CN104059016A - Intermediate for preparing tofacitinib and preparation method of intermediate - Google Patents
Intermediate for preparing tofacitinib and preparation method of intermediate Download PDFInfo
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- CN104059016A CN104059016A CN201410278509.2A CN201410278509A CN104059016A CN 104059016 A CN104059016 A CN 104059016A CN 201410278509 A CN201410278509 A CN 201410278509A CN 104059016 A CN104059016 A CN 104059016A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a novel intermediate for preparing tofacitinib, which is a compound (3R, 4R)-N,4-dimethyl-1-(oxopropionitrile)-3-piperidineamine shown in a structural formula (IV). The invention also discloses a preparation method of the tofacitinib intermediate. The preparation method of the tofacitinib intermediate comprises the following steps: (1) enabling a compound shown in a formula VII and a compound shown in a formula VI, namely cyanoacetic acid, to carry out acid amide condensation reaction and generate a compound shown in a formula V; and (2) removing a protective group of the compound shown in the formula V to obtain the compound shown in the formula IV. The preparation method is easily available in raw materials, easy to operate, fewer in steps, high in yield and suitable for industrialized production.
Description
Technical field
The present invention relates to synthetic holder method for a kind of new intermediate of cloth and the preparation method of described intermediate, and utilize above-mentioned intermediate to prepare the method for holder method for cloth.
Background technology
Holder method is a kind of new oral JAK pathway inhibitor of Pfizer's research and development for cloth (Tofacitinib).Different in extracellular target spot from other RA medicine Main Functions of current majority, holder method taking intracellular signal transduction path as target spot, acts on the core of cytokine network for cloth.Holder method is to 5 ~ 100 of JAK1 and JAK2 times for cloth (Tofacitinib) to the inhibition strength of JAK3.Holder method for cloth be exploitation for the pioneering medicine (first-in-class drug) of rheumatoid arthritis treatment, during FDA ratified that JAK inhibitor tofacitinib is used for the treatment of the activities of adults phase and is not good to methotrexate (MTX) reaction on November 6th, 2012 to severe rheumatoid arthritis (RA) patient.FDA represents, in to the rheumatoid arthritis people of severe, cannot benefit maybe cannot tolerate treatment from conventional oral therapeutic drug methotrexate (methotrexate) time, can use the new drug Xeljanz (holder method is replaced cloth) of Pfizer.Holder method can be alone for cloth, also can share with methotrexate and other specific standard care medicines.Its chemical structure is as follows:
。
Holder method mainly contains following several for the preparation method of cloth at present:
Method one
The synthetic route of the patent report (WO2003/048162, CN1325498C) of Pfizer company has two.
Route one is as follows:
。
This route is with compound (3) (3R, 4R)-methyl-(4-methyl-piperidines-3-yl)-(7H-pyrido [2,3-d] pyrimidine-4-yl) amine is raw material, with cyanoacetic acid 2, the reaction of 5-dioxo-pyrrolidin-1-yl ester, compound (3) is changed into corresponding compound (2) 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile compound.Compound (2) reacts with aqueous citric acid, by compound (2) 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile compound is converted into corresponding compound (1) 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile one Citrate trianion compound, i.e. Citric Acid holder method is for cloth.
Route two is as follows:
This route is with compound (4) (3R, 4R)-1-benzyl-4-methyl-(4-methyl-piperidines-3-yl)-methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl) amine is raw material, shortening obtains compound (3) (3R after sloughing benzyl, 4R)-methyl-(4-methyl-piperidines-3-yl)-(7H-pyrido [2,3-d] pyrimidine-4-yl) amine.Compound (3) and cyanoacetic acid 2, the reaction of 5-dioxo-pyrrolidin-1-yl ester, compound (3) is changed into corresponding compound (2) 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile compound.Compound (2) reacts with aqueous citric acid, by compound (2) 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile compound is converted into corresponding compound (1) 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile one Citrate trianion compound, i.e. Citric Acid holder method is for cloth.
The simple synthetic method of these two lines, route is shorter, but raw material costliness, cost is too high, and the difficult purchase in market of this raw material, is not suitable for suitability for industrialized production.
Method two
Citric Acid holder method is for the existing bibliographical information of Buddhist nun's synthetic route, bibliographical information be to synthesize (4-picoline-3-yl) Urethylane (3) taking 3-amino-4-methylpyridine (1) and methylcarbonate (2) as starting raw material; (3) obtain cis-(4-methyl piperidine-3-yl) Urethylane (4) through rhodium charcoal catalytic hydrogenation cis hydrogenation; (4) react with phenyl aldehyde and form imines, then obtain cis-(1-benzyl-4-methyl piperidine-3-yl) Urethylane (5) through sodium triacetoxy borohydride reduction; (5) by tetrahydrochysene lithium aluminium reducing, more obtain cis-1-benzyl-3-methylamino--4-methyl piperidine hydrochloride (6) with concentrated hydrochloric acid salify; (6) through L-bis-, toluyl tartrate (L-DTTA) is split and obtains (3R, 4R)-1-benzyl-3-methylamino--4-methyl piperidine-L-bis-to toluyl tartrate (7); (7) and 2, the chloro-7H-pyrrolo-［ 2 of 4-bis-, 3-d ］ pyrimidine (8) occur nucleophilic substitution reaction obtain the chloro-4-{ of 2-(methyl) [(3R, 4R)-1-benzyl-4-methyl piperidine-3-yl] amino }-7H-pyrrolo-［ 2,3-d ］ pyrimidine (9); (9) take off benzyl and chlorine generation N-methyl-N-[(3R, 4R by palladium-charcoal)-4-methyl piperidine-3-yl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (10); (10) there is nucleophilic reaction with ethyl cyanoacetate (11) and generate holder method for Buddhist nun, more obtain Citric Acid holder method for cloth (12) with Citric acid monohydrate Food grade salify.This route raw material market is easy to get, but reactions steps is more, and intermediate needs chiral separation, is unfavorable for suitability for industrialized production, and synthesis route is as follows:
Summary of the invention
Technical problem: the synthetic route that method one and method two are announced respectively has superiority, but all there is defect, method one is used (3R, 4R)-1-benzyl-4-methyl-(4-methyl-piperidines-3-yl)-methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl) amine or (3R, 4R)-methyl-(4-methyl-piperidines-3-yl)-(7H-pyrido [2,3-d] pyrimidine-4-yl) amine is as starting raw material, this commercially available reagent price is more expensive, and market is difficult for buying.And method two reactions steps is more, and intermediate needs chiral separation, is unfavorable for suitability for industrialized production.The present invention is devoted to solve these defects, and provide preparation holder method for the variation route, particularly some new intermediates of cloth be all before document do not report.In actual building-up process, the present invention can obtain the final product of high-quality and high yield.
Technical scheme:
Feature of the present invention has been to provide 3-[(3R, the 4R of formula I)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino ］ piperidin-1-yl] method of-3-oxo-propionitrile-Citrate trianion.
Comprise:
(a) make the compound shown in formula VII and formula VI compound, i.e. cyanoacetic acid, carries out the compound of acid amide condensation reaction production V.
(b) making compound shown in formula V slough protecting group obtains suc as formula compound shown in IV.
(c) making compound shown in formula IV and formula III compound, i.e., there is nucleophilic substitution and obtains suc as formula compound shown in II in 4-chloropyrrolo [2,3-d.
(d) make compound shown in formula II and Citric acid monohydrate Food grade salify obtain formula I compound 3-[(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino ］ piperidin-1-yl]-3-oxo-propionitrile-Citrate trianion.
For step (a), the general method of this acid amide condensation reaction has two kinds, and one is first carboxylic acid to be prepared into acyl chlorides, then reacts and is prepared into acid amides with amine with acyl chlorides.Carboxylic acid is prepared the reaction of acyl chlorides and can under suitable catalyzer and acylating reagent existence, in suitable inert solvent or thinner, be carried out, suitable catalyzer can be for example N, dinethylformamide (DMF), DMA, triethylamine and pyridine etc., preferably DMF; Suitable acylating reagent can be for example oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus oxychloride and triphosgene etc., preferably thionyl chloride; Suitable inert solvent or thinner can be for example methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), trichloromethane and toluene etc., preferably methylene dichloride.Acyl chlorides reacts the reaction of preparing acid amides can carry out with amine under suitable alkali exists in suitable inert solvent or thinner, and suitable alkali can be for example triethylamine, pyridine and DIPEA (DIPEA) etc., preferably triethylamine; Suitable inert solvent or thinner can be for example methylene dichloride, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) (DMSO) and DMF (DMF) etc., preferably methylene dichloride.
Another method is first carboxylic acid to be prepared into active ester intermediate with condensing agent (activator etc.), then is condensed into acid amides with amine.This acid amide condensation reaction can be carried out under suitable alkali and condensing agent (activator etc.) existence in suitable inert solvent or thinner, suitable alkali can be for example triethylamine, N-methylmorpholine (NMM) and N, N-diisopropylethylamine (DIPEA) etc., preferably triethylamine; Suitable condensing agent (activator etc.) can be for example N, N'-carbonyl dimidazoles (CDI), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCl)/I-hydroxybenzotriazole (HoBt) and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl (PyBOP) etc., preferably EDCl/HoBt; Suitable inert solvent or thinner can be for example methylene dichloride, acetonitrile, dimethyl sulfoxide (DMSO) (DMSO) and DMF (DMF) etc., preferably methylene dichloride.The mol ratio of its Chinese style VII compound and formula VI compound is between 1:1.2 ~ 1:1.5, and the temperature of reaction is 10 ~ 30 DEG C, preferably near 20 DEG C or its.
For step (b), deprotection reaction can adopt multiple currently known methods to carry out easily.This deprotection reaction can carry out with acid reagent, and acid reagent is trifluoroacetic acid (TFA), hydrochloric acid, sulfuric acid, Glacial acetic acid etc., preferably sulfuric acid.While reaction, reaction mixture is used the aqueous solution of alkali such as solution neutralizations such as sodium hydroxide, sodium carbonate, sodium bicarbonates, organic solvent extracting is obtained formula IV compound.Wherein select the vitriol oil to carry out deprotection, the mol ratio of formula V compound and sulfuric acid is between 1:1.5 ~ 1:2.0, and the temperature range of reacting suitable is 30-100 DEG C.
For step (c), this nucleophilic substitution reaction is a kind of ammonolysis reaction of routine, and this reaction is suitable to be carried out under suitable sour or suitable alkali exists.Suitable acid is as hydrogenchloride or hydrogen bromide.Such as organic bases of suitable alkali, as triethylamine, diisopropyl ethyl amine, pyridine, 2,6-lutidine, morpholine etc.; Or mineral alkali is such as carbonate or the oxyhydroxide of basic metal or alkaline-earth metal, as salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide etc.Suitable solvent is polar aprotic solvent, for example C
2-C
4alcohol; Or ester class is as ethyl acetate; Halogenated solvent, aromatic solvent etc., preferred alcohol.The mol ratio of its Chinese style IV compound and formula III compound is between 1:1.0 ~ 1:1.2, and the temperature range of reacting suitable is 30-100 DEG C.
For step (d), by formula II compound being reacted with aqueous citric acid in the situation that having a kind of polar solvent to exist, obtain and obtain formula I compound 3-[(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino ］ piperidin-1-yl]-3-oxo-propionitrile-Citrate trianion.Suitable polar solvent can be for example ethanol, acetone, methyl alcohol and ethyl acetate etc.The mol ratio of its Chinese style II compound and citric acid is between 1:1.0 ~ 1:2.0, and the temperature range of reacting suitable is 20-70 DEG C.
Each formula II, formula III, formula IV, formula V, formula VI, formula VII intermediate are used to prepare the holder method with pharmacological activity for cloth, in the method for formula I compound.
The present invention is further illustrated by following embodiment, but not limited to by this.
Beneficial effect: the invention has the advantages that, all raw materials and the reagent of use are easy to get, cheapness, environmental protection.Reaction scheme is succinctly easy to operate, reaction conditions gentleness, and yield is high, and all intermediate methods of purification are easy, and target product purity is very high.So invention is extremely applicable to suitability for industrialized production.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this.
Embodiment 1, formula V compound (3R, 4R)-N, 4-dimethyl-N-tertbutyloxycarbonyl-1-(oxo-propionitrile)-3-piperylhydrazine synthetic
Method one: by (3R, 4R)-N, 4-dimethyl-N-tertbutyloxycarbonyl-3-piperylhydrazine (40 g, 0.17 mol) is dissolved in methylene dichloride (100 mL), adds triethylamine (17.2 g, 0.17 mol).By cyanoacetic acid (21.6 g, 0.25 mol) be dissolved in methylene dichloride (200 mL), under room temperature, drip thionyl chloride (60.6 g, 0.51 mol), N, dinethylformamide (DMF) (0.5 mL), be heated to back flow reaction 2h, reaction solution is cooled to after room temperature, concentrating under reduced pressure solvent, debris is added drop-wise to above-mentioned (3R after being dissolved in methylene dichloride (100 mL), 4R)-N, in 4-dimethyl-N-tertbutyloxycarbonyl-3-piperylhydrazine solution, reacts 2h under room temperature, reaction finishes rear with saturated aqueous common salt (3 × 100 mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure solvent, obtains yellow solid 43.9 g, yield 85%.
Method two: by (3R, 4R)-N, 4-dimethyl-N-tertbutyloxycarbonyl-3-piperylhydrazine (50 g, 0.22 mol) and cyanoacetic acid (22.3 g, 0.26 mol) be dissolved in methylene dichloride (250 mL), add successively N-methylmorpholine (NMM) (44.5 g, 0.44 mol), I-hydroxybenzotriazole (HoBt) (29.7 g, 0.22 mol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCl) (63.2 g, 0.33 mol), at room temperature react 5h, reaction finishes the sodium bicarbonate alkaline aqueous solution (200g) of rear dropping 6%, extract with methylene dichloride (3 × 150 mL), merge organic layer, wash with saturated aqueous common salt (2 × 100 mL), anhydrous sodium sulfate drying.Concentrating under reduced pressure solvent, obtains yellow solid 56.9 g, yield 88%.
Embodiment 2, formula IV compound (3R, 4R)-N, 4-dimethyl-1-(oxo-propionitrile)-3-piperylhydrazine synthetic
Method one: by (3R, 4R)-N, 4-dimethyl-N-tertbutyloxycarbonyl-1-(oxo-propionitrile)-3-piperylhydrazine (43.9g, 0.15 mol) is dissolved in methylene dichloride (300 mL), drip concentrated hydrochloric acid (55g), be heated to back flow reaction 4h, reaction solution is cooled to after room temperature, adds 20% sodium hydroxide solution to be adjusted to neutrality under stirring, extract with methylene dichloride (3 × 100 mL), merge organic layer, water (2 × 80 mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure solvent, obtains off-white color solid 26.1 g, yield 90%.
Method two: by (3R, 4R)-N, 4-dimethyl-N-tertbutyloxycarbonyl-1-(oxo-propionitrile)-3-piperylhydrazine (56.9g, 0.19 mol) is dissolved in methylene dichloride (400 mL), drip the vitriol oil (40g), be heated to back flow reaction 4h, reaction solution is cooled to after room temperature, adds 20% sodium hydroxide solution to be adjusted to neutrality under stirring, extract with methylene dichloride (3 × 150 mL), merge organic layer, water (2 × 100 mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure solvent, obtains off-white color solid 34.6 g, yield 92%.
Embodiment 3, formula II compound 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile synthetic
By (3R, 4R)-N, 4-dimethyl-1-(oxo-propionitrile)-3-piperylhydrazine (34.6 g, 0.17 mol) be added in water (700 mL), add successively salt of wormwood (187.9 g, 1.36 mol), 4-chloropyrrolo [2,3-d (30.7 g, 0.2 mol), be heated to back flow reaction 8h, after being cooled to room temperature, filters reaction solution, obtain thick product, thick product, with methyl alcohol-re-crystallizing in ethyl acetate, obtains off-white color solid 46.2 g, yield 87%.
Embodiment 4, formula I compound 3-[(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino ］ piperidin-1-yl]-3-oxo-propionitrile-Citrate trianion synthetic
By 3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrido [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile (46.2 g, 0.15 mol) is added in acetone (170 mL), and (169.4 g) to drip 17.6% aqueous citric acid solution, be heated to 60 DEG C of back flow reaction 4h, then after being down to 0 DEG C of insulation 2h, filter, cold acetone for filter cake (30 mL) drip washing, thick product is with alcohol-water recrystallization, obtain white solid 63.4g, yield 85%.MS-ESI(m/z):313.30(M+H
+)。
Claims (6)
1. the compound of following formula IV, (3R, 4R)-N, 4-dimethyl-1-(oxo-propionitrile)-3-piperylhydrazine:
。
2. the compound of following formula V, (3R, 4R)-N, 4-dimethyl-N-tertbutyloxycarbonyl-1-(oxo-propionitrile)-3-piperylhydrazine:
。
3. according to a preparation method for the formula IV compound described in claim 1, comprising: make compound shown in formula V slough protecting group and obtain suc as formula compound shown in IV.
4. according to a preparation method for the formula V compound described in claim 2, comprising: make formula VII compound (3R, 4R)-N, 4-dimethyl-N-tertbutyloxycarbonyl-3-piperylhydrazine and formula VI compound, be cyanoacetic acid, carry out the compound of acid amide condensation reaction production V
。
5. preparation method according to claim 3, is characterized in that, selects the vitriol oil to carry out deprotection, and the mol ratio of formula V compound and sulfuric acid is between 1:1.5 ~ 1:2.0, and the temperature range of reacting suitable is 30-100 DEG C, is preferably 40 DEG C.
6. preparation method according to claim 4, is characterized in that, the mol ratio of formula VII compound and formula VI compound is between 1:1.2 ~ 1:1.5, and the temperature of reaction is 10 ~ 30 DEG C, is preferably 20 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530053A (en) * | 2014-12-08 | 2015-04-22 | 合肥远志医药科技开发有限公司 | Preparation method of medicinal crystal form tofacitinib citrate |
| 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 |
| CN108640923A (en) * | 2018-07-09 | 2018-10-12 | 湖南天地恒制药有限公司 | A kind of support method replaces the preparation method of cloth key intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1893952A (en) * | 2003-12-17 | 2007-01-10 | 辉瑞产品公司 | Pyrrolo[2,3-D]pyrimidine compounds for treating transplant rejection |
| CN102171211A (en) * | 2008-08-01 | 2011-08-31 | 拜奥克里斯特制药公司 | Piperidine derivatives as JAK3 inhibitors |
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2014
- 2014-06-20 CN CN201410278509.2A patent/CN104059016A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1893952A (en) * | 2003-12-17 | 2007-01-10 | 辉瑞产品公司 | Pyrrolo[2,3-D]pyrimidine compounds for treating transplant rejection |
| CN102171211A (en) * | 2008-08-01 | 2011-08-31 | 拜奥克里斯特制药公司 | Piperidine derivatives as JAK3 inhibitors |
Non-Patent Citations (1)
| Title |
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| GEHRINGER, MATTHIAS ET AL.: "tert-Butyl N-[(3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl]-N-methylcarbamate", 《ACTA CRYSTALLOGRAPHICA, SECTION E: STRUCTURE REPORTS ONLINE》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530053A (en) * | 2014-12-08 | 2015-04-22 | 合肥远志医药科技开发有限公司 | Preparation method of medicinal crystal form tofacitinib citrate |
| 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 |
| CN108640923A (en) * | 2018-07-09 | 2018-10-12 | 湖南天地恒制药有限公司 | A kind of support method replaces the preparation method of cloth key intermediate |
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Application publication date: 20140924 |