Process for preparing substituted pyrimidines

A process for preparation of substituted phthalides, heterocyclic phthalides and derivatives thereof by reacting an aromatic carboxylic acid mono- or di-anion with a reactive derivative of a pyrimidine carboxylic acid.

The present invention concerns a process for preparation of substituted 
phthalides, heterocyclic phthalides and derivatives thereof. 
In particular, the invention concerns preparing substituted phthalides, 
heterocyclic phthalides and derivatives thereof by reaction of an aromatic 
carboxylic acid or reactive derivative thereof by forming a mono- or 
di-anion and reacting this with a reactive derivative of a pyrimidine 
carboxylic acid. 
The present invention therefore provides a process for preparing a compound 
of formula I 
##STR1## 
wherein, A is phenyl or pyridyl, 
R is a carboxyl group which may be in the form of the free acid or in ester 
or salt form, a thiocarboxyl group which may be in the form of the free 
acid or in ester form or a di-substituted carbamoyl group, 
Y.sub.1, Y.sub.2 and Y.sub.3 are independently hydrogen or halogen; 
R.sub.1, R.sub.2, and R.sub.3 each is independently hydrogen; halogen; 
alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, 
alkenylthio or alkynylthio, each of which may in turn be substituted by 1 
to 6 halogen atoms; cycloalkyl, heterocycloalkoxy, aryloxy, aralkoxy or 
aralkylthio each of which may be substituted by 1 to 3 substituents 
selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, 
alkylthio, amino or di-substituted amino; di-substituted aminoxy; 
substituted iminoxy; di-substituted amino; substituted amido; or nitro; 
X and Y taken together represent .dbd.O; or 
X and R taken together may form the bridge, 
##STR2## 
wherein the carbonyl is attached to the phenyl ring, and Y is hydroxy, 
halogen, cyano, acyloxy, amino, substituted amino, alkoxycarbonyloxy, 
alkylsulfonyloxy, or carbamoyloxy which comprises reacting a compound of 
formula II 
##STR3## 
with a compound of formula III 
##STR4## 
wherein R, Y.sub.1, Y.sub.2, Y.sub.3, A, R.sub.1, R.sub.2 and R.sub.3 
have the meanings given above and R' represents cyano or a carboxylic 
ester group in the presence of a strong base. 
In the definitions of formula I the various radicals are preferably within 
the following scopes: 
A is preferably phenyl, but also pyridyl is preferred when linking to the 
--CXY-- bridge through the 2-, 3- or 4-position. 
The chain-type hydrocarbon radicals like alkyl, alkenyl, alkynyl, alkoxy, 
alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, haloalkyl, 
haloalkoxy, acyloxy, alkoxycarbonyloxy, alkylsulfonyloxy, or the ester 
radicals of the carboxyl group or the thiocarboxyl group, or in the 
disubstituted carbamoyl group, or in the various amino, aminoxy, iminoxy, 
or amido groups in general are preferred if the number of carbon atoms is 
eight or lower. 
Preferably R.sub.1, R.sub.2 and R.sub.3 are each independently hydrogen, 
halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8 
alkoxy, C.sub.2-8 alkenyloxy, C.sub.2-8 alkynyloxy, C.sub.1-8 alkylthio, 
C.sub.2-8 alkenylthio or C.sub.2-8 alkynylthio, each of which may in turn 
be substituted by 1 to 6 halogen atoms; C.sub.3-6 cycloalkyl, a 5- or 
6-membered heterocycloC.sub.1-8 alkoxy, aryloxy, arylC.sub.1-8 alkoxy or 
arylC.sub.1-8 alkylthio each of which may be substituted by 1 to 3 
substituents selected from halogen, C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 
C.sub.1-8 alkoxy, C.sub.1-8 haloalkoxy, nitro, C.sub.1-8 alkylthio, amino 
or di-C.sub.1-8 alkylamion, di-C.sub.1-8 alkylaminoxy; C.sub.1-8 
alkyliminoxy; di-C.sub.1-8 alkylamino; C.sub.1-8 alkylamido; or nitro. 
When X and R form the bridge --CO--O--, Y preferably is hydroxy, halogen, 
cyano, C.sub.1-8 acyloxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 
alkylamino, C.sub.1-8 alkoxycarbonyloxy, C.sub.1-8 alkylsulfonyloxy, or 
carbamoyloxy. 
Salt forms of the carboxyl and thiocarboxyl groups include salts with 
inorganic or organic cations. Examples for inorganic cations are the 
alkaline or alkaline earth metal cations like lithium, sodium, potassium, 
magnesium or calcium, with sodium being preferred. Examples for organic 
cations are ammonium salts both from quaternary ammonium compounds and 
mono-, di- or trialkylamines. Especially preferred organic cations are 
dimethylammonium or isopropyl ammonium. 
When, in the reaction according to the invention, a compound of formula II 
is employed wherein R represents a di-substituted carbamoyl group the 
compound of formula I thus obtained wherein X and Y taken together 
represent .dbd.O may, if desired, be converted to the corresponding 
compound of formula I wherein X and R taken together form the bridge 
##STR5## 
by ring closure in conventional manner. 
When, in the reaction according to the invention, a compound of formula II 
is employed wherein R represents a carboxyl group in free form or in the 
form of a metal caboxylate the compound of formula I thus obtained wherein 
X and R taken together form the bridge 
##STR6## 
may, if desired, be converted into a compound of formula I wherein X and Y 
taken together represent .dbd.O by hydrolysis in a conventional manner. 
As mentioned above, the reaction according to the invention is carried out 
in the presence of a strong base. Examples of such bases are lithium 
di-isopropylamide (LDA), n-butyllithium (n-BuLi), s-butyllithium (s-BuLi), 
n-hexyllithium. 
The reaction is typically carried out in a solvent which is inert under the 
reaction conditions. Examples of such solvents include ethers such as 
diethylether, t-butylmethyl ether, tetrahydrofuran (THF) and 
dimethoxyethane; hydrocarbons such as pentane or hexane; aromatic 
hydrocarbons such as toluene; and cyclic hydrocarbons such as cyclohexane. 
Particularly in the case of reactions where R is a carboxylic acid group, 
an amine such as tetramethylethylene diamine (TMEDA) can be added to the 
reaction mixture. 
Reaction temperatures range from -70.degree. to -20.degree. during addition 
of the strong base and -70.degree. to reflux temperature of the reaction 
mixture following addition of the compound formula III. 
The reaction is preferably carried out under an inert gas such as nitrogen 
or argon. 
Where a compound of formula II is employed wherein R is a carboxyl group in 
the form of its lithium salt it may be advantageous to carry out its 
preparation in a manner suitable for direct conversion into the di-lithium 
salt without isolation. 
In cases where a compound of formula II is employed wherein R is a carboxyl 
group, this can be achieved preferably by reacting this compound with 
butyl lithium or lithium diisopropylamide. The reaction is preferably 
carried out in an inert solvent such as THF under inert gas atmosphere, 
e.g. argon at temperatures between -80.degree. and 0.degree. C. 
In cases where a compound of formula II is employed wherein Y.sub.1 
represents halogen in ortho position to R this can also be achieved 
prefereably by reacting a compound of formula II wherein R is hydrogen 
with butyl lithium, or lithium diisopropylamide and carbon dioxide. The 
reaction is preferably carried out in an inert solvent such as THF under 
inert gas atmosphere e.g. argon at temperatures between -100.degree. and 
-40.degree. C., e.g. -70.degree. C. 
Ring closure of a compound of formula I wherein X and Y taken together 
represent .dbd.O to provide a compound of formula I wherein X and R taken 
together form the bridge 
##STR7## 
may be carried out in conventional manner e.g. by addition of an acid such 
as an inorganic acid e.g. hydrochloric acid (HCl), sulfuric acid (H.sub.2 
SO.sub.4) or an organic acid e.g. acetic acid (AcOH) or mixtures thereof. 
Examples of suitable solvents for this reaction include water, acetic acid. 
Reaction temperatures lie between room temperature and reflux temperature 
of the reaction mixture, especially -20.degree. to +25.degree.. 
Hydrolysis of a compound of formula I wherein X and R taken together form 
the bridge 
##STR8## 
to provide a compound of formula I wherein X and Y taken together 
represent .dbd.O may be carried out in conventional manner e.g. by 
addition of a base e.g. sodium hydroxide or an amine base such as 
isopropylamine. 
Examples of suitable solvents for this reaction include water optionally 
with an alcohol or a cyclic ether e.g. tetrahydrofuran or dichloromethane 
optionally with an alcohol or a cylic ether e.g. tetrahydrofuran (THF). 
The compounds of formula I may be recovered in the preferred form with 
respect particularly to substituent R and converted between the various 
forms in conventional manner. 
The compounds of formula I are useful i.a. as herbicides and are described 
along with other processes for their preparation, compositions containing 
them and their use as herbicides in U.S. Pat. No. 5,506,192 and 
EP-A-461,079 the contents of which are incorporated herein by reference. 
Particularly preferred compounds of formula I are those wherein R is a 
carboxyl group which may be in the free acid or preferably salt form; 
Y.sub.1, Y.sub.2 and Y.sub.3 are attached to carbon atoms and are 
independently hydrogen or chlorine; and 
R.sub.1 and R.sub.3 are lower alkoxy and R.sub.2 is hydrogen. 
Particularly preferred are compounds wherein A is phenyl. 
In the compounds of formula II, when employed in the process according to 
the invention, in addition to the preferences set out above for Y, R is 
preferably selected from 
a) di-substituted carbamoyl, especially dialkylcarbamoyl; 
b) carboxyl. 
In the compounds of formula III, when employed in the process according to 
the invention, in addition to the preferences set out above for R.sub.1, 
R.sub.2 and R.sub.3, R' is preferably cyano or an ester moiety of formula 
##STR9## 
wherein R" represents C.sub.1-10 alkyl, C.sub.2-10 alkenyl or alkynyl or 
phenyl; R" is especially C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl. 
Examples of carrying out the process according to the invention may be 
represented schematically as follows. 
##STR10##

The following examples illustrate the invention, temperatures are in 
degrees centigrade. 
EXAMPLE 1 
Preparation of 
4,7-dichloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxyphthalide 
54.5 g of N,N-diethyl-2,5-dichlorobenzamide are dissolved in 265 ml of THF, 
cooled to -30.degree. and 147.9 ml of 1.5M LDA added dropwise under 
N.sub.2 atmosphere. Stirring is continued for 10 min. whereupon the 
reaction mixture is added via cannula under N.sub.2 pressure to 44.4 g of 
2-methylpropyl-2-(4,6-dimethoxypyrimidinyl)carboxylate dissolved in 175 ml 
of toluene at -30.degree. with stirring. Following 5 min of additional 
stirring the reaction mixture is quenched with 250 ml of 1N HCl, 250 ml of 
toluene added and the organic phase washed with 2.times.250 ml of 1N HCl, 
water, brine and dried over Na.sub.2 SO.sub.4. The solvent is distilled 
off under high vacuum at 70.degree. and the residue dissolved in 200 ml 
AcOH, 1N HCl added until cloudy and further AcOH added until clear. 
Stirring is continued at RT for 3 days and the precipitate filtered, 
washed with a 1/1 mixture of AcOH/H.sub.2 O and dried under vacuum at 
70.degree. to yield the title compound. 
EXAMPLE 2 
Preparation of 
4,7-dichloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxyphthalide 
A mixture of 1.91 g of 2,5-dichlorobenzoic acid, 19.1 ml of toluene, and 
1.5 ml of N,N,N',N'-tetramethylethylenediamine is azeotroped for 3 hrs and 
cooled to -20.degree.. 13.4 ml of 1.5M lithium diisopropylamide 
mono(tetrahydrofuran) in cyclohexane is then added by syringe over 10 min. 
After addition of 8.4 mL of the LDA solution a solution of 2.03 g of 
2,2-dimethylpropyl-4,6-dimethoxy-2-pyrimidinecarboxylate in 4 mi of 
toluene is added dropwise over 7 minutes. The reaction mixture is stirred 
at -20.degree..+-.5.degree. for 1 hr with HPLC monitoring. The reaction 
mixture is quenched with water, 10 mL, stirred 10 min., and transferred to 
a separatory funnel. The mixture is allowed to stand 1 hr before 
separating the aqueous phase. The aqueous phase is acidified to pH 4.35 
with dilute hydrochloric acid (conc. HCl, 5 mL, water, 5 mL). The 
precipitated solid is filtered, washed with water and dried by dissolving 
in dichloromethane, filtering through phase separation paper and 
concentration. This crude concentrate is digested with 4 ml of n-butyl 
acetate at 50.degree. C. for 0.5 hr, cooled to room temperature and 
filtered. The product is washed with n-butyl acetate and hexane to give 
the title product, m.p. 197.degree.-198.degree.. 
EXAMPLE 3 
Preparation of 
4,7-dichloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxyphthalide 
A mixture of 1.22 g of TMEDA and 60 ml of THF is prepared under anhydrous 
condition and cooled to -10.degree. with stirring. 36.03 g of a 20.5% 
solution of n-BuLi in cyclohexane is added and after 30 mins stirring the 
solution is cooled to -60.degree.. A solution of 10.0 g of 
2,5-dichlorobenzoic acid in 40 ml of THF is added over 10 min. at 
-60.degree.. After a further 30 mins of stirring this solution is added 
over 15 min under argon pressure to a solution of 8.97 g of allyl 
4,6-dimethoxypyrimidine-2-carboxylate in 60 ml of THF at -25.degree. and 
the clear yellow solution cooled to -25.degree.. After stirring at 
-20.degree. for 60 mins, 60 ml of 10% HCl are added and the temperature 
allowed to rise to 13.degree. with stirring over a 15 min period. The 
organic phase is separated and evaporated to yield a viscous residue to 
which is added 17 ml of methanol. The resulting suspension is cooled in an 
ice/water bath, filtered and the crystals washed with 2.times.10 ml 
methanol and dried under vacuum at 70.degree. C. to yield the title 
product. 
EXAMPLE 4 
Preparation of 
4,7-dichloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxyphthalide 
a) 4.0 g of N,N-diethyl-2,5-dichlorobenzamide are dissolved in 75 ml of 
toluene, cooled to -20.degree. and 10.8 ml of 1.5M LDA added via syringe 
over 5 mins such that the temperature remains between -19.degree. and 
-23.degree.. This temperature is maintained for 5 mins and 2.0 g of 
2-cyano-4,6-dimethoxy-pyrimidine in 25 ml toluene added dropwise at a 
temperature between -15.degree. and -20.degree.. After 10 mins the mixture 
is quenched with 25 ml 1N H.sub.2 SO.sub.4, and the aqueous phase washed 
with ethylacetate. The combined organic phases are then washed with water 
and brine, dried and concentrated to give the intermediate product 
2-(4,6-dimethoxy-2-pyrimidinyl)-.alpha.-iminomethyl!-N,N-diethyl-2,5-dich 
lorobenzamide. 
b) 3.1 g of 
2-(4,6-dimethoxy-2-pyrimidinyl)-.alpha.-iminomethyl!-N,N-diethyl-2,5-dich 
lorobenzamide dissolved in 50 ml of acetic acid and 50 ml of water and 
heated on an oil bath at 100.degree. for 1 hour and refluxed for a further 
2 hours and 2 ml of conc. HCl added. Refluxing is continued overnight and 
the mixture then cooled in an ice bath. The precipitate is filtered off, 
washed with water, air dried and concentrated. The residue is diluted with 
100 ml of water, extracted with 3.times.50 ml of dichloromethane, washed 
with brine, dried and concentrated to give the title product. 
EXAMPLE 5 
Preparation of 4,7 
dichloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxyphthalide 
2.01 g of TMEDA and 79.3 ml of a 2.33M solution of butyl lithium in hexane 
are dissolved in 70 ml of THF at -10.degree. under argon atmosphere. After 
10 min the solution is cooled to -70.degree. whereupon a solution of 22.64 
g of 1,4-dichlorobenzene in 40 ml of THF is added within 1 hour. Stirring 
is continued for 20 min and then the solution is added via canula under 
argon pressure within 1 min into 14 g of CO.sub.2 dissolved in 160 ml of 
THF at -70.degree.. After completion of the addition another 7 g of 
CO.sub.2 (dry ice) are added. Stirring is continued for 50 min. The excess 
CO.sub.2 is removed in vacuo. To this mixture, 72.5 ml of a 2.33M solution 
of butyl lithium is added at -60.degree. over 20 min and stirred for 1 
hour. 
The reaction mixture is added via canula under argon pressure within 15 min 
to 27.3 g of allyl 4,6-dimethoxy-pyrimidine-2-carboxylate in 180 ml THF at 
-30.degree.. The mixture is stirred for 30 min at -25.degree. and quenched 
with 180 ml of 10% hydrochloric acid. After stirring for 15 min the 
organic layer is separated and concentrated at 60.degree. in vacuo. The 
residue is stirred with 50 ml of methanol for 30 min at 0.degree., 
filtered, washed with 50 ml of cold methanol and dried at 50.degree. in 
vacuo to give the title product.