CN106008392B - A kind of preparation method of the intermediate of cancer therapy drug Dasatinib - Google Patents
A kind of preparation method of the intermediate of cancer therapy drug Dasatinib Download PDFInfo
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- CN106008392B CN106008392B CN201610405209.5A CN201610405209A CN106008392B CN 106008392 B CN106008392 B CN 106008392B CN 201610405209 A CN201610405209 A CN 201610405209A CN 106008392 B CN106008392 B CN 106008392B
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- aminomethyl phenyls
- dasatinib
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- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000002067 L01XE06 - Dasatinib Substances 0.000 title claims abstract description 26
- 229960002448 dasatinib Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims abstract description 6
- 229940079593 drug Drugs 0.000 title claims abstract description 5
- 238000011275 oncology therapy Methods 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 30
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 18
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims abstract description 18
- -1 aminomethyl phenyl Chemical group 0.000 claims abstract description 17
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 10
- GGNIKGLUPSHSBV-UHFFFAOYSA-N thiazole-5-carboxamide Chemical class NC(=O)C1=CN=CS1 GGNIKGLUPSHSBV-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000007789 gas Substances 0.000 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 230000001681 protective effect Effects 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- 229910052801 chlorine Inorganic materials 0.000 abstract 2
- 239000000460 chlorine Substances 0.000 abstract 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-O 1-methylimidazole Chemical compound CN1C=C[NH+]=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-O 0.000 abstract 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 abstract 1
- DYDLYDZPQSPDRZ-UHFFFAOYSA-N ethanol;prop-2-enamide Chemical class CCO.NC(=O)C=C DYDLYDZPQSPDRZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000035484 reaction time Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- IBSQPLPBRSHTTG-UHFFFAOYSA-N 1-chloro-2-methylbenzene Chemical class CC1=CC=CC=C1Cl IBSQPLPBRSHTTG-UHFFFAOYSA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- RABBMOYULJIAFU-UHFFFAOYSA-N 1h-pyrrole;thiophene Chemical class C=1C=CNC=1.C=1C=CSC=1 RABBMOYULJIAFU-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 0 C*C=CC(N)=O Chemical compound C*C=CC(N)=O 0.000 description 1
- VVOXTERFTAJMAA-UHFFFAOYSA-N Cc(cccc1Cl)c1NC(c1cnc(N)[s]1)=O Chemical compound Cc(cccc1Cl)c1NC(c1cnc(N)[s]1)=O VVOXTERFTAJMAA-UHFFFAOYSA-N 0.000 description 1
- NVLHGZIXTRYOKT-UHFFFAOYSA-N Cc1c(C)c(Cl)ccc1 Chemical compound Cc1c(C)c(Cl)ccc1 NVLHGZIXTRYOKT-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- PMUIBVMKQVKHBE-UHFFFAOYSA-N [S].NC(N)=O Chemical compound [S].NC(N)=O PMUIBVMKQVKHBE-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960003925 parecoxib sodium Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a kind of preparation method of the intermediate of cancer therapy drug Dasatinib, this method includes：N (2 chlorine, 6 aminomethyl phenyl) 3 ethanol acrylamides are stirred with cuprous bromide and 1 butyl, 3 methyl imidazolium tetrafluoroborate；Then thiocarbamide is added to haptoreaction in the mixture obtained by above-mentioned mixing and obtains 2 amino N of Dasatinib intermediate (2 chlorine, 6 aminomethyl phenyl) thiazole, 5 formamide.The present invention's prepares Dasatinib method and step simple, mild condition and high income, meanwhile, the reaction time also greatly shortens.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular, to a kind of preparation of the intermediate of cancer therapy drug Dasatinib
Method
Background technology
Dasatinib (Parecoxib Sodium), entitled N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [[6- [4- (the 2- hydroxyls of chemistry
Ethyl) -1- piperazinyls] -2- methyl -4- pyrimidine radicals] amino] -5- thiazole carboxamides, it is a kind of tyrosine kinase inhibitor, uses
In the patient for the treatment of the past Endodontic failure or the Adult chronic's myelogenous leukemia (CML) not tolerated, treatment is also used for other treatments
The acute lymphatic leukemia adult patient of method drug resistance or the Philadelphia Chromosome Positive not tolerated.The medicine is applied by U.S.A when hundred
Gui Bao companies research and develop, and concrete structure is as follows：
At present, the Study of synthesis method on Dasatinib is more, these methods are substantially all with 2- amino-N- (the chloro- 6- of 2-
Aminomethyl phenyl) thiazole -5- formamides are intermediate, one kind be using thiazole cycle compound as starting material, such as
J.Med.Chem., 2004,6658 report the route on synthesizing Dasatinib, and specific route is as follows：
And CN1348370A discloses a kind of preparation method of Dasatinib, this method is with thiazolamine -5- carboxylic acids
Ethyl ester is starting material, and specific synthetic route is as follows：
The above method is all longer there are circuit, and the condition such as the harsh needs of multistep condition are anhydrous, anaerobic, low temperature, repeatedly uses
To synthesis and NaH, be not suitable for industrialized production, the defects of yield is low, poor selectivity.
Another kind of preparation process mainly prepares thiazole intermediate with non-thiazole raw material by condensation, such as
CN103483289B, CN103408542A etc., concrete technology route are as follows：
In the above method, the forming step 5 of thiazole ring largely uses NBS, and cost greatly improves, and NBS reactions are necessary
Carry out at low temperature, condition is harsh, in addition, also improving the workload of post processing.
Therefore, what this area still needed to a kind of method simple, mild condition and high income prepares Dasatinib intermediate
Method.
The content of the invention
It is an object of the invention to overcome existing to prepare Dasatinib intermediate 2-amino-N- (the chloro- 6- methylbenzenes of 2-
Base) thiazole -5- formamides the defects of method, there is provided a kind of mild condition, step be simple and high income prepares anticarcinogen
The method of the intermediate of thing Dasatinib.
Inventor has been surprisingly found that under study for action, can be by cuprous bromide and 1- butyl -3- methyl imidazolium tetrafluoroborates
Halo substitution product under special temperate condition, then collaboration promotes the ring-closure reaction with thiocarbamide to obtain thiazole ring, so as to be reached
Sand replaces Buddhist nun's intermediate, and reaction yield effectively improves, and reaction speed also greatly improves.
To achieve these goals, the present invention provides a kind of preparation method of Dasatinib intermediate, and this method includes：Will
N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides are stirred with cuprous bromide and 1- butyl -3- methyl imidazolium tetrafluoroborates
Mix mixing；Then thiocarbamide is added to haptoreaction in the mixture obtained by above-mentioned mixing and obtains Dasatinib intermediate 2- ammonia
Base-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides.
In invention, inventor first stirs cuprous bromide and 1- butyl -3- methyl imidazolium tetrafluoroborates with starting material
Mix, being conducive to react to carry out, and cause follow-up ring-closure reaction more stablize, yield higher, it is preferable that this method it is specific
Process includes：Room temperature is by N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides and cuprous bromide and 1- butyl -3- methyl
Tetrafluoroborate is stirred in THF；30~40 DEG C are then heated to, thiocarbamide is added to mixed obtained by above-mentioned mixing
Haptoreaction in compound.The time being stirred for example can be 20~40min.
In order to improve the Atom economy of reaction, it is preferable that N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides
Dosage molar ratio with thiocarbamide, cuprous bromide, 1- butyl -3- methyl imidazolium tetrafluoroborates is 1：1.5~3：0.5~1：0.2
~0.5.It is further preferred that N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides and thiocarbamide, cuprous bromide, 1- fourths
The dosage molar ratio of base -3- methyl imidazolium tetrafluoroborates is 1：2~3：0.6~0.8：0.2~0.4.
Although the reaction of the present invention can react under household condition, in order to avoid air etc. must be influenced on reacting, into one
Step improves reaction yield and efficiency, the haptoreaction and dehydrogenation reaction carry out all in the presence of protective gas, the protection gas
Body is nitrogen, helium or argon gas.
In the present invention, the solvent of reaction is preferably the one or more in THF, DMF.
In the present invention, the step of Dasatinib intermediate that can also include obtaining the above method purifies, institute
State purification process to be not particularly limited, the means of this area routine can be used to be purified, such as can be by 2- ammonia
Thiazole -5- formamides recrystallize or are dissolved in dichloromethane to base-N- (the chloro- 6- aminomethyl phenyls of 2-) in methanol/ethanol then makes
Product is separated out with stirrings such as petroleum ethers.
In the present invention, the method for this area routine can be used to be monitored tracking to reacting, such as TLC, LCMS,
GCMS etc., reaction finish refer to TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than
2%.
Obtained intermediate 2-amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides of method of the present invention, can be with
According to conventional technical means and Chloropyrimide, hydroxyethyl piperazine, necleophilic reaction obtains Dasatinib in alkaline conditions.
The specific route that the present invention prepares the method for Dasatinib is as follows：
Compared with prior art, using the method provided by the invention for preparing Dasatinib, reactions steps are simpler, instead
Yield is answered to effectively improve；Especially, thiazole ring avoids largely using NBS, mild condition, and yield also effectively improves, and reduces anti-
The workload that should be post-processed, simultaneous reactions time also greatly shorten.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Embodiment
With reference to specific embodiment, the present invention is further explained.But these embodiments be only limitted to explanation the present invention without
It is that the further of protection scope of the present invention is limited.
In the examples below, starting material N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [(6- chloro-2-methyl -4- pyrimidine radicals)
Amino] -5- thiazole carboxamides are prepared according to CN102010407A, and remaining reagent is commercially available product.
Embodiment 1
A kind of preparation method of Dasatinib intermediate 2-amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides,
This method includes：Room temperature is by N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides 23.9g (100mmol) and cuprous bromide
11.5g (80mmol) and 1- butyl -3- methyl imidazolium tetrafluoroborates 6.7g (30mmol) are added in flask in 120ml THF
In be stirred 30min；40 DEG C are then heated to, thiocarbamide 15.2g (200mmol) is added to the mixture obtained by above-mentioned mixing
When middle haptoreaction 1.5 is small, it is cooled to room temperature, is poured into frozen water, dichloromethane extraction, organic phase concentration, washing, then ethanol
Recrystallization, dry 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamide 26.5g, yield 98.9%, purity
99.66%.
Embodiment 2
A kind of preparation method of Dasatinib intermediate 2-amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides,
This method includes：Room temperature is by N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides 23.9g (100mmol) and cuprous bromide
10g (70mmol) and 1- butyl -3- methyl imidazolium tetrafluoroborates 9g (40mmol) are added in flask and are stirred in 120ml THF
Mix mixing 25min；35 DEG C are then heated to, thiocarbamide 22.8g (300mmol) is added in the mixture obtained by above-mentioned mixing and is connect
Touch reaction 2 it is small when, be cooled to room temperature, be poured into frozen water, dichloromethane extraction, organic phase concentration, washing, then ethanol is tied again
Crystalline substance, dry 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamide 26.3g, yield 98.2%, purity
99.57%.
Embodiment 3
A kind of preparation method of Dasatinib intermediate 2-amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides,
This method includes：Room temperature is by N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides 23.9g (100mmol) and cuprous bromide
8.6g (60mmol) and 1- butyl -3- methyl imidazolium tetrafluoroborates 4.5g (20mmol) are added in flask in 120ml THF
In be stirred 25min；30 DEG C are then heated to, thiocarbamide 19g (250mmol) is added in the mixture obtained by above-mentioned mixing
When haptoreaction 1.5 is small, it is cooled to room temperature, is poured into frozen water, dichloromethane extraction, organic phase concentration, washes, then ethanol weight
Crystallization, dry 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamide 26.3g, yield 98.4%, purity
99.64%.
Embodiment 4
A kind of preparation method of Dasatinib intermediate 2-amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides,
This method includes：Room temperature is by N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides 23.9g (100mmol) and cuprous bromide
14.3g (100mmol) and 1- butyl -3- methyl imidazolium tetrafluoroborates 11.3g (50mmol) are added in flask in 120ml
30min is stirred in THF；30 DEG C are then heated to, thiocarbamide 11.4g (150mmol) is added to mixed obtained by above-mentioned mixing
When haptoreaction 2 is small in compound, it is cooled to room temperature, is poured into frozen water, dichloromethane extraction, organic phase concentration, washing, Ran Houyi
Alcohol recrystallizes, dry 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamide 25.6g, yield 95.5%, purity
99.81%.
Embodiment 5
A kind of preparation method of Dasatinib intermediate 2-amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides,
This method includes：Room temperature is by N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides 23.9g (100mmol) and cuprous bromide
7.2g (50mmol) and 1- butyl -3- methyl imidazolium tetrafluoroborates 4.5g (20mmol) are added in flask in 120ml THF
In be stirred 20min；40 DEG C are then heated to, thiocarbamide 15.2g (200mmol) is added to the mixture obtained by above-mentioned mixing
When middle haptoreaction 2 is small, it is cooled to room temperature, is poured into frozen water, dichloromethane extraction, organic phase concentration, washing, then ethanol weight
Crystallization, dry 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamide 25.4g, yield 94.7%, purity
99.55%.
Embodiment 6
As the preparation method of 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides in embodiment 1, institute are different
, the dosage of cuprous bromide is 1.4g (10mmol), obtains 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides
24.3g, yield 90.9%, purity 99.53%.
Embodiment 7
As the preparation method of 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides in embodiment 1, institute are different
, the dosage of 1- butyl -3- methyl imidazolium tetrafluoroborates is 1.1g (5mmol), obtains 2- amino-N- (the chloro- 6- methylbenzenes of 2-
Base) thiazole -5- formamide 24.4g, yield 91.0%, purity 99.64%.
Comparative example 1
According to CN103483283289B embodiments 1 3) in method prepare 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiophene
Azoles -5- formamides, comprise the following steps that：
Into 1.5L reaction bulbs, 70gN- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethanol acrylamides and 0.7L isopropyls are added
Alcohol, is added portionwise 60g NBS under stirring, when charging controls 25 DEG C of temperature ＜.After adding, insulated and stirred 4h, then adds 26g sulphur
Urea, adds rear temperature rising reflux 5h.TLC detects that the reaction was complete to raw material.Reaction solution is down to room temperature, ammonium hydroxide tune pH=8-9 is added dropwise.
Reaction solution is concentrated into half volume, cool down analysis of material, and filtering, washing, obtain yellow solid crude product, use isopropanol：Water=1:3 it is mixed
Bonding solvent recrystallizes, and it is target compound 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- first to obtain 71.8g yellow solids
Acid amides, yield 91.8%, purity 98.21%.
Comparative example 2
Such as the preparation of 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides of embodiment 1, the difference is that
Cuprous bromide is added without, obtains 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamide 16.3g, yield 60.9% is pure
Degree 99.20%.
Comparative example 3
Such as the preparation of 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides of embodiment 1, the difference is that
1- butyl -3- methyl imidazolium tetrafluoroborates are added without, obtain 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) thiazole -5- formamides
13.8g, yield 51.4%, purity 97.92%.
The preferred embodiment of the present invention described in detail above, still, during present invention is not limited to the embodiments described above
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.In addition, any group can also be carried out between a variety of embodiments of the present invention
Close, as long as it without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.
Claims (5)
1. a kind of preparation method of the intermediate of cancer therapy drug Dasatinib, it is characterised in that this method includes：By N-, (2- is chloro-
6- aminomethyl phenyls) -3- ethanol acrylamides are stirred with cuprous bromide and 1- butyl -3- methyl imidazolium tetrafluoroborates；
Then thiocarbamide is added to haptoreaction in the mixture obtained by above-mentioned mixing and obtains Dasatinib intermediate 2-amino-N- (2-
Chloro- 6- aminomethyl phenyls) thiazole -5- formamides.
2. preparation method according to claim 1, it is characterised in that the detailed process of this method includes：Room temperature is by N- (2-
Chloro- 6- aminomethyl phenyls) -3- ethanol acrylamides and cuprous bromide and 1- butyl -3- methyl imidazolium tetrafluoroborates be in THF
It is stirred；30 ~ 40 DEG C are then heated to, thiocarbamide is added to haptoreaction in the mixture obtained by above-mentioned mixing.
3. preparation method according to claim 1 or 2, it is characterised in that N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethyoxyls
Acrylamide and the dosage molar ratio of thiocarbamide, cuprous bromide, 1- butyl -3- methyl imidazolium tetrafluoroborates are 1：1.5~3：0.5~
1：0.2~0.5.
4. preparation method according to claim 3, it is characterised in that N- (the chloro- 6- aminomethyl phenyls of 2-) -3- ethoxy propylenes
Acid amides and the dosage molar ratio of thiocarbamide, cuprous bromide, 1- butyl -3- methyl imidazolium tetrafluoroborates are 1：2~3：0.6~0.8：
0.2~0.4。
5. according to the preparation method described in any one in claim 1,2 and 4, it is characterised in that be stirred and contact
Reaction carries out all in the presence of protective gas, and the protective gas is nitrogen, helium or argon gas.
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| CN109503568B (en) * | 2018-12-29 | 2020-08-07 | 山东罗欣药业集团股份有限公司 | Preparation method of dasatinib |
Citations (2)
| 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 |
| WO2015049645A2 (en) * | 2013-10-04 | 2015-04-09 | Alembic Pharmaceuticals Limited | An improved process for the preparation of dasatinib |
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2016
- 2016-06-09 CN CN201610405209.5A patent/CN106008392B/en active Active
Patent Citations (2)
| 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 |
| WO2015049645A2 (en) * | 2013-10-04 | 2015-04-09 | Alembic Pharmaceuticals Limited | An improved process for the preparation of dasatinib |
Non-Patent Citations (2)
| Title |
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| A new facile synthesis of 2-aminothiazole-5-carboxylates;Rulin Zhao et al.;《Tetrahedron Letters》;20011231;第42卷;2101-2102 * |
| 达沙替尼的合成研究;黄睿等;《化学与生物工程》;20131231;第30卷(第10期);48-50 * |
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