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Synthesis of methyl ethyl and phenyl 4 2 methylpropoxy benzyl carbamates Disclosure Number: IPCOM000244271D
Publication Date: 2015-Nov-27
Document File: 3 page(s) / 33K

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Balazs Volk: AUTHOR [+2]

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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)-


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 (...