CN106854198A - A kind of preparation method of Imatinib - Google Patents
A kind of preparation method of Imatinib Download PDFInfo
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- CN106854198A CN106854198A CN201510899828.XA CN201510899828A CN106854198A CN 106854198 A CN106854198 A CN 106854198A CN 201510899828 A CN201510899828 A CN 201510899828A CN 106854198 A CN106854198 A CN 106854198A
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- imatinib
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of preparation method of Imatinib, with N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine and 4- ((4- methylpiperazine-1-yls) methyl) benzamide as raw material, add potassium phosphate, 1,10- phenanthrolines and cuprous iodide, room temperature reaction, it is post-treated to obtain Imatinib.The reaction condition of the inventive method is gentle, solves loss and high energy consumption issues, easy to operate, high income of the high temperature reaction for a long time to equipment, is a kind of preparation method of suitable industrial amplification production.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of preparation method of Imatinib.
Technical background
Imatinib (Imatinib) is the precursor for preparing imatinib mesylate, and it is used clinically for treating various tumours,
Particularly for treatment chronic myelognous chronic myeloid leukemia, initially succeeded in developing by Novartis Co., Ltd of Switzerland, and obtained in 2001
FDA approval listings.FDA have approved medicine of the medicine as treatment gastrointestinal stromal tumors again within 2002.
Imatinib, English entitled imatinib, chemical name is 4- [(4- methyl isophthalic acids-piperazine) methyl]-N- [4- methyl -3- [[4- (3- pyrroles
Pyridine) -2- pyrimidines] amino] phenyl]-benzamide, structural formula is as follows：
The preparation method for disclosing the Imatinib of report has many kinds.
Method 1
Chinese patent 200710067344.4 is with N- (4- methyl -3- aminophenyls) -4- (4- methyl-piperazinyl group -1- methyl) benzene
Formamide is raw material, and 2- halo -4- methyl-(3- pyridine radicals) pyrimidine reaction is obtained Imatinib, in synthesis during this
The halogenating agent such as POCl3 used during 2- halo -4- methyl-(3- pyridine radicals) pyrimidine belongs to toxic articles, environmental pollution
It is larger, and the strict control of working condition needs, the threat so as to cause the cost kept the safety in production to increase and for environmental pollution etc..
Method 2
Chinese patent CN1630648A is raw material using the bromo- 4- methylanilines of 3-, and 4- (4- methyl-piperazine is realized with trimethyl aluminium
Piperazine base -1- methyl) ammonolysis reaction of methyl benzoate obtains N- (4- methyl -3- bromophenyls) -4- (4- methyl-piperazinyl groups -1-
Methyl) benzamide, Imatinib is finally obtained with precious metal palladium catalysis and pyrilamine reaction, there are three for using in the method
Aluminium methyl is ignition control compound, and the violent shortcoming of water haptoreaction, and final product obtained by this method has 10%
Isomers, it is difficult to purify.
Method 3
US20060223817, US20080103305, WO2008051597, WO2004108699 etc. are using lower such as lower section
Method or the like prepares Imatinib.
Common drawback present in the above method is that purity is mostly 97~98%, to thionyl chloride (SOCl2) and organic base
Demand it is big and do not processed, environmental pollution.
Method 4
WO03066613 is adopted and is prepared Imatinib with the following method.
The shortcoming of method 4 is mainly bromide and (3- pyridine radicals) -2- aminopyrimidines are costly, and production cost is very high.
Method 5
Patent CN100347162 and CN101735196 also reported a kind of method of Imatinib synthesis, by 4- (3- pyrroles
Piperidinyl) there is bromo-reaction, the centre of generation with the bromo- 4- methylanilines of 3- (Part B) in the amino (Part A) on -2- aminopyrimidines
Body (V) and piperazine benzoic acid (Part C) reaction generation Imatinib (I).
The shortcoming of the above method is the raw material sources such as 4- (3- pyridine radicals) -2- aminopyrimidines difficulty, the presence of bromo side reaction and three
The application of the metal coupling reagent such as aluminium ethide, increased industrialized difficulty.
Method 6
Patent WO2010/14022 reports the preparation method of following Imatinib.
The shortcoming of the method is the reaction time long, and temperature is high, and post processing is complicated, it is difficult to realize industrialization.
Based on above said content, it is necessary to seek kind of a concise in technology, mild condition, in high yield, low stain and low cost it is new
Imatinib preparation method.
The content of the invention
It is an object of the invention to provide a kind of preparation method of new Imatinib, the preparation method concise in technology, mild condition,
In high yield, low stain, low cost, are adapted to industrialized production.
For achieving the above object, present invention employs following main technical schemes：A kind of preparation method of Imatinib, its
It is characterised by that the preparation method comprises the following steps：With N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidines -2-
Amine is raw material with 4- ((4- methylpiperazine-1-yls) methyl) benzamide, in organic solvent, adds potassium phosphate, 1,10-
Phenanthroline and cuprous iodide carry out room temperature reaction, post-treated to obtain Imatinib.Synthetic route is as follows：
Described N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine and 4- ((4- methylpiperazine-1-yls) first
Base) benzamide molar equivalent ratio be 1:1~1:2.5, preferably 1:1~1:1.5；N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridines
- 3- bases) the molar equivalent ratio of pyrimidine -2- amine and potassium phosphate is 1:2~1:5, preferably 1:2~1:2.5；N- (the iodo- 2- aminomethyl phenyls of 5-) -4-
(pyridin-3-yl) pyrimidine -2- amine is 1 with the molar equivalent ratio of 1,10- phenanthrolines:0.02~1:0.1, preferably 1:0.03~1:0.0.06；
N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine is 1 with the molar equivalent ratio of cuprous iodide:0.01~1:0.1,
It is preferred that 1:0.01~1:0.06.
Described organic solvent is tetrahydrofuran or Isosorbide-5-Nitrae-dioxane or benzene or toluene or DMF
Or the mixture of one or more in dimethyl sulfoxide (DMSO), preferably tetrahydrofuran.
The described reaction time is 3~8 hours, preferably 4~6 hours.
Described post-processing approach is：Reacting liquid filtering, filtrate are poured into water, solid is separated out, filtering is dried to obtain her horse
For Buddhist nun.
Described N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine (compound 4) refers to patent
WO2006/41773 and WO2010/14022 is obtained, and synthetic route is as follows：
Described 4- ((4- methylpiperazine-1-yls) methyl) benzamide (compound 5) refers to document " Journal of
Medicinal Chemistry, 2005,48,1,249-255 " is obtained, and synthetic route is as follows：
Compared to existing technology, the advantage of the invention is that avoiding using reagent such as thionyl chloride or POCl3 of high pollution etc.,
To introducing iodine on reaction substrate molecular structure, and appropriate catalyst and part is used in combination, significantly reduces reaction energy barrier,
Thus reaction can be carried out at room temperature, thus realize it is a kind of in a mild condition, low energy consumption, low cost, in high yield, produce
Product purity is high, up to the preparation method of more than 99% Imatinib, is adapted to industrial amplification production.
The present invention is further described by the following embodiment, and these descriptions are not to make further limit to present invention
It is fixed.It should be understood by those skilled in the art that the equivalent made to technical characteristic of the invention, or be correspondingly improved, still belong to
Within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
5g (12.9mmol) N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine and 3.6g (15.5mmol)
Benzamide is added in 90ml dry tetrahydrofurans 4- ((4- methylpiperazine-1-yls) methyl), then is separately added into 5.5g
(25.8mmol) potassium phosphate, 0.12g (0.65mmol) 1,10- phenanthrolines and 0.13g (0.65mmol) cuprous iodide, in argon
It is stirred at room temperature in gas atmosphere, after reacting 4 hours, the detection reaction of TLC points plate is complete, and filtering reacting liquid pours into filtrate
In 200ml water, solid is separated out, filter cake is washed in filtering with water and acetonitrile respectively, and 50 DEG C of reduced vacuums are dried, and obtain pale yellow white
Color solid Imatinib 5.8g, yield is 92%, HPLC purity 99.4%.
Embodiment 2
25g (64.4mmol) N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine and 21.0g (90.2mmol)
Benzamide is added in 90ml Isosorbide-5-Nitraes-dioxane 4- ((4- methylpiperazine-1-yls) methyl), then is separately added into 27g
(127.3mmol) potassium phosphate, 0.62g (3.2mmol) 1,10- phenanthrolines and 0.13g (0.65mmol) cuprous iodide, in argon
It is stirred at room temperature in gas atmosphere, after reacting 6 hours, the detection reaction of TLC points plate is complete, and filtering reacting liquid pours into filtrate
In 200ml water, solid is separated out, filter cake is washed in filtering with water and acetonitrile respectively, and 50 DEG C of reduced vacuums are dried, and obtain pale yellow white
Color solid Imatinib 26.6g, yield is 83.7%, HPLC purity 99.0%.
ES-MS m/z=494 [M+H+]。
1H NMR(DMSO-d6,400MHz)δ(ppm):10.21 (s, 1H, NH), 9.28 (d, 1H, 4J=1.8Hz), 8.87 (s, 1H,
), NH 8.77 (dd, 1H, 3J=4.7,4J=1.5Hz), 8.52 (d, 1H, 3J=6.9Hz), 8.47 (m, 1H), 8.05 (d, 1H, 4J=1.9Hz),
7.83 (d, 2H, 3J=8.2Hz), 7.47~7.38 (m, 5H), 7.15 (d, 1H, 3J=8.31Hz), 3.49 (s, 2H), 2.29 (bs, 8H),
2.18(s,3H,CH3),2.10(s,3H,CH3)。
Claims (5)
1. a kind of preparation method of Imatinib, specific method is：It is phonetic with N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl)
Pyridine -2- amine is raw material with 4- ((4- methylpiperazine-1-yls) methyl) benzamide, in organic solvent, addition potassium phosphate,
1,10- phenanthroline and cuprous iodide carry out room temperature reaction, post-treated to obtain Imatinib.
2. the preparation method of Imatinib according to claim 1, it is characterised in that N- (the iodo- 2- aminomethyl phenyls of 5-) -4-
(pyridin-3-yl) pyrimidine -2- amine is with the molar equivalent ratio of 4- ((4- methylpiperazine-1-yls) methyl) benzamide
1:1~1:2.5；N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine is with the molar equivalent ratio of potassium phosphate
1:2~1:5；The molar equivalent ratio of N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine and 1,10- phenanthrolines
It is 1:0.02~1:0.1；N- (the iodo- 2- aminomethyl phenyls of 5-) -4- (pyridin-3-yl) pyrimidine -2- amine and cuprous iodide mole are worked as
Amount is than being 1:0.01~1:0.1.
3. the preparation method of Imatinib according to claim 1, it is characterised in that described organic solvent is tetrahydrofuran
Or one kind in Isosorbide-5-Nitrae-dioxane or benzene or toluene or DMF or dimethyl sulfoxide (DMSO) or
Several mixtures.
4. the preparation method of Imatinib according to claim 1, the reaction time is 3~8 hours.
5. the preparation method of the Imatinib according to power requires 1, post-processing approach is：Reacting liquid filtering, filtrate are poured into water
In, solid is separated out, filtering is dried to obtain Imatinib.
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| CN201510899828.XA CN106854198B (en) | 2015-12-08 | 2015-12-08 | A kind of preparation method of Imatinib |
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| CN201510899828.XA CN106854198B (en) | 2015-12-08 | 2015-12-08 | A kind of preparation method of Imatinib |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010014022A1 (en) * | 2008-08-01 | 2010-02-04 | Temapharm Sp. Z O.O. | A process for the preparation of imatinib |
| CN102548987A (en) * | 2009-07-14 | 2012-07-04 | 江苏迈度药物研发有限公司 | Fluoro-substituted compounds as kinase inhibitors and methods of use thereof |
-
2015
- 2015-12-08 CN CN201510899828.XA patent/CN106854198B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010014022A1 (en) * | 2008-08-01 | 2010-02-04 | Temapharm Sp. Z O.O. | A process for the preparation of imatinib |
| CN102548987A (en) * | 2009-07-14 | 2012-07-04 | 江苏迈度药物研发有限公司 | Fluoro-substituted compounds as kinase inhibitors and methods of use thereof |
Non-Patent Citations (1)
| Title |
|---|
| SVETLANA TERENTJEVA等: ""Synthesis 6-perfluoroalkylpyrimidine analogues of imatinib"", 《JOURNAL OF CHEMICAL RESEARCH》 * |
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Effective date of registration: 20190924 Address after: 410200 Tongguan Circular Economy Industrial Base, Wangcheng Economic Development Zone, Changsha City, Hunan Province Applicant after: Hunan Hua Tang Pharmaceutical Co., Ltd. Address before: 410205 Hunan city high tech Development Zone Changsha Changsha Wenxuan Road No. 27 building C2 N Lu Valley Yuyuan Unit No. 1308 Applicant before: Hunan Hua Teng pharmaceutical Co. Ltd |
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