Title of Invention

METHOD OF PRODUCING NITROGUANIDINE- AND NITROENAMINE DERIVATIVES

Abstract A process for the preparation of the compound wherein Q is chlorine or bromine, in the presence of a solvent or diluent, a phase transfer catalyst and a base, the solvent or diluent being an ester of carbonic acid, the phase transfer catalyst being a quaternary ammonium salt and the base being a carbonate.
Full Text 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 materia! 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 alkyithio 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 (!) 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.



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 there¬of, may be present as salts. Compounds of formula (1) 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 Ci-Cialkanecarboxylic 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 phthaltc acid, such as hydroxycarboxylic acids, e.g. ascorbic, lactic, malic, tartaric or citric acid, or benzoic acid, or with organic sulphonic acids, such as Ci-C4alkanesulphonic 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 (1} 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 dimethylpropyiamine, 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 (1) to (II!) 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 subsfituent, such as in halogenalkyi, halogenalkylthio, halogenalkoxy, halogencycloalkyi, halogenalkenyl, halogenalkinyl, halogenallyloxy or halogenallylthio- Alkyl, alkylthio. aikenyl, aikinyl 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, tsopropylthio, propylthio or the isomeric butylthio- Alkyl, alkoxy, aikenyl, aikinyl 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 CHF2 or CF3; ethyl which is mono- to pentasubstituted by fluorine, chlorine and/or bromine, such as CH2CF3, CF2CF3, CF2CCI3, CFiCHCIj, CF2CHF2, CFjCFCIj, CF2CHBr2, CFjCHCIF, CF2CHBrF or CCIFCHCIF; propyl or isopropyl, mono- to heptasubstltuted by fluorine, chlorine and/or bromine, such as CH2CHBrCH2Br, CF2CHFCF3, CH2CF2CF3 or CH{CF3)2; butyl or one of its isomers, mono- to nonasubstituted by fluorine, chlorine and/or bromine, such as CF(CF3)CHFCF3 or CH2(CF2)2CF3; 2-chlorocyclopropyl or 2,2-difluoro-cyclopropyl; 2,2-difluorovinyl, 2.2-dichlorovinyl, 2-chloroalkyl, 2,3-dichlorovinyl or 2,3-dibromovinyl-
Typical representatives of aikenyl and aikinyl groups are allyl, methallyl, propargyl, vinyl and ethinyl. The double or triple bonds in allyloxy, propargyloxy, allylthio or propargylthio are separated from the connection point to the hetero atom (N, O or S) preferably by a saturated carbon atom.
If the defined alkyl, alkoxy, aikenyl, aikinyl or cycloalkyl groups are substituted by other substituents, they may be substituted once or many times by identical or different

substituents from those listed. In the substituted groups, it is preferable for one or two further substituents to be present. CydoalkyI is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Aryl signifies phenyl, naphthyl, phenanthrenyl or anthracenyl, especially phenyl.
In the context of the present invention, a heteroaryl radical preferably signifies a 5- to 7-membered, aromatic or non-aromatic ring with one to three hetero atoms selected from the group comprising N. O and S. Preference is given to aromatic 5- and 6-rings, which have , a nitrogen atom as the hetero atom and optionally one further hetero atom, preferably nitrogen, oxygen or sulphur, especially nitrogen,
A leaving group Q is understood to be hereinbefore and hereinafter all the removable groups that are usual in chemical reactions and are known to the person skilled in the art; in particular halogens such as fluorine, chlorine, bromine, iodine, -0-C(=0)-A, -O-P{=0)(W)2, -0-Si(C,-Cs-alkyl)3, -0-{Ci-C8-alkyl), -0-aryl, -0-S(=0)2W, -S-P(=0){W)2, -S-P(=S)(W);, -S-S-(C,-CB-a[kyl), -S-S-aryl, -S-(Ci-C8-alkyl), -S-aryl, -S(=0)W, or -S(=0)2W, wherein W is optionally substituted C,-Ce-alkyl, C2-Ca-alkenyl, C2-CB-alkinyl, optionally substituted aryl, optionally substituted benzyl, Ci-Cg-alkoxy or di-(Ci-C8-alkyl)amine, in which the alkyl groups are independent of one another; NO3, N02 or sulphate, sulphite, phosphate, phosphite, carboxylate, imlno ester, N2 or carbamate. Chlorine and bromine are especially preferred as the leaving group, particularly chlorine.
The compounds preferably produced in the process according to the invention are compounds of formula (I)
1) wherein Ri is hydrogen;
2) wherein R2 is a radical -N(R3)R^;
3) wherein R3 is hydrogen or Ci-C4-alkyI;
4) wherein R4 is hydrogen;
5) wherein R2 is a radical -N{R3)R4 and R3 and Re together are -CH2-CH2-, -CH2-O-CH2- or -CH2-N{CH3)-CH2-, especially -CH2-CH2- or -CH2-0-CH2-
6) wherein Re is hydrogen, C-Ca-alkyl, aryl or benzyl;
7) wherein X is CH-NOj or N-NO;, especially N-NO2;
8) wherein A is pyridyl thiazolyl ortetrahydrofuranyl, optionally substituted by halogen, Ci-C3-alky!, C,-C3-alkoxy, halogen-Ci-Cs-alkyI or Ci-Ca-halogenalkoxy; especially 2-chloro-thiazol-5-yl or 2-chloro-pyrid-5-yl.




The phase transfer catalysts may be ali customary compounds, i.e. quaternary ammonium ■ \(,,' ' salts, quaternary phosphonium salts, crown ethers, chelating agents, DABCO 1,4-diaza-bicyclo[2.2.2]octane and DBU (1,5-diazabicyclo{4.3.0]non-5-ene), and quaternary ammonium salts thereof; as well as polymeric phase transfer catalysts. They are listed in the paper "Phase Transfer Catalysis" by the company Fluka, Buchs, Switzerland, 1986 edition, pages 7 to 25. The phase transfer catalysts named therein are thus included by reference in the present invention.
Especially preferred quaternary ammonium salts as phase transfer catalysts are for example benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, benzyltributyl ammonium chloride, benzyltriethyl ammonium bromide, benzyltrimethyl ammonium methoxide, benzyltrimethyl ammonium hydroxide (thton B), glycidyl trimethyl ammonium chlohde, hexadecyl-trimethyl ammonium chloride, hexadecyl-thmethyl ammonium bromide, hexadecyl-pyridinium bromide, hexadecyl-pyridinium chloride, 2-hydroxy ethyl-trim ethyl-ammonium chloride, 2-hydroxyethyl-trimethylammonium hydroxide, phenyltrimethyl-ammonium chloride, phenyltrimethyl ammonium hydroxide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide, tetrabutyl ammonium tetrafluoroborate, tetrabutyl ammonium nitrate, tetradecyl ammonium chloride, tetradodecyl-ammonium acetate, tetraethyl ammonium chloride, tetraethyl ammonium hydroxide, tetrado-decylammonium nitrate, tetradodecyl ammonium toluene sulphonate, tetrahexyl ammonium chloride, tetrahexylammonium bromide, tetramethyl ammonium chloride, tetramethyl-ammonium bromide, tetramethyl ammonium hydroxide, tetramethyl ammonium iodide, tetra¬methyl ammonium toluene sulphonate, tetraoctyl ammonium chloride, tetrapropyl ammonium

chloride, tetrapropyl ammonium bromide, fributylmethyl ammonium chloride and tributylheptyl ammonium bromide,
most preferably quaternary ammonium hydroxides, particularly tetramethyl ammonium hydroxide in the form of the pentahydrate.
The quaternary phosphonium salts may be benzyltriphenylphosphonium chloride, hexadecyltributylphosphonium bromide, hexadecyltrimethylphosphonium bromide, tetrabutylphosphonium chloride.tetraphenylphosphonium chloride or tetraphenyl-phosphonium bromide; or hexyltributylphosphonium bromide fixed to a potymenc matrix.
The crown ethers as phase transfer catalysts for the synthesis process according to the invention may be for example: 12-Crown-4, 15-Crown-5, 18-Crown-6, dibenzo-18-Crown-6; polyethylene glycols, for example with an average molecular weight of IQOO, 1500 or 2000; tetraethylene glycol or tetraethylene glycol dimethylether.
Preferred solvents or diluents for carrying out the process according to the invention are esters, such as ethyl acetate; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert.-butylmethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone; amides, such as N,N-dimethyl-formamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone or hexamethylphosphoric acid triamide; nitriles, such as acetonitrile or propionifrile; and sulphoxides, such as dimethyl sulphoxide; or water.
Especially preferred are esters of carbonic acid; acetic acid; formic acid; ketones; nitriles;
ethers; N-alkylated acid amides; dimethyl sulphoxide; N-alkylpyrrolidones; r\(y>'" '
especially acetonitrile, dimethyl carbonate, diethyl carbonate, N-methylpyrrolidone, dimethylformamide, dimethyl acetamide, ethoxyethyl acetate, methyl acetate, propionitrile, butyrotiitrile, dimethyl sulphoxide, ethyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone.
Particularly preferred solvents are acetonitrile, dimethyl carbonate, diethyl carbonate, N-methylpyrrolidone, dimethylformamide, dimethylacetamide and ethoxyethyl acetate, in particular dimethyl carbonate.
An especially preferred combination is dimethyl carbonate as the solvent with tetramethyl-ammonium hydroxide as the phase transfer catalyst.



184 g of 100% 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine in 400 g of dimethyl carbonate are placed in a sulphonation flask, and 168 g of 100% 2-chloro-5-chloromethyl-thiazole (1.0 moles) are added as a melt- This mixture is heated to 65°C. A mixture consisting of 350 g of dimethyl carbonate, 4 g of tetramethylammonium hydroxide pentahydrate and 242 g of potassium carbonate powder is measured in whilst stirring over 60 minutes at 62 to 68°C.
The reaction mixture is held for 5 to 6 hours whilst stirring vigorously, until more than 99% of the 2-chloro-5-chloromethylthiazole has reacted (LC control).
The reaction mixture is subsequently cooled to 45-50°C and mixed with 600 g of water. The reaction mixture is adjusted to pH 6.5 with ca, 260 g of 32% hydrochloric acid and is then heated to 60 to 65°C until everything dissolves. The solution is left to stand until phase ' separation takes place, and the organic phase is separated- The aqueous phase is re-extracted at 50°C with 300 g of dimethyl cart>onate.
The organic phase from re-extraction is combined with the organic phase from the reaction mixture. The combined organic phases are concentrated under vacuum (350-400 mbar) at 60 to 65°C to a final weight of 600 g (480 ml). The mixture is slowly cooled to O-S^C and held for 1 hour. Then the resulting suspension is filtered.
The filter cake is washed with 300 g of dimethyl carbonate of 5-10°C in two portions and then with 300 ml of water in two portions, and the moist product is dried in a vacuum at 70° C.
Yield: 218-220 g of title product in a purity of 98 to 99 % (74 % of theory based on 100% 2-ch!oro-5-chloromethyithiazole). The above-mentioned isomer of formula (IV) is not found.
The title product may be obtained in a purity of 99.5% by recrystallisation from dimethyl carbonate-
An alternative preparation method comprises adding together the potassium carbonate, 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine and the tetramethylammonium hydroxide pentahydrate in 1100 g of dimethyl carbonate, and measuring in the 2-chloro-5-chloromethylthiazole over 60 minutes at 65'C. The subsequent reaction and working up are then carried out as above.


WE CLAIM:

wherein Q is chlorine or bromine, in the presence of a solvent or diluent, a phase transfer catalyst and a base, the solvent or diluent being an ester of carbonic acid, the phase transfer catalyst being a quaternary ammonium salt and the base being a carbonate.
2. The process according to claim 1 wherein the phase transfer catalyst is a
quaternary ammonium hydroxide,
3. The process according to claim 2 wherein the phase transfer catalyst is
tetramethyl ammonium hydroxide in the form of the pentahydrate.

4. The process according to any one of the preceding claims wherein the solvent
or diluent is dimethyl carbonate or diethyl carbonate.
5. The process according to claim 4 wherein the solvent or diluent employed is
dimethyl carbonate.
6. The process according to claim 1 wherein the solvent or diluent is dimethyl carbonate and the phase transfer catalyst is telramethyl ammonium hydroxide.
7. The process according to claim any one of the preceding claims wherein the base is potassium carbonate.
8. A process for the preparation of the compound substantially as herein described and exemplified.


Documents:

in-pct-2001-1800-che abstract-duplicate.pdf

in-pct-2001-1800-che abstract.pdf

in-pct-2001-1800-che claims-duplicate.pdf

in-pct-2001-1800-che claims.pdf

in-pct-2001-1800-che correspondence-others.pdf

in-pct-2001-1800-che correspondence-po.pdf

in-pct-2001-1800-che description (complete)-duplicate.pdf

in-pct-2001-1800-che descritpion (complete).pdf

in-pct-2001-1800-che form-1.pdf

in-pct-2001-1800-che form-19.pdf

in-pct-2001-1800-che form-26.pdf

in-pct-2001-1800-che form-3.pdf

in-pct-2001-1800-che form-5.pdf

in-pct-2001-1800-che others.pdf

in-pct-2001-1800-che pct.pdf

in-pct-2001-1800-che petition.pdf


Patent Number 201787
Indian Patent Application Number IN/PCT/2001/1800/CHE
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 28-Aug-2006
Date of Filing 21-Dec-2001
Name of Patentee SYNGENTA PARTICIPATIONS AG
Applicant Address Schwarzwaldallee 215, CH-4058 Basel
Inventors:
# Inventor's Name Inventor's Address
1 SEIFERT, GOTTFRIED Muehlemattweg 20, CH-4312 Magden
2 RAPOLD, THOMAS, ROBINIENWEG 671, CH-4323 WALLBACH,
3 GISIN, VERENA, KORNBERGSTRASSE 198, CH-5028 UEKEN
PCT International Classification Number C07D417/06
PCT International Application Number PCT/EP2000/005762
PCT International Filing date 2000-06-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 1171/99 1999-06-23 Switzerland