CN105949189B - A kind of preparation method for being used to treat the Pa Boxini of breast cancer - Google Patents
A kind of preparation method for being used to treat the Pa Boxini of breast cancer Download PDFInfo
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- CN105949189B CN105949189B CN201610398962.6A CN201610398962A CN105949189B CN 105949189 B CN105949189 B CN 105949189B CN 201610398962 A CN201610398962 A CN 201610398962A CN 105949189 B CN105949189 B CN 105949189B
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- pyrido
- pyrimidine
- cyclopenta
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- pyridine radicals
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 206010006187 Breast cancer Diseases 0.000 title claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 27
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 13
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 13
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 9
- 239000011630 iodine Substances 0.000 claims abstract description 9
- 230000002378 acidificating effect Effects 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 claims abstract description 6
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 229910003771 Gold(I) chloride Inorganic materials 0.000 claims description 10
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 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
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- -1 acetenyl Chemical group 0.000 abstract description 3
- 150000002576 ketones Chemical class 0.000 abstract 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 3
- 125000004193 piperazinyl group Chemical group 0.000 abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000010606 normalization Methods 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 238000000605 extraction Methods 0.000 description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- PMYDPQQPEAYXKD-UHFFFAOYSA-N 3-hydroxy-n-naphthalen-2-ylnaphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(NC(=O)C3=CC4=CC=CC=C4C=C3O)=CC=C21 PMYDPQQPEAYXKD-UHFFFAOYSA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000010970 precious metal Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229960001881 sodium selenate Drugs 0.000 description 2
- 235000018716 sodium selenate Nutrition 0.000 description 2
- 239000011655 sodium selenate Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of preparation method for being used to treat the Pa Boxini of breast cancer, this method includes：1) by N cyclopenta 5 methyl 2 [[5 (1 piperazinyl) 2 pyridine radicals] amino] pyrido [2,3 d] (8H) ketone of pyrimidine 7 in the presence of iodine and cesium carbonate with acetenyl 2 [[5 (1 piperazinyl) 2 pyridine radicals] amino] pyrido [2,3 d] pyrimidine 7 (8H) ketone of trimethylsilanylethyn reaction generation N cyclopenta 5 methyl 6；2) by step 1) obtained 5 methyl of N cyclopenta 6 acetenyl 2 [[5 (1 piperazinyl) 2 pyridine radicals] amino] pyrido [2,3 d] pyrimidine 7 (8H) ketone hydrolyzes in acidic aqueous solution and produces.The invention provides a kind of new way for preparing Pa Boxini, reaction condition is gentle, and overall yield is high, is more suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of preparation for being used to treat the Pa Boxini of breast cancer
Method.
Background technology
Pa Boxini, Palbociclib, cell cycle dependent kinase (CDK4/6) inhibitor, are opened by Pfizer
Hair, the line for estrogen receptor positive (ER+) and negative (HER2-) advanced breast cancer of human epidermal growth factor receptor 2 is controlled
Treat.Pa Boxini chemical entitled 6- acetyl group -8- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino]
Pyrido [2,3-d] pyrimidine -7 (8H) -one, concrete structure is as follows：
WO2008032157 discloses a kind of Pa Boxini synthetic method, and this method is with the chloro- 5- bromines of 2,4- bis- and ring penta
Base amine is that initiation material obtains target product by seven steps, and specific synthetic route is as follows：
The synthetic method route is long, wherein the reaction of the 5th step has Cl and Br competitive reaction, yield is not high and purifies tired
Difficulty, also and its strictly, in addition, Heck reacts this method twice, the use of precious metal palladium catalyst is also big for reaction condition requirement
Improve production cost greatly.
CN104447743B discloses a kind of Pa Boxini preparation method, and this method is with 2- acetyl group -2- butenoic acid first
Ester and malononitrile make initiation material, through cyclization, with Cyclopentane halide necleophilic reaction then with N- [5- (1- piperazinyls) -2- pyridines
Base] guanidine condensation, the obtained Pa Boxini of the dehydrogenation reaction that then grown prosperity in the presence of sodium selenate.Although this method is preparation Pa Boxini
There is provided new approach, but the overall yield of this method or relatively low, this is mainly due to the 3rd step and N- [5- (1- piperazines
Base) -2- pyridine radicals] yield is relatively low, the reaction time is long for guanidine condensation, and this method dehydrogenation reaction has used hypertoxic sodium selenate in addition, no
Preferably mass produce, and be unfavorable for the health of labourer.
Therefore, this area needs a kind of method for preparing Pa Boxini of simple, mild condition and high income badly.
The content of the invention
It is an object of the invention to overcome complex steps, product yield in the existing method for preparing Pa Boxini are low to lack
Fall into that there is provided a kind of suitable industrial-scale production and high income, the simple method for preparing Pa Boxini.
The present inventor has found under study for action, in Pa Boxini preparation process, in iodine and inorganic base (carbonic acid
Caesium) catalysis under, N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7
(8H) -one directly reacts the alkynyl on 6 with trimethylsilanylethyn, then directly obtains acetyl by the method for hydrolysis
Base, it is to avoid reacted with halide reagent halo and subsequent use precious metal and the harsh heck of condition, mild condition, always
Body yield is higher, while the residual of heavy metal in the product is it also avoid, so as to complete the present invention.
To achieve these goals, the present invention provides a kind of method for preparing Pa Boxini, and this method comprises the following steps：
1) by N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -
7 (8H) -one in the presence of iodine and cesium carbonate with trimethylsilanylethyn reaction generation N- cyclopenta -5- methyl -6- acetenyls -
2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one；
2) by step 1) obtained N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] pyrimidine -7 (8H) -one obtains Pa Boxini in acidic aqueous solution reclaimed water solution.
In the present invention, the inventory for each reactant is not particularly limited, can be according to conventional methods
It is determined, N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7
(8H) -one and trimethylsilanylethyn, iodine, the mol ratio of cesium carbonate are 1：1.1~2：0.05~0.2：1.5~3.
It is further preferred that N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,
3-d] (8H) -one of pyrimidine -7 and trimethylsilanylethyn, iodine, the mol ratio of cesium carbonate be 1：1.1~1.5：0.08~0.12：
1.8~2.
In the present invention, it is preferred to, step 1) reaction condition include：Reaction temperature is 40~50 DEG C, the solvent of reaction
For THF.
Step 2 in the present invention) hydrolysis, be not particularly limited for acid solution, for example 5~15 weights
Measure % aqueous sulfuric acid.Preferably, step 2) hydrolysis condition also include：Reaction temperature is 75~80 DEG C, the catalysis of hydrolysis
Agent is AuCl, and AuCl consumption is N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino]
The 3-6% of pyrido [2,3-d] pyrimidine -7 (8H) -one weight.
In order to avoid air etc. must influence on reacting, under preferable case, step 1) reaction exist in protective gas, institute
Protective gas is stated for nitrogen, helium or argon gas.
In the present invention, the compound shown in initiation material formula (I) used in the present invention is commercially available or root
Prepare, for example, can be prepared according to the preparation method in WO200832157 or WO2014128588 according to prior art.
In the present invention, the amount of solvent for use is not particularly limited in reaction, can be determined according to actual tests, example
Gross weight as fed intake per 1g adds 1~10ml solvents.
In the present invention, " room temperature " refers to 25 DEG C ± 5 DEG C.
In the present invention, can be monitored tracking to reaction using the conventional method in this area, such as TLC, LCMS,
GCMS etc., reaction finish finger TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than
2%.
Specifically, synthetic route of the invention is as follows：
The invention provides a kind of new way for preparing Pa Boxini, the step such as halogenation and metal coupling reaction is reduced
Suddenly, reaction condition is gentle, and overall yield is also higher, is more suitable for industrialized production.
Other features and advantages of the present invention will be described in detail in subsequent embodiment part.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without
It is the further restriction to protection scope of the present invention.
Embodiment 1
A kind of method for preparing Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,
3-d] (8H) the -one 40.5g of pyrimidine -7 (100mmol) in the presence of cesium carbonate 58.6g (180mmol) and iodine 2.5g (10mmol) with
Trimethylsilanylethyn 11.8g (120mmol) reacts 3 hours for 45 DEG C in THF, after reaction terminates, removes solvent, water under reduced pressure
Wash, recrystallizing methanol, dry N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino]
Pyrido [2,3-d] pyrimidine -7 (8H) -one 22.6g, yield is 84.5%, purity 99.79% (HPLC area normalization methods).
2) by step 1) obtained N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] (8H) -one of pyrimidine -7 10g is added in acidic aqueous solution (10% aqueous sulfuric acid) in AuCl 0.3g
(3%) it is catalyzed lower 75 DEG C to hydrolyze 2 hours, reaction end is cooled to room temperature, ether extraction is concentrated, washing, and recrystallizing methanol is done
Dry to obtain Pa Boxini 9.3g, yield is 89.0%, purity 99.95% (HPLC area normalization methods).
Embodiment 2
A kind of method for preparing Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido
[2,3-d] pyrimidine -7 (8H) -one 40.5g (100mmol) is in the presence of cesium carbonate 65.1g (200mmol) and iodine 2.1g (8mmol)
Reacted 4 hours for 40 DEG C in THF with trimethylsilanylethyn 10.8g (110mmol), after reaction terminates, remove solvent under reduced pressure,
Washing, recrystallizing methanol, dry N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] pyrimidine -7 (8H) -one 22.5g, yield is 83.7%, purity 99.89% (HPLC area normalization methods).
2) by step 1) obtain N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] (8H) -one of pyrimidine -7 10g is added in acidic aqueous solution (12% aqueous sulfuric acid) in AuCl 0.6g
(6%) it is catalyzed lower 80 DEG C to hydrolyze 3 hours, reaction end is cooled to room temperature, ether extraction is concentrated, washing, and recrystallizing methanol is done
Dry to obtain Pa Boxini 9.1g, yield is 86.7%, purity 99.87% (HPLC area normalization methods).
Embodiment 3
A kind of method for preparing Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido
[2,3-d] pyrimidine -7 (8H) -one 40.5g (100mmol) is in the presence of cesium carbonate 65.1g (200mmol) and iodine 3g (12mmol)
Reacted 3 hours for 50 DEG C in THF with trimethylsilanylethyn 14.7g (150mmol), after reaction terminates, remove solvent under reduced pressure,
Washing, recrystallizing methanol, dry N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] pyrimidine -7 (8H) -one 22.3g, yield is 83.4%, purity 99.80% (HPLC area normalization methods).
2) by step 1) obtained N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] (8H) -one of pyrimidine -7 10g is added in acidic aqueous solution (10% aqueous sulfuric acid) in AuCl 0.4g
(4%) it is catalyzed lower 75 DEG C to hydrolyze 3 hours, reaction end is cooled to room temperature, ether extraction is concentrated, washing, and recrystallizing methanol is done
Dry to obtain Pa Boxini 9.2g, yield is 88.6%, purity 99.92% (HPLC area normalization methods).
Embodiment 4
A kind of method for preparing Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido
[2,3-d] pyrimidine -7 (8H) -one 40.5g (100mmol) is in the presence of cesium carbonate 81.4g (250mmol) and iodine 1.3g (5mmol)
React 4.5 hours for 40 DEG C, after reaction terminates, removed under reduced pressure molten in THF with trimethylsilanylethyn 16.7g (170mmol)
Agent, washing, recrystallizing methanol, dry N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals]
Amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 21.6g, yield is 78.2%, (the HPLC area normalizations of purity 99.77%
Method).
2) by step 1) obtained N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] (8H) -one of pyrimidine -7 10g is added in acidic aqueous solution (5% aqueous sulfuric acid) in AuCl 0.6g
(6%) it is catalyzed lower 75 DEG C to hydrolyze 3.5 hours, reaction end is cooled to room temperature, ether extraction is concentrated, washing, recrystallizing methanol,
Pa Boxini 8.9g are dried to obtain, yield is 85.9%, purity 99.79% (HPLC area normalization methods).
Embodiment 5
A kind of method for preparing Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido
[2,3-d] pyrimidine -7 (8H) -one 40.5g (100mmol) exists in cesium carbonate 48.9g (150mmol) and iodine 5.1g (20mmol)
Lower and trimethylsilanylethyn 19.6g (200mmol) reacts 3.5 hours for 50 DEG C in THF, after reaction terminates, removes under reduced pressure
Solvent, washing, recrystallizing methanol, dry N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridines
Base] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 20.3g, yield is 74.6%, (the HPLC area normalizations of purity 99.61%
Method).
2) by step 1) obtained N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] ammonia
Base] pyrido [2,3-d] (8H) -one of pyrimidine -7 10g is added in acidic aqueous solution (10% aqueous sulfuric acid) in AuCl 0.3g
(3%) it is catalyzed lower 80 DEG C to hydrolyze 3.5 hours, reaction end is cooled to room temperature, ether extraction is concentrated, washing, recrystallizing methanol,
Pa Boxini 8.9g are dried to obtain, yield is 86.2%, purity 99.85% (HPLC area normalization methods).
Embodiment 6
The preparation method of Pa Boxini in such as embodiment 1, except that, in step 2) in, do not make AuCl, obtain handkerchief
Bo Xini 5.6g, yield is 53.4%, purity 89.82% (HPLC area normalization methods).
Embodiment 7
Such as the preparation method of the Pa Boxini in embodiment 1, except that, in step 1) temperature be 65 DEG C, dry
Obtain N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7
(8H) -one 19.6g, yield is 73.4%, purity 98.36% (HPLC area normalization methods).
Comparative example 1
The preparation method of Pa Boxini in such as embodiment 1, except that, in step 1) in, without using iodine, obtain N- rings
Amyl group -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -
Ketone 11.2g, yield is 42.0%, purity 96.81% (HPLC area normalization methods).
Comparative example 2
The preparation method of Pa Boxini bodies in such as embodiment 1, except that, in step 1) in, without using cesium carbonate
And iodine, obtain N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d]
Pyrimidine -7 (8H) -one 4.4g, yield is only 16.4%.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
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 is without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.
Claims (6)
1. a kind of preparation method for being used to treat the Pa Boxini of breast cancer, it is characterised in that this method comprises the following steps：
1）By N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7
(8H) -one in the presence of iodine and cesium carbonate with trimethylsilanylethyn reaction generation N- cyclopenta -5- methyl -6- acetenyls -
2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one；
2）By step 1）Obtained N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino]
Pyrido [2,3-d] (8H) -one of pyrimidine -7 obtains Pa Boxini in acidic aqueous solution reclaimed water solution, and the catalyst of hydrolysis is AuCl.
2. according to the method described in claim 1, it is characterised in that N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2-
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one and the mol ratio of trimethylsilanylethyn, iodine, cesium carbonate be
1：1.1~2：0.05 ~0.2：1.5~3.
3. method according to claim 1 or 2, it is characterised in that N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -
2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one and trimethylsilanylethyn, iodine, the mol ratio of cesium carbonate
For 1：1.1~1.5：0.08~0.12：1.8~2.
4. according to the method described in claim 1, it is characterised in that step 1）Reaction temperature be 40 ~ 50 DEG C, the solvent of reaction
For THF.
5. according to the method described in claim 1, it is characterised in that step 2）Reaction temperature be 75 ~ 80 DEG C, AuCl consumption
For N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -
The 3 ~ 6% of 7 (8H) -one weight.
6. according to the method described in claim 1, it is characterised in that step 1）Reaction exist in protective gas, it is described protect
Shield gas is nitrogen, helium or argon gas.
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