Method for production of 1,3-disubtituted 2-nitroguanidines

Details Method for production of 1,3-disubtituted 2-nitroguanidines Method for production of 1,3-disubtituted 2-nitroguanidines

2002-06-14

2003-03-04

Davis, Zinna Northington (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S205000, C549S495000

Reexamination Certificate

active

06528651

ABSTRACT:

The present invention relates to a novel type of process for the preparation of 1,3-disubstituted 2-nitroguanidines.
EP-A-0 483 062 discloses a process for the preparation of 1,3-disubstituted 2-nitroguanidines. They are obtained by hydrolysis of corresponding 2-nitroimino-1,3,5-triazacyclohexane derivatives. The hydrolysis is preferably carried out in the presence of strong mineral acids or organic acids.
Disadvantages of this process are the long reaction times and the formation of secondary products, which make it necessary to subject the desired end-products to a complex cleaning operation.
Moreover, as is known, when working in the presence of aqueous, strong acids, costly measures must be taken to protect, for example, the reactors, from corrosion.
Applications JP 03 291 267, JP 10067766 and JP 10147580 relate to similar processes.
The object of the present invention was to provide an improved process for the preparation of 1,3-disubstituted 2-nitroguanidines.
The present invention provides a process for the preparation of compounds of the formula (I)
in which
R
1
is hydrogen or alkyl,
R
2
is hydrogen, alkyl, cycloalkyl or —CH
2
R
3
,
R
3
is alkenyl, alkinyl, or aryl or heteroaryl, each of which is optionally substituted,
Het is an unsubstituted or substituted aromatic or non-aromatic, monocyclic or bicyclic heterocyclic radical, preferably from the series
characterized in that a compound of the formula (II)
in which
R
1
, R
2
and Het are as defined above, and
R
4
is alkyl, cycloalkyl, aryl, arylalkyl or heterocyclylalkyl, each of which may be unsubstituted or substituted,
is reacted with anhydrous hydrogen chloride or with one or more compounds which can generate hydrogen chloride in the presence or absence of a diluent.
The compounds of the formula (I) can also be in the form of double-bond isomers as regards the —N═C(2) bond and in their tautomeric forms (formulae Ia, Ib):
Formula (I) is accordingly to be taken to mean that it also includes the corresponding double-bond isomers and the formulae (Ia) and (Ib).
Surprisingly, the process according to the invention produces, selectively and in high yields, the end-products of the formula (I) in pure form after a short reaction time under mild reaction conditions.
For example, using 1-(2-chlorothiazol-5-ylmethyl)-2-nitro-imino-5-benzyl-3-methyl-1,3,5-triazacyclohexane as starting material, the course of the process according to the invention can be shown by the following equation:
The compounds required as starting materials for the process according to the invention are generally defined by the formula (II).
Preferred substituents and ranges of the radicals listed in the formulae mentioned above and below are illustrated below:
R
1
is preferably hydrogen or C
1
-C
4
-alkyl,
R
2
is preferably hydrogen, C
1
-C
6
-alkyl, C
3
-C
6
-cycloalkyl or —CH
2
R
3
,
R
3
is preferably C
2
-C
5
-alkenyl, C
2
-C
5
-alkinyl, phenyl, cyanophenyl, nitrophenyl, halogenophenyl having from 1 to 3 halogen atoms, phenyl substituted by C
1
-C
3
alkyl, C
1
-C
3
halogenoalkyl having from 1 to 7 halogen atoms, C
1
-C
3
-alkoxy or C
1
-C
3
-halogenoalkoxy having from 1 to 7 halogen atoms, 3-pyridyl, 5-thiazolyl, 5-thiazolyl substituted by one to two (preferably one) substituents from the group consisting of C
1
-C
3
-alkyl, C
1
-C
3
-halogenoalkyl having from 1 to 7 halogen atoms, cyclopropyl, halogenocyclopropyl, C
2
-C
3
-alkenyl, C
2
-C
3
-alkinyl, C
1
-C
3
-alkoxy, C
2
-C
3
-halogenoalkenyl having from 1 to 4 halogen atoms, C
2
-C
3
-halogenoalkinyl having from 1 to 3 halogen atoms, C
1
-C
3
-halogenoalkoxy having from 1 to 7 halogen atoms, C
1
-C
3
-alkylthio, C
1
-C
3
-halogenoalkylthio having from 1 to 7 halogen atoms, allyloxy, propargyloxy, allylthio, propargylthio, halogenoallyloxy, halogenoallylthio, halogen, cyano and nitro; or 3-pyridyl substituted by one to four (preferably one) radicals from the group consisting of C
1
-C
3
-halogenoalkyl having from 1 to 7 halogen atoms, cyclopropyl, halogenocyclopropyl, C
2
-C
3
-alkenyl, C
2
-C
3
-alkinyl, C
2
-C
3
-halogenoalkenyl having from 1 to 4 halogen atoms, C
2
-C
3
-halogenoalkinyl having from 1 to 3 halogen atoms, C
1
-C
3
-halogenoalkoxy having from 1 to 7 halogen atoms, C
1
-C
3
-alkylthio, C
1
-C
3
-halogenoalkylthio having from 1 to 7 halogen atoms, allyloxy, propargyloxy, allylthio, propargylthio, halogenoallyloxy, halogenoallylthio, cyano, nitro, C
1
-C
3
-alkyl, C
1-C
3
-alkoxy and halogen,
Het is preferably an unsubstituted or substituted aromatic or nonaromatic, monocyclic or bicyclic heterocyclic radical, preferably from the series
which, also depending on the type of heterocycle, can contain one or two substituents from the group consisting of C
1
-C
3
-halogenoalkyl having from 1 to 7 halogen atoms, cyclopropyl, halogenocyclopropyl having from 1 to 3 halogen atoms, C
2
-C
3
-alkenyl, C
2
-C
3
-alkinyl, C
2
-C
3
-halogenoalkenyl having from 1 to 4 halogen atoms, C
2
-C
3
-halogenoalkinyl having from 1 to 3 halogen atoms, C
1
-C
3
-halogenoalkoxy having from 1 to 7 halogen atoms, C
1
-C
3
-alkylthio, C
1
-C
3
-halogenoalkylthio having from 1 to 7 halogen atoms, allyloxy, propargyloxy, allylthio, propargylthio, halogenoallyloxy, halogenoallylthio, cyano, nitro, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy and halogen.
R
4
is preferably C
1
-C
10
-alkyl, C
3
-C
6
-cycloalkyl, C
1
-C
10
-alkyl substituted by from 1 to 6 radicals from the group consisting of halogen, hydroxyl, C
1
-C
4
-alkoxy, C
1
-C
4
-halogenoalkoxy having from 1 to 9 halogen atoms, di-(C
1
-C
4
-alkyl)-amino and C
1
-C
5
-alkoxycarbonyl, C
3
-C
6
-cycloalkyl substituted by from 1 to 4 radicals from the series C
1
-C
4
-alkyl and halogen, phenyl, benzyl, or phenyl or benzyl substituted by from 1 to 3 ring substituents from the group consisting of halogen, C
1
-C
4
-alkyl, C
1
-C
4
-halogenoalkyl having from 1 to 9 halogen atoms, C
1
-C
4
-alkoxy, C
1
-C
4
-halogenoalkoxy having from 1 to 9 halogen atoms, C
1
-C
4
-alkylthio, nitro or cyano, or heterocyclylmethyl where heterocyclyl is an unsaturated or saturated 5- or 6-membered heterocycle having one or two (preferably one) heteroatoms from the series nitrogen, oxygen and sulphur (in particular furyl, tetrahydrofuryl, thienyl or pyridyl).
R
1
is particularly preferably hydrogen, methyl, ethyl, n- or i-propyl,
R
2
is particularly preferably hydrogen, methyl, ethyl, n-propyl, i-propyl or n-butyl, cyclopropyl, cyclopentyl, cyclohexyl or —CH
2
R
3
,
R
3
is particularly preferably C
2
-C
5
-alkenyl, C
2
-C
5
-alkinyl, phenyl, cyanophenyl, nitrophenyl, halogenophenyl having from 1 to 3 halogen atoms, phenyl substituted by C
1
-C
3
-alkyl, C
1
-C
3
-halogenoalkyl having from 1 to 7 halogen atoms, C
1
-C
3
-alkoxy or C
1
-C
3
-halogenoalkoxy having from 1 to 7 halogen atoms, 3-pyridyl, 5-thiazolyl, or 5-thiazolyl substituted by one or two (preferably one) substituents from the group consisting of C
1
-C
3
-alkyl, C
1
-C
3
-halogenoalkyl having from 1 to 7 halogen atoms, cyclopropyl, halogenocyclopropyl, C
2
-C
3
-alkenyl, C
2
-C
3
-alkinyl, C
1
-C
3
-alkoxy, C
2
-C
3
-halogenoalkenyl having from 1 to 4 halogen atoms, C
2
-C
3
-halogenoalkinyl having from 1 to 3 halogen atoms, C
1
-C
3
-halogenoalkoxy having from 1 to 7 halogen atoms, C
1
-C
3
-alkylthio, C
1
-C
3
-halogenoalkylthio having from 1 to 7 halogen atoms, allyloxy, propargyloxy, allylthio, propargylthio, halogenoallyloxy, halogenoallylthio, halogen, cyano or nitro; or 3-pyridyl substituted by one to two (preferably one) radicals from the group consisting of C
1
-C
3
-halogenoalkyl having from 1 to 7 halogen atoms, cyclopropyl, halogenocyclopropyl, C
2
-C
3
-alkenyl, C
2
-C
3
-alkinyl, C
2
-C
3
-halogenoalkenyl having from 1 to 4 halogen atoms, C
2
-C
3
-halogenoalkinyl having from 1 to 3 halogen atoms, C
1
-C
3
-halogenoalkoxy having from 1 to 7 halogen atoms, C
1
-C
3
-alkylthio, C
1
-C
3
-halogenoalkylthio having from 1 to 7 halogen atoms, allyloxy, propargyloxy, allylthio, propargylthio, halogenoallyloxy, halogenoallylthio, cyano, nitro, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy or halogen.
Het is partic

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