Process for the preparation of 4,6-dichloropyrimidine

Abstract: A process for preparing 4,6-dichloropyrimidine from 4,6-dihydroxypyrimidine in the presence of a tertiary amine base characterised in that phosgene is added to a mixture of 4,6-dihydroxypyrimidine and a tertiary amine of formula R 1 R 2 R 3 N (wherein R 1 , R 2 and R 3 are, independently C 1-10 alkyl, phenyl, a 3-7 membered carbon nitrogen heteroaryl group or phenyl(C 1-4 )alkyl) in a chlorinated solvent, wherein the molar ratio of 4,6-dihydroxy-pyrimidine:base:phosgene is in the range 1:(0.8 to 2.5):(2.5 to 3.6).

Description: The present invention relates to a process for converting 4,6--dihydroxypyrimidine (1) into 4,6-dichloropyrimidine (2) using phosgene and a suitable base. 4,6-Dichloropyrimidine is useful as a chemical intermediate in the agrochemical industry. It is known, for example, that phosphoryl chloride in the presence of dimethylaniline will convert 4,6-dihydroxypyrimidine to 4,6-dichloropyrimidine (Journal Chemical Society (1943) 574-5, and ibid (1951) 2214). The problem with these methods is that, when used on a large scale, a considerable amount of phosphoric acid by-product is produced and this must be disposed of in some way. It is also known from FR-A-1310810 and EP-A-0173191 that phosgene may be used to chlorinate certain hydroxyl group-containing nitrogen heterocyclic compounds. The present invention provides a process for preparing 4,6-dichloropyrimidine from 4,6-dihydroxypyrimidine in the presence of a tertiary amine base characterised in that phosgene is added to a mixture of 4,6-dihydroxypyrimidine and a tertiary amine of formula R 1 R 2 R 3 N (wherein R 1 , R 2 and R 3 are, independently C 1-10 alkyl, phenyl, a 3-7 membered carbon nitrogen heteroaryl group or phenyl(C 1-4 )alkyl) in a chlorinated solvent, wherein the molar ratio of 4,6-dihydroxypyrimidine:base:phosgene is in the range 1:(0.8 to 2.5):(2.5 to 3.6). 4,6-Dihydroxypyrimidine (1) can also exist in the tautomeric forms (A) and (B) and references to 4,6-dihydroxypyrimidine include all its tautomeric forms. Examples of tertiary amines are triethylamine, 4-( N , N -dimethylamino)-pyridine, N , N -di iso propylethylamine and especially dimethylaniline. Alkyl groups are straight or branched chain and, unless stated otherwise, preferably contain from 1 to 6, especially from 1 to 4, carbon atoms. Examples are methyl, ethyl, iso -propyl, n -propyl, n -butyl and tert -butyl. The 3-7 membered carbon nitrogen heteroaryl group is, for example, pyridine, imidazole, pyrazole or pyrrolidine. The process is carried out in a chlorinated solvent (such as dichloromethane, 1,1,2,2-tetrachloroethane or chlorobenzene). The process is preferably carried out in the temperature range -10°C to 130°C, especially 0°C to 120°C, particularly 10°C to 90°C. In one aspect the present invention provides a process for preparing 4,6-dichloropyrimidine comprising adding phosgene to a mixture of 4,6-dihydroxypyrimidine and the base (such as dimethylaniline or di iso propylethylamine) in a chlorinated solvent, wherein the molar ratio of 4,6-dihydroxypyrimidine:suitable base:phosgene is in the range 1:(0.8 to 2.5):(2.5 to 3.6) especially in the range 1:(1.5 to 2.2):(2.9 to 3.3). In a further aspect the present invention provides a process for preparing 4,6-dichloropyrimidine the process comprising adding phosgene to a mixture of 4,6-dihydroxypyrimidine and the base (such as dimethylaniline) in a chlorinated solvent (such as dichloromethane), all the phosgene to be used in the process being added at the beginning of the process, and heating the reaction mixture (preferably for 1 to 30, especially 1 to 6 or 15 to 24 hours). The suitable base can be recovered (in salt form) during the product isolation and can be recycled. The following Examples illustrate the invention. The apparatus used in the following Examples was dried before use, and reactions were conducted under nitrogen using anhydrous conditions. EXAMPLE 1 4,6-Dihydroxypyrimidine (0.94g) was suspended in dichloromethane, dimethylaniline (1.12g) added and phosgene (5g) was then condensed into the mixture. The resulting mixture was heated at reflux for 24 hours, then cooled and poured into water. High pressure liquid chromatographic (hplc) analysis of the resulting organic layer showed a 4,6-dihydroxypyrimidine: 4,6-dichloropyrimidine ratio of 39:58. EXAMPLE 2 4,6-Dihydroxypyrimidine (20.5g) was dispersed with agitation in dichloromethane (400ml). Dimethylaniline (40.4g) was added to the agitated mixture and the system was sealed (except for a vent line to a scrubber). Phosgene gas (56g) was introduced from a cylinder and condensed onto a cold finger and collected in a pressure equalised dropping funnel. Once collected, the phosgene liquid was added to the reaction mixture over 15 minutes. The mixture was heated and agitated at reflux (29°C approximately) for 17 hours after which time the mixture was cooled to room temperature and the excess phosgene removed by sparging with nitrogen. Water (400ml) was added slowly to the agitated reaction mass with cooling to maintain the temperature at ambient. The organic layer was separated, and the aqueous was then extracted with dichloromethane (2 x 100ml). The combined extracts were dried over anhydrous sodium sulphate and concentrated by rotary evaporation to give 4,6-dichloropyrimidine as an orange crystalline solid (27g), equivalent ot a yield of 80% (hplc analysis).

Claims: A process for preparing 4,6-dichloropyrimidine from 4,6-dihydroxypyrimidine in the presence of a tertiary amine base characterised in that phosgene is added to a mixture of 4,6-dihydroxypyrimidine and a tertiary amine of formula R 1 R 2 R 3 N (wherein R 1 , R 2 and R 3 are, independently C 1-10 alkyl, phenyl, a 3-7 membered carbon nitrogen heteroaryl group or phenyl(C 1-4 )alkyl) in a chlorinated solvent, wherein the molar ratio of 4,6-dihydroxypyrimidine:base:phosgene is in the range 1:(0.8 to 2.5):(2.5 to 3.6). A process as claimed in claim 1 wherein the base is dimethylaniline or di iso propylethylamine. A process as claimed in claim 1 or 2 wherein the chlorinated solvent is dichloromethane.

Inventors: BOWDEN MARTIN CHARLES, BROWN STEPHEN MARTIN, JONES JOHN DAVID, BOWDEN, MARTIN CHARLES, BROWN, STEPHEN MARTIN, JONES, JOHN DAVID
Applicants: SYNGENTA LTD, SYNGENTA LIMITED
Application year: 1995
Main classification: C07D239
IPC codes: C07D239