CN108299422B - A kind of preparation method of pa pool former times benefit cloth intermediate - Google Patents
A kind of preparation method of pa pool former times benefit cloth intermediate Download PDFInfo
- Publication number
- CN108299422B CN108299422B CN201810170004.2A CN201810170004A CN108299422B CN 108299422 B CN108299422 B CN 108299422B CN 201810170004 A CN201810170004 A CN 201810170004A CN 108299422 B CN108299422 B CN 108299422B
- Authority
- CN
- China
- Prior art keywords
- preparation
- solvent
- bromo
- former times
- compound
- 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.)
- Active
Links
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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to pharmaceutical synthesis fields, disclose a kind of preparation method of pa pool former times benefit cloth intermediate, in preparation process of the present invention, with 5- bromo- 2,4- dichloro pyrimidine is starting material, promote ground palladium catalysed cross coupling reaction, BTC to promote ground cyclization reaction and NBS bromo-reaction by ammonification substitution reaction, green solvent PEG, finally obtains target compound V, and by the improvement to post-processing so that the HPLC purity of final product is up to 99% or more.Compared with traditional handicraft, beneficial effect of the present invention is mainly reflected in: mild, easy to operate, palladium catalyst the dosage of reaction condition is lower, high income, at low cost, " three wastes " amount less, be easy to industrialize, there are biggish implementary value and economic results in society.
Description
Technical field
The present invention relates to pharmaceutical synthesis field more particularly to a kind of preparation methods of pa pool former times benefit cloth intermediate.
Background technique
Pa pool former times benefit cloth (Palbociclib) is the cell cycle protein dependent kinase of Pfizer Inc.'s research and development
(CDK4/6) inhibitor, for treating the advanced breast cancer of postmenopausal women.Pa pool former times benefit cloth can act on cell mitogenic point
The key node split plays conclusive inhibiting effect to the mad proliferation of cancer cell.Associated mechanisms predict that pa moors former times benefit cloth
The year two thousand twenty sales volume will be up to 47.22 hundred million dollars, it may be said that have a vast market foreground.
The chemical name that pa moors former times benefit cloth is 6- acetyl group -8- cyclopenta -5- methyl -2- [[5- (1- piperazinyl) -2- pyrrole
Piperidinyl] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one, structure is as follows:
At present in pa pool former times benefit cloth synthetic method reported in the literature, key is how efficiently to construct key intermediate female ring
Simultaneously [2,3-d]-pyrimidine -7 (8H) -one (compound V), structural formula are as follows for the chloro- 8- cyclopenta -5- picoline of the bromo- 2- of molecule 6-
It is shown:
Patent WO2008032157, WO2014128588, WO2016030439 and document Org.Process
Res.Dev.2016, the synthetic route of report pa pool former times benefit cloth intermediate is as follows in 20,1191-1202: with bromo- 2, the 4- dichloro of 5-
Pyrimidine (compound I) is raw material, obtains the chloro- N- cyclopenta pyrimidine -4- amine (compound II) of the bromo- 2- of 5- by substitution, then exists
Heck coupling occurs under acetic acid palladium chtalyst with crotonic acid, is directly added into acetic anhydride, intramolecular dehydration cyclization shape without post-processing
At chloro- 8- cyclopenta -5- methyl -8H- pyrido [2, the 3-d] pyrimidin-7-ones (compound III) of 2-, most obtained afterwards through NBS bromo
The chloro- 8- cyclopenta -5- picoline of the bromo- 2- of 6- simultaneously [2,3-d]-pyrimidine -7 (8H) -one (compound V).
This route has used more palladium catalyst, and cost is not easy to control；And this step is coupled in Heck and has used boiling
The higher solvent N-methyl pyrilidone of point, it is more difficult to remove；And 99% cannot be reached by the purity of purification rear center body V.
Patent CN105968108 reports another synthetic method: using the chloro- 5- pyrimidine ethyl ketone of 4- amino -2- as raw material, and
It reacts to obtain the chloro- 8- cyclopenta -5- picoline of the bromo- 2- of 6- simultaneously again with cyclopenta chlorine after bromoacetate reaction cyclization
[2,3-d]-pyrimidine -7 (8H) -one.
But this route raw material is not easy to obtain, the operability of process route is not high.
Summary of the invention
In order to solve the above-mentioned technical problems, the present invention provides a kind of preparation method of pa pool former times benefit cloth intermediate, this hairs
Bright synthetic route reaction condition is mild, reaction yield is high, strong operability, production cost are low, environmentally protective.
The specific technical proposal of the invention is: a kind of preparation method of pa pool former times benefit cloth intermediate, synthetic route are as follows:
Wherein, Pd salt indicates that palladium catalyst, PEG indicate that polyethylene glycol, BTC indicate triphosgene, and NBS indicates N- bromo
Succimide.
Preferably, the preparation method of the pa pool former times benefit cloth intermediate specifically comprises the following steps:
(1) bromo- 2, the 4- dichloro pyrimidine of compound I:5- and alkali A are dissolved in solvent A, are cooled to -30~30 DEG C, ring is added dropwise
The mixed liquor of amylamine and solvent A reacts after dripping off and obtains within 0.5~5 hour the chloro- N- cyclopenta pyrimidine-of the bromo- 2- of compound II:5-
4- amine.
(2) under inert gas protection, by the chloro- N- cyclopenta pyrimidine -4- amine of the bromo- 2- of 5-, crotonic acid, palladium catalyst and alkali
B is added in organic solvent polyethylene glycol, is carried out Heck reaction at appropriate temperatures and is obtained compound III:3- in 5~30 hours
[2- chloro- 4- (clopentylamino) -5- pyrimidine radicals] -2- butenoic acid.
(3) at 20~100 DEG C, 3- [2- chloro- 4- (clopentylamino) -5- pyrimidine radicals] -2- butenoic acid and triphosgene exist
It carries out obtaining the chloro- 8- cyclopenta -5- methyl -8H- pyrido [2,3- of compound IV:2- in cyclization reaction 2~12 hours in solvent B
D] pyrimidin-7-ones.
(4) by chloro- 8- cyclopenta -5- methyl -8H- pyrido [2, the 3-d] pyrimidin-7-ones of 2-, N- bromo-succinimide,
Oxalic acid is dissolved in solvent C, and at 20~100 DEG C, it is bromo- that reaction obtains pa pool former times benefit cloth midbody compound V:6- for 2~24 hours
The chloro- 8- cyclopenta -5- picoline of 2- simultaneously [2,3-d]-pyrimidine -7 (8H) -one.
The palladium catalyst of small amount (1/10th of prior art dosage) has been used in Heck coupling reaction of the present invention, has been dropped
Low process costs.
The present invention uses environment-friendly type solvent PEG as the solvent of coupling reaction, the common solvent of the non-coupled reaction of the solvent,
System realizes the application in such reaction for the first time, reacts green high-efficient, and post-processing is easy, obtained intermediate purity is high.
The present invention uses triphosgene i.e. solid phosgene as cyclization reagent, and by-product is few, process stabilizing.Solid phosgene reaction
Activity is similar with phosgene, and solid phosgene is applied to pa by the optical self-encoding Related product of complete alternative severe toxicity, the present invention for the first time
In the synthetic reaction for mooring former times benefit cloth.
Preferably, the alkali A is selected from triethylamine, n,N-diisopropylethylamine, triethylenediamine, 1 in step (1),
One of 11 carbon -7- alkene of 8- diazabicylo [5.4.0]；The solvent A be selected from methanol, ethyl alcohol, isopropanol, n-butanol,
Isosorbide-5-Nitrae-one of dioxane or ethyl acetate.
Preferably, in step (1), mass ratio=1 of compound I, alkali A and solvent A: 1~3: 2~10.
Preferably, the palladium catalyst is bis-triphenylphosphipalladium palladium dichloride, tetra-triphenylphosphine palladium, two in step (2)
(tert-butyl phosphine) palladium, palladium acetate, palladium chloride, double benzonitrile palladium chlorides or diacetonitrile palladium chloride；The alkali B is organic base or nothing
Machine alkali, organic base are selected from sodium acetate, triethylamine, n,N-diisopropylethylamine, triethylenediamine or 1,8- diazabicylo
[5.4.0] 11 carbon -7- alkene, inorganic base are selected from potassium hydroxide, potassium phosphate, potassium carbonate, saleratus, sodium hydroxide or carbonic acid
Sodium；The polymerization scope of the polyethylene glycol is 200~4000.
Preferably, in step (2), compound II, crotonic acid, palladium catalyst, alkali B and polyethylene glycol mass ratio=
1: 1~3: 0.001~0.05: 2~6: 2~10；Reaction temperature is 20~100 DEG C.
As further preferred, in step (2), reaction temperature is 60-80 DEG C.
Preferably, the solvent B is selected from toluene, chlorobenzene, dimethylbenzene, dichloroethanes, acetonitrile, dioxy six in step (3)
One of ring or N-Methyl pyrrolidone.
Preferably, in step (3), mass ratio=1 of compound III, triphosgene and solvent B: 0.4~1: 2~10.
Preferably, the solvent C is selected from n,N-Dimethylformamide, dimethyl sulfoxide, methylene chloride, two in step (4)
One of chloroethanes, acetonitrile, toluene, dioxane or N-Methyl pyrrolidone.
Preferably, in step (4), mass ratio=1 of compound IV, N- bromo-succinimide, oxalic acid and solvent C
: 1~3: 0.1~0.5: 2~10.
It is compared with the prior art, the beneficial effects of the present invention are:
A) palladium catalyst of small amount (1/10th of prior art dosage) has been used in Heck coupling reaction of the present invention,
Reduce process costs.
B) present invention uses environment-friendly type solvent PEG as the solvent of coupling reaction, and commonly using for the non-coupled reaction of the solvent is molten
Agent is the application realized in such reaction for the first time, reacts green high-efficient, and post-processing is easy, obtained intermediate purity is high.
C) present invention uses triphosgene i.e. solid phosgene as cyclization reagent, and by-product is few, process stabilizing.Solid phosgene is anti-
Answer activity similar with phosgene, the optical self-encoding Related product of complete alternative severe toxicity, the present invention applies to solid phosgene for the first time
Pa is moored in the synthetic reaction of former times benefit cloth.
D) process route is advanced, environmentally protective, strong operability, has biggish implementary value and economic results in society.
Specific embodiment
The present invention will be further described with reference to the examples below.
Embodiment 1
1) preparation of intermediate II:
The ratio between the amount of substance of feeding intake is bromo- 2, the 4- dichloro pyrimidine I of 5-: cyclopentamine: triethylamine=1.0: 1.3: 1.3.
Bromo- 2, the 4- dichloro pyrimidine I (227.9g, 1mol) of 5-, ethyl alcohol (276g, 6mol) are sequentially added in 2L three-necked flask ,-
Ethyl alcohol (92g, the 2mol) solution of cyclopentamine (106.2g, 1.3mol) is added dropwise in 15 DEG C of addition triethylamines (131.5g, 1.3mol),
Reaction 2~3 hours crosses filter solid, takes filter cake in 2L reaction flask, is added petroleum ether (600g), stirs 1 hour, filters again,
Filter cake is washed with petroleum ether (100g).Filter cake is collected, 40 DEG C of vacuum dryings obtain 243.4g intermediate II, white solid, yield
88%, 442~443.5 DEG C of fusing point, HPLC purity 99.8%.
The hydrogen spectrum of intermediate II, mass spectral characteristi:
1H NMR (600MHz, CDCl3): δ 8.09 (s, 1H), 5.54 (d, J=4.5Hz, 1H), 4.42 (dd, J=14.0,
7.0Hz, 1H), 1.44-2.17 (m, 8H)；MS (ESI) m/z (percent): [M+H]+275.9.
2) preparation of intermediate III:
The ratio between the amount of substance of feeding intake is intermediate II: crotonic acid: triethylamine: double benzonitrile palladium chloride=1.0: 3.0: 3.0:
0.001。
Through N2In the 3L three-necked flask of purging be added intermediate II (138.3g, 0.5mol), crotonic acid (64.6g,
1.5mol), triethylamine (151.8g, 1.5mol), PEG-1000 (414g), N2 are bubbled 30 minutes, and double benzonitrile palladium chlorides are added
(0.19g, 0.0005mol), again N2Be bubbled 30 minutes, 80 DEG C insulation reaction 8 hours, be cooled to room temperature, into reaction solution plus
Enter water (1kg), adjusts pH to 4.5 or so with 15%HCl (about 120mL), filtering rinses filter cake, 40 DEG C of vacuum with the water of 300mL
134g intermediate III is dried to obtain, pale powder, yield 95%, 520.3~522 DEG C of fusing point, HPLC purity is 93.0%.
The hydrogen spectrum of intermediate III, mass spectral characteristi:
1H NMR (600MHz, CDCl3): δ 11.94 (s, 1H), 7.86 (d, J=2.5Hz, 1H), 6.02 (s, 1H), 5.14
(s, 1H), 2.44 (s, 3H), 1.44-2.11 (m, 8H)；MS (ESI) m/z (percent): [M+H]+282.1.
3) preparation of intermediate compound IV:
The ratio between the amount of substance of feeding intake is intermediate III: BTC=1.0: 0.4.
In 3L three-necked flask, compound III (112g, 0.4mol), dichloroethanes (330g) is added, 45 DEG C of temperature control, drips
Dichloroethanes (220g) solution of reinforcing body phosgene (47.8g, 0.16mol), drips off, it is small to be warming up to back flow reaction 3 for about 1 hour
When, it is evaporated under reduced pressure out solvent, the mashing of 300mL isopropanol, filtering is added, 40 DEG C of vacuum drying obtain 93.9g intermediate compound IV, yellowish
Color solid, yield 89%, fusing point are 452.5~454.0 DEG C, and HPLC purity is 99.3%.
The hydrogen spectrum of intermediate III, mass spectral characteristi:
1H NMR (600MHz, CDCl3): δ 8.76 (s, 1H), 6.55 (d, J=2.5Hz, 1H), 5.87 (m, 1H), 2.46
(d, J=1.2Hz, 3H), 1.71-2.24 (m, 8H)；MS (ESI) m/z (percent): [M+H]+264.0.
4) preparation of compound V:
The ratio between the amount of substance of feeding intake is intermediate compound IV: NBS: oxalic acid=1.0: 2.0: 0.5.
In 2L three-necked flask, be added compound IV (132g, 0.5mol), N- bromo-succinimide (178g,
1.0mol), oxalic acid (9.0g, 0.25mol), n,N-Dimethylformamide (527g), 65 DEG C of temperature control are reacted 10 hours, reaction knot
300mL water is added in beam, and filtering, filter cake methanol: acetonitrile=7: 3 (V/V, 200mL) are washed, then heavy with tetrahydrofuran (792g)
Crystallization, filtering, filter cake are dried in vacuo in 40 DEG C, obtain 152.3g compound V, white solid, yield 78%, fusing point 192.3
~194.0 DEG C, HPLC purity is 99.4%.
The hydrogen spectrum of compound V, mass spectral characteristi:
1H NMR (600MHz, CDCl3): δ 8.87 (s, 1H), 5.97 (m, 1H), 2.67 (s, 3H), 2.46 (d, J=
1.2Hz, 3H), 1.72-2.22 (m, 8H)；MS (ESI) m/z (percent): [M+H]+342.0.
Embodiment 2:
1) preparation of intermediate II:
The ratio between the amount of substance of feeding intake is bromo- 2, the 4- dichloro pyrimidine of 5-: cyclopentamine: triethylamine=1.0: 1.3: 1.3.
Sequentially added in 2L three-necked flask bromo- 2, the 4- dichloro pyrimidine (227.9g, 1mol) of 5-, isopropanol (360g,
6mol), -15 DEG C of addition triethylamines (131.5g, 1.3mol), be added dropwise cyclopentamine (106.2g, 1.3mol) isopropanol (120g,
2mol) solution reacts 2~3 hours, crosses filter solid, takes filter cake in 2L reaction flask, is added petroleum ether (600g), and stirring 1 is small
When, it filters again, filter cake is washed with petroleum ether (100g).Filter cake is collected, 40 DEG C of vacuum dryings obtain 262.8g intermediate II, white
Color solid, yield 95%, 442~443.5 DEG C of fusing point, HPLC purity 99.7%.
2) preparation of intermediate III:
The ratio between the amount of substance of feeding intake is intermediate II: crotonic acid: sodium carbonate: double benzonitrile palladium chloride=1.0: 3.0: 3.0:
0.001。
Through N2In the 3L three-necked flask of purging be added intermediate II (138.3g, 0.5mol), crotonic acid (64.6g,
1.5mol), sodium carbonate (159g, 1.5mol), PEG-1000 (414g), N2It is bubbled 30 minutes, double benzonitrile palladium chlorides is added
(0.19g, 0.0005mol), again N2Be bubbled 30 minutes, 80 DEG C insulation reaction 8 hours, be cooled to room temperature, into reaction solution plus
Enter water (1kg), adjusts pH to 4.5 or so with 15%HCl (about 120mL), filtering rinses filter cake, 40 DEG C of vacuum with the water of 300mL
131g intermediate III is dried to obtain, pale powder, yield 91%, 520.3~522 DEG C of fusing point, HPLC purity is 89.5%.
3) preparation of intermediate compound IV:
The ratio between the amount of substance of feeding intake is intermediate III: BTC=1.0: 0.4.
In 3L three-necked flask, compound III (112g, 0.4mol), toluene (330g) is added, 45 DEG C of temperature control, is added dropwise solid
Toluene (220g) solution of body phosgene (47.8g, 0.16mol), drips off, is warming up to back flow reaction 3 hours for about 1 hour, and decompression is steamed
Solvent is distillated, the mashing of 300mL isopropanol, filtering is added, 40 DEG C of vacuum drying obtain 91.8g intermediate compound IV, and faint yellow solid is received
Rate is 87%, and fusing point is 452.5~454.0 DEG C, and HPLC purity is 99.5%.
4) preparation of compound V:
The ratio between the amount of substance of feeding intake is intermediate compound IV: NBS: oxalic acid=1.0: 2.0: 0.5.
In 2L three-necked flask, be added compound IV (132g, 0.5mol), N- bromo-succinimide (178g,
1.0mol), oxalic acid (9.0g, 0.25mol), n,N-Dimethylformamide (527g), 80 DEG C of temperature control are reacted 4 hours, and reaction terminates,
300mL water is added, filtering, filter cake methanol: acetonitrile=7: 3 (V/V, 200mL) are washed, then are tied again with tetrahydrofuran (792g)
Crystalline substance, filtering, filter cake are dried in vacuo in 40 DEG C, obtain 142.5g compound V, white solid, yield 73%, and fusing point is 192.3~
194.0 DEG C, HPLC purity is 99.1%.
Embodiment 3
1) preparation of intermediate II:
The ratio between the amount of substance of feeding intake is bromo- 2, the 4- dichloro pyrimidine of 5-: cyclopentamine: diisopropylethylamine=1.0: 1.3: 1.3.
Sequentially added in 2L three-necked flask bromo- 2, the 4- dichloro pyrimidine (227.9g, 1mol) of 5-, isopropanol (360g,
6mol), the isopropanol of cyclopentamine (106.2g, 1.3mol) is added dropwise in -15 DEG C of addition diisopropylethylamine (167.7g, 1.3mol)
(120g, 2mol) solution reacts 2~3 hours, crosses filter solid, takes filter cake in 2L reaction flask, is added petroleum ether (600g), stirs
It mixes 1 hour, filters again, filter cake is washed with petroleum ether (100g).Filter cake is collected, 40 DEG C of vacuum dryings obtain 260.0g intermediate
II, white solid, yield 94%, 442~443.5 DEG C of fusing point, HPLC purity 99.9%.
2) preparation of intermediate III:
The ratio between the amount of substance of feeding intake is intermediate II: crotonic acid: triethylamine: palladium acetate=1.0: 3.0: 3.0: 0.001.
Through N2In the 3L three-necked flask of purging be added intermediate II (138.3g, 0.5mol), crotonic acid (64.6g,
1.5mol), triethylamine (151.5g, 1.5mol), PEG-1000 (414g), N2 are bubbled 30 minutes, addition palladium acetate (0.11g,
0.0005mol), N again2Be bubbled 30 minutes, 80 DEG C insulation reaction 8 hours, be cooled to room temperature, water be added into reaction solution
(1kg) adjusts pH to 4.5 or so with 15%HCl (about 120mL), and filtering rinses filter cake, 40 DEG C of vacuum dryings with the water of 300mL
120.9g intermediate III is obtained, pale powder, yield 84%, 520.3~522 DEG C of fusing point, HPLC purity is 87.3%.
3) preparation of intermediate compound IV:
The ratio between the amount of substance of feeding intake is intermediate III: BTC=1.0: 0.4.
In 3L three-necked flask, compound III (112g, 0.4mol), chlorobenzene (330g) is added, 45 DEG C of temperature control, is added dropwise solid
Chlorobenzene (220g) solution of body phosgene (47.8g, 0.16mol), drips off, is warming up to back flow reaction 3 hours for about 1 hour, and decompression is steamed
Solvent is distillated, the mashing of 300mL isopropanol, filtering is added, 40 DEG C of vacuum drying obtain 79.1g intermediate compound IV, and faint yellow solid is received
Rate is 75%, and fusing point is 452.5~454.0 DEG C, and HPLC purity is 99.2%.
4) preparation of compound V:
The ratio between the amount of substance of feeding intake is intermediate compound IV: NBS: oxalic acid=1.0: 2.0: 0.5.
In 2L three-necked flask, be added compound IV (132g, 0.5mol), N- bromo-succinimide (178g,
1.0mol), oxalic acid (9.0g, 0.25mol), n,N-Dimethylformamide (527g), 65 DEG C of temperature control are reacted 4 hours, and reaction terminates,
300mL water is added, filtering, filter cake methanol: acetonitrile=7: 3 (V/V, 200mL) are washed, then are recrystallized with acetonitrile (1980g), mistake
Filter, filter cake are dried in vacuo in 40 DEG C, obtain 171.9g compound V, white solid, yield 88%, fusing point is 192.3~194.0
DEG C, HPLC purity is 99.5%.
Embodiment 4
1) preparation of intermediate II:
The ratio between the amount of substance of feeding intake is bromo- 2, the 4- dichloro pyrimidine of 5-: cyclopentamine: potassium carbonate=1.0: 1.5: 1.5.
Bromo- 2, the 4- dichloro pyrimidine (227.9g, 1mol) of 5-, ethyl alcohol (684g) are sequentially added in 2L three-necked flask, -10 DEG C add
Enter potassium carbonate (207.3g, 1.5mol), cyclopentamine (127.7g, 1.5mol), react 8~10 hours, cross filter solid, take filter cake in
It in 2L reaction flask, is added petroleum ether (600g), stirs 1 hour, filter again, filter cake is washed with petroleum ether (100g).Collect filter
Cake, 40 DEG C of vacuum dryings obtain 194g intermediate II, white solid, yield 70%, and 442~443.5 DEG C of fusing point, HPLC purity
99.4%.
2) preparation of intermediate III:
The ratio between the amount of substance of feeding intake is intermediate II: crotonic acid: potassium phosphate: double benzonitrile palladium chloride=1.0: 1.5: 2:
0.001。
Through N2In the 3L three-necked flask of purging be added compound II (138.3g, 0.5mol), crotonic acid (64.6g,
0.75mol), potassium phosphate (212.3g, 1mol), PEG-2000 (414g), N2 are bubbled 30 minutes, and double benzonitrile palladium chlorides are added
(0.19g, 0.0005mol), again N2Be bubbled 30 minutes, 80 DEG C insulation reaction 8 hours, be cooled to room temperature, into reaction solution plus
Enter water (1kg), 15%HCl (300mL), adjust pH to 4.5 or so, filtering rinses filter cake with the water of 300mL, and 40 DEG C of vacuum are dried
125.4g intermediate III is done to obtain, pale powder, yield 89%, 520.3~522 DEG C of fusing point, HPLC purity is 89%.
3) preparation of intermediate compound IV:
The ratio between the amount of substance of feeding intake is intermediate III: BTC=1.0: 1.0.
In 3L three-necked flask, compound III (112g, 0.4mol), acetonitrile (330g) is added, 45 DEG C of temperature control, is added dropwise solid
Acetonitrile (220g) solution of body phosgene (119g, 0.4mol) is added dropwise 1 hour, is warming up to back flow reaction 3 hours, is evaporated under reduced pressure out
Solvent, is added the mashing of 300mL isopropanol, filtering, and 40 DEG C of vacuum drying obtain 80.2g intermediate compound IV, faint yellow solid, yield is
76%, fusing point is 452.5~454.0 DEG C, and HPLC purity is 99%.
4) preparation of compound V:
The ratio between the amount of substance of feeding intake is intermediate compound IV: NBS: oxalic acid=1.0: 1.5: 0.5.
In 2L three-necked flask, be added compound IV (132g, 0.5mol), N- bromo-succinimide (133.4g,
0.75mol), oxalic acid (22.5g, 0.25mol), DMSO (527g), 65 DEG C of temperature control are reacted 14 hours, and reaction terminates, and 300mL is added
Water, filtering, filter cake methanol: acetonitrile=5: 3 (V/V, 100mL) washing, then recrystallized with tetrahydrofuran (792g), it filters, filter
Cake is dried in vacuo in 40 DEG C, obtains 116.3g compound V, and white solid, yield 68%, fusing point is 192.3~194.0 DEG C,
HPLC purity is 99.5%.
Raw materials used in the present invention, equipment is unless otherwise noted the common raw material, equipment of this field；In the present invention
Method therefor is unless otherwise noted the conventional method of this field.
The above is only presently preferred embodiments of the present invention, is not intended to limit the invention in any way, it is all according to the present invention
Technical spirit any simple modification, change and equivalent transformation to the above embodiments, still fall within the technology of the present invention side
The protection scope of case.
Claims (9)
1. a kind of preparation method of pa pool former times benefit cloth intermediate, it is characterised in that synthetic route is as follows:
Wherein, Pd salt indicates that palladium catalyst, PEG indicate that polyethylene glycol, BTC indicate triphosgene, and NBS indicates N- bromo fourth two
Acid imide；
Specifically comprise the following steps:
(1) bromo- 2, the 4- dichloro pyrimidine of compound I:5- and alkali A are dissolved in solvent A, are cooled to -30~30 DEG C, cyclopentamine is added dropwise
With the mixed liquor of solvent A, is reacted after dripping off and obtain within 0.5~5 hour the chloro- N- cyclopenta pyrimidine -4- amine of the bromo- 2- of compound II:5-；
(2) under inert gas protection, the chloro- N- cyclopenta pyrimidine -4- amine of the bromo- 2- of 5-, crotonic acid, palladium catalyst and alkali B are added
Enter into organic solvent polyethylene glycol, carries out Heck reaction at appropriate temperatures and obtain compound III:3- [2- in 5~30 hours
Chloro- 4- (clopentylamino) -5- pyrimidine radicals] -2- butenoic acid；Wherein, the chloro- N- cyclopenta pyrimidine -4- amine of the bromo- 2- of 5-, crotonic acid,
Mass ratio=1 of palladium catalyst, alkali B and polyethylene glycol: 1~3: 0.001: 2~6: 2~10；
(3) at 20~100 DEG C, 3- [2- chloro- 4- (clopentylamino) -5- pyrimidine radicals] -2- butenoic acid and triphosgene are in solvent B
It is phonetic that middle progress obtains the chloro- 8- cyclopenta -5- methyl -8H- pyrido [2,3-d] of compound IV:2- for cyclization reaction 2~12 hours
Pyridine -7- ketone；
(4) by chloro- 8- cyclopenta -5- methyl -8H- pyrido [2, the 3-d] pyrimidin-7-ones of 2-, N- bromo-succinimide, oxalic acid
It is dissolved in solvent C, at 20~100 DEG C, it is chloro- that reaction obtains the pa pool bromo- 2- of former times benefit cloth midbody compound V:6- for 2~24 hours
8- cyclopenta -5- picoline simultaneously [2,3-d]-pyrimidine -7 (8H) -one.
2. a kind of preparation method of pa pool former times benefit cloth intermediate as described in claim 1, which is characterized in that in step (1), institute
It states alkali A and is selected from triethylamine, n,N-diisopropylethylamine, triethylenediamine, 1,8- diazabicylo [5.4.0], 11 carbon -7-
One of alkene；The solvent A in methanol, ethyl alcohol, isopropanol, n-butanol, Isosorbide-5-Nitrae-dioxane or ethyl acetate one
Kind.
3. a kind of preparation method of pa pool former times benefit cloth intermediate as claimed in claim 1 or 2, which is characterized in that step (1)
In, mass ratio=1 of compound I, alkali A and solvent A: 1~3: 2~10.
4. a kind of preparation method of pa pool former times benefit cloth intermediate as described in claim 1, which is characterized in that in step (2), institute
Stating palladium catalyst is bis-triphenylphosphipalladium palladium dichloride, tetra-triphenylphosphine palladium, two (tert-butyl phosphine) palladiums, palladium acetate, palladium chloride, double cyanogen
Benzene palladium chloride or diacetonitrile palladium chloride；The alkali B is organic base or inorganic base, and organic base is selected from sodium acetate, triethylamine, N,
N- diisopropylethylamine, triethylenediamine or 1,11 carbon -7- alkene of 8- diazabicylo [5.4.0], inorganic base are selected from hydrogen-oxygen
Change potassium, potassium phosphate, potassium carbonate, saleratus, sodium hydroxide or sodium carbonate；The polymerization scope of the polyethylene glycol be 200~
4000。
5. a kind of preparation method of pa pool former times benefit cloth intermediate as described in claim 1 or 4, which is characterized in that step (2)
In, reaction temperature is 20~100 DEG C.
6. a kind of preparation method of pa pool former times benefit cloth intermediate as described in claim 1, which is characterized in that in step (3), institute
It states solvent B and is selected from one of toluene, chlorobenzene, dimethylbenzene, dichloroethanes, acetonitrile, dioxane or N-Methyl pyrrolidone.
7. a kind of preparation method of pa pool former times benefit cloth intermediate as described in claim 1 or 6, which is characterized in that step (3)
In, mass ratio=1 of compound III, triphosgene and solvent B: 0.4~1: 2~10.
8. a kind of preparation method of pa pool former times benefit cloth intermediate as described in claim 1, which is characterized in that in step (4), institute
It states solvent C and is selected from n,N-Dimethylformamide, dimethyl sulfoxide, methylene chloride, dichloroethanes, acetonitrile, toluene, dioxane or N-
One of methyl pyrrolidone.
9. a kind of preparation method of pa pool former times benefit cloth intermediate as claimed in claim 1 or 8, which is characterized in that step (4)
In, mass ratio=1 of compound IV, N- bromo-succinimide, oxalic acid and solvent C: 1~3: 0.1~0.5:2~10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810170004.2A CN108299422B (en) | 2018-02-28 | 2018-02-28 | A kind of preparation method of pa pool former times benefit cloth intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810170004.2A CN108299422B (en) | 2018-02-28 | 2018-02-28 | A kind of preparation method of pa pool former times benefit cloth intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108299422A CN108299422A (en) | 2018-07-20 |
| CN108299422B true CN108299422B (en) | 2019-10-25 |
Family
ID=62849298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810170004.2A Active CN108299422B (en) | 2018-02-28 | 2018-02-28 | A kind of preparation method of pa pool former times benefit cloth intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108299422B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109320511A (en) * | 2018-10-26 | 2019-02-12 | 广安凯特制药有限公司 | A kind of high-purity Pa Boxini intermediate product and preparation method thereof |
| CN110256424A (en) * | 2019-07-03 | 2019-09-20 | 武汉工程大学 | A kind of synthetic method of Pa Boxini key intermediate V |
| CN111423437B (en) * | 2020-04-10 | 2021-02-26 | 天津法莫西医药科技有限公司 | Preparation method of palbociclib intermediate |
| CN111362939B (en) * | 2020-04-26 | 2021-08-03 | 山东梅奥华卫科技有限公司 | Preparation method of palbociclib parent nucleus structure compound |
| CN112457311B (en) * | 2020-12-04 | 2022-07-12 | 江苏豪森药业集团有限公司 | Preparation method of compound containing chloro-bromo-pyrrole-pyrimidone structure |
| CN112661753B (en) * | 2020-12-29 | 2022-06-03 | 山东铂源药业股份有限公司 | Preparation method of palbociclib intermediate |
| CN112898299B (en) * | 2021-01-26 | 2021-11-26 | 山东铂源药业有限公司 | Preparation method of palbociclib intermediate |
| CN113999227A (en) * | 2021-11-26 | 2022-02-01 | 常州大学 | Preparation method of palbociclib intermediate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2069344A2 (en) * | 2006-09-08 | 2009-06-17 | Pfizer Products Inc. | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
| CN105008357A (en) * | 2013-02-21 | 2015-10-28 | 辉瑞大药厂 | Solid forms of a selective CDK4/6 inhibitor |
| WO2016030439A1 (en) * | 2014-08-28 | 2016-03-03 | Ratiopharm Gmbh | Method of producing palbociclib and pharmaceutical compositions comprising the same |
-
2018
- 2018-02-28 CN CN201810170004.2A patent/CN108299422B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN108299422A (en) | 2018-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108299422B (en) | A kind of preparation method of pa pool former times benefit cloth intermediate | |
| DK2538785T3 (en) | Methods for the synthesis of diarylthiohydantoin and diarylhydantoin compounds | |
| MX2007015423A (en) | PROCESS FOR THE SYNTHESIS OF 5- (METHYL-lH-IMIDAZOL-l-YL) -3- (TRI FLUOROME TH YL) -BENZENEAMINE. | |
| CN107200741B (en) | Preparation method of anaplastic lymphoma kinase inhibitor | |
| CN108484702A (en) | A kind of synthetic method of emamection benaoate | |
| CN108129482A (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
| CN110741005A (en) | Process for preparing 1, 3-benzodioxole heterocycles | |
| CN102875537A (en) | Novel preparation method of antithrombosis medicine | |
| EP3702358A1 (en) | Process for preparing salts of a known pde1 inhibitor | |
| CN107531672A (en) | Prepare the chemical technology of pyrimidine derivatives and its intermediate | |
| WO2021223751A1 (en) | Synthesis method for anti-tumor compound and intermediate thereof | |
| CN107089982B (en) | 4,5- bis- substitute -1- hydrogen-pyrroles (2,3-f) quinoline -2,7,9- tricarboxylic esters compound and application | |
| CN114085225A (en) | Vardenafil analogue and synthetic method and application thereof | |
| CN115611803B (en) | Synthesis method of 2, 3-dichloropyridine | |
| CN109956871B (en) | Preparation method of 3,4, 5-trifluoro-2' -nitrobiphenyl | |
| CN106674281B (en) | A kind of Rosuvastatin midbody compound, preparation method and its usage | |
| CN113583003A (en) | Vardenafil analogue and synthetic method and application thereof | |
| CN109761914B (en) | Method for preparing 5-trifluoromethyl uracil | |
| CN114276324A (en) | Preparation method and application of icotinib intermediate | |
| CN102382053B (en) | A kind of method preparing tolvaptan intermediate | |
| EA036021B1 (en) | Process for the synthesis of 9,9-bis(methoxymethyl)fluorene | |
| KR20220018486A (en) | 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro- Alternative method for preparing 1H-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid | |
| CN108586282A (en) | The synthetic method of 1,3- diazido -2- propyl alcohol | |
| CN103265559A (en) | Substituted tricyclo-quinone compounds, and preparation method and application thereof | |
| CN111423437B (en) | Preparation method of palbociclib intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |