CA1207325A - Aryl-4-oxonicotinates - Google Patents
Aryl-4-oxonicotinatesInfo
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- CA1207325A CA1207325A CA000376847A CA376847A CA1207325A CA 1207325 A CA1207325 A CA 1207325A CA 000376847 A CA000376847 A CA 000376847A CA 376847 A CA376847 A CA 376847A CA 1207325 A CA1207325 A CA 1207325A
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Abstract
ABSTRACT OF THE DISCLOSURE
Disclosed herein are novel N-alkyl-2-aryl--4-oxonicotinates, N-alkyl-5-aryl-4-oxonicotinates, N-alkyl-6-aryl-4-oxonicotinates, and N-alkyl--2,6-diaryl-4-oxonicotinates. These compounds are useful as chemical gametocides and possess a high degree of male/female selectivity.
Disclosed herein are novel N-alkyl-2-aryl--4-oxonicotinates, N-alkyl-5-aryl-4-oxonicotinates, N-alkyl-6-aryl-4-oxonicotinates, and N-alkyl--2,6-diaryl-4-oxonicotinates. These compounds are useful as chemical gametocides and possess a high degree of male/female selectivity.
Description
;~ 732S
ARYL-4-O~ONICGTI~ATE
FI~LD OF~THE I~TVENTION
BACKGROUND OF THE IN~J~TTIOM
The use of chemical gametocid2s for the production of new cereal grains is a rapidly expandi.ng tech~ology.
Cereal grain such as corn, wheat, rice, ryer barley, millet, sorghum, triticale and various fo:rage crops are 0 the mai~ areas where research has be~n undertaken to im-pro~ both the productivity and the ~ood value of these crops. l~e utili~tion.of chemical hybridization agents in this research h2s made possible the hybridization of cereal grain crop~ on an economical scal~. Patents which pertain ~o this technology includle the Michael C. Seidel patents, U.S. Patents 3,761,240; 3,838,155; and 3,576,814, which disclose N~aryl-2-oxonicoti.nates as male sterilants ; and plant growth regulators; the Glenn R. Carlson patents, 20 U.s, PatentS 4,11S,101; 4,051rl42; and German Offen. 2~830, 700, which disclose the use of N-aryl-4-oxonicotina~s and N-aryl-6-oxonicotinates as male sterilants; an~ ~he Taylor patent, U.S. 4,152,136, which discloses the use of 3-aryl-4-pyridones as herbi~ides. A. Selva and A. Gennaro describe in Orq~ic Mass Spectrometry, Vol. 11~ pp 117-12G
(1976) the mass spectrometry data or the compound 2-` phenyl-6-methyl-3-carbethoxy-4-pyridone. No activity is disclosed ~or this compound.
'I .
:
3~;~
-la-Balogh et al~, J. Het. Chem., 17, 359 (1980), disclose the synthesis o~ varlous 5-substituted (5-aryl)-l-alkyl-4-oxo-1~4-dihydro-3-pyridine carboxylic acid derivatives for antimicrobial studiesD
R~ Johnstone et al., Aust. J. Chem.s 11, 562 (1968) ~Chem. Abs.g 53, 5310d (1968)) disclose 1-methyl~6-phenyl 4;pyridone-3-carboxylic acid as a decarbo~lation product of a quinolone compound.
T. Kametani et al.~ J. Het~ Chem., 14, 477 ~1977) clisdDse the synthesis of various 1,4-dihydro-4-oxonicotinic acid deriv~tives~ some of which bear a 6-phenyl group, which compounds have antibacterial properties Wick et al., Ger. OffenO 2,901,868 (Chem~ Abs., lS 91, 211273h (1979)) disclose 4-pyridone-3~carboxylic acid deriva~ives, for example, the 6-~henyl derivative thereof, which possess bactericidal and central nervous sYstem-stimulant properties~
Adachi, Chem - Pharm. Bull , 17 (11), 2209 (196g), discloses ring conversion reactions of isoxazolium salts, two of the products of which are ethyl 6 phenyl-1,2,5-trimethyl-4-pyridone-3-carboxylate and 6-pAenyl-1,2,5-trimethyl-4-pyridone-3-carboxylic acid. No biological activity is disclosed.
Kigasawa et al., Japan Kokai 78 65,882 (Chem. Abs., 89, 129415f (1978) disclose several 1,4-dihydro-4-oxonico-tinic acids having antibacterial activity. Among the com-pounds disclosed are 6-phenyl-5-methyl-1-ethyl-1~4-dihydro-4-oxonicotinic acid~ 6~methyl-5-phenyl-1-ethyl-1,4-dihydro-4-oxonicotinic acid, and 5,6-diphenyl-1-ethyl-1,4-dihydro-4-oxonicotinic acid.
~3'73~5 - -lb-The present invention relates to N-alkyl-2-aryl-4-oxonicotinates, N-alkyl-5-aryl-4-oxonicotinates, N-alkyl-6-aryl-4-oxonicotinates and N-alkyl-2,6 diaryl~4-oxonicotinates and their use as plant hybridization agents especially useful in whe-at, barley and corn. These compounds are particularly active as chemical gametocides and possess a high degree of male/
female selectivity. Moreover, these compounds are relatively noninjurious to both corn and wheat crops.
The fact that these chemicals possess a high degree of male sterility without affecting female fertility makes them very useful as chemical gametocides.
SUMMARY OF THE INV~NTION
This invention relates to compounds of the formula:
~ : `
~ z~73~
s ~ 2 Rl tI) wherein R1 is an optionally substituted ~C1-C6) alkyl or (C2-C6) alkenyl group; at least one of R2, R5 and R6 is ~ wherein (1) when R2 is ~ ~X)~ R5 is a hydrogen atom, an alkyl group or a halogen atom and R6 is a hydrogen atom or an alkyl group,
ARYL-4-O~ONICGTI~ATE
FI~LD OF~THE I~TVENTION
BACKGROUND OF THE IN~J~TTIOM
The use of chemical gametocid2s for the production of new cereal grains is a rapidly expandi.ng tech~ology.
Cereal grain such as corn, wheat, rice, ryer barley, millet, sorghum, triticale and various fo:rage crops are 0 the mai~ areas where research has be~n undertaken to im-pro~ both the productivity and the ~ood value of these crops. l~e utili~tion.of chemical hybridization agents in this research h2s made possible the hybridization of cereal grain crop~ on an economical scal~. Patents which pertain ~o this technology includle the Michael C. Seidel patents, U.S. Patents 3,761,240; 3,838,155; and 3,576,814, which disclose N~aryl-2-oxonicoti.nates as male sterilants ; and plant growth regulators; the Glenn R. Carlson patents, 20 U.s, PatentS 4,11S,101; 4,051rl42; and German Offen. 2~830, 700, which disclose the use of N-aryl-4-oxonicotina~s and N-aryl-6-oxonicotinates as male sterilants; an~ ~he Taylor patent, U.S. 4,152,136, which discloses the use of 3-aryl-4-pyridones as herbi~ides. A. Selva and A. Gennaro describe in Orq~ic Mass Spectrometry, Vol. 11~ pp 117-12G
(1976) the mass spectrometry data or the compound 2-` phenyl-6-methyl-3-carbethoxy-4-pyridone. No activity is disclosed ~or this compound.
'I .
:
3~;~
-la-Balogh et al~, J. Het. Chem., 17, 359 (1980), disclose the synthesis o~ varlous 5-substituted (5-aryl)-l-alkyl-4-oxo-1~4-dihydro-3-pyridine carboxylic acid derivatives for antimicrobial studiesD
R~ Johnstone et al., Aust. J. Chem.s 11, 562 (1968) ~Chem. Abs.g 53, 5310d (1968)) disclose 1-methyl~6-phenyl 4;pyridone-3-carboxylic acid as a decarbo~lation product of a quinolone compound.
T. Kametani et al.~ J. Het~ Chem., 14, 477 ~1977) clisdDse the synthesis of various 1,4-dihydro-4-oxonicotinic acid deriv~tives~ some of which bear a 6-phenyl group, which compounds have antibacterial properties Wick et al., Ger. OffenO 2,901,868 (Chem~ Abs., lS 91, 211273h (1979)) disclose 4-pyridone-3~carboxylic acid deriva~ives, for example, the 6-~henyl derivative thereof, which possess bactericidal and central nervous sYstem-stimulant properties~
Adachi, Chem - Pharm. Bull , 17 (11), 2209 (196g), discloses ring conversion reactions of isoxazolium salts, two of the products of which are ethyl 6 phenyl-1,2,5-trimethyl-4-pyridone-3-carboxylate and 6-pAenyl-1,2,5-trimethyl-4-pyridone-3-carboxylic acid. No biological activity is disclosed.
Kigasawa et al., Japan Kokai 78 65,882 (Chem. Abs., 89, 129415f (1978) disclose several 1,4-dihydro-4-oxonico-tinic acids having antibacterial activity. Among the com-pounds disclosed are 6-phenyl-5-methyl-1-ethyl-1~4-dihydro-4-oxonicotinic acid~ 6~methyl-5-phenyl-1-ethyl-1,4-dihydro-4-oxonicotinic acid, and 5,6-diphenyl-1-ethyl-1,4-dihydro-4-oxonicotinic acid.
~3'73~5 - -lb-The present invention relates to N-alkyl-2-aryl-4-oxonicotinates, N-alkyl-5-aryl-4-oxonicotinates, N-alkyl-6-aryl-4-oxonicotinates and N-alkyl-2,6 diaryl~4-oxonicotinates and their use as plant hybridization agents especially useful in whe-at, barley and corn. These compounds are particularly active as chemical gametocides and possess a high degree of male/
female selectivity. Moreover, these compounds are relatively noninjurious to both corn and wheat crops.
The fact that these chemicals possess a high degree of male sterility without affecting female fertility makes them very useful as chemical gametocides.
SUMMARY OF THE INV~NTION
This invention relates to compounds of the formula:
~ : `
~ z~73~
s ~ 2 Rl tI) wherein R1 is an optionally substituted ~C1-C6) alkyl or (C2-C6) alkenyl group; at least one of R2, R5 and R6 is ~ wherein (1) when R2 is ~ ~X)~ R5 is a hydrogen atom, an alkyl group or a halogen atom and R6 is a hydrogen atom or an alkyl group,
(2) ~rhen R5 is ~ , R2 is an alkyl group and R6 is a hyd~ gen ~tom or an alkyl group,
(3) when R6 is ~ (X)n , R2 is an Optionally substituted (C1-C6) alkyl or (C3-C6) alkenyl group and R5 is a hydrogen atom, a(C1 C6) alkyl group or a halogen atom, and
(4) when R2 and R6 are both independently ~ (X) : 15 R5 is a hydrogen atom or an alkyl grou; n Y is a hydrogen atom or an alkyl group; X is a hydrogen atom, a halogen atom, a trihalomethyl group, a (C1-C6) alkyl group, a nitro group, a cyano group or a (C1-C6) alkoxy group; n is an integer from 1 to 3; and the 20 agronomically acceptable alkali metal or acid addition salts thereof. These compounds are useful as chemical hybridization agents for monocotyledonous crops and are especially effective in wheat, corn, barley, rice9 rye, triticale, forage crops and the like~
"
~2~7325 -2a-Those compounds which are highly potent chemical gametocides and which produce a high percentage of male sterility without affecting female fertility of cereal grain and forage crops are es-pecially useful as chemical hybridization agents according to the invention. As will be seen in the examples which follow, some of the corlpounds, ~articularly at higher application rates, exhibit diminished female fertility along ~qith high male sterility. The latter group of compounds nonetheless have utility for producing new plant hybrids. Although some of the compounds may exhibit some phytotoxicity, the compounds are still useful for the purpose of producing new plant hybrids.
In addition to utility as chemical hybridization agents, the compounds of the invention are also useful as chemical gametocides in the agricultural production of ergot.
DETAILED DESCRIPTION 0~ T~E INV3NTION
This invention relates to M-a]kyl~2-aryl-4-oxonicotinates, Nalkyl-5-ary]-4-oxonicotinates~
N-alkyl-6-aryl-4-o~ nicotinates, and N-alkyl-2,6-diaryl-4-oxonicotinates and their use as plant hybridization agents n cereal grain and forage crops, especially in ~heat, barley and corn.
A~ N-alkyl-2-aryl-4-oxonicotinates In one preferred aspect, this invention relates to compounds of the formula:
~2~ 3~5 .. , ~5 ~ C2Y
R Nl ~ n ~II) By the term "optionally substituted alkyl or alkenyl group" as utilized in the present specification and claims is meant a straight or branched chain alkyl or alkanyl group which may be substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted ~ith up to two substituents selected from halogen f methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano.
Since the co~pounds o the present invention possess both acidic and basic functional groups, the term ~a~ronomically acceptable salts~ as utilized in the - present speci~i~ation and claims is meant to include salts o the carboxyl group such as lithlum, sodium, potassium, ammonium and the like as well a~ acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, perchlorate, acetate, oxalate and the like~
Among the preferred compounds of the present invention are compounds of Group A, EDrmula (II) above, wherein ~ is (Cl-C~) alkyl or allyl~ R~ is-hydrogen, (Cl-C3~
alkyl or bromine, R~ is (Cl~C~) alkyl, Y is hydro-gen or a sodium or potassium cation, X is hydrogen or : - h logen, and n is the integer 1 or 2.
Among the more preferred compounds of the present invention are compounds of Formula ~) wherein Rl is .
.. -; .
.. . ... . . ............. . . .
3~5 ~ 4 --(Cl-C3~ alkyl, R5 is hydrogen, R6 is (Cl-C3) alkyl, Y is hydrogen or a sodium or potassium cation, X
is hydrogen, chlorine or fluorine and n is the integer 1 or 2.
Among the most preferred compounds of thi~ invention aré compounds of Formula (~) wherein Rl is a methyl or ethyl group; RS is a hydrogen atom; R6 is a methyl group; and Y is a sodium or potassium cation and the agronomically acceptable acid addition sal~s thereof.
Typical compounds encompassed by the present i.nvention inrlude:
1,6-dimethyl-~-phenyl-4~oxonicotinic acid l-ethyl-6-methyl-2-phenyl-4-oxonicotinic acid 1,5,6-trimethyl-2-phenyl-4-oxonicotinic acid 1,6-diethyl-2-phenyl-4-oxonicotinic acid 6-ethyl-1-methyl-2-phenyl-4.-oxonicotinic acid l-methyl-2-phenyl-6-propyl-4-oxonicotinic acid
"
~2~7325 -2a-Those compounds which are highly potent chemical gametocides and which produce a high percentage of male sterility without affecting female fertility of cereal grain and forage crops are es-pecially useful as chemical hybridization agents according to the invention. As will be seen in the examples which follow, some of the corlpounds, ~articularly at higher application rates, exhibit diminished female fertility along ~qith high male sterility. The latter group of compounds nonetheless have utility for producing new plant hybrids. Although some of the compounds may exhibit some phytotoxicity, the compounds are still useful for the purpose of producing new plant hybrids.
In addition to utility as chemical hybridization agents, the compounds of the invention are also useful as chemical gametocides in the agricultural production of ergot.
DETAILED DESCRIPTION 0~ T~E INV3NTION
This invention relates to M-a]kyl~2-aryl-4-oxonicotinates, Nalkyl-5-ary]-4-oxonicotinates~
N-alkyl-6-aryl-4-o~ nicotinates, and N-alkyl-2,6-diaryl-4-oxonicotinates and their use as plant hybridization agents n cereal grain and forage crops, especially in ~heat, barley and corn.
A~ N-alkyl-2-aryl-4-oxonicotinates In one preferred aspect, this invention relates to compounds of the formula:
~2~ 3~5 .. , ~5 ~ C2Y
R Nl ~ n ~II) By the term "optionally substituted alkyl or alkenyl group" as utilized in the present specification and claims is meant a straight or branched chain alkyl or alkanyl group which may be substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted ~ith up to two substituents selected from halogen f methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano.
Since the co~pounds o the present invention possess both acidic and basic functional groups, the term ~a~ronomically acceptable salts~ as utilized in the - present speci~i~ation and claims is meant to include salts o the carboxyl group such as lithlum, sodium, potassium, ammonium and the like as well a~ acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, perchlorate, acetate, oxalate and the like~
Among the preferred compounds of the present invention are compounds of Group A, EDrmula (II) above, wherein ~ is (Cl-C~) alkyl or allyl~ R~ is-hydrogen, (Cl-C3~
alkyl or bromine, R~ is (Cl~C~) alkyl, Y is hydro-gen or a sodium or potassium cation, X is hydrogen or : - h logen, and n is the integer 1 or 2.
Among the more preferred compounds of the present invention are compounds of Formula ~) wherein Rl is .
.. -; .
.. . ... . . ............. . . .
3~5 ~ 4 --(Cl-C3~ alkyl, R5 is hydrogen, R6 is (Cl-C3) alkyl, Y is hydrogen or a sodium or potassium cation, X
is hydrogen, chlorine or fluorine and n is the integer 1 or 2.
Among the most preferred compounds of thi~ invention aré compounds of Formula (~) wherein Rl is a methyl or ethyl group; RS is a hydrogen atom; R6 is a methyl group; and Y is a sodium or potassium cation and the agronomically acceptable acid addition sal~s thereof.
Typical compounds encompassed by the present i.nvention inrlude:
1,6-dimethyl-~-phenyl-4~oxonicotinic acid l-ethyl-6-methyl-2-phenyl-4-oxonicotinic acid 1,5,6-trimethyl-2-phenyl-4-oxonicotinic acid 1,6-diethyl-2-phenyl-4-oxonicotinic acid 6-ethyl-1-methyl-2-phenyl-4.-oxonicotinic acid l-methyl-2-phenyl-6-propyl-4-oxonicotinic acid
5-bromo-1,6-dimethyl-2-phenyl-4-oxonicotinic acid l-allyl-6-methyl-2-phenyl-4--oxonicotinic acid 1,6-dimethyl-2-~4-chlorophenyl)-4-oxonicotinic acid l-ethyl-6-methyl-2-(4-chlorophenyl)-4-oxonicotinic acid l-ethyl-5,6-dimethyl-2-~4 clllorophenyl) 4-oxonicotinic acid 1,6-diethyl-2-(4-chlorophenyl)-4-oxonicotinic acid
6-ethyl-1-methyl-2-(4-chlorophenyl)-4-oxonicotinic acid 5-bromo-1-ethyl-6-methyl-2-(4-chlorophen~1)-4-oxonicotinic acid l-allyl-6-methyl-2-(4-chlorophenyl)-4-oxonicotinic acid 6-methyl-2-(4-chlorophenyl)-1-propyl-4-oxonicotinic acid 1-butyl-6-methyl-2-(4-chlorophenyl)-4-oxonicotinic acid 1,6-dimethyl-2-(3-chloroph~nyl)-4-oxonicotinic acid l-ethyl-6-methyl-2-(3-chlorophenyl)-4-oxonicotinic acid 6-methyl-~-(3-chlorophenyl)-1-propyl-4-oxonicotinic acid l-ethyl-5,6-dimethyl-~-(3-chlorophenyl)-4-oxonicotinic acid 3Z~i 5-chloro~l~ethyl-6-methyl-2-(3-chlorophenyl)-4-oxonicotinic acid l-hexyl-6-methyl-2-(3-chlorophenyl~-4-oxonicotinic acid l-allyl-6-ethyl-2-(3-chlorophenyl)-4-oxonic3tinic acid 1,6-diethyl-2-(3~chlorophenyl)-4-oxonicotinic acid l-ethyl-6-~ethyl-2-(4-trifluoromethylphenyl)-4-oxonicotinic acid l-ethyl-6-methyl-2-(4-trirluoromethylphenyl)-4-oxonicotinic acid 1,6-dimethyl-2-(4-fluorophe~yl)-4-oxonicotinic acid l-ethyl-6-me~hyl-2-(4-fluorophenyl)-4-oxonicotinic acid l-ethyl-6-methyl-2-(3-fluorophenyl)-4-oxonicotinic ac.id l-ethyl-6-methyl 2-(4-bromophenyl)-4-oxonicotinic acid 1,6-dimethyl-2-(3,4-dichloropbenyl)-4-oxonicotinic acid lS 1 ethyl-6-methyl-2-(3,4 dichlorophenyl)-4-oxonicotinic acid 6-methyl-2-(3,4-dichlorophenyl)-1-propyl-4-oxonicotinic acid 6-methyl-1-pentyl-2-(3,4-dichlorophenyl)-4-oxonicotinic acid 6-ethyl-1-~Pthyl-2-(3,4-dichlorophenyl)-4-oxonicotinic acid l-ethyl 2-(3,4-dichlorophenyl)-6-propyl-4-oxonicotinic acid 1,5,6-trimethyl--2-(3,4-dichlorophenyl)-4-oxonicotinic acid 5-~romo-1,6-dimethyl-2-(3,4-dichlorophenyl)-4-oxonicotinic acid 1,5-diethyl-6-methyl-2~(3,4-dichlorophenyl)-4-oxonicotinic acid 5-ethyl-1,6-dimethyl-2-(3,4-dichlorophenyl)-4-oxonicotinic acid l-ethy1-6 methyl-2-(2,4-dichlorophenyl)~4-oxonicotinic acid 1,6-dimethyl-2-(~,S-dichlorophenyl)-4-oxonicotinic acid 1-ethyl-6-methyl-2-(4-methylphenyl)-4-oxonicotinic acid 732~
6-butyl-l~methyl-2-(4-methylphenyl)-4-oxonicotinic acid and th~ aqronomically acceptable salts ~hereof.
The ccmpounds of Group A of the present invention can be prepare~ by various synthetic routes found in the art.
In particular, the com~ounds o~ the present invention can be prepared by the reaction of a suitably substituted 4-hydroxy=2-pyrone of the formula:
1~
R6 ¢~
(III) ~ herein R6 is as deined above with a benzoylhalide of the formula:
~3 COCl X
(IV) ; ~ wherein X is as defined above~in the presence of an acid scavenger such as pyridine, triethylamine and the like, at temperatures from about 0 to about 10C to Eorm a 4-lS benzoyloxy-2-pyrone of the formula:
0_11_~(X)r~
` ~ .
R
~,V) ... . . . .. .
3;;~
wherein R6 and X and n are as defined above.
This reaction is discussed in E. Marcus, J. F~
Stephen, J. K. Chan, Journal of Heterocyclic Chemistry, p. 13, 1966. This benzoate can undergo a Fries-type rearrangement with anhydrous aluminum chloride at elévated temperatures to give the product of the formula:
~ 1l ~ (x)n R
(VI) as discussed in the E. Marcu~, et al. re~erence, ibid.
The b~nzoylpyrone o the formula (U~ above can then be reacted with a suitable alcohol (RO~) in the presence of a similarly substituted trialkylorthoformate (RO)3CH
utilizing an acid catalyst selected from the group consisting of sulfuric, hydrochloric, trifluoroacetic, acetic, hydrobromic, and th~ like~ at t~mperatures from about n to about 200C. to ~orm the 3 carboxy-4-pyrone of the formula:
¢~_CO2~
R6 0~ x (VII ) .
~ 2~3~5 The 3-carboxy-4~pyrone esters of formula (VqI) can be reaeted with any suitably substituted amine of the formula:
Rl-NEt2 (VIII) S to yield a l-alkyl-2-aryl-4~onicotinate es~er of formula (IX) ~ where R5 is hydrogen.
~X)n (IX) This reaction is generally carried out in an inert solvent, such as toluene, xylene, benzene, chloroform, me~hylene ch~oride, methanol, ethanol or the like, at room tempera~ure or at a temperature at which the water formed during the reaction c:an be removed by azeotropic distillation, using about 0 to 5~ by weight of an acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, ~uluric acidt methanesulfonic acid, or the like.
The free acid, its salts, amides, and other esters can ~hen be p~epared by conventional techniques.
The reaction of 3~carboxy-4-pyrone ester of formula (V~I) with excess amine of formula (VIII) in methanol or ethanol at 0-50C also results in the formation of a 2:1 amine:pyrone adduct of formula (:Xj.
Rl-NEI p J~ C 2R
~N 1 ~(~tX) n .
' ~X) ., .... ..... . .. ., . .. ... . . - - - =
~gP~73ZS
Compound (X) can be converted to (lX) by hydrolysis with dilute a~ueous acids such as hydrochloric, sulfuric, trifluosacetic or methanesulfonic at 0-~0C.
Al'ernately, 2:1 adduct (X) can be alkylated with an ; alkyl halide in an inert solvent such as methylene chioride, benzene, tetrahydrofuran, diethyl ether and the li~e ~o provide a material of formula (~I~ wherein R5 is an alkyl group;
~ -N~ O
.~5 R J ~ (1]n (~1) This co~ound can be hydrolyzed in aqueous acids at 0 50C as described above ~o yield the coccespondin~ 1,5-dialXyl-2-aryl-4-oxonicotinate ester of formula -(IX) where R5~alkyl. ~he oxonicotinic acid ~sters produced in the above reactions can be conve~-ted to ~he f~ee acids . .
.
~;~tD73;~
by hydrolysis with a strong base such as sodium hydroxide - ~ - or potassium hydroxide and the like followed by neutralization with a strong acid.
Another route to the preparation of the compounds S according to Formula (II)where~n Rl and X are as de~ined above, R; is hydrogen and ~6 is methyl is depicted in the following reaction sequence:
~ N~ r~2Y~g- (1) c-c~ co Y ~ C ~
~x~ 2 2 solvent ~ t tx) n (XII~ (XIII) wherein ~ is a ~Cl-C~) alkyl group.
~r ~ C02Y =q. (2) (X~n c~2 N ~_~X) n (XIII) (XIV) (xv) wherein ~ is a ~Cl-C6) alkyl group.
... . .. ... . . . . . . . . ..
~2~3;25 1.saponification~ \ ~ O ~ Eq. (3) Formula XV 2 . H ~ f ~\N~3 ( X ) n (XVI ) `
In the above reaction sequence the solvents for Eq. (l) can be selected from methanol, ethanol, water and the like and the reaction is run at temperatures from about 20 to about lOO~C. In Eq. (2), tbe inert solvent is selected from ethers, methylene chlo~ide, aromatic hydrocarbons, acetone, acetorlitrile and the like and the reaction is run at temperatures from about lO~ to about 150C9 In Eq. (3) the saponification reaction is run at 10-100C with a strong base, such as sodium or po~assium hydroxide, and the alkali salt is converted to tha free acid v mineral acids such as hydrochloride, sulfuric and the like.
Another route to the compounds of the present invention wherein Rl and R6 are as defined above and R5 is hydrogen or alkyl is shown in equation ~4) below.
X~ + R9--C9 2 ~ R~(X)I~) lll~ (XVII) - - .
. i .
, j - - - . . .
~Z~:~73Z5 wherein Y is an alkyl group.
In the reaction sequence o Eq. (4) the reaction can be run eitber neat or in an inert cosolvent optionally in the presence of an acid catalyst such as toluene sulfonic S acid, sulfuric acid, acetic acid and the like at temperatures from a~out 100C to about 300~C.
A route to the 5-halo compounds encompassed by the present invention is shown in 2q. (5) below.
In this reaction sequence any protic solvent such as water, methanol, ethanol and the like can be utili2ed as the react.ion medium and the rea~tion can be carried out at temperatures from abou~ to about 50C.
Th~ ~aL~s o~ the oxonicotinic acids o~ the present invention can be prepared by generally known procedures such as dissolving the acids in a protic solvent such as methanol, ethanol, water and the like and trea~ing them with an e~uivaLen~ amount of a strong base such as sodium or po~assium hydroxide and the like, and recoverin~ the salt either by stripping o~ the solvent or precipitating the solid out with diethylether, hexane, benzene and the like.
Table I below is presented to illustrate the more pre~rred compqunds of the prese~t invention. This table-and Tables II and III in which the analytical data is presentedf or ~he~e compounds are not t~ be interpreted Ln any way ~1,t~
~Z~:373~5 as being limits orl the breadth and scope of the present invent ion:
TABLE I
.
5~ ~ CO 2Y
Il 11 6 ~ ( x) 5Example ~ X R R_ R, --( n) ~ _ G--2 ~ C~3 ~ CH3 C~2C~3 3 H C~I3 H C~3 CH2C~3 HCl 4 H C~I ~ H C~I3 H
4a H CE3 H CX3 Na El C~I2CH3 H C~I3 6 ~ 3 7 H C~3 H
6a H n C3X7 H CH3 Na
6-butyl-l~methyl-2-(4-methylphenyl)-4-oxonicotinic acid and th~ aqronomically acceptable salts ~hereof.
The ccmpounds of Group A of the present invention can be prepare~ by various synthetic routes found in the art.
In particular, the com~ounds o~ the present invention can be prepared by the reaction of a suitably substituted 4-hydroxy=2-pyrone of the formula:
1~
R6 ¢~
(III) ~ herein R6 is as deined above with a benzoylhalide of the formula:
~3 COCl X
(IV) ; ~ wherein X is as defined above~in the presence of an acid scavenger such as pyridine, triethylamine and the like, at temperatures from about 0 to about 10C to Eorm a 4-lS benzoyloxy-2-pyrone of the formula:
0_11_~(X)r~
` ~ .
R
~,V) ... . . . .. .
3;;~
wherein R6 and X and n are as defined above.
This reaction is discussed in E. Marcus, J. F~
Stephen, J. K. Chan, Journal of Heterocyclic Chemistry, p. 13, 1966. This benzoate can undergo a Fries-type rearrangement with anhydrous aluminum chloride at elévated temperatures to give the product of the formula:
~ 1l ~ (x)n R
(VI) as discussed in the E. Marcu~, et al. re~erence, ibid.
The b~nzoylpyrone o the formula (U~ above can then be reacted with a suitable alcohol (RO~) in the presence of a similarly substituted trialkylorthoformate (RO)3CH
utilizing an acid catalyst selected from the group consisting of sulfuric, hydrochloric, trifluoroacetic, acetic, hydrobromic, and th~ like~ at t~mperatures from about n to about 200C. to ~orm the 3 carboxy-4-pyrone of the formula:
¢~_CO2~
R6 0~ x (VII ) .
~ 2~3~5 The 3-carboxy-4~pyrone esters of formula (VqI) can be reaeted with any suitably substituted amine of the formula:
Rl-NEt2 (VIII) S to yield a l-alkyl-2-aryl-4~onicotinate es~er of formula (IX) ~ where R5 is hydrogen.
~X)n (IX) This reaction is generally carried out in an inert solvent, such as toluene, xylene, benzene, chloroform, me~hylene ch~oride, methanol, ethanol or the like, at room tempera~ure or at a temperature at which the water formed during the reaction c:an be removed by azeotropic distillation, using about 0 to 5~ by weight of an acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, ~uluric acidt methanesulfonic acid, or the like.
The free acid, its salts, amides, and other esters can ~hen be p~epared by conventional techniques.
The reaction of 3~carboxy-4-pyrone ester of formula (V~I) with excess amine of formula (VIII) in methanol or ethanol at 0-50C also results in the formation of a 2:1 amine:pyrone adduct of formula (:Xj.
Rl-NEI p J~ C 2R
~N 1 ~(~tX) n .
' ~X) ., .... ..... . .. ., . .. ... . . - - - =
~gP~73ZS
Compound (X) can be converted to (lX) by hydrolysis with dilute a~ueous acids such as hydrochloric, sulfuric, trifluosacetic or methanesulfonic at 0-~0C.
Al'ernately, 2:1 adduct (X) can be alkylated with an ; alkyl halide in an inert solvent such as methylene chioride, benzene, tetrahydrofuran, diethyl ether and the li~e ~o provide a material of formula (~I~ wherein R5 is an alkyl group;
~ -N~ O
.~5 R J ~ (1]n (~1) This co~ound can be hydrolyzed in aqueous acids at 0 50C as described above ~o yield the coccespondin~ 1,5-dialXyl-2-aryl-4-oxonicotinate ester of formula -(IX) where R5~alkyl. ~he oxonicotinic acid ~sters produced in the above reactions can be conve~-ted to ~he f~ee acids . .
.
~;~tD73;~
by hydrolysis with a strong base such as sodium hydroxide - ~ - or potassium hydroxide and the like followed by neutralization with a strong acid.
Another route to the preparation of the compounds S according to Formula (II)where~n Rl and X are as de~ined above, R; is hydrogen and ~6 is methyl is depicted in the following reaction sequence:
~ N~ r~2Y~g- (1) c-c~ co Y ~ C ~
~x~ 2 2 solvent ~ t tx) n (XII~ (XIII) wherein ~ is a ~Cl-C~) alkyl group.
~r ~ C02Y =q. (2) (X~n c~2 N ~_~X) n (XIII) (XIV) (xv) wherein ~ is a ~Cl-C6) alkyl group.
... . .. ... . . . . . . . . ..
~2~3;25 1.saponification~ \ ~ O ~ Eq. (3) Formula XV 2 . H ~ f ~\N~3 ( X ) n (XVI ) `
In the above reaction sequence the solvents for Eq. (l) can be selected from methanol, ethanol, water and the like and the reaction is run at temperatures from about 20 to about lOO~C. In Eq. (2), tbe inert solvent is selected from ethers, methylene chlo~ide, aromatic hydrocarbons, acetone, acetorlitrile and the like and the reaction is run at temperatures from about lO~ to about 150C9 In Eq. (3) the saponification reaction is run at 10-100C with a strong base, such as sodium or po~assium hydroxide, and the alkali salt is converted to tha free acid v mineral acids such as hydrochloride, sulfuric and the like.
Another route to the compounds of the present invention wherein Rl and R6 are as defined above and R5 is hydrogen or alkyl is shown in equation ~4) below.
X~ + R9--C9 2 ~ R~(X)I~) lll~ (XVII) - - .
. i .
, j - - - . . .
~Z~:~73Z5 wherein Y is an alkyl group.
In the reaction sequence o Eq. (4) the reaction can be run eitber neat or in an inert cosolvent optionally in the presence of an acid catalyst such as toluene sulfonic S acid, sulfuric acid, acetic acid and the like at temperatures from a~out 100C to about 300~C.
A route to the 5-halo compounds encompassed by the present invention is shown in 2q. (5) below.
In this reaction sequence any protic solvent such as water, methanol, ethanol and the like can be utili2ed as the react.ion medium and the rea~tion can be carried out at temperatures from abou~ to about 50C.
Th~ ~aL~s o~ the oxonicotinic acids o~ the present invention can be prepared by generally known procedures such as dissolving the acids in a protic solvent such as methanol, ethanol, water and the like and trea~ing them with an e~uivaLen~ amount of a strong base such as sodium or po~assium hydroxide and the like, and recoverin~ the salt either by stripping o~ the solvent or precipitating the solid out with diethylether, hexane, benzene and the like.
Table I below is presented to illustrate the more pre~rred compqunds of the prese~t invention. This table-and Tables II and III in which the analytical data is presentedf or ~he~e compounds are not t~ be interpreted Ln any way ~1,t~
~Z~:373~5 as being limits orl the breadth and scope of the present invent ion:
TABLE I
.
5~ ~ CO 2Y
Il 11 6 ~ ( x) 5Example ~ X R R_ R, --( n) ~ _ G--2 ~ C~3 ~ CH3 C~2C~3 3 H C~I3 H C~3 CH2C~3 HCl 4 H C~I ~ H C~I3 H
4a H CE3 H CX3 Na El C~I2CH3 H C~I3 6 ~ 3 7 H C~3 H
6a H n C3X7 H CH3 Na
7 H n-C4Hg H CH3 H
7a EI n~C4~9 H CH3 Na
7a EI n~C4~9 H CH3 Na
8 H C}I3 }I C}I2CH3 H
8a H CH3 H CH2CX3 Na g H . CH3 }~ 3 7 H
9a }~ c~3 n C3 7 Na ~ C~I2C~3 H ~}~2C~3 H
lOa E[ CH~C~3 H C~2CX3 Na ' ~L23t~732~
Exam~le ~ X R R R Y
- -- --( n ~ S~
3 C~3- C 3 llz E ca3 C~3 C~3 ~a 12 4~1 ~ i~ Cg3 12a 4-Cl ~; ~ rvE3 Nz 13 4-C1 C~3 ~ E3 13a 4~vl CE13 ~ c~3 Na 14 4-C1 ~1C~3 E~ C~3 ~:~3 4-C1 C~2C~3 El c~3 C~2C}~3 16 4~ 2C~3 ~ C~I3 16a 4OC1 C~2C~3 ca3 Na ~ ~17 4~ 2CE~3 ~v~3 C~3 17a 4~ 2C~3 CE13 C~3 Na 18 4-C1 n-C3~7 ~ C~3 3S 18a 4-C1 n-C3~7 a CEE3 Na 19 4-C1 C~I2C~20~ ~ C~3 l9a 4-C1 C~2C~2E~ ~ 6~3 Na ZO 4-C1 C~i2C02E~ ~ C~3 C~3 20a 4-Cl C~C02Na B CVi3 C33 4 0 2 1 4 v~v 1 C~ 2CO2 ~ C 3 21a 4--_1 C32CO2N2 ~ c~3 Na 22 ~-Cl C,. 2C~=C,V.2 ~ C~.3 E
22a ~vvcl C~ C~-C~I ~ c~3 Na 23 4~:1 n C6~13 c~3 vn 23a 4-Cl n-C6~13 C33 Na 24 4-C1 C~;2C~I2Ph ~ c~3 ~L2~7~32~
Example # X (n) ~ R5_ R6-- Y_ 24a 4-Cl CH2C}~2Ph H CH3-- Na 25a 4-CH3 CH3 H CH3 Na 526 4-CH3 C~2CH3 H C~3 H
26a 4-C~3 CH2CH3 E~ c~3 Na 27 4-F C~3 H C~3 H
27a 4-F ~H3 H CH3 28 4-F C~I:2CH3 H c~3 H
1028a 4-F . C~2CH3 H CH3 Na 29 4-F n ~3~1 H CH3 8 29a 4-F n C3~7 H C~13 Na 3-Cl CH3 ~ c~3 H
30a 3-Cl C~3 H C~I3 Na ~531 3-Cl C~2C~3 ~ ~13 C~3 32 3-Cl CH2C~3 H CH3 H
32a 3-Cl CH2C~I3 EI ~ c~3 Na 33 3-Cl rl~C3E17 H CH3 H
33a 3-Cl n C3~7 H CH3 Na 2034 3-Cl T~ C4~9 H CEI3 E~
34a 3-Cl n-C4ECg H CE3 Na 3-Cl CE~2Ph H CH3 35a 3-Cl 5~2Ph H CH3 Na 36 3-CH3 CH2CH3 H CH3 }i 2536a 3 CH3 ~ ~2C~3 H C~3 Na 37a 30F ~H3 H CH3 Na .
, ~ . .. ...
~2~7325 Examl~le # X R R R Y
--( n ) - --1~ --S-- --6--3 8 3 -F C~I C ~ C~ 3 38a 3 F CH2C~I3 H CX3 Na 39 2-Cl c~3 E~ CH3 H
39a 2 Cl CH3 ~ c~3 Wa 2-Cl C}~3 ~I c~3 a 40a 2-Cl C~I2C~3 H C~3 Na 41 3, 4-diCl }I E; C~3 C~I~
42 3, 4-diC1 ~13 ~ C~3 42a 3, 4 diCl C~3 E~ c~3 Na 43 3, 4-diCl C~I2C~3 ~ C~3 H
43a 3,4~diCl c~;2r~3 E~ c~3 Na 44 3, 4~diCl n-C3~I7 }I c~3 44a 3, 4~iCl n-C3H7 EI c~3 Na 2, 4-diCl C}I3 ~ ca3 EE
45a 2, 4-diCl C~I3 -- ~ C$3 ~ Na 46 2, 4-diCl C$2C:~3 a ca3 46a 2,4-diCl c~2C~I3 ~ c~3 Na 47 E~ c~3 B r C:~3 47a ~ c~3 Br CE3 Na TABIIE II
Example ~ ~ ~6 C 96El %N ~X .
226- 228 70002 5.88 5.45 --70.35 6.01 3.60 --2 244-24~ ~0.83 6.32 5.15 --70 . 92 6 . 17 3 229- 232 6~.44 s.ag 4.55 --~2 ~ 00 5 . 674. 78 - ~
4 246- 248 69 . 12 S . 395 . 7~ --3~ 6g . ~5 5 . 665 ~ 80 --..
73Z~
TABT,E II (Cont ) Exam~le ~ ~ 96 C ~ N %X
4a a 252-254 70.02 5.8B 5.45 --69.63 5.76 ;.64 --5a a 21n- 212 70 . 83 6 . 32 ~ .16 --70.67 5.93 5.33 --7 165-167 71.56 6.71 4.91 ~-73. 87 6. 80 S .30 --7a a 8 24J~-245 70.02 5.~8 5~44 --70.15 5.65 6.n7 --8a a -~
8a H CH3 H CH2CX3 Na g H . CH3 }~ 3 7 H
9a }~ c~3 n C3 7 Na ~ C~I2C~3 H ~}~2C~3 H
lOa E[ CH~C~3 H C~2CX3 Na ' ~L23t~732~
Exam~le ~ X R R R Y
- -- --( n ~ S~
3 C~3- C 3 llz E ca3 C~3 C~3 ~a 12 4~1 ~ i~ Cg3 12a 4-Cl ~; ~ rvE3 Nz 13 4-C1 C~3 ~ E3 13a 4~vl CE13 ~ c~3 Na 14 4-C1 ~1C~3 E~ C~3 ~:~3 4-C1 C~2C~3 El c~3 C~2C}~3 16 4~ 2C~3 ~ C~I3 16a 4OC1 C~2C~3 ca3 Na ~ ~17 4~ 2CE~3 ~v~3 C~3 17a 4~ 2C~3 CE13 C~3 Na 18 4-C1 n-C3~7 ~ C~3 3S 18a 4-C1 n-C3~7 a CEE3 Na 19 4-C1 C~I2C~20~ ~ C~3 l9a 4-C1 C~2C~2E~ ~ 6~3 Na ZO 4-C1 C~i2C02E~ ~ C~3 C~3 20a 4-Cl C~C02Na B CVi3 C33 4 0 2 1 4 v~v 1 C~ 2CO2 ~ C 3 21a 4--_1 C32CO2N2 ~ c~3 Na 22 ~-Cl C,. 2C~=C,V.2 ~ C~.3 E
22a ~vvcl C~ C~-C~I ~ c~3 Na 23 4~:1 n C6~13 c~3 vn 23a 4-Cl n-C6~13 C33 Na 24 4-C1 C~;2C~I2Ph ~ c~3 ~L2~7~32~
Example # X (n) ~ R5_ R6-- Y_ 24a 4-Cl CH2C}~2Ph H CH3-- Na 25a 4-CH3 CH3 H CH3 Na 526 4-CH3 C~2CH3 H C~3 H
26a 4-C~3 CH2CH3 E~ c~3 Na 27 4-F C~3 H C~3 H
27a 4-F ~H3 H CH3 28 4-F C~I:2CH3 H c~3 H
1028a 4-F . C~2CH3 H CH3 Na 29 4-F n ~3~1 H CH3 8 29a 4-F n C3~7 H C~13 Na 3-Cl CH3 ~ c~3 H
30a 3-Cl C~3 H C~I3 Na ~531 3-Cl C~2C~3 ~ ~13 C~3 32 3-Cl CH2C~3 H CH3 H
32a 3-Cl CH2C~I3 EI ~ c~3 Na 33 3-Cl rl~C3E17 H CH3 H
33a 3-Cl n C3~7 H CH3 Na 2034 3-Cl T~ C4~9 H CEI3 E~
34a 3-Cl n-C4ECg H CE3 Na 3-Cl CE~2Ph H CH3 35a 3-Cl 5~2Ph H CH3 Na 36 3-CH3 CH2CH3 H CH3 }i 2536a 3 CH3 ~ ~2C~3 H C~3 Na 37a 30F ~H3 H CH3 Na .
, ~ . .. ...
~2~7325 Examl~le # X R R R Y
--( n ) - --1~ --S-- --6--3 8 3 -F C~I C ~ C~ 3 38a 3 F CH2C~I3 H CX3 Na 39 2-Cl c~3 E~ CH3 H
39a 2 Cl CH3 ~ c~3 Wa 2-Cl C}~3 ~I c~3 a 40a 2-Cl C~I2C~3 H C~3 Na 41 3, 4-diCl }I E; C~3 C~I~
42 3, 4-diC1 ~13 ~ C~3 42a 3, 4 diCl C~3 E~ c~3 Na 43 3, 4-diCl C~I2C~3 ~ C~3 H
43a 3,4~diCl c~;2r~3 E~ c~3 Na 44 3, 4~diCl n-C3~I7 }I c~3 44a 3, 4~iCl n-C3H7 EI c~3 Na 2, 4-diCl C}I3 ~ ca3 EE
45a 2, 4-diCl C~I3 -- ~ C$3 ~ Na 46 2, 4-diCl C$2C:~3 a ca3 46a 2,4-diCl c~2C~I3 ~ c~3 Na 47 E~ c~3 B r C:~3 47a ~ c~3 Br CE3 Na TABIIE II
Example ~ ~ ~6 C 96El %N ~X .
226- 228 70002 5.88 5.45 --70.35 6.01 3.60 --2 244-24~ ~0.83 6.32 5.15 --70 . 92 6 . 17 3 229- 232 6~.44 s.ag 4.55 --~2 ~ 00 5 . 674. 78 - ~
4 246- 248 69 . 12 S . 395 . 7~ --3~ 6g . ~5 5 . 665 ~ 80 --..
73Z~
TABT,E II (Cont ) Exam~le ~ ~ 96 C ~ N %X
4a a 252-254 70.02 5.8B 5.45 --69.63 5.76 ;.64 --5a a 21n- 212 70 . 83 6 . 32 ~ .16 --70.67 5.93 5.33 --7 165-167 71.56 6.71 4.91 ~-73. 87 6. 80 S .30 --7a a 8 24J~-245 70.02 5.~8 5~44 --70.15 5.65 6.n7 --8a a -~
9 126-l28 7a~3 6.32 5.16 __ 70 . ~1 6 ~ 39 5 . 3~ --9a a 187-18~ 70~a3 6032 5.16 '-70 . 37 6 . 29 ~ . 66 lOa a 11 ~10-214 70.02 5.88 5.~
. 69.92 5.96 S.9~ --11a 2S 1~ 250-251 59.31 3~82 S.31 13.45 59 . 05 3 . 77 S . 38 13 . 4Z
12a a 13 242- 244 60.55 4.36 5.04 12.77 60.17 4.36 5.53 L3.07 30 13a a 14 ?17- 219 62 . 85 5 . 28 4. 58 11. 60 62~ 98 5 . 49 4. 55 11. 45 i ~j. .2~'~!`,, ~,~z5~3;Z 5 TABLE II (Cont) - Example ~ mp ~ C) % C ~ ~N ~X
16 235-237 61.75 4.84 4.ao 12.16 60.50 4.75 5.75 13.66 16a a -~
17 240- 242 62.85 5.28 4.58 11.60 62.86 5.37 4.71 11.48 17a a 18 213- 216 62.8S 5.27 ~.58 11.60 62.76 5.~5 5.05 11.50 18a a -- - __ __ i~ 217- 220 58.54 4.59 4.55 11.52 58.31 4.52 4.75 11.91 1519 a a -~
2~ 2'24 57.24 4.20 4.17 10. S7 57 ~ 21 4. ~0 4.66 10.30 20a a 21 158- lG2 50.36 4.51 3.32 9.91 (dihydrate) ;0.38 3.93 3.89 9.85 21a a -~
22 219 22l 63.26 4.65 4.61 11.67 63.30 4.59 5.09 11.75 22a a - -- ~~ ~~
23 17~- 179 65.63 6.38 ~ .03 10.1~
65.8~ 6.66 4.29 10. ~2 23a a 2~ 265 68.5~ 4.93 3.81 9.64 68 . 48 4 . g5 4 . 1~ - 9 . 44 30 24a a . ~5 250 70.02 5.88 5.44 --63.9~ 6.03 5.46 --- .
~ ~' , . .
3L;~(~73;~5 TABLE I I (Cont) - - Exam~le ~ ~ % C ~H ~ N - %X
25a a 26 248-249 70.~3 6.31 5~16 ~-7~.64 6.39 5.60 ~-26a a -~
27 263- ~65 64.3~ 4.63 5.36 7.27 64~60 4.63 5.53 7.10 27a a 2B 258- 260 65~44 S.13 5~0~ 6-90 65.60 5.26 5.24 6.80 28a a ~ -- -- --29 225-226 66.42 5.5~ 4.84 6.57 66.60 5.74 5.11 6.47 29a a --248-250 6~.55 4.36 5.0~ 12.77 60.~8 ~.47 5.41 12.77 30a a 31 173- 175 62.85 5.28 4.58 11.60 62.8~ 5.54 5.06 11.80 32 ~41- 244 61.75 4.84 4.80 12.16 62.01 - 4.83 4.97 12.25 32a a 33 164-169 62.85 5.28 4.58 11.60 6~.83 ~ 5.4~ 4.34 14.09 33a a ~ ~ __ __ 34 174-176 63.85 ~.67 4.38 ll.Og 63.65 5.86 4.41 11.19 34a a 23~- 235 67. 9 4.5~ 3~96 1~.02 ~.14 4.54 4.06 10.1 3Sa a - . . ..
7~:~5 TABI,E II ~Cont) ~_~ ~, % C ~H ~N %X
36 183 70.~3 6.31 5.1~ --70.29 6.38 5.24~ --36a a -- -~
37 243- 244 64.36 4.63 5.36 7. ~7 64.3~ 4.96 5.40 7. 07 37a a 38 226- 227 65.44 5.13 S.09 6.90 65.43 5.24 5.10 ~.93 3aa a -~
39 221-223 60.55 4.36 5.04 12.77 ~0O53 4-30 4.95 17.62 212- 215 61.75 4.84 4.80 12.16 lS 61.94 4.8~ 4.93 12.06 40a a -~ -- ~~ ~~
41 245- 249 53.87 3.55 4.49 22.72 53.79 3.57 4.95 23.09 42 246- 249 53.B7 3.55 4.49 22.72 53.~30 3.55 4.42 23.10 42a a --43 238- 239 55.23 4.02 4.3~ ~1.74 54.68 3.~0 4.06 23.06 43a a 44 ~32-233 S6.~8 ~.~4 4.19 2~.84 56.69 4.47 4.29 20.49 44a a ~2- 234 53,87 3.55 4.4~ 27. ~2 53.96 3. ~7 4.88 22.69 3C 45a a 46 195 55.23 4.02 4.3~ 21.72 55.82 4.02 4.~ 21.73 .
~ " ~
.. .. . . . . . . .
~2~'73~
- 20a -~ABLE III. NMR ~A~A
Example Solvent NMR-CHEMICAL SHIFT
_ CDC13 3H at 2.4 pFm(s); 3H at 3.3 pEm(s); 3H at 3.45 (s); lH at 6.4 pEm(s); 5H at 7~5 pFm(m) 3 -- _ 4 ~ CO2~ 3EI at 2.9E~n(s);3H at 3.8 p~m(s); 6H at 3 7.6 pEm(m) 4a CF3C02H 3H at 1.4 p~n(t); 3H at 2.9 ppn(s); 2H at 4.5 ppm(q); 6H at 7.7 ppm(m) 6a - 7 CD~ 3 7H iat 0.7-17 p~m(m); 3H at 2.5 pEm(s); 2H at 3-7 pEm(m); lH at 6.8 pEm(s); 5~ at 7.~ pFm(m) 7a 8a g 9a lOa lla 12 3 2 3H at 2.9 pEm~s); 5H at 7.6 pl~n(m) 12a - - ~
13 CDCl~DMSO-d6 3H at 2.5 pEm(s); 3Hat3.3p~m(s); lH at 3 6.3 pEmls); 4~I at 7.5 pEm(y) 13a 14 CDCl 3H at 1.1 ppm(t);3H at 2.4pFm(s~,3Hat 3 3.5pEm(s); 2H at 3.8 p~m(q), lH at 6.5 ppm(s) 4H at 7.5 ppm(q) _ 16 ~1 3Hat1~2~n~t);3H at 2.75 p~m~s); 2H at 3 4.2 ppm(q); 1~ at 6.9 pFm(s); 4H at 7.9 pEm (m) 16a D2O 3H at~ 0~8 pEm(t); 3H at 2.3p~(s);2H at 3.7p}m(q); lH at 6.6 pEm(s), 4H at 7.6 ppm(s) 17 ~ d 3H at 1.1 Fq~m(t);3H at 2.2 E~n(s); 3H at 2~6 6 pFm(s); 2H at 3.9 ~ (q); 4H at 7.6 p~m(q) ~L;2V~32~ii - 20b -TABLE III, NWR DAr~ (cont.) Ex~ple Solvent _ ~IR-CHEMICAL SHIFT
17a 18a 19 DMSC-d6 3H at 2.6 ppm(s); 2H at 3.4 ppm(m); 2H at 3.9 ppm(m); lH at 6.9 ppm~s); 4H at 7.4 ppm(q) 19a ~-d6 3H at 2.3 ppm(s); 3H at 3.4 ppm(s); 2H at 4.5 7 pE~[l(s3; lH at 6-4 ppm(s); 4H at 7.6 E~n(q) 20a 21a 22a 23a 24~ - _ CDCl ~ DMSO-d 3H at 2.4 pFm(s); 3H at 2.5 pp~(s); 3H at 3.3 3 6 ppm(s); lH at 6.8 ppm(s); 4H at 7.3 p~m(q) 25a 26a 27 CF3C02H 3H at 2.8 ppm(s); 3~ at 3.8 ppm(s); 5H at 7.5 p~n (m) 27a 28a - -3~ 29 29a ~ -30a 31 CDC13 3~ at 1.1 ppm(t); 3~ at 2.4 pEm(s); 3~ at 3.5 pFm(s); 2H at 3.8 pFm (q); lH at 6.4 p~m(s);
4H at 7.5 ppm(m) 32 -- _ . .
~F
~Z1 ~73z5 - 20c -TABLE III, NMR DATA (cont.) Example Solvent NMR-CHEMICAL SHIFT
-32a 33 CDCl 3H at 0.7 ppmtt), 2H at 1.5 ppm(m); 3H at Z.6 3 ppm(s); 2H at 3.6 ppm(q); lH at 6.8 ppm(s);
4H at 7.5 ppm(m) 33a 34 CDCl 7H at 0.7-1.7 ppm(m); 3H at 2.5 ppm(s); 2H at 3 3.7 ppm(m); lH at 6.8 ppm(s); 4H at 7.5 ppm(m) 34a - _ 35a - _ 36 CDCl 3H at 1.1 ppm(t); 3H at 2.4 ppm(S); 3H at 2.6 3 ppm(s); 2H at 3.9 ppm(q); lH at 6.8 ppm(s);
4H at 7.4 ppm(m) 36a 37a 38 ~MSO-d 3H ar 1.1 ppm~t); 3H at 2.6 ppm(s); 2H at 3.8 6 ppm(q); lH at 6.9 ppm(s); 4H at 7.5 ppm(m) 38a 39a 4~ - _ 40a - -41 CF ~ 3H at 2.8 ppm(s); 3H at 3.9 ppm(s); 4H at 7.6 3 2 ppm(m~
42 - _ 42a 43a - _ 44a 3 2 3H at 2.9 ppm(s); 3H at 3.9 p~m(s); 4H at 7.7 ppm(m) 45a 46 CDCl 3H at 1.2 ppm(t); 3H at 2.6 ppm(s); 2H a~ 3.8 3 ppm(q); lH at 6.8 ppm(s); 3H at 7.5 ppm(m) i 73~25 TABLE III, NMR DA~A (cont.) Example Solvent NMR-CHEMICAL SHIFT
:
46a - -47 - _ 47a s = singlet t = triplet q = quartet m = multiplet ~Z~7~Z~
TABLE II (Cont) Example ~ _mP ~C) % C ~ N ~X
46a a 47 252-~s3 52.19 3.76 4.35 24.81 551.7~ 3.67 4.26 Z4.78 47a a ~
a) no meltins point taken. To~ glassy.
The following.examples are presented to illustrate the methods for preparation of the compounds of the present invention. Again these examples are not to be interprete~
as being limits upon the breadth and scope of the present invention.
EXP ERh~lENTAL
~xamPle ~ 1 15]?art a A flask ~itted with a reflux condenser and calcium chloride drying tube ls charged with 70 ml dry methanol, 7.3 g- o~ 96~ sulfuric acid and 10.15 g. of trimethyl o~tho~ormate. 3-Benzoyl-4-hydroxy-6~methyl-2-pyrone (22 g ) is then added in small portions and ~he resulting reaction mixtur~ is re1uxed ~or 24 hours. The mixture is cooled and poured into water. Extraction with methylene chloride yields 17.7 g. of crude 3-methoxycarbonyl-6-me~hyl-~-phenYl-4-~yrcne~ mp (Erom methylene chloride~
2S ether - lOl-102.5C
Part b -3~8 g. of 3-methoxycarbonyl-6-methyl-2-phenyl-4-pyrone, 33.3 ~1 of methanol, 13.3 ml of 40% aaueous methylamine and ~ ml of glacial acetic acid are mixed in a stoppered flask at room temperature and stored for 18 hours. The reaction mixture is then poured into approxlmately 100 ml of water and the p~ ic adjusted to 5 ~addi~ion of dilute ~Cl). Extraction with methylene chloride (3 ~ 50 ml ) and evaporation o the organic .. . _ .. . .. , ... . . . .. . . , .. . .. .. _ _ . . . . .... . . . . .. . . _ . .
~2~73~5 solvent yields 3.0 g- o~ methyl 1,6-dimethyl-2-phenyl-4-oxonicotinate as a crystalline so~Ld. mp ~methylene chloride/ether~ = 226-228C.
Example ~2
. 69.92 5.96 S.9~ --11a 2S 1~ 250-251 59.31 3~82 S.31 13.45 59 . 05 3 . 77 S . 38 13 . 4Z
12a a 13 242- 244 60.55 4.36 5.04 12.77 60.17 4.36 5.53 L3.07 30 13a a 14 ?17- 219 62 . 85 5 . 28 4. 58 11. 60 62~ 98 5 . 49 4. 55 11. 45 i ~j. .2~'~!`,, ~,~z5~3;Z 5 TABLE II (Cont) - Example ~ mp ~ C) % C ~ ~N ~X
16 235-237 61.75 4.84 4.ao 12.16 60.50 4.75 5.75 13.66 16a a -~
17 240- 242 62.85 5.28 4.58 11.60 62.86 5.37 4.71 11.48 17a a 18 213- 216 62.8S 5.27 ~.58 11.60 62.76 5.~5 5.05 11.50 18a a -- - __ __ i~ 217- 220 58.54 4.59 4.55 11.52 58.31 4.52 4.75 11.91 1519 a a -~
2~ 2'24 57.24 4.20 4.17 10. S7 57 ~ 21 4. ~0 4.66 10.30 20a a 21 158- lG2 50.36 4.51 3.32 9.91 (dihydrate) ;0.38 3.93 3.89 9.85 21a a -~
22 219 22l 63.26 4.65 4.61 11.67 63.30 4.59 5.09 11.75 22a a - -- ~~ ~~
23 17~- 179 65.63 6.38 ~ .03 10.1~
65.8~ 6.66 4.29 10. ~2 23a a 2~ 265 68.5~ 4.93 3.81 9.64 68 . 48 4 . g5 4 . 1~ - 9 . 44 30 24a a . ~5 250 70.02 5.88 5.44 --63.9~ 6.03 5.46 --- .
~ ~' , . .
3L;~(~73;~5 TABLE I I (Cont) - - Exam~le ~ ~ % C ~H ~ N - %X
25a a 26 248-249 70.~3 6.31 5~16 ~-7~.64 6.39 5.60 ~-26a a -~
27 263- ~65 64.3~ 4.63 5.36 7.27 64~60 4.63 5.53 7.10 27a a 2B 258- 260 65~44 S.13 5~0~ 6-90 65.60 5.26 5.24 6.80 28a a ~ -- -- --29 225-226 66.42 5.5~ 4.84 6.57 66.60 5.74 5.11 6.47 29a a --248-250 6~.55 4.36 5.0~ 12.77 60.~8 ~.47 5.41 12.77 30a a 31 173- 175 62.85 5.28 4.58 11.60 62.8~ 5.54 5.06 11.80 32 ~41- 244 61.75 4.84 4.80 12.16 62.01 - 4.83 4.97 12.25 32a a 33 164-169 62.85 5.28 4.58 11.60 6~.83 ~ 5.4~ 4.34 14.09 33a a ~ ~ __ __ 34 174-176 63.85 ~.67 4.38 ll.Og 63.65 5.86 4.41 11.19 34a a 23~- 235 67. 9 4.5~ 3~96 1~.02 ~.14 4.54 4.06 10.1 3Sa a - . . ..
7~:~5 TABI,E II ~Cont) ~_~ ~, % C ~H ~N %X
36 183 70.~3 6.31 5.1~ --70.29 6.38 5.24~ --36a a -- -~
37 243- 244 64.36 4.63 5.36 7. ~7 64.3~ 4.96 5.40 7. 07 37a a 38 226- 227 65.44 5.13 S.09 6.90 65.43 5.24 5.10 ~.93 3aa a -~
39 221-223 60.55 4.36 5.04 12.77 ~0O53 4-30 4.95 17.62 212- 215 61.75 4.84 4.80 12.16 lS 61.94 4.8~ 4.93 12.06 40a a -~ -- ~~ ~~
41 245- 249 53.87 3.55 4.49 22.72 53.79 3.57 4.95 23.09 42 246- 249 53.B7 3.55 4.49 22.72 53.~30 3.55 4.42 23.10 42a a --43 238- 239 55.23 4.02 4.3~ ~1.74 54.68 3.~0 4.06 23.06 43a a 44 ~32-233 S6.~8 ~.~4 4.19 2~.84 56.69 4.47 4.29 20.49 44a a ~2- 234 53,87 3.55 4.4~ 27. ~2 53.96 3. ~7 4.88 22.69 3C 45a a 46 195 55.23 4.02 4.3~ 21.72 55.82 4.02 4.~ 21.73 .
~ " ~
.. .. . . . . . . .
~2~'73~
- 20a -~ABLE III. NMR ~A~A
Example Solvent NMR-CHEMICAL SHIFT
_ CDC13 3H at 2.4 pFm(s); 3H at 3.3 pEm(s); 3H at 3.45 (s); lH at 6.4 pEm(s); 5H at 7~5 pFm(m) 3 -- _ 4 ~ CO2~ 3EI at 2.9E~n(s);3H at 3.8 p~m(s); 6H at 3 7.6 pEm(m) 4a CF3C02H 3H at 1.4 p~n(t); 3H at 2.9 ppn(s); 2H at 4.5 ppm(q); 6H at 7.7 ppm(m) 6a - 7 CD~ 3 7H iat 0.7-17 p~m(m); 3H at 2.5 pEm(s); 2H at 3-7 pEm(m); lH at 6.8 pEm(s); 5~ at 7.~ pFm(m) 7a 8a g 9a lOa lla 12 3 2 3H at 2.9 pEm~s); 5H at 7.6 pl~n(m) 12a - - ~
13 CDCl~DMSO-d6 3H at 2.5 pEm(s); 3Hat3.3p~m(s); lH at 3 6.3 pEmls); 4~I at 7.5 pEm(y) 13a 14 CDCl 3H at 1.1 ppm(t);3H at 2.4pFm(s~,3Hat 3 3.5pEm(s); 2H at 3.8 p~m(q), lH at 6.5 ppm(s) 4H at 7.5 ppm(q) _ 16 ~1 3Hat1~2~n~t);3H at 2.75 p~m~s); 2H at 3 4.2 ppm(q); 1~ at 6.9 pFm(s); 4H at 7.9 pEm (m) 16a D2O 3H at~ 0~8 pEm(t); 3H at 2.3p~(s);2H at 3.7p}m(q); lH at 6.6 pEm(s), 4H at 7.6 ppm(s) 17 ~ d 3H at 1.1 Fq~m(t);3H at 2.2 E~n(s); 3H at 2~6 6 pFm(s); 2H at 3.9 ~ (q); 4H at 7.6 p~m(q) ~L;2V~32~ii - 20b -TABLE III, NWR DAr~ (cont.) Ex~ple Solvent _ ~IR-CHEMICAL SHIFT
17a 18a 19 DMSC-d6 3H at 2.6 ppm(s); 2H at 3.4 ppm(m); 2H at 3.9 ppm(m); lH at 6.9 ppm~s); 4H at 7.4 ppm(q) 19a ~-d6 3H at 2.3 ppm(s); 3H at 3.4 ppm(s); 2H at 4.5 7 pE~[l(s3; lH at 6-4 ppm(s); 4H at 7.6 E~n(q) 20a 21a 22a 23a 24~ - _ CDCl ~ DMSO-d 3H at 2.4 pFm(s); 3H at 2.5 pp~(s); 3H at 3.3 3 6 ppm(s); lH at 6.8 ppm(s); 4H at 7.3 p~m(q) 25a 26a 27 CF3C02H 3H at 2.8 ppm(s); 3~ at 3.8 ppm(s); 5H at 7.5 p~n (m) 27a 28a - -3~ 29 29a ~ -30a 31 CDC13 3~ at 1.1 ppm(t); 3~ at 2.4 pEm(s); 3~ at 3.5 pFm(s); 2H at 3.8 pFm (q); lH at 6.4 p~m(s);
4H at 7.5 ppm(m) 32 -- _ . .
~F
~Z1 ~73z5 - 20c -TABLE III, NMR DATA (cont.) Example Solvent NMR-CHEMICAL SHIFT
-32a 33 CDCl 3H at 0.7 ppmtt), 2H at 1.5 ppm(m); 3H at Z.6 3 ppm(s); 2H at 3.6 ppm(q); lH at 6.8 ppm(s);
4H at 7.5 ppm(m) 33a 34 CDCl 7H at 0.7-1.7 ppm(m); 3H at 2.5 ppm(s); 2H at 3 3.7 ppm(m); lH at 6.8 ppm(s); 4H at 7.5 ppm(m) 34a - _ 35a - _ 36 CDCl 3H at 1.1 ppm(t); 3H at 2.4 ppm(S); 3H at 2.6 3 ppm(s); 2H at 3.9 ppm(q); lH at 6.8 ppm(s);
4H at 7.4 ppm(m) 36a 37a 38 ~MSO-d 3H ar 1.1 ppm~t); 3H at 2.6 ppm(s); 2H at 3.8 6 ppm(q); lH at 6.9 ppm(s); 4H at 7.5 ppm(m) 38a 39a 4~ - _ 40a - -41 CF ~ 3H at 2.8 ppm(s); 3H at 3.9 ppm(s); 4H at 7.6 3 2 ppm(m~
42 - _ 42a 43a - _ 44a 3 2 3H at 2.9 ppm(s); 3H at 3.9 p~m(s); 4H at 7.7 ppm(m) 45a 46 CDCl 3H at 1.2 ppm(t); 3H at 2.6 ppm(s); 2H a~ 3.8 3 ppm(q); lH at 6.8 ppm(s); 3H at 7.5 ppm(m) i 73~25 TABLE III, NMR DA~A (cont.) Example Solvent NMR-CHEMICAL SHIFT
:
46a - -47 - _ 47a s = singlet t = triplet q = quartet m = multiplet ~Z~7~Z~
TABLE II (Cont) Example ~ _mP ~C) % C ~ N ~X
46a a 47 252-~s3 52.19 3.76 4.35 24.81 551.7~ 3.67 4.26 Z4.78 47a a ~
a) no meltins point taken. To~ glassy.
The following.examples are presented to illustrate the methods for preparation of the compounds of the present invention. Again these examples are not to be interprete~
as being limits upon the breadth and scope of the present invention.
EXP ERh~lENTAL
~xamPle ~ 1 15]?art a A flask ~itted with a reflux condenser and calcium chloride drying tube ls charged with 70 ml dry methanol, 7.3 g- o~ 96~ sulfuric acid and 10.15 g. of trimethyl o~tho~ormate. 3-Benzoyl-4-hydroxy-6~methyl-2-pyrone (22 g ) is then added in small portions and ~he resulting reaction mixtur~ is re1uxed ~or 24 hours. The mixture is cooled and poured into water. Extraction with methylene chloride yields 17.7 g. of crude 3-methoxycarbonyl-6-me~hyl-~-phenYl-4-~yrcne~ mp (Erom methylene chloride~
2S ether - lOl-102.5C
Part b -3~8 g. of 3-methoxycarbonyl-6-methyl-2-phenyl-4-pyrone, 33.3 ~1 of methanol, 13.3 ml of 40% aaueous methylamine and ~ ml of glacial acetic acid are mixed in a stoppered flask at room temperature and stored for 18 hours. The reaction mixture is then poured into approxlmately 100 ml of water and the p~ ic adjusted to 5 ~addi~ion of dilute ~Cl). Extraction with methylene chloride (3 ~ 50 ml ) and evaporation o the organic .. . _ .. . .. , ... . . . .. . . , .. . .. .. _ _ . . . . .... . . . . .. . . _ . .
~2~73~5 solvent yields 3.0 g- o~ methyl 1,6-dimethyl-2-phenyl-4-oxonicotinate as a crystalline so~Ld. mp ~methylene chloride/ether~ = 226-228C.
Example ~2
10.25 g. of ethyl beta-methylaminocinnamate, 9~4 gms of technical grade diketene and 25 ml. dry methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The reaction mixture is stored at room temperature for 117 hours. Approximately 75 ml of dry ether is added and the resulting crystalline solid is ~iltered to yield 8.5 g. of ethyl 1,6-dimethyl-2-phenyl 4-oxonicotinate. mp ttoluene) ~ 244-248C
6.0 g- of crude methyl 1,6~dimethyl-2-phenyl-4-oxonicotinate is ~uspended in 6~ g- of 5% aqueous sodium hydrox:Lde solution. The reaction mixture is heated on a steambath (85) or two hours. The resulting homogeneous ~olution is cooled and acidiied with dilute HCl. The resulting solid iq collected by filtra~ion yielding 4.~ g.
o~ 1,6-dimethyl-2~phenyl-4-o~onicotinic acid. mp (acetonitrile/methyLene chloride) a 246-249OC (dec.).
Example 4a:
1.69 ~. of 1,6-dimetbyl-2-phenyl-4-oxonicotinic aoid i~ suspended in approximately 50 ml.of methanol. NaOH
pellets (0.305 gms) are added with stirring . Af ~er both the acid and the s~dium hydroxide dissolve the-solution is evaporated to dryness n vacuo. Sodium 1, 6-dimethyl-2-ph~yl-4~xonicotinate is then isolated a~ ~ gl assy, somewhat hygroscopic solid. Yield = 1.6 g-Exam~e 8 -Part a:
__ 12 gms of ethyl beta-~ethylaminocinnamate, 18 g. o~
ethyl propio~ylace~ate and 100 ~g of toluenesulfonic acid monohydrate are added to a 50 ml 3neck flask fitted with a .. ...
732~
nitrogen inlet, magnetic stirring bar, ther~ometer and a short-path distillation head (with recei~er). The reaction mixture is heated to 170 175C under a slow stream of dry nitrogen. Ethanol and wat2r are collected in the distillation receiver. After four hours the reaction mixture is cooled and poured into a large volume o~ ether (150 ml 3. A pink s~lid forms which is collected by filtration to yield 4.1 g. or ethyl 5-ethyl-1-methyl-2-phenyl-4-~xonicoti~ate. mp l(EtoAc) = 210-212C.
Part b-- 2.2 gm of ethyl 6-ethyl-1-methyl-2-phenyl-4-oxonicotinate is suspended in 35 ml of 5% aqueous sodium hydroxide solution. The resulting suspension is heated on a steambath for 4 nours, cooled and acidified with dilute ~Cl to yield 2.0 g. of 6-ethyl-1-methyl-2-pheQyl-4-oxonicotinic acid. mp (C~3CN) = 2~4 -245Co E~e 11:
Part a?
12~0 g. o~ ethyl beta-rnethylaminocinnamat~, 18 g. of ethyl 2-methylacetoacetate and 100 mg toluenesulfonic acid monohydrate is mi~ed in a 50 ml 3-neck flask itted with a nitrogen inlet, magnetic stirring bar, thermometer and a short-path distillation head (with rec~iver~. The reaction mixture is heated (170- 175C.) for seven hours under a gentl~
stream of nitrogen. Ethanol ~nd water are collected in the distillation receiver. The rea tion mixture is cooled and poured into 100 ml of dry ether. E~hyl 1,5,6-trimethyl-2-phenyl-4-~xonicotinate forms as a brownish precipitate.
Yield = 1.03 gms.
30Part b:
1.03 g. of crude e~hyl 1,5,6-trimethyl-2-phenyl-4-oxonico~}na~e is suspended in 20 ml of warm (85) 5~
a~ue~us NaO~ solution for 4 hours. Acidiication with dilute hydrochloric acid yields 0.3 g. of 1,5,6-tri-35methyl-2-phenyl-4 oxonicotinate mp (C~3CN) ~10- 214 ~LZ~37;~
Example 14 Part a A 5~00 ml 3-neck flask is fitted with a N2 inlet, magnetic stirring bar, thermameter and a Dean-S~ark trap with cond~nser. 2300 ml of dry methanol is added to the flask along with 244 g of 95% ~2SO4 and 352 g. of trimethyl orthoformate. 173 g. of 3-(4'-chlorobenzoyl)-4-hydroxy-6-methyl-2-pyrone is added and the reaction mixture is gently brought to reflux. The most volatile by-product of the reaction (methyl for~ate) is condensed and collected in -the ~ean-Stark trap. After 28-1/2 hours o~ refl~x the reaction mixture is cooled to room temperature and poured into 6000 ml of brine. The resulting suspension is extracted with methvlene chloride (6 x 250 ml ). Evaporation of the solvent yields 153 cr.
of 3-methoxycarbonyl-6-methyl-2-(4'~chlorophenyl)-4-pyrone,. mp (methylene chloride/ether) = 132C.
Part b:
A 1000 ml flask is fitted with a magnetic stirring bar and a sidear~ addition funnel. 500 ml of methanol, 30 ml of glacial acetic acid and 6~ g. o~ 3-~e~hoxycarbonyl-6-m~thyl-2-(4'-chlorophenyl)-4-pyrone are added. 120 ml. of 70~ aqueous ethylamlne is pl~ced in the addition funnel and added very slowly ~4 hr. addi,tion time~. 5~ ml ~f water is then added followed by 100 ml of concentrated ~Cl (cooling required~. The reaction mixture is allowed to stand undisturbed for 30 minut~s. The bulk of the methanol îs then removed in vacuo leaving 46.1 g. of methyl l-ethyl-6-methyl-2-(4l-chlorophenyl)-4-oxonicotinate.mp (methylene chloride/ether) = 217 -219oc ~xam~le 16:
~6~1 ~. of crude m~thyl 1-ethyl-6-methyl-2-l4 chlorophenyl)-4-~xonicotinate is suspended in 600 ml of 5 aqueous NaO~ solution and warmed to 80-85. Ater 1-1 1/2 hours at this temperature the reaction mixture is cooled f`~ !
~' ~
_~,, _,,_, _,, _, __,_ ~,, _ _ _ _, ,, ... . . .... . . .. -~Z1~32~
and acidified with dilute ~Cl. The resulting solid precipitate is collected by ~iltration, yielding 42 g. of l ethyl-~-methyl~2-(4'-chlorophenyl)-4-oxonicotinic acid, mp (methylene chloride~ether) - 235-237C.
Example 15:
4.64 g. of ethyl beta-ethylamino-4-chlorocinnamate, 4.61 g of technical ~rade diketene and 15 ml of methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The mixture is maintained at room temperature for 137 hours. The methylene chloride i5 removed in vacuo and the residue triturated with ether to yield 3.2 g. of crude ethyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate. mp (215-217C.) Example 15:
6 g. of ethyl beta-ethylamino-4-cblorocinnamate and 12 g. of et~yl acetoa~etate is mixed in a 50 ml 3-neck flask itted with a N2-inlet, magnetic stirring bar, therm~metar and a short-path distillation head (with receiver). The ~eaction mixture is heated (170~) for 10 hours. Ethanol and wa~er is collected in the distillation receiver. The reaction mixture is cooled and ~riturated with ethyl acetate/ether to yield 2.52 g- of athyl 1-ethyl-~-methyl-2 (4'-chlorophenyl)-4-oxonicotinate.
Example 17 Part a __ _ 69 g. o 3-methoxycarbonyl-6-methyl-2-(4'-chloro-phenyl)-4~pyrone, 5~0 ml of metha~ol, 90 ~1 of water and 30 ~1 o~ glacial acetic acid are mixed in a 1000 ml flask fitted with a magnetic stirring bar and a sidearm addition unnel. 1~0 ml of 70% aqueous ethylamine is added over the course of one hour. The reaction ~ixture is then allowed to stand at rocm te~perature for one hour, neutralized with dilute ~Cl and extracted with methylene chloride (2 x 250 ml , ~ x 150 ml ). The organic extracts a~e evapora~ed and th~ residue tri~urated with ether. The f .. . _ _ . . . . _ 73~
- 26 ~
first crop of crystals is pure methyl l-ethyl 6-methyl-2-(4'-chi~rophenyl)-4-oxonicotinate (33.1 (g.). The solid that forms upon further concentration of the mother liquor is pure alpha-[3-ethylamino-2-buteno~l]-be~a~ethylamino-4-S chlorocinnamate~ Yield = 11 g-~ and mp = 144~C (ether).
Part b 7 g~ of alpha-[3-ethylamino-2~utenoyl]-beta~
ethylamino 4-chlorocinnamate, 5.7 ~g- methyl iodide, and 20 ml of methylene chloride are mixed in a sealed flask t and stored ~or 22 hours at zoom temperature. The contents of the flask a~e then poured into a separatory ~unnel and washed with waterO Evaporation of the organic layer leaves 9.4 g.; of oil which is dissolved in 80 ml of tetra-hydrouran- 60 ml. o~ water and 4 mls of tr ifluoroaceticacid i5 then added and the mixture is allowed to ~emain at room temperature for two hours. Suosequent dilution with ` water and e~traction ~ith methylene chloride provides 8~0 g. o~ crude 4~xonicotin~te ester. This ma~erial is then heat~d in 80 ~l of 5% aqueous scdium hydroxide s~lution (85C.2 hrs.) and acidiied t:o yield 2.3 ~. of l-ethyl-5, 6-dimethyl-2- ~4 ' chloropherlyl)-4-oxonicotLnic acid. mp =
240.-242C. (acetonitrile).
~xample 20 8.7 g. of 3-methoxycarbonyl-6-m~thyl-2-(4'-chloro-2~ phenyl~ 4-pyrone is suspendecl i~ 100 ml of methan~l and 10 ml ~f water. In a se~arate~ flask, 7.01 ~g. of glycine, 3.12 g. of sodium hydroxide and 50 ml. of methanol arP
mixed and allowed to stir for 30 minutes to form a solution of the sodium salt of glycine. ~his solution is then added to the pyrone suspension with stirring. The resulting reaction mixture i5 allowed to stir at room temperature for five hours. 80 ml of water and lO ml of concentrated hydrochloriG acid is added. A precipitate forlns within a few minutes. This Ls collected by fil~ration to yiel~ 7.0 ~. o~ methyl 1 carboxymethyl-6-methyl-2-(4'--chlorophenyl) ... .. ... .... .. . . .
~Z~3Z~
~, 4-oxonicotina~e. mp (me~hanol/water) = 224co ExamDle 2 1 4.0 g. of 1-carbox~methyl-6-methyl-2-(4'-chloro-phenyl~-4-oxonicotinate is suspended in 40 g. o~ 5~
aqueous sodium hydroxide solution and heated at 80-85aC. for two hours. The re~ction mixture is cooled and acidified to give a white precipita~e. This precipitate is collecte~ by filtration to yield 2.9 gn o~ 1-carboxymethyl-6-methyl-2-~4'-chlorophenyl)-4-~xonicotinic acid. mp ~C~3CN) =
.1~ 158-162C.
ExamPle 22 Part a 10 g. of 3-methoxycarbonyl-6-methyl-2-(4'-chlo~o-phenyl)-4-pyrone, 1.65 g. glacial ac~tic acid and 100 ml lS of methanol are mixed in ~ 500 ml ~las~ fi~ed with a magnetic stirring bar and sidearm addition funnel. 6.15 g. of allylamine are slowly added (one hour addition time). Three hours later 20 inl of water and 8 ml of concentrated ~Cl are added. This reaction mixture is allowed to stand at room temperature for one hour, then is poured into 400 ml of water and extracted with methylene c~loride (2 x 100 ml ). Remo~al of the s~lvent yields 10 g. of c~ude methyl l-allyl-6~-methyl~2-(~'-chlorophenyl)-4-~xonicotinate.
Part b The crude oxonicotinate ester isolated above is suspended in 80 ml of 5% ,aqueous sodium hydroxide solution and heated at 85C. for 2-2 1/2 hours. Acidification of this reaction mixture with dilute ~Cl provides 6.7 g. of 1 allyl-6-methyl-2~(41-chlorophenyl)-4.-oxonicotinic acid. mp (acetonitrile) = 219- 221 5æL_ 47 6.0 ~ of 1,6~dimet~yl~2-phenyl-4-oxonicotinic acid is suspended in 200 ml of methanol. 1.0 g. of s~dium hydroxide is added. ~s soon as the acid dissolves a 3~5 solution of 5.52 gO of Br2 in 50 n~ of methanol is slowly added with stirring. The pH of the reaction mixture is maintained at 8-9 by the addition of extra sodium hydroxide as required. A precipitate of 3,5-dibromo-1,6-dimethyl-2-phenyl-pyrid-4-one forms. This material is collected by filtration and discarded. ~cidification of the clear filtrate yields 3.4 g. of 5-bromo-1,6-dimethyl-2-phenyl-4-oxo-nicotinic acid as a white solid. mp = 252 -2530C. (acetonitrile) , 73~s `;
B. N alkyl-6-aryl-~-oxonicotinates In another preferred aspect, this invention relates to cffmpounds of .he formula:
R5 ~ C02Y
(X) ~1 ~R2 (XVIII) wherein Rl and R2 are, independently, an optionally sub-stituted (Cl C6) alkyl or a (C3-C6) alkenyl group; Rs is hydrogen or halogen; Y is a hydrogen atom or a (Cl-Cs3 alkyl group; X is a hydrogen atom, a halogen atom, a trihalomethyl group, a (Cl-C6j alkyl group, a nitro group, a cyano group or a (Cl-C6) alkoxy group; n is an integer from 1 to 3;
and the agronomically acceptable salts thereof.
A~ong the preferred compounds of ~-he present invention are compounds of Group 3, Formula XVIII, wherein R~ and R2 are, independently (Cl-C6) alkyl, (Cl-C4) haloalkyl, alkoxy (Cl-C4) alky~ (Cl-C~), aryl ~C6-Clo) alkyl (Cl-C4), or ~C3-C6~ alkenyl; Y is a hydrogen, (Cl-C6) alkyl, or an alkali or alkaline earth metal cation, Rs is hydrogen or halogen, X is hydrogen, h210~en, trihalomethyl, ~Cl-C6) alkyl, ~Cl-C6) alkoxy, nitro or cyano; and n iS a~ integer from ~0 1 ~o 3.
Among the more preferred compounds of the present inven-tion aze compoun~s of Grou? 9, Formula X~lII, wherein Rl and R2 are, independently, (Cl-C4) alkyl; v is hydrogen, CH3, C2ns, Na or K; Rs is hycrogen or bromine; X .s hydrogen, methoxy, metnyl, .rifluoromethvl, iodine, bromine, chlorine or fluorine and n is an integer from 1 to 3 Among the most preferred compounds of this invention are compounas of Group B, Formula XVIII, where Rl is a methyl or e~hyl group; R~ is a methyl, ethyl, or n-propyl group;
~Bt ~Z~7~325 Rs is hydrogen or a bromine a~om; X is hydrogen, methyl, trifluoromethyl; or bromine, chlorine or fluorine atom and n is 1 or 2; and Y is a sodium or potassium cation, hydrogen, or a methyl or ethyl group;.and the agronomically acceptable acid addition salts thereof.
Typical compounds encompassed by the present invention include: ~
1,2-dim~thyl-6-(3~fluorophenyl)-4-oxonicotinic acid;
2-n-butyl-1-ethyl-6-(4-methoxyphenyl)-4-oxonicotinic acid;
1 allyl-6-phenyl-2-n-propyl-4-oxonicotinic acid;.
1-(3-chloropropyl)-2-methyl-6-phenyl-4~oxonicotinic acid;
1-(2-ethoxy methyl)-2 methyl-6 phenyl-4-oxonicotinic acid;
l-~enzyl-2-n-propyl-6-(4-trifluoromethylphenyl)-4-oxoni-cotinic acid;
1,2-di-n-propyl-6-(4-1uorophenyl)-4-oxonicotinic acid;
1,2-dimeth~1-6-phenyl-4- oxonicotinic a~id;
6-(4-chloropheny~)-1,2-~iethyl-4-oxonicotinic acid;
S-bromo-6-(4-chlorophenyl)-1,2-dimethyl-4 oxonicotinic acid;
6-14-chlorophenyl)-1~2~5-trimethyl-4-oxonicotinic acid;
1,5-dimethyl-6~ fluorophenyl)-2-n-p~opyl-4-oxonicotinic acid;
1,2-dimethyl 6~ naphthyl)-4-oxonicotinic acid;
6-(3,5-dichlorophenyl)-1-methyl-2-n-pro.pyl-4-oxonicotinic acid;
5-(4-chlorophenyl)-1-i-propyl-2-methyl-4-oxonicotinic acid;
2-i-propyl-1-methyl-6-phenyl-4~oxonicotinic acid and metal salts thereof;
ethyl 1,2-dimethyl-6-(4~fluorophenyl)-4-oxonicotinate me~hyl 6- (4-chlorophenyl) -1-ethyl-2 met~yl-4-oxonicotinate n propyl l-me~hyl-6-phenyl-2-n-propyl-4-oxonicotinate l-propyl l-allyl-6-(4-bromophen~ 2-methyl-4-oxonicotinate n-butyl 6-(3-chlorophenyl)-1-ethyl-2-n-propyl-4-oxonicotinate n~hexyl 1,2-dimethyl-6-[4-iodophenyl)-4-oxoniootinat~
and ~he agronomically acceptable salts ~hereof.
~7 i ~
.. . . ~ ~
~07325 The Group B compounds of the present i~vention are prepared by various synthe~ic rou~es found in the art. In particular, the Group B ccmpounds of the présent invention can be prepared by the following reaction sequence:
X ~ Ccg2COC285 ~ ~ ~ X
.(XIX) (XX)' OH
~ O (C83C)20, 8254 ~
(~XI) OH 1l ~ COCH3 R NH2 CCH3 H3COH, ~ n CH H3COH
O'~ O (H3C0)3CH > 3 (XXII) ~XXIII) COCH3 1) NaOH ~ ~ COH
N CH X ll c~3 R R
, (~XIV) (XX~) ~ . .. , , ~
Alternatively, the Group B compounds can ~e prepared by the following reaction sequence:
X ~ CCH2COC2H5 + PC13+PC15 ~ ~~~
(XIX) L C-CH3Cl (~XVI) HN ~ ~ R2 ~ Rl~H +R2_ccH COC H
0. 0 ' ' coc2H5 ~ Cl HN R2 (X~VII) (acyclic C-acrylated intermediate) COC2~s g t~ , ~ (XXIX) ~XXVII-I) \ ~ ~ / 1) NaOH
~ n ~ 2 ) ~
.. ~ . .
., ~ . .
.
73;2~i ~ 33 -In the latter reaction sequence, the cyclization step yielded one or more of the pyridones, XXVIII, XXIX and XXX. In general, a pyrolysis (neat) of the acyclicC-acrylated intermediate (XXVlI) ! yielded the oxonicotinic acid (XXX) directly. Cyclization of the acyclic intermediate (XXVII) in aprotic solvents at lower temperatures gave varied results dependin~ on reaction conditions and the X, Rl and ~ substituent effects. In scme cases, mixtures of products were obtained (ester, ester hydrochloride and acid), in other cases only one of the products was isolated.
me salts of the Group B oxonicotinic acids of the present invention can be prepaxed by generally kncwn procedures such as dissolv-ing the acids Ln a protic solvent such as methanol, ethanol, water and the like and treating them with an equivalent amount of a strong base such as sodium or potassium h~droxide and the like, and recovering the salt either by stripping off the solvent or precipitating the solid out with diethylether, hexane, benzene and the like.
Table IV below is presented to illustrate the m~re preferred compounds of the present invention. miS table and Table V
in which the analytical data is presented for these ccmFo~nds are not 2~ to be interpreted in any way as being limits on the breadth and scope of the present invention:
TABLE rv. LIST OF a~ouNDs 2 (XXVIII) ~ l ~...,~
- X
~ _ ., r~ O
V s s _, ~
5 Z 5 ~ E I ; I c~ 1 2 1 1 1 ~ 5 .
O
,C
~ ~ r~ I ~ I o I o I o I ~ I 1` In ' I 1-- 1 ~1 dPI E3 Z ~: Z :s: Z ~: Z V ~ Z ~:
.L~
~ P~
r~ a~ ~ v ~ ~ X x a~ X O ~1 . .... ~V
. .
Q~
~L ~ ~ O ~I ~ W ~ 0 ~1 . .
.
.
V
~ X
O o t~
JJ ~
U~ ,1 s~ ~:
~ I I .1 1 ~ I I I I I I ~ I I t â) . ~
O
S ` `
~ ~5 dP
O
~1 , _ .
:æ ~ æ ~ z ~ z P9 z ~ z ~ ~ z ~ I z IY r ~; ~ ~c) u ~ u ~ v ~ u c~ u c~ c~ u c~ o ~ .
a~ U ~ ~ C~ V C) C~ O ~ ~ O ~
S~
~ u ~ ~ x ~
~1 ~ ) h ~ ~ _I ~ ~ ~ ~ ~ ~ _ 'V ~ ~ ~ ~ H H ~ ~ - O C) I~ C) U C ~ J ` /
C~
a) sUI '1 ~ ~ ~¢
X
~d :
~`~ . , ' .. - ~ ....... . ..
~2~73;~5 -C
o U~
-~, l l l l l l l l l ~; I I I I I I I I, ,_ ..~
o o ~' ....
æ z ~ z;
c.) c.) c.~ c.) c.
~ 1 cl I c ~ 3 ~ ~ u ~ ~ eG
c) u xl ~D 8 c~ æ
~ ~ .
X ~ ~ I~ - ~ -. . r~
~2~73Z5 TAE3LE V p;N~,yTICAL ~TA
~C02Y
( XXV-I I I ) X ~ ~
, ~ ' ' .
~
7;3Z5i Elemental _ Analysis a Example~ ~p (C) %C ~ ~ % ~
4~154 700 ~3 6.32 5.16 71.03 6.39 5.33 49~11 213 ~
502~0-222o5 69.12 5.39 5.76 68.65 5.34 6.1~ -S0 a _ _ __ __ __ _ 51 216- 217 70.02 5.88 S .45 70.26 5.93 5.69 51 a ___ __ _ __ _ 52 ~13 -211 70.83 ~ .32 5.16 70.40 6.29 5.60 52 ~ _ _ __ __ ~_ _ 129-l~o 72.82 7.40 4.47 1~ 53 72033 7.35 4.73 53 a 54 150 70 41 6 ~3 5 19 54 a ___ __ __ __ _ 213-215 70~02 5.88 5.44 69.3~ 5.69 5 ~ 2 55 a ~ 142 64 36 4 635 6 14 6 gi4 56 a 57 198 dec 62.85 5.~8 4.58 6~ ~ 82 5.31 4.~
58 236-238 dec 60.55 4 36 5.Ci4 58a 212-214 dec rl 75 4 84 4 80 59 ~
F~ . . ' , , .
.
~2C~73~
Table (~) (cont.) Elemental AnalYsisa Exam~le mP ~C) % C % ~ ~ N % X
59 -~
-1~7-129 ~5060 6.38 4.03 --6~.78 6.54 4.21 --218-220 a~c 70~02 5.88 5.4 69.75 5.96 5.62 271-2 dec 45.86 3.8~ 3.82 4~.R2 3.22 4.06 --62 29709 dec -~
__ __ _ _ _ ~
~83-4 dec 45.5$ 3.28 3,79 --45.63 3.37 3.79 --.
63 ~300 __ __ __ __ 265-6 dec -- -- -- --6~
226-236 dec 65.92 5.53 5.13 65.29 5.34 5.68 . __ 66 114 48,34 . 4~06 3.76 --48.45 ~.04 3.68 --269-271 dec 52019 3.76 4 ~s --3Q . 52.04 3.69 4.28 ~ ~~
67 294 6 dec ~ .
~ . .
'lZ~'7~;~ 5 Ta~le ( V` (cont.) Recryst. Elemental Analysisa Solvent m~ (C) % C % ~ % N % X
..
68 ~oluene 201-2.5 69.20 5.28 3~67 --68.93-5.29 3.54 ----169-173 67.89 4.56 3.96 --fi7.8 ~.50 4.25 --~ 9 ~
~ 70 --212-214dec 54.33 4.53 3.73 --~3.92 4.65 4.01 220-222dec 57.88 3.89 4.50 ~
58.07 3.8~1 5.3~ --71 ----) 310 ---- --~
_o _ ~ __ __ 72- __212-214dec 67.13 5.63 3~91 --67.20 5~59 3.40 --~-260-3 dec 73.70 5.15 4.7B --73.34 5~14 4.76 --2~ ?i 225-235de~ -- - ~- ~~
X=CI
74- --213-215dec 56.15 5.07 4.09 20.72 55.79 4.g; 4.62 20.34 ~~200-2-dec Poor elemental analysi~
--184-187 62.85 5.28 4.58 --62.03 ~.27 4.89 --76 . --16B-210dec -~
__ __ __ __ -- 121-3 dec 71.56 6.71 4.91 71.67 6~76 5.29 --~, ~ .
73;~5 ~ 41 Table ( vj ~cont.) i . - Recryst. Elemental Analvsisa .
~ ~olvent ~np (C~ ~ C ~ ~ ~ N ~ X
77 80 100 __ __ __ __ __ __ _ CCN 257-8 52.19 3.75 4.35Br 24~81 52.55 3.76 4.36Br 25.18 __ _ _ __ __ __ __ __ __ __ .
.
10 a/ Generally the elemental analysis for the Na salts were either not perforJned ~r gave poor rlesults due to the hygroscop~c nature of the results.
~ ,' . .
~Z[)73~'3 The following examples are presented to illustrate the methods for preparation o the compounds o~ the pres~nt invention. Again these examples are not to be int~rpreted as being limits upon the breadth and scope of the present invention.
~hlorocinnamoyl chloride A solution of 60g ~0.312 mol3 ethyl benzoyl acetate in 96 ml (150~) of phosphorus trichloride is addèd dropwise to lSOg(0.72 mol) Of phosphorus; pentachloride under nitrogen. The suspension that forms is cautiously brought to reflux temperature (ECl evolution observed) and is refluxed and stirred for 2-2 1/2 hrs. The solution that forms is stripped of phosphorus trichloride and ph~sphorus oxychloride at atmospheric pressure (76-82c). The pot residue is distilled at 97-1080G/0.75mm to give 54g ~86% yield) of produck as an isomeric mixture.
~Chloro(4-chloro)cinnamoYlchloride _ _ A solution of 22~67g(0~1 mol) ethyl (4-chloro benzoyl) acetate in 70 ml of phosphorus trichloride is added dropwise to 52~g(0~25 mol) o phosphorus pentachloride under nitrogen ~HCl e~olution ob~3rved). The suspension that forms is stored at room temperature for 1/2 hr. and at reflux tempera~cure for 2 1/2 hrs. The solution that ~orms is stripped of phosphorus; trichloride, phosphorus oxychloride and phosphorus; pentachloride at 80-90C
~pot temperature)/ambient pressure, 90-110C ~po~ temperature) ~ - ~ 0 mm and 90~-130 ~pot temperature)/0.15 mm. A
yield of 23~35g(99%) of crude product is obtained as the pot resi~ue;
. .
~Z~73~5 Ethyl~-methylamino crotonate 186g(1.43 ~oL) of ethyl acetoacetate is added dropwise over a period of 10 min. to a solution of 450 ~l. of methylamine ~40~ in water) in 150 ml. of water (exotherm from room temperature to 55C observed). The mixture is stirred at room temperature for 2 hrs. and is extracted ~ith chloroform. The chloroform extract is washed with water, dried over magnesium sulfate and concentrated ~n vacuo. The residue oil is vacuum distilled at 76-83C/0.1 mm to afford 143.6g(70~ yield) of yellow oil.
Ethyl 3-methylamino-2-hexeneoate A solution of 31.649(0.2 moL) ethyl butyryl acetate and 5 ml~ of ethanol is added dropwise ~ver a period of 5 min. to a solution o~f 38.7g(0.6 mol) ethylamine (70~ in water) and 50 ml o water (exotherm from 28C to 33C ob-served). The mixture is stirred at room temperature for 18 hrs. and is extracted with three 100 ml por~ions of methylene dichloride (MDC). The methylene dichloride ex-tract is dried over magnesium sulfate and concentrated in vacuo to af~ord 30.7g(83~ yield) o product, a colorless oilO
Example 48 Eth~l 1,2-dimethYl-6-~henYl-4-oxonicotinate .
2.0gl0.0065 mol.) of ethyl l,Z-dimethyl-6-ph~nyl-4-oxonicotinate hydrochloride (see Example 2 below3 is dis-solved in water and treated with dilute sodium hydroxide (p~ adjusted to about 8). The precipitate formed is isola~ed by vacuum filtration to afford l.gg of product, mp 154C (MDC/ether recrystallization)~
~ æ~ 9 .
Ethyl l r 2-dimethyl ~ -oxoni otinate Hydrochloride 9O2~(0~046 mol~ of ~-chlorocinnamoyl chloride (iso mer mixture)l di5solved in 75 ml of methylene dichloride is ~dd~d dropwise ~o a solution of 6~g(0.046 mol) of ethyl ~-methylaminocrotonate and 7.4g(0.0937 mol) of pyridin~ in 100 ml or methylene dichloride under nitrogen . . .
_ 44 -(5 min. addition time, slight exotherm from 25 to 35 C.
The reaction mixture is allowed to stand for 1 1/2 hrs.
I The methylene dichloride layer is isolated and passed through a 2 inch column of silica gel. The column is eluted with an additional 200 ml of methylene dichloride and the light yellow colored eluate is concentrated in vacuo to yield 15g of ethyl 2-(3-phenyl-3-chloro) acrylyl-3-methylamino crotonate, an oil.
15q (0.0488 mol) of e~hyl 2~(3-phenyl-3-chloro) acrylyl~-methyl aminocrotonate is suspended in 150 ml of xylene and refluxed for 3 hrs. The reaction mixture is cooled and the sus~ension is vacuum filtered. The filter cake i5 dried ~o afford 5.79(38% yield) of product, mp 211-213C.
lS Example 50 J
Sodium 1~2-di~ethyl-6-phenYl-4-oxonicotinate 42g (0.1366 mol) o~ ethyl 2-(3-phenyl-3-chloro) acrylyl-3-methyl aminocrotonate is placed in a flask and beated to 140C under nitrogen (nil:rogen sparge started at this time). The pot temperature was slowly raised to 157C over a period of 40 min. The~ rea~ion mixture was cooled and extracted into 5~ aqueous sodium hydroxide.
Acidification o the basic extracts provided lO~g (30%
yield) of 1,2-dimethyl-6-phenyl-4-oxonicotinic acid, mp Z5 220-225~C (MDC/ether).
15g (0.01617 mol) of 1,2-dimethyl-6-phenyl-4-oxonico-t ~ic acid is suspended in 200 ml of methanol and to it there is added 2.71g (0.0678 mol) of sodium hydroxide pelle~s. The solution formed is concentrated in vacuo to afford 159 (92% yield) of proauct.
Example 54 Sodium_l-methyl-6-~henyl -2-pro~yl-4-oxonicotlnate A solution of 11.4g (0.057 mol) k-chlorocinnamoyl chloride and 75 ml of methylene dichloride is added over a period of 20 min~ to a solution of 8.6g (0.054 mol) ethyl 3-methylamino-2~hexenoa~e, 9.0g (0.114 mol) pyridine ~2~73Z~
. ' ' .
and 100 ml of methylene dichloride under nitrogen (slight ', exotherm from 25-36C). The mixture is allowed to stand at room temperature for 1 1/2 hrs. and is washed with water. The methylene dichloride solution is passed through a 2 inch column of silica ~el and is concentra~ed in vacuo to afford 13g of ethyl ~3-phenyl-3-chloro~acrylyl-3-methylaminæ-hexeneoate, an oil.
13g (0.0387 mol) of ethyl ~3-phenyl-3-chloro~ acrylyl-3-methyl-amino-2 hexeneoate is dissolved in 200 ml of xylene and is refluxed and stirred for 4 hrs. The solu-tion is washed with 30 ml of 6N hydrochloric acid. The aqueous washings are neutralized and the precipitate formed is isolated to afford 4O5g of ethyl 1-methy~6-phenyl-2-propyl-4-oxonicotinate.
4.5g (0.015 mol~ of ethyl 1-methyl-6-phenyl-2-propyl-4-oxonic¢inate is suspended in 60g of 5~ sodium hydroxide in a 1:1 mixture of methanol and water. The mixture is heated at 85C and stirred fo~ 2 1/2 hxs. The solution formed is acidified and the suspension formed i5 vacuum filtered. ~he filter cake is dried to afford 2.7g of 1-methyl~6-phenyl-2-propyl-4-oxonicotinic acid, mpll50C
(MDC/ether). An additional 0.59 o~ 1-methyl-6-phenyl-2-propyl 4-oxonicotinic acid is obtained by extraction of the xylene solution with 30 ml of 1% sodium hydroxide and acidification of the basic extract.
- 2.19 (0.0067 mol) of 1-methyl-6-phenyl-2-propyl-4-oxonicotinic acid is suspended in 50 ml of methanol and to it there is added 0.295g (0.0074 mol) of sodium hydro-xide pellets. The solution is concentrated in vacuo to afford l.9g (97% yield) of product.
- Exam~lê 57 .
yl ~-(4-chlorophenyl)-1,2-dimethyl-4-oxonicotinate A solution of lOg (0.04~5 ml) ~-chloro~4-chloro) cinnamoyl chloride in 50 ml of methylene dichloride is added dropwise over a 10 min. period to a solution of 6.08g ~0.04~5 mol) ethyl ~-methylaminocrotonate, 6.72g (0.085 mol) of pyridine and 200 ml of methylene dichloride ~Z~32~i _ 46 -(slight exotherm from 25 to 34C). The mixture is stirred at room temperature for 18 hrs. and is washed with water.
The methylene dichloride solution is vacuum filtered through 25g of silica gel and the filtrate is concentrated in vacuo to aford 12~55g of ethyl [3-(4-chlorophenyl)~3-chloro] acrylyl-3-methylamino-crotonate, an oil.
A solution of 12.55g (0.037 mol) ethyl [3-(4-chloro-phenyl)-3-chloro] acrylyl-3-methylamino crotonate in 50 ml of xylene is refluxed and stirred for 2 1/2 hrs. under nitrogen. The suspension formed is vacuum filtered to afford 6.5g (52~ yield) of ethyl 6-(4-chlorophenyl~-1,2-dimethyl-4-oxonicotinate hydrochloride (Example 27~.
A suspension of 6.5g (0.019 mol~ ethyl 6-(4-~hloro-phenyl)-lt2-dime~hyl-4-oxonicotinate hydrochloride in 150 ml of water is treated with sodium hydroxide tpH adjusted to about 8). The suspension formed is vacuum filtered and the filter cake is washed with water and dried to afford 4.~9 (43.3% yield) of product, a white solid, mp 198C dec (Toluene).
_ample 58 Sodium 6-(4-ChloroP~yl)-l,2-dimethyl-4-oxonico~inate 1.5g (0.019 mol) of 50% aqueous sodium hydroxide is added to a suspension of 2.9g ~0.0095 mol) ethyl 6-(4-chlorophenyl)-1,2-dimethyl-4-oxonicotinate in 75 ml of water. The mixture is refluxed and stirred for 15 min.
and cooled to room temperature. The solution is extracted with methylene dichloride and the aqueous solution is acidifi~d to pHl with 12N hydrochloric acid. The suspen-sion formed is vacuum filtered and the filter cake is dried to afford 1.8g (68% yield) of 6-(4-chlorophenyl)-1,2-dimethyl-4Oxonicotinic acid, mp 236-238C dec. I
0.52g (0.0065 mol) o 5D% aqueous sodium ~Ydroxide is added ~o a suspension of 1.8g (0.0065 mol) 5-(~chlorophenyl)-1,2-dimethyl-4-oxonicotinic acid in 35 ~ 1 of meth~nol.
The solu~ion formed is allowed to stand at room temperature ,, , , , `
~2~73,~5 ~ 47 -for 1 hr. and then is concentrated in vacuo. The con-centrate is washed with two (25 ml) portions of diethyl ether and dried to afford 1.79 (87% yield) of product.
~xample 67 Sodium 6-(4-BromophenYl)-1,2-dimethyl-4-oxonicotinate A solution of 12g (0.043 mol) ~-chloro(4-bromo) cinnamoyl chloride in 25 ml of methylene dichloride is added dropwise over a 3 min. period to a solution of 6.15g (0.043 mol.) ethyl ~methylamino crotonate, 6.8g (0.086 mol) of pyridine and 200 ml of methylene dichloride (slight exotherm from 25C to 33C). The solution is stirred at room temperature for 3 days and is washed with 200 ml of water. The methylenP dichloride solution is vacuum filtered through 25g of silica gel and the fil-trate is concentrated in vacuo to aford llg (66~ yield) of ethyl ~3-(4-bromophenyl)-3-chloro~ acrylyl-3-methyl-amino crotonate, a brown oil.
119 (0.0284 mol) of ethyl [3-(4-bromophenyl)-3-chloro3 acrylyl-3~m~thylamino crotonate is dissolved in 10 ml of toluene and 50 ml of xylene and is re~luxed and stirred for 4 hrs. under nitroyen. The suspen~ion formed is stirred at room temperature for 18 hrs. and is vacuum filtered~ The filter cake is washed with hexane and dried to afford 5~3g (48.%) of ethyl 6-(4-bromophenyl)-1,~dimethyl-4-oxonicotinate h~drochloride, mp 206-210C dec.
5.3g (0.~14 mol) of ethyl Ç-~4-bromophenyl)-1,2-dimethy~4-oxonicotinate hydrochloride is suspended in 100 ml of water and to it there is added 5g (0.0625 mol) of 50% aqueous sodium hydroxide. The mixture is refluxed and stirred for 1 hr. and the solution formed is cooled to room temperature. The solution is extracted with methylenedichloride and the aqueous solu~ion is acidified to pH lwith 12N hydrochlorio acid The suspension formed is vacuum filtered and the filter cake is washed with water and dried to afford 4g (89% yield) of 6-(4-bromo - phenyl~-1,2-dimethyl-4-oxonicotinic acid, mp 269-271C
dec.
~ ' i ~L2073~5 . 48 _ 2g (0.0062 mol) of 6-(4-bromophenyl)-1,2-dimethy~4-oxonicotinic acid is suspended in 50 ml of methanol and to it there is added 0.5g (0.0062 mol) of 50~ aqueous sodium hydroxide. The solution formed is allowed to stand at room temperature for 1 hr. and is concentrated in vacuo~ The concentrate is washed with 50 ml of diethyl -ether and dried to afford l.9g (89% yield) of product.
Example 75 I Ethy~6-(4-chlorophenyl)-l-methyl-2-n-propyl-4-oxonicotinate h~drochloride A solution of 15g (0.064 mol) ~-chlor~ (4-chloro) cinnamoyl chloride in 50 ml of methlene dichloride is added dropwise over a 3 min. period to a stirred solution of lO.9g (0.064 mol) ethyl 3-methylamino-2-hexeneoate and lO.lg (0.128 mol) of pyridine in 200 ml of methylene dichloride ~slight exotherm from 25C to 34C). The solution formed is stirred at room temperature for 18 hrsO and is washed with water. The methylene dichloride solution is vacuum filtered throu~lh silica gel and the filtrate is concentrated in vacuo to afford 18.5g (78%
yield) of ethyl ~3-(4-chlorophenyl)-3-chloro3 acrylyl-3-methylamlno~2-hexeneoate, a brown oil.
A solution of 18.5g (0.05 mol) of ethyl [3-(4-chloro-phenyl)-3-chloro] acrylyl-3-methylamino-2-hexenéoate in 15 ml of toluene and 60 ml of xylene is refluxed and stirred for 3 hrs. under nitrogen. The suspension formed is allowed to stand at room temperature for 8 days and is v~cuum filteredO The filter cake is washed with toluene and hexane and dried to afford 4.3g (23% yield) of product, mp 200-202~ dec.
Example 76 - ~
-Sodium 6-(4-chlorophenyl)~l-methyl~2-~-pro~yl-4 oxonicotinate 4.09 (0.0 5 mol) of 50~ aqueous sodium hydroxide is added to a suspension of 2.7g (`0.01 mol) ethyl 6-~4-` 35 chlorophenyl)-1-methyl-2~n-propyl-4-oxonicotinate hydrochloride in S0 ml of water and 10 ml of ethanol. The mixture is refluxed and stirred ~or 3 hrs, allowed to 5tand at room .
~2~73~5 . 49 temperature for 18 hrs., refl'uxed for an additional 1 hr.
and cooled to room temperature. The solution formed is extracted with three 50 ml portions of methylene dichloride I and the aqueous solution is acidified to pH 1 with 12N
hydrochloric acid. The suspension formed is stirred at room temperature for 3 hrs. and is vacuum filtered. The filter cake is dried to afford 1.65g (54% yield) of 6-(4-chlorophenyl)-~methyl-2-n-propyl-4-oxonicotinic acid, mp 184-187C.
0.42g (0.0052 mol) of 50% aqueous sodium hydroxide is added to a suspension of 1.6g tO.0052 mol) 6-(4-chloro-phenyl)-l-methyl-2-n-propyl-4-oxonicotinic acid in 25 ml of methanol. The solution formed is allowed to stand at , room temperature for 1 hr. and is çoncentrated in vacuo.
15 The concentrate is dried to aord 1.5g (88~ yield3 of Product .
ExamPle 78 Sodium 5-Bromo-1,2-dimethyl-6-phenyl-4-oxonicotinate 2.0 g (0.0125 mol~ of bromine dissolved in 50 ml. of methanol is added dropwise over a l5 min. period to a solution of 2.7 g (0.00877 mol) ethyl 1,2-dimethyl-6-phenyl-4-oxonicotinate hydrochloride (Example 2) in 15 ml 'of methanol and 15 ml of water. The suspension formed is vacuum filtered and the filter cake, a yellow solid, is suspended in 60 9 of 5% a~ueous sodium hydroxide. The mixture is stirred and heated at 85C for 2-1/2 hrs. and is acidified with hydrochloric acid. The suspension formed is vacuum filtered to afford 2.4 9 (85~ yield) of 5-bromo-1,2-dimethyl 6-phenyl-4-oxonicotinic acid, mp 257-258C (CH3CN)-2.1 g (0.065 mol) of 5 bromo-1,2-dimethyl-6-phenyl-4-oxonicotinic acid is suspended in 50 ml of methanol and to it there i~ added 0.29 g (0.007 mol) of sodium hydroxide pellets. The solution formed is concentrated in vacuo to afford 2.1'g (94% yield) of product.
I
, . ~Z~
C~ N-alkyl-5-aryl-4-oxonicotinates In yet another preerred aspe~t, this lnvention relates to compounds of the formula:
(X)n ~ c~Z,y 6 ~ /~2 (X~XI) .
wherein Rl is an ~ptionally substituted (Cl-C6) alkyl group; R2 is a (Cl-C~) alkyl gxoup; R6 is a hydrogen atom or a (Cl-C4) alkyl group; Y is a hydrogen atom or a (Cl-C6) alkyl group or radical; X is a hydrogen atom, a halogen atom, a trihalomethyl group, a (Cl-C6) alkyl group, a nitro group, a cyano group or a (Cl-Cg) alkoxy group; and n is the integer 1 or 2; and the agronomically acceptable salts thereof.
Among the pre~erred compounc~s of the present inven-tion are compounds of Group C, Formula (X~XI) wherein Rl and R2 are, independently, ~Cl-C6) alkyl, (Cl-C4) haloalkyl, alkoxy ~Cl-C4) alkyl (Cl-C~), aryl ~C6-Clo) alkyl (Cl C4), or ~C3-C6) alkenyl; Y is hydrogen, ~Cl-C6) alkyl, or an alkali or alkaline earth metal cation; R6 is hydrogen~(Cl-C4) alkyl -: X is hydrogen, halogen, trihalomethyl, (Cl-C6) alkyl, ~Cl-C6) alkoxy, nitro or cyano; and n isthe integer 1 or 2.
Among the more preferred compounds o~ the present invention are compounds of Group C, Formula (XXXI) wherein Rl is (Cl C6) alkyl, R2 is (Cl-C3) alkyl; R6 is hydrogen or (Cl-C4) alkyl, Y is hydrogen, methyl, ethyl or a sodium or potassium cation, X is hydrogen, (Cl-C6) alkyl or F~
.
.
~ILZ~73;25 halogen and n is the integer 1 or 2.
I Among the most preferred compounds of this invention are compounds of Group C, Formula (XXXI) wherein Rl is a methyl or ethyl group; R2 is a methyl group; R6 is a hydrogen radical or a methyl group; and Y is ethyl or a sodium or potassium cation; and the agronomically acceptable acid salts thereof~
, ~2'C~732S
Typical compounds encompassed by the present invention include:
1 1,2-dimethyl-5-phenyl-4-oxonicotinic acid l-ethyl-2-methyl-5 phenyl-4-oxonicotinic acid 1,2,6-trimethyl-5-phenyl-4-oxonicotinic acid 1,2-diethyl-5-phenyl-4-oxonicotinic acid 2-ethyl-1-methyl-5-phenyl-4-oxonicotinic acid 1,2-dimethyl-5-(4-chlorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(4-chlorophenyl)-4-oxonicotinic acid 1-ethyl-2,6-dimethyl-5-(4-chlorophenyl)-4-oxonicotinic acid 1,2-diethyl-5-(4-chlorophenyl)-4-oxonicotinic acid 1,2-dimethyl-5-(3-chlorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(3-chorophenyl)-4-oxonicotinic acid 1-ethyl-2,6-dimethy~-5-(3-chlorophenyl)-4-oxonicotinic acid .
.., ,. , . _,:
,.. .
1-ethyl-2-methyl-5-(4-trifluoromethylphenyl)-4-oxonico-tinic acid ~ dimethyl-5-(4-fluorophenyl)-4-oxonicotinic acid 1-éthyl-2-methyl~5-~4-~luorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(3 fluorophenyl) 4-oxonicotinic acid l-~thyl-2-methyl-5-(4-bromophenyl)-4. oxonicotinic acid 1,2-dimethyl-5-(3,4-dichlorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(3,4-dichlorophenyl)-4-oxonicotinic : 25 acid 1,2,6-trimethyl-5-(3,4-dichlorophenyl)-4-oxonicotinic acid 1,2-diethyl-6~methyl 5-(3,4-dichlorophenyl)-4-oxonicotinic acid i ~L2~732~
2-ethyl-1,6-dimethyl-5-(3,4-dichlorophenyl)-4-oxonicotinic aoid l-ethyl-2-methyl-5-(2,4-dichlorophenyl)-4-oxonicotinic acid 1-ethyl-2-methyl-5-(4-methylphenyl)-4-o~onicotinic acid and the agronomically acceptable salts thereof.
The compounds of the present invention can be prepared by various synthetic routes found in the art.
Tables VI and VII below are presented to illu5-trate the more preferred compounds of this aspect of the presentinvention and related compounds and the analytical data for these compounds.
General Syntheses O, R2~C02Et ~ RlN~3i2 .. ~ C02Et lnert so vent ¦ ~
~ 2 St~p 2 _ ~ ~ ~
inert solvent X R2 optional acid acceptor Rl ~C33 P ~ ~ ~I R2 CH3 ~1 DMF, Et3N
Step 4 1) Na~H, H20, ~ ~
....... _ __ ~ X~-- C02H
2) H~
, 732~i - 53a -Ste~ 2 :
1) MCC, benzene, ether other inert solvent 2) acid acceptor cptional 3) 0 - 100, pref 0-50 ~:
1) DMF solvent, excess amide acetal 2) basic catalyst optional (Et3N) 3) 20-150, pref 50-100 ~:
1) aqueous NaOH, Na2C03 other bases 2) cptional miscible co-solvent (EtOH,MeOH) 3) acidification with HCl, H2SO4 etc~
:~L2~73~
TABLE VI - List of Group C Compounds X{~ co2Y
Rl Example ' Xl Rl R2 6 Y
_ _ _ _ 79 H H H Me Et H H H Me H
80a H H H Me Na 81 H Et H Me H
81a H Et H Me Na 82 H Me Me H Et 108 3 H Me Me H H
83a H Me Me H Na 84 H Et Me H H
; 84a H Et Me H Na H Et Me Me H
1585a H Et Me Me Na 86 H H Me Me H
. 86a H H Me Me Na 8 7 4-Cl Me Me H
8 8 4-Cl Me Me H H
208 8 a 4-Cl Me Me H Na 89 4-Cl Me Me Me H
89a 4-Cl Me Me Me Na 4-Br Me Me H H
90a 4-Br Me Me H Na 25 91 4-Br Me n-Pr H H
91 a 4-Br Me N-Pr H Na 92 4-Br n-Hex Me H H
9 2 a 4-Br N-Hex Me H Na 9 3 4-Br Me Me Me H
309 3 a 4-Br Me Me Me H
.
TABLE VI contd 55 Example Xl Rl 2 6 9 4 4-C1 0 Me H H
9 4 a 4-C1 0 Me H Na 9 5 H 4-Fp Me H Et 9 6 H 4-Fp Me H H
9 6 a H 4-F0 Me H Na ~Z~732S
TABLE VII - Analytical Data - Group C Compounds Example mD(C) %C ~H %N %X
79 178-180 -- _ _ 26~- 267 80a -- --81a -- -- --82 148- 150 70.83 6.32 5.16 70.71 6.gO 5.23 83 227-228 69.12 5.34 5.76 68.80 5.51 6.07 83a -- ~
84 167-170 70.02 5.88 5.4~ --70.04 6.04 5.57 84a -- -- -- -- --163- 16S 70.83 6.31 5.16 70.78 6.49 5.82 85a ~ _ 86 272- 273 69.12 5.39 5.76 69.00 5.41 5.95 86a -- ~ -- -- -- ~
87 200-201 62.85 5.28 4.5~ 11.60 63.14 5.33 4.79 11058 88 239- 240 6Q~5 4.36 5.04 12.77 60.33 4.27 5.28 12.82 88a -- -- -- --89 240- 243 61.75 4.84 ~L.80 12.16 52.13 4.90 4.96 12.26 39a _ _ _ _ _ 266- 268 52.19 3.75 4.35 24.81 52.32 3.69 4.33 34.75 90a -- -- -- --91 237-239 5~.3~ 4.61 4.00 22.82 55.22 4i68 ~.21 22.21 91a ~
92 148- 150 58.17 ~.65 3.57 20.37 57.86 5.51 4.51 20.23 92a ~
93 228- 230 53.59 4.20 4.17 23.77 53.65 ~19 4.64 23.34 ~ ~-J
~2~73~5i TABLE VI I con td .
E~xample mD(C) %C % H %N ~X
93a ~ ~
94 208- 209 ~7.16 4.15 4~12 10.44 67.4g 4.16 4~37 10.65 , 94~ _ _ _ _ 1~9- 181 71.78 5.16 3.99 5.41 71.38 5.26 4.07 5~25 96 19?- 198 70.58 4.36 4.33 5.88 70.32 4.25 4.56 5.8Q
96a ~2~37325 The following examples are presented to illustrate the methods for preparation of the Group C compounds of the present invention.
Experimental Procedures Example 79 The following procedure is a modified version of one reported by Kametani, et al., J. Het. Chem., 1977, 4, 477.
25 g. of diethyl aminomethylenemalonate, 18 5.
of phenylacetone dimethylketal, 300 ml. of dry diphenyl ether and 1.0 g. of TSA.H2O were mixed and heated under a nitrogen atmosphere at 135-145C. for three hours. The mixture was then brought to reflux. After 3Q minutes the solution was cooled and extracted with 200 ml. of 2-1/2%
aqueous NaOH solution. The basic extracts were acidified yielding a precipitate of ethyl 6-methyl-5-phenyl-4-oxo-nicotinate. Recrystallization of this material from methylene chloride/ether provided 12.3 g~ of white solid, m.p.~178-180C.
E ampie 80 4.0 g. of 6-methyl-5-phenyl-4-oxonicotinate was suspended in 40 g. of 5% aqueous NaOH solution. This_ suspension was heated at 85-90C. for ~hree hours, cooled, acidified. The resulting precipitate of 6-methyl-5-phenyl-4-oxonicotinic acid was dried and recrystallized from acetoni~rile. Yield = 2.3 g.; m.p.=265-267C.
Exam~le 80.~
2.31 g. of 6-methyl-5-phenyl-4-oconicotinic acid was mixed with 0.44 g. of NaOH and 50 ml. of methanol.
~vaporation of the solvent provided 2.4 g. of sodium 6-methyl~5-phenyl-4-oxonicotinate as a glassy solid.
Example 81 Part A
Ethyl 1-ethyl-6-methyl-5-phenyl-4-oxonicotinate was prepared according to the procedure described by Kametani, et al., J. Het. Chem., 1977, 14, 477.
~7~2~;
Part B
, Crude ethyl l-ethyl-6-methyl-5-phenyl-4-oxonicotinate was suspended in 80 g. of 5~ aqueous NaOH solution and heated on a steambath for one hour. Acidification of the aqueous mixture gave 1-ethyl-6-methyl-5-phenyl-4 -oxonicotinic acid as a whlte precipitate (3.3 g.). Recrystallization ~rom acetonitrile provided material melting at 177-1~8C.
Exam~le 3A
3.13 g. of 1-ethyl-6-methyl-5-phenyl-4-oxonicotinic acid, 0.54 g. of NaOH and 50 ml. of methanol were mixed.
Evaporation of the solvent provided 3.7 g. of glassy sodium l-ethyl-6-methyl-5-phenyl-4-oxonicotinate.
Example 82 Part A
16.S g. o~ ethyl ~-methylaminocrotonate, 9.3 ml.
of pyridine and 300 ml. of me-thylene chloride were mixed in a ~lask itted with a magnetic stirring bar, a sidearm addition funnel and a CaC12 drying tube. 18.3 g. of phenyl-acetyl chloride was slowly added. Two hours later the reaction mixture was poured into water. The organic layer was separated and e~aporated yielding 30 g. of crude ethyl 3-oxo-4-phenyl-2-(methylamino-ethylidene) butyrate as a yellow oil.
Part B
13.1 9. of crude ethyl 3-oxo-4-phenyl-2-(methyl-amino-ethylidene)butyrate~5.95 g. of dimethylformamide dimethyl ac~tal and 25 ml. of dry dimethylformamide were heated to 80C. under a nitrogen atmosphere for 19 hours.
2.0 ml. of trie~hylamine and an additional 5.95 g. of di-methylformamide dimethyl acetal were added and the reaction was heated at 80C. for another 6 hours. The reaction ~as cooled, poured into water and extracted with methylene chloride. The organic extract~ were thoroughly washed with water and dilute HCl and evaporated. The residue of ethyl 1,2-dimethyl-5-phenyl-4-oxonicotinate was triturated with ether and recrystalli~ed from methylene chloride/ether.
Yield=3,2 g.; m.p.=148-150C~
., I
.
73~5 Exam~l~ 83 _ 5.8 g. of ethyl 1~2-dimethyl-5-phenyl-4-oxonicotinate was suspended in 60 ml. of 5% aqueous NaOH solution and heated on a steambath for 2-l/2 hours. The mixture was cooled and acidified. The resulting solid was recrystallized from acetonitrile to yield 1,2-dimethyl-5-phenyl-4-oxonicotinic acid as 'an needles. m.p.=227-228C.
Ex _~_e 83A
1.69 g. of 1,2-dimethyl-5-phenyl-4-oxonicitonic acid was mixed with 0.31 g. of NaOH and sn ml. of methanol.
Evaporation of the solid provided l.9 9. of sodium 1,2-dimethyl-5-phenyl-4- o~nicotmate as a glassy solid.
Example 85 Part A
42.4 g. of ethyl ~-ethylaminocrotonate, 23.7 g. of pyridine and 700 ml. of methylene chloride were mixed.
46.4 g. of phenylacetyl chloride was added slowly with stirring. Three hours later the mixture was poured into water and the organic layer was separated and evaporated yielding g9 g. of ethyl 3-oxo-4-phenyl-2-(ethylamino~
ethylidene) but~rate as a yellow oil.
Part B
13.8 g. of 3-oxo-4-phenyl-2-(ethylaminoethylidene) butyrate, 13.3 g.`of dimethylacetamide dimethyl acetal, 25 g. of dry dimethylformamide and 2 ml. of triethylamine were heated at 75-80C. under nitrogen for 24 hours. The reaction mixture was cooled and poured into 600 ml. of water. The aqueous suspension was acidified with HCl and extracted with methylene chloride. Evaporation of the solvent provide 10.5 g. of crude ethyl l-ethyl-2,6-dimethyl-5-phenyl-4-oxonicotinate as a brown oil.
Part C
10.5 g. of crude ethyl 1-ethyl-2,6-dimethyl-5-phenyl-4-oxonicotinate was suspended in lOO g. of 5% aqueous NaOH solution and heated on a steambath for 2 hours. The reaction mixture was c0012d and acidified. Extraction with . ' .' I
methylene chloride and subsequent evaporation of the solvent yielded 3 g~ of 1-ethyl-2,6 dimethyl-5-phenyl-4~oxonicotinate.
Recrystallization from acetonitrile provided material with a melting point of 163-165C.
ExamPle 8SA
1.5 g. of 1-ethyl-2,6-dimethyl-5-phenyl-4-oxo-nicotinate, 0.24 g. of NaOH and 40 ml. of methanol we~e mixed. Evaporation of the solvent provided 1.4 g. of sodium l-ethyl-2,6-dimethyl-5-phenyl-4-oxonicotinate as a glassy solid.
Example 86 Part A
2.68 g. of diethyl aminoethylidene malonate, 18 g.
of phenylacetone dimethyl ketal, 1 g. of toluenesulfonic acid lS monohydrate and 300 ml. of diphenyl ether were heated at 180C. for 2 hours. Methanol and ethanol began to distill out of the reaction flask and was collected in a Dean-Stark trap. The reaction mixture was then allowed to heat up to 205 C~ for an additional 3 hours. A solid formed upon cooling.
This was collectedby filtratloni yielding 4.6 g. of ethyl 2,6~dimethyl-5-phenyl-4-oxonicotinate.
Part B
4.0 g. of ethyl 2,6-dimethyl-5-phenyl-4-oxo-nicotinate was suspended in 40 g~ of 5~ aqueous NaOH solution 2S and heated on a steambath for 2 hours. The mixture was cooled and acidified, yielding 3.2 g. of 2,6-dimethyl-5-phenyl-4-oxonicotinic acid. Recrystallization from methanol provided material with a melting point of 272-273C.
(decomposition).
~xample 8ÇA
1.53 g. of 2,6-dimethyl-5-~henyl-4-oxonicotinic acid, 0.23 g. of NaOH and 50 ml. of methanol were mixed.
Evaporation of the solvent provi.ded 1.53 g. of sodium 2,6 dimethyl-5-phenyl-4-oxonicotinate as a glassy sold.
.. . .. . . . _ .. .
3;~5 Example 87 Part A
42.9 g. of ethyl ~ -methylaminocrotonate, 25 gO
~ of pyridine and 600 ml. of dry methylene chloride were mixed. 56.7 g. of 4-chlorophenylacetyl chloride was added with stirring. Three hours later the reaction mixture was poured into 300 ml. of water. The methylene chloride layer was separated and evaporated yielding 91 g. of crude ethyl 3-oxo-4-(4'-chlorophenyl)-2-~methyla~inoe-thylidene)butyrate as a light yellow oilO
Part B
59.16 g. of ethyl 3-oxo-4-(4'-chlorophenyl)-2-(methylaminoethylidene)butyrate was heated at 80-85C. with 48 9. of dimethylEormamide dimethyl acetal, 100 ml. o~ dry lS dimethylformamide and 8 ml. o~ triethylamine. After 19 hours, the mixture was cooled, poured into 1000 ml. of water, acidified with dilute HC1 and extracted with methylene chloride. Evaporation of the solvent provided ethyl 1,2-dimethyl-5-(4'-chlorophenyl)-4-oxonicotinate as a white solid. m.p=200-201C. ~acetonitrile).
Example 88 Approximately 30 g. of ethyl 1,2-dime~hyl-5 (4'-chlorophenyl)-4-oxonicotinate was suspended in ~00 g~ of 5% aqueous NaOH solution. 300 ml. of methanol was added and the mixture was refluxed for 7 ho~rs. The ~esulting solution was cooled and acidified to yield 18~9 g. of 1,2-dimethyl-5-(4'-chlorophenyl)-4-oxonicotinic acid as a white solid, m~p.=239-240C. (acetonitrile).
Example 88~
18.5 g. of 1,2-dimethyl-4-(4'-chlorophenyl)-4-oxonicotinic acid was mixed with 2.93 g. of NaOH and 200 ml.
of methanol. Evaporation of the solvent provided 19.0 9.
of sodium 1,2-dimethyl-5-(4'-chlorophenyl)-4-oxonicotinate as a glassy s~lid.
~L2~7325 Exam~le 89 - - -Part A
14.8 g. of ethyl 3-oxo-4(4'-chlo.ophenyl)-2- --~
(methylamino-ethylidene) butyrate~lo 9. of dimethylacetamide dimethyl acetal, 25 ml. of dry dimethylformamide and 2 ml.
of triethylamine were heated at 85C. for 22-1/2 hours.
The reaction was cooled, poured into 400 ml. of water and extracted with methylene chloride. Evaporation of the solvent provided an oily residue of ethyl 1,2,6--trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate.
Part B
13.0 g. of crude ethyl 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate was suspended in 130 ml. of 5% NaOH in 1:1 methanol/water and refluxed for 6 hours.
The reaction mixture was cooled and acidified. Extraction of this material with methylene chloride provided 1.8 g.
of 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinic acid.
m.p. (acet~nitrile) 240-243C.
Example 87A
1.8 9. of 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate, n . 27 g. of NaOH arld 50 ml. of methanol were mixed. Evaporation of the solvent provided 1.9 g. of sodium 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate as a glassy solid.
Example 90 Part A
24.6 9. of ethyl ~-methylaminocro~onate waC mixed with 250 ml. o~ methylene chloride and 16 ml. of pyridine.
40 g. o 4-bromophenylacetyl chloride was added wi~h stirring.
2~1/2 hours later, the reaction mixture was poured into water. Separation of the organic layer provided 60.6 g.
of ethyl 3-oxo-4-~4'-bromophenyl)-2-(methylamino-ethylidene) bu~yrate after evaporation.
Part B
17 g. of ethyl 3-oxo-4-(4'-bromophenyl-2 (methyl-amino-ethylidene bUtyrate, 12 g. of dimethylformamide dimethyl .
73;~i acetal, 25 ml. of dry dimethyl formamide and 2 ml. of tri-ethylamine were heated under dry nitrogen at 85C. for 19 hours. The reaction mixture was cooled, poured into 500 ml.
of ~2~ acidified with dllute HCl and extracted with methylene chloride. Evaporation of the solid provided 14.3 g. of crude ethyl 1,2-dimethyl-5-14'-bromophenyl)-4-oxo~
nicoti.nate.
Part C
14.3 g. of ethyl 1,2-dimethyl-5-(4'-bromophenyl)-4-oxonicotinate was susp~nded in 140 g. of 5~ NaOH in 1:1 methanol~water and refluxed for 4-1/2 hours. The reaction was cooled, diluted with water and acidified. The resulting solid was recrystallized from acetonitrile to yield 6.2 g.
of 1,2-dimethyl-5 (4'-bromophenyl)-4-oxonicotinic acid as a white solicl, m.p.-266-268C. (decomposition).
Example 9OA
6.15 g. of 1,~dimethyl-5-(4'-bromophenyl)-4-oxonicotinic acid was mixed with 0.84 g. of NaOH and 100 ml.
of dry methanol. Evaporation of the solvent provided 6.7 g.
of sodium 1,2-dimethyl-5-(4'-bromophenyl)-4-oxonicotinate as a tan glassy solid.
Example91 Part A
15.7 g. of ethyl 3-methylamino-hex-2-enoate, 175 ml. of dry methylene chloride and 10 ml. o~ pyridine were mixed. 23 g. of 4-bromophenylacetyl chloride was added with stirring. Two hours later the reaction mixture was poured into water and the organic layer was separated and evaporated yielding 45 g. of ethyl 3-oxo-4-(4'-bromophenyl)-2-(methyl-aminopropylmethylene)kU~yrate as a brownish oil.
Part B
18.4 g. of 3-oxo 4-(4'-~romophenyl)-2-(methyl-aminopropylmethylene)butyrate was mixed with 12 g. of di-methylformamide dimethyl acetal, 25 ml. of dry dimethyl formamide, and 2 ml. of dry pyridine. The reaction was heated at 85C~ for 21 hours, then cooled, poured into water, ~7325 acidified and extracted with methylene chloride. Evaporation of the solvent provided 16.5 g. of crude ethyl 1-methyl-2-propyl-5-(4'-bromophenyl)-4-oxonicotinate.
Part C
1605 g. of ethyl 1-methyl-2-propyl-5-(4'-bromophenyl)-4~oxonicotinate was suspended in 160 g. of 5% NaOH in 1:1 methanol/water. The mixture was refluxed for 10 hours, cooled and acidified. Filtration of the resulting solid provided 9.0 g. of 1-methyl-2-propyl-5-(4' bromophenyl)-~-oxonicotinic acid. m.p. (acetonitrile)-237-239C. (decomposition~.
Example 91A
8.8 g. of 1-methyl-2-propyl~5-(4'-bromophenyl)-4-oxonicotinic acid was mixed with 1.1 9. of NaOH and 100 ml.
of methanol. Evaporation of the solid provided 8.8 g. of sodium 1-methyl-2-propyl-5-(4'-bromophenyl)-4-oxonicotinate as a glassy powder.
Example 93 Part A
17.0 g. of e~hyl 3-oxo-4-(4'-bromophenyl)-2-(methylamino-ethylidene)butyrate was mixed with 10 g. of dimethylacetamide dimethyl acetal, 25 ~. of dry dimethyl-ormamide and 2 ml. o triethylamine. The reaction mixture was hea~ed at 85C. for 24-1/2 hvurs ur.der a nitrogen atmosphere, cooled, poured into water, acidified and extract-ed with methylene chloride. Evaporation of ~he solvent and trituration of the residue with ether provided 2.7 g. of crude ethyl 1,2,5-trime~hyl~5-(4'-bromophenyl)-4-oxo-nicotinate as a brownish solid.
Part B
__ 3~ 2.7 9. of crude ethyl 1,2,6-trimethyl-5-(4'-bromo-phenyl) 4~oxonicotinate was suspended in 27 g. of 5~ NaOH in 1.1 methanol/water. The reaction mixture was refluxed for 2-1/2 hours, cooled and acidified. Filtration of the result-ing solid provided 2.2 g of 1,2/6-trimethyl-5-(4-bromo-3S phenyl3-4~oxonicotinic acid. m.p.=228-230C. (decomposition).
~`1 ~373ZS
Example 93A
1.96 9. of 1,2,6-trimethyl 5-(4'-bromophenyl)-4-oxonicotinic acid, 0.26 g. of NaOH and 30 ml. of methanol were mixed. Evaporation of the solvent provided 2.0 g. of S sodium 1,2,6-trimethyl-5-(4'-bromophenyl)-4-oxonicotinic acid as a tan glassy solid.
Example 94 Part A
18.4 g. o ethyl ~-anilinocrotonate was mixed with 80Q ml. of methylene c~loride and 8 ml. of pyridine.
17.0 g. of 4-chlorophenyl acetyl chloride was added with stirring. After 2-1/2 hours the reaction mixture was poured into 400 ml. of water and shaken. The methylene chloride layer was separated and evaporated yielding 32 g.
lS of crude ethyl 3-oxo-4-(4'-ehlorophenyl)-2-(anilino-ethylidene)butyrate as a light brown oil.
Part B
32 9. of ethyl 3-oxo~4-(4'-chlorophenyl)-2-(anilino-ethylidene)bUtyrate, 15.9 g. of dimethy~formamide dimethyl acetal, 40 ml. of dry di.methylformamide and 3.5 ml. of triethylamine were mixed and heated under nitrogen at 8Q-85C. for 18 hours. The r~action was cooled, poured into 600 ml. of water, acidified and extracted with methylene chloride. Evaporation of the solvent provided 35 g. of crude ethyl 2-methyl-1-phenyl-5-(4'~chlorophenyl)-4-oxonicotinate as a brown oil.
Part C
35 g. of crude ethyl 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate was suspended in 350 g. of 5~ NaOH in 1:1 methanol/water and refluxed for 6 hours.
The reaction mixture was cooled. This yielded a precipitate of sodium 2-methyl-1-phenyl-5-~4'-chlorophenyl~-4-oxQ
nicotinate which was collected by filtration and resuspended in dilute aqueous HCl to provide 5.3 9. of 2-methyl-1-phenyl-5-(4'-chl~rophenyl)-4-oxonicotinic acid, m.p.
(acetonitrile)=209-209C.
"
.. ........ . .
~zci,~3~
Example 94A
5.25 g. of 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinic acid, 0.68 g. of NaOH and 100 g. of dry methanol were mixed. Evaporation of the solvent provided 5.0 g. of sodium 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate as a glassy solid.
6~
D. N-alkyl-2,6-dlaryl-4-oxonicotinates In still another preferred aspect, this in~ention re-lates to compounds of the formula o R5~,co 2Y
n ~ R1 ~ (X)n (~) wherein Rl is a (Cl-C6) alkyl group; R5 is a hydrogen atom, a (Cl C4) alkyl group or a halogen atom; Y is a hydrogen atom or a (C~ C6) alkyl group; X is a hydrogen atom, a haloyen atomr a trihalomethyl group, a (Cl-C6) alkyl group, a nitro grou~, a cyano group or a (Cl-C6) alkoxy group; and n is the integer 1 or 2; and the agronomically acceptable salts thereof.
Among the preferred compounds of the present invention are compounds of Group D, formula ~XXXII) wherein ~1 is a 15 (C~-C6) alkyl, (Cl~C4) haloalkyl, alkoxy (C1-C4)alkyl-(Cl-C4), aryl(C6-ClO)alkyl(Cl-C4)~ or: (C3~C6)alkenyl; Y is hydrogen, ~Cl-C6)alkyl, an alkali metal or alkaline earth metal cation, or an ammonium or mono-, di-, tri-, or quaternary ammonium cation; Rs is hydrogen, (Cl-C6)alkyl, or halogen; X
~ is hydrogen, halogen, trihalomethyl, (Cl-C6)alkyl, (Cl-C6 ) alkoxy, nitro or cyano; and n is an integer from 1 to 2.
Among the more preferred compounds of the present in-vention are compounds of Group D, Formula (XXXII) wherein R
is (Cl-C3) alkyl; Rs is hydrogen or bromine; ~ is hydrogen, sodium or potassium; X is hydrogen or halogen; and n is the integer 1 or 2.
, .
~2C~73~5 Among the most preferred compounds of this in~ention are compounds Oc Group D Formula (XXXII) wherein Rl is methyl or ethyl; Rs is a hydrogen atom; and Y is hydrogen or a sodium or potassium cation; X is hydrogen, chlorine or fluorine; and 5 n is 1; and the agronomically acceptable acid addition salts : thereof.
Typical compounds encompassed by.the present invention include:
. l-methyl-2,6~diphenyl-4-oxonicotinic acid;
1-propyl-2,6-diphenyl-4-oxonicotinic acid;
l-hexyl-2,6-diphenyl-4-oxonicotinic acid;
5-bromo-1-methyl-2,6-diphenyl-4-oxonicotinic acid;
5-chloro-1-ethyl-2,6-diphenyl-4-oxonicotinic acid;
1,5-dimethyl-2,6-diphenyl-4-oxonicotinic acid;
1-methyl-2,6-di(4'-chlorophenyl)-4-oxonic.otinic acid;
l-hutyl-2,6~di(4'-chlorophenyl)-4 -oxoni cotinic acid;
l-ethyl-2,6-di(3'-chlorophenyl)-4-oxonicotinic acid;
l-methyl-2,6-di(2'-chlorophenyl)-4-c)xon.icotinic acid;
l-methyl-2,6-di(4'-fluorophenyl)-4-c)xonicotinic acid;
1-methyl-2,6-di(3'-~luorophenyl) 4-oxonicotinic acid;
: 5-bromo-1-me~hyl-2,6-di(4'-fluorophenyl-4-oxonicotinic acid;
l-ethyl-2,6-di(3',4'-dichlorophenyl)-4-oxonicotinic acid;
l-propyl-2,6-di(2',4'-dichlorophenyl~-4-oxonicotinic acid;
1 methyl-2,6-di(4'-trifluorophenyl)-4-oxonicotinic acid;
1 methyl-2-(4'-fluorophenyl)-6-phenyl-4-oxonicotinic acid;
l-methyl-2-(4'-chlorophenyl)-6-(4'-fluorophenyl)-4-oxonico-tinic acid;
l~chloro-2-(4'-chlorophenyl)-6-phenyl-4-oxonicotinic acid;
l-pentyl-6-(4'-fluorophenyl)-2-phenyl-4-oxonicotinic acid;
; 30 and the agronomically acceptable salts thereof.
73~,5 The compounds of the ~resent invention can be prepared by various synthetic routes found in the ar~. ~In particular, the compounds of the present invention can be prepared by the following reaction sequence:
OH o ~C02Et (STE P I ) ( X~ ,~ . NaHCO~
( >~XXIII) X~
(XXX f\~
O O
;[CSTEP 2~ ~C2CH3 ~,CO2C~3 x~f ~ x~
(XXX\/) (XXXVl) ~XX~ 1)STEP 4~ ~ ~)2 ~f Rl \~X
(,~>O<VI 1) ,, Step No. 1 (a) NaHCO3 .2 3.
~b~ chlorobenzene, dichlorobenzene. toluene, decahydronaphthalene, .other inert solvents;
~) temp.: 50 250C., preferably 100-200C. and (d) similar to procedure des~ribed F. Arndt, B. Eistert, H. Sckole s~d F. Aron, Ber., 69, 23~3 (1936).
' ' i'~ i ' ' ' - ~2~732 7~
Step No. 2 (a) methanol;
(b) trimethyl orthoformate desiccant;
(c) H2SO4~ HC1, other strong acids;
5~d) temp.: 25-200C., preferably 5~-150~.
Step No. 3 (a) alkyl amine;
(b) inert solvent, alcohols, ethers, hydrocarbons, water;
(c) acid catalyst optional;
10 (d) temp.: .Q-15~C., preferably ~S-50C.
Step No. 4 ___ __ _ (a) aqueous ~.~:
(b) optional ine.rt co-solvent, methanol, r~so;
~) temp~: 20-150C., p.referably 50-100C~
(d) any acid to neutralize.
Another route to the compounds of Growp D, formula (XXXII) is .' O .
X~ 5~ STI~? ~ (XXXVII) Step No. la X~ 1 2 : ~a) i:l0 P2O5/C~3S~3~ by weight;
2~ (b.~ temp~: 20-150~ ,.p.re.fer~.bly 20.-60C.
.
Other steps: same as abo~e __ ____ ___ . Still snother route to the compounds of Group D, formula (XXXII) of the present invention is shown by the following reaction sequence:
Z5 (XXX,~Il)~ ~02Ft~,' - ~' - ( XLi) ~! , ;3732~i 70b Step No. lb-__ _ __ (a) RNH2 (b) inert solvent, methanol, H20 (c) acid catalyst optional S (d) temp.: 20-150G., preferably 20-100C.
Step No. 2b:
(a) r~n in inert solvent (methylene chloride, benzene toluene, ether) (b) acid acceptor optional (pyridine, Et N) 10 (c) temp.: ~-150C., pre~erably 10-50 C.
(d) residue heated 100-200C., preferably 150-180C.
,~C2E~3 ~,~C`OCI
Yet another route to the compounds of Group D, formula (XXXII) of the present invention i5 shown by the ~ollowing 15 reaction equation:
~ ~ C O~ H X ~ ~ 2 H
X ~ ~X ~ ~ X[~ 1~X
. .
(a) carried out in a compatible solvent (MeOH, water) (b) room temperature (c) optional addition of base (N~OH~,Na CO , etc.) Tables VIII and IX below are presented to illustrate the more preferred compounds of this aspect of the present invention and related compounds and the analytical data for these com~ounds~
TABLE VIII. List of Group D Compounds o ~5 ~ C O 2Y
( X ) n ~ R ~ ( x)n (~:1) Example No. Rl ~ X X' Y
97a H H H H Na 98 Me H H H Et 99 Me H H H Me 100 Me H H H H
lOOa Me H H H Na lOl Et H H H H
lOla Et H H H Na 102 Me H 4-Br 4-Br H
102a Me H 4-Br 4-Br Na 103 Me H 4-Br 4-Br Et 104 Me H 4-F 4-F H
104a Me H 4-F 4-F Na 105 Me H 4-C1 4-Cl H
105a Me H 4-C1 4-Cl Na ! 1 0 6 Me H 4-CH3 4-CH3 H
; 106a Me H 4-CH3 4-C'H3 Na ~2~325 T~BLE VI I I ( ~ont . ) Example No . R1 ~ X X ' Y
107 Me H H 4-C~3 H
107a Me H H 4-C~3 Na 108 Me Br H H H
108a Me Br H ~ Na 109 - Pr H H H H
109a Pr H ~ H Na TABLE IX
Ex~ple No. mp ( C. ) - ~C ~H ~N
97228- 230 74.21 4.50 4.80 74.46 4.40 5.15 97a -~
98177-17g 75-65 5.74 4.20 7S.49 5.83 4.45 99255 757 75.22 5.37 4.39 75.13 5.51 4.46 1002~9- 211 74.74 4.95 4.59 74.04 5.04 4.47 lOOa ___ ___ 101210- 213 75.22 S .37 4.39 75.28 5.37 4.22 lOla --- --- ~ --- ---102 lg7 49.27 2.83 3.03 49.27 2.86 3.3 102~
103218- 220 51.35 3.49 2.85 50.45 3.43 3.03 .. . .
~q-~73;~5 TABLE IX (cont.) Example No. mp(C) %C %H ~N
104 191-193 66.86 3.84 4.10 58.41 3.67 4O25 5104a --- ~~- ~~~ ~~~
105 187-190 60.98 3.50 3.7~
60.75 3.53 4.29 105a -~
106 209- 212 75.65 5.74 4.2~
74.89 5.79 4.26 106a 107 158- 163 75.22 5.37 4.39 . 72.13 5.50 4.02 '07a --~
15-108 ~42- 2~3 59.39 3.67 3.65 60.44 3.77 4.15 108a --- -~- ~~~ ~~~
109 166 -167 75.20 6.31 - 4.18 75.14 5~5 4.28 20lO9a . ~ .
..,S~ i .^! i ~73~5 Example 98 Part a.
A 500 r.ll single neck flask was fitted with a magnetic stirrer and an N2 inlet. 20 g. of ethyI benzoy-lacetate (0.104 moles) was dissolved in 200 gms of 1:10 P20s/methanesulfonic acid and added to the flask. The homogeneous reaction mixture was heated to 40C. and main-tained at that temperature or four days. The mixture - was then cooled and diluted with 100 ml of methylene chloride. This solution was added in 50 ml portions to 1000 ml of cold water in a separatory funnel. The sep-aratory funnel was shaken vigorously after each addition.
The organic layer was then washed with water and evapo-rated leaving an oily residue that crystaliized from ether.
The isolated yield of 2,6-diphenyl-3-ethoxycarbonyl-4-pyrone was 10.5 g- ~63~. mp - ]02-103OC.
Part b:
3.5 ~. of 2,6~diphenyl-3-ethoxycarbonyl-4-pyrone was dissolved in 33 ml of methanol. 2 ml of glacial acetic acid was added. 13.3 ml of 40~ aqueous methylamine was then added very slowly at room teMperature.
After 6 hours the reaction mixture was diluted with 200 ml of water and extracted with methylene chloride. Evapo-ration yield~d 3.5 g. o~ ethyl 2,6-diphenyl-4 oxonico~i-2S nate which was recrystallized from methylene chloride/
ether. mp = 177-179~C.
.
,, ,i "j .
Example 99 Part a:
A 200 ml flask was fitted with a N2 inlet, a magnetic stirring bar and a condenser. 50 ml of methanol, 8.0 g of trimethyl orthoformate, 5.2 ~g. of concentrated H2SO4 and 5.0 g.i of 3-benzoyl-4-hydroxy-6-phenyl-pyr-2-one were added. The resulting mixture was then refluxed for 3 days, cooled, poured into water and extracted with methylene ahloride ~300 ~1 ). The ~rganic extracts were combined and washed with water. Re..moval of the solvent provided 4.4 Y- of 2,6-diphenyl-3-methoxy-carbonyl-pyr-4-one (85~). Recrystalllzation from methyl-ene chloride/ether provide material with a melting point = 150-151C.
Part b:
3.0 g.; of 2,6~diphenyl-3-methoxycarbonyl-pyr 4-onel 33 ml of methanol, 13.3 ml of 40% a~ueous methyl-amine and 2 mls of glacial acetic acid were rllixed at room temperature~ The naxt day the mixture was diluted with water. Eiltration of the resulting suspension yielded 2.5 g.; of methyl 2,6~diphenyl-1-methyl-4-oxonicotinate.
Recrystallization from methanol provided material at 255~257C.
Example 100 2.5 g. of methyl 2,6-diphenyl-1-methyl-4-oxonicoti-nate was suspended in 28 ml of 5% aqueous sodium hydro~ide for ~ hours, cooled, and filtered to remove residual insolubles.
The clear basic solution was then æi~ified with dilute HCl to provide a white precipitate of 2,6 diphenyl-1-methyl-4-oxonicotinic acid. Recrystalli2ation from methylene chlor-ide/ether provided 2.4 ~. of product. mp = 209-211C. (dec).
'-- .
Example 100a 1.73 g of 2,6-diphenyl-1-methyl-4-oxonico~ini~
acid was suspended in 50 ml of dry methanol. 0.25 g.
of NaOH was added. After the carboxylic acid and the _ NaOH dissolved the solvent was removed yielding 1.75 g.
of sodium 2,6-diphenyl-1-methyl-4-oxonicotinate as a glassy solid.
Example 101 3.5 g- of 2,6-diphenyl-3-ethoxycarbonyl-pyr-4-one, 33 ml of methanol, 5 ml of water and 2 ml of ~lacial acetic acid were mixed. 7.6 ml of 70% aqueous ethylamine was then added slowly~and the resulting mixture was allowed to stand at room temperature! for 24 hours. The mixture was then diluted with 100 ml of waterO The pH was ad-justed to 2. Extraction with methylene chloride andevaporation of the solvent provided 3.0 g. of crude ethyl 1-ethyl-2,6-diphenyl-4-oxonicotinate as a brown oil. This material was dissolved in 20 m~ of methanol. This solu-tion was then added to 40 ml o 5~ aqueous NaOH and heated on a steambath for S hours. The reaction mixture was cooled and acidified. Extraction with methylene chloride (3x50 ml ) yielded an oily solid after evaporation.
Crystallization from methylene chloride/ether yielded 1.6 g of l-ethyl-2,6-diphenyl-4-oxonicotini~ acid. mp =
2S 210 -213~C. (dec).
Exam~le 101a 1.38 g. of 1-ethyl-2,6-diphenyl-4-oxonicotinic acid was treated with 0.1~ g. of NaOH in 50 mls of dry methanol.
Evaporation o the solvent provided 1.40 g. o~ sodium 1-ethyl-2,~-diphenyl-4-oxonicotinate as a glassy solid.
. .~. .
.. . . . . . .
7;~5 j, Example l_ Part a~
g of ethyl 4-fluorobenzoylacetate was dissolved in 250 g- of 1:10 P20s/lnethanesulfonic acid and heated at 45C. for 4 days. The mixture was cooled, poured into 1200 ml of water and extracted with ~3x100 ml ) methylene chloride. Evaporation of the solvent and chroma-tography of the resulting oil (silica gel/ether) provided 12.9 , g of crystalline 2,6-dit4 -fluorophenyl)-3-10 ethoxycarbonyl-pyr-~ one. mp = 113 -114C.
Part b:
g. of 2,6-di(4 -fluorophenyl)-3-ethoxy-carbonyl-pyr-4-one, 47 ml of methanol and 2.9 ml of glacial acetic acid were mixed. 19 ml of 40~ aqueous methylamine was added slowly. Three hours later the reac-tion mixture was poured into 200 ml of water and extrac~ed with methylene chloride ~2x100 ml ). This pro~ided 5.4 gms of crude ethyl l~methyl-2,6-di(4 -fluorophenyl)-4-oxonicotinate as a brown oil.
The crude ester was suspended in 50 ml of 5%
aqueous NaOH solution and heated for 3 hours. The mixture was cooled and acidified. extraction with methylene chlor-ide provided a yellow solid which was recrystallized from methylene chloride/ether-to provide 3.6 g.: of l-methyl-25 2,6-di(4 -fluorophenyl)-4-oxonicotinic acid. mp = 19l-l93~c.
Example 10~a 3.45 g. of 1-methyl-2,6-dit4 -fluorophenyl)-4-oxonicotinic acid was mixed with 0.445 g. of NaOH and 70 ml of methanol. Evaporation of the solvent provided 3.1 30 g. of sodium 1-methyl-2,6-di(4 -fluorophenyl)-4-oxonicotinate as a glassy solid.
.
. .
Exam~le 105 Part a:
g. of ethyl 4-chloroben~oylacetate was mixed with 150 g. of 1:10 P2Os/methanesulfonic acid and heated at 45C. ~or 4 days. The cooled reaction mixture was poured into a separatory funnel containing 1500 ml of cold water and the res~lting mixture was shaken for several minutes. Extraction with methylene chloride and chromQtography o the resulting crude product (silica gPl/
ether) provided-5.5 g. of ethyl 2,6-dit4 -chlorophenyl)-3-ethoxycar~onyl-pyr-4-one. mp - 130 C.
Part b:
5.0 g. of ethyl 2,6-di(4 -chlorophenyl) 3-ethoxycarbonyl -pyr-4-one, 100 ml of methanol, 19 ml of 40% aqueou~ methylamine, 19 ml of water and 2.9 ml of glacial acetic acid were mixed and allowed to stand at room temperature Eor 3 hours. The mixture was poured into water and extracted with methylene chloride to provide 5 g-- of c~ude ethyl l~methyl-2,6-di(4-chlorophenyl)-4-oxonicotinate a~ a yellowish semi-solid.
The ester was then su~pended in 50 ml of 5 aqueous NaOH solution. 20 ml of methanol was added to improve solubility. The mixture was heated on a steambath fQr 3 hours, cooled, and acidifed with dilute H~l to pro-vide a white precipitate. Recrystalliza~ion from methylenechloride/ether, yielded 3.4 g. of 1-methyl-2,6-di(4 -chlorophenyl)-4-oxonicotinic acid. mp = 187 -190C.
.
c ., 4~ ~g Example lO5a 3.32 g. of l-methyl-2,6-di(4 -chlorophenyl)-4-oxo-nicotinic acid, 0.39 g.i of NaOH and 50 mls of methanol were mixed. Evaporation of the solvent provided 3.4 g.
of sodium l-methyl-2t6-di(4 -chlorophenyl)-4-oxonicotinate as a glassy solid.
Example 1 7 Part a?
A one liter flask was fitted with a mechanical stirrer, CaC12 drying ~ube~ condenser and a sidearm addi-tion funnel. lOO Y- of PCls was placed in the flask. 39 g- of ethyl 4-methylbenzoyl~cetate and lOO ~ of PCl3 were mixed and slowly added to the PCls at room temperature.
The reaction mixture e~lolved HCl. After 30 minutes the lS mix~ure was cautiously re1uxed for 2 hours. At this time PC13 and POCl3 were distilled from the reaction mixture at reduced pressure. The residue was then dis-tilled at O.S mm (bp = 116-121) to provide 32 g.i of ~ -chloro 4-methylcinnamoyl chloride as a clear oil.
Part b.
lO.O g- of ethyl ~ -methylaminocinnamate, 9.6 - of pyridine and 75 ml of dry methylene chloride were mixed in a flask under a dry nitrogen atmosphere. lO g.
of ~-chloro-4-inethylcinnamoyl chloride in 25 ml of meth-ylene chloride were added at ambient temperatures. After 2 hours the reaction mixture was poured into water and extracted with methylene chloride. Evaporation of the solvent provided 18 g. of a brown oil. This material wa~ heated (160-178) for lS minutes (HCl evolution), cooled, and taken up in dilute aqueous NaOH. Acidificatlon of the basic extracts an~ recrystallization of the result-ing solid from methanol provided ~.8 g. o 1-me~hyl-2-.
:~073;25 - 8~ -phenyl-6 (4 methylphenyl)--4-oxonicotinic acid.
np = 158 -163C, (dec).
Example 107a 0.64 g of l-methyl,2-phenyl-6-(4 -methylphènyl)-4-oxonicotinic acid, 0.09 g. of NaOH and 30 ml ofmethanol were mixedO Evaporation of the solvent provided 0.6 g. of sodiui,l l-methyl-2-phenyl-6-(4 -methylphenyl) 4-o~onicotinate as a glassy solid.
Exarnple 108 3~75 g., of l-methyl-2,6-diphenyl-4-oxonicotinic acid was dissolved in 40 ml of methanol. The pH was adjusted to 12 with the addition of aqueous NaOH. A me~hanolic solution of bromine (2.95 g. Br2 in 50 ml methanol) was added. Additional NaOH was added as required to maintain a basic medium. Removal of the solvent yielded a semi-solid that was taken up in 100 ml of water. Water insoluble material was removed by filtration. Acidifica-tion of the aqueous solution provided 3.0 g. of 5-bromo- ' 1-methyl-2,6-diphenyl-4-oxonicot:inic acid (mp 242-~43,C.~ with decompo~ition) as a white solid.
Exam ~e 108a 2.5 g. of,5-bromo-l-methyl-2,6-diphenyl-4-oxonico-tinic acid, 0.286 g. of NaOH and 50 mls of dry methanol were mixed. Evapora ion o the solvent provided 2.6 g-of sodium 5-bromo-l-methyl-2,6-diphenyl-4-oxonicotinate as a tan glassy solid.
Example 109 -4O0 g. o 2,6-diphenyl-3-ethoxycarbonyl-pyr~4-one, 50 ~1 of glacial acetic acid were mixed. 8.1 g~ of n-propylamine and 6 m~ of water was added slowly a. room ~ .. . . .. .. . . ..
~L2V73;~5 - 81 ~
temperature. After 3 hours an additional 14 ml of wa~er, 12 ml of 6% ~Cl and enough methanol to bring everything into solu~ion, was added. The next day this acidic reaction mixture was poured into water and extracted with methylene chloride (2x100 ml ~. Evaporation of the organic extracts yield 4.4 g. of crude nicotinate ester which was suspended in 50 ml of 5% aqueous NaOH and heated at 85C. for 4 hours. The resulting solution was acidif~ed with HCl and extracted with methylene chloride (2x50 ml ). Evaporation of the solvent yielded a solid mass. Recrystallization from ether provided 1.5 g. of l-propyl-2,6-diphenyl-4-oxonicotinic acid. rnp = 16~ -167C.
xample 109a 1.5 g. of 1-propyl-2,6-diphenyl-4-oxonicotinic acid, 0.202 g. of NaOH and 50 ml of dry methanol were mixed.
Evaporation of the solvent yielded 1.5 g. of sodium 1 propyl-2,6-diphenyl-4-oxonicotinate as a white glassy solid.
~ .
, . . i.
.
~207325 - 8~--The eompounds o~ the invention are particularly useful a~ che~ical hyb~idization agents in cereal crops, such as wheat, bar ley, corn, r iG~, s~rghum, millets, oat~, rye, triticale and the like~ Whe~ used as chemical 5 hybridi2ation agents, the cornpcunds effec~ively induc~ a high degree of selective male ster ility, that is, without also inducing significant female sterility, in the treated plants and w~ thou~ causing signif icant growth inhibition o~
the treatsd plants. As used ~rein, the term male 10 sterility includes both actual {sale s~oril~ty, as evideQced by a lac~ o~ male rlower parts or by s~erile pollen, and ~unctiollal male sterility, in which the male flower parts are unable to cause pollinatio~. Th~ co~pounds o the i~ven~ion also cause other plant growth re~ulatory response~, such. as or example, co~trol of floweringr control o~ fruiting and inhibition of seed formation in non-cereal species and other related growth regulatory responses.
Wh~n used as plant growth regulato~s, the compounds or 20 the invention are applied in any amount which wiLl be sufficient to ~ffect the desired plant res~onse without cau~ing any undesirable or phytotoxic response. ~or ~
example, when the comp~unds o4 the invention are used as ch~mical hybridi2ation agents, t~ey ar~ generally applied to the crops ~o be treated a~ a rate of about 1j32 to ab~ut 20 pounds pe~ acre and pr~erably ab~ut 1/8 to about 10 ~, .
, . , ,, . . . ~ . . . .... . . . . .. . .. . . .. .
~73%~
_ 83; _ ;
pounds per acre. ~he rate of application will vary depending on the crop being treated, the compound being used for treatment, and related factors.
To obtain hybrid seed, the following procedure is S generally employed. The two parents to be crossed are planted in alternate strips. The female parent is treated with a compound of the invention. The male-sterile ~emale parent thus produced will be pollinated by pollen from the other, male-fertile, male parent, and ~he seed produced by the female parent will be hybrid seed wbich can then be ha~vested by conventional means.
A pre~erred ~ethod of applyi~g a compound of the invention as a chemioal hybridization agent is by foLiar application. When this method is employed, selective male s~erility is most efectively induced when the com~ound is applied be~w~en anther initiatio~ a~d meiosis. The compounds o the inventions may also be appLied a~ a seed treat~ent by soaking t~e qeed in a liquid Eormulation containing the active compound or by coating the seed with the compound. In seed treatment applica~ions, the compounds o the invention will generally be applied at a rate o about 1/4 to about`l3 pounds per hundred weight of seed. The compounds o the in~ention are also effective when applied to the soil or to the water surfacP in rice crops.
The compounds of ~he invention can be used as plant grow~h regulators either individually or in mixtures. For example, they can be used in combination with other plant growth regulators, such as auxins, gibberellins, ethylene-releasing agents such as ethephon, pyridones,pyridazinones, cytokinins, maleic hydrazide t succinic acid 2j2-di~ethylhydrazide, chlorine and its salts (2-chlo~o-ethyl) tri~ethylammonium chloride, triiodobe~zoic acid, trihutyl-~, 4~diohlorobenzylpho~phonium ehloride, polymeric N-vinyl-2-oxazolidinones, tri~dimethylaminoethyl) phosphate ~` .
... . .. . . . .. . .. . . . . . . . . . . .
3;~S
_ 84 _ and i~s salts, and ~-dimethylamino-1,2,3,6~tetrahydro-phthalamic acid and its salts, and the like, and under some conditions may be used advantageously with other agricultural chemicals such as herbicides, fungicides, insecticides, and plant bactericide~.
A compound of the invention can be applied to the growth medium or to plants to be treated either by itself or, as is generally done, as a component in a growth regulant composition or formulation which also comprises an agronomically acceptable carrier. By ~agronomically acceptable carrier~ is meant any substance which can be used to dissolve, disperse, or diffuse a compound in the composition without impairing t~e effectiveness of the compound and which by itself has no significant detrimental effect on the soil, equipment, crops or agronomic environment. Mixtures o the compounds of the invention may also be used in any o these formulations. The compositions of the invention can be either solid or liquld formulations or solutions. For example, the compounds can be formulated as wettable powders, emulsiriable concentrates, dusts, granular formulations, ae_osols, or ~lowable emulsion concentrates. In such ormulations, the compounds are extended with a liquid or solid carrier and, when desired suitable surfactants are incorporated.
It is usually desirable, particularly in foli2r applications, to include adjuvants, such as wettinq agents, spreadin~ agents, dispersing ayents, stickers, adhesi~es, and the like, in accordance with agricultural practices.
Examples of adjuvants which are commonly used in the art can be found in the John W. McCutcheon, Inc. publication "Deter~e~ts and Emulsifiers Annual".
The compounds o ~he invention can be dissolved in any appropriate solvent. Examples of solvents which are useful in the practice of this invention include water, alcohols, ketones, aromatic hydrooar~ons, halogenated hydrocarbons, ~2~7325 ~ 85 -dimethylformamide, dioxane, dimethyl sulfoxide, and the like. Mixtures of these solvents can vary from about 2% to about 98% by weigh~ with a preferred range being from about 20% to about 75%.
For the preparation of emulsifiable concentrates, the compound can be dissolved in organic solvents, such as benzene, toluene, xylene, methylated naphthalene, corn oil, pine oil, o-dichlorobenzene, isophorone, cyclohexanone, methyl oleate, and the like, or in mixtures of these solvents, together with an emulsifying agent or surfactant which permits dispersion in water. Suitable emulsifiers include, for example, the ethylene oxide derivatives of alkylphenols or long-chain alcohols, mercaptans, carboxylic acids, and reactive amines and partially esteri~ied polyhydric alcohols. Solvent-soluble sulfates or sulfonates, such as the alkaline earth salts or amine salts of alkyl-benzenesulfonates and the fatty alcohol sodium sulfates, having surface-active properties can be used as emulsifiers either alone or in conjunction with an ethylene oxide reaction product. Flowable emulsion concentrates are ~ormulated similarly to the emulsifiabl~ concentrates and include, in addition to the above components, water and a stabilizing agent such as a water-soluble cellulose derivative or a water-soluble salt of a polyacrylic acid.
The concen~ration of ~he active ingredien~ in emulsifiable concentrates of usually abu~ 10~ tO 60% by weight and in flowable emulsion concentrates, this can be as high ~as abou~ 75%.
~ettable powders suitable for spraying, can be prepared by admixing the compound with a finely divided solid, such as clays, inorganic silicates and carbonates, and silicas and incorporating wettiny agents, sticking agents, and/or dispersing agents in such mixtures. The concentration of active ingredients in such formulations is usually in the range of about 20~ to 98~ by weight, 3~3~25 _ 86 -preferably about 40% to 75~. A dispersing agent may yenerally cons~itute about 0.5% to about 3% by weight of the composition, and a wetting agent may generally constitute from about 0.1% to about 5~ by weight of the composition.
Dusts can be prepared by mixing the compounds of the invention with finely divided inert solids which may be organic or inorganic in nature. Materials useful for this purpose include, for example, botanical flours, silicas, silicates/ carbonates and clays. One convenient method of preparing a dust is to dilute a wettable powder with a finely divided carrier. Dust concentrates containing abut 20% to ~0% of the active ingredient are commonly made and are subsequently diluted to about 1% to 10% by weight use concentration.
Granular formulations can be prepared by impregnating a solid such as granular ~uller's earth, vermiculite, ground corn cobs, seed hulls, including bran or other yrain hulls, or similar material. A solution of one or more of the compounds in a volatile or.ganic solvent can be sprayed or mixed with the granular so:Lid and the solvent then removed by evaporation. Th~ qranular material can have any suitable size, with a pre~erable size range of 16 to 60 mesh. The active compound will usually comprise about 2 to 15% by weight of the granular formula.ions.
Salts of the compounds of the i~vention can be formulated and applied as aqueous solutions. The salt will typically comprise a~out 0.05 to about 50% by weight preferably a~out 0.1~ to a~out 10%, of the salution.
These composi~ions can also be further diluted with water if desired prior to actual application. In some applications, the activity of these compositions can be enhanced by incorporating into the composition an adjuvan~
such as glycerin, methylethylcellulose, hydroxyethyl-cellulose, polyoxye~hylene~orbitan monooleate, polypropylene glycol, polyacrylic acid, polyethylene ~D7~2~
sodiun mQlate, polyethylene oxide, or the like. Ihe adjuvant will generally comQrise abou~ 0.1 to about 5% by weight, preferably about 0.5 to about 2Yo, of the coTposition. Sucn compositions can also optionally include an agrononically-aceeptable surfactant.
Ihe conQounds of the invention can be applied as sprays by methods commonly employed~ such as conventional hydraulic sprays, aerial sprays, and dusts. -For low~volume applications, a solution of the corpound is usually used. The dilution and volume of application will usually depend upon such factors as the type of equipment emQloyed, the ~ethod of application, the area to be treated and the type and stage of developTent of the crop being treated.
Ihe following is a typi¢al tank mix fo~mulation for the foliar application of sodiun l-ethyl-6-methyl-2-(4-chlorophenyl)-~-oxonicotinate on winter wheat at a rate o~ 0.25 lbs./A:
0.25 lbs. of oxonicotinate salt 1 pt. of Triton AG 98~
dulute to 50 gals. with water This mixture is then foliar spray-applied to the wheat plants at a rate of 50 gals./A.
Ihe following e.xamQles will further illustrate the ch~niaal hybridization activity of the corpounds of the invention but are not :~ intended to limit the invention in any U~Ly.
~ LE llt~
Chemical ~ybridization Activity The following proc~dures are used to evaluate the activity of the com~unds o~ the invention for inducins male sterility in cereals.
An awne~ variety (Fielder) and an awnless variety (Mayo-64) of spring wheat are planted a~ the ra~ of 6 to 8 seeds per 6 in~hes p~t cont~aining a Qterile medium of 3 parts ~oil and 1 part humus. ~he plants are grown under short day (9 h~ur) condi~ions for the first 4 weeks to obtain good vegatative growth ~e~ore flow~r initiation.
The plants are then moved to lons-day (16 hour) conditions which are provide~ by high in~ensity lights in the green-house. The plants are fertilized at ~, 4, and 8 weeks ~2C~73~ 5 `
after planting with a water soluble fertilizer (1~-25-16) at the rate of 1 tsp/gal o water, and are fre~uently sprayed with isotox for a2hid control and dusted with sulfur for powdery mildew control.
Test compounds are foliarly applied to the awned ~emale plants when these plants reach the flag leaf emergence stage (stage 8 on Feekes' scale).~ All compounds are applied in a carrier volume of 50 gal/A oontaining a surfactant, such as Triton X-100 at the rate of 20OZ/50 gal.
After spike emergence but before anthesis, 4 to 6 spikes per pot are bagged to prevent outcrossing. At the first signs of flower open;ng, two spikes per pot are cross pollinated, using the approach method, with the awnless male parent. As soon as the seeds become plainly visible, spike length is measured and seeds per spikelet counted in both bagged and crossed spikes. Male sterility can then be calcul~ed as percent inhibition of seed set in bagged spikes of treated plants, and female fertility in crossed spikes can be calculated as percent of control seed set.
After maturity the seed on crossed spikes are planted for determination of percent hybridization.
Percent sterility, percent fertility, and percent height inhibition are calculated from the following formulas.
a. % S~erility = (Sc - Sl/Sc) x 100 Sc ~ seeds/spikelet in bagged spikes of control plants.
S~ ~ seeds/spikelet in bagged spikes of treated plants.
b. ~ Fertility = (Ft/FC) x 100 Ft = seeds/spikelet in approach crossed spikes of treated plants Fc = seeds/spikelet in unbagged spikes of control plants c. % ~eight inhibition = (~c ~ ~t/HC) x 100 ~c ~ ~eight of con.rol plants ~t ~ Height of treated plants .
... .. .
~732S
~ 89 Table X sum~arizes typical results obtained in the evaluation o~ co~pound~ o~ the invention. A dash indi~ates that no deter~ination of value was made.
TABL~ X
Biol~ical Data (Wheat Greenhouse Data) ~ Male Sterilit~ at Dosage (lbs. A~
Exam~ 8 4 2 1 1/2 1/4 1/8 ' 1 not a tive at 8 lbs/A or below 2 not ac~ive at 8 lbs~ or b~iow ~3 not active at 8 lb~/~ or below 4a - 190 100 77 36 - -~
5a 100 - 100 - 43 - 2 6 - - - _ _ _ 6a 100 - 85 - 18 - 54 7 - - ~
7a not active at 8 lbs/A or below 8 ~ ~
8a - - 98 - 34 ~~a 99 - 88 - 32 - 5 1~ -- -- -- _ _, _ _ lOa . - - 1.00 - 100 - 13 12 _ _ 12a not active at 8 lbs/A or bel~w 13a - ~00 100 92 5; 12 - -14 not active at 8 lbs/A or below no~ ac`ti~e at 8 lbs/A or below 16 _ _ 16a - 100 100 100 96 91 .. . . . .. ~
; 17 - 100 10~ 100 9~
17a100 ; 100 18 0 - 0 18a - - ~ 100 66 100 41 19 ~
,~ ' . ' , ' ,.
~37;~5 9~
TABLE ~ (cont . ) _ _ ~ 8 4 _ 2 1 1/~ 1/4 1/8 19a not active at 8 lbs/A or below 2 0 -- ~
- 20a not active at 8 lbs/A or below 21 -- -- _ _ _ _ 21a not active at 8 lbs/A or below 22a 100 23 -- -- -- -- _ _ _ 23a not active at 8 lbs/A or below 2 4 ~
24a 10 8 - 19 - 15 2 S -- -- _ _ _ . ~
25a - 55 49 ~ ~
2 6 ~
26a - 94 7 15 0 2 2 0 2 7 ~
27a - 100 100 57 0 2 2 8 ~
28a - 100 100 100 39 7 0 2~ -- -- ~. -- _ _ _ 29a -~ 100 70 1 0 0 ~
30a. - 100 100 100 0 0 3 2 ~
32a - 100 .10~100 lOa 87 33 -- -- -- -- _ _ _ 33a 100 - 100 - 100 ~ 37 3 ~
34a 100 - 79 - 50 - 44 -- ~ . _ _ _ _ . . ` '` ' ' _ .
` ~,.~~3~
.
_ 91 _ ' _ ____ _ T_LE X(cont,. ) _ _ ~ ~4 2 11/2 _lf~1/8 ~ ~ . ; . . . .
35a not active at or below 8 lbs/A
36 ~
36a 100 - 100 - 13 - 1 37 -- _ _ _ ~ _ _ 37a - - - 90 57 38 -- -- -- ~
38a - - - 100 65 0 0 39a 100 - 100 - 45 - O
4 0 _ O _ ~
40a 100 - 92 - 14 - 0 41. not active a~t or below 8 lbs/A
42 ~
42a 100 - 100 - 90 - 43 4 3 ~
~3a 100 - ~ 00 - 100 -100 4 ~
4~a lQ~ - 100 - 80 - 4 4 5 -- -- ~ . _ _ 45a 100 - 100 - ~3 - 8 ~S 46 -- ~ _ _ _ _ 46a 100 - 100 73 - 0 4 7 ~
47a 100 - 84 - 0 - 0 :
' , ' ' .. . . . . . . . . . . ..... .
- ~zci~3;~5 _ 92 -TABLE X (c~n~. ) Exampl e # 8 4 2 1 1/2 1/4 1/8 9 2 21 -- 6 ~
4g. 100 ~ 9~ - 0 ~ 0 S0 - 100 100 61 0 - ~
51 ~ 92 - 7 - ~ - 0 53 11.1 - 9~4 - 0 - 0 5~ Noheads - 100 - 44 . 6 - 13 . 6 15.4 -- - 9~2 _ 2.2 -- 0 56 100 - 14 - ~ - 0 ~7 100 - 87 . ~ - 38 . 6 - ~8 . 3 58 1~0 - 9J. . 6 - 4~ . 9 - O
5a . 100 - 100 ~ 5i;.5 - 900 lS 60 . 2.2 _ 3.. 6 _ lO.B - 4.0 61 13.9 ~ g-g - 62 ~7.4 - 24.1 - 1~.7 - 22.4 63 35.1 - 6.1 - 1~3 - 18.9 64 100 - 100 - 65 . 7 8 . 3 ~ - 34.3 24.4 6B 4.7 ~ o 67 ~3.2 - 51.7 _ 0~.6 - 3.4 68 0 - 10 . 7 - 12 . ~ - 0 6~ . 48.~ - 51.2 - 2~.3 68 ~5 70 ~6.6 ~ 15.2 _ 22.8 -. 32.3 71 l~Q - 57 . 7 - 13 . Z - 0 7~ 14 . S - 19 . 4 - ~5 - - 16 ~ 19 . 8 16 0 0 - 19 . 8 - 19 30 . (32 lb~A-0% 8 lb/A-2.5% 2 lb/A-5~89 (16 lb/A~6~,2% 4 lb~A 0%
7~ 43.3 - 16.7 - 5.7 ~- 14.8 76 1~0 - 37.7 - 65.~ 1600 77 O _ _ _ _ _ 78 ~0 . 9 - 21 . ~ ~ 26 . 0 - ~ 22 . 3 ~ .
.. _ . . . .. . . .. . . . . ... . . _ .
.
TABLE X: (cont . ) ., Examl~le 8 4 2 1 1/2 1/41/81/64 -- ---- -- -- ----80a 5 - 0 2 - 3 8.1a - 7 5 5 5 5 5 82 0 ~ 0 -- 0 83 -- -- _ _ _ _ _ 10 83a 42 - 19 - 3 - 0 84 -- -- _ _ _ _ _ 8~a 12 8.5 -- _ _ _ _ _ _ 85a 69 22 - 0 - 0 15 86 -- _ _ _ _ _ _ 86a ~ ~ ~
87 99 ~ 90 - 63 - 28 88a . 100 - 98 _ 80 - 57 89a 100 - 100 - lOQ - 100 9 0 -- -- ~
90a. 100 - 100 - 44 _ 35 91a . 98 - 60 - 24 - 17 92 ~ _ _ _ _ _ _ 92a 66 - 16 - 8 - 3 93a _ _100 - 100 - 100 100 94 -- ---- -- _ _ -- _ 94a 39 ~ 1 '- 7 - 1 _ 96 _ _ _ _ _ _ _ _ 96a ~ ~
,' `1' , ~
... . . . ... ... . . .... . .. .. . . .. .. . ... . ~
.~L2C~32~i TABLE X (cont.) .
Example No. 8 4 2 1 1/21/4 1/3 37 ~
97a 0 - 0 ~ 0 9~ 16 - 0 . 4 - 9 100 -- _ _ _ _ _ _ rOOa - 100100 88 10 101 -- _ _ _ ~ _ _ lOla100 81 ~ 6 - 0 102a 0 0 2 104 _ ~ _ _ 104a ~ 100100 91 56 66 109 _ _ _ lO5a - 100100 97 18 11 106 ~
106a 0 6 - 0 - 4 107 . - ~
107a 32 - 0 0 - 0 108 ~
108a - - 78 - 11 - 2 lO9a 73 - 14.2 - 0 Table Xl belçw depicts the lnale/female selectivity of several of the ccmpounds of Group ~, forl~la I~, of ~he present invention. AFpllcation rate~ sufficient to effect hlgh levels of r.~.e sterility maLnta m high levels of female fertility. Substan-~ tial loss of female fertility occurs ~nly at cverdo æ application 3~ rates . ~
~, `' .
.. . . , . . . .. . . . .. . . . . _ . . .. . .
~Z~73~5 T~BL~ XI
Female ~ertility, Culm Inhibition, Height Inhibition_ (Wheat Greenhouse Data) Dosage % % Culm ~ Spike % Female 5 ~ ~ (lbs/A) Sterility Inhibition Inhibiéion Fertili~
13a 1 100 15 23 lû 1/16 10 0 O
16a 1 100 50 28 -1/8 10~ 25 g 70 lS . 1~16 83 0 4 44a 1 100 0 0 78 1/4 70 5 . 4 1/8 4û 10 5 ~0 Other ~rops upon which compounds of the present inventi~n have been shown to b? effective are eorn and barley.
The ~ollowing procedures are used to evaluate the activi~y of th~ compounds q~ ~his invention for inducing male stPrility in cor~.
Four rows of inbred variety B-73 are interplanted with two rows of inbred variety M~-17. Both lines are planted a rat~ of ~0, 000 speeds/A. rhe chemicals of this inven ion are applied to variety B-73 ~everal weeks later when the last lea~ of the plan~ is just beginning to ~
e~ongate and the tassel is approximately one inch long and not yet branched. All trea~ments are applied with a hand hela pres~urized sprayer e~uippe~ with a 3~nQzzle boom containiny D 3 disc/45 core Tee Jet cone spray tips. Each nozzle is direc~ed a~ the row with one place~ on either ~' ' ... . .. . ... . . . .. ... .. . .. . ... . . . . .. .. . . .
~Z(~73ZS
side and over the row. TritonR X-lOO surfactant (a trademark of Rohn and Haas C~mpsny) at 0.0~ is added as a surfactant. Dosage and oarrier volume calculations are based on rows 36 inches wide.
-Pollinating ability of treated plants is n~asured by crossing their pollen onto silks of untreated plants and recording the anount of seed set.
Table ,YII below damonstra~es the effect of compounds of Group A, forn~la II, of the present invention on the male sterility of field corn.
TABLE XII
13 ~ 8 4 2 1 1/2 1 16a - - ~ 100 100 100 100 100 The compounds of Group A, for~la II, of the present invention are also effective on barley.
Table XIII below demonstrates the nale sterility obtained with one of the coTpounds of Group A, formula II, of the present invention on barley grain under greenhouse conditions. (Variety Park) T~BL~ XIII
xampl~ ~ 1/4 ~J8 1/16 _~/32 16a 100 96 95 as ~Z~7325 g,7 Table XIV below sets forth field test data which demonstrate further the effect of several compounds of Group A, formula II,.of the present invention on the male sterility of field corn ¢B-73).
. . TABLE XIV
% Male Sterility of Fie ~
~ L~iale Sterility at ~arious Dosaqes (lbs~A) Example # 1 _ 1/8 1/4 i/2 1 ~ 2 4 8 43a 100 100 100 100 - - - -- 16a 13 67 99 100 100 - - -16, K salt 12 40 100 100 100 - - -32a 42 84 100 100 30a - 64 34 100 100 - - -13a - 29 59 62 90 100 100 18a - 8 30 80 100 100 5a - - 37 52 98 100 lnO
26a - - 70. 100 100 lnO 100 16 Not active at 2 lb/A and below - ~ ~
4a - - - 12 67 88 100 14 ~ot active at 8 lb/A and ~cw Table XV below sets forth additional field test ~ data which demonstrate further the effect of several compounds of the present invention on the male steri 1 ity and female sterility of field corn (B-~3).
'~`` ''' ' , ..... .... ..... .. j ... j ._ ...... .
. . . . ~
73~5 I ~ E~
c ~1 _~ h ~
~ ~ v c~
.~
~t ~ ~ r~¦ ~ o --E~op ~
O ~D O O
_t O ~ O 0 1~ ~P
C~
~ ~Q ~ ~I ~ co o o o ~
_1 O r-l ~ 1 0 u~ ~
-/ C~l o a: o ~ ~ ~ U~ O ~ O
o'p ~ ~l ~
o' r- o ~D
cr ~
-~ *
~ ~ ~ v a~ 0 u, 0 u~
- l ~ ~
~ ~ ~ ~ ~c ~ ~
X U~ (r) rl N
r~ l L~
.. .. . . . . ... . . . .. ... . . . . . . .
1 Z~73z5 Table XVI below sets forth field ~est data which demonstrate the effect of several compounds of Group A, fo~nula Il, of the present invention on the n~le sterility and feT~le sterility of sorghun (Inbred ~o. 8250).
... .
S T~BLE XVI
% Male Sterility and ~ Female Fertility of Sorghum at Various Dosaqes (lbs/A) (Field Test Data) ~ Sterility % FertilitY*
Exam~ e # 1~8 1/4 1/2 1 1/8 1/4 1/~ l _ 16, K salt 97 99 100 100 E E E F
43, K salt 10~ 100 100 100 P P P P
42, K salt 83 98 lOO lOO E E E G
*EaExcellent; G=Good; E=Fair; PaPoor.
Table XVII below sets forth additional field test dQta which demonstrate the effectiv of several compounds of Group A~ fo~Tula II, of the present invention on n~le sterility and fen~le fertility of sorghun (Inbred No. 7078).
TABLE ~ rI
9~ Male Sterility and ~ Female Fertility on Sorghum at Va,rious Dosages (lbs/A) (Field Test Data) Male SterilitY % Female FertilitY*
~ l/8 1~4 l/2 16, R salt 35 73 ~5 100 E E G F
43, K salt lOO lOO lOO 100 E F P P
42/ R salt 9 34 91 lOO E E E F
*E-Excellent; G~Good; F=Fair; P=Poor.
..
. ~ ~ . ...
.... . . . . _ _ ... . . . . _ . ... . ... .... . . . . . .. ..
7;~5 7 1~30 --T able XVIII below sets forth field test data which d~mons~rate the effect of several compounds of Group A, fo~nula II, of the present invention on m~le sterility and feT~le fertility of barley (Variety Henry).
TABLE XVIII
- ~ Male Sterility and % Female Fertility of Barley at arious Dosa~es (lbs/A) (Field Test Data) Sterility % Fertllity _ 16, R salt 32 56 92 99 93 96 75 56 10 13, K salt 2 4 4 8 95 100 100 96 43, K salt 4 22 48 77 99 97 94 76 42, K salt 3 4 4 43 96 100 100 81 Table XIX illustrates the activity of a representative co~pound according to this invention in corn.
TABLE XIX
Sterilant Activity in Corn .
Height Compound Dos~e Rate % Sterility Inhibition R .
,c~Na 12 l~o 18 O
(Exa~le 51) ~ ~ .
~7325 Table XX below sets forth field test data which illust~rates the activity of representative compounds of ~roup C, formula XXXI, of the present invention on male sterility o barley.
TABLE XX
__ _____ Examp1e 8 4 2 1 1/2 1/4 88a - 100 100 100 58 8~a - ~ 100 100 100 100 Table XXI below sets forth field test data which illustrates the activity of a representative compound of Group C, formula XXXI, of the present invention on male sterility of corn.
TABLE XXI
___ ____ Example 12 4 88,~ 100 ~.00 ~ . .
.
:: .. ...
~2~73~
Table XXII below sets forth field test data which illustrates the culm inhibition activity of several representative compounds of Group C, formula XXXI, of the present inven.tion on barley.
TABLE XXII
CULM INHIBITION (BARLEY) % INHIBITION AT RATE, LB/A
_______________________________________ ___________ Example a 4 2 1 1/2 1/4 8~a - 70 70 60 40 _ 89~ - - So 50 50 5~
Table XXIII below presents field test data which illustrates the hei~ht inhibition activity of a representative compound of Group CJ formula XgXI, of the present invention on corn~
TABLE XxIII
HEIG~T INHIBITION, % INHIBITION AT RATE, LB/A.
__ __________.__ ___________________________.___ .
xample 12 4 88~r 57 43 ~ , . . .
Table XXIV below sets forth field test data which - illustrates the e-ffect of several representative compounds of Group D,.formula XX~II, of the present invention as male sterility of corn.
TABLE XXIV
CORN, % MALE STERILITY AT RATE, LB/A
ample 4 2 1 1/2 1/4 1/8 IOOa - 100 80 62 85 lOl~ 100 9~ 96 74 6 lO5a - 100 100 28 25 Table XXV belo~ sets forth fiel~ .c t data which .:. .illustrates the effect of a representative compound of aroup ~, formula XXXII, of the present invention on male sterility of barley TA~LE XXV
BARLEY, % MALE_STERILITY AT RATE, LB/A
, ~X
~E~ 8 _~ 2 1 -~ 1/8 05a w - 100 100 100 100 .
. .
.
~2~ 5 _.
_ o o ~ --I ~ Ln 5:: C~ I
G~ 3 ~ _~
O
~ ~l s ~ ~1 e~ o ~ ~ I
J ~ ,cZl o 01 U~ ~ o U~
u~ ~n o --I ~ ~ f~
~ v - ml _~
~ C :
V ~
C ~ C5q 1 --o U~
I ~ ~ I o C: o U~
U~ o~1 --I
a~ ~ I
~, r ~;1 O ~-- O l_ C ~ I O ~ 0 o e O ~ I I I I ~
.'~ ~ .
) . 3 .
- :5 CS~ I O O O
O CO ~
C
i aJ
i~ ~ ~ (a cg "5 . ~ ~ GO C~
X
.. . .... .... . .
6.0 g- of crude methyl 1,6~dimethyl-2-phenyl-4-oxonicotinate is ~uspended in 6~ g- of 5% aqueous sodium hydrox:Lde solution. The reaction mixture is heated on a steambath (85) or two hours. The resulting homogeneous ~olution is cooled and acidiied with dilute HCl. The resulting solid iq collected by filtra~ion yielding 4.~ g.
o~ 1,6-dimethyl-2~phenyl-4-o~onicotinic acid. mp (acetonitrile/methyLene chloride) a 246-249OC (dec.).
Example 4a:
1.69 ~. of 1,6-dimetbyl-2-phenyl-4-oxonicotinic aoid i~ suspended in approximately 50 ml.of methanol. NaOH
pellets (0.305 gms) are added with stirring . Af ~er both the acid and the s~dium hydroxide dissolve the-solution is evaporated to dryness n vacuo. Sodium 1, 6-dimethyl-2-ph~yl-4~xonicotinate is then isolated a~ ~ gl assy, somewhat hygroscopic solid. Yield = 1.6 g-Exam~e 8 -Part a:
__ 12 gms of ethyl beta-~ethylaminocinnamate, 18 g. o~
ethyl propio~ylace~ate and 100 ~g of toluenesulfonic acid monohydrate are added to a 50 ml 3neck flask fitted with a .. ...
732~
nitrogen inlet, magnetic stirring bar, ther~ometer and a short-path distillation head (with recei~er). The reaction mixture is heated to 170 175C under a slow stream of dry nitrogen. Ethanol and wat2r are collected in the distillation receiver. After four hours the reaction mixture is cooled and poured into a large volume o~ ether (150 ml 3. A pink s~lid forms which is collected by filtration to yield 4.1 g. or ethyl 5-ethyl-1-methyl-2-phenyl-4-~xonicoti~ate. mp l(EtoAc) = 210-212C.
Part b-- 2.2 gm of ethyl 6-ethyl-1-methyl-2-phenyl-4-oxonicotinate is suspended in 35 ml of 5% aqueous sodium hydroxide solution. The resulting suspension is heated on a steambath for 4 nours, cooled and acidified with dilute ~Cl to yield 2.0 g. of 6-ethyl-1-methyl-2-pheQyl-4-oxonicotinic acid. mp (C~3CN) = 2~4 -245Co E~e 11:
Part a?
12~0 g. o~ ethyl beta-rnethylaminocinnamat~, 18 g. of ethyl 2-methylacetoacetate and 100 mg toluenesulfonic acid monohydrate is mi~ed in a 50 ml 3-neck flask itted with a nitrogen inlet, magnetic stirring bar, thermometer and a short-path distillation head (with rec~iver~. The reaction mixture is heated (170- 175C.) for seven hours under a gentl~
stream of nitrogen. Ethanol ~nd water are collected in the distillation receiver. The rea tion mixture is cooled and poured into 100 ml of dry ether. E~hyl 1,5,6-trimethyl-2-phenyl-4-~xonicotinate forms as a brownish precipitate.
Yield = 1.03 gms.
30Part b:
1.03 g. of crude e~hyl 1,5,6-trimethyl-2-phenyl-4-oxonico~}na~e is suspended in 20 ml of warm (85) 5~
a~ue~us NaO~ solution for 4 hours. Acidiication with dilute hydrochloric acid yields 0.3 g. of 1,5,6-tri-35methyl-2-phenyl-4 oxonicotinate mp (C~3CN) ~10- 214 ~LZ~37;~
Example 14 Part a A 5~00 ml 3-neck flask is fitted with a N2 inlet, magnetic stirring bar, thermameter and a Dean-S~ark trap with cond~nser. 2300 ml of dry methanol is added to the flask along with 244 g of 95% ~2SO4 and 352 g. of trimethyl orthoformate. 173 g. of 3-(4'-chlorobenzoyl)-4-hydroxy-6-methyl-2-pyrone is added and the reaction mixture is gently brought to reflux. The most volatile by-product of the reaction (methyl for~ate) is condensed and collected in -the ~ean-Stark trap. After 28-1/2 hours o~ refl~x the reaction mixture is cooled to room temperature and poured into 6000 ml of brine. The resulting suspension is extracted with methvlene chloride (6 x 250 ml ). Evaporation of the solvent yields 153 cr.
of 3-methoxycarbonyl-6-methyl-2-(4'~chlorophenyl)-4-pyrone,. mp (methylene chloride/ether) = 132C.
Part b:
A 1000 ml flask is fitted with a magnetic stirring bar and a sidear~ addition funnel. 500 ml of methanol, 30 ml of glacial acetic acid and 6~ g. o~ 3-~e~hoxycarbonyl-6-m~thyl-2-(4'-chlorophenyl)-4-pyrone are added. 120 ml. of 70~ aqueous ethylamlne is pl~ced in the addition funnel and added very slowly ~4 hr. addi,tion time~. 5~ ml ~f water is then added followed by 100 ml of concentrated ~Cl (cooling required~. The reaction mixture is allowed to stand undisturbed for 30 minut~s. The bulk of the methanol îs then removed in vacuo leaving 46.1 g. of methyl l-ethyl-6-methyl-2-(4l-chlorophenyl)-4-oxonicotinate.mp (methylene chloride/ether) = 217 -219oc ~xam~le 16:
~6~1 ~. of crude m~thyl 1-ethyl-6-methyl-2-l4 chlorophenyl)-4-~xonicotinate is suspended in 600 ml of 5 aqueous NaO~ solution and warmed to 80-85. Ater 1-1 1/2 hours at this temperature the reaction mixture is cooled f`~ !
~' ~
_~,, _,,_, _,, _, __,_ ~,, _ _ _ _, ,, ... . . .... . . .. -~Z1~32~
and acidified with dilute ~Cl. The resulting solid precipitate is collected by ~iltration, yielding 42 g. of l ethyl-~-methyl~2-(4'-chlorophenyl)-4-oxonicotinic acid, mp (methylene chloride~ether) - 235-237C.
Example 15:
4.64 g. of ethyl beta-ethylamino-4-chlorocinnamate, 4.61 g of technical ~rade diketene and 15 ml of methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The mixture is maintained at room temperature for 137 hours. The methylene chloride i5 removed in vacuo and the residue triturated with ether to yield 3.2 g. of crude ethyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate. mp (215-217C.) Example 15:
6 g. of ethyl beta-ethylamino-4-cblorocinnamate and 12 g. of et~yl acetoa~etate is mixed in a 50 ml 3-neck flask itted with a N2-inlet, magnetic stirring bar, therm~metar and a short-path distillation head (with receiver). The ~eaction mixture is heated (170~) for 10 hours. Ethanol and wa~er is collected in the distillation receiver. The reaction mixture is cooled and ~riturated with ethyl acetate/ether to yield 2.52 g- of athyl 1-ethyl-~-methyl-2 (4'-chlorophenyl)-4-oxonicotinate.
Example 17 Part a __ _ 69 g. o 3-methoxycarbonyl-6-methyl-2-(4'-chloro-phenyl)-4~pyrone, 5~0 ml of metha~ol, 90 ~1 of water and 30 ~1 o~ glacial acetic acid are mixed in a 1000 ml flask fitted with a magnetic stirring bar and a sidearm addition unnel. 1~0 ml of 70% aqueous ethylamine is added over the course of one hour. The reaction ~ixture is then allowed to stand at rocm te~perature for one hour, neutralized with dilute ~Cl and extracted with methylene chloride (2 x 250 ml , ~ x 150 ml ). The organic extracts a~e evapora~ed and th~ residue tri~urated with ether. The f .. . _ _ . . . . _ 73~
- 26 ~
first crop of crystals is pure methyl l-ethyl 6-methyl-2-(4'-chi~rophenyl)-4-oxonicotinate (33.1 (g.). The solid that forms upon further concentration of the mother liquor is pure alpha-[3-ethylamino-2-buteno~l]-be~a~ethylamino-4-S chlorocinnamate~ Yield = 11 g-~ and mp = 144~C (ether).
Part b 7 g~ of alpha-[3-ethylamino-2~utenoyl]-beta~
ethylamino 4-chlorocinnamate, 5.7 ~g- methyl iodide, and 20 ml of methylene chloride are mixed in a sealed flask t and stored ~or 22 hours at zoom temperature. The contents of the flask a~e then poured into a separatory ~unnel and washed with waterO Evaporation of the organic layer leaves 9.4 g.; of oil which is dissolved in 80 ml of tetra-hydrouran- 60 ml. o~ water and 4 mls of tr ifluoroaceticacid i5 then added and the mixture is allowed to ~emain at room temperature for two hours. Suosequent dilution with ` water and e~traction ~ith methylene chloride provides 8~0 g. o~ crude 4~xonicotin~te ester. This ma~erial is then heat~d in 80 ~l of 5% aqueous scdium hydroxide s~lution (85C.2 hrs.) and acidiied t:o yield 2.3 ~. of l-ethyl-5, 6-dimethyl-2- ~4 ' chloropherlyl)-4-oxonicotLnic acid. mp =
240.-242C. (acetonitrile).
~xample 20 8.7 g. of 3-methoxycarbonyl-6-m~thyl-2-(4'-chloro-2~ phenyl~ 4-pyrone is suspendecl i~ 100 ml of methan~l and 10 ml ~f water. In a se~arate~ flask, 7.01 ~g. of glycine, 3.12 g. of sodium hydroxide and 50 ml. of methanol arP
mixed and allowed to stir for 30 minutes to form a solution of the sodium salt of glycine. ~his solution is then added to the pyrone suspension with stirring. The resulting reaction mixture i5 allowed to stir at room temperature for five hours. 80 ml of water and lO ml of concentrated hydrochloriG acid is added. A precipitate forlns within a few minutes. This Ls collected by fil~ration to yiel~ 7.0 ~. o~ methyl 1 carboxymethyl-6-methyl-2-(4'--chlorophenyl) ... .. ... .... .. . . .
~Z~3Z~
~, 4-oxonicotina~e. mp (me~hanol/water) = 224co ExamDle 2 1 4.0 g. of 1-carbox~methyl-6-methyl-2-(4'-chloro-phenyl~-4-oxonicotinate is suspended in 40 g. o~ 5~
aqueous sodium hydroxide solution and heated at 80-85aC. for two hours. The re~ction mixture is cooled and acidified to give a white precipita~e. This precipitate is collecte~ by filtration to yield 2.9 gn o~ 1-carboxymethyl-6-methyl-2-~4'-chlorophenyl)-4-~xonicotinic acid. mp ~C~3CN) =
.1~ 158-162C.
ExamPle 22 Part a 10 g. of 3-methoxycarbonyl-6-methyl-2-(4'-chlo~o-phenyl)-4-pyrone, 1.65 g. glacial ac~tic acid and 100 ml lS of methanol are mixed in ~ 500 ml ~las~ fi~ed with a magnetic stirring bar and sidearm addition funnel. 6.15 g. of allylamine are slowly added (one hour addition time). Three hours later 20 inl of water and 8 ml of concentrated ~Cl are added. This reaction mixture is allowed to stand at room temperature for one hour, then is poured into 400 ml of water and extracted with methylene c~loride (2 x 100 ml ). Remo~al of the s~lvent yields 10 g. of c~ude methyl l-allyl-6~-methyl~2-(~'-chlorophenyl)-4-~xonicotinate.
Part b The crude oxonicotinate ester isolated above is suspended in 80 ml of 5% ,aqueous sodium hydroxide solution and heated at 85C. for 2-2 1/2 hours. Acidification of this reaction mixture with dilute ~Cl provides 6.7 g. of 1 allyl-6-methyl-2~(41-chlorophenyl)-4.-oxonicotinic acid. mp (acetonitrile) = 219- 221 5æL_ 47 6.0 ~ of 1,6~dimet~yl~2-phenyl-4-oxonicotinic acid is suspended in 200 ml of methanol. 1.0 g. of s~dium hydroxide is added. ~s soon as the acid dissolves a 3~5 solution of 5.52 gO of Br2 in 50 n~ of methanol is slowly added with stirring. The pH of the reaction mixture is maintained at 8-9 by the addition of extra sodium hydroxide as required. A precipitate of 3,5-dibromo-1,6-dimethyl-2-phenyl-pyrid-4-one forms. This material is collected by filtration and discarded. ~cidification of the clear filtrate yields 3.4 g. of 5-bromo-1,6-dimethyl-2-phenyl-4-oxo-nicotinic acid as a white solid. mp = 252 -2530C. (acetonitrile) , 73~s `;
B. N alkyl-6-aryl-~-oxonicotinates In another preferred aspect, this invention relates to cffmpounds of .he formula:
R5 ~ C02Y
(X) ~1 ~R2 (XVIII) wherein Rl and R2 are, independently, an optionally sub-stituted (Cl C6) alkyl or a (C3-C6) alkenyl group; Rs is hydrogen or halogen; Y is a hydrogen atom or a (Cl-Cs3 alkyl group; X is a hydrogen atom, a halogen atom, a trihalomethyl group, a (Cl-C6j alkyl group, a nitro group, a cyano group or a (Cl-C6) alkoxy group; n is an integer from 1 to 3;
and the agronomically acceptable salts thereof.
A~ong the preferred compounds of ~-he present invention are compounds of Group 3, Formula XVIII, wherein R~ and R2 are, independently (Cl-C6) alkyl, (Cl-C4) haloalkyl, alkoxy (Cl-C4) alky~ (Cl-C~), aryl ~C6-Clo) alkyl (Cl-C4), or ~C3-C6~ alkenyl; Y is a hydrogen, (Cl-C6) alkyl, or an alkali or alkaline earth metal cation, Rs is hydrogen or halogen, X is hydrogen, h210~en, trihalomethyl, ~Cl-C6) alkyl, ~Cl-C6) alkoxy, nitro or cyano; and n iS a~ integer from ~0 1 ~o 3.
Among the more preferred compounds of the present inven-tion aze compoun~s of Grou? 9, Formula X~lII, wherein Rl and R2 are, independently, (Cl-C4) alkyl; v is hydrogen, CH3, C2ns, Na or K; Rs is hycrogen or bromine; X .s hydrogen, methoxy, metnyl, .rifluoromethvl, iodine, bromine, chlorine or fluorine and n is an integer from 1 to 3 Among the most preferred compounds of this invention are compounas of Group B, Formula XVIII, where Rl is a methyl or e~hyl group; R~ is a methyl, ethyl, or n-propyl group;
~Bt ~Z~7~325 Rs is hydrogen or a bromine a~om; X is hydrogen, methyl, trifluoromethyl; or bromine, chlorine or fluorine atom and n is 1 or 2; and Y is a sodium or potassium cation, hydrogen, or a methyl or ethyl group;.and the agronomically acceptable acid addition salts thereof.
Typical compounds encompassed by the present invention include: ~
1,2-dim~thyl-6-(3~fluorophenyl)-4-oxonicotinic acid;
2-n-butyl-1-ethyl-6-(4-methoxyphenyl)-4-oxonicotinic acid;
1 allyl-6-phenyl-2-n-propyl-4-oxonicotinic acid;.
1-(3-chloropropyl)-2-methyl-6-phenyl-4~oxonicotinic acid;
1-(2-ethoxy methyl)-2 methyl-6 phenyl-4-oxonicotinic acid;
l-~enzyl-2-n-propyl-6-(4-trifluoromethylphenyl)-4-oxoni-cotinic acid;
1,2-di-n-propyl-6-(4-1uorophenyl)-4-oxonicotinic acid;
1,2-dimeth~1-6-phenyl-4- oxonicotinic a~id;
6-(4-chloropheny~)-1,2-~iethyl-4-oxonicotinic acid;
S-bromo-6-(4-chlorophenyl)-1,2-dimethyl-4 oxonicotinic acid;
6-14-chlorophenyl)-1~2~5-trimethyl-4-oxonicotinic acid;
1,5-dimethyl-6~ fluorophenyl)-2-n-p~opyl-4-oxonicotinic acid;
1,2-dimethyl 6~ naphthyl)-4-oxonicotinic acid;
6-(3,5-dichlorophenyl)-1-methyl-2-n-pro.pyl-4-oxonicotinic acid;
5-(4-chlorophenyl)-1-i-propyl-2-methyl-4-oxonicotinic acid;
2-i-propyl-1-methyl-6-phenyl-4~oxonicotinic acid and metal salts thereof;
ethyl 1,2-dimethyl-6-(4~fluorophenyl)-4-oxonicotinate me~hyl 6- (4-chlorophenyl) -1-ethyl-2 met~yl-4-oxonicotinate n propyl l-me~hyl-6-phenyl-2-n-propyl-4-oxonicotinate l-propyl l-allyl-6-(4-bromophen~ 2-methyl-4-oxonicotinate n-butyl 6-(3-chlorophenyl)-1-ethyl-2-n-propyl-4-oxonicotinate n~hexyl 1,2-dimethyl-6-[4-iodophenyl)-4-oxoniootinat~
and ~he agronomically acceptable salts ~hereof.
~7 i ~
.. . . ~ ~
~07325 The Group B compounds of the present i~vention are prepared by various synthe~ic rou~es found in the art. In particular, the Group B ccmpounds of the présent invention can be prepared by the following reaction sequence:
X ~ Ccg2COC285 ~ ~ ~ X
.(XIX) (XX)' OH
~ O (C83C)20, 8254 ~
(~XI) OH 1l ~ COCH3 R NH2 CCH3 H3COH, ~ n CH H3COH
O'~ O (H3C0)3CH > 3 (XXII) ~XXIII) COCH3 1) NaOH ~ ~ COH
N CH X ll c~3 R R
, (~XIV) (XX~) ~ . .. , , ~
Alternatively, the Group B compounds can ~e prepared by the following reaction sequence:
X ~ CCH2COC2H5 + PC13+PC15 ~ ~~~
(XIX) L C-CH3Cl (~XVI) HN ~ ~ R2 ~ Rl~H +R2_ccH COC H
0. 0 ' ' coc2H5 ~ Cl HN R2 (X~VII) (acyclic C-acrylated intermediate) COC2~s g t~ , ~ (XXIX) ~XXVII-I) \ ~ ~ / 1) NaOH
~ n ~ 2 ) ~
.. ~ . .
., ~ . .
.
73;2~i ~ 33 -In the latter reaction sequence, the cyclization step yielded one or more of the pyridones, XXVIII, XXIX and XXX. In general, a pyrolysis (neat) of the acyclicC-acrylated intermediate (XXVlI) ! yielded the oxonicotinic acid (XXX) directly. Cyclization of the acyclic intermediate (XXVII) in aprotic solvents at lower temperatures gave varied results dependin~ on reaction conditions and the X, Rl and ~ substituent effects. In scme cases, mixtures of products were obtained (ester, ester hydrochloride and acid), in other cases only one of the products was isolated.
me salts of the Group B oxonicotinic acids of the present invention can be prepaxed by generally kncwn procedures such as dissolv-ing the acids Ln a protic solvent such as methanol, ethanol, water and the like and treating them with an equivalent amount of a strong base such as sodium or potassium h~droxide and the like, and recovering the salt either by stripping off the solvent or precipitating the solid out with diethylether, hexane, benzene and the like.
Table IV below is presented to illustrate the m~re preferred compounds of the present invention. miS table and Table V
in which the analytical data is presented for these ccmFo~nds are not 2~ to be interpreted in any way as being limits on the breadth and scope of the present invention:
TABLE rv. LIST OF a~ouNDs 2 (XXVIII) ~ l ~...,~
- X
~ _ ., r~ O
V s s _, ~
5 Z 5 ~ E I ; I c~ 1 2 1 1 1 ~ 5 .
O
,C
~ ~ r~ I ~ I o I o I o I ~ I 1` In ' I 1-- 1 ~1 dPI E3 Z ~: Z :s: Z ~: Z V ~ Z ~:
.L~
~ P~
r~ a~ ~ v ~ ~ X x a~ X O ~1 . .... ~V
. .
Q~
~L ~ ~ O ~I ~ W ~ 0 ~1 . .
.
.
V
~ X
O o t~
JJ ~
U~ ,1 s~ ~:
~ I I .1 1 ~ I I I I I I ~ I I t â) . ~
O
S ` `
~ ~5 dP
O
~1 , _ .
:æ ~ æ ~ z ~ z P9 z ~ z ~ ~ z ~ I z IY r ~; ~ ~c) u ~ u ~ v ~ u c~ u c~ c~ u c~ o ~ .
a~ U ~ ~ C~ V C) C~ O ~ ~ O ~
S~
~ u ~ ~ x ~
~1 ~ ) h ~ ~ _I ~ ~ ~ ~ ~ ~ _ 'V ~ ~ ~ ~ H H ~ ~ - O C) I~ C) U C ~ J ` /
C~
a) sUI '1 ~ ~ ~¢
X
~d :
~`~ . , ' .. - ~ ....... . ..
~2~73;~5 -C
o U~
-~, l l l l l l l l l ~; I I I I I I I I, ,_ ..~
o o ~' ....
æ z ~ z;
c.) c.) c.~ c.) c.
~ 1 cl I c ~ 3 ~ ~ u ~ ~ eG
c) u xl ~D 8 c~ æ
~ ~ .
X ~ ~ I~ - ~ -. . r~
~2~73Z5 TAE3LE V p;N~,yTICAL ~TA
~C02Y
( XXV-I I I ) X ~ ~
, ~ ' ' .
~
7;3Z5i Elemental _ Analysis a Example~ ~p (C) %C ~ ~ % ~
4~154 700 ~3 6.32 5.16 71.03 6.39 5.33 49~11 213 ~
502~0-222o5 69.12 5.39 5.76 68.65 5.34 6.1~ -S0 a _ _ __ __ __ _ 51 216- 217 70.02 5.88 S .45 70.26 5.93 5.69 51 a ___ __ _ __ _ 52 ~13 -211 70.83 ~ .32 5.16 70.40 6.29 5.60 52 ~ _ _ __ __ ~_ _ 129-l~o 72.82 7.40 4.47 1~ 53 72033 7.35 4.73 53 a 54 150 70 41 6 ~3 5 19 54 a ___ __ __ __ _ 213-215 70~02 5.88 5.44 69.3~ 5.69 5 ~ 2 55 a ~ 142 64 36 4 635 6 14 6 gi4 56 a 57 198 dec 62.85 5.~8 4.58 6~ ~ 82 5.31 4.~
58 236-238 dec 60.55 4 36 5.Ci4 58a 212-214 dec rl 75 4 84 4 80 59 ~
F~ . . ' , , .
.
~2C~73~
Table (~) (cont.) Elemental AnalYsisa Exam~le mP ~C) % C % ~ ~ N % X
59 -~
-1~7-129 ~5060 6.38 4.03 --6~.78 6.54 4.21 --218-220 a~c 70~02 5.88 5.4 69.75 5.96 5.62 271-2 dec 45.86 3.8~ 3.82 4~.R2 3.22 4.06 --62 29709 dec -~
__ __ _ _ _ ~
~83-4 dec 45.5$ 3.28 3,79 --45.63 3.37 3.79 --.
63 ~300 __ __ __ __ 265-6 dec -- -- -- --6~
226-236 dec 65.92 5.53 5.13 65.29 5.34 5.68 . __ 66 114 48,34 . 4~06 3.76 --48.45 ~.04 3.68 --269-271 dec 52019 3.76 4 ~s --3Q . 52.04 3.69 4.28 ~ ~~
67 294 6 dec ~ .
~ . .
'lZ~'7~;~ 5 Ta~le ( V` (cont.) Recryst. Elemental Analysisa Solvent m~ (C) % C % ~ % N % X
..
68 ~oluene 201-2.5 69.20 5.28 3~67 --68.93-5.29 3.54 ----169-173 67.89 4.56 3.96 --fi7.8 ~.50 4.25 --~ 9 ~
~ 70 --212-214dec 54.33 4.53 3.73 --~3.92 4.65 4.01 220-222dec 57.88 3.89 4.50 ~
58.07 3.8~1 5.3~ --71 ----) 310 ---- --~
_o _ ~ __ __ 72- __212-214dec 67.13 5.63 3~91 --67.20 5~59 3.40 --~-260-3 dec 73.70 5.15 4.7B --73.34 5~14 4.76 --2~ ?i 225-235de~ -- - ~- ~~
X=CI
74- --213-215dec 56.15 5.07 4.09 20.72 55.79 4.g; 4.62 20.34 ~~200-2-dec Poor elemental analysi~
--184-187 62.85 5.28 4.58 --62.03 ~.27 4.89 --76 . --16B-210dec -~
__ __ __ __ -- 121-3 dec 71.56 6.71 4.91 71.67 6~76 5.29 --~, ~ .
73;~5 ~ 41 Table ( vj ~cont.) i . - Recryst. Elemental Analvsisa .
~ ~olvent ~np (C~ ~ C ~ ~ ~ N ~ X
77 80 100 __ __ __ __ __ __ _ CCN 257-8 52.19 3.75 4.35Br 24~81 52.55 3.76 4.36Br 25.18 __ _ _ __ __ __ __ __ __ __ .
.
10 a/ Generally the elemental analysis for the Na salts were either not perforJned ~r gave poor rlesults due to the hygroscop~c nature of the results.
~ ,' . .
~Z[)73~'3 The following examples are presented to illustrate the methods for preparation o the compounds o~ the pres~nt invention. Again these examples are not to be int~rpreted as being limits upon the breadth and scope of the present invention.
~hlorocinnamoyl chloride A solution of 60g ~0.312 mol3 ethyl benzoyl acetate in 96 ml (150~) of phosphorus trichloride is addèd dropwise to lSOg(0.72 mol) Of phosphorus; pentachloride under nitrogen. The suspension that forms is cautiously brought to reflux temperature (ECl evolution observed) and is refluxed and stirred for 2-2 1/2 hrs. The solution that forms is stripped of phosphorus trichloride and ph~sphorus oxychloride at atmospheric pressure (76-82c). The pot residue is distilled at 97-1080G/0.75mm to give 54g ~86% yield) of produck as an isomeric mixture.
~Chloro(4-chloro)cinnamoYlchloride _ _ A solution of 22~67g(0~1 mol) ethyl (4-chloro benzoyl) acetate in 70 ml of phosphorus trichloride is added dropwise to 52~g(0~25 mol) o phosphorus pentachloride under nitrogen ~HCl e~olution ob~3rved). The suspension that forms is stored at room temperature for 1/2 hr. and at reflux tempera~cure for 2 1/2 hrs. The solution that ~orms is stripped of phosphorus; trichloride, phosphorus oxychloride and phosphorus; pentachloride at 80-90C
~pot temperature)/ambient pressure, 90-110C ~po~ temperature) ~ - ~ 0 mm and 90~-130 ~pot temperature)/0.15 mm. A
yield of 23~35g(99%) of crude product is obtained as the pot resi~ue;
. .
~Z~73~5 Ethyl~-methylamino crotonate 186g(1.43 ~oL) of ethyl acetoacetate is added dropwise over a period of 10 min. to a solution of 450 ~l. of methylamine ~40~ in water) in 150 ml. of water (exotherm from room temperature to 55C observed). The mixture is stirred at room temperature for 2 hrs. and is extracted ~ith chloroform. The chloroform extract is washed with water, dried over magnesium sulfate and concentrated ~n vacuo. The residue oil is vacuum distilled at 76-83C/0.1 mm to afford 143.6g(70~ yield) of yellow oil.
Ethyl 3-methylamino-2-hexeneoate A solution of 31.649(0.2 moL) ethyl butyryl acetate and 5 ml~ of ethanol is added dropwise ~ver a period of 5 min. to a solution o~f 38.7g(0.6 mol) ethylamine (70~ in water) and 50 ml o water (exotherm from 28C to 33C ob-served). The mixture is stirred at room temperature for 18 hrs. and is extracted with three 100 ml por~ions of methylene dichloride (MDC). The methylene dichloride ex-tract is dried over magnesium sulfate and concentrated in vacuo to af~ord 30.7g(83~ yield) o product, a colorless oilO
Example 48 Eth~l 1,2-dimethYl-6-~henYl-4-oxonicotinate .
2.0gl0.0065 mol.) of ethyl l,Z-dimethyl-6-ph~nyl-4-oxonicotinate hydrochloride (see Example 2 below3 is dis-solved in water and treated with dilute sodium hydroxide (p~ adjusted to about 8). The precipitate formed is isola~ed by vacuum filtration to afford l.gg of product, mp 154C (MDC/ether recrystallization)~
~ æ~ 9 .
Ethyl l r 2-dimethyl ~ -oxoni otinate Hydrochloride 9O2~(0~046 mol~ of ~-chlorocinnamoyl chloride (iso mer mixture)l di5solved in 75 ml of methylene dichloride is ~dd~d dropwise ~o a solution of 6~g(0.046 mol) of ethyl ~-methylaminocrotonate and 7.4g(0.0937 mol) of pyridin~ in 100 ml or methylene dichloride under nitrogen . . .
_ 44 -(5 min. addition time, slight exotherm from 25 to 35 C.
The reaction mixture is allowed to stand for 1 1/2 hrs.
I The methylene dichloride layer is isolated and passed through a 2 inch column of silica gel. The column is eluted with an additional 200 ml of methylene dichloride and the light yellow colored eluate is concentrated in vacuo to yield 15g of ethyl 2-(3-phenyl-3-chloro) acrylyl-3-methylamino crotonate, an oil.
15q (0.0488 mol) of e~hyl 2~(3-phenyl-3-chloro) acrylyl~-methyl aminocrotonate is suspended in 150 ml of xylene and refluxed for 3 hrs. The reaction mixture is cooled and the sus~ension is vacuum filtered. The filter cake i5 dried ~o afford 5.79(38% yield) of product, mp 211-213C.
lS Example 50 J
Sodium 1~2-di~ethyl-6-phenYl-4-oxonicotinate 42g (0.1366 mol) o~ ethyl 2-(3-phenyl-3-chloro) acrylyl-3-methyl aminocrotonate is placed in a flask and beated to 140C under nitrogen (nil:rogen sparge started at this time). The pot temperature was slowly raised to 157C over a period of 40 min. The~ rea~ion mixture was cooled and extracted into 5~ aqueous sodium hydroxide.
Acidification o the basic extracts provided lO~g (30%
yield) of 1,2-dimethyl-6-phenyl-4-oxonicotinic acid, mp Z5 220-225~C (MDC/ether).
15g (0.01617 mol) of 1,2-dimethyl-6-phenyl-4-oxonico-t ~ic acid is suspended in 200 ml of methanol and to it there is added 2.71g (0.0678 mol) of sodium hydroxide pelle~s. The solution formed is concentrated in vacuo to afford 159 (92% yield) of proauct.
Example 54 Sodium_l-methyl-6-~henyl -2-pro~yl-4-oxonicotlnate A solution of 11.4g (0.057 mol) k-chlorocinnamoyl chloride and 75 ml of methylene dichloride is added over a period of 20 min~ to a solution of 8.6g (0.054 mol) ethyl 3-methylamino-2~hexenoa~e, 9.0g (0.114 mol) pyridine ~2~73Z~
. ' ' .
and 100 ml of methylene dichloride under nitrogen (slight ', exotherm from 25-36C). The mixture is allowed to stand at room temperature for 1 1/2 hrs. and is washed with water. The methylene dichloride solution is passed through a 2 inch column of silica ~el and is concentra~ed in vacuo to afford 13g of ethyl ~3-phenyl-3-chloro~acrylyl-3-methylaminæ-hexeneoate, an oil.
13g (0.0387 mol) of ethyl ~3-phenyl-3-chloro~ acrylyl-3-methyl-amino-2 hexeneoate is dissolved in 200 ml of xylene and is refluxed and stirred for 4 hrs. The solu-tion is washed with 30 ml of 6N hydrochloric acid. The aqueous washings are neutralized and the precipitate formed is isolated to afford 4O5g of ethyl 1-methy~6-phenyl-2-propyl-4-oxonicotinate.
4.5g (0.015 mol~ of ethyl 1-methyl-6-phenyl-2-propyl-4-oxonic¢inate is suspended in 60g of 5~ sodium hydroxide in a 1:1 mixture of methanol and water. The mixture is heated at 85C and stirred fo~ 2 1/2 hxs. The solution formed is acidified and the suspension formed i5 vacuum filtered. ~he filter cake is dried to afford 2.7g of 1-methyl~6-phenyl-2-propyl-4-oxonicotinic acid, mpll50C
(MDC/ether). An additional 0.59 o~ 1-methyl-6-phenyl-2-propyl 4-oxonicotinic acid is obtained by extraction of the xylene solution with 30 ml of 1% sodium hydroxide and acidification of the basic extract.
- 2.19 (0.0067 mol) of 1-methyl-6-phenyl-2-propyl-4-oxonicotinic acid is suspended in 50 ml of methanol and to it there is added 0.295g (0.0074 mol) of sodium hydro-xide pellets. The solution is concentrated in vacuo to afford l.9g (97% yield) of product.
- Exam~lê 57 .
yl ~-(4-chlorophenyl)-1,2-dimethyl-4-oxonicotinate A solution of lOg (0.04~5 ml) ~-chloro~4-chloro) cinnamoyl chloride in 50 ml of methylene dichloride is added dropwise over a 10 min. period to a solution of 6.08g ~0.04~5 mol) ethyl ~-methylaminocrotonate, 6.72g (0.085 mol) of pyridine and 200 ml of methylene dichloride ~Z~32~i _ 46 -(slight exotherm from 25 to 34C). The mixture is stirred at room temperature for 18 hrs. and is washed with water.
The methylene dichloride solution is vacuum filtered through 25g of silica gel and the filtrate is concentrated in vacuo to aford 12~55g of ethyl [3-(4-chlorophenyl)~3-chloro] acrylyl-3-methylamino-crotonate, an oil.
A solution of 12.55g (0.037 mol) ethyl [3-(4-chloro-phenyl)-3-chloro] acrylyl-3-methylamino crotonate in 50 ml of xylene is refluxed and stirred for 2 1/2 hrs. under nitrogen. The suspension formed is vacuum filtered to afford 6.5g (52~ yield) of ethyl 6-(4-chlorophenyl~-1,2-dimethyl-4-oxonicotinate hydrochloride (Example 27~.
A suspension of 6.5g (0.019 mol~ ethyl 6-(4-~hloro-phenyl)-lt2-dime~hyl-4-oxonicotinate hydrochloride in 150 ml of water is treated with sodium hydroxide tpH adjusted to about 8). The suspension formed is vacuum filtered and the filter cake is washed with water and dried to afford 4.~9 (43.3% yield) of product, a white solid, mp 198C dec (Toluene).
_ample 58 Sodium 6-(4-ChloroP~yl)-l,2-dimethyl-4-oxonico~inate 1.5g (0.019 mol) of 50% aqueous sodium hydroxide is added to a suspension of 2.9g ~0.0095 mol) ethyl 6-(4-chlorophenyl)-1,2-dimethyl-4-oxonicotinate in 75 ml of water. The mixture is refluxed and stirred for 15 min.
and cooled to room temperature. The solution is extracted with methylene dichloride and the aqueous solution is acidifi~d to pHl with 12N hydrochloric acid. The suspen-sion formed is vacuum filtered and the filter cake is dried to afford 1.8g (68% yield) of 6-(4-chlorophenyl)-1,2-dimethyl-4Oxonicotinic acid, mp 236-238C dec. I
0.52g (0.0065 mol) o 5D% aqueous sodium ~Ydroxide is added ~o a suspension of 1.8g (0.0065 mol) 5-(~chlorophenyl)-1,2-dimethyl-4-oxonicotinic acid in 35 ~ 1 of meth~nol.
The solu~ion formed is allowed to stand at room temperature ,, , , , `
~2~73,~5 ~ 47 -for 1 hr. and then is concentrated in vacuo. The con-centrate is washed with two (25 ml) portions of diethyl ether and dried to afford 1.79 (87% yield) of product.
~xample 67 Sodium 6-(4-BromophenYl)-1,2-dimethyl-4-oxonicotinate A solution of 12g (0.043 mol) ~-chloro(4-bromo) cinnamoyl chloride in 25 ml of methylene dichloride is added dropwise over a 3 min. period to a solution of 6.15g (0.043 mol.) ethyl ~methylamino crotonate, 6.8g (0.086 mol) of pyridine and 200 ml of methylene dichloride (slight exotherm from 25C to 33C). The solution is stirred at room temperature for 3 days and is washed with 200 ml of water. The methylenP dichloride solution is vacuum filtered through 25g of silica gel and the fil-trate is concentrated in vacuo to aford llg (66~ yield) of ethyl ~3-(4-bromophenyl)-3-chloro~ acrylyl-3-methyl-amino crotonate, a brown oil.
119 (0.0284 mol) of ethyl [3-(4-bromophenyl)-3-chloro3 acrylyl-3~m~thylamino crotonate is dissolved in 10 ml of toluene and 50 ml of xylene and is re~luxed and stirred for 4 hrs. under nitroyen. The suspen~ion formed is stirred at room temperature for 18 hrs. and is vacuum filtered~ The filter cake is washed with hexane and dried to afford 5~3g (48.%) of ethyl 6-(4-bromophenyl)-1,~dimethyl-4-oxonicotinate h~drochloride, mp 206-210C dec.
5.3g (0.~14 mol) of ethyl Ç-~4-bromophenyl)-1,2-dimethy~4-oxonicotinate hydrochloride is suspended in 100 ml of water and to it there is added 5g (0.0625 mol) of 50% aqueous sodium hydroxide. The mixture is refluxed and stirred for 1 hr. and the solution formed is cooled to room temperature. The solution is extracted with methylenedichloride and the aqueous solu~ion is acidified to pH lwith 12N hydrochlorio acid The suspension formed is vacuum filtered and the filter cake is washed with water and dried to afford 4g (89% yield) of 6-(4-bromo - phenyl~-1,2-dimethyl-4-oxonicotinic acid, mp 269-271C
dec.
~ ' i ~L2073~5 . 48 _ 2g (0.0062 mol) of 6-(4-bromophenyl)-1,2-dimethy~4-oxonicotinic acid is suspended in 50 ml of methanol and to it there is added 0.5g (0.0062 mol) of 50~ aqueous sodium hydroxide. The solution formed is allowed to stand at room temperature for 1 hr. and is concentrated in vacuo~ The concentrate is washed with 50 ml of diethyl -ether and dried to afford l.9g (89% yield) of product.
Example 75 I Ethy~6-(4-chlorophenyl)-l-methyl-2-n-propyl-4-oxonicotinate h~drochloride A solution of 15g (0.064 mol) ~-chlor~ (4-chloro) cinnamoyl chloride in 50 ml of methlene dichloride is added dropwise over a 3 min. period to a stirred solution of lO.9g (0.064 mol) ethyl 3-methylamino-2-hexeneoate and lO.lg (0.128 mol) of pyridine in 200 ml of methylene dichloride ~slight exotherm from 25C to 34C). The solution formed is stirred at room temperature for 18 hrsO and is washed with water. The methylene dichloride solution is vacuum filtered throu~lh silica gel and the filtrate is concentrated in vacuo to afford 18.5g (78%
yield) of ethyl ~3-(4-chlorophenyl)-3-chloro3 acrylyl-3-methylamlno~2-hexeneoate, a brown oil.
A solution of 18.5g (0.05 mol) of ethyl [3-(4-chloro-phenyl)-3-chloro] acrylyl-3-methylamino-2-hexenéoate in 15 ml of toluene and 60 ml of xylene is refluxed and stirred for 3 hrs. under nitrogen. The suspension formed is allowed to stand at room temperature for 8 days and is v~cuum filteredO The filter cake is washed with toluene and hexane and dried to afford 4.3g (23% yield) of product, mp 200-202~ dec.
Example 76 - ~
-Sodium 6-(4-chlorophenyl)~l-methyl~2-~-pro~yl-4 oxonicotinate 4.09 (0.0 5 mol) of 50~ aqueous sodium hydroxide is added to a suspension of 2.7g (`0.01 mol) ethyl 6-~4-` 35 chlorophenyl)-1-methyl-2~n-propyl-4-oxonicotinate hydrochloride in S0 ml of water and 10 ml of ethanol. The mixture is refluxed and stirred ~or 3 hrs, allowed to 5tand at room .
~2~73~5 . 49 temperature for 18 hrs., refl'uxed for an additional 1 hr.
and cooled to room temperature. The solution formed is extracted with three 50 ml portions of methylene dichloride I and the aqueous solution is acidified to pH 1 with 12N
hydrochloric acid. The suspension formed is stirred at room temperature for 3 hrs. and is vacuum filtered. The filter cake is dried to afford 1.65g (54% yield) of 6-(4-chlorophenyl)-~methyl-2-n-propyl-4-oxonicotinic acid, mp 184-187C.
0.42g (0.0052 mol) of 50% aqueous sodium hydroxide is added to a suspension of 1.6g tO.0052 mol) 6-(4-chloro-phenyl)-l-methyl-2-n-propyl-4-oxonicotinic acid in 25 ml of methanol. The solution formed is allowed to stand at , room temperature for 1 hr. and is çoncentrated in vacuo.
15 The concentrate is dried to aord 1.5g (88~ yield3 of Product .
ExamPle 78 Sodium 5-Bromo-1,2-dimethyl-6-phenyl-4-oxonicotinate 2.0 g (0.0125 mol~ of bromine dissolved in 50 ml. of methanol is added dropwise over a l5 min. period to a solution of 2.7 g (0.00877 mol) ethyl 1,2-dimethyl-6-phenyl-4-oxonicotinate hydrochloride (Example 2) in 15 ml 'of methanol and 15 ml of water. The suspension formed is vacuum filtered and the filter cake, a yellow solid, is suspended in 60 9 of 5% a~ueous sodium hydroxide. The mixture is stirred and heated at 85C for 2-1/2 hrs. and is acidified with hydrochloric acid. The suspension formed is vacuum filtered to afford 2.4 9 (85~ yield) of 5-bromo-1,2-dimethyl 6-phenyl-4-oxonicotinic acid, mp 257-258C (CH3CN)-2.1 g (0.065 mol) of 5 bromo-1,2-dimethyl-6-phenyl-4-oxonicotinic acid is suspended in 50 ml of methanol and to it there i~ added 0.29 g (0.007 mol) of sodium hydroxide pellets. The solution formed is concentrated in vacuo to afford 2.1'g (94% yield) of product.
I
, . ~Z~
C~ N-alkyl-5-aryl-4-oxonicotinates In yet another preerred aspe~t, this lnvention relates to compounds of the formula:
(X)n ~ c~Z,y 6 ~ /~2 (X~XI) .
wherein Rl is an ~ptionally substituted (Cl-C6) alkyl group; R2 is a (Cl-C~) alkyl gxoup; R6 is a hydrogen atom or a (Cl-C4) alkyl group; Y is a hydrogen atom or a (Cl-C6) alkyl group or radical; X is a hydrogen atom, a halogen atom, a trihalomethyl group, a (Cl-C6) alkyl group, a nitro group, a cyano group or a (Cl-Cg) alkoxy group; and n is the integer 1 or 2; and the agronomically acceptable salts thereof.
Among the pre~erred compounc~s of the present inven-tion are compounds of Group C, Formula (X~XI) wherein Rl and R2 are, independently, ~Cl-C6) alkyl, (Cl-C4) haloalkyl, alkoxy ~Cl-C4) alkyl (Cl-C~), aryl ~C6-Clo) alkyl (Cl C4), or ~C3-C6) alkenyl; Y is hydrogen, ~Cl-C6) alkyl, or an alkali or alkaline earth metal cation; R6 is hydrogen~(Cl-C4) alkyl -: X is hydrogen, halogen, trihalomethyl, (Cl-C6) alkyl, ~Cl-C6) alkoxy, nitro or cyano; and n isthe integer 1 or 2.
Among the more preferred compounds o~ the present invention are compounds of Group C, Formula (XXXI) wherein Rl is (Cl C6) alkyl, R2 is (Cl-C3) alkyl; R6 is hydrogen or (Cl-C4) alkyl, Y is hydrogen, methyl, ethyl or a sodium or potassium cation, X is hydrogen, (Cl-C6) alkyl or F~
.
.
~ILZ~73;25 halogen and n is the integer 1 or 2.
I Among the most preferred compounds of this invention are compounds of Group C, Formula (XXXI) wherein Rl is a methyl or ethyl group; R2 is a methyl group; R6 is a hydrogen radical or a methyl group; and Y is ethyl or a sodium or potassium cation; and the agronomically acceptable acid salts thereof~
, ~2'C~732S
Typical compounds encompassed by the present invention include:
1 1,2-dimethyl-5-phenyl-4-oxonicotinic acid l-ethyl-2-methyl-5 phenyl-4-oxonicotinic acid 1,2,6-trimethyl-5-phenyl-4-oxonicotinic acid 1,2-diethyl-5-phenyl-4-oxonicotinic acid 2-ethyl-1-methyl-5-phenyl-4-oxonicotinic acid 1,2-dimethyl-5-(4-chlorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(4-chlorophenyl)-4-oxonicotinic acid 1-ethyl-2,6-dimethyl-5-(4-chlorophenyl)-4-oxonicotinic acid 1,2-diethyl-5-(4-chlorophenyl)-4-oxonicotinic acid 1,2-dimethyl-5-(3-chlorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(3-chorophenyl)-4-oxonicotinic acid 1-ethyl-2,6-dimethy~-5-(3-chlorophenyl)-4-oxonicotinic acid .
.., ,. , . _,:
,.. .
1-ethyl-2-methyl-5-(4-trifluoromethylphenyl)-4-oxonico-tinic acid ~ dimethyl-5-(4-fluorophenyl)-4-oxonicotinic acid 1-éthyl-2-methyl~5-~4-~luorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(3 fluorophenyl) 4-oxonicotinic acid l-~thyl-2-methyl-5-(4-bromophenyl)-4. oxonicotinic acid 1,2-dimethyl-5-(3,4-dichlorophenyl)-4-oxonicotinic acid l-ethyl-2-methyl-5-(3,4-dichlorophenyl)-4-oxonicotinic : 25 acid 1,2,6-trimethyl-5-(3,4-dichlorophenyl)-4-oxonicotinic acid 1,2-diethyl-6~methyl 5-(3,4-dichlorophenyl)-4-oxonicotinic acid i ~L2~732~
2-ethyl-1,6-dimethyl-5-(3,4-dichlorophenyl)-4-oxonicotinic aoid l-ethyl-2-methyl-5-(2,4-dichlorophenyl)-4-oxonicotinic acid 1-ethyl-2-methyl-5-(4-methylphenyl)-4-o~onicotinic acid and the agronomically acceptable salts thereof.
The compounds of the present invention can be prepared by various synthetic routes found in the art.
Tables VI and VII below are presented to illu5-trate the more preferred compounds of this aspect of the presentinvention and related compounds and the analytical data for these compounds.
General Syntheses O, R2~C02Et ~ RlN~3i2 .. ~ C02Et lnert so vent ¦ ~
~ 2 St~p 2 _ ~ ~ ~
inert solvent X R2 optional acid acceptor Rl ~C33 P ~ ~ ~I R2 CH3 ~1 DMF, Et3N
Step 4 1) Na~H, H20, ~ ~
....... _ __ ~ X~-- C02H
2) H~
, 732~i - 53a -Ste~ 2 :
1) MCC, benzene, ether other inert solvent 2) acid acceptor cptional 3) 0 - 100, pref 0-50 ~:
1) DMF solvent, excess amide acetal 2) basic catalyst optional (Et3N) 3) 20-150, pref 50-100 ~:
1) aqueous NaOH, Na2C03 other bases 2) cptional miscible co-solvent (EtOH,MeOH) 3) acidification with HCl, H2SO4 etc~
:~L2~73~
TABLE VI - List of Group C Compounds X{~ co2Y
Rl Example ' Xl Rl R2 6 Y
_ _ _ _ 79 H H H Me Et H H H Me H
80a H H H Me Na 81 H Et H Me H
81a H Et H Me Na 82 H Me Me H Et 108 3 H Me Me H H
83a H Me Me H Na 84 H Et Me H H
; 84a H Et Me H Na H Et Me Me H
1585a H Et Me Me Na 86 H H Me Me H
. 86a H H Me Me Na 8 7 4-Cl Me Me H
8 8 4-Cl Me Me H H
208 8 a 4-Cl Me Me H Na 89 4-Cl Me Me Me H
89a 4-Cl Me Me Me Na 4-Br Me Me H H
90a 4-Br Me Me H Na 25 91 4-Br Me n-Pr H H
91 a 4-Br Me N-Pr H Na 92 4-Br n-Hex Me H H
9 2 a 4-Br N-Hex Me H Na 9 3 4-Br Me Me Me H
309 3 a 4-Br Me Me Me H
.
TABLE VI contd 55 Example Xl Rl 2 6 9 4 4-C1 0 Me H H
9 4 a 4-C1 0 Me H Na 9 5 H 4-Fp Me H Et 9 6 H 4-Fp Me H H
9 6 a H 4-F0 Me H Na ~Z~732S
TABLE VII - Analytical Data - Group C Compounds Example mD(C) %C ~H %N %X
79 178-180 -- _ _ 26~- 267 80a -- --81a -- -- --82 148- 150 70.83 6.32 5.16 70.71 6.gO 5.23 83 227-228 69.12 5.34 5.76 68.80 5.51 6.07 83a -- ~
84 167-170 70.02 5.88 5.4~ --70.04 6.04 5.57 84a -- -- -- -- --163- 16S 70.83 6.31 5.16 70.78 6.49 5.82 85a ~ _ 86 272- 273 69.12 5.39 5.76 69.00 5.41 5.95 86a -- ~ -- -- -- ~
87 200-201 62.85 5.28 4.5~ 11.60 63.14 5.33 4.79 11058 88 239- 240 6Q~5 4.36 5.04 12.77 60.33 4.27 5.28 12.82 88a -- -- -- --89 240- 243 61.75 4.84 ~L.80 12.16 52.13 4.90 4.96 12.26 39a _ _ _ _ _ 266- 268 52.19 3.75 4.35 24.81 52.32 3.69 4.33 34.75 90a -- -- -- --91 237-239 5~.3~ 4.61 4.00 22.82 55.22 4i68 ~.21 22.21 91a ~
92 148- 150 58.17 ~.65 3.57 20.37 57.86 5.51 4.51 20.23 92a ~
93 228- 230 53.59 4.20 4.17 23.77 53.65 ~19 4.64 23.34 ~ ~-J
~2~73~5i TABLE VI I con td .
E~xample mD(C) %C % H %N ~X
93a ~ ~
94 208- 209 ~7.16 4.15 4~12 10.44 67.4g 4.16 4~37 10.65 , 94~ _ _ _ _ 1~9- 181 71.78 5.16 3.99 5.41 71.38 5.26 4.07 5~25 96 19?- 198 70.58 4.36 4.33 5.88 70.32 4.25 4.56 5.8Q
96a ~2~37325 The following examples are presented to illustrate the methods for preparation of the Group C compounds of the present invention.
Experimental Procedures Example 79 The following procedure is a modified version of one reported by Kametani, et al., J. Het. Chem., 1977, 4, 477.
25 g. of diethyl aminomethylenemalonate, 18 5.
of phenylacetone dimethylketal, 300 ml. of dry diphenyl ether and 1.0 g. of TSA.H2O were mixed and heated under a nitrogen atmosphere at 135-145C. for three hours. The mixture was then brought to reflux. After 3Q minutes the solution was cooled and extracted with 200 ml. of 2-1/2%
aqueous NaOH solution. The basic extracts were acidified yielding a precipitate of ethyl 6-methyl-5-phenyl-4-oxo-nicotinate. Recrystallization of this material from methylene chloride/ether provided 12.3 g~ of white solid, m.p.~178-180C.
E ampie 80 4.0 g. of 6-methyl-5-phenyl-4-oxonicotinate was suspended in 40 g. of 5% aqueous NaOH solution. This_ suspension was heated at 85-90C. for ~hree hours, cooled, acidified. The resulting precipitate of 6-methyl-5-phenyl-4-oxonicotinic acid was dried and recrystallized from acetoni~rile. Yield = 2.3 g.; m.p.=265-267C.
Exam~le 80.~
2.31 g. of 6-methyl-5-phenyl-4-oconicotinic acid was mixed with 0.44 g. of NaOH and 50 ml. of methanol.
~vaporation of the solvent provided 2.4 g. of sodium 6-methyl~5-phenyl-4-oxonicotinate as a glassy solid.
Example 81 Part A
Ethyl 1-ethyl-6-methyl-5-phenyl-4-oxonicotinate was prepared according to the procedure described by Kametani, et al., J. Het. Chem., 1977, 14, 477.
~7~2~;
Part B
, Crude ethyl l-ethyl-6-methyl-5-phenyl-4-oxonicotinate was suspended in 80 g. of 5~ aqueous NaOH solution and heated on a steambath for one hour. Acidification of the aqueous mixture gave 1-ethyl-6-methyl-5-phenyl-4 -oxonicotinic acid as a whlte precipitate (3.3 g.). Recrystallization ~rom acetonitrile provided material melting at 177-1~8C.
Exam~le 3A
3.13 g. of 1-ethyl-6-methyl-5-phenyl-4-oxonicotinic acid, 0.54 g. of NaOH and 50 ml. of methanol were mixed.
Evaporation of the solvent provided 3.7 g. of glassy sodium l-ethyl-6-methyl-5-phenyl-4-oxonicotinate.
Example 82 Part A
16.S g. o~ ethyl ~-methylaminocrotonate, 9.3 ml.
of pyridine and 300 ml. of me-thylene chloride were mixed in a ~lask itted with a magnetic stirring bar, a sidearm addition funnel and a CaC12 drying tube. 18.3 g. of phenyl-acetyl chloride was slowly added. Two hours later the reaction mixture was poured into water. The organic layer was separated and e~aporated yielding 30 g. of crude ethyl 3-oxo-4-phenyl-2-(methylamino-ethylidene) butyrate as a yellow oil.
Part B
13.1 9. of crude ethyl 3-oxo-4-phenyl-2-(methyl-amino-ethylidene)butyrate~5.95 g. of dimethylformamide dimethyl ac~tal and 25 ml. of dry dimethylformamide were heated to 80C. under a nitrogen atmosphere for 19 hours.
2.0 ml. of trie~hylamine and an additional 5.95 g. of di-methylformamide dimethyl acetal were added and the reaction was heated at 80C. for another 6 hours. The reaction ~as cooled, poured into water and extracted with methylene chloride. The organic extract~ were thoroughly washed with water and dilute HCl and evaporated. The residue of ethyl 1,2-dimethyl-5-phenyl-4-oxonicotinate was triturated with ether and recrystalli~ed from methylene chloride/ether.
Yield=3,2 g.; m.p.=148-150C~
., I
.
73~5 Exam~l~ 83 _ 5.8 g. of ethyl 1~2-dimethyl-5-phenyl-4-oxonicotinate was suspended in 60 ml. of 5% aqueous NaOH solution and heated on a steambath for 2-l/2 hours. The mixture was cooled and acidified. The resulting solid was recrystallized from acetonitrile to yield 1,2-dimethyl-5-phenyl-4-oxonicotinic acid as 'an needles. m.p.=227-228C.
Ex _~_e 83A
1.69 g. of 1,2-dimethyl-5-phenyl-4-oxonicitonic acid was mixed with 0.31 g. of NaOH and sn ml. of methanol.
Evaporation of the solid provided l.9 9. of sodium 1,2-dimethyl-5-phenyl-4- o~nicotmate as a glassy solid.
Example 85 Part A
42.4 g. of ethyl ~-ethylaminocrotonate, 23.7 g. of pyridine and 700 ml. of methylene chloride were mixed.
46.4 g. of phenylacetyl chloride was added slowly with stirring. Three hours later the mixture was poured into water and the organic layer was separated and evaporated yielding g9 g. of ethyl 3-oxo-4-phenyl-2-(ethylamino~
ethylidene) but~rate as a yellow oil.
Part B
13.8 g. of 3-oxo-4-phenyl-2-(ethylaminoethylidene) butyrate, 13.3 g.`of dimethylacetamide dimethyl acetal, 25 g. of dry dimethylformamide and 2 ml. of triethylamine were heated at 75-80C. under nitrogen for 24 hours. The reaction mixture was cooled and poured into 600 ml. of water. The aqueous suspension was acidified with HCl and extracted with methylene chloride. Evaporation of the solvent provide 10.5 g. of crude ethyl l-ethyl-2,6-dimethyl-5-phenyl-4-oxonicotinate as a brown oil.
Part C
10.5 g. of crude ethyl 1-ethyl-2,6-dimethyl-5-phenyl-4-oxonicotinate was suspended in lOO g. of 5% aqueous NaOH solution and heated on a steambath for 2 hours. The reaction mixture was c0012d and acidified. Extraction with . ' .' I
methylene chloride and subsequent evaporation of the solvent yielded 3 g~ of 1-ethyl-2,6 dimethyl-5-phenyl-4~oxonicotinate.
Recrystallization from acetonitrile provided material with a melting point of 163-165C.
ExamPle 8SA
1.5 g. of 1-ethyl-2,6-dimethyl-5-phenyl-4-oxo-nicotinate, 0.24 g. of NaOH and 40 ml. of methanol we~e mixed. Evaporation of the solvent provided 1.4 g. of sodium l-ethyl-2,6-dimethyl-5-phenyl-4-oxonicotinate as a glassy solid.
Example 86 Part A
2.68 g. of diethyl aminoethylidene malonate, 18 g.
of phenylacetone dimethyl ketal, 1 g. of toluenesulfonic acid lS monohydrate and 300 ml. of diphenyl ether were heated at 180C. for 2 hours. Methanol and ethanol began to distill out of the reaction flask and was collected in a Dean-Stark trap. The reaction mixture was then allowed to heat up to 205 C~ for an additional 3 hours. A solid formed upon cooling.
This was collectedby filtratloni yielding 4.6 g. of ethyl 2,6~dimethyl-5-phenyl-4-oxonicotinate.
Part B
4.0 g. of ethyl 2,6-dimethyl-5-phenyl-4-oxo-nicotinate was suspended in 40 g~ of 5~ aqueous NaOH solution 2S and heated on a steambath for 2 hours. The mixture was cooled and acidified, yielding 3.2 g. of 2,6-dimethyl-5-phenyl-4-oxonicotinic acid. Recrystallization from methanol provided material with a melting point of 272-273C.
(decomposition).
~xample 8ÇA
1.53 g. of 2,6-dimethyl-5-~henyl-4-oxonicotinic acid, 0.23 g. of NaOH and 50 ml. of methanol were mixed.
Evaporation of the solvent provi.ded 1.53 g. of sodium 2,6 dimethyl-5-phenyl-4-oxonicotinate as a glassy sold.
.. . .. . . . _ .. .
3;~5 Example 87 Part A
42.9 g. of ethyl ~ -methylaminocrotonate, 25 gO
~ of pyridine and 600 ml. of dry methylene chloride were mixed. 56.7 g. of 4-chlorophenylacetyl chloride was added with stirring. Three hours later the reaction mixture was poured into 300 ml. of water. The methylene chloride layer was separated and evaporated yielding 91 g. of crude ethyl 3-oxo-4-(4'-chlorophenyl)-2-~methyla~inoe-thylidene)butyrate as a light yellow oilO
Part B
59.16 g. of ethyl 3-oxo-4-(4'-chlorophenyl)-2-(methylaminoethylidene)butyrate was heated at 80-85C. with 48 9. of dimethylEormamide dimethyl acetal, 100 ml. o~ dry lS dimethylformamide and 8 ml. o~ triethylamine. After 19 hours, the mixture was cooled, poured into 1000 ml. of water, acidified with dilute HC1 and extracted with methylene chloride. Evaporation of the solvent provided ethyl 1,2-dimethyl-5-(4'-chlorophenyl)-4-oxonicotinate as a white solid. m.p=200-201C. ~acetonitrile).
Example 88 Approximately 30 g. of ethyl 1,2-dime~hyl-5 (4'-chlorophenyl)-4-oxonicotinate was suspended in ~00 g~ of 5% aqueous NaOH solution. 300 ml. of methanol was added and the mixture was refluxed for 7 ho~rs. The ~esulting solution was cooled and acidified to yield 18~9 g. of 1,2-dimethyl-5-(4'-chlorophenyl)-4-oxonicotinic acid as a white solid, m~p.=239-240C. (acetonitrile).
Example 88~
18.5 g. of 1,2-dimethyl-4-(4'-chlorophenyl)-4-oxonicotinic acid was mixed with 2.93 g. of NaOH and 200 ml.
of methanol. Evaporation of the solvent provided 19.0 9.
of sodium 1,2-dimethyl-5-(4'-chlorophenyl)-4-oxonicotinate as a glassy s~lid.
~L2~7325 Exam~le 89 - - -Part A
14.8 g. of ethyl 3-oxo-4(4'-chlo.ophenyl)-2- --~
(methylamino-ethylidene) butyrate~lo 9. of dimethylacetamide dimethyl acetal, 25 ml. of dry dimethylformamide and 2 ml.
of triethylamine were heated at 85C. for 22-1/2 hours.
The reaction was cooled, poured into 400 ml. of water and extracted with methylene chloride. Evaporation of the solvent provided an oily residue of ethyl 1,2,6--trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate.
Part B
13.0 g. of crude ethyl 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate was suspended in 130 ml. of 5% NaOH in 1:1 methanol/water and refluxed for 6 hours.
The reaction mixture was cooled and acidified. Extraction of this material with methylene chloride provided 1.8 g.
of 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinic acid.
m.p. (acet~nitrile) 240-243C.
Example 87A
1.8 9. of 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate, n . 27 g. of NaOH arld 50 ml. of methanol were mixed. Evaporation of the solvent provided 1.9 g. of sodium 1,2,6-trimethyl-5-(4'-chlorophenyl)-4-oxonicotinate as a glassy solid.
Example 90 Part A
24.6 9. of ethyl ~-methylaminocro~onate waC mixed with 250 ml. o~ methylene chloride and 16 ml. of pyridine.
40 g. o 4-bromophenylacetyl chloride was added wi~h stirring.
2~1/2 hours later, the reaction mixture was poured into water. Separation of the organic layer provided 60.6 g.
of ethyl 3-oxo-4-~4'-bromophenyl)-2-(methylamino-ethylidene) bu~yrate after evaporation.
Part B
17 g. of ethyl 3-oxo-4-(4'-bromophenyl-2 (methyl-amino-ethylidene bUtyrate, 12 g. of dimethylformamide dimethyl .
73;~i acetal, 25 ml. of dry dimethyl formamide and 2 ml. of tri-ethylamine were heated under dry nitrogen at 85C. for 19 hours. The reaction mixture was cooled, poured into 500 ml.
of ~2~ acidified with dllute HCl and extracted with methylene chloride. Evaporation of the solid provided 14.3 g. of crude ethyl 1,2-dimethyl-5-14'-bromophenyl)-4-oxo~
nicoti.nate.
Part C
14.3 g. of ethyl 1,2-dimethyl-5-(4'-bromophenyl)-4-oxonicotinate was susp~nded in 140 g. of 5~ NaOH in 1:1 methanol~water and refluxed for 4-1/2 hours. The reaction was cooled, diluted with water and acidified. The resulting solid was recrystallized from acetonitrile to yield 6.2 g.
of 1,2-dimethyl-5 (4'-bromophenyl)-4-oxonicotinic acid as a white solicl, m.p.-266-268C. (decomposition).
Example 9OA
6.15 g. of 1,~dimethyl-5-(4'-bromophenyl)-4-oxonicotinic acid was mixed with 0.84 g. of NaOH and 100 ml.
of dry methanol. Evaporation of the solvent provided 6.7 g.
of sodium 1,2-dimethyl-5-(4'-bromophenyl)-4-oxonicotinate as a tan glassy solid.
Example91 Part A
15.7 g. of ethyl 3-methylamino-hex-2-enoate, 175 ml. of dry methylene chloride and 10 ml. o~ pyridine were mixed. 23 g. of 4-bromophenylacetyl chloride was added with stirring. Two hours later the reaction mixture was poured into water and the organic layer was separated and evaporated yielding 45 g. of ethyl 3-oxo-4-(4'-bromophenyl)-2-(methyl-aminopropylmethylene)kU~yrate as a brownish oil.
Part B
18.4 g. of 3-oxo 4-(4'-~romophenyl)-2-(methyl-aminopropylmethylene)butyrate was mixed with 12 g. of di-methylformamide dimethyl acetal, 25 ml. of dry dimethyl formamide, and 2 ml. of dry pyridine. The reaction was heated at 85C~ for 21 hours, then cooled, poured into water, ~7325 acidified and extracted with methylene chloride. Evaporation of the solvent provided 16.5 g. of crude ethyl 1-methyl-2-propyl-5-(4'-bromophenyl)-4-oxonicotinate.
Part C
1605 g. of ethyl 1-methyl-2-propyl-5-(4'-bromophenyl)-4~oxonicotinate was suspended in 160 g. of 5% NaOH in 1:1 methanol/water. The mixture was refluxed for 10 hours, cooled and acidified. Filtration of the resulting solid provided 9.0 g. of 1-methyl-2-propyl-5-(4' bromophenyl)-~-oxonicotinic acid. m.p. (acetonitrile)-237-239C. (decomposition~.
Example 91A
8.8 g. of 1-methyl-2-propyl~5-(4'-bromophenyl)-4-oxonicotinic acid was mixed with 1.1 9. of NaOH and 100 ml.
of methanol. Evaporation of the solid provided 8.8 g. of sodium 1-methyl-2-propyl-5-(4'-bromophenyl)-4-oxonicotinate as a glassy powder.
Example 93 Part A
17.0 g. of e~hyl 3-oxo-4-(4'-bromophenyl)-2-(methylamino-ethylidene)butyrate was mixed with 10 g. of dimethylacetamide dimethyl acetal, 25 ~. of dry dimethyl-ormamide and 2 ml. o triethylamine. The reaction mixture was hea~ed at 85C. for 24-1/2 hvurs ur.der a nitrogen atmosphere, cooled, poured into water, acidified and extract-ed with methylene chloride. Evaporation of ~he solvent and trituration of the residue with ether provided 2.7 g. of crude ethyl 1,2,5-trime~hyl~5-(4'-bromophenyl)-4-oxo-nicotinate as a brownish solid.
Part B
__ 3~ 2.7 9. of crude ethyl 1,2,6-trimethyl-5-(4'-bromo-phenyl) 4~oxonicotinate was suspended in 27 g. of 5~ NaOH in 1.1 methanol/water. The reaction mixture was refluxed for 2-1/2 hours, cooled and acidified. Filtration of the result-ing solid provided 2.2 g of 1,2/6-trimethyl-5-(4-bromo-3S phenyl3-4~oxonicotinic acid. m.p.=228-230C. (decomposition).
~`1 ~373ZS
Example 93A
1.96 9. of 1,2,6-trimethyl 5-(4'-bromophenyl)-4-oxonicotinic acid, 0.26 g. of NaOH and 30 ml. of methanol were mixed. Evaporation of the solvent provided 2.0 g. of S sodium 1,2,6-trimethyl-5-(4'-bromophenyl)-4-oxonicotinic acid as a tan glassy solid.
Example 94 Part A
18.4 g. o ethyl ~-anilinocrotonate was mixed with 80Q ml. of methylene c~loride and 8 ml. of pyridine.
17.0 g. of 4-chlorophenyl acetyl chloride was added with stirring. After 2-1/2 hours the reaction mixture was poured into 400 ml. of water and shaken. The methylene chloride layer was separated and evaporated yielding 32 g.
lS of crude ethyl 3-oxo-4-(4'-ehlorophenyl)-2-(anilino-ethylidene)butyrate as a light brown oil.
Part B
32 9. of ethyl 3-oxo~4-(4'-chlorophenyl)-2-(anilino-ethylidene)bUtyrate, 15.9 g. of dimethy~formamide dimethyl acetal, 40 ml. of dry di.methylformamide and 3.5 ml. of triethylamine were mixed and heated under nitrogen at 8Q-85C. for 18 hours. The r~action was cooled, poured into 600 ml. of water, acidified and extracted with methylene chloride. Evaporation of the solvent provided 35 g. of crude ethyl 2-methyl-1-phenyl-5-(4'~chlorophenyl)-4-oxonicotinate as a brown oil.
Part C
35 g. of crude ethyl 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate was suspended in 350 g. of 5~ NaOH in 1:1 methanol/water and refluxed for 6 hours.
The reaction mixture was cooled. This yielded a precipitate of sodium 2-methyl-1-phenyl-5-~4'-chlorophenyl~-4-oxQ
nicotinate which was collected by filtration and resuspended in dilute aqueous HCl to provide 5.3 9. of 2-methyl-1-phenyl-5-(4'-chl~rophenyl)-4-oxonicotinic acid, m.p.
(acetonitrile)=209-209C.
"
.. ........ . .
~zci,~3~
Example 94A
5.25 g. of 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinic acid, 0.68 g. of NaOH and 100 g. of dry methanol were mixed. Evaporation of the solvent provided 5.0 g. of sodium 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate as a glassy solid.
6~
D. N-alkyl-2,6-dlaryl-4-oxonicotinates In still another preferred aspect, this in~ention re-lates to compounds of the formula o R5~,co 2Y
n ~ R1 ~ (X)n (~) wherein Rl is a (Cl-C6) alkyl group; R5 is a hydrogen atom, a (Cl C4) alkyl group or a halogen atom; Y is a hydrogen atom or a (C~ C6) alkyl group; X is a hydrogen atom, a haloyen atomr a trihalomethyl group, a (Cl-C6) alkyl group, a nitro grou~, a cyano group or a (Cl-C6) alkoxy group; and n is the integer 1 or 2; and the agronomically acceptable salts thereof.
Among the preferred compounds of the present invention are compounds of Group D, formula ~XXXII) wherein ~1 is a 15 (C~-C6) alkyl, (Cl~C4) haloalkyl, alkoxy (C1-C4)alkyl-(Cl-C4), aryl(C6-ClO)alkyl(Cl-C4)~ or: (C3~C6)alkenyl; Y is hydrogen, ~Cl-C6)alkyl, an alkali metal or alkaline earth metal cation, or an ammonium or mono-, di-, tri-, or quaternary ammonium cation; Rs is hydrogen, (Cl-C6)alkyl, or halogen; X
~ is hydrogen, halogen, trihalomethyl, (Cl-C6)alkyl, (Cl-C6 ) alkoxy, nitro or cyano; and n is an integer from 1 to 2.
Among the more preferred compounds of the present in-vention are compounds of Group D, Formula (XXXII) wherein R
is (Cl-C3) alkyl; Rs is hydrogen or bromine; ~ is hydrogen, sodium or potassium; X is hydrogen or halogen; and n is the integer 1 or 2.
, .
~2C~73~5 Among the most preferred compounds of this in~ention are compounds Oc Group D Formula (XXXII) wherein Rl is methyl or ethyl; Rs is a hydrogen atom; and Y is hydrogen or a sodium or potassium cation; X is hydrogen, chlorine or fluorine; and 5 n is 1; and the agronomically acceptable acid addition salts : thereof.
Typical compounds encompassed by.the present invention include:
. l-methyl-2,6~diphenyl-4-oxonicotinic acid;
1-propyl-2,6-diphenyl-4-oxonicotinic acid;
l-hexyl-2,6-diphenyl-4-oxonicotinic acid;
5-bromo-1-methyl-2,6-diphenyl-4-oxonicotinic acid;
5-chloro-1-ethyl-2,6-diphenyl-4-oxonicotinic acid;
1,5-dimethyl-2,6-diphenyl-4-oxonicotinic acid;
1-methyl-2,6-di(4'-chlorophenyl)-4-oxonic.otinic acid;
l-hutyl-2,6~di(4'-chlorophenyl)-4 -oxoni cotinic acid;
l-ethyl-2,6-di(3'-chlorophenyl)-4-oxonicotinic acid;
l-methyl-2,6-di(2'-chlorophenyl)-4-c)xon.icotinic acid;
l-methyl-2,6-di(4'-fluorophenyl)-4-c)xonicotinic acid;
1-methyl-2,6-di(3'-~luorophenyl) 4-oxonicotinic acid;
: 5-bromo-1-me~hyl-2,6-di(4'-fluorophenyl-4-oxonicotinic acid;
l-ethyl-2,6-di(3',4'-dichlorophenyl)-4-oxonicotinic acid;
l-propyl-2,6-di(2',4'-dichlorophenyl~-4-oxonicotinic acid;
1 methyl-2,6-di(4'-trifluorophenyl)-4-oxonicotinic acid;
1 methyl-2-(4'-fluorophenyl)-6-phenyl-4-oxonicotinic acid;
l-methyl-2-(4'-chlorophenyl)-6-(4'-fluorophenyl)-4-oxonico-tinic acid;
l~chloro-2-(4'-chlorophenyl)-6-phenyl-4-oxonicotinic acid;
l-pentyl-6-(4'-fluorophenyl)-2-phenyl-4-oxonicotinic acid;
; 30 and the agronomically acceptable salts thereof.
73~,5 The compounds of the ~resent invention can be prepared by various synthetic routes found in the ar~. ~In particular, the compounds of the present invention can be prepared by the following reaction sequence:
OH o ~C02Et (STE P I ) ( X~ ,~ . NaHCO~
( >~XXIII) X~
(XXX f\~
O O
;[CSTEP 2~ ~C2CH3 ~,CO2C~3 x~f ~ x~
(XXX\/) (XXXVl) ~XX~ 1)STEP 4~ ~ ~)2 ~f Rl \~X
(,~>O<VI 1) ,, Step No. 1 (a) NaHCO3 .2 3.
~b~ chlorobenzene, dichlorobenzene. toluene, decahydronaphthalene, .other inert solvents;
~) temp.: 50 250C., preferably 100-200C. and (d) similar to procedure des~ribed F. Arndt, B. Eistert, H. Sckole s~d F. Aron, Ber., 69, 23~3 (1936).
' ' i'~ i ' ' ' - ~2~732 7~
Step No. 2 (a) methanol;
(b) trimethyl orthoformate desiccant;
(c) H2SO4~ HC1, other strong acids;
5~d) temp.: 25-200C., preferably 5~-150~.
Step No. 3 (a) alkyl amine;
(b) inert solvent, alcohols, ethers, hydrocarbons, water;
(c) acid catalyst optional;
10 (d) temp.: .Q-15~C., preferably ~S-50C.
Step No. 4 ___ __ _ (a) aqueous ~.~:
(b) optional ine.rt co-solvent, methanol, r~so;
~) temp~: 20-150C., p.referably 50-100C~
(d) any acid to neutralize.
Another route to the compounds of Growp D, formula (XXXII) is .' O .
X~ 5~ STI~? ~ (XXXVII) Step No. la X~ 1 2 : ~a) i:l0 P2O5/C~3S~3~ by weight;
2~ (b.~ temp~: 20-150~ ,.p.re.fer~.bly 20.-60C.
.
Other steps: same as abo~e __ ____ ___ . Still snother route to the compounds of Group D, formula (XXXII) of the present invention is shown by the following reaction sequence:
Z5 (XXX,~Il)~ ~02Ft~,' - ~' - ( XLi) ~! , ;3732~i 70b Step No. lb-__ _ __ (a) RNH2 (b) inert solvent, methanol, H20 (c) acid catalyst optional S (d) temp.: 20-150G., preferably 20-100C.
Step No. 2b:
(a) r~n in inert solvent (methylene chloride, benzene toluene, ether) (b) acid acceptor optional (pyridine, Et N) 10 (c) temp.: ~-150C., pre~erably 10-50 C.
(d) residue heated 100-200C., preferably 150-180C.
,~C2E~3 ~,~C`OCI
Yet another route to the compounds of Group D, formula (XXXII) of the present invention i5 shown by the ~ollowing 15 reaction equation:
~ ~ C O~ H X ~ ~ 2 H
X ~ ~X ~ ~ X[~ 1~X
. .
(a) carried out in a compatible solvent (MeOH, water) (b) room temperature (c) optional addition of base (N~OH~,Na CO , etc.) Tables VIII and IX below are presented to illustrate the more preferred compounds of this aspect of the present invention and related compounds and the analytical data for these com~ounds~
TABLE VIII. List of Group D Compounds o ~5 ~ C O 2Y
( X ) n ~ R ~ ( x)n (~:1) Example No. Rl ~ X X' Y
97a H H H H Na 98 Me H H H Et 99 Me H H H Me 100 Me H H H H
lOOa Me H H H Na lOl Et H H H H
lOla Et H H H Na 102 Me H 4-Br 4-Br H
102a Me H 4-Br 4-Br Na 103 Me H 4-Br 4-Br Et 104 Me H 4-F 4-F H
104a Me H 4-F 4-F Na 105 Me H 4-C1 4-Cl H
105a Me H 4-C1 4-Cl Na ! 1 0 6 Me H 4-CH3 4-CH3 H
; 106a Me H 4-CH3 4-C'H3 Na ~2~325 T~BLE VI I I ( ~ont . ) Example No . R1 ~ X X ' Y
107 Me H H 4-C~3 H
107a Me H H 4-C~3 Na 108 Me Br H H H
108a Me Br H ~ Na 109 - Pr H H H H
109a Pr H ~ H Na TABLE IX
Ex~ple No. mp ( C. ) - ~C ~H ~N
97228- 230 74.21 4.50 4.80 74.46 4.40 5.15 97a -~
98177-17g 75-65 5.74 4.20 7S.49 5.83 4.45 99255 757 75.22 5.37 4.39 75.13 5.51 4.46 1002~9- 211 74.74 4.95 4.59 74.04 5.04 4.47 lOOa ___ ___ 101210- 213 75.22 S .37 4.39 75.28 5.37 4.22 lOla --- --- ~ --- ---102 lg7 49.27 2.83 3.03 49.27 2.86 3.3 102~
103218- 220 51.35 3.49 2.85 50.45 3.43 3.03 .. . .
~q-~73;~5 TABLE IX (cont.) Example No. mp(C) %C %H ~N
104 191-193 66.86 3.84 4.10 58.41 3.67 4O25 5104a --- ~~- ~~~ ~~~
105 187-190 60.98 3.50 3.7~
60.75 3.53 4.29 105a -~
106 209- 212 75.65 5.74 4.2~
74.89 5.79 4.26 106a 107 158- 163 75.22 5.37 4.39 . 72.13 5.50 4.02 '07a --~
15-108 ~42- 2~3 59.39 3.67 3.65 60.44 3.77 4.15 108a --- -~- ~~~ ~~~
109 166 -167 75.20 6.31 - 4.18 75.14 5~5 4.28 20lO9a . ~ .
..,S~ i .^! i ~73~5 Example 98 Part a.
A 500 r.ll single neck flask was fitted with a magnetic stirrer and an N2 inlet. 20 g. of ethyI benzoy-lacetate (0.104 moles) was dissolved in 200 gms of 1:10 P20s/methanesulfonic acid and added to the flask. The homogeneous reaction mixture was heated to 40C. and main-tained at that temperature or four days. The mixture - was then cooled and diluted with 100 ml of methylene chloride. This solution was added in 50 ml portions to 1000 ml of cold water in a separatory funnel. The sep-aratory funnel was shaken vigorously after each addition.
The organic layer was then washed with water and evapo-rated leaving an oily residue that crystaliized from ether.
The isolated yield of 2,6-diphenyl-3-ethoxycarbonyl-4-pyrone was 10.5 g- ~63~. mp - ]02-103OC.
Part b:
3.5 ~. of 2,6~diphenyl-3-ethoxycarbonyl-4-pyrone was dissolved in 33 ml of methanol. 2 ml of glacial acetic acid was added. 13.3 ml of 40~ aqueous methylamine was then added very slowly at room teMperature.
After 6 hours the reaction mixture was diluted with 200 ml of water and extracted with methylene chloride. Evapo-ration yield~d 3.5 g. o~ ethyl 2,6-diphenyl-4 oxonico~i-2S nate which was recrystallized from methylene chloride/
ether. mp = 177-179~C.
.
,, ,i "j .
Example 99 Part a:
A 200 ml flask was fitted with a N2 inlet, a magnetic stirring bar and a condenser. 50 ml of methanol, 8.0 g of trimethyl orthoformate, 5.2 ~g. of concentrated H2SO4 and 5.0 g.i of 3-benzoyl-4-hydroxy-6-phenyl-pyr-2-one were added. The resulting mixture was then refluxed for 3 days, cooled, poured into water and extracted with methylene ahloride ~300 ~1 ). The ~rganic extracts were combined and washed with water. Re..moval of the solvent provided 4.4 Y- of 2,6-diphenyl-3-methoxy-carbonyl-pyr-4-one (85~). Recrystalllzation from methyl-ene chloride/ether provide material with a melting point = 150-151C.
Part b:
3.0 g.; of 2,6~diphenyl-3-methoxycarbonyl-pyr 4-onel 33 ml of methanol, 13.3 ml of 40% a~ueous methyl-amine and 2 mls of glacial acetic acid were rllixed at room temperature~ The naxt day the mixture was diluted with water. Eiltration of the resulting suspension yielded 2.5 g.; of methyl 2,6~diphenyl-1-methyl-4-oxonicotinate.
Recrystallization from methanol provided material at 255~257C.
Example 100 2.5 g. of methyl 2,6-diphenyl-1-methyl-4-oxonicoti-nate was suspended in 28 ml of 5% aqueous sodium hydro~ide for ~ hours, cooled, and filtered to remove residual insolubles.
The clear basic solution was then æi~ified with dilute HCl to provide a white precipitate of 2,6 diphenyl-1-methyl-4-oxonicotinic acid. Recrystalli2ation from methylene chlor-ide/ether provided 2.4 ~. of product. mp = 209-211C. (dec).
'-- .
Example 100a 1.73 g of 2,6-diphenyl-1-methyl-4-oxonico~ini~
acid was suspended in 50 ml of dry methanol. 0.25 g.
of NaOH was added. After the carboxylic acid and the _ NaOH dissolved the solvent was removed yielding 1.75 g.
of sodium 2,6-diphenyl-1-methyl-4-oxonicotinate as a glassy solid.
Example 101 3.5 g- of 2,6-diphenyl-3-ethoxycarbonyl-pyr-4-one, 33 ml of methanol, 5 ml of water and 2 ml of ~lacial acetic acid were mixed. 7.6 ml of 70% aqueous ethylamine was then added slowly~and the resulting mixture was allowed to stand at room temperature! for 24 hours. The mixture was then diluted with 100 ml of waterO The pH was ad-justed to 2. Extraction with methylene chloride andevaporation of the solvent provided 3.0 g. of crude ethyl 1-ethyl-2,6-diphenyl-4-oxonicotinate as a brown oil. This material was dissolved in 20 m~ of methanol. This solu-tion was then added to 40 ml o 5~ aqueous NaOH and heated on a steambath for S hours. The reaction mixture was cooled and acidified. Extraction with methylene chloride (3x50 ml ) yielded an oily solid after evaporation.
Crystallization from methylene chloride/ether yielded 1.6 g of l-ethyl-2,6-diphenyl-4-oxonicotini~ acid. mp =
2S 210 -213~C. (dec).
Exam~le 101a 1.38 g. of 1-ethyl-2,6-diphenyl-4-oxonicotinic acid was treated with 0.1~ g. of NaOH in 50 mls of dry methanol.
Evaporation o the solvent provided 1.40 g. o~ sodium 1-ethyl-2,~-diphenyl-4-oxonicotinate as a glassy solid.
. .~. .
.. . . . . . .
7;~5 j, Example l_ Part a~
g of ethyl 4-fluorobenzoylacetate was dissolved in 250 g- of 1:10 P20s/lnethanesulfonic acid and heated at 45C. for 4 days. The mixture was cooled, poured into 1200 ml of water and extracted with ~3x100 ml ) methylene chloride. Evaporation of the solvent and chroma-tography of the resulting oil (silica gel/ether) provided 12.9 , g of crystalline 2,6-dit4 -fluorophenyl)-3-10 ethoxycarbonyl-pyr-~ one. mp = 113 -114C.
Part b:
g. of 2,6-di(4 -fluorophenyl)-3-ethoxy-carbonyl-pyr-4-one, 47 ml of methanol and 2.9 ml of glacial acetic acid were mixed. 19 ml of 40~ aqueous methylamine was added slowly. Three hours later the reac-tion mixture was poured into 200 ml of water and extrac~ed with methylene chloride ~2x100 ml ). This pro~ided 5.4 gms of crude ethyl l~methyl-2,6-di(4 -fluorophenyl)-4-oxonicotinate as a brown oil.
The crude ester was suspended in 50 ml of 5%
aqueous NaOH solution and heated for 3 hours. The mixture was cooled and acidified. extraction with methylene chlor-ide provided a yellow solid which was recrystallized from methylene chloride/ether-to provide 3.6 g.: of l-methyl-25 2,6-di(4 -fluorophenyl)-4-oxonicotinic acid. mp = 19l-l93~c.
Example 10~a 3.45 g. of 1-methyl-2,6-dit4 -fluorophenyl)-4-oxonicotinic acid was mixed with 0.445 g. of NaOH and 70 ml of methanol. Evaporation of the solvent provided 3.1 30 g. of sodium 1-methyl-2,6-di(4 -fluorophenyl)-4-oxonicotinate as a glassy solid.
.
. .
Exam~le 105 Part a:
g. of ethyl 4-chloroben~oylacetate was mixed with 150 g. of 1:10 P2Os/methanesulfonic acid and heated at 45C. ~or 4 days. The cooled reaction mixture was poured into a separatory funnel containing 1500 ml of cold water and the res~lting mixture was shaken for several minutes. Extraction with methylene chloride and chromQtography o the resulting crude product (silica gPl/
ether) provided-5.5 g. of ethyl 2,6-dit4 -chlorophenyl)-3-ethoxycar~onyl-pyr-4-one. mp - 130 C.
Part b:
5.0 g. of ethyl 2,6-di(4 -chlorophenyl) 3-ethoxycarbonyl -pyr-4-one, 100 ml of methanol, 19 ml of 40% aqueou~ methylamine, 19 ml of water and 2.9 ml of glacial acetic acid were mixed and allowed to stand at room temperature Eor 3 hours. The mixture was poured into water and extracted with methylene chloride to provide 5 g-- of c~ude ethyl l~methyl-2,6-di(4-chlorophenyl)-4-oxonicotinate a~ a yellowish semi-solid.
The ester was then su~pended in 50 ml of 5 aqueous NaOH solution. 20 ml of methanol was added to improve solubility. The mixture was heated on a steambath fQr 3 hours, cooled, and acidifed with dilute H~l to pro-vide a white precipitate. Recrystalliza~ion from methylenechloride/ether, yielded 3.4 g. of 1-methyl-2,6-di(4 -chlorophenyl)-4-oxonicotinic acid. mp = 187 -190C.
.
c ., 4~ ~g Example lO5a 3.32 g. of l-methyl-2,6-di(4 -chlorophenyl)-4-oxo-nicotinic acid, 0.39 g.i of NaOH and 50 mls of methanol were mixed. Evaporation of the solvent provided 3.4 g.
of sodium l-methyl-2t6-di(4 -chlorophenyl)-4-oxonicotinate as a glassy solid.
Example 1 7 Part a?
A one liter flask was fitted with a mechanical stirrer, CaC12 drying ~ube~ condenser and a sidearm addi-tion funnel. lOO Y- of PCls was placed in the flask. 39 g- of ethyl 4-methylbenzoyl~cetate and lOO ~ of PCl3 were mixed and slowly added to the PCls at room temperature.
The reaction mixture e~lolved HCl. After 30 minutes the lS mix~ure was cautiously re1uxed for 2 hours. At this time PC13 and POCl3 were distilled from the reaction mixture at reduced pressure. The residue was then dis-tilled at O.S mm (bp = 116-121) to provide 32 g.i of ~ -chloro 4-methylcinnamoyl chloride as a clear oil.
Part b.
lO.O g- of ethyl ~ -methylaminocinnamate, 9.6 - of pyridine and 75 ml of dry methylene chloride were mixed in a flask under a dry nitrogen atmosphere. lO g.
of ~-chloro-4-inethylcinnamoyl chloride in 25 ml of meth-ylene chloride were added at ambient temperatures. After 2 hours the reaction mixture was poured into water and extracted with methylene chloride. Evaporation of the solvent provided 18 g. of a brown oil. This material wa~ heated (160-178) for lS minutes (HCl evolution), cooled, and taken up in dilute aqueous NaOH. Acidificatlon of the basic extracts an~ recrystallization of the result-ing solid from methanol provided ~.8 g. o 1-me~hyl-2-.
:~073;25 - 8~ -phenyl-6 (4 methylphenyl)--4-oxonicotinic acid.
np = 158 -163C, (dec).
Example 107a 0.64 g of l-methyl,2-phenyl-6-(4 -methylphènyl)-4-oxonicotinic acid, 0.09 g. of NaOH and 30 ml ofmethanol were mixedO Evaporation of the solvent provided 0.6 g. of sodiui,l l-methyl-2-phenyl-6-(4 -methylphenyl) 4-o~onicotinate as a glassy solid.
Exarnple 108 3~75 g., of l-methyl-2,6-diphenyl-4-oxonicotinic acid was dissolved in 40 ml of methanol. The pH was adjusted to 12 with the addition of aqueous NaOH. A me~hanolic solution of bromine (2.95 g. Br2 in 50 ml methanol) was added. Additional NaOH was added as required to maintain a basic medium. Removal of the solvent yielded a semi-solid that was taken up in 100 ml of water. Water insoluble material was removed by filtration. Acidifica-tion of the aqueous solution provided 3.0 g. of 5-bromo- ' 1-methyl-2,6-diphenyl-4-oxonicot:inic acid (mp 242-~43,C.~ with decompo~ition) as a white solid.
Exam ~e 108a 2.5 g. of,5-bromo-l-methyl-2,6-diphenyl-4-oxonico-tinic acid, 0.286 g. of NaOH and 50 mls of dry methanol were mixed. Evapora ion o the solvent provided 2.6 g-of sodium 5-bromo-l-methyl-2,6-diphenyl-4-oxonicotinate as a tan glassy solid.
Example 109 -4O0 g. o 2,6-diphenyl-3-ethoxycarbonyl-pyr~4-one, 50 ~1 of glacial acetic acid were mixed. 8.1 g~ of n-propylamine and 6 m~ of water was added slowly a. room ~ .. . . .. .. . . ..
~L2V73;~5 - 81 ~
temperature. After 3 hours an additional 14 ml of wa~er, 12 ml of 6% ~Cl and enough methanol to bring everything into solu~ion, was added. The next day this acidic reaction mixture was poured into water and extracted with methylene chloride (2x100 ml ~. Evaporation of the organic extracts yield 4.4 g. of crude nicotinate ester which was suspended in 50 ml of 5% aqueous NaOH and heated at 85C. for 4 hours. The resulting solution was acidif~ed with HCl and extracted with methylene chloride (2x50 ml ). Evaporation of the solvent yielded a solid mass. Recrystallization from ether provided 1.5 g. of l-propyl-2,6-diphenyl-4-oxonicotinic acid. rnp = 16~ -167C.
xample 109a 1.5 g. of 1-propyl-2,6-diphenyl-4-oxonicotinic acid, 0.202 g. of NaOH and 50 ml of dry methanol were mixed.
Evaporation of the solvent yielded 1.5 g. of sodium 1 propyl-2,6-diphenyl-4-oxonicotinate as a white glassy solid.
~ .
, . . i.
.
~207325 - 8~--The eompounds o~ the invention are particularly useful a~ che~ical hyb~idization agents in cereal crops, such as wheat, bar ley, corn, r iG~, s~rghum, millets, oat~, rye, triticale and the like~ Whe~ used as chemical 5 hybridi2ation agents, the cornpcunds effec~ively induc~ a high degree of selective male ster ility, that is, without also inducing significant female sterility, in the treated plants and w~ thou~ causing signif icant growth inhibition o~
the treatsd plants. As used ~rein, the term male 10 sterility includes both actual {sale s~oril~ty, as evideQced by a lac~ o~ male rlower parts or by s~erile pollen, and ~unctiollal male sterility, in which the male flower parts are unable to cause pollinatio~. Th~ co~pounds o the i~ven~ion also cause other plant growth re~ulatory response~, such. as or example, co~trol of floweringr control o~ fruiting and inhibition of seed formation in non-cereal species and other related growth regulatory responses.
Wh~n used as plant growth regulato~s, the compounds or 20 the invention are applied in any amount which wiLl be sufficient to ~ffect the desired plant res~onse without cau~ing any undesirable or phytotoxic response. ~or ~
example, when the comp~unds o4 the invention are used as ch~mical hybridi2ation agents, t~ey ar~ generally applied to the crops ~o be treated a~ a rate of about 1j32 to ab~ut 20 pounds pe~ acre and pr~erably ab~ut 1/8 to about 10 ~, .
, . , ,, . . . ~ . . . .... . . . . .. . .. . . .. .
~73%~
_ 83; _ ;
pounds per acre. ~he rate of application will vary depending on the crop being treated, the compound being used for treatment, and related factors.
To obtain hybrid seed, the following procedure is S generally employed. The two parents to be crossed are planted in alternate strips. The female parent is treated with a compound of the invention. The male-sterile ~emale parent thus produced will be pollinated by pollen from the other, male-fertile, male parent, and ~he seed produced by the female parent will be hybrid seed wbich can then be ha~vested by conventional means.
A pre~erred ~ethod of applyi~g a compound of the invention as a chemioal hybridization agent is by foLiar application. When this method is employed, selective male s~erility is most efectively induced when the com~ound is applied be~w~en anther initiatio~ a~d meiosis. The compounds o the inventions may also be appLied a~ a seed treat~ent by soaking t~e qeed in a liquid Eormulation containing the active compound or by coating the seed with the compound. In seed treatment applica~ions, the compounds o the invention will generally be applied at a rate o about 1/4 to about`l3 pounds per hundred weight of seed. The compounds o the in~ention are also effective when applied to the soil or to the water surfacP in rice crops.
The compounds of ~he invention can be used as plant grow~h regulators either individually or in mixtures. For example, they can be used in combination with other plant growth regulators, such as auxins, gibberellins, ethylene-releasing agents such as ethephon, pyridones,pyridazinones, cytokinins, maleic hydrazide t succinic acid 2j2-di~ethylhydrazide, chlorine and its salts (2-chlo~o-ethyl) tri~ethylammonium chloride, triiodobe~zoic acid, trihutyl-~, 4~diohlorobenzylpho~phonium ehloride, polymeric N-vinyl-2-oxazolidinones, tri~dimethylaminoethyl) phosphate ~` .
... . .. . . . .. . .. . . . . . . . . . . .
3;~S
_ 84 _ and i~s salts, and ~-dimethylamino-1,2,3,6~tetrahydro-phthalamic acid and its salts, and the like, and under some conditions may be used advantageously with other agricultural chemicals such as herbicides, fungicides, insecticides, and plant bactericide~.
A compound of the invention can be applied to the growth medium or to plants to be treated either by itself or, as is generally done, as a component in a growth regulant composition or formulation which also comprises an agronomically acceptable carrier. By ~agronomically acceptable carrier~ is meant any substance which can be used to dissolve, disperse, or diffuse a compound in the composition without impairing t~e effectiveness of the compound and which by itself has no significant detrimental effect on the soil, equipment, crops or agronomic environment. Mixtures o the compounds of the invention may also be used in any o these formulations. The compositions of the invention can be either solid or liquld formulations or solutions. For example, the compounds can be formulated as wettable powders, emulsiriable concentrates, dusts, granular formulations, ae_osols, or ~lowable emulsion concentrates. In such ormulations, the compounds are extended with a liquid or solid carrier and, when desired suitable surfactants are incorporated.
It is usually desirable, particularly in foli2r applications, to include adjuvants, such as wettinq agents, spreadin~ agents, dispersing ayents, stickers, adhesi~es, and the like, in accordance with agricultural practices.
Examples of adjuvants which are commonly used in the art can be found in the John W. McCutcheon, Inc. publication "Deter~e~ts and Emulsifiers Annual".
The compounds o ~he invention can be dissolved in any appropriate solvent. Examples of solvents which are useful in the practice of this invention include water, alcohols, ketones, aromatic hydrooar~ons, halogenated hydrocarbons, ~2~7325 ~ 85 -dimethylformamide, dioxane, dimethyl sulfoxide, and the like. Mixtures of these solvents can vary from about 2% to about 98% by weigh~ with a preferred range being from about 20% to about 75%.
For the preparation of emulsifiable concentrates, the compound can be dissolved in organic solvents, such as benzene, toluene, xylene, methylated naphthalene, corn oil, pine oil, o-dichlorobenzene, isophorone, cyclohexanone, methyl oleate, and the like, or in mixtures of these solvents, together with an emulsifying agent or surfactant which permits dispersion in water. Suitable emulsifiers include, for example, the ethylene oxide derivatives of alkylphenols or long-chain alcohols, mercaptans, carboxylic acids, and reactive amines and partially esteri~ied polyhydric alcohols. Solvent-soluble sulfates or sulfonates, such as the alkaline earth salts or amine salts of alkyl-benzenesulfonates and the fatty alcohol sodium sulfates, having surface-active properties can be used as emulsifiers either alone or in conjunction with an ethylene oxide reaction product. Flowable emulsion concentrates are ~ormulated similarly to the emulsifiabl~ concentrates and include, in addition to the above components, water and a stabilizing agent such as a water-soluble cellulose derivative or a water-soluble salt of a polyacrylic acid.
The concen~ration of ~he active ingredien~ in emulsifiable concentrates of usually abu~ 10~ tO 60% by weight and in flowable emulsion concentrates, this can be as high ~as abou~ 75%.
~ettable powders suitable for spraying, can be prepared by admixing the compound with a finely divided solid, such as clays, inorganic silicates and carbonates, and silicas and incorporating wettiny agents, sticking agents, and/or dispersing agents in such mixtures. The concentration of active ingredients in such formulations is usually in the range of about 20~ to 98~ by weight, 3~3~25 _ 86 -preferably about 40% to 75~. A dispersing agent may yenerally cons~itute about 0.5% to about 3% by weight of the composition, and a wetting agent may generally constitute from about 0.1% to about 5~ by weight of the composition.
Dusts can be prepared by mixing the compounds of the invention with finely divided inert solids which may be organic or inorganic in nature. Materials useful for this purpose include, for example, botanical flours, silicas, silicates/ carbonates and clays. One convenient method of preparing a dust is to dilute a wettable powder with a finely divided carrier. Dust concentrates containing abut 20% to ~0% of the active ingredient are commonly made and are subsequently diluted to about 1% to 10% by weight use concentration.
Granular formulations can be prepared by impregnating a solid such as granular ~uller's earth, vermiculite, ground corn cobs, seed hulls, including bran or other yrain hulls, or similar material. A solution of one or more of the compounds in a volatile or.ganic solvent can be sprayed or mixed with the granular so:Lid and the solvent then removed by evaporation. Th~ qranular material can have any suitable size, with a pre~erable size range of 16 to 60 mesh. The active compound will usually comprise about 2 to 15% by weight of the granular formula.ions.
Salts of the compounds of the i~vention can be formulated and applied as aqueous solutions. The salt will typically comprise a~out 0.05 to about 50% by weight preferably a~out 0.1~ to a~out 10%, of the salution.
These composi~ions can also be further diluted with water if desired prior to actual application. In some applications, the activity of these compositions can be enhanced by incorporating into the composition an adjuvan~
such as glycerin, methylethylcellulose, hydroxyethyl-cellulose, polyoxye~hylene~orbitan monooleate, polypropylene glycol, polyacrylic acid, polyethylene ~D7~2~
sodiun mQlate, polyethylene oxide, or the like. Ihe adjuvant will generally comQrise abou~ 0.1 to about 5% by weight, preferably about 0.5 to about 2Yo, of the coTposition. Sucn compositions can also optionally include an agrononically-aceeptable surfactant.
Ihe conQounds of the invention can be applied as sprays by methods commonly employed~ such as conventional hydraulic sprays, aerial sprays, and dusts. -For low~volume applications, a solution of the corpound is usually used. The dilution and volume of application will usually depend upon such factors as the type of equipment emQloyed, the ~ethod of application, the area to be treated and the type and stage of developTent of the crop being treated.
Ihe following is a typi¢al tank mix fo~mulation for the foliar application of sodiun l-ethyl-6-methyl-2-(4-chlorophenyl)-~-oxonicotinate on winter wheat at a rate o~ 0.25 lbs./A:
0.25 lbs. of oxonicotinate salt 1 pt. of Triton AG 98~
dulute to 50 gals. with water This mixture is then foliar spray-applied to the wheat plants at a rate of 50 gals./A.
Ihe following e.xamQles will further illustrate the ch~niaal hybridization activity of the corpounds of the invention but are not :~ intended to limit the invention in any U~Ly.
~ LE llt~
Chemical ~ybridization Activity The following proc~dures are used to evaluate the activity of the com~unds o~ the invention for inducins male sterility in cereals.
An awne~ variety (Fielder) and an awnless variety (Mayo-64) of spring wheat are planted a~ the ra~ of 6 to 8 seeds per 6 in~hes p~t cont~aining a Qterile medium of 3 parts ~oil and 1 part humus. ~he plants are grown under short day (9 h~ur) condi~ions for the first 4 weeks to obtain good vegatative growth ~e~ore flow~r initiation.
The plants are then moved to lons-day (16 hour) conditions which are provide~ by high in~ensity lights in the green-house. The plants are fertilized at ~, 4, and 8 weeks ~2C~73~ 5 `
after planting with a water soluble fertilizer (1~-25-16) at the rate of 1 tsp/gal o water, and are fre~uently sprayed with isotox for a2hid control and dusted with sulfur for powdery mildew control.
Test compounds are foliarly applied to the awned ~emale plants when these plants reach the flag leaf emergence stage (stage 8 on Feekes' scale).~ All compounds are applied in a carrier volume of 50 gal/A oontaining a surfactant, such as Triton X-100 at the rate of 20OZ/50 gal.
After spike emergence but before anthesis, 4 to 6 spikes per pot are bagged to prevent outcrossing. At the first signs of flower open;ng, two spikes per pot are cross pollinated, using the approach method, with the awnless male parent. As soon as the seeds become plainly visible, spike length is measured and seeds per spikelet counted in both bagged and crossed spikes. Male sterility can then be calcul~ed as percent inhibition of seed set in bagged spikes of treated plants, and female fertility in crossed spikes can be calculated as percent of control seed set.
After maturity the seed on crossed spikes are planted for determination of percent hybridization.
Percent sterility, percent fertility, and percent height inhibition are calculated from the following formulas.
a. % S~erility = (Sc - Sl/Sc) x 100 Sc ~ seeds/spikelet in bagged spikes of control plants.
S~ ~ seeds/spikelet in bagged spikes of treated plants.
b. ~ Fertility = (Ft/FC) x 100 Ft = seeds/spikelet in approach crossed spikes of treated plants Fc = seeds/spikelet in unbagged spikes of control plants c. % ~eight inhibition = (~c ~ ~t/HC) x 100 ~c ~ ~eight of con.rol plants ~t ~ Height of treated plants .
... .. .
~732S
~ 89 Table X sum~arizes typical results obtained in the evaluation o~ co~pound~ o~ the invention. A dash indi~ates that no deter~ination of value was made.
TABL~ X
Biol~ical Data (Wheat Greenhouse Data) ~ Male Sterilit~ at Dosage (lbs. A~
Exam~ 8 4 2 1 1/2 1/4 1/8 ' 1 not a tive at 8 lbs/A or below 2 not ac~ive at 8 lbs~ or b~iow ~3 not active at 8 lb~/~ or below 4a - 190 100 77 36 - -~
5a 100 - 100 - 43 - 2 6 - - - _ _ _ 6a 100 - 85 - 18 - 54 7 - - ~
7a not active at 8 lbs/A or below 8 ~ ~
8a - - 98 - 34 ~~a 99 - 88 - 32 - 5 1~ -- -- -- _ _, _ _ lOa . - - 1.00 - 100 - 13 12 _ _ 12a not active at 8 lbs/A or bel~w 13a - ~00 100 92 5; 12 - -14 not active at 8 lbs/A or below no~ ac`ti~e at 8 lbs/A or below 16 _ _ 16a - 100 100 100 96 91 .. . . . .. ~
; 17 - 100 10~ 100 9~
17a100 ; 100 18 0 - 0 18a - - ~ 100 66 100 41 19 ~
,~ ' . ' , ' ,.
~37;~5 9~
TABLE ~ (cont . ) _ _ ~ 8 4 _ 2 1 1/~ 1/4 1/8 19a not active at 8 lbs/A or below 2 0 -- ~
- 20a not active at 8 lbs/A or below 21 -- -- _ _ _ _ 21a not active at 8 lbs/A or below 22a 100 23 -- -- -- -- _ _ _ 23a not active at 8 lbs/A or below 2 4 ~
24a 10 8 - 19 - 15 2 S -- -- _ _ _ . ~
25a - 55 49 ~ ~
2 6 ~
26a - 94 7 15 0 2 2 0 2 7 ~
27a - 100 100 57 0 2 2 8 ~
28a - 100 100 100 39 7 0 2~ -- -- ~. -- _ _ _ 29a -~ 100 70 1 0 0 ~
30a. - 100 100 100 0 0 3 2 ~
32a - 100 .10~100 lOa 87 33 -- -- -- -- _ _ _ 33a 100 - 100 - 100 ~ 37 3 ~
34a 100 - 79 - 50 - 44 -- ~ . _ _ _ _ . . ` '` ' ' _ .
` ~,.~~3~
.
_ 91 _ ' _ ____ _ T_LE X(cont,. ) _ _ ~ ~4 2 11/2 _lf~1/8 ~ ~ . ; . . . .
35a not active at or below 8 lbs/A
36 ~
36a 100 - 100 - 13 - 1 37 -- _ _ _ ~ _ _ 37a - - - 90 57 38 -- -- -- ~
38a - - - 100 65 0 0 39a 100 - 100 - 45 - O
4 0 _ O _ ~
40a 100 - 92 - 14 - 0 41. not active a~t or below 8 lbs/A
42 ~
42a 100 - 100 - 90 - 43 4 3 ~
~3a 100 - ~ 00 - 100 -100 4 ~
4~a lQ~ - 100 - 80 - 4 4 5 -- -- ~ . _ _ 45a 100 - 100 - ~3 - 8 ~S 46 -- ~ _ _ _ _ 46a 100 - 100 73 - 0 4 7 ~
47a 100 - 84 - 0 - 0 :
' , ' ' .. . . . . . . . . . . ..... .
- ~zci~3;~5 _ 92 -TABLE X (c~n~. ) Exampl e # 8 4 2 1 1/2 1/4 1/8 9 2 21 -- 6 ~
4g. 100 ~ 9~ - 0 ~ 0 S0 - 100 100 61 0 - ~
51 ~ 92 - 7 - ~ - 0 53 11.1 - 9~4 - 0 - 0 5~ Noheads - 100 - 44 . 6 - 13 . 6 15.4 -- - 9~2 _ 2.2 -- 0 56 100 - 14 - ~ - 0 ~7 100 - 87 . ~ - 38 . 6 - ~8 . 3 58 1~0 - 9J. . 6 - 4~ . 9 - O
5a . 100 - 100 ~ 5i;.5 - 900 lS 60 . 2.2 _ 3.. 6 _ lO.B - 4.0 61 13.9 ~ g-g - 62 ~7.4 - 24.1 - 1~.7 - 22.4 63 35.1 - 6.1 - 1~3 - 18.9 64 100 - 100 - 65 . 7 8 . 3 ~ - 34.3 24.4 6B 4.7 ~ o 67 ~3.2 - 51.7 _ 0~.6 - 3.4 68 0 - 10 . 7 - 12 . ~ - 0 6~ . 48.~ - 51.2 - 2~.3 68 ~5 70 ~6.6 ~ 15.2 _ 22.8 -. 32.3 71 l~Q - 57 . 7 - 13 . Z - 0 7~ 14 . S - 19 . 4 - ~5 - - 16 ~ 19 . 8 16 0 0 - 19 . 8 - 19 30 . (32 lb~A-0% 8 lb/A-2.5% 2 lb/A-5~89 (16 lb/A~6~,2% 4 lb~A 0%
7~ 43.3 - 16.7 - 5.7 ~- 14.8 76 1~0 - 37.7 - 65.~ 1600 77 O _ _ _ _ _ 78 ~0 . 9 - 21 . ~ ~ 26 . 0 - ~ 22 . 3 ~ .
.. _ . . . .. . . .. . . . . ... . . _ .
.
TABLE X: (cont . ) ., Examl~le 8 4 2 1 1/2 1/41/81/64 -- ---- -- -- ----80a 5 - 0 2 - 3 8.1a - 7 5 5 5 5 5 82 0 ~ 0 -- 0 83 -- -- _ _ _ _ _ 10 83a 42 - 19 - 3 - 0 84 -- -- _ _ _ _ _ 8~a 12 8.5 -- _ _ _ _ _ _ 85a 69 22 - 0 - 0 15 86 -- _ _ _ _ _ _ 86a ~ ~ ~
87 99 ~ 90 - 63 - 28 88a . 100 - 98 _ 80 - 57 89a 100 - 100 - lOQ - 100 9 0 -- -- ~
90a. 100 - 100 - 44 _ 35 91a . 98 - 60 - 24 - 17 92 ~ _ _ _ _ _ _ 92a 66 - 16 - 8 - 3 93a _ _100 - 100 - 100 100 94 -- ---- -- _ _ -- _ 94a 39 ~ 1 '- 7 - 1 _ 96 _ _ _ _ _ _ _ _ 96a ~ ~
,' `1' , ~
... . . . ... ... . . .... . .. .. . . .. .. . ... . ~
.~L2C~32~i TABLE X (cont.) .
Example No. 8 4 2 1 1/21/4 1/3 37 ~
97a 0 - 0 ~ 0 9~ 16 - 0 . 4 - 9 100 -- _ _ _ _ _ _ rOOa - 100100 88 10 101 -- _ _ _ ~ _ _ lOla100 81 ~ 6 - 0 102a 0 0 2 104 _ ~ _ _ 104a ~ 100100 91 56 66 109 _ _ _ lO5a - 100100 97 18 11 106 ~
106a 0 6 - 0 - 4 107 . - ~
107a 32 - 0 0 - 0 108 ~
108a - - 78 - 11 - 2 lO9a 73 - 14.2 - 0 Table Xl belçw depicts the lnale/female selectivity of several of the ccmpounds of Group ~, forl~la I~, of ~he present invention. AFpllcation rate~ sufficient to effect hlgh levels of r.~.e sterility maLnta m high levels of female fertility. Substan-~ tial loss of female fertility occurs ~nly at cverdo æ application 3~ rates . ~
~, `' .
.. . . , . . . .. . . . .. . . . . _ . . .. . .
~Z~73~5 T~BL~ XI
Female ~ertility, Culm Inhibition, Height Inhibition_ (Wheat Greenhouse Data) Dosage % % Culm ~ Spike % Female 5 ~ ~ (lbs/A) Sterility Inhibition Inhibiéion Fertili~
13a 1 100 15 23 lû 1/16 10 0 O
16a 1 100 50 28 -1/8 10~ 25 g 70 lS . 1~16 83 0 4 44a 1 100 0 0 78 1/4 70 5 . 4 1/8 4û 10 5 ~0 Other ~rops upon which compounds of the present inventi~n have been shown to b? effective are eorn and barley.
The ~ollowing procedures are used to evaluate the activi~y of th~ compounds q~ ~his invention for inducing male stPrility in cor~.
Four rows of inbred variety B-73 are interplanted with two rows of inbred variety M~-17. Both lines are planted a rat~ of ~0, 000 speeds/A. rhe chemicals of this inven ion are applied to variety B-73 ~everal weeks later when the last lea~ of the plan~ is just beginning to ~
e~ongate and the tassel is approximately one inch long and not yet branched. All trea~ments are applied with a hand hela pres~urized sprayer e~uippe~ with a 3~nQzzle boom containiny D 3 disc/45 core Tee Jet cone spray tips. Each nozzle is direc~ed a~ the row with one place~ on either ~' ' ... . .. . ... . . . .. ... .. . .. . ... . . . . .. .. . . .
~Z(~73ZS
side and over the row. TritonR X-lOO surfactant (a trademark of Rohn and Haas C~mpsny) at 0.0~ is added as a surfactant. Dosage and oarrier volume calculations are based on rows 36 inches wide.
-Pollinating ability of treated plants is n~asured by crossing their pollen onto silks of untreated plants and recording the anount of seed set.
Table ,YII below damonstra~es the effect of compounds of Group A, forn~la II, of the present invention on the male sterility of field corn.
TABLE XII
13 ~ 8 4 2 1 1/2 1 16a - - ~ 100 100 100 100 100 The compounds of Group A, for~la II, of the present invention are also effective on barley.
Table XIII below demonstrates the nale sterility obtained with one of the coTpounds of Group A, formula II, of the present invention on barley grain under greenhouse conditions. (Variety Park) T~BL~ XIII
xampl~ ~ 1/4 ~J8 1/16 _~/32 16a 100 96 95 as ~Z~7325 g,7 Table XIV below sets forth field test data which demonstrate further the effect of several compounds of Group A, formula II,.of the present invention on the male sterility of field corn ¢B-73).
. . TABLE XIV
% Male Sterility of Fie ~
~ L~iale Sterility at ~arious Dosaqes (lbs~A) Example # 1 _ 1/8 1/4 i/2 1 ~ 2 4 8 43a 100 100 100 100 - - - -- 16a 13 67 99 100 100 - - -16, K salt 12 40 100 100 100 - - -32a 42 84 100 100 30a - 64 34 100 100 - - -13a - 29 59 62 90 100 100 18a - 8 30 80 100 100 5a - - 37 52 98 100 lnO
26a - - 70. 100 100 lnO 100 16 Not active at 2 lb/A and below - ~ ~
4a - - - 12 67 88 100 14 ~ot active at 8 lb/A and ~cw Table XV below sets forth additional field test ~ data which demonstrate further the effect of several compounds of the present invention on the male steri 1 ity and female sterility of field corn (B-~3).
'~`` ''' ' , ..... .... ..... .. j ... j ._ ...... .
. . . . ~
73~5 I ~ E~
c ~1 _~ h ~
~ ~ v c~
.~
~t ~ ~ r~¦ ~ o --E~op ~
O ~D O O
_t O ~ O 0 1~ ~P
C~
~ ~Q ~ ~I ~ co o o o ~
_1 O r-l ~ 1 0 u~ ~
-/ C~l o a: o ~ ~ ~ U~ O ~ O
o'p ~ ~l ~
o' r- o ~D
cr ~
-~ *
~ ~ ~ v a~ 0 u, 0 u~
- l ~ ~
~ ~ ~ ~ ~c ~ ~
X U~ (r) rl N
r~ l L~
.. .. . . . . ... . . . .. ... . . . . . . .
1 Z~73z5 Table XVI below sets forth field ~est data which demonstrate the effect of several compounds of Group A, fo~nula Il, of the present invention on the n~le sterility and feT~le sterility of sorghun (Inbred ~o. 8250).
... .
S T~BLE XVI
% Male Sterility and ~ Female Fertility of Sorghum at Various Dosaqes (lbs/A) (Field Test Data) ~ Sterility % FertilitY*
Exam~ e # 1~8 1/4 1/2 1 1/8 1/4 1/~ l _ 16, K salt 97 99 100 100 E E E F
43, K salt 10~ 100 100 100 P P P P
42, K salt 83 98 lOO lOO E E E G
*EaExcellent; G=Good; E=Fair; PaPoor.
Table XVII below sets forth additional field test dQta which demonstrate the effectiv of several compounds of Group A~ fo~Tula II, of the present invention on n~le sterility and fen~le fertility of sorghun (Inbred No. 7078).
TABLE ~ rI
9~ Male Sterility and ~ Female Fertility on Sorghum at Va,rious Dosages (lbs/A) (Field Test Data) Male SterilitY % Female FertilitY*
~ l/8 1~4 l/2 16, R salt 35 73 ~5 100 E E G F
43, K salt lOO lOO lOO 100 E F P P
42/ R salt 9 34 91 lOO E E E F
*E-Excellent; G~Good; F=Fair; P=Poor.
..
. ~ ~ . ...
.... . . . . _ _ ... . . . . _ . ... . ... .... . . . . . .. ..
7;~5 7 1~30 --T able XVIII below sets forth field test data which d~mons~rate the effect of several compounds of Group A, fo~nula II, of the present invention on m~le sterility and feT~le fertility of barley (Variety Henry).
TABLE XVIII
- ~ Male Sterility and % Female Fertility of Barley at arious Dosa~es (lbs/A) (Field Test Data) Sterility % Fertllity _ 16, R salt 32 56 92 99 93 96 75 56 10 13, K salt 2 4 4 8 95 100 100 96 43, K salt 4 22 48 77 99 97 94 76 42, K salt 3 4 4 43 96 100 100 81 Table XIX illustrates the activity of a representative co~pound according to this invention in corn.
TABLE XIX
Sterilant Activity in Corn .
Height Compound Dos~e Rate % Sterility Inhibition R .
,c~Na 12 l~o 18 O
(Exa~le 51) ~ ~ .
~7325 Table XX below sets forth field test data which illust~rates the activity of representative compounds of ~roup C, formula XXXI, of the present invention on male sterility o barley.
TABLE XX
__ _____ Examp1e 8 4 2 1 1/2 1/4 88a - 100 100 100 58 8~a - ~ 100 100 100 100 Table XXI below sets forth field test data which illustrates the activity of a representative compound of Group C, formula XXXI, of the present invention on male sterility of corn.
TABLE XXI
___ ____ Example 12 4 88,~ 100 ~.00 ~ . .
.
:: .. ...
~2~73~
Table XXII below sets forth field test data which illustrates the culm inhibition activity of several representative compounds of Group C, formula XXXI, of the present inven.tion on barley.
TABLE XXII
CULM INHIBITION (BARLEY) % INHIBITION AT RATE, LB/A
_______________________________________ ___________ Example a 4 2 1 1/2 1/4 8~a - 70 70 60 40 _ 89~ - - So 50 50 5~
Table XXIII below presents field test data which illustrates the hei~ht inhibition activity of a representative compound of Group CJ formula XgXI, of the present invention on corn~
TABLE XxIII
HEIG~T INHIBITION, % INHIBITION AT RATE, LB/A.
__ __________.__ ___________________________.___ .
xample 12 4 88~r 57 43 ~ , . . .
Table XXIV below sets forth field test data which - illustrates the e-ffect of several representative compounds of Group D,.formula XX~II, of the present invention as male sterility of corn.
TABLE XXIV
CORN, % MALE STERILITY AT RATE, LB/A
ample 4 2 1 1/2 1/4 1/8 IOOa - 100 80 62 85 lOl~ 100 9~ 96 74 6 lO5a - 100 100 28 25 Table XXV belo~ sets forth fiel~ .c t data which .:. .illustrates the effect of a representative compound of aroup ~, formula XXXII, of the present invention on male sterility of barley TA~LE XXV
BARLEY, % MALE_STERILITY AT RATE, LB/A
, ~X
~E~ 8 _~ 2 1 -~ 1/8 05a w - 100 100 100 100 .
. .
.
~2~ 5 _.
_ o o ~ --I ~ Ln 5:: C~ I
G~ 3 ~ _~
O
~ ~l s ~ ~1 e~ o ~ ~ I
J ~ ,cZl o 01 U~ ~ o U~
u~ ~n o --I ~ ~ f~
~ v - ml _~
~ C :
V ~
C ~ C5q 1 --o U~
I ~ ~ I o C: o U~
U~ o~1 --I
a~ ~ I
~, r ~;1 O ~-- O l_ C ~ I O ~ 0 o e O ~ I I I I ~
.'~ ~ .
) . 3 .
- :5 CS~ I O O O
O CO ~
C
i aJ
i~ ~ ~ (a cg "5 . ~ ~ GO C~
X
.. . .... .... . .
Claims (49)
1. A compound of the formula wherein R1 is an unsubstituted (C1-C6) alkyl or (C2-C6) alkenyl group or a straight or branched chain alkyl or alkenyl group substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted with up to two substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano;
at least one of R2, R5 and R6 is wherein (1) when R2 is , R5 is a hydrogen atom, an alkyl group or a halogen atom and R6 is a hydrogen atom or an alkyl group, (2) when R5 is , R2 is an alkyl group and R6 is a hydrogen atom or an alkyl group, (3) when R6 is , R2 is an unsubstituted (C1-C6 alkyl or (C3-C6 alkenyl group ox a straight or branched chain alkyl or alkenyl group substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted with up to two substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl nitro or cyano, and R5 is a hydrogen atom, a (C1-C6) alkyl group or a halogen atom, and (4) when R2 and R6 are both independently , R5 is a hydrogen or halogen atom or an alkyl group;
Y is a hydrogen atom or an alkyl group;
X is a hydrogen atom, a halogen atom, a trihalomethyl group, a (C1-C6) alkyl group, a nitro group, a cyano group or a (C1-C6) alkoxy group;
and n is an integer from 1 to 3;
and the agronomically acceptable alkali metal or acid addition salts thereof.
at least one of R2, R5 and R6 is wherein (1) when R2 is , R5 is a hydrogen atom, an alkyl group or a halogen atom and R6 is a hydrogen atom or an alkyl group, (2) when R5 is , R2 is an alkyl group and R6 is a hydrogen atom or an alkyl group, (3) when R6 is , R2 is an unsubstituted (C1-C6 alkyl or (C3-C6 alkenyl group ox a straight or branched chain alkyl or alkenyl group substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted with up to two substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl nitro or cyano, and R5 is a hydrogen atom, a (C1-C6) alkyl group or a halogen atom, and (4) when R2 and R6 are both independently , R5 is a hydrogen or halogen atom or an alkyl group;
Y is a hydrogen atom or an alkyl group;
X is a hydrogen atom, a halogen atom, a trihalomethyl group, a (C1-C6) alkyl group, a nitro group, a cyano group or a (C1-C6) alkoxy group;
and n is an integer from 1 to 3;
and the agronomically acceptable alkali metal or acid addition salts thereof.
2. A compound according to claim 1 of the formula:
where in R1 is a (C1-C6) alkyl group or a (C2-C6) alkenyl group;
R5 is a hydrogen atom, (C1-C6) alkyl group or a halogen atom;
R6 is a hydrogen atom or a (C1-C6) alkyl group;
Y is a hydrogen or a (C1-C6) alkyl group;
X is a hydrogen or halogen atom, a trihalomethyl, a (C1-C6) alkyl, a nitro, a cyano, or a (C1-C4) alkoxy group and n is the integer 1, 2 or 3;
and the agronomically acceptable alkali metal or acid addition salts thereof.
where in R1 is a (C1-C6) alkyl group or a (C2-C6) alkenyl group;
R5 is a hydrogen atom, (C1-C6) alkyl group or a halogen atom;
R6 is a hydrogen atom or a (C1-C6) alkyl group;
Y is a hydrogen or a (C1-C6) alkyl group;
X is a hydrogen or halogen atom, a trihalomethyl, a (C1-C6) alkyl, a nitro, a cyano, or a (C1-C4) alkoxy group and n is the integer 1, 2 or 3;
and the agronomically acceptable alkali metal or acid addition salts thereof.
3. A compound according to claim 2 wherein R1 is a (C1-C6) alkyl or allyl group;
R5 is a hydrogen or bromine atom or a (C1-C3) alkyl group;
R6 is a (C1-C6) alkyl group;
Y is hydrogen;
X is a hydrogen or halogen atom; and n is the integer 1 or 2 or the agronomically acceptable acid addition, sodium or potassium salts thereof.
R5 is a hydrogen or bromine atom or a (C1-C3) alkyl group;
R6 is a (C1-C6) alkyl group;
Y is hydrogen;
X is a hydrogen or halogen atom; and n is the integer 1 or 2 or the agronomically acceptable acid addition, sodium or potassium salts thereof.
4. A compound according to claim 3 wherein R1 is (C1-C3) alkyl;
R5 is hydrogen;
R6 is (C1-C3) alkyl;
Y is hydrogen;
X is hydrogen, chlorine or fluorine; and n is the integer 1 or 2.
R5 is hydrogen;
R6 is (C1-C3) alkyl;
Y is hydrogen;
X is hydrogen, chlorine or fluorine; and n is the integer 1 or 2.
5. A compound according to claim 4 wherein R1 is a methyl or ethyl group; R6 is a methyl group; and Y is a sodium or potassium cation.
6. A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
7. A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
8 A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
9. A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
10. A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
11. A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
12. A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
13. A compound according to claim 4 having the formula wherein Y is a sodium or potassium cation.
14. A method for inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to produce male sterility in the plant of a compound according to claim 1.
15. A method for inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to produce male sterility in the plant of a compound according to claim 2.
16. A method for inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to produce male sterility in the plant of a compound according to claim 4.
17. Process for the manufacture of a compound according to claim 2 which comprises:
a) reacting an alkyl benzoylacetic ester of the formula wherein Y is a (C1-C6)alkyl group with an amine of the formula R1NH2 in a protic solvent at temperatures from about 20°C to about 100°C to form an aminocinnamic ester of the formula b) reacting said aminocinnamic ester with diketene in an inert solvent at temperatures from about 10°C to about 150°C.
a) reacting an alkyl benzoylacetic ester of the formula wherein Y is a (C1-C6)alkyl group with an amine of the formula R1NH2 in a protic solvent at temperatures from about 20°C to about 100°C to form an aminocinnamic ester of the formula b) reacting said aminocinnamic ester with diketene in an inert solvent at temperatures from about 10°C to about 150°C.
18. A process according to claim 17 which comprises the additional step of saponificiation with sodium or potassium hydroxide to form the sodium or potassium salt.
19. A process according to claim 18 which comprises the additional step of converting the sodium or potassium salt to the free acid by treatment with a strong mineral acid.
20. A compound according to claim 1 of the formula:
wherein R1 and R2 are, independently, an unsubstituted (C1-C6)alkyl group or a (C2-C6)alkenyl or a straight or branched chain alkyl or alkenyl group susbstituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted with up to two substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano;
R5 is a hydrogen atom, (C1-C6)alkyl group or a halogen atom;
Y isa hydrogen or a (C1-C6)alkyl group;
X is a hydrogen, a halogen atom, a trihalomethyl, a (C1-C6)alkyl, a nitro, a cyano, or a (C1-C4)alkoxy group;
and n is an integer from 1 to 3;
and the agronomically acceptable alkali metal, alkaline earth metal, or acid addition salts thereof, or transition metal salt complexes thereof.
wherein R1 and R2 are, independently, an unsubstituted (C1-C6)alkyl group or a (C2-C6)alkenyl or a straight or branched chain alkyl or alkenyl group susbstituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted with up to two substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano;
R5 is a hydrogen atom, (C1-C6)alkyl group or a halogen atom;
Y isa hydrogen or a (C1-C6)alkyl group;
X is a hydrogen, a halogen atom, a trihalomethyl, a (C1-C6)alkyl, a nitro, a cyano, or a (C1-C4)alkoxy group;
and n is an integer from 1 to 3;
and the agronomically acceptable alkali metal, alkaline earth metal, or acid addition salts thereof, or transition metal salt complexes thereof.
21. A compound according to claim 20 wherein R1 and R2 are, independently, a (C1-C4)alkyl group;
R5 is a hydrogen or a bromine atom;
Y is a hydrogen, methyl, ethyl, sodium, or potassium;
X is a hydrogen, methoxy, methyl, trifluoromethyl, iodine, bromine, chlorine or fluorine; and n is an integer from 1 to 3;
and the agronomically acceptable addition salts thereof.
R5 is a hydrogen or a bromine atom;
Y is a hydrogen, methyl, ethyl, sodium, or potassium;
X is a hydrogen, methoxy, methyl, trifluoromethyl, iodine, bromine, chlorine or fluorine; and n is an integer from 1 to 3;
and the agronomically acceptable addition salts thereof.
22. A compound according to claim 21 wherein R1 is a methyl, ethyl R2 is a methyl, ethyl, or n-propyl group;
R5 is hydrogen or a bromine atom;
Y is hydrogen, a sodium, or potassium cation, or a methyl or ethyl group;
X is hydrogen, methyl, trifluoromethyl, bromine, chlorine or fluorine; and n is the integer 1 or 2.
R5 is hydrogen or a bromine atom;
Y is hydrogen, a sodium, or potassium cation, or a methyl or ethyl group;
X is hydrogen, methyl, trifluoromethyl, bromine, chlorine or fluorine; and n is the integer 1 or 2.
23. A compound according to claim 22 wherein Y is a sodium or potassium cation.
24. A compound according to claim 22 having the formula:
25. A compound according to claim 22 having the formula:
26. A compound according to claim 23 having the formula:
27. A compound according to claim 23 having the formula:
28. A compound according to claim 21 having the formula:
29. A compound according to claim 23 having the formula:
30. A compound according to claim 23 having the formula:
31. A compound according to claim 23 having the formula:
32. A method for inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to produce male sterility in the plant of a compound according to claim 20.
33. A method for inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to produce male sterilty in the plant of a compound according to claim 23.
34. A compound according to claim 1 of the formula:
wherein R1 is an unsubstituted (C1-C6)alkyl group or a straight or branched chain alkyl or alkenyl group substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted with up to two substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano;
R2 is a (C1-C4)alkyl group;
R6 is a hydrogen atom or a (C1-C4)alkyl group;
Y is a hydrogen or a (C1-C6)alkyl group or radical;
X is a hydrogen, a halogen atom, a trihalomethyl, a (C1-C6)alkyl group; a nitro, a cyano, or a (C1-C4)alkoxy group; and n is the integer 1, or 2 and the agronomically acceptable alkali metal, alkaline earth metal or acid addition salts thereof or transition metal salt complexes thereof.
wherein R1 is an unsubstituted (C1-C6)alkyl group or a straight or branched chain alkyl or alkenyl group substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted with up to two substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano;
R2 is a (C1-C4)alkyl group;
R6 is a hydrogen atom or a (C1-C4)alkyl group;
Y is a hydrogen or a (C1-C6)alkyl group or radical;
X is a hydrogen, a halogen atom, a trihalomethyl, a (C1-C6)alkyl group; a nitro, a cyano, or a (C1-C4)alkoxy group; and n is the integer 1, or 2 and the agronomically acceptable alkali metal, alkaline earth metal or acid addition salts thereof or transition metal salt complexes thereof.
35. A compound according to claim 34 wherein:
R1 is a (C1-C6)alkyl group;
R2 is a (C1-C3)alkyl group;
R6 is a (C1-C4)alkyl group.
Y is a hydrogen, methyl, ethyl, sodium or potassium group or radical;
X is a hydrogen, a (C1-C6)alkyl group, or halogen atom;
and n is the integer 1 or 2;
and the agronomically acceptable addition salts thereof.
R1 is a (C1-C6)alkyl group;
R2 is a (C1-C3)alkyl group;
R6 is a (C1-C4)alkyl group.
Y is a hydrogen, methyl, ethyl, sodium or potassium group or radical;
X is a hydrogen, a (C1-C6)alkyl group, or halogen atom;
and n is the integer 1 or 2;
and the agronomically acceptable addition salts thereof.
36. A compound according to claim 35 wherein R1 is a methyl or ethyl group;
R2 is a methyl group;
R6 is a hydrogen radical or a methyl group;
Y is hydrogen, methyl, ethyl, sodium or potassium;
X is hydrogen or chlorine; and n is the integer 1 or 2.
R2 is a methyl group;
R6 is a hydrogen radical or a methyl group;
Y is hydrogen, methyl, ethyl, sodium or potassium;
X is hydrogen or chlorine; and n is the integer 1 or 2.
37. A compound according to claim 36 wherein R1 is a methyl group; Y is an ethyl group or a sodium or potassium cation; and n is 1.
38. A compound according to claim 37 having the formula:
39. A compound according to claim 37 having the formula:
40. A compound according to claim 37 having the formula::
41. A method for inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to product male sterility in the plant of a compound according to claim 34.
42. A method for inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to produce male sterility in the plant of a compound according to claim 37.
43. A compound according to claim 1 of the formula:
wherein R1 is an unsubstituted (C1-C6)alkyl group or a straight or branched chain alkyl group substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted wtih up to two substituents selcted from halogen, methyl, ethyl, methoxy, ethoxy, trifluoro-methyl, nitro or cyano;
R5 is a hydrogen atom, a (C1-C4)alkyl group or a halogen atom;
Y is a hydrogen or a (C1-C6)alkyl group;
X is a hydrogen, a halogen atom, a trihalomethyl, a (C1-C6)alkoxy group and n is the integer 1 or 2;
and the agronomically acceptable alkali metal, alkaline earth metal, ammonium or mono-, di-, tri-, or quaternary ammonium or acid addition salts thereof or transition metal salt complexes thereof.
wherein R1 is an unsubstituted (C1-C6)alkyl group or a straight or branched chain alkyl group substituted with a hydroxy group, a carboxy group, an aryl group or an aryl group substituted wtih up to two substituents selcted from halogen, methyl, ethyl, methoxy, ethoxy, trifluoro-methyl, nitro or cyano;
R5 is a hydrogen atom, a (C1-C4)alkyl group or a halogen atom;
Y is a hydrogen or a (C1-C6)alkyl group;
X is a hydrogen, a halogen atom, a trihalomethyl, a (C1-C6)alkoxy group and n is the integer 1 or 2;
and the agronomically acceptable alkali metal, alkaline earth metal, ammonium or mono-, di-, tri-, or quaternary ammonium or acid addition salts thereof or transition metal salt complexes thereof.
44. A compound according to claim 43 wherein R1 is a (C1-C3)alkyl group;
R5 is a hydrogen or bromine atom;
Y is hydrogen, sodium-or potassium;
X is hydrogen or halogen; and n is the integer 1 or 2.
R5 is a hydrogen or bromine atom;
Y is hydrogen, sodium-or potassium;
X is hydrogen or halogen; and n is the integer 1 or 2.
45. A compound according to claim 44 wherein R1 is methyl or ethyl;
R5 is hydrogen or bromine;
v is hydrogen, sodium or potassium;
X is hydrogen, chlorine or fluorine; and n is the integer 1 or 2 .
R5 is hydrogen or bromine;
v is hydrogen, sodium or potassium;
X is hydrogen, chlorine or fluorine; and n is the integer 1 or 2 .
46. A compound according to claim 45 having the formula:
47. A compound according to claim 45 having the formula:
48. A compound according to claim 45 having the formula:
49. A compound according to claim 45 having the formula:
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14807980A | 1980-05-12 | 1980-05-12 | |
| US148,079 | 1980-05-12 | ||
| US25071181A | 1981-04-16 | 1981-04-16 | |
| US250,711 | 1981-04-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1207325A true CA1207325A (en) | 1986-07-08 |
Family
ID=26845494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000376847A Expired CA1207325A (en) | 1980-05-12 | 1981-05-05 | Aryl-4-oxonicotinates |
Country Status (7)
| Country | Link |
|---|---|
| AR (1) | AR228154A1 (en) |
| BR (1) | BR8102912A (en) |
| CA (1) | CA1207325A (en) |
| DK (1) | DK161314C (en) |
| ES (1) | ES8303345A1 (en) |
| GR (1) | GR74540B (en) |
| PT (1) | PT72996B (en) |
-
1981
- 1981-05-05 CA CA000376847A patent/CA1207325A/en not_active Expired
- 1981-05-08 PT PT7299681A patent/PT72996B/en not_active IP Right Cessation
- 1981-05-11 BR BR8102912A patent/BR8102912A/en not_active IP Right Cessation
- 1981-05-11 DK DK207781A patent/DK161314C/en not_active IP Right Cessation
- 1981-05-11 AR AR28527481A patent/AR228154A1/en active
- 1981-05-12 ES ES502155A patent/ES8303345A1/en not_active Expired
- 1981-05-12 GR GR64914A patent/GR74540B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES502155A0 (en) | 1983-02-01 |
| DK207781A (en) | 1981-11-13 |
| AR228154A1 (en) | 1983-01-31 |
| ES8303345A1 (en) | 1983-02-01 |
| GR74540B (en) | 1984-06-29 |
| PT72996A (en) | 1981-06-01 |
| DK161314B (en) | 1991-06-24 |
| BR8102912A (en) | 1982-02-02 |
| DK161314C (en) | 1991-12-30 |
| PT72996B (en) | 1983-02-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |