Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-02-22
2001-12-11
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C562S869000, C564S230000, C564S234000
Reexamination Certificate
active
06329521
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for preparing substituted benzoyl cyanide amidinohydrazones. More particularly, the present invention pertains to the preparation of these compounds by a reaction of substituted benzoyl cyanides with aminoguanidine in the presence of polyphosphoric acid.
BACKGROUND OF THE INVENTION
It is known that certain 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines are active in the treatment of CNS disorders, such as psychiatric and neurological disorders, and are also useful as anticonvulsants, for example in the treatment of epilepsy. These triazines are also non-depressant at therapeutic dose levels and are therefore advantageous as compared with depressant anti-epileptics such as phenobarbitone.
A particularly preferred compound of this type is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (e.g. European Patent 21121).
A known process for preparing 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines, comprises reacting substituted benzoyl cyanides with aminoguanidine in aqueous solutions of strong acids such as nitric acid (J. A. Settepani and A. B. Borkovec, J. Heterocycl. Chem., 1966, 3, 188, U.S. Pat. Nos. 3,637,688; 4,486,354; 4,602,017; 4,649,139, R. W. A. Rees et al, J. Med. Chem., 1972, 15, 859; European Patent Nos. 21,121; 142,306; 247,892, Israeli Patent Nos. 60,201; 73,332; 82,710) and sulfuric acid (European Patent No. 247,892, Israeli Patent No. 82,710) to produce amidinohydrazone of the general formula (A):
wherein
R
1
is halogen, C
1-4
alkyl or trifluoromethyl, R
2
is hydrogen, halogen, C
1-4
alkyl or trifluoromethyl, or R
1
and R
2
form a —CH═CH—CH═CH— group optionally substituted by a halogen atom or a C
1-4
alkyl or trifluoromethyl group, R
3
and R
4
are independently selected from hydrogen, halogen, C
1-4
alkyl or trifluoromethyl groups and R
5
is hydrogen, methyl or fluorine.
3,5-Diamino-6-(substituted phenyl)-1,2,4-triazines (compounds of the general formula (B):
wherein
R
1
-R
5
are as hereinbefore defined) are obtained by ring closure of a compound of the formula A.
The ring closure is normally carried out by refluxing in an alcohol, such as methanol, ethanol, 1-propanol and the like, in the presence of a strong base, such as sodium hydroxide, potassium hydroxide and the like.
However, the reaction of substituted benzoyl cyanides with aminoguanidine in the aqueous solutions of strong acids is very slow and usually from 2 to 21 days are required to complete this reaction. On the other hand, substituted benzoyl cyanides are hydrolyzed at the reaction conditions, and overall yield of the triazines is low (from 2 to 41%) (Table).
TABLE
Yield
of the
Temper-
compound
Compounds
ature
Time of
of the
of the
Solvent of the
of the
the
formula
formula (A)
reaction
reaction
reaction
(B)
R
6
═R
7
═Cl
a) DMSO and 8N
25° C.
7 days
15.6%*
R
8
═R
9
═R
10
═H
aqueous nitric
acid
b) Acetonitrile
20-30° C.
48 hours
41%**
and 63%
aqueous sulfuric
acid
R
6
═R
7
═R
9
═Cl
DMSO and 8N
20-30° C.
21 days
1.6%*
R
8
═R
10
═H
aqueous nitric
acid
R
6
═R
8
═Cl
DMSO and 8N
25° C.
24 hours
8%***
R
7
═R
9
═R
10
═H
aqueous nitric
acid
R
7
═R
8
═Cl
DMSO and 8N
25° C.
24 hours
23%***
R
6
═R
9
═R
10
═H
aqueous nitric
acid
R
8
═Cl
DMSO and 8N
25° C.
24 hours
37%***
R
6
═R
7
═R
9
═
aqueous nitric
R
10
═H
acid
*U.S. Pat. No. 4,486,354
**European Patent No. 247,892
***R. W. A. Rees et al, J. Med. Chem., 1972, 15, 859.
SUMMARY OF THE INVENTION
As a result of research to solve the drawbacks of the prior art methods, the present inventors have found the method for preparing the substituted benzoyl cyanide amidinohydrazones by a reaction of substituted benzoyl cyanides with aminoguanidine in a mixture of polyphosphoric acid and a solvent in the absence of water which minimizes the hydrolysis of the benzoyl cyanides.
According to the present invention substituted benzoyl cyanide amidinohydrazones can be prepared in higher yield after the reaction of substituted benzoyl cyanide with aminoguanidine in a mixture of polyphosphoric acid and acetonitrile for 24 hours.
Other objects and advantages of the present invention will be apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
More specifically the present invention provides a process for preparing a compound of the general formula (I):
wherein
R
1
to R
5
are independently selected from hydrogen, halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl or C
1-6
alkoxy, all optionally substituted by one or more of halogen, hydroxy and aryl groups, as well as being independently selected from amino, mono- or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups, which process comprises reacting a compound of the general formula (II):
wherein
R
1
to R
5
are as defined in formula (I), with aminoguanidine bicarbonate in a mixture of a water-soluble solvent and polyphosphoric acid.
Suitably the total number of carbon atoms in R
1
to R
5
is less than eight.
The phenyl ring will suitably contain up to three substituents and preferably one or two substituents.
R
1
to R
5
are preferably independently selected from halogen and hydrogen. Particularly preferred substitutions are 4 or 2,3 or 2,4 or 3,4 mono- or di- halo (especially chloro).
Preferred compounds are:
4- Chlorobenzoyl cyanide amidinohydrazone,
2,3-Dichlorobenzoyl cyanide amidinohydrazone,
2,4- Dichlorobenzoyl cyanide amidinohydrazone,
3,4- Dichlorobenzoyl cyanide amidinohydrazone.
The preparation of the compounds of the formula (II) is analogous to that described in the literature, i.e. U.S. Pat. No. 3,637,688; R. W. A. Rees et al, J. Med. Chem., 1972,15, 859.
The amount of aminoguanidine bicarbonate is preferable more than one equivalent and more preferable 1.5 molar equivalents relative to compound of the formula (II).
The amount of polyphosphoric acid is preferably from 4 to 8 g, and more preferably 5.5 g to one gram of the compound of formula (II).
The reaction solvents are preferably water-soluble solvents such as acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane (monoglyme), 2-methoxyethyl ether (diglyme) and the like and more preferably acetonitrile.
The amount of the reaction solvent is preferably from 2 to 8 ml, and more preferably 5 ml to one gram of the compound of the formula (II).
The reaction temperature may be chosen from ambient temperature to the reflux temperature of the solvent, and more preferably the temperature is between 50-70° C.
Since the progress of the reaction can be monitored by using high performance liquid chromatography, the reaction may be stopped after the disappearance of the starting material.
Although amidinohydrazones of the formula (II) exist as two isomers (E-and Z-forms), for the purpose of the present invention, these compounds may exist as either of the isomers or as a mixture thereof.
After completion of the reaction, water is added to the reaction mixture to obtain a clear homogeneous mixture. The mixture is dropped to water, and a colourless precipitate is collected by filtration to obtain a wet phosphate of the compound of the formula (I).
The wet phosphate of the compound of the formula (I) is added to an aqueous alkali solution, e.g., sodium hydroxide and the like, and the mixture is stirred at ambient temperature for one hour. A precipitate is then collected by filtration, washed with water and dried at 80° C. to give a free base of the compound of the formula (I).
Triazines of the general formula (III):
wherein
R
1
to R
5
are as defined in the formula (I), can be obtained from the compound of the formula (I) by a procedure similar to that described in the literature, i.e. Beyer et al,
Chem. Ber
. 1960, 93, 2209; J. A. Settepani and A. B. Borkovec, J. Heterocycl. Chem., 1966, 3, 188, U.S. Pat. Nos. 3,637,688; R. W. A. Rees et al,
J. Med. Chem
., 1972, 15, 859; European Patent Nos, 21,121; 247,892.
According to the present invention, the compounds of the formula (I) can be
Kaspi Joseph
Lexmer Jael
Nadaka Vladimir
Balasubramanian Venkataraman
Banner & Witcoff
Chemagis Ltd.
Shah Mukund J.
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