Process for 4,6-di-substituted 2-aminopyrimidines

New compounds useful as intermediates for biologically-active compounds have the formula I ##STR1## wherein Y is a group having the formula --CH.sub.2 X in which X is F, Cl, or Br, or Y is a group having the formula ##STR2## in which R.sup.2 is F, Cl or Br and R.sup.3 is H, F, Cl, Br or a group having the formula --CR.sup.4 R.sup.5 R.sup.6, in which R.sup.4, R.sup.5 and R.sup.6, independently, are F, Cl or Br; A is H, OH, SH, F, Cl, Br or a group --OR.sup.7 or --SR.sup.7 in which R.sup.7 is C.sub.1 -C.sub.4 straight- or branched chain alkyl, C.sub.2-4 straight- or branched chain alkyl substituted with 1 to 3 F, Cl or Br atoms, or A is a group --NR.sup.8 R.sup.9 in which R.sup.8 and R.sup.9, independently, are H, C.sub.1 -C.sub.4 straight- or branched chain alkyl or C.sub.3 -C.sub.4 alkenyl, or R.sup.8 and R.sup.9 together may form a C.sub.3 -C.sub.7 polymethylene chain, which is optionally interrupted by an oxygen atom; as well as salts of compounds of formula I with acids; provided that: when Y is CH.sub.2 F, then A is as hereinbefore defined other than OH, Cl or OCH.sub.3.

The present invention relates to new chemical compounds, in particular 
2-aminopyrimidines, to processes for their production and to their use as 
intermediates for biologically-active compounds. 
According to the method described in "The Chemistry of Heterocyclic 
Compounds", Vol. XVI, Interscience Publishers, New York; 
2-amino-4-hydroxypyrimidines are produced by reacting the appropriate 
beta-keto ester derivative with guanidine. Moreover, E. D. Bergmann et al. 
J. Chem Soc. 3278 (1959) disclose the reaction of guanidine with the ethyl 
ester of gamma-fluoro-acetoacetic acid to give quantitative yields of the 
compound of formula 
##STR3## 
The art-skilled would, therefore, have had reason to expect that the 
reaction of guanidine with the ethyl ester of gamma-chloro-acetoacetic 
acid would provide good yields of the compound of formula 
##STR4## 
While this reaction has not been reported in the literature, we have found 
that only very low yields of the expected product are obtained. 
Surprisingly, we have now found that, by reacting gamma-haloacetoacetyl 
halides with guanidine (or a salt thereof) good yields of certain 
2-amino-4,6-disubstituted pyrimidine compounds, most of which are new 
compounds, are obtained. 
It is therefore an object of the present invention to provide new 
2-amino-4,6-disubstituted pyrimidines, and processes for producing these 
new compounds. 
According to the present invention, there are provided compounds having the 
formula 
##STR5## 
wherein Y is a group having the formula --CH.sub.2 X in which X is F, Cl, 
or Br, or Y is a group having the formula 
##STR6## 
in which R.sup.2 is F, Cl or Br and R.sup.3 is H, F, Cl, Br or a group 
having the formula --CR.sup.4 R.sup.5 R.sup.6, in which R.sup.4, R.sup.5 
and R.sup.6, independently, are F, Cl or Br; A is H, OH, SH, F, Cl, Br or 
a group --OR.sup.7 or --SR.sup.7 in which R.sup.7 is C.sub.1 -C.sub.4 
straight- or branched chain alkyl, C.sub.2-4 straight- or branched chain 
alkyl substituted with 1 to 3 F, Cl or Br atoms, or A is a group 
--NR.sup.8 R.sup.9 in which R.sup.8 and R.sup.9, independently, are H, 
C.sub.1 -C.sub.4 straight- or branched chain alkyl or C.sub.3 -C.sub.4 
alkenyl, or R.sup.8 and R.sup.9 together may form a C.sub.3 -C.sub.7 
polymethylene chain, which is optionally interrupted by an oxygen atom; as 
well as salts of compounds of formula I with acids; provided that: when Y 
is CH.sub.2 F, then A is as hereinbefore defined other than OH, Cl or 
OCH.sub.3. 
Examples of acids which form salts with the compounds of formula I include 
both inorganic acids, e.g. hydrochloric-, sulphuric-, perchloric- and 
phosphoric acids, and organic acids, e.g. methane-sulphonic-, 
trifluoroacetic- and para-toluene sulphonic acids. 
It will be appreciated that, when substituent A is OH or SH, the 
corresponding compounds of formula I may exist in the following tautomeric 
forms Ia and Ib 
##STR7## 
wherein Z is O or S. 
Such compounds of formula I are amphoteric and also form salts with bases, 
e.g. the hydroxides of the alkali metals. 
When Y is a group of formula --CH.dbd.CR.sup.2 R.sup.3 in which R.sup.2 and 
R.sup.3 have their previous significance, examples of such groups Y 
include --CH.dbd.CF.sub.2, --CH.dbd.CCl.sub.2, --CH.dbd.CBr.sub.2, 
--CH.dbd.C(Cl)CF.sub.3, --CH.dbd.C(Cl)Br and --CH.dbd.C(Cl)F. 
When A is a group --OR.sup.7 or --SR.sup.7, wherein R.sup.7 has its 
previous significance, examples of such groups A include OCH.sub.3, 
OC.sub.2 H.sub.5, OCH.sub.2 CH.sub.2 CH.sub.3, OCH(CH.sub.3).sub.2, 
OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3, OCH.sub.2 CH(CH.sub.3).sub.2, 
OCH.sub.2 CH.sub.2 Cl, OCH.sub.2 CF.sub.3, OCH.sub.2 CH.sub.2 Br, 
SCH.sub.3, SC.sub.2 H.sub.5, SCH.sub.2 CH.sub.2 CH.sub.3, 
SCH(CH.sub.3).sub.2, SCH.sub.2 CH(CH.sub.3).sub.2, SCH.sub.2 CH.sub.2 
CH.sub.2 CH.sub.3, SCH.sub.2 CH.sub.2 Cl, and SCH.sub.2 CH.sub.2 Br. 
When A is a group --NR.sup.8 R.sup.9 in which R.sup.8 and R.sup.9 have 
their previous significance, examples of such groups A include NH.sub.2, 
NHCH.sub.3, N(CH.sub.3).sub.2, NHC.sub.2 H.sub.5, N(CH.sub.3)C.sub.2 
H.sub.5, NHCH.sub.2 CH.sub.2 CH.sub.3, NH(CH.sub.2 CH.sub.3).sub.2, 
N[CH(CH.sub.3).sub.2 ].sub.2, N(CH.sub.2 CH.sub.2 CH.sub.2 
CH.sub.3).sub.2, NHCH.sub.2 CH.dbd.CH.sub.2, N(CH.sub.2 
CH.dbd.CH.sub.2).sub.2, 
##STR8## 
Preferred compounds of formula I are those wherein Y is CH.sub.2 X in 
which X has its previous significance, or Y is --CH.dbd.CR.sup.2 R.sup.3 
in which R.sup.2 and R.sup.3 are Br or, especially Cl, and A has its 
previous significance. 
More preferred are those compounds of formula I, wherein Y is CH.sub.2 X in 
which X is F or Cl, or Y is --CH.dbd.CCl.sub.2, and A is H, OH, SH, F, Cl 
or Br or a group OR.sup.7 or SR.sup.7 in which R.sup.7 is methyl, ethyl or 
2,2,2-trifluoroethyl or A is a group NR.sup.8 R.sup.9 in which R.sup.8 and 
R.sup.9, independently, are hydrogen, methyl or ethyl. 
Still more preferred compounds of formula I are those wherein Y is CH.sub.2 
X in which X is F or Cl and A is F, Cl, Br or a group OR.sup.7 or NR.sup.8 
R.sup.9 in which R.sup.7 is methyl, ethyl or 2,2,2-trifluoroethyl and 
R.sup.8 and R.sup.9, independently, are hydrogen or methyl. 
The new compounds of the formula I are useful as intermediates for the 
preparation of biologically active compounds. For example, they can be 
reacted with a phenylsulfonylisocyanate which is optionally substituted on 
the phenyl ring to form the corresponding 
N-phenylsulfonyl-N'-pyrimidin-2-yl ureas which possess excellent 
herbicidal activity. 
Specific examples of compounds of formula I, and their salts, are set out 
as follows in tabular form: 
______________________________________ 
Compound Y A 
______________________________________ 
1 CH.sub.2 F H 
2 CH.sub.2 F OH 
3 CH.sub.2 F SH 
4 CH.sub.2 F F 
5 CH.sub.2 F Cl 
6 CH.sub.2 F Br 
7 CH.sub.2 F OCH.sub.3 
8 CH.sub.2 F OCH.sub.2 CH.sub.3 
9 CH.sub.2 F OCH.sub.2 CH(CH.sub.3).sub.2 
10 CH.sub.2 F OCHF.sub.2 
11 CH.sub.2 F OCH.sub.2 CF.sub.3 
12 CH.sub.2 F SCH.sub.3 
13 CH.sub.2 F SCH(CH.sub.3).sub.2 
14 CH.sub.2 F SCH.sub.2 CF.sub.3 
15 CH.sub.2 F NH.sub.2 
16 CH.sub.2 F NHCH.sub.3 
17 CH.sub.2 F N(CH.sub.3).sub.2 
18 CH.sub.2 F N(CH.sub.3).sub.2 Hydrochloride 
19 CH.sub.2 F N(CH.sub.3).sub.2 Sulphate 
20 CH.sub.2 F 
##STR9## 
21 CH.sub.2 Cl H 
22 CH.sub.2 Cl OH 
23 CH.sub.2 Cl F 
24 CH.sub.2 Cl Cl (and hydrochloride salt) 
25 CH.sub.2 Cl Br 
26 CH.sub.2 Cl OCH.sub.3 
27 CH.sub.2 Cl OCH.sub.2 CH.sub.2 Cl 
28 CH.sub.2 Cl OCH.sub.2 CF.sub.3 
29 CH.sub.2 Cl OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 
30 CH.sub.2 Cl SH 
31 CH.sub.2 Cl SCH.sub.2 CH.sub.3 
32 CH.sub.2 Cl SCH.sub.2 (CH.sub.3).sub.2 
33 CH.sub.2 Cl SCH.sub.2 CF.sub.3 
34 CH.sub.2 Cl NH.sub.2 
35 CH.sub.2 Cl NHCH.sub.3 
36 CH.sub.2 Cl NHCH.sub.2 CH.sub.3 
37 CH.sub.2 Cl NHCH.sub.2 CHCH.sub.2 
38 CH.sub.2 Cl N(CH.sub.2 CH.sub.3).sub.2 
39 CH.sub.2 Cl N(CH.sub.3).sub.2 
40 CH.sub.2 Cl N[CH(CH.sub.3).sub.2 ].sub.2 
41 CH.sub.2 Cl N(CH.sub.2 CHCH.sub.2).sub.2 
42 CH.sub.2 Cl 
##STR10## 
43 CH.sub.2 Br H 
44 CH.sub.2 Br OH 
45 CH.sub.2 Br F 
46 CH.sub.2 Br Cl 
47 CH.sub.2 Br Br 
48 CH.sub.2 Br OCH.sub.2 CH.sub.2 CH.sub.3 
49 CH.sub.2 Br SH 
50 CH.sub.2 Br SCH.sub. 2 CH.sub.2 CH.sub.3 
51 CH.sub.2 Br NHCH.sub.2 CH.sub.2 CH.sub.3 
52 CH.sub.2 Br N(CH.sub.2 CH.sub.2 CH.sub.3).sub.2 
53 CHCF.sub.2 H 
54 CHCF.sub.2 OH 
55 CHCF.sub.2 F 
56 CHCF.sub.2 OCH.sub.3 
57 CHCF.sub.2 SH 
58 CHCF.sub.2 SCH.sub.3 
59 CHCF.sub.2 NHCH(CH.sub.3).sub.2 
60 CHCF.sub.2 N[CH.sub.2 CH(CH.sub.3).sub.2 ].sub.2 
61 CHCCl.sub.2 H 
62 CHCCl.sub.2 OH 
63 CHCCl.sub.2 OCH.sub.3 
64 CHCCl.sub.2 OCH.sub.2 CH.sub.2 Cl 
65 CHCCl.sub.2 OCH.sub.2 CF.sub.3 
66 CHCCl.sub.2 OCH(CH.sub.3).sub.2 
67 CHCCl.sub.2 SH 
68 CHCCl.sub.2 SCH.sub.2 CH.sub.3 
69 CHCCl.sub.2 SCH.sub.2 CH(CH.sub.3).sub.2 
70 CHCCl.sub.2 Cl 
71 CHCCl.sub.2 SCH.sub.2 CF.sub.3 
72 CHCCl.sub.2 NH.sub.2 
73 CHCCl.sub.2 NHCH.sub.3 
74 CHCCl.sub.2 N(CH.sub.3).sub.2 
75 CHCCl.sub.2 NHCH.sub.2 CH.sub.3 
76 CHCCl.sub.2 N(CH.sub.2 CH.sub.3).sub.2 
77 CHCCl.sub. 2 
##STR11## 
78 CHCCl.sub.2 NHCH.sub.2 CHCH.sub.2 
79 CHCCl.sub.2 N(CH.sub.2 CHCH.sub.2).sub.2 
80 CHCCl.sub.2 
##STR12## 
81 CHCBr.sub.2 H 
82 CHCBr.sub.2 OH 
83 CHCBr.sub.2 F 
84 CHCBr.sub.2 Cl 
85 CHCBr.sub.2 Br 
86 CHCBr.sub.2 OCH.sub.2 CH.sub.3 
87 CHCBr.sub.2 OCH.sub.2 CH.sub.2 CH.sub.3 
88 CHCBr.sub.2 OCH(CH.sub.3).sub.2 
89 CHCBr.sub.2 OCH.sub.2 CF.sub.3 
90 CHCBr.sub.2 SH 
91 CHCBr.sub.2 SCH.sub.3 
92 CHCBr.sub.2 NHCH.sub.2 CH.sub.2 CH.sub.3 
93 CHCBr.sub.2 N(CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3).sub.2 
94 
##STR13## OH 
______________________________________ 
The present invention also provides a first process for producing a 
compound of formula I' 
##STR14## 
wherein A.sup.1 is the same as A as hereinbefore defined or is OCH.sub.3 
or SCH.sub.3 substituted by 1 to 3 Cl, Br or F atoms, comprising: 
(a) reacting, at elevated temperature, a compound having the formula II 
EQU XCH.sub.2 COCH.sub.2 COX.sup.o II 
wherein X and X.sup.o independently, are F, Cl or Br, and X.sup.o is 
especially Cl, with guanidine or a guanidine salt, preferably guanidine 
hydrochloride, to produce a compound having the formula III 
##STR15## 
or the corresponding salt thereof, wherein X has its previous 
significance; 
(b) optionally reacting the compound of formula III with an halogenating 
agent to produce a compound having the formula IV 
##STR16## 
wherein X has its previous significance and halogen is F, Cl or Br; and 
(c) optionally reacting compound IV with a reagent capable of converting 
the halogen substituent into a different substituent A.sup.1, as 
hereinbefore defined. 
Conveniently, the acid halide compound of formula II is heated with an 
excess of a guanidine salt, e.g. the hydrochloride, preferably in the 
absence of a solvent, at a temperature within the range of from 50.degree. 
to 200.degree. C., especially from 100.degree. to 120.degree. C. The 
compound of formula III is then obtained as its salt, e.g. the 
hydrochloride salt, from which the free base may be liberated by 
neutralisation. 
The starting materials of formula II are compounds which are known per se, 
or may be prepared by methods which are well-known to the art-skilled. In 
particular, the preparation of the compound Cl.CH.sub.2.COCH.sub.2 COCl is 
described by C. D. Hurd and J. L. Abernethy, JACS, 1940, 62, 1147. 
In a second process according to the invention: 
(a) a beta-lactone having the formula V 
##STR17## 
is reacted with guanidine, or a guanidine salt, preferably guanidine 
hydrochloride, at elevated temperature, to produce a compound having the 
formula IIIa: 
##STR18## 
or the corresponding salt thereof, and optionally: 
(b) the compound of formula IIIa is reacted with a halogenating agent to 
produce a compound of formula IVa 
##STR19## 
wherein halogen has its previous significance; and optionally 
(c) reacting the compound of formula IVa with a reagent capable of 
converting the ring halogen substituent into a different substituent 
A.sup.1, as hereinbefore defined. 
The first stage of this second process according to the present invention 
is conveniently effected by heating a mixture of the lactone of formula V 
with an excess of a guanidine salt, e.g. guanidine hydrochloride, 
preferably in the absence of a solvent, at a temperature within the range 
of from 50.degree. to 200.degree. C., preferably from 100.degree. to 
120.degree. C. The product of formula IIIa is obtained as its salt, from 
which the free base may be liberated by neutralisation with a basic 
substance such as sodium bicarbonate. 
The starting materials of formula V may be produced by reacting a compound 
having the formula VI 
##STR20## 
with sulphuryl chloride, in the presence of a radical initiator. 
In a third process according to the invention, compounds of formula I" 
##STR21## 
wherein A.sup.1 is the same as A or OCH.sub.3 or SCH.sub.3 substituted by 
1 to 3 Cl, Br of F atoms are produced by: 
(a) reacting a lactone of formula VII 
##STR22## 
wherein R.sup.1 is F, Cl or Br, R.sup.2 and R.sup.3 have their previous 
significance and X.sup.1 is Cl, Br or I with the priviso that when X.sup.1 
is Cl, none of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 can 
be Br, with guanidine or a guanidine salt, preferably the hydrochloride, 
at elevated temperature, to produce a compound having the formula VIII 
##STR23## 
or the corresponding salt thereof, wherein R.sup.2 and R.sup.3 have their 
previous significance; and 
(b) optionally reacting the compound of formula VIII with an halogenating 
agent to produce a compound having the formula IX 
##STR24## 
wherein halogen is F, Cl or Br, R.sup.2 and R.sup.3 have their previous 
significance; and 
(c) optionally reacting the compound of formula IX with a reagent capable 
of converting the ring halogen substituent into a different substituent 
A.sup.1, as hereinbefore defined. 
The third process of the invention is conveniently effected by heating a 
mixture of lactone VII with an excess of guanidine or a guanidine salt, 
preferably the hydrochloride, at 50.degree. to 200.degree. C., especially 
100.degree. to 160.degree. C., for at least one hour. Compound VIII is 
obtained as its salt from which the free base may be obtained by 
neutralisation with a basic substance such as sodium acetate. 
The starting materials of formula VII are described in French Patent 
Specification No. 2 479 215. 
The individual optional process stages (b) are conveniently effected by 
reacting, at elevated temperature, the corresponding starting material 
(compound III, IIIa or VIII) with an halogenating agent conventionally 
used for replacing an OH group by a halogen atom, e.g. phosphorus halides, 
phosphorous oxyhalides and sulphur oxyhalides, in particular phosphorus 
tri- and pentachloride, phosphorus tri- and pentabromide, phosphoryl 
chloride, phosphoryl bromide, thionyl chloride or thionyl bromide; as well 
as cyanuric fluoride. 
The individual optional process stages (c) each involve well-known 
conversion techniques, for instance the reaction of the respective 
starting materials IV, IVa or IX, in which A.sup.1 is F, Cl or Br, with a 
nucleophilic reagent, e.g. alkoxides and amines capable of displacing the 
halogen group. 
Further illustrative, non-limiting reaction schemes for the respective 
optional steps (c) are outlined below: 
##STR25## 
wherein Y, R.sup.7, R.sup.8 and R.sup.9 have their previous significance; 
##STR26## 
wherein A is Cl or Br and X is Cl or Br; 
##STR27## 
wherein A is F, Cl or Br.

The present invention is further illustrated by the following Examples, in 
which parts and percentages shown therein are by weight. 
EXAMPLE 1 
2-Amino-4-chloromethyl-6-hydroxypyrimidine 
(a) 2.5 parts of benzoyl peroxide (containing 25% of water) was suspended 
in 408 parts of carbon tetrachloride. The mixture was stirred to dissolve 
the benzoyl peroxide, then dried over magnesium sulphate. To this solution 
was added 67.5 parts of sulphuryl chloride and the resulting solution was 
added dropwise over 1.5 hours to a refluxing solution of 42 parts of 
diketene in 816 parts of carbon tetrachloride. At the end of the addition, 
the mixture was heated under reflux for a further 1.5 hours, then the 
carbon tetrachloride was removed at the water pump. Distillation of the 
residue at 0.01 mb gave 4-chloro-4-chloromethyloxetan-2-one b.p. 
35.degree.-36.degree. C. which crystallised on cooling below 20.degree. C. 
(b) 620 parts of 4-chloro-4-chloromethyloxetan-2-one and 440 parts of 
guanidine hydrochloride were charged to a reaction flask and the mixture 
was stirred and heated under nitrogen purge as the bath temperature was 
gradually raised to 120.degree. C. When the bath temperature approached 
100.degree. C., reaction commenced accompanied by evolution of hydrogen 
chloride. When the initial reaction subsided after a few minutes the bath 
temperature was raised to 130.degree. C. and held until the reaction 
ceased as indicated by cessation of gassing (about 1 hour). The reaction 
mixture was allowed to cool about 60.degree. C. and 1750 parts of water 
was added to the syrup. The solution was extracted with 500 parts of ethyl 
acetate and the extract was discarded. The aqueous phase was treated with 
decolourising charcoal, filtered and the pH was adjusted to pH 8 by the 
addition of saturated aqueous sodium bicarbonate solution. The 
precipitated solid was filtered, washed with water and dried to constant 
weight at 80.degree. C. in a vacuum oven to give 
2-amino-4-chloromethyl-6-hydroxypyrimidine, m.p. 195.degree.-197.degree. 
C. 
C.sub.5 H.sub.6 ClN.sub.3 O requires C, 37.63; H, 3.79; N, 26.33; Cl, 22.22 
Found C, 37.54; H, 3.81; N, 26.16; Cl, 22.36 
EXAMPLE 2 
2-Amino-4-chloromethyl-6-hydroxypyrimidine 
A solution of 7.1 parts of chlorine in 80 parts of carbon tetrachloride was 
added, dropwise, with stirring, to a solution of 8.4 parts of diketene in 
carbontetrachloride (160 parts) at -20.degree. to -25.degree. C. When the 
addition was complete, the solution was allowed to warm to 0.degree. C., 
and the solvent was removed in vacuo at below 20.degree. C. To the 
residual 4-chloroacetoacetyl chloride was added 19.0 parts of guanidine 
hydrochloride and the mixture was heated in an oil bath at 100.degree. C. 
for 1 hour, with stirring. The temperature was raised to 120.degree. C. 
for 15 minutes and the mixture was then cooled. The product was dissolved 
in 200 parts of warm water and extracted with 50 parts of ethyl acetate. 
The extract was discarded and the aqueous phase was stirred with 0.5 parts 
of decolourising charcoal, filtered and neutralised by the addition of 
saturated sodium acetate solution. The solid product was filtered, washed 
with water and dried to give 2-amino-4-chloromethyl-6-hydroxy-pyrimidine 
identical to that obtained in Example 1. 
EXAMPLE 3 
2-Amino-4-(2,2-dichlorovinyl)-6-hydroxypyrimidine 
119 Parts of 4-chloro-4-(2,2,2-trichloroethyl)-oxetan-2-one and 95.5 parts 
of guanidine hydrochloride were charged to a reaction flask and heated in 
an oil bath at 140.degree. C. for 15 minutes. The solid dissolved and HCl 
gas was evolved. The oil bath temperature was raised to 160.degree. C. and 
heating was continued for a further 45 minutes. The heat was removed and 
the reaction mass was stirred until cool and solidified. The solid was 
stirred with 250 parts of ethyl acetate and filtered. The filtrate was 
discarded and the solid dissolved in 1000 parts of hot water, treated with 
charcoal and filtered. The aqueous solution was cooled and neutralised by 
the addition of saturated sodium acetate solution. The precipitated solid 
was filtered and washed with water. This crude product was then dissolved 
in 550 parts of concentrated hydrochloric acid, diluted with 800 parts of 
water and stirred with 5 parts of charcoal for 20 minutes. The solution 
was filtered and the product precipitated by the addition of saturated 
sodium acetate solution to pH 6. The solid was filtered, washed with water 
and dried in a vacuum oven at 110.degree. C. to give 
2-amino-4-(2,2-dichloro-vinyl)-6-hydroxypyrimidine m.p. 
245.degree.-248.degree. C. (decomposition). 
C.sub.6 H.sub.5 Cl.sub.2 N.sub.3 O requires C, 34.98; H, 2.45; N, 20.40 
Found C, 35.08; H, 2.35; N, 20.10 
EXAMPLE 4 
2-Amino-4-chloro-6-chloromethylpyrimidine 
47.9 Parts of 2-amino-4-chloromethyl-6-hydroxypyrimidine was added 
portionwise to 410 parts of phosphorus oxychloride with stirring. The 
mixture was placed in an oil bath at 130.degree. C. and stirred until all 
the solid had dissolved and then for a further 10 minutes. The solution 
was cooled and the excess of phosphorus oxychloride was removed in vacuo. 
The residual viscous oil was poured onto 300 parts of ice with stirring 
and the pH of the resulting mixture was adjusted to pH 8 by the 
portionwise addition of solid sodium bicarbonate. The mixture was 
extracted four times with diethyl ether. The ether extracts were combined, 
dried over anhydrous magnesium sulphate and evaporated to give a 
pale-yellow solid. Recrystallisation from carbon tetrachloride gave pure 
2-amino-4-chloro-6-chloromethylpyrimidine m.p. 126.degree.-128.degree. C. 
C.sub.5 H.sub.5 Cl.sub.2 N.sub.3 requires C, 33.73; H, 2.83; N, 23.60; Cl, 
39.83 
Found C, 33.80; H, 2.82; N, 23.40; Cl, 40.19 
EXAMPLE 5 
2-Amino-4-chloro-6-(2,2-dichlorovinyl)pyrimidine 
10 Parts of 2-amino-4-(2,2-dichlorovinyl)-6-hydroxypyrimidine and 66 parts 
of phosphorus oxychloride were heated together under reflux for 1 hour 
with stirring. The solution was cooled and excess phosphorus oxychloride 
was removed in vacuo on a rotary evaporator. The residual viscous oil was 
poured onto ice, with stirring. Solid sodium bicarbonate was added 
portionwise until the solution had pH 7-8. The precipitated solid was 
filtered, washed with water and dried. Recrystallisation from aqueous 
methanol gave 2-amino-4-chloro-6-(2,2-dichlorovinyl)pyrimidine m.p. 
119.degree.-120.degree. C. 
C.sub.6 H.sub.4 Cl.sub.3 N.sub.3 requires C, 32.10; H, 1.79; N, 18.72 
Found C, 32.36; H, 1.76; N, 18.67 
EXAMPLE 6 
2-Amino-4-chloromethyl-6-methoxypyrimidine 
8.9 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine was dissolved in 200 
parts of dry methanol at 35.degree. C. A solution of sodium methoxide, 
prepared by dissolving 1.2 parts of sodium in 20 parts of dry methanol, 
was added dropwise over 1.5 hour. The solution was stirred at room 
temperature for 3 hours then evaporated in vacuo. 
The residue was partitioned between 150 parts of diethyl ether and 100 
parts of water. The ether phase was separated, washed three times with 
water, dried over anhydrous magnesium sulphate, filtered and evaporated. 
The residue was chromatographed on a silica column, eluted with a mixture 
of 40.degree.-60.degree. C. petroleum ether and diethyl ether (2:1 
respectively) to give 2-amino-4-chloromethyl-6-methoxypyrimidine m.p. 
89.degree.-90.degree. C. 
C.sub.6 H.sub.8 ClN.sub.3 O requires C, 41.51; H, 4.65; N, 24.21; Cl, 20.42 
Found C, 41.48; H, 4.53; N, 23.92; Cl, 19.87 
EXAMPLE 7 
2-Amino-4-(2,2-dichlorovinyl)-6-methoxypyrimidine 
22.0 Parts of 2-amino-4-chloro-6-(2,2-dichlorovinyl)pyrimidine was 
dissolved in 500 parts of dry methanol and stirred whilst a solution of 
sodium methoxide, prepared by dissolving 4.6 parts of sodium in 200 parts 
of dry methanol, was added dropwise, over 30 minutes at ambient 
temperature. The resulting solution was stirred for 4 hours by which time 
all the starting material had been consumed. The product was precipitated 
by the addition of water, filtered and dried. The solid obtained was 
purified by chromatography on silica using diethyl ether as eluent. Final 
purification was effected by recrystallisation from carbon tetrachloride 
to give 2-amino-4-(2,2-dichlorovinyl)-6-methoxypyrimidine m.p. 
90.degree.-91.degree. C. 
C.sub.7 H.sub.7 Cl.sub.2 N.sub.3 O requires C, 38.20; H, 3.21; N, 19.09 
Found C, 38.23; H, 3.09; N, 18.90 
EXAMPLE 8 
2-Amino-4-chloromethyl-6-dimethylaminopyrimidine 
8.1 Parts of dimethylamine hydrochloride was added to a solution of 2.3 
parts of sodium in 20 parts of methanol. The resulting mixture was added 
dropwise with stirring over about 10 minutes to a solution of 9.9 parts of 
2-amino-4-chloro-6-chloromethylpyrimidine in 50 parts of methanol. The 
reaction was monitored by TLC and when reaction was complete the solvent 
was evaporated and the residue stirred with about 20 parts of water. The 
solid obtained was filtered and dried. The product was purified by 
chromatography on silica, eluted with ethyl acetate, followed by 
sublimation at 110.degree. C./0.04 mb to give 
2-amino-4-chloromethyl-6-dimethylaminopyrimidine m.p. 
127.degree.-129.degree. C. 
C.sub.7 H.sub.11 ClN.sub.4 requires C, 45.04; H, 5.94; N, 30.02 
Found C, 45.19; H, 5.90; N, 29.78 
EXAMPLE 9 
2-Amino-4-fluoro-6-fluoromethylpyrimidine 
A mixture of 26.7 parts of 2-amino-4-chloro-6-chloromethylpyrimidine, 79.0 
parts of caesium fluoride and 200 parts of dry dimethylformamide was 
stirred under reflux for 2 hours. The mixture was cooled and evaporated in 
vacuo. The residue was partitioned between ethyl acetate and water and 
some insoluble solid was removed by filtration. The ethyl acetate phase 
was separated and the aqueous phase was extracted four times with ethyl 
acetate. The organic extracts were combined, washed twice with water, 
dried over magnesium sulphate and evaporated. The crude product was 
purified by chromatography on silica, eluted with mixtures of ethyl 
acetate and dichloromethane, the concentration of ethyl acetate being 
gradually increased from 25% to 80%, to give 
2-amino-4-fluoro-6-fluoromethylpyrimidine m.p.189.degree.-190.degree. C. 
C.sub.5 H.sub.5 F.sub.2 N.sub.3 requires C, 41.38; H, 3.48; N, 28.96 
Found C, 41.34; H, 3.47; N, 29.07 
EXAMPLE 10 
2-Amino-4-fluoromethyl-6-methoxypyrimidine 
A mixture of 17.0 parts of 2-amino-4-chloromethyl-6-methoxypyrimidine, 59.5 
parts of caesium fluoride and 130 parts of dry dimethylformamide was 
stirred under reflux for 2 hours. The mixture was cooled and evaporated in 
vacuo. The residue was taken up in ethyl acetate and the solution was 
washed four times with water. The organic phase was dried with anhydrous 
magnesium sulphate, stirred with decolourising charcoal, filtered and 
evaporated. The crude product was purified by chromatography on silica, 
eluted with ethyl acetate to give 
2-amino-4-fluoromethyl-6-methoxypyrimidine m.p. 119.degree.-121.degree. C. 
C.sub.6 H.sub.8 FN.sub.3 O requires C, 45.86; H, 5.13; N, 26.74 
Found C, 45.83; H, 5.06; N, 26.64 
EXAMPLE 11 
2-Amino-4-chloro-6-fluoromethylpyrimidine 
(a) A mixture of 20 parts of 2-amino-4-chloro-6-chloromethylpyrimidine, 70 
parts of dry caesium fluoride and 390 parts of dry acetonitrile was 
stirred under reflux for 17 hours. The mixture was cooled and evaporated 
in vacuo. 
The resulting residue was purified by chromatography on silica, eluted with 
mixtures of ethyl acetate and dichloromethane, the concentration of ethyl 
acetate being gradually increased from 25% to 35% to give a mixed product 
containing 2-amino-4-chloro-6-fluoromethylpyrimidine and 
2-amino-4-fluoro-6-fluoromethyl-pyrimidine. 
(b) 6.7 parts of a mixture of 2-amino-4-chloro-6-fluoromethylpyrimidine (A) 
and 2-amino-4-fluoro-6-fluoromethylpyrimidine (B) containing 20% B was 
suspended in 160 parts of absolute ethanol. To this suspension was added 
15.2 parts of 0.5M ethanolic sodium ethoxide dropwise over 15 minutes. The 
reaction mixture was heated to 45.degree. C. and stirred for a further 30 
minutes. Evaporation of the reaction mixture gave a white solid which was 
partitioned between water and ethyl acetate and the aqueous phase 
extracted four times with ethyl acetate. The organic extracts were 
combined, washed with water, dried over magnesium sulphate and evaporated 
to give a white solid. The white solid product was purified by 
chromatography on silica, eluted with mixtures of ethyl acetate and 
dichloromethane, the concentration of ethyl acetate being gradually 
increased from 25% to 70%. The first fifteen fractions were combined and 
evaporated to dryness and the solid product so obtained was recrystallised 
from cyclohexane containing 15% ethyl acetate to give 
2-amino-4-chloro-6-fluoromethylpyrimidine m.p. 159.degree. C. 
The remaining fractions were combined and evaporated to give a solid (C). 
EXAMPLE 12 
2-Amino-4-ethoxy-6-fluoromethylpyrimidine 
Solid C prepared according to Example 11b was recrystallised from 
cyclohexane to give 2-amino-4-ethoxy-6-fluoromethylpyrimidine m.p. 
85.degree.-87.degree. C. 
C.sub.7 H.sub.10 FNO requires C, 49.12; H, 5.89; N, 24.55 
Found C, 49.23; H, 5.94; N, 24.65 
EXAMPLE 13 
2-Amino-4-fluoromethyl-6-methylthiopyrimidine 
A mixture of 1.0 part of 2-amino-4-fluoro-6-fluoromethylpyrimidine, 3.0 
parts of methanethiol and 50 parts of dry tetrahydrofuran was stirred at 
5.degree. C. whilst a solution of 0.16 parts of sodium in 20 parts of dry 
methanol was added dropwise. The temperature was kept below 10.degree. C. 
with ice-bath cooling. When the addition was complete, stirring was 
continued for 1 hour. The resulting solution was evaporated and the 
residue was diluted with water and extracted three times with 50 parts of 
ether. The ethereal solutions were combined and dried (MgSO.sub.4). The 
solvent was evaporated and the crude product was purified by 
recrystallisation from carbon tetrachloride to give 
2-amino-4-fluoromethyl-6-methylthiopyrimidine m.p. 95.degree.-97.degree. 
C. 
C.sub.6 H.sub.8 FN.sub.3 S requires C, 41.61; H, 4.66; N, 24.27 
Found C, 41.71; H, 4.89; N, 24.24 
EXAMPLE 14 
2-Amino-4-n-butoxy-6-chloromethylpyrimidine 
3,56 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine and 2.24 parts of 
potassium t-butoxide were dissolved in 60 parts of n-butanol at room 
temperature then the solution was heated at 50.degree. C. for 2 hours, 
with stirring. After this time, the solution was cooled and evaporated in 
vacuo. The residue was partitioned between ethyl acetate and water and the 
organic phase was separated and washed three times with water then dried 
(MgSO.sub.4). Evaporation of the solvent gave the crude product which was 
purified by chromatography on silica (Merck Kieselgel 60) eluted with 
ether to give 2-amino-4-n-butoxy-6-chloromethylpyrmidine as an oil. 
C.sub.9 H.sub.14 ClN.sub.3 O requires C, 50.12; H, 6.54; N, 19.48 
Found C, 49.89; H, 6.52; N, 19.50 
EXAMPLE 15 
2-Amino-4-chloromethyl-6-(N-morpholino)pyrimidine 
3.56 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine was stirred with 40 
parts of dry methanol and a solution of 3.5 parts of morpholine in 12 
parts of dry methanol was added dropwise over 10 minutes during which time 
all the solid dissolved. The solution was stirred at room temperature for 
5 hours then left to stand overnight. The solvent was evaporated and the 
residue was dissolved in ethyl acetate and the solution was washed three 
times with water, dried (MgSO.sub.4) and evaporated. The product was 
recrystallised from toluene and then further purified by chromatography on 
silica (Merck Kieselgel 60) eluted first with ether and then with ethyl 
acetate. Recrystallisation from ethyl acetate gave 
2-amino-4-chloro-methyl-6-(N-morpholino)pyrimidine m.p. 
138.degree.-140.degree.. 
C.sub.9 H.sub.13 ClN.sub.4 O requires C, 47.26; H, 5.74; N, 24.50 
Found C, 47.34; H, 5.82; N, 24.64 
EXAMPLE 16 
2-Amino-4-chloromethyl-6-diallylaminopyrimidine 
3.56 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine and 3.9 parts of 
diallylamine were reacted together according to the method of Example 15 
to give 2-amino-4-chloromethyl-6-diallylaminopyrimidine m.p. 
53.degree.-55.degree. C. 
C.sub.11 H.sub.15 ClN.sub.4 requires C, 55.33; H, 6.34; N, 23.47 
Found C, 55.34; H, 6.37; N, 23.49 
EXAMPLE 17 
2-Amino-4-chloro-6-chloromethylpyrimidine hydrochloride 
3.56 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine was dissolved in 53 
parts of dry diethyl ether and dry hydrogen chloride was bubbled through 
the solution, with stirring, until no further solid precipitated the solid 
was filtered, washed with ether and dried in vacuo. Recrystallisation from 
acetone gave 2-amino-4-chloro-6-chloromethyl-pyrimidine hydrochloride m.p. 
145.degree.-150.degree. C. (decomposition). 
C.sub.5 H.sub.6 Cl.sub.3 N.sub.3 requires C, 28.00; H, 2.82; N, 19.59 
Found C, 28.05; H, 2.82; N, 19.65 
EXAMPLE 18 
2-Amino-4-chloromethyl-6-(2,2,2-trifluoroethoxy)pyrimidine 
0.23 Parts of sodium metal was added to 10 parts of 2,2,2-trifluoroethanol 
with stirring and ice-bath cooling. The mixture was then stirred for 
several hours at room temperature until the sodium dissolved. This 
solution was added dropwise, over 30 minutes, to a stirred suspension of 
1.78 parts of 2-amino-4-chloro-6-chloromethyl-pyrimidine in 25 parts of 
2,2,2-trifluoro-ethanol and the resulting mixture was stirred at 
60.degree. C. for 18 hours. A further 0.1 parts of sodium was dissolved in 
10 parts of 2,2,2-trifluoroethanol and added to the reaction mixture. 
Stirring at 60.degree. C. was continued for a further 24 hours then the 
reaction mixture was cooled and evaporated in vacuo. The residue was 
partitioned between ethyl acetate and water. The organic layer was 
separated, washed with water, dried (MgSO.sub.4) and evaporated. The crude 
product was purified by chromatography on silica (Merck Kieselgel 60 using 
a 50:50 mixture of ether and 40.degree.-60.degree. petroleum ether as 
eluent followed by recrystallisation from a mixture of 
60.degree.-80.degree. petroleum ether and ethyl acetate to give 
2-amino-4-chloromethyl-6-(2,2,2-trifluoroethoxy)pyrimidine m.p. 
77.degree.-78.degree. C. 
C.sub.7 H.sub.7 ClF.sub.3 N.sub.3 O requires C, 34.79; H, 2.93 
Found C, 34.70; H, 3.04 
EXAMPLE 19 
2-Amino-6-fluoromethylpyrimidin-4-one 
12.1 Parts of 2-amino-4-fluoro-6-fluoromethylpyrimidine was dissolved in 
200 parts of 20% aqueous acetic acid at reflux, with stirring. The mixture 
was heated under reflux for 1 hour then cooled. The precipitated solid was 
filtered, washed with 50% aqueous acetic acid and then with acetone. The 
solid was dried in vacuo at 140.degree. C. to give 
2-amino-6-fluoromethylpyrimidine-4-one, m.p. 237.degree.-238.degree. C. 
(decomposition). 
'H NMR: (.delta., DMSO-d.sub.6); 5.05 (d, 2H); 5.60 (S, 1H); 6.85 (br. s, 
2H), D.sub.2 O replaceable); 8.60 (br. s, 1H, D.sub.2 O replaceable).