CN112358467A - Preparation process of pyrroltinib - Google Patents
Preparation process of pyrroltinib Download PDFInfo
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- CN112358467A CN112358467A CN202011176733.2A CN202011176733A CN112358467A CN 112358467 A CN112358467 A CN 112358467A CN 202011176733 A CN202011176733 A CN 202011176733A CN 112358467 A CN112358467 A CN 112358467A
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
A preparation process of pirfenib belongs to the technical field of pharmaceutical chemistry synthesis, and comprises the step of carrying out substitution reaction on (2E) -N- (4-amino-3-cyano-7-ethoxyquinoline-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide as a formula I and 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine as a formula II in a solvent under the action of an alkali catalyst to obtain the pirtinib. The technical effects are as follows: has the characteristics of easily obtained raw materials, simple process, economy, environmental protection and the like, is beneficial to controlling and improving the quality of the raw material medicine of the final product, and can meet the requirement of industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a preparation process of pyrroltinib.
Background
The pyrroltinib (Pyrotinib) is an irreversible human epidermal growth factor receptor 2(HER2) and Epidermal Growth Factor Receptor (EGFR) dual-target tyrosine kinase inhibitor which is independently developed by Henry pharmaceutical company of Jiangsu province, and has the action mechanism of being covalently combined with Adenosine Triphosphate (ATP) binding sites of HER2 and EGFR kinase zones in cells, preventing the formation of homo-and hetero-dimers of HER2 and EGFR in tumor cells, inhibiting the self-phosphorylation of the homodimers and blocking the activation of downstream signal channels, thereby inhibiting the growth of the tumor cells. Pirtinib maleate tablets have been officially approved by the national food and drug administration (CFDA) for marketing in 2018 for the treatment of recurrent or metastatic breast cancer patients who are epidermal growth factor receptor 2(HER2) positive, have not received or have received trastuzumab.
Pyrroltinib has the chemical name (2E) -N- [4- [ [ 3-chloro-4- [ (pyridin-2-yl) methoxy ] phenyl ] amino ] -3-cyano-7-ethoxyquinolin-6-yl ] -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide. Based on the pharmacophore structure of a double-target (HER2 and EGFR) inhibitor Neratinib (Neratinib), the structural design of the pirtinib reserves the main structures of the quinoline mother nucleus and the (pyridine-2-yl) methoxy benzene ring of the Neratinib, and only the enamide side chain is modified into a chiral 3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide group. Patent application publication No. CN102933574A reports that pyrroltinib has obvious drug effect advantages, and is superior to neratinib in the aspects of tumor cell inhibition strength, bioavailability, safety and the like.
In the existing patents and documents on the preparation method of the pirfenib, the main synthetic route of the neratinib is basically used, and the three synthetic routes are summarized, wherein the route I and the route II use different methods to prepare the same key intermediate (formula 1), and the formula 1 and (2E) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acryloyl chloride undergo amidation reaction to obtain the pirtinib; and the third route is that the intermediate (formula 2) containing the diethyl phosphate side chain fragment is generated by amidation reaction of the intermediate (formula 1) and phosphoric acid diethyl ester acetic acid under the action of a condensing agent, and then the intermediate and (2R) -1-methyl pyrrolidine-2-formaldehyde are subjected to Wittig-Horner reaction under the conditions of strong alkali and ultralow temperature to carry out condensation to construct an olefinic bond, so that the pyrroltinib is obtained.
Route one (WO2005034955A1 and WO2017186140A1) is shown as follows, excessive toxic and strong-acid phosphorus oxychloride or thionyl chloride is needed to carry out chlorination reaction in step 1, and a large amount of waste liquid with strong corrosivity and strong irritation is generated by post-treatment, so that the operation is complex, the reaction time is long (>10h), the yield and the purity are not high, and the method is not suitable for industrial scale-up production.
The second route (WO2019076316A1, CN101180269A) is as follows, wherein the 2 nd step cyclization reaction also needs to use phosphorus oxychloride which is highly toxic and strong in acid, and is not suitable for popularization of industrial production.
Route three (WO2011029265A1, WO2012122865A2) is a reaction step of (2R) -1-methylpyrrolidine-2-formaldehyde, which is unstable and easy to oxidize and deteriorate, and no commercial product is available, which needs to be synthesized in advance, and the synthesis difficulty is high, so the cost is high, on the other hand, the Wittig-Hunnel reaction between (2R) -1-methylpyrrolidine-2-formaldehyde and formula 2 needs to be carried out at ultralow temperature (minus 50 ℃), the yield is low, so the cost of the route is high, and the value and significance of industrial production are low.
Aiming at the defects of the prior art, the preparation process of the pirfenib with simple process, mild conditions, economy, environmental protection and high purity and yield is explored, and particularly the preparation process of the pirfenib which can be suitable for industrial production is sought, so that the raw material drug has good positive significance in embodying due value.
Disclosure of Invention
The invention aims to provide a preparation process of pyrroltinib, which has the advantages of easily available raw materials, simple process, economy and environmental protection and can meet the requirements of industrial production.
The purpose of the invention is achieved by a preparation process of pirtinib, which comprises the following steps of carrying out substitution reaction on (2E) -N- (4-amino-3-cyano-7-ethoxyquinoline-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide and 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine serving as a formula II in a solvent under the action of an alkali catalyst to obtain the pirtinib, wherein the reaction formula is as follows:
in a specific embodiment of the invention, the molar ratio of the (2E) -N- (4-amino-3-cyano-7-ethoxyquinolin-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide to the 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine to the base catalyst is 1.0: 1.0 to 1.5: 2.0 to 3.5.
In another specific embodiment of the invention, the base catalyst is N, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 2, 6-lutidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] -non-5-ene or 1, 4-diazabicyclo [2.2.2] octane.
In yet another embodiment of the present invention, the solvent is ethanol, isopropanol, 1, 2-dichloroethane, chloroform or toluene.
In a further embodiment of the present invention, the temperature of the substitution reaction is 70 to 110 ℃.
In still another embodiment of the present invention, the 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine represented by the formula II is prepared by the following method: firstly, diazotizing 3-chloro-4- [ (pyridine-2-yl) methoxyl ] aniline serving as a formula III, and then carrying out a methyl sulfhydrylation reaction with sodium methyl mercaptide to obtain 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine serving as a formula II, wherein the reaction formula is as follows:
in a more specific embodiment of the present invention, the molar ratio of the 3-chloro-4- [ (pyridin-2-yl) methoxy ] aniline to the sodium methyl mercaptide is 1.0: 2.5-4.5.
In a further specific embodiment of the present invention, the temperature of the diazotization reaction is-10 to 0 ℃, and the reaction time is 30min to 1 h.
In yet another specific embodiment of the present invention, the temperature of the sulfhydrylation reaction is-10 to 0 ℃ and the reaction time is 6 to 18 hours.
Compared with the prior art, the technical scheme provided by the invention has the technical effects that: has the characteristics of easily obtained raw materials, simple process, economy, environmental protection and the like, is beneficial to controlling and improving the quality of the raw material medicine of the final product, and can meet the requirement of industrial production.
Detailed Description
The technical solution of the present invention will be further described in the following non-limiting examples, which are provided in connection with the following embodiments, and it is obvious that the scope of the present invention is not limited to the examples, and other examples of the present invention made by those skilled in the art are within the scope of the present invention.
Example 1:
dissolving (2E) -N- (4-amino-3-cyano-7-ethoxyquinolin-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide (20.0g,55mmol) as a formula I and 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine (16.0g,60mmol) as a formula II in ethanol (500mL), adding N, N-diisopropylethylamine (15.0g,116mmol), heating to 75 ℃ to react completely, concentrating under reduced pressure to remove the organic solvent, adding dichloromethane for extraction, washing with brine, drying over anhydrous sodium sulfate, rotary evaporating under reduced pressure to dryness, recrystallizing the crude product with isopropanol-ethyl acetate mixed solvent, vacuum drying to obtain pirfenib (28.0g), yield 88%, the reaction of this example is as follows:
the 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine of the formula II used in this example 1 was obtained by the following preparation method:
3-chloro-4- [ (pyridin-2-yl) methoxy group as formula III]Dissolving aniline (18.0g,77mmol) in concentrated hydrochloric acid (150mL), cooling to-5 ℃, dropwise adding sodium nitrite (8.0g,116mmol) solution (80mL), keeping the temperature and stirring for 50min, dropwise adding 150mL sodium methyl mercaptide solution (14.0g, 200mmol), keeping the temperature and reacting for 8h at-10 ℃, extracting dichloromethane, washing with salt water in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure to remove organic solvent, recrystallizing crude product with ethyl acetate-petroleum ether mixed solvent, and drying under vacuum to obtain 2- [ (2-chloro-4-methylthiophenoxy) methyl]Pyridine (17.5g), yield 86%, the reaction formula is as follows:
example 2:
(2E) -N- (4-amino-3-cyano-7-ethoxyquinolin-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide (30.0g,82mmol) and 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine (27.0g,102mmol) were dissolved in isopropanol (800mL), triethylamine (22.0g,217mmol) is added, the temperature is raised to 80 ℃ for reaction until the TLC is completely controlled, the organic solvent is removed by concentration under reduced pressure, dichloromethane is added for extraction, the obtained product is washed by brine, dried by anhydrous sodium sulfate, and then is dried by rotary evaporation under reduced pressure, the crude product is recrystallized by an isopropanol-ethyl acetate mixed solvent, and then is dried under vacuum, thus obtaining pyrroltinib (43.0g), the yield is 90%, and the reaction formula is the same as that in example 1.
The 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine used in this example 2 was obtained by the following preparation method:
3-chloro-4- [ (pyridin-2-yl) methoxy ] aniline (30.0g,128mmol) was dissolved in concentrated hydrochloric acid (250mL), cooled to-8 ℃, added dropwise with sodium nitrite (14.0g) solution (150mL), stirred at the same temperature for 1h, added dropwise with sodium methyl mercaptide solution (30.0g,428mmol), reacted at-5 ℃ for 12h, extracted with dichloromethane, washed with brine in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, the crude product was recrystallized from ethyl acetate-petroleum ether mixed solvent, dried under vacuum to give 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine (28.5g), yield 84%, the reaction scheme was the same as in example 1.
Example 3:
(2E) -N- (4-amino-3-cyano-7-ethoxyquinolin-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide (35.0g,96mmol) and 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine (36.0g,136mmol,1.4eq) were dissolved in toluene (1000mL), pyridine (25.0g,316mmol) is added, the temperature is raised to 100 ℃ for reaction until the TLC is completely controlled, the organic solvent is removed by concentration under reduced pressure, dichloromethane is added for extraction, the obtained product is washed by brine, dried by anhydrous sodium sulfate, and then is dried by rotary evaporation under reduced pressure, the crude product is recrystallized by an isopropanol-ethyl acetate mixed solvent, and then is dried under vacuum, thus obtaining the pyrroltinib (50.0g), the yield is 90%, and the reaction formula is the same as that in example 1.
The 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine used in this example 3 was obtained by the following preparation method:
3-chloro-4- [ (pyridin-2-yl) methoxy ] aniline (38.0g,162mmol) was dissolved in concentrated hydrochloric acid (300mL), cooled to-10 deg.C, added dropwise with sodium nitrite (20.0g,290mmol) solution (150mL), stirred at constant temperature for 1h, added dropwise with sodium methyl mercaptide solution (50.0g, 713mmol), reacted at-5 deg.C for 15h, extracted with dichloromethane, washed with brine in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, the crude product was recrystallized from ethyl acetate-petroleum ether mixed solvent, dried under vacuum to give 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine (37.6g), yield 87%, the reaction scheme was the same as in example 1.
Claims (9)
1. A process for preparing pyrroltinib, characterized in that it comprises reacting (2E) -N- (4-amino-3-cyano-7-ethoxyquinolin-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl group as formula I]Acrylamide with 2- [ (2-chloro-4-methylthiophenoxy) methyl group as formula II]Pyridine is subjected to substitution reaction in a solvent under the action of an alkali catalyst to obtain pyrroltinib, wherein the reaction formula is as follows:
2. the process for preparing pyrroltinib according to claim 1, wherein the molar ratio of (2E) -N- (4-amino-3-cyano-7-ethoxyquinolin-6-yl) -3- [ (2R) -1-methylpyrrolidin-2-yl ] acrylamide, 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine and the base catalyst is 1.0: 1.0-1.5: 2.0-3.5.
3. The process according to claim 1 or 2, wherein the base catalyst is N, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 2, 6-lutidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane.
4. The process according to claim 1, wherein the solvent is ethanol, isopropanol, 1, 2-dichloroethane, chloroform or toluene.
5. The process for preparing pyrroltinib according to claim 1, wherein the temperature of the substitution reaction is 70-110 ℃.
6. The process for preparing pyrroltinib according to claim 1, wherein 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine of formula ii is prepared by the following steps: firstly, diazotizing 3-chloro-4- [ (pyridine-2-yl) methoxyl ] aniline serving as a formula III, and then carrying out a methyl sulfhydrylation reaction with sodium methyl mercaptide to obtain 2- [ (2-chloro-4-methylthiophenoxy) methyl ] pyridine serving as a formula II, wherein the reaction formula is as follows:
7. the process for preparing pyrroltinib according to claim 6, wherein the molar ratio of 3-chloro-4- [ (pyridin-2-yl) methoxy ] aniline to sodium thiomethoxide is 1.0: 2.5-4.5.
8. The preparation process of pyrroltinib according to claim 6, wherein the diazotization reaction is carried out at a temperature of-10 to 0 ℃ for 30min to 1 h.
9. The preparation process of pyrroltinib according to claim 6, characterized in that the temperature of the thiomethylation reaction is-10 to 0 ℃ and the reaction time is 6 to 18 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113045546A (en) * | 2021-03-25 | 2021-06-29 | 浙江天宇药业股份有限公司 | Azolidinib impurity, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110724086A (en) * | 2019-11-26 | 2020-01-24 | 山东铂源药业有限公司 | Synthetic method of pyrroltinib intermediate |
| WO2020211860A1 (en) * | 2019-04-19 | 2020-10-22 | 正大天晴药业集团股份有限公司 | Quinoline compound or pharmaceutically acceptable salt thereof for treating ewing's sarcoma |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020211860A1 (en) * | 2019-04-19 | 2020-10-22 | 正大天晴药业集团股份有限公司 | Quinoline compound or pharmaceutically acceptable salt thereof for treating ewing's sarcoma |
| CN110724086A (en) * | 2019-11-26 | 2020-01-24 | 山东铂源药业有限公司 | Synthetic method of pyrroltinib intermediate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045546A (en) * | 2021-03-25 | 2021-06-29 | 浙江天宇药业股份有限公司 | Azolidinib impurity, preparation method and application thereof |
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