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A kind of synthetic method of abemaciclib mesylate

A technology of mesylate and synthesis method, applied in the field of medicine and chemical industry, can solve the problems of multiple reaction yield, high environmental protection pressure, low yield and the like, and achieve the effects of avoiding precious metal catalyst, reducing route cost and high product purity

Active Publication Date: 2020-09-08
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route step is longer, and three-step coupling reaction needs to use expensive palladium catalyst and phosphine ligand, and coupling reaction by-product is more and reaction yield is low; Synthetic intermediate 5-((4-ethylpiperazine-1 -Bromo-4-fluoro-1-isopropyl-2-methyl-1H is synthesized from 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H - Benzo[d]imidazole requires the use of a large amount of phosphorus oxychloride, which is highly toxic and produces a lot of waste water, and the pressure on environmental protection is relatively high
[0010] Generally speaking, the overall total yield of the existing method is low, the cost is high, and the process is difficult to scale up, so it is still necessary to find a simpler and more efficient new synthesis method

Method used

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  • A kind of synthetic method of abemaciclib mesylate
  • A kind of synthetic method of abemaciclib mesylate
  • A kind of synthetic method of abemaciclib mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047] Add N-(4-bromo-2,6-difluorophenyl)acetamide compound 1 (25.00g, 100mmol), isopropylamine (6.50g, 110mmol), and acetonitrile (125mL) into the sealed reactor, and stir well. Add triethylamine (20.24g, 200mmol), increase the temperature to 90~95℃ and react for 8-10 hours. After the reaction, cool to room temperature, add water, spin off the acetonitrile and extract twice with dichloromethane (125mL). The combined organic phase was washed twice with saturated brine (125 mL), dried over sodium sulfate, filtered, and concentrated to obtain an oily compound 2 which was directly used for the next reaction.

[0048] In Example 1, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate, diisopropylethylamine, 1,8-diazabicyclo[5.4.0] eleven carbon can be used for triethylamine. -7-ene (DBU) or triethylenediamine instead, the solvent acetonitrile can be replaced by dimethylformamide, dimethylacetamide, NMP or 1,4-dioxane.

Embodiment 2

[0050]

[0051] Compound 2 (100mmol, obtained from Example 1) and toluene (125mL) were added to a three-necked flask, p-toluenesulfonic acid (38.04g, 200mmol) was added, and the temperature was raised and refluxed for 16-24 hours. The reaction was cooled to room temperature and added Adjust the pH to 11-12 with 5% sodium hydroxide solution, separate the liquids, extract the aqueous phase with ethyl acetate (125mL) once, combine the organic phases and wash twice with saturated brine (125mL), dry with sodium sulfate, filter and concentrate to remove Part of the solvent was added with petroleum ether (125 mL), the solid was precipitated, and the slurry was filtered and dried to obtain compound 3 (21.42 g, two-step yield 79%).

[0052] In Example 2, p-toluenesulfonic acid can be replaced by hydrochloric acid, acetic acid, trifluoroacetic acid or fluoromethanesulfonic acid; the solvent toluene can be dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, Replace with ethyl...

Embodiment 3

[0054]

[0055] Add compound 3 (27.11g, 100mmol) and tetrahydrofuran (136mL) into a three-necked flask, stir to dissolve and cool to 0~5℃ in an ice-salt bath, switch nitrogen to the vacuum 3 times, and add 2.0M isopropylmagnesium chloride tetrahydrofuran solution (110mmol, 55.0mL), keep the internal temperature at 0~5℃ for 0.5~1 hour. Dissolve 2,4-dichloro-5-fluoropyrimidine (18.37g, 110mmol) in tetrahydrofuran (136mL) under the protection of nitrogen, add the catalyst iron triacetylacetonate (1.78g, 5mmol), stir evenly, the prepared Grignard The reagent solution was added dropwise to the reaction flask containing pyrimidine, and after the dropping, the temperature was raised to 55-60°C for 4-6 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction. The mixture was extracted 3 times with ethyl acetate (216 mL), the combined organic phase was washed twice with water (216 mL), dried over sodium sulfate, filtered, and...

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Abstract

The invention discloses a synthesis method of Abemaciclib mesylate. The method comprises steps as follows: (1), a compound 9 in the description is subjected to a reaction with a compound 5 in the description under the action of strong base, and a compound 10 in the description is obtained; (2), the compound 10 is salified in a proper solvent under the action of methanesulfonic acid, and Abemaciclib mesylate is obtained. The invention further discloses synthesis methods of the compound 5 and the compound 9. The synthesis route is simple to operate, a noble metal catalyst is not required, routecost and heavy metal residues of a product are reduced, so that not only is the yield higher, but also product purity is higher, and the synthesis method is suitable for enlarged production.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical engineering, and specifically relates to a method for synthesizing Abemaciclib mesylate. Background technique [0002] Abemaciclib mesylate (code name LY-2835219) is a new oral anti-cancer drug developed by Eli Lilly and Company. It is a highly specific dual cell cycle dependent kinase (CDK4 / 6) inhibitor that can selectively inhibit Cyclin-dependent kinase 4 / 6 restores cell cycle control and blocks tumor cell proliferation. Its single drug has a significant effect on metastatic breast cancer. It was awarded "Breakthrough Therapy" certification by the US FDA in October 2015. It is currently developing treatments for multiple cancers. The clinical research is progressing smoothly and the market prospects are broad. [0003] Abemaciclib mesylate is chemically named N-[5-[(4-ethyl-1-piperazine)methyl]2-pyridyl]-5-fluoro-4-[4-fluoro-1-isopropyl -2-Methyl-1H-benzimidazol-6-yl]-2-pyrimidinamine methanesul...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D403/04C07D213/73C07C309/04C07C303/32
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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