Browse Prior Art Database

Synthesis of 2,2-difluoro-1-keto-5-tosylbenzazepine

IP.com Disclosure Number: IPCOM000019408D
Publication Date: 2003-Sep-12
Document File: 2 page(s) / 68K

Publishing Venue

The IP.com Prior Art Database

Abstract

A procedure for the preparation of the title compound was developed. This is shown schematically below. The keto benzazepine,1 was treated with lithium hexamethyldisilazane in THF to generate the lithium enolate. This was reacted with trimethyl silyl chloride to furnish the silyl enol ether, 2. After distillation of the solvents, and excess chloride, the enol ether was reacted with the SelectfluorTM Reagent , (1-chloromethyl-4-fluoro)-1,4-diazabicyclo(2.2.2)ooctane bis(tetrafluoroborate) in acetonitrile to produce the monofluoro compouind, 3. The sequence of enolization, silylether formation and fluorination with Selectfluor was applied to the monofluoro ketone in order to obtain the difluoro compound,4.

This text was extracted from a Microsoft Word document.
At least one non-text object (such as an image or picture) has been suppressed.
This is the abbreviated version, containing approximately 67% of the total text.

Synthesis of 2,2-difluoro-1-keto-5-tosylbenzazepine

A procedure for the preparation of the title compound was developed. This is shown schematically below. The keto benzazepine,1 was treated with lithium hexamethyldisilazane in THF to generate the lithium enolate. This was reacted with trimethyl silyl chloride to furnish the silyl enol ether, 2. After distillation of the solvents, and excess chloride, the enol ether was reacted with the SelectfluorTM Reagent , (1-chloromethyl-4-fluoro)-1,4-diazabicyclo(2.2.2)ooctane bis(tetrafluoroborate) in acetonitrile to produce the monofluoro compouind, 3. The sequence of enolization, silylether formation and fluorination with Selectfluor was applied to the monofluoro ketone in order to obtain the difluoro compound,4.

The product by this procedure was obtained in ~90% yield as a mixture of difluoro/monofluoroketone (94/6). Subsequent distillation afforded the difluoro product containing ~2 % of the monofluoro contaminant.

Via an enol acetate intermediate.

Another procedure for the preparation of the difluorobenzazepam was developed via an enol acetate intermediate. This is illustrated in the scheme below. While it was not possible to obtain the enolacetate,2 by reaction of 1 with refluxing isopropenyl acetate/pTsOH, it could be generated by the reaction of the starting ketone with Ac2O at 150oC in the presence of a catalytic amount of pTsOH. This enol acetate, on reaction with Selectfluor in CH3CN, gave the monofluoro ketone, 3 which on ...