Production of triazinones

Compounds of the formula (I) ##STR1## (in which X represents HS-- or a group R.sub.1 R.sub.2 N-- wherein R.sub.1 and R.sub.2 which may be the same or different represent hydrogen or a straight or branched chain alkyl group containing from 1 to 4 carbon atoms or a benzyl group and R.sub.3 represents a C.sub.3-7 alkyl group or a C.sub.3-7 cycloalkyl group) are prepared by reacting an .alpha.-ketoester of the formula (II) ##STR2## (in which Alk represents an alkyl group) or a precursor thereof with a compound of the formula (III) ##STR3## The precursor of the compound of formula (II) may be a mixture of isomeric enol esters ##STR4## The compounds of formula (I) may be converted into compounds of formula VIII ##STR5## in which R.sub.1 and R.sub.2 which may be the same or different represent hydrogen or a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, and R.sub.3 is as defined above.

This invention relates to an improved process for the preparation of 
heterocyclic compounds, in particular triazinones and to the use thereof 
in the production of compounds which have pharmacological activity in 
particular imidazotriazinones. 
In United Kingdom patent specification No. 1,400,999 there are described 
and claimed certain imidazo [5,1-f] triazinones which have pharmacological 
activity. 
It is an object of the present invention to provide an improved process for 
the preparation of these compounds, which not only offers advantages in 
the number of process steps involved but also in the yield of the desired 
end product. 
The present invention is particularly concerned with the preparation of 
triazinones of the formula (1) 
##STR6## 
in which X represents HS-- or a group R.sub.1 R.sub.2 N-- wherein R.sub.1 
and R.sub.2 which may be the same or different, represent hydrogen or a 
straight or branched chain alkyl group containing from 1 to 4 carbon atoms 
or a benzyl group, and R.sub.3 represents a C.sub.3-7 alkyl group or a 
C.sub.3-7 cycloalkyl group; 
and their conversion into imidazo [5,1-f]-1,2,4-triazin-4(3H)-ones. 
According to one aspect of the invention we have found that triazinones of 
formula (I) may readily be prepared by the reaction of an 
.alpha.-ketoester of the general formula (II): 
##STR7## 
in which R.sub.3 has the meanings given above and Alk is an alkyl group 
preferably having 1 to 3 carbon atoms, or a precursor thereof, with a 
compound of the formula (III): 
##STR8## 
in which X has the meanings given above. 
It will be appreciated that the compound of formula (III) may exist in 
tautomeric forms, and it is intended that all such tautomers should be 
included. 
When X represents --NR.sub.1 R.sub.2, the above reaction may conveniently 
be effected in a suitable solvent, such as an alkanol e.g. ethanol, or 
dimethylformamide, with heating. 
When X represents --SH, the reaction requires the presence of a base, e.g. 
sodium ethoxide, to proceed to completion and maybe carried out in two 
stages, if desired. 
The compound of formula (III) may, if desired, be in the form of an acid 
addition salt, such as a bicarbonate, hydrochloride, nitrate or 
hydroiodide. 
The reaction is particularly applicable to the production of compounds in 
which --NR.sub.1 R.sub.2 is NH.sub.2 Examples of the group R.sub.3 are 
propyl and isobutyl. 
The conversion of the triazinones into imidazo[5,1-f]triazinones may be 
effected by processes generally described in United Kingdom patent 
specification No. 1,400,999. Thus triazinones of formula (I) in which X is 
R.sub.1 R.sub.2 N-- may be cyclised directly to the desired end product by 
heating with a cyclodehydrating agent such as phosphorous oxychloride or 
polyphosphoric acid. Triazinones of formula I in which R.sub.1 and/or 
R.sub.2 represents benzyl may be debenzylated on cyclisation. 
Triazinones of formula (I) in which X is a thiol group (--SH) may be 
converted into triazinones of formula (I) in which X represents R.sub.1 
R.sub.2 N by S-alkylation with an alkyl halide (e.g. methyl iodide) and 
reaction of the alkylthio compound of formula (IV) so produced, in which 
Alk' is a lower alkyl group (e.g. methyl) and R.sub.3 is as defined 
previously, with an amine of the formula R.sub.1 R.sub.2 NH or, in the 
case where X represents --NH.sub.2, with an ammonium salt (e.g. ammonium 
sulphate). 
##STR9## 
The .alpha.-ketoesters of general formula (II) may be prepared from an 
N-acylamino acid of the formula (V) 
EQU R.sub.3 CONHCH(CH.sub.3)COOH (V) 
by acylation with a suitable oxalyl halide in a manner similar to the 
Dakin-West reaction using for example an alkyl oxalyl chloride, in the 
presence of a suitable base such as pyridine or picoline optionally in the 
presence of a catalyst (e.g. dimethylaminopyridine) and with an additional 
solvent (e.g. tetrahydrofuran), at reflux. The products of this reaction 
are the intermediate isomeric enol esters of the formulae (VI) and (VII). 
##STR10## 
These esters may then be hydrolysed, for example, with a mild acid or base 
to the .alpha.-ketoester of formula (II), or preferably they may be 
reacted with a compound of formula (III), particularly an aminoguanidine 
salt in which --NR.sub.1 R.sub.2 is NH.sub.2, to give a triazinone of 
formula (I). 
The N-acylamino acid of formula (V) may be prepared by the acylation of 
DL-alanine with an appropriate acylating agent for example an acid 
anhydride. 
The present invention is particularly of interest for the production of 
2-amino-5-methyl-7-propylimidazo[5,1-f]1,2,4-triazin-4(3H)-one, which is 
disclosed and claimed in the United Kingdom specification referred to 
above and which is obtained by the cyclisation of a compound of formula 
(I) in which R.sub.3 is propyl and X is --NH.sub.2. As disclosed in that 
specification this compound of formula (I) can be prepared from 
diethyloxalopropionate and aminoguanidine, however only in a six stage 
process and in low yield. According to the present process the appropriate 
compound of formula I may be prepared from a more readily available 
starting material, DL-alanine in fewer stages and in good yield. 
PREATION OF STARTING MATERIALS 
Preparation 1 
Ethyl-3-butyramido-2-oxo-butyrate 
Ethyl oxalyl chloride (409.5 g) was added dropwise with stirring to a 
solution of butyrylalanine (238.5 g), anhydrous pyridine (355.5 g) and 
4-dimethylaminopyridine (6 g) in anhydrous tetrahydrofuran (1 liter) at a 
rate sufficient to initiate refluxing. The mixture was heated to maintain 
a gentle reflux for 11/2 hours, then cooled, diluted with water (1 liter) 
and extracted with ethyl acetate (3.times.500 ml). The extract was washed 
with water (2.times.250 ml) and dried (anhydrous sodium sulphate). Removal 
of the solvent gave a mixture of enol esters as an orange syrup. This 
material contained polar impurities which were removed by column 
chromatography in two batches. The crude product was absorbed onto silica 
gel (2.times.700 g) and eluted with cyclohexane-ethyl acetate (3:1) to 
give the purified enol esters (293 g). 
This material was dissolved in absolute ethanol (270 ml) and heated at 
reflux in the presence of sodium bicarbonate (66 g) for 21/2 hours. The 
mixture was cooled and sodium bicarbonate removed by filtration. The 
filtrate was concentrated to give the .alpha.-ketoester as a golden-yellow 
syrup (200 g). 
Purification of the product could be effected by chromatography on a column 
of silica gel (cyclohexaneethyl acetate, 3:1.fwdarw.1:1), to give a pale 
yellow viscous oil that crystallised on trituration with pentane-ether at 
ca. 10.degree.. Recrystallisation from pentane-ether gave the title 
compound m.p. 46.5.degree.-49.5.degree.. 
Preparation 2 
Ethyl-3-isovaleramido-2-oxo-butyrate 
Ethyl oxalyl chloride (212 g) was added dropwise with stirring to a 
solution of isovalerylalanine (136 g) and pyridine (186.5 g) in anhydrous 
tetrahydrofuran (500 ml) at a rate sufficient to initiate refluxing. The 
reaction mixture was stirred and heated at reflux for 5 hours. The cooled 
reaction mixture was treated with water (1000 ml) and extracted with ethyl 
acetate (4.times.400 ml). The combined organic extracts were washed with 
water (3.times.200 ml) and dried (anhydrous sodium sulphate). Removal of 
solvent provided a yellow syrup which was evaporated with benzene 
(2.times.200 ml) to yeild the isomeric enol esters of the title compound. 
These were dissolved in absolute ethanol (400 ml) and heated at reflux in 
the presence of sodium bicarbonate (70 g) for 3 hours. After cooling, the 
sodium bicarbonate was filtered off and the filtrate was evaporated in 
vacuo. The resultant residue was taken up in ethyl acetate (500 ml) and 
washed with water (4.times.100 ml). The dried (anhydrous sodium sulphate) 
ethyl acetate phase was evaporated in vacuo to provide crude 
.alpha.-ketoester as a golden syrup, 147 g. 
Purification using a similar procedure to that described in Preparation 1 
gave the title compound, m.p. 52.degree.-53.5.degree. (from pentane-ether) 
.

EXAMPLE 1 
N-[1-(3-Amino-2,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]butyramide 
Aminoguanidine bicarbonate (2.4 g) was suspended in a solution of ethyl 
3-butyramido-2-oxo-butyrate (3.8 g) in absolute ethanol (40 ml) and the 
mixture was heated under reflux for 5 hours. During this period 
aminoguanidine bicarbonate gradually dissolved and a new product 
precipitated as a white solid. The mixture was cooled and the solid (2.62 
g) collected and taken up in 2 N hydrochloric acid (30 ml). The solution 
was filtered to remove a small amount of undissolved solid, then adjusted 
to pH 8 by adding solid sodium carbonate. The triazinone separated as a 
white solid which was collected, washed with water and dried in vacuo at 
100.degree. to give material m.p. 308.degree. (dec.), (2.0 g) (50% 
approx.). 
EXAMPLE 2 
N-[1-(3-Mercapto-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]-butyramide 
(a) Ethyl 3-butyramido-2-oxo-butyrate, thiosemicarbazone 
A mixture of ethyl 3-butyramido-2-oxo-butyrate (30 g) and thiosemicarbazide 
(8 g) in absolute ethanol (100 ml) was added under reflux for 4 hours. The 
mixture was cooled to 0.degree. and the thiosemicarbazone crystallised 
out. This was collected and the filtrate concentrated to give a second 
crop which was combined with the first to give a total of 8.3 g. This 
material was used in the next stage without further purification. 
(i) In a similar manner was prepared ethyl 3-isovaleramido-2-oxo-butyrate, 
thiosemicarbazone, m.p. 179.degree.-181.degree. (4.6 g) from ethyl 
3-isovaleramido-2-oxo-butyrate (5.75 g) and thiosemicarbazide (2.3 g). 
(b) N-[1-(3-Mercapto-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)-ethyl]butyramide 
Ethyl 3-butyramido-2-oxo butyrate, thiosemicarbazone (8.3 g) was added to a 
solution of sodium ethoxide (from 0.63 g of sodium) in absolute ethanol 
(250 ml) and the mixture heated under reflux for 2 hours, and then cooled. 
Ethanol was removed in vacuo and the residual solid dissolved in water (15 
ml). The solution was acidified with 2 N hydrochloric acid and the solid 
that precipitated was collected and recrystallised from ethyl acetate to 
give the mercaptotriazinone, m.p. 213.degree.-215.degree. (4.34 g). 
(i) In a similar manner was prepared 
N-[1-(3-mercapto-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]3-methylbutyra 
mide (10.0 g) m.p. 195.degree.-196.degree. (from ethyl acetate) from ethyl 
3-isovaleramido-2-oxo-butyrate, thiosemicarbazone (16.56 g). 
EXAMPLE 3 
N-[1-(3-Methylthio-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]butyramide 
A solution of 
N-[1-(3-mercapto-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]butyramide 
(4.0 g), methyl iodide (2 ml) and 85% potassium hydroxide (1.28 g) in 
ethanol (70 ml) and water (35 ml) was stirred at room temperature for 4 
hours. The solvent was removed in vacuo and the pale yellow residue 
partitioned between water (20 ml) and ethyl acetate (150 ml). The ethyl 
acetate layer was separated and the aqueous phase extracted again with 
ethyl acetate (4.times.100 ml). The extracts were combined dried (Na.sub.2 
SO.sub.4) and evaporated in vacuo to give a pale yellow solid. 
Recrystallisation from ethanol-ethyl acetate furnished the 
methylthiotriazinone, m.p. 180.degree.-183.degree. (2.55 g). 
(i) In a similar manner was prepared 
N-[1-(3-methylthio-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]-3-methylbut 
yramide (1.0 g) m.p. 193.degree.-194.degree. (from ethyl acetate) from 
N-[1-(3-mercapto-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]-3-methylbutyr 
amide (2.0 g). 
EXAMPLE 4 
N-[1-(3-Amino-2,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]-butyramide 
Ethyl oxalyl chloride (67 ml) was added over 30 minutes to a stirred 
solution of N-butyrylalanine (47.7 g), 4-dimethylaminopyridine (1.0 g), 
and pyridine (73 ml) in tetrahydrofuran (200 ml). The mixture was stirred 
under reflux for 3 h and then allowed to cool overnight. The mixture was 
diluted with water (200 ml), extracted with ethyl acetate (3.times.100 ml) 
and the extracts were washed with water (2.times.100 ml), dried 
(MgSO.sub.4), and the solvent removed in vacuo at 40.degree. C. to give 
the (E)- and (Z)- isomers of 
4-[1-[(propylcarbonyl)amino]ethylidene]-3-oxa-2-oxopentanedioic acid, 
diethyl ester as an orange oil (104 g). N.m.r. .tau.(CDCl.sub.3) ca 1.0 
(1H, br, NH), 5.5-6.0 (4H, 2.times.q, CO.sub.2 CH.sub.2 CH.sub.3), 7.3 and 
7.65 (3H, 2.times.s, C.dbd.CCH.sub.3), 7.48 (t, CH.sub.3 CH.sub.2 CH.sub. 
2 CO), 8.25 (m, CH.sub.3 CH.sub.2 CH.sub.2 CO) and 8.5-9.1 (m, CO.sub.2 
CH.sub.2 CH.sub.3 plus CH.sub.3 CH.sub.2 CH.sub.2 CO). 
The oil was added to a suspension of aminoguanidine bicarbonate (81.6 g) in 
methanol (600 ml) and the mixture was heated under reflux for 5 h. During 
this period aminoguanidine bicarbonate gradually dissolved and a new 
product precipitated as a white solid. The mixture was allowed to cool 
overnight and the solid was filtered off, washed with methanol (150 ml), 
and dissolved in 2 N hydrochloric acid (450 ml). The solution was filtered 
through a diatomaceous earth to remove a small amount of precipitated 
solid and then adjusted to pH8 by adding 70% sodium hydroxide solution. 
The triazinone separated as an off-white solid which was filtered off, 
washed with water, and dried in vacuo at 80.degree. C. Yield=37.0 g; m.p. 
309.degree.-310.degree. C. (decomp). 
EXAMPLE 5 
2-Amino-5-methyl-7-propyl-imidazo[5,1-f]1,2,4-triazin-4(3H)-one 
N-[1-(3-Amino-2,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]butyramide (37.0 
g) was added to stirred polyphosphoric acid (260 g) at 90.degree. C. over 
30 minutes and then the mixture was stirred at 150.degree. C. for 2 h. The 
mixture was allowed to cool overnight, then warmed to 100.degree. C. and 
poured into a mixture of ice (370 g) and water (370 g). The solution was 
adjusted to pH6 by adding 70% sodium hydroxide solution (ca. 230 ml). The 
precipitated solid was filtered off and was dissolved in 1 N hydrochloric 
acid (740 ml). The solution was clarrified and adjusted to pH8 by adding 2 
N sodium hydroxide solution to give the 
imidazo[5,1-f]1,2,4-triazin-4(3H)-one as an off-white solid which was 
filtered off, washed with water, and dried in vacuo at 80.degree. C. 
Yield=30.2 g; m.p. 266.degree. C. 
EXAMPLE 6 
N-[1-(3-N'-benzyl-N'-methylamino-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl 
]-3-methylbutyramide 
1-amino-2-benzyl-2-methylguanidinium hydroiodide (7.65 g) and 
ethyl-3-isovaleramido-2-oxo-butyrate (5.75 g) were heated in absolute 
ethanol (20 ml) under reflux for 3 h. The resultant brown solution was 
concentrated in vacuo and the residue was dissolved in ethyl acetate:water 
(50:50, total 100 ml). The aqueous layer was separated, basified with 8% 
sodium bicarbonate solution and extracted with ethyl acetate (8.times.20 
ml). The latter extracts and the above ethyl acetate phase were combined 
and evaporated in vacuo to give a brown oil. The oil was redissolved in 
ethyl acetate (150 ml) and the solution treated with charcoal, filtered 
and concentrated. Dilution with anhydrous ether gave a brown oil which 
solidified upon stirring under anhydrous ether. The ether was removed in 
vacuo at 25.degree. to provide 6.65 g of a light brown solid, m.p. ca. 
110.degree.. This solid was dissolved in ethanol and purified by 
filtration through a column of silica gel followed by recrystallisation 
from ethanolethyl acetate to give white crystals m.p. 
169.degree.-170.degree. . 
EXAMPLE 7 
5-Methyl-2-methylamino-7-(2-methyl)propylimidazo[5,1-f]-1,2,4-triazin-4(2H) 
-one, hydrochloride 
Polyphosphoric acid (6.0 g) was heated to 75.degree. C. and 
N-[1-(3-N'-benzyl-N'-methylamino-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethy 
l]-3-methyl butyramide was added. The mixture was heated at 
120.degree.-130.degree. for 8 h with occasional stirring and then cooled 
to room temperature and neturalised with 8% sodium bicarbonate solution. 
The buff precipitate was collected by filtration (0.52 g) and converted 
into a hydrochloride salt m.p. 276.degree.-280.degree. (decomp). 
EXAMPLE 8 
N-[1-(3-N'-benzyl-N'-methylamino-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl 
]-3-methylbutyramide 
A mixture of 
N-[1-(3-methylthio-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl)ethyl]-3-methylbut 
yramide (0.5 g) was heated with N-benzyl-N-methylamine (0.224 g) in 
refluxing n-butanol for 4 days. Removal of solvent in vacuo left a brown 
oil which was absorbed onto a column of silica gel (20 g, Merck Kieselgel 
60). Elution with 1:10 benzene:ethyl acetate followed by concentration of 
the appropriate fractions provided the title compound, 0.35 g m.p. 
176.degree.-8.degree. (ethyl acetate-ethanol).