CN108484607A - Novel preparation method of tofacitinib citrate - Google Patents
Novel preparation method of tofacitinib citrate Download PDFInfo
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- CN108484607A CN108484607A CN201810253318.9A CN201810253318A CN108484607A CN 108484607 A CN108484607 A CN 108484607A CN 201810253318 A CN201810253318 A CN 201810253318A CN 108484607 A CN108484607 A CN 108484607A
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- tofacitinib
- citrate
- tofacitinib citrate
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- 229960004247 tofacitinib citrate Drugs 0.000 title claims abstract description 45
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000004012 Tofacitinib Substances 0.000 claims abstract description 57
- 229960001350 tofacitinib Drugs 0.000 claims abstract description 57
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 claims abstract description 57
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000000243 solution Substances 0.000 claims abstract description 30
- 239000000047 product Substances 0.000 claims abstract description 28
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000012043 crude product Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 238000001816 cooling Methods 0.000 claims abstract description 19
- 238000001035 drying Methods 0.000 claims abstract description 16
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 238000005406 washing Methods 0.000 claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 13
- 230000008025 crystallization Effects 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001179 sorption measurement Methods 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 29
- 239000002245 particle Substances 0.000 claims description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- 239000013078 crystal Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 24
- 239000000049 pigment Substances 0.000 abstract description 10
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 abstract 1
- 229960002303 citric acid monohydrate Drugs 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 41
- 238000001514 detection method Methods 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- 238000000634 powder X-ray diffraction Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000004455 differential thermal analysis Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 239000003463 adsorbent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- -1 cyanoacetate compound Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007561 laser diffraction method Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a novel preparation method of tofacitinib citrate, and particularly provides a preparation method of tofacitinib citrate, which comprises the steps of adding a coarse product of a tofacitinib intermediate into a solvent, completely dissolving at a higher temperature, adding medicinal activated carbon and activated alumina, and stirring for adsorption; filtering to remove medicinal active carbon and active alumina, adding a precooled alkaline aqueous solution into the filtrate, cooling to 0-5 ℃ for crystallization, washing and drying to obtain a refined product of the tofacitinib intermediate; and dissolving citric acid monohydrate into an ethanol water solution, adding the tofacitinib intermediate refined product, and crystallizing to obtain the tofacitinib citrate. The method can obviously reduce the pigments and impurities which are difficult to remove in the tofacitinib intermediate crude product, thereby obtaining the high-purity tofacitinib intermediate refined product.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a novel preparation method of tofacitinib citrate.
Background
Tofacitinib citrate (Tofacitinib citrate), a Janus kinase inhibitor developed by Pfizer, U.S. a chemical name of 3- { (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -piperidin-1-yl ] -3-oxo-propionitrile citrate with the following structural formula:
the united states Food and Drug Administration (FDA) approved the drug for marketing in 2012 for the treatment of moderate to severe active Rheumatoid Arthritis (RA) that is poorly responsive or intolerant to methotrexate treatment.
In the prior art, N-methyl-N- [ (3R,4R) -4-methylpiperidine-3-yl ] -7-H-pyrrolo [2,3-d ] pyrimidine-4-amine is used as a raw material and reacts with a cyanoacetate compound under an alkaline condition to prepare tofacitinib, such as the preparation method reported in the patent document WO2007012953A2, the yield is low (about 60%), the by-product impurities are more, the refining and purifying process is complex, and the cost for obtaining high-purity refined tofacitinib citrate is high. Therefore, the person skilled in the art is working to optimize the process for the preparation of tofacitinib citrate.
Disclosure of Invention
In view of the defects in the prior art, the technical problem to be solved by the invention is to provide a novel preparation process of tofacitinib citrate, and obtain a high-purity tofacitinib citrate refined product at a lower cost.
In order to achieve the above object, a first aspect of the present invention provides a method for preparing tofacitinib citrate, comprising the steps of:
(1) adding the tofacitinib intermediate crude product into a solvent, completely dissolving at a higher temperature, adding medicinal activated carbon and activated alumina, and stirring for adsorption;
(2) filtering to remove medicinal active carbon and active alumina, adding a precooled alkaline aqueous solution into the filtrate, cooling to 0-5 ℃ for crystallization, washing and drying to obtain a refined product of the tofacitinib intermediate;
(3) citric acid (C) monohydrate6H8O7·H2O) is dissolved in an ethanol water solution, then the refined tofacitinib intermediate is added, crystallization is carried out after complete dissolution, and drying is carried out after washing, thus obtaining the tofacitinib citrate.
In another preferred example, in the step (1), the solvent is ethanol.
In another preferable example, in the step (1), the amount of the medicinal activated carbon is 0.5-1.5% of the mass of the tofacitinib intermediate crude product; and/or the using amount of the activated alumina is 0.5-1.5% of the mass of the tofacitinib intermediate crude product.
In another preferable example, in the step (1), after the medicinal activated carbon and the activated alumina are added, stirring and adsorbing are carried out for 0-10 min, then the temperature is reduced to a lower temperature, stirring and adsorbing are carried out for 20-50 min at the lower temperature, then the temperature is increased to a higher temperature, and stirring and adsorbing are carried out continuously for 10-40 min.
In another preferred example, in the step (2), the alkaline aqueous solution is an aqueous sodium bicarbonate solution; preferably, the mass concentration of the sodium bicarbonate aqueous solution is 0.1-1%.
In another preferred example, in the crude product of the tofacitinib intermediate, the HPLC content of the tofacitinib intermediate is less than or equal to 97 percent; preferably 95% or less.
In another preferred example, in the step (3), the volume ratio of ethanol to water in the ethanol aqueous solution is 3: 1 to 3.
In another preferred example, the step (3) includes the following steps:
citric acid (C) monohydrate6H8O7·H2O) dissolving in an ethanol water solution, adding the refined tofacitinib intermediate, heating and refluxing until the refined tofacitinib intermediate is completely dissolved, cooling to 30-40 ℃, adding water precooled to 0-5 ℃ under an ultrasonic condition, wherein the water is added at a high speedThe temperature is 5ml/min, the ultrasonic frequency is 20kHz, and the power is 500-600W/kg of solution (based on the total volume after the addition is finished); and after the water is added, stopping ultrasonic treatment, maintaining the temperature of the solution at 0-5 ℃, and carrying out heat preservation and crystallization.
In another preferred embodiment, the tofacitinib citrate is a crystalline particle.
In another preferred embodiment, said crystalline particles have an X-ray powder diffraction pattern showing characteristic peaks at about 9.89 °, 10.08 °, 12.77 °, 13.48 °, 15.51 °.
In another preferred example, the X-ray powder diffraction pattern of said crystalline particles shows characteristic peaks at about 3.24 °, 5.21 °, 6.72 °, 8.13 °, 9.89 °, 10.08 °, 11.66 °, 12.77 °, 13.48 °, 14.08 °, 15.51 °, 16.32 °, 19.04 °, 20.52 °, 21.83 °, 23.81 °, 24.36 °, 25.27 °, 26.78 °, 27.26 °.
The invention provides a tofacitinib citrate bulk drug, wherein the tofacitinib citrate bulk drug contains tofacitinib citrate crystal particles with HPLC purity of more than or equal to 99%, and the X-ray powder diffraction pattern of the crystal particles shows characteristic peaks at about 9.89 degrees, 10.08 degrees, 12.77 degrees, 13.48 degrees and 15.51 degrees.
In another preferred example, the X-ray powder diffraction pattern of said crystalline particles shows characteristic peaks at about 3.24 °, 5.21 °, 6.72 °, 8.13 °, 9.89 °, 10.08 °, 11.66 °, 12.77 °, 13.48 °, 14.08 °, 15.51 °, 16.32 °, 19.04 °, 20.52 °, 21.83 °, 23.81 °, 24.36 °, 25.27 °, 26.78 °, 27.26 °.
In another preferred embodiment, the tofacitinib citrate is prepared by the method of the first aspect of the invention.
In a third aspect of the invention, the application of the tofacitinib citrate bulk drug in preparing the drug for treating rheumatoid arthritis is provided.
Technical effects
According to the preparation method of tofacitinib citrate, the pigments and impurities which are difficult to remove in the tofacitinib intermediate crude product are adsorbed by using activated carbon and activated alumina, and the pigments and impurities which are difficult to remove in the tofacitinib intermediate crude product can be obviously reduced by matching with a temperature changing step, so that a high-purity tofacitinib intermediate refined product is obtained. The method can be used for efficiently preparing the high-purity tofacitinib citrate crystal particles, and the prepared tofacitinib citrate crystal particles have good fluidity and uniform particle size, and the solubility in water is not reduced while the particle size is increased.
Drawings
FIG. 1 shows a typical synthetic route for tofacitinib intermediates;
FIG. 2 shows an X-ray powder diffraction pattern of tofacitinib citrate crystals;
FIG. 3 shows DSC results;
FIG. 4 shows the HPLC detection pattern in comparative example 1.
Detailed Description
Before the present invention is described, it is to be understood that this invention is not limited to the particular methodology and experimental conditions described, as such methodologies and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now exemplified.
The invention provides a preparation method of tofacitinib citrate, which comprises the following steps:
(1) adding the tofacitinib intermediate crude product into a solvent, completely dissolving at a higher temperature (such as about 65 ℃), adding medicinal activated carbon and activated alumina, stirring and adsorbing for 0-10 min, then cooling to a lower temperature (such as about 30-40 ℃), stirring and adsorbing for 20-50 min at a lower temperature, then heating to a higher temperature (such as about 65 ℃), and continuing stirring and adsorbing for 10-40 min;
(2) filtering to remove medicinal active carbon and active alumina, adding a precooled alkaline aqueous solution into the filtrate, cooling to 0-5 ℃ for crystallization, washing and drying to obtain a refined product of the tofacitinib intermediate;
(3) citric acid (C) monohydrate6H8O7·H2O) dissolving in an ethanol water solution, adding the refined tofacitinib intermediate, heating and refluxing to completely dissolve, cooling to 30-40 ℃, adding water precooled to 0-5 ℃ under an ultrasonic condition, wherein the water adding speed is 5ml/min, the ultrasonic frequency is 20kHz, and the power is 500-600W/kg of solution (based on the total volume after the addition is finished); and after the water is added, stopping ultrasound, maintaining the temperature of the solution at 0-5 ℃, preserving heat, crystallizing, washing and drying to obtain the tofacitinib citrate crystal particles.
A typical synthetic route for the crude tofacitinib intermediate is shown in FIG. 1, and is also commercially available from commercial sources, and its HPLC detection method is a conventional method known in the art.
The refining method of tofacitinib citrate provided by the invention is simple to operate, good in batch-to-batch stability and high in yield, and the complex operation of repeated crystallization is avoided by adsorbing the pigments and impurities which are difficult to remove in the tofacitinib intermediate crude product by using activated carbon and activated alumina.
In the research of the inventor, experiments are carried out on various adsorbing materials such as activated carbon, molecular sieves and the like, and the inventors have surprisingly found that pigments and impurities which are difficult to remove in the Tofacitinib intermediate crude product are adsorbed by using the activated carbon and the activated alumina, and further found through repeated experiments that the pigments and the impurities in the Tofacitinib intermediate crude product can be more thoroughly removed by matching with a temperature changing step, and further a high-purity Tofacitinib intermediate refined product can be obtained. In the preparation process, the dosage of the activated alumina is less than 10% of the mass of the crude product of the tofacitinib intermediate, and the yield of the target substance is obviously reduced when the dosage is too large.
In addition, in the salt forming crystallization process, specific ultrasonic conditions are introduced, so that high-purity tofacitinib citrate crystal particles with large particle size can be efficiently prepared, the prepared tofacitinib citrate crystal particles are good in flowability and uniform in particle size, direct tabletting can be carried out, the solubility in water is not reduced while the particle size is increased, and an accelerated test shows that the tofacitinib citrate crystal particles prepared by the method are more stable than tofacitinib citrate crystal particles prepared by a conventional method.
The present invention will be described in further detail with reference to the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures in the following examples, where no detailed conditions are indicated, are generally carried out according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Example 1
Adding 2.0kg of the tofacitinib intermediate crude product (the HPLC purity is about 92%) into 20L of ethanol, heating to 65 ℃ to completely dissolve the tofacitinib intermediate crude product, adding 200g of medicinal activated carbon and 100g of activated alumina, stirring for 10min, continuously stirring, cooling to 10-15 ℃, maintaining for 30min, heating to 65 ℃, continuously stirring for 30min, and filtering while the product is hot. Adding 50L (mass fraction) of sodium bicarbonate solution into the filtrate, cooling to 0-5 ℃, crystallizing for 6h, filtering, washing with cold water, and drying to obtain the refined product of the tofacitinib intermediate, wherein the yield is 89.4%, and the HPLC purity is 99.61%.
Citric acid (C) monohydrate6H8O7·H2O)7.4g was dissolved in 150ml of an aqueous ethanol solution (volume ratio of ethanol to water 3: 2) then adding 10g of tofacitinib intermediate refined product, heating and refluxing to completely dissolve, cooling to 35 ℃, transferring the solution to an ultrasonic processor, adding 100ml of water precooled to 5 ℃ under the ultrasonic condition, wherein the adding speed is 5ml/min, the ultrasonic frequency is 20kHz, and the power is 500W/kg (so as to obtain the total solution after the addition is finished)Product counting); and after the water is added, stopping ultrasonic treatment, maintaining the temperature of the solution at 0-5 ℃, keeping the temperature for crystallization for 2 hours, filtering, washing with cold water, and drying in vacuum to obtain the tofacitinib citrate refined product, wherein the yield is 92.3%, and the HPLC purity is 99.93%.
An X-ray powder diffraction pattern obtained by measuring the tofacitinib citrate crystal prepared in the above way by using a Cu-K alpha ray is shown in figure 2, and the crystal shows characteristic peaks (expressed by 2 theta +/-0.2 diffraction angle) at 3.24 degrees, 5.21 degrees, 6.72 degrees, 8.13 degrees, 9.89 degrees, 10.08 degrees, 11.66 degrees, 12.77 degrees, 13.48 degrees, 14.08 degrees, 15.51 degrees, 16.32 degrees, 19.04 degrees, 20.52 degrees, 21.83 degrees, 23.81 degrees, 24.36 degrees, 25.27 degrees, 26.78 degrees and 27.26 degrees.
The results of differential thermal analysis (DSC) are shown in FIG. 3, and show an endothermic peak at 212-214 ℃. Therefore, the melting point is determined to be 212 to 214 ℃.
Particle size detection was carried out by Malvern laser diffraction method and the median particle size (D50) was determined to be 58.62. mu.m.
The refined tofacitinib citrate product obtained by the embodiment is a new crystal form shown by an XRPD detection result, has larger crystal granularity and good fluidity, and is very convenient for the subsequent use of raw material medicines. The water solubility is detected within 30 minutes at 35 ℃, and the detection result shows that the water solubility can reach 18.67 mg/ml. The accelerated test is carried out under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, after the mixture is placed for 6 months, the HPLC purity is 99.87%, impurities with obviously increased content are not observed, the phase is not obviously changed, and the stability is excellent.
Example 2
Adding 1.0kg of the tofacitinib intermediate crude product (the HPLC purity is about 92%) into 15L of ethanol, heating to 65 ℃ to completely dissolve the tofacitinib intermediate crude product, adding 150g of medicinal activated carbon and 100g of activated alumina, stirring for 10min, continuously stirring, cooling to 10-15 ℃, maintaining for 30min, heating to 65 ℃, continuously stirring for 35min, and filtering while the product is hot. Adding 40L (mass fraction) of sodium bicarbonate solution into the filtrate, cooling to 0-5 ℃, crystallizing for 6h, filtering, washing with cold water, and drying to obtain the refined product of the tofacitinib intermediate, wherein the yield is 86.3%, and the HPLC purity is 99.81%.
Citric acid (C) monohydrate6H8O7·H2O)7.4g was dissolved in 200ml of an aqueous ethanol solution (volume ratio of ethanol to water 3: 2) then adding 10g of the tofacitinib intermediate refined product, heating and refluxing to completely dissolve, cooling to 35 ℃, transferring the solution to an ultrasonic processor, adding 120ml of water precooled to 5 ℃ under the ultrasonic condition, wherein the adding speed is 5ml/min, the ultrasonic frequency is 20kHz, and the power is 600W/kg (based on the total volume after the addition is finished); and after the water is added, stopping ultrasonic treatment, maintaining the temperature of the solution at 0-5 ℃, keeping the temperature for crystallization for 2 hours, filtering, washing with cold water, and drying in vacuum to obtain the tofacitinib citrate refined product, wherein the yield is 91.2%, and the HPLC purity is 99.91%.
XRPD detection showed characteristic peaks substantially in accordance with example 1. The differential thermal analysis (DSC) results are consistent with those of example 1. The median particle diameter (D50) was found to be 46.81. mu.m. The water solubility is detected within 30 minutes at 35 ℃, and the detection result shows that the water solubility can reach 18.35 mg/ml. The accelerated test is carried out under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, after the mixture is placed for 6 months, the HPLC purity is 99.82%, impurities with obviously increased content are not observed, the phase is not obviously changed, and the stability is excellent.
Example 3
Adding 1.0kg of the tofacitinib intermediate crude product (the HPLC purity is about 92%) into 10L of ethanol, heating to dissolve completely, adding 100g of medicinal activated carbon and 150g of activated alumina, stirring for 10min, then continuously stirring, cooling to 10-15 ℃, maintaining for 30min, heating to 65 ℃, continuously stirring for 35min, and filtering while hot. Adding 30L of sodium bicarbonate solution (mass fraction of 0.3%) into the filtrate, cooling to 0-5 ℃, crystallizing for 6h, filtering, washing with cold water, and drying to obtain the refined product of the tofacitinib intermediate, wherein the yield is 74.8%, and the HPLC purity is 99.65%.
Citric acid (C) monohydrate6H8O7·H2O)7.4g was dissolved in 150ml of an aqueous ethanol solution (volume ratio of ethanol to water 1: 1) then adding 10g of tofacitinib intermediate refined product, heating and refluxing to completely dissolve, cooling to 35 ℃, transferring the solution to an ultrasonic processor, adding 100ml of water precooled to 5 ℃ under the ultrasonic condition, wherein the adding speed is 5ml/min, and performing ultra-sonicationThe sound wave frequency is 20kHz, and the power is 500W/kg of solution (based on the total volume after the addition is finished); and after the water is added, stopping ultrasonic treatment, maintaining the temperature of the solution at 0-5 ℃, keeping the temperature for crystallization for 2 hours, filtering, washing with cold water, and drying in vacuum to obtain the tofacitinib citrate refined product, wherein the yield is 88.6%, and the HPLC purity is 99.87%.
XRPD detection showed characteristic peaks substantially in accordance with example 1. The differential thermal analysis (DSC) results are consistent with those of example 1. The median particle diameter (D50) was found to be 42.35. mu.m. The water solubility is detected within 30 minutes at 35 ℃, and the detection result shows that the water solubility can reach 18.14 mg/ml. The accelerated test is carried out under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, after the mixture is placed for 6 months, the HPLC purity is 99.84%, impurities with obviously increased content are not observed, the phase is not obviously changed, and the stability is excellent.
Comparative example 1
2.0kg of the tofacitinib intermediate crude product (HPLC purity is about 92%) is added into 20L of ethanol, heated to 65 ℃ and dissolved completely, then 200g of medicinal activated carbon is added, stirred for 30min and filtered while hot. Adding 50L (mass fraction) of sodium bicarbonate solution into the filtrate, cooling to 0-5 ℃, crystallizing for 6h, filtering, washing with cold water, and drying to obtain the refined product of the tofacitinib intermediate, wherein the yield is 88.6%, and the HPLC purity is 97.82%.
In the comparative example, no activated alumina adsorbent is used, the obtained refined tofacitinib intermediate product is obviously reddish in color and low in purity, and an HPLC detection result shows that the content of the impurity 1 adjacent to a main peak is still high (an HPLC detection map is shown in figure 4, the content of the impurity 1 is about 1.16 percent), and the refined tofacitinib intermediate product can be used after recrystallization is needed. The content of impurity 1 in the crude tofacitinib intermediate used in the invention was about 1.78% (HPLC), and the HPLC content of impurity 1 in the refined tofacitinib intermediate obtained in example 1 was only 0.16%. Therefore, through comparison, the pigment and the impurities can be obviously removed by adsorbing the pigment and the impurities by using the medicinal activated carbon and the activated alumina, so that a high-quality refined product of the tofacitinib intermediate can be obtained.
Comparative example 2
2.0kg of the tofacitinib intermediate crude product (with HPLC purity of about 92%) is added into 20L of ethanol, heated to 65 ℃ and dissolved completely, then 200g of medicinal activated carbon and 100g of activated alumina are added, stirred for 30min and filtered while hot. Adding 50L (mass fraction) of sodium bicarbonate solution into the filtrate, cooling to 0-5 ℃, crystallizing for 6h, filtering, washing with cold water, and drying to obtain the refined product of the tofacitinib intermediate, wherein the yield is 92.3%, and the HPLC purity is 98.35%.
In the comparative example, medicinal activated carbon and activated alumina adsorbent are used for adsorbing pigment and impurities, a temperature change step is not arranged in the middle, the purity of the obtained refined product of the tofacitinib intermediate is obviously lower, and HPLC detection results show that the content of the impurity 1 is still higher (the content of the impurity 1 is about 0.86%), only about 51.7% of the impurity 1 is removed compared with the crude product, and more than 90% of the impurity 1 can be removed in example 1. Therefore, the temperature changing step has obvious influence on impurity adsorption, medicinal activated carbon and activated alumina are used for adsorption, and pigments and impurities can be removed more thoroughly after one-time temperature changing treatment.
Comparative example 3
Citric acid (C) monohydrate6H8O7·H2O)7.4g was dissolved in 150ml of an aqueous ethanol solution (volume ratio of ethanol to water 3: 2) then adding 10g of the refined tofacitinib intermediate product (prepared in example 1), heating and refluxing until the intermediate product is completely dissolved, cooling to 35 ℃, adding 100ml of water precooled to 5 ℃, and adding at the speed of 5 ml/min; after the water is added, maintaining the temperature of the solution at 0-5 ℃, keeping the temperature for crystallization for 2h, filtering, washing with cold water, and drying in vacuum to obtain the tofacitinib citrate refined product with the yield of 86.3% and the HPLC purity of 99.76%.
XRPD detection results show that the characteristic peak is remarkably different from that of example 1, and differential thermal analysis (DSC) results show that the melting point is 202-203 ℃. The median particle diameter (D50) was found to be 11.56 μm. The water solubility was measured at 35 ℃ within 30 minutes and the results showed that the water solubility was only 16.16 mg/ml. The accelerated test was carried out at a temperature of 40 + -2 deg.C and a relative humidity of 75 + -5%, and after standing for 6 months, the HPLC purity was reduced to 99.41%, and two impurities with a content of more than 0.1% appeared.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (10)
1. A preparation method of tofacitinib citrate is characterized by comprising the following steps:
(1) adding the tofacitinib intermediate crude product into a solvent, completely dissolving at a higher temperature, adding medicinal activated carbon and activated alumina, and stirring for adsorption;
(2) filtering to remove medicinal active carbon and active alumina, adding a precooled alkaline aqueous solution into the filtrate, cooling to 0-5 ℃ for crystallization, washing and drying to obtain a refined product of the tofacitinib intermediate;
(3) citric acid (C) monohydrate6H8O7·H2O) is dissolved in an ethanol water solution, then the refined tofacitinib intermediate is added, crystallization is carried out after complete dissolution, and drying is carried out after washing, thus obtaining the tofacitinib citrate.
2. The method of claim 1, wherein in step (1), the solvent is ethanol.
3. The method of claim 1, wherein in the step (1), the amount of the medicinal activated carbon is 10-15% of the mass of the tofacitinib intermediate crude product; and/or the using amount of the activated alumina is 5-15% of the mass of the tofacitinib intermediate crude product.
4. The method according to claim 1, wherein in the step (1), after the medicinal activated carbon and the activated alumina are added, stirring and adsorbing are carried out for 0-10 min, then the temperature is reduced to a lower temperature, stirring and adsorbing are carried out for 20-50 min at the lower temperature, then the temperature is increased to a higher temperature, and stirring and adsorbing are carried out for 10-40 min continuously.
5. The method according to claim 1, wherein in the step (2), the basic aqueous solution is an aqueous sodium bicarbonate solution; preferably, the mass concentration of the sodium bicarbonate aqueous solution is 0.1-1%.
6. The method of claim 1, wherein the HPLC content of the tofacitinib intermediate in the crude tofacitinib intermediate is less than or equal to 97%; preferably 95% or less.
7. The method according to claim 1, wherein in the step (3), the volume ratio of ethanol to water in the ethanol aqueous solution is 3: 1 to 3.
8. The method of claim 1, wherein the tofacitinib citrate is produced as crystalline particles.
9. A tofacitinib citrate bulk drug is characterized in that the tofacitinib citrate bulk drug contains tofacitinib citrate crystal particles with HPLC purity of more than or equal to 99%, and the tofacitinib citrate is prepared by the method of claim 1.
10. The use of tofacitinib citrate bulk drug as claimed in claim 9 for the preparation of a medicament for the treatment of rheumatoid arthritis.
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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 |
CN112430235A (en) * | 2019-08-26 | 2021-03-02 | 东莞市东阳光仿制药研发有限公司 | Preparation method of PF-06651600 intermediate |
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