increased production cost; Adopt the product of lyophilize gained, product porous, fluffy, character is unstable.
Summary of the invention
Preparation method not enough for prior art and a kind of economic environment-friendly type lysine-ketoprofen that provide is provided, and the method reaction conditions is gentle, and drying temperature is suitable and the time is short.
The present invention solves this technical problem by the following technical programs: to lysine solution, add Ketoprofen BP 93 (being Ketoprofen), room temperature reaction salify, after reaction finishes, add dehydrated alcohol crystallization, suction filtration, filter cake make product lysine-ketoprofen through vacuum-drying.
Further, in the preparation method of lysine-ketoprofen provided by the invention, in step (1), the add-on proportioning of each component and concrete reaction parameter are preferably: 25～35 weight part Methionins are joined in 260～270 weight parts waters, stirring at room, treat that it all dissolves, add 45～55 weight part Ketoprofen BP 93s, room temperature reaction 10～40min.
Preferably, Methionin is 29.2 weight parts, and purified water is 263 weight parts, and Ketoprofen BP 93 is 50.8 weight parts.
Preferably, the reaction times in step (1) is 30min.
Preferably, the measure of step (2) is: to the middle reaction solution of step (1), add dehydrated alcohol, crystallization, balance 1～4h.
Preferably, with respect to every 25～35 grams of Methionins that add in step (1), every 260～270 grams of water and every 45～55 grams of Ketoprofen BP 93s, in step (2), the add-on of dehydrated alcohol is 300-800ml, and starting time is 2-3h.Preferred dehydrated alcohol add-on is 600ml, and starting time is 3h.
Preferably, in step (4), vacuum-drying temperature is 45-50 ℃, and the vacuum-drying time is 7-9h.More preferably, in step (4), vacuum-drying temperature is 50 ℃, and the vacuum-drying time is 8h.
Preferably, the suction filtration of the crystallization of step (2), step (3) all at room temperature carries out.Preferably, described Methionin is D-Lys, 1B or DL-Lys; Described Ketoprofen is left-handed Ketoprofen, dexketoprofen or racemization Ketoprofen.
One provided by the invention preferably the preparation method of lysine-ketoprofen is as follows:
25～35g Methionin is joined in 260～270g purified water, and stirring at room, treats that it all dissolves, and adds 45～55g Ketoprofen BP 93, room temperature reaction 10～40min.To reaction solution in step 1), add 300～800ml dehydrated alcohol, crystallization, balance 1～4h.Suction filtration.Filter cake is placed in 30～70 ℃ of vacuum-drying 4～12h, obtains lysine-ketoprofen product.
The preparation method of a best lysine-ketoprofen provided by the invention is as follows:
29.2g Methionin is joined in 263g purified water, and stirring at room, treats that it all dissolves, and adds 50.8g Ketoprofen BP 93, room temperature reaction 30min.To reaction solution in step 1), add 600ml dehydrated alcohol, crystallization, balance 3h.Suction filtration.Filter cake is placed in 50 ℃ of vacuum-drying 8h, obtains lysine-ketoprofen product.
Preferably, above-mentioned preparation method is only comprised of described four steps, no longer comprises other treatment steps, thereby can shorten the production time to the full extent.
In the chemosynthesis of lysine-ketoprofen, the conditions such as the ratio of raw material and temperature of reaction have very large impact to the trend of building-up reactions, the present invention passes through great many of experiments, suitable proportioning raw materials and reaction conditions have been selected, can realize maximized synthetic, productive rate is improved, and the finished product also have higher purity.
Useful technique effect of the present invention is: (1) product yield is high, can reach 95.3%.(2) reaction conditions is gentle, and the reaction times is short.(3) drying temperature is suitable, has greatly reduced production cost.(4) technique is simple, is applicable to suitability for industrialized production.(5) products obtained therefrom has not only kept physiologically active and the bioavailability of Ketoprofen, and is dissolvable in water water, can be used for being prepared into various pharmaceutical dosage forms, reduces untoward reaction.The product of method gained of the present invention, meets national standard, solves the technical barriers such as the condition of traditional processing technology is harsh, with high costs, and productive rate and product purity are lower.
Embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is described in further detail.Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.If not specified, the present invention's raw material, reagent used is commercially available.
The preparation of embodiment 1 lysine-ketoprofen
29.2g Methionin is joined in 263g purified water, and stirring at room, treats that it all dissolves, and adds 50.8g Ketoprofen BP 93, room temperature reaction 30min.To reaction solution, add 400ml dehydrated alcohol, crystallization, balance 3h, suction filtration.Filter cake, in 50 ℃ of vacuum-drying 8h, obtains lysine-ketoprofen product 73.9g, and yield is 92.4%.Gained lysine-ketoprofen is white crystalline powder, and odorless is soluble in water, is 162.5 ℃,, it is 99.2% that HPLC method detects gained lysine-ketoprofen product purity, single contaminant≤0.02%, total assorted≤0.02%.
The preparation of embodiment 2 lysine-ketoprofens
29.2g Methionin is joined in 263g purified water, and stirring at room, treats that it all dissolves, and adds 50.8g Ketoprofen BP 93, room temperature reaction 30min.To reaction solution, add 600ml dehydrated alcohol, crystallization, balance 3h, suction filtration.Filter cake, in 50 ℃ of vacuum-drying 8h, obtains lysine-ketoprofen product 76.2g, and yield is 95.3%.Gained lysine-ketoprofen is white crystalline powder, and odorless is soluble in water, and fusing point is 162.5 ℃, and it is 99.1% that HPLC method detects gained lysine-ketoprofen product purity, single contaminant≤0.02%, total assorted≤0.02%.
The preparation of embodiment 3 lysine-ketoprofens
31g Methionin is joined in 265g purified water, and stirring at room, treats that it all dissolves, and adds 53.9g Ketoprofen BP 93, room temperature reaction 30min.To reaction solution, add 700ml dehydrated alcohol, crystallization, balance 3h, suction filtration.Filter cake, in 50 ℃ of vacuum-drying 8h, obtains lysine-ketoprofen product 81.3g, and yield is 96.2%.Gained lysine-ketoprofen is white crystalline powder, and odorless is soluble in water, and fusing point is 162.5 ℃, and it is 99.5% that HPLC method detects gained lysine-ketoprofen product purity, single contaminant≤0.02%, total assorted≤0.02%.The product of method gained of the present invention, meets national standard, solves the technical barriers such as the condition of traditional processing technology is harsh, with high costs, and productive rate and product purity are lower.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, do not departing under the prerequisite of the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (8)
1. a preparation method for lysine-ketoprofen, is characterized in that in turn including the following steps:
(1) to lysine solution, add Ketoprofen BP 93, room temperature reaction salify;
(2) after reaction finishes, add dehydrated alcohol crystallization;
(3) suction filtration;
(4) filter cake, through vacuum-drying, makes lysine-ketoprofen product.
2. preparation method according to claim 1, is characterized in that, the method comprises the following steps successively:
(1) 25～35 weight part Methionins are joined in 260～270 weight parts waters, stirring at room, treats that it all dissolves, and adds 45～55 weight part Ketoprofen BP 93s, room temperature reaction 10～40min;
(2) to the middle reaction solution of step (1), add dehydrated alcohol, crystallization, balance 1～4h;
(3) suction filtration;
(4) filter cake is placed in 30～70 ℃ of vacuum-drying 4～12h, obtains lysine-ketoprofen product.
3. method according to claim 2, is characterized in that in step (1), Methionin is 29.2 weight parts, and water is 263 weight parts, and Ketoprofen BP 93 is 50.8 weight parts.
4. method according to claim 2, wherein the reaction times of step (1) is preferably 30min.
5. method according to claim 2, wherein the suction filtration of the crystallization of step (2), step (3) all at room temperature carries out.
6. method according to claim 2, wherein with respect to the amount of each component adding in step (1), in step (2), the add-on of dehydrated alcohol is: with respect to every 25～35 grams of Methionins, every 260～270 grams of water and every 45～55 grams of Ketoprofen BP 93s, dehydrated alcohol is 300-800ml, be preferably 600ml, the starting time of step (2) is 2-3h, is preferably 3h.
7. method according to claim 1 and 2, is characterized in that in step (4), vacuum-drying temperature is 45-55 ℃, is preferably 50 ℃, and the vacuum-drying time is 7-9h, is preferably 8h.
8. preparation method according to claim 1 and 2, is characterized in that, described Methionin is D-Lys, 1B or DL-Lys; Described Ketoprofen is left-handed Ketoprofen, dexketoprofen or racemization Ketoprofen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310395437.5A CN103524365A (en) | 2013-09-03 | 2013-09-03 | Method for preparing lysine ketoprofen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310395437.5A CN103524365A (en) | 2013-09-03 | 2013-09-03 | Method for preparing lysine ketoprofen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103524365A true CN103524365A (en) | 2014-01-22 |
Family
ID=49926774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310395437.5A Pending CN103524365A (en) | 2013-09-03 | 2013-09-03 | Method for preparing lysine ketoprofen |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103524365A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987287A (en) * | 2015-06-10 | 2015-10-21 | 上海现代制药海门有限公司 | Preparation method for spherical ketoprofen lysine |
| CN115038686A (en) * | 2019-12-23 | 2022-09-09 | 导博药物公司 | Ketoprofen eutectic, preparation thereof, pharmaceutical composition containing ketoprofen eutectic and application thereof |
| CN115038686B (en) * | 2019-12-23 | 2024-04-30 | 导博药物公司 | Ketoprofen co-crystal and preparation thereof, pharmaceutical composition containing ketoprofen co-crystal and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939893A (en) * | 2005-09-28 | 2007-04-04 | 北京赛生药业有限公司 | Lysine-ketoprofen and its production |
| CN101255121A (en) * | 2008-04-15 | 2008-09-03 | 中国医学科学院医药生物技术研究所 | Preparation technique of lysine rhein and use thereof in tumour therapy |
| CN101935293A (en) * | 2010-09-03 | 2011-01-05 | 蚌埠丰原涂山制药有限公司 | Method for preparing arginine ketoprofenate |
-
2013
- 2013-09-03 CN CN201310395437.5A patent/CN103524365A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939893A (en) * | 2005-09-28 | 2007-04-04 | 北京赛生药业有限公司 | Lysine-ketoprofen and its production |
| CN101255121A (en) * | 2008-04-15 | 2008-09-03 | 中国医学科学院医药生物技术研究所 | Preparation technique of lysine rhein and use thereof in tumour therapy |
| CN101935293A (en) * | 2010-09-03 | 2011-01-05 | 蚌埠丰原涂山制药有限公司 | Method for preparing arginine ketoprofenate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987287A (en) * | 2015-06-10 | 2015-10-21 | 上海现代制药海门有限公司 | Preparation method for spherical ketoprofen lysine |
| CN115038686A (en) * | 2019-12-23 | 2022-09-09 | 导博药物公司 | Ketoprofen eutectic, preparation thereof, pharmaceutical composition containing ketoprofen eutectic and application thereof |
| CN115038686B (en) * | 2019-12-23 | 2024-04-30 | 导博药物公司 | Ketoprofen co-crystal and preparation thereof, pharmaceutical composition containing ketoprofen co-crystal and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Improving the dissolution and bioavailability of 6-mercaptopurine via co-crystallization with isonicotinamide | |
| CN102827153B (en) | Crystal formation of Azilsartan and preparation method thereof | |
| CN109503462B (en) | Synthesis method of tofacitinib intermediate (3R, 4R) -N, 4-dimethyl-1-benzyl-3-piperidylamine | |
| FI89598C (en) | FREQUENCY REFRIGERATION OF A WATER FRAME, CRYSTALLINE SODIUM SALT OF 5-CHLORO-3- (2-TENOYL) -2-OXINDOL-1-CARBOXAMIDE SOM LAEMPAR SIG FOER ANVAENDNING SOM ANALGETISKT ELLER ANTIINFLAMMATORISKT MEDEL | |
| EP0271709B1 (en) | Salt of diclofenac with a cyclic organic base and pharmaceutical compositions which contain it | |
| US8680329B2 (en) | Process for preparation of α-ketoglutaric acid | |
| CN103524365A (en) | Method for preparing lysine ketoprofen | |
| CA3112205A1 (en) | Process for making calcium alpha-ketoglutarate | |
| CN110511156B (en) | Preparation method of aspirin-lysine | |
| CN105193749A (en) | Medicinal tadalafil composition tablets for treating urological diseases | |
| CN106397294B (en) | A kind of preparation method of nootropics (S)-Oxiracetam | |
| CN102030807B (en) | Theasapogenol derivative with anti-HIV (Human Immunodeficiency Virus) activity, preparation method and application thereof | |
| CN112645862B (en) | Pirfenidone photodegradation impurities and preparation method thereof | |
| FR2544718A1 (en) | NIFLUMIC ACID MORPHOLINOETHYL ESTER DINIFLUMATE, PREPARATION, THERAPEUTIC USE AS ANALGESIC AND ANTI-INFLAMMATORY | |
| CN102093254B (en) | Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate | |
| TWI599571B (en) | Process for prepararing intermediate compound of ixazomib citrate, and ixazomib citrate made thereby | |
| CN101337903A (en) | Method for preparing ethyl levodopa | |
| CN106279267B (en) | A kind of purification process of Creatine Phosphate Sodium and its preparation of aseptic powder | |
| CN104130168B (en) | A kind of oxalic acid valnemulin crystal and preparation method thereof | |
| CN103864718B (en) | A kind of method preparing two thiadiazoles diamines | |
| JP2008156282A (en) | SALT OF alpha-LIPOIC ACID AND L-ORNITHINE, AND METHOD FOR PREPARING THE SAME | |
| CN112839934B (en) | Vonoprazan salt and preparation method and application thereof | |
| CN102180785A (en) | Synthesis and application of ibuprofen lysine | |
| CN107721881A (en) | The preparation method of 2 guanidine radicals benzenpropanoic acids | |
| CN106748965A (en) | A kind of preparation method of onglyza intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140122 |