Claims:
1. A process for the preparation of compound formula I,

comprising the steps of:
reacting compound of formula II

with compound of formula III

in presence of diphenyl phosphoryl azide and a base to obtain compound formula I.

2. The process according to claim 1, wherein the base is N-methylmorpholine or alkylamine.

3. The process according to claim 1, wherein the reaction of compound formula II with compound formula III is carried out at 50 °C to reflux temperature.
, Description:Field of the Invention
Present invention relates to a novel process for the preparation of phenyl substituted urea derivatives such as compound formula I by using diphenyl phosphoryl azide and further use of the compound formula I for the preparation of Letermovir.

Background of the Invention
Letermovir is suitable for use as antiviral agent, in particular against cytomegaloviruses, such as described in WO 04/096778.

The IUPAC name of compound formula I is 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl) urea.

Compound formula I and a process for the preparation thereof were described in WO 04/096778. The process for the preparation of Letermovir using the compound formula I was described in WO 06/133822.

Traditional synthesis of phenyl substituted urea derivative such as compound formula I involves the reaction of amines with phosgene, carbonic acid derivatives or isocyanate, which has tremendous toxic and associate with environmental problem. Alternative routes have also been developed, which involve amines reacting with urea, ethylene carbonate or diethyl carbonate. However, these expensive reagents originate from by reaction of carbon dioxide with ammonium, ethylene oxide or ethanol. Hence, these processes unfeasible for the industrial scale production.

The present invention relates to a process for the preparation phenyl substituted urea derivative such as compound formula I from carboxylic acid compound and amine compound in presence of diphenyl phosphoryl azide in a one-pot synthesis. The use of diphenyl phosphoryl azide is advantageous over earlier reported processes as it does not require pre-activation of the carboxy group of carboxylic acid compound before reaction with azide donors of amine compound. The process of the present invention also avoids a sequence of multi-step syntheses viz., the formation of acid azide, its rearrangement into isocyante and coupling with an amine and completes in one step.

The process of the present invention for the preparation of compound formula I is also involved usage of easily and commercially available raw materials. The process of the invention is cost effective and industrial viable process. The process of the invention is also useful for the preparation of unsymmetrical urea compound.

Summary of the Invention
One aspect of the present invention is to provide a process for the preparation of phenyl substituted urea derivatives such as compound formula I.

Another aspect of the present invention is to provide a one-pot process for the preparation of phenyl substituted urea derivatives, such as compound formula I.

Another aspect of the present invention is to provide a process for the preparation of unsymmetrical phenyl substituted urea derivatives, such as compound formula I.

Yet another aspect of the present invention is to use of compound formula I for the preparation of Letermovir.

Detailed Description of the Invention
The present invention relates to a process for the preparation of phenyl substituted urea derivatives, such as compound formula I, which allows large-scale industrial production of compound formula I without using toxic reagents.

In one aspect, the present invention is directed to a process for the preparation of compound formula I,

includes the steps of:
a) reacting compound formula II

with compound formula III

in presence of diphenyl phosphoryl azide and a base to obtain compound formula I.

In another aspect of the present invention, compound formula II is reacted with compound formula III in presence of diphenyl phosphoryl azide and a base in a suitable solvent at a suitable temperature to yield compound formula I.

The base is selected from the group comprising of N-methylmorpholine or alkylamines. The alkylamines are selected from triethylamine, di-isopropyl amine or diisopropyl ethylamine. The suitable solvent is selected from methylene chloride, ethyl acetate, tetrahydrofuran, toluene, dimethylformamide or mixture thereof. The reaction is carried out at 50 ºC to reflux temperature.

In one more aspect of the present invention, compound formula I obtained by the process described herein can be used for the preparation of Letermovir.

Present invention is further illustrated with the following non-limiting examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Examples:
Example-1: Preparation of 1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl) phenyl) urea:

To a solution of 2-bromo-6-fluorobenzoic acid (5 gm) and 2-methoxy-5-(trifluoromethyl) aniline (7.45 gm) in toluene (35 mL), diphenyl phosphoryl azide (10.08 gm) and triethyl amine (7.94 g) were added. The mixture was stirred for 15 min. at room temperature. Then, the reaction mixture was heated at 110oC for 18 h. After completion of reaction, the reaction mixture was allowed to cool at room temperature and evaporated under reduced pressure at 50oC. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 X 25 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield off white solid. (7.3 g).

Example-2: Preparation of 2-bromo-6-fluorobenzoic acid

To ice cooled solution of diisopropylamine (33.3 g) in anhydrous THF (400 mL), 2.5 M n-BuLi in n-Hexane (125.7 mL) was slowly added at 0oC and the reaction mixture was stirred at same temperature for 1h. Then, the reaction mixture was cooled to -78°C and solution of 1-bromo-3-fluorobenzene (50 g) in anhydrous THF (100 mL) was added slowly with maintaining reaction temperature below -70°C. After complete addition, the temperature of the reaction mixture was maintained for 1 h. After completion of reaction, the reaction was quenched with dry ice and allowed to warm at room temperature for overnight. The reaction mixture was acidified by using ice cooled 6 N hydrochloric acid till pH ~1 and product was extracted with dichloromethane (3 x 100 mL). The organic layer was washed with water (2 X 100 mL) followed by brine (100 mL). The organic layer was concentrated to yield as off-white solid (60 g).

Example-3: Preparation 1-chloro-2-nitro-4-(trifluoromethyl)benzene

To a cooled solution of concentrated sulphuric acid (200 mL), potassium nitrate (30.8 gm) was added slowly under vigorous stirring at -5 to 0°C and stirred for 1h. 1-chloro-4-(trifluoromethyl) benzene (50 g) was slowly added in 30 min. under vigorous stirring and further stirred for 1 h at 0-10°C temperature. After completion of reaction, the reaction mixture was poured slowly into ice water and stirred for 30 min. The mixture was extracted with ethyl acetate (3 X 500 mL) and the organic layer was then washed by water followed by saturated aq. sodium carbonate (100 mL), water (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated to yield product as a colorless liquid (61.8 g).

Example-4: Preparation of 1-methoxy-2-nitro-4-(trifluoromethyl)benzene

To ice cooled solution of anhydrous methanol (200 mL) under nitrogen atmosphere, sodium metal pieces (8.5 g) were added slowly and stirred for 30 min. To the above solution, 1-chloro-2-nitro-4-(trifluoromethyl) benzene (60.67gm) was slowly added at the same temperature and the reaction mixture was stirred for overnight at room temperature. After completion of reaction, ice water (50 mL) was added with vigorous stirring. The reaction mixture was evaporated under reduced pressure at 40°C, filtered solid and washed with cold water (50 mL). The solid was dried under reduced pressure at 40°C to yield pale-yellow solid (52 gm).

Example-5: Preparation of 2-methoxy-5-(trifluoromethyl)aniline

To a mixture of 1-methoxy-2-nitro-4-(trifluoromethyl) benzene (33 gm), isopropanol (330 mL) and water (86 ml), conc. hydrochloric acid (6.6 ml) was added. Iron powder (60.7 gm) was added in to 2 to 3 lots at 70°C and continued at 70°C for 2 h. After completion of reaction, the reaction mixture was cooled to 50°C and filtered. Ethyl acetate (200 mL) was added in to filtrate and was washed by water (2 X 100 mL) followed by brine (50 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield crude product as pale-yellow solid (27.1 gm).