CA1115283A - Process for preparing 3-carbalkoxy-4-pyrone derivatives - Google Patents

Abstract

Abstract of the Disclosure A process is described for preparing compounds of the formula wherein R is a (C1-C4) alkyl group, R2 is a (C1-C4) alkyl group, R6 is a hydrogen atom or a (C1-C4) alkyl group, and R8 is a hydrogen atom, a halogen atom, or a (C1-C4) alkyl group. The process comprises reacting a compound of the formula wherein R6 and R8 are as defined above, R9 is a halogen atom, and X is a halogen atom or an acetyl group, with a .beta.-ketoester salt of the formula wherein R and R2 are as defined above and M is a cation, in an inert solvent at a temperature of from about 0°C to the reflux temperature of the solvent.

The above compounds are useful as intermediates for the preparation of 1-aryl-4-pyridone compounds which are active as plant growth regulators, and particularly as chemical hybridiza-tion agents.

Description

5~3 The Disclosure This invention relates to novel compounds which show activity as plant growth regulators, particularly as chemical hydridization agents, to growth regulant compositions which comprise these compounds, and to methods of regulating the growth of plants, particularly by inducin~ selective male sterility, with these compounds and compositions.
The cereal grains, such as corn, wheat, rice, rye, barley, millets, sorghum, and teff are among the major food crops throughou~ the world. This importance has led to exten-sive research to improve both the productivity and food value of these crops. One of the most important approaches taken to improve the quality and yield of the cereal grains has been hybridization. While hybridization has been an effective technique for some crops, most notably corn, there have been a number of problems with present techniques. For example, corn hybridization requires time-consuming hand detasselin~ or inefficient mechanical de-tasseling, possibly injuring the corn plant. Corn, barley, and wheat hybridization by means of cytoplasmic male sterile varieties can only be done with a limited genetic base, requiring a maintainer line and a restore line. Furthermore, cytoplasmic male sterile techniques with barley and wheat necessitate a highly sophisticated approach to deal with the genetic complexities of these crops) and great success has not yet been achieved in developing a suit-able approach. Since the ind~ction of selecti~e male sterility by chemical means would obviate many of the problems confront~
in~ the present hybridization ~echniques, new compounds which produce the desired sterility would be extremely desirable 3n in dependably and economically supplying the male sterile '' "

:: ' .' S~
plants needed for hybridiz2tion.
A new class o~ compounds has now been found which can be used to induce male sterility in cereal grains. The compounds of` the invention are 4-pyridones having the formula , R ~ Rl R3 Nl ~ R2 wherein Rl is a carboxy group (-COOH) or an a~ronomically-acceptable salt thereof, a carbalkoxy group . .. -.
(-COOR, wherein R is an alkyl group, pre~erably .
. having up to 12 carbon atoms,most pre~erably up .
to 4 carbon atoms), a carbamoyl group (-CONH2), an .
alkyl or dialkyl carbamoyl group (-CONHR or -CONR2), :
or a cyano group, R2 is an alkyI group, prererably having up to 4 car-bon atoms, R3 is a hydrogen atom or an alkyl group, pre~erably hav~ng up to 4 carbon atoms, R4 is a hydrogen atom, an alkyl group, prefer~bly having up to 4 carbon atoms, or a halogen atom?
preferably a bromine or a c~llorine atom, and

2~ R is a substituted phenyl group having up to three substituents selected from halogen atoms, :
(Cl-C4)alkyl groups, (Cl-C4)a~koxy groups, tri- ~:
fluoromethyl groups, and nitro groups, or, when ., ; R3 is a hydrogen atom, additionally an unsub- !
stituted phen~l group; or when R and R are mPthyl groups,R is an unsu~s~itutecl phenyl group or a phenyl group substituted with up to three substituents selected from chlorine/ bromine and ~3~ : ~:

'I
Z~ ;

iodine in any position on the ring, meta and para fluorine, (Cl-C4~ alkyl groups, (C1-C4) alXo~y groups, trifluoromethyl groups and nitro grou~s.
These compounds are also disclosed, and are claimed, in Canadian Application No. 274,511, now Canad.ian Patent No. 1,095,049, issued Feb. 3, 1981, of which this application is a divisional.
The present rnvention, in another aspect, resides in a method of inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an z~ount effective to produce male sterility in the plant of a compound of the formula .

R4 ~ Rl Il 11 :
~ ~\ .
R3~ ¦ R2 , wherein Rl is a carboxy group or ~n agronomically-acceptable salt thereof, a carb(Cl-C4)alkoxy group, a carba-moyl group, a tCl~C4)alkyl or di(Cl-C4)alkyl carbamoyl group, or a cyano group, R is a (Cl-C4)alkyl group, R3 is a hy~rogen atom or a (Cl-C4)alkyl group, R4 is a hydrogen atom, a (Cl-C4)alkyl group, or a halogen atom, and R5 is an unsubstituted phenyl group or a substituted - phenyl grou~ having up to three substituents havin~ a total of up to 6 carbon atoms.
In a further asp~ct, this inv~ntion resides in a method of producing hybrid cereal grain seed which compxises trezlting the female parent of the cereal grain prior to meiosis with a compound of the formula -3a- -5'2~33 R4 ~Rl :

~3 N R2 whereirl Rl is a carbo~y group or an agronomlcally-acceptable salt thereof, a carb(Cl-C4)alkoxy group, a c rb~ -moyl group, a (Cl-CI~)al~yl or di(Cl-C4)ah~cyl car~amoyl group, or a cyano group, R is a ( Cl-C4 )alkyl group ~ ;
R3 is a hydrogen atom or a (Cl-C4)alkyl group, R is a hydr~gen atom, a (Cl-C4)alkyl group, or a haîogen atom, and R5 is a phenyl group or a substituted phenyl group having up to three substituents ha~ring a 'cotal of' up to 6 carbon atoms, ln an amou~at sufficient to produce male sterility in the ~emale parent 9 causing the ~emale parent to be pollinated wl~h pollen ~rom a male parent o~ the cereal grain, allowin6 the ~emale parent to mature until seed ~ormation is subst~n-tia}ly complete, and har~estln$ the ma~ure seed ~rom the ~emale pa~ent.
The above aspects of the invention are disclosed, and are -:
: claimed,in the aforesaid Canadian Patent No. l,095,049, granted '~
Feb. 3, 1981, of which this application is a divisional.
The invention, in a further aspect) resides in a method for preparing a compound of the formula ~:

3b -' : ', R8 ~`~ C02R

wherein R is a (Cl-C4) alkyl group, R2 is a (Cl-C4) alkyl group, and R6 is a hydrogen atom or a (Cl-C4) alkyl group, and R8 is a hydrogen atom, a halogen atom or a ~Cl-C4) alkyl group, which comprises reacting a compound of the formula /C--~ C

wherein R6 and R8 are as defined above, R9 is a halogen atom, and - ;
X is a halogen atom or an acetyl group, with a ~-ketoester salt of the formula - ;
:~

o~M ~ / CO2R M~ f e 1 C - CH ~--t R2-C--CH=C-OR~ R2-C-C--COOR ~ :.
~2 10M~
' wherein R and R2 are. as defined above and M is a cation, in :~
an inert ~olvent at a temperature of from abouk 0C to the :
reflux temperature of the solvent.
In a preferred embodiment of the invention, R is a . .:
carboxy group OL a salt thereof, R2 is a methyl group~ R3 is - :

- 3c ~

-2~

a hydrogen atom or a methyl group, R4 is a hydrogen atom or a halogen atom, and R5 is a substituted phenyl group.
When Rl is a salt o~ a carboxy group, an alkali metal, alkaline earth metal, or transition metal car. provide the cation. The cation can also be ammonium or substituted a~monium. Representative metal salt cations include alkali metal cations, such as sodium, potassium, lithium, or the like, alkaline earth metal cations, such as calcium, ma~nesium bariu~, strontiumg or the like, or heavy metal cations, such as zinc, manganese, cupric, cuprous, ferric, ferrous, titanium aluminum, or the like. Among the ammonium salts are those in which the am~onium cation has the ~ormula NZlZ2Z3Z4, wherein each of zl, z2, z3, and Z4 is lndividually a hydrogen atom, a hydroxy group, a (Cl-C4)alkoxy group, a (Cl-C20)alkyl group, a (C3-C8)alkenyl group, a (C3-C8)alkynyl group, a (C2~C8)hydrox~alkyl group, a (C2-C8)alkoxyalkyl group, a (C2-C6)aminoalkyl group, a (C2-C6)haloalkyl group, a sub-stituted or unsubstituted phenyl group9 a substituted or unsubstituted phenylalkyl group, having up to 4 carbon atoms in alkyl moiety, an amino or alkyl-substituted amino group, or any two of zl, z2, z3, or Z4 can be taken together to form with the nitrogen atom a 5- or 6-member heterocyclic ring, optionally having up to one additional hetero oxygen, nitro- `
gen, or sulfur atom in the ring, and preferably saturated, sucn as a piperidine~ morpholine, pyrrolidine, or piperazine ring, or the like~ or any three of zl, z2, Z3, or Z4 can be taken together to ~orm with the nitrogen atom a 5- or 6-member aromatic heterocyclic ring, such as a piperazole or - pyridine ring. When ~he ammonium group contains a substituted alkyl, substituted phenyl or substituted phenylalkyl ~roup~

2~33 the substituents will generally be selected ~rom halogen atoms, (Cl-C8)alkyl groups, (C1-C4)alXoxy groups, hydroxy groups, nitro groups, trifluoromethyl groups, cyano groups, amlno groups, (Cl-C4)alkylthio groups, and the like. Such substituted phenyl groups preferably have up to two such sub~
stituents. Representative ammonium cations include ammonium, dimethylammonium, 2-ethylhexylammonium, bis(2-hydroxyethyl)-ammonium, tris~2-hydroxyethyl)ammonium, dicyclohexylammonium,.:
t-octylar~nonium, 2-hydroxyethylammonium, morphol:Lnium,PiPer~
dinlum, 2-phenethylammonium, 2-methylbenzylammonium, n-hexyl-ammonium, triethylammoniurn, trlmethylarnmonium, tri(n-butyl)- ..
ar~onium, methoxyethylammonium, diisopropylammon~um, pyridi-nium, diallylammcnium, pyrazolium, propargylammonium, di-methylhydrazinium, hydroxyar¢monium, methoxyammonium, dodecyl-armmonlum, octadecylammonium, 4-dichlorophenylammonium, 4-nitrobenzylammonium, benzyltrimethylammonium, 2-hydroxy- :
ethyldimethyloctadecyl~mmonium, 2-hydro~yethyldiethyloctyl- :
~nonium, decyltrimethylammonium, hexyltr~ethylammonium, 4-methylbenzyltrimethylarnmonium, and the like. .
Among ~he substituents which R5 can contain are alkyl groups, preferably having up to 4 carbon atoms, aryl groups, preferably phenyl or substituted phenyl groups, alkyloxy groups, preferably having up to 4 carbon atoms, phen .
oxy or substituted phenoxy groups, halogen a~oms, such as ~luorine, chlorine, bromine, and iodine atoms, nitro groups, ;
perhalo21kyl groups, such as trifluoromethyl groups, alkoxy-alkyl groups, pre~rably having up to 6 carbon atoms, alkoxy-alkoxy groups, preferably having up to 6 carbon atoms, amino groups, alkyl or dial~yl amino groups, preferably ha~ing up ~o 4 carbon atoms in each alkyl substituent, cyano groups~

5~

SZ~3 carbalkoxy groups, pre~erably having up to 4 carbon atoms in the alkoxy moiety, carb~moyl groups, alkyl or dialkyl carbamoyl groups, preferably having up to 4 carbon atoms in each alkyl substituents, sulfo groups, 5 sulfonamide groups, alkylc~rbonyl or carboxyalkyl g~oups, .. . . . . _ .. . ,.. _ . ...
pre~er~bly having up to 4 carbon atoms in the alkyl moiety~
alkanoyloxy groups, preferably having up to 4 carbon atoms, haloalkyl groups, alkanoylamido ~roups, prefer2bly having up to 4 carDon atoms, alkylthio ~roups, preferably having up to 4 car~on atoms, al~ylsulfinyl ~roups, pre~era~ly having up to 4 carbon atoms, alkylsul~onyl groups, preferably having up to 4 carbon atoms, and the like. ~he pre~erred : -substituents are halogen atoms, (Cl-C4)alkyl groups~ (Cl-C4)-¦
alkoxy groups, trifluoromethyl ~roups, and nitro groups.
Typlcal compounds within the scope of this inven-tion include~
N (4-chlcrophenyl)-2,6-dimethylpyrid-4-one-3-c2r~oxyl~c acid N-(3-chlorophenyl)-2,6-d1methylpyrid-4-one-3-c2rboxylic acid N (3-bromophenyl)-2,6-dimethylpyrid-4-one-3~carboxyl~c acid N-(2-chlorophenyl)-2,6-dimethylpyrid-4 one-3~carboxylic acid N-~2-iodophenyl)-2,6-dimethylpyrid 4-one-3-carboxylic acid N-(2-~luorophenyl)-2,6-dimethylpyrid-4-one-3-c~rboxylic acid N-(4-~luorophenyl) 2~6-dimethylpyrid-4-one-3-c~rboxylic acid N-(4-trifluoromethylphenyl)-2,6-dimethylpyrid-4-one-3-c2r-boxylic acid N-(4-methoxyphenyl)-2~6 dimethylpyrid-4-one-~-carboxylic acid N-t3-nitrophenyl)-2,6-dimethylpyrid-4-one-3-c2rboxylic acid N-(4-cyanophenyl)-2,6-dimethylpyrid-4-one-3-carboxylic acid N-(4-chloro~henyl)-2-methyl?yrid-4-one-3-carboxylic acid N-(4-nitrophenyl)-2-methylpyrid-4-one-3-carboxylic acid , ~:
: -6-.~
.

~ ~L52~

N-(4-cyanophenyl)-2,6-dimethylpyrid-4-one-3-carboxylic acid N-(3-ethoxyphenyl)-~-methylpyrid-4~one-3-carboxylic acid N-(4-methylphenyl)-2-methylpyrId-4-orle-3-carbQxylic acid N-(3,4-dichlorophenyl)-2-methylpyrid--4-one-3-carboxylic acid N-(4-methyl-3-chlorophenyl)-2-methylpyrid-4-one-3-carboxylic acid N-(4-chlorophenyl)-2,5,6-trimethylpyrid 4-one-3-carboxylic acid 5-bromo~N-(4-chlorophenyl)-2,6-dimethylpyrid-4-one-3-carboxy- ~
lic acid : :
5-brcmo-N-(4-fluorophenyl-2,6-dimethylpyrid-4-one 3-carboxylic.
acid 5-chloro-N-(2,4-dichlorophenyl)-2,6-dimethylpyrid-4-one-3- ,.
carboxylic acid 5-fluoro-N-(3-chlorophenyl)-2,6-dimethylpyrid-4-one-3-carboxylic acid 5-bromo-N-(4-trifluoromethylphenyl)-2-methylpyrid-4-one-3-carboxylic acid and a~ronomically-acceptable salts of the above acids, . .
N-(4-chlorophenyl)-3-carbomethoxy-2,6-dimethylpyrid-4-one 20 N-(4-~luorophenyl)-3-carbethoxy-2,6 dimethylpyrid-4-one N-(3-methylphenyl)-3-carbobutoxy-2,6-dimethylpyrid-4-one N-(3,4-dichlorophenyl)-3-carbethoxy-2-methylpyrid-4-one N-phenyl-3-carbmethoxy-2-methylpyrid-4-one N-(3-trifluoromethylphenyl)-3-cyano-2,6-dimethylpyrid-4-one 25 N-(4-chlorophenyl)-3-carbamoyl-2,6-dimethylpyrid-4_one N-(2-methylphenyl)-3-methylcarbamoyl-2-methylpyrid-4-one 5-bromo-N-(4-chlorophenyl)-3-dimethylcarbamoyl-2,6-dimethyl-pyrid-4-one, and the like.

~he compounds of the in~ention can be prepared by . :~.
several convenient preparative routes. In the first method, ::
a 4-hydroxy-2-pyFone ; -7 ~, , . .,.,~ . . :

5~33 1.' ~", o~ :

~ (II) R O
wherein R6 is a hydrogen atom or an alkyl group, is reacted with an acid chloride o~ the formula R7C~Cl (III) ~:
wherein R7 is an alkyl group, in the presence of a suitable :
.
acylation catalyst such as trifluoroacetic acid, or the like.
Th~ product 3-alkylcarbonyl-4-hydroxy-2-pyrone is then i treated with a strong acid, such as concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, methanesulfonic .
acid, trifluoroacetic acid, or the like, to yield a 3-carb-oxy-4-pyrone o~ the formula .
'O
11 .
C02H (I~) :

wherein R and R7 are as defined above. This reaction is . .
usually run at a temperature of about O to lOO~C, usin~ the I
acid itsel~ as the solvent. The 3-carboxy-4-pyrone is then esterified with a suitable alcohol~ pre~erably a (Cl-C43- -alkanol. One convenient technique is a Fischer esterifi- ~:~
: .
cation, using anhydrous hydrochloric acid as a catalyst and :
the alcohol as the solvent. This esteri~ication is generally carried out at about 35 to about 150~C~ optionaLly using an ¦~
. : ine~t cosolvent such as methylene chloride, et;hylene c:hloride, I

, :, :

diethyl ether, toluene, xylene, or the li~e. When R6 is a methyl group, an ester of the pyrone o~ Formula IV can be .. . .. .
prepared directly from dehydroacetic acid by reaction with a strong acid, such as SU1LUriC acid, in an alcohol, such as methanol, with removal of water during the reaction. This reaction is generally carried out at a reflux temperature o~ the system.
A 3-carbalkoxy-4-pyri done o~ the ~ormula J~ CO R
,~ 2 (V) whereln R, R5, R6, and R7 are as defined above is then pre-pared-by reacting the 3-carbalkoxy-4-pyrGne with an equimolar or excess amount of the amine o~ the formula NH2-R5 (VI ?
wherein R~ is as de~ined above. This reaction is generally 15 carried out in an inert solvent~ such as toluene, xylene, benzene, chloroform, methylene chloride, or the like, at a temperature at wh~ch the water formed during the reaction can be removed by azeotropic dl stillation, using about 1 to 5 by weignt of an acid catalyst such as ~-toluenesulfonic acid~
hydrochloric acid, sulfuric acid, methanesulfonic acid, or the like. The ~ree acid, its saltsg amides, and other esters can then be prepared by conventional techniques.
In a second method for preparing compounds of the invention, a ~-haloacrylohalide of the for~ula ;i R9 ~ R8 25~ C - C \ (VII~
R6 COR9 . , ..
_9_ ~

. . . . . ... . . . . .
.. . .. . .: . . . .. . . . ..

wherein R is as defined a~ove, R is a hydrp~en or halogen atom or an alkyl group, and R is a ~alogen atom, preferably a chlorine atom, is reacted with a~ -ket~ester salt of the formula R2 - C~ ~ C 2 ~ _C~=~ C~ 2-C-C-cooR (VIII) wherein R and ~ are as defined above and ~ is a cation, to yield a 3-carbalkoxy-4-pyrone of the foxmula O

R ~ ~ CO2R (IX) where~n R, R2, R6, and R8 are as de~ined above. In the inl-tial step o~ this method, the ~-ketoester salt is prepared by reacting the corresponding ~-ketoester with a strong baseg such as sodium hydroxide, potassium hydroxide, sodium hydride, -~:
potassium hydride, sodium methoxlde, sodium t-butoxlde, ~otass~um methoxide, or the like in an inert solvent such as tetr~hydrofuran, diethyl ether, benzene, toluene, heptane, or the like, at a temperature o~ about -20 to about 20C.

Generally without isolatlon, the anion is then reacted direc- -.
tly with the ~-haloacrylohalide at a temperature o~ 2bout 0 ~`.
. .
to about 150C. The corresponding ~-acetylacrylohali~de can also be us~ed in this reaction. ~he ~yrone o~ Formula IX
is-then reacted with an amlne of Formul:a VI by the same procedure outlined above to yield the corresponding 3-carb- ;
alkoxy-4-pyridone. The ~ree acid, its salts, amides, and oth~r esters can then be prepared by conventional te~hniques.

- ~ 0- `
' ~$~2~33 The compounds of the invention in which R is a halogen atom can be prep~red by reacting the corresponding 4-pyridones in which R4 is a hydrogen atom with one equiv-alent o~ a halogenating agent such as bromine, chlorine, sulfuryl bromide, sulfuryl chloride, or the like in a suitable inert solvent such as ethylene dichloride, meth-anol, or the like.
The following examples will further illustrate the compounds o~ the invention and their preparation, but are not -intended to limit the invention in any way. A11 temperaturesare in degrees centigrade and parts and percentag s are by weight, unless otherwise indicated. Speci~ic illustrative preparations o~ the compounds o~ Examples 1, 2, 3, 4, 5, 35, and 36 are provided. Table I lists typlcal compounds o~ ~he invention and Table II lists their melting points and ele-mental analyses.
Examples 1 to 3 Preparation of N-(4-chlorophenyl)-3-carboxy-2~6-dimethyl~
pyrid-4-one~ its methyl ester, and its_sod um salt Method A
(a) 200 g of dehydroacetic acid is dissolved in 1000 g 85%
H2SO4 and heated to 85 for four hours. The reaction is quenched in 2000 ml ice-water, and the water extracted with 3x300 ml of chloroform. After evaporation, the resulting solid is recrystallized twice ~rom benzene to give 55-105 g o~ 3 carboxy-2,6-dimethylpyr-4-one (m p 98) (b) 42 ~ of 3-carboxy-2,6-dimethylpyr-4-one is dissolved in 250 ml of methylene chloride. In a second flask, .
20 ml o~ acetyl chloride is cautiously added to 400 ml - 1 1- . .

.. .. . . . .. ..

S;2~33 of methanol. The two solutions are mixed and refluxed ~`
for five hours. Solid sodium carbonate ~s added and the solvent removed a~ter a water wash. The residue is distilled (115-125 at 0.1 mm) to gi.ve 40 g of.3-carbo-methoxy-2,6-dimethylpyr-4-one as a waxy solid.
~c) 40 g of 3-carbomethoxy-2,6-dimethylpyr-4~one and 30.2 g of 4-chloroaniline are dissolved in 400 ml o~ toluene along with 400 mg of p-toluenesulfonic acid monohydrate.
The reaction mixture is refluxed for four hours. The solvent is removed and the product cryst~llized ~rom ether to yield 30 g o~ N-(4-chlorophenyl)-3-carbomethoxy-2,6-dimethylpyrld-4-one (m.p. 189-90).
td) 16 g of N-(4-chlorophenyl)-3-carbomethoxy--2,6-dimethyl-pyrid-4-one is suspended in 450 g of 5% aqueous sodium hydroxide and stirred at room temperature.~or 24 hours~ :~
Acidification yields 14.2 g of N~(4-chlorophenyl)-3-carboxy-2,6-dimethylpyrid-4-one (m.p. 260-61.5 decomp.) ...
which is converted to its sodium salt (m.p. >310) by neutralization with sodium hydroxide.
Method B
1.68 g o~ 2,6-dimethylpyr-4-one-3-carboxylic acid and 1 30 g o~ 4-chloroaniline are dissolved in 10 ml of benzene along with 120 mg of p-toluenesulfonic acid mono- -hydrate. The reaction m~xture is then refluxed fvr 2 .1/2 hours. Extraction with dilute base and acidification of the basic extracts yields 250 mg of N-(4-chlorophenyl~-2,6-dimethylpyrid-4-one~3-carboxylic acid.
Method C
: 100 g of dehydroacetic acid is added to a one liter :

3-neck flask containing 500 ml of dry metllanol and 25 g of .

96% sulfuric acid. The flask is fitted with a magnetic stirring bar, thermometer and a Soxhlet extractor ~illed with 100 g of Linde-type 3A molecular sieves. The reaction mixture is brought to rellux~ allowing the condensed sol-vent vapors to percolate through the sieves. After 30 hours,the reaction mixture is cooled, 250 ml of methylene chloride ' is added and the pH adjusted to 6 with aqueous sodium hydrox-ide. 400 ml of water is added causing a phase separation.
The methylene chloride phase is collected and the aqueous phase is extracted with methylene chloride (lx200, 2xlO0 ml)~
The extracts are combined and backwashed with 400'ml of waterO Evaporation o~ the solvent yields 90 g of crude `
3-carbomethoxy-2,6-dimethylpyr-4-one which is purified by vacuum distillatlon. Yield of the purified material is 65 g (b.~. 131-5 at 1.0 mm).
' Examples 4' and 5 - Preparation of N-phenyl-3-carboxy-2,6-dimethylpyrid-4-one ; " ' and it's sodium salt '-.
(a) 16.8 g of 3-carboxy-2,6-dimethylpyr-4-one and 18.5 g of ~
anili~e are dissolved in 150 ml methylene chloride along' with 1.0 g p-toluenesulfonic acid monohydrate and ~' gently refluxed for 24 hours. Extraction with dilute ~' base and acidification o~ the basic extracts yields

4 to 5 g of N-phenyl-3-carboxy-2,6-dimethylpyr-4-one (m.p. 274-5), which can be converted in~o a water '' ;
soluble sodium salt (m.p. 212, decomp.).
Exam~le 35 :

Preparation of 5-Bromo-N-(4-chlorophenyl)-2,6-dimethylpyrid-4-Qne-3-carboxYlic acid and its sodium salt Sodium N-(4-chlorophenyl)-2,6-dimethylpyrid-4-one-3-carboxylate (3.0 g) is dissolved in 300 ml o~ dry methanol~

-13_ ,: ; .. .

Z~

A dilute methanolic bromine solut~on is added until a yellow color persists for 30 seconds after the addition of a single drop. A white precipitate forms which is dissolved in dilute base. The solution is ~iltered and reacidified to give 2.4 g of 5-bromo-N-(4-chlorophenyl)-2,6-dimethyl-pyrid-4-one-3-carboxylic acid (mp >200, decomp) which is isolated as a white powder. This material is transformed into its sodium salt (mp >200 decomp), by neutralization with sodium hydroxide.
Example 36 Preparation of N-phenyl-2-methylpyrid-4-one-~-carboxylic acid (a) 6.5 g of acetoacetic ester (ethyl acetoacetate) is dissolved in 35 ml of dry tetrahydrofuran and slowly added via syringe to a three-neck flask c~ntainin~ 2.5 g of a 50% sodium hydride dispersion. The reaction flask is cooled in an ice bath and ma~ntained under a nitrogen atmosphere throughout the addition. The resulting solution is then allowed to stand at 25 for about one-hour prior to use.
6.2 g of trans-~-chloroacryloyl chloride is dissolved in 35 ml of dry tetrahydrofuran added dropwise to the reaction mixture over the course of l 1/2 hours while maintalning a temperature of 10 to 15. The reaction mixture is then allowed to stand at room temperature for 1 1~2 hours, followed by 2 hours of reflux. The reaction mixture is then cooled and dumped into wat`er and extracted several times with ether. Evaporation of the solvent ylelds 5.5g of an o~l containing 3-carb-oethoxy-2-methylpyr-2-one.
(b) The crude 3-car~oethoxy-2-methylpyr-4 one isolated from I

.

2~;3 .

the previous reaction is dissolved in 50 ml toluene.
~.4 g Or aniline and 400 mg of p-toluenesulfonic acid monohydrate are added and the mixture refluxed for one hour. ~vaporation of the solvent leaves 6.3 g o~ crude 3-carboethoxy-N-phenyl-2-methylpyrid-4-one. -(c) 6~3 g of crude 3 carboethoxy-N-phenyl-2-methylpyrid-4~
one is suspended in 100 g of 5~ aqueous sodium hydroxide ...
and placed on a steambath for approximately one hour. ~ :
The mixture is cooled, filtered and acidified to yield 2.3 g of N-phenyl-2-methylpyrid-4-one-3-carboxylic .: :
acid which is recrystallized ~rom methylene chloride/
ether (mp 203-4~).
~.
. .

":

, -~: ' '.' ': ' . . .
~''".

..

': " .

15~

.. . . .. . .. - . .. ..

5~3 ~ BLE I
l-Ary1-4-Pyridones :~

O
R4 ~ COOR . . ;

~ '":"~ ' .
X ' :

Example 4 No. R R2 R3 R X
H CH3 CH3 H 4-Cl 2 Na 3 , 3 H 4-Cl 3 CH3CH3 C~3 H 4-Cl 5 NaCH3 CH,3 H H

6 NaCH3 CH3 ~ 3, 4-diCl

7 H~ CH3 CH3 H 4-I

8 NaCH3 CH3 H 4-I :
..................... ...... ....... ... ....... ...... ............. ........ ...... ~.
g H C~3 CH3 H 4 Br 1G NaCH3 CH3 H 4-13r :
11 H CH3 CH3 H 4~
12 NaCH3 CH3 H 4-F -14 NaCH3 CH3 H 4~0CH3 16 NaCH3 3 4-C~i3 -' ~ .

~S;~3 1' ~' Table I (cont'd) Example R R2 R3 R X

17 H CH3 CH3 H 4-~F3 !::
18 Na CH3 3 4-CF3 :

Na CH3 3 4ONO2 21 H CH3 CH3 H 3-Gl 22 Na CH3 CH3 H 3-Cl ¦~

24 Na CH CH H 3-F :~
H CH3 CH3 H 2-Cl .
26 Na CH3 CH3 H 2-Cl ~ :
27 H CH3 CH3 H 2-F :
28 Na CH3 CH3 H 2-F :
29 H CH3 CH3 H 3~4-diCH3 : .
Na CH3 CH3 H 3,4-diCH3 ;. :
31 H CH3 CH3 H 4--CH3-3-Cl .
32 Na CH3 CH3 H 4-CX3-3-Cl .
33 H CH3 CH3 H 2,4-diCl 34 Na CH3 3 2,4-diCl Na CH3 CH3 Br 4-C1 :.
36 H CH3 H H H `
37 . Na CH3 H H H
38 H CH3 CH3 Br 4-F
39 Na CH3 CH3 ~r 4-F ..
H 3 ~ 3 3-Br 41 Na CH3 3 3-Br I .
42 H CH3 CH3 H 3 C~
43 Na CH3 CH3 H 3-CF`3 .

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44 H CH3 3 2, 4 diF ~
Na CH3CH3 H 2, 4-diF .

47 Na CH3 H H 4-I

4 9 Na CH3 H H 4-Cl 51 Na CH3 H H 4-F .
52 CH3 CH3 3 4-F :
53 H CH3CH3 Br. 3-F
54 H CH3 3 4-Br H CX3 3 4-I .
.
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i The compounds o~ the invention are particularly useful as chemical hybridization agents in cereal crops, such as wheat, barley, corn, rice, sorghum, millets, oats, I
rye and the like. When used as chemical hybridiz~tion agents, 5 the compounds effectively induce a high degree o~ selective male sterility, that is without also inducin~ signi~icant female sterility, in the trea~ed plants and without caus~ng significant growth inhibition of the treated plants. As used herein, the term male sterility inc~udes both actual male sterility, as evidenced by a lack of male flower parts or by sterile pollen~ and functional male sterility, in which the male ~lower parts are unable to cause pollination.
The compounds of the invention also cause other plant growth regulatory responses, such as for example, control of flowering~ control of fruiting and inhibition of seed for-mation in non-cereal species, and other related growth regulatory responses.
When used as plant growth regulators, the com-pounds of the invention are applied in any amount which will be su~ficient to ef~ect the desired plant response without causing any undesirable or phytotoxic response.
For example~ when the compounds of the invention are used as che~ical hybridization agents, they are generally applied to the crops to be treated as a rate of about 1/32 to about 20 pounds per acre and preferably about 1/8 to about 10 pounds per acre. The rate of application will vary depending on the crop being treated, the compound being used ~or treatment, and related factors.
To obtain hybrid seed, the followin~ procedure is 30~ generally employed. The two parents to be cros~ed are ~ -24-- ~ :. . - . .

planted ln 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 fe~tile, male parent, and the seed produced by the female parent will be hybrid seed which can then be harvested by conventional means.
A preferred method of applying a compound of the invention as a chemical hybridi ation agent is by foliar applicat~on. When this method is employed, selective male sterility is most e~ectively induced when the co~pound is applied between flower initiation and meiosis~ ~he com-pounds o~ the inventions may also be applied as a seed --treatment by soaking the seed ln a liquid ~ormulation con-taining the active compound or by coating the seed with the .... ~ . .. . .. . .. ... .. . . . _ . .. . .. ...... . . . . .
compound. Xn seed treatment applications, the compounds _ _ _ . .. .. . . . . . _ . .. _ .. . . _ . . .. .... _ . _ . .
of the invention w~ll generally be applied at a rate o~
about 1~4 to about 10 pounds per hundred weiæht of seed.
The compounds of the invention are also effective when appIied to the soil or to the water sur~ace in rice crops. :
The compounds of the invention can be used as plant growth regulators either individually or in mixtures. For example, they can be used in combination with other plant growth regula~ors, such as auxins, gibberellins, ethylene releasing agenks such as ethephon, pyridones, cytokinins~
m~leic hydra~ide, succinic acid 2,2-dimethylhydrazide, choline and its salts, (2-chloroethyl) trimethylammonium chloride, triiodobenzoic acid, tributyl-2,4-dichlorobenzyl-phosphonium chloride, polymerlc N-vlnyl-2-oxa~olidinones, tri(dimethylaminoethyl) phosphate 2nd its salts, and N-di-methylamino-1,2,3~6-tetrahydrophthalamic acid and its salts, ~. '.

., . : . ~ ; . ~

52~

and the like, and under some conditions may be used advan-tageously with other agricultural chemicals such as herbi-cides, fungicides, insecticides, and plant bactericides.
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 accep-- table carrier" is meant any substance which can be used to dissolve, disperse, or di~fuse a compound in the composition without impairing the ef~ectiveness of the compound and which by ltsel~ has no significant detrimental ef~ect on the soil, equipment, crops, or agronomic environment. Mixtures of the compounds of the lnvention may also be used in any o~ these formuiations. The composit~ons of the invention can be either solid or liquid formulations or solutions. For ¦
example, the compounds can be formulated as wettable powders, emulsi~iable concentrates, dusts, ~ranular for~ulations, aeroscls, or flowable emulsion concentrates~ In such formu-lations, the compounds aré extended with a liquid or solid carrier and, when deslred suitable surfactants are incor~
ported.
It is usually desirable, particularly in foliar applications, to include adjuvants~ such as wettin~ gents, spreading agents, dispersing agents, stickers, adhesives, and the like, in accordance with agricultural practices. I
Examples of adjuvants which are commonly us d in the art can be found in the John W. McCutcheon, Inc. publication "Detergents and Emulsi~iers Annua1."
The compounds of the invention can be dissolved in . ~
-26~ :~
...
- , .. . - -., . ~

~L5~

any appropriate solvent. Examples o~ solvents which are useful in the practice of this invention lnclude water, alcohols, ke~ones, aromatic hydrocarbons, halogenated ',, hydrocarbons, dimethyl~ormamide, d~oxane, dimethyl sul~
foxide, and the like. Mixtures of these solvents can also '' be used. The concentratio~ of the solution can vary from about 2% to about 98% by weight with a preferred range being about 20% to ~bout 75~.
For the preparation of emulsifiable concentrates, the compound can be dissolved in organic solvents, such as . -benæene, toluene, xylene, methylated naphthalene, corn oil, : '' pine oil~' o-dichlorobenzene, isophorone, cyclohexanone, methyl oleate, and the like, or in mixtures o~ these sol- , vents,. togethe~ with an emulsi~ying agent or sur~actant ..
15 which'permits dispersion în.water. Sul.table emulsifiers - .
include, for example, the ethylene oxide derivati~es o~ - ' alkylphenols or lon~-chain alcohols, mercaptans, carboxylic acids, and reactive amines and partially esterified pcly- ~ , hydr~c alcohols. Solvent soluble sul~ates or sulfonates, such as the alkaline earth salts or amine salts of alkyl-benzenesulfonates and the fatty alcohol sodium sul,ates, havln~ surface-active properties can be used as emulsifiers either alone or~in conJunction with an ethylene oxide reaction product.' Flowable emulsion concentrates are ~ormulated sim~l~rly to the emulsi~iable:concentrates and include, in zddition to the above components, water and a stabilizing agent such as a water-soluble cellulose der~vative or a water,-soluble salt o~ a polyacrylic acld. ~he concentration o~
the active ingredient in emulsi~iable concentr~tesis usuallY : '~
about 10% to 60~ by weight, and in fIowable emulsion concentra~, ~
: .
'~'7~ ',:

2~
, ~his can be as high as about 75%.
Wettable powders suitable for spray~ng, can be prepared by admixing the compound with a finely divided solid~ such as clays, inorganic silicates and c.a~bonates, 5 and silicas and incorporating wetting agents, sticking agents, and/or dispersing agents in such mixtures. The concentration of active ingredients in such ~ormulations is usually in the range ot about 20/o to 98% by weight, prefer-ably about 40~ to 75%. A dispersi~g agent may generally ~onstitute about 0.5~ to about ~ by weight o~ the compo- .
sition, and a wetting agent may generally constitute from about 0.1% to about 5% by weight of the composition.
Dusts can be prepared by mixin~ the compounds o~
. the.lnvention with ~inely divided inert sol1ds which may be organic or inorganic in nature. Materials use~ul ~or this purpose include~ for example, botanical flours, silicas, silicates, carbonates and clays. One convenier,t method of preparing a dust is to dilute a wettable powder with a ~.
~inely divided carrier. Dust concentrates contain~ng about 20% to ~0% of the actlve in.gredient are commonly made and are subsequently diluted to about 1% to 10~ by we~ght use concentrat~on.
Qranular formulations can be prepared by impreg- -~nating a solid such as granular fuller's earth~ vermicullte, .
ground corn cobs, seed hulls, including bran or other grain hulls, or similar material. A solut~on o~ one or more ol. the compounds in a volatile organic. solvent c~n ~e sprayed or mixed with the granular solid and the~solvent then removed ~
by evaporation. The granulPr material can have ny suitable : : ;
. . . . ..
s~ ze ~ with a preferable size range of 16 to 60 l~esh. ~he ;:

. -28 ' . . . . . :
. - . .

~ ~5~33 ~:
. . . .

active compound will usually comprise about 2 to 15% by weight of the granular formulation.
Salts of the compounds of the invention can be formulated and 2ppl ied as aqueous solutions. The salt will typically comprise about 0.05 to about 50% by weight, pre-~erably about 0.1% to about lOZ, o~ the solution. These compositions can also be further diluted with water i~
desired prior to actual application. In some applications, the activity o~ these compositions can be enhanced by incor-pora~ing into the composition an adjuvant such as glycerin,methylethylcellulose, hydroxyethylcellulose, polyoxy-ethylenesorbitan monooleate, polypropylene glycol, polyacrylic acid, polyethylene sodium malate, polyethylene oxide, or the like. The adjuvant will generally comprise about 0.1 to about 5% by weight, pre~erably about 0.5 to about 2%, of the compo-sition. Such compositions can also optionally include an agronomically--acceptable surfactant.
The compounds o~ the invention can be applied as sprays by methods co~monly employed, such as conventi;onal hydraulic sprays, aerial sprays~ and dusts. For low-volume applications a solution o~ the compound is usually used.
The dilution and volume o~ application will usually depend upon such ~actors as the type of equipment employed, the method o~ application, the area to be treated and the type and stage of development of the crop being treated.
; The following examples will further illustrate ....
the ~rowth regulatory activity o~ the compounds of the inven- ~
,.
tlon but are not intended to limit the invention in any way.

~29-Exam~le 56 l~lS283 Chemical Hybridizatio _Ac*ivity.
!
The following procedures are used to e~aluate the activity of the compounds of the invention for inducing male sterility in cereals. !::
An awned variety (Fielder) and an awnless variety l:
(Mayo-64) of spring wheat are planted at the rate of 6 to 8 seeds per 6" pot containing a sterile medi~m o~ 3 parts soil :
and 1 part humus. The plants ar~ grown under short-day (9 hour) conditions for the ~irst 4 weeks to obt2in goo~ : .
vegetative growth before flower ini~iation. The plants are then moved to long-day (16 hour) conditlons which are pro- ~ .
vided by high intensity lights in the greenhouse. The plants are ~ertilized at 2, 4, and 8 weeks a~ter planting .
with a water soluble fertilizer (16-25-16) at the rate of 1 ts~/gal of water, and are frequently sprayed With"Isotox"**
~or aphid control and dus~ed with sulfur for powdery mildew control.
Test oompounds are ~ollarly applied to the awned ~emale plants when these plants reach the ~lag lea~ emer-gence stage (stage 8 on Feekes' scale). All compounds are .
applied in a carrier volume o~ 50 gal/A containing a sur- ~ :
ractant, .such as"~riton X-100"* at the rate of 2 oz/50 galO
After spike emergence but before anthesis, 4 to 6 j-spikes:per pot are bagged to prevent outcrossing. At the ~ ~.
first slgns of flower opening~ two spikes per pot are cross pollinated~ using the approach method, with the awnless male l.
~, :....
parent. As soon as the seeds became pl~inly visible, spike length is measured and seeds per spikelet counted in both `- ~
bagge~ and crossed s~ikes. Male sterlllty can then be - .

*Trademark of Rohm and Haas Company ~or octylphenoxy polyethoxy ethanol; it is a nonionic surfactant.
**Trademark ~or an insecticide which contains lindane. :
~30-- . . . , . ~ . ~

- - `

calculated as percent lnhlbltion of seed set ln ba~ged spikes of treated plants, and ~emale fertillty in crossed spikes can be calculated as percent of control seed set. After maturity the seed on crossed spikes are planted ~or deter-mination of percent hybridization.
Percent sterility~ percent fert,ility~ and percent height inhibition are calculated from the following formulas:

a) % Sterility _ Sc ~ St ~ X 100 Sc - seeds/spikelet in bagged spikes of control plants St = seeds/spikelet in bagged spikes o~ treated plants b) % Fertility = Ft X 100 Fc Ft = seeds/spikelets in approach crossed spikes o~
treated plants ~ `
Fc = seeds/spikelet in unbagged spikes of control plants c) % H~ight inhibition = c t X lQ0 Hc Hc = height of control plants Ht = helght of treated plants Table III summarizes typical results ob~ained in the evaluation of compounds of the invention. A dash indi-cates that no determination o~ value was made.

,.''.

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.

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' 'TABLE III
Male Ster'i'li'ty, Fertili'ty and 'S'~'i'ke Len~th_Inhibit'ion Ex. Rate Male Fertility' Spike No. (lb/A) Sterility ~% of CK) Length _ ('%) _ (% Inhibition) 4* 65 100 0 2 6~ 93 2 3 1/2 7 - . O
~ 3 6 . 1/2 - -4 26' 79 10 2 ~ _ O

9 1 73 - O

8 lOQ O
. . .
11 1 ~ 59 - O ': --2 95 _ O
4 100 _ o .,.

.

phytotoxic , ,, -32- .
. ' :' -. . : .
. . .

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Table III ( cont ' d ) Ex. RateMale Fertility Spike No. (lb/A)Sterility (% of CF)Len~th _( % ) _ _( 7 In-hib it i on ) 4 39 _ 0 18 1 45 . - 3 2 93 ~ 0 .
1* 31 - 1 2~ 10 - 0 -4* 25 . - 0 8* 18 - 0 4 87 ~ 0 22 ' 80 _ 5 4 100 _ o * phytoto~;ic S2~3 Table III (cont'd) Ex. Rate Mal~ Fertility Spike No. (lb/A) Sterility (p of CF) Length (~0) (% Inhibition) 2 ~

42 ~ 0 8 96 ~ - 0 1/2 26 - . 2 1/2 3 - o ~, 2 ~ - 0 ; 4 6 _ 0 o _ O

33 1 10 _ 0 2 10 - ~
4 53 _ 8 8** 38 - 0 **incomplete soluability :

,: . ~ ,- ' . . -, ., . :, -~L5Z83 Table III ( cont ' d) _ _ _ _ Ex. Rate Male Fertility Spike No. (lb/A) Sterility (.% of C'F) Len~th (%~ (% Inhibition) 34 1 8 - o 2 5 ~
1~ 56 - 4 8 57 _ O
35 1 100 û

36 1/2 4 _ 1 . 4 3 - 7 :~ - O

43 1~2 0 - O
. 1 19 98 0 : -3~-5~3 It is to be understood that changes and variations may be made without departing from the sp~rit and scope of the invention as de~ined by the appended claims.
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Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method for preparing a compound of the formula wherein R is a (C1-C4) alkyl group, R2 is a (C1-C4) alkyl group, and R6 is a hydrogen atom or a (C1-C4) alkyl group, and R8 is a hydrogen atom, a halogen atom or a (C1-C4) alkyl group, which comprises reacting a compound of the formula wherein R6 and R8 are as defined above, R9 is a halogen atom, and X is a halogen atom or an acetyl group, with a .beta.-ketoester salt of the formula wherein R and R2 are as defined above and M is a cation, in an inert solvent at a temperature of from about 0°C to the reflux temperature of the solvent.

2. The method of claim 1 wherein R2 is a methyl group and R8 is a hydrogen atom.

3. The method of claim 2 wherein R6 is a methyl group.

4. The method of claim 2 wherein R6 is a hydrogen atom.

5. The method of claim 1 wherein R2 is a methyl group and R8 is a halogen atom.

6. The method of claim 5 wherein R6 is a methyl group.