PROCESS FOR THE PREPARATION OF PYRIMIDINONE DERIVATIVES

Abstract: The invention comprises a process for the preparation of a compound of formula (I), wherein A is a fused 5-membered heterocyclic ring which may be saturated or unsaturated, aromatic or non-aromatic and which may contain one or two hetero atoms O, S and/or N, or is fused benzo, pyrido or pyridazino; R1 and R2 are groups which are inert to the reactions; R3 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C6cycloalkyl or C3-C6cycloalkyl-C1-C6alkyl, each of which is unsubstituted or substituted, in which process (a) a compound of formula (II), wherein A, R1 and R2 are as defined for formula (I), and R5 is a group which does not impair the reactions, is reacted with an imidocarbonate of formula (III), wherein R3 and R4 are as defined for formula (I), to give the intermediate compound of formula (IV); and subsequently (b) the compound of formula (IV) is cyclized to a compound of formula (I).

Description: Process for the Preparation of Pyrimidinone Derivatives The invention relates to a process for the preparation of compounds of formula I wherein A is a fused 5-membered heterocyclic ring which may be saturated or unsaturated, aromatic or non-aromatic and which may contain one or two hetero atoms O, S and/or N, or is fused benzo, pyrido or pyridazino; Ri and R 2 are groups which are inert to the reactions; R 3 is d-Cβalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl-Cι-C 6 alkyl, each of which is unsubstituted or substituted by halogen, C C 4 haloalkyl, C C alkoxy, S-C C 4 alkyl, SO-d-dalkyl, SO 2 -C C 4 alkyl, CO-Cι-C 4 alkyl, N=CH-C r C alkyl, N=C(C 1 -C 4 alkyl) 2 , NH-C 1 -C 4 alkyl, N(C C 4 alkyl) 2 , COO-Cι-C 4 alkyl, COO-aryl, cyano, nitro, Si-(CrC 4 alkyl) 3 , phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; and R is Cι-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl-Cι-C 6 alkyl, each of which is unsubstituted or substituted by halogen, C C haloaikyl, C C alkoxy, S-C C 4 alkyl, SO-CrC 4 alkyl, SO 2 -CrC 4 alkyl, CO-C C 4 alkyl, N=CH-C r C 4 alkyl, N=C(C 1 -C 4 alkyl) 2 , NH-Cι-C 4 alkyl, N(Cι-C 4 alkyl) 2 , COO-C r C 4 alkyl, COO-aryl, cyano, nitro, Si-(Cι-C alkyl) 3 , phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; in which process (a) a compound of the formula II, wherein A, ^ and R 2 are as defined for formula I, and R 5 is a group which does not impair the reactions, e.g. hydrogen, optionally substituted alkyl or optionally substituted aryl, is reacted with an imidocarbonate of the formula III, wherein R 3 and R 4 are as defined for formula I, to give the intermediate compound of formula IV; and subsequently (b) the compound of the formula IV is cyclized to a compound of the formula I. The invention relates also to new intermediates of formula IV wherein A, R 1 ( R 2 , R 3 , R 4 and R 5 are as defined above. Compounds of formula I having plant protecting, in particular fungicidal properties are known e.g. from WO 97/48684, WO 97/33890, WO 97/02262 and WO 94/26722. In the syntheses of these compounds as described therein thiophosgene or an isothiocyanate is used for the preparation of the pyrimidinone moiety; in an additional subsequent reaction step, the sulfur introduced with the above reagents has to be eliminated. The known processes for the preparation of compounds of formula I are accordingly unsatisfactory for safety, economic and ecological reasons. The method provided herewith is distinguished by good technical feasibility and is economically and ecologically more favorable. Compounds of formula II are known e.g. from WO 97/33890. Imidocarbonates of formula III are known or can be prepared by known methods, as described e.g. in EP 519'868 and WO 98/40363. Reaction steps (a) and (b) are carried out with or without a solvent; the temperature is not critical and may vary from 20° to 200°C; preferably is a temperature of 80° to 170°C, most preferably at or near the boiling temperature of the solvent. The reaction is advantageously carried out in the presence of catalytic amounts of an acid, e.g 1-20% or 1-5% per weight related to the educt of formula II, and in the absence of water. Suitable acids are mineral acids, as sulfuric acid, phosphoric acid and hydrogen halide, as HCI, HBr, HF; organic carboxylic acids, as acetic acid, trifluoroacetic acid and oxalic acid; organic sulfonic acids as methanesulfonic acid and p-toluenesulfonic acid; Lewis acids, as AICI 3 , AIBr 3 , SnCI 4 and BF 3 . Suitable solvents or diluents for both reaction steps (a) and (b) are for example: aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, typically benzene, toluene, xylene, chlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichioroethane or trichloroethane; ethers, typically diethyl ether, tert-butylmethyl ether, glyme, diglyme, tetrahydrofuran or dioxane; ketones, typically acetone or methyl ethyl ketone; alcohols, typically methanol, ethanol, propanol, butanol, ethylene glycol or glycerol; esters, typically ethyl acetate or butyl acetate; amides, typically N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; nitriles, typically acetonitrile; and sulfoxides, typically dimethylsulfoxide. In a preferred mode the intermediate compound of formula IV is not isolated; according to this procedure compounds of formulae II and III are mixed and reacted together, optionally in presence a solvent and of an acid as described above, until the reaction is completed. The substituents Ri and/or R 2 in ring A may be introduced or interchanged in the compounds of formula I as described in WO 97/33890. In a particular embodiment of the present invention, Ri and/or R 2 in ring A may be introduced or interchanged also on the intermediate compounds of formula IV. This is particularly advantageous for the preparation of compounds of formula I, wherein Ri and/or R 2 are halogen. In this process, a compound of the formula IV, in which Ri and/or R 2 are hydrogen, is halogenated prior to reaction step (b). For example, if Ri is hydrogen and R 2 is as defined for formula I, this reaction can be shown by the following scheme: Particularly preferred are the chlorination and bromination of compounds of formula IV, in which A is thieno and Ri and R are both hydrogen. Methods for halogenation [step (c)] are described e.g.in WO 97/33890 and include iodination with l 2 , bromination with NBS (N-Bromsuccinimide) or Br 2 , chlorination with NCS (N-Chlorosuccinimide) or Cl or SO 2 CI 2 , f luorination with FCI or other F * reagents, in solvents as halogenated hydrocarbons, typically chlorobenzene, bromobenzene, chloroform, dichloromethane, trichloromethane, dichloroethane or trichloroethane; ethers, typically diethyl ether, tert-butylmethyl ether, glyme, diglyme, tetrahydrofuran or dioxane, as well as nitrogen containing compounds like triethylamine, piperidine, pyridine, alkylated pyridine, quinoline and isoquinoline. Particularly preferred is the chlorination with NCS (N-Chlorsuccinimide), CI 2 or SO 2 CI 2 . The general terms used hereinabove and hereinbelow have the following meanings, unless otherwise defined: 5-Membered heterocyclic rings A are for example thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, isothiazolyl and the corresponding partially or completely hydrogenated rings. Alkyl groups are, in accordance with the number of carbon atoms, straight-chain or branched and will typically be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-amyl, tert-amyl, 1-hexyl or 3-hexyl. Alkenyl is straight-chain or branched alkenyl such as allyl, methallyl, 1 -methylvinyl or but-2-en-1 -yl. Preferred alkenyl radicals contain 3 to 4 carbon atoms in the chain. Alkynyl can be straight-chain or branched and is typically propargyl, but-1-yn-1-yl or but-1 -yn-3-yl; preferred is propargyl. Halogen and halo substituents are fluoro, chloro, bromo or iodo. Fluoro, chloro and bromo are preferred. Haloalkyl can contain identical or different halogen atoms, typically fluoromethyl, difluoro- methyl, difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 3,3,3-trifluoropropyl. Alkoxy is typically methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec- butyloxy and tert-butyloxy. Methoxy and ethoxy are preferred. Haloalkoxy is typically difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy and 2,2-difluoroethoxy. Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl-alkyl is typically cyclopropylmethyl, 2-cylopropylethyl, cyclopropylpropyl, 1-cyclopropylethyl, cyclopentylmethyl, 2-cyclopentylethyl, 1 -cyclopentylethyl, cyclohexyl- methyl, 2-cyclohexylethyl, or 1-cyclohexylethyl. Alkanoyl is either straight-chain or branched. Typical examples are formyl, acetyl, propionyl, butyryl, or pivaloyl. Aryl is phenyl, benzyl or naphthyl; phenyl and benzyl are preferred. Ri and R 2 groups which are inert to the reactions are for example independently of the other hydrogen, halogen, Cι-C 4 alkyl, d-C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 2 -C 4 haloalkynyl, Si-(Cι-C 6 alkyl) 3 , COO-d-C 4 alkyl, COO-aryl, COOH, CH=N-d-C 4 alkyl, C(CH 3 )=N-Cι-C 4 alkyl, SO-C C 4 alkyl, SO 2 -Cι-C 4 alkyl, OR 5 , SR 6l NR 7 R 8 or COR 9 ; R 5 and R 6 are each independently of the other Cι-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, each of which is unsubstituted or substituted by halogen, Cι-C haloalkyl, Cι-C 4 alkoxy, S-C C 4 alkyl, SO-d-C 4 alkyl, SO 2 -Cι-C 4 alkyl, CO-Cι-C 4 alkyl, N=d-C 4 alkyl, NH-C C 4 alkyl, N(Cι-C 4 alkyl) 2 , COO-d-C 4 alkyl, COO-aryl, cyano, nitro, Si-(d-C 4 alkyl) 3 , phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; R 7 and R 8 are each independently of the other Cι-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, each of which is unsubstituted or substituted by halogen, Cι-C 4 haloalkyl, C r C 4 alkoxy, halo-C C 4 alkoxy, S-C C 4 alkyl, SO-C C 4 alkyl, SO 2 -CrC 4 alkyl, CO-C C 4 -alkyl, N=Cι-C 4 alkyl, NH-C r C 4 alkyl, N(d-C 4 alkyl) 2 , COO-C C 4 alkyl, COO-aryl, cyano, nitro, Si-(Cι-C alkyl) 3 , phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; R 9 = hydrogen, d-C 4 alkyl, phenyl or benzyl, wherein the aromatic moieties are unsubstituted or substituted by halogen, d-C 4 alkyl, C C 4 haloalkyl, Cι-C 4 alkoxy, CrC 4 haloalkoxy, cyano or nitro; Rs is not part of the end product and may be any group which does not impair the reactions, e.g. hydrogen, optionally substituted alkyl or optionally substituted aryl, in particular Cι-C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl or phenyl-CrC 3 alkyl , each of which is unsubstituted or substituted by halogen, C C 4 haloalkyl, Cι-C alkoxy or C C haloalkoxy. Preferred are d-C 6 alkyl, phenyl and benzyl. Preferred compounds of formula I which may be prepared by the process according to the invention are those, wherein a) A is benzo, thieno, pyrido or pyridazino; or b) Ri and R 2 are independently hydrogen, halogen or halo-Cι-C alkyl; in particular those, wherein not both Ri and R 2 are simultaneously hydrogen; or c) R 3 and R 4 are independently d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-Cι-C 6 alkyl. The method of this invention is particularly preferred for the preparation of compounds of formulae 1.1 I.2 I.3 wherein Ri and R 2 are independently hydrogen, halogen or CF 3 ; R 3 and R 4 are independently CrC 5 alkyl or cyclopropylmethyl. Preferred intermediates are those of formulae IV.1 IV.2 IV.3 wherein Ri and R 2 are independently hydrogen, halogen or CF 3 ; R 3 and R 4 are independently d-C 5 alkyl or cyclopropylmethyl. R 5 is Cι-C 6 alkyl, phenyl or benzyl. Preparation Examples Example P-1 : 2-propoxv-3-propylthienof2.3-dlpvrimidine-4-one In a sulfonation flask, 3.2 g (0.02 mol) of 2-aminothiophene-3-carboxylic acid methyl ester, 5.4 g (0.03 mol) of N-(n)-propylimidocarbonic acid dipropyl ester and 5 drops of waterfree CH 3 SO3H are reacted during 2 hours at 160°C. Then again 5 drops of CH 3 SO 3 H are added and reaction is continued for 2 hours at 170°C. The reaction mixture is diluted with ethyl acetate, washed twice with water and dried with Na 2 SO 4 . The solvent is removed in a water jet vacuum and the resulting crude product is purified by column chromatography over silica gel (eluant: hexane/ ethyl acetate 5:1). Yield: 1.4 g 2-propoxy-3-propylthieno[2.3- d]pyrimidin-4-one in the form of a reddish oil. Example P-2: 2-propoxv-3-n-butvlthieno[ ' 2.3-d ' lpyrimidine-4-one is prepared analogeously to the procedure of Example P-1 , using N-(n)-butylimidocarbonic acid dipropyl ester and p-toluene sulfonic acid as catalyst. The product is obtained in form of a brownish oil. In analogous manner, the compounds of WO 97/48684, WO 97/33890, WO 97/02262 and WO 94/26722 may be prepared, as well as the new intermediate compounds of the Tables 1-3. Table 1 : Compounds of the formula wherein Ri, R 2 , R3, R 4 and R 5 have the meanings given in Table A Table 2: Compounds of the formula wherein R 1 ( R 2 , R3, R 4 and R 5 have the meanings given in Table A Table 3: Compounds of the formula wherein R 1 f R 2 , R 3 , R 4 and R 5 have the meanings given in Table A m.p. = melting point Table A No. Ri R 2 R 3 R 4 R 5 phys. data (m.pJC) 3 H H n-propyl n-propyl CH 3 4 Cl H n-propyl n-propyl CH 3 5 Br H n-propyl n-propyl CH 3 6 Br H n-propyl n-propyl C2H5 7 1 H n-propyl n-propyl C2H5 8 Br H n-propyl i-propyl C2H5 9 1 H n-propyl i-propyl C2H5 10 Cl H n-propyl n-butyl phenyl 11 Br H n-propyl n-butyl H 12 Br H n-propyl i-butyl phenyl 13 Cl H n-butyl n-propyl phenyl 14 Br H n-butyl n-propyl benzyl 15 Br H n-butyl i-propyl benzyl 16 1 H n-butyl i-propyl i-propyl 17 Br H n-butyl n-butyl i-propyl 18 1 H n-butyl n-butyl i-propyl 19 Cl H i-butyl n-propyl n-propyl 20 Br H i-butyl n-propyl n-propyl 21 Br H i-butyl i-propyl i-propyl 22 1 H i-butyl i-propyl i-propyl 23 Br H CH 2 -cyclopropyl n-propyl CH 3 24 Br H CH 2 -cyclopropyl i-propyl CH 3 25 Br H CH 2 -cyclopropyl n-butyl CH 3 26 Br H n-propyl CH 2 -cyclopropyl CH 3 27 Br H n-butyl CH 2 -cyclopropyl CH 3 Ri R 2 R 3 R 4 R 5 phys. data (m.pJC) Br Br C2H5 n-propyl n-propyl Cl Cl n-propyl i-propyl H Br Br n-propyl i-propyl benzyl 1 1 n-propyl i-propyl benzyl Br Br n-propyl n-butyl CH 3 Br Br n-butyl n-propyl CH 3 Br Br i-butyl n-propyl CH 3 Br Br CH 2 -cyclopropyl n-propyl CH 3 1 1 CH 2 -cyclopropyl n-propyl CH 3 Br Br n-propyl CH 2 -cylcopropyl CH 3 Cl Cl n-propyl n-pentyl CH 3 Br Br n-propyl ally! CH 3 1 1 n-propyl allyl CH 3 Br Br n-propyl propargyl CH 3 H Br n-propyl n-propyl C2H5 H Br n-propyl i-propyl C2H5 H Cl n-propyl n-butyl phenyl H Cl n-propyl n-butyl H H Cl n-butyl n-propyl phenyl

Claims: Claims 1. A process for the preparation of a compound of the formula I wherein A is a fused 5-membered heterocyclic ring which may be saturated or unsaturated, aromatic or non-aromatic and which may contain one or two hetero atoms O, S and/or N, or is fused benzo, pyrido or pyridazino; Ri and R 2 are groups which are inert to the reactions; R 3 is CrC 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl-CrC 6 alkyl, each of which is unsubstituted or substituted by halogen, Cι-C 4 haloalkyl, d-C 4 alkoxy, S-Cι-C 4 alkyl, SO-Cι-C 4 alkyl, SO 2 -d-C 4 alkyl, CO-d-C 4 alkyl, N=CH-C C 4 alkyl, N=C(Cι-C 4 alkyl) 2 , NH-C C 4 alkyl, N(d-C 4 alkyl) 2 , COO-C r C 4 alkyl, COO-aryl, cyano, nitro, Si-(C C alkyl) 3 , phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; and R is Cι-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl-Cι-C 6 alkyl, each of which is unsubstituted or substituted by halogen, Cι-C 4 haloalkyl, Cι-C 4 alkoxy, S-Cι-C 4 alkyl, SO-C C 4 alkyl, SO 2 -d-C 4 alkyl, CO-d-C 4 alkyl, N=CH-C r C 4 alkyl, N=C(Cι-C 4 alkyl) 2 , NH-Cι-C 4 alkyl, N(d-C 4 alkyl) 2 , COO-C C alkyl, COO-aryl, cyano, nitro, Si-(d-C alkyl) 3 , phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; in which process (a) a compound of the formula II, wherein A, R and R 2 are as defined for formula I, and R 5 is a group which does not impair the reactions, is reacted with an imidocarbonate of the formula III, wherein R 3 and R 4 are as defined for formula I, to give the intermediate compound of formula IV; and subsequently (b) the compound of the formula IV is cyclized to a compound of the formula I. 2. A process according to claim 1 , wherein reaction steps (a) and (b) are carried out in the presence of an acid and in the absence of water. 3. A process according to claim 1 , wherein in formula I Ri and/or R 2 are halogen, in which process a compound of the formula IV, in which Ri and/or R 2 are hydrogen, is halogenated prior to reaction step (b). 4. A process according to claim 1 , wherein in formula II R 5 is d-C 6 alkyl, phenyl or benzyl. 5. A process according to claim 1 , wherein the compound of the formula IV is not isolated. 6. A process according to claim 1 , wherein in the compounds of the formulae I to IV A is benzo, thieno, pyrido or pyridazino; Ri and R are independently hydrogen, halogen or halo-d-C 4 alkyl; R 3 and R 4 are independently d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-Cι-C 6 alkyl; 7. A process according to claim 6 for the preparation of a compound of the formula wherein R and R 2 are independently hydrogen, halogen or CF 3 ; R 3 and R 4 are independently d-C alkyl or cyclopropylmethyl. 8. A process according to claim 6 for the preparation of a compound of the formula wherein Ri and R 2 are independently hydrogen, halogen or CF 3 ; R 3 and R 4 are independently d-C 5 alkyl or cyclopropylmethyl. 9. A process according to claim 6 for the preparation of a compound of the formula wherein Ri and R 2 are independently hydrogen, halogen or CF 3 ; R 3 and R are independently d-C 5 alkyl or cyclopropylmethyl. 10. A compound of the formula wherein A, R^ R 2 , R 3 and R 4 are as defined for formula I and R 5 is a group which does not impair the reactions.

Inventors: WALTER HARALD, WALTER, HARALD
Applicants: NOVARTIS AG, NOVARTIS ERFIND VERWALT GMBH, WALTER HARALD, NOVARTIS-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT M.B.H., WALTER, HARALD
Application year: 1999
Main classification: C07D495
IPC codes: C07D239, C07D333, C07D471, C07D495