JP2001519409A - Recovery and recycling of catalyst components used in palladium catalyzed production of aryl carboxylic acids - Google Patents

Abstract

  (57) [Summary] Aryl carboxylic acids, especially polycyclic aryl carboxylic acids, are separated from the remaining catalyst components by use of a phase separation step. This avoids the need to use vacuum distillation with its attendant high investment and operating costs. Also, the phase separation step provides an organic soluble catalyst residue that is active for reuse via recirculation without the need for catalyst regeneration. Thus, the aryl olefin is reacted with carbon monoxide and water in the presence of a palladium catalyst and an organic phosphine ligand to form a reaction mass comprising (a) an aryl carboxylic acid and (b) the remaining catalytic species. . The reaction mass is treated with an aqueous inorganic base to form (i) an aqueous phase containing a dissolved water-soluble salt of an aryl carboxylic acid and (ii) an organic phase containing dissolved residual catalyst species. The phases are separated and at least a portion of the separated phase (ii) is recycled for use in performing additional reactions. Often, in addition to phases (i) and (ii), there are solid phases containing a portion of the palladium catalytic value present, and preferably these solid phases are recovered (eg, by filtration) and recycled for recycling. If not sufficiently catalytically active, at least a portion is converted to an active palladium catalyst component for use in subsequent reactions. The phase separation thus allows the separation of the catalyst residue in the form of an organic solution and as a solid, while concomitantly isolating the desired product in the form of an aqueous solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

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

[0002] Vinyltoluene has been reported as the product of a homogeneous palladium-catalyzed coupling of ethylene with bromotoluene. This reaction is carried out in a two-phase solvent system composed of N, N-dimethylformamide and water. Devries (R.
A. DeVries) et al., Organometallics, 13, 2405 (
1994).

[0003] US Pat. No. 5,136,069 to RA DeVries et al.
And 5,243,068 disclose (a) a homogeneous zero-valent palladium catalyst complex, (b)
) A hydrolytically stable, vinylically unsaturated precursor in the presence of an inorganic hydrogen halide acceptor and (c) a diluent, either aqueous or an aqueous solution containing up to 95% by volume of an organic solvent. The preparation of vinylically unsaturated compounds by the reaction of a halogenated organic compound with a base compound is described.

[0004] The arylation of propylene, ethylene, styrene and methyl acrylate with iodobenzene has been found to be catalyzed by metal palladium in methanol to give methyl styrene, styrene, t-stilbene and methyl cinnamate, respectively. Was. Their yield and selectivity were significantly increased by the addition of excess potassium acetate as an acceptor of hydroiodic acid formed. Mori et al., Bull. Chem. Soc. , Japan, 46, 1505 (1973).

Various styrene derivatives and 3-vinylpyridine have been produced 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 (1
978)).

[0006] J. Chem Soc. Chem. Comm. , 1983, 1270-127.
Disclose that alkenes can react with carbon monoxide, water, hydrochloric acid and mixtures of palladium and copper to produce hydrocarboxylated branched chain carboxylic acids. Oxygen is needed to accomplish the reaction.

A method for producing a branched-chain ibuprofen carboxylate is disclosed in a Japanese patent application (publication).
No. 59-10545 (Mitsubishi Yuka, published January 1984), which describes:
It 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 such as cumyl hydroperoxide.

[0008] A process for preparing aryl-substituted aliphatic carboxylic acids or their alkyl esters is disclosed in US Pat. No. 5,315,026. The 1-aryl substituted olefin is reacted with carbon monoxide in the presence of water or alcohol at a temperature between 25C and 200C. Mixtures useful as catalysts are palladium and copper compounds with at least one acid-stable ligand. Ligands that can be used include monodentate or polydentate electron donors, such as those containing the 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; benzonitrile and n-propionitrile Lower ligands containing π electrons such as allyl compounds or 1,5-cyclooctadiene; piperidine, piperazine, trichlorostannate (II) and acetylacetonate.

US Pat. No. 5,536,870 discloses a process for preparing substituted olefins by palladium-catalyzed coupling of vinyl or substituted vinyl compounds with organic halides, and also carboxylic acids and esters from such substituted olefins Is also described. The substituted olefin compounds can be prepared by reacting an organic halide with vinyl or vinyl in the presence of a catalytically effective amount of palladium or a salt of palladium having a valency of 1 or 2 and a tertiary phosphine ligand such as neomenthyldiphenylphosphine. It is formed by reacting with a substituted vinyl compound. This reaction is performed 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 carboxylic acid of such substituted olefins by carbonylation with carbon monoxide using the catalyst system and reaction conditions described in US Pat. No. 5,536,870. Or subsequent conversion to a derivative thereof such as a salt or ester (eg, a profen compound).

[0010] Commonly owned co-pending application Ser. No. 08/78, filed Jan. 8, 1997.
No. 0,308 discloses, inter alia, (a) (1) boiling below the boiling temperature of the solvent / diluent if only one solvent / diluent is used, or (2) one or more solvents. If a solvent / diluent is used, it will boil below the boiling temperature of at least one (but not necessarily all) of the polar solvents / diluents used in forming the medium, (i.
) Palladium olefin catalyzed with aryl halides in a liquid medium formed from one or more liquid polar organic solvents / diluents and (ii) one or more secondary or tertiary amines To perform the arylation
Forming a reaction mixture comprising an olefinically substituted aromatic compound, an amine hydrohalide and one or more polar organic solvents; (b
(I) combining a concentrated aqueous solution of an inorganic base having a base strength greater than that of the secondary or tertiary amine (s) with at least a portion of the reaction mixture from (ii) Mixing converts the amine hydrohalide therein to free amine and alkali metal halide and (i) an aqueous phase containing dissolved alkali metal halide and (ii) olefinically substituted Forming an organic phase comprising an aromatic compound, one or more polar organic solvents and a free amine; (c) separating the phases from one another; (d) olefins contained in the remaining liquid phase Essentially all of the amine is distilled off from the organic phase under low temperature and pressure conditions that inhibit the thermal oligomerization of the partially substituted aromatic compound, To form a distilland composed of olefinically substituted aromatics and one or more polar organic solvents; and (e) distilled from (d) Performing palladium-catalyzed carboxylation of at least a portion of the olefinically substituted aromatic compound with carbon monoxide and water and / or an alcohol in a liquid medium comprising at least a portion of the substance. One method is described.

[0011] Commonly owned co-pending application Ser. No. 08/78, filed Jan. 8, 1997.
No. 0,310 discloses, inter alia, that the aryl olefinic compound comprises (a) a secondary or tertiary amine as a hydrogen halide acceptor (b) (i) Pd or Pd
d (0) compounds and / or Pd (I) or Pd (II) salts and (
ii) in the presence of a catalyst system formed from a tertiary phosphine ligand and (c) a polar liquid reaction medium containing water in a reaction promoting amount ranging from 0.5 to 5 weight percent of the total weight of the reaction mixture. Describes a method produced by reacting an aryl halide with an olefin compound. The aryl olefin compound is reacted in a reaction medium which is amine-free and contains water and a Pd catalyst system such as the one above (in which the copper component can be included and preferably includes an ether such as tetrahydrofuran). Can be converted to aryl carboxylic acids by hydrocarboxylation with CO.

[0012] Palladium catalysts and tertiary phosphine ligands, which are highly effective catalyst components in the production of aryl carboxylic acids such as profen type drugs, are extremely expensive. While US Pat. No. 5,055,611 describes an effective method for recovering and regenerating the carbonylation catalyst used in the production of ibuprofen, this method employs vacuum distillation to separate ibuprofen from carbonylation residues. Need. Vacuum distillation is an expensive and capital intensive operation when performed on a plant scale. In addition, there are practical limitations and economic constraints on materials that can be separated and recovered by vacuum distillation. In particular, polycyclics such as racemic 2- (6-methoxy-2-naphthyl) propionic acid, α-dl-2- (3-phenoxyphenyl) propionic acid; and 2- (3-benzoylphenyl) propionic acid Aryl carboxylic acids have a significantly higher boiling point than ibuprofen. Thus, separation of such materials from the catalyst residues would require special equipment and operating conditions where possible by vacuum distillation, such as high vacuum and wiped film evaporators. Also, under the conditions required for such operations, it is possible that some product and / or catalyst component loss may be encountered.

[0013] Therefore, there is no need for vacuum distillation with its attendant high investment and operating costs, and such residues can be reused via recycling without having to regenerate the active, organic soluble catalyst residues. There is a need for an efficient method of separating aryl carboxylic acids, especially polycyclic aryl carboxylic acids, from the expensive residual catalyst components used to provide them. The present invention makes it possible to fulfill this need effectively.

SUMMARY OF THE INVENTION In one aspect, A) an aryl olefin is reacted with carbon monoxide and water in the presence of a palladium catalyst formed at least from (1) palladium or a palladium compound and (2) an organic phosphine ligand. Reacting with (a) an arylcarboxylic acid and (b) a reaction mass comprising one or more residual catalyst species; B) at least a portion of such a reaction mass and aqueous Mix the inorganic bases together (
i) an aqueous phase comprising a water-soluble salt of an arylcarboxylic acid dissolved therein; and (ii)
C) forming an organic phase having at least a portion of the residual catalyst species dissolved therein; C) separating these phases, and replacing at least a portion of the separated phase (ii) with A) according to A). Recirculating to A) for use in carrying out the reaction. Often, in B) of this embodiment, phase (i)
In addition to (ii) and (ii), there is a solid phase containing a portion of the palladium catalytic value. Preferably, such a solid phase is recovered (eg, by filtration) and, if not sufficiently catalytically active for recycling, at least a portion thereof is A
) Is converted to an active palladium catalyst component for use in subsequent reactions.

[0015] Another aspect of the present invention is to provide: A) the presence of an aryl halide with a hydrogen halide acceptor and a palladium catalyst formed at least from (1) palladium or a palladium compound and (2) an organic phosphine ligand. Reacting with a vinyl olefin below to form a reaction mass containing the aryl olefin; B) converting at least a portion of the so formed aryl olefin to (1) palladium or a palladium compound and (2) an organic phosphine coordination. Reaction with carbon monoxide and water in the presence of a palladium catalyst at least formed from
a) forming a reaction mass comprising the arylcarboxylic acid and (b) one or more residual catalytic species; C) mixing at least a portion of the reaction mass of B) and the aqueous base together ( i) an aqueous phase comprising a water-soluble metal salt of an aryl carboxylic acid dissolved therein; and (ii)
Forming an organic phase having at least a portion of the residual catalyst species dissolved therein; D) separating these phases and adding at least a portion of the separated phase (ii) according to A) Recycling to A) for use in carrying out the reaction and / or B) for use in carrying out an additional reaction according to B). Also in this embodiment, in C), there is often a solid phase which, in addition to phases (a) and (b), contains a portion of the palladium catalytic value.
In such cases, the solid phase may be recovered (as by filtration) and, if it is not sufficiently catalytically active for recycle, at least a portion thereof may be A
) And / or conversion to active palladium catalyst components for use in subsequent reactions following B).

The active fresh catalytic species is preferably formed in situ by the addition of the aforementioned individual components, namely palladium or a palladium compound and an organophosphine ligand, to the first reaction mixture. . However, the catalyst can be preformed externally to the reaction mixture and can be charged to the reactor as a preformed catalyst composition.

In the practice of the present invention, it has been found that the separation between the aryl carboxylic acid and the remaining catalytic species involves phase separation (eg, phase cut or decantation) and does not require vacuum distillation. Will be. In addition, it is organic soluble, catalytically active and highly effective when a significant portion of the catalyst residue is used as catalyst recycle.

[0018] These and other aspects and features of the present invention will become even more apparent from the following description and appended claims.

Further Detailed Description Reaction of Aryl Olefin with Carbon Monoxide and Water This reaction is a palladium catalyzed hydrocarboxylation reaction in which the aryl olefin is converted to an aryl carboxylic acid. Aryl olefins typically have the formula

[0020]

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Wherein Ar is aryl, functionally-substituted
substituted) aryl, heteroaryl, heteroaryl substituted with a functional group,
Aralkyl (especially benzyl) or aralkyl substituted with a functional group (particularly benzyl substituted with a functional group), and R ¹ , R ² and R ³ are the same or different and are a hydrogen atom, a hydrocarbyl group, It is selected from a hydrocarbyl group substituted with a functional group and a halogen atom. Preferably, Ar is aryl or aryl substituted with a functional group, and R ¹ , R ² and R ³ are the same or different and are selected from hydrogen atoms and aliphatic hydrocarbyl groups. More preferably, Ar is aryl or aryl substituted with a functional group, and R ¹ , R ² and R ³ are hydrogen atoms. Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl and biphenylyl, all of which may be one or more such as alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl. The above hydrocarbyl substituents, and similar hydrocarbyl substituents attached to an aromatic ring by a non-aromatic carbon atom, can be substituted on the ring. An aryl group substituted with a functional group is an aryl group containing at least one functional group attached to an aromatic ring or hydrocarbyl substituent, which in turn is attached to the aromatic ring. Examples of such functional substituents are
Includes hydroxyl groups, alkoxy groups, cycloalkoxy groups, aryloxy groups, halogen atoms, mono or polyhaloalkyl groups, mono or polyhalocycloalkyl groups, mono or polyhaloaryl groups, and similar functional groups. Critical (c
Although not critical, aryl olefins can typically contain up to about 30 carbon atoms in the molecule. Isobutylphenyl, methoxynaphthyl, phenoxyphenyl, fluorobiphenylyl and benzoylphenyl are preferred groups, designated Ar in formula (I).

Alkoxy vinyl naphthalene wherein the alkoxy group has up to about 4 carbon atoms, such as 6-methoxy-2-vinyl naphthalene; vinyl benzophenone, such as 3-vinyl benzophenone; 2-fluoro-4-vinyl biphenyl ( Or 2
Fluorovinylbiphenyl, such as -fluoro-4-phenylstyrene);
Vinyl diphenyl oxides, such as vinyl diphenyl oxide (or 3-phenoxystyrene); and alkyl styrenes, such as 4-isobutyl styrene, where the alkyl group has up to about 6 carbon atoms are particularly preferred aryl olefins. Similar compounds described above wherein the vinyl group is substituted 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 aryl olefin reactants.

The aryl carboxylic acid formed in this reaction is typically of the formula

[0024]

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Wherein Ar, R ¹ , R ² and R ³ are as defined above. The present invention includes the formation of any racemic and individual optical isomers of the compounds of formula (II) having a chiral carbon atom. For example, if 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.

Typically, palladium catalyzed hydrocarboxylation reactions are carried out at 25 ° C. and 200 ° C.
C. at one or more temperatures, preferably in the range from 25.degree. To 120.degree. C., and most preferably in the range from 25.degree. At any temperature, at least a portion of the compound of formula (I) must be converted in this reaction to a 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 filled). Any higher carbon monoxide can be used up to the pressure limit of the reactor. Pressures up to about 3000 psig are convenient in the method. More preferred is a pressure of 0 to 3000 psig at the reaction temperature, and most preferred is a pressure of 0 to 1000 psig. It should be noted that the presence of oxygen is undesirable in hydrocarboxylation reactions. Therefore, 10
An atmosphere of 0% carbon monoxide is most preferred to carry out this reaction. A variety of inert gases (nitrogen and argon), however, can be incorporated into the reaction mass, but the only criterion is slowed to the point that this method requires an exceptionally long period of time to complete the reaction It should not be.

At least about 1 mole of water per mole of aryl olefin should be used, and in the case of 6-methoxy-2-vinylnaphthalene (MVN) at least about 4 moles per mole of aryl olefin. Molar water is typically used. It is worth noting that excess water can inhibit or even kill the reaction when using MVN. In hydrocarboxylation reactions with other compounds of formula (I), excess water can sometimes be used. In these cases, it is probably pragmatic (pra
(e.g. reaction vessel size and reaction kinetics)
Although there can be no real upper limit for the amount of water except for (kinetics)), up to about 100 moles, and preferably up to about 50 moles, per mole of compound of formula (I) Amounts can be considered for use in the method, and water in an amount of from 2 to 24 moles per mole of aryl olefin compound is more preferred.

If desired, any alcohol that produces an ester of the carboxylic acid can be used in place of or with water in the performance of this process step. However, this is clearly less preferred because the resulting ester must be saponified by the aqueous base used in the subsequent process step, and as a result another component, the free alcohol, is included in the reaction mass. Absent.

In some cases, the hydrocarboxylation reaction can be initiated under neutral conditions, ie, without an acid such as HCl being added. However, at least in the case of hydrocarboxylation of MVN, the inclusion of aqueous HCl in the reaction mixture may be important if it is hardly essential for most efficient operations. Thus, in one preferred embodiment of the present invention, the hydrocarboxylation reaction may preferably have a concentration of, for example, up to about 25 wt%, but preferably ranges from 5 to 15 wt%, and more preferably ranges from 7 to 15 wt%. Starting from the presence of halide ions, which are best provided by the use of aqueous acids, especially halogen acids, which can have a concentration of It is particularly preferred to use approximately 10 wt% aqueous HCl. Dilute aqueous HCl also provides water to effect hydrocarboxylation. Gaseous HCl can be used to generate hydrochloric acid in situ when water is present when performing this reaction. HBr and hydrobromic acid can be used, but they appear to be less effective based on studies performed to date. Other acids may be considered for use, but the most effective substance to date is aqueous hydrochloric acid. Any suitable ratio, typically of formula (I)
A reaction-promoting amount in a range that provides up to 1 mole of hydrogen ions per mole of the compound of
And preferably, an amount of hydrochloric acid that provides in the range of 0.1 to 0.5 moles of hydrogen ions per mole of the compound of formula (I) can be used. In the case of hydrocarboxylation of MVN, the preferred range is 0.1 to 0.3, more preferably 0.15.
HCl: MV from 0.27 to 0.27, and most preferably from 0.18 to 0.22.
N molar ratio.

The catalytic hydrocarboxylation process step comprises: (iii) a reaction-promoting amount of (i) palladium with at least one organic phosphine ligand, preferably a tertiary phosphine, and / or zero palladium therein; At least one palladium compound having a valence of 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 Implemented in the presence. If no copper compound is used, the palladium and / or one or more compounds of palladium used in forming the catalyst are sometimes collectively referred to herein for convenience as the "Pd component"; Combinations of palladium and / or one or more compounds of palladium and one or more compounds of copper (if copper compounds are used) used in the formation of the catalyst are sometimes collectively In the specification, it is referred to as “Pd—Cu component” for convenience.

To start the reaction for continuous operation, or in the first run of a series of batch reactions, it is desirable to use fresh catalyst, the term “fresh” being used herein as unused. Used to refer to the catalyst and thereby distinguish it from the recirculated catalyst residues. The term does not refer to the time at which the catalyst was formulated, as fresh catalyst can be pre-formed and stored under suitable conditions before use.
After the start of the reaction, and the start of catalyst recycle in continuous operation, the recycled catalyst residue can be charged to the reactor continuously or in portions and fresh whenever necessary or desirable. Can be provided by the supply of a suitable catalyst. Similarly, if the reaction is performed as a series of batch operations, the second and subsequent reactions may utilize recycled catalyst residues, either as a single catalyst or with fresh catalyst.

While palladium metal or various types of compounds of palladium, such as complexes or chelates of palladium, can be used as the Pd component in the formation of a fresh catalyst for the reaction, the use of salts of palladium is preferred. This is because fresh catalyst compositions formed from palladium salts appear to have at least greater activity compared to those made from palladium metal itself. Of the salt, P
Most preferred are palladium (II) salts such as d (II) halides (chloride, bromide, iodide) and Pd (II) carboxylates (eg acetate and propionate).

The organic phosphine ligands for use in the process can also be of various types, as long as their use with the Pd component results in an active fresh catalyst. Normally, although organic phosphine ligands can contain up to about 30 total carbon atoms in the molecule, this does not appear to be a critical limitation. One preferred classification of ligands, consists tertiary phosphine ligand of the formula ^{R 4 R 5 R 6 P (} III), wherein R ^4, R ⁵ and R ⁶ are identical also properly are different and are selected from alkyl, R ⁴ , selected from aryl, aryl substituted with a functional group, heteroaryl, heteroaryl substituted with a functional group, aralkyl, aralkyl substituted with a functional group, cycloalkyl and cycloalkyl substituted with a functional group; From one of R ⁵ and R ⁶ are aryl Le substituted aryl or a functional group, wherein the functional substituents are those of the type described above. Preferably, at least one of R ⁴ , R ⁵ and R ⁶ is aryl and at least one of R ⁴ , R ⁵ and R ⁶ is cycloalkyl.

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

[0036]

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Is one or more tertiary phosphines, wherein R ′ and R ″ are the same or different and are independently hydrogen, alkyl or aryl, Ar is phenyl or naphthyl, and n is Is an integer from 3 to 6. Preferably, R ′ and R ″ are the same or different and are C ₁ -C ₆ alkyl, Ar is phenyl, alkylphenyl, naphthyl or alkylnaphthyl, and n is 3 or 4. Most preferably, R ′ is methyl or ethyl, R ″ is C ₃ -C ₆ branched alkyl, Ar is phenyl and n is 4. Neomenthyldiphenylphosphine is the phosphine ligand Particularly preferred.

If it is desired to use a copper compound in forming a fresh hydrocarboxylation catalyst system, a copper complex such as copper acetylacetonate, copper alkyl acetoacetate, or other chelated forms of copper is used. sell. Preferred copper compounds for this application are, however, salts, especially copper (II) halides (chloride, bromide, iodide) and copper (II) acetate and copper (II) propionate
And a divalent copper salt such as a copper (II) carboxylate.

In one embodiment, the Pd component and the copper compound are inorganic salts and, for example, a complex formed from palladium (II) chloride or bromide, copper (II) chloride or bromide and carbon monoxide or any Or as a preformed complex of another similar complex. In one preferred embodiment, the freshly active catalytic species comprises individual components, i.e. (i) at least one organic phosphine ligand and at least one organic phosphine ligand such as inorganic palladium (II) or palladium (II) carboxylate. One palladium compound or (ii) at least one organic phosphine ligand, inorganic palladium (
II) and at least one copper compound and at least one palladium compound, such as copper (II) or palladium (II) and copper (II) carboxylate, to the reaction mixture Formed in situ. These inorganic salts include chlorides, bromides, nitrates and sulfates. Organopalladium and / or copper compounds which can be used include complexes and salts such as carboxylate, for example acetate or propionate. In one preferred embodiment, neomenthyldiphenylphosphine, copper (II) chloride and palladium (II) chloride are used in making the fresh catalyst and added to the reactor either simultaneously or sequentially, individually or together. You. In another preferred embodiment, neomenthyldiphenylphosphine and palladium (II) chloride are used in the preparation of a fresh catalyst and are added to the reactor either simultaneously or sequentially, individually or together.

The Pd or Pd—Cu component can be supported on carbon, silica, alumina, zeolites, clays and other polymeric materials, but the use of a homogeneous catalyst system is clearly preferred.

The amount of the Pd or Pd—Cu component used in the formation of a fresh catalyst is preferably 4 per mole of the Pd component or per mole of the total Pd—Cu component.
To 8000 moles of the compound of formula (I). Pd component 1
More preferred is an amount that provides from 40 to 4000 moles (most preferably 20 to 2000 moles) of the compound of formula (I) per mole or per mole of total Pd-Cu component. The proportion of organic phosphine ligand used is at least about 1 mole per mole of Pd component or 1 mole of Pd-Cu component in total. More preferably, 1 to 40 moles of the organic phosphine ligand is used per mole of Pd component or per mole of Pd-Cu component in total, and most preferably, 1 to 20 moles of organic phosphine is used for the Pd component. Or a total of 1 mol of the Pd-Cu component.

Although the presence of a solvent is not always required in the hydrocarboxylation reaction, it is desirable in some circumstances. Solvents which can be used are the following: ketones, such as acetone, methyl ethyl ketone, diethyl ketone, methyl n
-Propyl ketones, acetophenone and cyclohexanone; linear, poly and cyclic ethers such as diethyl ether, di-n-propyl ether, di-n
-Butyl ether, ethyl n-propyl ether, glyme (dimethyl ether of ethylene glycol), diglyme (dimethyl ether of diethylene glycol)
, Tetrahydrofuran, dioxane, 1,3-dioxolane and similar compounds; and one or more aromatic hydrocarbons such as toluene, ethylbenzene, xylene and similar compounds. Alcohols such as methanol, ethanol, 1-propanol, the 2-propanol isomer of butanol and the isomer of pentanol can be used as solvents. Esters such as ethyl acetate can also be used as a solvent. If an ester or alcohol is used as the solvent, the product is usually the corresponding ester of the carboxylic acid, and therefore the use of an alcohol or ester is not preferred. Most highly preferred are ethers, especially tetrahydrofuran, or a mixture of one or more ethers and one or more ketones, especially a mixture of tetrahydrofuran and diethyl ketone. If a solvent is used, the amount can be up to about 100 mL per gram of the compound of formula (I), but the process comprises:
Most advantageously, it is carried out in the presence of 1 to 30 ml per gram of the compound of formula (I).

The rate and / or ratio of catalyst recycle is primarily at the discretion, provided that the palladium catalyst is active in promoting the desired hydrocarboxylation reaction. From an economic point of view of the process, the greater the rate and / or amount of palladium catalyst residue that can be effectively utilized while achieving a suitable reaction rate and yield, the better. Therefore, in any given situation, several pilot experiments should be performed to optimize the rate and / or rate of catalyst recycle.

It will be appreciated and appreciated that the actual composition of the catalyst residue used as recycle cannot be specified with rigor. The residue recovered for recycle contains palladium-containing and phosphorus-containing residues that are catalytically active.
It is not currently known whether these residues consist of reaction products, compounds, chemical complexes and / or physical mixtures of two or more substances. All that is known is that this residue is catalytically active and suitable for use as catalyst recycle. If and when the residue loses sufficient catalytic activity to be effectively used for recycle, it may regenerate one or more catalyst components whenever possible. ) Or at least for palladium reclamation. Arylcarboxylic Acid Neutralization Upon completion of the hydrocarboxylation reaction, an aqueous alkali metal base is mixed with all or at least a portion of the resulting reaction mass. This results in the formation of an aqueous solution of the alkali metal salt of the aryl carboxylic acid. The coexistence forms a separate organic phase from which the aryl carboxylic acid is recovered, thereby leaving two readily separable liquid phases, each containing one of the components to be separated. 1
One such phase is the aqueous phase in which the alkali metal salt of the aryl carboxylic acid is dissolved. The other liquid phase is the organic phase in which the catalyst residues are dissolved. If desired, a low boiling solvent such as tetrahydrofuran (THF) can be used.
Vent or diluent can be removed from the reaction mass to form a more concentrated reaction mass before performing the neutralization with aqueous alkali metal base. Simple distillation can be used to remove such low boiling solvents or diluents.

As indicated above, there may be yet another phase, a solid phase containing the insoluble portion of the palladium catalyst residue. These solids can be physically separated and recovered by other suitable means such as filtration or centrifugation. If suitably active, the solid can be recycled for use in the hydrocarboxylation reaction. Otherwise, the solid can be subjected to furnace firing to produce ash, from which palladium content can be recovered and used to produce a suitable palladium catalyst component such as palladium (II) chloride. In this regard, U.S. Pat.
611. This describes a suitable procedure for the regeneration of palladium catalysts, but it requires vacuum distillation to effect separation between the catalyst residues and the carboxylic acid formed in the palladium catalyzed process .

In many cases, the hydrocarboxylation reaction is carried out with an aryl carboxylic acid (eg, racemic 2- (6-methoxy-2-naphthyl) propionic acid, 2- (3-benzoylphenyl) propionic acid or 2- (4 -Isobutylphenyl) propionic acid) and a polar organic solvent (preferably ketone or nitrile or a mixture thereof), water and / or alcohol, HCl and preferably at least one of such polar solvents. At least 1 with below boiling temperature
A liquid medium comprising the seed ether (eg, THF) is formed. There is also catalyst residue and some by-products typically formed during the reaction.

A preferred procedure for preparing and isolating purified aryl carboxylic acids from the aqueous phase, namely commonly owned co-pending application Ser. No. 08 / 780,310, filed Jan. 8, 1997. According to the procedure described in the above paragraph, the aryl carboxylic acids in the reaction mass are converted in situ by reaction with aqueous solutions of inorganic bases to water-soluble inorganic salts of such acids (neutralization step). In addition, the reaction product composition may comprise (
If i) at least one low-boiling ether (eg, THF) and / or (ii) at least one low-boiling polar solvent, either or both such low-boiling substances are included in the reaction mass. When boiling below the boiling temperature of at least one polar solvent, some or all of these low-boiling substances are distilled from the reaction product composition (distillation step). If the overheads of the reactor are susceptible to attack by aqueous HCl and the HCl is present in the reaction mass, this neutralization step should precede or at least be performed simultaneously with the distillation step.
On the other hand, if the reactor overhead is formed from an acid-resistant structural material, the distillation step may precede and / or follow and / or be performed concurrently with the neutralization step; Even preceding the sum does not cause excessive corrosion of the reactor overhead. Whatever the order of the neutralization and distillation steps is carried out, the mixture of the remaining organic phase and the aqueous phase containing the dissolved inorganic salt of the aryl carboxylic acid is the distillation residue (the substance to be distilled or the pot residue ( (pot residue)) in the reactor. These phases are separated from each other. The aqueous phase is then subjected to distillation, preferably at or near atmospheric pressure, to remove residual organic impurities such as THF. At this point, ensure that the remaining aqueous phase has a concentration in the range of 10 and 35 wt% of the dissolved inorganic salt of the arylcarboxylic acid, and if necessary, reduce the concentration of the aqueous phase by removal or addition of water. It is desirable to adjust to 10 and 35 wt% solutions. The aqueous solution is then washed (extracted), preferably at least twice, with an essentially non-polar liquid organic solvent, preferably an aromatic hydrocarbon solvent such as toluene or xylene. The free aryl carboxylic acid is then mixed with a non-oxidizing inorganic acid (eg, sulfuric acid) in an aqueous phase in the presence of an essentially non-polar liquid solvent, and (i) mixing the aryl acid in the essentially non-polar liquid solvent. It is prepared by forming an organic phase composed of a solution of a carboxylic acid and (ii) an aqueous phase. After separating these phases from each other, the aryl carboxylic acid is crystallized from an essentially non-polar liquid solvent.

The aqueous solution of the 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 2 O, K 2 O,} Ca (OH) 2, CaO, and _{Na 2 CO 3, K 2 CO} 3 and similar basic other inorganic bases. Such a solution is used in an amount at least sufficient to neutralize the aryl carboxylic acid and HCl present in the reaction mass.

If the carboxylation reaction is carried out using an alcohol such that an ester of an aryl carboxylic acid or a substituted aryl carboxylic acid is present in the reaction product composition, the ester is converted to a salt such as NaOH or KOH. Mixing the concentrated aqueous solution of the strong inorganic base with the reaction product composition and applying sufficient heat (eg, heating to a temperature ranging up to about 80 ° C.) to obtain the aryl carboxylic acid or substituted aryl carboxylic acid. It is preferred to saponify in situ by forming an inorganic salt of the acid. Thereafter, processing procedures for the carboxylation product as described above are performed.

The low boilers recovered in the first distillation stage are preferably recycled for use in the hydrocarboxylation reaction.

Examples of compounds that can be prepared by use of the present invention are ibuprofen, 2- (4-
Isobutylphenyl) propionic acid (US Pat. Nos. 3,228,831 and 3,328)
385,886); 2- (3-fluoro-4-biphenylyl) propionic acid (
Racem, which can be resolved to d-2- (6-methoxy-2-naphthyl) propionic acid (also known as naproxen) (also known as flurbiprofen) (U.S. Pat. No. 3,755,427). Isomeric 2- (6-methoxy-2-naphthyl) propionic acid (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) (US Pat. No. 3,641)
, 127). Reaction of aryl halides with vinyl olefins Preferred process steps for producing aryl olefins in embodiments of the invention where the aryl olefin is prepared, converted to an aryl carboxylic acid, and then subjected to the aforementioned catalyst separation and recycling steps Is an aryl halide,
Reacting with a vinyl olefin in the presence of a hydrogen halide acceptor and (1) a palladium catalyst formed at least from palladium or a palladium compound and (2) an organic phosphine ligand. Since this reaction involves the formation of an aryl olefin, the reaction can be referred to as either an arylation reaction or a vinylation reaction. For convenience, the reaction is referred to herein as an arylation reaction. The reaction mass formed in the arylation reaction thus contains the desired aryl olefin intermediate and, as indicated above, at least a portion of the so formed aryl olefin is present in the presence of the above-described palladium catalyst. By reacting with carbon monoxide and water, the aryl carboxylic acid is formed in a hydrocarboxylation reaction (or via a carboxylation reaction in the presence of an alcohol followed by saponification of the resulting aryl carboxylic acid ester).

In the practice of this embodiment, the aryl olefin formed by the reaction can be separated from the remainder of the reaction mass from the arylation reaction, if desired. However, such separation is not necessary. Instead, it is preferred to leave the aryl olefin in the reaction mass and to subject at least a portion (usually all) of the arylation reaction mass to a hydrocarboxylation reaction. If the reaction mass suitably contains an excess of a low boiling amine-type hydrogen halide acceptor and / or volatile components such as volatile solvents or diluents, these may pre-form all or a portion of the arylation reaction mass. Before performing the hydrocarboxylation by subjecting it to a flash or simple distillation.

Palladium-catalyzed arylation of olefins with aryl halides is known and reported in the literature. For example, Ziegler (CB Ziegle
r, Jr. ) And Heck (RF Heck), J. Mol. Org. Chem. , 1
978,43,2941 and U.S. Patent No. 5,536,931 to TC Wu.
See No. 870. In the practice of the present invention, a preferred arylation reaction is 1997
-Owned co-pending application Ser. No. 08 / 780,308 filed Jan. 8, 2008
As described in the issue. The following description up to but not including Example 1 is based primarily on that co-pending application.

Preferred arylation reactions are of the formula Ar—X, where Ar is as defined above in connection with FIG. (I) and X is a halogen atom with an atomic number greater than 9,
Aryl halides which are diazonium groups or triflates or other leaving groups) or are substituted with a functional group;

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Wherein R ¹ , R ² and R ³ are as defined above in connection with FIG. (I), by reacting with at least one olefinic compound of the formula (I) Need to form a compound. The aryl group of the aryl halide or the aryl halide substituted with a functional group is preferably substituted with alkylphenyl, naphthyl substituted with alkoxy, phenyl substituted with aryloxy or substituted aryloxy (especially phenoxy), fluoro. Aryl, 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 are those wherein the substituted aryl group is an isobutylphenyl group, a methoxynaphthyl group, a phenoxyphenyl group, a fluorobiphenylyl group, a benzoylphenyl group, wherein the halogen atom is chlorine, iodine or most preferably bromine. Includes compounds that are atoms.

Preferred olefin compounds of formula (V) are those in which R ¹ , R ² and R ³ are hydrogen, C ₁ -C ₆ alkyl, substituted or unsubstituted phenyl, and / or trifluoromethyl. Examples include compounds of formula (V) where R ¹ , R ² and R ³ are hydrogen, methyl and / or trifluoromethyl. Olefins in which R ³ is a hydrogen atom are more preferred, and vinyl olefins in which R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group and R ² and R ³ are hydrogen atoms are particularly preferred. Ethylene is the most preferred olefin reactant.

The reaction may be carried out by (1) boiling below the boiling temperature of the solvent / diluent if only one solvent / diluent is used in forming the medium, or (2) one or more solvents / diluents. B) below the boiling temperature of at least one (but not necessarily all) of the polar solvents / diluents used in the formation of the medium, if any of the solvents / diluents used in the formation of the medium, ) One or more liquid polar organic solvents / diluents and (
ii) carried out in a liquid medium formed from one or more secondary or tertiary amines. The solvent / diluent should have at least a measurable polarity at a temperature in the range of 20 to 25 ° C. and still prevent, or otherwise impair or otherwise physically prevent the arylation reaction. Should not contain any functionalities that would interfere with the Examples include 1,4-dioxane, diglyme, triglyme, acetonitrile, propionitrile, benzonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, nitrobenzene, sulfolane, acetone, butanone and cyclohexanone. I do.
Preferred solvents / diluents each have a minimum of about 10 (
In particular, one or more aprotic solvents having a dielectric constant of 10 to 30). From a cost-effective point of view, hydrocarbyl ketones having 4 or more carbon atoms (for example 4 to 8) in the molecule are particularly preferred. Examples are diethyl ketone, methyl isobutyl ketone, 2-pentanone, 2-hexanone, 2-heptanone, 3-heptanone, 4-heptanone and similar liquid ketones,
And mixtures of two or more such ketones. Diethyl ketone (3-pentanone) is most preferred. The arylation reaction tends to be inherently exothermic, and 10 to 30 such as ketones meeting this suitability.
The use of a diluent having a dielectric constant in the range (as measured at 20-25 ° C) provides an easily controllable reaction.

Secondary or tertiary amines are used as hydrogen halide acceptors and are therefore preferably used in at least stoichiometric amounts with respect to the aryl halide and / or substituted aryl halide used. However, although less desirable, the reaction with less than stoichiometric amounts of amines is
It is possible to use less than the stoichiometric amount of amine by proceeding only in the same way and by recycling the reaction mixture for further reaction in the presence of additional amine added to it. .

It does not contain any functional groups that would prevent or physically impair, inhibit or otherwise interfere with the arylation reaction, and only one species is involved in forming a liquid medium for the reaction. Boiling below the boiling temperature of the polar solvent / diluent used, if used, or at least an essential amount (eg, solvent / diluent) if one or more is used in forming the liquid medium for the reaction. (At least 20 or 30% of the total volume of diluent) boiling below at least one of the polar solvents / diluents used and the HCl, HBr and / or HI formed in the arylation reaction
Any liquid secondary or tertiary amine having sufficient basicity to serve as a hydrogen halide acceptor for can be utilized. Liquid tertiary amines are preferred. The amine is, for example, N, N, N ′, N′-tetramethylethylenediamine (b
. p. (About 120-122 ° C.), but in most cases monoamines are preferred. Diethylamine (bp 55 ° C), N, N-dimethylethylamine (bp 36 to 38 ° C), N, N-diethylmethylamine (bp6
3-65 ° C), diisopropylamine (bp 84 ° C), triethylamine (bp
About 89 ° C), dipropylamine (bp about 105 to 110 ° C) and di-sec-
Butylamine (bp about 135 ° C.) is a useful liquid amine with a suitably low boiling point. Triethylamine is a particularly preferred amine.

Diethyl ketone and acetonitrile including triethylamine (eg, 1:
From 9 to 4: 1 and more preferably in a weight ratio in the range from 1: 3 to 3: 1) or diethyl ketone with triethylamine and N, N-
A liquid medium formed from dimethylformamide (eg, in a weight ratio ranging from 1: 9 to 9: 1) is a typical desirable liquid medium for use in the present invention.

Liquid media formed from diethyl ketone and triethylamine or methyl isobutyl ketone and triethylamine are particularly preferred.

The arylation reaction typically comprises (a) palladium and / or at least one compound of palladium in which palladium has a valency of 0, 1 or 2, and (b) an organic phosphine moiety. The reaction is carried out in the presence of a catalytically effective amount of a catalyst system formed from a ligand, usually a tertiary phosphine ligand. Therefore, in general, P
The d component and the organophosphine ligand are of the same type as those described above in connection with the hydrocarboxylation reaction. In fact, the same preferred types of materials that are preferred for use in hydrocarboxylation reactions are preferred for use in arylation reactions. However, fresh catalyst is used for each such reaction. The same Pd component and the same tertiary phosphine ligand need not be used in these two reactions. Either such component or both may be different. Thus, for example, palladium (II) chloride and triphenylphosphine can be used in the arylation, and palladium (II) acetate and tri-o-tolylphosphine can be used in the hydrocarboxylation; Or vice versa, but in most preferred cases the same species (PdCl ₂ and neomethyldiphenylphosphine) is actually used in both such reactions.

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

Desirably, a small reaction promoting amount of water is included in the reaction mixture as described in commonly owned co-pending US application Ser. No. 08 / 780,310 filed Jan. 8, 1997. Done or exists. This amount is typically in the range 0.5 to 5 wt% of the total weight of the total reaction mixture. Within the range of 0.5 to 5 weight percent water, there is often an optimal amount of water that gives the highest or peak reaction rate that falls when more or less water is used. This optimal amount of water may vary depending on the identity and ratio of the components used in forming the reaction mixture. Thus, in any given situation, it may be desirable to perform several preliminary experiments with the particular reaction to be performed, where the amount of water increases the optimal rate in the mixture It is varied within the range of 0.5 to 5 wt% to locate the quantity of water. Preferably, the amount of water used is such that if such a mixture is allowed to stir at 25 ° C. for 10 minutes and stand still at the same temperature for 15 minutes, (i) the liquid organic solvent chosen for use / Amount of diluent (s), (ii) secondary and / or secondary liquid selected for use
Or a selected amount of a tertiary amine (s); and (iii)
A) The amount may not be sufficient to form a second liquid phase (ie, a separate aqueous layer) in a mixture of the selected amount of water. Thus, when performing the process on a large scale with recycle of solvent (s) and amine, the amount of water carried over from processing the product is such that the water content of the reaction mixture is about 5 wt.
% Should be monitored and / or controlled to remain below. Conversely, if the amount of water recycled is not sufficient to maintain the desired water content in the reaction mixture, additional water will bring the water content to the desired amount, preferably within the aforementioned ranges. To be added. Preferably, the arylation reaction mixture has a water content ranging from 1 to 3.5 weight percent. (I) liquid organic solvent / diluent (s), (ii) secondary and / or tertiary amines (1
In the practice of operations where a mixture of water which does not separate into a two-phase system is used, as well as (iii) a liquid mixture of these components is nevertheless cloudy
It can be hazy or cloudy, but a separate combined second liquid phase is not and should not be present as a separate layer in such a liquid mixture.

The arylation reaction is performed under conditions such that an olefin compound of formula (I) above is formed. These conditions are usually associated with aryl halides and / or olefin compounds with functionally substituted aryl halides (formula (
Although an equimolar ratio of V)) is required, excess olefin compounds are preferred. The palladium catalyst and phosphine ligand are typically used in a ratio of about 0.0005 mole of palladium or 1 mole of organic halide to palladium compound. The ligand is present in the same or a higher molar ratio as palladium or the palladium compound. It should be noted that the levels of (a) palladium or palladium compound and (b) ligand can be substantially higher (up to 10-fold). When relatively inert species of olefin compounds or aryl halides and / or substituted aryl halides are used, for example highly substituted olefins and / or substituted aryl halides bearing strongly electron donating substituents , Higher amounts of these catalysts and ligands may be required. Accordingly, the molar ratio of aryl halide and / or substituted aryl halide: Pd: ligand used is generally 200 to 20,000, respectively.
Suitable ratios can be in the range of 0: 1: 1 to 20.

The temperature of the reaction in the arylation reaction is very moderate, varying from 25 ° C. to 200 ° C. (preferably 60 ° C. to 150 ° C.), and the pressure (for gaseous vinyl compounds) from atmospheric pressure to about 3000 psi. (Preferably 300 to 1000 psi
). With the preferred catalyst systems and liquid media cited above, the reaction time is usually short, typically in the range of 1 to 24 hours, typically in the range of 2 to 6 hours, to give a complete reaction. Higher temperatures and lower pressures tend to cause increased by-product formation.

Preferred and optimal conditions are, to some extent, the nature of the particular raw material used.
(identity). Thus, for example, as an olefin reactant
Ethylene, PdCl as catalyst or catalyst precursor_Two(II) salt and neomenthyldiphenylphosphine (NMDP), such as _Four -C₈Ketones, especially diethyl ketone and C_Four-C₉Trialkylamine
Tribromoamine and 2-bromo-6-methoate using a reaction promoting amount of water.
From xinaphthalene (BMN) to 6-methoxy-2-vinylnaphthalene (MVN)
Is preferably formed, the molar ratio of BMN: Pd: NMDP is preferably 10
00: 3000: 1: 2-10, and the amine: BMN molar ratio was 0.1.
２2: 1, and preferably each in the range 1-2: 1,
The molar ratio of ketone: amine is preferably in the range of 1.0 to 4.0: 1 respectively.
, BMN + ketone + amine + Pd catalyst component + tertiary phosphine ligand + total weight of water
The weight of water based on is preferably in the range of 1 to 3.5 wt%,
The temperature is typically in the range 60 to 150 ° C, and preferably 80 to 11
0 ° C. and the pressure of the ethylene used is preferably between 400 and 1
000 psig. Under these conditions, the reaction takes less than 1 to 24 hours
To 70% to 9%, for example, 95% conversion and 85% yield.
With 9% MVN conversion and yield (both based on BMN used)
The olefin time is within 2 to 6 hours. The preceding article given in this paragraph
The conditions are preferred conditions for performing the specified reaction as stated.
Should be clearly understood. Based on the information presented in this disclosure,
Those skilled in the art can easily operate outside the ranges given in this paragraph, and still
To achieve good results. Therefore, an ally as described herein
The reaction is not limited to using the conditions given in this paragraph. Any given
In any of these areas whenever deemed necessary or desirable in a particular situation
Departure from one or more of the above.

For best results, the entire arylation reaction mixture should contain some precipitation of palladium and the formation of any solid by-products, such as amine hydrohalide salts, and aryl halide and / or substituted aryl halogen monster(
Excluding products formed by the interaction of BMN) with vinylation products (eg MVN) and / or by dimerization of such vinylated products that may occur as the reaction proceeds. Essentially free of solids at the reaction temperature. Since the reaction tends to be exothermic, it is desirable to utilize a reactor equipped with internal cooling coils, cooling baths or other highly effective cooling means to ensure proper temperature control.

Some examples of desirable laboratory reaction parameters in the reaction of BMN with ethylene at 95 ° C. and 420 psig ethylene using PdCl ₂ and NMDP are as follows: a) 5: Gives relatively fast reaction rates in the range of 1-6: 1 NMDP: Pd molar ratio: b) moles of BMN: Pd: NMDP of 2000: 1: 6, 2500: 1: 5 and 3000: 1: 10 In ratio, high conversions and good yields are given; ratios of 3000: 1: 6 and 3500: 1: 5 are operable but give low conversions. c) Increasing the stirring speed from 300 to 1500 rpm reduces the reaction time to completion to almost 2 hours. d) 2000: 1: 6 BMN: Pd: NMDP molar ratio, ethylene pressure ranging from 190 psig to 955 psig, 9
At 5 ° C. gives good results. That is, at 190 psig, the yield of MVN was 86%, and at 900 psig, the yield was 96%. At higher pressure ranges the reaction time was shorter and less solid by-product was formed. e) With a BMN: Pd: NMDP molar ratio of 2000: 1: 6, the BMN concentration is 20-35% by weight above the upper end of the range.
When used at the lower end of the range, the MVN yield is higher and the amount of solid by-products formed is lower. f) The reaction with a molar ratio of BMN: Pd: NMDP of 2000: 1: 6 using 1.6% by weight of water as reaction promoter proceeds at 95 ° C. with a reaction rate higher than 85 ° C. g) The maximum rate of reaction is about 3% by weight of water, 95 ° C, 420 psig ethylene, 2000: 1: 6.
Achieved when operating at a BMN: Pd: NMDP molar ratio, a BMN concentration of 30% by weight. This rate is about 150% when no water is added. Under these specific conditions, water levels above about 4% result in termination of the reaction with less than complete conversion. h) Successful use of recycled DEK solvent in four consecutive experiments: no new impurities were found in the MVN product solution after four recycles. The addition of make-up water required to maintain the desired level of water in the reaction mixture is desirable to achieve a beneficial reaction and promotes the effect of water from experiment to experiment.

Accordingly, the reaction of 6-methoxy-2-vinylnaphthalene (MVN) with ethylene
In the production of the 2-bromo-6-methoxynaphthalene (BMN), using palladium (II) salts and Neo-methyl diphenyl phosphine, such as PdCl ₂ a (NMDP) as catalyst or catalyst precursors, the preferred reaction medium is a mixture comprising a C ₄ -C ₈ ketone (especially diethyl ketone) and C ₄ -C ₉ trialkyl amine (especially triethylamine). The reaction medium preferably contains an amount of water that accelerates the reaction in the range of 1 to 3.5 weight percent of the total weight of the reaction mixture. The BMN: Pd: NMDP molar ratio is preferably in the range of 1000: 3000: 1: 2 to 10 respectively (eg 2000: 1: 6 BMN: Pd: NMDP
The molar ratio of amine: BMN is preferably in the range of 1-2: 1 respectively, the molar ratio of ketone: amine is preferably 1.0-4.0: 1, respectively, and the reaction temperature is preferably 80-110. ° C (eg, about 95 ° C) and the pressure of ethylene used is preferably between 400 and 1000 psig (eg, about 420 psig).

Examples of compounds prepared by use of the present invention include ibuprofen, 2- (4-isobutylphenyl) propionic acid (US Pat. Nos. 3,228,831 and 3,385,886); 2- (3-fluoro-4-biphenylyl) ) -Propionic acid (also known as flurbiprofen) (US Pat. No. 3,755,427); racemic 2- (6-methoxy-2-naphthyl) propionic acid, which is d-2- (6 -Methoxy-2-naphthyl) propionic acid (also known as naproxen) (US Pat. No. 3,637,767); α-dl-2- (3-phenoxyphenyl) propionic acid (fenoprophene) (Also known as US Pat. No. 3,600,437); and 2- (3-benzoylphenyl) propionic acid (also known as ketoprofen) (US Pat. No. 3,641).
, 127 specification). As described herein, the bromo precursor of each of the above compounds is treated with an olefinic compound of formula (III) (most preferably ethylene) and a one-phase organic liquid medium (most preferably liquid ketone, especially diethyl ketone and triketone). (A mixture of a liquid secondary or tertiary amine such as an alkylamine, especially a trialkylamine), which also preferably reacts with the palladium catalyst system (described herein) in an amount to accelerate the above reaction. In the presence of Pd, Pd
It is formed from an (I) salt or preferably a Pd (III) salt and a tertiary phosphine ligand such as neomenthyldiphenylphosphine. The amine should be selected so as to avoid β-hydride elimination under the reaction conditions and should not measurably react with the olefin or bromo precursor. The bromo precursor is substituted on ethylene to provide a substituted olefin, which is then treated as described above and then carboxylated (as described herein with carbon monoxide and palladium-phosphine or Using a palladium-copper-phosphine catalyst system), the corresponding acid product (if water forms part or all of the solvent system), or the corresponding ester (such as methyl, ethyl or isoamyl alcohol). Alcohol) is used as part or all of the solvent.

Some of the above reactions can be illustrated as follows:

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In the reaction represented above, the ethylene pressure is between 50 and 3000 psi (preferably between 300 and 1000 psi).
psi) and the temperature is between 30 ° C and 200 ° C (preferably 60-150 ° C). Temperature and pressure are selected to minimize by-product formation. Palladium is preferably used in its salt form (eg, Pd (II) acetate or chloride) and used together with a tertiary phosphine ligand as described above (ie, in the reaction layer) to form neomenthyl ditolyl phosphine. Cycloalkyldi (alkylphenyl) phosphines such as are preferred, and cycloalkyldiphenylphosphines such as neomenthyldiphenylphosphine are particularly preferred.

The bromo precursor is often commercially available and / or readily available to those of skill in the art.
Can be manufactured. For example, Aldrich Chemical Company
pany) sells m-bromophenol and m-bromoanisole, while Albemarle PPC (Tan, France) sells 2-bromo-6-methoxynaphthalene
I am selling. The bromo precursor of ibuprofen is a standard Friedel-Crafts catalyst
Can be produced by bromination using a medium (eg, zinc bromide or iron bromide).
You. The bromo precursor of ketoprofen is a benzoic acid mesylate using aluminum chloride.
Bromination of chill (or similar lower hydrocarbon esters) followed by NaOH hydrolysis, acid
Conversion to chloride (eg SOCl_Two) And reaction with benzene (again, AlCl _Three Using a Friedel Crafts catalyst such as (
±) -2- (6-Methoxy-2-naphthyl) propionic acid, i.e., 2-bromo-6-methoxyna
Phthalene is disclosed in co-owned U.S. Patent Application Serial No. 08 / 780,309, filed January 8, 1997.
It is best manufactured by the methods described in the textbook.

In addition to the above profen compounds, other profen compounds that can be prepared under appropriate conditions by use of the above arylation reaction to convert to the corresponding bromo precursor by reaction with ethylene include protidine Including acids, thiaprofenic acid, indoprofen, benoxaprofen, carprofen, pirprofen, pranoprofen, aluminoprofen, suprofen and loxoprofen.

Example 1 illustrates the present invention specifically.

Example 1 Part A A reaction mass containing racemic 2- (6-methoxy-2-naphthyl) -propionic acid (MNPA) was prepared by previously adding PdCl ₂ , neomenthyldiphenylphosphine (NMDPP) and aqueous HCl. Formed by hydrocarboxylation of 6-methoxy-2-vinyl-naphthalene (MVN) with carbon monoxide in an added tetrahydrofuran-diethyl ketone (THF-DEK) solvent mixture. At the end of the reaction, the reaction mass was treated with aqueous NaOH to neutralize HCl and stripped from the resulting mixture to form THF. The crude MNPA content in the mixture was converted to the sodium salt of MNPA by adding aqueous NaOH to the mixture and reacting with the MNPA therein. A two-phase liquid system was thus formed. MNPA
After removal of the aqueous phase contained in the sodium salt of, the organic phase containing the catalyst residue and other neutral by-products from the hydrocarboxylation was used in another hydrocarboxylation experiment to remove the catalyst residue therein. It was determined whether it could be used as a catalyst source for performing hydrocarboxylation, and the recyclability of this ligand was confirmed. The following is the method used for hydrocarboxylation. To Hastelloy B Parr reactor part B 1 liter, MVN (133.8g, 96.4%, 0.7 molar), PdCl ₂ (0.062 g, 0.00035 mol), of 10 wt% aqueous HCl (60.5 g) and the part A The organic phase cut (414 g) from the hydrocarboxylation experiment was charged. Reactions were performed at 70 ° C. and 330-350 psig carbon monoxide pressure. Samples were removed from time to time and analyzed by GC for completion of the reaction. MVN conversion is 4.5 hours, 6 hours and 7 hours
At time, they were 68.3%, 97.5% and 98.6%, respectively. Racemic 2- (6-methoxy-2-
The yield of (naphthyl) -propionic acid was 93.3%.

The following Examples 2-12 and their accompanying text are taken from co-pending co-pending US patent application Ser. No. 08 / 780,308, filed Jan. 8, 1997, and include Preferred methods for performing the operations described are specifically described herein. All parts are by weight unless otherwise indicated. Examples 2 to 12
In the following, the following abbreviations 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, “racemic 2- (6-methoxy-2-naphthyl) propionic acid” and “(±) -2- (6-methoxy-2-naphthyl) -propionic acid The term "or" means exactly the same thing. For convenience, "racemic sodium" may be used in the examples to indicate racemic sodium 2- (6-methoxy-2-naphthyl) propionate.

Example 2 demonstrates the use of a new DEK to scale (1000 gallons) racemic 2- (6-methoxy)
A preferred overall procedure for producing (-2-naphthyl) -propionic acid is specifically described.

Embodiment 2Arylation reaction In a 1000 gallon reactor, 750 kg BMN, 1305 kg DEK, 368 kg TEA, 0.3 kg PdCl _Two Add 3.1 kg of NMDP and 37 kg of water. The reactor is sealed, pressurized with ethylene to 100 psig, and the reactor temperature is adjusted to 95 ° C. The reactor was then brought to 420-450 psig.
Pressurize with Tylene and maintain this pressure until ethylene uptake is complete
. Cool the reactor to 60 ° C. and vent excess ethylene from the reactor. The reaction is
It typically takes 4-6 hours to complete and often results in> 95% BMN conversion and 85-95% MVN yield.Product processing and solvent exchange To the reaction product from the arylation reaction is added 557 kg of a 25% by weight aqueous sodium hydroxide solution. The mixture is heated to 50-60 <0> C for 15 minutes and then allowed to stand for 15 minutes. The bottom aqueous solution is drained from the container. The organic phase is then reduced under reduced pressure, typically from 200 mmHg to 350
Subject to distillation in the range of mmHg to distill TEA until the weight ratio of TEA: MVN is less than 0.016. THF is added to the remaining organic phase (distillate or pot residue) and the weight of THF: DEK in
After forming a mixture with a volume ratio of about 1: 1 the mixture is filtered to remove solids (palladium catalyst residue and oligomeric or dimeric co-products).Hydrocarboxylation reaction 1000 gallon reactor containing 550 kg MVN, 825 kg DEK and 825 kg THF
The filtered THF-DEK-MVN solution produced in the above procedure, followed by 0.3 kg of PdCl_Two, 0.64k
g CuCl_Two, 3.1 kg of NMDP and 200 kg of 10% by weight HCl. Reactor to 100 psig
Pressurize with carbon monoxide pressure and adjust reactor temperature to 70 ° C. Next, the reaction tank is 360p
The sig is pressurized with carbon monoxide and this pressure is maintained until carbon monoxide uptake is complete. The reactor is then cooled and depressurized. The reaction is typical to go to> 95% MVN conversion and about 90% racemic 2- (6-methoxy-2-naphthyl) -propionic acid
It usually takes 4 to 8 hours.Racemic product processing and recovery Aqueous sodium hydroxide (25% by weight solution) is added to the reaction vessel and racemic 2- (6-methoxy-2-naphthyl) -propionic acid is converted to racemic 2- (6-methoxy-2-naphthyl) -propionic acid. It is converted to sodium and neutralizes the HCl remaining in the reaction mixture. Then THF
Is distilled from the reaction mixture at atmospheric pressure. (Such a neutralization and distillation step is a reaction
The reverse is possible if the structural material at the top of the tank is resistant to HCl). The aqueous phase formed is separated from the organic phase, which mainly consists of DEK and impurities. Organics (eg, DEK) remaining in the aqueous phase are distilled at atmospheric pressure from the aqueous racemic sodium 2- (6-methoxy-2-naphthyl) -propionate phase. Racemic sodium solution is desirably 10
~ 35% by weight, and this concentration further removes or adds water if necessary
By doing so, it is adjusted to this range. The aqueous racemic sodium phase is then washed with toluene
Purification to remove neutral impurities. Typically 1-3 times, preferably at least
Use two toluene washes. At a suitable temperature, typically 60-80 ° C, racemic 2-
Prevents precipitation of sodium (6-methoxy-2-naphthyl) -propionate. next
The aqueous solution is acidified with sulfuric acid at about 97 ° C. in the presence of toluene. Aqueous phase in reactor
And remove the remaining (±) -2- (6-methoxy-2-naphthyl) -propionic acid in toluene solution at about 95 ° C (typically twice) to remove residual sulfuric acid. I do.
Next, racemic 2- (6-methoxy-2-naphthyl) -propionic acid is crystallized from a toluene solution.
I do.

Example 3 shows that the recycled solvent from the method performed in Example 2 above (mainly DEK and TEA
) Illustrates a preferred overall procedure for preparing (1000 gallons) racemic 2- (6-methoxy-2-naphthyl) -propionic acid on a large scale.

Example 3 A 1000 gallon reactor was charged with 750 kg of a mixture of BMN, a recycled solvent (typically a DEK and TEA mixture containing about 1% by weight of water), and 1305 kg of DEK and 368 kg of
Get TEA. A catalyst consisting of 0.3 kg of PdCl ₂ and 3.1 kg of NMDP is charged to the reactor. The water in the reaction mixture is raised to about 1.6% by weight by adding fresh water (if necessary). The reactor is pressurized to 100 psig with ethylene and the reactor temperature is adjusted to 95 ° C. The reactor is then pressurized with ethylene to 420-450 psig and maintained at this pressure until ethylene uptake is complete. The reactor is cooled to 60 ° C. and excess ethylene is vented from the reactor. The reaction typically takes 4-6 hours to complete and often results in> 95% BMN conversion and 85-95% MVN yield.

An aqueous caustic (25% aqueous NaOH) is added to the reaction mixture containing MVN to liberate TEA from triethylamine hydrobromide. The aqueous phase is then separated from the organic layer, and the TEA is then recovered from the MVN, DEK and TEA mixture by distillation. The distillate consisting of DEK, TEA and water is then recycled for use in the arylation reaction. THF contains about a 1: 1 weight ratio of THF and DEK, suitable for carboxylation, in addition to the distillation residue (distillate or pot residue) consisting mainly of the MVN / DEK mixture plus some solids. Produce an MVN mixture. The product mixture is filtered to remove solids therefrom. Fresh catalyst and HCl are added in proportions corresponding to Example 2, and the hydrocarboxylation reaction is carried out as in Example 2. Next, (±) -2- (6-methoxy-2-naphthyl) -propionic acid was added to a 25% by weight aqueous solution of sodium hydroxide to obtain (±) -2- (6-methoxy-2-naphthyl) propionic acid. It is converted to sodium and performs the remaining processing and recovery procedures of the racemic product of Example 2.

The procedure of Example 2 above can be carried out in the same manner except that the reaction promoting amount of water is omitted in the arylation reaction. The reaction proceeds, but the reaction proceeds more slowly if water is present in the aryl reaction. This is specifically described in Example 4 of the present specification.

Example 4 Twelve consecutive arylation experiments were performed in a 2 liter reactor, wherein the material ratios and reaction conditions in the reactor used were the same for each experiment except for some small minor differences. The only independent variable was moisture and their amounts. The reaction mixture was NMDP BMN, the 529~530g DEK, TEA of 147～148G, of PdCl ₂ and 1.23~1.26g of 0.112~0.116g of 300 g. Some experiments were performed without added water, and the remaining experiments measured the amount of water added. All reactions were performed at 95 ° C. under 420-450 psig of ethylene. The criterion for the reaction rate was the maximum rate of ethylene consumption during each reaction. That is, the higher the value, the better. The results of these experiments on reaction rates are summarized in the table below.

[0090]

[Table 1]

In the arylation reaction, the inclusion or presence of water as an accelerator in an amount in the range of 0.5 to 5 percent of the total arylation reaction mixture was confirmed by the above-cited January 8, 1997. U.S. patent application Ser.
/ 780,310, consistent with the subject matter fully disclosed.

By experimental work, it is better to separate the solid from the arylation reaction product after separation of the free amine and replenishment by addition of THF or a similar solvent (Examples 2 and 3). It has been shown to be more advantageous than before separation and solvent addition. In particular, the filtration time is significantly reduced in this manner.

As mentioned above, if one or more solvents / diluents are used in the arylation reaction,
The amine must not boil under all such solvents / diluents. Alternatively, the amine should boil below at least one of the solvents / diluents that make up a substantial portion (eg, at least 20 or 30%) of the total weight of such solvents / diluents. For example, the reaction typically performed using acetonitrile (ACN) and diethyl ketone (DEK) 1: 1 (weight: weight) as a solvent / diluent, generally as in Example 2 above, involves triethylamine over ACN, But the situation of boiling under DEK is involved. In such a case, various processing procedures can be used. In one such procedure, ACN is distilled from the reaction mixture (stripping), and then an aqueous inorganic base solution is added, followed by phase separation and distillation of triethylamine from the remaining organic phase. Another procedure involves the addition of an aqueous inorganic base solution, the phases are separated, and then the ACN and triethylamine are distilled off, leaving a diethyl ketone solution behind.

Example 5 Production of 6-Methoxy-2-vinylnaphthalene 19.45k in a 20 gallon jacketed stainless steel reactor equipped with a stirrer
g of acetonitrile (ACN) and 12.45 kg of 2-bromo-6-methoxynaphthalene (BM
N) and 4.8 g of PdCl ₂ are charged. The reactor is pressurized and evacuated three times with 50 psig of nitrogen. The reactor is then charged with 5.3 kg of ACN and 5.64 kg of triethylamine (TEA). The stirrer was set at 158 rpm and the reactor was pressurized and pressurized with 80 psig of nitrogen.
Exhaust twice. The reactor is then purged with nitrogen for 10 minutes. Next, a mixture of 48.6 g of neomenthyl diphenylphosphine (NMDP) dissolved in 0.35 kg of TEA is put into the reaction vessel. The agitator is set at 412 rpm and the reactor is heated with jacket steam. The reaction temperature is initially in the range of 91-109 ° C, while the pressure varies between 412 and 519 psig. The reaction causes a heat kick and after 30 minutes the temperature rises to 109 ° C with 26 ° C cooling water in the jacket. Total reaction time is 1.75 hours, 100% BMN conversion. The reactor is cooled, evacuated, and the reaction contents are transferred to a 30 gallon glass lined reactor for processing. Treatment of 6-methoxy-2-vinylnaphthalene The crude 6-methoxy-2-vinylnaphthalene (MVN) solution in a 30 gallon reaction vessel was
Strip ACN to remove ACN. The total stripping time is 6.33 hours, with a maximum bottom temperature of about 91 ° C. The final overhead temperature is about 68 ° C. Use zero reflux for the first 35 minutes of operation. The reflux ratio is then set to 5 and 34.95 kg of diethyl ketone (DEK) are added to the reaction contents. The reflux ratio is maintained at 5 during this stripping.

After adding 9.25 kg of 25% NaOH to the stripped reaction product in a 30 gallon reactor, the resulting mixture is stirred for 30 minutes. Turn off the stirrer and remove the aqueous phase 1.
Let stand for 75 hours. The mixture is phase cut at 57 ° C. and the aqueous phase is collected and discarded. The TEA is removed by stripping the organic phase and the lag layer in the reactor. The stripping pressure is 330mmHg. The total stripping time is 4.9 hours. Start the column under total reflux for the first 30 minutes of the run. The reflux ratio is then reduced to 3 for 3.5 hours. The reflux ratio is reduced to 2 with the remaining stripping. The final top temperature is about
It is 79 ° C and the final bottom temperature is about 86 ° C.

To the cooled stripping mixture in a 30 gallon reactor, add 8 kg of tetrahydrofuran (THF). The resulting MVN solution is filtered through a 10 micron back filter and a 1 micron cartridge filter. Hydrocarboxylation of 6-methoxy-2-vinylnaphthalene A 20 gallon Hastelloy reactor was purged three times with 80 psig of nitrogen and then 3.8 g of PdCl ₂ and 8.8 g of CuCl ₂ were added to the reactor, followed by Add MVN solution. 8 reactors
Purge 3 more times with 0 psig nitrogen and set the stirrer to 118 rpm. 3.6kg TH
F and 3.55 kg of 10% HCl are charged to the reactor, the reactor is again purged three times with 80 psig of nitrogen, and then nitrogen is bubbled through the dip leg for 10 minutes. Then 42.2
g of NMDP and 0.35 kg of THF are charged to the reactor and the stirrer is set at 402 rpm.
The reactor is pressurized and evacuated three times with 50 psig CO and then heated to the reaction temperature and pressurized with CO. Reaction temperatures are in the range of 70-78 ° C, while pressures vary from 247-450 psig. After a total reaction time of 8.5 hours, the reactor is cooled and evacuated and transferred to a 30 gallon glass lined reactor for processing the contents. The treated hydrocarboxylation mixture of the product is neutralized with 20.5 kg of 25% NaOH. THF is stripped from the contents of the processing reactor at atmospheric pressure for 2.5 hours. Water (30.7 kg) is put on the strip for 1.4 hours. The final overhead temperature is about 97 ° C and the final bottom temperature is about 108 ° C. 7 kg of 25% NaOH is added to the stripped reactor contents and the mixture is stirred at 50-60 ° C. for 30 minutes. After a standing time of 35 minutes, the aqueous and organic phases separate from one another. The aqueous phase is returned to the treatment reactor with 10 kg of toluene. The mixture is stirred for 15 minutes and left at 55 ° C. for 30 minutes. The phases separate again. The aqueous phase is returned to the treatment reactor with 10 kg of toluene, the mixture is stirred for 15 minutes and allowed to stand. Then the mixture is heated to 65 ° C. and the phases are separated from one another. The aqueous phase is again returned to the reactor with 10 kg of toluene. This mixture
Stir for 15 minutes and let stand at 70 ° C. for 30 separations and make a final phase cut. 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 essentially repeated, with the main changes as described below: The first addition to the first reactor is 21.4 kg of diethyl ketone (DEK), 12.4 kg BMN and 4.6 g of PdCl ₂ . The second addition is 3.2 kg of DEK and 6.34 kg of TEA. TE
Remove the 10 minute nitrogen purge after A addition. Add NMDP (50.9kg) to 0.27kg DEK
Add as a solution in. Pressurization with ethylene is started up to 100 psig before heating of the reactants begins. The arylation reaction is performed at 92-98 ° C and 393-429 psig.

For the MVN treatment, add 10.15 kg of DEK, heat to 75 ° C., then wash caustic soda, phase cut, water wash, another phase cut and a final overhead temperature of about 79 ° C. and a maximum of about 97 ° C. Involves stripping of TEA using bottom temperature.

The hydrocarboxylation solvent is a mixture of the residual DEK and 8.2 kg of THF added. Another component to add is 37.9 g NMDP in 3.5 g PdCl ₂ , 7.9 g CuCl ₂ , 3.25 kg 10% HCl, 160 g DEK. The hydrocarboxylation reaction is carried out for 8.7 hours, the temperature ranges from 74 to 84 ° C, and the pressure ranges from 321 to 476 psig.

The crude (±) -2- (6-methoxy-2-naphthyl) propionic acid is converted to sodium (±) -2- (6-methoxy-2-naphthyl) propionate by stripping THF. Wash three times with 5 kg of toluene to obtain an aqueous solution of sodium (±) -2- (6-methoxy-2-naphthyl) propionate.

Example 7 Production of 6-methoxy-2-vinylnaphthalene 12.8 kg in a 20 gallon jacketed stainless steel reactor equipped with a stirrer
ACN, 12.45 kg DEK and 12.4 kg 2-bromo-6-methoxynaphthalene (BMN), 4.6
g of PdCl ₂ and 50.9 kg of NMDP. The reactor is pressurized and evacuated three times with 50 psig of nitrogen. Next, 6.27 kg of TEA is charged into the reaction tank. The agitator is set at 158 rpm and the reactor is pressurized and evacuated with 50 psig of nitrogen. The stirrer is set at 416 rpm, the reactor is pressurized to 100 psig with ethylene and heated with conditioned water in a jacket. Reaction temperatures range from 87-98 ° C, while pressures vary from 394-458 psig. The total reaction time is 3.5 hours, with 99.6% BMN conversion within 2 hours.
The reactor is cooled, evacuated, and at 60 ° C. the contents of the reactor are transferred to a 30 gallon glass lined reactor equipped with a 6 inch column for processing. Then into a 20 gallon reactor
Charge 12.5 kg of DEK, heat it to 60 ° C. and transfer to a 30 gallon reactor. Treatment of 6-methoxy-2-vinylnaphthalene The crude 6-methoxy-2-vinylnaphthalene (MVN) solution in a 30 gallon reaction vessel was
Strip ACN to remove ACN. The total stripping time is 4 hours, with a maximum bottom temperature of about 73 ° C. The final overhead temperature is about 59 ° C. The reflux ratios used were 5: 1 1.9 hours, 3: 1 1.6 hours, and 4: 1 1.5 hours.

After charging 9.3 kg of 25% NaOH to the stripped reaction product in a 30 gallon reactor, the resulting mixture is stirred at 35 ° C. for 15 minutes. The stirrer is then stopped and the aqueous phase is left for 30 minutes. The mixture is phase cut and the organic phase is washed in the reaction vessel with 1.2 kg of water for 15 minutes while stirring. After allowing to stand for 30 minutes, perform a further phase cut. The TEA stripping of the organic phase is performed at 150 mmHg. The total stripping time is 5.25 hours. The maximum overhead temperature is about 59 ° C and the maximum bottom temperature is about 91 ° C. The reflux ratio is 50: 1 at the start and when the column stabilizes,
The reflux ratio was reduced to 5: 1 in 2.25 hours and 7: 1 in the last 2.5 hours of stripping.
And The reaction product is then diluted by adding 12.05 kg of THF and 2.05 kg of DEK to the reaction phase. The resulting solution is then filtered through a 10 micron back filter and a 1 micron cartridge filter. Hydrocarboxylation of 6-methoxy-2-vinylnaphthalene The filtered MVN solution was placed in a 20 gallon Hastelloy reactor followed by an additional 4.65 kg.
Insert DEK. Next, 4.6 g of PdCl ₂ and 10.5 g of CuCl ₂ are charged to the reactor. The reaction tank
Purge three more times with 50 psig nitrogen and charge with 4.2 kg of 10% HCl. The reactor is pressurized to 80 psig with nitrogen and evacuated. A solution of 50.9 g of NMDP in 255 g of DEK is charged to the reactor and the reactor is pressurized and evacuated twice with 50 psig of nitrogen and the stirrer is turned on only when pressurized. The stirrer speed was set to 399 rpm, and the reactor was pressurized and evacuated three times with 50 psig CO, where again the stirrer was operated only when pressurized. The reactor is then pressurized with CO to 280 psig and heated to 75 ° C. The reaction temperature is maintained within the range of 73-77 ° C, while the pressure varies between 339-350 psig. After a total reaction time of 6 hours, the reactor is cooled and evacuated and transferred to a 30 gallon glass lined reactor for processing the contents. The treated hydrocarboxylation mixture of the product is neutralized with 2.15 kg of 25% NaOH. THF is stripped from the hydrocarboxylation mixture at atmospheric pressure for 1.2 hours. The final bottom temperature is about 100 ° C and the final overhead temperature is about 92 ° C. Water (3
0.7 kg) into the strip for 1.4 hours. The final overhead temperature is about 97 ° C, and the final bottom temperature is about 108 ° C. DEK (4.95 kg) was added to the stripped reactor contents, followed by 14 kg of water and 7.55 kg of 25% NaOH, and the mixture was added.
Stir at 70-80 ° C for 30 minutes. After a standing time of 30 minutes, the aqueous and organic phases separate from one another. The aqueous phase is returned to the treatment reactor and the DEK stripping is at a final bottom temperature of about 95 ° C, and a final overhead temperature of 95 ° C. 2.0 kg of water is added along with 5.15 kg of toluene. The mixture is stirred for 20 minutes and allowed to stand overnight with conditioned water in a jacket at 60 ° C. The phases separate. The aqueous phase is washed twice more with toluene (first time 5.1 kg, second time 4.95 kg), and the phases are subsequently separated. The product is recovered as an aqueous solution of sodium (±) -2- (6-methoxy-2-naphthyl) propionate.

Example 8 Preparation of 6-Methoxy-2-vinylnaphthalene In a 20 gallon jacketed stainless steel reactor, 12.5 kg of ACN, 12.5 kg of methyl isobutyl ketone (MIBK) and 12.45 kg of BMN, 4.6 g PdCl ₂ and 50.9 kg N
Insert MDP. The reactor is pressurized and evacuated three times with 50 psig of nitrogen. Next 6.8kg
Put TEA. The agitator was set at 160 rpm and the reactor was pressurized and 50 psi
Exhaust with g of nitrogen. The stirrer was set at 415 rpm, and the reactor was 100 ps using ethylene.
Pressurize to ig and heat with conditioned water in jacket. Reaction temperature is 94 ~ 10
The range is 0 ° C., while the pressure varies from 388 to 432 psig. The total reaction time is 2.6 hours, but reaches approximately 99% conversion within approximately 1.8 hours. Cool the reactor and vent the ethylene pressure. After operating for about 16 hours while operating the stirrer, cool the reaction tank to about 60 ° C.
And transfer the reactor contents to a 30 gallon glass lined reactor for processing. 12.4 kg of MIBK is placed in a 20 gallon reaction vessel, which is heated to 60 ° C. and transferred to the treatment reaction vessel. Treatment of 6-methoxy-2-vinylnaphthalene The ACN is removed by stripping the crude MVN solution at 150 mmHg. The total stripping time is 3.3 hours, with a maximum bottom temperature of about 76 ° C. Use a reflux ratio of 50 to perform the column. After the column has stabilized, the reflux ratio is reduced to 5. This reflux ratio is 45
Hold for 3 minutes and then reduce to 3 for 30 minutes. Set the reflux ratio to 2 for the next 55 minutes,
Then switch to a final reflux for at least 25 minutes.

After cooling to 47 ° C., 9.4 kg of 25% NaOH are added to the stripped mixture. The temperature decreases with the addition of caustic soda. The reaction vessel is stirred for 15 minutes and then the stirring is stopped and the aqueous phase is left for 30 minutes. The phases are separated and 1.05 kg of washing water are placed in the organic phase and mixed with them for 20 minutes. This is allowed to stand for 80 minutes, and the aqueous phase is cut from the bottom of the reactor.

The TEA stripping pressure is initially 150 mmHg and through the stripping
Lower to a final value of 70mmHg. The total stripping time is 4.25 hours and the maximum bottom temperature is about 78 ° C. The column starts at zero reflux for the first 35 minutes of operation. This reflux ratio is then set to 5 and maintained for 25 minutes. The reflux ratio is reduced to 2 during the last 3.25 hours of stripping. 8.1 kg of THF in the stripped product mixture
And filter the resulting MVN solution through a 10 micron back filter and a 1 micron cartridge filter. An additional 4.05 kg of THF is charged to the treatment reactor and also filtered. The 6-methoxy-2-vinylnaphthalene hydrocarboxylated MVN solution is transferred to the hydrocarboxylation reactor described above. This is charged with 4.3 kg of PdCl ₂ and 9.8 g of CuCl ₂ . The reactor is purged once with 50 psig of nitrogen. Set the stirrer to 118 rpm and charge 3.95 kg of 10% HCl. The reactor is pressurized to 80 psig with nitrogen and evacuated twice (stirring during pressurization and not during evacuation). 248g
Put a solution of 47.6 g NMDP in DEK. The stirring speed was set at 401 rpm and the reactor was pressurized and evacuated three times with 50 psig of CO (stirring during pressurization and not during evacuation). The reactor is pressurized with CO to 276 psig and heated to 75 ° C. Reaction tank temperature is 7
It varies between 2 and 80 ° C and the pressure ranges from 334 to 355 psig. The reaction is stopped after 8.8 hours. The treated (±) -2- (6-methoxy-2-naphthyl) propionic acid solution of the product is placed in the treatment reactor and neutralized with 2.0 kg of 25% NaOH. THF is stripped at atmospheric pressure for 20 minutes. The final bottom temperature is about 79 ° C and the final overhead temperature is about 77 ° C. Cool the stripped mixture to 60 ° C., and add 14.0 kg of water and 8.
Add 0 kg of caustic soda. The mixture is stirred for 30 minutes at 75 ° C. Turn off the stirrer and let the reactor contents stand for 30 minutes. The phases separate. The aqueous phase is returned to the reaction vessel and left stirring for about 16 hours. Next, the aqueous solution is stripped at atmospheric pressure for 1.5 hours. The aqueous phase in the column is cut back to the reactor. Perform another stripping using steam in the jacket. Further distillate is discharged from the column following the strip. The final bottom temperature of this stripping is about 101 ° C, and the final overhead temperature is about 100 ° C. An addition of 5.05 kg of toluene is added to the stripped product mixture, and the mixture is stirred at 68 ° C. for 20 minutes and then allowed to stand 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, resulting in a reddish-purple clear aqueous solution and a cloudy olive-green organic solution. Third toluene wash (
5.05 kg, 71 ° C.) yields a clear purple aqueous solution and a cloudy yellow organic solution.

Example 9 The procedure of Example 8 is essentially repeated, with the main changes as described below: The first addition to the first reactor is 12.4 kg ACN, 12.65 g DEK, book Example 8 of description
12.45 kg of BMN, 4.6 g of PdCl ₂ and 51 g of NMDP produced in the above. The second addition is 6.
17 kg TEA. This 2.5 hour arylation reaction is 88-99 ° C and 318-458 ps.
Perform with ig.

The ACN distillation in the MVN process is 150 mmHg and involves a total stripping time of 5.25 hours at a maximum bottom temperature of 71.8 ° C. TEA stripping pressure is initially 150mm
Hg and is lowered to a final value of 90 mmHg through 4 hours of stripping.

The hydrocarboxylation solvent is a mixture of the residual DEK and about 12 kg of added THF. Another component to add is 44.7 g NMDP in 4.1 g PdCl ₂ , 9.2 g CuCl ₂ , 3.65 kg 10% HCl, 222 g DEK. The hydrocarboxylation reaction is performed for 6.6 hours, the temperature is in the range of 74-77 ° C, and the pressure is in the range of 333-358 psig.

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

Example 10 The procedure of Example 8 is essentially repeated, with the main changes as described below: The first addition to the first reactor is 12.55 kg of ACN, 12.5 g of MIBK, 12.5 kg of BMN, 4.6 g of PdCl ₂ and 51 g of NMDP produced in Example 8 of the specification. The second addition is 6
.19 kg TEA. The 2.7-hour arylation reaction was performed at 88-97 ° C. and 371-441 p.
Do it with sig.

The ACN distillation in the MVN process is 150 mmHg and involves a total stripping time of 3.8 hours at a maximum bottom temperature of 71 ° C. The TEA stripping pressure is initially 150 mmHg and is reduced to a final value of 70 mmHg through 5.3 hours of stripping.

The hydrocarboxylation solvent is a mixture of the residual MIBK and about 12 kg of added THF. Another component to add is 4.6 g PdCl ₂ , 9.5 g CuCl ₂ , 3.85 kg 10% HCl, 226
47g NMDP in g DEK. The hydrocarboxylation reaction is carried out for 7 hours and the temperature is 7 hours.
The range is 2 to 77 ° C, and the pressure is in the range 333 to 357 psig.

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

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

Example 11 Bromination of 2-Naphthol 2-Naphthol (144.8 g, 1.00 mol), EDC (537 g) and water (162 g) were added to a 2 liter reflux condenser, mechanical stirrer and peristaltic pump addition system. Into a reaction vessel equipped with. Heat the reactor to about 55 ° C until most of the β-naphthol is dissolved. Bromine (336.9 g, 2.11 mol) is then added through the pump at a rate such that the reaction temperature is maintained at 60 ° C. (subsurface). After the addition of bromine, the reaction temperature is raised to 60 ° C. 1.
Hold for 5 hours. The reaction is then cooled slowly and the lower phase (aqueous HBr) is sucked off. The remaining EDC solution (841 g) is removed from the reactor and analyzed by GC. In experiments performed in this manner, analysis showed 0.4% of 2-naphthol, 92.6% of 1,6-dibromo-2-naphthol (DBN), and 4.9% of the other isomer. DBN (271 g) in ethylene dichloride (EDC) (551 g) obtained by hydrodebromination of 1,6-dibromo-2-naphthol
, 0.9 mol) into a 1000 mL Hastalloy B autoclave. Tungsten carbide (82 g, 30% by weight) and tetrabutylammonium bromide (0
.2 g, 0.1% by weight) and seal the reaction vessel. Purging the reactor with hydrogen (
Evacuate 50 psig) and 3 times, then pressurize with hydrogen and heat to 90 ° C. The hydrogen purge is kept constant so that the pressure stays in the range of 120-125 psig. Analysis of the reaction mixture formed 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, evacuated to a dust collector, and the catalyst is allowed to settle. The EDC solution (747 g in a reaction performed in this manner) is collected through a dip tube. Methylation of 6-bromo-2-naphthol with MeCl The EDC solution produced above is placed in a 1.4 liter (3 pint) Chemco glass reactor equipped with a stainless steel head. Neutralize this with the diluted acid first,
Then it is concentrated by distillation. Add water (50 mL) to remove azeotropically trace amounts of EDC remaining in the residue. Isopropyl alcohol (242 g) and sodium hydroxide (44 g, 1.1 mol; 88 g of a 50% solution) are charged to the reaction vessel. The reaction vessel is sealed, purged with nitrogen and heated to 70 ° C. Methylene chloride (66 g, 1.3 mol) is charged over one hour (40-50 psig). After stirring at 80 ° C. for another hour, the isopropyl alcohol is distilled off. The residue is heated to dissolution conditions (90-95 ° C.) and then washed with water (400 g). The water is removed and the residue is distilled under vacuum (1 mm Hg). After removing a small amount of volatiles, the BMN is distilled as a white solid at 160-165 ° C (operating in this manner yields 169 g). Isopropyl alcohol (490 g) is added and the solution is heated to reflux and cooled slowly to about 10 ° C. The solid BMN is removed and washed with cold (0 ° C.) isopropyl alcohol (180 g) and then
Dry under vacuum at 7575 ° C. Analysis of the white crystalline product thus formed showed 99.7% by weight of BMN.

Example 11 includes the procedures and subject matter fully described in commonly-owned co-pending US patent application Ser. No. 08 / 780,309 filed Jan. 8, 1997.

Example 12 illustrates a dilute acid treatment procedure to separate the arylation product and the use of a secondary or tertiary amine as a hydrogen halide acceptor in the arylation reaction.

Example 12 A 5 gallon stainless steel magnetic stirring autoclave was charged with DEK (3296 g), BMN (1
Add 502 g, 6.34 mol), NMDP (6.170 g, 19.0 mmol), PdCl ₂ (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 at 95 ° C under ethylene pressure (609-640 psig) for 4.5 hours, and then cooled to 60 ° C and evacuated slowly. Emptying the reactor produces a mixture of a yellow solid and a yellow liquid. A 5000 g portion of the reaction mixture is poured into a 12 liter flask having a mechanical stirrer and an outlet at the bottom. Water (695 g) and 10% by weight aqueous HCl (209 g) are added to the reaction mixture, and the mixture is stirred and warmed to 65 ° C., and then allowed to settle and settle. The aqueous phase is removed from the yellow organic phase. The organic phase is washed a second time with a mixture of water (250 g) and 10% by weight aqueous HCl at 64 ° C., and the aqueous phase is separated from the washed organic phase which mainly consists of MVN and DEK. The washed organic phase is hydroxycarbonylated as described above, preferably after stripping some DEK and replacing it with THF. The aqueous phase contains triethylamine hydrochloride, from which TEA can be recovered by addition of a strong base such as aqueous NaOH, followed by phase separation.

As used herein or in the claims, reactants and components designated by a chemical name or formula may be referred to by a chemical name or species (eg, another reactant or solvent), even if singular or plural. It is considered the same as existing before coming into contact with the other materials shown. What preliminary chemical changes, transformations and / or reactions take place in the resulting mixture or solution or reaction medium (if any)
It does not matter as such changes, transformations, and / or reactions are the natural consequences of the particular reactants and / or components that are brought together under the conditions required to practice the present disclosure. That is, the reactants and components are the same materials that are involved in performing the desired chemical reaction or that are brought together in forming the mixture used to perform the desired reaction. Accordingly, even if a substance, ingredient, and / or material can be indicated in the present tense in the following claims ("comprising" or "is"), this indication may be expressed in one or more other forms in accordance with this disclosure. Refers to a substance, component or material that is present prior to first contacting, blending or mixing with the substance, component and / or material. Without limiting the generality described above as an illustrative example,
When the claims specify that the catalyst is a palladium compound in combination with a tertiary phosphine ligand, this means that, expressly, the individual substances are combined separately or simultaneously with one or more other materials, And / or to be mixed, and in addition, when the catalyst actually performs its catalytic function, the catalyst need not have the original make-up, but instead has any transformation that occurs in situ as a catalytic reaction (if If any) are intended to be covered by the appended claims. Thus, the fact that a substance, component or material may have lost its identity to its original through a chemical reaction or transformation in the course of the contacting, blending or mixing operation is a consequence of this disclosure and common-sense applications and chemicals. When performed according to one of ordinary skill in the art, there is no problem in accurately understanding and recognizing the true meaning and substance of the present disclosure and the claims.

[0120] Further, expressions herein for the catalyst residue (s) or in the claims herein refer to the composition (s) or form (s).
Nevertheless, it means that a new and / or recycled catalyst is obtained or comes in the course of performing the specified reaction. Without limiting the generality of the foregoing, such residue (s) may be (i) a platinum-containing component (s) or (ii) a phosphorus-containing component (s). ) Or (iii) containing and containing any combination of two or all of the platinum- and phosphorus-containing component (s) or (i), (ii) and (iii). Or may include.

[Procedure amendment]

[Submission date] July 6, 2000 (200.7.6)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0027

[Correction method] Change

[Correction contents]

The partial pressure of carbon monoxide in the reaction vessel is at least about 1 atmosphere ( 101.4 kPa ; 0 psig) at ambient temperature (or the temperature at which the vessel is filled). Any higher carbon monoxide can be used up to the pressure limit of the reactor. Pressures up to about 20786.4 kPa (3000 psig) are convenient in the method. More preferably pressure (from 0 3000psi g) 20786.4kPa to about 101.4 at the reaction temperature, and pressure from about 101.4 to 6996.4KPa (1000 psig 0) is most preferred. It should be noted that the presence of oxygen is undesirable in hydrocarboxylation reactions. Hence, an atmosphere of 100% carbon monoxide is most preferred for carrying out this reaction. A variety of inert gases (nitrogen and argon), however, can be incorporated into the reaction mass, but the only criterion is slowed to the point that this method requires an exceptionally long period of time to complete the reaction It should not be.

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0067

[Correction method] Change

[Correction contents]

The temperature of the reaction in the arylation reaction is very moderate, varying from 25 ° C. to 200 ° C. (preferably 60 ° C. to 150 ° C.), and the pressure (for gaseous vinyl compounds) from atmospheric pressure to about 20785 kPa ( 3000 psi) (preferably about 2068.5 to 6895 kPa; or preferably 300 to 1000 psi) . With the preferred catalyst systems and liquid media cited above, the reaction time is usually short, typically in the range of 1 to 24 hours, typically in the range of 2 to 6 hours, to give a complete reaction. Higher temperatures and lower pressures tend to cause increased by-product formation.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

Preferred and optimal conditions are, to some extent, the nature of the particular raw material used.
(identity). Thus, for example, as an olefin reactant
Ethylene, PdCl as catalyst or catalyst precursor_Two(II) salt and neomenthyldiphenylphosphine (NMDP), such as _Four -C₈Ketones, especially diethyl ketone and C_Four-C₉Trialkylamine
Tribromoamine and 2-bromo-6-methoate using a reaction promoting amount of water.
From xinaphthalene (BMN) to 6-methoxy-2-vinylnaphthalene (MVN)
Is preferably formed, the molar ratio of BMN: Pd: NMDP is preferably 10
00: 3000: 1: 2-10, and the amine: BMN molar ratio was 0.1.
２2: 1, and preferably each in the range 1-2: 1,
The molar ratio of ketone: amine is preferably in the range of 1.0 to 4.0: 1 respectively.
, BMN + ketone + amine + Pd catalyst component + tertiary phosphine ligand + total weight of water
The weight of water based on is preferably in the range of 1 to 3.5 wt%,
The temperature is typically in the range 60 to 150 ° C, and preferably 80 to 11
And the pressure of ethylene used is preferably in the range of 0 ° C.About 2859.4 or less 6996.4kPa (400 to 1000psig) In the range. Under these conditions, there is no reaction
And complete within 24 hours, and such as 95% conversion and 85% yield
Conversion and yield of MVN from 70% to 99% (both based on BMN used)
Olefin time is within 2 to 6 hours. Given in this paragraph
The above mentioned conditions are preferred for performing the specified reaction as stated.
Should be clearly understood. Information presented in this disclosure
On the basis of this, the person skilled in the art can easily operate outside the range given in this paragraph,
And still good results according to the invention can be achieved. Therefore, as described herein
Such arylation reactions are not limited to using the conditions given in this paragraph. Izu
Do this whenever deemed necessary or desirable in any given situation.
Departures from any one or more of these ranges.

[Procedure amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0070

[Correction method] Change

[Correction contents]

Using PdCl ₂ and NMDP at 95 ° C. and about 420 psig ethylene,
A few examples of desirable laboratory reaction parameters for the reaction of MN with ethylene are as follows: a) Relatively fast reaction in the range of 5: 1-6: 1 NMDP: Pd molar ratio. Gives speed: b) gives molar ratios of BMN: Pd: NMDP of 2000: 1: 6, 2500: 1: 5 and 3000: 1: 10 giving high conversion and good yields; 3000: 1: 6 and 3500 The: 1: 5 ratio is operable, but gives a lower conversion. c) Increasing the stirring speed from 300 to 1500 rpm reduces the reaction time to completion to almost 2 hours. d) Good results at a BMN: Pd: NMDP molar ratio of 2000: 1: 6, ethylene pressure in the range of about 1411.4 to 6686.1 kPa (190 psig to 955 psig ) , 95 ° C. Thus, at about 1411.4 kPa ( 190 psig) , the yield of MVN was 86%, and at about 6306.9 kPa (900 psig) , the yield was 96%. At higher pressure ranges, reaction times were shorter and less solid by-product was formed. e) With a BMN: Pd: NMDP molar ratio of 2000: 1: 6, the BMN concentration is 20-35% by weight above the upper end of the range.
When used at the lower end of the range, the MVN yield is higher and the amount of solid by-products formed is lower. f) The reaction with a molar ratio of BMN: Pd: NMDP of 2000: 1: 6 using 1.6% by weight of water as reaction promoter proceeds at 95 ° C. with a reaction rate higher than 85 ° C. g) Maximum reaction rate is about 3 wt% water, operating at 95 ° C, about 2997.3 kPa (420 psig) ethylene, 2000: 1: 6 BMN: Pd: NMDP molar ratio, 30 wt% BMN concentration. Achieved when This rate is about 150% when no water is added. Under these specific conditions, water levels above about 4% will result in termination of the reaction with less than complete conversion. h) Successful use of recycled DEK solvent in four consecutive experiments: no new impurities were found in the MVN product solution after four recycles. The addition of make-up water required to maintain the desired level of water in the reaction mixture is desirable to achieve a beneficial reaction and promotes the effect of water from experiment to experiment.

[Procedure amendment 6]

[Document name to be amended] Statement

[Correction target item name] 0071

[Correction method] Change

[Correction contents]

Accordingly, the reaction of 6-methoxy-2-vinylnaphthalene (MVN) with ethylene
In the production of the 2-bromo-6-methoxynaphthalene (BMN), using palladium (II) salts and Neo-methyl diphenyl phosphine, such as PdCl ₂ a (NMDP) as catalyst or catalyst precursors, the preferred reaction medium is a mixture comprising a C ₄ -C ₈ ketone (especially diethyl ketone) and C ₄ -C ₉ trialkyl amine (especially triethylamine). The reaction medium preferably contains an amount of water that accelerates the reaction in the range of 1 to 3.5 weight percent of the total weight of the reaction mixture. The BMN: Pd: NMDP molar ratio is preferably in the range of 1000: 3000: 1: 2 to 10 respectively (eg 2000: 1: 6 BMN: Pd: NMDP
The molar ratio of amine: BMN is preferably in the range of 1-2: 1 respectively, the molar ratio of ketone: amine is preferably 1.0-4.0: 1, respectively, and the reaction temperature is preferably 80-110. C. (e.g., about 95 DEG C.), and the pressure of ethylene used is preferably about 400-1000 psig (e.g., about 2997.3 kPa or about 420 psig) .

[Procedure amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0076

[Correction method] Change

[Correction contents]

In the reaction represented above, the ethylene pressure should be between about 50-3000 psi ( preferably about 2068.5-6895 kPa; or 300-1000 psi) and the temperature is between 30 ° C. and 200 ° C. Preferably it is 60-150 degreeC). Temperature and pressure are selected to minimize by-product formation. Palladium is preferably used in its salt form (eg, Pd (II) acetate or chloride) together with a tertiary phosphine ligand as described above (ie, placed in the reaction layer) to form neomenthylditolylphosphine. Cycloalkyldi (alkylphenyl) phosphines such as are preferred, and cycloalkyldiphenylphosphines such as neomenthyldiphenylphosphine are particularly preferred.

[Procedure amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0080

[Correction method] Change

[Correction contents]

Example 1 Part A A reaction mass containing racemic 2- (6-methoxy-2-naphthyl) -propionic acid (MNPA) was prepared by previously adding PdCl ₂ , neomenthyldiphenylphosphine (NMDPP) and aqueous HCl. Formed by hydrocarboxylation of 6-methoxy-2-vinyl-naphthalene (MVN) with carbon monoxide in an added tetrahydrofuran-diethyl ketone (THF-DEK) solvent mixture. At the end of the reaction, the reaction mass was treated with aqueous NaOH to neutralize HCl and stripped from the resulting mixture to form THF. The crude MNPA content in the mixture was converted to the sodium salt of MNPA by adding aqueous NaOH to the mixture and reacting with the MNPA therein. A two-phase liquid system was thus formed. MNPA
After removal of the aqueous phase contained in the sodium salt of, the organic phase containing the catalyst residue and other neutral by-products from the hydrocarboxylation was used in another hydrocarboxylation experiment to remove the catalyst residue therein. It was determined whether it could be used as a catalyst source for performing hydrocarboxylation, and the recyclability of this ligand was confirmed. The following is the method used for hydrocarboxylation. To Hastelloy B Parr reactor part B 1 liter, MVN (133.8g, 96.4%, 0.7 molar), PdCl ₂ (0.062 g, 0.00035 mol), of 10 wt% aqueous HCl (60.5 g) and the part A The organic phase cut (414 g) from the hydrocarboxylation experiment was charged. The reaction was carried out at 70 ° C. and carbon monoxide pressure of about 2376.7-2514.6 kPa (330-350 psig) . Samples were removed from time to time and analyzed by GC for completion of the reaction. MVN conversion was 68.3%, 97.5% and 98.6% at 4.5, 6 and 7 hours, respectively. The yield of racemic 2- (6-methoxy-2-naphthyl) -propionic acid was 93.3%.

[Procedure amendment 9]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

Embodiment 2Arylation reaction In a 1000 gallon reactor, 750 kg BMN, 1305 kg DEK, 368 kg TEA, 0.3 kg PdCl _Two Add 3.1 kg of NMDP and 37 kg of water. Close the reaction tank,About 790.9kPa (100psig ) And pressurize the reactor temperature to 95 ° C. Next, the reaction tankAbout 303 1.7-3204.1kPa (420-450psig) And pressurized with ethylene
Maintain this pressure until is complete. Cool the reactor to 60 ° C and remove excess
Vent the ren from the reactor. The reaction typically takes 4-6 hours to complete, and
In many cases,> 95% BMN conversion and 85-95% MVN yield are obtained.Product processing and solvent exchange To the reaction product from the arylation reaction is added 557 kg of a 25% by weight aqueous sodium hydroxide solution. The mixture is heated to 50-60 <0> C for 15 minutes and then allowed to stand for 15 minutes. The bottom aqueous solution is drained from the container. The organic phase is then reduced under reduced pressure, typically from 200 mmHg to 350
Subject to distillation in the range of mmHg to distill TEA until the weight ratio of TEA: MVN is less than 0.016. THF is added to the remaining organic phase (distillate or pot residue) and the weight of THF: DEK in
After forming a mixture with a volume ratio of about 1: 1 the mixture is filtered to remove solids (palladium catalyst residue and oligomeric or dimeric co-products).Hydrocarboxylation reaction 1000 gallon reactor containing 550 kg MVN, 825 kg DEK and 825 kg THF
The filtered THF-DEK-MVN solution produced in the above procedure, followed by 0.3 kg of PdCl_Two, 0.64k
g CuCl_Two, 3.1 kg of NMDP and 200 kg of 10% by weight HCl. The reaction tankAbout 790.9kP a (100psig) And the reactor temperature is adjusted to 70 ° C. next
The reaction tankAbout 2583.6kPa (360psig)Pressurized with carbon monoxide and pressurize this pressure
Maintain until carbon uptake is complete. Then cool the reactor and release the pressure
. The reaction typically takes 4-8 hours to go to> 95% MVN conversion and about 90% racemic 2- (6-methoxy-2-naphthyl) -propionic acid.Racemic product processing and recovery Aqueous sodium hydroxide (25% by weight solution) is added to the reaction vessel and racemic 2- (6-methoxy-2-naphthyl) -propionic acid is converted to racemic 2- (6-methoxy-2-naphthyl) -propionic acid. It is converted to sodium and neutralizes the HCl remaining in the reaction mixture. Then THF
Is distilled from the reaction mixture at atmospheric pressure. (Such a neutralization and distillation step is a reaction
The reverse is possible if the structural material at the top of the tank is resistant to HCl). The aqueous phase formed is separated from the organic phase, which mainly consists of DEK and impurities. Organics (eg, DEK) remaining in the aqueous phase are distilled at atmospheric pressure from the aqueous racemic sodium 2- (6-methoxy-2-naphthyl) -propionate phase. Racemic sodium solution is desirably 10
~ 35% by weight, and this concentration further removes or adds water if necessary
By doing so, it is adjusted to this range. The aqueous racemic sodium phase is then washed with toluene
Purification to remove neutral impurities. Typically 1-3 times, preferably at least
Use two toluene washes. At a suitable temperature, typically 60-80 ° C, racemic 2-
Prevents precipitation of sodium (6-methoxy-2-naphthyl) -propionate. next
The aqueous solution is acidified with sulfuric acid at about 97 ° C. in the presence of toluene. Aqueous phase in reactor
And remove the remaining (±) -2- (6-methoxy-2-naphthyl) -propionic acid in toluene solution at about 95 ° C (typically twice) to remove residual sulfuric acid. I do.
Next, racemic 2- (6-methoxy-2-naphthyl) -propionic acid is crystallized from a toluene solution.
I do.

[Procedure amendment 10]

[Document name to be amended] Statement

[Correction target item name] 0089

[Correction method] Change

[Correction contents]

Example 4 Twelve consecutive arylation experiments were performed in a 2 liter reactor, wherein the material ratios and reaction conditions in the reactor used were the same for each experiment except for some small minor differences. The only independent variable was moisture and their amounts. The reaction mixture of 300 g BMN, DEK of 529~530g, TEA of 147～148G, of PdCl ₂ and 1.2~1.26g of 0.112~0.116g
NMDP. Some experiments were performed without added water, and the remaining experiments measured the amount of water added. All reactions were performed at 95 ° C. under about 2997.3-3204.1 (420-450 psig) of ethylene. The criterion for the reaction rate was the maximum rate of ethylene consumption during each reaction. That is, the higher the value, the better. The results of these experiments on reaction rates are summarized in the table below.

[Procedure amendment 11]

[Document name to be amended] Statement

[Correction target item name] 0090

[Correction method] Change

[Correction contents]

[0090]

[Table 1]

[Procedure amendment 12]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

Example 5 Production of 6-Methoxy-2-vinylnaphthalene 19.45k in a 20 gallon jacketed stainless steel reactor equipped with a stirrer
g of acetonitrile (ACN) and 12.45 kg of 2-bromo-6-methoxynaphthalene (BM
N) and 4.8 g of PdCl ₂ are charged. The reactor is pressurized and evacuated three times with 50 psig of nitrogen. Next, 5.3 kg of ACN and 5.64 kg of triethylamine were added to the reactor.
(TEA). The stirrer is set at 158 rpm and the reactor is pressurized and evacuated three times with about 80 psig of nitrogen. The reactor is then purged with nitrogen for 10 minutes. Next, 48.6 g of neomenthyl diphenylphosphine (NMDP) dissolved in 0.35 kg of TEA
) Put the mixture into the reaction vessel. The agitator is set at 412 rpm and the reactor is heated with jacket steam. The reaction temperature is initially in the range of 91-109 ° C, while the pressure varies between about 412-519 psig . The reaction produces a heat kick and 30
After a minute, the temperature rises to 109 ° C with 26 ° C cooling water in the jacket. The total reaction time is 1.75 hours, 100% BMN conversion. The reactor is cooled, evacuated, and the reaction contents are transferred to a 30 gallon glass lined reactor for processing. Treatment of 6-methoxy-2-vinylnaphthalene The crude 6-methoxy-2-vinylnaphthalene (MVN) solution in a 30 gallon reaction vessel was
Strip ACN to remove ACN. The total stripping time is 6.33 hours, with a maximum bottom temperature of about 91 ° C. The final overhead temperature is about 68 ° C. Use zero reflux for the first 35 minutes of operation. The reflux ratio is then set to 5 and 34.95 kg of diethyl ketone (DEK) are added to the reaction contents. The reflux ratio is maintained at 5 during this stripping.

[Procedure amendment 13]

[Document name to be amended] Statement

[Correction target item name] 0096

[Correction method] Change

[Correction contents]

To the cooled stripping mixture in a 30 gallon reactor was added 8 kg of tetrahydro
Add furan (THF). The resulting MVN solution is used for a 10 micron back filter and
And filtered through a 1 micron cartridge filter.Hydrocarboxylation of 6-methoxy-2-vinylnaphthalene 20 gallon Hastaloy reactorAbout 653kPa (80psig)Purge with nitrogen three times and then 3.8 g of PdCl_TwoAnd 8.8g CuCl_TwoInto the reactor, followed by the MVN solution. The reaction tankAbout 653kPa (80psig)Purge with nitrogen at least 3 times and stirrer at 118 rpm
Set to. Put 3.6 kg of THF and 3.55 kg of 10% HCl into the reactor and re-fill the reactor. About 653kPa (80psig) Purge three times with nitrogen and then dip the nitrogen with the dip leg
Vent through for 10 minutes. Next, put 42.2 g of NMDP and 0.35 kg of THF into the reaction vessel,
Then, the stirrer is set to 402 rpm. Pressurize the reactor andAbout 466.1kPa (50psig) Evacuate three times with CO and then heat to the reaction temperature and pressurize with CO. reaction
The temperature is in the range of 70-78 ° C, while the pressure isApprox. 1804.4 to 3204.1 kPa (247 to 450 psig ) It fluctuates. After a total reaction time of 8.5 hours, the reactor is cooled and evacuated and the contents are
Transfer to a 30 gallon glass lined reactor for processing.Product processing The hydrocarboxylation mixture is neutralized with 20.5 kg of 25% NaOH. THF is stripped from the contents of the processing reactor at atmospheric pressure for 2.5 hours. Water (30.7kg)
Put on strip for 1.4 hours. The final overhead temperature is about 97 ° C and the final bottom temperature is about 108 ° C. 7 kg of 25% NaOH is added to the stripped reactor contents and the mixture is stirred at 50-60 ° C. for 30 minutes. After a standing time of 35 minutes, aqueous
And the organic phase separates from each other. The aqueous phase is added to the treatment reactor with 10 kg of toluene
return. The mixture is stirred for 15 minutes and left at 55 ° C. for 30 minutes. Phases separate again
You. The aqueous phase is returned to the treatment reactor with 10 kg of toluene and the mixture is stirred for 15 minutes.
Stir and let stand. Then the mixture is heated to 65 ° C. and the phases are separated from one another
You. The aqueous phase is again returned to the reactor with 10 kg of toluene. This mixture
Stir for 15 minutes and let stand at 70 ° C. for 30 separations, and final phase cut
Do. The separated aqueous phase was sodium (±) -2- (6-methoxy-2-naphthyl) propionate.
Is a clear, amber aqueous solution of water.

[Procedure amendment 14]

[Document name to be amended] Statement

[Correction target item name] 0097

[Correction method] Change

[Correction contents]

Example 6 The procedure of Example 5 is essentially repeated, with the main changes as described below: The first addition to the first reactor is 21.4 kg of diethyl ketone (DEK), 12.4 kg BMN and 4.6 g of PdCl ₂ . The second addition is 3.2 kg of DEK and 6.34 kg of TEA. TE
Remove the 10 minute nitrogen purge after A addition. Add NMDP (50.9kg) to 0.27kg DEK
Add as a solution in. Pressurization with ethylene begins to about 790.9 kPa (100 psig) before heating of the reactants begins. The arylation reaction is carried out at 92-98 ° C and about 2811.1-3059.3 kPa (393-429 psig) .

[Procedure amendment 15]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

The hydrocarboxylation solvent is a mixture of the residual DEK and 8.2 kg of THF added. Another component to add is 37.9 g NMDP in 3.5 g PdCl ₂ , 7.9 g CuCl ₂ , 3.25 kg 10% HCl, 160 g DEK. The hydrocarboxylation reaction is performed for 8.7 hours, the temperature is in the range of 74-84 ° C, and the pressure is in the range of about 2314.7-3383.4 kPa (321-476 psig) .

[Procedure amendment 16]

[Document name to be amended] Statement

[Correction target item name] 0101

[Correction method] Change

[Correction contents]

Example 7 Production of 6-methoxy-2-vinylnaphthalene 12.8 kg in a 20 gallon jacketed stainless steel reactor equipped with a stirrer
ACN, 12.45 kg DEK and 12.4 kg 2-bromo-6-methoxynaphthalene (BMN), 4.6
g of PdCl ₂ and 50.9 kg of NMDP. The reaction vessel was pressurized, and evacuated three times with nitrogen at about 446.1kPa (50p sig). Next, 6.27 kg of TEA is charged into the reaction tank. 158rp agitator
m and pressurize the reactor and evacuate with 50 psig of nitrogen. The stirrer is set at 416 rpm, the reactor is pressurized with ethylene to about 100 psig and heated with a jacket of conditioned water. Reaction temperature is 87-98 ° C
, While the pressure varies from about 394-458 psig . The total reaction time is 3.5 hours, with 99.6% BMN conversion within 2 hours. The reactor is cooled, evacuated, and at 60 ° C. the contents of the reactor are transferred to a 30 gallon glass lined reactor equipped with a 6 inch column for processing. The 12.5 kg DEK is then charged to a 20 gallon reactor, which is heated to 60 ° C. and transferred to a 30 gallon reactor. Treatment of 6-methoxy-2-vinylnaphthalene The crude 6-methoxy-2-vinylnaphthalene (MVN) solution in a 30 gallon reaction vessel was
Strip ACN to remove ACN. The total stripping time is 4 hours, with a maximum bottom temperature of about 73 ° C. The final overhead temperature is about 59 ° C. The reflux ratios used were 5: 1 1.9 hours, 3: 1 1.6 hours, and 4: 1 1.5 hours.

[Procedure amendment 17]

[Document name to be amended] Statement

[Correction target item name] 0102

[Correction method] Change

[Correction contents]

After charging 9.3 kg of 25% NaOH to the stripped reaction product in a 30 gallon reactor, the resulting mixture is stirred at 35 ° C. for 15 minutes. Then stop the stirrer, and
Let the aqueous phase stand for 30 minutes. The mixture is phase cut and the organic phase
Is washed with 1.2 kg of water for 15 minutes while stirring. After allowing to stand for 30 minutes, perform a further phase cut. The TEA stripping of the organic phase is performed at 150 mmHg. All strips
The ping time is 5.25 hours. The maximum overhead temperature is about 59 ° C and the maximum bottom temperature
Is about 91 ° C. The reflux ratio is 50: 1 at the start and when the column stabilizes,
The reflux ratio was reduced to 5: 1 in 2.25 hours and 7: 1 in the last 2.5 hours of stripping.
And The reaction product is then diluted by adding 12.05 kg of THF and 2.05 kg of DEK to the reaction phase. The resulting solution is then passed through a 10 micron back filter and
And filter through a 1 micron cartridge filter.Hydrocarboxylation of 6-methoxy-2-vinylnaphthalene The filtered MVN solution was placed in a 20 gallon Hastelloy reactor followed by an additional 4.65 kg.
Insert DEK. Then 4.6 g of PdCl_TwoAnd 10.5g CuCl_TwoInto a reaction vessel. The reaction tank About 446.1kPa (50psig) Purge three more times with nitrogen and add 4.2 kg of 10% HCl. Reactor with nitrogenAbout 653.0kPa (80psig)Pressurize and exhaust. 255g DE
Put 50.9 g NMDP solution in K into the reactor and pressurize the reactor, andAbout 446.1k Pa (50psig) The mixture is evacuated twice with nitrogen, and the stirrer is operated only when pressurized. Stirrer speed
Set the degree to 399 rpm and pressurize the reactor andAbout 446.1kPa (50psig)In the CO
Evacuate three times, again operating the stirrer only during pressurization. Next, the reaction tank isAbout 20 32.0kPa (280psig) Press and heat to 75 ° C. Reaction temperature is 73-77 ° C
Range, while the pressure is2438.8-2514.6pKa (339-350psig)It fluctuates. After a total reaction time of 6 hours, the reactor was cooled and evacuated and the contents were processed.
Transfer to a 30 gallon glass lined reaction vessel.Product processing The hydrocarboxylation mixture is neutralized with 2.15 kg of 25% NaOH. THF is stripped from the hydrocarboxylation mixture at atmospheric pressure for 1.2 hours. The final bottom temperature is about 100 ° C and the final overhead temperature is about 92 ° C. Water (3
0.7 kg) into the strip for 1.4 hours. The final overhead temperature is about 97 ° C, and the final bottom temperature is about 108 ° C. Reaction tank stripped of DEK (4.95kg)
To the contents, followed by 14 kg of water and 7.55 kg of 25% NaOH, and the mixture
Stir at 70-80 ° C for 30 minutes. After a standing time of 30 minutes, the aqueous and organic phases are separated from one another.
Let go. The aqueous phase is returned to the treatment reactor and the DEK stripping is at a final bottom temperature of about 95 ° C, and a final overhead temperature of 95 ° C. 2.0 kg of water is added together with 5.15 kg of toluene. The mixture is stirred for 20 minutes and
Allow to stand overnight with conditioned water in jacket. The phases separate. Aqueous phase more than twice
The upper part is washed with toluene (the first time is 5.1 kg, the second time is 4.95 kg), and the phases are separated. The product is sodium (±) -2- (6-methoxy-2-naphthyl) propionate
As an aqueous solution.

[Procedure amendment 18]

[Document name to be amended] Statement

[Correction target item name] 0103

[Correction method] Change

[Correction contents]

Example 8 Preparation of 6-Methoxy-2-vinylnaphthalene In a 20 gallon jacketed stainless steel reactor, 12.5 kg of ACN, 12.5 kg of methyl isobutyl ketone (MIBK) and 12.45 kg of BMN, 4.6 g PdCl ₂ and 50.9 kg N
Insert MDP. The reactor is pressurized and evacuated three times with 50 psig of nitrogen. Next, add 6.8 kg of TEA. The agitator is set at 160 rpm and the reactor is pressurized and evacuated with about 50 psig of nitrogen. The stirrer is set at 415 rpm, the reactor is pressurized to about 790.9 kPa (100 psig) with ethylene, and heated with regulated water in the jacket. Reaction temperatures range from 94-100 ° C, while pressures vary from about 388-432 psig . The total reaction time is 2.6 hours, but approximately
Reach about 99% conversion within 1.8 hours. The reactor is cooled and the ethylene pressure is vented. After about 16 hours of operation with the agitator, the reactor is heated to about 60 ° C. and the contents of the reactor are transferred to a 30 gallon glass lined reactor for processing. 12.4 kg of MIBK is placed in a 20 gallon reaction vessel, which is heated to 60 ° C. and transferred to the treatment reaction vessel. Treatment of 6-methoxy-2-vinylnaphthalene The ACN is removed by stripping the crude MVN solution at 150 mmHg. The total stripping time is 3.3 hours, with a maximum bottom temperature of about 76 ° C. Use a reflux ratio of 50 to perform the column. After the column has stabilized, the reflux ratio is reduced to 5. This reflux ratio is 45
Hold for 3 minutes and then reduce to 3 for 30 minutes. Set the reflux ratio to 2 for the next 55 minutes,
Then switch to a final reflux for at least 25 minutes.

[Procedure amendment 19]

[Document name to be amended] Statement

[Correction target item name] 0105

[Correction method] Change

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The TEA stripping pressure is initially 150 mmHg and through the stripping
Lower to a final value of 70mmHg. The total stripping time is 4.25 hours and the maximum bottom temperature is about 78 ° C. The column starts at zero reflux for the first 35 minutes of operation. This reflux ratio is then set to 5 and maintained for 25 minutes. The reflux ratio is reduced to 2 during the last 3.25 hours of stripping. 8.1 kg of THF in the stripped product mixture
And filter the resulting MVN solution through a 10 micron back filter and a 1 micron cartridge filter. An additional 4.05 kg of THF is charged to the treatment reactor and also filtered. The 6-methoxy-2-vinylnaphthalene hydrocarboxylated MVN solution is transferred to the hydrocarboxylation reactor described above. This is charged with 4.3 kg of PdCl ₂ and 9.8 g of CuCl ₂ . The reactor is purged once with about 50 psig of nitrogen. Set the stirrer to 118 rpm and charge 3.95 kg of 10% HCl. The reactor is pressurized with nitrogen to about 80 psig and evacuated twice (stirring during pressurization and not during evacuation). Charge 47.6 g NMDP solution in 248 g DEK. The agitation speed was set at 401 rpm and the reactor was pressurized and 3 psi with about 446.1 kPa (50 psig) CO.
Evacuate twice (stir during pressurization, do not stir during exhaust). The reaction vessel about 2004.4kPa (276p sig) pressurized with CO up and heated to 75 ° C.. The reactor temperature fluctuates between 72-80 ° C,
And the pressure ranges from about 2404.3 to 2549.1 kPa (334 to 355 psig) . The reaction is stopped after 8.8 hours. The treated (±) -2- (6-methoxy-2-naphthyl) propionic acid solution of the product is placed in the treatment reactor and neutralized with 2.0 kg of 25% NaOH. THF is stripped at atmospheric pressure for 20 minutes. The final bottom temperature is about 79 ° C and the final overhead temperature is about 77 ° C. Cool the stripped mixture to 60 ° C., and add 14.0 kg of water and 8.
Add 0 kg of caustic soda. The mixture is stirred for 30 minutes at 75 ° C. Turn off the stirrer and let the reactor contents stand for 30 minutes. The phases separate. The aqueous phase is returned to the reaction vessel and left stirring for about 16 hours. Next, the aqueous solution is stripped at atmospheric pressure for 1.5 hours. The aqueous phase in the column is cut back to the reactor. Perform another stripping using steam in the jacket. Further distillate is discharged from the column following the strip. The final bottom temperature of this stripping is about 101 ° C, and the final overhead temperature is about 100 ° C. An addition of 5.05 kg of toluene is added to the stripped product mixture, and the mixture is stirred at 68 ° C. for 20 minutes and then allowed to stand 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, resulting in a reddish-purple clear aqueous solution and a cloudy olive-green organic solution. Third toluene wash (
5.05 kg, 71 ° C.) yields a clear purple aqueous solution and a cloudy yellow organic solution.

[Procedure amendment 20]

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[Correction target item name] 0106

[Correction method] Change

[Correction contents]

Example 9 The procedure of Example 8 is essentially repeated, with the main changes as described below: The first addition to the first reactor is 12.4 kg ACN, 12.65 g DEK, book Example 8 of description
12.45 kg of BMN, 4.6 g of PdCl ₂ and 51 g of NMDP produced in the above. The second addition is 6.
17 kg TEA. The 2.5 hour arylation reaction is performed at 88-99 ° C. and about 318-458 psig .

[Procedure amendment 21]

[Document name to be amended] Statement

[Correction target item name] 0108

[Correction method] Change

[Correction contents]

The hydrocarboxylation solvent is a mixture of the residual DEK and about 12 kg of added THF. Another component to add is 44.7 g NMDP in 4.1 g PdCl ₂ , 9.2 g CuCl ₂ , 3.65 kg 10% HCl, 222 g DEK. The hydrocarboxylation reaction is performed for 6.6 hours, the temperature is in the range of 74-77 ° C, and the pressure is in the range of about 2397.4-2569.8 kPa (333-358 psig) .

[Procedure amendment 22]

[Document name to be amended] Statement

[Correction target item name] 0110

[Correction method] Change

[Correction contents]

Example 10 The procedure of Example 8 is essentially repeated, with the main changes as described below: The first addition to the first reactor is 12.55 kg of ACN, 12.5 g of MIBK, 12.5 kg of BMN, 4.6 g of PdCl ₂ and 51 g of NMDP produced in Example 8 of the specification. The second addition is 6
.19 kg TEA. The 2.7 hour arylation reaction is performed at 88-97 ° C and about 371-441 psig .

[Procedure amendment 23]

[Document name to be amended] Statement

[Correction target item name] 0112

[Correction method] Change

[Correction contents]

The hydrocarboxylation solvent is a mixture of the residual MIBK and about 12 kg of added THF. Another component to add is 4.6 g PdCl ₂ , 9.5 g CuCl ₂ , 3.85 kg 10% HCl, 226
47g NMDP in g DEK. The hydrocarboxylation reaction is carried out for 7 hours and the temperature is 7 hours.
The pressure ranges from 2 to 77 ° C, and the pressure ranges from about 333 to 357 psig .

[Procedure amendment 24]

[Document name to be amended] Statement

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[Correction method] Change

[Correction contents]

Embodiment 11Bromination of 2-naphthol 2-naphthol (144.8 g, 1.00 mol), EDC (537 g) and water (162 g)
Reflux cooler, mechanical stirrer and peristaltic pump addition system
Put in the tank. Heat the reactor to about 55 ° C until most of the β-naphthol is dissolved. Bromine (336.9 g, 2.11 mol) is then added through the pump at a rate such that the reaction temperature is maintained at 60 ° C. (subsurface). After the addition of bromine, the reaction temperature is raised to 60 ° C. 1.
Hold for 5 hours. The reaction is then cooled slowly and the lower phase (aqueous HBr) is blotted
You. The remaining EDC solution (841 g) is removed from the reactor and analyzed by GC. In experiments performed in this manner, analysis showed 0.4% of 2-naphthol, 92.6% of 1,6-dibromo-2-naphthol (DBN), and 4.9% of the other isomer.Hydrodebromination of 1,6-dibromo-2-naphthol DBN (271 g) in ethylene dichloride (EDC) (551 g) obtained by bromination reaction
, 0.9 mol) into a 1000 mL Hastalloy B autoclave. Tungsten carbide (82 g, 30% by weight) and tetrabutylammonium bromide (0
.2 g, 0.1% by weight) and seal the reaction vessel. Purging the reactor with hydrogen ( About 446.1kPa (50psig) ) And evacuate three times and then pressurize with hydrogen and 90
Heat to ° C. When purging hydrogen, the pressureAbout 928.8-963.2kPa (120-125psig)Keep it constant so that it stays within the range. Analysis of the reaction mixture formed after 5.5 hours in this manner shows 90% 6-bromo-2-naphthol, 2% DBN and 2% 2-naphthol
It has been shown. Cool the reactor to room temperature, evacuate to a dust collector, and precipitate the catalyst
. The EDC solution (747 g in a reaction performed in this manner) is collected through a dip tube.Methylation of 6-bromo-2-naphthol with MeCl 1.4 liter (3 pint) stainless steel EDC solution generated as above
Place in a Chemco glass reactor equipped with a head. Neutralize this with the diluted acid first,
Then it is concentrated by distillation. Add water (50 mL) to remove azeotropically trace amounts of EDC remaining in the residue. Isopropyl alcohol (242g) and sodium hydroxide
(44 g, 1.1 mol; 88 g of a 50% solution) is charged to the reaction vessel. The reaction vessel is sealed, purged with nitrogen and heated to 70 ° C. Methylene chloride (66 g, 1.3 mol) for 1 hour
Span(377.2-446.1kPa) (40-50psig). After stirring at 80 ° C for another hour, isopropyl alcohol is distilled off. Heat the residue to dissolution conditions (90-95 ° C)
And then wash with water (400 g). Remove the water and remove the residue under vacuum (1 mmHg)
Distill with. After removing a small amount of volatiles, the BMN is distilled as a white solid at 160-165 ° C (operating in this manner produces 169 g). Isopropyl alcohol(
490 g) are added and the solution is heated to reflux and slowly cooled to about 10 ° C.
The solid BMN is removed and washed with cold (0 ° C) isopropyl alcohol (180 g) and then dried under vacuum at 70-75 ° C. The white color thus formed
Analysis of the crystalline product showed 99.7% by weight of BMN.

────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Chiyokalingham, Canapan Sea, 70816 Baton, Louisiana, United States of America 70,000 Ruton New Jacuzzi avenue 12074 (72) Inventor Huocto, Gary Day 70808 Baton, Louisiana, United States of America 70808 Baton, Luigiille Cloverdale 1956 F-term (reference) 4H006 AA02 AC21 AD16 BA25 BA28 BA37 BA48 BB25 BD41 BD51 BE40 BJ50 BS10 4H039 CA65 CF10

Claims (31)

[Claims] 1. A) reacting an aryl olefin with carbon monoxide and water in the presence of at least (1) palladium or a palladium compound and (2) a palladium catalyst freshly formed from an organic phosphine ligand; Forming a reaction mass comprising (a) an arylcarboxylic acid and (b) one or more residual catalyst species; B) mixing at least a portion of such reaction mass and an aqueous inorganic base together (
i) an aqueous phase comprising a water-soluble salt of an arylcarboxylic acid dissolved therein; and (ii)
A) forming an organic phase having at least a portion of the residual catalyst species dissolved therein; c) separating these phases, and replacing at least a portion of the separated phase (ii) with A) according to A). Recycling to A) for use in carrying out the reaction. 2. The palladium catalyst of A) comprising the residual catalyst species contained in that portion of the separated phase (ii) which is recycled to A) following C). The method described in. 3. The palladium catalyst of A) comprising: I) a fresh catalyst formed at least from (1) palladium or a palladium compound and (2) an organic phosphine ligand; and II) following A) following C) The method of claim 1 comprising the remaining catalyst species contained in that portion of the separated phase (ii) to be recycled. 4. The process according to claim 1, wherein the reaction in A) is carried out in the presence of an additional aqueous hydrochloric acid. 5. The palladium catalyst of A) comprising the remaining catalytic species contained in that portion of the separated phase (ii) recycled to A) following C), The catalytic species is originally formed by the addition of (1) at least one palladium compound and (2) tertiary phosphine to the mixture subjected to the reaction of A).
The method according to claim 4. 6. The palladium catalyst of A) comprising: I) a fresh catalyst formed at least from (1) at least one palladium compound and (2) tertiary phosphine; and II) following A) following C) 5. The method of claim 4, comprising the remaining catalyst species contained in that portion of the separated phase (ii) that is recycled. 7. The method of claim 4, wherein the reaction of A) is performed in the presence of at least one additional organic solvent / diluent. 8. The palladium catalyst of A) comprising the remaining catalyst species contained in that portion of the separated phase (ii) that is recycled to A) following C), 8. A process according to claim 7, wherein the catalytic species is originally formed by the addition of (1) at least one palladium (II) salt and (2) trihydrocarbylphosphine to the mixture subjected to the reaction of A). 9. The palladium catalyst of A) comprising: I) (1) a fresh catalyst formed at least from at least one palladium (II) salt and (2) trihydrocarbylphosphine; and II) C) 8. The process of claim 7, comprising the remaining catalyst species contained in that portion of the separated phase (ii) recycled to A). 10. The reaction of A) wherein at least one ether which boils at a lower temperature than said aryl carboxylic acid, and more sufficiently than said ether to enable said ether to be stripped from said reaction mass. 5. The method of claim 4, wherein the reaction is carried out in the presence of at least one ketone boiling at the above temperature and at least a portion of the ether is stripped from the reaction mass after completing the reaction of A). Method. 11. The palladium catalyst of A) comprising the remaining catalyst species contained in that portion of the separated phase (ii) recycled to A) following C),
Said residual catalytic species have (1) at least one palladium (II) halide or carboxylate and (2) at least two aryl groups in the molecule to the mixture subjected to the reaction of A). 11. The method of claim 10, wherein the method was originally formed by the addition of trihydrocarbyl phosphine. 12. The method of claim 1, wherein the palladium catalyst of A) comprises: (1) at least one palladium (II) to the mixture subjected to the reaction of A)
Fresh catalyst formed by the addition of a halide or carboxylate and (2) a trihydrocarbylphosphine having at least two aryl groups in the molecule; and II) the separated, recycled to A) following C) 11. The method of claim 10, comprising the residual catalyst species contained in said portion of phase (ii). 13. The method of claim 1, wherein the ether consists essentially of tetrahydrofuran, the ketone consists essentially of diethyl ketone, and at least a portion of the tetrahydrofuran is stripped from the reaction mass before performing B).
The method according to 0. 14. The palladium catalyst of A) comprising the remaining catalyst species contained in that portion of the separated phase (ii) recycled to A) following C),
14. The method of claim 13, wherein the residual catalyst species is originally formed by the addition of (1) palladium (II) chloride and (2) neomenthyldiphenylphosphine to the mixture subjected to the reaction of A). 15. The palladium catalyst of A) comprising: (I) palladium (II) chloride and (I) to a mixture subjected to the reaction of A)
2) fresh catalyst formed by the addition of neomenthyl diphenylphosphine, and II) the remaining catalyst species contained in that part of the separated phase (ii) which is recycled to A) following C) 14. The method of claim 13, wherein the method comprises: 16. The reaction of A) is carried out in a liquid medium comprising a polar organic solvent, water and HCl; the phase formed in B) is (iii) present, albeit in said solid phase Or a solid phase containing palladium and / or one or more palladium compounds in any chemical composition in which they are present; and in C) the aqueous phase, the organic phase and the solid phase The method of claim 1, wherein the method is separated from: 17. In any chemical composition in which the separated solids-free organic phase being recycled to A) is dissolved in said separated solids-free organic phase while it is present 17. The method according to claim 16, further comprising at least one organic phosphine ligand. 18. The separated organic phosphine ligand in the reaction mass of A), but in any chemical composition (s) in which it is present, and which has been recycled to A). 20. The method of claim 17, wherein the trihydrocarbyl phosphine in any chemical composition (s) dissolved in the solid-free organic phase while it is present. 19. The separated organic phosphine ligand in the reaction mass of A), but in any chemical composition (s) in which it is present and which is recycled to A). 18. The method according to claim 17, wherein neomenthyldiphenylphosphine is in any chemical composition (s) which is present while dissolved in an organic phase which does not contain solids. 20. The method according to claim 16, wherein the palladium value is recovered from at least a part of the solid phase separated in C). 21. A portion of a polar organic solvent is removed from the reaction mass of A) to form a more concentrated reaction product mixture, and such a more concentrated reaction product mixture is a mixture of the aqueous inorganic of B) 17. The method of claim 16, wherein said portion of the reaction mass is mixed with a base. 22. Recovering at least a portion of the solid phase and using the recovered solid phase for fresh palladium-containing use in performing an additional reaction with the aryl olefin carbon monoxide according to A). 22. The method of claim 21, further comprising converting to a catalyst. 23. The process of claim 21, wherein the catalyst is freshly formed from (1) a palladium (II) halide or carboxylate and (2) a trihydrocarbylphosphine ligand. 24. The aryl halide used in A) is converted to a palladium aryl halide using the olefin in a reaction mixture formed from at least an aryl halide, a polar organic solvent, a hydrogen halide acceptor and a palladium vinylation catalyst. To carry out at least the arylolefin, polar organic solvent, hydrogen halide and hydrogen halide acceptor products as components and catalyst residue (s) in any chemical composition The method of claim 1, further comprising producing a reaction product mixture comprising: and forming the respective components present in the reaction product mixture. 25. I) The aryl olefin used in A) is an aryl halide using the olefin in a reaction mixture formed from at least an aryl halide, a polar organic solvent, a hydrogen halide acceptor and a palladium vinylation catalyst. The palladium catalyzed vinylation of is carried out to produce at least the aryl olefins, polar organic solvent, hydrogen halide and hydrogen halide acceptor products as components and catalyst residues (one or more) in any chemical composition Multiple)
Producing a reaction product mixture comprising: and forming said respective components present in said reaction product mixture; and II) as if that were the case, A) a part of the reaction mixture for the reaction between the aryl olefin according to A) and carbon monoxide, or (ii) to serve as part of a reaction mixture for said palladium-catalyzed vinylation of aryl halides. Recycling at least a portion of the separated organic phase containing dissolved catalyst residue (s) to the palladium-catalyzed vinylation of A) or an aryl halide; or A portion of the reaction mixture for the reaction between the aryl olefin and carbon monoxide according to (i) A), respectively. And (ii) separating the separated organic phase containing dissolved catalyst residue (s) to serve as part of the reaction mixture for the palladium-catalyzed vinylation of the aryl halide. 17. The method of claim 16, further comprising recycling a portion of A) to the palladium-catalyzed vinylation of the aryl halide and the aryl halide. 26. Recovering at least a portion of said solid phase and subjecting the recovered solid phase to (i) the reaction between an aryl olefin and carbon monoxide according to A), and / or (ii) the aryl 26. The method of claim 25, further comprising converting the halide to fresh palladium-containing catalyst for use in performing the palladium-catalyzed vinylation. 27. The method of claim 25, wherein the vinylation catalyst is formed at least freshly from (1) palladium or a palladium compound and (2) an organic phosphine ligand. 28. The method of claim 25, wherein the vinylation catalyst is formed at least freshly from (1) a palladium (II) halide or carboxylate and (2) a trihydrocarbylphosphine ligand. 29. The palladium catalyst of A) is fresh (1) palladium (II)
26. The method of claim 25, wherein the method is formed at least from a halide or carboxylate and (2) a trihydrocarbylphosphine ligand. 30. The vinylation catalyst is freshly formed at least from (1) a palladium (II) halide or carboxylate and (2) a trihydrocarbylphosphine ligand, and the palladium catalyst of A) is freshly formed. 26. The method of claim 25, wherein the method is formed at least from (1) a palladium (II) halide or carboxylate and (2) a trihydrocarbylphosphine ligand. 31. The trihydrocarbylphosphine ligand forming the vinylation catalyst is fresh neomenthyldiphenylphosphine, and the trihydrocarbylphosphine ligand forming a palladium catalyst in A) is fresh neomenthyldiphenyl. 31. The method of claim 30, which is a phosphine.