CN110054626A - A kind of preparation method of Pyridopyrimidine derivatives - Google Patents
A kind of preparation method of Pyridopyrimidine derivatives Download PDFInfo
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- 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
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Abstract
The invention discloses a kind of preparation methods of Pyridopyrimidine derivatives, this method is condensed preparation 1- cyclopenta -4- picoline -2 through amidation using 3- methyl -2- glutaconate diester and cyclopentamine, 6- (1H, 5H)-diketone, then successively with methene reagent (N, dinethylformamide contracting glycol), urea " one kettle way " be condensed to yield 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone.Then through chlorination and the bromo-reaction preparation bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone.The present invention replaces ethyl crotonate without using higher three halogenated pyrimidine of price, palladium salt catalyst and 3- borate, raw materials used cheap and easy to get, easily operated, and reaction yield is stablized, and quantity of three wastes is few, and reaction of atomic economy is high, at low cost, is easy to green industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods for preparing Pa Boxini key intermediate Pyridopyrimidine derivatives, especially relate to
And the preparation method of a kind of bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone, belong to medicine
Technical field of chemistry.
Background technique
Pa Boxini (VII), trade name Ibrance, the entitled Palbociclib of English, Chinese name be also known as Pa Bosaibu or
Pa wins XiLin, is a kind of breakthrough breast cancer medicines of Pfizer's exploitation, and U.S. FDA approval was obtained on 2 3rd, 2015, is used
In selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6), restores cell cycle control, block tumour cell
Proliferation, joint Aromatase Inhibitor Letrozole are used for ER+/HER2-post menopausal metastatic breast cancer first-line treatment.Pa Bo
Western Buddhist nun is the CDK4/6 inhibitor of the first listing in the whole world.No. CAS of Pa Boxini is [571190-30-2], chemical name are as follows: 6-
Acetyl group -8- cyclopenta -5- methyl -2- [[5- (piperazine -1- base) pyridine -2- base] amino] -8H- pyrido [2,3-D] pyrimidine -
7- ketone.It is with the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine-that research and development route is declared by its Central Plains company of grinding
8- hydrogen -7- ketone (I) is key intermediate to prepare Pa Boxini, and related chemical structure formula is as follows:
Patent WO2008032157, US20160002223, CN105130986 and CN105622638 use the chloro- 5- of 2-
The bromo- 8- cyclopentyl pyridine [2,3-d] of methyl -6- and pyrimidine -8- hydrogen -7- ketone (II) prepare Pa Boxini, and being described in detail
The preparation method of object II is closed, i.e., is that raw material and cyclopentamine carry out 4- substitution reactions and obtain 2- with chloro- 5- bromine (iodine) pyrimidine of 2,4- bis-
Then chloro- 4- clopentylamino -5- bromine (iodine) pyrimidine passes through under palladium salt catalytic action with 3- borate substitution ethyl crotonate
Suzuki reaction coupling, lactamization obtain the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone, then
Using NBS or bromine through the bromo-reaction preparation bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7-
Ketone, total recovery are 35.9% to 60.6%, and reaction process is described as synthetic route 1.
Chloro- 5- bromine (iodine) the pyrimidine price of above-mentioned raw materials used 2, the 4- bis- of preparation route is higher, is not easy to obtain, palladium salt catalysis
Agent, 3- borate replace ethyl crotonate price high, and yield is unstable, and reaction of atomic economy is low, is unfavorable for the green of intermediate I
Color industrialized production and cost reduce.
Summary of the invention
In view of the deficiencies of the prior art, in order to prepare Pa Boxini with the process flow of raw material cheap and easy to get, simplification, this
Invention provides a kind of preparation method for preparing key intermediate Pyridopyrimidine derivatives needed for Pa Boxini, the i.e. chloro- 5- first of 2-
The preparation method of the bromo- 8- cyclopentyl pyridine [2,3-d] of base -6- and pyrimidine -8- hydrogen -7- ketone (I).
Technical solution of the present invention is as follows:
A kind of preparation side of the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone (I)
Method, comprising steps of
(1) in the presence of solvent and catalyst, 3- methyl -2- glutaconate diester (II) and cyclopentamine contract through amidation
Close preparation 1- cyclopenta -4- picoline -2,6- (1H, 5H)-diketone (III)；Gained compound (III) is with methene reagent in molten
In agent, condensation preparation 1- cyclopenta -4- methyl -5- dialkyl amido methene yl pyridines -2,6- (1H, 5H)-diketone (IV), then with
Urea condensation obtains 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone (V)；
(2) under solvent or excessive chlorinating agent, 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8-
Hydrogen -7- ketone (V) and the chlorinating agent reaction preparation chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone
(Ⅵ)；
(3) the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone (VI) are in a solvent through bromo
The reaction preparation bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone (I).
Wherein, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, normal-butyl or sec-butyl；R' is methyl or ethyl.
According to the method for the present invention, preferred processing condition and substance amount ratio are as follows in each step:
Preferably, solvent described in step (1) is toluene, dimethylbenzene, n,N-Dimethylformamide, N, N- dimethylacetamide
One or a combination set of amine, dimethyl sulfoxide, chlorobenzene, the mass ratio of II compound of the solvent and formula are (2-20): 1；
Preferably, catalyst described in step (1) is piperidines, 4- methyl piperidine, 4-dimethylaminopyridine, 1,8- diaza
One or a combination set of two rings, 11 carbon -7- alkene (DBU), 1,5- diazabicyclo [4.3.0] -5- nonene (DBN)；The catalyst
II compound of dosage and formula mass ratio be 0.3-5%；
Preferably, the molar ratio (0.9-3.0) of compound ii described in step (1) and cyclopentamine: 1；Amidation process with
It is carried out under temperature programming, prior to 50~100 DEG C reaction time 2-8 hour, then 80~150 DEG C of reaction time 2-8 hour；
Preferably, methene reagent described in step (1) is n,N-Dimethylformamide contracting glycol, further preferred N, N-
Dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal；The molar ratio of II compound of methene reagent and formula
For (1.0-3.0): 1；
Preferably, methene reaction temperature is 80~130 DEG C in step (1), and condensation reaction time is 3~10 hours；
Preferably, the molar ratio of II compound of urea described in step (1) and formula is (1.0-3.0): 1；The urea contracting
Closing pyrimidine cyclisation reaction temperature is 40~110 DEG C, and the reaction time is 3-8 hours；Further preferably, it is stirred to react 2- for 60~95 DEG C
3 hours；
Preferably, solvent described in step (2) be one or a combination set of toluene, dimethylbenzene, 1,2- dichloroethanes, acetonitrile,
The mass ratio of V compound of the solvent and formula is (0-8): 1；
Preferably, chlorinating agent described in step (2) be phosphorus oxychloride, phosphorus pentachloride, solid phosgene, surpalite, phosgene,
One or a combination set of thionyl chloride, the molar ratio of V compound of chlorinating agent and formula are (2.0-8.0): 1；
Preferably, chlorination temperature described in step (2) is 20~120 DEG C, reaction time 2-18 hour, further excellent
Choosing, chlorination temperature 60 C~100 DEG C, reaction time 4-8 hour；
Preferably, solvent described in step (3) is n,N-Dimethylformamide (DMF), acetic acid, acetonitrile, methylene chloride, chlorine
One or a combination set of imitative, tetrahydrofuran, dioxanes, the mass ratio of VI compound of the solvent and formula are (5-15): 1；
Preferably, brominated reagent described in step (3) be one or a combination set of bromine, N-bromosuccinimide (NBS),
The molar ratio of VI compound of brominated reagent and formula is (1.0-3.0): 1；
Preferably, bromo-reaction temperature described in step (3) is 20~120 DEG C, and the reaction time is 2-20 hours, further
Preferably, bromo-reaction temperature 60 C~100 DEG C, reaction time 3-11 hour.
The present invention utilizes 3- methyl -2- glutaconate diester (II) and cyclopentamine in the presence of solvent and catalyst, through acyl
Amination condensation preparation 1- cyclopenta -4- picoline -2,6- (1H, 5H)-diketone (III), then with methene reagent (N, N- bis-
Methylformamide contracting glycol) condensation preparation 1- cyclopenta -4- methyl -5- dialkyl amido methene yl pyridines -2,6- (1H, 5H) -
Diketone (IV), then 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone are obtained with urea condensation
(V), above procedure " one kettle way " is completed.Gained 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7-
Ketone (V) is successively by chlorination and the bromo-reaction bromo- 8- cyclopentyl pyridine [2,3-d] of the preparation chloro- 5- methyl -6- of 2- and phonetic
Pyridine -8- hydrogen -7- ketone (I), can be used for preparing Pa Boxini.Method of the invention uses following reaction route 2:
Wherein, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, normal-butyl or sec-butyl；R' is methyl or ethyl.
Beneficial effects of the present invention:
1. the present invention replaces ethyl crotonate, raw materials used valence without using higher three halogenated pyrimidine of price and 3- borate
It is honest and clean to be easy to get, it is easily operated.
2. the present invention does not use palladium salt catalyst, is conducive to avoid product heavy-metal residual, using cyclopentamine amidation, have
Conducive to the stability of each step intermediate, is conducive to the specificity that functional group carries out goal response, therefore products obtained therefrom purity is high, receives
Rate is stablized, and purity can reach 99% or more, and total recovery can reach 71%, and quantity of three wastes is few, reaction of atomic economy is high, is conducive to
The cost of mesosome I reduces and green industrialized production.
Detailed description of the invention
Fig. 1 is the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- prepared by embodiment 1 and pyrimidine -8- hydrogen -7-
The HPLC of ketone (I) schemes.
Specific embodiment
Embodiments discussed below has carried out detailed complete explanation to technical solution of the present invention, but the present invention is not only
It is limited to following embodiment.Based on the embodiment of the present invention, what anyone skilled in the art combination the technical program derived appoints
Why not creative scheme or embodiment are had, or any change for not having creative implementation sequence based on the present invention program
Change, all belongs to the scope of protection of the present invention.
3- methyl -2- glutaconate diester used in embodiment is provided by Jinan Rui Hui pharmaceuticals, and content is greater than 99.0%,
Wherein 3- methyl -2- glutaric acid diester impurity content is small less than 0.5%, 3- methyl -3- hydroxyl -2- glutaric acid diester impurity content
In 0.2%, remaining raw materials and reagents is commercial product." % " described in embodiment is mass percent, special instruction
Except.
The preparation of the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of embodiment 1:2- and pyrimidine -8- hydrogen -7- ketone (I)
Step (1): the preparation of 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone (V)
To be connected to stirring, thermometer, distilling apparatus 500 milliliters of four-hole boiling flasks in, 120 grams of N, N- dimethyl formyl is added
Amine, 17.2 grams of (0.1 mole) 3- methyl -2- glutaconate dimethyl esters, 8.6 grams of (0.1 mole) cyclopentamines, 0.2 gram of DBU, 80 to
85 DEG C are stirred to react 4 hours, and 110 to 115 DEG C are stirred to react 4 hours, while steaming the methanol of generation.It is cooled to 50-60 DEG C, is added
Enter 14.3 grams of (0.12 mole) n,N-Dimethylformamide dimethyl acetals (DMF-DMA), 110 to 115 DEG C are reacted 5 hours, cooling
To 50-60 DEG C, 10.0 grams of (0.17 mole) urea are added, 80 to 85 DEG C are reacted 5 hours, and recovery section solvent (80- is evaporated under reduced pressure
85 grams of solvents), it to be down to room temperature, 300 grams of water are added, is filtered, filter cake is washed with 20 grams of isopropanols, and it is dry, obtain 21.7 grams of whites
Solid 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone, yield 88.6%, liquid phase purity
99.7%.
Step (2): the preparation of the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone (VI)
42.5 grams of (0.3 mole) phosphorus oxychloride are added in equipped with thermometer, churned mechanically 250 milliliters of four-hole boiling flasks,
12.3 grams of (0.05 mole) 2- hydroxy-5-methyl base -8- cyclopentyl pyridines [2,3-d] and pyrimidine -8- hydrogen -7- ketone, 120 DEG C of stirrings are anti-
4h is answered, excessive phosphorus oxychloride is recovered under reduced pressure, is cooled to 60-65 DEG C, gained thick liquid is slowly poured into 300 grams of ice water, mistake
Filter, filter cake are washed with 20 grams of methyl tertiary butyl ethers, dry, obtain the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 12.3 grams of 2- simultaneously
Pyrimidine -8- hydrogen -7- ketone, yield 93.2%, liquid phase purity 99.8%.
Step (3): the preparation of the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone (I)
85 milliliters of DMF are added in equipped with thermometer, churned mechanically 250 milliliters of four-hole boiling flasks, 13.2 grams (0.05 rubs
You) the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone, 13.36 grams of (0.075 mole) NBS are molten
In 25 milliliters of DMF, the DMF solution of NBS is added drop-wise in reaction flask at room temperature, 60 DEG C is warming up to and is stirred to react 5h, is reacted
Terminate, 10% aqueous solution of sodium bisulfite (5 grams of sodium sulfites are dissolved in 45 milliliters of water) is added, cools to 0-5 DEG C and stirs
It is filtered after mixing 3 hours, crude product is beaten with 60 milliliters of isopropanols and is washed, filtered, dry to obtain the chloro- 5- methyl-of 14.8 grams of 2-
The bromo- 8- cyclopentyl pyridine [2,3-d] of 6- and pyrimidine -8- hydrogen -7- ketone, yield 86.1%, purity 99.6%.
The nuclear magnetic data of products therefrom is as follows:
1HNMR (400MHz, DMSO-d6) δ:
9.19(s,1H),5.86–5.77(m,1H),2.64(s,3H),2.17–1.99(m,4H),1.90–1.82(m,
2H),1.69–1.59(m,2H)。
HPLC figure is as shown in Fig. 1:
The peak < table >
Detector A280nm
| Peak number | Retention time | Area | Highly | Area percentage |
| 1 | 4.360 | 1290 | 122 | 0.036 |
| 2 | 4.988 | 1381 | 167 | 0.039 |
| 3 | 5.720 | 3538017 | 361500 | 99.693 |
| 4 | 6.955 | 1719 | 148 | 0.048 |
| 5 | 8.000 | 6537 | 413 | 0.184 |
| It amounts to | 3548944 | 362349 | 100.000 |
The preparation of the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of embodiment 2:2- and pyrimidine -8- hydrogen -7- ketone (I)
Step (1): the preparation of 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone (V)
To be connected to stirring, thermometer, distilling apparatus 500 milliliters of four-hole boiling flasks in, be added 150 grams of toluene, 20.0 grams
(0.1 mole) 3- methyl -2- glutaconate diethylester, 8.6 grams of (0.1 mole) cyclopentamines, 0.2 gram of DBU, 80 to 85 DEG C of stirrings are anti-
It answers 4 hours, 100 to 105 DEG C are stirred to react 4 hours, while steaming the ethyl alcohol of generation.It is cooled to 50-60 DEG C, is added 14.3 grams
(0.12 mole) n,N-Dimethylformamide dimethyl acetal (DMF-DMA), 100 to 105 DEG C are reacted 7 hours, are cooled to 50-60
DEG C, 10.0 grams of (0.17 mole) urea are added, 85 to 90 DEG C are reacted 7 hours, and vacuum distillation recovered solvent is down to room temperature, are added
300 grams of water, filtering, filter cake are washed with 20 grams of isopropanols, dry, obtain 20.5 grams of white solid 2- hydroxy-5-methyl base -8- rings penta
Yl pyridines [2,3-d] and pyrimidine -8- hydrogen -7- ketone, yield 83.7%, liquid phase purity 99.3%.
Step (2): the preparation of the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone (VI)
150 grams of toluene, 35.5 (0.3 mole) chlorine are added in equipped with thermometer, churned mechanically 500 milliliters of four-hole boiling flasks
Change sulfoxide, 12.3 grams of (0.05 mole) 2- hydroxy-5-methyl base -8- cyclopentyl pyridines [2,3-d] and pyrimidine -8- hydrogen -7- ketone, 70-
75 DEG C are stirred to react 7 hours, and excessive thionyl chloride and toluene is recovered under reduced pressure, is cooled to 40-45 DEG C, and gained thick liquid is slow
Slowly it pouring into 300 grams of ice water, filters, filter cake is washed with 20 grams of methyl tertiary butyl ethers, and it is dry, obtain the chloro- 5- methyl -8- of 12.1 grams of 2-
Cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone, yield 91.8%, liquid phase purity 99.6%.
Step (3): the preparation of the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone (I)
200 milliliters of chloroforms are added in equipped with thermometer, churned mechanically 500 milliliters of four-hole boiling flasks, 39.6 grams (0.15 rubs
You) the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone, it stirs evenly, is added dropwise into reaction flask
14.61 milliliters of (45.6 grams, 0.285 mole) bromines, are stirred 8 hours, reaction terminates, and thinks to be added in reaction flask at 50 DEG C
30% aqueous solution of sodium bisulfite (22 grams of sodium sulfites are dissolved in 52 milliliters of water), layering, organic phase is evaporated and recycling design,
Remaining solid is beaten with isopropanol and is washed, and obtains the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 45.3 grams of 2- and phonetic
Pyridine -8- hydrogen -7- ketone, yield 88.0%, purity 99.7%.
The preparation of the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of embodiment 3:2- and pyrimidine -8- hydrogen -7- ketone (I)
Step (1): the preparation of 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone (V)
To be connected to stirring, thermometer, distilling apparatus 500 milliliters of four-hole boiling flasks in, 120 grams of N, N- dimethyl formyl is added
Amine, 25.5 grams of (0.1 mole) 3- methyl -2- glutaconate di tert butyl carbonates, 8.6 grams of (0.1 mole) cyclopentamines, 0.3 gram of DBU, 90
It is stirred to react 4 hours to 95 DEG C, 120 to 125 DEG C are stirred to react 4 hours, while steaming the tert-butyl alcohol alcohol of generation.It is cooled to 50-
60 DEG C, 14.3 grams of (0.12 mole) n,N-Dimethylformamide dimethyl acetals (DMF-DMA) are added, 110 to 115 DEG C of reactions 5 are small
When, it is cooled to 50-60 DEG C, 10.0 grams of (0.17 mole) urea are added, 90 to 95 DEG C are reacted 5 hours, and recovery section is evaporated under reduced pressure
Solvent (80-85 grams of solvent), is down to room temperature, and 300 grams of water are added, and filtering, filter cake is washed with 20 grams of isopropanols, dry, obtains
21.2 grams of white solid 2- hydroxy-5-methyl base -8- cyclopentyl pyridines [2,3-d] and pyrimidine -8- hydrogen -7- ketone, yield 86.5%, liquid
Phase purity 99.6%.
Step (2): the preparation of the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone (VI)
50 grams of toluene of addition in equipped with thermometer, churned mechanically 250 milliliters of four-hole boiling flasks, 21.5 grams (0.15 mole)
Phosphorus oxychloride, 12.3 grams of (0.05 mole) 2- hydroxy-5-methyl base -8- cyclopentyl pyridines [2,3-d] and pyrimidine -8- hydrogen -7- ketone,
105-110 DEG C is stirred to react 6 hours, and excess toluene and phosphorus oxychloride is recovered under reduced pressure, is cooled to 60-65 DEG C, by gained viscous fluid
Body slowly pours into 300 grams of ice water, and filtering, filter cake is washed with 20 grams of methyl tertiary butyl ethers, dry, obtains the chloro- 5- first of 12.1 grams of 2-
Base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone, yield 91.7%, liquid phase purity 99.5%.
Step (3): the preparation of the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone (I)
100 milliliters of chloroforms are added in equipped with thermometer, churned mechanically 250 milliliters of four-hole boiling flasks, 13.2 grams (0.05 rubs
You) the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone, 10.7 grams of (0.06 mole) NBS, 55-60
DEG C it is stirred to react 6h, reaction terminates, and 30 gram 10% of aqueous solution of sodium bisulfite is added, cools to 0-5 DEG C, and stirring 3 is small
When after filter, with 60 milliliters of isopropanols to crude product be beaten wash, filtered, dry the chloro- 5- methyl -6- of 15.1 grams of 2- is bromo-
8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone, yield 88.0%, purity 99.4%.
Claims (10)
1. the preparation method of a kind of bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone (I),
Comprising steps of
(1) in the presence of solvent and catalyst, 3- methyl -2- glutaconate diester (II) and cyclopentamine are condensed through amidation and make
Standby 1- cyclopenta -4- picoline -2,6- (1H, 5H)-diketone (III)；Gained compound (III) and methene reagent are in solvent
In, condensation preparation 1- cyclopenta -4- methyl -5- dialkyl amido methene yl pyridines -2,6- (1H, 5H)-diketone (IV), then with urine
Element is condensed to yield 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7- ketone (V)；
(2) under solvent or excessive chlorinating agent, 2- hydroxy-5-methyl base -8- cyclopentyl pyridine [2,3-d] and pyrimidine -8- hydrogen -7-
Ketone (V) and the chlorinating agent reaction preparation chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone (VI)；
(3) the chloro- 5- methyl -8- cyclopentyl pyridine [2,3-d] of 2- and pyrimidine -8- hydrogen -7- ketone (VI) are in a solvent through bromo-reaction
Prepare the bromo- 8- cyclopentyl pyridine [2,3-d] of the chloro- 5- methyl -6- of 2- and pyrimidine -8- hydrogen -7- ketone (I)；
Wherein, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, normal-butyl or sec-butyl；R' is methyl or ethyl.
2. the preparation method of type I compound as described in claim 1, which is characterized in that include appointing in step (1) in the following conditions
One or two:
A1) solvent is toluene, dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, chlorobenzene
One or a combination set of, the mass ratio of II compound of the solvent and formula is (2-20): 1；
A2) catalyst is piperidines, 4- methyl piperidine, 4-dimethylaminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo
(DBU), one or a combination set of 1,5- diazabicyclo [4.3.0] -5- nonene (DBN)；The dosage and formula II of the catalyst are changed
The mass ratio for closing object is 0.3-5%.
3. the preparation method of type I compound as described in claim 1, which is characterized in that include appointing in step (1) in the following conditions
One or two:
B1) the molar ratio (0.9-3.0) of the compound ii and cyclopentamine: 1；
B2) amidation process under temperature programming to carry out, prior to 50~100 DEG C reaction time 2-8 hour, and then 80~150 DEG C
Reaction time 2-8 hour.
4. the preparation method of type I compound as described in claim 1, which is characterized in that include appointing in step (1) in the following conditions
It is one or more:
C1) the methene reagent is n,N-Dimethylformamide contracting glycol, further preferred n,N-Dimethylformamide contracting two
Methanol, N,N-dimethylformamide diethyl acetal；
C2) molar ratio of II compound of methene reagent and formula is (1.0-3.0): 1；
C3) methene reaction temperature is 80~130 DEG C, and condensation reaction time is 3~10 hours.
5. the preparation method of type I compound as described in claim 1, which is characterized in that include appointing in step (1) in the following conditions
One or two:
D1) molar ratio of II compound of the urea and formula is (1.0-3.0): 1；
D2) the urea condensation pyrimidine cyclisation reaction temperature is 40~110 DEG C, and the reaction time is 3-8 hours；Further preferably,
60~95 DEG C are stirred to react 2-3 hours.
6. the preparation method of type I compound as described in claim 1, which is characterized in that solvent described in step (2) be toluene,
One or a combination set of dimethylbenzene, 1,2- dichloroethanes, acetonitrile, the mass ratio of V compound of the solvent and formula are (0-8): 1.
7. the preparation method of type I compound as described in claim 1, which is characterized in that chlorinating agent described in step (2) is three
One or a combination set of chlorethoxyfos, phosphorus pentachloride, solid phosgene, surpalite, phosgene, thionyl chloride, V chemical combination of chlorinating agent and formula
The molar ratio of object is (2.0-8.0): 1.
8. the preparation method of type I compound as described in claim 1, which is characterized in that chlorination temperature described in step (2)
It is 20~120 DEG C, reaction time 2-18 hour, it is further preferred that chlorination temperature 60 C~100 DEG C, reaction time 4-8
Hour.
9. the preparation method of type I compound as described in claim 1, which is characterized in that include appointing in step (3) in the following conditions
One or two:
E1) solvent be N,N-dimethylformamide (DMF), acetic acid, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, two dislike
One or a combination set of alkane, the mass ratio of VI compound of the solvent and formula are (5-15): 1；
E2) brominated reagent is one or a combination set of bromine, N-bromosuccinimide (NBS), and brominated reagent and formula VI are changed
The molar ratio for closing object is (1.0-3.0): 1.
10. the preparation method of type I compound as described in claim 1, which is characterized in that bromo-reaction temperature described in step (3)
Degree is 20~120 DEG C, and the reaction time is 2-20 hours, it is further preferred that bromo-reaction temperature 60 C~100 DEG C, when reaction
Between 3-11 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447743A (en) * | 2014-11-26 | 2015-03-25 | 苏州明锐医药科技有限公司 | Preparation method for palbociclib |
| CN105237533A (en) * | 2015-10-26 | 2016-01-13 | 中国药科大学 | Tetrahydropyridine [4,3-d] miazines Hsp90 inhibitor and medical application thereof |
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2018
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447743A (en) * | 2014-11-26 | 2015-03-25 | 苏州明锐医药科技有限公司 | Preparation method for palbociclib |
| CN105237533A (en) * | 2015-10-26 | 2016-01-13 | 中国药科大学 | Tetrahydropyridine [4,3-d] miazines Hsp90 inhibitor and medical application thereof |
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| Title |
|---|
| 李婧瑶等: "帕博西尼合成路线图解", 《中国药物化学杂志》 * |
| 马庆童等: "帕博昔布的合成", 《中国医药工业杂志》 * |
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Denomination of invention: A Preparation Method of Pyridine Pyrimidine Derivatives Effective date of registration: 20221213 Granted publication date: 20200428 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |