Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-16
2002-10-08
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S215000
Reexamination Certificate
active
06462043
ABSTRACT:
The present invention relates to a novel type of method of producing substituted 2-nitroguanidine derivatives.
It is known that, in order to produce 1,3-disubstituted 2-nitroguanidines, a further substituent may be introduced into monosubstituted 2-nitroguanidines (e.g. by alkylation) (see e.g. 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 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 mentioned EP patent applications describe 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 addition, in EP-A-0-483.062, a method of producing the compounds of formula (I) by hydrolysis of hexahydro-triazines is 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. It has now surprisingly been found that the method according to the invention is able to satisfy these requirements to a large extent.
Accordingly, it is the aim of the present invention to provide an improved method of producing 1-monosubstituted and 1,3-disubstituted 2-nitroguanidines from readily obtainable starting compounds, which allows specific 1,3-disubstitution without obtaining major amounts of undesired by-products.
The object of the invention is
a) a method of producing a compound of formula
and, if appropriate, the E/Z isomers, E/Z isomeric mixtures and/or tautomers thereof, each in free form or in salt form, wherein
R
1
is hydrogen or C
1
-C
4
-alkyl;
R
2
is hydrogen, C
1
-C
6
-alkyl, C
3
-C
6
-cycloalkyl or a radical —CH
2
B;
Het 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, halogencyclopropyl, 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 by hydrolysing a compound of formula
Q—A—Q (IIa),
wherein A is a direct bond or an organic radical; or of formula
wherein U is an organic radical; and in compounds (IIa) and (IIb) Q signifies
and R
1
, R
2
and Het are as defined above for formula (I), and optionally the E/Z isomers, E/Z isomeric mixtures and/or tautomers thereof, each in free form or in salt form.
The compounds of formula (I) may be present as E/Z isomers, e.g. in the following two isomeric forms
Accordingly, any reference to compounds of formula (I) hereinbefore and hereinafter is understood to include also their corresponding E/Z isomers, even if the latter are not specifically mentioned in each case.
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. sulfuric acid, a phosphoric acid or a hydrohalic acid, or 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 sulfonic acids, typically C
1
-C
4
alkane or arylsulfonic acids substituted where appropriate for example by halogen, e.g. methane-, trifluoromethane- or p-toluene-sulfonic 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, typically 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, or 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.
The statements made about the free compounds of formula (I) or the E/Z isomers and tautomers and salts thereof also apply by analogy to the compounds of formulae (IIa) and (IIb), as well as the compounds of formulae (IIIa) and (IIIb) below.
In the definitions of the above formulae (I), (IIa), (IIb) and of the compounds of formulae (IIIa) and (IIIb) below, the individual generic terms are to be understood as follows:
The halogen atoms considered as substituents may be both fluorine and chlorine, and 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, halogenalkynyl, halogenallyloxy or halogenallylthio. The alkyl, alkylthio, alkenyl, alkynyl and alkoxy radicals considered as substituents may be straight-chained or branched. Examples of such alkyls which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl. Suitable alkoxy radicals which may be mentioned are, inter alia: methoxy, ethoxy, propoxy, isopropoxy or butoxy and the isomers thereof. Alkylthio is for example methylthio, ethylthio, isopropylthio, propylthio or the isomeric butylthio. If the alkyl, alkoxy, alkenyl, alkynyl or cycloalkyl groups considered as substituents are substituted by halogen, they may be only partially halogenated or also perhalogenated.
Allen Rose M.
Balasubramanian Venkataraman
Shah Mukund J.
Syngenta Crop Protection Inc.
Teoli, Jr. William A.
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