Process for the preparation of nitroguanidine derivatives

Details Process for the preparation of nitroguanidine derivatives Process for the preparation of nitroguanidine derivatives

2000-09-18

2003-02-11

Ford, John M. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S491000, C548S205000, C546S264000, C546S280700, C546S283100

Reexamination Certificate

active

06518433

ABSTRACT:

The invention relates to a process for the production of a compound of formula
wherein
R
1
is hydrogen or C
1
-C
4
-alkyl;
R
2
is hydrogen, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkinyl, C
3
-C
6
cycloalkyl or a radical —CH
2
B;
A is an unsubstituted aromatic or non-aromatic, monocyclic or bicyclic heterocyclic radical, or—depending on the substitution possibilities of the ring system—one which is mono- to penta-substituted by substituents selected from the group comprising halogen, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, halogen-C
1
-C
3
-alkyl, C
1
-C
3
-halogenalkoxy, cyclopropyl, halogencyclopropyl, C
2
-C
3
-alkenyl, C
2
-C
3
-alkinyl, C
2
-C
3
-halogenalkenyl and C
2
-C
3
-halogenalkinyl, C
1
-C
3
alkylthio, C
1
-C
3
-halogenalkylthio, allyloxy, propargyloxy, allylthio, propargylthio, halogenallyloxy, halogenallylthio, cyano and nitro; and
B is phenyl, 3-pyridyl or thiazolyl, which are optionally substituted by one to three substituents from the group comprising C
1
-C
3
-alkyl, C
1
-C
3
-halogenalkyl, cyclopropyl, halogencyclopropyl, C
2
-C
3
-alkenyl, C
2
-C
3
-alkinyl, C
1
-C
3
-alkoxy, C
2
-C
3
-halogenalkenyl, C
2
-C
3
-halogenalkinyl, C
1
-C
3
-halogenalkoxy, C
1
-C
3
-alkylthio, C
1
-C
3
-halogenalkylthio, allyloxy, propargyloxy, allylthio, propargylthio, halogenallyloxy, halogenallylthio, halogen, cyano and nitro;
and optionally the possible E/Z isomers, E/Z isomeric mixtures and/or tautomers thereof, respectively in free form or in salt form;
characterised in that a compound of formula
wherein
R
1
, R
2
and A have the same significances as in formula (I), and
X is O or S;
is hydrolysed with a strong acid.
The compounds of formula (I) may exist as E/Z isomers, e.g. in the two following isomeric forms
Accordingly, where reference is made hereinafter to the compounds of formula (I), this is understood to apply also to the corresponding E/Z isomers, even if the latter are not mentioned specifically in each case.
The compounds of formula (I) may also exist in part as tautomers, for example in the forms
Accordingly, where reference is made hereinbefore and hereinafter to the compounds of formula (I), this is understood to apply also to the corresponding tautomers, even if the latter are not mentioned specifically in each case.
The compounds of formula (1), and optionally their E/Z isomers and tautomers, may exist as salts. Compounds of formula (I) which have at least one basic centre may form e.g. acid addition salts. These are formed for example with strong inorganic acids, such as mineral acids. e.g. sulphuric acid, a phosphoric acid or hydrohalic acid, with strong organic carboxylic acids, such as C
1
-C
4
-alkanecarboxylic acids that are optionally substituted, e.g. by halogen, for example acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. oxalic acid, malonic acid, maleic acid, fumaric acid or phthalic acid, such as hydroxy-carboxylic acids, e.g. ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or such as benzoic acid, or with organic sulphonic acids, such as C
1
-C
4
-alkane- or aryl-sulphonic acids that are optionally substituted, e.g. by halogen, for example methane- or p-to-luenesulphonic acid. Salts of compounds of formula (I) with acids of the types mentioned are preferably obtained during working up of the reaction mixtures.
In addition, compounds of formula (I) with at least one acidic group can form salts with bases. Suitable salts with bases are for example metal salts, such as alkali metal salts or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, piperidine, pyrrolidine, a mono-, di- or tri- lower alkyl amine, e.g. ethyl, diethyl, triethyl or dimethyl propyl amine, or with a mono-, di- or trihydroxy lower alkyl amine, e.g. mono-, di- or triethanol amine. Furthermore, if required, corresponding internal salts may be formed. Agrochemically advantageous salts are preferred within the scope of the invention. Where reference is made hereinbefore and hereinafter to the free compounds of formula (I) or their salts, this is understood to apply also to the corresponding salts or the free compounds of formula (I). The same applies to the E/Z isomerc and tautomers of compounds of formula (I) and their salts. The free form is preferred.
In the definition of the present formulae (I) and (II), the individual generic terms are to be understood as follows:
The halogen atoms considered as substituents are fluorine and chlorine and also bro-mine and iodine, whereby fluorine, chlorine and bromine are preferred, especially chlorine. Here, halogen is understood to be an independent substituent or part of a substituent as in halogenalkyl, halogenalkylthio, halogenalkoxy, halogencycloalkyl, halogenalkenyl, halogenalkinyl, halogenallyloxy or halogenallylthio. The alkyl, alkylthio, alkenyl, alkinyl and alkoxy radicals considered as substituents may be straight-chained or branched. Examples of such alkyls are methyl, ethyl, propyl, isopropyl, butyl, i-butyl, sec.-butyl or tert.-butyl. Suitable alkoxy radicals that may be mentioned are inter alia: methoxy, ethoxy, propoxy, iso-propoxy or butoxy and their isomers. Alkylthio is for example methylthio, ethylthio, isopropylthio, propylthio or the isomeric butylthio. If the alkyl, alkoxy, alkenyl, alkinyl or cycloalkyl groups considered as substituents are substituted by halogen, they can be only partly or even perhalogenated. The above-mentioned definitions apply to halogen, alkyl and alkoxy. Examples of the alkyl elements of these groups are methyl which is mono- to tri-substituted by fluorine, chlorine and/or bromine, for example CHF
2
or CF
3
; ethyl which is mono- to penta-substituted by fluorine, chlorine and/or bromine, for example CH
2
CF
3
, CF
2
CF
3
, CF
2
CCl
3
, CF
2
CHCl
2
, CF
2
CHF
2
, CF
2
CFCl
2
, CF
2
CHBr
2
, CF
2
CHClF, CF
2
CGBrF or CClFCHClF; propyl or isopropyl which is mono- to hepta-substituted by fluorine, chlorine and/or bromine, for example CH
2
CHBrCH
2
Br, CF
2
CHFCF
3
, CH
2
CF
2
CF
3
or CH(CF
3
)
2
; butyl which is mono- to nona-substituted by fluorine, chlorine and/or bromine, or one of its isomers, for example CF(CF
3
)CHFCF
3
or CH
2
(CF
2
)
2
CF
3
; 2-chlorocyclopropyl or 2,2-difluoro-cyclopropyl; 2,2-difluorovinyl, 2,2-dichlorovinyl, 2-chloroalkyl, 2,3-dichlorovinyl or 2,3-dibromovinyl.
If the defined alkyl, alkoxy or cycloalkyl groups are substituted by other substituents, they may be substituted once or more by the same or different substituents from those listed. There are preferably one or two further substituents present in the substituted groups. The cycloalkyl radicals considered as substituents are for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Alkenyl and alkinyl groups contain an unsaturated carbon-carbon bond. Typical representatives are allyl, methallyl or propargyl, but also vinyl and ethinyl. The double or triple bonds in allyloxy, propargyloxy, alkylthio or propargylthio are separated from the binding site to the hetero atom (O or S) preferably by a saturated carbon atom.
It is already known that, to produce 1,3-disubstituted 2-nitroguanidines, a further substituent may be introduced (e.g. by alkylation) into monosubstituted 2-nitroguanidines (see for example EP patent applications 0.375.907, 0.376.279 and 0.383.091). Owing to the presence of three reactive hydrogen atoms in the monosubstituted 2-nitroguanidines used as starting material in these reactions, the previously proposed substitution reactions of this kind are often non-selective and lead to undesired substitution products. The EP patent applications mentioned describe the preparation of 1,3-disubstituted 2-nitroguanidines by reacting monosubstituted nitroisothioureas with primary amines whilst cleaving mercaptan. However, these nitroisothiourea compounds which contain alkylthio leaving groups and are proposed as starting compounds in the known processes can only be obtained with difficulty.
In addition, in EP-A-0.483.062, a process for the preparation of the compounds

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