Process for the preparation of coumarin compounds

Disclosed is a three-step process for the preparation of 3-chloro-4-alkyl-7-hydroxy or alkoxycoumarin compounds starting with resorcinol or a monoalkyl ester of resorcinol and chlorinating an intermediate compound with sulfuryl chloride in the presence of acetic acid or an alkyl acetate.

DESCRIPTION 
This invention relates to a novel process for the preparation of certain 
coumarin compounds. More particularly, this invention comprises the 
preparation of 7-alkoxy-4-alkyl-3-chlorocoumarine and 
4-alkyl-3-chloro-7-hydroxycoumarins by first reacting 
3-chloro-7-alkoxy-4-alkylcoumarins and resorcinol or a monoalkyl ether of 
resorcinol with a .beta.-keto ester in the presence of an inert organic 
solvent and a protonic acid condensation catalyst and treating the 
intermediate compound thus obtained with sulfuryl chloride in the presence 
of acetic acid or an alkyl acetate. 
Known procedures for preparing the above-described coumarins employ two 
distinct and separate operations wherein a .beta.-ketoester such as an 
acetoacetic acid ester is selectively chlorinated to produce an 
.alpha.-chloro-.beta.-ketoester which is then condensed with a resorcinol 
compound in concentrated sulfuric acid. Such a procedure requires that the 
intermediate .alpha.-chloro-.beta.-ketoester be separated prior to its 
condensation with the resorcinol compound. Furthermore, the condensation 
reaction is carried out in a reaction medium of concentrated sulfuric acid 
in which the product is soluble. Thus, recovery of the product requires 
dilution of the reaction mixture with large volumes of water which limits 
the size or amount of product which can be obtained from each 
manufacturing batch. 
In accordance with my invention the aforesaid coumarin compounds may be 
prepared from a .beta.-ketoester and a resorcinol compound using a single 
reactor (one pot process). Furthermore, the condensation reaction involved 
in my process does not require the use of substantial quantities of 
sulfuric acid which greatly simplifies product recovery. Overall, my 
process is advantageously efficient and economical due to lower capital, 
labor and material costs. 
This invention provides a process for the preparation of coumarin compounds 
having the structure 
##STR1## 
which comprises 
(1) reacting a resorcinol compound having the structure 
##STR2## 
with a .beta.-ketoester having the structure 
##STR3## 
at elevated temperature in the presence of a catalytic amount of a 
protonic acid condensation catalyst and an inert organic solvent while 
distilling off reaction by-products to form an intermediate having the 
structure 
##STR4## 
(2) forming a mixture of acetic acid or an alkyl acetate with the reaction 
mixture obtained from (1); and 
(3) adding sulfuryl chloride to the mixture obtained from (2) and heating 
the resulting mixture; wherein 
R.sup.1 is hydrogen or alkyl of about 1 to 8 carbon atoms such as methyl, 
ethyl, propyl, butyl, isobutyl, amyl, hexyl, 2-ethylhexyl, octyl, etc.; 
R.sup.2 is hydrogen, alkyl of about 1 to 6 carbon atoms, chlorine, bromine 
or an aryl radical such as phenyl and phenyl substituted with alkyl of 1 
to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, bromine, etc.; 
and 
R.sup.3 is alkyl of about 1 to 6 carbon atoms. 
The condensation reaction of step (1) normally is carried out at 
temperatures in the range of about 100 to 160.degree. C. with a range of 
about 120 to 140.degree. C. being preferred. Pressures moderately below 
and above atmospheric pressure can be used if desired, e.g., to control 
the volatility of the reactants and reaction by-products. However, the 
process normally is carried out at atmospheric pressure or pressures 
slightly above atmospheric such as those generated in the reactor in which 
the process is carried out. 
The protonic acid condensation catalysts useful in the condensation 
reaction are well known in the art. See, for example, Chemistry and 
Industry, July 18, 1983, page 568. Such catalysts are moderate to strong 
acids and include sulfuric acids, phosphoric acids such as polyphosphoric 
acid and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid 
and toluene-sulfonic acid. The amount of condensation catalyst can be 
varied substantially depending on other process variables such as the 
particular reactants, solvent temperatures, and catalyst employed. Amounts 
in the range of about 0.1 to 5.0 mole percent based on reactant (I) will 
give satisfactory results although amounts in the range of about 0.5 to 
2.0 mole percent are preferred. 
The organic solvents suitable for use in the condensation step should be 
inert relative to the reactants and catalyst employed and be capable of 
being vaporized at the temperature at which the condensation reaction is 
carried out as a component of a constant boiling mixture with one or both 
of the reaction by-products (water and R.sup.3 OH). Examples of suitable 
solvents include hydrocarbons such as heptane and octane and chlorinated 
hydrocarbons such as chlorobenzene and dichlorobenzene. The amount of 
solvent used typically is about 0.5 to 3 times the weight of the 
reactants. 
The reactants used in the condensation reaction are known compounds 
available from various sources and/or can be prepared according to known 
procedures. Although the mole ratio of the reactants can be varied 
considerably, the process can be carried out most economically with 
approximately equimolar amounts of each. 
At the conclusion of step (1) the resulting reaction mixture should be 
essentially free of the by-products of the condensation reaction. Thus, 
the by-products, as in typical condensation reactions, may be removed 
during the reaction by vaporizing them separately or as an azeotrope with 
the inert, organic solvent. 
In the second step of my novel process the mixture, comprising an 
intermediate coumarin, catalyst, residual solvent and some unreacted 
material, resulting from step (1) is combined with acetic acid or a 
C.sub.1 -C.sub.4 ester of acetic acid, preferably methyl or ethyl acetate. 
While the step (1) mixture may be added to the acetic acid or ester, the 
process is most efficient and economical if the acetic acid or ester is 
added to the reactor in which the condensation step was carried out and in 
which contains the mixture resulting from step (1). 
The amount of sulfuryl chloride added to the mixture obtained from step (2) 
normally will be equimolar to the amount of intermediate courmarin present 
although up to a 20 percent mole excess may be used. When approximately 
equimolar amounts of reactants are used in step (1) the mole ratio of 
compound (I) to sulfuryl chloride usually will be in the range of about 
1.0 to 1.2. The sulfuryl chloride may be added continuously or 
intermittently over a period of time so that the addition rate gives 
selective chlorination of the intermediate coumarin. 
The temperature at which the third step is carried out can be varied 
substantially although too low of temperatures result in a slow 
chlorination rate and possibly decreased selectivity of chlorination. 
Exccessively high temperatures cause the sulfuryl chloride to decompose at 
a rapid rate with loss of the decomposition products resulting in 
incomplete chlorination. Temperatures in the range of about 40 to 
100.degree. C. can be used depending on the particular chlorination 
solvent employed. The chlorination reaction preferably is conducted at 
temperatures in the range of about 60.degree.-80.degree. C. 
The process of the invention is particularly useful for the preparation of 
3-chloro-7-hydroxy-4-methylcoumarin, a compound used in the preparation of 
coumaphos, a fungicide and bactericide used on livestock.

The process is further illustrated by the following example. 
EXAMPLE 1 
A mixture of resorcinol (11.0 g; 0.1 mol), methyl acetoacetate (13.9 g; 
0.12 mol), sulfuric acid (0.1 g) and octane (40 ml) was heated to reflux 
for five minutes at about 100.degree. C. (pot) and 75.degree. C. (head). 
After 18.5 ml of distillate were removed slowly and continuously over a 
period of 20 minutes, the pot temperature rose to 120.degree.-5.degree. C. 
The reaction mixture was heated at 120.degree.-5.degree. C. for one hour 
and then cooled to 60.degree. C. Acetic acid (200 ml) was added and the 
mixture was heated to 75.degree. C. Sulfuryl chloride (15 g; 0.11 mol) was 
added slowly to the mixture at below 85.degree. C. over a period of 11 
minutes. The resulting mixture was heated at 75.degree.-80.degree. C. for 
two hours and then acetic acid (160 to 180 ml) was distilled off under 
reduced pressure at a temperature below 100.degree. C. The viscous 
reaction mixture was cooled to room temperature and 200 ml water was added 
with vigorous stirring. After cooling to 10.degree.-15.degree. C. the 
reaction mixture was filtered and the product was washed with water and 
dried. The yield of crude product (20.7 g) was 98% based on the resorcinol 
used. The product assayed 88% 3-chloro-7-hydroxy-4-methylcoumarin by G. C. 
analysis. 
The invention has been described in detail with particular reference to 
preferred embodiments thereof, but it will be understood that variations 
and modification can be effected within the spirit and scope of the 
invention.