CN109369638A - A kind of preparation process of Dasatinib - Google Patents
A kind of preparation process of Dasatinib Download PDFInfo
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- CN109369638A CN109369638A CN201811388270.9A CN201811388270A CN109369638A CN 109369638 A CN109369638 A CN 109369638A CN 201811388270 A CN201811388270 A CN 201811388270A CN 109369638 A CN109369638 A CN 109369638A
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Abstract
The present invention relates to a kind of preparation processes of Dasatinib, this method comprises the following steps: 3- ethyl 3-oxopropanoate is heated to reflux with the chloro- 6- methylaniline of 2- under alkaline condition, copper bromide is added, temperature rising reflux, thiocarbamide and catalyst heteropolyacid salt is added, is stirred at room temperature and reacts up to 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide；2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide, the chloro- 2- methylpyrimidine of 4,6- bis- and N- hydroxyethyl piperazine are subjected to " one pot reaction " under the effect of the catalyst to get Dasatinib afterwards.Mild condition of the present invention, step be simple, environmentally friendly and high income, is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of preparation process of Dasatinib.
Background technique
Dasatinib (Dasatinib, trade name Sprycel), entitled N- (the chloro- 6- aminomethyl phenyl of the 2-) -2- [6- of chemistry
[4- (2- ethoxy) -1- piperazinyl] -2- methyl -4- pyrimidine radicals] amino -5- thiazole carboxamides are by Mei Shi your company when hundred
A kind of oral tyrosine kinase inhibitor of research and development.The medicine obtains FDA approval listing in June, 2006, for treating chronic marrow
Property leukaemia, can also treat the acute lymphatic leukemia of Philadelphia Chromosome Positive.This product is a variety of to Bcr-Ab1 kinases
Mutant has inhibiting effect, and inhibition strength improves a lot compared with Imatinib (Imatinib), and does not find drug resistance.It is tied
Structure formula is as follows:
About the synthesis of Dasatinib, there are many domestic and foreign literature report, are that intermediate 2- ammonia is synthesized by distinct methods mostly
Base-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, carry out a series of substitution reactions afterwards.Synthetic route is as follows:
(1) document J.Med.Chem.2004,47,6658-6661；It is mentioned in J.Med.Chem.2006,49,6819-6832
The route of confession is as follows:
This route needs n-BuLi to react at subzero 78 degree, and need to repeatedly use sodium hydride, severe reaction conditions, is not suitable for
Industrialized production, and 2- methyl -4- amino -6- chlorine pyrimidine price is relatively high, and should not buy.
(2) patent CN200580011916.6 discloses two lines.Synthetic route is as follows:
Route one:
Route two:
One total recovery of route is lower, and only 36%, 2- methyl -4- amino -6- chlorine pyrimidine price is relatively high, and should not purchase
It buys, and intermediate 14 (E) -3- ethoxy propylene acyl chlorides volatility is big, not easy to maintain, purchase is difficult, the raw material oneself is prepared,
It needs to do starting material and triphosgene reaction using to the big vinyl ethyl ether of risk, nor being conducive to very much industrialized production.
The total recovery of route two is 55%, but uses expensive Pd (OAc)2It is catalyst with BINAP (dinaphthalene hexichol phosphorus), is not inconsistent
The theories such as environmental-friendly, low in cost and easy to operate are closed, and severe reaction conditions yield is not high, is not easy large-scale production.
(3) CN1348370A discloses a kind of preparation method of Dasatinib, and this method is with thiazolamine -5- carboxylic acid second
Ester is starting material, and specific synthetic route is as follows:
It is longer all to there is route in the above method, and multistep condition harshness needs the conditions such as anhydrous, anaerobic, low temperature, repeatedly uses
To synthesis and NaH, be not suitable for industrialized production, yield is low, poor selectivity defect.And intermediate 2-amino-
N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides easily with can be generated in the chloro- 2- methylpyrimidine reaction process of 4,6- bis- it is a kind of double
Pyrimidine ring compound by-product, the by-product property are close with title intermediate, it is difficult to separate, and easily bring into and react in next step
In, it is reacted in next step reaction with compounds such as N- hydroxyethyl piperazines and generates more by-products, to Dasatinib finished product
Quality causes very big influence.
And the synthesis of 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides is in addition to the above method, there are also with
Lower synthetic method:
Patent US200737978 is first hydrolyzed into 2,3- dichloropropylene acid using mucochloric acid as starting material, after use thionyl chloride
It is processed into acyl chlorides, then is connected with the chloro- 6- methylaniline of 2-, then dimethylacetal is generated with methanol-sodium methoxide processing, finally in acid
Property under the conditions of deprotection and in situ and thiocarbamide cyclization obtain target compound, synthetic route is as follows:
Be related to multi-step pressure reducing distillation, energy consumption and the high requirements on the equipment in the reaction process, and used it is volatile,
The bigger chlorinating agent of environmental pollution such as thionyl chloride.
Document Synthesis, 2001,2:239-242 and patent WO2005077945A2 is with oxalyl chloride and vinyl ethyl ether
For starting material, 4- ethyoxyl -3- oxo crotonyl chloride is first produced, reheating is degraded into 3- ethoxy propylene acyl chlorides, Hou Zheyu
2- chloro- 6- methylaniline reaction connects, and obtains N- (the chloro- 6- aminomethyl phenyl of 2-) -3- ethanol acrylamides, then with NBS, thiocarbamide
Reaction obtains target compound, and reaction route is as follows.
The synthetic route is shorter, is that one kind is suitble to good synthesis thinking, but this method has the disadvantage in that the first step
Reaction is done starting material using the big vinyl ethyl ether of risk and is reacted with trichloro-acetic chloride, (E) -3- ethoxy propylene of synthesis
Acyl chlorides volatility is big, not easy to maintain；Second step will degrade decarboxylation, with this condition, second step product 3- ethyoxyl at high temperature
Acryloyl chloride is easy polymerization, causes yield reduction, intermediate product impure, needs to be evaporated under reduced pressure purification, requirement of the energy consumption to equipment
It is higher；In addition, third step and the 4th step use solvents tetrahydrofurane and dioxane respectively, cost cost is also higher, and the
Four steps largely use NBS, and cost greatly improves, and NBS reaction must carry out at low temperature, and condition is harsh, in addition, also improving
The workload of post-processing.
Patent WO2010/144338 report with the basic hydrolysis of 3- ethoxy ethyl acrylate at 3- ethoxy-c olefin(e) acid sodium,
The latter directly handles to obtain 3- ethoxy propylene acyl chlorides with thionyl chloride, raw material 3- ethoxy-c diluted acid ethyl ester by trichloro-acetic chloride and
Vinyl ethyl ether is made, and entire synthetic route is as follows:
This method improves the synthesis of 3- ethoxy propylene acyl chlorides, but synthetic route is elongated, cumbersome, and reacts
Chlorinating agent volatile, that environmental pollution is bigger has been used in the process.
Therefore, this field still needs to a kind of simple method, mild condition, environmentally friendly and high income synthesis are replaced up to sand
The method of Buddhist nun.
Summary of the invention
It is an object of the invention to overcome deficiency in the prior art, a high income is provided, environmentally protective one kind reaches
Sand replaces the preparation process of Buddhist nun.Technical scheme is as follows:
A kind of preparation process of Dasatinib, it is characterised in that including following operating procedure:
1) 3- ethyl 3-oxopropanoate is heated to reflux with the chloro- 6- methylaniline of 2- under alkaline condition, is added dissolved with copper bromide
Solvent, temperature rising reflux, filtering, thiocarbamide is added in filtrate, 2- amino-N- (the chloro- 6- methylbenzene of 2- is cyclized to obtain under catalyst
Base) thiazole -5- formamide；
2) the chloro- 2- methylpyrimidine of 4,6- bis- is dissolved in organic solvent, N- hydroxyethyl piperazine, 2- amino-N- (2- is successively added
Chloro- 6- aminomethyl phenyl) thiazole -5- formamide is stirred to react under certain temperature under the action of alkali and catalyst, and it is made and reaches
Sand replaces Buddhist nun；
In step 1), the solvent is tetrahydrofuran, and the alkali is sodium methoxide；The catalyst is heteropoly acid
Salt, cyclization temperature are 20~25 DEG C；The mass ratio of the material of the chloro- 6- methylaniline of 3- ethyl 3-oxopropanoate, alkali, 2- is 1:
1.0~2.0:0.8~1.0；3- ethyl 3-oxopropanoate, copper bromide the mass ratio of the material be 1:2.0~3.0；3- oxopropanoic acid second
Ester, thiocarbamide, catalyst the mass ratio of the material be 1:1.0~2.0:0.05~0.1.Wherein, the heteropolyacid salt is (NH4)3
[PMo12O40] or H18N3O43PW12；The mass ratio of the material of the chloro- 6- methylaniline of 3- ethyl 3-oxopropanoate, alkali, 2- be 1:1.2~
1.3:0.9；3- ethyl 3-oxopropanoate, copper bromide the mass ratio of the material be 1:2.6~2.8；3- ethyl 3-oxopropanoate, is urged at thiocarbamide
The mass ratio of the material of agent is 1:1.3~1.4:0.08.
In step 2), the organic solvent is dimethylformamide；The alkali is K3PO4Or K2CO3；Described urges
Agent is CuI, and ligand is n,N-Dimethylglycine；Reaction temperature is 120 DEG C；The chloro- 2- methylpyrimidine of 4,6- bis-, N- ethoxy
Piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide the mass ratio of the material be 1:1.0~1.2:1.0~
1.2；The chloro- 2- methylpyrimidine of 4,6- bis-, alkali, CuI, N, the mass ratio of the material of N- dimethylglycine are 1:1.5~2.5:0.05
~0.15:0.1~0.5.Wherein, the chloro- 2- methylpyrimidine of 4,6- bis-, K3PO4, CuI, N, the amount of the substance of N- dimethylglycine
Than for 1:1.9~2.1:0.09~0.11:0.2~0.3.Preferably, 4,6- bis- chloro- 2- methylpyrimidines, N- hydroxyethyl piperazine,
The mass ratio of the material of 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide is 1:1.1:1.1；The chloro- 2- first of 4,6- bis-
Yl pyrimidines, K3PO4, CuI, N, the mass ratio of the material of N- dimethylglycine is 1:2.0:0.10:0.25.
Compared with prior art, advantageous effects of the invention are embodied in:
1, for the present invention using 3- ethyl 3-oxopropanoate as starting material, reaction step is simple, and only a step can synthesize target production
Product 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide avoids big, the not easy to maintain intermediate of synthesis volatility
(E) -3- ethoxy propylene acyl chlorides；
2, it uses copper bromide for brominated reagent, avoids largely using NBS, mild condition, yield is also effectively improved, reduced
Pollution of the bromine to environment is handled, while using cheap raw material thiocarbamide, reduces production cost；
3, catalysis is used as using heteropolyacid salt when synthesizing 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
Agent, the catalyst can be removed by simple filtration, and catalytic activity is high and processing is convenient, can be reused several times and catalytic activity
Still stable, meet green chemical concept；
4, of the invention by the chloro- 2- methylpyrimidine of 4,6- bis-, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-)
Thiazole -5- formamide " one kettle way " under the action of CuI and ligand n,N-Dimethylglycine synthesizes Dasatinib, synthesis yield
Height, purity is high, reaction time are short.
Specific embodiment
Technical solution of the present invention is further non-limitingly described below in conjunction with several preferred embodiments.
The preparation of embodiment 1:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 36mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, 2- chloro- 6- methylaniline 27mmol, temperature rising reflux 45min is added, after reaction, 60mL is added dissolved with 78mmol bromination
The tetrahydrofuran of copper is heated to reflux 1h, filters while hot, leaves and takes filtrate, and 39mmol thiocarbamide, 2.4mmol (NH will be added in filtrate4)3
[PMo12O40], 15min is stirred to react at 20~25 DEG C, TLC monitoring reaction (tracking reaction to raw material disappears), reaction terminates
Afterwards, by catalyst filtration, solvent is evaporated off in filtrate decompression, adds 50mL ether stirring and crystallizing 20min, filters and obtain 2- after drying
Amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.58g, yield 90.94%, purity 99.88%.
The preparation of embodiment 2:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 39mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, 2- chloro- 6- methylaniline 27mmol, temperature rising reflux 45min is added, after reaction, 60mL is added dissolved with 84mmol bromination
The tetrahydrofuran of copper is heated to reflux 1h, filters while hot, leaves and takes filtrate, and 42mmol thiocarbamide, 2.4mmol will be added in filtrate
H18N3O43PW12, 15min is stirred to react at 20~25 DEG C, TLC monitoring reaction (tracking reaction to raw material disappears), reaction terminates
Afterwards, by catalyst filtration, solvent is evaporated off in filtrate decompression, adds 50mL ether stirring and crystallizing 20min, filters and obtain 2- after drying
Amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.59g, yield 91.07%, purity 99.86%.
The preparation of embodiment 3:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 30mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, 2- chloro- 6- methylaniline 24mmol, temperature rising reflux 45min is added, after reaction, 60mL is added dissolved with 60mmol bromination
The tetrahydrofuran of copper is heated to reflux 1h, filters while hot, leaves and takes filtrate, and 30mmol thiocarbamide, 1.5mmol (NH will be added in filtrate4)3
[PMo12O40], 15min is stirred to react at 20~25 DEG C, TLC monitoring reaction (tracking reaction to raw material disappears), reaction terminates
Afterwards, by catalyst filtration, solvent is evaporated off in filtrate decompression, adds 50mL ether stirring and crystallizing 20min, filters and obtain 2- after drying
Amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.50g, yield 85.31%, purity 99.69%.
The preparation of embodiment 4:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 60mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, 2- chloro- 6- methylaniline 30mmol, temperature rising reflux 45min is added, after reaction, 60mL is added dissolved with 90mmol bromination
The tetrahydrofuran of copper is heated to reflux 1h, filters while hot, leaves and takes filtrate, and 60mmol thiocarbamide, 3.0mmol will be added in filtrate
H18N3O43PW12, 15min is stirred to react at 20~25 DEG C, TLC monitoring reaction (tracking reaction to raw material disappears), reaction terminates
Afterwards, by catalyst filtration, solvent is evaporated off in filtrate decompression, adds 50mL ether stirring and crystallizing 20min, filters and obtain 2- after drying
Amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.96g, yield 86.47%, purity 99.72%.
Embodiment 5: the preparation of Dasatinib
By 5mmol n,N-Dimethylglycine, the chloro- 2- methylpyrimidine of 2mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 22mmol N- hydroxyethyl piperazine, 40mmol K is added in 100mL DMF3PO4, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 8.64g, 88.41% or more yield, 99.92% or more purity.
Embodiment 6: the preparation of Dasatinib
By 4mmol n,N-Dimethylglycine, the chloro- 2- methylpyrimidine of 1.8mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 20mmol N- hydroxyethyl piperazine, 38mmol K is added in 100mL DMF3PO4, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 20mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 8.48g, 86.72% or more yield, 99.77% or more purity.
Embodiment 7: the preparation of Dasatinib
By 6mmol n,N-Dimethylglycine, the chloro- 2- methylpyrimidine of 2.2mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 24mmol N- hydroxyethyl piperazine, 42mmol K is added in 100mL DMF2CO3, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 24mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 8.52g, 87.14% or more yield, 99.82% or more purity.
Embodiment 8: the preparation of Dasatinib
By 2mmol n,N-Dimethylglycine, the chloro- 2- methylpyrimidine of 1mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 22mmol N- hydroxyethyl piperazine, 22mmol K is added in 100mL DMF3PO4, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 30mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 8.17g, 83.38% or more yield, 99.57% or more purity.
Embodiment 9: the preparation of Dasatinib
By 10mmol n,N-Dimethylglycine, the chloro- 2- methylpyrimidine of 3mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 22mmol N- hydroxyethyl piperazine, 50mmol K is added in 100mL DMF3PO4, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 8.37g, 85.49% or more yield, 99.71% or more purity.
The preparation of comparative example 1:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 36mmol sodium methoxide is dissolved in 80mL methanol, after 10min is stirred at room temperature, is added
Enter 2- chloro- 6- methylaniline 27mmol, temperature rising reflux 45min, after reaction, 60mL is added dissolved with the first of 78mmol copper bromide
Alcohol is heated to reflux 1h, filters while hot, leaves and takes filtrate, and 39mmol thiocarbamide, 2.4mmol (NH will be added in filtrate4)3[PMo12O40],
15min, TLC monitoring reaction (tracking reaction to raw material disappears), after reaction, by catalyst are stirred to react at 20~25 DEG C
Filtering, is evaporated off solvent for filtrate decompression, adds 50mL ether stirring and crystallizing 20min, filter and obtain 2- amino-N- (2- after drying
Chloro- 6- aminomethyl phenyl) thiazole -5- formamide 5.47g, yield 74.36%, purity 98.28%.
The preparation of comparative example 2:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 36mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, 2- chloro- 6- methylaniline 27mmol, temperature rising reflux 45min is added, after reaction, 60mL is added dissolved with 78mmol bromination
The tetrahydrofuran of copper is heated to reflux 1h, filters while hot, leaves and takes filtrate, 39mmol thiocarbamide will be added in filtrate, at 20~25 DEG C
It is stirred to react 15min, TLC monitoring reaction (tracking reaction to raw material disappears), after reaction, by catalyst filtration, by filtrate
Evaporating solvent under reduced pressure adds 50mL ether stirring and crystallizing 20min, filters and obtains 2- amino-N- (the chloro- 6- methylbenzene of 2- after drying
Base) thiazole -5- formamide 4.40g, yield 59.42%, purity 97.65%.
The preparation of comparative example 3:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 36mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, 2- chloro- 6- methylaniline 27mmol, temperature rising reflux 45min is added, after reaction, 60mL is added dissolved with 30mmol bromination
The tetrahydrofuran of copper is heated to reflux 1h, filters while hot, leaves and takes filtrate, and 39mmol thiocarbamide, 2.4mmol (NH will be added in filtrate4)3
[PMo12O40], 15min is stirred to react at 30~35 DEG C, TLC monitoring reaction (tracking reaction to raw material disappears), reaction terminates
Afterwards, by catalyst filtration, solvent is evaporated off in filtrate decompression, adds 50mL ether stirring and crystallizing 20min, filters and obtain 2- after drying
Amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.34g, yield 72.75%, purity 98.40%.
Comparative example 4: the preparation of Dasatinib
By 5mmol N, N- dimethyl-ethylenediamine, the chloro- 2- methylpyrimidine of 2mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 22mmol N- hydroxyethyl piperazine, 40mmol K is added in 100mL DMF3PO4, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 7.20g, 72.58% or more yield, 98.42% or more purity.
Comparative example 5: the preparation of Dasatinib
By 5mmol n,N-Dimethylglycine, 2mmol Cu2The chloro- 2- methylpyrimidine of O, 20mmol 4,6- bis- is dissolved in
Under stirring, 22mmol N- hydroxyethyl piperazine, 40mmol K is added in 100mL DMF2CO3, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 7.52g, 75.94% or more yield, 98.59% or more purity.
Comparative example 6: the preparation of Dasatinib
By 5mmol sarcosine, the chloro- 2- methylpyrimidine of 2mmol CuI, 20mmol 4,6- bis- is dissolved in 100mL
Under stirring, 22mmol N- hydroxyethyl piperazine, 40mmol K is added in DMF3PO4, 40min is stirred at room temperature, is added with stirring 2- ammonia
Base-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol.Logical N2, after reacting 6h at 120 DEG C, add 50mL ammonium hydroxide molten
Mantoquita is solved, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 7.71g, 78.36% or more yield, 99.17% or more purity.
Comparative example 7: the preparation of Dasatinib
By 5mmol n,N-Dimethylglycine, the chloro- 2- methylpyrimidine of 2mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 22mmol N- hydroxyethyl piperazine, 40mmol K is added in 100mL dehydrated alcohol3PO4, 40min is stirred at room temperature, under stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol is added.Logical N2, after reacting 6h at 120 DEG C, add
50mL ammonia solvent mantoquita is extracted, combined ethyl acetate phase, with saturated common salt water washing, organic layer with the ethyl acetate of 50mL × 3
Use anhydrous Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon is added,
Flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry, i.e.,
Obtain white solid 7.36g, 74.68% or more yield, 99.03% or more purity.
Comparative example 8: the preparation of Dasatinib
By 5mmol n,N-Dimethylglycine, the chloro- 2- methylpyrimidine of 2mmol CuI, 20mmol 4,6- bis- is dissolved in
Under stirring, 22mmol N- hydroxyethyl piperazine, 40mmol K is added in 100mL DMF3PO4, 40min is stirred at room temperature, is added with stirring
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol.Logical N2, after reacting 6h at 80 DEG C, add 50mL ammonia
Water dissolves mantoquita, is extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, and with saturated common salt water washing, organic layer is with anhydrous
Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g active carbon, reflux is added
30min is filtered while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs, dry to get white
Color solid 6.94g, 70.25% or more yield, 98.86% or more purity.
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, it is ripe its object is to allow
The personage for knowing technique cans understand the content of the present invention and implement it accordingly, and protection model of the invention can not be limited with this
It encloses.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of preparation process of Dasatinib, it is characterised in that including following operating procedure:
1) 3- ethyl 3-oxopropanoate is heated to reflux with the chloro- 6- methylaniline of 2- under alkaline condition, is added dissolved with the molten of copper bromide
Thiocarbamide is added in filtrate, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) is cyclized to obtain under catalyst for agent, temperature rising reflux, filtering
Thiazole -5- formamide；
2) the chloro- 2- methylpyrimidine of 4,6- bis- is dissolved in organic solvent, successively be added N- hydroxyethyl piperazine, (2- is chloro- by 2- amino-N-
6- aminomethyl phenyl) thiazole -5- formamide is stirred to react under certain temperature under the action of alkali and catalyst, and it is made and is replaced up to sand
Buddhist nun；
2. a kind of preparation process of Dasatinib according to claim 1, which is characterized in that in step 1), described is molten
Agent is tetrahydrofuran, and the alkali is sodium methoxide.
3. a kind of preparation process of Dasatinib according to claim 1, which is characterized in that in step 1), described is urged
Agent is heteropolyacid salt, and cyclization temperature is 20~25 DEG C.
4. a kind of preparation process of Dasatinib according to claim 1, which is characterized in that in step 1), 3- oxo third
The mass ratio of the material of the chloro- 6- methylaniline of acetoacetic ester, alkali, 2- is 1:1.0~2.0:0.8~1.0；3- ethyl 3-oxopropanoate, bromine
The mass ratio of the material for changing copper is 1:2.0~3.0；3- ethyl 3-oxopropanoate, thiocarbamide, catalyst the mass ratio of the material be 1:1.0~
2.0:0.05~0.1.
5. a kind of preparation process of Dasatinib according to claim 1, which is characterized in that in step 2), described has
Solvent is dimethylformamide；The alkali is K3PO4Or K2CO3；The catalyst is CuI, ligand N, N- dimethyl
Glycine；Reaction temperature is 120 DEG C.
6. a kind of preparation process of Dasatinib according to claim 1, which is characterized in that 4,6- bis- is chloro- in step 2)
2- methylpyrimidine, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide the mass ratio of the material be
1:1.0~1.2:1.0~1.2；The chloro- 2- methylpyrimidine of 4,6- bis-, alkali, CuI, N, the mass ratio of the material of N- dimethylglycine are
1:1.5~2.5:0.05~0.15:0.1~0.5.
7. a kind of preparation process of Dasatinib according to claim 3, which is characterized in that in step 1), described is miscellaneous
Multi-acid salt is (NH4)3[PMo12O40] or H18N3O43PW12。
8. a kind of preparation process of Dasatinib according to claim 4, which is characterized in that in step 1), 3- oxo third
The mass ratio of the material of the chloro- 6- methylaniline of acetoacetic ester, alkali, 2- is 1:1.2~1.3:0.9；3- ethyl 3-oxopropanoate, copper bromide
The mass ratio of the material is 1:2.6~2.8；3- ethyl 3-oxopropanoate, thiocarbamide, catalyst the mass ratio of the material be 1:1.3~1.4:
0.08。
9. a kind of preparation process of Dasatinib according to claim 6, which is characterized in that 4,6- bis- is chloro- in step 2)
2- methylpyrimidine, K3PO4, CuI, N, the mass ratio of the material of N- dimethylglycine be 1:1.9~2.1:0.09~0.11:0.2~
0.3。
10. a kind of preparation process of Dasatinib according to claim 9, which is characterized in that 4,6- bis- is chloro- in step 2)
2- methylpyrimidine, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide the mass ratio of the material be
1:1.1:1.1；The chloro- 2- methylpyrimidine of 4,6- bis-, K3PO4, CuI, N, the mass ratio of the material of N- dimethylglycine is 1:2.0:
0.10:0.25。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN102827156A (en) * | 2012-09-11 | 2012-12-19 | 湖南欧亚生物有限公司 | Novel industrial synthetic method of dasatinib |
| CN105753808A (en) * | 2014-12-18 | 2016-07-13 | 湖南化工研究院有限公司 | Thiazole amide compounds, preparing method thereof and applications of the compounds |
| CN106008392A (en) * | 2016-06-09 | 2016-10-12 | 青岛辰达生物科技有限公司 | Preparation method for intermediate of anti-cancer drug dasatinib |
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2018
- 2018-11-21 CN CN201811388270.9A patent/CN109369638B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN102827156A (en) * | 2012-09-11 | 2012-12-19 | 湖南欧亚生物有限公司 | Novel industrial synthetic method of dasatinib |
| CN105753808A (en) * | 2014-12-18 | 2016-07-13 | 湖南化工研究院有限公司 | Thiazole amide compounds, preparing method thereof and applications of the compounds |
| CN106008392A (en) * | 2016-06-09 | 2016-10-12 | 青岛辰达生物科技有限公司 | Preparation method for intermediate of anti-cancer drug dasatinib |
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| PERRY T. KAYE ET AL.: "N,N-Disubstituted 2-Aminothiazole-5-carboxylates : Preparation and Rotation of Functional Groups", 《J. CHEM. SOC》 * |
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