WO2000034286A2 - Process for the preparation of pyrimidinone derivatives - Google Patents
Process for the preparation of pyrimidinone derivatives Download PDFInfo
- Publication number
- WO2000034286A2 WO2000034286A2 PCT/EP1999/009707 EP9909707W WO0034286A2 WO 2000034286 A2 WO2000034286 A2 WO 2000034286A2 EP 9909707 W EP9909707 W EP 9909707W WO 0034286 A2 WO0034286 A2 WO 0034286A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- formula
- compound
- propyl
- halogen
- Prior art date
Links
- 0 Cc1c(*)[s]c(N=C(N2*)O*)c1C2=O Chemical compound Cc1c(*)[s]c(N=C(N2*)O*)c1C2=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the invention relates to a process for the preparation of compounds of formula I
- 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 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
- the invention relates also to new intermediates of formula IV
- R 1 R 2 , R 3 , R 4 and R 5 are as defined above.
- the method provided herewith is distinguished by good technical feasibility and is economically and ecologically more favorable.
- 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
- 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.
- Ri and/or R 2 in ring A may be introduced or interchanged also on the intermediate compounds of formula IV.
- 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 isoquino
- 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,
- 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,
- Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- Cycloalkyl-alkyl is typically cyclopropylmethyl, 2-cylopropylethyl, cyclopropylpropyl,
- 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, C ⁇ -C 4 alkyl, d-C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl,
- CH N-d-C 4 alkyl
- C(CH 3 ) N-C ⁇ -C 4 alkyl
- SO-C C 4 alkyl SO 2 -C ⁇ -C 4 alkyl
- OR 5 SR 6l NR 7 R 8 or
- R 5 and R 6 are each independently of the other C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or
- R 7 and R 8 are each independently of the other C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or
- N C ⁇ -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-(C ⁇ -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, C ⁇ -C 4 alkoxy,
- 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 C ⁇ -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, C ⁇ -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-C ⁇ -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-C ⁇ -C 6 alkyl.
- Ri and R 2 are independently hydrogen, halogen or CF 3 ; R 3 and R 4 are independently CrC 5 alkyl or cyclopropylmethyl.
- 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 C ⁇ -C 6 alkyl, phenyl or benzyl.
- Example P-2 2-propoxv-3-n-butvlthieno[ ' 2.3-d ' lpyrimidine-4-one
- Example P-1 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.
- R 1 R 2 , R3, R 4 and R 5 have the meanings given in Table A
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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 R2 are groups which are inert to the reactions;
R3 is d-Cβalkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C6cycloalkyl or C3-C6cycloalkyl-Cι-C6alkyl, each of which is unsubstituted or substituted by halogen, C C4haloalkyl, C C alkoxy, S-C C4alkyl, SO-d-dalkyl, SO2-C C4alkyl, CO-Cι-C4alkyl, N=CH-CrC alkyl, N=C(C1-C4alkyl)2, NH-C1-C4alkyl, N(C C4alkyl)2, COO-Cι-C4alkyl, COO-aryl, cyano, nitro, Si-(CrC4alkyl)3, phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; and R is Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl or C3-C6cycloalkyl-Cι-C6alkyl, each of which is unsubstituted or substituted by halogen, C C haloaikyl, C C alkoxy, S-C C4alkyl, SO-CrC4alkyl, SO2-CrC4alkyl, CO-C C4alkyl, N=CH-CrC4alkyl, N=C(C1-C4alkyl)2, NH-Cι-C4alkyl, N(Cι-C4alkyl)2, COO-CrC4alkyl, 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 R2 are as defined for formula I, and
R5 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 R3 and R4 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
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 AICI3, AIBr3, SnCI4 and BF3.
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 R2 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 R2 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 R2 are halogen. In this process, a compound of the formula IV, in which Ri and/or R2 are hydrogen, is halogenated prior to reaction step (b).
For example, if Ri is hydrogen and R2 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 l2, bromination with NBS (N-Bromsuccinimide) or Br2, chlorination with NCS (N-Chlorosuccinimide) or Cl or SO2CI2, 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), CI2or SO2CI2.
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 R2 groups which are inert to the reactions are for example independently of the other hydrogen, halogen, Cι-C4alkyl, d-C4haloalkyl, C2-C4alkenyl, C2-C4haloalkenyl,
C2-C4alkynyl, C2-C4haloalkynyl, Si-(Cι-C6alkyl)3, COO-d-C4alkyl, COO-aryl, COOH,
CH=N-d-C4alkyl, C(CH3)=N-Cι-C4alkyl, SO-C C4alkyl, SO2-Cι-C4alkyl, OR5, SR6l NR7R8 or
COR9 ;
R5 and R6 are each independently of the other Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or
C3-C6cycloalkyl, each of which is unsubstituted or substituted by halogen, Cι-C haloalkyl,
Cι-C4alkoxy, S-C C4alkyl, SO-d-C4alkyl, SO2-Cι-C4alkyl, CO-Cι-C4alkyl, N=d-C4alkyl,
NH-C C4alkyl, N(Cι-C4alkyl)2, COO-d-C4alkyl, COO-aryl, cyano, nitro, Si-(d-C4alkyl)3, phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl;
R7 and R8 are each independently of the other Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or
C3-C6cycloalkyl, each of which is unsubstituted or substituted by halogen, Cι-C4haloalkyl,
CrC4alkoxy, halo-C C4alkoxy, S-C C4alkyl, SO-C C4alkyl, SO2-CrC4alkyl, CO-C C4-alkyl,
N=Cι-C4alkyl, NH-CrC4alkyl, N(d-C4alkyl)2, COO-C C4alkyl, COO-aryl, cyano, nitro,
Si-(Cι-C alkyl)3, phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl;
R9 = hydrogen, d-C4alkyl, phenyl or benzyl, wherein the aromatic moieties are unsubstituted or substituted by halogen, d-C4alkyl, C C4haloalkyl, Cι-C4alkoxy,
CrC4haloalkoxy, 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-C8alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, phenyl or phenyl-CrC3alkyl , each of which is unsubstituted or substituted by halogen, C C4haloalkyl, Cι-C alkoxy or C C haloalkoxy. Preferred are d-C6alkyl, 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 R2 are independently hydrogen, halogen or halo-Cι-C alkyl; in particular those, wherein not both Ri and R2 are simultaneously hydrogen; or c) R3and R4 are independently d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C3-C6cycloalkyl-Cι-C6alkyl.
The method of this invention is particularly preferred for the preparation of compounds of formulae
1.1 I.2 I.3 wherein
Ri and R2 are independently hydrogen, halogen or CF3; R3 and R4 are independently CrC5alkyl or cyclopropylmethyl.
Preferred intermediates are those of formulae
IV.1 IV.2 IV.3
wherein
Ri and R2 are independently hydrogen, halogen or CF3;
R3 and R4 are independently d-C5alkyl or cyclopropylmethyl.
R5 is Cι-C6alkyl, 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 CH3SO3H are reacted during 2 hours at 160°C. Then again 5 drops of CH3SO3H 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 Na2SO4. 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
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
Table 2: Compounds of the formula
Table 3: Compounds of the formula
No. Ri R2 R3 R4 R5 phys. data (m.pJC)
3 H H n-propyl n-propyl CH3
4 Cl H n-propyl n-propyl CH3
5 Br H n-propyl n-propyl CH3
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 CH2-cyclopropyl n-propyl CH3
24 Br H CH2-cyclopropyl i-propyl CH3
25 Br H CH2-cyclopropyl n-butyl CH3
26 Br H n-propyl CH2-cyclopropyl CH3
27 Br H n-butyl CH2-cyclopropyl CH3
Ri R2 R3 R4 R5 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 CH3
Br Br n-butyl n-propyl CH3
Br Br i-butyl n-propyl CH3
Br Br CH2-cyclopropyl n-propyl CH3
1 1 CH2-cyclopropyl n-propyl CH3
Br Br n-propyl CH2-cylcopropyl CH3
Cl Cl n-propyl n-pentyl CH3
Br Br n-propyl ally! CH3
1 1 n-propyl allyl CH3
Br Br n-propyl propargyl CH3
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
1. A process for the preparation of a compound of the formula I
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 R2 are groups which are inert to the reactions;
R3 is CrC8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C6cycloalkyl or C3-C6cycloalkyl-CrC6alkyl, each of which is unsubstituted or substituted by halogen, Cι-C4haloalkyl, d-C4alkoxy, S-Cι-C4alkyl, SO-Cι-C4alkyl, SO2-d-C4alkyl, CO-d-C4alkyl, N=CH-C C4alkyl, N=C(Cι-C4alkyl)2, NH-C C4alkyl, N(d-C4alkyl)2, COO-CrC4alkyl, COO-aryl, cyano, nitro, Si-(C C alkyl)3, phenyl, halophenyl, phenoxyphenyl, halophenoxyphenyl or naphthyl; and R is Cι-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl or C3-C6cycloalkyl-Cι-C6alkyl, each of which is unsubstituted or substituted by halogen, Cι-C4haloalkyl, Cι-C4alkoxy, S-Cι-C4alkyl, SO-C C4alkyl, SO2-d-C4alkyl, CO-d-C4alkyl, N=CH-CrC4alkyl, N=C(Cι-C4alkyl)2, NH-Cι-C4alkyl, N(d-C4alkyl)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 R2 are as defined for formula I, and R5 is a group which does not impair the reactions, is reacted with an imidocarbonate of the 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 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 R2 are halogen, in which process a compound of the formula IV, in which Ri and/or R2 are hydrogen, is halogenated prior to reaction step (b).
4. A process according to claim 1 , wherein in formula II R5 is d-C6alkyl, 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-C4alkyl;
R3and R4 are independently d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl,
C3-C6cycloalkyl-Cι-C6alkyl;
7. A process according to claim 6 for the preparation of a compound of the formula
wherein
R and R2 are independently hydrogen, halogen or CF3; R3 and R4 are independently d-C alkyl or cyclopropylmethyl.
8. A process according to claim 6 for the preparation of a compound of the formula
Ri and R2 are independently hydrogen, halogen or CF3;
R3 and R4 are independently d-C5alkyl or cyclopropylmethyl.
9. A process according to claim 6 for the preparation of a compound of the formula
Ri and R2 are independently hydrogen, halogen or CF3;
R3 and R are independently d-C5alkyl or cyclopropylmethyl.
10. A compound of the formula
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU16579/00A AU1657900A (en) | 1998-12-10 | 1999-12-09 | Process for the preparation of pyrimidinone derivatives |
| EP99959395A EP1137649A2 (en) | 1998-12-10 | 1999-12-09 | Process for the preparation of pyrimidinone derivatives |
| BR9915983-0A BR9915983A (en) | 1998-12-10 | 1999-12-09 | Process for preparing pyrimidinone derivatives |
| JP2000586731A JP2002531570A (en) | 1998-12-10 | 1999-12-09 | Method for producing pyrimidinone derivative |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9827162.0A GB9827162D0 (en) | 1998-12-10 | 1998-12-10 | Organic compounds |
| GB9827162.0 | 1998-12-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000034286A2 true WO2000034286A2 (en) | 2000-06-15 |
| WO2000034286A3 WO2000034286A3 (en) | 2000-10-26 |
Family
ID=10843958
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1999/009707 WO2000034286A2 (en) | 1998-12-10 | 1999-12-09 | Process for the preparation of pyrimidinone derivatives |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1137649A2 (en) |
| JP (1) | JP2002531570A (en) |
| AU (1) | AU1657900A (en) |
| BR (1) | BR9915983A (en) |
| GB (1) | GB9827162D0 (en) |
| WO (1) | WO2000034286A2 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994026722A1 (en) * | 1993-05-12 | 1994-11-24 | E.I. Du Pont De Nemours And Company | Fungicidal fused bicyclic pyrimidinones |
| WO1997002262A1 (en) * | 1995-07-05 | 1997-01-23 | E.I. Du Pont De Nemours And Company | Fungicidal pyrimidinones |
| WO1997033890A1 (en) * | 1996-03-11 | 1997-09-18 | Novartis Ag | Pyrimidin-4-one derivatives as pesticide |
| WO1997048684A1 (en) * | 1996-06-18 | 1997-12-24 | E.I. Du Pont De Nemours And Company | Preparation of fungicidal quinazolinones and useful intermediates |
-
1998
- 1998-12-10 GB GBGB9827162.0A patent/GB9827162D0/en not_active Ceased
-
1999
- 1999-12-09 EP EP99959395A patent/EP1137649A2/en not_active Withdrawn
- 1999-12-09 JP JP2000586731A patent/JP2002531570A/en active Pending
- 1999-12-09 AU AU16579/00A patent/AU1657900A/en not_active Abandoned
- 1999-12-09 WO PCT/EP1999/009707 patent/WO2000034286A2/en not_active Application Discontinuation
- 1999-12-09 BR BR9915983-0A patent/BR9915983A/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994026722A1 (en) * | 1993-05-12 | 1994-11-24 | E.I. Du Pont De Nemours And Company | Fungicidal fused bicyclic pyrimidinones |
| WO1997002262A1 (en) * | 1995-07-05 | 1997-01-23 | E.I. Du Pont De Nemours And Company | Fungicidal pyrimidinones |
| WO1997033890A1 (en) * | 1996-03-11 | 1997-09-18 | Novartis Ag | Pyrimidin-4-one derivatives as pesticide |
| WO1997048684A1 (en) * | 1996-06-18 | 1997-12-24 | E.I. Du Pont De Nemours And Company | Preparation of fungicidal quinazolinones and useful intermediates |
Non-Patent Citations (7)
| Title |
|---|
| G BIAGI ET AL: "Xanthine Oxidase (XO): Relative Configuration of Complexes Formed by the Enzyme, 2- or 8-N-alkyl-hypoxanthines and 2-N-alkyl-8-azahypoxanthines. XII" FARMACO,IT,SOCIETA CHIMICA ITALIANA, PAVIA, vol. 48, no. 3, 1993, pages 357-374-374, XP002123378 ISSN: 0014-827X * |
| G. ROMEO ET AL.: "Synthesis of New Thieno[2,3-dÜpyrimidine-2,4-(1H,3H)-diones with Analgesic and Anti-inflammatory Activities" ARZNEIMITTEL FORSCHUNG DRUG RESEARCH., vol. 48, no. 1, 1998, pages 167-172, XP002139815 AULENDORF DE * |
| I. LALEZARI ET AL.: "A Simple One-Step Synthesis of 3-Amino-2,4(1H,3H)quinazolinediones" JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 21, 1984, pages 5-7, XP002139814 PROVO US * |
| P SCHEINER ET AL: "1,3,4-Benzotriazepinones. Formation and Rearrangement" JOURNAL OF HETEROCYCLIC CHEMISTRY,US,HETEROCORPORATION. PROVO, vol. 21, no. 21, November 1984 (1984-11), pages 1817-1824-1824, XP002123377 ISSN: 0022-152X * |
| P.G. BARALDI ET AL.: "Unusual Ring-Opening Reaction of 6,7-Dihydrothieno[3,2-dÜpyrimidine-2,4-dio ne Derivatives Leading to 5-(Alkylthio)-6-vinylureas" JOURNAL OF ORGANIC CHEMISTRY, vol. 60, 1995, pages 461-1463, XP002139813 EASTON US * |
| See also references of EP1137649A2 * |
| T. SANDMEYER: "Ueber die Einwirkung von Imidokohlens{ureester auf aromatische Orthoverbindungen." BERICHTE DER DEUTSCHEN CHEMISCHEN GESELLSCHAFT ZU BERLIN, vol. 19, 1886, pages 2650-2657, XP000920991 DE * |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9915983A (en) | 2001-09-11 |
| AU1657900A (en) | 2000-06-26 |
| EP1137649A2 (en) | 2001-10-04 |
| GB9827162D0 (en) | 1999-02-03 |
| WO2000034286A3 (en) | 2000-10-26 |
| JP2002531570A (en) | 2002-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4903819B2 (en) | Hydroxyacetic acid ester derivatives, their production and use as synthetic intermediates | |
| EP3882236B1 (en) | Production method for 2,5-dicyano-3,6-dihalogenopyrazine | |
| CZ283215B6 (en) | Process for preparing 3-(alpha-methoxy)methylenebenezofuranones | |
| EP1863770A2 (en) | Ring closing and related methods and intermediates | |
| CA2137976A1 (en) | Thienothiazine derivatives | |
| EP0780372B1 (en) | 3-Amino-2-mercaptobenzoic acid derivatives and processes for their preparation | |
| WO2008021491A2 (en) | Method for synthesis of 8-alkoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones | |
| EP1137649A2 (en) | Process for the preparation of pyrimidinone derivatives | |
| KURASAWA et al. | Synthesis and Reactions of 3-(1, 3, 4-Oxadiazol-2-yl) methylene-2-oxo-1, 2, 3, 4-tetrahydroquinoxalines | |
| US20010018405A1 (en) | Process for preparation of pyrimidinone derivatives | |
| Raslan et al. | Reactivity of 3‐(benzothiazol‐2‐yl)‐3‐oxopropanenitrile: A facile synthesis of novel polysubstituted thiophenes | |
| HU181928B (en) | Process for preparing thieno-pyridine derivatives | |
| Kakehi et al. | Preparation of new nitrogen-bridged heterocycles. 21. A facile synthesis of 2-indolizinethiols using new protecting groups. | |
| JP5527923B2 (en) | Heterocyclic compound having perfluoroalkyl group and method for producing the same | |
| WO2016142918A1 (en) | Pyrazole derivatives and relative use for the preparation of 1,3,4-thiadiazoles | |
| WO2003027103A1 (en) | Synthesis of key azole-antifungal intermediates | |
| US6812348B1 (en) | Method for producing 2-chloro-5-chloromethyl-1,3-thiazol | |
| EP1544196B1 (en) | Process for the production of gamma-keto acetals | |
| US5527917A (en) | Process for the preparation of 1,2-benzisothiazoles | |
| WO1997014688A1 (en) | A PROCESS FOR THE PREPARATION OF α-CHLOROMETHYLPHENYLACETIC ACID DERIVATIVES | |
| CN106317079B (en) | A kind of solid-phase synthesis of Ceftriaxone Sodium | |
| CN112204015A (en) | Process for preparing halogenated N-arylpyrazoles | |
| CN119100992A (en) | Preparation method of tergolian intermediate and derivative thereof | |
| US7176321B2 (en) | Method for producing 3-amino-4-substituted-5-pyrazolones | |
| JP2024505177A (en) | Method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| ENP | Entry into the national phase in: |
Ref country code: AU Ref document number: 2000 16579 Kind code of ref document: A Format of ref document f/p: F |
|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1999959395 Country of ref document: EP |
|
| ENP | Entry into the national phase in: |
Ref country code: JP Ref document number: 2000 586731 Kind code of ref document: A Format of ref document f/p: F |
|
| WWP | Wipo information: published in national office |
Ref document number: 1999959395 Country of ref document: EP |
|
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1999959395 Country of ref document: EP |