CN104530053A - Preparation method of medicinal crystal form tofacitinib citrate - Google Patents
Preparation method of medicinal crystal form tofacitinib citrate Download PDFInfo
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- CN104530053A CN104530053A CN201410740110.1A CN201410740110A CN104530053A CN 104530053 A CN104530053 A CN 104530053A CN 201410740110 A CN201410740110 A CN 201410740110A CN 104530053 A CN104530053 A CN 104530053A
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- preparation
- citric acid
- buddhist nun
- acid holder
- holder method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides a preparation method of medicinal crystal form tofacitinib citrate. The preparation method comprises the following steps of 1, taking a tofacitinib citrate raw material, pumping a solvent into the raw material in vacuum, heating the mixture for dissolution, and carrying out thermal insulation stirring for 1-2h, 2, carrying out slow cooling to 0-50 DEG C, and carrying out thermal insulation stirring for 4-10h for crystallization, and 3, carrying out filtration and drying to obtain the medicinal crystal form tofacitinib citrate. Through strict control of a crystallization temperature, crystallization time and a use amount of a solvent in the process, the preparation method greatly improves a yield and purity of tofacitinib citrate, the highest yield is 90% and purity is more than 99.7% The preparation method has less total impurities and has all single impurity contents less than 0.1%. A powdery X-ray diffractometer test proves that the finished product obtained by the preparation method has a single and stable crystal form and satisfies medicinal-grade bulk drug requirements.
Description
Technical field
The invention belongs to pharmaceutical production technical field, be specifically related to the preparation method of a kind of medicinal crystal-form Citric Acid holder method for Buddhist nun.
Background technology
Citric Acid holder method is for a kind of new oral JAK inhibitor of Ni Shi Pfizer Inc. exploitation, the listing that in November, 2012 is ratified through U.S. FDA, commodity are called Xeljanz, for methotrexate for treatment response insufficient or in not tolerating to the treatment of the adult patient of severe active rheumatoid arthritis.
Chinese patent ZL02823587.8(Pfizer Inc.) disclose its crystal formation, to be its differential scanning calorimetric curve have characteristic peak the temperature of about 203 ~ 210 DEG C to its characteristic feature, has the beginning melt temperature of about 199 ~ 206 DEG C.The feather weight amplification technique of this patent report is tested through repeated authentication, and take through influence factor experiment investigation such as high temperature, high humidity, illumination after product, the change of its impurity has the trend of rising.
Chinese patent CN103073552A reports the preparation method of unformed Citric Acid holder method for Buddhist nun, it mentions finished product through factors influencing, product quality is more stable, and cannot repeat embodiment according to the temperature in this patent documentation embodiment and quantity of solvent, and finished product also cannot dissolve in methyl alcohol.
Based on the above fact, consider the market outlook of Citric Acid holder method for Buddhist nun, develop new Citric Acid holder method and replace the preparation technology of Buddhist nun's medicinal crystal-form to be very important.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of method that applicable Citric Acid holder method is prepared for Buddhist nun's medicinal crystal-form, and the production of the method short and easy handling consuming time, total impurities is few simultaneously, and single impurity meets medicinal requirements.
Technical scheme of the present invention is as follows:
Medicinal crystal-form Citric Acid holder method, for a Buddhist nun's preparation method, comprises the steps:
(1) get Citric Acid holder method for Buddhist nun's bulk drug, pump into solvent aqueous solution under vacuum, heating makes it dissolve, then insulated and stirred 1 ~ 2 hour;
(2) slow cooling to 0 ~ 50 DEG C, insulated and stirred 4 ~ 10 hours crystallizatioies;
(3) filter, and collect the xln of separating out, finally xln is carried out vacuum-drying in 30 ~ 60 DEG C, obtain medicinal crystal-form Citric Acid holder method for Buddhist nun.
Preferred technical scheme is, adds Citric Acid holder method and carry out crystallization for Buddhist nun's crystal seed in described step (2) before insulated and stirred, and described Citric Acid holder method is the 2-4% of Citric Acid holder method for Buddhist nun's bulk drug quality for the add-on of Buddhist nun's crystal seed.
Solvent in described step (1) be by ethanol, Virahol or propyl carbinol to form mass concentration be at least one in the aqueous solution of 50-75%.
Citric Acid holder method in described step (1) is 1:10 ~ 1:20 for the mass ratio of Buddhist nun's bulk drug and solvent.
The temperature of the heating for dissolving in described step (1) is 60 ~ 95 DEG C; The time of slow cooling to 0 ~ 50 DEG C is 1 ~ 3 hour in described step (2).
Compared with prior art, the present invention has following beneficial effect to preparation method of the present invention:
1, the medicinal crystal-form Citric Acid holder method that prepared by the present invention can produce the character of different spectrum for Buddhist nun, it is that Citric Acid holder method is for Buddhist nun's crystal formation that the present invention detects product prepared by preparation method of the present invention by powder x-ray diffraction, and the fusing point of crystal is determined by differential scanning calorimetry (TGA-DSC), this crystal formation does not have relevant speciality bibliographical information at present, has certain novelty.
2, the present invention is by strictly controlling the consumption of solvent in recrystallization temperature, time and process, and greatly increase yield and purity that Citric Acid holder method replaces Buddhist nun, its productive rate is the highest can reach 90%, high purity more than 99.7%.
3, production technique of the present invention is easy and simple to handle, and cost is low, be suitable for high purity, high yield Citric Acid holder method for Buddhist nun's suitability for industrialized production, there is very high economic benefit.
4, beneficial effect of the present invention is further illustrated by following test:
Citric Acid holder method prepared by the present invention replaces Buddhist nun for Buddhist nun's medicinal crystal-form and the Citric Acid holder method prepared by Chinese patent ZL 02823587.8, and the situation that the related substance under each influence factor compares is as shown in table 1 below:
Table 1: Performance comparision
Table 1 test-results shows, medicinal crystal-form Citric Acid holder method prepared by the present invention all shows satisfactory stability for Buddhist nun under high temperature, super-humid conditions, it is under each influence factor, the Citric Acid holder method that its fusing point is all prepared higher than patent (ZL02823587.8) method replaces Buddhist nun, and the Citric Acid holder method that its foreign matter content is prepared lower than patent (ZL02823587.8) method replaces Buddhist nun.
Accompanying drawing explanation
Fig. 1 is the powder X-ray-ray collection of illustrative plates of the Citric Acid holder method prepared of the present invention for Buddhist nun;
Fig. 2 is the powder TGA-DSC collection of illustrative plates of the Citric Acid holder method prepared of the present invention for Buddhist nun.
Embodiment
The present invention is further illustrated below by embodiment.Should correct understanding: the method in embodiments of the invention is only used for specification sheets invention and provides, instead of limitation of the present invention, institute all belongs to the scope of protection of present invention to simple modifications of the present invention under prerequisite with the inventive method.
Following examples Material Source used is described as follows:
Citric Acid holder method for Buddhist nun's bulk drug be currently available products, commercially can buy and also can prepare voluntarily according to its production method, other reagent Chemical Reagent Co., Ltd., Sinopharm Group and Xilong Chemical Co., Ltd all on sale.
Embodiment 1
Drop into 70g Citric Acid holder method in the reactor for Buddhist nun's bulk drug, vacuum pumps into 0.7kg aqueous ethanolic solution simultaneously, and wherein the mass ratio of isopropyl alcohol and water is 1:1; Slowly being heated to about 60 DEG C makes it dissolve, and then insulated and stirred 2 hours, obtains clear transparent solutions; Then 2 hours consuming time slow coolings to 15 DEG C, insulated and stirred 4 hours crystallizatioies; Centrifuge dripping is carried out to the crystal of separating out and obtains 63g off-white color wet product, and in 50 DEG C of reduced vacuum dryings 8 hours, obtain the white solid of 60g drying.
Carry out X-ray diffraction detection to it, its X-ray collection of illustrative plates as shown in Figure 1, illustrates that white solid is that medicinal crystal-form Citric Acid holder method is for Buddhist nun; Determined the fusing point of crystal by differential scanning calorimetry (TGA-DSC), its fusing point is 214 ~ 220 DEG C, and its TGA-DSC collection of illustrative plates as shown in Figure 2.In addition with HPLC detect Citric Acid holder method for the purity of Buddhist nun's medicinal crystal-form be about 99.7%, single assorted be all less than 0.1%, yield is about 90%.
Embodiment 2:
Drop into 70g Citric Acid holder method in the reactor for Buddhist nun's bulk drug, vacuum pumps into 1.05kg isopropanol water solution simultaneously, and wherein the mass ratio of isopropyl alcohol and water is 2:1, and be slowly heated to about 80 DEG C and make it dissolve, then insulated and stirred 1 hour, obtains clear transparent solutions; Then 2 hours consuming time slow coolings are to about 15 DEG C, insulated and stirred 4 hours crystallizatioies; 65g off-white color wet product is obtained to its centrifuge dripping, in 30 DEG C of reduced vacuum dryings 8 hours, obtains the white medicinal crystal-form Citric Acid holder method of 61g drying for Buddhist nun's solid.
Embodiment 3:
Drop into 70g Citric Acid holder method in the reactor for Buddhist nun's bulk drug, vacuum pumps into 1.4kg isopropanol water solution simultaneously, and wherein the mass ratio of isopropyl alcohol and water is 3:1, and be slowly heated to about 95 DEG C and make it dissolve, then insulated and stirred 2 hours, obtains clear transparent solutions; 1 hour consuming time slow cooling to 10 DEG C again, insulated and stirred 8 hours crystallizatioies; 66g off-white color wet product is obtained to its centrifuge dripping, and in 60 DEG C of reduced vacuum dryings 8 hours, obtains the white medicinal crystal-form Citric Acid holder method of 59g drying for Buddhist nun's solid.
Embodiment 4
Drop into 70g Citric Acid holder method in the reactor for Buddhist nun's bulk drug, vacuum pumps into 1.05kg isopropanol water solution (mass ratio, Virahol: water=3:1) simultaneously, is slowly heated to about 95 DEG C and makes it dissolve, and insulated and stirred 1.5 hours, obtain clear transparent solutions; Within 2 hours consuming time, slowly reduce temperature to about 25 DEG C, add 2g Citric Acid holder method again for Buddhist nun's crystal seed, insulated and stirred 10 hours, centrifuge dripping obtains 73g off-white color wet product, by it in 30 DEG C of reduced vacuum dryings 9 hours, obtain the white medicinal crystal-form Citric Acid holder method of 66g drying for Buddhist nun's solid.
Embodiment 5
Drop into 70g Citric Acid holder method in the reactor for Buddhist nun's bulk drug, vacuum pumps into the moisture butanol solution of 0.7kg (Virahol: water=1:1 mass ratio) simultaneously, slowly being heated to about 80 DEG C makes it dissolve, then insulated and stirred 2 hours, obtain clear transparent solutions, within 3 hours consuming time, slowly reduce temperature to about 0 DEG C, add the crystal seed of 1.4g Citric Acid holder method for Buddhist nun, insulated and stirred 4 hours, centrifuge dripping obtains 71g off-white color wet product, 50 DEG C of drying under reduced pressure 9 hours, obtain the white medicinal crystal-form Citric Acid holder method of 68g drying for Buddhist nun's solid.
Embodiment 6
Drop into 70g Citric Acid holder method in the reactor for Buddhist nun's bulk drug, vacuum pumps into the moisture butanol solution of 1.4kg (Virahol: water=2:1 mass ratio) simultaneously, slowly being heated to about 80 DEG C makes it dissolve, then insulated and stirred 2 hours, obtain clear transparent solutions, within 1.5 hours consuming time, slowly reduce temperature to about 25 DEG C, add 2.8g Citric Acid holder method again for Buddhist nun's crystal seed, insulated and stirred 6 hours, centrifuge dripping obtains 72g off-white color wet product, spread with 100g ice acetone and wash 2 times, after recentrifuge dries, in 60 DEG C of reduced vacuum dryings 9 hours, obtain the white medicinal crystal-form Citric Acid holder method of 67.5g drying for Buddhist nun's solid.
Above embodiment is not limited only to protection domain of the present utility model, all modify based on basic thought of the present utility model or change all belong to protection domain of the present utility model.
Claims (5)
1. medicinal crystal-form Citric Acid holder method is for a Buddhist nun's preparation method, it is characterized in that: comprise the steps:
(1) get Citric Acid holder method for Buddhist nun's bulk drug, pump into solvent under vacuum, heating makes it dissolve, then insulated and stirred 1 ~ 2 hour;
(2) slow cooling to 0 ~ 50 DEG C, insulated and stirred 4 ~ 10 hours crystallizatioies;
(3) filter, and collect the xln of separating out, finally xln is carried out vacuum-drying in 30 ~ 60 DEG C, obtain medicinal crystal-form Citric Acid holder method for Buddhist nun.
2. preparation method according to claim 1, it is characterized in that: before insulated and stirred, add Citric Acid holder method in described step (2) carry out crystallization for Buddhist nun's crystal seed, described Citric Acid holder method is the 2-4% of Citric Acid holder method for Buddhist nun's bulk drug quality for the add-on of Buddhist nun's crystal seed.
3. preparation method according to claim 1, is characterized in that: the solvent in described step (1) be by ethanol, Virahol or propyl carbinol to form mass concentration be at least one in the aqueous solution of 50-75%.
4. preparation method according to claim 1, is characterized in that: the Citric Acid holder method in described step (1) is 1:10 ~ 1:20 for the mass ratio of Buddhist nun's bulk drug and solvent.
5. preparation method according to claim 1, is characterized in that: the temperature of the heating for dissolving in described step (1) is 60 ~ 95 DEG C; The time of slow cooling to 0 ~ 50 DEG C is 1 ~ 3 hour in described step (2).
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| CN201410740110.1A CN104530053A (en) | 2014-12-08 | 2014-12-08 | Preparation method of medicinal crystal form tofacitinib citrate |
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| CN201410740110.1A CN104530053A (en) | 2014-12-08 | 2014-12-08 | Preparation method of medicinal crystal form tofacitinib citrate |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153166A (en) * | 2015-08-07 | 2015-12-16 | 湖北丽益医药科技有限公司 | N- [ (3R,4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine crystal |
| CN106967072A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN107814802A (en) * | 2016-09-12 | 2018-03-20 | 江苏艾立康药业股份有限公司 | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form |
| CN108358929A (en) * | 2017-11-03 | 2018-08-03 | 江苏正大清江制药有限公司 | Refining method of tofacitinib citrate |
| CN108484607A (en) * | 2018-03-26 | 2018-09-04 | 山东科兴生物制品有限公司 | Novel preparation method of tofacitinib citrate |
| CN108948020A (en) * | 2018-07-03 | 2018-12-07 | 南京正大天晴制药有限公司 | Refining method of tofacitinib citrate |
| CN109516991A (en) * | 2018-12-29 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof |
| CN110437234A (en) * | 2019-08-07 | 2019-11-12 | 广州一品红制药有限公司 | Tofacitinib citrate crystal form compound and preparation method and application thereof |
Citations (3)
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| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| WO2014102826A1 (en) * | 2012-12-28 | 2014-07-03 | Glenmark Pharmaceuticals Limited; | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
| CN104059016A (en) * | 2014-06-20 | 2014-09-24 | 湖南天地恒一制药有限公司 | Intermediate for preparing tofacitinib and preparation method of intermediate |
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Patent Citations (3)
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| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| WO2014102826A1 (en) * | 2012-12-28 | 2014-07-03 | Glenmark Pharmaceuticals Limited; | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
| CN104059016A (en) * | 2014-06-20 | 2014-09-24 | 湖南天地恒一制药有限公司 | Intermediate for preparing tofacitinib and preparation method of intermediate |
Non-Patent Citations (1)
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| 赵方露: "枸橼酸托法替尼的合成", 《中国医药工业杂志》, vol. 45, no. 3, 31 March 2014 (2014-03-31), pages 201 - 253 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153166A (en) * | 2015-08-07 | 2015-12-16 | 湖北丽益医药科技有限公司 | N- [ (3R,4R) -1-benzyl-4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine crystal |
| CN107814802A (en) * | 2016-09-12 | 2018-03-20 | 江苏艾立康药业股份有限公司 | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form |
| CN106967072A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN106967072B (en) * | 2017-04-12 | 2019-05-03 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN108358929A (en) * | 2017-11-03 | 2018-08-03 | 江苏正大清江制药有限公司 | Refining method of tofacitinib citrate |
| CN108484607A (en) * | 2018-03-26 | 2018-09-04 | 山东科兴生物制品有限公司 | Novel preparation method of tofacitinib citrate |
| CN108948020A (en) * | 2018-07-03 | 2018-12-07 | 南京正大天晴制药有限公司 | Refining method of tofacitinib citrate |
| CN109516991A (en) * | 2018-12-29 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof |
| CN110437234A (en) * | 2019-08-07 | 2019-11-12 | 广州一品红制药有限公司 | Tofacitinib citrate crystal form compound and preparation method and application thereof |
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Application publication date: 20150422 |