WO1999019289A1

WO1999019289A1 - Recovery and recycle of catalyst components used in palladium-catalyzed preparation of arylcarboxylic acids

Info

Publication number: WO1999019289A1
Application number: PCT/US1998/022055
Authority: WO
Inventors: Robert Carl Herndon, Jr.; Robert H. Allen; Kannappan C. Chockalingam; Gary D. Focht
Original assignee: Albemarle Corporation
Priority date: 1997-10-16
Filing date: 1998-10-16
Publication date: 1999-04-22
Also published as: EP1025074A1; CA2306425A1; JP2001519409A

Abstract

Arylcarboxylic acids, especially polycyclic arylcarboxylic acids, are separated from residual catalyst components by use of a phase separation process. This avoids need for use of reduced pressure distillation with its attendant high investment and operating costs. Also, the phase separation process provides an active organic-soluble catalyst residue for reuse via recycle without need for catalyst regeneration. Thus, arylolefin is reacted with carbonmonoxide and water in the presence of palladium catalyst and organophosphine ligand, to form a reaction mass comprising (a) arylcarboxylic acid, and (b) residual catalyst species. The reaction mass is treated with aqueous inorganic base to form (i) an aqueous phase containing dissolved water-soluble salt of the arylcarboxylic acid, and (ii) an organic phase containing dissolved residual catalyst species. The phases are separated, and at least a portion of separated phase (ii) is recycled for use in performing additional reaction. Oftentimes in addition to phases (i) and (ii), a solids phase containing a portion of the palladium catalyst values exists, and preferably, these solids are recovered (e.g., by filtration) and if not sufficiently catalytically active for recycle, at least a portion is converted into an active palladium catalyst component for use in subsequent reaction. The phase separation thus enables separation of catalyst residues in organic solution form and as solids, while concurrently isolating the desired product in water solution form.

Description

RECOVERY AND RECYCLE OF CATALYST COMPONENTS USED IN PALLADIUM-CATALYZED PREPARATION OF ARYLCARBOXYLIC ACIDS

BACKGROUND The palladium-catalyzed vinylation of organic halides provides a very convenient method for forming carbon-carbon bonds at unsubstituted vinylic positions. The reaction, reported by Heck {Palladium Reagents in Organic Synthesis, Academic Press, Canada 1985) can be used to prepare fine organics, pharmaceuticals, and specialty monomers. For example, the reaction allows a one-step synthesis of substituted styrenes from aryl bromides and is an excellent method for preparation of a wide variety of styrene derivatives. Heitz et al., Makromol. Chem. , 189, 119 (1988).

Vinyl toluenes have been reported as the product of a homogeneous palladium-catalyzed coupling of ethylene with bromotoluenes. The reaction is performed in a two-phase solvent system composed of N,N-dimethyl formamide and water. R. A. DeVries et al., Organometallics , 13, 2405 (1994).

U.S. Pat. Nos. 5,136,069 and 5,243,068 to R. A. DeVries et al. describe preparation of vinylically-unsaturated compounds by reaction of a halogenated organic compound with a hydrolytically-stable, vinylically-unsaturated precursor compound in the presence of (a) a homogeneous zerovalent palladium catalyst complex, (b) an inorganic hydrogen halide acceptor and (c) a diluent which is either water or an aqueous solution containing up to 95 % by volume of organic solvent.

Arylation of propylene, ethylene, styrene, and methyl aery late with iodobenzene was found to be catalyzed by metallic palladium in methanol to give methylstyrene, styrene, t-stilbene, and methyl cinnamate, respectively. Their yields and selectivities increased significantly by the addition of excess potassium acetate as an acceptor of hydriodic acid formed. Mori et al. , Bull.

Chem. Soc, Japan, 46, 1505 (1973).

A variety of styrene derivatives and 3-vinylpyridine were prepared in moderate to good yields by the palladium-tri-o-tolylphosphine catalyzed reaction of ethylene with aryl bromides or 3-bromopyridine, respectively. (Plevyak et al., J. Org. Chem., 43, 2454 (1978).

Alper et al. in /. Chem Soc. Chem. Comm. , 1983, 1270-1271, discloses that alkenes can react with carbon monoxide, water, hydrochloric acid and a mixture of palladium and copper to produce the hydrocarboxylated branched chain carboxylic acid. Oxygen is necessary to succeed in the reaction.

A process for preparing the branched chain carboxylic acid ibuprofen is described in

Japanese Patent Application (Kokai) No. 59-10545 (Mitsubishi Petrochemical, published January,

1984), which teaches that ibuprofen can be prepared by reacting p-isobutylstyrene with carbon monoxide and water or an alcohol in the presence of a palladium(II) catalyst and a peroxide, e.g. , cumyl hydroperoxide.

A process for preparing aryl substituted aliphatic carboxylic acids or their alkyl esters is disclosed in U. S. Patent No. 5,315,026. A l-aryl substituted olefin is reacted with carbon monoxide in the presence of water or an alcohol at a temperature between 25 °C and 200°C. A mixture useful as a catalyst is a palladium compound and a copper compound with at least one acid-stable ligand. Ligands which may be used include monodentate or multidentate electron- donating substances such as those containing elements P, N, O, and those containing multiple bonds such as olefinic compounds. Examples of such acid-stable ligands are trihydrocarbylphosphines, including trialkyl- and triarylphosphines, such as tri-n-butyl-, tricyclohexyl-, and triphenylphosphine; lower alkyl and aryl nitriles, such as benzonitrile and n- propionitrile; ligands containing pi-electrons, such as an allyl compound or 1,5-cyclooctadiene; piperidine, piperazine, trichlorostannate(II), and acetylacetonate.

U.S. Pat. No. 5,536,870 describes the preparation of substituted olefins by the palladium- catalyzed coupling of vinyl or substituted vinyl compounds with organic halides, and also the formation of carboxylic acids and esters from such substituted olefins. The substituted olefinic compounds are formed by reacting an organic halide with a vinyl or substituted vinyl compound in the presence of a catalytically effective amount of palladium or a salt of palladium having a valence of 1 or 2, and a tertiary phosphine ligand such as neomenthyldiphenylphosphine. This reaction is carried out in the presence or absence of a solvent such as acetonitrile, tetrahydrofuran, dioxane, or dimethylformamide. An important utility of the substituted olefins formed in this manner is the subsequent conversion of such substituted olefins to carboxylic acids or derivatives thereof such as salts or esters (e.g., profen compounds) by carbonylation with carbon monoxide using catalytic systems and reaction conditions described in U.S. Pat. No. 5,536,870.

Commonly-owned copending application Serial No. 08/780,308, filed January 8, 1997 describes, inter alia, a process which comprises: (a) conducting a palladium-catalyzed arylation of an olefin with aryl halide in a liquid medium formed from (i) one or more liquid polar organic solvent/diluents, and (ii) one or more secondary or tertiary amines that (1) boil(s) below the boiling temperature of the solvent/diluent if only one solvent/diluent is used or (2) that boil(s) below the boiling temperature of at least one, but not necessarily all, of the polar solvent/diluents used in forming the medium if more than one solvent/diluent is used, to form a reaction mixture comprising olefinically-substituted aromatic compound, amine-hydrohalide and one or more of the polar organic solvents; (b) mixing (i) a concentrated aqueous solution of inorganic base that has a base strength that is greater than the base strength of the secondary or tertiary amine(s), with (ii) at least a portion of the reaction mixture from (a) to convert amine-hydrohalide therein to free amine and alkali metal halide, and to form (i) an aqueous phase containing dissolved alkali metal halide, and (ii) an organic phase comprising olefinically-substituted aromatic compound, one or more of the polar organic solvents and free amine; (c) separating the phases from each other; (d) distilling off substantially all of the amine from the organic phase under low temperature and pressure conditions that suppress thermal oligomerization of the olefinically-substituted aromatic compound contained in the residual liquid phase, to thereby form a distilland composed predominately of olefinically-substituted aromatic compound and one or more of the polar organic solvents; and (e) conducting a palladium-catalyzed carboxylation of at least a portion of the olefinically-substituted aromatic compound with carbon monoxide and water and/or alcohol in a liquid medium comprising at least a portion of the distilland from (d).

Commonly-owned copending application Serial No. 08/780,310, filed January 8, 1997 describes, inter alia, a process in which arylolefinic compounds are prepared by reacting aryl halide with an olefinic compound in the presence of a polar liquid reaction medium containing (a) secondary or tertiary amine as a hydrogen halide acceptor (b) a catalyst system formed from (i) Pd or Pd(0) compound, and/or Pd(I) salt or Pd(II) salt, and (ii) a tertiary phosphine ligand, and (c) a reaction accelerating amount of water in the range of 0.5 to 5 weight percent of the total weight of the reaction mixture. The arylolefinic compounds can be converted to an arylcarboxylic acid by hydrocarboxylation with CO in a reaction medium freed of amine and containing water and a Pd catalyst system as above in which a copper component may be included, and which preferably includes an ether such as tetrahydrofuran.

Palladium catalysts and tertiary phosphine ligands which are highly effective catalyst components in the preparation of arylcarboxylic acids such as profen-type pharmaceuticals are quite expensive. While U. S. Pat. No. 5,055,611 describes an effective way of recovering and regenerating a carbonylation catalyst used in the preparation of ibuprofen, the process requires a reduced pressure distillation in order to separate the ibuprofen from the carbonylation residue. Reduced pressure distillation when conducted on a plant scale is an expensive and capital-intensive operation. Moreover, there are practical limitations and economic constraints on the materials which can be separated and recovered by reduced pressure distillation. In particular, polycyclic arylcarboxylic acids, such as racemic 2-(6-methoxy-2-naphthyl)propionic acid, α-dl-2-(3- phenoxypheny propionic acid; and 2-(3-benzoylphenyl)propionic acid, have significantly higher boiling points than ibuprofen. Thus separating such substances from catalyst residues, if possible by reduced pressure distillation, would require special equipment and operating conditions, e.g., high vacuum, and wiped film evaporators. Also under the conditions needed for such operations, the possibility exists for some product and/or catalyst component losses to be encountered. Thus a need exists for an efficient way of separating arylcarboxylic acids, especially polycyclic arylcarboxylic acids, from expensive residual catalyst components used in their preparation, which does not require reduced pressure distillation with its attendant high investment and operating costs, and which provides an active organic-soluble catalyst residue for reuse via recycle without need for regenerating such residue. This invention makes it possible to effectively fulfill this need.

SUMMARY OF THE INVENTION In one embodiment, a process is provided which comprises:

A) reacting arylolefin with carbon monoxide and water in the presence of palladium catalyst formed at least from (1) palladium or palladium compound and (2) organophosphine ligand, to form a reaction mass comprising (a) arylcarboxylic acid, and (b) one or more residual catalyst species;

B) mixing together at least a portion of such reaction mass and aqueous inorganic base to form (i) an aqueous phase with water-soluble salt of the arylcarboxylic acid dissolved therein, and (ii) an organic phase having at least a portion of the residual catalyst species dissolved therein;

C) separating these phases, and recycling at least a portion of the separated phase (ii) to A) for use in performing additional reaction pursuant to A).

Oftentimes in B) of this embodiment there is, in addition to phases (i) and (ii), a solids phase containing a portion of the palladium catalyst values. Preferably, such solids phase is recovered (e.g., by filtration) and if not sufficiently catalytically active for recycle, at least a portion thereof is converted into an active palladium catalyst component for use in subsequent reaction pursuant to A).

Another embodiment of the invention is a process which comprises:

A) reacting aryl halide with vinylolefin in the presence of hydrogen halide acceptor and palladium catalyst formed at least from (1) palladium or palladium compound and (2) organophosphine ligand, to form a reaction mass containing arylolefin;

B) reacting at least a portion of the arylolefin so formed with carbon monoxide and water in the presence of palladium catalyst formed at least from (1) palladium or palladium compound and (2) organophosphine ligand, to form a reaction mass comprising (a) arylcarboxylic acid, and (b) one or more residual catalyst species; C) mixing together at least a portion of the reaction mass of B) and aqueous base to form (i) an aqueous phase with water-soluble metal salt of the arylcarboxylic acid dissolved therein, and (ii) an organic phase having at least a portion of the residual catalyst species dissolved therein; D) separating these phases, and recycling at least a portion of the separated phase (ii) to A) for use in performing additional reaction pursuant to A) and/or to B) for use in performing additional reaction pursuant to B). In this embodiment also, there is often present in C) in addition to phases (a) and (b), a solids phase containing a portion of the palladium catalyst values. In such cases it is preferable to recover this solids phase (such as by filtration) and if it is not sufficiently catalytically active for recycle, to convert at least a portion thereof into an active palladium catalyst component for use in subsequent reaction pursuant to A) and/or B).

Active fresh catalytic species are preferably formed in situ by the addition to the initial reaction mixture of the foregoing individual components, viz., palladium or palladium compound and organophosphine ligand. However the catalyst can be preformed externally to the reaction mixture and charged to the reactor as a preformed catalyst composition.

It will be seen that in the practice of this invention the separation between the arylcarboxylic acid and the residual catalyst species involves a phase separation (e.g., a phase cut or decantation), and requires no reduced pressure distillation. Moreover, a substantial portion of the catalyst residue is organic-soluble, catalytically active, and highly efficacious when used as catalyst recycle.

These and other embodiments and features of the invention will become still further apparent from the ensuing description and appended claims. FURTHER DETAILED DESCRIPTION Reaction of Arylolefin with Carbon Monoxide and Water

This reaction is a palladium-catalyzed hydrocarboxylation reaction wherein an arylolefin is converted to an arylcarboxylic acid. The arylolefin typically is a compound of the formula R¹ R³

I I c = C (I)

I I

R² Ar

where Ar is aryl, functionally-substituted aryl, heteroaryl, functionally-substituted heteroaryl, aralkyl (especially benzyl), or functionally-substituted aralkyl (especially functionally-substituted benzyl), and R¹, R², and 12 are the same or different and are selected from hydrogen atoms, hydrocarbyl groups, functionally-substituted hydrocarbyl groups, and halogen atoms. Preferably, Ar is aryl or functionally-substituted aryl, and R¹, R², and R³ are the same or different and are selected from hydrogen atoms and aliphatic hydrocarbyl groups. More preferably, Ar is aryl or functionally-substituted aryl, and R¹, R², and R³ are hydrogen atoms. Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, and biphenylyl, any of which may be substituted on a ring by one or more hydrocarbyl substituents such as alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl, and like hydrocarbyl substituents attached to an aromatic ring by a non-aromatic carbon atom. Functionally-substituted aryl groups are aryl groups which contain at least one functional group attached to an aromatic ring or to a hydrocarbyl substituent that is in turn attached to an aromatic ring. Examples of such functional substituent include a hydroxyl group, an alkoxy group, a cycloalkoxy group, an aryloxy group, a halogen atom, a mono or poly-haloalkyl group, a mono or poly-halocycloalkyl group, a mono or polyhaloaryl group, and like functional groups. Although not critical, the arylolefin will typically contain up to about 30 carbon atoms in the molecule. Among preferred groups designated Ar in Formula (I) are an isobutylphenyl group, a methoxynaphthyl group, a phenoxyphenyl group, a fluorobi-phenylyl group, and a benzoylphenyl group.

Among particularly preferred arylolefins are alkoxyvinylnaphthalenes where the alkoxy group has up to about 4 carbon atoms, such as 6-methoxy-2-vinylnaphthalene; vinylbenzo- phenones, such as 3-vinylbenzophenone; fluorovinylbiphenyls, such as 2-fluoro-4-vinylbiphenyl (or 2-fluoro-4-phenylstyrene); vinyldiphenyloxides, such as 3-vinyldiphenyloxide (or 3- phenoxy styrene); and alkylstyrenes where the alkyl group has up to about 6 carbon atoms, such as 4-isobutylstyrene. Compounds analogous to the foregoing wherein the vinyl group is replaced by a 1-alkenyl group having in the range of 3 to 18 carbon atoms, such as a propenyl group are also desirable for use as the arylolefin reactant. The arylcarboxylic acid formed in this reaction is typically a compound of the formula

R¹ R³

I I

H - C - C - C(0)OH (II)

I I R² Ar

where Ar, R¹, R², and R³ are as defined above. The present invention embraces the formation of any racemates and individual optical isomers of the compounds of Formula (II) having a chiral carbon atom. For example, when the acid, 2-(6-methoxy-2-naphthyl)propionic acid, is subjected to resolution as taught in U.S. Pat. No. 4,246,164, the analgesic compound naproxen is produced. Ordinarily, the palladium-catalyzed hydrocarboxylation reaction is conducted at one or more temperatures between 25 °C and 200 °C, preferably in the range of 25° to 120°C, and most preferably in the range of 25° to 100 °C. Whatever the temperature, at least a portion of compound of Formula (I) must be converted in the reaction to compound of Formula (II). The best yields are obtained when the temperature is maintained at a relatively low level throughout the reaction.

The partial pressure of carbon monoxide in the reaction vessel is at least about 1 atmosphere (0 psig) at ambient temperature (or the temperature at which the vessel is charged). Any higher pressures of carbon monoxide can be used up to the pressure limits of the reaction apparatus. A pressure up to about 3000 psig is convenient in the process. More preferred is a pressure from 0 to 3000 psig at the reaction temperature, and most preferred is a pressure from 0 to 1000 psig. It should be noted that the presence of oxygen is undesirable in the hydrocarboxylation reaction. Hence, an atmosphere of 100% carbon monoxide is most preferred for carrying out this reaction. Various inert gases can, however, be incorporated in the reaction mass (nitrogen, and argon), the only criterion being that the process should not be slowed to the point of requiring exceptionally long periods to complete the reaction.

At least about one (1) mole of water per mole of the arylolefin should be used, and at least in the case of 6-methoxy-2-vinylnaphthalene (MVN) about four moles of water per mole of the arylolefin is typically employed. It is worth noting that an excessive amount of water can inhibit or even kill the reaction when using MVN. In hydrocarboxylation reactions with other compounds of Formula (I), an excess amount of water may sometimes be used. In such cases, although possibly there may be no real upper limit to the amount of water except that imposed by practicality (e.g. the size of the reaction vessel, and the kinetics of the reaction), an amount up to about 100 moles, and preferably up to about 50, moles per mole of the compounds of Formula (I) may be considered for use in the process, and an amount from 2 to 24 moles of water per mole of the arylolefin compound is more preferred.

If desired, any alcohol which produces an ester of the carboxylic acid may be used instead of, or together with, water in the conduct of this process step. However, this is decidedly less preferable as the resultant ester has to be saponified by the aqueous base used in the ensuing process step, and as a result of this, another component — the free alcohol — is included in the reaction mass.

In some cases, the hydrocarboxylation reaction may be initiated under neutral conditions, i.e., with no added acid such as HC1. However, at least in the case of hydrocarboxylation of

MVN, the inclusion of aqueous HC1 in the reaction mixture is deemed important, if not almost essential for most efficient operation. Thus in a preferred embodiment of this invention, the hydrocarboxylation reaction is initiated in the presence of halide ions which are best provided by use of a halogen acid, especially hydrochloric acid, which preferably is an aqueous acid which may for example have a concentration up to about 25 wt%, but preferably has a concentration in the range of 5 to 15 wt% , and more preferably in the range of 7 to 15 wt% . It is especially preferred to use approximately 10 wt% aqueous HC1. Dilute aqueous HC1 also provides water for effecting the hydrocarboxylation. Gaseous HC1 can be used to generate hydrochloric acid in situ when water is present when conducting this reaction. HBr and hydrobromic acid may be used, but these appear less effective based on studies conducted to date. Other acids may be considered for use but to date the most effective material is the aqueous hydrochloric acid. Any suitable proportion of hydrochloric acid may be used, typically a reaction accelerating quantity in the range that provides up to 1 mole of hydrogen ion per mole of compound of Formula (I), and preferably a quantity that provides in the range of 0.1 to 0.5 mole of hydrogen ion per mole of the compounds of Formula (I). In the case of hydrocarboxylation of MVN, the preferred range is an HO: MVN mole ratio of 0.1 to 0.3, more preferably 0.15 to 0.27, and most preferably 0.18 to 0.22.

The catalytic hydrocarboxylation process step is conducted in the presence of a reaction- promoting quantity of (i) palladium and/or at least one palladium compound in which the palladium has a valence of zero, 1 or 2, (most preferably 2) or (ii) a mixture of (a) palladium and/or at least one palladium compound, and (b) at least one copper compound, with (iii) at least one organophosphine ligand, preferably a tertiary phosphine. When a copper compound is not employed, the palladium and/or one or more compounds of palladium used in forming the catalyst is/are sometimes collectively referred to herein for convenience as "the Pd ingredient", and the combination of palladium and/or one or more compounds of palladium and one or more compounds of copper used in forming the catalyst (when a copper compound is employed) is sometimes collectively referred to herein for convenience as "the Pd-Cu ingredient" . To start up the reaction for continuous operation, or in conducting the first of a series of batch reactions, it is desirable to use fresh catalyst, the term "fresh" being used herein to refer to unused catalyst, and to thereby distinguish from recycled catalyst residues. The term does not refer to the time at which the catalyst was formulated, as fresh catalyst can be preformed and stored under suitable conditions prior to use. After reaction initiation and commencement of catalyst recycle in a continuous operation, recycled catalyst residues can be charged continuously or portionwise to the reactor and implemented whenever deemed necessary or desirable by feed of fresh catalyst. Similarly, when conducting the reaction as a series of batch operations, the second and subsequent reactions can utilize recycled catalyst residues either as the sole catalyst or in combination with fresh catalyst. While palladium metal, or various types of compounds of palladium, e.g., complexes or chelates of palladium, can be used as the Pd ingredient in forming fresh catalyst for the reaction, the use of salts of palladium is preferable because fresh catalyst compositions formed from palladium salts appear to have greater activity at least as compared to those made from palladium metal itself. Of the salts, palladium(Η) salts such as the Pd(Q) halides (chloride, bromide, iodide) and Pd(II) carboxylates (e.g., acetate, and propionate) are most preferred.

Organophosphine ligands for use in the process can also be of various types as long as their use with the Pd ingredient results in an active fresh catalyst. Normally the organophosphine ligand will contain a total of up to about 30 carbon atoms in the molecule, although this is not deemed a critical limitation. A preferred class of ligands is comprised of tertiary phosphine ligands of the formula

R⁴R⁵R⁶P (III)

where R⁴, R⁵, and R⁶ are the same or different and are selected from alkyl, aryl, functionally- substituted aryl, heteroaryl, functionally-substituted heteroaryl, aralkyl, functionally-substituted aralkyl, cycloalkyl, and functionally-substituted cycloalkyl, at least one of R⁴, R⁵, and R⁶ being aryl or functionally-substituted aryl, in which the functional substituents are of the types described above. Preferably at least one of R⁴, R⁵, and R⁶ is aryl and at least one of R⁴, R⁵, and R⁶ is cycloalkyl.

A highly preferred type of tertiary phosphine ligand used is one or more tertiary phosphine of the formula

where R' and R" are the same or different and are individually hydrogen, alkyl or aryl, Ar is phenyl or naphthyl, and n is an integer from 3 to 6. Preferably, R' and R" are the same or different and are C_t to C₆ alkyl, Ar is phenyl, alkylphenyl, naphthyl or alkylnaphthyl, and n is 3 or 4. Most preferably, R' is methyl or ethyl, R" is to C₆ branched alkyl, Ar is phenyl and n is 4. Especially preferred as the phosphine ligand is neomenthyl-diphenylphosphine.

When it is desired to use a copper compound in forming fresh hydrocarboxylation catalyst system, copper complexes such as copper acetylacetonates, copper alkylaceto-acetates, or other chelated forms of copper may be used. The preferred copper compounds for this use, however, are salts especially divalent copper salts such as the halides (chloride, bromide, iodide) of copper(II) and the carboxylates of copper(II) such as copper(H) acetate, and copper(II) propionate.

In one embodiment, the Pd ingredient and copper compounds are inorganic salts and are added as a preformed complex of, for example, a complex formed from palladium(II) chloride or bromide, copper(II) chloride or bromide and carbon monoxide, or any other similar complex. In a preferred embodiment, fresh active catalytic species are formed in situ by the addition to the reaction mixture of the individual components, i.e., either (i) at least one organophosphine ligand and at least one palladium compound such as the inorganic or carboxylate salts of palladium(II), or (ii) at least one organophosphine ligand, at least one copper compound, and at least one palladium compound such as the inorganic or carboxylic salts of palladium(II) and copper(II). These inorganic salts include the chlorides, bromides, nitrates, and sulfates. Organic palladium and/or copper compounds that may be used include complexes and salts such as the carboxylates, e.g., the acetates or propionates. In one preferred embodiment, neomenthyldiphenylphosphine, copper (II) chloride, and palladium(II) chloride are used in making the fresh catalyst and are added to the reactor individually or together, either simultaneously or sequentially. In another preferred embodiment, neomenthyldiphenyl-phosphine and palladium(II) chloride are used in making fresh catalyst and are added to the reactor individually or together, either simultaneously or sequentially. The Pd ingredient or the Pd-Cu ingredient may be supported on carbon, silica, alumina, zeolite, clay and other polymeric materials, but use of a homogeneous catalyst system is definitely preferable.

The amount of the Pd ingredient or of the Pd-Cu ingredient employed in forming fresh catalyst is preferably such as to provide from 4 to 8000 moles of the compound of Formula (I) per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient. More preferred is an amount to provide from 40 to 4000 moles (most preferably 20 to 2000 moles) of the compounds of Formula (I) per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient. The proportion of organophosphine ligand used is at least about one mole per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient. More preferably, 1 to 40 moles of organophosphine ligand are used per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient, and most preferably 1 to 20 moles of the organophosphine are used per mole of the Pd ingredient or per total moles of the Pd-Cu ingredient.

The presence of a solvent is not always required in the hydrocarboxylation reaction, although it is desirable in some circumstances. Solvents which can be used include one or more of the following: ketones, for example, acetone, methyl ethyl ketone, diethyl ketone, methyl n- propyl ketone, acetophenone, and cyclohexanone; linear, poly and cyclic ethers, for example, diethyl ether, di-n-propyl ether, di-n-butyl ether, ethyl n-propyl ether, glyme (the dimethyl ether of ethylene glycol), diglyme (the dimethyl ether of diethylene glycol), tetrahydrofuran, dioxane, 1,3-dioxolane, and similar compounds; and aromatic hydrocarbons, for example, toluene, ethyl benzene, xylenes, and similar compounds. Alcohols, for example, methanol, ethanol, 1-propanol, 2-propanol isomers of butanol, and isomers of pentanol, can be used as solvents. Esters, such as ethyl acetate, may also be used as solvents. When an ester or an alcohol is used as solvent, the product is usually the corresponding ester of the carboxylic acid, and thus the use of alcohols or esters is not preferred. Most highly preferred are ethers, especially tetrahydrofuran, or mixtures of one or more ethers and one or more ketones, especially mixtures of tetrahydrofuran and diethylketone. When solvents are used, the amount can be up to about 100 mL per gram of the compounds of Formula (I), but the process is most advantageously conducted in the presence of 1 to 30 mL per gram of the compound of Formula (I).

Rate and/or proportions of catalyst recycle are largely discretionary provided the palladium catalyst is active in promoting the desired hydrocarboxylation reaction. From the standpoint of process economics, the greater the rate and/or amount of palladium catalyst residue that can be effectively utilized while achieving suitable reaction rates and yields, the better. Thus in any given situation, a few pilot experiments should be conducted in order to optimize the rate and/or proportion of catalyst recycle.

It will be understood and appreciated that the actual composition of the catalyst residue used as recycle cannot be specified with exactitude. The residue recovered for recycle contains palladium-containing and phosphorus-containing residues which are catalytically active. Whether these residues are composed of reaction products, chemical compounds, chemical complexes, and/or physical mixtures of two or more substances, or is not presently known. All that is known is that the residues are catalytically active and are suitable for use as catalyst recycle. If and when the residue loses sufficient catalyst activity to be effectively used for recycle, it should be segregated for regeneration of one or more catalyst components or at least reclamation of palladium values whenever possible. Neutralization of Arylcarboxylic Acid

On completion of the hydrocarboxylation reaction, aqueous alkali metal base is mixed with all or at least a portion of the resultant reaction mass. This results in formation of an aqueous solution of the alkali metal salt of the arylcarboxylic acid. Concurrently, there is formed a separate organic phase from which the arylcarboxylic acid has been removed, thereby leaving two readily separable liquid phases, each containing one of the components to be separated. One such phase is the aqueous phase in which the alkali metal salt of the arylcarboxylic acid is dissolved. The other liquid phase is the organic phase in which catalyst residues are dissolved. If desired low boiling solvent or diluent, such as tetrahydrofuran (THF), can be removed from the reaction mass to form a more concentrated reaction mass before conducting the neutralization with aqueous alkali metal base. A simple distillation can be used for removing such low boiling solvent or diluent.

As noted above, still another phase may exist, namely, a solids phase containing an insoluble portion of the palladium catalyst residues. These solids can be physically separated and recovered by filtration or other suitable means, such as centrifugation. If suitably active, the solids can be recycled for use in the hydrocarboxylation reaction. Otherwise, the solids can be subjected to combustion in a furnace to produce an ash from which the palladium content can be recovered and used for preparation of a suitable palladium catalyst component, such as palladium(II) chloride. See in this connection U.S. Pat. No. 5,055,611 which describes a suitable procedure for palladium catalyst regeneration, but which, however, requires reduced pressure distillation to effect the separation between catalyst residues and the carboxylic acid formed in the palladium- catalyzed process.

In many cases the hydrocarboxylation reaction forms a reaction mass comprising arylcarboxylic acid (e.g., racemic 2-(6-methoxy-2-naphthyl)propionic acid, 2-(3-benzoyl- phenyl)propionic acid, or 2-(4-isobutylphenyl)propionic acid, and a liquid medium comprising polar organic solvent (preferably ketone or nitrile or mixture thereof), water and/or alcohol, HCl, and preferably at least one ether (e.g. , THF) with a boiling temperature below that of at least one such polar solvent. Also present are catalyst residues and typically some coproducts formed during the reaction.

Pursuant to a preferred workup procedure for producing and isolating the purified arylcarboxylic acid from the aqueous phase — a procedure described in commonly-owned copending application Serial No. 08/780,310, filed January 8, 1997 ~ the arylcarboxylic acid in the reaction mass is converted in situ into a water-soluble inorganic salt of such acid by reaction with an aqueous solution of inorganic base (neutralization step). In addition, when the reaction product composition contains (i) at least one low boiling ether (e.g., THF) and/or (ii) at least one low boiling polar solvent, where either or both such low boiling materials boil(s) below the boiling temperature of at least one polar solvent contained in the reaction mass, some or all of such low boiling materials are distilled from the reaction product composition (distillation step). If the reactor overheads are susceptible to attack by aqueous HCl, and HCl is present in the reaction mass, the neutralization step should precede or at least be conducted concurrently with the distillation step. On the other hand, if the reactor overheads are formed from acid-resistant materials of construction, the distillation step can precede and/or follow and/or be conducted concurrently with the neutralization step; HCl in the mixture will not cause excessive corrosion of the reactor overheads even if the distillation precedes the neutralization. In whatever sequence the neutralization step and the distillation step are conducted, a mixture of residual organic phase and an aqueous phase containing dissolved inorganic salt of the arylcarboxylic acid remain in the reactor as a distillation residue (distilland or pot residue). These phases are separated from each other. The aqueous phase is then subjected to a distillation, preferably at or near atmospheric pressure, to remove residual organic impurities such as THF. At this point it is desirable to ensure that the residual aqueous phase has a concentration in the range of 10 and 35 wt% of dissolved inorganic salt of the arylcarboxylic acid and where necessary, adjusting the concentration of the aqueous phase to 10 and 35 wt% solution by removal or addition of water. The aqueous solution is then washed (extracted) with substantially non-polar liquid organic solvent (preferably aromatic hydrocarbon solvent, such as toluene or xylene), preferably at least twice. The free arylcarboxylic acid is then produced by mixing non-oxidizing mineral acid (e.g., sulfuric acid) with the aqueous phase in the presence of substantially non-polar liquid solvent to form (i) an organic phase composed of a solution of arylcarboxylic acid in substantially non-polar liquid solvent and (ii) an aqueous phase. After separating these phases from each other, the arylcarboxylic acid is crystallized from the substantially non-polar liquid solvent.

The aqueous solution of inorganic base used in the above neutralization step is preferably a 10 to 40 wt% solution of NaOH or KOH. However other inorganic bases that can be used include Na , K₂O, Ca(OH)₂, CaO, Na O₃, KJ O₃, and other inorganic bases of similar basicity. Such solutions are used in an amount at least sufficient to neutralize the arylcarboxylic acid and the HCl present in the reaction mass.

When the carboxylation reaction is conducted using an alcohol so that an ester of the arylcarboxylic acid or substituted arylcarboxylic acid is present in the reaction product composition, it is preferred to saponify the ester in situ by mixing a concentrated aqueous solution of a strong inorganic base such as NaOH or KOH with the reaction product composition and applying sufficient heat (e.g., heating to a temperature in the range of up to about 80 °C) to form the inorganic salt of the arylcarboxylic acid or substituted arylcarboxylic acid. Then the workup procedure for the carboxylation product as described above is carried out.

The low boiling materials recovered in the initial distillation step are preferably recycled for use in the hydrocarboxylation reaction. Examples of compounds that can be produced by use of the invention include ibuprofen,

2-(4-isobutylphenyl)propionic acid (U.S. Pat. Nos. 3,228,831 and 3,385,886); 2-(3-fluoro-4- biphenylyl)-propionic acid (also known as flurbiprofen) (U.S. Pat. No. 3,755,427); racemic 2-(6- methoxy-2-naphthyl)propionic acid which can be resolved to d-2-(6-methoxy-2-naphthyl)propionic acid (also known as naproxen) (U.S. Pat. No. 3,637,767); α-dl-2-(3-phenoxyphenyl)propionic acid (also known as fenoprofen) (U.S. Pat. No. 3,600,437); and 2-(3-benzoylphenyl)propionic acid (also known as ketoprofen) (U.S. Pat. No. 3,641,127). Reaction of Arylhalide with Vinylolefin

In the embodiments of this invention wherein the arylolefin is prepared, converted to arylcarboxylic acid, and then subjected to the forgoing catalyst separation and recycle steps, the preferred process step for producing the aryl olefin comprises reacting aryl halide with vinylolefin in the presence of hydrogen halide acceptor and palladium catalyst formed at least from (1) palladium or palladium compound and (2) organophosphine ligand. Since this reaction involves the formation of arylolefin, the reaction can be referred to either as the arylation reaction or the vinylation reaction. For convenience, the reaction is referred to herein as the arylation reaction. The reaction mass formed in the arylation reaction thus contains the desired arylolefin intermediate and as noted above, by reacting at least a portion of the arylolefin so formed with carbon monoxide and water in the presence of the above-described palladium catalyst, the arylcarboxylic acid is formed in the hydro-carboxylation reaction (or via the carboxylation reaction in the presence of alcohol, followed by saponification of the resulting arylcarboxylic acid ester).

In conducting this embodiment, the arylolefin formed by the reaction can be separated from the remainder of the reaction mass from the arylation reaction, if desired. However, such a separation is not necessary. Instead, it is preferred to leave the arylolefin in the reaction mass and subject at least a portion (usually, all) of the arylation reaction mass to the hydrocarboxylation reaction. If the reaction mass contains suitably volatile components, such as excess low-boiling amine-type hydrogen halide acceptor and/or volatile solvent or diluent, such can be removed prior to conducting the hydrocarboxylation by subjecting all or part of the arylation reaction mass to a preliminary flash or simple distillation.

Palladium-catalyzed arylations of olefins with aryl halides are well known and reported in the literature. See for example, CB. Ziegler, Jr., and R.F. Heck, /. Org. Chem. , 1978, 43, 2941, and U.S. Pat. No. 5,536,870 to T-C Wu. In the practice of this invention the preferred arylation reaction is as described in commonly-owned copending application Serial No. 08/780,308 filed January 8, 1997. The ensuing description up to but not including Example 1 is largely based on that copending application.

The preferred arylation reaction involves forming a compound of Formula (I) above by reacting an aryl halide or functionally-substituted aryl halide of the formula, Ar-X, where Ar is as defined above in connection with Figure (I) and X is a halogen atom of atomic number greater than 9, a diazonium group or triflate or other leaving group; with at least one olefinic compound of the formula R¹ R³

I I

C = C (V)

I I R² H

where R¹, R², and R³ are as defined above in connection with Figure (I). The aryl group of the aryl halide or functionally-substituted aryl halide is preferably alkylphenyl, naphthyl substituted with alkoxy, phenyl substituted with aryloxy or substituted aryloxy (especially phenoxy), aryl substituted with fluoro, or phenyl substituted with aroyl, and the halogen atom of the aryl halide or substituted aryl halide is preferably a bromine atom. Examples of substituted aryl halides include compounds wherein the substituted aryl group is an isobutylphenyl group, a methoxy naphthyl group, a phenoxyphenyl group, a fluoro-biphenylyl group, a benzoylphenyl group, and where the halogen atom is a chlorine, an iodine, or most preferably, a bromine atom.

The preferred olefinic compounds of Formula (V) are those in which R¹, R², and R³ are hydrogen atoms, C_t to C₆ alkyl, substituted or unsubstituted phenyl, and/or trifluoromethyl. Examples include compounds of Formula (V) wherein R¹, R², and R³ are hydrogen atoms, methyl, and/or trifluoromethyl. Olefins in which R³ is a hydrogen atom are more preferred, and vinyl olefins in which R¹ is a hydrogen atom or a to C₆ alkyl group, and R² and R³ are hydrogen atoms especially preferred. Ethylene is the most preferred olefinic reactant. The reaction is conducted in a liquid medium formed from (i) one or more liquid polar organic solvent/diluents, and (ii) one or more secondary or tertiary amines that (1) boil(s) below the boiling temperature of the solvent/diluent if only one solvent/diluent is used in forming the medium or (2) that boil(s) below the boiling temperature of at least one, but not necessarily all, of the polar solvent/diluents used in forming the medium if more than one solvent/diluent is used in forming the medium. The solvent/diluent should have at least a measurable polarity at a temperature in the range of 20 to 25 °C, and yet be free of functionality that would prevent or materially impair, inhibit or otherwise materially interfere with the arylation reaction. Examples include 1,4-dioxane, diglyme, triglyme, acetonitrile, propionitrile, benzonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, dimethylsulf oxide, nitrobenzene, sulfolane, acetone, butanone and cyclohexanone. Preferred solvent/diluents are one or more aprotic solvents each having a dielectric constant of at least about 10 (especially 10 to 30) at a temperature in the range of 20 to 25 °C. From the cost-effectiveness standpoint, hydrocarbyl ketones with 4 or more carbon atoms in the molecule (e.g., 4 to 8) are especially preferable. Examples include diethyl ketone, methyl isobutyl ketone, 2-pentanone, 2-hexanone, 2-heptanone, 3-heptanone, 4-heptanone, and like liquid ketones, as well as mixtures of two or more such ketones. Most preferred is diethyl ketone (3-pentanone). The arylation reaction inherently tends to be an exothermic reaction, and the use of diluents having a dielectric constant in the range of 10 to 30 (as measured at 20 to 25 °C), such as a ketone meeting this qualification provides a readily controllable reaction.

The secondary or tertiary amines are used as hydrogen halide acceptors and thus preferably are used in at least a stoichiometric amount relative to the aryl halide and/or substituted aryl halide being used. However it is possible, though less desirable, to use less than a stoichiometric amount of amine, by allowing the reaction with less than a stoichiometric amount of amine to proceed only part way, and by recycling the reaction mixture for further reaction in the presence of additional amine added thereto.

Use can be made of any liquid secondary or tertiary amine that is free of functionality that would prevent or materially impair, inhibit or otherwise materially interfere with the arylation reaction, that boils below the boiling temperature of the polar solvent/diluent used when only one is used in forming the liquid medium for the reaction, or that boils below at least one of a plurality of polar solvent/diluents used in at least a substantial amount (e.g., at least 20 or 30% of the total volume of the solvent/diluents), when more than one is used in forming the liquid medium for the reaction, and that has sufficient basicity to serve as a hydrogen halide acceptor for the HCl, HBr and/or HI, formed in the arylation reaction. Preferred are liquid tertiary amines. The amines may be polyamines such as for example, N,N,N',N'-tetramethylethylenediamine (b.p. ca. 120-122°C), but in most cases monoamines are preferable. Among useful liquid amines having suitably low boiling points are diethylamine (bp 55°C), N,N-dimethylethylamine (bp 36-38°C), N,N- diethylmethylamine (bp 63-65 °C), diisopropylamine (bp 84°C), triethylamine (bp ca. 89°C), dipropylamine (bp ca. 105-110°C), and di-sec-butylamine (bp ca. 135 °C). Triethylamine is a particularly preferred amine.

Liquid media formed from diethyl ketone and acetonitrile (e.g. in a weight ratio in the range of 1 :9 to 4: 1, and more preferably in the range of 1:3 to 3:1) plus triethylamine, or from diethyl ketone and N,N-dimethylformamide (e.g., in a weight ratio in the range of 1:9 to 9:1) plus triethylamine are typical desirable liquid media for use in this invention.

Liquid media formed from diethyl ketone and triethylamine or from methyl isobutyl ketone and triethylamine are particularly preferred. The arylation reaction is typically conducted in the presence of a catalytically effective amount of a catalyst system formed from (a) palladium and/or at least one compound of palladium in which the palladium has a valence of zero, 1 or 2, and (b) a organophosphine ligand, normally a tertiary phosphine ligand. Thus in general the Pd ingredient and the organophosphine ligand are the same type of materials as described above in connection with the hydrocarboxylation reaction. Indeed the same preferred types of materials preferred for use in the hydrocarboxylation reaction are preferred for use in the arylation reaction. Fresh catalyst is employed for each such reaction, however. The same species of Pd ingredient and the same species of tertiary phosphine ligand need not be used in these two reactions. Either such component or both of them might differ. Thus, for example, palladium(H) chloride and triphenylphosphine might be used in the arylation and palladium(H) acetate and tri-o-tolylphosphine might be used in the hydrocarboxylation, or vice versa, but in the most preferred case the same species (PdC^ and neomenthyldiphenylphosphine) are in fact used in both such reactions.

As in the case of the hydrocarboxylation reaction, active catalytic species are preferably formed in situ by the addition to the reaction mixture of the individual components. However the catalyst can be preformed externally to the reaction mixture and charged to the reactor as a preformed catalyst composition.

Desirably, a small reaction-accelerating amount of water is included or present in the reaction mixture, as described in commonly-owned copending U.S. application Serial No. 08/780,310, filed January 8, 1997. This amount is typically in the range of 0.5 to 5 wt% of the total weight of the entire reaction mixture. Within the range of 0.5 to 5 weight percent water there is often an optimum amount of water which gives the highest or peak reaction rate which falls off if more or less water is used. This optimum amount of water may vary depending upon the identity and proportions of the ingredients used in forming the reaction mixture. Thus in any given situation it may be desirable to perform a few preliminary experiments with the particular reaction to be conducted, wherein the amount of water is varied within the range of 0.5 to 5 wt% to locate the optimum rate-enhancing amount of water in the mixture. Preferably, the amount of water used will be insufficient to form a second liquid phase (i.e., a separate water layer) in a mixture consisting of (i) the amount of the liquid organic solvent diluent(s) selected for use, (ii) the selected amount of the liquid secondary and/or tertiary amine(s) selected for use, and (iii) the selected amount of water, when such mixture is agitated for 10 minutes at 25 °C and allowed to stand for 15 minutes at the same temperature. Thus when conducting the process on a large scale with recycle of solvent(s) and amine, the amount of water carried over from product workup should be monitored and/or controlled such that the water content of the reaction mixture remains at or below about 5 wt% of the total weight thereof. Conversely if the amount of recycled water is insufficient to maintain the desired water content in the reaction mixture, additional water is preferably added to bring the water content up to the desired amount within the foregoing range. Preferably the arylation reaction mixtures have a water content in the range of 1 to 3.5 weight percent. In conducting an operation wherein a mixture of (i) liquid organic solvent/diluent(s), (ii) secondary and/or tertiary amine(s), and (iii) water that does not separate into a two-phase system is used, the liquid mixture of these components may nonetheless be hazy or cloudy, but a distinct coalesced second liquid phase does not and should not exist as a separate layer in such liquid mixture.

The arylation reaction is performed under conditions such that olefinic compound of Formula (I) above is formed. Such conditions usually require an equimolar ratio of olefinic compound (Formula (V) above) to aryl halide and/or functionally-substituted aryl halide, although an excess of olefinic compound is preferred. The palladium catalyst and the phosphine ligand are typically used at about a ratio of 1 mole of organic halide to 0.0005 mole of palladium or palladium compound. The ligand is present in the same or higher molar proportion as the palladium or palladium compound. It should be noted that levels of (a) palladium or palladium compound, and (b) ligand can be substantially higher (up to 10 times). When relatively inactive species of olefinic compound or aryl halide and/or substituted aryl halide are employed, for example, highly substituted olefins and/or substituted aryl halides bearing strongly electron donating substituents, these higher amounts of catalyst and ligand may be required. Thus the mole ratio of aryl halide and/or substituted aryl halide :Pd: ligand used will generally be a suitable ratio within the range of 200-20,000:1:1-20, respectively.

Temperatures of reaction in the arylation reaction are quite modest, varying from 25 °C to 200 °C (preferably 60 °C to 150°C) with pressures (for the gaseous vinyl compounds) being from atmospheric up to about 3000 psi (preferably 300 to 1000 psi). With the preferred catalyst systems and liquid media referred to above, reaction times are unusually short, typically giving complete reaction in the range of 1 to 24 hours, typically in the range of 2 to 6 hours. Higher temperatures and lower pressures tend to cause increased by-product formation. The preferred and the optimum conditions will depend to some extent upon the identity of the particular ingredients being used. Thus, for example, when forming 6-methoxy-2- vinylnaphthalene (MVN) from 2-bromo-6-methoxynaphthalene (BMN) using ethylene as the olefinic reactant, a palladium (II) salt such as PdC^ and neomenthyldiphenylphosphine (NMDP) as catalyst or catalyst precursors, a C₄-C₈ ketone especially diethyl ketone and a C₄-C₉ trialkyl amine especially triethylamine as the liquid medium and a reaction accelerating amount of water, the BMN:Pd:NMDP mole ratio is preferably in the range of 1000:3000:1:2-10, respectively, the mole ratio of amine :BMN can be in the range of 0.1-2: 1 and preferably is in the range of 1-2:1 respectively, the mole ratio of ketone: amine is preferably in the range of 1.0-4.0:1 respectively, the weight of water based on the total weight of BMN + ketone + amine + Pd catalyst ingredient + tertiary phosphine ligand + water is preferably in the range 1 to 3.5 wt%, the reaction temperature is typically in the range of 60 to 150°C and preferably in the range of 80 to 110°C, and the pressure of the ethylene used is preferably in the range of 400 to 1000 psig. Under these conditions, reaction is complete within 1 to 24 hours, and oftentimes within 2 to 6 hours, with conversions and yields of MVN (both based on BMN used) of 70% to 99% , such as, for example, 95% conversion and 85% yield. It is to be clearly understood that the foregoing conditions given in this paragraph are, as stated, preferred conditions for carrying out the specified reaction. On the basis of the information presented in this disclosure, one skilled in the art could readily operate outside of the ranges given in this paragraph, and still achieve good performance in accordance with this invention. Thus the arylation reaction as herein described is not limited to use of the conditions given in this paragraph. It is permissible to depart from any one or more of such ranges, whenever deemed necessary or desirable in any given situation. For best results, the overall arylation reaction mixture is essentially solids-free when at reaction temperatures, except for some precipitation of palladium and formation of some solid co- products such as amine-hydrohalide salt and products formed by interaction of the aryl halide and/or substituted aryl halide (e.g., BMN) with the vinylated product (e.g., MVN), and/or by dimerization of such vinylated product that may occur as the reaction proceeds. Since the reaction tends to be exothermic, it is desirable to utilize reactors equipped with internal cooling coils, cooling jackets or other highly effective cooling means to ensure suitable temperature control.

A few examples of desirable laboratory reaction parameters in the reaction of BMN with ethylene using PdCl₂ and NMDP at 95 °C and 420 psig ethylene are as follows: a) NMDP:Pd mole ratios in the 5:1-6: 1 range give relatively fast reaction rates. b) BMN:Pd:NMDP mole ratios of 2000: 1:6, 2500: 1 :5 and 3000: 1 : 10 give high conversions and good yields; ratios of 3000:1:6 and 3500:1:5 are operable but give lower conversions. c) As agitator speeds increase from 300 to 1500 rpm, reaction times to completion decrease by almost two hours. d) At a BMN :Pd: NMDP mole ratio of 2000:1:6, ethylene pressures ranging from 190 psig to 955 psig at 95 °C give good results. Thus at 190 psig the yield of MVN was 86%, and at 900 psig the yield was 96% . At the higher pressures of the range, reaction times were shorter and the amount of solid by-products formed was less. e) At a BMN:Pd:NMDP mole ratio of 2000: 1:6, MVN yields are higher and the amount of solid by-products formed is lower, when using BMN concentrations at the lower end of the range of 20 to 35 wt% than at the higher end of the range. f) Reactions at a BMN :Pd: NMDP mole ratio of 2000:1:6 using 1.6 wt% water as reaction accelerator proceed at a higher reaction rate at 95 °C than at 85 °C. g) Maximum rate of reaction is achieved at about 3 wt% water when operating at 95 °C, 420 psig ethylene, BMN:Pd:NMDP mole ratio of 2000: 1:6, at 30 wt% BMN concentration. The rate is about 150% of the rate when no added water is present. Under these particular conditions, water levels greater than about 4% caused the reaction to stop at less than complete conversion. h) Use of recycled DEK solvent in four successive runs was successful; no new impurities were found in the MVN product solutions after four recycles. Addition of makeup water when needed to maintain the desired level of water in the reaction mixture is desirable in order to achieve the beneficial reaction accelerating effect of the water from run to run. Therefore, in producing 6-methoxy-2-vinylnaphthalene (MVN) from 2-bromo-6- methoxynaphthalene (BMN) by reaction with ethylene, using a palladium (II) salt such as PdCl₂ and neomenthyldiphenylphosphine (NMDP) as catalyst or catalyst precursors, the preferred reaction medium is a mixture comprising a C₄-C₈ ketone (especially diethyl ketone) and a - trialkyl amine (especially triethylamine). This reaction medium preferably contains a reaction accelerating amount of water in the range of 1 to 3.5 weight percent of the total weight of the reaction mixture. The BMN:Pd:NMDP mole ratio is preferably in the range of 1000:3000: 1 :2-10, respectively, (e.g., a BMN:Pd:NMP mole ratio of 2000:1:6), the mole ratio of amine: BMN is preferably in the range of 1-2:1 respectively, the mole ratio of ketone: amine is preferably in the range of 1.0-4.0:1 respectively, the reaction temperature is preferably in the range of 80 to 110°C (e.g. , about 95 °C), and the pressure of the ethylene used is preferably in the range of 400 to 1000 psig (e.g., about 420 psig).

Examples of compounds that can be produced by use of the invention include ibuprofen, 2-(4-isobutylphenyl)propionic acid (U.S. Pat. Nos. 3,228,831 and 3,385,886); 2-(3-fluoro-4- biphenylyl)-propionic acid (also known as flurbiprofen) (U.S. Pat. No. 3,755,427); racemic 2-(6- methoxy-2-naphthyl)propionic acid which can be resolved to d-2-(6-methoxy-2-naphthyl)propionic acid (also known as naproxen) (U.S. Pat. No. 3,637,767); α-dl-2-(3-phenoxyphenyl)propionic acid (also known as fenoprofen) (U.S. Pat. No. 3,600,437); and 2-(3-benzoylphenyl)propionic acid

(also known as ketoprofen) (U.S. Pat. No. 3,641,127). As described herein, the bromo precursor of each of the above compounds is reacted with an olefinic compound of Formula (III) (most preferably ethylene) in a one-phase organic liquid medium (most preferably a mixture of a liquid ketone, especially diethyl ketone, and a liquid secondary or tertiary amine such as a trialkyl amine, especially triethyl amine), that also preferably contains the above-described reaction accelerating amount of water) in the presence of a palladium catalyst system (as described herein), which is formed from Pd, Pd(I) salt or preferably Pd(II) salt and a tertiary phosphine ligand such as neomenthyldiphenylphosphine. The amine should be selected to avoid beta hydride elimination under reaction conditions and should not react with the olefin or bromo precursor to any appreciable extent. The bromo precursor substitutes on the ethylene to provide the substituted olefin which is then worked up as described above, and then carboxylated (using carbon monoxide and a palladium-phosphine or a palladium-copper-phosphine catalyst system as described herein) to produce the corresponding acid product (if water forms part or all of the solvent system) or the corresponding ester (if an alcohol such as methyl, ethyl or isoamyl alcohol) is used as all or part of the solvent.

Some of the above reactions can be exemplified as follows:

I B U P R O F E N

FLURB I PROFEN

KETOPROFEN

NAPROX EN

CH,

NAPROXEN

FENOPROFEN :

In the above depicted reactions the ethylene pressure should be 50 to 3000 psi (preferably 300 to 1000 psi), the temperature is 30°C to 200°C (preferably 60°C to 150°C). Temperatures and pressures are selected to minimize by-product formation. Palladium is used (i.e., charged to the reactor) preferably in the form of its salts, (e.g., Pd(II) acetate or chloride) along with a tertiary phosphine ligand as described above, with a cycloalkyldi(alkylphenyl)phosphine such as neomenthylditolylphosphine being preferred, and a cycloalkyldiphenylphosphine such as neomenthyldiphenylphosphine being particularly preferred.

The bromo precursors are frequently commercially available and/or can be readily prepared by those skilled in the art. For example, Aldrich Chemical Company sells m-bromophenol and m-bromoanisole while Albemarle PPC (Thann, France) sells 2-bromo-6-methoxynaphthalene. The bromo precursors of ibuprofen can be prepared by bromination using standard Friedel-Crafts catalysts (e.g., zinc bromide or ferric bromide). The bromo precursor of ketoprofen can be prepared by bromination of methyl benzoate (or a similar lower hydrocarbon ester) using aluminum chloride followed by NaOH hydrolysis, conversion to the acid chloride (e.g., with SOCl₂) and reaction with benzene (again, using a Friedel-Crafts catalyst such as A1C1,) . The precursor for (±)-2-(6-methoxy-2-naphthyl)propionic acid, viz., 2-bromo-6-methoxynaphthal- ene, is best made by the process described in commonly-owned U.S. application Serial No. 08/780,309, filed January 8, 1997.

In addition to the profen compounds described above, other prof en compounds which can be prepared under appropriate conditions by use of the above-described arylation reaction to convert the corresponding bromo precursors by reaction with ethylene include protizinic acid, tiaprofenic acid, indoprofen, benoxaprofen, carprofen, pirprofen, pranoprofen, alminoprofen, suprofen and loxoprofen.

Example 1 is illustrative of the present invention.

EXAMPLE 1

Part A. A reaction mass containing racemic 2-(6-methoxy-2-naphthyl)-propionic acid (MNPA) was formed by hydrocarboxylation of 6-methoxy-2- vinyl-naphthalene (MVN) with carbon monoxide in a tetrahydrofuran-diethyl ketone (THF-DEK) solvent mixture to which had been added PdCl₂, neomenthyldiphenylphosphine (NMDPP) and aqueous HCl. At the end of the reaction, the reaction mass was treated with aqueous NaOH solution to neutralize the HCl, and the THF was stripped from the resultant mixture. The content of crude MNPA in the mixture was converted to the sodium salt of MNPA by adding to the mixture and reacting the MNPA therein with aqueous NaOH solution. A two-phase liquid system was thus formed. After removing the aqueous phase containing the sodium salt of MNPA, the organic phase, containing the catalyst residues and other neutral by-products from the hydrocarboxylation, was then used in another hydrocarboxylation run to determine whether the catalyst residues therein could be used as a catalyst source in this ensuing hydrocarboxylation, and thus ascertain the recyclability of the ligand. Following is the procedure used in this ensuing hydrocarboxylation.

Part B. A 1-liter Hastelloy B Parr reactor was charged with MVN (133.8 g, 96.4% ,

0.7 mol), PdCl₂ (0.062 g, 0.00035 mol), 10 wt% aqueous HCl (60.5 g), and a portion of the organic phase cut from the hydrocarboxylation run of Part A above (414 g). The reaction was carried out at 70°C and 330-350 psig carbon monoxide pressure. Samples were removed at intervals and analyzed by GC for completion of reaction. The MVN conversions were 68.3%, 97.5%, and 98.6% after 4.5 hours, 6 hours, and 7 hours, respectively. The yield of racemic 2-(6- methoxy-2-naphthyl)propionic acid was 93.3% .

The following Examples 2-12 and the text accompanying them are taken from commonly- owned copending application Serial No. 08/780,308 filed January 8, 1997, and are presented herein to illustrate preferred ways of conducting the operations therein described. Unless otherwise specified all parts and percentages are by weight. In Examples 2-12 the following designations are used:

BMN is 2-bromo-6-methoxynaphthalene. TEA is triethylamine.

DEK is diethyl ketone. NMDP is neomenthyldiphenylphosphine.

MVN is 6-methoxy-2-vinylnaphthalene.

THF is tetrahydrofuran.

ACN is acetonitrile. As is well known in the art, the terms or designations "racemic 2-(6-methoxy-2-naphthyl)propionic acid" and "(±)-2-(6-methoxy-2-naphthyl)propionic acid" mean exactly the same thing. For convenience, "sodium racemate" is sometimes used in the examples to refer to racemic sodium 2- (6-methoxy-2-naphthy l)propionate .

Example 2 illustrates a preferred overall procedure for producing racemic 2-(6-methoxy-2- naphthyl) propionic acid on a large (1000 gallon) scale using fresh DEK.

EXAMPLE 2

Arylation Reaction

To a 1000 gallon reactor are charged 750 kg of BMN, 1305 kg of DEK, 368 kg of TEA,

0.3 kg of PdCl₂, 3.1 kg of NMDP, and 37 kg of water. The reactor is sealed, pressured to 100 psig with ethylene and the reactor temperature is adjusted to 95 °C. The reactor is then pressured to 425-450 psig with ethylene and held at this pressure until the uptake of ethylene is completed.

The reactor is cooled to 60 °C and excess ethylene is vented from the reactor. The reaction typically takes 4-6 hours to go to completion and typically gives a > 95 % BMN conversion and a MVN yield of 85-95%. Product Workup and Solvent Exchange

To the reaction product from the arylation reaction is added 557 kg of a 25 wt% aqueous sodium hydroxide solution. The mixture is stirred for 15 minutes at 50-60°C and then allowed to stand for 15 minutes. The bottom aqueous solution is drained from the vessel. The organic phase is then subjected to distillation at reduced pressure, typically in the range of 200 mm Hg to 350 mm Hg to distill off TEA to a level at which the weight ratio of TEA:MVN is less than 0.016.

After adding THF to the residual organic phase (distilland or pot residue) to form a mixture in which the THF: DEK weight ratio is approximately 1:1, this mixture is filtered to remove solids

(palladium catalyst residues and oligomeric or dimeric coproduct).

Hydrocarboxylation Reaction Charged to a 1000 gallon reactor are a filtered THF-DEK-MVN solution produced as in the above workup procedure containing 550 kg of MVN, 825 kg of DEK, and 825 kg of THF, followed by 0.3 kg of PdCl₂, 0.64 kg of CuClj, 3.1 kg of NMDP, and 200 kg of 10 wt% HCl. The reactor is then pressured to 100 psig with carbon monoxide and the reactor temperature is adjusted to 70°C. The reactor is then pressured to 360 psig with carbon monoxide and held at this pressure until the uptake of carbon monoxide is completed. The reactor is then cooled and the pressure is vented. The reaction typically takes 4-8 hours to go to completion with > 95 % MVN conversion and a yield of racemic 2-(6-methoxy-2-naphthyl)propionic acid of about 90% . Racemic Product Workup and Recovery

Aqueous sodium hydroxide (25 wt% solution) is added to the reactor to convert the racemic 2-(6-methoxy-2-naphthyl)propionic acid to racemic sodium 2-(6-methoxy-2-naphthyl)propionate, and to neutralize the HCl remaining in the reaction mixture. The THF is then distilled from the reaction mixture at atmospheric pressure. (These neutralization and distillation steps can be reversed if the materials of construction of the reactor overhead are resistant to HCl). The resultant aqueous phase is separated from the organic phase which is composed mainly of DEK and impurities. The residual organics (e.g., DEK) contained in the aqueous phase are distilled from the aqueous racemic sodium 2-(6-methoxy-2-naphthyl)propionate phase at atmospheric pressure. This sodium racemate solution is desirably a 10-35 wt% solution, and if necessary, the concentration is adjusted to fall in this range by removal or addition of water. The aqueous sodium racemate phase is then washed with toluene to remove neutral impurities. Typically one to three toluene washes, preferably at least two, are used. A suitable temperature, typically 60-80°C, is maintained to prevent the racemic sodium 2-(6-methoxy-2-naphthyl)propionate from precipitating. The aqueous solution is then acidified with sulfuric acid in the presence of toluene at about 97 °C. The aqueous phase is cut from the bottom of the reactor and the toluene solution of (+)-2-(6- methoxy-2-naphthyl)propionic acid is washed with water (typically twice) at about 95 °C to remove residual sulfuric acid. Racemic 2-(6-methoxy-2-naphthyl)propionic acid is then crystallized from the toluene solution.

Example 3 illustrates a preferred overall procedure for producing racemic 2-(6-methoxy-2- naphthyl)propionic acid on a large (1000 gallon) scale using recycle solvent (principally DEK and TEA) from a process conducted as in Example 2 above.

EXAMPLE 3 To a 1000 gallon reactor are charged 750 kg of BMN, a mixture of recycle solvent (DEK and TEA mixture containing typically about 1 wt% water) to give approximately 1305 kg of DEK and 368 kg of TEA. Catalyst consisting of 0.3 kg of PdCL, and 3.1 kg of NMDP is charged to the reactor. Fresh water is added (if necessary) to raise the water content of the reaction mixture to approximately 1.6 wt% . The reactor is then pressured to 100 psig with ethylene and the reactor temperature is adjusted to 95 °C. The reactor is then pressured to 425-450 psig with ethylene and held at this pressure until the uptake of ethylene is completed. The reactor is cooled to 60 °C and excess ethylene is vented from the reactor. The reaction typically takes 4-6 hours to go to completion and typically gives a > 95% BMN conversion and a MVN yield of 85-95% .

Aqueous caustic (25% aqueous NaOH solution) is added to the reaction mixture containing MVN to liberate the TEA from the triethylamine hydrobromide salt. The aqueous layer is then separated from the organic layer, and the TEA is then recovered from the MVN, DEK, and TEA mixture by distillation. The distillate composed of DEK, TEA, and water is then recycled for use in the arylation reaction. THF is added to the distillation residue (distilland or pot residue) composed mainly of a MVN/DEK mixture plus some solids to produce a MVN mixture containing THF and DEK in a weight ratio of about 1 : 1 suitable for carboxylation. The resultant mixture is filtered to remove the solids therefrom. Fresh catalyst and HCl are added in proportions corresponding to those of Example 2 and the hydrocarboxylation reaction is carried out as in Example 2. Then the (+)-2-(6-methoxy-2-naphthyl)propionic acid is converted to sodium (±)-2- (6-methoxy-2-naphthyl)propionate by the addition of 25 wt% aqueous sodium hydroxide solution, and the remainder of the racemic product workup and recovery procedure of Example 2 is carried out.

The procedure of Example 2 above can be conducted in the same manner except for the omission of the reaction accelerating amount of water in the arylation reaction. The reaction proceeds, but proceeds more slowly than if the water is present in the arylation reaction. This is illustrated in Example 4 hereof.

EXAMPLE 4

A series of 12 arylation runs was conducted in a 2-liter reactor in which the proportions of the ingredients and the reaction conditions used were, except for some small inconsequential differences, the same from run to run, the only independent variable being water content and the amount thereof. The reaction mixtures were composed of 300 g of BMN, 529-530 g of DEK, 147- 148 g of TEA, 0.112-0.116 g of PdC^, and 1.23-1.26 g of NMDP. Several runs were conducted with no added water, and the remainder had measured quantities of added water. All reactions were performed at 95 °C under ethylene at 420 to 450 psig. The criterion for reaction rate was maximum rate of ethylene consumption during each reaction. Thus the higher this value, the better. The results of these runs as regards reaction rates are summarized in the table.

Table

The inclusion or presence of small amounts of water in the range of 0.5 to 5 percent of the total weight of the arylation reaction mixture as a reaction accelerator in the arylation reaction is in accordance with the subject matter of, and as disclosed in full in, commonly-owned copending application Serial No. 08/780,310, filed January 8, 1997, referred to above.

Experimental work has shown that it is advantageous to carry out the separation of solids from the arylation reaction product after the separation of the free amine and the replenishment of the solvent by addition of THF or like solvent (as in Examples 2 and 3), rather than before such separation and solvent addition. In particular, the filtration time is reduced significantly in this manner.

As noted above, if in the arylation reaction more than one solvent/diluent is used, the amine does not have to boil below all such solvent/diluents. Instead it should boil below at least one of the solvent/diluents that makes up a substantial portion (e.g., at least 20 or 30%) of the total weight of such solvent/diluents. For example, a reaction conducted generally as in Example 2 above using a 1:1 (wt:wt) mixture of acetonitrile (ACN) and diethyl ketone (DEK) as the solvent/diluents, involves a situation in which the triethylamine boils above the ACN, but below the DEK. In such case, different workup procedures can be used. In one such procedure the ACN can be distilled (stripped) from the reaction mixture, and then the aqueous inorganic base solution is added followed by the phase separation and distillation of the triethylamine from the remaining organic phase. Another procedure involves adding the aqueous inorganic base solution, conducting the phase separation, and then distilling off the ACN and the triethylamine, leaving the diethyl ketone solution behind.

EXAMPLE 5 Preparation of 6-Methoxy-2-Vinylnaphthalene

A 20-gallon jacketed stainless steel reactor equipped with a mechanical agitator is charged with 19.45 kg of acetonitrile (ACN) and 12.45 kg of 2-bromo-6-methoxynaphthalene (BMN), and 4.8 g of PdCl₂. The reactor is pressured and vented three times with 50 psig nitrogen. The reactor is then charged with 5.3 kg of ACN and 5.64 kg of triethylamine (TEA). The agitator is set at 158 rpm and the reactor is pressured and vented three times with 80 psig nitrogen. The reactor is then purged for ten minutes with nitrogen. Next a mixture of 48.6 g of neomenthyldiphenylphosphine (NMDP) dissolved in 0.35 kg of TEA is charged to the reactor. The agitator is set to 412 rpm and the reactor is heated with steam on the jacket. The reaction temperature is initially in the range of 91-109°C, while the pressure varies from 412-519 psig. The reaction produces a heat kick, and after 30 minutes the temperature rises to 109°C with 26°C cooling water on the jacket. The total reaction time is 1.75 hours with a BMN conversion of 100%. The reactor is cooled, vented, and the reactor contents are transferred to a 30-gallon glass lined reactor for workup. Workup of 6-Methoxy-2-Vinylnaphthalene The crude 6-methoxy-2-vinylnaphthalene (MVN) solution in the 30-gallon reactor is stripped at 330 mm Hg to remove the ACN. The total strip time is 6.33 hours with a maximum bottoms temperature of about 91 °C. The final overhead temperature is about 68°C. Zero reflux is used for the first 35 minutes of operation. The reflux ratio is then set to five, and 34.95 kg of diethyl ketone (DEK) is added to the reactor contents. The reflux ratio remains at five for the duration of the strip.

After charging 9.25 kg of 25% NaOH to the stripped reaction product in the 30-gallon reactor, the resultant mixture is agitated for 30 minutes. Then the agitator is shut off and the aqueous phase is allowed to settle for 1.75 hours. The mixture is phase cut at 57°C, and the aqueous phase is collected and discarded. The organic phase and rag layer in the reactor are stripped to remove TEA. The strip pressure is 330 mm Hg. The total strip time is 4.9 hours. The column is started up under total reflux for the first 30 minutes of operation. The reflux ratio is then lowered to three for 3.5 hours. The reflux ratio is reduced to two for the remainder of the strip. The final overhead temperature is about 79 °C and the final bottoms temperature is about 86°C.

To the cooled-down stripped mixture in the 30-gallon reactor is added 8 kg of tetrahydrofuran (THF). The resultant MVN solution is filtered through a 10 micron bag filter and a 1 micron cartridge filter. Hydrocarboxylation of 6-Methoxy-2-Vinylnaphthalene

A 20-gallon Hastalloy reactor is purged three times with 80 psig nitrogen, and then 3.8 g of PdCl₂ and 8.8 g of CuCl₂ are charged to the reactor, followed by the MVN solution. The reactor is purged three more times with 80 psig nitrogen and the agitator is set to

118 rpm. After charging 3.6 kg of THF and 3.55 kg of 10% HCl to the reactor, the reactor is again purged three times with 80 psig nitrogen and then nitrogen is bubbled through a dip leg for ten minutes. Next, a mixture of 42.2 g of NMDP and 0.35 kg of THF is charged to the reactor and the agitator is set at 402 rpm. The reactor is pressured and vented three times with 50 psig CO, and then heated to reaction temperature and pressured with CO. The reaction temperature is in the range of 70 to 78 °C, while the pressure varies from 247 to 450 psig. After a total reaction time of 8.5 hours the reactor is cooled and vented, and the contents transferred to a 30- gallon glass-lined reactor for workup. Product Workup The hydrocarboxylation mixture is neutralized with 2.05 kg of 25% NaOH. THF is stripped at atmospheric pressure from the workup reactor contents over 2.5 hours. Water (30.7 kg) is charged 1.4 hours into the strip. The final overhead temperature is about 97 °C and the final bottoms temperature is about 108°C. To the stripped reactor contents is added 7 kg of 25% NaOH, and the mixture is agitated for 30 minutes at 50-60°C. After a 35-minute settling time, the aqueous and organic phases are separated from each other. The aqueous phase is charged back to the workup reactor along with 10 kg of toluene. This mixture is agitated for 15 minutes and allowed to settle for 30 minutes at 55 °C. The phases are again separated. The aqueous phase is charged back to the workup reactor along with 10 kg of toluene, the mixture is stirred for 15 minutes and then allowed to settle. The mixture is then heated to 65 °C and the phases are separated from each other. The aqueous phase is again charged back to the reactor along with 10 kg of toluene. The mixture is stirred for 15 minutes and allowed to settle for 30 minutes at 70°C, and a final phase cut is made. The separated aqueous phase is a clear amber aqueous solution of sodium ( ± )-2-(6-methoxy-2-naphthyl)propionate .

EXAMPLE 6

The procedure of Example 5 is repeated substantially as described with the following principal changes: The initial charge to the first reactor is 21.4 kg of diethyl ketone (DEK), 12.4 kg of BMN, and 4.6 g of PdCl₂. The second charge is 3.2 kg of DEK and 6.34 kg of TEA. The 10-minute nitrogen purge after the addition of the TEA addition is eliminated. The NMDP charge (50.9 kg) is added as a solution in 0.27 kg of DEK. The pressurizing with ethylene is started to 100 psig before beginning the heat up of the reactants. This arylation reaction is conducted at 92-98 °C and 393-429 psig.

The MVN workup involves addition of 10.15 kg of DEK, heating to 75 °C, followed by the caustic wash, a phase cut, a water wash, another phase cut, and the TEA strip with a final overhead temperature of about 79 °C and a maximum bottoms temperature of about 97 °C.

The hydrocarboxylation solvent is a mixture of residual DEK and 8.2 kg of added THF. The other components charged are 3.5 g of PdC^, 7.9 g of CuCl₂, 3.25 kg of 10% HCl, 37.9 g of NMDP in 160 g of DEK. The hydrocarboxylation reaction is performed for 8.7 hours, with temperatures in the range of 74 to 84 °C and pressures in the range of 321 to 476 psig.

The crude (+)-2-(6-methoxy-2-naphthyl)propionic acid is stripped of THF, converted to sodium (±)-2-(6-methoxy-2-naphthyl)propionate and washed three times with 5 kg of toluene to yield an aqueous solution of sodium (±)-2-(6-methoxy-2-naphthyl)propionate.

EXAMPLE 7

Preparation of 6-Methoxy-2-Vinylnaphthalene

A 20-gallon jacketed stainless steel reactor equipped with a mechanical agitator is charged with 12.8 kg of ACN, 12.45 kg of DEK and 12.4 kg of 2-bromo-6-methoxynaρhthalene (BMN), 4.6 g of PdCl₂, and 50.9 g of NMDP. The reactor is pressured and vented three times with 50 psig nitrogen. The reactor is then charged with 6.27 kg of TEA. The agitator is set at 158 rpm and the reactor is pressured and vented with 50 psig nitrogen. The agitator is set to 416 rpm, the reactor is pressured to 100 psig with ethylene and heated with tempered water on the jacket. The reaction temperature ranges from 87 to 98°C, while the pressure varies from 394 to 458 psig. The total reaction time is 3.5 hours with a BMN conversion of 99.6% in two hours. The reactor is cooled, vented, and the reactor contents at 60°C are transferred for workup, to a 30-gallon glass lined reactor equipped with a 6-inch column. The 20-gallon reactor is then charged with 12.5 kg of DEK, which is then heated to 60°C and transferred to the 30-gallon reactor. Workup of 6-Methoxy-2-Vinylnaphthalene The crude 6-methoxy-2-vinylnaphthalene (MVN) solution in the 30-gallon reactor is stripped at 150 mm Hg to remove the ACN. The total strip time is 4 hours with a maximum bottoms temperature of about 73 °C. The final overhead temperature is about 59 °C. Reflux ratios used are 5: 1 for 1.9 hours, 3: 1 for 1.6 hours, and 4:1 for 1.5 hours.

After charging 9.3 kg of 25% NaOH to the stripped reaction product in the 30-gallon reactor, the resultant mixture is agitated for 15 minutes at 35 °C. Then the agitator is shut off and the aqueous phase is allowed to settle for 30 minutes. The mixture is phase cut and the organic phase is washed in the reactor with 1.2 kg of water with stirring for 15 minutes. After allowing a settling period of 30 minutes, another phase cut is made. A TEA strip of the organic phase is conducted at 150 mm Hg. The total strip time is 5.25 hours. The highest overhead temperature is about 59°C and the maximum bottoms temperature is about 91 °C. The reflux ratios were 50: 1 at start up, and when the column stabilized, the reflux ratio was reduced to 5:1 for 2.25 hours and 7: 1 for the final 2.5 hours of the strip. The reaction product is then diluted by addition to the reactor of 12.05 kg of THF and 2.05 kg of DEK. The resulting solution is then filtered through a ten-micron bag filter and a one-micron cartridge filter. Hydrocarboxylation of 6-Methoxy-2-Vinylnaphthalene

The filtered MVN solution is charged to a 20-gallon Hastalloy reactor followed by an additional 4.65 kg of DEK. Then 4.6 g of PdC^ and 10.5 g of CuCl₂ are charged to the reactor. The reactor is purged three times with 50 psig nitrogen, and 4.2 kg of 10% Hcl is charged. The reactor is pressured to 80 psig with nitrogen and vented. A solution of 50.9 g of NMDP in 255 g of DEK is charged to the reactor and the reactor is pressured and vented twice with 50 psig nitrogen with the agitator running only when pressurizing. The agitator speed is set at 399 rpm and the reactor is pressured and vented three times with 50 psig CO, again agitating only during pressurization. The reactor is then pressured to 280 psig with CO and heated to 75 °C. The reaction temperature is kept in the range of 73 to 77°C, while the pressure varies from 339 to 350 psig. After a total reaction time of 6 hours the reactor is cooled and vented, and the contents transferred to a 30-gallon glass-lined reactor for workup. Product Workup

The hydrocarboxylation mixture is neutralized with 2.15 kg of 25% NaOH. THF is stripped from the hydrocarboxylation mixture at atmospheric pressure over 1.2 hours. The final bottoms temperature is 100°C and the final overhead temperature is 92°C. Water (30.7 kg) is charged 1.4 hours into the strip. The final overhead temperature is about 97 °C and the final bottoms temperature is about 108 °C. DEK (4.95 kg) is added to the stripped reactor contents, followed by 14 kg of water and 7.55 kg of 25 % NaOH, and the mixture is agitated for 30 minutes at 70-80°C. After a 30-minute settling time, the aqueous and organic phases are separated from each other. The aqueous phase is charged back to the workup reactor and stripped of DEK with a final bottoms temperature of about 95 °C and a final overhead temperature of about 95 °C. A 2.0 kg water charge is added along with 5.15 kg of toluene. This mixture is agitated for 20 minutes and allowed to settle overnight with 60°C tempered water in the jacket. The phases are then separated. The aqueous phase is washed two more times with toluene (the first time with 5.1 kg, the second time with 4.95 kg) each time followed by a phase separation. The product is recovered as a water solution of sodium (±)-2-(6-methoxy-2-naphthyl)propionate.

EXAMPLE 8

Preparation of 6-Methoxy-2-Vinylnaphthalene

The 20-gallon jacketed stainless steel reactor is charged with a 12.5 kg of ACN, 12.5 kg of methyl isobutyl ketone (MIBK), and 12.45 kg of BMN, 4.6 g of PdQ, and 50.9 g of NMDP. The reactor is pressured and vented three times with 50 psig nitrogen. Then 6.8 kg of TEA is charged. The agitator is set at 160 rpm and the reactor is pressured and vented with 50 psig nitrogen. The agitator is set to 415 rpm, the reactor is pressured to 100 psig with ethylene, and heated with tempered water on the jacket. The reaction temperature ranges from 94 to 100°C, while the pressure varies from 388 to 432 psig. The total reaction time is 2.6 hours, but the reaction reaches about 99% conversion in about 1.8 hours. The reactor is cooled and the ethylene pressure is vented. After standing for about 16 hours with the agitator in operation, the reactor is heated to approximately 60 °C and the reactor contents are transferred to the 30-gallon glass- lined workup reactor. The 20-gallon reactor is charged with 12.4 kg of MIBK, which is then heated to about 60 °C and also transferred to workup reactor. Workup of 6-Methoxy-2-Vinylnaphthalene

The crude MVN solution is stripped at 150 mm Hg to remove the ACN. The total strip time is 3.3 hours with a maximum bottoms temperature of about 76 °C. A reflux ratio of 50 is used to line out the column. After the column stabilizes, the reflux ratio is reduced to five. This reflux ratio is maintained for 45 minutes and then reduced to three for 30 minutes. The reflux ratio is set at two for the next 55 minutes before finally switching to zero reflux for the last 25 minutes. After cooling to 47°C, 9.4 kg of 25% NaOH is charged to the stripped mixture. The temperature drops with the addition of the caustic. The reactor is agitated for 15 minutes and then the agitator is shut off and the aqueous phase is allowed to settle for 30 minutes. The phases are separated, and a 1.05 kg water wash is charged to the organic phase and mixed therewith for 20 minutes. This is allowed to settle for 80 minutes and the aqueous phase is cut from the bottom of the reactor.

The TEA strip pressure is initially 150 mm Hg and is lowered throughout the strip to a final value of 70 mm Hg. The total strip time is 4.25 hours with a maximum bottoms temperature of about 78 °C. The column is started up with a zero reflux ratio for the first 35 minutes of operation. The reflux ratio is then set at five and held there for 25 minutes. The reflux ratio is decreased to two for the final 3.25 hours of the strip. To the stripped product mixture is charged 8.1 kg of THF and the resultant MVN solution is filtered through a ten micron bag filter and a one micron cartridge filter. An additional 4.05 kg of THF is charged to the workup reactor and this is also filtered. Hydrocarboxylation of 6-Methoxy-2-Vinylnaphthalene The MVN solution is transferred to the above hydrocarboxylation reactor. To this are charged 4.3 g of PdCl₂ and 9.8 g of CuCl_? The reactor is purged once with 50 psig nitrogen. The agitator is set to 118 rpm and 3.95 kg of 10% HCl is charged. The reactor is pressured to 80 psig with nitrogen and vented twice (agitating during pressurization, no agitation during the vent). A solution of 47.6 g NMDP in 248 g DEK is charged. The agitator speed is set at 401 rpm and the reactor is pressured and vented three times with 50 psig CO (agitating during pressurization, no agitation during the vent). The reactor is then pressured to 276 psig with CO and heated to 75 °C. The reactor temperature varies from 72 to 80 °C and the pressure range is 334 to 355 psig. The reaction is shutdown after 8.8 hours. Product Workup

The (±)-2-(6-methoxy-2-naphthyl)propionic acid solution is charged to a workup reactor and neutralized with 2.0 kg of 25% NaOH. THF is stripped at atmospheric pressure over 20 minutes. The final bottoms temperature is about 79 °C and the final overhead temperature is about 77°C. The stripped mixture is cooled to 60°C and to this are charged 14.0 kg of water and 8.0 kg of caustic. The mixture is agitated for 30 minutes at 75 °C. The agitator is shut off and the contents of the reactor are allowed to settle for 30 minutes. The phases are separated. The aqueous solution is charged back to the reactor and left agitating for about 16 hours. The aqueous solution is then stripped at atmospheric pressure for 1.5 hours. The aqueous phase in the column is cut back to the reactor. One more strip is done using steam on the jacket. Additional distillate is drained from the column following the strip. The final bottoms temperature for the strip is about 101 °C and the final overhead temperature is about 100 °C. A 5.05 kg charge of toluene is added to stripped product mixture, and the mixture is agitated for 20 minutes at 68 °C then allowed to settle for 30 minutes. The phases are cut to give an amber-orange aqueous solution and a dark- green organic solution. The aqueous solution is washed with 5.0 kg of toluene, giving a reddish- purple clear aqueous solution and a cloudy olive-green organic solution. The third toluene wash (5.05 kg, 71 °C) produces a clear purple aqueous solution and a cloudy yellow organic solution.

EXAMPLE 9 The procedure of Example 8 is repeated substantially as described with the following principal changes:

The initial charge to the first reactor is 12.4 kg of ACN, 12.65 kg of DEK, 12.45 kg of

BMN made as in Example 8 hereof, 4.6 g of PdClj, and 51 g of NMDP. The second charge is

6.17 kg TEA. This 2.5-hour arylation reaction is conducted at 88-99°C and 318-458 psig. The ACN distillation in the MVN workup is at 150 mm Hg and involves a total strip time of 5.25 hours with a maximum bottoms temperature of 71.8 °C. The TEA strip pressure is initially 150 mm Hg and is lowered throughout the 4-hour strip to a final value of 90 mm Hg.

The hydrocarboxylation solvent is a mixture of residual DEK and about 12 kg of added THF. The other components charged are 4.1 g of PdC^, 9.2 g of CuCl₂, 3.65 kg of 10% HCl,

44.7 g of NMDP in 222 g of DEK. The hydrocarboxylation reaction runs for 6.6 hours, with temperatures in the range of 74 to 77 °C and pressures in the range of 333 to 358 psig.

As in Example 8, the crude (±)-2-(6-methoxy-2-naphthyl)propionic acid is converted to sodium (+)-2-(6-methoxy-2-naphthyl)propionate, stripped of THF, and washed three times, each time with 5 kg of toluene, to yield an aqueous solution of sodium (±)-2-(6-methoxy-2- naphthyl)propionate.

EXAMPLE 10

The procedure of Example 8 is repeated substantially as described with the following principal changes:

The initial charge to the first reactor is 12.55 kg of ACN, 12.5 kg of MIBK, 12.5 kg of BMN made as in Example 8 hereof, 4.6 g of PdC^, and 51 g of NMDP. The second charge is 6.19 kg TEA. This 2.7-hour arylation reaction is conducted at 88-97 °C and 371-441 psig.

The ACN distillation in the MVN workup is at 150 mm Hg and involves a total strip time of 3.8 hours with a maximum bottoms temperature of 71 °C. The TEA strip pressure is initially 150 mm Hg and is lowered throughout the 5.3-hour strip to a final value of 70 mm Hg. The hydrocarboxylation solvent is a mixture of residual MIBK and about 12 kg of added

THF. The other components charged are 4.6 g of PdClj, 9.5 g of CuCl₂, 3.85 kg of 10% HCl, 47 g of NMDP in 226 g of DEK. The hydrocarboxylation reaction is conducted for 7 hours, with temperatures in the range of 72 to 77°C and pressures in the range of 333 to 357 psig.

As in Example 8, the crude (±)-2-(6-methoxy-2-naphthyl)propionic acid is converted to sodium (+)-2-(6-methoxy-2-naphthyl)propionate, stripped of THF, and washed three times, each time with 5 kg of toluene, to yield an aqueous solution of sodium (±)-2-(6-methoxy-2- naphthyl)propionate .

Example 11 illustrates a preferred procedure for producing BMN starting material.

EXAMPLE 11 Bromination of 2-Naphthol

2-Naphthol (144.8 g, 1.00 mol), EDC (537 g), and water (162 g) are charged to a 2-L reactor equipped with a reflux condenser, mechanical stirrer and peristaltic pump addition system. The reactor is heated to about 55 °C until most of the β-naphthol is dissolved. Bromine (336.9g, 2.11 mol) is then added (sub-surface) via a pump at such a rate so as to maintain the reaction temperature at 60°C. After the bromine addition, the reaction temperature is maintained at 60°C for 1.5 hour. The reaction is then cooled slightly and the lower phase (aq. HBr) siphoned off. The remaining EDC solution (841 g) is transferred out of the reactor and analyzed by GC. In a run conducted in this manner, the analysis showed 0.4% 2-naphthol, 92.6% l,6-dibromo-2- naphthol (DBN), and 4.9% of other isomers. Hydrodebromination of 1 ,6-Dibromo-2-Naphthol

A solution of DBN (271 g, 0.9 mol) in ethylene dichloride (EDC) (551 g), obtained from the bromination reaction, is charged in a 1000 mL Hastalloy B autoclave. Tungsten carbide (82 g, 30 wt%) and tetrabutylammonium bromide (0.2 g, 0.1 wt%) are added and the reactor is sealed. The reactor is purged with hydrogen (50 psig) and vented three times and then pressured with hydrogen and heated to 90 °C. A constant purge of hydrogen is maintained in such a rate that the pressure remains in the 120-125 psig range. Analysis of a reaction mixture produced after 5.5 hours in this manner showed 90% 6-bromo-2-naphthol, 2% DBN, and 2% 2-naphthol. The reactor is cooled to room temperature, vented to scrubbers, and the catalyst is permitted to settle. The EDC solution (747 g in a reaction conducted in this manner) is removed through the dip tube. Methylation of 6-Bromo-2-Naphthol with MeCl

The EDC solution formed as above is transferred to a 1.4-liter (three pints) Chemco glass reactor with stainless steel head. It is first neutralized with dilute acid and then concentrated by distillation. Water (50 mL) is added to azeotropically remove traces of EDC left in the residue. Isopropyl alcohol (242 g) and sodium hydroxide (44 g, 1.1 mol; 88 g of 50% solution) are charged into the reactor. The reactor is sealed, purged with nitrogen, and heated to 70°C. Methyl chloride (MeCl) (66 g, 1.3 mol) is charged over a period of one hour (40-50 psig). After stirring at 80°C for another hour, isopropyl alcohol is removed by distillation. The residue is heated to melted condition (90-95 °C) and then it is washed with water (400 g). Water is removed and the residue is distilled under vacuum (1 mm Hg). After removing small amounts of volatile materials, BMN is distilled at 160-165 °C as a white solid (169 g was formed in an operation conducted in this manner). Isopropyl alcohol (490 g) is added and the solution was heated to reflux and then slowly cooled down to about 10°C. Solid BMN is removed and washed with cold (0°C) isopropyl alcohol (180 g) and then dried under vacuum at 70-75 °C. Analysis of the white crystalline product formed in this manner showed 99.7 wt% BMN. Example 11 involves procedures and subject matter described in full in commonly-owned copending application Serial No. 08/780,309, filed January 8, 1997.

Example 12 illustrates the dilute acid wash workup procedure for separating the arylation product and the secondary or tertiary amine use as the hydrogen halide acceptor in the arylation reaction.

EXAMPLE 12

To a 5 gallon stainless steel magnetically stirred autoclave are added DEK (3296 g), BMN (1502 g, 6.34 mol), NMDP (6.170 g, 19.0 mmol), PdC^ (0.574 g, 3.2 mmol), and TEA (684 g,

6.76 mol). The reactor is purged with nitrogen and then filled with ethylene and heated to 95 °C. The reaction mixture is stirred for 4.5 hours at 95 °C under ethylene pressure (609 to 640 psig) and then cooled to 60 °C and slowly vented. The reactor is emptied yielding a mixture of yellow solids and yellow liquid. A 5000 g portion of this reaction mixture is poured into a 12 L flask fitted with a mechanical stirrer and a bottom outlet. Water (695 g) and 10 wt% aqueous HCl (209 g) are added to the reaction mixture, and the mixture is stirred and warmed to 65 °C, and then allowed to stand and settle. The aqueous phase is removed from the yellow orgamc phase. The organic phase is washed a second time with a mixture of water (250 g) and 10 wt% aqueous HCl at 64 °C, and the aqueous phase is separated from the washed organic phase which is composed mainly of MVN and DEK. The washed organic phase is hydrocarboxylated as described above, preferably after stripping off some of the DEK and replacing it with THF. The aqueous phases contain triethylamine hydrochloride, from which TEA can be recovered by addition of a strong base such as aqueous NaOH, followed by a phase separation.

It is to be understood that the reactants and components referred to by chemical name or formula anywhere in the specification or claims hereof, whether referred to in the singular or plural, are identified as they exist prior to coming into contact with another substance referred to by chemical name or chemical type (e.g., another reactant, or a solvent). It matters not what preliminary chemical changes, transformations and/or reactions, if any, take place in the resulting mixture or solution or reaction medium as such changes, transformations and/or reactions are the natural result of bringing the specified reactants and/or components together under the conditions called for pursuant to this disclosure. Thus the reactants and components are identified as ingredients to be brought together in connection with performing a desired chemical reaction or in forming a mixture to be used in conducting a desired reaction. Accordingly, even though the claims hereinafter may refer to substances, components and/or ingredients in the present tense ("comprises", or "is"), the reference is to the substance, component or ingredient as it existed at the time just before it was first contacted, blended or mixed with one or more other substances, components and/or ingredients in accordance with the present disclosure. Without limiting the generality of the foregoing, as an illustrative example, where a claim specifies that a catalyst is a palladium compound in combination with a tertiary phosphine ligand, this phraseology refers to the makeup of the individual substances before they are combined and/or mixed separately or concurrently with one or more other materials, and in addition, at the time the catalyst is actually performing its catalytic function it need not have its original makeup — instead whatever transformations, if any, that occur in situ as the catalytic reaction is conducted is what the claim is intended to cover. Thus the fact that a substance, component or ingredient may have lost its original identity through a chemical reaction or transformation during the course of contacting, blending or mixing operations, if conducted in accordance with this disclosure and with the application of common sense and the ordinary skill of a chemist, is thus wholly immaterial for an accurate understanding and appreciation of the true meaning and substance of this disclosure and the claims thereof.

In addition, reference in this specification or in the claims hereof to catalyst residue(s) means whatever composition(s) or form(s) the fresh and/or recycled catalyst acquires or becomes in the course of conducting the reaction specified. Without in any way limiting the generality of the foregoing, such residue(s) may contain, comprise or include (i) platinum-containing component(s), or (ii) phosphorus-containing com-ponent(s), or (iii) platinum- and phosphorus- containing component(s), or any combination of any two, or all three of (i), (ii) and (iii).

Claims

1. A process which comprises:

A) reacting arylolefin with carbon monoxide and water in the presence of palladium catalyst formed when fresh at least from (1) palladium or palladium compound and (2) organophosphine ligand, to form a reaction mass comprising (a) arylcarboxylic acid, and (b) one or more residual catalyst species;

B) mixing together at least a portion of such reaction mass and aqueous inorganic base to form (i) an aqueous phase with water-soluble salt of the arylcarboxylic acid dissolved therein, and (ii) an organic phase having at least a portion of the residual catalyst species dissolved therein; C) separating these phases, and recycling at least a portion of the separated phase (ii) to

A) for use in performing additional reaction pursuant to A).

2. A process according to Claim 1 wherein said palladium catalyst in A) comprises residual catalyst species contained in the portion of separated phase (ii) recycled to A) pursuant to C).

3. A process according to Claim 1 wherein said palladium catalyst in A) comprises I) fresh catalyst formed at least from (1) palladium or palladium compound and (2) organophosphine ligand, and II) residual catalyst species contained in the portion of separated phase (ii) recycled to A) pursuant to C).

4. A process according to Claim 1 wherein the reaction in A) is conducted in the additional presence of aqueous hydrochloric acid.

5. A process according to Claim 4 wherein said palladium catalyst in A) comprises residual catalyst species contained in the portion of separated phase (ii) recycled to A) pursuant to C), said residual catalyst species having been originally formed by addition of (1) at least one palladium compound and (2) tertiary phosphine to the mixture subjected to reaction in A).

6. A process according to Claim 4 wherein said palladium catalyst in A) comprises

I) fresh catalyst formed at least from (1) at least one palladium compound and (2) tertiary phosphine, and

II) residual catalyst species contained in the portion of separated phase (ii) recycled to A) pursuant to C).

7. A process according to Claim 4 wherein the reaction in A) is conducted in the additional presence of at least one organic solvent/diluent.

8. A process according to Claim 7 wherein said palladium catalyst in A) comprises residual catalyst species contained in the portion of separated phase (ii) recycled to A) pursuant to C), said residual catalyst species having been originally formed by addition of (1) at least one palladium(II) salt and (2) trihydrocarbylphosphine to the mixture subjected to reaction in A).

9. A process according to Claim 7 wherein said palladium catalyst in A) comprises

I) fresh catalyst formed at least from (1) at least one palladium(II) salt and (2) trihydrocarbyl phosphine, and

10. A process according to Claim 4 wherein the reaction in A) is conducted in the additional presence of at least one ether that boils at a lower temperature than said arylcarboxylic acid, and at least one ketone that boils at a temperature sufficiently above said ether to enable said ether to be stripped from said reaction mass, and wherein at least a portion of said ether is stripped from said reaction mass after completing the reaction in A).

11. A process according to Claim 10 wherein said palladium catalyst in A) comprises residual catalyst species contained in the portion of separated phase (ii) recycled to A) pursuant to C), said residual catalyst species having been originally formed by addition to the mixture subjected to reaction in A) of (1) at least one palladium(II) halide or carboxylate salt and (2) trihydrocarbylphosphine having at least two aryl groups in the molecule.

12. A process according to Claim 10 wherein said palladium catalyst in A) comprises

I) fresh catalyst formed by addition to the mixture subjected to reaction in A) of (1) at least one palladium(II) halide or carboxylate salt and (2) trihydrocarbyl phosphine having at least two aryl groups in the molecule, and

13. A process according to Claim 10 wherein said ether consists essentially of tetrahydrofuran, wherein said ketone consists essentially of diethylketone, and wherein at least a portion of the tetrahydrofuran is stripped from said reaction mass before conducting B).

14. A process according to Claim 13 wherein said palladium catalyst in A) comprises residual catalyst species contained in the portion of separated phase (ii) recycled to A) pursuant to C), said residual catalyst species having been originally formed by addition to the mixture subjected to reaction in A) of (1) palladium(II) chloride and (2) neomenthyldiphenylphosphine.

15. A process according to Claim 13 wherein said palladium catalyst in A) comprises

I) fresh catalyst formed by addition to the mixture subjected to reaction in A) of (1) palladium(II) chloride and (2) neomenthyldiphenylphosphine, and

16. A process according to Claim 1 wherein the reaction in A) is conducted in a liquid medium comprising polar organic solvent, water, and HCl; wherein the phases formed in B) include (iii) a solids phase containing palladium and/or one or more palladium compounds in whatever chemical composition it exists or they exist while in said solids phase; and wherein in C) said aqueous phase, said organic phase, and said solids phase are separated from each other.

17. A process according to Claim 16 wherein the separated solids-free organic phase being recycled to A) additionally contains at least one organophosphine ligand in whatever chemical composition it exists while dissolved in said separated solids-free organic phase.

18. A process according to Claim 17 wherein the organophosphine ligand is trihydrocarbylphosphine in whatever chemical composition(s) it exists while in the reaction mass of A) and in whatever chemical composition(s) it exists while dissolved in the separated solids-free organic phase being recycled to A).

19. A process according to Claim 17 wherein said organophosphine ligand is neomenthyldiphenylphosphine in whatever chemical composition(s) it exists while in the reaction mass of A) and in whatever chemical compositions) it exists while dissolved in the separated solids-free organic phase being recycled to A).

20. A process according to Claim 16 wherein palladium values are recovered from at least a portion of the solids phase separated in C).

21. A process according to Claim 16 wherein a portion of the polar organic solvent is removed from the reaction mass of A) to form a more concentrated reaction product mixture, and wherein such more concentrated reaction product mixture is said portion of reaction mass that is mixed with said aqueous inorganic base in B).

22. A process according to Claim 21 further comprising recovering at least a portion of said solids phase and converting recovered solids phase into fresh palladium-containing catalyst for use in conducting additional reaction of arylolefin with carbon monoxide pursuant to A).

23. A process according to Claim 21 wherein said catalyst when fresh is formed at least from (1) palladium(II) halide or carboxylate and (2) trihydrocarbylphosphine ligand.

24. A process according to Claim 1 which further comprises producing the arylolefin used in A) by conducting a palladium-catalyzed vinylation of aryl halide with olefin in a reaction mixture formed at least from aryl halide, polar organic solvent, hydrogen halide acceptor, and palladium vinylation catalyst to produce a reaction product mixture comprising as constituents at least arylolefin, polar organic solvent, product of hydrogen halide and hydrogen halide acceptor, and catalyst residue(s) in whatever chemical composition and form said respective constituents exist in said reaction product mixture.

25. A process according to Claim 16 which further comprises

I) producing the arylolefin used in A) by conducting a palladium-catalyzed vinylation of aryl halide with olefin in a reaction mixture formed at least from aryl halide, polar organic solvent, hydrogen halide acceptor, and palladium vinylation catalyst to produce a reaction product mixture comprising as constituents at least arylolefin, polar organic solvent, product of hydrogen halide and hydrogen halide acceptor, and catalyst residue(s) in whatever chemical composition and form said respective constituents exist in said reaction product mixture; and

II) recycling to A) or to said palladium-catalyzed vinylation of aryl halide at least a portion of the separated organic phase containing dissolved catalyst residue(s) to serve as (i) a portion of the reaction mixture for reaction between arylolefin and carbon monoxide pursuant to A), or (ii) a portion of the reaction mixture for said palladium-catalyzed vinylation of aryl halide, as the case may be, or alternatively, recycling to A) and to said palladium-catalyzed vinylation of aryl halide separate portions of the separated organic phase containing dissolved catalyst residue(s) to serve respectively as (i) a portion of the reaction mixture for reaction between arylolefin and carbon monoxide pursuant to A), and (ii) a portion of the reaction mixture for said palladium-catalyzed vinylation of aryl halide.

26. A process according to Claim 25 further comprising recovering at least a portion of said solids phase and converting recovered solids phase into fresh palladium-containing catalyst for use in conducting (i) reaction between arylolefin and carbon monoxide pursuant to A), and/or (ii) said palladium-catalyzed vinylation of aryl halide.

27. A process according to Claim 25 wherein said vinylation catalyst when fresh is formed at least from (1) palladium or palladium compound and (2) organophosphine ligand.

28. A process according to Claim 25 wherein said vinylation catalyst when fresh is formed at least from (1) palladium(II) halide or carboxylate and (2) trihydrocarbyl-phosphine ligand.

29. A process according to Claim 25 wherein the palladium catalyst in A) when fresh is formed at least from (1) palladium(II) halide or carboxylate and (2) trihydrocarbyl-phosphine ligand.

30. A process according to Claim 25 wherein said vinylation catalyst when fresh is formed at least from (1) palladium(II) halide or carboxylate and (2) trihydrocarbyl-phosphine ligand, and wherein the palladium catalyst in A) when fresh is formed at least from (1) palladium(II) halide or carboxylate and (2) trihydrocarbylphosphine ligand.

31. A process according to Claim 30 wherein the trihydrocarbylphosphine ligand that forms said vinylation catalyst when fresh is neomenthyldiphenylphosphine, and wherein the trihydrocarbylphosphine ligand that forms the palladium catalyst in A) when fresh is neomenthyldiphenylphosphine.