CN103554099A - Preparation method of Dasatinib - Google Patents
Preparation method of Dasatinib Download PDFInfo
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- CN103554099A CN103554099A CN201310537381.2A CN201310537381A CN103554099A CN 103554099 A CN103554099 A CN 103554099A CN 201310537381 A CN201310537381 A CN 201310537381A CN 103554099 A CN103554099 A CN 103554099A
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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Abstract
The invention relates to a preparation method of Dasatinib. The preparation method comprises the following steps: respectively reacting (E)-N-(2-chlorine-6-methyl phenyl)-3-ethyoxyl acrylamide as well as N-bromo-succinimide and thiourea to form rings to obtain 2-amino-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide, performing butt joint on 2-amino-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide and 4,6-dichlone-2-methylpyrimidine to generate N-(2-chloride-6-methyl phenyl)-2-[(6-chlorine-2-methyl-4-pyrimidyl)amino]-5-thiazole carboxamide, continuously performing butt joint on N-(2-chloride-6-methyl phenyl)-2-[(6-chlorine-2-methyl-4-pyrimidyl)amino]-5-thiazole carboxamide and N-hydroxyethyl piperazine to generate a target compound Dasatinib, and recrystallizing the Dasatinib crude product to obtain the Dasatinib end product.
Description
Technical field
The present invention relates to a kind of preparation method of Dasatinib, belong to medical technical field.
Background technology
Dasatinib chemistry is by name: the chloro-6-aminomethyl phenyl of N-(2-)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-1,3-thiazoles-5-acid amides
Structural formula is:
Molecular formula: C
22h
26clN
7o
2s
Molecular weight: 488.01
Dasatinib, trade(brand)name Sprycel, also claim before this BMS-354825, be a kind of tyrosine kinase inhibitor that Bristol-Myers Squibb Co. produces, it is mainly used in the chronic myelocytic leukemia (chronic myelogenous leukemia) in imatinib (imatinib) treatment later stage and acute myeloid leukaemia (Ph+ALL) patient that Philadelphia chromosome is positive.This medicine is also proved to be the cancer that can treat many other types, comprises the prostate cancer of acceleration period.Dasatinib is mainly for Philadelphia chromosome (Philadelphia chromosome), SRC gene (Src Gene), c-Kit, compound not kinases and other Tyrosylprotein kinases, but not for erbB kinases such as EGFR, Her2.This medicine can suppress Bcr-Abl ，SRC kinases family (SRC, LCK, YES, FYN), c-KIT, the multiple kinases such as EPHA2 and PDGFR-B.By suppressing above-mentioned kinase whose effect, can suppress the propagation of leukemia cell in CML and Ph+ALL marrow, but normoerythrocyte, white corpuscle and thrombocyte still can continue propagation.
Bristol-Myers Squibb Co discloses a kind of method of synthetic Dasatinib in Chinese patent application in (publication number CN1348370A).The method is for will [the chloro-6-aminomethyl phenyl of 5-[[(2-) amino] carbonyl]-2-thiazolyl] carboxylamine, the trifluoroacetic acid solution of 1,1-dimethyl ethyl ester at room temperature stirs 3 hours, concentrating under reduced pressure, resistates dilutes by ethyl acetate, uses 5%KHCO
3the aqueous solution, water and salt washing, dry, obtain the chloro-6-aminomethyl phenyl of 2-amino-N-(2-)-5-thiazole carboxamides.Suspension to NaH in THF adds the chloro-6-aminomethyl phenyl of 2-amino-N-(2-) the THF solution of-5-thiazole carboxamides, and at room temperature stir, add 4, the THF solution of the chloro-2-methylpyrimidine of 6-bis-also at room temperature stirs and spends the night, add acetic acid that reaction is stopped, removal of solvent under reduced pressure adds water and NaHCO in resistates
3saturated solution is also used CH
3cl
2extraction, organic layer is removed in decompression, then obtains target product through reaction.
Bristol-Myers Squibb Co has recorded five kinds of crystalline form of Dasatinib and preparation method thereof in the patent (publication number CN1980909) of China's application, and these five kinds of crystalline form comprise: monohydrate, butanols solvate, alcohol solvent compound, the N-6 of pure form and the T1H1-7 of pure form.
Still there is certain shortcoming in prior art, cannot be effectively in preparation process, effectively reduces the related substance, particularly starting raw material (E) of product-N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethoxy propylene acid amides and improve the quality of products.
Therefore, this area exists such demand at present, is suitable for the product of commercial scale production, physicochemical property excellence.
Summary of the invention
The object of the invention is and purification technique synthetic to existing Dasatinib and be optimized, obtain not containing the Dasatinib compound of crystal water, this product has the feature of good stability.
For this reason, the invention provides a kind ofly not containing the preparation method of the Dasatinib compound of crystal water, described method has that cost is low, yield is high, quality controllable, easy and simple to handle, be conducive to realize the advantages such as industrialization.
Of the present invention not containing the Dasatinib compounds process for production thereof of crystal water, comprise the following steps:
(1) (E)-N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethoxy propylene acid amides (starting raw material) reacts and obtains 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide (compound 1) under the effect of NBS and thiocarbamide, reacts as follows:
During this is anti-, the material ratio of NBS and starting raw material is 1 ﹕ 1, and thiocarbamide and initial original material ratio are 1.1 ﹕ 1.Before middle reaction, reacting liquid temperature is-15 ℃～-5 ℃, preferably-15 ℃～-10 ℃; During NBS application of sample, temperature is-10 ℃～0 ℃, preferably-10 ℃～-5 ℃; During reaction, temperature is 25 ℃～28 ℃ of room temperatures; The temperature of reaction of thiocarbamide is 75 ℃～90 ℃; Preferably 80 ℃～85 ℃.
(2) compound 1 and 4, the chloro-2-methylpyrimidine of 6-bis-generates N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl under the condition of tetrahydrofuran (THF) and sodium tert-butoxide existence) amino]-5-thiazole carboxamides (compound 2), reacts as follows:
In reaction 4, the material ratio of the chloro-2-methylpyrimidine of 6-bis-and compound 1 is 1.2 ﹕ 1.Reaction solvent is selected from: a kind of in DMF, methyl-sulphoxide, N,N-dimethylacetamide, tetrahydrofuran (THF), preferably tetrahydrofuran (THF).Before reaction, reacting liquid temperature is-15 ℃～-5 ℃, preferably-15 ℃～-12 ℃; During sodium tert-butoxide application of sample, temperature is-10 ℃～0 ℃, preferably-10 ℃～-5 ℃; During reaction, temperature is-10 ℃～-5 ℃, preferably-10 ℃.
(3) compound 2 generates target compound Dasatinib under the effect of N-hydroxyethyl piperazine, tri-n-butylamine and propyl carbinol, reacts as follows:
The material ratio of N-hydroxyethyl piperazine and compound 2 is 4.46 ﹕ 1.In agitation condition downhill reaction device, add compound 2, N-hydroxyethyl piperazine, tri-n-butylamine and propyl carbinol, be heated to reflux, be cooled to after completion of the reaction 25 ℃～28 ℃ of room temperatures.After filtration, add 80% ethanol, be heated to dissolve, add water to be heated to reflux.Be cooled to 25 ℃～28 ℃ of room temperatures, centrifugal, filter cake embathes with 50% ethanol.
(4) Dasatinib crude product, through recrystallization, obtains Dasatinib finished product.
In this purification process, Dasatinib crude product is through twice recrystallization.Recrystallization is added to Dasatinib crude product and methyl alcohol in reactor for the first time, is heated to entirely moltenly, and press filtration is to crystallizer, and filtrate is cooled to 20 ℃.Centrifugal, dry under 60 ℃～70 ℃, vacuum tightness≤-0.09MPa condition.Dried product exhibited and methyl alcohol are added in reactor and carry out recrystallization for the second time, be heated to entirely moltenly, press filtration, to crystallizer, is cooled to 20 ℃.Centrifugal, dry under 60 ℃～70 ℃, vacuum tightness≤-0.09MPa condition, obtain Dasatinib finished product.
The refining employing methyl alcohol of Dasatinib, as the solvent of recrystallization, can obtain not containing the target compound of crystal water.Target compound after testing, does not contain crystal water, and its moisture content is not higher than 0.7%, and product purity reaches 99.9%, and impurity is few, and yield is high, is better than prior art.
The present invention is suitable for commercial scale production, and process recovery ratio is high, and cost is low, and impurity is easy to control, and product is new crystal, has good stability.
Below data further illustrate beneficial effect of the present invention by experiment:
Experiment one, product stability contrast experiment:
The present invention is not containing Dasatinib and the documents 1CN1348370A of crystal water, and the Dasatinib that documents 2CN1980909 obtains carries out stability experiment comparison, the results are shown in following table:
Experiment two, product purity contrast experiment:
The present invention is not containing Dasatinib and the documents 1CN1348370A of crystal water, and the Dasatinib that documents 2CN1980909 obtains carries out purity comparative experiments, the results are shown in following table:
Through detecting, the content of starting raw material of the present invention (E)-N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethoxy propylene acid amides is below 0.01%.
Compared with prior art, major advantage of the present invention is:
Advantage 1: product is that physicochemical property is excellent, good stability not containing the new chemical form of crystal water.
Advantage 2: technique treating process is simple, removes impurity respond well.
Beneficial effect:
The present invention is by technical optimization, provides a kind of raw material sources to be easy to get, reaction preference is high, easy and simple to handle, production efficiency is high, the preparation method of quality controllable, the Dasatinib that is suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1 preparation 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide
In reactor, add water 63L, starting raw material 11.5kg, Isosorbide-5-Nitrae-dioxane 63L, cool to-15 ℃～-12 ℃.Add NBS9.5kg, control temperature-10 ℃～-5 ℃, finish 1.5 hours and be warming up to 25 ℃～28 ℃ of room temperatures, stir 3.5 hours.Add thiocarbamide 3.7kg, at 80 ℃～85 ℃ of temperature, stir 2.5 hours.Reaction solution is cooled to 25 ℃～28 ℃ of room temperatures, drip strong aqua 9.7L.Water-bath, remove certain solvent under reduced pressure, residual reaction liquid is cooled to 0 ℃ of crystallization 10～12 hours.Centrifugal rear purified water is embathed, and vacuum-drying obtains product 12.2kg.
Embodiment 2 preparation N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides
In reactor, add 230L tetrahydrofuran (THF), 12kg compound 1 and 8.82kg4 while stirring, the chloro-2-methylpyrimidine of 6-bis-, cools to-15 ℃～-12 ℃.Add sodium tert-butoxide 26.5kg ,-10 ℃ are stirred 3 hours.React complete dropping 2mol/L hydrochloric acid to neutral, stir 4 hours at 0 ℃.Centrifugal embathe once with purified water 2L afterwards, vacuum-drying obtains product 14.3kg.
Embodiment 3 prepares Dasatinib
In agitation condition downhill reaction device, add 14kg compound 2,16.5kg N-hydroxyethyl piperazine, 13.5L tri-n-butylamine and 102L propyl carbinol, be heated to reflux, back flow reaction 6 hours.Be cooled to after completion of the reaction 25 ℃～28 ℃ of room temperatures.After filtration, be added in reactor, add 80% ethanol 215kg, be heated to dissolve, add water 140L, be heated to reflux 10 minutes.Be cooled to 25 ℃～28 ℃ of room temperatures, centrifugal, filter cake embathes with 50% ethanol 2L.Vacuum-drying, obtains Dasatinib crude product 13.7kg.
The refining Dasatinib of embodiment 4
Dasatinib crude product 13.5kg and methyl alcohol 410L are added in reactor, are heated to entirely moltenly, press filtration is to crystallizer, and filtrate is cooled to 20 ℃.Centrifugal, vacuum-drying, obtains Dasatinib fine work 11.0kg.Dasatinib fine work and methyl alcohol 330L are added in reactor, are heated to entirely moltenly, press filtration, to crystallizer, is cooled to 20 ℃.Centrifugal, vacuum-drying, obtains Dasatinib finished product 9.3kg, yield 68.9%, product purity 99.9%.
The method of the refining Dasatinib of prior art:
Dasatinib crude product 13.5kg and ethanol 500L are added in reactor, are heated to entirely moltenly, press filtration is to crystallizer, and filtrate is cooled to 20 ℃.Centrifugal, vacuum-drying, obtains Dasatinib fine work 10.6kg.Dasatinib fine work and ethanol 500L are added in reactor, are heated to entirely moltenly, press filtration, to crystallizer, is cooled to 20 ℃.Centrifugal, vacuum-drying, obtains Dasatinib finished product 8.1kg, yield 60.0%, product purity 99.4%.
Claims (10)
1. a preparation method for Dasatinib, is characterized in that the method comprises the following steps:
(1) (E)-N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethoxy propylene acid amides is reacted and obtains 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide under the effect of N-bromo-succinimide (NBS) and thiocarbamide.
(2) docking under the condition of tetrahydrofuran (THF) and sodium tert-butoxide existence of 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide and the chloro-2-methylpyrimidine of 4,6-bis-generates N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides.
(3) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides generates target compound Dasatinib under the effect of N-hydroxyethyl piperazine, tri-n-butylamine and propyl carbinol.
(4) Dasatinib crude product, through recrystallization, obtains Dasatinib finished product.
2. according to the Dasatinib preparation method of claim 1, it is characterized in that: in step (1), reactant NBS is 1 ﹕ 1 with the material ratio of (E)-N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethoxy propylene acid amides, thiocarbamide is 1.1 ﹕ 1 with the material ratio of (E)-N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethoxy propylene acid amides; In step (1), before reaction, reacting liquid temperature is-15 ℃～-5 ℃, and during NBS application of sample, temperature is-10 ℃～0 ℃, and during reaction, temperature is 25 ℃～28 ℃ of room temperatures; The temperature of reaction of thiocarbamide is 75 ℃～90 ℃.
3. according to the Dasatinib preparation method of claim 1, it is characterized in that:
In step (1), before reaction, reacting liquid temperature is-15 ℃～-10 ℃; During NBS application of sample, temperature is-10 ℃～-5 ℃; During reaction, temperature is 25 ℃～28 ℃ of room temperatures; The temperature of reaction of thiocarbamide is 80 ℃～85 ℃.
4. according to the Dasatinib preparation method of claim 1, it is characterized in that: in step (2) 4, the material ratio of the chloro-2-methylpyrimidine of 6-bis-and 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide is 1.2 ﹕ 1.
5. according to the Dasatinib preparation method of claim 1, it is characterized in that: reaction solvent is selected from step (2): a kind of in DMF, methyl-sulphoxide, N,N-dimethylacetamide, tetrahydrofuran (THF), preferably tetrahydrofuran (THF).In step (2), before reaction, reacting liquid temperature is-15 ℃～-5 ℃; During sodium tert-butoxide application of sample, temperature is-10 ℃～0 ℃, and during reaction, temperature is-10 ℃～-5 ℃.
6. according to the Dasatinib preparation method of claim 1, it is characterized in that: in step (2), before reaction, reacting liquid temperature is-15 ℃～-12 ℃; During sodium tert-butoxide application of sample, temperature is-10 ℃～-5 ℃; During reaction, temperature is-10 ℃.
7. according to the Dasatinib preparation method of claim 1, it is characterized in that: N-hydroxyethyl piperazine and N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl in step (3)) amino] the material ratio of-5-thiazole carboxamides is 4.46 ﹕ 1.
8. according to the Dasatinib preparation method of claim 1, it is characterized in that: in step (4), Dasatinib crude product recrystallization solvent is selected from: one or more in ethanol, methyl alcohol, in step (4), Dasatinib crude product is through twice recrystallization.
9. according to the Dasatinib preparation method of claim 1, it is characterized in that: after methyl alcohol reflux, be cooled to 20 ℃ in step (4), filter, dry under 60 ℃～70 ℃, vacuum tightness≤-0.09MPa condition, obtain Dasatinib fine work.
10. according to the Dasatinib preparation method of claim 1, it is characterized in that: step is as follows:
(1) preparation of 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide
In reactor, add water 63L, (E)-N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethoxy propylene acid amides 11.5kg, Isosorbide-5-Nitrae-dioxane 63L, cool to-15 ℃～-12 ℃.Add NBS9.5kg, control temperature-10 ℃～-5 ℃, finish and be warming up to 25 ℃～28 ℃ of room temperatures, stir.Add thiocarbamide 3.7kg, at 80 ℃～85 ℃ of temperature, stir.Reaction solution is cooled to 25 ℃～28 ℃ of room temperatures, drip strong aqua 9.7L.Water-bath, remove certain solvent under reduced pressure, residual reaction liquid is cooled to 0 ℃ of crystallization.Centrifugal rear purified water is embathed, and vacuum-drying obtains 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide 11～13kg,
(2) N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino] preparation of-5-thiazole carboxamides
In reactor, add tetrahydrofuran (THF) 230L, 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide 12kg and the chloro-2-methylpyrimidine of 4,6-bis-8.82kg while stirring, cool to-15 ℃～-12 ℃.Add sodium tert-butoxide 26.5kg ,-10 ℃ of stirrings.Reaction finish to drip hydrochloric acid to neutral, stirs at 0 ℃.Centrifugal embathe by purified water afterwards, vacuum-drying obtains compound N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides 13～15kg,
(3) preparation of Dasatinib
In agitation condition downhill reaction device, add N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides 14kg, N-hydroxyethyl piperazine 16.5kg, tri-n-butylamine 13.5L and propyl carbinol 102L, be heated to reflux, be cooled to after completion of the reaction 25 ℃～28 ℃ of room temperatures.After filtration, be added in reactor, add 80% ethanol 215kg, be heated to dissolve, add water 140L, be heated to reflux.Be cooled to 25 ℃～28 ℃ of room temperatures, centrifugal, vacuum-drying, obtains Dasatinib crude product 13～14kg,
(4) Dasatinib is refining
Dasatinib crude product 13.5kg and methyl alcohol 410L are added in reactor, are heated to entirely moltenly, press filtration is to crystallizer, and filtrate is cooled to 20 ℃.Centrifugal, vacuum-drying, obtains Dasatinib fine work 10.5～11.5kg.Dasatinib fine work 11kg and methyl alcohol 330L are added in reactor, are heated to entirely moltenly, press filtration, to crystallizer, is cooled to 20 ℃, centrifugal.Dry under 60 ℃～70 ℃, vacuum tightness≤-0.09MPa condition, obtain Dasatinib finished product 8.5～9.5kg.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130979A (en) * | 2015-08-10 | 2015-12-09 | 青岛蓝盛洋医药生物科技有限责任公司 | Drug dasatinib compound for treatment of leukemia and preparation method thereof |
| CN106117196A (en) * | 2016-06-09 | 2016-11-16 | 青岛辰达生物科技有限公司 | A kind of method preparing cancer therapy drug Dasatinib |
| CN107089976A (en) * | 2017-06-29 | 2017-08-25 | 华润双鹤利民药业（济南）有限公司 | A kind of preparation method of Dasatinib |
| CN110862387A (en) * | 2018-08-27 | 2020-03-06 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
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| CN1980909B (en) * | 2004-02-06 | 2010-08-25 | 布里斯托尔-迈尔斯·斯奎布公司 | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN102898424A (en) * | 2011-07-29 | 2013-01-30 | 江苏奥赛康药业股份有限公司 | Novel polymorphs of dasatinib, and preparation method thereof |
| WO2013065063A1 (en) * | 2011-11-03 | 2013-05-10 | Cadila Healthcare Limited | Anhydrous form of dasatinib, process for its preparation and its use |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1980909B (en) * | 2004-02-06 | 2010-08-25 | 布里斯托尔-迈尔斯·斯奎布公司 | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN102898424A (en) * | 2011-07-29 | 2013-01-30 | 江苏奥赛康药业股份有限公司 | Novel polymorphs of dasatinib, and preparation method thereof |
| WO2013065063A1 (en) * | 2011-11-03 | 2013-05-10 | Cadila Healthcare Limited | Anhydrous form of dasatinib, process for its preparation and its use |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130979A (en) * | 2015-08-10 | 2015-12-09 | 青岛蓝盛洋医药生物科技有限责任公司 | Drug dasatinib compound for treatment of leukemia and preparation method thereof |
| CN106117196A (en) * | 2016-06-09 | 2016-11-16 | 青岛辰达生物科技有限公司 | A kind of method preparing cancer therapy drug Dasatinib |
| CN107089976A (en) * | 2017-06-29 | 2017-08-25 | 华润双鹤利民药业（济南）有限公司 | A kind of preparation method of Dasatinib |
| CN110862387A (en) * | 2018-08-27 | 2020-03-06 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
| CN110862387B (en) * | 2018-08-27 | 2023-05-16 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
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