Method of producing nitroguanidine- and nitroenamine...

Details Method of producing nitroguanidine- and nitroenamine... Method of producing nitroguanidine- and nitroenamine...

2002-12-20

2004-06-08

O'Sullivan, Peter (Department: 1621)

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

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S212000, C546S270700, C546S274700, C546S330000, C546S332000, C548S205000, C549S495000

Reexamination Certificate

active

06747146

ABSTRACT:

The present invention relates to a novel type of method of producing substituted 2-nitro-guanidine and nitroenamine derivatives.
It is known that in order to produce substituted nitroguanidines, nitroenamines or cyano-enamines, a further substituent may be introduced (e.g. by alkylation) into those compounds that may already be substituted once to several times (see e.g. EP patent application 0.375.907). Owing to the presence of several hydrogen atoms in the educts used as the starting material in these reactions, the previously proposed substitution reactions of this kind are often non-selective and lead to undesired substitution products. The afore-mentioned EP patent applications describe by way of example the production of 1,3-disubstituted 2-nitroguanidines by reacting monosubstituted nitroisothioureas with primary amines whilst cleaving mercaptan. However, these nitroisothiourea compounds, containing alkylthio leaving groups, which are proposed as starting compounds in the known processes, can only be obtained with difficulty. In EP-A-0-483.062, a process for the production of the compounds of formula (I) by hydrolysis of hexahydro-triazines is also described.
It has now been shown that the above-described methods of producing compounds of formula (I) do not satisfy the requirements demanded of a chemical production process, such as availability, toxicity, stability in storage and purity of the starting materials and excipients, reaction time, energy consumption and volumes yielded by the process, quantity and recovery of the accruing by-products and waste products, as well as purity and yield of the end product. There is therefore a need to provide improved methods of producing these compounds.
Accordingly, it is the aim of the present invention to provide an improved method of producing substituted 2-nitroguanidines, 2-nitroenamines, 2-cyanoenamines and 2-cyano-amines from readily obtainable starting compounds, which allows specific substitution without obtaining major amounts of undesired by-products.
Accordingly, the invention relates to a process for the preparation of compounds of formula
wherein
R
1
is hydrogen or C
1
-C
4
-alkyl;
R
2
is hydrogen, C
1
-C
8
-alkyl, C
3
-C
6
-cycloalkyl, or a radical —N(R
3
)R
4
; or R
2
and R
6
together are —CH
2
—CH
2
—S—, whereby the ethylene group is bonded to the nitrogen;
R
3
and R
4
, independently of one another, are hydrogen, C
1
-C
4
-alkyl, C
3
-C
6
-cycloalkyl or a radical —CH
2
B;
R
6
is hydrogen, C
1
-C
8
-alkyl, aryl or benzyl;
or R
3
and R
6
together are —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH
2
—O—CH
2
—, —CH
2
—S—CH
2
— or —CH
2
—N(R
5
)—CH
2
—;
X is N—CN, CH—CN; CH—NO
2
or N—NO
2
;
A is an aromatic or non-aromatic, monocyclic or bicyclic heterocyclic radical which is unsubstituted or—depending on the substitution possibilities of the ring system—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
-alkynyl, C
2
-C
3
-halogenalkenyl and C
2
-C
3
-halogenalkynyl, 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, halo-gencyclopropyl, C
2
-C
3
-alkenyl, C
2
-C
3
-alkynyl, C
1
-C
3
-alkoxy, C
2
-C
3
-halogenalkenyl, C
2
-C
3
-halogenalkynyl, 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;
characterised in that a compound of formula
which is known or may be produced by methods known per se, and wherein R
2
, R
6
and X have the same significance as indicated above for formula (I), is reacted in the presence of a phase transfer catalyst and a base with a compound of formula
which is known or may be produced by methods known per se, and wherein A and R
1
have the same significance as indicated above for formula (I) and Q is a leaving group.
The compounds of formula (I) may be present partly in the form of tautomers. Accordingly, any reference to compounds of formula (I) hereinbefore and hereinafter is understood to include also their corresponding tautomers, even if the latter are not specifically mentioned in each case.
The compounds of formula (I) and, where appropriate, the E/Z isomers and tautomers thereof, may be present as salts. Compounds of formula (I) having 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 a hydrohalic acid, with strong organic carboxylic acids, such as C
1
-C
4
alkanecarboxylic acids substituted where appropriate for example by halogen, e.g. acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. oxalic, malonic, maleic, fumaric or phthalic acid, such as hydroxycarboxylic acids, e.g. ascorbic, lactic, malic, tartaric or citric acid, or benzoic acid, or with organic sulphonic acids, such as C
1
-C
4
alkanesulphonic or arylsulphonic acids substituted where appropriate for example by halogen, e.g. methanesulphonic or p-toluenesulphonic acid. Salts of compounds of formula (I) with acids of the said kind are preferably obtained when working up the reaction mixtures.
In a broader sense, compounds of formula (I) with at least one acid group can form salts with bases. Suitable salts with bases are for example metal salts, such as alkali 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 alkylamine, e.g. ethyl-, diethyl-, triethyl- or dimethylpropylamine, or a mono-, di- or trihydroxy-lower alkylamine, e.g. mono-, di- or triethanolamine. Corresponding internal salts where appropriate may also be formed. Preferred compounds within the scope of this invention are agrochemically advantageous salts. Hereinbefore and hereinafter, the free compounds of formula (I) are understood where appropriate to include also by analogy the corresponding salts, and the salts are understood to include also the free compounds of formula (I). The same applies to E/Z isomers and tautomers of compounds of formula (I) and salts thereof. The free form is preferred.
In the definition of formulae (I) to (III) given above and below, the individual generic terms are to be understood as follows:
Halogen signifies fluorine, chlorine, bromine and iodine, whereby fluorine, chlorine and bromine are preferred, especially chlorine. Halogen in this context is understood to be an independent substituent or part of a substituent, such as in halogenalkyl, halogenalkylthio, halogenalkoxy, halogencycloalkyl, halogenalkenyl, halogenalkinyl, halogenallyloxy or halogenallylthio. Alkyl, alkylthio, alkenyl, alkinyl and alkoxy radicals may be straight-chained or branched. If not defined otherwise, alkyl groups have up to 6 carbon atoms. Examples of such alkyls which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl. Alkoxy radicals are for example methoxy, ethoxy, propoxy, isopropoxy or butoxy and the isomers thereof. Alkylthio is for example methylthio, ethylthio, isopropylthio, propylthio or the isomeric butylthio. Alkyl, alkoxy, alkenyl, alkinyl or cycloalkyl groups that are substituted by halogen can be only partly or also perhalogenated. The above-mentioned definitions apply here to halogen, alkyl and alkoxy. Examples of the alkyl elements of these groups are methyl which is mono- to trisubstituted by fluorine, chlorine and/or bromine, such as CHF
2
or CF
3
; ethyl which is mono- to pentasubstituted by fluorine, chlorine and/or bromine, such as CH
2
CF
3
, CF
2
CF
3
, CF
2
CCl
3
, CF
2
CHCl
2
, CF
2
CHF
2
, CF
2
CFCl

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