CN105968109A - Method for preparing palbociclib intermediate - Google Patents
Method for preparing palbociclib intermediate Download PDFInfo
- Publication number
- CN105968109A CN105968109A CN201610320997.8A CN201610320997A CN105968109A CN 105968109 A CN105968109 A CN 105968109A CN 201610320997 A CN201610320997 A CN 201610320997A CN 105968109 A CN105968109 A CN 105968109A
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- chloro
- methyl
- cyclopenta
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 38
- 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 title abstract description 5
- 229960004390 palbociclib Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 12
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims abstract description 12
- 230000002378 acidificating effect Effects 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 claims description 11
- 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
- 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
- 239000007789 gas Substances 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 239000003054 catalyst Substances 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
- SYISHRLXIIZBHJ-UHFFFAOYSA-N 1-(3-methylpyridin-2-yl)ethanone Chemical compound CC(=O)C1=NC=CC=C1C SYISHRLXIIZBHJ-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052794 bromium Inorganic materials 0.000 abstract description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 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
- 238000002360 preparation method Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 5
- 239000012259 ether extract Substances 0.000 description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical group N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000006356 dehydrogenation reaction Methods 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000010970 precious metal 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
- -1 Cyclopentane halide Chemical class 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- 238000007341 Heck reaction Methods 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
- 239000002253 acid Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011655 sodium selenate Substances 0.000 description 2
- 229960001881 sodium selenate Drugs 0.000 description 2
- 235000018716 sodium selenate Nutrition 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
- 206010006187 Breast cancer Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 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
- 230000009471 action Effects 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 108010038795 estrogen receptors Proteins 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
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000007344 nucleophilic reaction Methods 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
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing a palbociclib intermediate. The method comprises the following steps: (1) enabling a compound N-cyclopentyl-5-methyl-2-chloro-6-bromine pyridino[2,3-d]pyrimidine-7(8H)-ketone as shown in a formula (I) to react with trimethyl silicon alkyl acetylene to form a compound N-cyclopentyl-5-methyl-2-chloro-6-acetenyl pyridino[2,3-d]pyrimidine-7(8H)-ketone as shown in a formula (II) under the existence of cuprous bromide and potassium tert-butoxide; (2) hydrolyzing the compound N-cyclopentyl-5-methyl-2-chloro-6-acetenyl pyridino[2,3-d]pyrimidine-7(8H)-ketone which is obtained in step (1) and as shown in the formula (II) in an acidic aqueous solution, thus obtaining the palbociclib intermediate N-cyclopentyl-5-methyl-2-chloro-6-acetyl pyridino[2,3-d]pyrimidine-7(8H)-ketone; the formula (I) and the formula (II) are shown in the description. According to the method disclosed by the invention, a new path is developed for preparing the palbociclib intermediate, the conditions are gentle, and the yield is high.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of method preparing Pa Boxini intermediate.
Background technology
Pa Boxini (Palbociclib), is a kind of cell cycle dependent kinase (CDK4/ developed by Pfizer
6) inhibitor, for negative (HER2-) advanced breast cancer of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2
First-line treatment.Chemistry entitled 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(1-the piperazinyl)-2-pyridine of Pa Boxini
Base] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one, concrete structure is as follows:
WO2008032157 discloses the synthetic method of a kind of Pa Boxini, the method with 2,4-bis-chloro-5-bromine and ring penta
Base amine is that initiation material obtains target product through seven steps, and concrete synthetic route is as follows:
This synthetic method route is long, and wherein the 5th step reaction exists the competitive reaction of Cl Yu Br, and yield is the highest and purification is stranded
Difficulty, reaction condition requires also and strictly, it addition, twice Heck reaction of the method, the use of precious metal palladium catalyst is the biggest
Improve greatly production cost.
CN104447743B discloses the preparation method of a kind of Pa Boxini, and the method is with 2-acetyl group-2-butylene acid first
Initiation material made by ester and Cyanoacetyl-Cyacetazid, through cyclization and Cyclopentane halide necleophilic reaction, then with N-[5-(1-piperazinyl)-2-pyridine
Base] guanidine condensation, then occur dehydrogenation reaction to prepare Pa Boxini in the presence of sodium selenate.Although the method is preparation Pa Boxini
Provide new approach, but the overall yield of the method or relatively low, and this is mainly due to the 3rd step and N-[5-(1-piperazine
Base)-2-pyridine radicals] yield is relatively low, the response time is long in guanidine condensation, and additionally the method dehydrogenation reaction employs severe toxicity sodium selenate, no
Preferably large-scale production, and it is unfavorable for the health of labourer.
Therefore, this area needs a kind of simple, mild condition and the high method preparing Pa Boxini of yield badly.
Summary of the invention
It is an object of the invention to overcome the defect of above-mentioned prior art, it is provided that a kind of new preparation Pa Boxini intermediate
Method, the method is simple, mild condition, and yield is higher, is particularly suitable for industrial-scale production.
The present inventor finds under study for action, in the preparation process of Pa Boxini, can use and trimethyl silicane
Alkyl acetylene molecule connects alkynyl, then obtains acetyl group by the method for hydrolysis, this method avoid use precious metal and bar
The heck reaction of part harshness and use toxic reagent catalytic dehydrogenation etc., mild condition, overall yield is higher, it also avoid simultaneously
Heavy metal residual in the product, thus complete the present invention.
To achieve these goals, the present invention provides a kind of method preparing Pa Boxini intermediate, the method include with
Lower step:
1) by the compound N shown in formula (I)-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-d] pyrimidine-7
(8H)-one reacts generation compound shown in formula (II) in the presence of cuprous bromide and potassium tert-butoxide with trimethylsilanylethyn
N-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine also [2,3-d] pyrimidine-7 (8H)-one；
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine of obtaining is also
[2,3-d] pyrimidine-7 (8H)-one hydrolyzes in acidic aqueous solution that to obtain Pa Boxini intermediate N cyclopenta-5-methyl-2-chloro-
6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one；
In the case of in the present invention, it is preferred to, N N-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-d] pyrimidine-7
(8H)-one is 1:1.2～2.5:0.3～0.6:1.2 with trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide
～2.
In the case of Jin Yibuyouxuan, N-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one
It is 1:1.5～2:0.35～0.5:1.5～1.6 with trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide.
In the present invention, due to the existence of 2 chlorine, competitive reaction can be formed when generating the reaction of acetenyl with bromine, for
Avoid competition, under preferable case, step 1) condition reacted includes: reaction temperature is 45～50 DEG C, the solvent of reaction is
THF.Under the conditions of Gai, step 1) reaction 3～within 5 hours, can complete.
Although the reaction of the present invention under household condition can be reacted, affect reacting to obtain in order to avoid air etc., preferably
In the case of, step 1) reaction carry out in the presence of protective gas, described protective gas is nitrogen, helium or argon.
Step 2 in the present invention) hydrolysis, acid solution is not particularly limited, such as 5～15 weights
The aqueous sulfuric acid of amount %.Preferably, step 2) condition that hydrolyzes includes: reaction temperature is 65～70 DEG C, the catalyst of hydrolysis
Consumption for AuCl, AuCl is N-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine also [2,3-d] pyrimidine-7 (8H)-one weight
The 6～8% of amount.In the conditions of the invention, the reaction 2 of hydrolysis～can complete for 3 hours.
In the present invention, the compound shown in initiation material formula (I) used in the present invention is commercially available or root
Prepare according to prior art, such as, can prepare according to the preparation method in WO200832157 or WO2014128588.
In the present invention, in reaction, the amount of solvent for use is not particularly limited, and can determine according to actual tests, example
The gross weight fed intake such as every 1g adds 1～10ml solvent.
The Pa Boxini intermediate N cyclopenta-5-methyl-2-chloro-6-acetylpyridine that the method that the present invention provides obtains
And [2,3-d] pyrimidine-7 (8H)-one, can be with 4-(6-amino-pyridine-3-base)-piperazine-1-carboxylate generation nucleophilic
Reaction obtains finalization compound Pa Boxini, and this step is referred in this area conventional method, such as CN104910149A
Related manufacturing processes.
The room temperature of indication of the present invention refers to 25 DEG C ± 5 DEG C.
In the present invention, reaction is monitored following the tracks of by the method that this area can be used conventional, such as TLC, LCMS,
GCMS etc., react complete finger TLC monitor not excess raw material disappeared or in LCMS, GCMS not excess raw material residue be less than
2%.
Specifically, the synthetic route of the present invention is as follows:
The invention provides a kind of new way preparing Pa Boxini, it is provided that a kind of Pa Boxini key intermediate N-ring penta
The preparation method of base-5-methyl-2-chloro-6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one, it is to avoid use precious metal
Or poisonous dehydrating agent etc., reaction condition is gentle, and overall yield is the highest, is more suitable for industrialized production.
Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to illustrate the present invention and not
It it is the further restriction to protection scope of the present invention.
Embodiment 1
A kind of method preparing Pa Boxini intermediate, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-
D] pyrimidine-7 (8H)-one 34.3g (100mmol) deposits at cuprous bromide 5.7g (40mmol) and potassium tert-butoxide 16.8g (150mmol)
Lower with trimethylsilanylethyn 19.6g (200mmol) in THF 45～50 DEG C react 3 hours, after reaction terminates, decompression
Solvent is evaporated off, washing, recrystallizing methanol, it is dried to obtain the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-acetylene
Yl pyridines also [2,3-d] pyrimidine-7 (8H)-one 23.7g, yield is 82.4%, purity 99.96% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine of obtaining is also
[2,3-d] pyrimidine-7 (8H)-one 10g joins in acidic aqueous solution (10% aqueous sulfuric acid) and is catalyzed at AuCl 0.7g 7%
Lower 65 DEG C hydrolyze 2 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, and recrystallizing methanol is dried to obtain Pa Bo
Western Buddhist nun's intermediate N cyclopenta-5-methyl-2-chloro-6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one 9.2g, yield is
86.3%, purity 99.98% (HPLC area normalization method).
Embodiment 2
A kind of method preparing Pa Boxini intermediate, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-
D] pyrimidine-7 (8H)-one 34.3g (100mmol) exists at cuprous bromide 5g (35mmol) and potassium tert-butoxide 17.9g (160mmol)
Lower with trimethylsilanylethyn 14.7g (150mmol) in THF 65 DEG C react 4 hours, react after terminating, remove under reduced pressure molten
Agent, washing, recrystallizing methanol, it is dried to obtain the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine
And [2,3-d] pyrimidine-7 (8H)-one 23.4g, yield is 81.3%, purity 99.95% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine of obtaining is also
[2,3-d] pyrimidine-7 (8H)-one 10g joins in acidic aqueous solution (15% aqueous sulfuric acid) and is catalyzed at AuCl 0.6g (6%)
Lower 70 DEG C hydrolyze 3 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, and recrystallizing methanol is dried to obtain Pa Bo
Western Buddhist nun's intermediate N cyclopenta-5-methyl-2-chloro-6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one 9.2g, yield is
87.2%, purity 99.91% (HPLC area normalization method).
Embodiment 3
A kind of method preparing Pa Boxini intermediate, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-
D] pyrimidine-7 (8H)-one 34.3g (100mmol) deposits at cuprous bromide 7.2g (50mmol) and potassium tert-butoxide 17.9g (160mmol)
Lower with trimethylsilanylethyn 19.6g (200mmol) in THF 60 DEG C react 3 hours, after reaction terminates, remove under reduced pressure
Solvent, washing, recrystallizing methanol, it is dried to obtain the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-acetenyl pyrrole
Pyridine also [2,3-d] pyrimidine-7 (8H)-one 22.9g, yield is 79.6%, purity 99.91% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine of obtaining is also
[2,3-d] pyrimidine-7 (8H)-one 10g joins in acidic aqueous solution (10% aqueous sulfuric acid) and is catalyzed at AuCl 0.8g (8%)
Lower 70 DEG C hydrolyze 3 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, and recrystallizing methanol is dried to obtain Pa Bo
Western Buddhist nun's intermediate N cyclopenta-5-methyl-2-chloro-6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one 9.2g, yield is
86.5%, purity 99.91% (HPLC area normalization method).
Embodiment 4
A kind of method preparing Pa Boxini intermediate, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-
D] pyrimidine-7 (8H)-one 34.3g (100mmol) deposits at cuprous bromide 4.3g (30mmol) and potassium tert-butoxide 22.4g (200mmol)
Lower with trimethylsilanylethyn 24.6g (250mmol) in THF 55 DEG C react 4.5 hours, after reaction terminates, decompression is steamed
Except solvent, washing, recrystallizing methanol, it is dried to obtain the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-acetenyl
Pyrido [2,3-d] pyrimidine-7 (8H)-one 21.9g, yield is 76.1%, purity 99.78% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine of obtaining is also
[2,3-d] pyrimidine-7 (8H)-one 10g joins in acidic aqueous solution (5% aqueous sulfuric acid) and is catalyzed at AuCl 0.5g (5%)
Lower 65 DEG C hydrolyze 3.5 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, and recrystallizing methanol is dried to obtain handkerchief
Bo Xini intermediate N cyclopenta-5-methyl-2-chloro-6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one 8.9g, yield
It is 84.2%, purity 99.84% (HPLC area normalization method).
Embodiment 5
A kind of method preparing Pa Boxini intermediate, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-
D] pyrimidine-7 (8H)-one 34.3g (100mmol) deposits at cuprous bromide 8.6g (60mmol) and potassium tert-butoxide 13.5g (120mmol)
Lower with trimethylsilanylethyn 6.1g (120mmol) in THF 65 DEG C react 3.5 hours, after reaction terminates, remove under reduced pressure
Solvent, washing, recrystallizing methanol, it is dried to obtain the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-acetenyl pyrrole
Pyridine also [2,3-d] pyrimidine-7 (8H)-one 22.1g, yield is 76.6%, purity 99.81% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine of obtaining is also
[2,3-d] pyrimidine-7 (8H)-one 10g joins in acidic aqueous solution (10% aqueous sulfuric acid) and is catalyzed at AuCl 1g (10%)
Lower 60 DEG C hydrolyze 3.5 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, and recrystallizing methanol is dried to obtain handkerchief
Bo Xini intermediate N cyclopenta-5-methyl-2-chloro-6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one 9.1g, yield
It is 85.7%, purity 99.79% (HPLC area normalization method).
Embodiment 6
Such as the preparation method of the Pa Boxini intermediate in embodiment 1, except that, in step 2) in, do not make AuCl,
Obtain Pa Boxini intermediate N cyclopenta-5-methyl-2-chloro-6-acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one
11.0g, yield is 53.2%, purity 87.91% (HPLC area normalization method).
Comparative example 1
Such as the preparation method of the Pa Boxini intermediate in embodiment 1, except that, in step 1) in, do not use bromine
Change cuprous, obtain the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine also [2,3-d] pyrimidine-7
(8H)-one 15.6g, yield is 54.2%, purity 96.46% (HPLC area normalization method)
Comparative example 2
Such as the preparation method of the Pa Boxini intermediate in embodiment 1, except that, in step 1) in, do not use bromine
Change cuprous and potassium tert-butoxide, obtain the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine also [2,3-
D] pyrimidine-7 (8H)-one 4.8g, yield is 16.4%.
Comparative example 3
Such as the preparation method of the Pa Boxini intermediate in embodiment 1, except that, in step 1) in, use identical
The potassium carbonate of mole substitutes potassium tert-butoxide, obtains the compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-acetenyl
Pyrido [2,3-d] pyrimidine-7 (8H)-one 17.8g, yield is 61.9%, purity 98.70% (HPLC area normalization method).
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited in above-mentioned embodiment
Detail, in the technology concept of the present invention, technical scheme can be carried out multiple simple variant, this
A little simple variant belong to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, at not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to various can
The compound mode of energy illustrates the most separately.Additionally, any group can also be carried out between the various different embodiment of the present invention
Closing, as long as it is without prejudice to the thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (6)
1. the method preparing Pa Boxini intermediate, it is characterised in that the method comprises the following steps:
1) by the compound N shown in formula (I)-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one
React generation compound N-ring penta shown in formula (II) with trimethylsilanylethyn in the presence of cuprous bromide and potassium tert-butoxide
Base-5-methyl-2-chloro-6-ethynyl pyridine also [2,3-d] pyrimidine-7 (8H)-one；
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine of obtaining also [2,
3-d] pyrimidine-7 (8H)-one hydrolyzes in acidic aqueous solution and obtains the Pa Boxini intermediate N cyclopenta-5-chloro-6-of methyl-2-
Acetylpyridine also [2,3-d] pyrimidine-7 (8H)-one；
Method the most according to claim 1, it is characterised in that N-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-
D] pyrimidine-7 (8H)-one and trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide be 1:1.2～2.5:0.3～
0.6:1.2～2.
Method the most according to claim 2, it is characterised in that N-cyclopenta-5-methyl-2-chloro-6-bromopyridine also [2,3-
D] pyrimidine-7 (8H)-one and trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide be 1:1.5～2:0.35～
0.5:1.5～1.6.
Method the most according to claim 1, it is characterised in that step 1) condition reacted includes: reaction temperature be 45～
50 DEG C, the solvent of reaction is THF.
Method the most according to claim 1, it is characterised in that step 2) condition that hydrolyzes includes: reaction temperature be 65～
70 DEG C, the catalyst of hydrolysis be the consumption of AuCl, AuCl be N-cyclopenta-5-methyl-2-chloro-6-ethynyl pyridine also [2,3-
D] pyrimidine-7 (8H)-one weight 6～8%.
6. according to the method described in claim 1-5, it is characterised in that step 1) reaction exist in protective gas, institute
Stating protective gas is nitrogen, helium or argon.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610320997.8A CN105968109B (en) | 2016-05-13 | 2016-05-13 | A kind of method for preparing Pa Boxini intermediates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610320997.8A CN105968109B (en) | 2016-05-13 | 2016-05-13 | A kind of method for preparing Pa Boxini intermediates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105968109A true CN105968109A (en) | 2016-09-28 |
| CN105968109B CN105968109B (en) | 2017-11-17 |
Family
ID=56955356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610320997.8A Expired - Fee Related CN105968109B (en) | 2016-05-13 | 2016-05-13 | A kind of method for preparing Pa Boxini intermediates |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105968109B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565707A (en) * | 2016-11-03 | 2017-04-19 | 杭州科巢生物科技有限公司 | Novel synthetic method of Palbociclib |
| CN106970177A (en) * | 2017-06-06 | 2017-07-21 | 北京元延医药科技股份有限公司 | The analyzing detecting method of Pa Boxini intermediates and its impurity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020025968A1 (en) * | 1998-04-15 | 2002-02-28 | Rifat Pamukcu | Method for inhibiting neoplastic cells and related conditions by exposure to 4-aminoquinazoline derivatives |
| CN104892604A (en) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor |
| CN105294681A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application therefore |
-
2016
- 2016-05-13 CN CN201610320997.8A patent/CN105968109B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020025968A1 (en) * | 1998-04-15 | 2002-02-28 | Rifat Pamukcu | Method for inhibiting neoplastic cells and related conditions by exposure to 4-aminoquinazoline derivatives |
| CN105294681A (en) * | 2014-07-26 | 2016-02-03 | 广东东阳光药业有限公司 | CDK small-molecule inhibitor compounds and application therefore |
| CN104892604A (en) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| ANNA-MARIE LORD ET AL.: "Design, Synthesis, and Evaluation in Vitro of Quinoline-8-carboxamides, a New Class of Poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) Inhibitor", 《J. MED. CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565707A (en) * | 2016-11-03 | 2017-04-19 | 杭州科巢生物科技有限公司 | Novel synthetic method of Palbociclib |
| CN106565707B (en) * | 2016-11-03 | 2019-01-04 | 杭州科巢生物科技有限公司 | Pa Boxini novel synthesis |
| CN106970177A (en) * | 2017-06-06 | 2017-07-21 | 北京元延医药科技股份有限公司 | The analyzing detecting method of Pa Boxini intermediates and its impurity |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105968109B (en) | 2017-11-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104130261B (en) | The synthetic method of Chinese mugwort Delibes | |
| CN107936029B (en) | Method for synthesizing Ribociclib | |
| CN106478641A (en) | The novel synthesis of Rui Boxini intermediate | |
| CN106083691B (en) | A kind of preparation method of arbidol HCl monohydrate | |
| CN108033922B (en) | Preparation method of 3-acyl quinoxalinone derivative | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| EP3004047B1 (en) | Compounds of '3-(5-substituted oxy-2,4-dinitro-phenyl)-2-oxo-propionic acid ester', process and applications thereof | |
| CN105085544B (en) | A kind of synthetic method of Tazobactam Sodium benzhydryl ester | |
| CN114437031A (en) | Synthetic method of 6-methyl nicotine | |
| CN105968109A (en) | Method for preparing palbociclib intermediate | |
| CN106008499B (en) | A kind of method for preparing CDK46 kinase inhibitors Pa Boxini | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| CN107759596A (en) | A kind of synthesis Pa Boxini method | |
| CN104311485A (en) | Preparation method of medicine bosutinib for treating leukemia | |
| CN105949189B (en) | A kind of preparation method for being used to treat the Pa Boxini of breast cancer | |
| CN110016023B (en) | Simple preparation method of palbociclib | |
| CN108675972B (en) | Preparation method of amiodarone hydrochloride intermediate 2-butyl benzofuran | |
| CN113234076B (en) | Preparation method of doxofylline | |
| CN106083844B (en) | A kind of method for preparing anti-breast cancer medicines Pa Boxini intermediates | |
| CN108047133A (en) | A kind of preparation method of quinolinones compound | |
| CN113637003B (en) | Method for preparing 2-amino-6- (piperidine-4-acyl) pyridine derivative | |
| CN107903209A (en) | A kind of synthetic method of 2 amino, 5 fluorine pyridine, 3 methyl formate | |
| CN108484617B (en) | Novel benzofuran azanaphthalene dione derivative and preparation method thereof | |
| CN109369772B (en) | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives | |
| CN105198864B (en) | A kind of non-solvent preparation of cyclopenta pyrimidine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Nie Hongmei Inventor after: Li Jianai Inventor after: Yu Mingxia Inventor before: Wang Chuanxiu |
|
| CB03 | Change of inventor or designer information | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20171024 Address after: 276399 No. 2, unit 14, building 70, building 401, Yuquanlu Road, Linyi, Shandong, Yinan Applicant after: Nie Hongmei Applicant after: Li Jianai Applicant after: Yu Mingxia Address before: 266109 Shandong, Qingdao, Chengyang District, No. 825 Zhengyang Road, building, room 1, office, room 205 Applicant before: The skies, Qingdao Bioisystech Co., Ltd |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171117 Termination date: 20180513 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |