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A kind of simple and convenient preparation method of Abecicil intermediate and Abecicil

A technology for intermediates and compounds, which is applied in the field of abecilil intermediates, can solve the problems of reduced Friedel-Crafts reaction activity, inability to obtain products, and large amount of waste water.

Active Publication Date: 2020-10-30
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The 1-(4-amino-2,6-difluorophenyl)-2-fluoroethanone used above is prepared by using 2,6-difluoroaniline and 2-fluoroacetonitrile under the action of strong acids such as methanesulfonic acid, In the presence of strong acid, amino groups are transformed into ammonium salts, resulting in reduced Friedel-Crafts reactivity and poor positioning selectivity, low purity, and a large amount of wastewater
Method 1 uses the condensation reaction of 1-(4-amino-2,6-difluorophenyl)-2-fluoroethanone with N,N-dimethylformamide dimethyl acetal, preferably N,N-di The reaction of methyl formamide dimethyl acetal and amino group gives 2,6-difluoro-4-fluoroacetyl dimethylaminomethylene aniline, but the product described in the original text cannot be obtained, and the dimethylaminomethylene group has poor stability , easy to polymerize during the subsequent intramolecular cyclization reaction, poor operability
Method 2 is easy to cause the decomposition of the fluoroacetyl group during the intramolecular ring closure reaction
In addition, the base-catalyzed cyclization of the intermediate 1-isopropyl-2-methyl-4-fluoro-6-(3-dimethylamino-fluoro)acryloyl-1H-benzimidazole and guanidine to prepare Abbe The yield of Xili is low (73.1%), and the industrial operation is poor

Method used

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  • A kind of simple and convenient preparation method of Abecicil intermediate and Abecicil
  • A kind of simple and convenient preparation method of Abecicil intermediate and Abecicil
  • A kind of simple and convenient preparation method of Abecicil intermediate and Abecicil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: Preparation of 3-fluoro-4-nitro-5-isopropylaminobenzonitrile (II)

[0070] In a 250 ml stainless steel autoclave, add 120 g of N,N-dimethylformamide, 18.5 g (0.1 moles) of 3,5-difluoro-4-nitrobenzonitrile, 15.0 g of potassium carbonate, 6.0 g (0.1 mol) isopropylamine, sealed autoclave, 60 to 65 ℃ stirring reaction for 5 hours, cooled to 20 to 25 ℃, removed the material, filtered, the filtrate recovered solvent by vacuum distillation, cooled to 20 to 25 ℃, added 20 grams of methyl Tert-butyl ether was filtered and dried to obtain 20.7 g of 3-fluoro-4-nitro-5-isopropylaminobenzonitrile (II), with a yield of 92.8% and a liquid phase purity of 99.5%.

Embodiment 2

[0071] Example 2: Preparation of 3-fluoro-4-nitro-5-isopropylaminobenzonitrile (II)

[0072] In a 250 ml stainless steel autoclave, add 150 g of tetrahydrofuran, 18.5 g (0.1 mole) of 3,5-difluoro-4-nitrobenzonitrile, 15.0 g of potassium carbonate, 6.0 g (0.1 mole) of isopropylamine, and seal the autoclave , stirred and reacted at 50 to 55°C for 7 hours, cooled to 20 to 25°C, removed the material, filtered, and the filtrate was distilled under reduced pressure to recover the solvent, cooled to 20 to 25°C, added 20 grams of methyl tert-butyl ether, filtered, and dried. 20.2 g of 3-fluoro-4-nitro-5-isopropylaminobenzonitrile were obtained with a yield of 90.6% and a liquid phase purity of 99.3%.

Embodiment 3

[0073] Example 3: Preparation of 1-isopropyl-2-methyl-4-fluoro-6-cyano-1H-benzimidazole (III)

[0074] Add 180 grams of THF, 22.3 grams (0.1 mole) of 3-fluoro-4-nitro-5-isopropylaminobenzonitrile prepared in Example 1, 50 grams (0.5 mole) of acetic anhydride in a 500 milliliter stainless steel autoclave, 0.8 grams of 5wt% palladium carbon catalyst, after nitrogen replacement three times, pass in hydrogen, keep hydrogen pressure at 0.2-0.3MPa, react at 40-45°C for 4 hours, react at 90-95°C for 5 hours, cool to 20-25°C, nitrogen Replaced three times, filtered to remove palladium carbon, concentrated the filtrate, added 20 grams of methyl tert-butyl ether, filtered, and dried to obtain 19.8 grams of 1-isopropyl-2-methyl-4-fluoro-6-cyano-1H-benzene And imidazole, yield 91.2%, liquid phase purity 99.5%.

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Abstract

The invention relates to an Abemaciclib intermediate and a simple preparation method of Abemaciclib. The Abemaciclib intermediate is 1-isopropyl-2-methyl-4-fluorine-6-(3-dimethylamino-2-fluorine) acryloyl-1H-benzimidazole (V), and also provides a preparation method of the Abemaciclib intermediate. The Abecheli intermediate and 5-(4-ethylpiperazine-1-yl) methyl-2-pyridylguanidine are subjected to pyrimidine cyclization reaction to prepare Abemaciclib (I). The method has the advantages of cheap and easily available raw materials, good stability of raw materials and intermediate products, mild reaction conditions, high reaction selectivity, high atom economy in the reaction process, high product purity and yield, low cost, less three wastes, environmental protection and contribution to the industrial production of Abemaciclib.

Description

technical field [0001] The invention relates to a simple and convenient preparation method of an abeciclib intermediate and abeciclib, belonging to the technical field of medicinal chemistry. Background technique [0002] Abemaciclib (Ⅰ), the English name is Abemaciclib or bemaciclib, the CAS number is [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, the structural formula of the free base is as shown in formula Ⅰ Show. Abecicil, an oral cell cycle inhibitor (product code LY2835219) developed by Eli Lilly, can block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases (CDK4 and CDK6) . Based on the safety and efficacy of Abeciclib in women with advanced or metastatic breast cancer, based on data from the breast cancer cohort expansion study of the phase I trial JPBA, the US FDA granted it the title of "Breakthrough Therapy Drug" in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/08C07D401/14
CPCC07D235/08C07D401/14
Inventor 戚聿新刘月盛朱成臣张明峰王涛
Owner XINFA PHARMA
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