Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine compounds

The invention relates to a new process for preparing 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine of the formula (I), ##STR1## which comprises reacting a pyrimidine derivative of the general formula (II), ##STR2## wherein R.sub.1 stantds for hydrogen or a ##STR3## group, wherein R means a C.sub.1-6 alkyl group or an aryl group optionally substituted by halogen; PA1 R.sub.2 stands for a hydroxyl group or an ##STR4## group, wherein R is as defined above; and PA1 X represents chlorine or bromine or an optionally mono- or polysubstituted arenesulfonyloxy group, with the proviso that R.sub.2 is different from a hydroxyl group when R.sub.1 stands for hydrogen, with piperidine and hydrolyzing, optionally after isolation, the thus-obtained 4-piperidino derivative of the general formula (III), ##STR5## wherein R.sub.1 and R.sub.2 are as defined above.

The invention relates to a new process for preparing 
6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine of the 
formula (I). 
##STR6## 
Being an excellent antihypertensive agent Drugs 22, 257 (1981), the 
compound of the formula (I) (generic name: minoxidil) is the active 
ingredient of a number of blood pressure lowering compositions 
commercially available in many countries. 
In the recent years, the utilization of the compound of formula (I) as a 
therapeutical cosmetic has become more and more conspicuous since it 
effectively stimulates hair growth in an externally used dilute solution 
Pharm. Ind. 46, 937 (1984); ibidem 47. 506 (1985). 
Owing to its two possible tautomeric forms, minoxidil has two chemical 
names in the literature: in the Chemical Abstracts, it has been named 
6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine up to 1972 
and 6-(1 piperidinyl)-2,4-pyrimidinediamine-3-oxide after 1972. In the 
present patent application the first name is used by which the chemical 
principle of our preparation process is better reflected; it should be 
understood, however, that our process relates to the preparation of both 
tautomeric forms. 
Although several methods have been described for preparing the compound of 
formula (I), owing to the low yields and the poor availability of the 
starting materials, none of them can be considered to be an effective and 
economical process useful at an industrial scale. 
First the substance of the formula (I) was synthetized from 4-chloro 
2,6-diaminopyrimidine British patent specification No. 1,167,735; CA. 68, 
21947h by heating the latter compound with 2,4-dichlorophenol at 
150.degree. C. in the presence of 85% aqueous potassium hydroxide solution 
to give 2,6-diamino-4-(2,4-dichlorophenoxy)pyrimidine. This substance was 
oxidized in a low yield to 6 amino 4-(2,4 
dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-iminopyrimidine, which was then 
transformed at 150.degree. C. with piperidine to the target compound of 
the formula (I). The overall yield of this synthesis amounts to about 2.5% 
with a 45% yield in the last step. This is mainly caused by the fact that 
the replacement of the 2,4-dichlorophenoxy group by piperidine requires 
severe reaction conditions and long heating periods which favour 
unrequired side reactions, too. 
An other method J. Org. Chem. 41, 3304 (1975) cannot be considered to be 
useful for industrial realization either because specific conditions 
(exclusion of moisture, very low temperature) and difficultly available, 
expensive substances ("magic methyl", trimethyloxonium fluoborate) are 
required to carry out the key step of the synthesis comprising the 
activation of the acid amide carbonyl group of cyanoacetylpiperidine. 
The synthesis of the compound of formula (I) has been achieved in somewhat 
better yields by other known processes. According to the published German 
patent application No. 2,114,887, 
6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine is used as 
starting material, whereas the corresponding 4-(p-toluenesulfonyloxy) 
derivative is described as starting substance in the Hungarian patent 
specification No. 177,601. According to the Examples of this Hungarian 
patent specification, the reaction can be carried cut in a yield of 55 to 
65%. A further improvement in the yield is hampered, however, by the 
relatively long reaction period and high temperature favouring even here 
the formation of side products. The target compound becomes contaminated 
by the side products arising from the damage of the free amino groups of 
the molecule, whereby a further purification is required to achieve 
appropriate purity. Another drawback of the above processes is that the 
starting substances are prepared by the rather complicated method of 
oxidizing with perbenzoic or m-chloroperbenzoic acid. 
Thus, the aim of the present invention is to provide an economically 
practicable synthesis of the compound of formula (I), which renders 
possible to easily produce this compound in a good yield and in a high 
purity at an industrial scale, too. 
According to the invention, 6 amino 
1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine of the formula (I) is 
prepared by reacting a pyrimidine derivative of the general formula (II), 
##STR7## 
wherein R.sub.1 stands for hydrogen or a 
##STR8## 
group, wherein R means a C.sub.1-6 alkyl group or an aryl group 
optionally substituted by halogen; 
R.sub.2 stands for a hydroxyl group or an 
##STR9## 
group, wherein R is as defined above; and 
X represents chlorine or bromine or an optionally mono- or polysubstituted 
arenesulfonyloxy group, 
with the proviso that R.sub.2 is different from a hydroxyl group when 
R.sub.1 stands for hydrogen, with piperidine and hydrolyzing, optionally 
after isolation, the thus-obtained 4-piperidino derivative of the general 
formula (III) 
##STR10## 
wherein R.sub.1 and R.sub.2 are as defined above. 
X defined as an "optionally mono- or polysubstituted arenesulfonyloxy 
group" in the general formula (II) preferably means a benzenesulfonyloxy 
group substituted by one or more C.sub.1-3 alkyl group(s), preferably by a 
methyl group on the benzene ring. Preferred representatives of such groups 
are the tosyloxy and mesitylenesulfonyloxy group. Most preferably, X means 
chlorine. 
The meaning "C.sub.1-6 alkyl group" of R in the definition of R.sub.1 and 
R.sub.2 in the general formulae (II) and (III) may mean any C.sub.1-6 
straight or branched chain, saturated hydrocarbyl group such as methyl, 
ethyl, n-propyl, isopropyl, n-butyl, secondary and tertiary butyl, 
n-pentyl, isopentyl, n-hexyl and isohexyl group, preferably C.sub.1-4 
alkyl group and more preferably methyl group. 
R as an aryl group may represent any C.sub.6-12 aryl, preferably phenyl, 
group optionally substituted by one or more halogen(s), preferably by one 
or more chlorine atom(s) 
The pyrimidine derivatives of the general formula (II) used as starting 
materials in the process of the invention are new compounds which can be 
prepared by reacting an appropriate 2,6-diaminopyrimidine derivative 
substituted by a suitable X group in position 4 with an appropriate acid 
anhydride in the presence of water and hydrogen peroxide. This process has 
been described in our simultaneously filed Hungarian patent application 
No. 2856/86. 
The key step of the process of the invention is the nucleophilic 
substitution reaction of the compounds of the general formula (II) with 
piperidine, which readily proceeds under mild conditions owing to the 
electron-attracting properties of the acyl or acyloxy groups defined as 
R.sub.1 or R.sub.2, respectively. The temperature of this reaction as 
depending on other conditions, such as the solvent, is 0.degree. to 
100.degree. C., preferably room temperature. The reaction proceeds within 
a period lasting from 5 minutes to several hours; at room temperature at 
most 2 hours are usually enough for completing this reaction, whereas this 
period can substantially be abbreviated by increasing the reaction 
temperature. An excess of piperidine may serve as solvent of this 
reaction, though other solvents such as protic solvents, e.g. ethanol; 
dipolar aprotic solvents, e.g. acetonitrile; or apolar aprotic solvents, 
e.g. chloroform may also be used. Under such conditions, the yield of the 
4-piperidino derivative of the general formula (III) is practically 
quantitative. 
It is surprisingly easy to remove by hydrolysis the acyl or acyloxy groups, 
e.g. the acetyl or acetoxy group defined as R.sub.1 or R.sub.2, 
respectively, from the thus obtained 4-piperidino derivatives of the 
general formula (III). On using piperidine as solvent, this reaction 
rapidly proceeds even at room temperature in such a way that the 
derivatives containing the acyl or acyloxy group, respectively, cannot 
even be isolated; or, it proceeds within a few minutes under the 
conditions of the working-up, under the effect of water and a base, e.g. 
on the effect of an aqueous alkali metal hydroxide solution. This process, 
however, may also be carried out in such a way that the intermediate 
product of the general formula (III) is isolated in a high yield and 
purity. 
The compound of the formula (I) obtained as a result of the process of the 
invention is isolated in a crystalline form and high purity without any 
detectable side products. 
The drawbacks of the known processes for preparing the compound of the 
formula (I) are eliminated by using the process of the invention. 
The most important advantages of the process of the invention can be 
summarized as follows: 
The starting compounds of the general formula (II) can easily be prepared 
in a high yield by using the process described in our simultaneously filed 
Hungarian patent application No. 2856/86. 
The starting materials are more reactive than any starting substance known 
in the prior art. This is due to the electron-attracting properties of the 
acyl or acyloxy groups, respectively, whereby the electron density in 
position 4 of the pyrimidine ring is decreased and thus the nucleophilic 
substitution by piperidine proceeds more readily. 
The most sensitive sites of the molecule are simultaneously protected by 
the acyl or acyloxy groups, respectively, whereby the process will not be 
accompanied by any side reaction. 
Surprisingly, the acyl and acyloxy groups can very easily be removed, e.g. 
by hydrolysis with an equivalent amount of an alkali metal hydroxide 
solution for a few minutes at room temperature. This ready elimination is 
a structural feature of the molecule, which is due to the N-oxide moiety. 
The hydrolysis of the acyl group proceeds on the oxygen atom bound to the 
nitrogen in the 1 position. Any acyl group present in an other position 
migrates to this position under the effect of acids or alkali metal 
hydroxides and is hydrolyzed with a rate corresponding to that of the 
esters. 
As a result of all these advantages, the target compound of the formula (I) 
can be prepared under mild reaction conditions, in a high yield, i.e. in 
yields of 70 to 80% under the optimum conditions, and in a high purity by 
using starting substances which are easily available and can also be 
obtained in a good yield. 
The process of the invention is illustrated in detail by the following 
non-limiting Examples.

EXAMPLE 1 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
1.01 g (5 mmoles) of 
1-acetoxy-6-amino-4-chloro-1,2-dihydro-2-iminopyrimidine are added under 
stirring to a mixture containing 10 ml of ethanol and 3 ml of piperidine. 
The mixture is refluxed while stirring for 30 minutes, then 5 ml of 1N 
aqueous sodium hydroxide solution are added and the boiling is continued 
for additional 30 minutes. Thereafter, the mixture is evaporated under 
reduced pressure and the residue is mixed with 10 ml of water. The 
crystalline precipitate is filtered, washed with water and dried to give 
the aimed compound in a yield of 0.85 g (82%), m.p.: 
262.degree.-266.degree. C. 
IR (cm.sup.-1) 3450, 3420, 3400, 3370, 3260, 1655, 1250, 1210, 1165, 1020. 
.sup.1 H-NMR (DMSO-d.sub.6): 1.52; 3.40; 5.36; 6.84. 
.sup.13 C-NMR (DMSO-d.sub.6 +CD.sub.3 OD): 156.6; 153.7; 152.1; 74.1; 45.7; 
25.7; 24.7. 
EXAMPLE 2 
Preparation of 
6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidino-pyrimidine 
2.02 g (10 mmoles) of 
1-acetoxy-6-amino-4-chloro-1,2-dihydro-2-iminopyrimidine are added to 8 ml 
of piperidine at room temperature while stirring. The mixture is stirred 
at room temperature for 2 hours, then piperidine is evaporated under 
reduced pressure. The residue is taken up in a mixture containing 20 ml of 
ethanol and 10 ml of 1N aqueous sodium hydroxide solution and refluxed for 
30 minutes, then evaporated under reduced pressure. The residue is taken 
up in 20 ml of water, the crystals are filtered, washed with water and 
dried to give 1.74 g (86% yield) of the aimed compound which shows no 
melting point depression when mixed with the product of Example 1. 
EXAMPLE 3 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
0.3 g (0.88 mmole) of 
1-acetoxy-6-amino-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidine 
is added to a solution containing 10 ml of chloroform and 2 ml of 
piperidine while stirring. The mixture is refluxed under stirring for 30 
minutes, then evaporated under reduced pressure. To the residue, 5 ml of 
ethanol and 1 ml of 1N aqueous sodium hydroxide solution are added. The 
mixture is set aside at room temperature for one hour, then evaporated 
under reduced pressure. The residue is triturated with 10 ml of water, the 
crystals are filtered, washed with water and dried to give 0.14 g (75% 
yield) of the aimed compound which shows no melting point depression when 
mixed with the product of Example 1. 
EXAMPLE 4 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
After adding 0.49 g (2 mmoles) of 
6-acetamido-1-acetoxy-4-chloro-1,2-dihydro-2-iminopyrimidine to a solution 
containing 10 ml of chloroform and 2 ml of piperidine, the mixture is 
refluxed for 30 minutes, then evaporated under reduced pressure. The 
residue is dissolved in the mixture of 10 ml of ethanol and 3 ml of 1N 
aqueous sodium hydroxide solution. The reaction mixture is left to stand 
at room temperature for one hour and then again evaporated under reduced 
pressure. After taking up the residue in 10 ml of water, the crystals are 
filtered, washed with water and dried to give 0.34 g (80% yield) of the 
aimed compound which shows no melting point depression when mixed with the 
product of Example 1. 
EXAMPLE 5 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
76 g (0.2 mole) of 
6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidi 
ne are added to 760 ml of anhydrous piperidine at a temperature of 
0.degree. to 5.degree. C. while stirring. The mixture is stirred at the 
same temperature for additional 2 hours, then let to warm to room 
temperature and stirred for additional 24 hours. The piperidine is 
distilled off under reduced pressure, 500 ml of water are added to the 
residue, then the mixture is left to stand in the refrigerator overnight. 
The precipitate is filtered, washed with water and filtered by strong 
suction. The filter cake is washed by suspending it 3 times with 50 ml of 
ether each and dried to give the aimed product in a yield of 23.0 g (55%). 
75 ml of 10% sodium hydroxide solution are added to the mother liquor and 
then the reaction mixture is evaporated under reduced pressure. After 
adding 200 ml of water to the residue, the pH value of the solution is 
adjusted to 7. After standing overnight in the refrigerator, the crystals 
are filtered, washed with water and dried to give an additional yield of 
8.9 g (21%) of the aimed compound. 
In such a way, a total yield of 31.9 g (76%) of the aimed compound is 
obtaIned, which shows no melting point depression when mixed with the 
product of Example 1. 
EXAMPLE 6 
Preparation of 
6-acetamido-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
After adding 1.01 g (5 mmoles) of 
2-acetamido-6-amino-4-chloropyrimidine-1-oxide to the mixture of 20 ml of 
chloroform with 5 ml of piperidine, the solution is refluxed while 
stirring for 30 minutes. After cooling down, the solution is extracted 3 
times with 10 ml of 1N hydrochloric acid each, then washed 3 times with 10 
ml of water each. The chloroformic phase is dried over anhydrous sodium 
sulfate and evaporated under reduced pressure. The residue is thoroughly 
triturated with 50 ml of ether, the crystals are filtered, washed with 
ether and dried to give the aimed compound in a yield of 0.86 g (69%), 
m.p.: 204.degree.-205.degree. C. 
IR (KBr, cm.sup.-1) 1670, 1600, 1570, 1500. 
UV (ethanol, nm): 245, 325. 
.sup.1 H-NMR (CDCl.sub.3 +CD.sub.3 OD): 1.63, (m, 6H), 2.30 (s, 3H), 3.57 
(m, 6H), 7.04 (s, 1H). 
EXAMPLE 7 
Preparation of 
6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-piperidinopyrimidine 
A mixture containing 0.5 g (0.0013 mole) of 
6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidi 
ne in 20 ml of acetonitrile and 0.5 ml of piperidine is stirred at room 
temperature for 3 hours, then evaporated under reduced pressure. After 
adding 30 ml of ether to the residue, the crystalline precipitate is 
filtered, washed with ether and then with water, finally dried to give the 
aimed product in a yield of 0.24 g (64%), m.p.: 217.degree.-218.degree. C. 
(with decomposition). 
IR (KBr, cm.sup.-1): 1710, 1680, 1630, 1570, 1530. 
UV (ethanol, nm): 241, 293, 323. 
.sup.1 H-NMR (CDCl.sub.3 +TFA-d): 1.76 (m, 6H), 2.43 (s, 3H), 2.57 (s, 3H), 
3.80 (m, 4H), 7.55 (s, 1H). 
EXAMPLE 8 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
0 5 g (2 mmoles) of 
6-acetamido-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine prepared 
as described in Example 6 is dissolved in a mixture containing 10 ml of 
ethanol and 4 ml of 1N sodium hydroxide solution, the mixture is refluxed 
for 30 minutes, then evaporated under reduced pressure. After taking up 
the residue in 10 ml of water, the crystals are filtered, washed with 
water and dried to give the aimed compound in a yield of 0.35 g (85%), 
which shows no melting point depression when mixed with the product of 
Example 1. 
EXAMPLE 9 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
1.0 g (3.4 mmoles) of 
6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-piperidinopyrimidine prepared 
as described in Example 7 is dissolved in a mixture containing 20 ml of 
ethanol and 5 ml of 1N aqueous sodium hydroxide solution, the mixture is 
refluxed for 30 minutes, then evaporated under reduced pressure. Taking up 
the residue in 10 ml of water, the crystals are filtered, washed with 
water and dried to give the aimed compound in a yield of 0.54 g (76%), 
which shows no melting point depression when mixed with the product of 
Example 1. 
EXAMPLE 10 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
2.0 g (0.0093 mole) of 
6-amino-4-chloro-1,2-dihydro-2-imino-1-propionyloxy-pyrimidine is boiled 
in 10 ml of water, in the presence of 3 ml piperidene for 30 minutes, 
then, after adding 10 ml of 1N aqueous sodium hydroxide solution and 5 ml 
of water, the solution is refluxed for additional 30 minutes, and then 
After standing for one hour, the precipitated crystals are filtered and 
washed with water to give the aimed compound in a yield of 1.36 g (83%). 
EXAMPLE 11 
Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine 
In a 500 ml round-bottom flask fitted with a stirrer and thermometer, 40.8 
g (0.1 mole) of crude 
6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-mesitylenesulfonyl 
oxypyrimidine are reacted with 380 ml (327 g; 3.84 moles) of piperidine 
under stirring and cooling by ice. After warming up of the reaction 
mixture to room temperature, the stirring is continued till the 
disappearing of the starting materials as detected by thin layer 
chromatography. This lasts about 24 hours. Then piperidine is evaporated 
under reduced pressue on a bath kept at 60.degree. C. and 250 ml of water 
are added to the residue. After cooling, the precipitated product is 
filtered, washed with water and dried on the filter. From the solid filter 
cake remaining on the filter, the sulfonamide side product is washed out 
with a little amount of toluene. 
After evaporating the toluene solution to dryness, 3.9 g (14.5% yield) of 
N-mesitylenesulfonyl piperidine are obtained; the substance remaining on 
the filter, which is the aimed product, amounts to 13 g. 
The mother liquor is subjected to a further working up: after adding 38 ml 
of 10% aqueous sodium hydroxide solution, it is evaporated to oily 
consistency under reduced pressure, whereby the residual piperidine can be 
removed. After adding 100 ml of water, the pH value of the solution is 
adjusted to 7 by adding 10% hydrochloric acid solution. After a prolonged 
cooling, the precipitate is filtered and washed with water to give 
additional 5.3 g of the aimed compound. 
In such a way, a total yield of 17.9 g (85.5%) of 
6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine are obtained, 
m.p.: 240.degree.-260.degree. C. (with decomposition). 
The chromatographic and spectroscopic characteristics of this product are 
in agreement with those prepared as described in the above Examples.