Production of propiophenone

In the production of propiophenone by a vapor-phase, cross-decarboxylation process, an undesirable by-product, isobutyrophenone, is suppressed by addition of water or steam to the reactant stream.

BACKGROUND OF THE INVENTION 
This invention pertains to the production of propiophenone by a 
vapor-phase, cross-decarboxylation process and more particularly to the 
suppression of by-product formation. 
Propiophenone is used as a starting material in pharmaceutical applications 
particularly for the manufacture of dextropropoxyphene or 
alpha-d-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol propionate. 
Propiophenone can be produced by a Friedel-Crafts reaction of benzene and 
propionic acid, propionic anhydride or propionyl chloride catalyzed by 
Lewis acids. Although Friedel-Crafts processes produce no significant 
amounts of aromatic ketone by-products, such processes suffer from very 
high costs involved in corrosion of production facilities and waste 
disposal required for environmental protection. 
An attractive alternative synthesis of propiophenone and other specialty 
ketones utilizes a vapor-phase cross-decarboxylation process. In the case 
of propiophenone, benzoic acid is reacted with propionic acid at high 
temperatures over a catalyst. Propiophenone, diethyl ketone, carbon 
dioxide, and water are the major products. Numerous by-products are also 
formed in small amounts, including other dialkyl ketones, other 
phenylalkyl ketones and biphenol. One of the by-products produced in the 
vapor-phase process is isobutyrophenone. Depending upon the process 
conditions used, isobutyrophenone production may equal 10 percent or more 
of the propiophenone production. Separation of isobutyrophenone from 
propiophenone is impossible using conventional distillation techniques, 
inasmuch as the boiling points of these two compounds are within 1.degree. 
C. of each other. Other separation techniques, such as fractional 
crystallization or extractive distillation are costly and have not been 
perfected for this particular separation problem. 
Dextropropoxyphene is used medically as an analgesic. Drug dependence 
associated with its use has been found to be uncommon. Unfortunately, its 
isomer prepared from isobutyrophenone rather than propiophenone has been 
found to be an addictive narcotic. Therefore, it is essential that 
propiophenone used for the preparation of dextropropoxyphene be of high 
purity such that the isobutyrophenone content shall be as low as possible. 
It is therefore an object of this invention to provide a vapor-phase, 
cross-decarboxylation synthesis for the preparation of alkyl aryl ketones 
with a minimum of by-products. 
It is a specific object of this invention to prepare propiophenone by the 
catalytic vapor-phase cross-decarboxylation of benzoic acid with propionic 
acid, in which the content of the by-product isobutyrophenone is held to a 
minimum. 
SUMMARY OF THE INVENTION 
In the process for the production of propiophenone by the catalytic, 
vapor-phase cross-decarboxylation of an aromatic carboxylic acid having 6 
to about 14 carbon atoms with propionic acid, an improvement has been 
devised whereby the formation of by-products is suppressed which comprises 
introducing at least about 0.5 to 25 moles of water or a secondary alcohol 
having 3 to about 6 carbon atoms per mole of aromatic carboxylic acid into 
a feed stream comprising a mole ratio of aromatic carboxylic acid: 
propionic acid of about 1:1 to about 1:10 prior to the entrance of said 
feed stream into a reaction zone maintained at a temperature of about 
400.degree. C. to about 600.degree. C. 
The preferred aromatic carboxylic acid used in this invention is benzoic 
acid although other aromatic carboxylic acids such as benzoic acid alkyl 
substituted derivatives where the alkyl group contains 1 to about 4 carbon 
atoms can also be used. 
It is preferred to use about 4 to about 8 moles of water or secondary 
alcohol per mol of aromatic carboxylic acid. Of the two, water is the 
preferred modifying agent. The preferred secondary alcohol is isopropanol 
although other secondary alcohols such as 2-butanol, 2 or 3-pentanol, 2 or 
3-hexanol can also be used if desired. In this regard it is surprising 
that primary alcohols and particularly methanol, ethanol, n-propanol, 
n-butanol, isobutanol and the like have a deleterious effect on the 
generation of the by-product isobutyrophenone. 
It is preferred to use a ratio of aromatic carboxylic acid to propionic 
acid of about 1:2 to about 1:4. 
The preferred reaction temperature is about 440.degree. to about 
520.degree. C. 
The nature of the catalyst used in this reaction is not critical. Thus, 
although calcium acetate supported on alumina has been found to serve 
satisfactorily, other catalysts which can be used include cobalt acetate, 
manganous oxide, and the like. It is preferred to use superatmospheric 
pressure of about 10 to about 100 psig but this is not critical and other 
pressures above and below atmospheric pressure as well as atmospheric 
pressure can be used if desired. 
No special equipment is needed other than that known to those skilled in 
the art for handling materials and reactions at high temperature, means 
for supporting a catalytic bed in a high temperature reactor, and metering 
means for introducing reaction stream and withdrawing product. 
Residence time is not narrowly critical. It has been found convenient to 
use a residence time of about 0.4-1.0 grams of reactants per gram of 
catalyst per hour. 
Although the ratio of reactor surface to reactor volume is not critical, it 
was found that in some instances a slight depressing effect on the 
formation of isobutyrophenone resulted by increasing the surface to volume 
ratio by 55 percent by dispersing pieces of stainless steel tubing in the 
catalyst bed. 
Isopropanol is more effective on a molar basis than steam in suppressing 
isobutyrophenone formation but is more expensive. Steam can be used to 
virtually eliminate isobutyrophenone by-product formation by adding steam 
to a propionic acid:benzoic acid feed stream. 
The invention can be practiced as a batch or continuous system with the 
latter being more efficient. 
The reactions involved in this invention are dilineated in the equation 
shown below: 
##STR1##

The invention is further described in the Examples which follow. All parts 
and percentages are by weight unless otherwise specified. 
EXAMPLE 1 
The reactor used for the preparation of propiophenone in accordance with 
this invention consisted of a reactor fabricated from 1-inch by 48-inch 
stainless steel pipe, insulated and electrically heated. Temperatures were 
determined at four points by thermocouples positioned in a 1/4" thermowell 
which extended through the entire length of the reactor. 
Reactants were fed, via a small diaphram pump from a calibrated feed tank 
through a steam-jacketed line to the top of the reactor. The feed tank and 
pump were warmed by infrared heat lamps to prevent crystallization of 
benzoic acid. 
The catalyst bed consisted of two layers. A 13" bed of inert material in 
the top end of the vertically oriented reactor served as a preheat 
section. The bottom 31" consisted of calcium acetate on alumina. 
Activated alumina (Alcoa F-1 grade, 4-8 mesh) is immersed in a 25 percent 
aqueous solution of calcium acetate for 2 to 24 hours. The calcium acetate 
solution is drained off, and most of the excess water adhering to the 
alumina is removed by vacuum evaporation. The impregnated catalyst is then 
heated overnight at 500.degree. C. to remove the last traces of water. The 
amount of calcium impregnated on the catalyst depends on how long the 
alumina is dipped in the calcium acetate solution and on how many times 
the procedure is repeated. The catalyst used in these examples contained 
2.95 percent calcium by weight (3.87 percent by weight when calculated as 
calcium oxide). 
The reactants consisted of a 2:1 mole ratio of propionic and benzoic acids, 
with water or secondary alcohol diluent added as indicated in Table I. 
Controls A and C where no diluent was used and Control B where methanol 
was used are also shown in Table I. 
TABLE I 
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PROPIOPHENONE SUPPRESSION 
OF ISOBUTYROPHENONE CO-PRODUCTION 
Effect of Water 
Isobutyro- 
S/V Diluent phenone Acetophenone 
Example Ratio .sup.(1) 
Ratio .sup.(2) 
Production.sup.(3) 
Production.sup.(3) 
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Control A 
4.0 0 5.04 13.2 
1 4.0 4 4.68 18.3 
2 4.0 8 2.31 18.9 
3 4.0 1(iPrOH) 3.19 23.3 
Control B 
4.0 1(MeOH) 10.43 13.4 
Control C 
6.2 0 6.40 18.2 
4 6.2 1 4.68 18.5 
5 6.2 4 3.53 22.1 
6 6.2 8 2.75 25.2 
______________________________________ 
.sup.(1) Surface-to-volume ratio of the reactor. 
.sup.(2) Moles of diluent per mole of benzoic acid in the feed stream. Th 
diluent is water unless otherwise specified.? 
.sup. (3) Pounds per pound of propiophenone produced. 
In Example 1, using the reactor described above, together with ancillary 
equipment, a mixture containing 2 moles of propionic acid per mole of 
benzoic acid was fed to the reactor together with 4 moles of water per 
mole of benzoic acid at a rate of 249 ml/hr. for 4.5 hours. The reaction 
temperature was maintained between 445.degree. C. and 450.degree. C. 
Analysis of the condensed organic layer by gas chromatography indicated 
that 4.68 pounds of isobutyrophenone were produced per 100 pounds of 
propiophenone. These data are delineated in Table I. The instrument used 
was a Bendix Model 2300 dual column programmed temperature gas 
chromatograph having a thermal conductivity detector. The bridge current 
was 200 ma. with a 0-1 mv. recorder. The column consisted of two, 10 feet 
by 1/8 inch stainless steel tubing packed with silicone on an inert 
support. The column temperature was 190.degree. C. The carrier gas was 
helium at 30 cc/minute. 
CONTROL A 
Example 1 was repeated except that no water was present in the feed mixture 
fed to the reactor; the feed rate was 279 ml/hr, the reaction time was 5.5 
hours. Analysis of the condensed organic layer by gas chromatography 
indicated that 5.04 pounds of isobutyrophenone were produced per 100 
pounds of propiophenone. 
EXAMPLE 2 
Example 1 was repeated except that the reactant mixture contain 8 moles of 
water per mole of benzoic acid and feed rate was 292 ml/hr. After 5 hours, 
production of isobutyrophenone was 2.31 pounds per 100 pounds of 
propiophenone as demonstrated by gas chromatographic analysis. 
EXAMPLE 3 
Example 1 was repeated except that the reactant mixture contained 1 mole of 
isopropanol per mole of benzoic acid and the feed rate was 214 ml/hr. 
After 6.5 hours, production of isobutyrophenone was 3.19 pounds per 100 
pounds of propiophenone as shown by gas chromatographic analysis. 
CONTROL B 
Example 1 was repeated with the exception that the reactant mixture 
contained 1 mole of methanol per mole of benzoic acid and the feed rate 
was 269 ml/hr. After 4 hours, analysis by gas chromatography indicated the 
production rate of isobutyrophenone was 10.43 pounds per 100 pounds of 
propiophenone. 
In Examples 1 to 3 and Controls A and B, the ratio of the surface area to 
the volume of the stainless steel reaction tube was 4.0m.sup.2 /m.sup.3. 
CONTROL C 
Control A was repeated with the exception that the ratio of the surface 
area to volume of the stainless steel reaction tube was increased to 6.2 
m.sup.2 /m.sup.3 by dispersing small pieces of 1/8 inch stainless steel 
tubing in the catalyst bed and the feed rate was 281 ml/hr. The production 
of isobutyrophenone, as determined by gas chromatographic analysis was 
6.40 pounds per 100 pounds of propiophenone. 
EXAMPLE 4 
Example 1 was repeated except that the reactant mixture contains 1 mole of 
water per mole of benzoic acid, the feed rate was 285 ml/hr, and the ratio 
of the surface area to volume of the stainless steel reaction tube was 
increased to 6.2 m.sup.2 /m.sup.3 by dispersing small pieces of 1/8 inch 
stainless steel tubing in the catalyst bed. Production of isobutyrophenone 
as determined by gas chromatographic analysis was 4.68 pounds per 100 
pounds propiophenone. 
EXAMPLE 5 
Experiment 1 was repeated except that the feed rate was 276 ml/hr, and the 
surface area to the volume of the stainless steel tube reaction was 
increased to 6.2 m.sup.2 /m.sup.3 by dispersing small pieces of 1/8 inch 
stainless steel tubing in the catalyst bed. Analysis by gas chromatography 
indicated that the production of isobutyrophenone was 3.53 pounds per 100 
pounds of propiophenone. 
EXAMPLE 6 
Example 2 was repeated with the exception that the surface area to volume 
of the stainless steel reaction tube was increased to 6.2 m.sup.2 /m.sup.3 
by dispersing small pieces of 1/8 inches stainless steel tubing in the 
catalyst bed. Production of isobutyrophenone as determined by gas 
chromatographic analysis was 2.75 pounds per 100 pounds of propiophenone. 
EXAMPLE 7 
In a plant scale run, a charge consisting of propionic acid, benzoic acid 
and steam was charged to a vaporizer at a rate of 625 lbs/hr., 375 
lbs/hr., and 175 lbs/hr., respectively. This mixture exited from the 
vaporizer at a temperature of 135.degree. C. The vaporized charge was 
heated in a preheater to 325.degree. C. and thence to the first of three 
catalyst bed zones maintained at a temperature of 470.degree. C. The 
catalyst was calcium acetate on alumina. The stream of reactants and 
products was led from the first to the second catalyst bed zone maintained 
at a temperature of 490.degree. C., together with steam at 0 to 25 lbs/hr. 
The second catalyst zone effluent was passed to the third catalyst bed 
zone maintained at a temperature of 510.degree. C., together with steam at 
a rate of 25-50 lbs/hr. Analysis of the organic layer of the product 
mixture by gas chromatography indicated the following: 
Diethyl ketone--43-44% 
Propiophenone--54-56% 
Acetophenone--0.5-1.0% 
Isobutyrophenone--0-0.15% 
Butyrophenone--0 
The following conclusions can be drawn from an examination of the 
experimental data. Co-production of isobutyrophenone on a laboratory scale 
decreased steadily as the water concentration in the feed stream was 
increased. Addition of 8 moles of water per mole of benzoic acid resulted 
in an isobutyrophenone content of 2.3-2.8 percent based on contained 
propiophenone. With no water, isobutyrophenone production increased to 
5.0-6.4 percent. 
Addition of isopropanol at ratio of 1 mole per mole of benzoic acid to the 
mixed acid feed gave low production of isobutyrophenone (3.2 percent) 
while methanol at the same level showed exactly the opposite trend 
affording 10.4 percent isobutyrophenone. This demonstrated the unexpected 
finding that whereas secondary aliphatic alcohols suppress the formation 
of the undesirable by-product, isobutyrophenone, a primary alcohol had the 
opposite effect, actually increasing the production of isobutyrophenone. 
It was also found that water could be added to the reaction stream in the 
form of steam to suppress isobutyrophenone production. This is important 
for plant-scale production of propiophenone containing minimum amounts of 
isobutyrophenone. In plant-scale runs the effect of steam was even greater 
than for the bench-scale run so that production runs of propiophenone 
routinely contained from about 0.15 percent isobutyrophenone down to no 
measurable amount. This is important for pharmaceutical use where a limit 
of about 0.5% is required. 
Surface-to-volume ratio of the reactor appeared to have no major effect on 
by-product formation. 
In laboratory runs addition of water to the reaction stream resulted in a 
slight increase in another by-product, i.e., acetopheone. In the plant, 
however, acetophenone production was 1% or lower. Without steam addition, 
plant runs usually produced about 0.05 to about 0.1 pound of acetophenone 
per pound of propiophenone. 
While isopropanol is more effective on a molar basis than water or steam in 
suppressing isobutyrophenone formation, it is not as economical. 
Although the invention has been described in its preferred forms with a 
certain degree of particularity, it is understood that the present 
disclosure of the preferred forms has been made only by way of example and 
that numerous changes may be resorted to without departing from the spirit 
and scope of the invention.