Process for the preparation of substituted pyrimidines

Details Process for the preparation of substituted pyrimidines Process for the preparation of substituted pyrimidines

2001-06-29

2003-05-06

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S295000

Reexamination Certificate

active

06559307

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to an improved process for the preparation of substituted pyrimidines.
Pyrimidines, which are substituted in the 4-position by a hydrocarbyloxy or hydrocarbylthio group are of great commercial interest as highly effective pesticides or pharmaceuticals. U.S. Pat. No. 3,498,984 discloses 2-phenyl-4-thiopyrimidines with interesting pharmaceutical properties. U.S. Pat. No. 5,824,624 describes herbicidal compositions comprising 2-phenyl-4-oxypyrimidines. The International Patent Applications WO 98/40379 and WO 98/56789 disclose herbicidal 4-oxypyrimidines, in which a 5-membered heteroaromatic group is attached to the 2-position position of the pyrimidine moiety.
These compounds can be prepared for example in a multi-step process including the steps of treating a benzamidine hydrochloride with a substituted acetylacetate in the presence of a strong base to form a 2-phenylpyrimid-4-one, which is subsequently treated with a halogenating agent, in particular a phosphoryl halide to yield a 4-halo-2-phenylpyrimidine, which is reacted with an alcohol or a thioalcohol.
However, this process cannot be used for manufacture of relatively large quantities on an industrial scale due to the high risk of uncontrollable heat generation during the aqueous work up of the halogenation step.
W. Schroth et al., disclose the preparation of 1,3-thiazin-6-thiones by condensation of 3,3-dichloroacrolein and thioamides in the presence of trifluoroborane.
However, there is no motivation to apply this reaction on the manufacture of substituted pyrimidines, especially, since trifluoroborane is not applicable in large scale productions.
SUMMARY OF THE INVENTION
The present invention provides an effective and efficient process for the preparation of substituted pyrimidines of formula I,
wherein
R
1
and R
2
each independently represent an optionally substituted alkyl, cycloalkyl, phenyl or heteroaryl group,
R
3
and R
4
each independently represent a hydrogen atom or an optionally substituted alkyl or phenyl group, and
X represents O or S.
which comprises
reacting an amidine of formula II,
or a salt thereof, wherein R
1
has the meaning given for formula I, with a 3,3-disubstituted vinylcarbonyl compound of formula III
wherein R
3
and R
4
have the meaning given, and
L represent a halogen atom or a group of formula —X—R
2
,
(a) in an inert solvent, in the presence of a base and a compound of formula IV
H—X—R
2
  (IV)
 wherein X and R
2
have the meaning given, in the event that L represent a halogen atom, or
(b) in an inert solvent and in the presence of a base, in the event that L represents a group of formula —X—R
2
.
It is, therefore, an object of the present invention to provide an efficient new process for the preparation of substituted pyrimidines.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the following description and the appended claims.


REFERENCES:
patent: 3498984 (1970-03-01), Santilli et al.
patent: 4824949 (1989-04-01), Lachhein et al.
patent: 4831138 (1989-05-01), Lachhein
patent: 4831139 (1989-05-01), O'Murchu
patent: 5824624 (1998-10-01), Kleeman et al.
patent: 5840892 (1998-11-01), Bessard et al.
patent: 5849758 (1998-12-01), Kleeman et al.
patent: WO 90/06918 (1990-06-01), None
patent: WO 98/30549 (1998-07-01), None
patent: WO 98/40379 (1998-09-01), None
patent: WO 98/56789 (1998-12-01), None
J. Medwid et al., “Preparation of Triazolo [1,5-c] pyridines as Potential Dichlorides and Antiasthma Agents”, J. Med. Chem. 1990 33, 1230-1241.
W. Schroth et al., “Synthesis of 1,3-thiazine-6-thiones From Formylketene Dichlorides and Thioamides”, Z. Chem. 24 (1984), 435-436.
Chemical Abstracts, 103 : 6290 (1985).

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