Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1995-08-12
1998-05-12
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C07D23930
Patent
active
057506949
DESCRIPTION:
BRIEF SUMMARY
This is a 35 U.S.C. .sctn.371 national stage application of PCT/GB 95/00676, filed 27 Mar. 1995.
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 especially useful in the preparation of ICIA5504.
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.
The present invention provides a process for preparing 4,6-dichloropyrimidine comprising treating 4,6-dihydroxypyrimidine with phosgene in the presence of a suitable base.
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.
Suitable bases include tertiary amines of formula R.sup.1 R.sup.2 R.sup.3 N (wherein R.sup.1, R.sup.2 and R.sup.3 are, independently, C.sub.1-10 alkyl, aryl, heteroaryl or aryl(C.sub.1-4)alkyl) and heterocyclic amines optionally substituted by C.sub.110 alkyl. Examples of tertiary amines are triethylamine, 4-(N,N-dimethylamino)-pyridine, N,N-diisopropylethylamine and especially dimethylaniline. Examples of heterocyclic amines are pyridine, 2-methylpyridine, 4-methylpyridine, imidazole and N-alkyl pyrrolidines (such as N-methylpyrrolidine).
It is preferred that the base:phosgene molar ratio is in the range 1:10 to 10:1, especially in the range 1:1 to 1:4 (such as 2:3 and 2:4.5).
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.
Aryl is preferably phenyl.
Heterocyclic amines are preferably saturated or unsaturated 3-7 membered carbon nitrogen rings. They are, for example, pyridine, imidazole, pyrrolidine or piperidine.
Heteroaryl is a 3-7 membered carbon nitrogen ring. It is, for example, pyridine, imidazole, pyrazole or pyrrolidine.
It is preferred that the process is carried out in a solvent or mixture of solvents. Chlorinated solvents (such as dichloromethane, 1,1,2,2-tetrachloroethane or chlorobenzene), ethers (such as tetrahydrofuran, glyme, diglyme or triglyme), polar aprotic solvents are preferred. Mixtures of solvents include, for example, a mixture of acetonitrile and dichloromethane.
The process is preferably carried out in the temperature range -10.degree. C. to 130.degree. C., especially 0.degree.C. to 120.degree. C., particularly 10.degree. C. to 90.degree. 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 a suitable base.
In a further aspect the present invention provides a process for preparing 4,6-dichloropyrimidine comprising adding phosgene to a mixture of 4,6-dihydroxypyrimidine and a suitable base, wherein all the phosgene to be used in the process is added at the beginning of the process.
In another aspect the present invention provides a process for preparing 4,6-dichloropyrimidine comprising adding phosgene to a mixture of 4,6-dihydroxypyrimidine and a suitable base (such as dimethylaniline or diisopropylethylamine) 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 yet another aspect the present invention provides a process for preparing 4,6-dichloropyrimidine comprising adding phosgene to a mixture of 4,6-dihydroxypyrimidine and a suitable base (such as dimethylaniline or diusopropylethylamine) in a nitrile solvent, wherein the molar ratio of 4,6-dihydroxypyrimidine:suit
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Bowden Martin Charles
Brown Stephen Martin
Jones John David
Ford John M.
Snyder Joseph R.
Thomson Marian T.
Zeneca Limited
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