CN113912548A - Abelide and preparation method of intermediate thereof - Google Patents
Abelide and preparation method of intermediate thereof Download PDFInfo
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- CN113912548A CN113912548A CN202111373976.XA CN202111373976A CN113912548A CN 113912548 A CN113912548 A CN 113912548A CN 202111373976 A CN202111373976 A CN 202111373976A CN 113912548 A CN113912548 A CN 113912548A
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- C07D401/00—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
- 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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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
Abstract
The invention discloses a preparation method of Abelide and an intermediate thereof. The Abelide intermediate is 3- (dimethylamino) -2-fluoro-1- (1-isopropyl-2-methyl-1H-benzo [ d]Imidazol-6-yl) prop-2-en-1-one (V), and a process for the preparation of this intermediate. And (3) carrying out cyclization reaction on the intermediate V and N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridine-2-yl) guanidine (VI) to obtain Abelide (I). The preparation method has the advantages of easily available raw materials, low cost, less side reaction, safety and environmental protection.
Description
Technical Field
The invention relates to a preparation method of Abelide and an intermediate thereof, belonging to the field of pharmaceutical chemicals.
Background
Abelix is an oral cyclin-dependent kinase CDK4/6 inhibitor developed by Li Lai, and has main indications of hormone receptor positive (HR +) and HER2 negative (HER2-) breast cancer. Abbeli english name abemaciciclib or bemaciciclib, free base CAS number: 1231929-97-7, the chemical name is N- [5- [ (4-ethyl-1-piperazine) methyl ] -2-pyridyl ] -5-fluoro-4- [ 4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl ] -2-pyrimidinamine, and the structural formula is shown as the formula I. Abelian is favorable for obtaining American FDA approval to be listed in 2017, and is approved to be listed in China in 2020. The results of clinical studies show that Abelix is the first and the only CDK4/6 inhibitor that has been used to achieve extended Progression Free Survival (PFS) mainly in Chinese patients. The medicine can bring benefits to a plurality of domestic patients.
The li-lai company reports a synthesis method for synthesizing Abeli starting from 4-bromo-2, 6-difluoroaniline in a patent of a primary compound US20100160340, and the reaction route is as follows:
the above reaction routes suffer from several disadvantages: firstly, the last three chemical reactions adopt homogeneous palladium catalysts, the recovery is difficult, the cost is high, the legal limit of palladium residue in the raw material medicines is below 10ppm, and the quality control is difficult; secondly, the use of phosphorus oxychloride can cause larger environmental protection treatment pressure; finally, there are two chlorine competing reactions in the coupling of the boronic ester intermediate with 2, 4-dichloro-5-fluoropyrimidine Suzuki, and impurities are difficult to control.
Still another method reported in the known literature for Abelide synthesis is to use the pyrimidine ring in the framework product of the cyclization reaction of guanidine compounds.
PCT patent WO2016110224 first discloses a method for synthesizing abbeli by cyclization of guanidine compounds, the reaction route is as follows:
this reaction route suffers from similar disadvantages: three fluorine-containing raw materials, namely 2, 6-difluoroaniline, fluoroacetonitrile and trifluoromethanesulfonic acid, are used in the reaction, so that the cost is high, and more fluorine-containing three wastes which are difficult to treat are generated. The use of phosphorus trichloride also makes environmental disposal difficult. Sodium hydride has potential safety hazard in production. The corrosiveness of the trifluoromethanesulfonic acid to equipment is also relatively large.
Chinese patent CN110218189 reports another method for synthesizing abbeli by cyclization reaction of guanidine compounds, and the reaction route is as follows:
the reaction route has obvious advantages in raw material cost, and raw materials such as phosphorus oxychloride, phosphorus trichloride, sodium hydride and the like with environmental protection and high safety pressure are abandoned. However, the raw material of the fluoromethyl magnesium bromide is not sold on the market, a synthesis method cannot be found in a Scfiner database, the synthesis is difficult, and whether the synthesis of the fluoromethyl magnesium bromide can directly influence the success or failure of the whole synthesis process can be avoided.
Disclosure of Invention
The invention provides a novel preparation method of Abelide and an intermediate thereof, the preparation method has the advantages of cheap and easily-obtained raw materials, relatively green and environment-friendly process, and the palladium residue meets the drug supervision requirement.
A preparation method of an Abelide intermediate comprises the following steps:
(1) reacting 1-isopropyl-2-methyl-4-fluoro-1H-benzo [ d ] imidazole-6-carbonitrile (II) with a Grignard reagent to obtain a compound III;
(2) carrying out condensation reaction on the compound III and N, N-dimethylformamide acetal to obtain a compound IV;
(3) carrying out fluorination reaction on the compound IV under the action of a selective fluorine reagent (Selectfluor) to obtain an Abeli intermediate V;
in the invention, the use of fluoromethyl magnesium bromide which is difficult to obtain and synthesize is effectively avoided, and the cheap and easily available methyl magnesium chloride on the market is used and then fluorinated by industrial fluorine reagent-selective fluorine. Since fluorine is selected to easily generate free radical fluorination on active hydrogen such as methyl hydrogen of the raw material compound IV (the literature references: Angew. chem. int. Ed., 2014,53,1-5 and org. biomol. chem., 2015,13,2890-2894), the side reaction is effectively inhibited by adding a free radical trapping agent, and the directional fluorinated product V is obtained. The process does not relate to other raw materials with more safety and environmental protection problems.
In the step (1), the Grignard reagent is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
In the step (2), the N, N-dimethylformamide acetal is N, N-dimethylformamide dimethyl acetal (DMF-DMA) or N, N-dimethylformamide diethyl acetal (DMF-DEA). The reaction solvent is toluene, xylene, N-dimethylformamide, dimethyl sulfoxide or acetonitrile.
In the step (3), the selective fluorine reagent (Selectfluor) is 1-chloromethyl-4-fluoro-1, 4-diazidobicyclo [2.2.2] octane bistetrafluoroborate (Selectfluor) or 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane tetrafluoroborate (Selectfluor II). The reaction is carried out under basic conditions, the base being sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate or organic amines such as triethylamine, 4-Dimethylaminopyridine (DMAP). Preferably, the base is sodium acetate. The reaction needs to add a free radical trapping agent, and the used free radical trapping agent is 2,2,6, 6-tetramethylpiperidine oxide (TEMPO) or a phenolic compound. Preferably, the phenolic compound is 2, 6-di-tert-butyl-p-cresol (BHT). The reaction solvent is dichloromethane, acetone, tetrahydrofuran, acetonitrile or an alcohol solvent, preferably, the alcohol solvent comprises methanol and ethanol which is isopropanol.
The invention also provides a preparation method of Abelide, which comprises the following steps:
(A) preparing the Abelide intermediate V according to the preparation method;
(B) carrying out cyclization reaction on the Abelix intermediate V and the guanidine intermediate VI under the action of alkali to obtain Abelix;
the guanidine intermediate VI is free base or salt thereof such as nitrate and hydrochloride. The base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium methoxide or an organic amine such as triethylamine, 1, 8-diazabicycloundecen-7-ene (DBU). Preferably, the base is sodium methoxide.
Compared with the prior art, the method avoids using various expensive fluorine-containing raw materials and palladium catalysts, has the advantages of easily available process raw materials, low cost, less competitive side reactions, relative greenness, low carbon, safety and environmental protection. The fluorine atom on the pyrimidine ring is derived from a relatively inexpensive and readily available industrial raw material selection fluorine reagent. The process abandons phosphorus oxychloride, phosphorus trichloride and sodium hydride which have great environmental protection and safety problems.
Drawings
FIG. 1 shows a high-resolution mass spectrum of Abelide obtained by the present invention.
Detailed Description
Specific embodiments of the present invention are illustrated with reference to the following examples. These examples are intended to illustrate the invention and are not intended to limit it in any way.
The synthesis method of the raw material 1-isopropyl-2-methyl-4-fluoro-1H-benzo [ d ] imidazole-6-carbonitrile (II) is disclosed in Chinese patent CN 110218189.
Example 1 synthesis of compound III:
1-isopropyl-2-methyl-4-fluoro-1H-benzo [ d ] imidazole-6-carbonitrile II (21.73g,0.1 mol) was weighed into a reaction flask, and tetrahydrofuran (60mL) was added thereto and dissolved by stirring. Cooling to 0-5 ℃ in ice water bath, dropwise adding a methylmagnesium chloride tetrahydrofuran solution (3M,34mL), and heating to room temperature for reaction for 1 hour after dropwise adding. The reaction was quenched by the addition of 10% ammonium chloride solution (60mL), dichloromethane (80mL) was added, the layers were separated after stirring for 15 minutes, the organic layer was separated, washed with water for 2 times, dried over anhydrous sodium sulfate, filtered under suction, washed with dichloromethane and spin-dried to give intermediate III (21.37g) in 91% yield.
Example 2 synthesis of compound III:
1-isopropyl-2-4-fluoro-methyl-1H-benzo [ d ] imidazole-6-carbonitrile II (21.73g,0.1 mol) was weighed into a reaction flask, and tetrahydrofuran (60mL) was added thereto and dissolved by stirring. Cooling to 0-5 ℃ in ice water bath, dropwise adding a methylmagnesium bromide 2-methyltetrahydrofuran solution (3M,34mL), and heating to room temperature for reaction for 1 hour after dropwise adding. Adding 10% ammonium chloride solution (60mL) to quench the reaction, adding methyl tert-butyl ether (100mL), stirring for 15 min, then layering, separating an organic layer, washing with water for 2 times, drying with anhydrous sodium sulfate, performing suction filtration, washing with dichloromethane, and spin-drying to obtain intermediate III (21.63g) with a yield of 92%.
Example 3 synthesis of compound III:
1-isopropyl-2-methyl-4-fluoro-1H-benzo [ d ] imidazole-6-carbonitrile II (21.73g,0.1 mol) was weighed into a reaction flask, and tetrahydrofuran (60mL) was added thereto and dissolved by stirring. Cooling to 0-5 ℃ in ice water bath, dropwise adding a methylmagnesium iodide tetrahydrofuran solution (1M,100mL), and heating to room temperature for reaction for 1 hour after dropwise adding. The reaction was quenched by the addition of 10% ammonium chloride solution (60mL), dichloromethane (100mL) was added, the layers were separated after stirring for 15 minutes, the organic layer was separated, washed with water for 2 times, dried over anhydrous sodium sulfate, filtered under suction, washed with dichloromethane and spin-dried to give intermediate III (20.46g) in 87% yield.
Example 4 synthesis of compound IV:
compound III (23.43g,0.1mol) and N, N-dimethylformamide dimethyl acetal (17.87 g,0.15mol) were weighed into a reaction flask, added with toluene (60mL), stirred and dissolved for 5 minutes, and heated under reflux for 10 hours. The reaction was concentrated under reduced pressure to give intermediate III (28.94g) in 100% yield.
Example 5 synthesis of compound IV:
compound III (23.43g,0.1mol) and N, N-dimethylformamide diethylacetal (22.08 g,0.15mol) were weighed out into a reaction flask, and N, N-dimethylformamide (60mL) was added thereto, stirred and dissolved for 5 minutes, and then the reaction was refluxed for 10 hours at elevated temperature. The reaction was concentrated under reduced pressure to give intermediate III (31.74g) in 100% yield.
Example 6 synthesis of compound V:
compound IV (28.94g,0.1mol), 1-chloromethyl-4-fluoro-1, 4-diazidobicyclo [2.2.2] octane bistetrafluoroborate (35.43g,0.1mol), sodium acetate (8.2g,0.1mol) and 2, 6-di-tert-butyl-p-cresol (66.11g,0.3mol) were weighed out in a reaction flask. Tetrahydrofuran (200mL) was added and the reaction stirred at room temperature for 5 hours. After the reaction, the solvent was spin-dried, dichloromethane (160mL) and water (160mL) were added, the mixture was stirred for 15 minutes, and then the layers were separated, the organic layer was separated, washed with ice 5% sodium hydroxide solution 2 times, dried over anhydrous sodium sulfate, filtered, washed with dichloromethane, and spin-dried to obtain intermediate III (25.87 g) with a yield of 84%.
Example 7 synthesis of compound V:
compound IV (28.94g,0.1mol), 1-chloromethyl-4-fluoro-1, 4-diazidobicyclo [2.2.2] octane bistetrafluoroborate (35.43g,0.1mol), 4-dimethylaminopyridine (12.22g,0.1mol) and 2,2,6, 6-tetramethylpiperidine oxide (3.13g,0.02mol) were weighed out in a reaction flask. Methanol (200mL) was added and the reaction was stirred at room temperature for 5 hours. After the reaction, the solvent was spin-dried, dichloromethane (160mL) and water (160mL) were added, the mixture was stirred for 15 minutes, and then the layers were separated, the organic layer was separated, washed with ice 5% sodium hydroxide solution 2 times, dried over anhydrous sodium sulfate, filtered, washed with dichloromethane, and spin-dried to obtain intermediate III (20.68g) in 67% yield.
Example 8 synthesis of compound V:
compound IV (28.94g,0.1mol), 1-chloromethyl-4-fluoro-1, 4-diazidobicyclo [2.2.2] octane bistetrafluoroborate (35.43g,0.1mol), potassium carbonate (13.82g,0.1mol) and 2, 6-di-tert-butyl-p-cresol (6.61g,0.03mol) were weighed out in a reaction flask. Acetone (200mL) was added and the reaction stirred at room temperature for 5 hours. After the reaction, the solvent was spin-dried, dichloromethane (160mL) and water (160mL) were added, the mixture was stirred for 15 minutes, and then the layers were separated, the organic layer was separated, washed with ice 5% sodium hydroxide solution 2 times, dried over anhydrous sodium sulfate, filtered, washed with dichloromethane, and spin-dried to give intermediate III (23.64) g) in 77% yield.
Example 9 synthesis of compound V:
compound IV (28.94g,0.1mol), 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane tetrafluoroborate (31.98g,0.1mol), sodium acetate (8.2g,0.1mol) and 2, 6-di-tert-butyl-p-cresol (22.04g,0.1mol) were weighed out in a reaction flask. Dichloromethane (200mL) was added and the reaction stirred at room temperature for 5 hours. After the reaction, water (160mL) was added, the mixture was stirred for 15 minutes, and then the layers were separated, the organic layer was separated, washed with ice 5% sodium hydroxide solution for 2 times, dried over anhydrous sodium sulfate, filtered, washed with dichloromethane, and spin-dried to obtain intermediate III (24.1g) in 78% yield.
Example 10 synthesis of abbeli (I):
compound V (30.73g,0.1mol), compound VI nitrate (32.54g,0.1mol) and 27% sodium methoxide methanol solution (20g,0.1mol) were weighed into a reaction flask, N-dimethylformamide (130mL) was added thereto, the temperature was slowly raised to about 100 ℃ for reaction, and the low boiling point material was distilled off, and after 5 hours of reaction, the solvent was distilled off under reduced pressure. Recrystallization from 95% ethanol (165mL) gave white product I (44.13 g, 98.0% HPLC purity) in 87% yield, HRMS: calcd for C27H33F2N8[M +H]+507.2791 found 507.2788。
Claims (10)
1. A preparation method of an Abelide intermediate is characterized by comprising the following steps:
(1) reacting 1-isopropyl-2-methyl-4-fluoro-1H-benzo [ d ] imidazole-6-carbonitrile (II) with a Grignard reagent to obtain a compound III;
(2) carrying out condensation reaction on the compound III and N, N-dimethylformamide acetal to obtain a compound IV;
(3) carrying out fluorination reaction on the compound IV under the action of a selective fluorine reagent (Selectfluor) to obtain an Abeli intermediate V;
2. the method for preparing an abbe intermediate according to claim 1, wherein in step (1), the grignard reagent is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
3. The method for preparing an abbeli intermediate as claimed in claim 1, wherein in step (2), the N, N-dimethylformamide acetal is N, N-dimethylformamide dimethyl acetal (DMF-DMA), N-dimethylformamide diethyl acetal (DMF-DEA).
4. The method for preparing an abbe intermediate according to claim 1, wherein in the step (2), the reaction solvent is toluene, xylene, N-dimethylformamide, dimethylsulfoxide or acetonitrile.
5. The method for preparing an Abelide intermediate according to claim 1, wherein in the step (3), the selective fluorine reagent (Selectfluor) is 1-chloromethyl-4-fluoro-1, 4-diazidobicyclo [2.2.2] octane bistetrafluoroborate (Selectfluor) or 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane tetrafluoroborate (Selectfluor II).
6. The method for preparing an abbeli intermediate as claimed in claim 1, wherein in step (3), the reaction is carried out under alkaline conditions, and the base used is sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate or organic amine compound.
7. The method for preparing the Abelide intermediate as claimed in claim 1, wherein in the step (3), a radical scavenger is added, and the radical scavenger is 2,2,6, 6-tetramethylpiperidine oxide (TEMPO) or a phenolic compound.
8. The method for preparing an abbe intermediate according to claim 1, wherein in step (3), the reaction solvent is dichloromethane, acetone, tetrahydrofuran, acetonitrile or an alcohol solvent.
9. A preparation method of an Abelide intermediate is characterized by comprising the following steps:
(A) obtaining an Abelide intermediate V according to the method of any one of claims 1 to 8;
(B) carrying out cyclization reaction on the Abelix intermediate V and the guanidine intermediate VI under the action of alkali to obtain a novel antitumor drug Abelix I;
10. the method of claim 9, wherein in step (B), the guanidine intermediate VI is a free base or a salt thereof;
the alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium methoxide or organic amine compounds.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109721565A (en) * | 2017-10-27 | 2019-05-07 | 都创(上海)医药科技有限公司 | A kind of important fluorine intermediate synthesis technology |
| CN110218189A (en) * | 2018-03-01 | 2019-09-10 | 新发药业有限公司 | A kind of simple and convenient process for preparing of Abbe Seeley intermediate and Abbe Seeley |
| CN111777604A (en) * | 2020-07-17 | 2020-10-16 | 常州大学 | Synthesis method of 2-aminothiazole pyrimidine serving as CDK2 inhibitor |
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- 2021-11-19 CN CN202111373976.XA patent/CN113912548A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109721565A (en) * | 2017-10-27 | 2019-05-07 | 都创(上海)医药科技有限公司 | A kind of important fluorine intermediate synthesis technology |
| CN110218189A (en) * | 2018-03-01 | 2019-09-10 | 新发药业有限公司 | A kind of simple and convenient process for preparing of Abbe Seeley intermediate and Abbe Seeley |
| CN111777604A (en) * | 2020-07-17 | 2020-10-16 | 常州大学 | Synthesis method of 2-aminothiazole pyrimidine serving as CDK2 inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| QING-LAN ZHAO等: "A BHT-regulated chemoselective access to monofluorinated chromones", 《TETRAHEDRON》 * |
| SOLOMON TADESSE等: "Highly Potent, Selective, and Orally Bioavailable 4‑Thiazol‑N‑(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation", 《J. MED. CHEM.》 * |
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