Method for the preparation of substituted 1,4-dihydro-4-oxo-cinnoline-3-carboxylic acid, esters and salts thereof, and intermediates used in their preparation

A method for the preparation of a substituted cinnoline of the formula:

• ##STR18## wherein X represents formula OR.sub.1 or NR.sub.1 R.sub.2, wherein R.sub.1 represents C.sub.1 -C.sub.4 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy, 1 to 3 halogen atoms, or carboxy or C.sub.1 -C.sub.4 alkoxycarbonyl;
• a C.sub.2 -C.sub.4 alkenyl optionally substituted with 1 to 3 halogen atoms;
• or C.sub.2 -C.sub.4 alkynyl;
• and R.sub.2 independently represent H or alkyl;
• Y is H or C.sub.1 -C.sub.22 linear alkyl or alkenyl having up to four carbon-carbon double bonds, C.sub.3 -C.sub.6 branched alkyl or alkenyl, C.sub.1 -C.sub.4 alkoxyalkyl, cyclohexylmethyl, halogenated C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, --(CH.sub.2 CH.sub.2 O).sub.m CH.sub.2 CH.sub.3 in which m is an integer from 1 to 5, or --CH(CH.sub.2 OR.sub.4)CH.sub.2 OR.sub.5 or --CH.sub.2 CHOR.sub.4 CH.sub.2 OR.sub.5 in which either R.sub.4 or R.sub.5 but not both represent a C.sub.1 -C.sub.22 linear alkyl- or alkenylcarbonyl having up to four carbon-carbon double bonds and the other of R.sub.4 or R.sub.5 is H;
• R is C.sub.1 -C.sub.4 alkyl, phenyl, naphthyl, or phenyl or naphthyl substituted with one to three substituents selected from the group consisting of halogen, CONH.sub.2, C.sub.1 -C.sub.4 alkyl or haloalkyl, C.sub.1 -C.sub.4 alkoxy or haloalkoxy, and cyano;
• each R.sub.3 independently represents H or C.sub.1 -C.sub.4 alkyl, or haloalkyl, C.sub.1 -C.sub.4 alkoxy or haloalkoxy, C.sub.1 -C.sub.4 alkanoyl, cyano, nitro, hydroxy or halo;
• and
• n is an integer from 0 to 3;
• which comprises:
• reacting a compound of the formula ##STR19## wherein R.sub.3 and n have the previously defined meanings;
• W is either F or Cl;
• and
• Z is a leaving group selected from the group consisting of H, halogen, and ester leaving groups;
• with a compound of the formula ##STR20## wherein R.sub.9 is a hydrocarbon and Y has the previously defined meanings to form a trione of the formula ##STR21## wherein Y, W, R.sub.3, R, and n have the meanings as previously defined, (1) converting said trione to a dione by heating in an organic solvent, said dione compound having the formula ##STR22## wherein Y, W, R.sub.3, and n have the meanings as previously defined, and reacting said dione with a diazonium salt of the formula
• RN.sup.+.sub.2 A.sup.-
• wherein R has the meanings as previously defined and A.sup.- is any counter ion, to form a hydrazone of the formula ##STR23## wherein Y, W, R.sub.3, R, and n have the meanings as previously defined, or (2) converting said trione directly to the hydrazone of formula VIII by reacting said trione with said diazonium salt of the formula RN.sup.+.sub.2 A.sup.-, wherein R and A have the meanings as previously defined;
• causing said hydrazone to undergo a self-condensation reaction to produce a cinnoline precursor compound of the formula ##STR24## wherein Y, R.sub.3, R, and n have the means as previously defined, and reacting said cinnoline precursor compound with
• (1) a compound of the formula
• R.sub.1 OH or R.sub.1 O.sup.- M.sup.+
• wherein M.sup.+ is a metal cation and R.sub.1 has the meanings as previously defined, or
• (2) a compound of the formula
• NHR.sub.1 R.sub.2
• wherein R.sub.1 and R.sub.2 have the meanings as previously defined to form the desired compound of formula I.

In a method for the preparation of a substituted cinnoline of the formula:

• ##STR25## wherein X represents formula OR.sub.1 or NR.sub.1 R.sub.2, wherein R.sub.1 is C.sub.1 -C.sub.4 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy, 1 to 3 halogen atoms, or carboxy or C.sub.1 -C.sub.4 alkoxycarbonyl;
• a C.sub.2 -C.sub.4 alkenyl optionally substituted with 1 to 3 halogen atoms;
• or C.sub.2 -C.sub.4 alkynyl and R.sub.2 independently represent H or alkyl;
• Y is H, alkali metal ion or C.sub.1 -C.sub.22 linear alkyl or alkenyl having up to four carbon-carbon double bonds, C.sub.3 -C.sub.6 branched alkyl or alkenyl, C.sub.1 -C.sub.4 alkoxyalkyl, cyclohexylmethyl, halogenated C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, --(CH.sub.2 CH.sub.2 O).sub.m CH.sub.2 CH.sub.3 in which m is an integer from 1 to 5, or --CH(CH.sub.2 OR.sub.4)CH.sub.2 OR.sub.5 or --CH.sub.2 CHOR.sub.4 CH.sub.2 OR.sub.5 in which either R.sub.4 or R.sub.5 but not both represent a C.sub.1 -C.sub.22 linear alkyl- or alkenylcarbonyl having up to four carbon-carbon double bonds and the other of R.sub.4 or R.sub.5 is H;
• R is C.sub.1 -C.sub.4 alkyl, phenyl, naphthyl, or phenyl or naphthyl substituted with one to three substituents selected from the group consisting of halogen, CONH.sub.2, C.sub.1 -C.sub.4 alkyl or haloalkyl, C.sub.1 -C.sub.4 alkoxy or haloalkoxy, and cyano;
• each R.sub.3 independently represents H or C.sub.1 -C.sub.4 alkyl, or haloalkyl, C.sub.1 -C.sub.4 alkoxy or haloalkoxy, C.sub.1 -C.sub.4 alkanoyl, cyano, nitro, hydroxy or halo;
• and
• n is an integer from 0 to 3;
• in which an intermediate hydrazone of the formula ##STR26## in which W is Cl or F, and Y, R.sub.3, R, and n have the meanings as previously defined,
• is cyclized by displacement of W to form a cinnoline ring, after which Cl is converted to X,
• an improvement which comprises:
• preparing an intermediate of formula ##STR27## wherein Y, W, R.sub.3, R, and n have the meanings as previously defined, by reacting a compound of formula ##STR28## wherein W, R.sub.3 and n have the meanings as previously defined;
• and Z is a leaving group selected from the group consisting of H, halogen, ester, and amide leaving groups;
• with a ketocarboxy compound of the formula ##STR29## wherein Y has the meaning previously defined and R.sub.9 is hydrocarbon, to form a trione of the formula ##STR30## wherein Y, W, R.sub.3, R.sub.9, and n have the meanings as previously defined,
• and (1) heating said trione to form a dione of Formula VII ##STR31## wherein Y, W, R.sub.3, and n have the meanings as previously defined, and reacting said dione with a diazonium salt of the formula
• RN.sup.+.sub.2 A.sup.-
• wherein R has the meanings as previously defined and A.sup.- is any counter ion, to form said hydrazone, or
• (2) converting said trione to said hydrazone by reacting said trione directly with said diazonium salt.

In a method for the preparation of a substituted cinnoline of the formula:

• ##STR33## wherein X represents formula OR.sub.1 or NR.sub.1 R.sub.2, wherein R.sub.1 is C.sub.1 -C.sub.4 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy, 1 to 3 halogen atoms, or carboxy or C.sub.1 -C.sub.4 alkoxycarbonyl;
• a C.sub.2 -C.sub.4 alkenyl optionally substituted with 1 to 3 halogen atoms;
• or C.sub.2 -C.sub.4 alkynyl and R.sub.2 independently represent H or alkyl;
• Y is H, alkali metal ion or C.sub.1 -C.sub.22 linear alkyl or alkenyl having up to four carbon-carbon double bonds, C.sub.3 -C.sub.6 branched alkyl or alkenyl, C.sub.1 -C.sub.4 alkoxyalkyl, cyclohexylmethyl, halogenated C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, --(CH.sub.2 CH.sub.2 O).sub.m CH.sub.2 CH.sub.3 in which m is an integer from 1 to 5, or --CH(CH.sub.2 OR.sub.4)CH.sub.2 OR.sub.5 or --CH.sub.2 CHOR.sub.4 CH.sub.2 OR.sub.5 in which either R.sub.4 or R.sub.5 but not both represent a C.sub.1 -C.sub.22 linear alkyl- or alkenylcarbonyl having up to four carbon-carbon double bonds and the other of R.sub.4 or R.sub.5 is H;
• R is C.sub.1 -C.sub.4 alkyl, phenyl, naphthyl, or phenyl or naphthyl substituted with one to three substituents selected from the group consisting of halogen, CONH.sub.2, C.sub.1 -C.sub.4 alkyl or haloalkyl, C.sub.1 -C.sub.4 alkoxy or haloalkoxy, and cyano;
• each R.sub.3 independently represents H or C.sub.1 -C.sub.4 alkyl, or haloalkyl, C.sub.1 -C.sub.4 alkoxy or haloalkoxy, C.sub.1 -C.sub.4 alkanoyl, cyano, nitro, hydroxy or halo;
• and
• n is an integer from 0 to 3;
• in which an intermediate hydrazone of the formula ##STR34## in which W is Cl or F, and Y, R.sub.3, R, and n have the meanings as previously defined,
• is cyclized by displacement of W to form a cinnoline ring, after which Cl is converted to X,
• an improvement which comprises:
• preparing an intermediate of formula ##STR35## wherein Y, W, R.sub.3, R, and n have the meanings as previously defined, by reacting a compound of formula ##STR36## wherein W, R.sub.3 and n have the meanings as previously defined;
• and Z is a leaving group selected from the group consisting of H, halogen, ester, and amide leaving groups;
• with a ketocarboxy compound of the formula ##STR37## wherein Y has the meaning previously defined and R.sub.9 is hydrocarbon, to form a trione of the formula ##STR38## wherein Y, W, R.sub.3, R.sub.9, and n have the meanings as previously defined,
• and (1) heating said trione to form a dione of Formula VII ##STR39## wherein Y, W, R.sub.3, and n have the meanings as previously defined, and reacting said dione with a diazonium salt of the formula
• RN.sup.+.sub.2 A.sup.-
• wherein R has the meanings as previously defined and A.sup.- is any counter ion, to form said hydrazone, or
• (2) converting said trione to said hydrazone by reacting said trione directly with said diazonium salt.