CN109879869A - A kind of preparation method of Dasatinib - Google Patents
A kind of preparation method of Dasatinib Download PDFInfo
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- CN109879869A CN109879869A CN201910123117.1A CN201910123117A CN109879869A CN 109879869 A CN109879869 A CN 109879869A CN 201910123117 A CN201910123117 A CN 201910123117A CN 109879869 A CN109879869 A CN 109879869A
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Abstract
The present invention relates to a kind of preparation methods of Dasatinib, and this method comprises the following steps: 3- ethyl 3-oxopropanoate is first reacted with the chloro- 6- methylaniline of 2- under alkaline condition, is added the solution reaction dissolved with copper bromide, is obtained compound 3；It is reacted again with thiocarbamide, obtains 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide；It afterwards by the chloro- 2- methylpyrimidine of 4,6- bis- under the conditions of alkali, catalyst system, organic solvent, is successively reacted with N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide, compound 1, i.e. Dasatinib is made.Mild condition of the present invention, step is simple, the reaction time is short, rate is fast, 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 method 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
Solution, react to obtain compound 3；
2) compound 3 is reacted with thiocarbamide, post-treated to obtain compound 2, i.e. 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiophene
Azoles -5- formamide；
3) by the chloro- 2- methylpyrimidine of 4,6- bis- under the conditions of alkali, catalyst system, organic solvent, successively with N- ethoxy piperazine
Piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide are reacted, and compound 1, i.e. Dasatinib is made；
In step 1), reaction dissolvent is tetrahydrofuran, and the alkali is sodium methoxide；Copper bromide uses tetrahydrofuran molten in advance
Solution, the solution concentration of the copper bromide are 1.3~1.4mol/L；The chloro- 6- methylaniline of 3- ethyl 3-oxopropanoate, alkali, 2-
The mass ratio of the material is 1:1.2~1.3:0.8~1.0；3- ethyl 3-oxopropanoate, copper bromide the mass ratio of the material be 1:2.6~
2.8.Wherein, the solution concentration of copper bromide is 1.35mol/L；The substance of the chloro- 6- methylaniline of 3- ethyl 3-oxopropanoate, alkali, 2-
Amount ratio be 1:1.25:0.9；3- ethyl 3-oxopropanoate, copper bromide the mass ratio of the material be 1:2.7.
In step 2), the reaction is microwave radiation reaction, microwave power 110W, reaction time 3min40s；Change
The mass ratio of the material for closing object 3 and thiocarbamide is 1:1.0~2.0；The post-processing step are as follows: mixture is cooled to room temperature, is used
A small amount of ethyl alcohol is transferred in cold water, with a small amount of NH4HCO3Aqueous solution neutralizes, and solid, filtering, the second for being 50% with volume fraction is precipitated
Alcohol solution washing, dry, crude product is recrystallized with ethanol solution, is filtered and is obtained 2- amino-N- after drying (2- is chloro-
6- aminomethyl phenyl) thiazole -5- formamide.Wherein, the mass ratio of the material of compound 3 and thiocarbamide is 1:1.2~1.4；The second
The volume fraction of alcoholic solution is 80%, preferably, the mass ratio of the material of compound 3 and thiocarbamide is 1:1.3.
In step 3), the organic solvent is n,N-Dimethylformamide；The alkali is K3PO4；The catalytic body
System is made of metallic catalyst and ligand, and the metallic catalyst is CuI, and ligand is n,N-Dimethylglycine；Reaction temperature
Degree is 120 DEG C；The chloro- 2- methylpyrimidine of 4,6- bis-, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5-
The mass ratio of the material of formamide is 1:1.0~1.2:1.0~1.2；The chloro- 2- methylpyrimidine of 4,6- bis-, K3PO4, CuI, N, N- diformazan
The mass ratio of the material of base glycine is 1:1.9~2.1:0.09~0.11:0.2~0.3；The chloro- 2- methylpyrimidine of 4,6- bis- it is dense
Degree is 0.125~0.25mol/L.Wherein, the chloro- 2- methylpyrimidine of 4,6- bis-, N- hydroxyethyl piperazine, 2- amino-N- (the chloro- 6- of 2-
Aminomethyl phenyl) 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；The concentration of the chloro- 2- methylpyrimidine of 4,6- bis- is
0.2mol/L。
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 two steps 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 is reacted using microwave radiation, reaction speed
Degree is 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 " 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.
Embodiment 1: the synthesis of compound 3
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 1h is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 81mmol copper bromide is heated to reflux 2h, filters while hot, and filter cake is washed with hot tetrahydrofuran 50mL milliliters, filtrate
Merge with washing lotion, be washed to neutrality, vacuum distillation removes solvent, and residue is poured into 50mL ice water, stirs 0.5h, and decompression is taken out
Filter, filter cake are washed with ice water, dry, obtain 7.19g compound 3, yield 91.60%, purity 99.92%.
Embodiment 2: the synthesis of compound 3
3- ethyl 3-oxopropanoate 30mmol, 39mmol 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 1h is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 84mmol copper bromide is heated to reflux 2h, filters while hot, and filter cake is washed with hot tetrahydrofuran 50mL milliliters, filtrate
Merge with washing lotion, be washed to neutrality, vacuum distillation removes solvent, and residue is poured into 50mL ice water, stirs 0.5h, and decompression is taken out
Filter, filter cake are washed with ice water, dry, obtain 7.89g compound 3, yield 90.43%, purity 99.90%.
Embodiment 3: the synthesis of compound 3
3- ethyl 3-oxopropanoate 30mmol, 36mmol 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 1h is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 78mmol copper bromide is heated to reflux 2h, filters while hot, and filter cake is washed with hot tetrahydrofuran 50mL milliliters, filtrate
Merge with washing lotion, be washed to neutrality, vacuum distillation removes solvent, and residue is poured into 50mL ice water, stirs 0.5h, and decompression is taken out
Filter, filter cake are washed with ice water, dry, obtain 5.99g compound 3, yield 85.72%, purity 99.82%.
Embodiment 4: the synthesis of compound 3
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 30mmol of 2- is added, temperature rising reflux 1h is cooled to room temperature after reaction, be added 60mL dissolved with
The tetrahydrofuran of 81mmol copper bromide is heated to reflux 2h, filters while hot, and filter cake is washed with hot tetrahydrofuran 50mL milliliters, filtrate
Merge with washing lotion, be washed to neutrality, vacuum distillation removes solvent, and residue is poured into 50mL ice water, stirs 0.5h, and decompression is taken out
Filter, filter cake are washed with ice water, dry, obtain 7.75g compound 3, yield 88.68%, purity 99.71%.
The synthesis of embodiment 5:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
20mmol compound 3,26mmol thiocarbamide are mixed, react 3min40s, reaction knot in 110W microwave radiation under stirring
Mixture is cooled to room temperature by Shu Hou, is transferred in 10mL cold water with a small amount of ethyl alcohol, with a small amount of NH4HCO3Aqueous solution neutralizes, and is precipitated
Solid, filtering are washed with the ethanol water that volume fraction is 50%, dry, the ethyl alcohol that crude product volume fraction is 80%
Solution is recrystallized, and 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.21g is filtered and obtain after drying,
Yield 97.23%, purity 99.92%.
The synthesis of embodiment 6:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
20mmol compound 3,28mmol thiocarbamide are mixed, react 3min40s, reaction knot in 110W microwave radiation under stirring
Mixture is cooled to room temperature by Shu Hou, is transferred in 10mL cold water with a small amount of ethyl alcohol, with a small amount of NH4HCO3Aqueous solution neutralizes, and is precipitated
Solid, filtering are washed with the ethanol water that volume fraction is 50%, dry, the ethyl alcohol that crude product volume fraction is 80%
Solution is recrystallized, and 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.12g is filtered and obtain after drying,
Yield 95.41%, purity 99.86%.
The synthesis of embodiment 7:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
20mmol compound 3,24mmol thiocarbamide are mixed, react 3min40s, reaction knot in 110W microwave radiation under stirring
Mixture is cooled to room temperature by Shu Hou, is transferred in 10mL cold water with a small amount of ethyl alcohol, with a small amount of NH4HCO3Aqueous solution neutralizes, and is precipitated
Solid, filtering are washed with the ethanol water that volume fraction is 50%, dry, the ethyl alcohol that crude product volume fraction is 80%
Solution is recrystallized, and 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 5.09g is filtered and obtain after drying,
Yield 94.92%, purity 99.87%.
Embodiment 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 n,N-Dimethylformamide (DMF)3PO4, room temperature stirs
40min is mixed, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol is added with stirring.Logical N2, in 120 DEG C
After lower reaction 6h, add 50mL ammonia solvent mantoquita, extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase uses saturated common salt
Water washing, organic layer 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, filtering, and 80% ethyl alcohol of filter cake ice is water-soluble
Liquid washing, it is dry to get white solid 8.64g, yield 88.41%, purity 99.92%.
Embodiment 9: 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 n,N-Dimethylformamide (DMF)3PO4, room temperature stirs
40min is mixed, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 20mmol is added with stirring.Logical N2, in 120 DEG C
After lower reaction 6h, add 50mL ammonia solvent mantoquita, extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase uses saturated common salt
Water washing, organic layer 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, filtering, and 80% ethyl alcohol of filter cake ice is water-soluble
Liquid washing, it is dry to get white solid 8.48g, yield 86.72%, purity 99.77%.
Embodiment 10: 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 n,N-Dimethylformamide (DMF)3PO4, room temperature stirs
40min is mixed, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 24mmol is added with stirring.Logical N2, in 120 DEG C
After lower reaction 6h, add 50mL ammonia solvent mantoquita, extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase uses saturated common salt
Water washing, organic layer 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, filtering, and 80% ethyl alcohol of filter cake ice is water-soluble
Liquid washing, it is dry to get white solid 8.52g, yield 87.14%, purity 99.82%.
Embodiment 11: 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, 22mmol N- hydroxyethyl piperazine, 38mmol K is added in 80mL n,N-Dimethylformamide (DMF)3PO4, room temperature stirs
40min is mixed, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol is added with stirring.Logical N2, in 120 DEG C
After lower reaction 6h, add 50mL ammonia solvent mantoquita, extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase uses saturated common salt
Water washing, organic layer 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, filtering, and 80% ethyl alcohol of filter cake ice is water-soluble
Liquid washing, it is dry to get white solid 8.17g, yield 83.38%, purity 99.57%.
Embodiment 12: 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, 22mmol N- hydroxyethyl piperazine, 42mmol K is added in 160mL n,N-Dimethylformamide (DMF)3PO4, room temperature stirs
40min is mixed, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol is added with stirring.Logical N2, in 120 DEG C
After lower reaction 6h, add 50mL ammonia solvent mantoquita, extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase uses saturated common salt
Water washing, organic layer 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, filtering, and 80% ethyl alcohol of filter cake ice is water-soluble
Liquid washing, it is dry to get white solid 8.37g, yield 85.49%, purity 99.71%.
Comparative example 1: the synthesis of compound 3
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 1h is cooled to room temperature after reaction, and 60mL is added dissolved with 78mmol
The methanol of copper bromide is heated to reflux 2h, filters while hot, and filter cake is washed with hot tetrahydrofuran 50mL milliliters, and filtrate merges with washing lotion,
It is washed to neutrality, vacuum distillation removes solvent, and residue is poured into 50mL ice water, stirs 0.5h, and decompression filters, filter cake ice
Water washing, it is dry, obtain 5.83g compound 3, yield 72.48%, purity 97.47%.
Comparative example 2: the synthesis of compound 3
3- ethyl 3-oxopropanoate 30mmol, 37.5mmol sodium methoxide is dissolved in 80mL chloroform, after 10min is stirred at room temperature,
The chloro- 6- methylaniline 27mmol of 2- is added, temperature rising reflux 1h is cooled to room temperature after reaction, and 60mL is added dissolved with 78mmol
The chloroform of copper bromide is heated to reflux 2h, filters while hot, and filter cake is washed with hot tetrahydrofuran 50mL milliliters, and filtrate merges with washing lotion,
It is washed to neutrality, vacuum distillation removes solvent, and residue is poured into 50mL ice water, stirs 0.5h, and decompression filters, filter cake ice
Water washing, it is dry, obtain 5.49g compound 3, yield 68.89%, purity 98.46%.
The synthesis of comparative example 3:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
20mmol compound 3,26mmol thiocarbamide are mixed, react 3min40s, reaction knot in 130W microwave radiation under stirring
Mixture is cooled to room temperature by Shu Hou, is transferred in 10mL cold water with a small amount of ethyl alcohol, with a small amount of NH4HCO3Aqueous solution neutralizes, and is precipitated
Solid, filtering are washed with the ethanol water that volume fraction is 50%, dry, the ethyl alcohol that crude product volume fraction is 80%
Solution is recrystallized, and 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 4.33g is filtered and obtain after drying,
Yield 78.84%, purity 97.43%.
The preparation of comparative example 4:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
20mmol compound 3,26mmol thiocarbamide are mixed, react 3min in 110W microwave radiation under stirring, reaction terminates
Afterwards, mixture is cooled to room temperature, is transferred in 10mL cold water with a small amount of ethyl alcohol, with a small amount of NH4HCO3Aqueous solution neutralizes, and is precipitated solid
Body, filtering are washed with the ethanol water that volume fraction is 50%, dry, and the ethyl alcohol that crude product volume fraction is 80% is molten
Liquid is recrystallized, and 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 4.71g is filtered and obtain after drying, and is received
Rate 86.36%, purity 98.28%.
The preparation of comparative example 5:2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide
20mmol compound 3,26mmol thiocarbamide are mixed, react 3min40s, reaction knot in 110W microwave radiation under stirring
Mixture is cooled to room temperature by Shu Hou, is transferred in 10mL cold water with a small amount of ethyl alcohol, with a small amount of NH4HCO3Aqueous solution neutralizes, and is precipitated
Solid, filtering are washed with the ethanol water that volume fraction is 50%, dry, the ethyl alcohol that crude product volume fraction is 70%
Solution is recrystallized, and 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide 4.60g is filtered and obtain after drying,
Yield 82.75%, purity 96.40%.
Comparative example 6: 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 solid
Body 7.20g, yield 72.58%, purity 98.42%.
Comparative example 7: 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 n,N-Dimethylformamide (DMF)3PO4, room temperature stirs
40min is mixed, 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol is added with stirring.Logical N2, at 80 DEG C
After reacting 6h, add 50mL ammonia solvent mantoquita, extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase uses saturated salt solution
Washing, organic layer anhydrous Na2SO4It is dry, obtain crude product.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 solid 7.52g, yield 75.94%, purity 98.59%.
Comparative example 8: the preparation of Dasatinib
By 5mmol sarcosine, the chloro- 2- methylpyrimidine of 2mmol CuI, 20mmol 4,6- bis- is dissolved in 100mL N,
Under stirring, 22mmol N- hydroxyethyl piperazine, 40mmol K is added in dinethylformamide (DMF)3PO4, 40min is stirred at room temperature,
It is added with stirring 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) -5- thiazole carboxamides 22mmol.Logical N2, 6h is reacted at 120 DEG C
Afterwards, add 50mL ammonia solvent mantoquita, extracted with the ethyl acetate of 50mL × 3, combined ethyl acetate phase, with saturated common salt water washing,
Organic layer anhydrous Na2SO4It is dry, obtain crude product.Crude product is added to 80% ethanol water 100mL, under stirring, 2g is added
Active carbon, flow back 30min, filters while hot, and filtrate refrigerates crystallization and stays overnight, and filtering, 80% ethanol water of filter cake ice washs,
Drying is to get solid 7.71g, yield 78.36%, purity 99.17%.
Comparative example 9: 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 solid 7.36g, yield 74.68%, purity 99.03%.
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
Liquid reacts to obtain compound 3；
2) compound 3 is reacted with thiocarbamide, post-treated to obtain compound 2, i.e. 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5-
Formamide；
3) by the chloro- 2- methylpyrimidine of 4,6- bis- under the conditions of alkali, catalyst system, organic solvent, successively with N- hydroxyethyl piperazine, 2-
Amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide is reacted, 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), copper bromide is pre-
It is first dissolved with tetrahydrofuran, the solution concentration of the copper bromide is 1.3~1.4mol/L；3- ethyl 3-oxopropanoate, alkali, 2-
The mass ratio of the material of chloro- 6- methylaniline is 1:1.2~1.3:0.8~1.0；The substance of 3- ethyl 3-oxopropanoate, copper bromide
Amount is than being 1:2.6~2.8.
4. a kind of preparation method of Dasatinib according to claim 1, which is characterized in that in step 2), described is anti-
It should be microwave radiation reaction, microwave power 110W, reaction time 3min40s；Compound 3 and the mass ratio of the material of thiocarbamide are
1:1.0~2.0；The post-processing step are as follows: mixture is cooled to room temperature, is transferred in cold water with a small amount of ethyl alcohol, with a small amount of
NH4HCO3Aqueous solution neutralizes, and solid is precipitated, and filtering is washed with the ethanol water that volume fraction is 50%, and dry, crude product is used
Ethanol solution is recrystallized, and is filtered and is obtained 2- amino-N- (the chloro- 6- aminomethyl phenyl of 2-) thiazole -5- formamide after drying.
5. a kind of preparation method of Dasatinib according to claim 1, which is characterized in that in step 3), described has
Solvent is N,N-dimethylformamide；The alkali is K3PO4；The catalyst system is made of metallic catalyst and ligand,
The metallic catalyst is CuI, and ligand is n,N-Dimethylglycine；Reaction temperature is 120 DEG C.
6. a kind of preparation method of Dasatinib according to claim 5, which is characterized in that in step 3), 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
1:1.0~1.2:1.0~1.2；The chloro- 2- methylpyrimidine of 4,6- bis-, K3PO4, CuI, N, the mass ratio of the material of N- dimethylglycine
For 1:1.9~2.1:0.09~0.11:0.2~0.3；The concentration of the chloro- 2- methylpyrimidine of 4,6- bis- is 0.125~0.25mol/L.
7. a kind of preparation method of Dasatinib according to claim 3, which is characterized in that in step 1), copper bromide
Solution concentration is 1.35mol/L；The mass ratio of the material of the chloro- 6- methylaniline of 3- ethyl 3-oxopropanoate, alkali, 2- is 1:1.25:
0.9；3- ethyl 3-oxopropanoate, copper bromide the mass ratio of the material be 1:2.7.
8. a kind of preparation method of Dasatinib according to claim 4, which is characterized in that in step 2), compound 3 with
The mass ratio of the material of thiocarbamide is 1:1.2~1.4；The volume fraction of the ethanol solution is 80%.
9. a kind of preparation method of Dasatinib according to claim 8, which is characterized in that in step 2), compound 3 with
The mass ratio of the material of thiocarbamide is 1:1.3.
10. a kind of preparation method of Dasatinib according to claim 6, which is characterized in that in step 3), 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 1:1.1:1.1；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；The concentration of the chloro- 2- methylpyrimidine of 4,6- bis- is 0.2mol/L.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827156A (en) * | 2012-09-11 | 2012-12-19 | 湖南欧亚生物有限公司 | Novel industrial synthetic method of dasatinib |
| CN109678853A (en) * | 2018-12-29 | 2019-04-26 | 山东罗欣药业集团股份有限公司 | A kind of preparation process of Dasatinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827156A (en) * | 2012-09-11 | 2012-12-19 | 湖南欧亚生物有限公司 | Novel industrial synthetic method of dasatinib |
| CN109678853A (en) * | 2018-12-29 | 2019-04-26 | 山东罗欣药业集团股份有限公司 | A kind of preparation process of Dasatinib |
Non-Patent Citations (1)
| Title |
|---|
| PERRY T. KAYE ET AL.: "N,N-Disubstituted 2-Aminothiazole-5-carboxylates : Preparation and Rotation of Functional Groups", 《J. CHEM. SOC. PERKIN TRANS. I》 * |
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