IES64136B2

IES64136B2 - Process for manufacturing imidazole derivatives

Info

Publication number: IES64136B2
Authority: IE
Inventors: Nigel Mcsweeney; Philip Sheridan
Original assignee: Vandros Limited
Priority date: 1994-01-19
Filing date: 1994-01-19
Publication date: 1995-07-12
Also published as: IES940039A2

Abstract

1. A process for manufacturing imidazole derivatives of the general formula: wherein R1 represents propyl, and R2 represents 2, 4, 6-trichlorophenoxyethyl;

Description

PROCESS FOR MANUFACTURING IMIDAZOLE DERIVATIVES The present invention relates to a process for manufacturing i imidazole derivatives. In particular the invention relates to a process for the manufacture of N-propyl-N-[2-(2,4,6-trichlorophenoxy) ethyl] carbamoyl imidazole, commonly known as prochloraz. Prochloraz is known to be an ergosterol biosynthesis inhibitor and its resulting fungicidal properties are well documented.

British Patent No. 1,469,772 of The Boots Co. Ltd. discloses a number of processes for the manufacture of imidazole derivatives of the general formula: CYNR'R (1) where Y is oxygen or sulphur and R' and R, amongst other possibilities may be alkyl and substituted phenoxyalkyl respectively.

Specifically, Example 6 of the aboyementioned Boots patent relates to a process for preparing compounds of formula (1) which are structurally very similar to prochloraz. This process may be outlined as follows: 1) A primary amine, R'NHg, is reacted with an alkyl halide RX, to produce a secondary amine R*RNH. 2) The secondary amine is added to a phosgene (carbonyl dichloride) saturated solvent to give the carbamoyl chloride derivative of the amine.

S-.41 36 - 2 3) The carbamoyl chloride is then reacted with imidazole to yield the final product. As disclosed in Example 6, the secondary amine and carbamoyl chloride are each formed in and subsequently isolated in solid form from different solvents, and the carbamoyl chloride/ i 5 imidazole reaction is carried out in a third solvent.

It is an object of the present invention to provide a manufacturing process more simplified than that disclosed in the prior art, which reduces or eliminates the need to isolate reactive intermediates and disposes of the need for three different solvents.

It is a further object of the present invention to provide a manufacturing process in which the reaction times are reduced compared to those required by prior art processes.

Clearly economic benefits may be obtained by the realisation of these objectives.

Accordingly, the present invention provides a process for 20 manufacturing imidazole derivatives of the general formula ; 1 1 2 CONR1R2 2 wherein R represents propyl, and R represents 2,4,6-trichlorophenoxyethyl; comprising the steps of : 1) reacting a primary amine of formula R^NH«, wherein R^ is 2^ 2 defined above, with an alkyl halide of formula R X, wherein R is defined above and X represents Br, Cl or I, to form a secondary amine of formula R^R^NH; - 3 2) reacting the secondary amine thus obtained with carbonyl dichloride to form the equivalent carbamoyl chloride, and 3) reacting said carbamoyl chloride with imidazole to yield a product of general formula (2) above; characterized in that a) step 1) is carried out in excess primary amine which acts as a first solvent; b) the secondary amine formed in step 1) is dissolved in a second s solvent, and c) steps 2) and 3) are carried out in said second solvent.

Preferably, the second solvent is toluene Further preferably, step 2) is carried out at a temperature of between 0°C and 110°C, and step 3) is carried out at a temperature of between 50°C and 110°C.

In step 1) the primary amine is used both as solvent and in an excess of between 5 and 10 fold.

The following example further describes the process according to the present invention.

Example 1 (Preparation of 2-(2,4,6-trichlorophenoxy)ethylbromide) To 1 litre of acetone was added 200g trichlorophenol and 140g potassium carbonate. This was agitated and heated to 45°C. 286g of 1,2-dibromoethane was added and heating and agitation continued for 40 hours. The insoluble inorganic material was removed by filtration and washed with a little acetone. The filtrate was evaporated to yield an oil which solidified on cooling, yielding an off-white solid. This was sufficiently pure for use in the next stage. - 4 (Preparat ion of n-propy1-N-[2-(2,4,6-tr i ch1orophenoxy)]ethy1ami ne. 240g of bromoether was mixed with 234g of n-propylamine and refluxed for 6 hours. On completion, the excess solvent was removed by evaporation. The residue was dissolved in toluene and washed with water and 5N sodium hydroxide. The toluene solution of secondary amine was azeotropically distilled in preparation for the next stage.

(Preparation of n-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl] carbamoyl chloride) 300ml of toluene was saturated with phosgene and heated to reflux. 35g of secondary amine in 150ml of toluene was added dropwise below the surface of the liquid and heating and flow of phosgene was continued for one hour. On completion reaction was purged with dry nitrogen and then azeotropically distilled to yield a dry toluene solution of carbamoyl chloride ready for coupling with imidazole.

(Preparation of n-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl] carbamoyl imidazole) 16g of carbamoyl chloride and 7.8g of imidazole were heated to reflux in 250ml of toluene for 12 hours. Imidazole hydrochloride was separated and the toluene evaporated to yield a viscous oil which solidified on cooling. The prochloraz product was characterized spectroscopically.

Claims

1. ) reacting a primary amine of formula R^NH 9 , wherein R 1 is 2 d 2 defined above, with an alkyl halide of formula R X, wherein R is defined above and X represents Br, Cl or I, to form a secondary amine of formula R^NH; 1 2 wherein R represents propyl, and R represents 2,4,6-trichlorophenoxyethyl; comprising the steps of :

1. A process for manufacturing imidazole derivatives of the j. general formula : conr’r’

2. A process according to Claim 1 wherein the second solvent is toluene. - 6 3. A process according to either of Claims 1 or 2 wherein step 2) is carried out at a temperature of between 0°C and 110°C. 2) reacting the secondary amine thus obtained with carbonyl dichloride to form the equivalent carbamoyl chloride, and

3. ) reacting said carbamoyl chloride with imidazole to yield a product of general formula (2) above; characterized in that a) step 1) is carried out in excess primary amine which acts as a first solvent; b) the secondary amine formed in step 1) is dissolved in a second solvent, and 4 c) steps 2) and 3) are carried out in said second solvent. <

4. A process according to any of Claims 1 to 3 wherein step 3) is > 5 carried out at a temperature of between 50°C and 110°C.

5. A process for manufacturing imidazole derivatives substantially as described herein by way of Example.