Browse Prior Art Database

Synthesis of methyl ethyl and phenyl 4 2 methylpropoxy benzyl carbamates

IP.com Disclosure Number: IPCOM000244271D
Publication Date: 2015-Nov-27
Document File: 3 page(s) / 33K

Publishing Venue

The IP.com Prior Art Database

Related People

Balazs Volk: AUTHOR [+2]

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 53% of the total text.

Synthesis of methyl, ethyl and phenyl [4-(2-methylpropoxy)benzyl] carbamates

Molnárné Samu, Erika; Volk, Balázs

Directorate of Drug Substance Development

Egis Pharmaceuticals Plc

The aim of this study is to present a favorable manufacturing process of pharmaceutically interestingurea compounds by avoiding the use of highly toxic phosgene derivatives.

Here, we describe the synthesis of the new phenyl [4-(2-methylpropoxy)benzyl]carbamate (1) entity, and also its ethyl (2) and methyl (3) analogues (Fig. 1.). Isocyanates can be replaced by the corresponding carbamates in the syntheses of ureas, e.g. 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea.

Figure 1. Structure of new precursors of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea

Carbamate precursors were synthetized as outlined in Scheme 1. The known primary amine 4 was reacted with the corresponding chlorocarbonates to give carbamates 1-3 as solid materials in high yields.

Scheme 1. Synthesis of carbamates

(a) toluene, K2CO3; Ph-, Et- or Me-chlorocarbonate; 60-110 °C; 2 h; 80-95%

Carbamates 1-3 can be reacted with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (5)leading to 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea (Scheme 2.).

Scheme 2. Synthesis of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-

3-[4-(2-methylpropoxy)benzyl]urea

The patent application of Jiao, Peifu et al. (CN 104844502) presented a synthesis with a similar aim and concept, in which carbamate derivatives of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (5) and the primary amine 4 intermediates were reacted togive1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea.

Phenyl [4-(2-methylpropoxy)benzyl]carbamate (1).

Potassium carbonate (276 mg, 2 mmol) was added to a solution of 1-[4-(2-methylpropoxy)phenyl]methanamine (4, 359 mg, 2 mmol) in toluene (10 mL), then a toluene solution (10 mL) of phenyl chlorocarbonate(313 mg, 2 mmol) was added slowly. The reaction mixture was stirred for 2 h at reflux temperature. The solid phase was filtered, the filtrate was washed with water, and the organic phase was evaporated in vacuo. The crude product was purified by dry column vacuum chromatography.

Yield: 485 mg, 81%. White crystals. Mp 101 °C.

IR (...