CN106608876A - Preparation method of high-purity palbociclib - Google Patents
Preparation method of high-purity palbociclib Download PDFInfo
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- CN106608876A CN106608876A CN201510689997.0A CN201510689997A CN106608876A CN 106608876 A CN106608876 A CN 106608876A CN 201510689997 A CN201510689997 A CN 201510689997A CN 106608876 A CN106608876 A CN 106608876A
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- 0 CC(C)(C)OC(N(CC1)CCN1C(C=*1)=CCC1N*=N)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1C(C=*1)=CCC1N*=N)=O 0.000 description 2
- VDJDNFTVFTXRKN-UHFFFAOYSA-O CC(C)=CCC(C=[NH2+])N1CCNCC1 Chemical compound CC(C)=CCC(C=[NH2+])N1CCNCC1 VDJDNFTVFTXRKN-UHFFFAOYSA-O 0.000 description 1
- HBWGDGHGYGHWKD-UHFFFAOYSA-N CN(CC1)CCN1c1cccnc1 Chemical compound CN(CC1)CCN1c1cccnc1 HBWGDGHGYGHWKD-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparation method of high-purity palbociclib. The method comprises using acetoacetate for reflux dehydration in the function of an acid catalyst to prepare 2-acetyl-3-methyl-2-diethyl (methyl) glutaconate (III), condensing the compound (III) and trimethyl orthoformate for methanol removal to obtain 2-acetyl-3-methyl-4-methoxymethylene-2-diethyl (methyl) glutaconate (IV), cyclizing the compound (IV) and N-(5-(4-tertbutoxycarbonyl-1-hexahydropiperazinyl)-2-pyridyl) guanidine (V) with pyrimidine to obtain 2-acetyl-3-[[5-(4-tertbutoxycarbonylpiperazinyl-1-yl) pyridine-2-yl] amino]-3H-4-one-dihydropiperazinyl-2-ethyl (methyl) butenyl ester (VI), and finally cyclizing the compound (VI) and cyclopentylamine to remove Boc protecting groups, thereby obtaining palbociclib. The preparation method is cheap and available in raw materials, short in technical process, simple and convenient to operate, good in reaction selectivity, and high in product yield and purity and is green and eco-friendly.
Description
Technical field
The present invention relates to a kind of preparation method of high-purity Pa Boxini, belongs to medicine bioengineering chemical field.
Background technology
Pa Boxini, trade name Ibrance, English entitled palbociclib, Chinese name is also known as Pa Bosaibu or the rich XiLin of handkerchief.
Pa Boxini 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), recover cell cycle control, block tumor cell
Propagation, as joint Aromatase Inhibitor Letrozole the first-line treatment of ER+/HER2-post menopausal metastatic breast cancer is used for.Handkerchief
Bo Xini is the CDK4/6 inhibitor of global first listing.The medicine is compared with standard care medicine song azoles (letrozole), is had
Obvious curative effects advantage.No. CAS of Pa Boxini is [571190-30-2], and chemical name is:6- acetyl group -8- cyclopenta -5- methyl
- 2- [[5- (piperazine -1- bases) pyridine -2- bases] amino] -8H- pyridos [2,3-D] pyrimidin-7-ones, structural formula is as follows：
WO2003062236, WO2010039997 and WO2012068381 prepare Pa Boxini, synthesis using synthetic route 1
Route 1 is as follows：
Above synthetic route 1 uses the chloro- 5- carbethoxyl groups pyrimidine of 2- methyl mercaptos -4 as initiation material, through aminating reaction,
Reduction reaction, methylol be oxidized to aldehyde, grignard reaction, the step of oxidation reaction 5 reaction obtain 5- acetyl 4- Aminocyclopentane base -2- first
Sulfenyl pyrimidine, reactions steps are long, and used the lithium aluminium hydride reduction of costliness as reducing agent.Although document report yield is higher,
Actually it is difficult to.By the use of sulfoxide as leaving group, and the nucleophilic substitution that aminopyrazole derivatives (J) carry out pyrimidine,
The very low 28-35% of yield so that synthesis cost is greatly improved.It is coupled using Stille and introduces acetyl group, yield reaches
80%, however it is necessary that using expensive Pd as catalyst, and ethoxy vinyltributyltin, triphenylphosphine etc. and inconvenience
Suitable reagent.Total recovery 9.49% (relative to the chloro- 5- carboxylic acid, ethyl esters pyrimidine of 2- methyl mercaptos -4), yield is relatively low and step is superfluous
Long, technique is loaded down with trivial details, it is difficult to industrialization.
WO2008032157 and WO2014128588 is improved the synthetic method of Pa Boxini, is employed as follows
Synthetic route 2, use the chloro- 5- Bromopyrimidines of 2,4- bis- as initiation material, Aminocyclopentane base is introduced by Aminocyclopentane amination, two
Secondary utilization Heck reactions introduce respectively double bond and acetyl group so that synthesis step is very succinct.The precursor of acetyl group is vinyl
Butyl ether, can easily slough in acid condition simultaneously with amino protecting group Boc, and the by-product for generating easily divides
From, deprotection with can complete in one pot into salt.Aminopyridine uses highly basic Lithamide. or different with the nucleophilic substitution of pyrimidine
Propyl group magnesium chloride, yield brings up to 92-93%.WO2014128588 report total recoverys bring up to 43.55% (with 2,4- dichloros
- 5- Bromopyrimidine meters).
Above synthetic route 2 is disadvantageous in that and react with Heck twice, need to use noble metal Palladous chloride. or palladium,
And more expensive part, synthesis cost is improve, it is difficult industrial operation.
In order to be able to the generation for shortening technological process, improve product purity and yield and reduce waste water and waste liquid, the present invention is proposed for this.
The content of the invention
For the deficiencies in the prior art, present invention offer is a kind of in high yield, the preparation method of high-purity Pa Boxini, is a kind of
The Pa Boxini commercial production new methods of simple flow, product purity good, safe green in high yield.
Technical solution of the present invention is as follows：
A kind of preparation method of Pa Boxini (I), including step is as follows：
(1) in toluene, the dehydration under acid catalyst effect obtains compound III to acetoacetic ester：2- acetyl group -3- methyl
- 2- glutaconate diester；
Reactant liquor directly carries out without isolation next step；
(2) trimethyl orthoformate, Jing separating methanols is added to be condensed to yield compounds Ⅳ in the above-mentioned reactant liquor containing compound III：
2- acetyl group -3- methyl -4- methoxy methylene base -2- glutaconate diester；
Reactant liquor directly carries out without isolation next step；
(3) N- (5- (4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- are added in the above-mentioned reactant liquor containing compounds Ⅳ
Pyridine radicals) guanidine (V), Jing pyrimidine cyclizations obtain compound VI：2- acetyl group -3- [[5- (4- tert-butoxycarbonyls
Piperazine -1- bases) pyridine -2- bases] amino] -3H--4- ketone-dihydro-pyrimidin base -2-butylene ester；
Reactant liquor directly carries out without isolation next step；
(4) add Aminocyclopentane to carry out cyclization in the above-mentioned reactant liquor containing compound VI, after de- Boc protection groups handkerchief is obtained
Bo Xini (I),
The method according to the invention, preferred processing condition and material amount ratio are as follows in each step：
Preferably, acetoacetic ester described in step (1) is ethyl acetoacetate or methyl acetoacetate, the acid catalyst
For the concentrated sulphuric acid of p-methyl benzenesulfonic acid, pyrovinic acid or mass fraction 98%；The solvent toluene and acetoacetic ester mass ratio
For (5-15):1；The catalyst amount is the 0.5-2% of acetoacetic ester quality；The acetoacetic ester dehydration temperature
Spend for 100～120 DEG C, the response time is 2-10 hours.Further preferably, it is stirred at reflux at a temperature of 110 to 115 DEG C de-
Water reacts 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 consumption is the 0.6-1.0% of acetoacetic ester quality.
Preferably, in step (2)：The mol ratio (0.5-0.7) of the trimethyl orthoformate and acetoacetic ester:1；It is described de-
Carbinol condensation reaction temperature is 10～50 DEG C, and the response time is 2-10 hours；Further preferably, first by the anti-of step (1)
Answer liquid to be cooled to 20-25 DEG C, add trimethyl orthoformate, in 30 to 35 DEG C of stirring reaction 4-5 hours.
Preferably, N- described in step (3) (5- (4- tert-butoxycarbonyl -1- hexahydropyrazine bases) 2- pyridine radicals) guanidine (V)
It is (0.5-0.6) with the mol ratio of acetoacetic ester:1；The pyrimidine cyclisation reaction temperature is 50～80 DEG C, and the response time is 3-8
Hour；Further preferably, 60 to 65 DEG C of stirring reaction 2-3 hours.
Further preferably, N- described in step (3) (5- (4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- pyridine radicals)
Guanidine (V), can be by N- (5- (4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- pyridine radicals) guanidine Hemisulphates and
N- (5- (4- tert-butoxycarbonyl -1- hexahydro the piperazinyls) -2- pyrroles that equimolar methanol solution of sodium methylate neutralization reaction is obtained
Piperidinyl) guanidine methanol solution, it is directly used in the pyrimidine cyclization with acetoacetic ester.
Preferably, the mol ratio (0.5-0.6) of Aminocyclopentane and acetoacetic ester described in step (4):1；Cyclization temperature is
50～100 DEG C, response time 2-10 hour.Further preferably, cyclization temperature is 70 to 75 DEG C, is reacted 3 hours.
Preferably, it is to add water in gained cyclization products therefrom BOC protection groups to be taken off described in step (4),
10～30 DEG C, response time 2-5 hour.
After the completion of step (4) reaction, proceed post processing：20 DEG C are cooled to, are filtered, filter cake recrystallisation from isopropanol,
Obtain white high purity solid Pa Boxini (I).
The method of the present invention adopts following reaction scheme 3：
The technical characterstic and excellent beneficial effect of the present invention：
The present invention utilizes acetoacetic ester (ethyl acetoacetate or methyl acetoacetate) in toluene under acid catalyst effect,
Refluxing toluene dehydration prepare 2- acetyl group -3- methyl -2- glutaconate diethyl (first) esters (III), compound III again with primitive nail
Sour trimethyl separating methanol is condensed to yield 2- acetyl group -3- methyl -4- methoxy methylenes base -2- glutaconate diethyl (first) esters (IV),
Compounds Ⅳ is cyclized again with N- (5- (4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- pyridine radicals) guanidine (V) Jing pyrimidines
Reaction obtains 2- acetyl group -3- [[5- (4- t-butoxycarbonylpiperazin -1- bases) pyridine -2- bases] amino] -3H--4- ketone-dihydro
Pyrimidine radicals -2-butylene second (first) ester (VI), final compound VI and Aminocyclopentane cyclisation, de- Boc protection groups obtain Pa Boxi
Buddhist nun (I).The present invention prepares Pa Boxini (I) by acetoacetic ester Jing " one kettle way ", and waste water and waste liquid amount is few, meets
Environment protection requirement, is conducive to industrialized production, is conducive to the cost of Pa Boxini and reduces.
The present invention it is raw materials used cheap and easy to get, technological process is short, easy to operate, and simultaneous reactions selectivity is good, product yield and
Purity is high.Product yield 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 commercially available prod." % " is mass percent described in embodiment, special instruction
Except.Wherein, N- (5- (4- tert-butoxycarbonyl -1- hexahydro the piperazinyls) -2- pyridine radicals) guanidine (V) be by
N- (5- (4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- pyridine radicals) guanidine Hemisulphates and equimolar methanolic sodium methoxide
Solution is neutralized, and obtains N- (5- (4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- pyridine radicals) guanidine methanol solution, directly
For reacting.
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 funnel, add
200 grams of toluene, 0.2 gram of toluene sulfonic acide, 26.0 grams of (0.2 mole) ethyl acetoacetates, 110 to 115 DEG C are stirred back
Stream dehydration 5 hours.20 DEG C are cooled to, 11.1 grams of (0.11 mole) trimethyl orthoformates are added, 30 to 35 DEG C are stirred
Mix reaction 4 hours.20.0 gram of 28% methanol solution of sodium methylate is added, 34.3 gram (0.105 is dividedly in some parts between 30 to 40 DEG C
Mole) N- (5- (4- tert-butoxycarbonyl -1- hexahydropyrazine bases) 2- pyridine radicals) guanidine Hemisulphate, finish, 60 to 65 DEG C
Stirring reaction 3 hours, adds 9.4 grams of (0.11 mole) Aminocyclopentanes at 60 to 65 DEG C, react 3 hours at 70 to 75 DEG C.
20 DEG C are cooled to, 50 grams of water are added, 20 DEG C are stirred 3 hours, are filtered, and filter cake is obtained with 250 grams of recrystallisation from isopropanol
40.3 grams of white solid Pa Boxini (I), yield 90.1%, liquid phase purity 99.9%.
Product analyses 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 funnel, add
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 5 hours.20 DEG C are cooled to, 11.1 grams of (0.11 mole) trimethyl orthoformates, 30 to 35 DEG C of stirrings are added
Reaction 4 hours.20.0 gram of 28% methanol solution of sodium methylate is added, 34.3 gram (0.105 is dividedly in some parts between 30 to 40 DEG C
Mole) N- (5- (4- tert-butoxycarbonyl -1- hexahydropyrazine bases) 2- pyridine radicals) guanidine Hemisulphate, finish, 60 to 65 DEG C
Stirring reaction 3 hours, adds 9.4 grams of (0.11 mole) Aminocyclopentanes at 60 to 65 DEG C, react 3 hours at 70 to 75 DEG C.
20 DEG C are cooled to, 50 grams of water are added, 20 DEG C are stirred 3 hours, are filtered, and filter cake is obtained with 250 grams of recrystallisation from isopropanol
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 funnel, add
200 grams of toluene, 0.2 gram of 98% concentrated sulphuric acid, 26.0 grams of (0.2 mole) ethyl acetoacetates, 110 to 115 DEG C are stirred back
Stream dehydration 5 hours.20 DEG C are cooled to, 11.1 grams of (0.11 mole) trimethyl orthoformates are added, 30 to 35 DEG C are stirred
Mix reaction 4 hours.20.0 gram of 28% methanol solution of sodium methylate is added, 34.3 gram (0.105 is dividedly in some parts between 30 to 40 DEG C
Mole) N- (5- (4- tert-butoxycarbonyl -1- hexahydropyrazine bases) 2- pyridine radicals) guanidine Hemisulphate, finish, 60 to 65 DEG C
Stirring reaction 3 hours, adds 9.4 grams of (0.11 mole) Aminocyclopentanes at 60 to 65 DEG C, react 3 hours at 70 to 75 DEG C.
20 DEG C are cooled to, 50 grams of water are added, 20 DEG C are stirred 3 hours, are filtered, and filter cake is obtained with 250 grams of recrystallisation from isopropanol
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)
With 26.0 grams of (0.2 mole) acetoacetic acid second that 23.2 grams of (0.2 mole) methyl acetoacetates replace embodiment 1
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)
With 26.0 grams of (0.2 mole) acetoacetic acid second that 23.2 grams of (0.2 mole) methyl acetoacetates replace embodiment 2
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)
With 26.0 grams of (0.2 mole) acetoacetic acid second that 23.2 grams of (0.2 mole) methyl acetoacetates replace embodiment 3
Ester, remaining obtains 40.1 grams of white solid Pa Boxini (I), yield 89.6%, liquid phase purity 99.9% with embodiment 3.
Claims (10)
1. a kind of preparation method of Pa Boxini (I), including step is as follows：
(1) in toluene, the dehydration under acid catalyst effect obtains compound III to acetoacetic ester：2- acetyl group -3- methyl
- 2- glutaconate diester；
Reactant liquor directly carries out without isolation next step；
(2) trimethyl orthoformate, Jing separating methanols is added to be condensed to yield compounds Ⅳ in the above-mentioned reactant liquor containing compound III：
2- acetyl group -3- methyl -4- methoxy methylene base -2- glutaconate diester；
Reactant liquor directly carries out without isolation next step；
(3) N- (5- (4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- are added in the above-mentioned reactant liquor containing compounds Ⅳ
Pyridine radicals) guanidine (V), Jing pyrimidine cyclizations obtain compound VI：2- acetyl group -3- [[5- (4- tert-butoxycarbonyls
Piperazine -1- bases) pyridine -2- bases] amino] -3H--4- ketone-dihydro-pyrimidin base -2-butylene ester；
Reactant liquor directly carries out without isolation next step；
(4) add Aminocyclopentane to carry out cyclization in the above-mentioned reactant liquor containing compound VI, after de- Boc protection groups handkerchief is obtained
Bo Xini (I),
2. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that acetoacetic ester described in step (1)
For ethyl acetoacetate or methyl acetoacetate.
3. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that acid catalyst is described in step (1)
The concentrated sulphuric acid of p-methyl benzenesulfonic acid, pyrovinic acid or mass fraction 98%.
4. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that solvent toluene and second described in step (1)
Ethyl sodio acetoacetic ester mass ratio is (5-15):1；The catalyst amount is the 0.5-2% of acetoacetic ester quality.
5. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that acetylacetic ester described in step (1)
Dehydration temperature is 100～120 DEG C, and the response time is 2-10 hours；Preferably, stir back at a temperature of 110～115 DEG C
Stream dehydration 4-6 hour.
6. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that trimethyl orthoformate described in step (2)
It is (0.5-0.7) with the mol ratio of acetoacetic ester:1；The separating methanol setting-up point is 10～50 DEG C, and the response time is
2-10 hours；Preferably, first the reactant liquor of step (1) is cooled to into 20-25 DEG C, adds trimethyl orthoformate, then
In 30 to 35 DEG C of stirring reaction 4-5 hours.
7. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that N- (5- (4- described in step (3)
Tert-butoxycarbonyl -1- hexahydropyrazine bases) 2- pyridine radicals) mol ratio of guanidine (V) and acetoacetic ester is (0.5-0.6):1；
The pyrimidine cyclisation reaction temperature is 50～80 DEG C, and the response time is 3-8 hours；It is preferred that 60～65 DEG C of stirring reaction 2-3 hours.
8. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that Aminocyclopentane and acetyl described in step (4)
The mol ratio (0.5-0.6) of acetass:1；Cyclization temperature is 50～100 DEG C, response time 2-10 hour；It is preferred that being cyclized
Reaction temperature is 70 to 75 DEG C, is reacted 3 hours.
9. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that N- (5- (4- described in step (3)
Tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- pyridine radicals) guanidine (V) is by N- (5- (4- tert-butoxycarbonyl -1-
Hexahydro piperazinyl) -2- pyridine radicals) N- (5- that obtain of guanidine Hemisulphate and equimolar methanol solution of sodium methylate neutralization reaction
(4- tert-butoxycarbonyl -1- hexahydro piperazinyls) -2- pyridine radicals) guanidine methanol solution, it is directly used in phonetic with acetoacetic ester
Pyridine cyclization.
10. the preparation method of Pa Boxini as claimed in claim 1, it is characterised in that BOC protections are taken off described in step (4)
Base is that water is added in gained cyclization products therefrom, 10～30 DEG C, response time 2-5 hour.
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| CN107722005A (en) * | 2017-10-12 | 2018-02-23 | 山东裕欣药业有限公司 | A kind of process for purification of pa Berkeley |
| CN107722003A (en) * | 2017-10-12 | 2018-02-23 | 山东裕欣药业有限公司 | A kind of synthetic method of Pabuk former times profit cloth |
| CN107722004A (en) * | 2017-10-12 | 2018-02-23 | 山东裕欣药业有限公司 | A kind of preparation method of Pabuk former times profit cloth |
| CN107739376A (en) * | 2017-10-12 | 2018-02-27 | 山东裕欣药业有限公司 | A kind of preparation method of pa Berkeley |
| 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 |
| 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 |
| 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 |
| CN110016023A (en) * | 2018-01-08 | 2019-07-16 | 新发药业有限公司 | A kind of simple and convenient process for preparing of Pa Boxini |
| WO2022091001A1 (en) | 2020-10-29 | 2022-05-05 | Pfizer Ireland Pharmaceuticals | Process for preparation of palbociclib |
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