Method for the manufacture of dimethyl, octyl - or pentyl - para-aminobenzoic acid

A method for the manufacture of dimethyl octyl (or pentyl) para-amino benzoic acid is described. The method consists in the carbonylation of para-bromo-dimethyl aniline, in the absence of any promoter, in a reaction system having a pH of above 8 in the presence of an alcohol selected from octanol, pentanol or isomers thereof using a palladium catalyst on an inert support. The reaction is carried out at a temperature in the range of 140.degree. to 200.degree. C. and a pressure of between 1 to 5 atmospheres. The product obtained is characterized by its high purity being substantially free of any impurities.

The present invention relates to an improved method for the manufacture of 
reagents adapted for application as sun screening substances. More 
particularly the invention relates to an improved method for the 
manufacture of dimethyl-octyl (or pentyl) --p-aminobenzoic esters which 
are substantially pure. 
BACKGROUND OF THE INVENTION 
In U.S. Pat. No. 3,403,207 (S.I. Kreps et.al.) are disclosed sun screen 
compositions based on derivatives of para-aminobenzoic esters. The common 
preparation of these esters is carried out by esterification of the 
corresponding acid using the appropriate alcohol. The particular acid can 
be obtained by reductive methylation of p-nitrobenzoic acid in an 
ethanolic solution. Another process for directly obtaining the esters 
comprises the N-methylation of p-aminobenzoic acid using a system based on 
Me.sub.2 SO.sub.4 - KOH (cf chemical Abstracts 77, 5110K). 
An interesting process is described in J.Org.Chem. 44 (13), 2199, 1979, in 
which the carbonylation of p-Br-dimethylaniline is carried out with CO in 
the presence of a catalyst based on NaH-RONaCo(OAc).sub.2. The process has 
the disadvantage that products with very low carbonylation yields (35-40%) 
and high content of impurities are obtained. 
In U.S. Pat. No. 2,640,071 a method is described for the preparation of 
carboxylic acid derivatives based on the carbonylation of aromatic 
halides. The reaction is catalyzed by compounds of metals from group VIII 
at temperatures in the range of 250 to 450.degree. C. and carbon monoxide 
pressures in the range of 300 to 1000 atmospheres. 
In a very recent U.S. Pat. No. 4,654,436, aromatic carboxylic acid esters 
are obtained by reacting an aromatic halide, such as benzene halide, 
naphthalene halide, with carbon monoxide in the presence of a palladium 
catalyst promoted with metal carbonyls, said metal being selected from 
group VIB. As mentioned in the specification, the most preferred reaction 
temperatures are in the range of between 100.degree. to 125.degree. C. 
From the Examples given, conversions in the range of 67% to 95% are 
claimed to be obtained, but no data are specified concerning the 
impurities present in the products. However, it is stipulated and 
examplified in the specification, that in the absence of a promoter very 
poor conversions in the order of 16% to 20% are obtained. 
It should be clearly understood that for human skin protection, the problem 
of impurities present in the reagents used therein is very critical. 
It is an object of the present invention to provide a simple method for the 
manufacture of dimethyl-octyl (or pentyl) para- aminobenzoic ester. It is 
another object of the present invention to provide a simple method for the 
manufacture of the above compounds at very high conversions. It is yet 
another object of the present invention to provide a simple method for the 
manufacture of the above compounds in a substantially pure form. 
BRIEF DESCRIPTION OF THE INVENTION 
The invention relates to a method for the manufacture of dimethyl octyl (or 
pentyl) para-aminobenzoic esters which comprises the carbonylation of 
p-bromo-dimethylaniline in a reaction system having a pH of above 8 in the 
presence of an alcohol selected from octanol, pentanol and isomers thereof 
using a palladium catalyst. It was unexpectedly found that according to 
this method very high yields of above 80% and even above 90% are achieved. 
Moreover, the products obtained are very pure being substantially free of 
impurities as shown by gas chromatography analysis. 
The catalytic reaction goes very smoothly without requiring any promoter, 
suggested in reactions using the palladium catalytic system. 
It was found that a certain amount of carbonylation of the substrate 
occurred in the presence of the promoter, but before the start of the 
introduction the carbon monooxide into the heated mixture. Accordingly, a 
certain conversion of the bromosubstrate to the corresponding ester 
resulted from its stoichiometric reaction with the coordinated (CO) 
ligands of the promoter molecule, without any connection to the catalytic 
process. This of course is quite undesirable; Example 6 illustrates this 
point. 
The alcohol used in the reaction has a two-fold purpose: first, use as 
reaction medium and second to participate in the formation of the 
corresponding ester. 
The reaction conditions may be varied over a very broad range of 
temperatures and pressures. Of course lower temperatures will require a 
longer reaction time. Preferred temperatures will be in the range of 
between 140 to 200.degree. C. and most preferred in the range of between 
160 to 170.degree. C. It was found that the preferred temperature is quite 
important concerning the high conversions and for reduction of the 
reaction time. This is illustrated in Example 5. Generally, the reaction 
will be complete after 2 to 12 hours depending on the temperature 
prevailing in the reactor. The pressure in the reaction system is quite 
uncritical and even atmospheric or slightly above, will be sufficient, the 
purpose being to assist the carbonylation by the carbon monoxide. Most 
preferred pressures will be in the range of 1 to 4 atmospheres. This is of 
great importance from a technological point of view since robust 
autoclaves are not required. This feature, is also contrary to known 
methods where pressures of about 10 to 1000 atmospheres, are stated as 
required during the carbonylation reaction. 
The catalyst to be used is palladium metal on an inert support, most 
preferably carbon. The amount of palladium present is about 0.1% to 0.3% 
mole based on the p-bromodimethylaniline introduced in the reaction. 
One of the requirements of the reaction is a basic medium with a pH above 
8. This may be accomplished by adding a common alkaline substance such as 
sodium or potassium carbonate, calcium or magnesium oxide, calcium or 
magnesium carbonate or any mixture thereof. The alkaline reagent is 
preferably added in a solid state, the presence of an aqueous medium being 
most undesirable for the ester preparation The amount of alkali will 
depend on the reagent used, generally being in the range of between 1 to 
1.6 mole to 1 mole of the p-bromo-dimethylaniline introduced in the 
reaction. 
It was unexpectedly found that aromatic halides such as bromobenzene or 
dibromobenzene, mentioned in the prior art as starting reagents for this 
type of reaction, give lower conversion rates in a given reaction time 
compared with the p-bromodimethylaniline. Moreover, the product obtained 
will contain various impurities (such as aldehydes, coupling products 
etc.). This will be illustrated in the experimental section by Example 2 
carried out under the conditions of the present invention except with 
replacement of the organic halide by the bromobenzene. 
An important advantage of the method is the fact that the alcohol and the 
catalyst (palladium on carbon support) can be recycled. This clearly has a 
beneficial effect on the economy of the method. A detailed description of 
this embodiment is illustrated in Example 8. 
The entire method is very simple and requires common equipment. The 
reagents: p-bromodimethylaniline, an alkaline compound (in a solid form), 
the palladium on an inert support and the alcohol are introduced into a 
reactor. The mixture is agitated and flushed with nitrogen gas followed by 
bubbling therein carbon monoxide, the reactor being maintained with 
stirring at a temperature range of between 130-180.degree. C. At the end 
of the reaction, the reactor is cooled and vented and water is added 
separating out an organic layer. This layer is subsequently subjected to 
fractional distillation whereby the respective ester, of a very high 
purity is obtained. 
The process may be carried out in the presence of inert solvents as media 
of reaction, although generally these are not necessary, since the alcohol 
employed in the reaction will also fulfill this function. 
Summing up, the novel method according to the present invention provides 
improved rates of conversion and high purity of the products. Accordingly, 
the products obtained after distillation can be utilized directly for 
human skin protection such as sun-screen reagents, without requiring any 
additional purification step. While the invention will now be described in 
connection with certain preferred embodiments in the following Examples, 
it will be understood that it is not intended to limit the invention to 
these particular embodiments. On the contrary, it is intended to cover all 
alternatives, modifications and equivalents as may be included within the 
scope of the invention as defined by the appended Claims. Thus the 
following Examples which include preferred embodiments will serve to 
illustrate the practice of this invention, it being understood that the 
particulars described are by way of example and for purposes of 
illustrative discussion of preferred embodiments of the present invention 
only. 
In the Examples the percentages given are by weight unless otherwise 
stated. Examples 2, 5 and 6 do not illustrate the invention and are 
presented only for comparison purpose. The gas chromatography analyses 
were carried out on a HP 5890 A instrument using a SE 30 capillary 
containing 100% dimethyl siloxane.

EXAMPLE 1 
The reactor consisted of a 300 ml round-bottomed flask equipped with a 
condenser, thermometer, gas bubbler and a sampler device. 
The following reagents were introduced into the reactor: 
15 g of p-bromo-dimethylaniline (p-BrDMA). 
6 g of sodium carbonate (solid form). 
128 mg of palladium on carbon support (10%), and 
160 ml of 2-ethyl-1-hexanol. 
The mixture was flushed with nitrogen for about forty minutes then heated 
at 160.degree. C. for about 5 hours while a stream of carbon monoxide was 
bubbled in, under continuous stirring. A sample taken out from the reactor 
indicated a conversion of 97% as shown by gas chromoatography. After the 
reactor was cooled and vented, about 100 ml of water were added and the 
whole mixture was filtered. The organic layer was separated and subjected 
to fractional distillation, whereby 16.6 g of 
dimethyloctyl-p-amino-benzoic ester were obtained with a purity of above 
98.5%. 
EXAMPLE 2 
The experiment as in Example 1 was repeated using the same reactor, amounts 
and reaction conditions except that instead of p-bromo-dimethyl aniline, 
15 g of p-bromobenzene were utilized. In this experiment, the conversion 
into the product was only 80% and the percentage of impurities was much 
higher than in Example 1. 
EXAMPLE 3 
The operation was carried out in the same equipment and according to the 
same method as Example 1. 
A mixture of 6 g (0,03 M) p-bromo-N,N.-dimethylaniline, 2.4 g (0.023 M) 
sodium carbonate, 60 ml 2-ethyl-1-hexanol and 106.5 mg Pd/C (10%) was 
carbonylated under 1 Atm, pressure of carbon monoxide at 160-165 C. After 
four hours, the conversion into the product was 96%. 
EXAMPLE 4 
Example 1 was repeated except that the catalyst used consisted of 212 mg 
Pd/C (5%). Over 99% conversion of the p-bromo-dimethylaniline occurred 
after four hours and about 97% of the pure product was detected. 
EXAMPLE 5 
Example 2 was repeated except that the reaction mixture was heated to 125 
C, instead of 160-170 C. About 54% product was detected after 5 hours 
reaction time. 
EXAMPLE 6 
The experiment as described in the U.S. Pat. No. 4,654,436 was performed in 
the equipment as in Example 1. 5.07 g p-BrDMA, 2.1 g Na.sub.2 CO.sub.3, 
0.193 g Pd/C (4.5%) and 0.193g Mo(CO).sub.6 were introduced into a 100cc 
glass reactor with 50 ml 2-ethyl-1-hexanol and the mixture was heated to 
125.degree. C. under a N.sub.2 atmosphere for 30 min. At this stage, a 
conversion of about 16% ester was detected although CO had not yet been 
introduced. A sample was taken out and found to contain other by-products 
together with the desired ester. 
A stream of carbon monoxide was introduced into the reaction mixture and 
further heated at 125.degree. C. for 3 hours. The total yield of ester 
formed in the reaction was 73.7%. 
EXAMPLE 7 
The experiment as in Example 6 was repeated, using the same amounts of 
reagents but without the promoter, the reaction being carried out at 
165.degree. C. 
The conversion to the ester formed after about 3 hours was 95%. 
EXAMPLE 8 
(Multicycled-alkoxycarbonylation of p-BrDMA). 
Four batches of the ester were prepared recycling the Pd/C and the alcohol 
each time. 
The following components were used in each cycle of the 
alkoxycarbonylation: 40.5 g p-BrDMA (0.203 M), 16.5 g Na.sub.2 CO.sub.3 
(0.157 M), 400 ml (428 g) 2-ethyl-1-hexanol (recovered from a previous 
cycle), and 102 mg fresh Pd/C,(in addition to the 1.043 g 4.5% Pd/C used 
in the first cycle). A stream of carbon monoxide (20 ml/min) was applied 
during the reaction at 169-173.degree. C., with mechanical stirring. 
The Pd/C from the previous cycle was washed with water and acetone then 
dried and used on a fresh batch of p-Br-dimethyl-aniline along with 20% 
fresh Pd/C. The 2-ethyl-1-hexanol was distilled from the reaction mixture 
and reused for the next batch. A further portion of 10% Pd/c was added 
before the end of the first three runs to finish off the starting 
material. It was found that each run took 12-14 hours, where the last 3-4 
hours were required for only 5-8% unreacted starting material. The total 
amount of Pd metal used throughout the 4-cycle process corresponds to a 
substrate/Pd molar ratio of 1298. 
Distillation of the 4-cycle batch of the ester gave an overall yield of 
71.45% with a purity of above 99.5%. Quantitative analysis of the oily 
crude residue prior to the distillation revealed an optimal yield (86.5%) 
of the desired product. 
The total Pd/C waste filtered from the 4-cycle process was washed with 
ethyl acetate and distilled water and dried in a vacuum oven, then 
analysed for Pd metal; 63.7% of the Pd used for the four carbonylation 
cycles were found.