CN107722003B - A kind of synthetic method of Pabuk former times profit cloth - Google Patents
A kind of synthetic method of Pabuk former times profit cloth Download PDFInfo
- Publication number
- CN107722003B CN107722003B CN201710945480.2A CN201710945480A CN107722003B CN 107722003 B CN107722003 B CN 107722003B CN 201710945480 A CN201710945480 A CN 201710945480A CN 107722003 B CN107722003 B CN 107722003B
- Authority
- CN
- China
- Prior art keywords
- compound
- added
- synthetic method
- room temperature
- organic solvent
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical synthesis fields, are related to a kind of synthetic method of antitumor drug Pabuk former times profit cloth.The present invention provides a kind of synthetic methods of new Pabuk former times profit cloth, it is starting material with compound 4, annulation occurs in organic solvent with compound 5, compound 3 is made, then compound 3 is reacted with compound 2, cyclopentamine progress " one kettle way " is made compound 1.This method starting material is easy to get, and reaction condition is mild, and process route is simply controllable, and by-product is low, and total yield of products improves, and is suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the synthetic method of antitumor drug Pabuk former times profit cloth.
Background technology
Pabuk former times profit cloth (Palbociclib) is swashed by a kind of cell cycle dependant that Pfizer (Pfizer) company develops
Enzyme (CDK4/6) inhibitor obtains " breaking through sex therapy " qualification of U.S. FDA in April, 2013.Due to its III phase clinically good
Good performance, application for quotation is submitted in August, 2014 to U.S. FDA by Pfizer, and obtains preferential examination qualification, is used for estrogen
The first-line treatment of receptor positive (ER+) and negative (HER2-) advanced breast cancer of human epidermal growth factor receptor 2.The research of the medicine
Success will provide another important new selection for metastatic breast cancer patient.
The chemistry of Pabuk former times profit cloth (Palbociclib, I) is entitled：6- acetyl group -8- cyclopenta -5- methyl -2- [[5-
(1- piperazinyls) -2- pyridyl groups] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one, structural formula is：
It is as follows about Pabuk former times profit cloth synthetic route and preparation method report situation at present：
The synthetic route that 1.PCT applications WO2008032157 is disclosed：
The reaction synthetic route is longer, and cumbersome, total yield of products is low, and has used to the disagreeableness deep-etching of environment
The reagent bromine of property.
2. Yuan Yan companies PCT Patent WO2003062236, WO2008032157, WO2012018540 and WO2012068381
The synthetic route of report, there are the rare problem of 2,5,6- trisubstituted pyrimidine ring raw material of primary raw material, even synthesis needs more
Step reaction, the problem of side reaction complexity, while there are competitive reactions in synthesizing Pabuk former times profit cloth subsequent reactions, influence product
Total recovery.
3. patent CN104447743B is directed to prior art problem, the new route of another synthesis is disclosed：
The problem of raw material is rare although this route solves in the prior art, shortening process route, still remains step
Compounds Ⅳ and the problem of V condensation reaction yield of compound low (58.2%) in rapid three, can influence the total recovery of finished product.
For a series of problems of the existing technology, seek raw material and be easy to get, reaction step is few, and product yield is high, by-product
Object is low, is suitble to industrialized production synthetic route, has great importance.
Invention content
It is an object of the invention to overcome the deficiencies of existing technologies, a kind of synthesis side of new Pabuk former times profit cloth is provided
Method, this method starting material are easy to get, and reaction condition is mild, and process route is simply controllable, and by-product is low, and total yield of products improves,
It is suitble to industrialized production.
To achieve the purpose of the present invention, as follows using technical solution：
A kind of synthetic method of Pabuk former times profit cloth, includes the following steps：
(1) the obtained compound of annulation 3 occurs in lewis acid, organic solvent 1 and alkali for compound 4 and compound 5；
(2) compound 3 is mixed with organic solvent 2, is sequentially added cyclopentamine, sodium alkoxide, compound 2 and is carried out " one kettle way " reaction
Compound 1 is made；
Synthetic route of the present invention is as follows：
Preferably, the compound 4 described in step (1), compound 5, lewis acid, alkali molar ratio be 1~1.1:1:1~
1.5:1~2.
Lewis acid described in step (1) is alchlor, ferric trichloride or zinc dichloride.
Organic solvent 1 described in step (1) is ethyl alcohol, methanol, normal propyl alcohol, dichloromethane or DMF.
Alkali described in step (1) is sodium hydroxide, potassium hydroxide or potassium carbonate.
Compound 3, cyclopentamine, sodium alkoxide, 2 molar ratio of compound described in step (2) are 1:0.9~1:1~2:1.
Organic solvent 2 described in step (2) is isopropanol, ethyl alcohol, methanol or dichloromethane.
Sodium alkoxide described in step (2) is sodium methoxide or sodium ethoxide.
The synthetic method is as follows：
1) compound 4, compound 5, lewis acid are added in there-necked flask, organic solvent 1 is added, 4h is stirred at room temperature, adds
Enter alkali, 3h is stirred at room temperature, adjusts pH to 5 with dilute hydrochloric acid, rise to 60 DEG C after stirring 30min, wait for that solid is completely dissolved postcooling extremely
Room temperature is filtered under diminished pressure, and compound 3 is obtained after dry；
2) compound 3 is mixed with organic solvent 2, and cyclopentamine is added, and is controlled 20~60 DEG C of temperature, is heated to reflux 4h, is added
Sodium alkoxide after stirring 30min, is added compound 2 and carries out back flow reaction 3h, be down to room temperature, filter, washed with deionized water,
Vacuum drying, obtains compound 1.
Preferably, a concentration of 2M of dilute hydrochloric acid described in step (1).
Compared with prior art, the present invention obtaining following advantageous effect：
(1) starting material is easy to get, and step (1) annulation mild condition, the step reaction yield reach 80% or more；
(2) it is reacted using " one kettle way " in step (2), simplifies reaction route, improve total yield of products；
(3) whole route only has two steps, and process route is simple, and reaction condition is mildly controllable, and by-product is low, and total recovery is high,
It is suitble to industrialized production.
Specific implementation mode
The invention content of the present invention is described in further detail below by specific embodiment, but is not therefore limited
Determine present disclosure.Wherein, the preparation of N- [5- (1- piperazinyls) -2- piperidyls] guanidine (5) is referring to document WO2006095159
Preparation method.
Embodiment 1
(1) preparation of compound 3
18.62g compounds 4,22.03g compounds 5,13.33g alchlors are added in there-necked flask, 250ml second is added
4h is stirred at room temperature in alcohol, and 4.00g sodium hydroxides are added, 3h is stirred at room temperature, and adjusts pH to 5 in right amount with 2M dilute hydrochloric acid, stirs 30min
After rise to 60 DEG C, wait for that solid is completely dissolved postcooling to room temperature, be filtered under diminished pressure, it is dry after 29.02g compounds 3, yield are
84.69%, purity 99.92%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml isopropanols, and 4.26g cyclopentamines are added, and control 20~60 DEG C of temperature, heating
Flow back 4h, and 2.70g sodium methoxides are added, and after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature, mistake
Filter, is washed with deionized water, is dried in vacuo, is obtained 20.15g compounds 1, yield 89.87%, purity 99.81%.
Embodiment 2
(1) preparation of compound 3
20.18g compounds 4,22.03g compounds 5,24.33g ferric trichlorides are added in there-necked flask, 250ml bis- is added
4h is stirred at room temperature in chloromethanes, and 11.22g potassium hydroxide is added, 3h is stirred at room temperature, pH to 5 is adjusted in right amount with 2M dilute hydrochloric acid, stirs
60 DEG C are risen to after 30min, waits for that solid is completely dissolved postcooling to room temperature, is filtered under diminished pressure, and are obtained 28.91g compounds 3 after dry, are received
Rate is 84.33%, purity 99.87%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml dichloromethane, and 3.83g cyclopentamines are added, and are controlled 20~60 DEG C of temperature, are added
Heat reflux 4h, is added 6.81g sodium ethoxides, after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature,
Filtering, is washed with deionized water, is dried in vacuo, is obtained 18.23g compounds 1, yield 90.32%, purity 99.76%.
Embodiment 3
(1) preparation of compound 3
19.55g compounds 4,22.03g compounds 5,16.36g zinc dichlorides are added in there-necked flask, 250ml first is added
4h is stirred at room temperature in alcohol, and 3h is stirred at room temperature in 13.8g potassium carbonate, adjusts pH to 5 in right amount with 2M dilute hydrochloric acid, is risen to after stirring 30min
60 DEG C, wait for that solid is completely dissolved postcooling to room temperature, be filtered under diminished pressure, it is dry after 28.98g compounds 3, yield 84.56%,
Purity 99.90%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml ethyl alcohol, and 4.26g cyclopentamines are added, and are controlled 20~60 DEG C of temperature, are heated back
4h is flowed, 5.40g sodium methoxides are added, after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature, mistake
Filter, is washed with deionized water, is dried in vacuo, is obtained 20.10g compounds 1, yield 89.65%, purity 99.80%.
Embodiment 4
(1) preparation of compound 3
18.99g compounds 4,22.03g compounds 5,14.67g alchlors are added in there-necked flask, 250ml is being added just
4h is stirred at room temperature in propyl alcohol, and sodium hydroxide 6.0g is added, 3h is stirred at room temperature, and adjusts pH to 5 in right amount with 2M dilute hydrochloric acid, stirs 30min
After rise to 60 DEG C, wait for that solid is completely dissolved postcooling to room temperature, be filtered under diminished pressure, it is dry after 28.78g compounds 3, yield are
83.96%, purity 99.89%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml methanol, and 4.09g cyclopentamines are added, and are controlled 20~60 DEG C of temperature, are heated back
4h is flowed, 5.11g sodium ethoxides are added, after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature, mistake
Filter, is washed with deionized water, is dried in vacuo, is obtained 19.40g compounds 1, yield 90.17%, purity 99.83%.
Embodiment 5
(1) preparation of compound 3
19.55g compounds 4,22.03g compounds 5,16.00g alchlors are added in there-necked flask, DMF is added
4h is stirred at room temperature in 250ml, and 6.00g sodium hydroxides are added, 3h is stirred at room temperature, pH to 5 is adjusted in right amount with 2M dilute hydrochloric acid, stirs
60 DEG C are risen to after 30min, waits for that solid is completely dissolved postcooling to room temperature, is filtered under diminished pressure, and are obtained 28.82g compounds 3 after dry, are received
Rate is 84.07%, purity 99.87%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml dichloromethane, and 4.05g cyclopentamines are added, and are controlled 20~60 DEG C of temperature, are added
Heat reflux 4h, is added 4.05g sodium methoxides, after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature,
Filtering, is washed with deionized water, is dried in vacuo, is obtained 19.39g compounds 1, yield 91.06%, purity 99.82%.
Embodiment 6
(1) preparation of compound 3
19.55g compounds 4,22.03g compounds 5,19.46g ferric trichlorides are added in there-necked flask, 250ml second is added
4h is stirred at room temperature in alcohol, and 8.42g potassium hydroxide is added, 3h is stirred at room temperature, and adjusts pH to 5 in right amount with 2M dilute hydrochloric acid, stirs 30min
After rise to 60 DEG C, wait for that solid is completely dissolved postcooling to room temperature, be filtered under diminished pressure, it is dry after 28.63g compounds 3, yield are
83.51%, purity 99.88%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml ethyl alcohol, and 4.05g cyclopentamines are added, and are controlled 20~60 DEG C of temperature, are heated back
4h is flowed, 5.10g sodium ethoxides are added, after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature, mistake
Filter, is washed with deionized water, is dried in vacuo, is obtained 19.25g compounds 1, yield 90.38%, purity 99.79%.
Embodiment 7
(1) preparation of compound 3
19.55g compounds 4,22.03g compounds 5,16.36g zinc dichlorides are added in there-necked flask, 250ml second is added
4h is stirred at room temperature in alcohol, and 20.73g potassium carbonate is added, 3h is stirred at room temperature, and pH to 5 is adjusted in right amount with 2M dilute hydrochloric acid, after stirring 30min
60 DEG C are risen to, waits for that solid is completely dissolved postcooling to room temperature, is filtered under diminished pressure, obtains 28.39g compounds 3 after dry, yield is
82.78%, purity 99.83%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml isopropanols, and 4.05g cyclopentamines are added, and control 20~60 DEG C of temperature, heating
Flow back 4h, and 4.05g sodium methoxides are added, and after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature, mistake
Filter, is washed with deionized water, is dried in vacuo, is obtained 19.17g compounds 1, yield 89.99%, purity 99.78%.
Embodiment 8
(1) preparation of compound 3
19.55g compounds 4,22.03g compounds 5,16.00g alchlors are added in there-necked flask, 250ml second is added
4h is stirred at room temperature in alcohol, and 6.00g sodium hydroxides are added, 3h is stirred at room temperature, and adjusts pH to 5 in right amount with 2M dilute hydrochloric acid, stirs 30min
After rise to 60 DEG C, wait for that solid is completely dissolved postcooling to room temperature, be filtered under diminished pressure, it is dry after 29.05g compounds 3, yield are
84.81%, purity 99.95%.
(2) preparation of compound 1
17.12g compounds 3 are mixed with 200ml isopropanols, and 4.05g cyclopentamines are added, and control 20~60 DEG C of temperature, heating
Flow back 4h, and 5.10g sodium ethoxides are added, and after stirring 30min, 6.46g compounds 2 is added and carry out back flow reaction 3h, are down to room temperature, mistake
Filter, is washed with deionized water, is dried in vacuo, is obtained 19.55g compounds 1, yield 91.89%, purity 99.91%.
Claims (10)
1. a kind of synthetic method of Pabuk former times profit cloth, which is characterized in that the synthetic method includes the following steps：
(1) compound 3 is made in the annulation in lewis acid, organic solvent 1 and alkali to compound 4 with compound 5；
(2) compound 3 is mixed with organic solvent 2, sequentially add cyclopentamine, sodium alkoxide, compound 2 carry out " one kettle way " reaction be made
Compound 1；
2. synthetic method as described in claim 1, which is characterized in that compound 4, compound 5 described in step (1), Louis
This sour, alkali molar ratio is 1~1.1:1:1~1.5:1~2.
3. synthetic method as described in claim 1, which is characterized in that the lewis acid described in step (1) is alchlor, three
Iron chloride or zinc dichloride.
4. synthetic method as described in claim 1, which is characterized in that organic solvent 1 described in step (1) be ethyl alcohol, methanol,
Normal propyl alcohol, dichloromethane or DMF.
5. synthetic method as described in claim 1, which is characterized in that the alkali described in step (1) is sodium hydroxide, potassium hydroxide
Or potassium carbonate.
6. synthetic method as described in claim 1, which is characterized in that compound 3, cyclopentamine, sodium alkoxide described in step (2),
2 molar ratio of compound is 1:0.9~1:1~2:1.
7. synthetic method as described in claim 1, which is characterized in that the organic solvent 2 described in step (2) is isopropanol, second
Alcohol, methanol or dichloromethane.
8. synthetic method as described in claim 1, which is characterized in that the sodium alkoxide described in step (2) is sodium methoxide or sodium ethoxide.
9. synthetic method as described in claim 1, which is characterized in that be as follows：
1) compound 4, compound 5, lewis acid are added in there-necked flask, organic solvent 1 is added, 4h is stirred at room temperature, alkali is added,
3h is stirred at room temperature, adjusts pH to 5 with dilute hydrochloric acid, 60 DEG C is risen to after stirring 30min, waits for that solid is completely dissolved postcooling to room temperature,
It is filtered under diminished pressure, compound 3 is obtained after dry；
2) compound 3 is mixed with organic solvent 2, and cyclopentamine is added, and controls 20~60 DEG C of temperature, is heated to reflux 4h, and sodium alkoxide is added,
After stirring 30min, compound 2 is added and carries out back flow reaction 3h, is down to room temperature, filters, is washed with deionized water, vacuum is dry
It is dry, obtain compound 1.
10. synthetic method as claimed in claim 9, which is characterized in that a concentration of 2M of dilute hydrochloric acid described in step (1).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710945480.2A CN107722003B (en) | 2017-10-12 | 2017-10-12 | A kind of synthetic method of Pabuk former times profit cloth |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710945480.2A CN107722003B (en) | 2017-10-12 | 2017-10-12 | A kind of synthetic method of Pabuk former times profit cloth |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107722003A CN107722003A (en) | 2018-02-23 |
| CN107722003B true CN107722003B (en) | 2018-11-06 |
Family
ID=61210325
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710945480.2A Active CN107722003B (en) | 2017-10-12 | 2017-10-12 | A kind of synthetic method of Pabuk former times profit cloth |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107722003B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105111205B (en) * | 2015-09-12 | 2017-01-04 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Pa Boxini |
| CN106608876A (en) * | 2015-10-21 | 2017-05-03 | 新发药业有限公司 | Preparation method of high-purity palbociclib |
| US20170247380A1 (en) * | 2014-11-26 | 2017-08-31 | Suzhou Miracpharma Technology Co., Ltd. | Method for preparing palbociclib |
-
2017
- 2017-10-12 CN CN201710945480.2A patent/CN107722003B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170247380A1 (en) * | 2014-11-26 | 2017-08-31 | Suzhou Miracpharma Technology Co., Ltd. | Method for preparing palbociclib |
| CN105111205B (en) * | 2015-09-12 | 2017-01-04 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Pa Boxini |
| CN106608876A (en) * | 2015-10-21 | 2017-05-03 | 新发药业有限公司 | Preparation method of high-purity palbociclib |
Non-Patent Citations (3)
| Title |
|---|
| Discovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6;Peter L. Toogood等;《J. Med. Chem.》;20051231;第48卷;第2388-2406页 * |
| 帕博西尼合成路线图解;李婧瑶等;《中国药物化学杂志》;20160630;第26卷(第3期);第263-265页 * |
| 帕布昔利布合成路线图解;周海平等;《中国医药工业杂志》;20170601;第48卷(第5期);第758-761页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107722003A (en) | 2018-02-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105111205B (en) | A kind of preparation method of Pa Boxini | |
| CN111362923A (en) | Method for preparing RET inhibitor pracetib, intermediate of pracetib and preparation method of pracetib | |
| CN102911164A (en) | Method for preparing lapatinib key intermediate | |
| CN104910158B (en) | 5,6,7,8-tetrahydropyrido[3,4-d] pyrimidine compound with bioactivity as well as preparation method and application thereof | |
| CN106366073B (en) | A kind of hydrochloric acid replaces the preparation method of pyrimidine | |
| CN103755648B (en) | New impurity of a kind of Gefitinib and preparation method thereof | |
| CN111440151A (en) | Method for preparing antitumor drug prasutinib | |
| CN105017176B (en) | A kind of hydrobromic acid Vortioxetine crystal and preparation method thereof | |
| CN107722003B (en) | A kind of synthetic method of Pabuk former times profit cloth | |
| CN103613582A (en) | Rosuvastatin lactone | |
| CN108840868B (en) | The preparation method and application of trypoline ketone compounds with anti-tumor activity | |
| CN103896858A (en) | Technology for preparing cytosine | |
| CN108283940B (en) | Preparation method of palbociclib intermediate | |
| CN106243092A (en) | A kind of method that high selectivity prepares maleic acid Afatinib | |
| CN105859691A (en) | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof | |
| CN108558745A (en) | A kind of pa wins the synthetic method of XiLin intermediate | |
| CN103896889B (en) | Lapatinib intermediate and its preparation method and application | |
| CN106083740B (en) | The 4- anilinoquinazoline derivatives and preparation method of a kind of triazole containing 1,2,3- | |
| CN109761914B (en) | Method for preparing 5-trifluoromethyl uracil | |
| CN109369772B (en) | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives | |
| CN109020900B (en) | Preparation method of 6-chloro-3-methyl uracil | |
| CN111362957A (en) | Preparation method of icotinib key intermediate | |
| CN106146494B (en) | For preparing the brilliant solvent of Pabuk former times profit cloth A types and preparation method | |
| CN108117523B (en) | Preparation method of halogenated uracil compound | |
| CN107739376B (en) | A kind of preparation method of pa Berkeley |
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 | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20180912 Address after: 273400 west side of Yan Bin Road, Feixian County Economic Development Zone, Linyi, Shandong Applicant after: Shandong Luoxin Pharmaceutical Group Hengxin Pharmacy Co., Ltd. Address before: 276017 west side of Luo Qi Road, Luozhuang District, Linyi, Shandong Applicant before: Shandong Yu Xin pharmaceutcal corporation, Ltd |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |