CN106608876B - A kind of preparation method of high-purity Pa Boxini - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The present invention relates to a kind of preparation methods of high-purity Pa Boxini.This method is that reflux dewatering prepares 2 acetyl group, 3 methyl, 2 glutaconate diethyl (first) ester (III) under acid catalyst effect using acetoacetic ester, 2 acetyl group, 3 methyl, 4 methoxy methylene base 2 glutaconate diethyl (first) ester (IV) is condensed to yield with trimethyl orthoformate separating methanol again, 2 acetyl group 3 [[5 (4 t-butoxycarbonylpiperazin, 1 base) pyridine, 2 base] amino] 4 ketone dihydro-pyrimidin bases of 3H 2 butylene second (first) esters (VI) are obtained by the reaction through pyrimidine cyclisation with N (5 (4 tert-butoxycarbonyl, 1 hexahydro piperazinyl) 2 pyridyl groups) guanidines (V) again, final compound VI and cyclopentamine cyclisation, de- Boc protecting groups obtain Pa Boxini.The raw materials used in the present invention is cheap and easy to get, and technological process is short, easy to operate, environmentally protective, and simultaneous reactions are selectively good, and product yield and purity are high.
Description
Technical field
The present invention relates to a kind of preparation methods of high-purity Pa Boxini, belong to medicine bioengineering chemical field.
Background technology
Pa Boxini, trade name Ibrance, the entitled palbociclib of English, Chinese name is also known as Pa Bosaibu or pa is won
XiLin.Pa Boxini is a kind of breakthrough breast cancer medicines of Pfizer's exploitation, and U.S. FDA batch was obtained on 2 3rd, 2015
Standard for selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6), restores cell cycle control, blocks tumour
Cell Proliferation is controlled as joint Aromatase Inhibitor Letrozole for a line of ER+/HER2-post menopausal metastatic breast cancer
It treats.Pa Boxini is the CDK4/6 inhibitor of the first listing in the whole world.The medicine and standard care drug song azoles (letrozole) phase
Than having obvious curative effects advantage.No. CAS of Pa Boxini is [571190-30-2], and chemical name is:6- acetyl group -8- rings penta
Base -5- methyl -2- [[5- (piperazine -1- bases) pyridine -2- bases] amino] -8H- pyridos [2,3-D] pyrimidin-7-ones, structural formula is such as
Under：
WO2003062236, WO2010039997 and WO2012068381 prepare Pa Boxini, synthesis using synthetic route 1
Route 1 is as follows：
More than synthetic route 1 uses -4 chloro- 5- carbethoxyl groups pyrimidine of 2- methyl mercaptos as starting material, anti-by ammonification
It answers, reduction reaction, methylol are oxidized to aldehyde, grignard reaction, 5 step of oxidation reaction and 5- acetyl 4- cyclopentamine base -2- first are obtained by the reaction
Sulfenyl pyrimidine, reaction step is long, and has used expensive lithium aluminium hydride reduction as reducing agent.It is real although document report yield is higher
Border is difficult to realize.By the use of sulfoxide as leaving group, the nucleophilic substitution of pyrimidine is carried out with aminopyrazole derivatives (J), is received
The very low 28-35% of rate so that synthesis cost greatly improves.It being coupled using Stille and introduces acetyl group, yield has reached 80%,
But need the examination for using expensive Pd not cheap as catalyst and ethoxy vinyltributyltin, triphenylphosphine etc.
Agent.Total recovery 9.49% (relative to -4 chloro- 5- carboxylic acid, ethyl esters pyrimidine of 2- methyl mercaptos), yield is relatively low and step is tediously long, technique is numerous
It is trivial, it is difficult to industrialize.
WO2008032157 and WO2014128588 improves the synthetic method of Pa Boxini, employs following institute
Using 2,4-, bis- chloro- 5- Bromopyrimidines as starting material, cyclopentamine base is introduced by cyclopentamine amination for the synthetic route 2 shown, and two
It is secondary to introduce double bond and acetyl group respectively with Heck reactions so that synthesis step is very succinct.The precursor of acetyl group is vinyl
Butyl ether can be sloughed easily in acid condition simultaneously with amino protecting group Boc, and the by-product generated easily divides
From deprotection with can complete in one pot into salt.The nucleophilic substitution of aminopyridine and pyrimidine uses highly basic lithium amide or different
Propyl magnesium chloride, yield are increased to 92-93%.It is (chloro- with 2,4- bis- that WO2014128588 report total recoverys are increased to 43.55%
5- Bromopyrimidines meter).
More than synthetic route 2 is disadvantageous in that reacts twice with Heck, needs to use noble metal palladium bichloride or acetic acid
Palladium and more expensive ligand, improve synthesis cost, are not easy industrial operation.
In order to the generation for shortening technological process, improving product purity and yield and reducing waste water and waste liquid, this is proposed thus
Invention.
Invention content
In view of the deficiencies of the prior art, the present invention provide it is a kind of in high yield, the preparation method of high-purity Pa Boxini, be one
Kind of simple flow, product purity be good in high yield, safe green Pa Boxini industrial productions new method.
Technical solution of the present invention is as follows：
A kind of preparation method of Pa Boxini (I) is as follows including step：
(1) acetoacetic ester is dehydrated under acid catalyst effect in toluene and obtains compound III：2- acetyl group -3- first
Base -2- glutaconate diester；
Reaction solution directly carries out next step without isolation；
(2) trimethyl orthoformate is added in into the above-mentioned reaction solution containing compound III, compound is condensed to yield through separating methanol
Ⅳ：2- acetyl group -3- methyl -4- methoxy methylene base -2- glutaconate diester；
Reaction solution directly carries out next step without isolation；
(3) into the above-mentioned reaction solution containing compounds Ⅳ add in N- (5- (4- tert-butoxycarbonyl -1- hexahydros piperazinyl) -
2- pyridyl groups) guanidine (V), through pyrimidine cyclization, obtain compound VI：2- acetyl group -3- [[5- (4- tert-butoxycarbonyl piperazines
Piperazine -1- bases) pyridine -2- bases] amino] -3H--4- ketone-dihydro-pyrimidin base -2- butene esters；
Reaction solution directly carries out next step without isolation；
(4) cyclopentamine is added in into the above-mentioned reaction solution containing compound VI and carries out cyclization, is obtained after de- Boc protecting groups
Pa Boxini (I),
According to the method for the present invention, preferred processing condition and substance amount ratio are as follows in each step：
Preferably, acetoacetic ester described in step (1) be ethyl acetoacetate or methyl acetoacetate, the acid catalysis
Agent is the concentrated sulfuric acid of p-methyl benzenesulfonic acid, pyrovinic acid or mass fraction 98%；The solvent toluene and acetoacetic ester quality
Than for (5-15):1；The catalyst amount is the 0.5-2% of acetoacetic ester quality；The acetoacetic ester dehydration temperature
It is 100~120 DEG C to spend, and the reaction time is 2-10 hours.Further preferably, it is anti-that dehydration is stirred at reflux at a temperature of 110 to 115 DEG C
It answers 4-6 hours.
It is further preferred that solvent toluene described in step (1) and acetoacetic ester mass ratio are (6-10)：1；It is described to urge
Agent dosage is the 0.6-1.0% of acetoacetic ester quality.
Preferably, in step (2)：The molar ratio of the trimethyl orthoformate and acetoacetic ester (0.5-0.7):1；It is described
Separating methanol setting-up point is 10~50 DEG C, and the reaction time is 2-10 hours；Further preferably, first by the reaction of step (1)
Liquid is cooled to 20-25 DEG C, adds trimethyl orthoformate, is stirred to react at 30 to 35 DEG C 4-5 hours.
Preferably, N- described in step (3) (5- (4- tert-butoxycarbonyl -1- hexahydropyrazines base) 2- pyridyl groups) guanidine (V)
Molar ratio with acetoacetic ester is (0.5-0.6):1；The pyrimidine cyclisation reaction temperature is 50~80 DEG C, reaction time 3-
8 hours；Further preferably, it is stirred to react 2-3 hours for 60 to 65 DEG C.
Further preferably, N- described in step (3) (5- (4- tert-butoxycarbonyl -1- hexahydros piperazinyl) -2- pyridyl groups)
Guanidine (V) can be by N- (5- (4- tert-butoxycarbonyl -1- hexahydros piperazinyl) -2- pyridyl groups) guanidine Hemisulphates and equimolar
Obtained N- (5- (4- tert-butoxycarbonyl -1- hexahydros the piperazinyl) -2- pyridyl groups) guanidine of methanol solution of sodium methylate neutralization reaction
Methanol solution is directly used in the pyrimidine cyclization with acetoacetic ester.
Preferably, the molar ratio of cyclopentamine and acetoacetic ester (0.5-0.6) described in step (4):1；Cyclization temperature
It is 50~100 DEG C to spend, reaction time 2-10 hour.Further preferably, cyclization temperature is 70 to 75 DEG C, is reacted 3 hours.
Preferably, it is that water is added in into gained cyclization products therefrom BOC protecting groups to be taken off described in step (4), 10~
30 DEG C, reaction time 2-5 hour.
After the completion of step (4) reaction, continue to post-process：20 DEG C are cooled to, is filtered, filter cake recrystallisation from isopropanol,
Obtain white high purity solid Pa Boxini (I).
The method of the present invention uses following reaction route 3：
The technical characterstic and excellent beneficial effect of the present invention：
The present invention is made using acetoacetic ester (ethyl acetoacetate or methyl acetoacetate) in toluene in acid catalyst
Under, refluxing toluene dehydration prepare 2- acetyl group -3- methyl -2- glutaconates diethyl (first) ester (III), compound III again with original
Trimethyl orthoformate separating methanol is condensed to yield 2- acetyl group -3- methyl -4- methoxy methylene base -2- glutaconates diethyl (first) ester
(IV), compounds Ⅳ is cyclized again with N- (5- (4- tert-butoxycarbonyl -1- hexahydros piperazinyl) -2- pyridyl groups) guanidine (V) through pyrimidine
2- acetyl group -3- [[5- (4- t-butoxycarbonylpiperazin -1- bases) pyridine -2- bases] amino] -3H--4- ketone-dihydro is obtained by the reaction
Pyrimidine radicals -2- butylene second (first) ester (VI), final compound VI and cyclopentamine cyclisation, de- Boc protecting groups obtain Pa Boxini
(Ⅰ).The present invention prepares Pa Boxini (I) by acetoacetic ester through " one kettle way ", and waste water and waste liquid amount is few, meets environmentally protective want
It asks, is conducive to industrialized production, be conducive to the cost reduction of Pa Boxini.
The raw materials used in the present invention is cheap and easy to get, and technological process is short, easy to operate, and simultaneous reactions are selectively good, product yield
With purity height.Product yield is up to more than 90%, liquid phase purity 99.9%.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
Embodiment is raw materials used and reagent is commercial product." % " described in embodiment is mass percent, especially
Except illustrating.Wherein, N- (5- (4- tert-butoxycarbonyl -1- hexahydros the piperazinyl) -2- pyridyl groups) guanidine (V) is by N-
(5- (4- tert-butoxycarbonyl -1- hexahydros piperazinyl) -2- pyridyl groups) guanidine Hemisulphate and equimolar methanol solution of sodium methylate
It neutralizes, obtains N- (5- (4- tert-butoxycarbonyl -1- hexahydros piperazinyl) -2- pyridyl groups) guanidine methanol solution, be directly used in reaction.
Embodiment 1：The preparation of Pa Boxini (I)
To being connected in 500 milliliters of four-hole boiling flasks of stirring, thermometer, water knockout drum, reflux condensing tube and dropping funel, add in
200 grams of toluene, 0.2 gram of toluenesulfonic acid, 26.0 grams of (0.2 mole) ethyl acetoacetates, 110 to 115 DEG C are stirred at reflux dehydration
Reaction 5 hours.20 DEG C are cooled to, adds in 11.1 grams of (0.11 mole) trimethyl orthoformates, 30 to 35 DEG C are stirred to react 4 hours.
20.0 gram of 28% methanol solution of sodium methylate is added in, 34.3 grams of (0.105 mole) N- (5- (uncles 4- are added portionwise between 30 to 40 DEG C
Butoxy carbonyl -1- hexahydropyrazines base) 2- pyridyl groups) guanidine Hemisulphate, it finishes, 60 to 65 DEG C are stirred to react 3 hours, and 60 to 65
9.4 grams of (0.11 mole) cyclopentamines are added at DEG C, are reacted 3 hours at 70 to 75 DEG C.It is cooled to 20 DEG C, adds in 50 grams of water, 20 DEG C
Stirring 3 hours, filtering, 250 grams of recrystallisation from isopropanol of filter cake obtain 40.3 grams of white solid Pa Boxini (I), yield
90.1%, liquid phase purity 99.9%.
Product analysis data are as follows：
LC-MS(ESI)m/Z:448(M+1)。
1H NMR (frequency 400MHz, the deuterated heavy water of solvent)：1.7 (multiplet, 2H), 2.0-2.1 (multiplet, 6H), 2.4
(unimodal, 3H), 2.5 (unimodal, 3H), 2.7 (broad peak, 2H), 3.5-3.6 (multiplet, 8H), 5.7-5.8 (multiplet, 1H), 7.5
(doublet, 1H), 7.8 (doublet, 1H), 8.1 (multiplet, 1H), 9.1 (unimodal, 1H).
Embodiment 2：The preparation of Pa Boxini (I)
To being connected in 500 milliliters of four-hole boiling flasks of stirring, thermometer, water knockout drum, reflux condensing tube and dropping funel, add in
200 grams of toluene, 0.18 gram of pyrovinic acid, 26.0 grams of (0.2 mole) ethyl acetoacetates, 110 to 115 DEG C are stirred at reflux dehydration instead
It answers 5 hours.20 DEG C are cooled to, adds in 11.1 grams of (0.11 mole) trimethyl orthoformates, 30 to 35 DEG C are stirred to react 4 hours.Add
Enter 20.0 gram of 28% methanol solution of sodium methylate, 34.3 grams of (0.105 mole) N- (5- (tertiary fourths of 4- are added portionwise between 30 to 40 DEG C
Epoxide carbonyl -1- hexahydropyrazines base) 2- pyridyl groups) guanidine Hemisulphate, it finishes, 60 to 65 DEG C are stirred to react 3 hours, 60 to 65 DEG C
It is lower to add in 9.4 grams of (0.11 mole) cyclopentamines, it is reacted 3 hours at 70 to 75 DEG C.20 DEG C are cooled to, adds in 50 grams of water, 20 DEG C are stirred
It mixes 3 hours, filters, 250 grams of recrystallisation from isopropanol of filter cake obtain 39.5 grams of white solid Pa Boxini (I), yield
88.3%, liquid phase purity 99.9%.
Embodiment 3：The preparation of Pa Boxini (I)
To being connected in 500 milliliters of four-hole boiling flasks of stirring, thermometer, water knockout drum, reflux condensing tube and dropping funel, add in
200 grams of toluene, 0.2 gram of 98% concentrated sulfuric acid, 26.0 grams of (0.2 mole) ethyl acetoacetates, 110 to 115 DEG C are stirred at reflux dehydration
Reaction 5 hours.20 DEG C are cooled to, adds in 11.1 grams of (0.11 mole) trimethyl orthoformates, 30 to 35 DEG C are stirred to react 4 hours.
20.0 gram of 28% methanol solution of sodium methylate is added in, 34.3 grams of (0.105 mole) N- (5- (uncles 4- are added portionwise between 30 to 40 DEG C
Butoxy carbonyl -1- hexahydropyrazines base) 2- pyridyl groups) guanidine Hemisulphate, it finishes, 60 to 65 DEG C are stirred to react 3 hours, and 60 to 65
9.4 grams of (0.11 mole) cyclopentamines are added at DEG C, are reacted 3 hours at 70 to 75 DEG C.It is cooled to 20 DEG C, adds in 50 grams of water, 20 DEG C
Stirring 3 hours, filtering, 250 grams of recrystallisation from isopropanol of filter cake obtain 38.1 grams of white solid Pa Boxini (I), yield
85.2%, liquid phase purity 99.9%.
Embodiment 4：The preparation of Pa Boxini (I)
26.0 grams of (0.2 mole) acetoacetate second of embodiment 1 are replaced with 23.2 grams of (0.2 mole) methyl acetoacetates
Ester, remaining obtains 40.0 grams of white solid Pa Boxini (I), yield 89.3%, liquid phase purity 99.9% with embodiment 1.
Embodiment 5：The preparation of Pa Boxini (I)
26.0 grams of (0.2 mole) acetoacetate second of embodiment 2 are replaced with 23.2 grams of (0.2 mole) methyl acetoacetates
Ester, remaining obtains 39.3 grams of white solid Pa Boxini (I), yield 87.9%, liquid phase purity 99.9% with embodiment 2.
Embodiment 6：The preparation of Pa Boxini (I)
26.0 grams of (0.2 mole) acetoacetate second of embodiment 3 are replaced with 23.2 grams of (0.2 mole) methyl acetoacetates
Ester, remaining obtains 40.1 grams of white solid Pa Boxini (I), yield 89.6%, liquid phase purity 99.9% with embodiment 3.
Claims (14)
1. a kind of preparation method of Pa Boxini (I), as follows including step：
(1) acetoacetic ester is dehydrated under acid catalyst effect in toluene and obtains compound III：2- acetyl group -3- methyl -2-
Glutaconate diester；The acetoacetic ester is ethyl acetoacetate or methyl acetoacetate；
Reaction solution directly carries out next step without isolation；
(2) trimethyl orthoformate is added in into the above-mentioned reaction solution containing compound III, compound IV is condensed to yield through separating methanol：2-
Acetyl group -3- methyl -4- methoxy methylene base -2- glutaconate diester；
Reaction solution directly carries out next step without isolation；
(3) N- (5- (4- tert-butoxycarbonyl -1- hexahydros piperazinyl) -2- pyrroles are added in into the reaction solution of the above-mentioned IV containing compound
Piperidinyl) guanidine (V), through pyrimidine cyclization, obtain compound VI：2- acetyl group -3- [[5- (4- t-butoxycarbonylpiperazins -1-
Base) pyridine -2- bases] amino] -3H--4- ketone-dihydro-pyrimidin base -2- butene esters；
Reaction solution directly carries out next step without isolation；
(4) cyclopentamine is added in into the above-mentioned reaction solution containing compound VI and carries out cyclization, Pa Bo is obtained after de- Boc protecting groups
Western Buddhist nun (I),
2. the preparation method of Pa Boxini as described in claim 1, it is characterised in that acid catalyst described in step (1) is pair
The concentrated sulfuric acid of toluenesulfonic acid, pyrovinic acid or mass fraction 98%.
3. the preparation method of Pa Boxini as described in claim 1, it is characterised in that solvent toluene and acetyl described in step (1)
Acetic acid esters mass ratio is (5-15):1；The catalyst amount is the 0.5-2% of acetoacetic ester quality.
4. the preparation method of Pa Boxini as described in claim 1, it is characterised in that acetylacetic ester described in step (1) is dehydrated
Reaction temperature is 100~120 DEG C, and the reaction time is 2-10 hours.
5. the preparation method of Pa Boxini as described in claim 1, it is characterised in that the reaction in step (1) is 110~115
Dehydration is stirred at reflux at a temperature of DEG C 4-6 hours.
6. the preparation method of Pa Boxini as described in claim 1, it is characterised in that trimethyl orthoformate described in step (2) and
The molar ratio of acetoacetic ester is (0.5-0.7):1；The separating methanol setting-up point is 10~50 DEG C, reaction time 2-
10 hours.
7. the preparation method of Pa Boxini as described in claim 1, it is characterised in that in step (2), first by the reaction of step (1)
Liquid is cooled to 20-25 DEG C, adds trimethyl orthoformate, is then stirred to react at 30 to 35 DEG C 4-5 hours.
8. the preparation method of Pa Boxini as described in claim 1, it is characterised in that (5- (the tertiary fourth oxygen of 4- of N- described in step (3)
Base carbonyl -1- hexahydropyrazines base) 2- pyridyl groups) molar ratio of guanidine (V) and acetoacetic ester is (0.5-0.6):1.
9. the preparation method of Pa Boxini as described in claim 1, it is characterised in that pyrimidine cyclization temperature described in step (3)
It is 50~80 DEG C to spend, and the reaction time is 3-8 hours.
10. the preparation method of Pa Boxini as described in claim 1, it is characterised in that pyrimidine cyclization described in step (3)
Temperature is 60~65 DEG C, is stirred to react 2-3 hours.
11. the preparation method of Pa Boxini as described in claim 1, it is characterised in that cyclopentamine and acetyl described in step (4)
The molar ratio (0.5-0.6) of acetic acid esters:1；Cyclization temperature is 50~100 DEG C, reaction time 2-10 hour.
12. the preparation method of Pa Boxini as described in claim 1, it is characterised in that cyclization temperature described in step (4)
It is 70 to 75 DEG C, reacts 3 hours.
13. the preparation method of Pa Boxini as described in claim 1, it is characterised in that (5- (the tertiary fourths of 4- of N- described in step (3)
Epoxide carbonyl -1- hexahydros piperazinyl) -2- pyridyl groups) guanidine (V) is by N- (5- (4- tert-butoxycarbonyl -1- hexahydro piperazines
Base) -2- pyridyl groups) obtained N- (5- (the 4- tert-butoxies of guanidine Hemisulphate and equimolar methanol solution of sodium methylate neutralization reaction
Carbonyl -1- hexahydros piperazinyl) -2- pyridyl groups) guanidine methanol solution, it is directly used in the pyrimidine cyclization with acetoacetic ester.
14. the preparation method of Pa Boxini as described in claim 1, it is characterised in that Boc protecting groups are taken off described in step (4) is
Add in water into gained cyclization products therefrom, 10~30 DEG C, reaction time 2-5 hour.
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| CN107759596A (en) * | 2017-12-05 | 2018-03-06 | 安庆奇创药业有限公司 | A kind of synthesis Pa Boxini method |
| CN109897034A (en) * | 2017-12-07 | 2019-06-18 | 南京卡文迪许生物工程技术有限公司 | A kind of high-purity crystal form A Pabuk former times benefit cloth and preparation method thereof and pharmaceutical composition |
| CN110016023B (en) * | 2018-01-08 | 2020-05-08 | 新发药业有限公司 | Simple preparation method of palbociclib |
| CN108929321A (en) * | 2018-07-03 | 2018-12-04 | 威海贯标信息科技有限公司 | A kind of Pa Boxini novel crystal forms |
| WO2022091001A1 (en) | 2020-10-29 | 2022-05-05 | Pfizer Ireland Pharmaceuticals | Process for preparation of palbociclib |
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Denomination of invention: A Preparation Method of High Purity Pabosinib Effective date of registration: 20221213 Granted publication date: 20180619 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |