CN109503568A - A kind of preparation method of Dasatinib - Google Patents
A kind of preparation method of Dasatinib Download PDFInfo
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- CN109503568A CN109503568A CN201811641893.2A CN201811641893A CN109503568A CN 109503568 A CN109503568 A CN 109503568A CN 201811641893 A CN201811641893 A CN 201811641893A CN 109503568 A CN109503568 A CN 109503568A
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Abstract
The present invention relates to a kind of preparation methods of Dasatinib, this method comprises the following steps: 3- ethyl 3-oxopropanoate is first reacted with the chloro- 6- methylaniline of 2- under alkaline condition, add the solvent reaction dissolved with copper bromide, then thiocarbamide is added, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide is cyclized to obtain under catalyst；Afterwards by the chloro- 2- methylpyrimidine of 4,6- bis- and N- hydroxyethyl piperazine and 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide, one pot process Dasatinib under the action of alkali and ionic liquid 1-butyl-3-methyl imidazolium glycinate.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 method 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 Bristol Myers Squibb public affairs
Take charge of a kind of oral tyrosine kinase inhibitor of research and development.The medicine obtains FDA approval listing in June, 2006, chronic for treating
Myelogenous leukemia can also treat the acute lymphatic leukemia of Philadelphia Chromosome Positive.This product is more to Bcr-Ab1 kinases
Kind mutant has inhibiting effect, and inhibition strength improves a lot compared with Imatinib (Imatinib), and does not find drug resistance.Its
Structural 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 method of Dasatinib, it is characterised in that including following operating procedure:
1) 3- ethyl 3-oxopropanoate is first reacted with the chloro- 6- methylaniline of 2- under alkaline condition, is added dissolved with copper bromide
Solvent reaction, thiocarbamide is then added, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formyl is cyclized to obtain under catalyst
Amine, i.e. compound 2；
2) by the chloro- 2- methylpyrimidine of 4,6- bis-, alkali soluble in solvent, the reaction of N- hydroxyethyl piperazine is first added, adds 2- ammonia
Base-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide, is stirred to react under certain temperature, and compound 1 is made, i.e., replaces up to sand
Buddhist nun；
In step 1), reaction dissolvent is tetrahydrofuran, and the alkali is sodium methoxide, and 3- ethyl 3-oxopropanoate, alkali, 2- are chloro-
The mass ratio of the material of 6- methylaniline is 1:1.0~2.0:0.8~1.0；The mass ratio of the material of 3- ethyl 3-oxopropanoate, copper bromide
For 1:2.0~3.0；The mass ratio of the material of 3- ethyl 3-oxopropanoate and thiocarbamide is 1:1.0~2.0；3- ethyl 3-oxopropanoate with urge
The mass ratio of the material of agent is 1:0.1~1.0, and the catalyst is ionic liquid [Bmim] Br, and cyclization temperature is 20
~25 DEG C.Wherein, the mass ratio of the material of the chloro- 6- methylaniline of 3- ethyl 3-oxopropanoate, alkali, 2- is 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；The mass ratio of the material of 3- ethyl 3-oxopropanoate and thiocarbamide
For 1:1.2~1.6；The mass ratio of the material of 3- ethyl 3-oxopropanoate and catalyst is 1:0.1~0.4.Preferably, 3- oxo third
The mass ratio of the material of the chloro- 6- methylaniline of acetoacetic ester, alkali, 2- is 1:1.25:0.9；The substance of 3- ethyl 3-oxopropanoate, copper bromide
Amount ratio be 1:2.7, the mass ratio of the material of 3- ethyl 3-oxopropanoate and thiocarbamide is 1:1.4；3- ethyl 3-oxopropanoate and catalyst
The mass ratio of the material be 1:0.15.
In step 2), the solvent is 1- butyl -3- methylimidazole glycinate；The alkali is K3PO4Or K2CO3；
Reaction temperature is 80 DEG C, 4,6- bis- chloro- 2- methylpyrimidines, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiophene
The mass ratio of the material of azoles -5- formamide is 1:1.0~1.1:1.0~1.1；The chloro- 2- methylpyrimidine of 4,6- bis-, alkali, 1- butyl -3-
The mass ratio of the material of methylimidazole glycinate is 1:1.0~3.0:0.5~2.0.Wherein, the chloro- 2- methylpyrimidine of 4,6- bis-,
Alkali, 1- butyl -3- methylimidazole glycinate the mass ratio of the material be 1:1.5~2.0:0.6~1.0, preferably, 4,6- bis-
Chloro-2-methyl pyrimidine, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide substance amount
Than for 1:1.05:1.05；The mass ratio of the material of the chloro- 2- methylpyrimidine of 4,6- bis-, alkali, 1- butyl -3- methylimidazole glycinate
For 1:1.75:0.8.
Compared with prior art, advantageous effects of the invention are embodied in:
1, the present invention is using 3- ethyl 3-oxopropanoate as starting material, and reaction step is simple, it is only necessary to which a step can synthesize target
Product 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide avoids big, the not easy to maintain centre of synthesis volatility
Body (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, when synthesizing 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide, traditional synthetic method needs
It reacts in acid condition, the reaction time is longer, and yield is also not highly desirable, and the present invention uses [Bmim] Br for catalyst, instead
Answer speed fast, easy to operate, no pollution to the environment, yield purity is high；
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 is dissolved in ionic liquid 1-butyl-3-methyl imidazolium glycinate, and " one kettle way " synthesizes Dasatinib,
In, 1- butyl -3- methylimidazole glycinate can not only make solvent, but also can make catalyst, and synthesis yield is high, purity is high, instead
It is short between seasonable, while ionic liquid is easily recycled, it is reusable.
Specific embodiment
Technical solution of the present invention is further non-limitingly described below in conjunction with several preferred embodiments.Wherein, bromine
It is as follows to change preparing for 1- butyl -3- methylimidazole ([Bmim] Br) ionic liquid: weighing 0.1mol N- methylimidazole 8mL in three
In neck bottle, heating water bath is to 70 DEG C, under the stirring of 300r/min, 0.12mol 1- bromobutane 13mL is slowly added dropwise, at 70 DEG C
Back flow reaction 20h, obtains weak yellow liquid.It is washed 2 times, is vibrated, static layering with ethyl acetate.Subnatant is put into single neck bottle
In, vacuum distillation removes ethyl acetate, and dry 20h at 80 DEG C obtains [Bmim] Br after purification.
Preparing for hydroxide 1- butyl -3- methylimidazole ([Bmim] OH) ionic liquid is as follows: weighing 13g intermediate
[Bmim] Br is slowly added to 20mL KOH/methanol solution in wide-mouth bottle, reacts 10h under constant temperature stirring.It filters, during which uses first
Alcohol washs for several times.Filtrate decompression distillation removes methanol to get target product hydroxide 1- butyl -3- methylimidazole ([Bmim] is arrived
OH)。
(preparing for [Bmim] [Gly] is as follows: using [Bmim] [OH] solution for 1- butyl -3- methylimidazole glycinate
The hydrochloric acid of 0.1mol/L is titrated, and is then added into the slightly excessive amion acetic acid of molar ratio (Gly) aqueous solution, room temperature is stirred
It mixes for 24 hours.Products obtained therefrom rotary evaporation is removed into excessive water (temperature 70 C, 50~60r/min, RE-52AA Rotary Evaporators),
It is put into vacuum drying oven, is dried in vacuo 48h (80 DEG C), is taken out after being cooled to room temperature.Anhydrous methanol (10mL)/acetonitrile is added
(90mL), being vigorously stirred 12h with PARAFILM sealing is precipitated unreacted amino acid.After filtering, methanol/acetonitrile rotary evaporation
(RE-52AA Rotary Evaporators, 60 DEG C, 50~60r/min) remove, obtained [Bmim] [Gly] vacuum drying 2d, set temperature
It is 80 DEG C.After being repeated 3 times, gained sample is placed on spare in desiccator.
The preparation of embodiment 1:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 37.5mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, the chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 81mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 42mmol thiocarbamide,
4.5mmol [Bmim] Br is stirred to react 30min at 20~25 DEG C, and TLC monitoring reaction (tracks reaction to raw material to disappear), instead
It after answering, is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter
And 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.68g, yield 92.31%, purity are obtained after drying
99.91%.
The preparation of embodiment 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, the chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 78mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 36mmol thiocarbamide,
3mmol [Bmim] Br is stirred to react 30min, TLC monitoring reaction (tracking reaction to raw material disappears), reaction at 20~25 DEG C
After, it is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter simultaneously
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.53g, yield 90.17%, purity are obtained after drying
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, 39mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, the chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 84mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 48mmol thiocarbamide,
12mmol [Bmim] Br is stirred to react 30min, TLC monitoring reaction (tracking reaction to raw material disappears), reaction at 20~25 DEG C
After, it is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter simultaneously
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.65g, yield 91.87%, purity are obtained after drying
99.88%.
The preparation of embodiment 4:2- 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, the chloro- 6- methylaniline 24mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 60mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 30mmol thiocarbamide,
3mmol [Bmim] Br is stirred to react 30min, TLC monitoring reaction (tracking reaction to raw material disappears), reaction at 20~25 DEG C
After, it is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter simultaneously
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.49g, yield 85.24%, purity are obtained after drying
99.76%.
The preparation of embodiment 5:2- 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, the chloro- 6- methylaniline 30mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 90mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 60mmol thiocarbamide,
30mmol [Bmim] Br is stirred to react 30min, TLC monitoring reaction (tracking reaction to raw material disappears), reaction at 20~25 DEG C
After, it is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter simultaneously
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.86g, yield 85.19%, purity are obtained after drying
99.72%.
The preparation of embodiment 6:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 37.5mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, the chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 78mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 48mmol thiocarbamide,
4.5mmol [Bmim] Br is stirred to react 30min at 20~25 DEG C, and TLC monitoring reaction (tracks reaction to raw material to disappear), instead
It after answering, is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter
And 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.59g, yield 91.07%, purity are obtained after drying
99.89%.
The preparation of embodiment 7:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 37.5mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, the chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 81mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 48mmol thiocarbamide,
12mmol [Bmim] Br is stirred to react 30min, TLC monitoring reaction (tracking reaction to raw material disappears), reaction at 20~25 DEG C
After, it is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter simultaneously
2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 6.53g, yield 90.25%, purity are obtained after drying
99.86%.
Embodiment 8: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 35mmol K3PO4It is dissolved in 16mmol 1- butyl -3- methylimidazole
It is stirred in glycinate, 21mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to be added
21mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, after completion of the reaction,
Be cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, obtain crude product (ionic liquid with
Methylene chloride extracts, and is dried in vacuo to remove a small amount of solvent therein, after remaining sticky ionic liquid is sufficiently washed with ether
It is directly used in following reaction, is not required to be further purified).Crude product is added to 80% ethanol water 100mL, under stirring, is added
Enter 2g active carbon, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, filtering, 80% ethanol water of filter cake ice
Washing, it is dry to get white solid 9.01g, yield 92.27%, purity 99.94%.
Embodiment 9: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 30mmol K2CO3It is dissolved in 12mmol 1- butyl -3- methylimidazole
It is stirred in glycinate, 21mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to be added
21mmol 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, end of reaction
Afterwards, it is cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, and obtains crude product (ionic liquid
Body is extracted with methylene chloride, is dried in vacuo to remove a small amount of solvent therein, remaining sticky ionic liquid is sufficiently washed with ether
It is directly used in following reaction after washing, is not required to be further purified).Crude product is added to 80% ethanol water 100mL, stirring
Under, 2g active carbon is added, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, filtering, 80% ethanol water of filter cake ice
Solution washing, it is dry to get white solid 8.73g, yield 89.32%, purity 99.90%.
Embodiment 10: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 40mmol K3PO4It is dissolved in 20mmol 1- butyl -3- methylimidazole
It is stirred in glycinate, 21mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to be added
21mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, after completion of the reaction,
Be cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, obtain crude product (ionic liquid with
Methylene chloride extracts, and is dried in vacuo to remove a small amount of solvent therein, after remaining sticky ionic liquid is sufficiently washed with ether
It is directly used in following reaction, is not required to be further purified).Crude product is added to 80% ethanol water 100mL, under stirring, is added
Enter 2g active carbon, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, filtering, 80% ethanol water of filter cake ice
Washing, it is dry to get white solid 8.87g, yield 90.86%, purity 99.93%.
Embodiment 11: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 20mmol K3PO4It is dissolved in 10mmol 1- butyl -3- methylimidazole
It is stirred in glycinate, 20mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to be added
20mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, after completion of the reaction,
Be cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, obtain crude product (ionic liquid with
Methylene chloride extracts, and is dried in vacuo to remove a small amount of solvent therein, after remaining sticky ionic liquid is sufficiently washed with ether
It is directly used in following reaction, is not required to be further purified).Crude product is added to 80% ethanol water 100mL, under stirring, is added
Enter 2g active carbon, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, filtering, 80% ethanol water of filter cake ice
Washing, it is dry to get white solid 8.19g, yield 83.45%, purity 99.42%.
Embodiment 12: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 60mmol K3PO4It is dissolved in 40mmol 1- butyl -3- methylimidazole
It is stirred in glycinate, 22mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to be added
22mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, after completion of the reaction,
Be cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, obtain crude product (ionic liquid with
Methylene chloride extracts, and is dried in vacuo to remove a small amount of solvent therein, after remaining sticky ionic liquid is sufficiently washed with ether
It is directly used in following reaction, is not required to be further purified).Crude product is added to 80% ethanol water 100mL, under stirring, is added
Enter 2g active carbon, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, filtering, 80% ethanol water of filter cake ice
Washing, it is dry to get white solid 8.59g, yield 87.87%, purity 99.88%.
Embodiment 13: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 30mmol K3PO4It is dissolved in 12mmol 1- butyl -3- methylimidazole
It is stirred in glycinate, 20mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to be added
20mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, after completion of the reaction,
Be cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, obtain crude product (ionic liquid with
Methylene chloride extracts, and is dried in vacuo to remove a small amount of solvent therein, after remaining sticky ionic liquid is sufficiently washed with ether
It is directly used in following reaction, is not required to be further purified).Crude product is added to 80% ethanol water 100mL, under stirring, is added
Enter 2g active carbon, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, filtering, 80% ethanol water of filter cake ice
Washing, it is dry to get white solid 8.40g, yield 85.87%, purity 99.72%.
The preparation of comparative example 1:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 37.5mmol sodium methoxide is dissolved in 80mL methanol, after 10min is stirred at room temperature,
The chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The methanol of 81mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 42mmol thiocarbamide,
4.5mmol [Bmim] Br is stirred to react 30min at 20~25 DEG C, and TLC monitoring reaction (tracks reaction to raw material to disappear), instead
It after answering, is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter
And 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.51g, yield 74.89%, purity are obtained after drying
98.17%.[267.73]
The preparation of comparative example 2:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 37.5mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, the chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 81mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, 42mmol thiocarbamide will be added in filtrate, in
30min is stirred to react at 20~25 DEG C, TLC monitoring reaction (tracking reaction to raw material disappears) after reaction, is poured into ice water
In, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter and obtain 2- ammonia after drying
Base-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 4.57g, yield 61.85%, purity 97.86%.
The preparation of comparative example 3:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
3- ethyl 3-oxopropanoate 30mmol, 37.5mmol sodium methoxide is dissolved in 80mL tetrahydrofuran, 10min is stirred at room temperature
Afterwards, the chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 45min is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 30mmol copper bromide is heated to reflux 1h, filters while hot, leaves and takes filtrate, will in filtrate be added 42mmol thiocarbamide,
4.5mmol[Bmim]BH4, 30min is stirred to react at 30~35 DEG C, TLC monitoring reaction (tracks reaction to raw material to disappear), instead
It after answering, is poured into ice water, methylene chloride extraction, organic phase concentration, washing add 50mL ether stirring and crystallizing 20min, filter
And 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.48g, yield 74.52%, purity are obtained after drying
98.27%.
Comparative example 4: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 35mmol K3PO4It is dissolved in 16mmol 1- butyl -3- methylimidazole
It is stirred in tetrafluoroborate, 21mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to add
Enter 21mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, end of reaction
Afterwards, it is cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, and obtains crude product (ionic liquid
It is extracted, is dried in vacuo to remove a small amount of solvent therein, remaining sticky ionic liquid is sufficiently washed with ether with methylene chloride
It is directly used in following reaction afterwards, is not required to be further purified).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, filtering, and 80% ethyl alcohol of filter cake ice is water-soluble
Liquid washing, it is dry to get white solid 7.54g, yield 76.45%, purity 98.94%.
Comparative example 5: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 35mmol K3PO4It is dissolved in 16mmol 1- normal-butyl -3- methyl miaow
It is stirred in azoles bromide, 21mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to be added
21mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, after completion of the reaction,
Be cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, obtain crude product (ionic liquid with
Methylene chloride extracts, and is dried in vacuo to remove a small amount of solvent therein, after remaining sticky ionic liquid is sufficiently washed with ether
It is directly used in following reaction, is not required to be further purified).Crude product is added to 80% ethanol water 100mL, under stirring, is added
Enter 2g active carbon, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, filtering, 80% ethanol water of filter cake ice
Washing, it is dry to get white solid 7.37g, yield 74.86%, purity 99.09%.
Comparative example 6: the preparation of Dasatinib
By the chloro- 2- methylpyrimidine of 20mmol 4,6- bis-, 35mmol K3PO4It is dissolved in 16mmol 1- butyl -3- methylimidazole
It is stirred in hexafluorophosphate, 21mmol N- hydroxyethyl piperazine is first added, after reacting 1.5h at 80 DEG C, be cooled to room temperature, it is rear to add
Enter 21mmol2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides, the reaction was continued at 80 DEG C 2h, end of reaction
Afterwards, it is cooled to room temperature, mixture extracts 3 times (3 × 50mL) with ether, and combining extraction liquid is simultaneously concentrated, and obtains crude product (ionic liquid
It is extracted, is dried in vacuo to remove a small amount of solvent therein, remaining sticky ionic liquid is sufficiently washed with ether with methylene chloride
It is directly used in following reaction afterwards, is not required to be further purified).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, filtering, and 80% ethyl alcohol of filter cake ice is water-soluble
Liquid washing, it is dry to get white solid 6.99g, yield 70.73%, purity 98.81%.
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 method of Dasatinib, it is characterised in that including following operating procedure:
1) 3- ethyl 3-oxopropanoate is first reacted with the chloro- 6- methylaniline of 2- under alkaline condition, is added dissolved with the molten of copper bromide
Agent reaction, is then added thiocarbamide, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide is cyclized to obtain under catalyst；
2) by the chloro- 2- methylpyrimidine of 4,6- bis-, alkali soluble in solvent, the reaction of N- hydroxyethyl piperazine is first added, adds 2- amino-N-
(the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide, is stirred to react under certain temperature, and compound 1, i.e. Dasatinib is made；
2. a kind of preparation method of Dasatinib according to claim 1, which is characterized in that in step 1), reaction dissolvent
For tetrahydrofuran, the alkali is sodium methoxide.
3. a kind of preparation method of Dasatinib according to claim 1, which is characterized in that in step 1), described is urged
Agent is ionic liquid [Bmim] Br, and cyclization temperature is 20~25 DEG C.
4. a kind of preparation method 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；The mass ratio of the material of 3- ethyl 3-oxopropanoate and thiocarbamide is 1:1.0~2.0；3-
The mass ratio of the material of ethyl 3-oxopropanoate and catalyst is 1:0.1~1.0.
5. a kind of preparation method of Dasatinib according to claim 1, which is characterized in that in step 2), described is molten
Agent is 1- butyl -3- methylimidazole glycinate；The alkali is K3PO4Or K2CO3；Reaction temperature is 80 DEG C.
6. a kind of preparation method of Dasatinib according to claim 5, which is characterized in that in step 2), 4,6- bis- is chloro-
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
1:1.0~1.1:1.0~1.1；The chloro- 2- methylpyrimidine of 4,6- bis-, alkali, 1- butyl -3- methylimidazole glycinate substance
Amount is than being 1:1.0~3.0:0.5~2.0.
7. a kind of preparation method 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；The mass ratio of the material of 3- ethyl 3-oxopropanoate and thiocarbamide is 1:1.2~1.6；3- oxo third
The mass ratio of the material of acetoacetic ester and catalyst is 1:0.1~0.4.
8. a kind of preparation method of Dasatinib according to claim 7, 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 1:1.25:0.9；The substance of 3- ethyl 3-oxopropanoate, copper bromide
Amount ratio be 1:2.7, the mass ratio of the material of 3- ethyl 3-oxopropanoate and thiocarbamide is 1:1.4；3- ethyl 3-oxopropanoate and catalyst
The mass ratio of the material be 1:0.15.
9. a kind of preparation method of Dasatinib according to claim 6, which is characterized in that in step 2), 4,6- bis- is chloro-
2- methylpyrimidine, alkali, 1- butyl -3- methylimidazole glycinate the mass ratio of the material be 1:1.5~2.0:0.6~1.0.
10. a kind of preparation method of Dasatinib according to claim 6, which is characterized in that in step 2), 4,6- bis-
Chloro-2-methyl pyrimidine, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide substance amount
Than for 1:1.05:1.05；The mass ratio of the material of the chloro- 2- methylpyrimidine of 4,6- bis-, alkali, 1- butyl -3- methylimidazole glycinate
For 1:1.75:0.8.
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