BACKGROUND OF THE INVENTION

Field of the Invention The present invention relates to a process for the preparation of omega-arylalkanoic acids of the general formula.

R-Ar-R'-COOH wherein R is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, or aryl; wherein R ¹ is C _r C ₄ alkyl; and wherein Ar is an aryl group which can be further substituted with at least one of hydroxy, C,-C ₈ alkyl, C,-C ₈ alkoxy, aryl, amino with the amino nitrogen bonded to hydrogen or -

C _g alkyl, or acetamido. More particularly, this invention relates to an improved process for the preparation of omega-arylalkanoic acids via the Willgerodt-Kindler reaction and to methods of removing sulfur from the product produced by this

improved process.

Background Information and Description of the Related Art

Omega-arylalkanoic acids are useful intermediates in the production of various chemicals and pharmaceuticals. For example, 4'- methoxyphenylacetic acid is an intermediate in the production of dextromethorphan, anti-cough medicine; homoveratricacid, obtained from 3,4- dimethoxyacetophenone (DMAP) is an important pharmaceutical intermediate; and 4-biphenylacetic acid, an analgesic, is produced from 4- acetylbiphenylacetophenone.

The omega-arylalkanoic acids can be synthesized from a thioamide which is produced via the Willgerodt-Kindler reaction. The thioamide can be synthesized by reaction of an aryl alkyl ketone or other starting material, sulfur and a primary or secondary amine. Following the preparation of the thioamide, it can be hydrolyzed to the corresponding omega- arylalkanoic acid. The Willgerodt reaction is well known in the art as the reaction between an aryl alkyl ketone and aqueous ammonium polysulfide to produce an aromatic amide and/or ammonium salt of the corresponding acid.

In addition to aryl alkyl ketones, the reaction has been shown to be applicable to the production of amides from other compounds such asdialkyl ketones, aliphatic mercaptans, secondary and tertiary alcohols, acetals and aromatic hydrocarbons. It is also known that a mixture of sulfur and ammonia is equivalent to ammonium polysulfide in obtaining the reaction.

In the Kindler modification of the Willgerodt reaction, an aryl alkyl ketone or other reactant can be reacted with sulfur and a primary or secondary amine

such as morpholine and the product is the thioamide.

C. G. Joshi, in J. Sci. Ind. Res., 21B, 1962, 284-5, discloses a method for the preparation of arylacetic acids from aryl-alkyl ketones by a

modification of the Willgerodt-Kindler reaction. This process involved the use of morpholine and sulfur in reflux with the ketone, followed by basification, cooling, filtration and acidification. However, this article does not disclose the

use of a catalyst or the sulfur removal techniques disclosed in this application. U.S. Patent 2,489,348 issued Nov. 29, 1949 to Wenner discloses the production of arylacetic acids and amides. Some examples disclose the purification of the crude acids by basification, filtering and acidification to yield the free acids. However, the production method disclosed does not employ sulfur nor function in the manner of the Willgerodt- Kindler reaction.

F. Ansinger et al., in Monatshefte fur Chemie, 103, 1972, 1661-1668, disclose to the preparation of various materials comprising sulfur, nitrogen and aryl components, wherein acetophenone is treated with sulfur and amines. In particular, hexathiocanethiones were obtained by treating RC^COMe with R'NH ₂ and S in the presence of HO Ac.

SUMMARY OF THE INVENTION

In accordance with the present invention, a process is provided for the preparation of omega-arylalkanoic acids. More particularly, a process is provided for the preparation of omega-arylalkanoic acids via an improved Willgerodt-Kindler reaction which employs various catalysts which surprisingly improve the yield of the thioamide precursor of the acid product. Use of the catalysts also significantly decreases the amount of sulfur necessary to convert the starting material to the thioamide as well as the reaction pressure generated during the reaction. Additionally, a process is provided for the separation of the omega-arylalkanoic acid product from sulfur and other sulfur-containing compounds which are generated as part of the Willgerodt-Kindler reaction.

In view of the above, it is an object of the invention to prepare omega-arylalkanoic acids in high yield under conditions wherein less sulfur is employed. It is another object of the invention to prepare omega- arylalkanoic acids which are more easily isolated from sulfur and other sulfur- containing compounds.

It is a further object of this invention to economically prepare omega-arylalkanoic acids via the Willgerodt-Kindler reaction which can be commercially useful in the preparation of chemicals and pharmaceutical intermediates.

It is a further object of the invention to prepare omega- arylalkanoic acids which are essentially free from contamination by sulfur and other sulfur-containing compounds such as methyl mercaptan, dimethyl sulfide, and dimethyl disulfide by a separation process which removes residual sulfur and sulfur-containing compounds by careful control of the pH during the acidification step and by prolonged thermal-treatment prior to and during a vacuum distillation step.

DETAILED DESCRIPTION TO THE INVENTION The reaction carried out by the process of the invention is shown in the following steps:

I. Improved Willgerodt-Kindler Reaction

Aryl alkyl keto (A)

Amine + Catalyst + Sulfur

+Sul-ur-containing Compounds

π. Base Hydrolysis base

(A) +S+ Sulfur-containing Compounds \ R-Ar-R'CO-jM (B)

H,O +

Excess sulfur (sol.)+M ₂ S

+ Sulfur-containing Compounds m. pH Adjustment

(B)+ Excess Sulfur +M ₂ S acid R-Ar-R'-CO-jM

+ Sulfur-containing Compounds J,Excess

+Sulfur-containing Compounds

IV. Sulfur Removal

R-Ar-R'-CO-jM +Residual Sulfur

-> + Sulfur-containing Compounds

V. Acidification acid ,

R-Ar-R'-CO ₂ M R-Ar-R'-CO^ + Residual Sulfur -i-Residual Sulfur + S ulfur-containing +Sulfur-containing Compounds Compounds

VI. Distillation

+ es ua u ur - u ur-conta n ng + Sulfur-containing Compounds via Compounds overhead light ends and via bottoms

In the above reactions the substituents R, R ¹ , R ² , R ³ and M are defined as follows: R is hydrogen, hydroxy, C _r C _g alkyl, C,-C ₈ alkoxy, or aryl;

R ¹ is C _r C ₄ alkyl; R ² is hydrogen or alkyl; R ³ is hydrogen or alkyl, so long as both R ² and R ³ are not both hydrogen;

Ar is an aryl group which can be further substituted with at least one of hydroxy, C C _g alkyl, C,-C ₈ alkoxy, aryl, halide, amino, or acetamido; and,

M is an alkali metal selected from the group consisting of Na, K and Li, wherein the base of step II is comprised of said alkali metal. Ar may be, for example, phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 2- phenanthryl, 1-pyrenyl or 2-benzyloxyphenyl with these groups being unsubstituted or having at least one ring hydrogen atom substituted with hydroxy; -Cg alkyl; C _r C ₈ alkoxy; aryl; halide, including chloride, bromide, iodide and fluoride; amino with the amino nitrogen bonded to hydrogen or C,- C _g alkyl, or acetamido. In general, it is preferred that not more than two ring atoms are substituted. Phenyl is the preferred aryl group.

In Step I, the aryl alkyl ketone, sulfur, and amine, along with a catalyst selected from acetic acid, acetic anhydride, sulfuric acid, hydrogen

sulfide dimethylacetamide, dimethylformamide and sodium sulfate are reacted to form a thioamide intermediate:

Aryl alkyl ketone Sulfur

Amine

+ Catalyst + Sulfur

+ Sulfur-containing Compounds wherein R and R ¹ are as previously described, and where R ₂ and R ₃ are hydrogen or alkyl, so long as R ₂ and R ₃ are not both hydrogen. The use of the catalyst results in a reduction in the amount of sulfur that is necessary in the

Willgerodt-Kindler reaction of the ketone, and results in improved yield over that previously known in the art. The amine used in Step 1 is selected from primary and secondary amines, such as, for example, methylamine, dimethylamine, diethylamine,. morpholine and pyrrolidine.

In carrying out the method of this invention, sulfur may be initially present in an amount of about 0.5 to 10 moles per mole of ketone. A preferred ratio is about 1 to 5 moles with a most preferred molar ratio of about

1.3 to 2.5.

No solvent need be initially employed in the Willgerodt-Kindler reaction portion of the invention. However, it is advantageous in some instances to have a solvent present. For instance, a solvent may be necessary

to aid in the stirring of the reaction mixture. The choice of solvent will depend largely on the solubilities of the reactants.

The reaction can be carried out at a temperature in the range of

110°C to 180°C, preferably in a range of 120°C-150°C; most preferably about

130°C-140°C.

The use of the catalyst results in a faster reaction rate and can result in a reduction in the pressure which occurs during the reaction. The

pressure (psig) is not critical, but is permitted to increase as dictated by other reaction parameters. Typical reaction pressures range from about 30 psig-200 psig.

The catalyst employed can be present in an amount that depends largely on the amount of ketone, sulfur and amine present in the reaction. The

ratio of catalyst to sulfur is typically in the range of 1 equivalent of catalyst to 1-10 equivalents of sulfur. A preferred ratio is 1 equivalent of catalyst to 2-4 equivalents of sulfur. The typical ratio of sulfur to amine ranges from about 1 equivalent of sulfur to 0.1 - 3 equivalents of amine. In Step II, the base hydrolysis of the thioamide can be accomplished by using an alkali metal base such as sodium, potassium, or lithium hydroxide in a large quantity of water. Typically, the hydroxide solution ranges from about 10%-50% by weight alkali metal base, preferably 20%-30% by weight alkali metal base. The resultant reaction mixture typically exhibits a pH > 11. The base employed is preferably sodium

hydroxide. At this step the sulfur containing compounds include the alkali

metal base sulfide, which is later converted to hydrogen sulfide, in Step III, for easier removal.

Steps HI and IV are optional in the formation of the omega- arylalkanoic acid and are for the purpose of removing sulfur from the reaction medium. After Step IV, an additional optional step can be included wherein the reaction medium is treated with activated carbon to remove color bodies, some fine sulfur particles and sulfur-containing compounds, which may have been formed during the process through Step IV.

In Step III, the pH of the solution can be adjusted by addition of hydrochloric, sulfuric, phosphoric or other suitable acids, which results in the formation of H ₂ S which can subsequently be removed from the reaction mixture by purging of the mixture with an inert gas such as nitrogen, for example. Additionally much of the bulk sulfur remaining from the Willgerodt- Kindler reaction precipitates out. It has been found that the solubility of sulfur in aqueous solution greatly decreases as concentration of the sulfur-containing compounds such as the sulfϊdes decreases. Therefore, as these sulfur- containing compounds are removed by the pH adjustment of Step HI, followed by inert gas purging of the reaction mixture, the sulfur precipitates out of the solution and can be removed by filtration, centrifugation or similar, known-in- the-art separation methods. The pH of the solution in this step is adjusted, using an acid, to a range of between 1 and 7, preferably to a pH range of 6-

6.5, since the R-Ar-R'-CO-jM tends to precipitate out of solution at a pH of less than about 6.

If the pH of the reaction mixture is adjusted below about 6.0 in Step III (during the conversion of M ₂ S to H ₂ S, prior to the Step IV Sulfur Removal, the pH must be readjusted to greater than about 6, to ensure that the omega-arylalkanoic acid salt will be in solution (and not removed with the sulfur in Step IV).

Following the above-described pH adjustment, the system is purged with a inert gas such as nitrogen or argon to further remove H ₂ S and other sulfur-containing compounds and to precipitate out the sulfur.

In Step IV, the bulk sulfur can be removed by methods known in the art to leave primarily the omega-arylalkanoic acid salt in the reaction solution. Following the Step IV removal of the bulk sulfur, the remaining salt is acidified in Step V, to convert the salt to the desired omega-arylalkanoic

acid product. The acidified reaction solution is acidified to a pH of about 4 or less using an acid such as a mineral acid. The crude omega-arylalkanoic acid product can then be separated from the aqueous reaction solution by at least two techniques. When the reaction medium is acidified to a pH of less than about 4, if the reaction medium temperature is about 60°C or less, the crude product precipitates from the aqueous reaction medium. If the reaction medium temperature is greater than about 60°C (eg. 70°C or more), two phases are formed, an organic phase containing the crude product and an aqueous

phase; the crude product can then be decanted from the aqueous phase. Use of the precipitation technique provides more complete crude product recovery, but requires more time. The product is subsequently, optionally subjected to high temperature vacuum distillation in Step VI, to remove residual sulfur and sulfur-containing compounds. This distillation step is typically carried out at a temperature ranging from about 180°C to 210°C, at a vacuum ranging from about 5mm Hg-lOmm Hg, for a time period of about 6 to about 20 hours.

During distillation, a high reflux ratio is maintained during removal of the light ends which are distilled off prior to the omega-arylalkanoic acid product. Light ends removal can require a distillation time period ranging from about 6 to about 20 hours. During removal of the light ends, significant quantities of sulfur-containing compounds are decomposed and carried off with the light

ends. Some sulfur-containing compounds also remain in the bottoms, with the desired omega-arylalkanoic acid product containing less than about lOOppm of total sulfur (total sulfur being only the sulfur portion of sulfur-containing compounds). Typically, total sulfur in the omega-arylalkanoic acid product ranges from about 25ppm to about 80ppm.

There are other methods which can be used to separate the omega-arylalkanoic acid product from the organic portion of the reaction mixture, such as crystallization.

The inventive method may be further illustrated by the following examples:

EXAMPLE 1

PREPARATION OF 4 -METHOXYPHENYLACETIC ACID

420g (2.8 mol) of 4-methyacetophenone (4-MAP) was heated between 120°C and 160°C for 3 to 4 hours in the presence of 116.5g (3.6 mol) of sulfur in 189g (4.2 mol) of dimethylamine and 84g (1.4 mol) of acetic acid.

Typical reaction pressure at about 160°C was 90-95 psig. The resultant thioamide reaction mixture was cooled to room temperature, and 896g of 50 wt% NaOH solution, along with 896g of H ₂ 0 were charged to the reaction mixture. The mixture was heated under reflux (105°C -110°C) for 3 to 4 hours. After cooling, the pH value of the reaction medium was adjusted to 6.0 to 6.5 by addition of HC1. Hydrogen sulfide was observed to be liberated vigorously during the pH adjustment of the reaction medium. Nitrogen was then sparged through the reaction medium until the residual hydrogen sulfide had been reduced to less than 10 ppm. The removal of H ₂ S and other sulfur-

containing compounds resulted in the precipitation of the majority of excess sulfur which was subsequently removed by filtration. The aqueous filtrate was treated with activated carbon at room temperature for one hour to further remove fine sulfur particles, sulfur-containing compounds and other color bodies. The resultant aqueous solution was acidified to pH < 4 with

HC1, at a temperature of 60°C, to precipitate out the crude product, which was subsequently separated from the aqueous solution by filtration.

The above-described, precipitated crude 4 ^' -methoxyphenylacetic acid, containing about 15% to 20% water, was heated at 180°-200°C under

vacuum (typically 5 mmHg - 20 mmHg). The water distilled off immediately, with light ends being recovered over a time period of up to about 18 hours. During the light ends removal, residual sulfur and sulfur-containing compounds were also removed. The 4 -methoxypehnylacetic acid product was distilled off after light ends removal. Two hundred and sixty (260) g (1.57 mol) of

4 methoxypehnylacetic acid was obtained, which contained less than 100 ppm of total sulfur. EXAMPLE 2

PREPARATION OF 4'-HYDROXYPHENYLPROPIONIC ACID

To a one gallon autoclave reactor is charged 420g (2.8 mol) of

4 -hydroxyphenylpropiophenone, 116.5g (3.6 mol) of sulfur, 84g (1.4 mol) of acetic acid and 189g (4.2 mol) of dimethylamine. The procedure described in Example 1 is followed and 4 ^' -hydroxyphenylacetic acid product containing less than 100 ppm of total sulfur is obtained.

EXAMPLE 3

PREPARATION OF 4 ^' -BUTOX YPHENYLACETIC ACID

To a one-gallon autoclave reactor is charged 537.6g (2.8 mol) of 4 ^' -butoxyacetophenone, 116.5g (3.6 mol) sulfur, 84g (1.4 mol) acetic acid and

189g (4.2 mol) dimethylamine. The procedure described in Example 1 is

followed and 4 -butoxyphenylacetic acid product containing 3 less than 100 ppm of total sulfur is obtained.

Reactions run under similar conditions to those described in

Example 1 are reported below in Tables 1-5. The starting material and the catalysts used were varied to show the effectiveness of the process employing various catalysts versus the uncatalyzed reactions.

TABLE 1

The starting ketone for this series of experiments was acetophenone, sulfur equivalents were 1.3, dimethylamine equivalents were

1.5. The temperature for each run was 130°C.

The starting material was 3,4-dimethoxyacetophenone (DMAP); the thioamide formed from DMAP is a precursor of homoveratric acid, an important pharmaceutical intermediate. The temperature for each run was 130°C and the reaction time was 1 hour. Sulfur (eq.) DMA (eq.) HOAc (eq.) Yield PSIG

2.5 1.5 1.1 79 40 2.5 1.5 0.0 30 150

1.3 68 68

1.3 51 145

The starting material was 4-acetylbiphenyl; the thioamide formed from which is a direct precursor of a 4-biphenylacetic acid, an analgesic drug. A solvent, t-butyl methyl ether, was employed to aid stirring. The temperature for each run was 130°C.

PSIG

Sulfur (e .) A . HOAc (e .) Time Yield Max.

Various hydrocinnamic acids which are of commercial value, can also be prepared by the Willgerodt-Kindler reaction of propiophenones, followed by hydrolysis. As shown below, acetic acid improves the yield when 4-methoxypropiophenone is used as the starting ketone. The temperature for each run was 130°C and the reaction time was 2 hours.

PSIG

This series of experiments demonstrates the use of Step I catalysts other than acetic acid. The arylalkyl ketone starting material was 4 - methoxyacetophenone. The reaction temperature for each experiment was about 130°C.

The embodiments described above are not intended to place undue limitations on the scope of the present invention, particularly regarding non-critical features of the invention, wherein one skilled in the art can make modifications which provide obvious variations of the invention. Such variations are intended to fall within the scope of the present invention, particularly regarding non-critical features of the invention, wherein one skilled in the art can make modifications which provide obvious variations of the invention. Such variations are intended to fall within the scope of the present invention as defined in the following claims.