CN104926816A - Tofacitinib analog and preparation method and application thereof - Google Patents
Tofacitinib analog and preparation method and application thereof Download PDFInfo
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- CN104926816A CN104926816A CN201410101534.3A CN201410101534A CN104926816A CN 104926816 A CN104926816 A CN 104926816A CN 201410101534 A CN201410101534 A CN 201410101534A CN 104926816 A CN104926816 A CN 104926816A
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- compound
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- reaction solvent
- cloth
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000004940 Tofacitinib derivatives Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000004744 fabric Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical group OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 6
- 238000004262 preparative liquid chromatography Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims description 4
- GPWDPLKISXZVIE-UHFFFAOYSA-N cyclo[18]carbon Chemical group C1#CC#CC#CC#CC#CC#CC#CC#CC#C1 GPWDPLKISXZVIE-UHFFFAOYSA-N 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- GEQZTCMVWVDEDF-UHFFFAOYSA-N 2-cyanoacetyl chloride Chemical compound ClC(=O)CC#N GEQZTCMVWVDEDF-UHFFFAOYSA-N 0.000 claims description 3
- XIVBKXMBKBOIOC-UHFFFAOYSA-N C(#N)CC(=O)O.ON1C(CCC1=O)=O Chemical compound C(#N)CC(=O)O.ON1C(CCC1=O)=O XIVBKXMBKBOIOC-UHFFFAOYSA-N 0.000 claims description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical group [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 2
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000003908 quality control method Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 6
- 239000004012 Tofacitinib Substances 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 3
- 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 abstract description 3
- 229960001350 tofacitinib Drugs 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 2
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 14
- 238000001819 mass spectrum Methods 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- UZOFELREXGAFOI-UHFFFAOYSA-N CC1CCNCC1 Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OFLGUADWZSEQEI-UHFFFAOYSA-N CC(CC1)CCN1C(CC#N)=O Chemical compound CC(CC1)CCN1C(CC#N)=O OFLGUADWZSEQEI-UHFFFAOYSA-N 0.000 description 1
- CHCPZZWLJJYACZ-UHFFFAOYSA-N C[NH+2]c1c(CCN2)c2ncn1 Chemical compound C[NH+2]c1c(CCN2)c2ncn1 CHCPZZWLJJYACZ-UHFFFAOYSA-N 0.000 description 1
- AXWBJJJQRJBTMI-UHFFFAOYSA-O C[NH2+]c1c(cc[nH]2)c2ncn1 Chemical compound C[NH2+]c1c(cc[nH]2)c2ncn1 AXWBJJJQRJBTMI-UHFFFAOYSA-O 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 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
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a tofacitinib analog as shown in the formula II and a preparation method and an application thereof. According to the preparation method, a compound as shown in the formula IV is subjected to a hydrogenation reaction so as to obtain a compound as shown in the formula III, and the compound as shown in the formula III further reacts with a cyano-acetylation reagent to obtain a compound as shown in the formula II. The compound as shown in the formula II can be used as a reference substance for detection of a tofacitinib or its salt related substance and is used in purity control of raw materials or a preparation of tofacitinib or its salt.
Description
Technical field
The present invention relates to and a kind ofly hold in the palm method analogue replacing cloth and preparation method thereof and application.
Background technology
Holder method is a kind of new oral non-receptor type tyrosine protein kinase (JAK) inhibitor for cloth (Tofacitinib), be used for the treatment of to the insufficient or not tolerant moderate of methotrexate response to severe activity rheumatoid arthritis adult patients, the holder method that can be used clinically for cloth or Citric Acid holder method for cloth.Holder method replaces the chemical structural formula of cloth such as formula shown in I:
Study for the relative substance of cloth for cloth or Citric Acid holder method about holder method, there is not yet bibliographical information both at home and abroad.
3-((3R of the present invention, 4R)-4-methyl-3-((6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-yl) methylamino) piperidin-1-yl)-3-oxypropionitrile is holder method for cloth analogue, can control holder method for cloth or the Citric Acid holder method purity for cloth raw material or preparation as impurity reference substance.
Summary of the invention
An aspect of of the present present invention is to provide a kind of new compound and salt thereof, and its chemical structural formula is such as formula shown in II:
The chemical name of compound shown in formula II is: 3-((3R, 4R)-4-methyl-3-((6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-yl) methylamino) piperidin-1-yl)-3-oxypropionitrile, described salt is selected from Citrate trianion or hydrochloride.
Formula II compound structure is through nuclear magnetic resonance spectrum and mass spectrum confirmation, and attached data declaration is as follows.
1. mass spectrum (MS) shows the nucleo plasmic relation at [the M+H]+peak of this product is 315, shows that the molecular weight of this product is 314, compares holder method for cloth molecular weight many 2.
2. high resolution mass spectrum (HRMS) shows the measured value of the mass-to-charge ratio at this product [M+H]+peak is 315.1938, and the molecular composition of its correspondence is C
16h
23n
6o
+, illustrate that this product molecular composition is C
16h
22n
6o.
3.
1h-NMR and
13c-NMR
Hydrogen spectrum measurement result
Carbon spectrum measurement result
Another aspect of the present invention is to provide a kind of formula II compound 3-((3R, 4R)-4-methyl-3-((6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-yl) methylamino) piperidin-1-yl) preparation method of-3-oxypropionitrile.
Said method comprising the steps of:
Step (1): formula IV compound is carried out hydrogenation under the existence of the first reaction solvent and catalyzer, obtains formula III compound; Step (2): formula III compound and cyano-acetamide reagent are reacted in the second reaction solvent, obtains formula II compound,
In described step (1) the first reaction solvent be selected from one or more of methyl alcohol, ethanol or tetrahydrofuran (THF) etc.; Catalyzer is selected from palladium carbon, palladium hydroxide or platinum oxide.
Second reaction solvent of described step (2) is selected from one or more in methylene dichloride, toluene or ethanol; Cyano-acetamide reagent is selected from cyanoacetic acid, ethyl cyanacetate, cyanoacetyl chloride or cyanoacetic acid N-hydroxysuccinimide ester.
Final formula II compound HPLC analyzes its purity, and adopts nuclear magnetic resonance spectrum and its structure of mass spectrum confirmation.
Formula II compound 3-((3R prepared by the present invention, 4R)-4-methyl-3-((6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-yl) methylamino) piperidin-1-yl)-3-oxypropionitrile, can be used as holder method replaces cloth related substance detection reference substance for cloth or Citric Acid holder method, replace cloth or Citric Acid holder method to replace the quality control of cloth and related preparations thereof for method of holding in the palm.
The present invention provides described III compound more on the other hand, and its preparation method is separated for using high performance preparative liquid chromatography, and chromatographic condition is: chromatographic column is carbon 18 bonded silica gel post; Moving phase is A:0.03-0.08% trifluoroacetic acid aqueous solution; B: acetonitrile; Gradient elution, carries out separation and purification.Preferred flow is mutually for A is 0.05% trifluoroacetic acid aqueous solution.
Embodiment
The present invention will in hereafter by the more detailed description of embodiment, and these embodiments exemplarily for further illustrating, and should not be considered as limitation of the present invention.
Embodiment 1: the preparation of formula III compound
Method 1
Compounds Ⅳ (15g), ethanol (300ml) and 10% palladium carbon (4.5g) mix and blend, be heated to 50 DEG C, pass into hydrogen reaction 3 days, filter, filtrate reduced in volume, residuum uses high performance preparative liquid chromatography (concrete chromatographic condition: chromatographic column is carbon 18 bonded silica gel post; Moving phase is A:0.05% trifluoroacetic acid aqueous solution; B: acetonitrile; Gradient elution 0 ~ 35%B, 35 minutes; Flow velocity 80ml/min) be separated obtain 1.42g compound III.MS：m/z=248[M+H]
+。
Method 2
Compounds Ⅳ (20g), methyl alcohol (400ml) and 10% palladium carbon (6g) mix and blend, be heated to 40 DEG C, pass into hydrogen reaction 4 days, filters, filtrate reduced in volume, and residuum uses high performance preparative liquid chromatography to be separated and obtains 1.78g compound III.MS：m/z=248[M+H]
+。
Method 3
Compounds Ⅳ (15g), ethanol (300ml) and palladium hydroxide (2g) mix and blend, be heated to 50 DEG C, passes into hydrogen reaction 5 days, filters, filtrate reduced in volume, and residuum uses high performance preparative liquid chromatography to be separated and obtains 1.33g compound III.MS：m/z=248[M+H]
+。
Embodiment 2: the preparation of formula II compound
Method 1
Compound III (0.98g, 4mmol), methylene dichloride (30ml), I-hydroxybenzotriazole (1.08g, 8mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.53g, 8mmol) with triethylamine (2.2ml, 16mmol) mix and blend, add cyanoacetic acid (0.68g, 8mmol), react 10 hours under room temperature, add water 30ml × 2 time washing, organic phase concentrates, and residuum is separated through column chromatography [V (methylene dichloride): V (methyl alcohol)=50:1], obtains 0.72g compound ii.MS：m/z=315[M+H]
+。This compound is through nuclear magnetic resonance spectrum and mass spectrum confirmation, and data as previously mentioned.
Method 2
Compound III (0.86g, 3.6mmol), ethanol (9ml), cyanoacetic acid N-hydroxysuccinimide ester (0.77g, 5.7mmol) with triethylamine (0.59g, 5.8mmol) mix and blend, room temperature reaction 2 hours, concentrating under reduced pressure, residuum adds 9ml methylene dichloride and dissolves, wash with saturated sodium bicarbonate solution 9ml and water 9ml successively, organic phase concentrating under reduced pressure, residuum is separated through column chromatography [V (methylene dichloride): V (methyl alcohol)=50:1], obtains 0.68g compound ii.MS：m/z=315[M+H]
+。
Method 3
Compound III (1.1g, 4.5mmol), methylene dichloride (30ml) and triethylamine (2.5ml, 18mmol) mix and blend, at-5 DEG C, add cyanoacetyl chloride (0.93g, 9mmol), react 3 hours, add saturated aqueous sodium carbonate 30ml, organic phase concentrates, and residuum is separated through column chromatography [V (methylene dichloride): V (methyl alcohol)=50:1], obtains 0.71g compound ii.MS：m/z=315[M+H]
+。
Claims (9)
1. the compound or its salt shown in following formula II:
2. compound or its salt according to claim 1, is characterized in that described salt is Citrate trianion or hydrochloride.
3. a preparation method for compound described in claim 1, is characterized in that comprising step as follows:
Formula IV compound is carried out hydrogenation by step (1) under the existence of the first reaction solvent and catalyzer, obtains formula III compound;
Formula III compound and cyano-acetamide reagent react by step (2) under the second reaction solvent exists, and obtain formula II compound,
4. preparation method according to claim 3, is characterized in that: the first described reaction solvent is selected from one or more in methyl alcohol, ethanol or tetrahydrofuran (THF); Catalyzer is selected from palladium carbon, palladium hydroxide or platinum oxide.
5. preparation method according to claim 3, is characterized in that: described second reaction solvent is selected from one or more in methylene dichloride, toluene or ethanol; Cyano-acetamide reagent is selected from cyanoacetic acid, ethyl cyanacetate, cyanoacetyl chloride or cyanoacetic acid N-hydroxysuccinimide ester.
6. compound or its salt according to claim 1 product in contrast, replace cloth or Citric Acid holder method for the application in the raw material of cloth or the quality control of preparation in holder method.
7. formula III compound according to claim 2.
8. the preparation method of compound described in claim 7, is characterized in that, use high performance preparative liquid chromatography to be separated, chromatographic condition is: chromatographic column is carbon 18 bonded silica gel post; Moving phase is A:0.03-0.08% trifluoroacetic acid aqueous solution; B: acetonitrile; Gradient elution, carries out separation and purification.
9. the preparation method of compound described in claim 7, is characterized in that, use high performance preparative liquid chromatography to be separated, chromatographic condition is: chromatographic column is carbon 18 bonded silica gel post; Moving phase is A:0.05% trifluoroacetic acid aqueous solution; B: acetonitrile; Gradient elution 0 ~ 35%B, 35 minutes; Flow velocity 80ml/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410101534.3A CN104926816A (en) | 2014-03-19 | 2014-03-19 | Tofacitinib analog and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410101534.3A CN104926816A (en) | 2014-03-19 | 2014-03-19 | Tofacitinib analog and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104926816A true CN104926816A (en) | 2015-09-23 |
Family
ID=54114264
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410101534.3A Pending CN104926816A (en) | 2014-03-19 | 2014-03-19 | Tofacitinib analog and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104926816A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113896730A (en) * | 2020-06-22 | 2022-01-07 | 浙江晖石药业有限公司 | Preparation method of tofacitinib citrate and intermediate thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102574863A (en) * | 2009-08-27 | 2012-07-11 | 拜奥克里斯特制药公司 | Heterocyclic compounds as JANUS kinase inhibitors |
| WO2013090490A1 (en) * | 2011-12-15 | 2013-06-20 | Ratiopharm Gmbh | Tofacitinib salts |
| WO2013181217A2 (en) * | 2012-05-29 | 2013-12-05 | Galleon Pharmaceuticals, Inc. | Novel compounds and compositions for treatment of breathing control disorders or diseases |
| CN103459394A (en) * | 2011-04-08 | 2013-12-18 | 辉瑞大药厂 | Tofacitinib in crystalline and non-crystalline forms, and pharmaceutical compositions comprising tofacitinib and a penetration enhancer |
-
2014
- 2014-03-19 CN CN201410101534.3A patent/CN104926816A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102574863A (en) * | 2009-08-27 | 2012-07-11 | 拜奥克里斯特制药公司 | Heterocyclic compounds as JANUS kinase inhibitors |
| CN103459394A (en) * | 2011-04-08 | 2013-12-18 | 辉瑞大药厂 | Tofacitinib in crystalline and non-crystalline forms, and pharmaceutical compositions comprising tofacitinib and a penetration enhancer |
| WO2013090490A1 (en) * | 2011-12-15 | 2013-06-20 | Ratiopharm Gmbh | Tofacitinib salts |
| WO2013181217A2 (en) * | 2012-05-29 | 2013-12-05 | Galleon Pharmaceuticals, Inc. | Novel compounds and compositions for treatment of breathing control disorders or diseases |
Non-Patent Citations (2)
| Title |
|---|
| JIAN-KANG JIANG等，: ""Examining the Chirality, Conformation and Selective Kinase Inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550)"及其其Supporting Information", 《J. MED. CHEM.》 * |
| 尤宏等主编: "《环境实验化学》", 31 December 2013 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113896730A (en) * | 2020-06-22 | 2022-01-07 | 浙江晖石药业有限公司 | Preparation method of tofacitinib citrate and intermediate thereof |
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