Method for preparing hydroxypicolinic scid derivatives

A process for preparing compounds of general formula (I):

• in which:
• n represents 0 or 1,
• Q1 is chosen from an oxygen or sulfur atom, a group NR1 and a group N—NR4R5,
• Q2 is chosen from a group OR2 or SR3 and a group —NR4R5, or
• Q1 and Q2 may together form a ring of 5 to 7 atoms containing 2 to 3 oxygen and/or nitrogen atoms, optionally substituted with one or more radicals, which may be identical or different, chosen from halogens and alkyl and haloalkyl radicals,
• Z is chosen from a hydrogen atom, a cyano radical and an alkyl, allyl, aryl, arylalkyl, propargyl, cycloalkyl, halocycloalkyl, alkenyl, alkynyl, cyanoalkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, acyl, thioacyl, alkoxythiocarbonyl, N-alkylaminothiocarbonyl, N,N-dialkylaminothiocarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxysulfonyl, aminosulfonyl, N-alkylaminosulfonyl, N,N-dialkylaminosulfonyl, arylsulfinyl, arylsulfonyl, aryloxysulfonyl, N-arylaminosulfonyl, N,N-diarylaminosulfonyl or N,N-arylalkylaminosulfonyl radical;
• Y is chosen from a hydrogen atom, a halogen atom, a hydroxyl, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical, an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl, cyanoalkoxy, cyanoalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl or alkoxysulfonyl radical, a cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio or alkynylthio group, an amino, N-alkylamino, N,N-dialkylamino, —NHCOR10, —NHCSR10, N-alkylaminocarbonylamino, N,N-dialkylaminocarbonylamino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acylaminoalkyl, thioacylamino, alkoxythiocarbonylamino, N-alkylaminothiocarbonylamino, N,N-dialkylaminothiocarbonylamino, N,N-arylalkylaminocarbonylamino, N-alkylsulfinylamino, N-alkylsulfonylamino, N-arylsulfinylamino, N-arylsulfonylamino, N-alkoxysulfonylamino, N-alkoxysulfinylamino, N-haloalkoxysulfinylamino, N-haloalkoxysulfonylamino, N-arylamino, N,N-diarylamino, arylcarbonylamino, alkoxycarbonylamino, N-arylaminocarbonylamino, N,N-diarylaminocarbonylamino, arylthiocarbonylamino, aryloxythiocarbonylamino, N-arylaminothiocarbonylamino, N,N-diarylaminothiocarbonylamino or N,N-arylalkylaminothiocarbonylamino group, an acyl, carboxyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, lower alkoxycarbonyl, N-arylcarbamoyl, N,N-diarylcarbamoyl, aryloxycarbonyl or N,N-arylalkylcarbamoyl group, and an imino group of formula:
• X1 and X2 are identical or different and chosen, independently of each other, from a hydrogen atom, a halogen atom, a hydroxyl, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical, and an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl, cyanoalkoxy, cyanoalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl or alkoxysulfonyl radical, or
• X1 and X2 may be joined together, thus forming a saturated, partially unsaturated or totally unsaturated 4- to 8-membered ring optionally comprising one or more hetero atoms chosen from sulfur, oxygen, nitrogen and phosphorus,
• R2 and R3 or different and chosen, independently of each other, from an alkyl radical comprising from 1 to 12 carbon atoms, a haloalkyly, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl or acyl radical, a nitro, cyano, carboxyl, carbamoyl or 3-oxetanyloxycarbonyl radical, and an N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, alkylthiocarbonyl, haloalkoxycarbonyl, alkoxythiocarbonyl, haloalkoxythiocarbonyl, alkylthiothiocarbonyl, alkenyl, alkynyl, N-alkylamino, N,N-dialkylamino, N-alkylaminoalkyl or N,N-dialkylaminoalkyl radical, or a radical chosen from aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, optionally substituted with one or more radicals R9 and/or aryl and/or arylalkyl, which may be identical or different, and/or a group -T-R8, or
• R1, R4, R5, R6 and R7 are identical or different and chosen, independently of each other, from a hydrogen atom, an optionally substituted alkyl radical comprising from 1 to 12 carbon atoms in a linear or branched chain, a haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, aryloxy, arylalkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, cyanoalkyl or acyl radical, a nitro, cyano, carboxyl, carbamoyl or 3-oxetanyloxycarbonyl radical, and an N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, alkylthiocarbonyl, haloalkoxycarbonyl, alkoxythiocarbonyl, haloalkoxythiocarbonyl, alkylthiothiocarbonyl, alkenyl, alkynyl, N-alkylamino, N,N-dialkylamino, N-alkylaminoalkyl or N,N-dialkylaminoalkyl radical, or a radical chosen from aryl, arylalkyl, heterocyclyl and heterocyclylalkyl, optionally substituted with one or more radicals R9 and/or aryl and/or arylalkyl, which may be identical or different, and/or a group -T-R8, or
• R4 and R5, on the one hand, or R6 and R7, on the other hand, may be joined together, thus forming a saturated, partially unsaturated or totally unsaturated 4- to 8-membered ring optionally comprising one or more hetero atoms chosen from sulfur, oxygen, nitrogen and phosphorus,
• T represents a direct bond or a divalent radical chosen from a radical —(CH2)m—, m taking a value between 1 and 12, limits included, the said radical optionally being interrupted or ending with one or two hetero atoms chosen from nitrogen, oxygen and/or sulfur, and an oxyalkylene, alkoxyalkylene, carbonyl (—CO—), oxycarbonyl (—O—CO—), carbonyloxy (—CO—O—), sulfinyl (—SO—), sulfonyl (—SO2—), oxysulfonyl (—O—SO2—), sulfonyloxy (—SO2—O—), oxysulfinyl (—O—SO—), sulfinyloxy (—SO—O—), thio (—S—), oxy (—O—), vinyl (—C═C—), ethynyl (—C≡C—), —NR9—, —NR9O—, —ONR9—, —N═N—, —NR9—NR10—, —NR9—S—, —NR9—SO—, —NR9—SO2—, —S—NR9—, —SO—NR9—, —SO2—NR9—, —CO—NR9—O— or —O—NR9—CO— radical,
• R8 is chosen from a hydrogen atom and an aryl or heterocyclyl radical,
• R9 and R10, which may be identical or different, are chosen, independently of each other, from a hydrogen atom, a halogen atom, a hydroxyl, mercapto, nitro, thiocyanato, azido, cyano or pentafluorosulfonyl radical, and an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl, haloalkylthioalkyl, arylalkyl, cyanoalkyl, cyanoalkoxy, cyanoalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl or alkoxysulfonyl radical,
• as well as the optional N-oxides, geometrical and/or optical isomers, enantiomers and/or diastereoisomers, tautomeric forms, their salts and metal and metalloid complexes,
• a process characterized in that a compound of formula (II)
• in which X1 and X2 are as previously defined, is reacted with a cyanide, alkali metal derivatives or alkaline-earth metal derivatives of hydrocyanic acid in the presence of an alkylating agent and a solvent, or with trimethylsilyl cyanide in the presence of dimethylcarbamoyl chloride and a solvent, to give the compounds of formula (III).
• in which X1 and X2 are as previously defined,
• the compounds of formula (III) above can be converted into corresponding halo derivatives of formula (IVa):
• in which X1 and X2 are as previously defined and X represents a halogen atom chosen from fluorine, chlorine, bromine and iodine, by reaction with an acyl halide in the presence of a solvent,
• the halo derivatives of formula (IVa) then being hydrolyzed to compounds of formula (Ia):
• in which X, X1 and X2 are as previously defined,
• by the action of hot hydracid—or of a strong mineral base, optionally in the presence of aqueous hydrogen peroxide solution—and optionally of boron tribromide,
• the compounds of formula (III) or (IVa) then possibly being placed in contact with an alcohol or an alkoxide in the presence of a solvent such as, preferably, but not exclusively, a protic or aprotic polar solvent, to give the compounds of formula (IVb):
• in which X1 and X2 are as previously defined, and then used in a hydrolysis reaction under operating conditions similar to those used for the formation of the compounds of formula (Ia), to give the compounds of respective formulae (Ib) and (Ib′)
• in which X1 and X2 are as previously defined, the compounds of formula (IVa) also possibly being converted into picolinic acid derivatives of formula (Va):
• in which X1, X2 and R6 are as previously defined, by reacting a compound of formula R6SH, or a corresponding alkali metal salt or alkaline-earth metal salt, in an aprotic polar solvent, at a temperature of between 0° C. and the boiling point of the solvent, the nitrites of formula (Va) then being used in a hydrolysis reaction to give the corresponding acids of formula (Ic):
• in which X1, X2 and R6 are as previously defined, according to a reaction similar to that used to form the compounds of formula (Ia),
• the halides of formula (IVa) also possibly being treated with an azothydric acid salt, to give the compounds of formula (Vb):
• in which X1 and X2 are as previously defined, this reaction being carried out at a temperature of between 0° C. and the boiling point of the solvent, the compounds of formula (Vb) can then be hydrolyzed according to techniques similar to those presented for the preparation of the acids of formula (Ia) above, to give the acids of formula (Id):
• in which X1 and X2 are as previously defined, the azides of formula (Id) then being optionally reduced to amine derivatives of formula (Ie):
• in which X1 and X2 are as previously defined, by the action of a reducing agent,
• the acids of formulae (Ia) to (Ie) possibly being converted into thio acids, imino derivatives (—C(═NR1)) or amino imino derivatives (—C(═N—NR4R5)) according to conventional techniques, that are well known to those skilled in the art of organic synthesis, the acids (Ia) to (Ie), or the thio, imino and imino-amino derivatives thereof defined above, substituted in position 3 (relative to the pyridine nitrogen atom) with —OH or -methoxy then possibly being subjected to various reactions already known in the prior art in order to give the corresponding derivatives substituted in position 3 (relative to the pyridine nitrogen atom) with —O-Z, Z being as defined for the compounds of formula (I),
• the compounds of formula (I) previously defined for which Y represents an amino radical (—NH2) possibly being placed in contact with an acylating agent in the presence of a solvent and optionally of a base, to give the compounds of formulae (VIa) and (VIb):
• in which X1, X2, Q1, Q2, Z and R10 are as previously defined, the picolinic acid derivatives of formula (VII):
• in which X1, X2, Q1, n, Z and Y are as previously defined,
• capable of being placed in contact with a reagent of formula R2OH, R3SH or HNR4R5, R2, R3, R4 and R5 being as previously defined, at a temperature between −80° C. and 180° C. (preferably between 0° C. and 150° C.) or at the boiling point of the solvent, to give the respective compounds of formulae (VIIIa), (VIIIb) and (VIIIc), which form the set of compounds of formula (VIII):
• which are special cases of the compounds of formula (I) in which Q2 represents —OR2, —SR3 and —NR4R5, respectively, the compounds of general formula (IX):
• which are special cases of the compounds of formula (I) for which n is equal to 1,
• can be obtained by a process consisting in placing a compound of formula (X):
• which is a special case of the compounds of formula (I) for which n is equal to zero,
• in contact with an oxidizing agent, aqueous hydrogen peroxide solution or carboxylic, boronic or sulfuric peracids.