CN108822112A - A kind of preparation method of tropsch imatinib compound - Google Patents
A kind of preparation method of tropsch imatinib compound Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of tropsch imatinib compound; using 4- methyl piperidine -3- keto hydrochloride (II) under alkali and solvent existence condition; it is reacted with benzyl chloride and compound III is made; compound V is made in acid catalysis, then carries out the reactions such as asymmetric catalytic hydrogenation, deprotection, condensation and finally obtain finished product tropsch imatinib (I), and the preparation method process route is short; reaction condition is mild; total recovery and purity is high, by-product is few, is suitble to industrialized production.
Description
Technical field
A kind of preparation method of tropsch imatinib compound of the present invention, belongs to field of medicine preparing technology.
Background technique
Tropsch imatinib (tofacitinib), the entitled 3- of chemistry (3R, 4R) -4- methyl -3- [methyl (7H- pyrrolo- [2,
3-d] pyrimidine-4-yl) amino] piperidin-1-yl } -3- oxo propionitrile is that a kind of novel Janus of Pfizer Inc.'s research and development swashs
The activity of JAK1 and JAK3 can be effectively suppressed in enzyme inhibitor, blocks the signal transduction of a variety of inflammatory cytokines.In November, 2012
Ratify to list through U.S. FDA, tropsch imatinib citrate (trade name:Xeljanz it is " breakthrough) to obtain Food and Drug Adminstration of the US
Therapy " assert, approval listing for methotrexate for treatment response it is insufficient or in not tolerating to severe activity rheumatoid
The arthritic adult patient of property, is a kind of new oral JAK inhibitor.Some researches show that tropsch imatinibs simultaneously to ulcerative colitis
The inflammations related disease such as inflammation, psoriasis has good response to treatment, shown in chemical structural formula such as formula (I):
Currently, the synthetic route of tropsch imatinib reported in the literature have it is following several:
1) synthetic route of 103819474 A of patent CN report is as follows:
This route reacts to form pyridiniujm with pyridine using bromobenzyl as raw material, by sodium borohydride hydro-reduction, hydroboration
Sodium and mixed solution act on lower selective oxidation, mitsunobu alkylated reaction, and catalytic hydrogenation debenzylation, acylated get Tuo Fa are replaced
Buddhist nun, although the present invention solves the problems, such as that expensive raw material price, route hydroboration need largely in post-processing and separation
Solvent, and boron trifluoride ether is toxic, therefore is not suitable for large-scale production, and total recovery is not high.
2) synthetic route of 106146507 A of patent CN report is as follows:
This method is using (4- picoline -3- base) methyl carbamate as raw material, and through catalytic hydrogenation, benzyl protection is restored,
It at salt, splits, deprotection, tropsch imatinib is prepared in amide chemical conversion salt.Using fractionation so that yield reduction, makes in synthetic route
It is restored with Lithium Aluminium Hydride, it is dangerous, and synthetic route is long, is unfavorable for industrial production.
3) synthetic route of the patent report (US6627754, CN1409712) of Pfizer company is with 1- benzyl -4- methyl -
Piperidines -3- ketone is raw material, methylamino on reduction amination, be substituted, catalytic hydrogenation debenzylation, it is acylated after split and obtain support method and replace
Buddhist nun.This route final product will not be split through resolving and purifying, synthetic route, so that isomer impurities are more difficult to control, cost
Height, yield is low, is not suitable with industrialized production.Synthetic route is as follows:
Later, Pfizer company has carried out process modification to its former synthetic method, patent No. WO2007012953, and 2008
In Chinese Publication No. CN 101233138A.The method of two kinds of synthesis tropsch imatinibs, one of specific conjunction are disclosed in patent
At route using 3- amido -4- picoline as raw material, first amido esterification is protected, rhodium catalysis reduction pyridine ring, on reduction amination
Benzyl protection, Lithium Aluminium Hydride reduction, then with two toluoyl tartaric acid fractionation enantiomer, and 4- chloropyrrolo [2,3-d aminolysis,
Finally acylation obtains tropsch imatinib, this process route is long, at high cost.Another route using 3- amido -4- picoline as raw material,
First amido is esterified and is protected, obtains pyridiniujm with benzyl bromine reaction, rhodium catalysis restores pyridine ring, then Lithium Aluminium Hydride reduction is used
Two toluoyl tartaric acid split enantiomer, and with 4- chloropyrrolo [2,3-d aminolysis, finally acylation obtains tropsch imatinib.This route
There are preparation process route is long, reaction time is long, at high cost, is not suitable for industrialized production.
Summary of the invention
It, should present invention aims at a kind of preparation method of tropsch imatinib compound in view of the deficiencies of the prior art, is provided
Preparation method synthetic route is short, and yield and purity are higher, and product by-product is few, and entire synthetic route is not required to splitting step, is suitble to
Industrialized production.
Synthetic route of the present invention is as follows:
A kind of preparation method of tropsch imatinib compound, includes the following steps:
A, starting material 4- methyl piperidine -3- keto hydrochloride (II) under alkaline condition, reacts with benzyl chloride and chemical combination is made
Object III;
B, compound III and N- methyl -7H- pyrrolo- [2,3-d] pyrimidine -4- amine (IV) obtainedization under the action of catalyst
Close object V;
C, compound V carries out catalytic asymmetric hydrogenation under metallic catalyst and ligand effect and compound VI is made;
D, compound VI is deprotected under the effect of catalyst, acid and hydrogen and compound VII is made;
E, tropsch imatinib (I) is made under condensing agent and solvent action in compound VII and cyanoacetic acid;
Wherein, alkali used in step a is selected from sodium hydroxide or potassium hydroxide;Reaction dissolvent is water and toluene Mixed Solvent;
Compound II, alkali, benzyl chloride molar ratio are 1:1.5~3:1~1.5.
Catalyst used in step b is HClO4-SiO2;Compound III, compound IV and catalyst molar ratio are 1:1.05
~1.2:0.002~0.004,20~25 DEG C of reaction temperature.
Catalyst used in step c is (1,5- cyclo-octadiene) two (methylallyl) ruthenium [Ru (COD)
(Methallyl)2], ligand (R)-(+) -2,2 '-bis- (diphenylphosphino) -6,6 '-dimethoxy -1,1 '-biphenyl [(R) -
MEO-BIPHEP];Compound IV, catalyst, ligand molar ratio are 1:0.002~0.004:0.004~0.008;Hydrogen Vapor Pressure
1.01~2.00MPa, preferably pressure are 2.00Mpa;Reaction dissolvent is methylene chloride, methanol or isopropanol, further preferred
Organic solvent is methylene chloride.
Catalyst used in step d is 20%Pd (OH)2/C;Reaction dissolvent is methanol;Acid be acetic acid, reaction temperature 30~
35℃。
Condensing agent used in step e is N, N '-carbonyl dimidazoles;Compound VII, cyanoacetic acid, condensing agent molar ratio 1:
1.0~1.2:1.2~2,20~25 DEG C of reaction temperature.
Compared with the prior art, the beneficial effects of the present invention are:
(1) step b compound III of the present invention and compound IV generate enamine under acidic catalysis conditions, using HClO4-
SiO2For catalyst, reaction does not need solvent not only and participates in reaction, but also the reaction time is short, and yield is up to 96%.
(2) reaction condition of the present invention is mild, and synthetic route is short, and post-processing operation is convenient, can in actual synthesis process
It is not required to splitting step to obtain final product and the entire synthetic route of high-quality and high yield, is easy to industrialize.
Specific embodiment
Summary of the invention of the invention is described in further detail below by specific embodiment, but is not therefore limited
Determine the contents of the present invention.
Embodiment 1
The preparation of compound III
In 250mL there-necked flask, sequentially add 4- methyl piperidine -3- keto hydrochloride (II) 14.9g, 50mL distilled water and
50mL toluene, 0~5 DEG C is cooled under condition of ice bath, and stirring weighs 8.41g potassium hydroxide, is added portionwise in reaction flask, instead
2h between seasonable, removes condition of ice bath, is to slowly warm up to that benzyl chloride 12.6g is added dropwise under room temperature, and 30min is added dropwise, and continues
Stirring, is heated to back flow reaction 6h, and after reaction, stratification separates organic phase, washing, anhydrous sodium sulfate, and filtering subtracts
Pressure boils off solvent toluene, obtains colourless liquid 19.31g, yield 95.46%, HPLC purity 99.76%.
Embodiment 2
The preparation of compound III
In 250mL there-necked flask, sequentially add 4- methyl piperidine -3- keto hydrochloride (II) 14.96g, 50mL distilled water and
50mL toluene, 0~5 DEG C is cooled under condition of ice bath, and stirring weighs 16.8g sodium hydroxide, is added portionwise in reaction flask, instead
2h between seasonable, removes condition of ice bath, is to slowly warm up to that benzyl chloride 19g is added dropwise under room temperature, 30min is added dropwise, and continues to stir
It mixes, is heated to back flow reaction 6h, after reaction, stratification separates organic phase, washing, and anhydrous sodium sulfate filters, decompression
Solvent toluene is boiled off, colourless liquid 19.81g, yield 97.23%, HPLC purity 98.37% are obtained.
Embodiment 3
The preparation of compound III
In 250mL there-necked flask, sequentially add 4- methyl piperidine -3- keto hydrochloride (II) 14.96g, 50mL distilled water and
50mL toluene is cooled to 0~5 DEG C under condition of ice bath, and stirring weighs potassium carbonate 27.64g, is added portionwise in reaction flask, reacts
Time 2h, removes condition of ice bath, is to slowly warm up to that benzyl chloride 15.2g is added dropwise under room temperature, and 30min is added dropwise, and continues to stir
It mixes, is heated to back flow reaction 6h, after reaction, stratification separates organic phase, washing, and anhydrous sodium sulfate filters, decompression
Solvent toluene is boiled off, colourless liquid 17.68g, yield 87.34%, HPLC purity 97.26% are obtained.
Embodiment 4
The preparation of compound V
Weigh Compound III 19.72g, N- methyl -7H- pyrrolo- [2,3-d] pyrimidine -4- amine N- methyl -7H- pyrrolo-
[2,3-d] pyrimidine -4- amine (IV) 15.09g and HClO4-SiO2Solid 31mg is added in 250mL there-necked flask, and 20~25 DEG C of room temperature
Under the conditions of be stirred to react 20min, TLC is monitored to fully reacting, and methylene chloride dilution is added, and is filtered to remove solid, and organic phase is used
Anhydrous sodium sulfate dries, filters revolving, enriched compound V 31.36g, yield 96.98%, HPLC purity 97.33%.
Embodiment 5
The preparation of compound V
Weigh 19.72g compound III, 17.24g N- methyl -7H- pyrrolo- [2,3-d] pyrimidine -4- amine N- methyl -7H-
Pyrrolo- [2,3-d] pyrimidine -4- amine (IV) and 62mg HClO4-SiO2Solid is added in 250mL there-necked flask, room temperature 20~25
20min is stirred to react under the conditions of DEG C, TLC is monitored to fully reacting, and methylene chloride dilution is added, is filtered to remove solid, organic phase
Revolving, enriched compound V 30.72g, yield 95.24%, HPLC purity 97.78% are dried, filtered with anhydrous sodium sulfate.
Embodiment 6
The preparation of compound V
Weigh 19.72g compound III, 17.24g N- methyl -7H- pyrrolo- [2,3-d] pyrimidine -4- amine N- methyl -7H-
Pyrrolo- [2,3-d] pyrimidine -4- amine (IV) and 0.18g acetic acid are added in 250mL there-necked flask, are stirred under the conditions of 20~25 DEG C of room temperature
Reaction 20min is mixed, TLC is monitored to fully reacting, and methylene chloride dilution is added, is filtered to remove solid, organic phase anhydrous slufuric acid
Sodium dries, filters revolving, enriched compound V 26.62g, yield 82.32%, HPLC purity 93.22%.
Embodiment 7
The preparation of compound V
Weigh 19.72g compound III, 17.24g N- methyl -7H- pyrrolo- [2,3-d] pyrimidine -4- amine N- methyl -7H-
Pyrrolo- [2,3-d] pyrimidine -4- amine (IV) and 0.4g anhydrous aluminum chloride are added in 250mL there-necked flask, 20~25 DEG C of items of room temperature
20min is stirred to react under part, TLC is monitored to fully reacting, and methylene chloride dilution is added, is filtered to remove solid, organic phase nothing
Aqueous sodium persulfate dries, filters revolving, enriched compound V 23.10g, yield 71.42%, HPLC purity 91.61%.
Embodiment 8
The preparation of compound VI
In 250mL there-necked flask, 31.01g compound V, 100mg Ru (COD) (Methallyl) is sequentially added2With
0.226g (R)-MEO-BIPHEP, is dissolved in 100mL dichloromethane solution, successively replace nitrogen three times, hydrogen three times, hydrogen
1.01MPa, is stirred to react 12h by 20~25 DEG C of reaction temperature, filters, is concentrated to give compound VI 29.78g, yield 95.48%,
HPLC purity 98.69%, ee value 98%.
Embodiment 9
The preparation of compound VI
In 250mL there-necked flask, 31.01g compound V, 50mg Ru (COD) (Methallyl) is sequentially added2With
0.433g (R)-MEO-BIPHEP, is dissolved in 100mL methanol, successively replaces nitrogen three times, and three times, hydrogen 2MPa reacts hydrogen
20~25 DEG C of temperature, it is stirred to react 12h, filters, is concentrated to give compound VI 29.4g, yield 94.24%, HPLC purity
97.61%, ee value 97%.
Embodiment 10
The preparation of compound VI
In 250mL there-necked flask, 31.01g compound V, 25mg Ru (COD) (Methallyl) is sequentially added2With
0.325g (R)-MEO-BIPHEP, is dissolved in 100mL isopropanol, successively replace nitrogen three times, hydrogen three times, hydrogen 1.01MPa,
20~25 DEG C of reaction temperature, it is stirred to react 12h, filters, is concentrated to give compound VI 26.3g (0.078mol, molecular weight
335.45), yield 84.33%, HPLC purity 94.35%, ee value 92%.
Embodiment 11
The preparation of compound VI
In 250mL there-necked flask, 31.01g compound V, 0.2g Ru (COD) (Methallyl) is sequentially added2With
0.541g (R)-MEO-BIPHEP, is dissolved in 100mL isopropanol, successively replace nitrogen three times, hydrogen three times, hydrogen 2MPa, instead
20~25 DEG C of temperature are answered, 12h is stirred to react, filters, is concentrated to give compound VI 24.4g (0.073mol, molecular weight 335.45),
Yield 78.22%, HPLC purity 94.35%, ee value 86%.
Embodiment 12
The preparation of compound VII
In 250mL there-necked flask, VI 33.5g compound, 20%Pd (OH) are sequentially added2/ C (5.8g, it is aqueous 50%),
6g acetic acid and 100ml methanol, are uniformly mixed.Successively displacement nitrogen three times, hydrogen three times after, by Hydrogen Vapor Pressure control exist
0.4-0.6MPa, 50 DEG C of reaction l2h.It filtering, solvent is evaporated off in filtrate decompression, and residue is dry, compound VII 19.95g is obtained,
Yield 92.38%, HPLC purity 99.21%.
Embodiment 13
The preparation of tropsch imatinib
7.23g cyanoacetic acid is dissolved in 20mL methylene chloride, condensing agent 16.54g CDI is added portionwise, TCL tracking is anti-
It answers, reacted solution is added in constant pressure funnel, 20.86g compound VII is added in reaction flask and 80mL methylene chloride is molten
Solution, the solution in constant pressure funnel is added drop-wise in reaction flask, and drop finishes, and 40 DEG C of reaction temperature, reaction time 10h, after reaction,
Organic phase is washed, anhydrous sodium sulfate, which dries, filters, is concentrated to give tropsch imatinib 23.68g, yield 89.21%, HPLC purity
98.38%.
Embodiment 14
The preparation of tropsch imatinib
Cyanoacetic acid 8.16g is dissolved in 20mL methylene chloride, condensing agent 15.94g CDI is added portionwise, TCL tracking is anti-
It answers, reacted solution is added in constant pressure funnel, 24.5g compound VII is added in reaction flask and 80mL methylene chloride is molten
Solution, the solution in constant pressure funnel is added drop-wise in reaction flask, and drop finishes, and 40 DEG C of reaction temperature, reaction time 10h, after reaction,
Washing, anhydrous sodium sulfate, which dries, filters, is concentrated to give tropsch imatinib 22.22g, yield 88.92%, HPLC purity 96.37%.
Claims (9)
1. a kind of preparation method of tropsch imatinib compound, it is characterised in that the preparation method includes the following steps:
A, starting material 4- methyl piperidine -3- keto hydrochloride (II) under alkaline condition, reacts with benzyl chloride and compound is made
III;
B, compound is made in compound III and N- methyl -7H- pyrrolo- [2,3-d] pyrimidine -4- amine (IV) under the action of catalyst
V;
C, compound V carries out catalytic asymmetric hydrogenation under metallic catalyst and ligand effect and compound VI is made;
D, compound VI is deprotected under the effect of catalyst, acid and hydrogen and compound VII is made;
E, tropsch imatinib (I) is made under condensing agent and solvent action in compound VII and cyanoacetic acid;
Its synthetic route is as follows:
2. changing the method according to claim 1, wherein alkali described in step a is sodium hydroxide or potassium hydroxide
Close object II, alkali, benzyl chloride molar ratio be 1:1.5~3:1~1.5, reaction dissolvent is the one or two of water or toluene.
3. the method according to claim 1, wherein catalyst described in step b is HClO4-SiO2。
4. the method according to claim 1, wherein compound III, compound IV described in step b and catalysis
Agent molar ratio is 1:1.05~1.2:0.002~0.004.
5. the method according to claim 1, wherein catalyst described in step c is (1,5- cyclo-octadiene) two
(methylallyl) ruthenium, ligand are (R)-(+) -2,2 '-bis- (diphenylphosphino) -6,6 '-dimethoxy -1,1 '-biphenyl, chemical combination
Object IV, catalyst, ligand molar ratio are 1:0.002~0.004:0.004~0.008.
6. the method according to claim 1, wherein Hydrogen Vapor Pressure 1.01MPa~2.00MPa used in step c.
7. the method according to claim 1, wherein reaction dissolvent used in step c is methylene chloride, methanol or different
Propyl alcohol.
8. the method according to claim 1, wherein catalyst described in step d is 20%Pd (OH)2/ C, reaction
Solvent is methanol, and acid is acetic acid.
9. the method according to claim 1, wherein condensing agent described in step e be N, N '-carbonyl dimidazoles,
Compound VII, cyanoacetic acid, condensing agent molar ratio 1:1.0~1.2:1.2~2.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112679506A (en) * | 2021-01-12 | 2021-04-20 | 山东天铭医药科技有限公司 | Preparation method of tofacitinib citrate |
CN114315607A (en) * | 2021-12-29 | 2022-04-12 | 万华化学集团股份有限公司 | Preparation method of secondary diamine |
CN115236261A (en) * | 2022-05-10 | 2022-10-25 | 汉瑞药业(荆门)有限公司 | HPLC-UV detection method for purity of tofacitinib intermediate |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1409712A (en) * | 1999-12-10 | 2003-04-09 | 辉瑞产品公司 | Pyrrolo [2,3-d] pyrimidine compounds |
CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
CN103819474A (en) * | 2013-11-04 | 2014-05-28 | 湖南华腾制药有限公司 | Preparation method of tofacitinib |
CN104837817A (en) * | 2012-07-25 | 2015-08-12 | 力奇制药公司 | New synthetic route for preparation of 3-amino-piperidine compounds |
CN106146507A (en) * | 2015-03-10 | 2016-11-23 | 济南扬诺生物科技有限公司 | A kind of expelling pathogens by strengthening vital QI is for the new synthetic method of Buddhist nun |
EP3301087A1 (en) * | 2016-09-30 | 2018-04-04 | DPx Fine Chemicals Austria GmbH & Co KG | Process for preparing chiral amines |
-
2018
- 2018-08-13 CN CN201810917603.6A patent/CN108822112B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1409712A (en) * | 1999-12-10 | 2003-04-09 | 辉瑞产品公司 | Pyrrolo [2,3-d] pyrimidine compounds |
CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
CN104837817A (en) * | 2012-07-25 | 2015-08-12 | 力奇制药公司 | New synthetic route for preparation of 3-amino-piperidine compounds |
CN103819474A (en) * | 2013-11-04 | 2014-05-28 | 湖南华腾制药有限公司 | Preparation method of tofacitinib |
CN106146507A (en) * | 2015-03-10 | 2016-11-23 | 济南扬诺生物科技有限公司 | A kind of expelling pathogens by strengthening vital QI is for the new synthetic method of Buddhist nun |
EP3301087A1 (en) * | 2016-09-30 | 2018-04-04 | DPx Fine Chemicals Austria GmbH & Co KG | Process for preparing chiral amines |
Non-Patent Citations (2)
Title |
---|
曹运华等: "托法替尼合成路线图解", 《中国新药杂志》 * |
赵方露等: "枸橼酸托法替尼的合成", 《中国医药工业杂志》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112679506A (en) * | 2021-01-12 | 2021-04-20 | 山东天铭医药科技有限公司 | Preparation method of tofacitinib citrate |
CN114315607A (en) * | 2021-12-29 | 2022-04-12 | 万华化学集团股份有限公司 | Preparation method of secondary diamine |
CN114315607B (en) * | 2021-12-29 | 2024-02-02 | 万华化学集团股份有限公司 | Preparation method of secondary diamine |
CN115236261A (en) * | 2022-05-10 | 2022-10-25 | 汉瑞药业(荆门)有限公司 | HPLC-UV detection method for purity of tofacitinib intermediate |
CN115236261B (en) * | 2022-05-10 | 2024-04-19 | 武汉海特生物创新医药研究有限公司 | HPLC-UV detection method for tofacitinib intermediate purity |
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CB03 | Change of inventor or designer information |
Inventor after: Li Minghua Inventor after: Hou Junkai Inventor after: Zhang Han Inventor after: Huang Chunyan Inventor before: Hou Junkai Inventor before: Zhang Han Inventor before: Huang Qingyan |