CN104788445B - A kind of synthetic method of Dasatinib intermediate - Google Patents
A kind of synthetic method of Dasatinib intermediate Download PDFInfo
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- CN104788445B CN104788445B CN201510169818.0A CN201510169818A CN104788445B CN 104788445 B CN104788445 B CN 104788445B CN 201510169818 A CN201510169818 A CN 201510169818A CN 104788445 B CN104788445 B CN 104788445B
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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
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- C07D417/12—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 linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to pharmaceutical technology field, a kind of specifically related to synthetic method of 5 thiazole carboxamides of Dasatinib intermediate N (aminomethyl phenyl of 2 chlorine 6) 2 [(pyrimidine radicals of 6 chlorine, 2 methyl 4) amino], specific method is, first under cryogenic, to in aprotic solvent, sequentially add organic base, 2 amino Ns (aminomethyl phenyl of the 2 chlorine 6) formamide of thiazole 5 and 2 methyl 4, 6 dichloro pyrimidines, then rising high-temperature carries out reaction preparation N (aminomethyl phenyl of 2 chlorine 6) 2 [(pyrimidine radicals of 6 chlorine, 2 methyl 4) amino] 5 thiazole carboxamides, compared to existing technology, present invention tool yield higher and the single miscellaneous content of lower maximum, it is adapted to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of Dasatinib intermediate N (the chloro- 6- aminomethyl phenyls of 2-)-
The synthetic method of 2- [(6- chloro-2-methyl -4- pyrimidine radicals) amino] -5- thiazole carboxamides.
Background technology
Dasatinib (I), chemical name：N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [[6- [4- (2- ethoxys) -1- piperazinyls] -
2- methyl -4- pyrimidine radicals] amino] -5- thiazole carboxamides monohydrates, English name：N-(2-chloro-6-
methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-
Pyrimidinyl] amino] -5-thiazolecarboxamide, monohydrate, molecular formula：C22H26ClN7O2S·H2O,
It is a kind of oral tyrosine kinase inhibitor researched and developed by Bristol-Myers Squibb Co., the medicine passes through the U.S. in June, 2006
FDA is examined, for the past Endodontic failure or each stage chronic myeloid leukemia (CML) of the adult not tolerated, it is also possible to
In treatment to other therapies resistance or the acute lymphatic leukemia adult patient (ph of the Philadelphia Chromosome Positive not tolerated
+ALL)。
At present, the synthetic method of Dasatinib mainly has following several：
Method one：The chloro- 6- methylanilines of 2- obtain (E)-N- (chloro- 6- methyl of 2- with (E) -3- ethoxy propylene acyl chloride reactions
Phenyl) -3- ethanol acrylamides, then with N- bromo-succinimides (NBS), water, thiocarbamide through " one kettle way " be obtained 2- amino -
N- (the chloro- 6- aminomethyl phenyls of 2-) -5- thiazole carboxamides (III), (III) carries out nucleophilic with the chloro- 2- methylpyrimidines (IV) of 4,6- bis-
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [(6- chloro-2-methyl -4- pyrimidine radicals) amino] -5- thiazole carboxamides (II) are reacted to obtain,
(II) finally there is nucleophilic substitution with 1- (2- hydroxyethyls) piperazine to obtain (I).
Method two：Tetrahydrofuran (THF) solution of 2- diurils azoles and the chloro- 6- methylphenyl isocyanates of 2- in n-BuLi
In, at -78 DEG C, be condensed to yield amide intermediate, after the N of amide intermediate is protected with 4- methoxy-benzyl chlorine, then with 4-
Amino -6- chloro-2-methyls pyrimidine (IV) reacts, and after deprotection, nucleophilic displacement of fluorine finally occurs with 1- (2- hydroxyethyls) piperazine anti-
Deserved (I).
Method three：The experience N-Boc protections of 2- amino -5- thiazole ethyl formates, NaOH hydrolysis, hydrochloric acid acidifying, oxalyl chloride acyl
Change and the chloro- 6- methylanilines of 2- react [5- (the chloro- 6- aminomethyl phenyls carbamyls of 2-) thiazol-2-yl] tertiary fourth of-carbamic acid
Ester, then deprotection obtains (III), and (III) reacts (II) with (IV) again, and (II) is finally obtained with 1- (2- hydroxyethyls) piperazine condensation
(I)。
It follows that synthesizing Dasatinib using above method, compound II is indispensable.At present, Formula II
Compound III and compound IV being used the synthesis of compound with 60%NaH or sodium tert-butoxide as acid binding agent, in aprotic solvent four more
Reaction is obtained in hydrogen furans.
Ou Xiangyang etc. exists《The new synthesising process research of antineoplastic Dasatinib》([J]《Chinese disability medical science》2010,18
(5)：86-87) one a kind of synthetic method of midbody compound II is disclosed herein, it is first under agitation by NaH and nothing
Water tetrahydrofuran mix, then at room temperature successively be added dropwise 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides and
The anhydrous tetrahydrofuran solution of 4,6- bis- chloro- 2- methylpyrimidines is to being reacted in reaction system, plus acetic acid is quenched reaction, is concentrated into
It is dry.Plus saturation NaHCO3Solution, is extracted with dichloromethane.Anhydrous sodium sulfate drying, filtering, is concentrated to dryness, and obtains product.The preparation
The yield of midbody compound II is low obtained in method, it is impossible to the need for meeting further production well.
Zang Jialiang etc. exists《The synthesis of Dasatinib》([J]《Chinese Journal of Pharmaceuticals》2009,40 (5):321-323) one
A kind of method of improved synthetic intermediate compound II is disclosed herein, it is first by 2- amino-N- (the chloro- 6- methylbenzenes of 2-
Base) during -5- thiazole carboxamides, the chloro- 2- methylpyrimidines of 4,6- bis- and THF add to three-necked bottle, ice salt bath is cooled to -10~-5 DEG C,
Add freshly prepared sodium tert-butoxide, -10 DEG C of stirring reaction 1.5h.Plus 2mol/L hydrochloric acid is adjusted to neutrality, 0 DEG C of stirring 1.5h, mistake
Filter, filter cake is washed with a small amount, and dries, and obtains midbody compound II.The temperature of reaction is this method reduce, and increases tertiary fourth
The consumption of sodium alkoxide, finally improves the yield of product.But the maximum single miscellaneous content of products obtained therefrom is high, and the impurity is easily introduced into down
Single step reaction and form more accessory substances, the quality to Dasatinib finished product causes very big influence.
Therefore, in view of those skilled in the art further improve Dasatinib intermediate to the requirements at the higher level of product quality
The synthesis yield of compound II, it is one of current problem demanding prompt solution to reduce maximum single miscellaneous content.
The content of the invention
It is an object of the invention to provide a kind of preparation method of Dasatinib midbody compound II, the preparation method phase
There is yield and the single miscellaneous content of lower maximum higher than the Dasatinib midbody compound II that prior art synthesizes.
During invention, inventor first mixes highly basic with aprotic solvent, two kinds of reaction raw materials is added, in room temperature
The preparation of compound II is carried out under to reflux temperature, is as a result shown, the yield of product is low；Inventor is then using first anti-by two kinds
Answer raw material to mix with aprotic solvent, be cooled to low temperature, add highly basic and reacted, it is found that product yield starts to improve, but
It is that maximum single miscellaneous content is higher in the midbody compound II for now preparing.In order to obtain product yield high simultaneously
With the single miscellaneous content of low maximum, inventor carried out substantial amounts of scientific experimentation, attempted changing reaction temperature, the species of highly basic and add
The experimental conditions such as amount, the order by merging of reactant, are found surprisingly that first under -30~-20 DEG C of cryogenic conditions to aprotic solvent
In sequentially add highly basic, 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides, 2- methyl -4,6- dichloro pyrimidines, so
Temperature is increased into -10~-5 DEG C again afterwards to be reacted, reaction yield is significantly increased, it is more surprisingly now maximum single miscellaneous
Content substantially reduce.On this basis, inventor is to highly basic, the species of aprotic solvent, 2- amino-N- (the chloro- 6- methyl of 2-
Phenyl) thiazole -5- formamides and 2- methyl -4,6- dichloro pyrimidines, highly basic, the proportioning of aprotic solvent in the reaction time, terminate anti-
The condition answered is optimized, and completes this invention.
A kind of preparation method of Dasatinib intermediate, comprises the following steps：
It is down in -30~-20 DEG C of aprotic solvent to temperature, adds highly basic, stirs 10-30min；It is slowly added to 2- ammonia
Base-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides (III), adition process control temperature -30~-20 DEG C；To match somebody with somebody in advance
Good 2- methyl -4, the tetrahydrofuran solution of 6- dichloro pyrimidines (IV) is disposably added in reaction system, is heated up after stabilization, control
- 10~-5 DEG C, stirring reaction 2-12 hours of temperature；The reaction of 1mol/L hydrochloric acids is slowly added dropwise, pH 5-6 are adjusted, acid adding is excessively program control
0~5 DEG C of temperature processed；0~5 DEG C of temperature control, crystallization 1-3h, centrifugation, THF washings are dried, and obtain intermediate N (the chloro- 6- methylbenzenes of 2-
Base) -2- [(6- chloro-2-methyl -4- pyrimidine radicals) amino] -5- thiazole carboxamides (II), synthetic route is,
Wherein, described aprotic solvent is selected from tetrahydrofuran, dioxane, glycol dimethyl ether, methyl tertiary butyl ether(MTBE)
In one or more.It is preferred that tetrahydrofuran.
Described highly basic is selected from lithium diisopropylamine, Sodamide, hydrofining, sodium hydride, sodium methoxide, caustic alcohol, tertiary fourth
One kind in potassium alcoholate, sodium tert-butoxide.It is preferred that hydrofining.
Described 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides are 1 with the mol ratio of highly basic:3-4.
Described 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides and the mass volume ratio of aprotic solvent
G/ml is 1:6-16.
Described 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides and 2- methyl -4,6- dichloro pyrimidines
Mol ratio is 1:1-1.2.
2- methyl -4,6- dichloro pyrimidines and tetrahydrochysene furan in the tetrahydrofuran solution of described 2- methyl -4,6- dichloro pyrimidines
The mass volume ratio g/ml for muttering is 1:2-4.
The described reaction time is preferred 4-6 hours.
Dasatinib midbody compound II prepared by technical scheme of the present invention has the receipts higher than prior art
Rate (more than 95%) and the single miscellaneous content (less than 0.06%) of lower maximum, are more suitable for industrial applications.
Specific embodiment
Beneficial effects of the present invention are now further illustrated by the examples that follow, following examples are only used for the mesh of illustration
, should not be construed as limiting the invention.
Embodiment 1
Cooled to 80ml in -25 DEG C of tetrahydrofuran, add 8.73g hydrofinings (30% content, 65.38mmol)；Plus
Finish, stir 10min；It is slowly added to 5.00g 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides, adition process control
- 25 DEG C of temperature；Tetrahydrofuran (7ml) solution for -4,6- dichloro pyrimidines of methyl containing the 2- 3.65g that will be prepared in advance is disposably added to
In reaction system, heated up after stabilization, -10 DEG C of stirring reaction 4h；Then the reaction of 1mol/L hydrochloric acids is slowly added dropwise, regulation pH is
6,0-5 DEG C of temperature control, crystallization 2h, centrifugation, THF washings are dried, and obtain crude product 7.27g.Yield is 98.7%, and purity is 99.95%
(HPLC), maximum single miscellaneous content is 0.03%.
Embodiment 2
Cooled to 70ml in -30 DEG C of tetrahydrofuran, add 2.84g sodium hydrides (60% content, 70.98mmol)；Plus
Finish, stir 10min；It is slowly added to 5.00g 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides, adition process control
- 30 DEG C of temperature；Tetrahydrofuran (10ml) solution for -4,6- dichloro pyrimidines of methyl containing the 2- 3.65g that will be prepared in advance is disposably added
To in reaction system, heated up after stabilization, -8 DEG C of stirring reaction 6h；Then the reaction of 1mol/L hydrochloric acids is slowly added dropwise, pH is adjusted
It is 6,0-5 DEG C of temperature control, crystallization 2h, centrifugation, THF washings are dried, and obtain crude product 7.15g.Yield is 97.1%, and purity is 99.90%
(HPLC), maximum single miscellaneous content is 0.04%.
Embodiment 3
Cooled to 70ml in -20 DEG C of tetrahydrofuran, add 2.19g Sodamides；Finish, stir 10min；It is slowly added to
5.00g 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides, -20 DEG C of adition process temperature control；By what is prepared in advance
Tetrahydrofuran (10ml) solution of methyl containing 2- -4,6- dichloro pyrimidines 3.35g is disposably added in reaction system, is risen after stabilization
Temperature, -10 DEG C of stirring reaction 2h；Then the reaction of 1mol/L hydrochloric acids is slowly added dropwise, regulation pH is 5,0-5 DEG C of temperature control, crystallization 3h,
Centrifugation, THF washings, dries, and obtains crude product 7.13g.Yield is 96.8%, and purity is 99.82% (HPLC), and maximum single miscellaneous content is
0.06%.
Embodiment 4
Cooled to 80ml in -30 DEG C of tetrahydrofuran, add 7.34g potassium tert-butoxides；Finish, stir 10min；It is slow to add
Enter 5.00g 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides, -30 DEG C of adition process temperature control；To prepare in advance
Tetrahydrofuran (15ml) solution of methyl containing 2- -4,6- dichloro pyrimidines 3.65g be disposably added in reaction system, after stabilization
Heat up, -8 DEG C of stirring reaction 12h；Then the reaction of 1mol/L hydrochloric acids is slowly added dropwise, regulation pH is 6,0-5 DEG C of temperature control, crystallization
2h, centrifugation, THF washings are dried, and obtain crude product 7.1g.Yield is 96.5%, and purity is 99.86% (HPLC), maximum single miscellaneous content
It is 0.06%.
Embodiment 5
Cooled to 90ml in -25 DEG C of tetrahydrofuran, add 7.06g sodium methoxides；Finish, stir 10min；It is slowly added to
10.00g 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides, -25 DEG C of adition process temperature control；By what is prepared in advance
Tetrahydrofuran (25ml) solution of methyl containing 2- -4,6- dichloro pyrimidines 6.09g is disposably added in reaction system, is risen after stabilization
Temperature, -5 DEG C of stirring reaction 8h；Then the reaction of 1mol/L hydrochloric acids is slowly added dropwise, regulation pH is 5,0-5 DEG C of temperature control, crystallization 1h,
Centrifugation, THF washings, dries, and obtains crude product 14.08g.Yield is 95.6%, and purity is 99.88% (HPLC), maximum single miscellaneous content
It is 0.05%.
Comparative example 1
200ml anhydrous tetrahydro furans are added equipped with churned mechanically four-hole boiling flask, (60% contains addition 7.2g NaH
Amount, 0.18mol), anhydrous the four of amino containing 2--N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides 16.1g is added dropwise at room temperature
Hydrogen tetrahydrofuran solution (100ml).Room temperature is added dropwise the tetrahydrofuran (100ml) containing the chloro- 2- methylpyrimidines 19.6g of 4,6- bis- after 30 minutes
Solution, room temperature reaction 24h.Plus acetic acid is quenched reaction, is concentrated to dryness.Plus saturation NaHCO3Solution (300ml), uses dichloromethane
(300ml × 2) extract.Anhydrous sodium sulfate drying, filtering, is concentrated to dryness, and obtains faint yellow solid 17.88g.Yield is 75.4%,
Purity is 99.45% (HPLC), and maximum single miscellaneous content is 0.12%.
Comparative example 2
200ml anhydrous tetrahydro furans are added and is furnished with churned mechanically four-hole boiling flask, addition 7.2gNaH (60% content,
0.18mol), the anhydrous tetrahydrochysene of amino containing 2--N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides 16.1g is added dropwise at -15 DEG C
Tetrahydrofuran solution (100ml).- 15 DEG C are added dropwise the tetrahydrofuran (100ml) containing the chloro- 2- methylpyrimidines 19.6g of 4,6- bis- after 30 minutes
Solution, -10 DEG C of reaction 24h.Plus acetic acid is quenched reaction, is concentrated to dryness.Plus saturation NaHCO3Solution (300ml), uses dichloromethane
(300ml × 2) extract.Anhydrous sodium sulfate drying, filtering, is concentrated to dryness, and obtains faint yellow solid 2.96g.
Comparative example 3
By 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) -5- thiazole carboxamides of 5.5g, the chloro-2-methyls of 4,6- bis- of 4.0g
The THF of pyrimidine and 105ml is added in three-necked bottle.Ice salt bath is cooled to -10~-5 DEG C, adds freshly prepared sodium tert-butoxide
12.0g, -10 DEG C of stirring reaction 1.5h.Plus 2mol/L hydrochloric acid is adjusted to neutrality, there is crystallization to separate out.0 DEG C of stirring 1.5h, filtering, filter cake
It is washed with a small amount, dries, obtains faint yellow solid 7.15g.Yield is 88.5%, and purity is 99.55% (HPLC), maximum single miscellaneous
Content is 0.14%.
Comparative example 4
By 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) -5- thiazole carboxamides of 5.5g, the chloro-2-methyls of 4,6- bis- of 4.0g
The THF of pyrimidine and 105ml is added in three-necked bottle.Ice salt bath is cooled to -20 DEG C, adds freshly prepared sodium tert-butoxide 12.0g, -
20 DEG C of stirring reaction 1.5h.Plus 2mol/L hydrochloric acid is adjusted to neutrality, there is crystallization to separate out.0 DEG C of stirring 1.5h, filtering, filter cake is with a small quantity
Water washing, dries, and obtains faint yellow solid 1.9g.
Claims (5)
1. a kind of preparation method of Dasatinib intermediate, it is characterised in that comprise the following steps that：
It is down in -30~-20 DEG C of aprotic solvent to temperature, adds highly basic, is stirred 10-30 minutes；Be slowly added to 2- amino-
N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides, adition process control temperature -30~-20 DEG C；The 2- first that will be prepared in advance
Base -4, the tetrahydrofuran solution of 6- dichloro pyrimidines is disposably added in reaction system, is heated up after stabilization, temperature control -10~-5 DEG C,
Stirring reaction 2-12 hours；The reaction of 1mol/L hydrochloric acids is slowly added dropwise, pH 5-6, acid adding process control temp 0~5 is adjusted
℃；0~5 DEG C of temperature control, crystallization 1-3 hours, centrifugation, THF washings were dried, and obtain intermediate N (the chloro- 6- aminomethyl phenyls of 2-) -2-
[(6- chloro-2-methyl -4- pyrimidine radicals) amino] -5- thiazole carboxamides, synthetic route is：
；
Described aprotic solvent be selected from tetrahydrofuran, dioxane, glycol dimethyl ether, methyl tertiary butyl ether(MTBE) in one kind or
It is various；
Described highly basic be selected from lithium diisopropylamine, Sodamide, hydrofining, sodium hydride, sodium methoxide, caustic alcohol, potassium tert-butoxide,
One kind in sodium tert-butoxide；
Described 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides are 1 with the mol ratio of highly basic:3-4；
Described 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides and the mass volume ratio g/ml of aprotic solvent
It is 1:6-16；
Described 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides and 2- methyl -4,6- dichloro pyrimidines mole
Than being 1:1-1.2.
2. the preparation method of Dasatinib intermediate according to claim 1, it is characterised in that described aprotic solvent
It is tetrahydrofuran.
3. the preparation method of Dasatinib intermediate according to claim 1, it is characterised in that described highly basic is hydrogenation
Potassium.
4. the preparation method of Dasatinib intermediate according to claim 1, it is characterised in that described 2- methyl -4,
2- methyl -4,6- dichloro pyrimidines and the mass volume ratio g/ml of tetrahydrofuran are 1 in the tetrahydrofuran solution of 6- dichloro pyrimidines:2-
4。
5. the preparation method of Dasatinib intermediate according to claim 1, it is characterised in that the described reaction time is
4-6 hours.
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| US7491725B2 (en) * | 2004-02-06 | 2009-02-17 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN102838595B (en) * | 2012-09-13 | 2014-09-24 | 江苏奥赛康药业股份有限公司 | Preparation method of high-purity dasatinib and by-product of dasatinib |
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