CN103819474A - Preparation method of tofacitinib - Google Patents
Preparation method of tofacitinib Download PDFInfo
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- CN103819474A CN103819474A CN201310537835.6A CN201310537835A CN103819474A CN 103819474 A CN103819474 A CN 103819474A CN 201310537835 A CN201310537835 A CN 201310537835A CN 103819474 A CN103819474 A CN 103819474A
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- 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
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Abstract
The invention discloses a preparation method of tofacitinib, namely 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile. According to the preparation method, an onium pyridine salt is formed by using benzyl bromide as a raw material; then reduction, selective oxidation, alkylation, deprotection and an acylation reaction are conducted to obtain a compound, namely 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile shown as the formula I.
Description
Technical field
The present invention relates to 3-{ (3R, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidin-1-yl } preparation method of-3-oxypropionitrile (holder method for Buddhist nun, Tofacitinib), belong to technical field prepared by medicine.
Background technology
3-{ (3R, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidin-1-yl } (holder method is for Buddhist nun for-3-oxypropionitrile citrate, Tofacitinib, trade(brand)name: Xeljanz), its structural formula, suc as formula shown in I, is a kind of Janus kinases (JAKs) inhibitor of Pfizer Inc. (Pfizer) research and development.FDA (Food and Drug Adminstration) (FDA) was on November 6th, 2012, approval Citric Acid holder method is for Buddhist nun (Xeljanz) listing, for methotrexate for treatment is replied to the treatment of moderate insufficient or that do not tolerate to severe Active rheumatoid arthritis (RA) adult patient, it is a kind of new oral JAK inhibitor.
Holder method mainly contains following several for Buddhist nun's preparation method at present:
The synthetic route of the patent report (US6627754, CN1409712) of method one, Pfizer company is as follows:
This route is take 1-benzyl-4-methyl-piperidines-3-ketone as raw material, and methylamino on reduction amination is substituted, obtains holder method for Buddhist nun through splitting after catalytic hydrogenation debenzylation, acidylate.This route raw material costliness, end product will be through resolving and purifying, the more difficult control of isomer impurities, cost is high, is not suitable with suitability for industrialized production.
Method two, Pfizer company have carried out process modification to its former synthetic method, have applied for patent in 2006, patent No. WO2007012953, and open in China in 2008, its publication number is CN101233138A.In patent, announced the method for two kinds of synthetic holder methods for Buddhist nun, wherein a kind of concrete synthetic route is as follows:
This route is take 3-amido-4-picoline as raw material, first by amido esterification protection, rhodium catalytic reduction pyridine ring; benzyl protection on reduction amination, Lithium Aluminium Hydride reduction, then splits enantiomorph with two toluoyl tartrate; with 4-chloropyrrolo [2,3-d aminolysis, last acidylate obtains holder method for Buddhist nun.This route raw material is more expensive, and reduction pyridine ring has been used expensive rhodium catalyst, and route is long, and cost is high.
Method three, Pfizer company have carried out process modification to its former synthetic method, have applied for patent in 2006, patent No. WO2007012953, and open in China in 2008, its publication number is CN101233138A.In patent, announced the method for two kinds of synthetic holder methods for Buddhist nun, wherein another kind of concrete synthetic route is as follows:
This route, take 3-amido-4-picoline as raw material, first, by amido esterification protection, obtains pyridinium salt with benzyl bromine reaction; rhodium catalytic reduction pyridine ring, Lithium Aluminium Hydride reduction, then splits enantiomorph with two toluoyl tartrate; with 4-chloropyrrolo [2,3-d aminolysis, last acidylate obtains holder method for Buddhist nun.This route also exists raw material more expensive, and reduction pyridine ring has been used expensive rhodium catalyst, and route is long, and the cycle is long, and cost is high, is not suitable for suitability for industrialized production.
Summary of the invention
Technical problem: the synthetic route raw material costliness that CN1409712 patent is announced, end product will be through resolving and purifying, and enantiomeric impurity limit is difficult to be controlled, and production cost is high; The two lines that the WO2007012953 of Pfizer company patent is announced all exist raw material more expensive, have used expensive rhodium catalyst and have reduced pyridine ring, and synthetic route is long, and the cycle is long, and cost is high, is not suitable for suitability for industrialized production.The present invention is devoted to solve these defects, and provides and invented preparation holder method for Buddhist nun's variation route.In actual building-up process, final product and whole synthetic route that the present invention can obtain high-quality and high yield do not need splitting step.
Technical scheme:
Feature of the present invention has been to provide 3-{ (3R, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino of preparation formula I] piperidin-1-yl } method of-3-oxypropionitrile, comprising:
(a) make formula II compound react and obtain pyridinium salt with formula III compound, obtain the compound of formula IV through sodium borohydride reduction.
(b) selective oxidation formula IV compound obtains the compound of the formula V of single configuration.
(c) compound of the compound of formula V and formula VI obtains formula VII compound through mitsunobu alkylated reaction.
(d) formula VII compound Deprotection under the existence of hydrogen or hydrogen source and catalyzer obtains formula VIII compound.
(e) make formula VIII compound and cyano group Acetyl Chloride 98Min. carry out acylation reaction, obtain formula I compound 3-{ (3R, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidin-1-yl }-3-oxypropionitrile.
For step (a), become pyridinium salt one step, the currently known methods that can be used for conversion is a lot.Commonly benzyl chloride, bromobenzyl carry out in pyridine or in other inert solvent, preferably bromobenzyl; Pyridine self is that solvent is also alkali, and suitable alkali can be for example mineral alkali, as salt of wormwood, sodium carbonate, cesium carbonate, sodium bicarbonate or saleratus; Or organic bases is such as triethylamine, diisopropyl ethyl amine, pyridine, 2,6-lutidine, morpholine, Trimethylamine 99 or tripropyl amine etc., preferably pyridine.Follow-up reduction step is can be for example C at thinner
1-C
4alcohol, halogenated solvent, aromatic solvent, polar aprotic solvent, as acetonitrile, ethyl acetate etc.; Or dipolar aprotic solvent, as carried out in DMF, N,N-dimethylacetamide, NMP or methyl-sulphoxide etc., preferred alcohol; Suitable reductive agent can be lithium aluminum hydride, sodium triacetoxy borohydride, POTASSIUM BOROHYDRIDE, sodium borohydride or metal catalyst as Pd/C, Pt/C, thunder Buddhist nun Ni etc., preferably sodium borohydride.Wherein the mol ratio of formula III compound and reductive agent is between 1:1.1～1:2.0, and the temperature of reaction is 0-20 ℃, preferably near 0 ℃ or its.
For step (b), the oxidation of C-B key can adopt multiple currently known methods to carry out easily.Suitable oxygenant can be for example hydrogen peroxide, trimethylamine oxide, peroxide acids, chromium class oxygenant, Sodium peroxoborate, SPC-D etc., preferably potassium hydrogen persulfate composite salt.The mol ratio of its Chinese style IV compound and oxygenant is between 1:1～1:4.0, and the temperature of reaction is 0-20 ℃, preferably near 0 ℃ or its.
For step (c), mitsunobu alkylated reaction is common name reaction, and the currently known methods that can be used for conversion is a lot.Suitable phosphine part can be triphenylphosphine, tributylphosphine etc., triphenylphosphine; Suitable azo-compound can be diisopropyl azodiformate, diethyl azodiformate etc., preferably diisopropyl azodiformate.Reaction is can be for example halogenated solvent, aromatic solvent, polar aprotic solvent at inert solvent or thinner, as carried out in dioxane, tetrahydrofuran (THF), acetonitrile, ethyl acetate etc., and preferably dioxane.The mol ratio of its Chinese style V compound and formula VI compound is between 1:1～1:2.0, and the temperature of reaction is 0-100 ℃, preferably near 100 ℃ or its.
For step (d), this deprotection reaction for example can be by the hydrogenation of protecting group compound solution is carried out, and hydrogenation is as Pd/C, Pd (OH) at suitable metal catalyst
2/ C, Pt/C, PtO
2under/C exists, preferably Pd (OH)
2/ C, inert solvent, polar aprotic solvent as methyl alcohol or ethanol or polar aprotic solvent as ethyl acetate etc. in, preferred alcohol.Range of reaction temperature is 10-50 ℃, preferably near 20 ℃ or its.
For step (e), acylation reaction can adopt multiple currently known methods to carry out easily.Suitable alkali can be for example mineral alkali, as salt of wormwood, sodium carbonate, cesium carbonate, sodium bicarbonate or saleratus; Or organic bases is such as triethylamine, diisopropyl ethyl amine, pyridine, 2,6-lutidine, morpholine, Trimethylamine 99 or tripropyl amine etc., preferably pyridine.Reaction is can be for example halogenated solvent, aromatic solvent, polar aprotic solvent at inert solvent or thinner, as carried out in dioxane, methylene dichloride, tetrahydrofuran (THF), acetonitrile, ethyl acetate etc., preferably and methylene dichloride.The mol ratio of its Chinese style VIII compound and formula IX compound is between 1:1～1:3.0, and the temperature of reaction is 0-80 ℃, preferably near 20 ℃ or its.
Feature of the present invention has been to provide that applicable suitability for industrialized production, operation and aftertreatment are simple, the method for the high scale operation formula of yield I compound.
The important feature of another one of the present invention is also that selective reduction formula IV compound obtains the compound (de >=98%) of the formula V of highly purified single configuration, and reduction process is reacted at low temperatures, reductive agent is solid, and easy handling and amplification are produced.
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, and limit of impurities is low.So invention is extremely applicable to suitability for industrialized production.
Embodiment:
Embodiment 1,
1-benzyl-4-methyl isophthalic acid, 2,3,6-tetrahydropyridine (IV) synthetic
Bromobenzyl (17.1g, 100mmol) and pyridine (7.9g, 100mmol) react 24h at 20 ℃, and viscous fluid is heated to 130 ℃ of reaction 1h, and reaction solution is cooled to room temperature.Add ethanol (120mL) to dissolve, the yellow solution obtaining is cooled to 0 ℃, and sodium borohydride (5.0g, 130mmol) adds in batches in 2h.Reaction solution continues to react 12h at 20 ℃.Slowly drip water (60mL) hierarchy of control temperature at 5～10 ℃, add diatomite (4.0g).At 0 ℃, continue to stir 5h, filter, ethanol for filter cake (3 × 15mL) washing, merges organic phase, and its volume of concentrating under reduced pressure is about 50～60mL, drip sodium hydroxide solution (0.25M, 50mL), methyl tertiary butyl ether (3 × 40mL) extraction, merges organic layer, saturated aqueous common salt (2 × 30mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure solvent, obtains anhydrous oily matter 10.2g, yield 59%.
Embodiment 2,
Synthesizing of (3R, 4R)-4-methyl isophthalic acid-(phenyl methyl)-3-piperidine alcohols (V)
By 1-benzyl-4-methyl isophthalic acid, 2,3,6-tetrahydropyridine (18.7g, 100mmol) is dissolved in tetrahydrofuran (THF) (150mL), adds sodium borohydride (6.5g, 170mmol) under nitrogen protection in batches.Reaction solution is cooled to 0 ℃, slowly drips the mixing solutions of boron trifluoride diethyl etherate (16.8g, 118.3mmol) and tetrahydrofuran (THF) (25mL), hierarchy of control temperature≤0 ℃, dropwise, continue at 0 ℃ to stir 1h, then return to stirring at room temperature 1.5h.Reaction solution is cooled to 0 ℃ again, and water (50mL) is slowly added dropwise to system to destroy excessive borine.Reaction solution at room temperature continues to stir after 2h, is down to 0 ℃, slowly drips the mixing solutions of potassium hydrogen persulfate composite salt (110g, 342.8mmol) and water (500mL), dropwises, and system rises to room temperature reaction 12h.The excessive oxygenant of sodium bisulfite cancellation for reaction solution, regulates pH value 1～2.Ethyl acetate for reaction solution (3 × 50mL) extraction, water regulates its pH to 12 with 6N sodium hydroxide, with ethyl acetate (4 × 100mL) extraction.Merge organic layer, saturated aqueous common salt (2 × 30mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure solvent, obtains anhydrous oily matter 19.1g, yield 92%.
Embodiment 3,
Synthesizing of N-methyl-N-((3R, 4R)-4-methyl isophthalic acid-phenyl methyl piperidines-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (VII)
N-methyl-7H-pyrrolo-[2, 3-d] pyrimidine-4-amine (14.8g, 100mmol) with (3R, 4R)-4-methyl isophthalic acid-(phenyl methyl)-3-piperidine alcohols (20.5g, 100mmol) be dissolved in dioxane (200mL), under stirring, add triphenylphosphine (26.2g, 100mmol), reaction solution is cooled to 0 ℃, drip diisopropyl azodiformate (20.2g, 100mmol), dropwise, return to room temperature reaction 2h, then be warming up to 100 ℃ of reaction 2h, be cooled to room temperature, concentrating under reduced pressure obtains brown solid, add methylene dichloride (200mL) to dissolve, use successively saturated sodium bicarbonate (2 × 50mL), saturated aqueous common salt (2 × 50mL) washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure solvent obtains anhydrous oily liquids 22.8g, yield 68%.
Embodiment 4,
Synthesizing of N-methyl-N-((3R, 4R)-4-methyl piperidine-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (VIII)
To compound N-methyl-N-((3R, 4R)-4-methyl isophthalic acid-phenyl methyl piperidines-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (33.5g, in ethanol (500mL) solution 100mmol), add 2N hydrochloric acid (10mL), pass into nitrogen replacement three times.Then in reaction mixture, add 20% palladium hydroxide (50% water), gained mixture is reacted to 12h under 50psi nitrogen atmosphere and room temperature, by diatomite filtration reaction solution, concentration of reaction solution, to dry, obtains pale yellow oily liquid body 21g, yield 86%.
Embodiment 5,
3-{ (3R, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidin-1-yl }-3-oxypropionitrile (I) synthetic
To N-methyl-N-((3R stirring, 4R)-4-methyl piperidine-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (24.5g, in 150mL10:1 methylene dichloride/pyridine solution 100mmol), add cyano group Acetyl Chloride 98Min. (20.7g, 200mmol), gained mixture is at room temperature stirred to 12h.Then make reaction mixture distribute between methylene dichloride (100mL) and saturated sodium bicarbonate solution (80mL).Organic phase is used to saturated sodium bicarbonate solution (80mL) washing again, through anhydrous sodium sulfate drying, be concentrated in a vacuum dry amber color liquid 23.6g, yield 76%.
1HNMR(400MHz,CDCl
3),δ:1.10(d,J=7.0Hz,3H),1.58-1.81(m,2H),1.82-1.99(m,1H),2.44-2.59(m,1H),2.78-3.10(m,3H),3.25-3.40(m,1H),3,46(s,3H),3.96(s,2H),4.85-5.00(m,1H),6.59(d,J=3.5Hz,1H),7.05(t,J=3.5Hz,1H),8.33(m,1H).
Claims (2)
1. a 3-{ (3R, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidin-1-yl } preparation method of-3-oxypropionitrile, it is characterized in that this preparation method is:
1.) take bromobenzyl as raw material, react with pyridine and form pyridinium salt, obtain 1-benzyl-4-methyl isophthalic acid through sodium borohydride reduction again, 2,3,6-tetrahydropyridine, wherein the mol ratio of bromobenzyl and borane reducing agent sodium hydride is between 1:1.1～1:2.0, preferably 1:1.3, the temperature of reaction is 0-20 ℃, preferably near 0 ℃ or its.
2.) selective oxidation 1-benzyl-4-methyl isophthalic acid, 2,3,6-tetrahydropyridine obtains (3R, 4R)-4-methyl isophthalic acid-(phenyl methyl)-3-piperidine alcohols.
3.) (3R, 4R)-4-methyl isophthalic acid-(phenyl methyl)-3-piperidine alcohols and N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine obtains N-methyl-N-((3R through alkylated reaction, 4R)-4-methyl isophthalic acid-phenyl methyl piperidines-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine, wherein N-methyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine and (3R, the mol ratio of 4R)-4-methyl isophthalic acid-(phenyl methyl)-3-piperidine alcohols is between 1:1～1:2.0, preferably 1:1, the temperature of reaction is 0-100 ℃, preferably near 100 ℃ or its.
4.) N-methyl-7H-pyrrolo-[2; 3-d] pyrimidine-4-amine and (3R; 4R)-4-methyl isophthalic acid-(phenyl methyl)-3-piperidine alcohols debenzylation protecting group under the existence of hydrogen or hydrogen source and palladium hydroxide catalyzer obtains N-methyl-N-((3R; 4R)-4-methyl piperidine-3-yl)-7H-pyrrolo-[2; 3-d] pyrimidine-4-amine; range of reaction temperature is 10-50 ℃, preferably near 20 ℃ or its.
5.) N-methyl-N-((3R, 4R)-4-methyl piperidine-3-yl)-7H-pyrrolo-[2, 3-d] pyrimidine-4-amine and cyano group Acetyl Chloride 98Min. carry out acylation reaction, obtain formula I compound 3-{ (3R, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2, 3-d] pyrimidine-4-yl) amino] piperidin-1-yl }-3-oxypropionitrile, wherein N-methyl-N-((3R, 4R)-4-methyl piperidine-3-yl)-7H-pyrrolo-[2, 3-d] mol ratio of pyrimidine-4-amine and cyano group Acetyl Chloride 98Min. is between 1:1～1:3.0, preferably 1:2, the temperature of reaction is 0-80 ℃, preferably near 20 ℃ or its.
2. 3-{ (3R according to claim 1, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2, 3-d] pyrimidine-4-yl) amino] piperidin-1-yl } preparation method of-3-oxypropionitrile, it is characterized in that selective oxidation 1-benzyl-4-methyl isophthalic acid, 2, 3, 6-tetrahydropyridine obtains the (3R of highly purified single configuration, 4R)-4-methyl isophthalic acid-(phenyl methyl)-3-piperidine alcohols (de >=98%), wherein 1-benzyl-4-methyl isophthalic acid, 2, 3, the mol ratio of 6-tetrahydropyridine and oxygenant potassium hydrogen persulfate composite salt is between 1:1～1:4.0, preferably 1:3, the temperature of reaction is 0-20 ℃, preferably near 0 ℃ or its.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387392A (en) * | 2014-08-22 | 2015-03-04 | 山东潍坊制药厂有限公司 | Method for preparing tofacitinib |
| CN104693175A (en) * | 2015-03-14 | 2015-06-10 | 长沙深橙生物科技有限公司 | Preparation method of benzylpiperidine derivative |
| 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 |
| CN108822112A (en) * | 2018-08-13 | 2018-11-16 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of tropsch imatinib compound |
| CN109053737A (en) * | 2018-08-16 | 2018-12-21 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of tofacitinib citrate compound |
| CN111233866A (en) * | 2018-11-29 | 2020-06-05 | 浙江京新药业股份有限公司 | Process for the preparation of tofacitinib or a salt thereof |
| CN113717152A (en) * | 2021-09-08 | 2021-11-30 | 上海皓鸿生物医药科技有限公司 | Preparation method of specific MRK small molecule inhibitor |
| WO2024193496A1 (en) * | 2023-03-17 | 2024-09-26 | 北京普祺医药科技股份有限公司 | Method for preparing pyrrolopyrimidine compound or pharmaceutically acceptable salt thereof |
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| CN104387392A (en) * | 2014-08-22 | 2015-03-04 | 山东潍坊制药厂有限公司 | Method for preparing tofacitinib |
| CN104693175A (en) * | 2015-03-14 | 2015-06-10 | 长沙深橙生物科技有限公司 | Preparation method of benzylpiperidine derivative |
| CN104693175B (en) * | 2015-03-14 | 2016-08-31 | 长沙深橙生物科技有限公司 | A kind of preparation method of benzyl piepridine derivs |
| 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 |
| CN108822112B (en) * | 2018-08-13 | 2019-12-20 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of tofacitinib compound |
| CN108822112A (en) * | 2018-08-13 | 2018-11-16 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of tropsch imatinib compound |
| CN109053737A (en) * | 2018-08-16 | 2018-12-21 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of tofacitinib citrate compound |
| CN111233866A (en) * | 2018-11-29 | 2020-06-05 | 浙江京新药业股份有限公司 | Process for the preparation of tofacitinib or a salt thereof |
| CN111233866B (en) * | 2018-11-29 | 2021-07-02 | 浙江京新药业股份有限公司 | Process for the preparation of tofacitinib or a salt thereof |
| CN113717152A (en) * | 2021-09-08 | 2021-11-30 | 上海皓鸿生物医药科技有限公司 | Preparation method of specific MRK small molecule inhibitor |
| CN113717152B (en) * | 2021-09-08 | 2022-06-17 | 上海皓鸿生物医药科技有限公司 | Preparation method of specific MRK small molecule inhibitor |
| WO2024193496A1 (en) * | 2023-03-17 | 2024-09-26 | 北京普祺医药科技股份有限公司 | Method for preparing pyrrolopyrimidine compound or pharmaceutically acceptable salt thereof |
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