MXPA98002946A - Process for preparing carboxylic acids optically acti - Google Patents

Abstract

This invention relates to a process for preparing optically active carboxylic acids by oxidizing an optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide selected from the group consisting of a substituted or unsubstituted alkylamine, N- alkylamine oxide, aromatic amine, aromatic amine N-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof, in order to produce the optically active carboxylic acid. These optically active carboxylic acids have utility for example in pharmaceutical compounds

Description

"PROCESS FOR PREPARING OPTICALLY ACTIVE CARBOXYLIC ACIDS" BRIEF DIGEST OF THE INVENTION RELATED REQUESTS The following are the commonly assigned applications filed on the same date as this: US Patent Application Serial Number (D-17378) and US Patent Application Serial Number Serial Number (D-17379), both of which are incorporated in the present by reference.

TECHNICAL FIELD This invention relates to a process for preparing optically active carboxylic acids, by oxidizing an optically active aldehyde with a peracid, in the presence of an amine catalyst and / or amine N-oxide to produce the optically active carboxylic acid.

BACKGROUND OF THE INVENTION Asymmetric synthesis is of importance, for example, in the pharmaceutical industry, since frequently only one optically active isomer (enantiomer) is therapeutically active. An example of this pharmaceutical product is the non-steroidal anti-inflammatory drug naxopren. The S-enantiomer is a potent anti-arthritic agent while the R-enantiomer is a liver toxin. Therefore, it is often desirable to selectively produce a specific enantiomer in relation to its mirror image. It is known that special precautions must be taken to ensure the production of a desired enantiomer, due to the tendency to produce optically inactive racemic mixtures, ie, equal amounts of each mirror image enantiomer, whose opposite optical activities are canceled one with respect to the another, or partially optically active mixtures, that is, others that are not of equal amounts of each enantiomer that can be viewed as a mixture of the optically inactive racemic mixture, and of the enantiomer of optically active ratio that is in excess. In order to obtain the desired enantiomer (or the mirror image stereoisomer) of this racemic mixture, the racemic mixture must be separated into its optically active components. This separation, known as optical resolution, can be carried out by effective physical classification, direct crystallization of the racemic mixture or other methods known in the art (see, for example, US Patent Number 4,242,193). These optical resolution procedures are often laborious and costly as well as destructive to the desired enantiomer. Due to these difficulties, an increased attention has been focused on asymmetric synthesis, in which one of the enantiomers is obtained in significantly larger amounts than the other enantiomer. Efficient asymmetric synthesis provides a high degree of control in stereoselectivity and, desirably, regioselectivity when applicable, e.g., the branched / normal isomer ratio in the hydroformylation of alpha-olefin.

EXHIBITION OF THE INVENTION This invention relates to a process for producing an optically active carboxylic acid, which process comprises oxidizing an optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide, which is selected from the group consisting of a substituted or unsubstituted alkylamine, alkylamine N-oxide, aromatic amine, aromatic amine N-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof, to produce the optically active carboxylic acid, wherein the catalyst of amine and / or of N-oxide of amine has a sufficient basicity to catalyze the oxidation of the optically active aldehyde in an optically active carboxylic acid. This invention also relates to a process for producing an optically active carboxylic acid, which process comprises: (1) reacting a prochiral or chiral compound with carbon monoxide and hydrogen, in the presence of an optically active metal complex catalyst / coordinator group in order to produce an optically active aldehyde; and (2) oxidizing the optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide selected from the group consisting of a substituted or unsubstituted alkylamine, alkylamine N-oxide, aromatic amine, Aromatic amine n-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof, in order to produce the optically active carboxylic acid, wherein the amine catalyst and / or amine N-oxide has sufficient basicity to catalyze the oxidation of the optically active aldehyde, in optically active carboxylic acid. This invention is further related to a process for producing an optically active carboxylic acid, which process comprises: (1) reacting a prokaryl or chiral olefinically unsaturated organic compound with carbon monoxide and hydrogen in the presence of an optically active rhodium complex catalyst - coordinating group in order to produce an optically active aldehyde; and (2) oxidizing the optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide, which is selected from the group consisting of a substituted or unsubstituted alkylamine, alkylamine N-oxide, amine aromatic, aromatic amine N-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof, in order to produce the optically active carboxylic acid, wherein the amine catalyst and / or amine N-oxide has a sufficient basicity to catalyze the oxidation of optically active aldhehyde in an optically active carboxylic acid.

DETAILED DESCRIPTION FORMATION OF THE MIXTURE OF THE ENANTIOMERIC ALDEHYDE This invention includes first providing a mixture of suitable enantiomeric aldehyde. These mixtures can be provided by known processes such as non-asymmetric processes (e.g., hydroformylation or asymmetric, non-asymmetric olefin isomerization or non-asymmetric aldol condensation) followed by conventional resolution processes (e.g., chromatography, kinetic resolution or other known resolution methods). However, mixtures of the enantiomeric aldehyde are preferably provided by carrying out any of the known conventional non-asymmetric syntheses of the aldehyde mixtures in an asymmetric manner. In these preferred processes, the catalyst of a conventional non-asymmetric synthesis is replaced by a complex catalyst of an optically active metal and a coordinating group and the process is carried out to produce an appropriate optically active aldehyde mixture. They are illustrative of these asymmetric processes and include, for example, asymmetric hydroformylation, asymmetric olefin isomerization and asymmetric aldol condensation. Preferably, the first step of the process of this invention comprises forming a mixture of the enantiomeric aldehyde by asymmetric hydroformylation. These asymmetric hydroformylation processes involve the use of a complex catalyst of optically active metal-phosphorus coordinating group and, optionally, the free coordinating group to produce optically active aldehydes by reacting a pro-chiral or chiral olefinic compound, with carbon monoxide and hydrogen. The optically active aldehydes produced in this first preferred step of the process of this invention are the compounds obtained by the addition of an olefinically unsaturated formyl group in the starting material, with the simultaneous saturation of the olefinic bond. The processing techniques of this preferred first step of the process of this invention may correspond to any of the known processing techniques employed hitherto in conventional asymmetric synthesis reactions, including asymmetric hydroformylation reactions. For example, asymmetric processes can be carried out in a continuous, semi-continuous or intermittent manner and can involve a liquid recycling operation if desired. This step of the asymmetric hydroformylation process is preferably carried out intermittently. Also, the manner or order of addition of the reaction ingredients, the catalyst and the solvent, are also not critical and can be achieved in any conventional manner. Alternatively, in the first step in the process of this invention, asymmetric olefin isomerization can be carried out in accordance with conventional procedures known in the art, in order to produce the enantiomeric aldehyde mixtures used in this invention. For example, allyl alcohols can be isomerized under isomerization conditions in the presence of a complex catalyst of the optically active metal and the coordinating group described herein, to produce optically active aldehydes. Also alternatively, as the first step in the process of this invention, the asymmetric aldol condensation can be carried out in accordance with conventional procedures known in the art in order to produce the enantiomeric aldehyde mixtures used in this invention. For example, optically active aldehydes can be prepared by reacting a prochiral aldehyde and an enol silyl ether under aldol condensation conditions, in the presence of a complex catalyst of an optically active metal and a coordinating group as described herein. . In general, the asymmetric synthesis processes mentioned above are carried out in a liquid reaction medium containing a solvent for the optically active catalyst., preferably in one wherein the reaction ingredients, including the catalyst are essentially soluble. In addition, it may be desirable for the asymmetric processes to be carried out in the presence of a free coordinating group, as well as in the presence of the optically active complex catalyst. By the term "free coordinating group" is meant a coordinating group that is not complexed with the metal atom, in the optically active complex catalyst. The prochiral and chiral starting materials useful in the processes for producing the mixtures of the enantiomeric aldehyde employed in the process of this invention, are selected depending on the specific asymmetric synthesizing process that is used. These starting materials are well known in the art and can be used in conventional amounts in accordance with conventional methods. Illustrative starting material reagents include, for example, substituted and unsubstituted aldehydes (for aldol condensation processes), prochiral olefins (for hydroformylation processes) and ketones (for aldol condensation processes (and the like). illustrative olefin starting material reagents useful in certain of the asymmetric synthesis processes to produce the mixtures of the enantiomeric aldehyde employed in this invention (e.g., asymmetric hydroformylation), include those which may not be terminally or internally saturated and The olefins may contain from 2 to 40 carbon atoms or more and may contain one or more unsaturated or ethylenic groups, and these olefins may contain non-interfering groups or sub-constituents. detrimentally in an essential way with the process of asymmetric synthesis such as carbonyl , carbonyloxy, oxy, hydroxy, oxycarbonyl, halogen, alkoxy, aryl, haloalkyl and the like. Exemplary olefinic unsaturated compounds include substituted and unsubstituted alpha-olefin, internal olefins, alkyl alkenoates, alkenyl alkanoates, alkenyl alkyl ethers, alkenols and the like, e.g., 1-butene, 1-pentene, 1- hexene, 1-octene, 1-decene, 1-dodecene, 1-octadecene, 2-butene, isomylene, 2-pentene, 2-hexene, 3-hexene, 2-heptene, cyclohexene, propylene dimers, propylene trimers, tetramers of propylene, 2-ethylhexene, 3-phenyl-1-propene, 1,4-hexadiene, 1,7-octadiene, 3-cyclohexyl-1-butene, alcoolic alcohol, hex-l-en-4-ol, oct -l-en-4-ol, vinyl acetate, allyl acetate, 3-butenyl acetate, vinyl propionate, allyl propionate, allyl butyrate, methyl methacrylate, 3-butenyl acetate, vinylethyl ether, ether of allylethyl, n-propyl-7-octenoate, 3-butenonitrile, 5-hexanamide, styrene, norbornene, alpha-methylstyrene and the like. Preferred illustrative olefinic unsaturated compounds include, for example, p-isobutylstyrene, 2-vinyl-6-methoxynaphthalene, 3-ethenylphenylphenyl ketone, 4-ethenylphehyl-2-thienylketone, 4-ethenyl-2-fluorobiphenyl, 4- (1, 3- dihydro-l-oxo-2H-isoindol-2-yl) styrene, 2-ethenyl-5-benzoylthiophene, 3-ethenylphenyl- - - phenyl ether, propenylbenzene, isobutyl-4-propenylbenzene, phenylvinyl ether, vinyl chloride and the like. Appropriate olefinic unsaturated compounds useful in certain asymmetric synthesis processes of this invention include the substituted aryl ethylenes described in the North American Patent Number 4,329,507, the disclosure of which is incorporated herein by reference. Mixtures of different olefinic starting materials can be used, if desired, in the synthesis processes asymmetric used as the first step of the process of this invention. More preferably, the first step involves hydro- or: n? - ar alpha-olefms containing from 4 to 40 carbon atoms or a larger number and internal olefins containing from 4 to 40 carbon atoms or a number major, and mixtures of these alpha-olefins and the internal olefins. Illustrative prochiral and chiral olefins useful in the processes that can be employed to produce the mixtures of the enaniomeric aldehyde that can be employed in this invention include those represented by the formula: £ > \ / / \ ^ 25 - "t, sr -" ..? - x? ----- íw. A .. * ss-jAí "- ... i * ..-. wherein R ^, R2, R3 and R4 are the same or different (with the proviso that R ^ is different from R2 or R3 is different from R4) and are selected from hydrogen; I rent; substituted alkyl; the substitution being selected from dialkylamino such as benzylamino and dibenzylamino, alkoxy such as methoxy and ethoxy, acyloxy such as acetoxy, halo, nitro, nitrile, thio, carbonyl, carboxamide, carboxaldehyde, carboxyl, carboxylic ester; aryl including phenyl; substituted aryl including phenyl, the substitution of alkyl, amine including alkylamino and dialkylamino such as benzylamino and dibenzylamino, hydroxy, alkoxy such as methoxy and ethoxy, acyloxy such as acetoxy, halo, nitrile, nitro, carboxyl, carboxaldehyde, carboxylic ester, carbonyl and thio; acyloxy such as acetoxy; alkoxy such as methoxy and ethoxy; amine including alkylamino and dialkylamino such as benzylamine and dibenzylamine, acylamino and diacylamino such as acetylbenzylamino and diacetylamino; nitro; carbonyl; nitrile; carboxyl; carboxamide; carboxaldehyde; carboxylic ester; dialkylmercapto such as methylmercapto. It will be understood that the prochiral and chiral olefins of this definition also include molecules of the aforementioned general formula wherein the R groups are connected to form the ring compounds, e.g., 3-methyl-1-cyclohexane and the like.

The optically active catalyst useful in the production of aldehyde mixtures which are employed in this invention includes an optically active metal complex catalyst and coordinating group wherein the coordinating group is optically active, preferably optically pure. The permissible metals that constitute the optically active metal complexes and coordinating group include Group VIII metals that are selected from rhodium (Rh), cobalt (Co), iridium (Ir), Ruthenium (Ru), Iron (Fe), nickel ( Ni), palladium (Pd), platinum (Pt), Osmium (Os) and mixtures thereof, with the preferred metals being rhodium, cobalt, iridium and ruthenium, most preferably rhodium and ruthenium, especially rhodium. Other permissible metals include Group IB metals that are selected from copper (Cu), silver (Ag), gold (Au) and mixtures thereof, and also Group VIB metals that are selected from chromium (Cr), molybdenum (Mo), Tungsten (W) and mixtures thereof, and also the metals of the Group VA that are selected from arsenic (As), and antimony (Sb) and mixtures thereof. The mixtures of the metals of Group VIII, Group IB, Group VIB and Group VA can be used in this invention. It should be noted that the satisfactory practice of this invention does not depend on or is predicated on the exact structure of the complex species of the optically active metal and coordinating group, which may be present in its mononuclear forms, dinuclear or superior nuclearity, with the exception that the coordinating group is optically active. Of course, the exact optically active structure is not known. Although it is not intended herein to be bound by any theory or mechanistic dissertation, it appears that the optically active catalytic species may in its simplest form consist essentially of the metal in the complex combination or in the optically active coordinating group and, in the hydroformylation, carbon monoxide, hydrogen and an olefin. The term "complex" as used herein and in the claims means a coordination compound formed by the union of one or more electronically rich molecules or atoms, capable of existing independently with one or more electronically deficient molecules or atoms, each of which is also able to exist independently. For example, the preferred optically active coordinator groups employable herein, ie, the phosphorus coordinator groups may possess one or more phosphorus donor atoms, each having a pair of available or non-shared electrons that each is capable of forming a covalent bond independently coordinated or possibly in a manner that matches (eg, through chelation) with the metal. As may be assumed from the aforementioned discussions, carbon monoxide (which is also appropriately classified as a coordinating group) may also be present and complexed with the metal. The final composition of the optically active complex catalyst may also contain an additional coordinating group eg, hydrogen or an anion which satisfies the coordination sites or the nuclear charge of the metal. Illustrative additional coordinating groups include e.g., halogen (Cl, Br, I), alkyl, aryl, substituted aryl, acyl, CF3, C2F5, CN, R2PO and RP (0) (OH) O (wherein each R is alkyl or aryl) acetate, acetylacetonate, S04, PF, PF6, N02, N03, CH3O, CH2 = CHCH2, C6H5CN, CH3CN, NO, NH3, pyridine, (C2H5) 3N, mono-olefins, diolefins and triolefins, tetrahydrofuran and similar. Of course it will be understood that the species of the optically active complex is preferably free of any additional organic coordinating group or anion that could contaminate the catalyst and have an undue detrimental effect on catalyst performance. It is preferred in the rhodium-catalyzed asymmetric hydroformylation directions of this invention that the active catalysts be free of halogen and sulfur directly linked to rhodium, although this may not be absolutely necessary.

The number of coordination sites available in these metals is well known in the art. In this way, the optically active species can comprise a mixture of the complex catalyst in its monomeric, dimeric, higher-nuclear forms, which are preferably characterized by at least one phosphorus-containing molecule complexed by a rhodium molecule. As mentioned above, it is considered that the optically active species of the preferred rhodium catalyst used in this invention during asymmetric hydroformylation can be complexed with carbon monoxide and hydrogen in addition to the optically active phosphorus coordinating groups, in view of the carbon monoxide gas and hydrogen used by the asymmetric hydroformylation process. In addition, regardless of whether the optically active complex catalyst is formed prior to introduction into the reaction zone or if the active catalyst is prepared in situ during the reaction of asymmetric synthesis processes (especially asymmetric hydroformylation processes) if desired , it can be carried out in the presence of a free coordinating group. The coordinating groups capable of being employed to produce the mixtures of the enantiomeric aldehyde useful in this invention include those optically active coordinating groups having the general formula: where each W is the same or different and is phosphorus, arsenic or antimony, each X is the same or different and is oxygen, nitrogen or a covalent bond that intertwines W and Y, Y in a substituted or unsubstituted hydrocarbon residue N-valent , each Z is the same or different and is a substituted or unsubstituted hydrocarbon residue, preferably a hydrocarbon residue containing at least one heteroatom that is bonded to, or Z-substituents linked to W can be connected together to form a residue of substituted or unsubstituted cyclic hydrocarbon, preferably a cyclic hydrocarbon residue containing at least two heteroatoms which are each linked to W, and M is a value equal to the free valence of Y, preferably a value of 1 to 6, with - 1 the proviso that at least one of Y and Z is optically active. Referring to the aforementioned general formula, it is appreciated that when m is a value of 2 or greater, the coordinating group may include any combination of permissible cyclic hydrocarbon residues and / or acyclic hydrocarbon residues that satisfy the valence of Y. it will be appreciated that the hydrocarbon residues represented by Z may include one or more heteroatoms and this heteroatom may be directly linked to W. The optically active coordinating groups in the aforementioned general structure should be capable of being easily ascertained by a person skilled in the art. . Illustrative optically active coordinating groups capable of being employed in the first step of the processes of this invention include those of the formulas: wherein W, Y, Z and m are as defined above, in Y "» 'is the same or different and is hydrogen or a substituted or unsubstituted hydrocarbon residue. Illustrative preferred optically active coordinating groups encompassed by the aforementioned formulas include, for example, (poly) phosphites, (poly) phosphinites, (poly) phosphonites and the like. Illustrative preferred optically active coordinating groups that are capable of being employed in this invention include the following: (i) optically active polyphosphites having the formula: wherein each Ar group is the same or different and is a substituted or unsubstituted aryl radical; Y 'is a substituted or unsubstituted m-valent hydrocarbon radical which is selected from alkylene, alkylene-alkylene, arylene and arylene- (CH2) and- (Q) n- (CH2) y-arylene; each y is the same or different and is a value of 0 or 1; each n is the same or different and is a value of 0 or 1; each Q is the same or different and is a substituted or unsubstituted divalent connection group selected from -SR ^ -R2-, -O-, -S-, -NR3-, -SiR R5- and -CO-, in where R1 and R2 are the same or different and are hydrogen or a substituted or unsubstituted radical selected from alkyl of 1 to 12 carbon atoms, phenyl, tolyl and anisyl, and R3, R4 and R5 are the same or different and are a radical selected from hydrogen or methyl; and m1 is of a value of 2 to 6; (ii) optically active diorganophosphites having the formula: wherein Y "is a substituted or unsubstituted monovalent hydrocarbon radical and Ar, Q, n and y are as defined above; and (iii) optically active, open-ended bisphosphites having the formula wherein Ar, Q, n, y, Y 'and Y' 'are as defined in the foregoing and Y "' may be the same or different Aryl radicals illustrative of groups Ar and Y 'of the formulas above cited include aryl residues which may contain from 6 to 18 carbon atoms such as phenylene, naphthylene, anthracycline and the like In the above-mentioned formulas preferably m is from 2 to 4 and each "y" and each n is has a value However, when n is 1, Q is preferably a connection group of CR ^ -R2 as defined above and more preferably methylene (-CH2-) or alkylidene (-CHR2-) wherein R 2 is an alkyl radical of 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, dodecyl, etc.), especially methyl.The m-valent hydrocarbon radicals represented by Y "in the polyphosphite coordinating group of the aforementioned formula are hydrocarbons containing from 2 to 30 carbon atoms which are selected of the alkylene, alkylene-oxy-alkylene, arylene and arylene- (CH2-) and- (Q) n- (-CH2-) and -arylene radicals, wherein Q, ne, are the same as defined above foregoing. Preferably, the alkylene radical residues contain from 12 to 18 carbon atoms and more preferably from 2 to 12 carbon atoms, while the arylene radical residues preferably contain from 6 to 18 carbon atoms. The divalent linking group presented by Y1 in the open-ended bisphosphite coordinating group of the above formula are divalent hydrocarbons containing from 2 to 30 carbon atoms which are selected from the alkylene, alkylene-oxy-alkylene, arylene and arylene- (CH2-) and- (Q) n ~ (-CH2-) and -arylene, where Q, ne and Y are the same as defined above. Preferably, the alkylene residues of the radicals contain from 2 to 18 carbon atoms and more preferably from 2 to 12 carbon atoms, while the arylene residues of the radicals preferably contain from 6 carbon atoms. The hydrocarbon radicals represented by Y "in the aforementioned phosphite coordinating group of the formulas include monovalent hydrocarbon radicals containing from 1 to 30 carbon atoms which are selected from the alkyl radicals including primary, secondary or linear or branched tertiary such as methyl, ethyl, n-propyl, isopropyl, amyl, secondary amyl, tertiary amyl, 2-ethylhexyl and the like; aryl radicals such as phenyl, naphthyl and the like radicals; aralkyl radicals such as benzyl, phenylethyl, triphenylmethylethane and the like, alkaryl radicals such as tolyl, xylyl and the like; and cycloalkyl radicals such as cyclopentyl, cyclohexyl, cyclohexylethyl and the like. Preferably, Y "is selected from alkyl and aryl radicals containing from about 1 to 30 carbon atoms, preferably, the alkyl radicals contain from 1 to 18 carbon atoms, more preferably from 1 to 10 carbon atoms. of carbon, while the aryl, aralkyl, alkaryl and cycloalkyl radicals preferably contain from 6 to 18 carbon atoms. Furthermore, even though each group Y '' is the open-ended bisphosphite coordinating group of the above formula which may differ from one another, they are preferably identical. The aryl radicals in the aforementioned formulas can also be substituted with any substituent radical which does not unduly detrimentally affect the processes of this invention. Illustrative substituents include radicals containing from 1 to 18 carbon atoms such as alkyl, aryl, aralkyl, alkaryl and cycloalkyl radicals; alkoxy radicals; silyl radicals such as -Si (R9> 3 and -Si (OR9) 3, -Amino radicals such as -N (R9) 2, * acyl radicals such as -C (0) R ^, acyloxy radicals such as -OC (0) R ^, carbonyloxy radicals such as -COOR9; amido radicals such as -C (0) N (R9) 2 and -N (R9) COR9; sulfonyl radicals such as -SO2R9; sulfinyl such as -SOR9; sulfenyl radicals such as -SR9; phosphonyl radicals such as -P (O) (R9) 2"as well as the halogen, nitro, cyano, trifluoromethyl and hydroxy radicals and the like, wherein each R9 it may be a monovalent hydrocarbon radical such as alkyl, aryl, alkaryl, aralkyl and cycloalkyl radicals, with the provisos that in amino substituents such as -N (R9) 2, each R9 taken together may comprise a linking group divalent which forms a heterocyclic radical with the nitrogen atom, in the amido substituents such as -C (0) N (R9) 2 and -N (R9) COR9, each R9 linked to N can also be hydrogen and in the phosphonyl substituents such as -P (0) (R9) 2 ^ one R9 can be hydrogen. It will be understood that each R9 group in a specific substituent may be the same or different. These hydrocarbon substituent radicals could, in turn, possibly be substituted with a substituent such as those mentioned above already mentioned herein, with the proviso that when this occurs no undue harmful effect would occur in this invention. At least one ionic residue selected from the salts of the carboxylic acid and the sulfonic acid can be substituted in an aryl residue in the aforementioned formulas. Among the especially preferred phosphite coordinating groups useful in the first step in the process of this invention are the coordinating groups wherein two Ar groups linked through the connection group represented by - (CH2) and- (Q) n- (CH2) and - in the above formulas, they are linked through their ortho positions in relation to the oxygen atoms that connect the Ar groups with the phosphorus atom. It is also preferred that any substituent radical when present in these Ar groups, is linked in the para and / or ortho position on the aryl relative to the oxygen atom that binds the substituent Ar group on its phosphorus atom. Exemplary monovalent hydrocarbon residues represented by the groups Z, Y, Y "and Y '" in the aforementioned formulas include substituted or unsubstituted monovalent hydrocarbon radicals containing from 1 to 30 carbon atoms which are selected from radicals Alkyl, aryl, alkaryl, aralkyl and substituted or unsubstituted alicyclics Although group Z and Y "in a given formula can individually be the same or different, preferably both are the same, the more specific illustrative monovalent hydrocarbon residues represented by Z, Y, Y '' and Y '' 'include primary, secondary and tertiary chain alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, neopentyl, secondary amyl, tertiary amyl, iso-octyl, 2-ethylhexyl, iso-nonyl, iso-decyl, octadecyl and the like, aryl radicals such as phenyl, naphthyl, anthracyl and the like; of aralkyl such as benzyl, phenylethyl and the like; alkaryl radicals such as tolyl, xylyl, p-alkylphenyl and the like and alicyclic radicals such as cyclopentyl, cyclohexyl, cyclooctyl, cyclohexylethyl, 1-methylcyclohexyl and the like. Preferably, the unsubstituted alkyl radicals can contain from 1 to 18 carbon atoms, more preferably from 1 to 10 carbon atoms, while the unsubstituted aryl, aralkyl, alkaryl and alicyclic radicals preferably contain from 6 to 18 carbon atoms. Among the residues of Z, Y, Y '' and Y''1, especially preferred are phenyl radicals and substituted phenyl radicals. The illustrative divalent hydrocarbon residues represented by Z, Y and Y '' in the abovementioned formulas include substituted and unsubstituted radicals which are selected from alkylene, alkylene-oxy-alkylene, arylene, -arylene-oxy-arylene-, alicyclic, phenylene, naphthylene, arylene- radicals ( CH2-) and- (Q) n - (- CH2-) and -arylene, such as phenylene- (CH2-) and- (Q) n- (-CH2-) and -phenylene-, naphthylene- (CH2) radicals -) and - (Q) n- (-CH2-) y-naphthylene, wherein Q, Y and n are defined above. The more specific illustrative divalent radicals represented by Z, Y and Y 'include eg, 1,2-ethylene, 1,3-propylene, 1,6-hexylene, 1,8-octylene, 1,12-dodecylene, 1, 4-phenylene, 1,8-naphthylene, 1,1 '-biphenyl-2,2'-diyl, 1, 1-binaphthyl-2,2'-diyl, 2, 2 • -bubblethyl-1, 1 '-diilo and similar. The alkylene radicals may contain from 2 to 12 carbon atoms, while the arylene radicals may contain from 6 to 18 carbon atoms. Prably Z is an arylene radical, Y is an alkylene radical and Y 'is an alkylene radical. In addition, the above described radicals represented by Z, Y, Ar, Y 'and Y "of the above formulas can further be substituted with any substituent that does not unduly detrimentally affect the desired results of this invention. Exemplary substituents are, for example, monovalent hydrocarbon radicals having from 1 to about 18 carbon atoms such as the alkyl, aryl, alkaryl, aralkyl, cycloalkyl and other radicals as defined above. In addition, the various other substituents that may be present include eg, halogen, chlorine or fluorine prential, N02, -CN, -CF3, -OH, -Si (CH3) 3, -Si (OCH3) 3, -Yes (C3H7) 3 >; -C (0) C2H5, -OC (0) C6H5, -C (0) OCH3, -N (CH3) 2 / -NH2, -NHCH3, -NH (C2H5), -CONH2, -CON (CH3) 2, -S (O) 2C2H5, -OC2H5, -OC6H5, -C (0) C6H5, -0 (t-C4C9), -SC2H5, -0CH2CH20CH3, - (OCH2CH2) 2? CH3 '- (OCH2CH2) 3OCH3, -SCH3 , -S (0) CH3, -SC6H5, -P (0) (C6H5) 2, -P (O) (CH3) 2, -P (O) (C2H5) 2 / -P (0) (C3H7) 2 . -P (0) (C H9) 2, -P (0) (C6H13) 2, -P (O) CH3 (C6H5), -P (O) (H) (CgHs), -NHC (0) CH3 and similar. In addition, each group Z, Y, Ar, Y 'and Y1' may contain one or more of these substituent groups which may also be the same or different in any molecule of the given coordinating group. Preferred substituent radicals include alkyl and alkoxy radicals containing from 1 to 18 carbon atoms and more preferably from 1 to 10 carbon atoms, especially tertiary butyl and methoxy. The optically active coordinating groups used in the complex catalysts useful in the first step of the process of this invention are uniquely adaptable and suitable for asymmetric synthesis processes, especially asymmetric hydromormylation catalyzed by rhodium. For example, optically active phosphorus coordinating groups can provide very good rhodium complex stability in addition to providing good catalytic activity for the asymmetric hydroformylation of all types of permissible olefins. In addition, its unique chemical structure must provide the coordinating group with very good stability against secondary reactions such as hydrolyzing during asymmetric hydroformylation as well as during storage. The optically active types and coordinating groups of the generic class capable of being employed in the first step of the process of this invention can be prepared by methods known in the art. For example, optically active phosphorus coordinating groups capable of being employed in this invention can be prepared through a series of conventional condensation reactions of phosphorus halide and alcohol or amine, wherein at least one of the ingredients, alcohol or the amine is optically active or optically pure. These types of condensation reactions and the manner in which they can be carried out are well known in the art. In addition, the phosphorus coordinating groups usable herein can be easily identified and characterized by conventional analytical techniques such as Phosphorus-31 nuclear magnetic resonance spectroscopy, and Fast Atomic Bombardment Mass spectroscopy, if desired. As mentioned above, the optically active coordinating groups can be used both as the coordinating group of the optically active metal complex catalyst-coordinator group described above as well as the free coordinating group that can be present in the reaction medium of the processes of this invention. Further, even when the typically active coordinating group of the complex metal catalyst-coordinating group in any excess of the free coordinating group preferably present in a given process of this invention are usually of the same coordinating group, they may be employed for each object in any given process different optically active coordinating group as well as mixtures of two or more different optically active groups. The complex or optically active metal-coordinating group catalysts of this invention can be formed by methods known in the art. See, for example, U.S. Patent Nos. 4,769,498, 4,717,775, 4,774,361, 4,737,588, 4,885,401, 4,748,261, 4,599,206, 4,668,651, 5,059,710 and 5,113,022, all of which are incorporated herein by reference. For example, preformed hydrido-carbonyl metal catalysts can possibly be prepared and introduced into the reaction medium of an asymmetric synthesis process. More preferably, the metal complex catalysts and a coordinating group of this invention can be derived from a metal catalyst precursor that can be introduced into the reaction medium for in situ formation of the active catalyst. For example, rhodium catalyst precursors such as rhodium dicarbonyl acetylacetonate, Rh2? 3, Rh4 (CO) 2 >; Rhg (CO)? G, Rh (N03) 3, similar can be introduced into the reaction medium together with the coordinating group for in situ formation of the active catalyst. In a preferred embodiment, rhodium dicarbonyl acetylacetonate is used as a rhodium precursor and is reacted in the present solvent with a phosphorus coordinating compound compound to form a precursor of the rhodium-phosphorus catalytic complex that is introduced into the the reactor, optionally together with the excess of the free phosphorus coordinating group, for the in situ formation of the active catalyst. In any case, it is sufficient for the purposes of this invention to understand that the complex catalyst of optically active metal-coordinating group is present in the reaction medium under asymmetric synthesis conditions and most preferably the asymmetric hydroformylation process. In addition, the amount of the optically active complex catalyst present in the reaction medium need only be the minimum amount necessary to provide the concentration of the particular metal that is desired to be employed and which will provide the basis for at least that catalytic amount of metal necessary to catalyze the specific asymmetric synthesis process desired. Usually, metal concentrations within the scale of about 1 part per million to about 10,000 parts per million, which is calculated as free metal, and the molar ratios of the coordinator group to metal in the catalyst vary from 0.5: 1 at approximately 200: 1, it should be sufficient for most asymmetric synthesis processes. Also, in the rhodium catalyzed asymmetric hydroformylation processes of this invention it is generally preferred to employ from about 10 to 1000 parts per million rhodium and more preferably from 25 to 750 parts per million rhodium, which is calculated as the metal free. An additional aspect of the first step of the process of this invention involves the use of a catalyst precursor composition consisting essentially of a solubilized metal complex precursor catalyst and a coordinating group, an organic solvent and a free coordinating group. These precursor compositions can be prepared by forming a solution of a metal starting material, for example metal oxide, hydride, carbonyl or a salt, eg, a nitrate, which may or may not be in complex combination with the group optically active coordinator, an organic solvent and a free coordinating group as defined herein. Any suitable metal starting material can be used, e.g., rhodium dicarbonyl acetylacetonate, RI12O3, Rh (CO) 2 'Rhg (CO)? 6, Rh (03) 3, polyphosphite rhodium carbonyl hydrides, iridium carbonyl, iridium hydrides, poly-phosphite, osmium halide, chlorosmic acid, osmium carbonyls, palladium hydride, palladium halides, platinic acid, platinum halides, ruthenium carbonyls, as well as salts of other metals and carboxylates of acids of 2 to 16 carbon atoms such as cobalt chloride, cobalt nitrate, cobalt acetate, cobalt octoate, ferric acetate, ferric nitrate, nickel fluoride, nickel sulfate, palladium acetate, osmium octoate, iridium sulfate, ruthenium nitrate and the like. Of course, any suitable solvent such as those used in the asymmetric synthesis process that is desired can be used. The desired asymmetric synthesis process can of course also regulate the different amounts of solvent metal and the optically active coordinating group present in the precursor solution. Optically active coordinating groups, if not already complexed in the initial metal, can be complexed with the metal either before or in situ, during the process of asymmetric synthesis.

The optically active catalyst used in the first step of the process of this invention may be optionally supported. The advantages of a supported catalyst can include the ease of separation of the catalyst and the recovery of the coordinating group. Illustrative examples of the supports include alumina, silica gel, ion exchange resins, polymeric supports and the like. Process conditions that are employed in asymmetric processes can be employed in the first step of the process of this invention that are selected depending on the specific asymmetric synthesis process. These process conditions are well known in the art. All asymmetric synthesis processes useful in this invention can be carried out in accordance with conventional procedures known in the art. Illustrative reaction conditions for carrying out the symmetric synthesis processes of this invention are described for example, in Bosnich, B. Asymmetric Catalysis, Martinus Nijhoff Publishers, 1986 and Morrison, James D., Asymmetric Synthesis, Volume 5, Chiral Catalysis , Academic Press, Inc., 1985, both of which are incorporated herein by reference. Depending on the specific process, the operating temperatures may vary from about -80 ° C or less to about 500 ° C or more and the operating pressures may vary from about .0703 kilogram per square centimeter gauge or less to about 703.00 kilograms per centimeter square manometric or greater. The reaction conditions may effect the preferred asymmetric hydroformylation process which may be employed in the first step of the process of this invention may be those conventionally used previously and many comprise a reaction temperature of about -25 ° C or less than about 200 ° C. C and pressures that vary from .0703 to 703.00 kilograms per absolute square centimeter. Although the preferred asymmetric synthesis process is the hydroformylation of the olefinically unsaturated compounds of carbon monoxide and hydrogen to produce optically active aldehydes, it will be understood that the optically active metal complexes-coordinator group can be used as catalysts in other types of process Asymmetric synthesis in order to obtain good results. As mentioned, the first step of the preferred process of this invention involves the production of optically active aldehydes through the asymmetric hydroformylation of a prochiral or chiral unsaturated olefinic compound with carbon monoxide and hydrogen in the presence of an optically active metal complex catalyst. - phosphorus coordinating group and, optionally, a free phosphorus coordinating group, especially a complex catalyst of optically active rhodium-phosphorus coordinating group. Although the optimization of the reaction conditions necessary to achieve the best results and efficiency desired depends on the experience in the use of this invention, only a certain measure of experiments must be necessary to ensure those conditions that are optimal for a given situation. and should be within the knowledge of a person skilled in the art and readily obtained by following the especially preferred aspects of this invention as explained herein and / or by simple routine experiments. For example, the pressure of hydrogen gas, carbon monoxide and the unsaturated olefinic starting compound of the preferred asymmetric hydroformylation process of this invention may range from about .0703 to 703.00 kilograms per absolute square centimeter. The minimum total pressure of the reactants is not particularly critical and is predominantly limited only by the amount of reagents necessary to obtain a desired reaction rate. More specifically, the partial pressure of the carbon monoxide of the asymmetric hydroformylation process of this invention is preferably from about .0703 to about 703.00 kilograms per absolute square centimeter. More preferably, however, in the asymmetric hydroformylation of the prochiral olefins to produce optically active aldehydes, it is preferred that the process be operated at a total gas pressure of hydrogen, carbon monoxide and the unsaturated olefinic starting compound of less of about 105.45 kilograms per absolute square centimeter, and more preferably less than about 70.30 kilograms per absolute square centimeter. The minimum total pressure of the reagents is not particularly critical and is predominantly limited only by the amount of reagents necessary to obtain a desired reaction rate. More specifically, the partial pressure of the carbon monoxide of the asymmetric hydroformylation process of this invention is preferably from about 0.703 to about 25.86 kilograms per absolute square centimeter, and most preferably from about 2.21 to about 18.98 kilograms per centimeter. absolute square, while the hydrogen partial pressure is preferably from about 1.05 to about 33.44 kilograms per absolute square centimeter and more preferably from about 2.11 to about 21.09 kilograms per absolute square centimeter. Generally, the molar ratio of gaseous hydrogen to carbon monoxide can vary from about 1:10 to 100: 1 or greater, with the especially preferred molar ratio of hydrogen to carbon monoxide being from about 1: 1 to about 1:10 . The higher molar ratios of carbon monoxide to gaseous hydrogen can generally tend to favor higher branched / normal isomer ratios. Furthermore, as mentioned above, the preferred asymmetric hydroformylation process useful in the first step of the process of this invention can be carried out at a reaction temperature of about -25 ° C or less than about 200 ° C. The preferred reaction temperature employed in a given process will of course depend on the specific olefinic starting material and the optically active metal complex catalyst-coordinator group employed as well as the desired efficiency. Lower reaction temperatures can generally tend to favor higher enantiomeric excesses (ee) and branched / normal relationships. In general, asymmetric hydrodroformilations at reaction temperatures from about 0 ° C to about 120 ° C are preferred for all types of olefinic starting materials. More preferably, alpha-olefins can be effectively hydroformylated at a temperature from about 0 ° C to about 90 ° C while olefins less reactive than conventional linear alpha-olefins and internal olefins as well as mixtures of alpha-olefins and the internal olefins are hydroformylated effectively and preferably at temperatures from about 25 ° C to about 120 ° C. Of course, in the rhodium catalyzed asymmetric hydroformylation process of this invention, no considerable benefit is seen in operating at reaction temperatures well above 120 ° C and this is considered to be less desirable. The processes employed in the first step of the process of this invention are carried out for a sufficient period of time to produce a mixture of the enantiomeric aldehyde. The exact reaction time employed depends, in part, on factors such as temperature, nature and proportion of starting materials and the like. The reaction time will usually be within the range of about half to about 200 hours or more, and preferably less than about one to about 10 hours.

The asymmetric synthesis processes preferably the asymmetric hydroformylation processes useful in the first step in the process of this invention, can be carried out either in the liquid or gaseous state and involve an intermittent, continuous liquid or recycle system. gas in combination of these systems. An intermittent system is preferred to carry out these processes. Preferably, this asymmetric hydroformylation involves a batch of the homogeneous catalysis process wherein the hydroformylation is carried out in the presence of both the free phosphorus coordinating group and any suitable conventional solvent as will be further described herein. The asymmetric synthesis processes, and preferably the asymmetric hydroformylation process, useful in the first step of the process of this invention can be carried out in the presence of an organic solvent for the optically active metal complex catalyst and coordinating group depending on the catalyst Specific and the reagents employed, suitable organic solvents include, for example, alcohols, alkanes, alkenes, alkynes, ethers, aldehydes, ketones, esters, acids, amides, amines, aromatics and the like. Any suitable solvent that does not unduly detrimentally interfere with the proposed asymmetric synthesis process can be employed and these solvents can include those commonly employed hitherto in the known metal catalyzed processes. Increasing the dielectric constant or polarity of a solvent can generally tend to favor increased reaction and selectivity regimes. The amount of the solvent employed is not critical to this invention and it only needs to be that amount sufficient to provide the reaction medium with a specific concentration of the metal, substrate and product desired for a given process. In general, the amount of the solvent when employed can vary from about 5 weight percent to about 95 weight percent or more, based on the total weight of the reaction medium. As mentioned above, asymmetric synthesis processes catalyzed by metal-coordinating group (and especially the asymmetric hydroformylation process) useful as the first step in the process of this invention can be carried out in the presence of a coordinating group free, that is, a coordinating group that is not complexed with the metal of the complex catalyst of the optically active metal and coordinating group used. Even though it is preferred to employ a free coordinating group which is the same as the coordinating group of the complex catalyst metal-coordinating group, these coordinating groups need not be the same in a given process, but may be different if desired. Although the asymmetric synthesis and preferably the asymmetric hydroformylation process can be carried out in any excessive amount of the desired free coordinating group, the use of the free coordinating group may not be absolutely necessary. Accordingly, in general, the amounts of the coordinating group from about 2 to about 100 or greater, if desired, moles per mole of metal (e.g., rhodium) present in the reaction medium should be appropriate for most the ends, particularly with respect to rhodium-catalyzed hydroformylation; these amounts of the coordinating group used being the sum of both the amount of the coordinating group remaining bound (formed in complex) and the present metal and the amount of the free coordinating group (not forming a complex) present. Of course, if desired, the replacement coordinating group can be supplied to the reaction medium of the asymmetric hydroformylation process at any time, and in any appropriate manner, to maintain a predetermined level of the free coordinating group in the reaction medium. The ability to carry out the useful processes as the first step of the process of this invention in the presence of the free coordinating group can be a beneficial aspect of this invention since it removes the criticality of using very low precise concentrations of the coordinating group that may be required of certain complex catalysts whose activity may be retarded even when any amount of the free coordinating group is also present during the process, particularly when large-scale commercial operations are involved, thus helping to provide the operator with the highest processing attitude. As indicated above, the aldehyde forming processes useful in this invention can be carried out intermittently or continuously, with the recycling of the raw materials not consumed if required. The reaction can be carried out in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it can be carried out batchwise or continuously in an elongated tubular zone or a series of these zones. The construction materials used must be inert to the starting materials during the reaction and the manufacture of the equipment must be able to withstand the temperatures and pressures of reaction. The means for introducing and / or adjusting the amount of starting materials or ingredients introduced intermittently or continuously into the reaction zone during the course of the reaction can be conveniently used in the processes especially to maintain the desired molar ratio of the starting materials. . The reaction steps can be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the co-addition of the starting materials to the complex catalyst of optically active metal and coordinating group. When a complete conversion is not desired or is not obtainable, the starting materials can be separated from the product and then recycled back to the reaction zone. The processes can be carried out either in a glass-lined, stainless steel or similar type reaction equipment. The reaction zone can be equipped with one or more internal and / or external heat exchangers in order to control undue temperature fluctuations or to prevent any of the possible "fugitive" reaction temperatures. The aldehyde forming processes useful in the first step in the process of this invention are useful for preparing mixtures of substituted optically active aldehydes. The aldehyde forming processes useful in this invention stereoselectively produce a chiral center. The optically illustrative aldehydes prepared by the processes of this invention include, for example, substituted aldehydes. Illustrative preferred optically active aldehyde compounds prepared by the asymmetric hydroformylation process of this invention include, for example, S-2- (p-isobutylphenyl) propionaldehyde, S-2- (6-methoxy-2-naphile) propionaldehyde, S -2- (3-benzoylphenyl) -propionaldehyde, S-2- (p-thienoylphenyl) propionaldehyde, S-2- (3-fluoro-4-phenyl) phenylpropionaldehyde, S-2- [4- (1,3-dihydro) -l-oxo-2H-isoindol-2-yl) phenyl] propionaldehyde, S-2- (2-methylacetaldehyde) -5-benzoylthiophene and the like. The optically active aldehyde illustrative compounds of the appropriate optically active aldehyde (including the derivatives of the optically active aldehydes) and the prochiral and chiral starting material compounds include those compounds of permissible optically active and prochiral and chiral aldehyde starting material which are describe in the Chemical Technology Encyclopedia of Kirk-Othmer, Third Edition of 1984, the relevant portions of which are incorporated herein by reference, and The Merck Index, An Encyclopedia of Chemical Substances, Drugs and Biologicals, Déci Opi Edition of 1989, the pertinent portions of which are incorporated herein by reference. The aldehyde forming processes useful as the first step in the process of the invention can provide optically active aldehydes having very high enantioselectivity and regioselectivity. Enantiomeric excesses preferably greater than 50 percent, more preferably greater than 75 percent and especially preferred greater than 90 percent, can be obtained through these processes. Branched / normal molar ratios preferably greater than 5: 1, more preferably greater than 10: 1 and especially preferred greater than 25: 1, can be obtained by these processes. In the process of this invention, the aldehyde mixtures can be separated from the other components of the crude reaction mixtures, wherein the aldehyde mixtures are produced by any suitable method. Suitable separation methods include, for example, solvent extraction, crystallization, distillation, vaporization, evaporation of cleaned film, descending film evaporation and the like. It may be desirable to remove the optically active products from the crude reaction mixture as they are formed through the use of entrapment agents as described in the Patent Cooperation Treaty Patent Application Number WO 88/08835. A preferred method for separating the mixtures of the enantiomeric aldehyde from the other components of the crude reaction mixtures is by membrane separation. This membrane separation can be achieved as noted in U.S. Patent No. 5,430,194 and copending U.S. Patent Application Serial No. 08 / 430,790, filed May 5, 1995, both incorporated herein by reference. In the process of this invention, the enantiomeric purity of the mixtures of the optically active aldehyde isomers can be improved by crystallization as described in the aforementioned US Patent No. 5,430,194. The generic scope of this invention includes a process for preparing optically active carboxylic acids by oxidizing an optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide in order to produce the optically active carboxylic acid. The generic scope of this invention is not intended to be limited in any way by any specific reaction to form the enantiomeric aldehyde mixtures.

Oxidation Once the required mixture of enantiomeric aldehydes has been provided, the next step of the process of this invention involves oxidizing the optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide to produce an acid. optically active carboxylic acid Appropriate solutions can be provided using liquid aldehydes or by melting the solid aldehydes. However, appropriate solutions usually consist of aldehydes dissolved in a suitable solvent, eg, in the solvent from which the first step of the process of this invention was carried out). Any solvent that dissolves the aldehyde mixtures and is not reactive with the peracids can be used. Examples of suitable solvents are ketones, (e.g., acetone), esters (e.g., ethyl acetate), hydrocarbons (e.g., toluene), nitrohydrocarbons (e.g., nitrobenzene), ethers (e.g., tetrahydrofuran (THF) and 1,2-dimethoxyethane) and water. A mixture of two or more solvents can be used to maximize the purity and yield of the desired aldehyde. The solution used may also contain materials present in the crude reaction product of the aldehyde-forming reaction (e.g., a catalyst, a coordinating group and heavier materials). Preferably, however, the solution consists essentially of only aldehyde and the solvent. The concentration of the aldehyde in the solvent solution will be limited by the solubility of the aldehyde in the solvent.

The oxidizing agent useful in the process of this invention is a peracid. Exemplary peracids include, for example, peracetic acid, performic acid, perpropionic acid, perbenzoic acid and the like. The preferred oxidizing agent is anhydrous peracetic acid. These peracid oxidizing agents are well known in the art and can be used in amounts which will be described below and in accordance with conventional methods. The oxidizing agent is used in an amount sufficient to allow complete oxidation of the optically active aldehyde. Preferably, the oxidizing agent can be stoichiometrically varied from about 1 to about 10 molar equivalents with respect to the optically active aldehyde, preferably from about 1 to about 2 molar equivalents with respect to the optically active aldehyde, and especially preferably from about 1 to about 1.3 molar equivalents with respect to the optically active aldehyde. Catalysts useful in the oxidation step of the process of this invention include amines and N-oxides of primary, secondary and tertiary amines and mixtures thereof. The catalysts have sufficient basicity to catalyze the oxidation of an optically active aldehyde with an optically active carboxylic acid. The catalysts are desirable since little or no racemization of the optically active aldehyde occurs. Illustrative primary, secondary, and tertiary amine N-oxide catalysts include, for example, aliphatic amines, aliphatic amine N-oxides, aromatic amines, aromatic amine N-oxides, heterocyclic amines, heterocyclic amine N-oxides , polymeric amines supported N-oxides of supported polymeric amine_ and the like, including mixtures thereof. Illustrative aliphatic amines include substituted and unsubstituted alkyl amines such as butylamine, diethylamine, triethylamine and the like include the N-oxides thereof. Illustrative aromatic amines (those in which nitrogen is directly attached to an aromatic ring) include substituted and unsubstituted anilines and the N-oxides thereof, eg, aniline, toluidine, diphenylamine, N-ethyl-N- methylaniline, 2,4,6-tribromoaniline and the like. Illustrative heterocyclic amines (those in which nitrogen replaces a part of an aromatic or non-aromatic ring) include substituted and unsubstituted pyridines, pyrimidines, pyrrolidines, piperidines, pyrroles, purines and the like, including the N-oxides thereof. Preferred oxidation catalysts include, for example, 2,6-lutidine N-oxide, 4-methoxypyridine N-oxide and 2,5-lutidine N-oxide. Amine N-oxide catalysts are the preferred oxidation catalysts and can affect, e.g., decrease the amount of the formate by-product formed in the oxidation process of this invention. The amine and / or amine N-oxide catalyst has a high boiling temperature in order to reduce or eliminate the impurities of the amine resulting from the catalyst in the product. As indicated above, the catalysts have sufficient basicity to catalyze the oxidation of an optically active aldehyde in an optically active carboxylic acid. This basicity can result in the operation of the catalyst as a Lewis base or a Bronsted-Lowry base. The catalysts must be sufficiently basic to promote or activate the decomposition of any aldehyde-peracid adduct but relatively unreactive with respect to oxidation by the peracid. The basicity of the catalysts must also be sufficient to favor the oxidation reaction in optically active carboxylic acids through any of the competitive aldehyde racemization reactions. In one embodiment of this invention, if the amine and / or amine N-oxide catalyst has excessive basicity by causing the racemisation of optically active aldehyde, the racemisation of the optically active aldehyde can be suppressed by adding a weak organic acid to the reaction mixture. Various weak organic acids, e.g., the aliphatic and aromatic carboxylic acids can be employed in the process of this invention. The weak organic acids should be sufficient to moderate the basicity of the catalyst to suppress racemization. Preferred weak organic acids have a pKa of 3 to 6 and include, for example, acetic acid. The weak organic acid is used in an amount sufficient to moderate the basicity of the catalyst in order to suppress racemization, preferably 1 equivalent with respect to the catalyst. The amine and / or amine N-oxide catalyst is used in a catalytically effective amount, ie, an amount sufficient to catalyze the oxidation reaction. Preferably, the stoichiometry of the amine and / or the amine N-oxide can vary from about 0.1 to about 10 molar equivalents with respect to the optically active aldehyde, preferably from about 0.5 to about 2 molar equivalents with respect to the optically active aldehyde , and especially preferably from about 0.7 to about 1.2 molar equivalents with respect to the optically active aldehyde. The stoichiometry of the amine and / or the amine N-oxide can affect the amount of the formate by-product formed in the process of this invention. The catalysts used in the oxidation step of the process of this invention can be optionally supported. The advantages of a supported catalyst can include ease of catalyst separation. Illustrative examples of supports include alumina, silica gel, ion exchange resins, polymeric supports and the like. The process conditions employable in the oxidation step of the process of this invention are selected to minimize the racemisation of aldehyde and reduce the formate by-products. The mode of addition of the reaction ingredients in the oxidation step of the process of this invention is not narrowly critical. The mode of addition must be such that an optically active carboxylic acid is obtained. As an illustration, if the peracid is added to a mixture of the optically active aldehyde and the amine catalyst and / or amine N-oxide, the oxidation must be carried out before base-catalyzed racemization occurs.

The oxidation step of the process of this invention can be carried out at a reaction temperature of about -25 ° C or less than about 60 ° C. Lower reaction temperatures will generally tend to minimize the formation of the formate by-product. In order to minimize the racemisation of aldehyde, the temperature should not exceed about 10 ° C during the addition of the exothermic peracid when amines are used as the catalysts. When the amine N-oxides are used as catalysts, the temperatures should not exceed about 25 ° C to minimize the formation of methyl ketone when the alkyl-methyl-substituted benzylic aldehydes are oxidized. In general, oxidations at reaction temperatures of about -10 ° C to about 25 ° C are preferred. The oxidation step of the process of this invention is carried out for a period of time sufficient to produce a mixture of enantiomerically enriched carboxylic acid. The exact reaction time employed depends, in part, on factors such as temperature, the nature and proportion of the starting materials, and the like. The reaction time will normally be within the range of about one half to about 200 hours or more, and preferably less than about one to about 10 hours. The oxidation step of the process of this invention can be carried out in a liquid state and can involve an intermittent or continuous liquid recycling system. An intermittent system is preferred to carry out these processes. Preferably this oxidation involves the intermittent homogeneous catalysis process wherein the oxidation is carried out in the presence of any suitable conventional solvent as further described herein. The oxidation step of the process of this invention can be carried out in the presence of an organic solvent. Depending on the specific catalyst and the reagents employed, suitable organic solvents include, for example, alcohols, alkanes, ethers, aldehydes, esters, acids, amides, amines, aromatics and the like. Any suitable solvent that does not unduly detrimentally interfere with the proposed oxidation process can be employed and such solvents can include those commonly employed above in the known processes. Mixtures of one or more different solvents can be used, if desired. Solvents that completely or partially dissolve aldehyde and do not react with peracids can be useful. Organic esters are the preferred solvents. Water and water / ethanol mixtures can also be useful solvents. The amount of the solvent employed is not critical to this invention and only needs to be that amount sufficient to provide in the reaction medium a specific substrate and a concentration of the desired product for a given process. In general, the amount of the solvent when employed can vary from about 5 weight percent to about 95 weight percent or more, based on the total weight of the reaction medium. As indicated above, the carboxylic acid forming process of this invention can be carried out intermittently or continuously, with the recycling of unconsumed starting materials, if required. The reaction can be carried out in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it can be carried out intermittently or continuously in an elongated tubular zone or a series of these zones. The construction materials used must be inert to the starting materials during the reaction and the equipment must be capable of withstanding reaction temperatures and pressures. The means for introducing and / or adjusting the amount of the starting materials and the ingredients introduced intermittently or continuously into the reaction zone during the course of the reaction, they can be conveniently used in the processes especially to maintain the desired molar ratio of the starting materials. The reaction steps can be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the co-addition of the starting materials to the amine catalyst and / or the amine N-oxide. The processes can be carried out either in reaction equipment lined with glass, stainless steel or of a similar type. The reaction zone may be equipped with one or more of the internal and / or external heat exchangers in order to control undue temperature fluctuations, or to prevent any of the possible "fugitive" reaction temperatures. The carboxylic acid forming process of this invention is useful for preparing mixtures of the substituted optically active carboxylic acids. Exemplary optically active carboxylic acids prepared by the process of this invention include, for example, substituted carboxylic acids. Illustrative preferred optically active carboxylic acid compounds prepared by the oxidation process of this invention include, for example, S-2- (p-isobutylphenyl) propionic acid, S-2- (6-methoxy-2-naphthyl) acid. propionic, S-2- (3-benzoylphenyl) propionic acid, S-2- (p-thienoylphenyl) propionic acid, S-2- (3-fluoro-4-) phenylpropionic acid, S-2- [4- ( 1,3-dihydro-l-oxo-2H-isoindol-2-yl) phenyl] propionic acid and the like. Illustrative of the appropriate optically active carboxylic acids which can be prepared by the process of this invention are those permissible optically active carboxylic acids which are described in Kirk-Othmer Chemical Technology Encyclopedia, Third Edition, 1984, the relevant portions of which are incorporated herein by reference, and the Merck Index, An Encyclopedia of Chemical and Biological Substances, Eleventh Edition of 1989, the relevant portions of which are incorporated herein by reference. The carboxylic acid forming process of this invention can provide optically active carboxylic acids having very high enantioselectivity and regioselectivity. Enantiomeric excesses preferably greater than 50 percent, more preferably greater than 85 percent and especially preferred greater than 95 percent, can be obtained by these processes. A number of pharmaceutically important compounds can be prepared 4-ethenylphenyl-2- (p-thienoylphenyl) -s-suprofen 2-thienylketone propionaldehyde 4-ethenyl-2- S-2- (3-fluoro-4-phenyl) S-flurbi-fluorobiphenyl phenylpropionaldheido profen 4- (1,3-dihydro-S-2- [4- (1,3-dihydro-l-S-indoprofen-l-oxo-2H-isoindol-oxo-2H-isoindol-2-yl) -2-yl ) -styrene phenyl] propionaldehyde 2-ethenyl-5- S-2- (5-benzoyl-2-benzoyl-thiophene thienyl) - S-thiaprophepropionaldehyde Phenyl ether of S-2- (3-phenoxy) S-pheno-3-ethenyl phenyl propionaldehyde profen Propylbenzene S-2-S-butetamate phenylbutyraldehyde of S-phenatamid phenyl-S-2-phenoxypropional-phenethylglycine vinyl dehyde vinyl chloride S-2-chloropropionic acid S-2-chloropropionic acid - (4-hydroxy) 5- (4-hydroxy) ketorolac benzoyl-benzoyl-l-formyl-2, 3- derivative 3H-pyrrolizine dihydropyrrolizine Phenyl ketone R-2- (3-benzoylphenyl) -R-keto-3-ethenylphenyl propionaldehyde profen 4-ethenyl-2-R-2- (3-fluoro-4-phenyl) -R-flurbi-fluorobiphenyl phenylpropionaldehyde profen The optically active derivatives of the products of the process of this invention have a wide utility scale which is well known and documented in the prior art, e.g., they are especially useful as pharmaceutical compounds, flavoring agents, fragrances, chemicals agricultural and similar. Illustrative therapeutic applications include, for example, non-steroidal anti-inflammatory drugs, ACE inhibitors, beta-blockers, analgesics, bronchodilators, spasmolytics, antihistimines, antibiotics, antitumor agents and the like.

As used herein, the following terms have the indicated meanings: Chiral - compounds having a non-superimposable mirror image. Aguiral - compounds that do not have a non-superimposable mirror image. Prochiral - compounds that have the potential to become a chiral compound in a specific process. Chiral center - any structural feature of a compound that is a site of asymmetry. Racemic - a 50/50 mixture of two enantiomers of a chiral compound. Stereoisomers - compounds that have identical chemical constitution, but that differ with respect to the arrangement of atoms or groups in space. Enantiomers - stereoisomers that are speculative images not superimposable to one another. Stereoselective - a process that produces a specific stereoisomers in favor of others. Enantiomeric excess (ee) - a measure of the relative amounts of two enantiomers present in a product. ee can be calculated by the formula [amount of the main enantiomer - amount of the small enantiomer] / [amount of principal enantiomer + amount of the small enantiomer] and converted into a percentage. Optical activity - an indirect measure of the relative amounts of stereoisomers present in a given product. The chiral compounds have the ability to rotate plane polarized light. When one enantiomer is present in excess relative to the other, the mixture is optically active. Optically active mixture - a mixture of stereoisomers that rotates plane polarized light due to an excess of one of the stereoisomers in relation to the others. Optically pure compound - a single enantiomer that rotates plane polarized light. Regioisomers - compounds that have the same molecular formula but differ in the connectivity of the atoms. Regióselectivo - a process that favors the production of a specific regioisómeros in relation to the others. Cloridite of IsoBHA-1, 1 '-biphenyl-3,3-di-t-butyl-5,5'-dimethoxy-2,2' -diylchlorophosphite. (IsoBHA-P)? ~ 2R, 4R-pentanediol - A coordinating group that has the formula: The last coordinating group can be produced from Iso BHA chloridite by the process described in Example 1 of the aforementioned PCT Patent Application No. 93/03839. The complete chemical name of this coordinating group is (2R, 4R) -Di [2, 2 '- (3, 3'-di-tert-butyl-5, 5'-dimethoxy-1, 1-biphenyl)] 2,4-pentyl diphosphite. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of Elements, the CAS version, Handbook of Chemistry and Physics, Edition 67, 1986-1987, interior pulp. Also for purposes of this invention, the term "hydrocarbon" is proposed as including all the compounds that it has. at least one hydrogen and one carbon atom. In a broad aspect, the hydrocarbons include the acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which may be substituted or unsubstituted. As used herein, the term "substituted" is intended to include all permissible substituents of the organic compounds. In a broad aspect, the permissible substituents include the acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compounds. Illustrative substituents include, for example, those described above. The permissible substituents may be one or more and the same or different for the appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen may be hydrogen substituents and / or any of the permissible substituents of the organic compounds described herein that fulfill or satisfy the valences of the heteroatoms. This invention is not intended to be limited in any way by the permissible substituents of the organic compounds. As used herein, the following symbols have the indicated meanings: L liter ml ml milliliter% by weight% by weight ml / min milliliters per minute ppm parts per million by weight g grams mg milliligram kg / cm2 kilograms per square centimeter ° C Celsius degrees b / n ratio of branched isomer to normal ce cubic centimeter DSC Differential Scanning Calorimeter GC HPLC Gas Chromatography High Performance Liquid Chromatography mm mmmmol millimole TLC Thin Layer Chromatography The following Examples are provided to illustrate the process of this invention.

Example 1 Improve the Enantiomeric Purity of an Aldehyde Via Crystallization in Acetone A solution consisting of 6-methoxy-2-vinylnaphthalene (395 grams), Iso (BHA-) 2 ~ 2R, 4R-pentanediol (6.041 grams), Rh (CO)? 2 '0.862 grams) and acetone (1500 milliliters) it was loaded in a reactor of capacity of 3,785 liters that was pressurized to 17.93 kilograms per square centimeter with 1: 1 of H2 / CO. The reaction mixture was stirred at room temperature for four days to effect hydroformylation. The crude reaction product produced from this product was removed from the reactor and an aliquot was removed to determine the composition of the product. GC analysis of the aliquot of the crude reaction product indicated that 98.8 percent of the olefin starting material had been converted to aldehydes and that a 95: 1 ratio of 2- (6-methoxy-2-naphthyl) propionaldehyde to 3- (6-methoxy-2-naphthyl) -propionaldehyde had been obtained. Oxidation of the aldehydes in the aliquot followed by analysis of Chiral High Performance Liquid Chromatography (HPLC) of the resulting carboxylic acids indicated that 81 percent ee of desired S-aldehyde was produced [ie, S2- (6- methoxy-2-naphthyl) -propionaldehyde]. The aforementioned oxidation and HPLC analysis were carried out in the following manner: 3 milliliters of the crude reaction product were diluted in 50 milliliters of acetone and mixed with 0.3 gram of potassium permanganate and 0.32 gram of magnesium sulfate. The mixture thus formed was stirred at ambient temperature for 30 minutes to effect the oxidation of the aldehydes in the crude reaction product in the corresponding carboxylic acids. The acetone was then removed under reduced pressure. The residue produced in this way was extracted three times with 50 milliliters of hot water and the three aqueous solutions obtained in this way were combined, filtered and washed with 50 milliliters of chloroform. The aqueous layer was then acidified with HCl to a pH of 2 at which time a white solid precipitate formed was filtered. The precipitated material was filtered, washed with water and dried to isolate the carboxylic acids. The carboxylic acids were analyzed by HPLC on a CHIRACEL ™ OD-H column that could separate the enantiomers of the resulting 2- (6-methoxy-2-naphthyl) propionic acid. The rest of the crude reaction product was milled at -22 ° C overnight and during that time crystals formed. These crystals were filtered, washed with cold acetone and dried under vacuum to yield 111 grams of the whitish crystals and a first filtrate. Analysis of the crystals indicated that the ratio of the b / n isomer had been increased to hatas > 250: 1. Oxidation of the aldehydes in carboxylic acids and chiral HPLC of the resulting carboxylic acids indicated that 93 percent ee of the S-enantiomer had been obtained. The first filtrate was stored overnight at -22 ° C and additional crystals were formed. These crystals were filtered, washed with cold acetone and dried in vacuo to yield a second filtrate and 70 grams of white crystals with a b / n isomer ratio of 250: 1 and 93 percent ee of the S-enantiomer . The second filtrate was stored at -22 ° C overnight and crystals were again formed. The filtration, washing and vacuum drying of these crystals resulted in the isolation of 50 grams of a product of a crystalline aldehyde product having a b / n isomer ratio of 200: 1 and an ee of 92. percent of the S-enantiomer.

Example 2 Improving the Enantiomer Purity of Aldehydes Through the Crystallization of Ethyl Acetate A solution consisting of 6-methoxy-2-vinylnaphthalene (60 grams), Iso (BHA-P) 2"2R, 4R-pentanediol (1.25 grams), Rh4 (CO) 2 (0.131 gram) and ethyl acetate (180 grams) was charged to a 300 milliliter capacity reactor that was pressurized to 17.58 kilograms per square centimeter with 1: 1 H2 / CO. The reaction mixture formed in this manner was stirred at room temperature for four days to effect hydroformylation. The crude reaction product was removed from the reactor and an aliquot was removed to determine the composition of the product. GC analysis of the aliquot indicated that 99 percent of the olefin starting material had been converted to aldehydes and that a ratio of 59: 1 of 2- (6-methoxy-2-naphthyl) propionaldehyde had been obtained with respect to to 3- (6-methoxy-2-naphthyl) -propionaldehyde. Oxidation of the aldehyde products followed by chiral HPLC analysis of the resulting carboxylic acids indicated that 80% ee of the desired S-aldehyde was prod [i.e., S-2- (6-methoxy-2-naphthyl) -propionaldehyde]. The remainder of the crude reaction product was then stored at -22 ° C overnight, during which time the crystals were formed in the vessel. These crystals were filtered, washed with cold acetone and dried under vacuum to yield 32 grams of off-white crystals. Subsequent analysis of these crystals indicated that the b / n isomer ratio had increased to >; 129: 1. Oxidation of the crystalline aldehyde and the chiral HPLC of the resulting carboxylic acid indicated that 92 percent ee of the S-enantiomer had been obtained.

Example 3 Membrane Separation of an Aldehyde from the Acetone Solution A. A crude hydroformylation reaction product similar to the crude reaction product produced in Example 1 above was processed through a membrane to remove the rhodium and the coordinating group. The crude reaction product contained 2- (6-methoxy-2-naphthyl) propionaldehyde (30 weight percent) dissolved in acetone (70 weight percent). The crude reaction product also contained rhodium (263.3 parts per million) and a coordinating group. The membrane was placed and used as follows: Three 5.08 centimeter circles were cut from a sheet of 20.32 by 27.94 centimeters from the MPF-50 membranes (Lot # 021192, code 5107) sold by Membrane Products Kiryat Weizmann Ltd. and which are believed to fall within the scope of the aforementioned European Patent Application Number 0 532,199 Al. These circles were placed in three Osmonics membrane holders. The crude reaction product (feed) was placed in a 2L Hoke cylinder under nitrogen. The feed was pumped to 35.15 kilograms per square centimeter at a flow rate of approximately 380 milliliters per minute. The feed flowed through a 60 micron filter and then divided into three streams that were routed to the membranes. Flow meters were used to ensure that the flow had equally divided towards the membrane holders. The permeate of the membranes was combined and collected under a nitrogen atmosphere. The refining flowed to a back pressure regulator and then returned to the Hoke cylinder. Approximately 1500 grams of the crude reaction product were infiltrated and the rhodium content of the resulting first permeate was 69.4 parts per million. The membrane and the equipment were washed with acetone and the acetone was discarded. The membrane separation described above was repeated in 150 grams of the first permeate material (containing 69.4 parts per million rhodium) and 1000 grams of a solution (containing 19.2 parts per million rhodium) was separated as a second permeate material. The composition of the second permeate material was 80 percent acetone and 20 percent solids. The b / n isomer ratio of the solids was 64: 1 and contained 1.4 percent of the normal isomer, 9.9 percent of R-isomer, and 88.7 percent of S-isomer [ie S-2- (6-methoxy). 2-naphthyl) -propionaldehyde]. The enantiomeric excess (ee) of the crystalline solids was 80.7 percent. The second permeate material obtained in this manner was then concentrated and crystallized as described above. A portion of the second permeate product produced as described above was concentrated by evaporating the acetone at 18 ° C and 63.50 centimeter mercury pressure to produce a concentrated solution containing 70 percent acetone and 30 percent solids. The concentrated material obtained in this manner was charged to a crystallizer described below. The crystallizer consisted of a vertical cylinder with a jacket of 250 cubic centimeters capacity (A) equipped with an agitator (B) and an internal filter (C). The crystallization was initiated by cooling the jacket to -14 ° C thereby cooling the contents of the cylinder to about -14 ° C. In order to dissolve the small crystals that formed on the inner surface of the cylinder and improve the crystal size, the crystallizer was reheated to 3 ° C and cooled again to -14 ° C using the cooler (D). This procedure was repeated three times. Since the internal filter (C) was clogged with the solid crystals formed in the cylinder and the liquid was removed from the crystallizer and separated in a laboratory vacuum filter. The resulting filter cake was washed with one part by weight of cold acetone (0 ° C) by two parts (by weight) of wet solids (filter cake). The resulting crystalline filter cake contained 13 percent acetone and 87 percent crystalline solids and had an isomer ratio of b / n of 386: 1. The solids contained 0.3 of the normal isomer, 2.4 percent of the R-isomer and 97.3 percent of the S-isomer. The enantiomeric excess of the solids was 95.2 percent. The Scanning Electron Microscope (SEM) photographs indicated that the solid particles were uniform and approximately 100 microns in size. B. The process of concentration and crystallization of A above was repeated with another portion of the second permeate material obtained in the membrane separation previously untreated and the crystals produced a b / n isomer ratio of about 446: 1 and contained 0.2 percent of the normal isomer, 2.7 percent of the R-isomer, and 97.1 percent of the S-isomer. The ee of the crystals was 94.6 percent. C. The wet filter cakes produced through the above-mentioned processes of A and B were combined and dissolved in two parts by weight of acetone per part by weight of the combined wet filter cake. The solution obtained in this way was crystallized using the crystallization procedure of A above, separated and washed according to the procedure of A mentioned above. The resulting crystals had a b / n isomer ratio of 921: 1 and contained 0.1 of the normal isomer, 1.3 percent of the R-isomer, and 98.6 percent of the S-isomer. The ee of the crystals was 97.4 percent. D. The wet crystalline filter cake produced by the procedure C above was dissolved in two parts (by weight) of acetone by the combined wet cake and crystallized using the above crystallization procedure of A, separated and washed according to the procedure of A previously cited. The final cistals obtained in this way had a b / n isomer ratio of 1836: 1. The crystal contained 0.05 percent of the normal isomer, .6 percent of the R isomer, 99.35 percent of the S isomer, and 4 parts per million of rhodium. The ee of the crystals was 98.8 percent. The melting temperature of the crystals was 72.5 ° C which was determined in a Differential Scanning Calorimeter (DSC).

Example 4 Refining an Aldehyde from an Ethyl Acetate Solution A. A crude hydroformylation reaction product was used which was similar to the crude reaction product produced from Example 2 above and which was composed of 62.9 percent ethyl acetate and 37.1 percent solids containing 2- (6-methoxy) -2-naphthyl) propionaldehyde. The solids had a b / n ratio of 42.1 which were composed of 2.3 percent of the normal isomer, 11.7 percent of the R-isomer and 86 percent of the S-isomer [ie, S-2- (6-methoxy-2- naphthyl) -propionaldehyde] and had an ee of 76 percent. The crude reaction product was crystallized in the following manner: B. Seven successive bursts of 250 milliliters of the crude reaction product were cooled to -7 ° C in the crystallizer used in Example 3 above. The crystals and the liquid resulting from the crystallization were separated on an external vacuum filter and the crystals were washed with 0.5 part ethyl acetate from the wet cake. The composite cake resulting from the seven crystallizations contained 24 percent ethyl acetate and 76 percent crystalline solids. The b / n isomer ratio of the crystalline solids was 123: 1 and the solids contained 0.8 percent normal isomer, 6.0 percent R-isomer, and 93.2 percent S-isomer. The ee of crystalline solids was 87.9 percent. C. The wet filter cake of step B above was dissolved in two parts by weight of ethyl acetate per part (parts by weight) of the wet filter cake. The solution was cooled to -13 ° C in the laboratory crystallizer used in Example 3 above. The crystallizer content was then reheated to 3 ° C and again cooled to -13 ° C. This cooling-reheating cycle was repeated twice to improve the size of the crystal. The solid-liquid mixture produced in this manner was separated in an external vacuum filter and the wet filter cake 50 produced was washed with 0.5 part of cold ethyl acetate (-10 ° C) from the wet filter cake. The cake cake contained 25 percent ethyl acetate and 75 percent crystalline solids. The crystalline solids had an isomer ratio of b / n of 483: 1 and had a normal isomer content of .2 percent, an R-isomer content of 1.6 percent and an S-isomer content of 98.2 percent. The ee of the crystalline solids was 96.8 percent.

Example 5 Refining an Aldehyde from the Acetone Solution in a Descending Film Crystallizer The crude hydroformylation reaction product was similar to the crude reaction product produced in Example 1 above and containing 70 percent acetone and 30 percent solids was refined in a falling film crystallizer from the laboratory. The solids in the crude reaction product had an isomer ratio of b / n of 69: 1 and the solids composition was 1.4 percent of normal isomer, 8.9 percent of the R-isomer and 89.7 percent of the S-isomer [i.e. , S-2- (6-methoxy-2-naphthyl) propionaldehyde]. The enantiomeric excess of the solids was 81.9 percent. The crude reaction product was concentrated by evaporating 30 weight percent of the solution. The resulting concentrate material consisted of 57 percent acetone and 43 percent solids. This was crystallized in a falling film crystallizer from the laboratory by the following procedure. The crystallizer consisted of a container (A), a column (B) with a shirt (the column was a vertical tube with a meter long shirt that had an internal opening with a diameter of 2.54 centimeters) and (D) a means for pumping (ie, flowing) of the liquid from the container to the film device (C) at the top of the falling film crystallizer The crystallizer jacket was fixed to a supply of the refrigerant (E) flowing in parallel with the descending movie., both the descending film and the coolant in the jacket melted down in a parallel manner. The crystallizer used is similar in principle to those described in the aforementioned US Patent No. 3,621,664. Two thousand milliliters of the concentrated material produced as defined above was charged to the container (A) of the falling film crystallizer used in Example 5. The material concentrated in the container was circulated briefly down through the column (B) to moisten the internal walls and then the circulation was discontinued. Since the column walls were maintained at -20 ° C by the circulating coolant, a thin frosting of solids quickly formed on the inner walls of the column. The flow through the falling film crystallizer was resumed by depositing crystals inside the wall of the column. After the vessel temperature was reduced to -16 ° C, the recirculation flow was stopped. During cooling, a slight amount of heat was added to the container by a heating mantle (F) to prevent crystallization in the container. To compensate for this heating, the circulating liquid was cooled slightly by the circulating refrigerant from the bath (G) to the coolers (H). After completion of crystallization, the residual liquid in the container was emptied and the solids within the walls of the crystallizer were washed with 50 cubic centimeters of washing liquid that were added from the top of the column and this washing liquid was discarded . The composition of the container residue was 61 percent acetone and 39 percent solids. The solids in the vessel had a b / w isomer ratio of 60: 1 and contained 1.6 percent of the normal isomer, 12.8 percent of the R-isomer and 85.6 percent of the S-isomer. The ee of the vessel solids was 74.0 percent. 600 cubic centimeters of reactive-grade acetone were added to the vessel and circulated to the falling film device at 20 ° C and then down the inner wall of the column to dissolve the solids adhering to the inside of the column. This was a very fast and efficient technique to recover the adhering solids and is a unique method for recovering solids from the falling film crystallizer. The acetone solution recovered from the column wall contained 78 percent acetone and 22 percent crystalline solids. The crystalline solids had a b / n isomer ratio of 111: 1 and contained 0.9 percent normal isomer, 6.9 percent R-isomer and 92.2 percent S-isomer. The ee of crystalline solids was 86.1 percent.

Example 6 Refining an Aldehyde from an Acetone Solution Using Cooling Crystallization Three circles of 5.08 centimeters from a sheet of 20.32 by 27.94 centimeters from the membranes of MPF-50 (Lot # 021192, code 5102). These were placed in three Osmonics membrane holders. The feed was placed in a 2L Hoke cylinder under a nitrogen atmosphere. The feed was pumped up to 35.15 kilograms per square centimeter at a flow rate of approximately 380 milliliters per minute. The feed flowed through a 60 micron filter and then divided into three streams that went to the membranes. Flow meters were used to ensure that the flow was equally divided. The permeate material from the membranes was combined and collected under a nitrogen atmosphere. The refining was flowed to a back pressure regulator and then returned to the Hoke cylinder. The feed was a 4 liter batch of the crude hydroformylation reaction product containing 2- (6-methoxy-2-naphthyl) -propionaldehyde (30 weight percent) in acetone (70 weight percent). The mixture also contained rhodium (389.3 parts per million) and Iso (BHA-P) 2- 2R, 4R-pentanediol. Approximately 3325 grams of this solution was infiltrated through the membrane, and the resulting permeate solution had a rhodium content of about 36.3 parts per million. The system was emptied, cleaned with acetone and the residue was discarded. The 3325 grams of the permeate solution containing 36.3 parts per million of rhodium was placed back into the Hoke cylinder and approximately 1439 grams of this solution again infiltrated through the membrane. The solution of the resulting permeate material contained approximately 5.6 parts per million rhodium. The 1439 grams of the solution containing 5.6 parts per million of rhodium were put back into the Hoke cylinder and passed through the membrane again for the third time. Approximately 935 grams of this solution was infiltrated through the membrane and the resulting permeate material had approximately 1.2 parts per million rhodium. This permeate material was then used as a feed for the crystallization process which will be described below. The recovery and refining of S-2- (6-methoxy-2-naphthyl) -propionaldehyde aldehyde from the permeate obtained as described above, was achieved by the sequence of operations that will be described below. In summary, the feed solution of the permeate material was batch crystallized by cooling to -10 ° C. The slurry obtained in this way was filtered to remove the crystals and the crystals were washed with half a gram of acetone per gram of wet solids. The filtrate was combined and the solution concentrated to 40 percent solids by evaporation of the acetone. The crystallization, filtration and washing were repeated in this concentrated solution. The crystals of this second stage were combined with crystals of the first crystallization and were dissolved in one and a half parts by weight of acetone by the wet solids. This solution was processed in the same manner as the feed solution of the original permeate material. The solids that were recovered and washed from each of 14 - the crystallization steps were combined again and dissolved in acetone. The final recrystallization was also carried out in the manner described above in this Example. The refined crystalline solids of this last step represented the final product (ie, S-2- (6-methoxy-2-naphthyl) propionaldehyde). The final ee was 96.8. The yield of S-2- (6-methoxy-2-naphthyl) propionaldehyde as a fraction of that supplied in the feed was 26.8 percent.

Example 7 A. Melt Temperature Diagram of Naproxen Aldehyde The data of the experimental melting temperature was obtained using the crystallizer described in Example 3 above. Samples were obtained during the crystallization tests in acetone solutions. The solid samples were removed from the slurry by filtration. The samples were then slowly heated in a Perkin / Elmer DSC7 to obtain the melting temperature. The data are tabulated in Table 1. The melting temperature of the pure S-enantiomer (S-α- (6-methoxy-2-naphthyl) propionaldehyde) is discernible. It is difficult to develop a complete liquid curve due to a variety of reasons. A problem with determining the melting temperature of these solid samples is that the N-isomer is present in a sufficient concentration to reduce the melting temperature of the mixture.

Table 1 Data of the Melting Point of Naproxen Aldehyde Sample Composition Fusion Temperature, ° C % of S% of R% of N 98. 2 1.7 0.1 73.5 94.3 5.0 0.7 66.1 98.2 1.6 0.2 72.7 94.8 4.7 0.5 69.4 87.4 10.8 1.8 63.7 95.5 4.0 0.5 72.5 88.1 8.7 3.2 57.2 92.3 7.0 0.7 66.9 B. Solubility of Aldehyde Naproxen The solubility data for solids in the solvent in acetone were obtained by visually obtaining a "turbidity" temperature for a solution of the known composition by slowly cooling the solution. After obtaining a "turbidity" temperature the solution slowly warmed up until a "clearing" temperature was observed. The "clearing temperature" represents the saturation temperature of the solution and the "turbidity" temperature the temperature at which massive spontaneous nucleation occurs. The data shown in Table 2. The aldehydes naproxen [ie, R- and S-2- (6-methoxy-2-naphthyl) propionaldehyde] are very soluble in acetone. The solubility of these aldehydes is very sensitive to temperature and a high degree of subcooling of the solution is required to nuclear the solution.

Table 2 Solubility Data of Aldehyde in Naproxen in Acetone Solids Temperature Ratio Temperature (% by weight) Solids / Clearance-Turbidity, Liquid liquids, ° C ° C 29. 0 0.41 6 -17 35.3 0.55 15 -9 30.0 0.43 11 -6 22.0 0.28 1 -15 47.0 0.89 25 5 Example 8 Recovery of Aldehyde S-Naproxen from the Acetone Solution A crude reaction product of an asymmetric hydroformylation reaction was produced with low ee (62 percent) to experimentally investigate the quality of S-naproxen aldehyde [ie, S-2- (6-methoxy-2-naphthyl) propionaldehyde ] which can be recovered from solutions with high concentrations of the corresponding R- and N-isomeric aldehydes. Using the cooling crystallization procedure described in Example 3 above (ie, the solution is cooled to -15 ° C, reheated to 0 ° C and this technique is repeated three times before (from final cooling to minus 15 °) , a feed solution containing 77.6 percent of the S-isomer, 18.2 percent of the R-isomer and 4.2 percent of the N-isomer, and having an enantiomeric excess (ee) of 62 percent, was processed.The resulting crystals were recovered in a vacuum filter and washed with cold acetone The composition of the crystals was 95.5 percent of the S-isomer, 4.0 percent of the R-isomer, and 0.5 percent N-isomer providing an enantiomeric excess of 92 percent. recovered from the crystallization process described above in this Example and having a solids concentration of 65.5 percent of the S-isomer, 26.8 percent of the R-isomer and 7.7 percent of the N-isomer. it concentrated up to 53 percent solids by evaporating the acetone in vacuum. The concentrated material obtained in this manner was crystallized using the crystallization process described above in this Example. The composition of the crystalline solids obtained by the last crystallization was 92.3 percent of the S-isomer, 7.0 percent of the R-isomer and 0.7 percent of the N-isomer. The enantiomeric excess of those solids was 85.9 percent. The composition of the solids of the final filtrate was 54.1 percent of the S-isomer, 37.6 percent of the R-isomer and 8.3 percent of the N-isomer.

Example 9 Enhancing the Enantiomeric Purity of 2- (p-Isobutylphenyl) propionaldehyde Via Fusion Crystallization A solution consisting of p-isobutylstyrene (100.2 grams), Iso (BHA-P) -2R, 4R-pentanediol (0.85 gram), and Rh (CO) 12 (0.091 gram) was prepared. It is 9 - charged 100 milliliters of the mixture formed in this way in a reactor of 300 milliliter capacity that was pressurized with 1: 1 H2 / CO. The mixture was stirred at 25 ° C for 46 hours and pressure of 9.14 kilograms per square centimeter to effect hydroformylation. The crude reaction product was removed from the reactor and an aliquot was removed to determine the composition of the product. Analysis of GC in a chiral capillary column of beta-cyclodextrin (Cyclodex-BTM) indicated that 99.4 percent of the olefin starting material had been converted to aldehydes and that the ratio of 42: 1 to 2- (p-isobutylphenyl) ) propionaldehyde with respect to 3- (p-isobutylphenyl) propionaldehyde was obtained. Oxidation of the aldehyde products followed by chiral gas chromatography of the resulting carboxylic acids indicated that an ee of 85 + 5 percent of the desired S-aldehyde was produced [ie, S-2- (p-isobutylphenyl) propionaldehyde] . A portion (25 milliliters, 23.54 grams) of the crude product was distilled by evaporation to separate the products from the catalyst. The first fraction obtained from distillation (12.4 grams) at a temperature of 89 ° C-92 ° C at a pressure of 1 millimeter of mercury. A second fraction obtained from the distillation (9.4 grams) was obtained at a temperature of 83 ° C-4 ° C at 0.6 mm of mercury, and a small amount was left as residue. The second fraction obtained from the distillation was partially frozen and some liquid (3.27 grams) was removed first, with a pipette and then with a fried glass filter with the liquid at -12 ° to -17 ° C. Oxidation of the liquid and crystal portions with sodium chlorite followed by chiral gas chromatography of the resulting carboxylic acids indicated 92 + 1 and 75 + 2 percent ee for the S-aldehyde in the crystals and the liquid, respectively. The ratios of the concentrations of the other impurities in the liquid to their concentrations in the crystals averaged 2.2 and the ratio of b / n in the crystals was 54: 1. The oxidation with sodium chlorite referenced above was carried out in the following manner: A mixture of 0.28 gram of aldehyde and 2.0 milliliters of distilled water was cooled to 0 ° C and agitated. The aqueous sodium sulphamate (3 milliliters of 1 M, adjusted to a pH of 5 with phosphoric acid) and the sodium chlorite solutions (0.61 milliliter of 20 percent) were added. After 15 minutes, the cooling bath was removed and the solution was stirred for an additional 15 minutes and allowed to warm to room temperature. The pH was adjusted to 9.5 with 0.5 milliliter of 1 N sodium hydroxide and the material was rinsed with water in a separate funnel. The solution was stirred with added dichloromethane (10 millimeters) to extract the neutral compounds. The aqueous layer was separated and acidified to a pH of < 2 with concentrated hydrochloric acid. The turbid mixture that formed was extracted with 20 milliliters of dichloromethane, toluene was added as an internal normal and a small sample was taken to determine the yields of the branched and normal acids by gas chromatography. The remaining solution was dried through anhydrous magnesium sulfate and filtered. The dichloromethane was removed with a rotary vacuum evaporator (-150 millimeters of mercury) with the bath at 60 ° C. The residue (0.02 gram) was dissolved in toluene and analyzed by chiral gas chromatography.

Example 10 Refining an Aldehyde from an Acetone Solution Using Cooling Crystallization and No Addition of the Solvent The crude hydroformylation reaction product (47 grams) which was similar to the crude reaction product produced in Example 1 above and which contained 70.5 grams of acetone, was partially refined in a laboratory crystallizer in a manner similar to Example 6. The solids in the partially refined reaction product had 97.65 percent of the S-isomer [ie, S-2 (6-methoxy-2-naphthyl) propionaldehyde]. The partially refined product was further precipitated by adding a non-solvent product (water) in the final condition of the crystallizer. The amount of water added was 0.5 cubic centimeter per cubic centimeter of the thick slurry. The quality of the S-isomer recovered after vacuum filtration and washing with 150 cubic centimeters of water was 97.87 percent. The amount of material recovered was 40 grams. Repeating this procedure four times, the product quality increased up to 99.10 percent (98.2 percent ee) with a recovery of 28 grams.

Example 11 Refining an Aldehyde from an Acetone Solution Using Vacuum Cooling The crude hydroformylation reaction product (666 grams) which was similar to the crude reaction product produced in Example 1 above and containing 40 percent acetone and 60 percent solids, was added to a crystallization apparatus designed to provide vacuum cooling as described continuation. The solids had a ratio of b / n (2- (6-methoxy-2-naphthyl) propionaldehyde to 3- (6-methoxy-2-naphthyl) -propionaldehyde) of 82.76: 1 and 76 percent of • ee of the S-isomer [i.e., S-2 (6-methoxy-2-naphthyl) propionaldehyde]. The apparatus consisted of a one-liter capacity jacketed vessel equipped with condenser stirrer and vacuum pump. The solution was cooled to 5 ° C where the crystals were formed and then at 0 ° C slowly reducing the vacuum to a final reading of 50 mm absolute. The contents of the container were kept at 0 ° C for 15 minutes and then heated to 8 ° C increasing the pressure of the system to 150 millimeters and heating the jacket of the container to 10 ° C to heat the contents. The conditions in the vessel were maintained at 8 ° C for 10 minutes, again the vacuum was reduced to 50 millimeters and the temperature of the vessel was reduced to 0 ° C. This heat contratécnica was used to dissolve the fine crystals and re-deposit the supersaturation towards the existing crystals improving in this way the size of the crystal. After maintaining the temperature of the vessel at 0 ° C for 10 minutes, the contents were separated on a centrifugal filter from the laboratory and washed with cold acetone. Approximately 60 grams of dry solids were recovered in a b / n ratio of 440: 1 and an ee of 92.3 percent.

Example 12 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen Using Lysidine / Acetic Acid as the Catalyst To a stirred solution of 16.67 grams (77.8 mmol) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde (naproxen aldehyde) in ethyl acetate (78 milliliters) cooled in a wet ice bath (approximately 2 ° C) 4.67 grams (77.8 millimoles) of glacial acetic acid and 8.33 grams (77.8 millimoles) of 2,6-dimethylpyridine (2,6-lutidine) were added simultaneously. To this solution were then added slowly by drops an amount of 8.87 grams (116.7 millimoles) of a 23.7 weight percent solution of peracetic acid in ethyl acetate, a flow rate sufficiently so that the reaction temperatures did not exceed of 10 ° C (approximately 1 hour). After the initial exothermic reaction, the temperature returned to 2 ° C and the reaction was maintained at this temperature for an additional 3.5 hours. The conversion of aldehyde during this time was approximately 99 percent, as monitored by GC (DB-1 column). The cold reaction solution was then transferred to a separatory funnel, diluted with ethyl acetate (300 milliliters) and washed with a 5 percent aqueous solution of sodium thiosulfate (Na2S2? 3, 100 milliliters). The ethyl acetate layer was further washed with two portions of water (each 110 milliliters) and those washed with the combined water were counter-extracted with ethyl acetate (100 milliliters). The combined ethyl acetate layers were extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, each 110 milliliters). The combined NaOH solutions of sodium naproxenate were acidified to pH = 1 with the 10 percent aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet ice bath and then vacuum filtered through a Whatman # 4 filter. The white solid obtained in this way was dried under vacuum and overnight at 45 ° C (25 millimeters of mercury), providing 15.85 grams (88.5 percent (naproxen) HPLC analysis of this material (Chiracel column of OD- H) indicated an 'S' acid content of 99.2 percent, same as the starting aldehyde as measured after oxidation with KMn04.

Example 13 Oxidation of (S) -2- (4-Isobutylphenyl) propionaldehyde in (S) - Ibuprofen Using Lysidine / Acetic Acid as the Catalyst To a stirred solution of 109 grams (573 mmol) of 2- (4-isobutylphenyl) propionaldehyde (ibuprofen aldehyde) in ethyl acetate (512 milliliters) cooled in a wet ice bath (approximately 2 ° C) were added 34.4 simultaneously. grams (573 millimoles) of glacial acetic acid and 61.4 grams (573 millimoles) of 2,6-dimethylpyridine (2,6-lutidine). A quantity of 276 milliliters was slowly added dropwise to this solution. (859 millimoles) of a 23.7 weight percent solution of peracetic acid in ethyl acetate, a sufficiently slow regime so that the reaction temperature did not exceed 7 ° C (about 1 hour 40 minutes). After the initial exothermic reaction, the temperature returned to 2 ° C and the reaction was maintained at this temperature for an additional 2 hours. Aldehyde conversion during this time was approximately 99 percent, as monitored by GC (DB-1 column). The cold reaction solution was then transferred to a separatory funnel, diluted with ethyl acetate (650 milliliters) and washed with a 7 percent aqueous solution of sodium thiosulfate (Na2S2? 3, 500 milliliters). The ethyl acetate layer was further washed with two portions of water (750 milliliters each) and those washed with the combined water were back-extracted with ethyl acetate (300 milliliters). The combined ethyl acetate layers were extracted with three portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 750 milliliters twice and then 500 milliliters). The combined NaOH solutions were acidified to pH = 1 with a 10 percent aqueous solution of hydrochloric acid. The resulting solution was extracted with three portions of dichloromethane (500 milliliters twice and then 300 milliliters) and the extract was dried through anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to provide 109 grams (92.2 percent) of ibuprofen as a whitish solid. HPLC analysis of this material indicated an 83% "S" acid content, same as the starting aldehyde as measured after oxidation with KMn04.

EXAMPLE 14 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen Using L-Nitide Oxide as the Catalyst To a stirred solution of 3.32 grams (15.5 millimoles) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde (98.8 percent pure by GC) in n-butyl acetate (15.5 milliliters) cooled in a bath of wet ice (about 2 ° C) were added 1.91 (15.5 millimoles) of the 2,6-dimethylpyridine n-oxide (2,6-lutidine N-oxide). To this solution were then added dropwise 1.77 grams (23.2 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a sufficiently slow rate so that the reaction temperatures did not exceed 10. ° C (approximately 30 minutes). After the initial exothermic reaction, the temperature returned to 2 ° C and the reaction was maintained at this temperature for an additional 2 hours. The conversion of aldehyde during this time was approximately 99 percent, as monitored by GC (DB-1 column). The reaction solution was transferred to a separatory funnel, diluted with n-butyl acetate (70 milliliters) and washed with a 5 percent aqueous solution of sodium thiosulfate (Na2S2? 3, 15 milliliters). The butyl acetate layer was further washed with water (50 milliliters) and the washings of the combined water were counter-extracted with n-butyl acetate (30 milliliters). The combined butyl acetate layers were extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 65 milliliters each). The combined NaOH solutions of sodium naproxenate were acidified to pH = 1 with a 5 percent aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet ice bath and then filtered under vacuum through a filter paper.

Whatman # 1. The filter cake was washed with cold water (50 milliliters) and the white solid obtained in this way was dried in a vacuum oven for 60 hours at 55 ° C. (25 millimeters of mercury), providing 3.51 grams (98.4 percent) of naproxen.

Example 15 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen Using Pyridine N-Oxide / Acetic Acid as the Catalyst To a stirred solution of 2.00 grams (9.3 mmol) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde in ethyl acetate (10 milliliters) cooled in a wet ice bath (ca. simultaneously added 0.89 grams (9.3 millimoles of pyridine N-oxide and 0.56 gram (9.3 millimoles) of acetic acid.) To this solution was then added slowly 5.8 milliliters (14.0 millimoles) of a 20.4 weight-percent solution of acid peracetic in ethyl acetate, at a sufficiently slow rate in such a way that the reaction temperature did not exceed 10 ° C (approximately 15 minutes) After the initial exothermic reaction, the temperature returned to 2 ° C and the reaction maintained at this temperature for an additional 4 hours.The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate (15 milliliters) and washed with an aqueous solution of 0.1 N concentration of sodium thiosulfate (Na2S2? 3 , 25 milliliters) The ethyl acetate layer was further washed with water (10 milliliters) and the combined water washings were counter-extracted with ethyl acetate (10 mmol). The combined ethyl acetate layers were extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (KaOH, 65 milliliters and then 25 milliliters). The combined KaOH solutions of potassium naproxenate were acidified to pH = 1 with a 5 percent aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet ice bath and then vacuum filtered through a Whatman # 1 filter. The filter cake was washed with cold water (20 milliliters) and the white solid obtained in this way was dried in a vacuum oven for 18 hours at 55 ° C (25 millimeters of mercury), providing 1.72 grams (80.0 percent) of naproxen.

Example 16 Oxidation of (S) -2- (4-Isobutylphenyl) propionaldehyde in (S) -Ibuprofen, Using N-Oxide of Lutidine as the Catalyst To a stirred solution of 10.0 grams (52.6 millimoles) of 2- (4-isobutylphenyl) propionaldehyde (ibuprofen aldehyde) in n-butyl acetate (53 milliliters) cooled in a wet ice bath (approximately 2 ° C) were added. 6.5 (52.6 millimoles) of 2,6-dimethylpyridine n-oxide (2,6-lutidine N-oxide). To this solution, 29 milliliters were slowly added dropwise (78.8 millimoles) of a 20.0 weight percent solution of peracetic acid in ethyl acetate, at a sufficiently slow rate so that the reaction temperature did not exceed 10 ° C (about 25 minutes). After the initial exothermic reaction, the temperature returned to 2 ° C and the reaction was maintained at this temperature for an additional 4 hours. The cold reaction solution was then transferred to a separatory funnel, diluted with n-butyl acetate (100 milliliters) and washed with a 1 percent aqueous solution of sodium thiosulfate.

(Na2S2? 3, 100 milliliters). The butyl acetate layer was further washed with two portions of water (100 milliliters each) and the combined water washings were counter-extracted with n-butyl acetate (100 milliliters). The combined butyl acetate layers were extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 100 milliliters each). The combined NaOH solutions were acidified to a pH = 1 with a 10 percent aqueous solution of hydrochloric acid. The resulting solution was extracted with two portions of chloromethane (100 milliliters each) and the extracross was dried through anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to provide 10.3 grams (94.0 percent) of ibuprofen as a whitish solid.

Example 17 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen with Peracetic Acid (1.5 Equivalents) Using the N-Oxide of 4-Methylmorpholine (1.0 Equivalent) as the Catalyst To a stirred solution of 3.0 grams (14.0 mmol) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde (about 95 percent pure by GC) in n-butyl acetate (14.0 milliliters) cooled in a wet ice bath (approximately 2 ° C) was added 1.64 (14.0 mmol) of n-methylmorpholine N-oxide. To this solution, 7.7 milliliters were slowly added dropwise (21.0 mmol) of a 23.0 weight percent solution of peracetic acid in ethyl acetate, at a sufficiently slow rate such that the reaction temperature did not exceed 5 ° C (exothermic, approximately 60 minutes) . TLC analysis of the reaction mixture 10 minutes after the addition of the peracetic acid indicated that the conversion of the aldehyde had been completed and a sample (0.5 milliliter) was removed for GC analysis. The reaction solution was transferred to a separatory funnel with the aid of n-butyl acetate (25 milliliters) and washed with an aqueous solution of 1 M concentration of sodium thiosulfate (Na 2 S 2 3 3.5 milliliters). The butyl acetate layer was further washed with water (50 milliliters). The solution of butyl acetate of naproxen acid was then extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 50 milliliters each). The combined NaOH solutions of sodium naproxenate were acidified with stirring to pH = 1 with a 5 percent aqueous solution of hydrochloric acid (105 milliliters), precipitating the naproxen acid. The mixture was filtered under vacuum through a Whatman # 1 filter and the solids were washed with cold water (5 milliliters). The white solid obtained in this manner was dried in a vacuum oven for 14 hours at 55 ° C (25 millimeters of mercury), providing 2.52 grams (76.2 percent) not including the withdrawn sample) of naproxen. HPLC analysis of chiral phase indicated a ratio of S: R naproxen of 50: 1: 49.9 (racemic).

Example 18 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen with Peracetic Acid (1.5 Equivalents) Using the N-Oxide of 4-Methoxypyridine (1.0 Equivalent) as the Catalyst To a stirred solution of 3.0 grams (14.0 mmol) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde (approximately 95 percent pure by GC) in n-butyl acetate (14.0 milliliters) cooled in a wet ice bath (approximately 2 ° C) was added 1.75 (14.0 mmol) of 4-methoxypyridine N-oxide. To this solution, 7.7 milliliters were slowly added dropwise (21.0 mmol) of a 23.0 weight percent solution of peracetic acid in ethyl acetate, at a sufficiently slow rate such that the reaction temperature did not exceed 5 ° C (highly exothermic, approximately 60 minutes). TLC analysis of the reaction mixture 10 minutes after the addition of the peracetic acid indicated that the conversion of the aldehyde had been completed and a sample (0.5 milliliter) was removed for GC analysis. The reaction solution was transferred to a separatory funnel with the aid of n-butyl acetate (25 milliliters) and washed with an aqueous solution of 1 M concentration of sodium thiosulfate (Na 2 S 2 3 3.5 milliliters). The butyl acetate layer was further washed with water (50 milliliters). The solution of butyl acetate of naproxen acid was then extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 50 milliliters each). The combined NaOH solutions of sodium naproxenate were acidified with stirring to pH = 1 with a 5 percent aqueous solution of hydrochloric acid (105 milliliters), precipitating the naproxen acid. The mixture was filtered under vacuum through a Whatman # 1 filter and the solids were washed with cold water (5 milliliters). The white solid obtained in this manner was dried in a vacuum oven for 14 hours at 55 ° C (25 millimeters of mercury), providing 2.75 grams (85.4 percent) not including the removed sample) of naproxen. HPLC analysis of chiral phase indicated a ratio of S: R naproxen of 88.5: 11.4 (77.1 percent ee), the same ratio in the starting aldehyde within the experimental error.

Example 19 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen with Peracetic Acid (1.5 Equivalents) Using N-Oxide of 4-Methoxypyridine (0.5 Equivalent) as the Catalyst at a Temperature of 2 ° C to 5 ° C To a stirred solution of 5.0 grams (23.3 millimoles) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde (approximately 95 percent pure by GC) in n-butyl acetate (24.0 milliliters) cooled in a wet ice bath (approximately 2 ° C) was added 1.46 grams (11.67 millimoles) of 4-methoxypyridine n-oxide. To this solution were then slowly added dropwise 1.95 grams (25.67 millimoles) of a 23.0 weight percent solution of peracetic acid in ethyl acetate, at a sufficiently slow rate so that the reaction temperature did not exceed 5%. ° C (get exothermic, approximately 45 minutes). TLC analysis of the reaction mixture 30 minutes after the addition of the peracetic acid indicated that the conversion of the aldehyde was complete. The reaction solution was transferred to a separating funnel with the aid of n-butyl acetate (50 milliliters) and treated with an aqueous solution of 1 M sodium thiosulfate (Na 2 S 2 3 3, 1.3 milliliters). A sample (0.5 milliliter) was removed for GC analysis. The butyl acetate layer was washed with water (50 milliliters twice), and the washings were counter-extracted with n-butyl acetate (20 milliliters). The combined naproxen-butyl acetate solutions were then extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 60 milliliters each). The combined NaOH solutions of sodium naproxenate were acidified with stirring at pH = 1 with a 5 percent aqueous solution of hydrochloric acid (125 milliliters), precipitating the naproxen acid. The mixture was cooled in a wet ice bath, filtered under vacuum through a Whatman # 1 filter and the solids were washed with cold water (5 milliliters). The white solid obtained in this way was dried in a vacuum oven for 14 hours at 55 ° C (25 millimeters of mercury), providing 4.91 grams (91.4 percent) not including the withdrawn sample) of naproxen. HPLC analysis of the chiral phase indicated a ratio of naproxen S: R of 88.6: 11.4 (77.2 percent ee), the same ratio as the starting aldehyde within the experimental error.

Example 20 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen with Peracetic Acid (1.5 Equivalents) Using N-Oxide of 4-Methoxypyridine (0.5 Equivalent) as the Catalyst at -25 ° CA a stirred solution of 1.0 gram (4.67 mmol) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde (approximately 95 percent pure by GC) in n-butyl acetate (5 milliliters) cooled in a C 2 / CCl 4 bath (-25 ° C) were added 292 milligrams (2.3 millimoles) of 4-methoxypyridine N-oxide. To this solution was then added dropwise 391 milligrams (0.1 millimoles) of a 23.0 percent solution of peracetic acid in ethyl acetate, at a sufficiently slow rate so that the reaction temperatures did not exceed -18 °. C (get exothermic, approximately 20 minutes). TLC analysis of the reaction mixture 10 minutes after the addition of the peracetic acid indicated that the conversion of the aldehyde was complete. The reaction solution was then treated with an aqueous solution of 0.1 M sodium thiosulfate (Na 2 S 2? 3, 11 milliliters). A sample (0.5 milliliter) was removed from the organic layer for GC analysis. The content of the reactor was transferred to a separatory funnel using n-butyl acetate (20 milliliters) and the butyl acetate layer was washed with water (50 milliliters). The solution of butyl acetate of naproxen acid was then extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 30 milliliters each). The combined NaOH solutions of sodium naproxenate were acidified with stirring to pH = 1 with a 5 percent aqueous solution of hydrochloric acid (65 milliliters), precipitating the naproxen acid. The mixture was filtered under vacuum through a Whatman # 1 filter. The white solid obtained in this manner was dried in a vacuum oven for 14 hours at 55 ° C (25 millimeters of mercury), providing 0.804 gram (74.7 percent) not including the withdrawn sample); 85 percent corrected for the withdrawn sample) of naproxen. HPLC analysis of chiral phase indicated a ratio of S: R naproxen of 88.7: 11.33 (77.4 percent ee) the same ratio as the starting aldehyde within the experimental error.

Example 21 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen with Peracetic Acid (1.5 Equivalents) Using N-Oxide of 4-Methylmorpholine (1.0 Equivalent) / Acetic Acid (1.0 Equivalent) as the Catalyst To a stirred solution of 3.0 grams (14.0 mmol) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde (approximately 94 percent pure by GC) in n-butyl acetate (14.0 milliliters) cooled in a wet ice bath (approximately 2 ° C) was added 0.84 gram (14.0 mmol) of glacial acetic acid followed by 1.64 grams (14.0 mg). millimoles) of 4-methylmorpholine N-oxide. To this solution, 7.7 milliliters (21.0 millimoles) of a 23.0 percent solution of the peracetic acid in ethyl acetate were slowly added dropwise at a sufficiently slow rate so that the reaction temperature did not exceed 5 ° C. . The reaction mixture was stirred at 2 ° C for 4 hours and then the excess of peracetic acid was neutralized by the addition of an aqueous solution of 1.0 M sodium thiosulfate (Na 2 S 2 3 3, 10 milliliters). The solution was transferred to a separatory funnel with the aid of n-butyl acetate (25 milliliters) and the aqueous layer was separated and discarded. The solution of butyl acetate of naproxen acid was then extracted with two portions of a 5 percent aqueous solution of sodium hydroxide (NaOH, 50 milliliters each). The combined NaOH solutions of sodium naproxenate were acidified with stirring to pH = 2 with a 2 percent aqueous solution of hydrochloric acid (100 milliliters), precipitating the naproxen acid. The mixture was cooled in a wet ice bath and filtered under vacuum through a Whatman # 2 filter. The white solid obtained in this manner was dried in a vacuum oven for 14 hours at 55 ° C (25 millimeters of mercury), providing 2.58 grams (80.0 percent) of naproxen. HPLC analysis of chiral phase indicated a ratio of S: R naproxen of 78.0: 22.0 (partial racemization, this lot of aldehyde is known to provide acid with an S: R content of 88.1: 21.9).

Example 22 Oxidation of (S) -2- (6-Methoxy-2-naphthyl) propionaldehyde in S-Naproxen with Peracetic Acid (3.0 Equivalents) Using Triethanolamine (1.0 Equivalent) / Acetic Acid (1.0 equivalent) as the Catalyst To a stirred solution of 1.0 gram (4.67 mmol) of (S) -2- (6-methoxy-2-naphthyl) propionaldehyde in absolute ethanol (5.0 milliliters) was cooled in a wet ice bath (approximately 2 ° C). added 0.27 milliliter (0.28 grams, 4.67 millimoles) of glacial acetic acid followed by 0.62 milliliter (0.70 grams, 4.67 millimoles) of triethanolamine. To this solution were then added dropwise 2.25 milliliters (7.0 millimoles) of a 23.0 weight percent solution of peracetic acid in ethyl acetate, at a sufficiently slow rate so that the reaction temperature did not exceed 10. ° C. The reaction mixture was stirred at 2 ° C for 2 hours and then an additional 2.25 milliliters (7.0 mmol) of the paracetic acid solution was added to complete the conversion of aldehyde (4 hours in total). The solution was transferred to a larger flask with the help of ethanol (5 milliliters), heated to 50 ° C and then diluted with water (40 milliliters). The solution was cooled in a wet ice bath causing precipitation and filtered under vacuum through a Whatman # 2 filter. The light purple solid obtained in this way was washed with 20 milliliters of water and dried in a vacuum oven for 14 hours at 55 ° C (25 millimeters of mercury), providing 0.79 gram (73.5 percent) of naproxen. HPLC analysis of chiral phase indicated a ratio of S: R naproxen of 95.8: 4.2 same as that obtained by the method of independent oxidation. Even though the invention has been illustrated by certain of the foregoing examples, it should not be construed as being limited thereby; instead, the organization covers the generic area as it has been known in the foregoing. Various modifications and modalities can be made without deviating from the spirit and scope of it.

Claims (20)

R E I V I N D I C A C I O N E S:

1. A process for producing an optically active carboxylic acid whose process comprises oxidizing an optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide which is selected from the group consisting of a substituted or unsubstituted alkylamine , in the alkylamine N-oxide, aromatic amine, aromatic amine N-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof to produce the optically active carboxylic acid, wherein the amine catalyst and / or Amine N-oxide has a sufficient basicity to catalyze the oxidation of the optically active aldehyde in the optically active carboxylic acid.

2. The process of claim 1, which is carried out in the presence of a weak organic acid. The process of claim 1, wherein the optically active aldehyde is selected from S-2- (p-isobutyl-phenyl) propionaldehyde, S-2- (6-methoxy-2-naphthyl) propionaldehyde, S-2- (3-benzoylphenyl) -propionaldehyde, S-2- (p-thienoylphenyl) -propionaldehyde, S-2- (3-fluoro-4-phenyl) phenylpropionaldehyde, S-2- [4- (1,3-dihydro-l) -oxo-2H-isoindol-2-yl) phenyl] propionaldehyde, S-2- (3-phenoxy (propionaldehyde, S-2-phenylbutylaldehyde, S-2- (4-isobutylphenyl) butylaldehyde, S-2-phenoxypropionaldehyde, S -2-chloropropionaldehyde, R-2- (3-benzoylphenyl) propionaldehyde and R-2- (3-fluoro-4-phenyl) phenylpropionaldehyde 4. The process of claim 1, wherein the peracid is selected from peracetic acid, Performanic acid, perpropionic acid and perbenzoic acid 5. The process of claim 1, wherein the amine catalyst and / or amine N-oxide is selected from 2,6-lutidine N-oxide, 5-ethyl- 2-methylpyridine, 5-ethyl-2-methylpyridine N-oxide, N-oxide of 4-methoxypyridine and 2,5-lutidine N-oxide. The process of claim 1, wherein the optically active carboxylic acid is selected from the S- 2- (6-methoxy-2-naphthyl) propionic acid S-2- (p-isobutylphenyl) propionic acid, S acid -2- (3-benzoylphenyl) propionic, S-2- (p-thienoylphenyl) propionic acid, S-2- (3-fluoro-4-phenyl) phenylpropionic acid, S-2- [4- (1, 3 -dihydro-l-oxo-2H-isoindol-2-yl) phenylpropionic acid, S-2- (3-phenoxy) propionic acid, S-2-phenylbutyric acid, S-2- (4-isobutylphenyl) butyric acid, S-acid -2-phenoxypropionic acid, S-2-chloropropionic acid, R-2- (3-benzoylphenyl) propionic acid and R-2- (3-fluoro-4-phenyl) -phenylpropionic acid 7. The process of claim 1, wherein the optically active aldehyde is produced by asymmetric hydroformylation, symmetric olefin isomerization or asymmetric aldol condensation 8. A process to minimize the racemisation of aldehyde and reduce formation of the formate by-product in a process to produce an optically active carboxylic acid whose process comprises oxidizing an optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide which is selected from the group consisting of a substituted or unsubstituted alkylamine, N- alkylamine oxide, aromatic amine, aromatic amine N-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof to produce the optically active carboxylic acid with reduced aldehyde racemisation and reduced formation of the formate by-product, wherein the amine catalyst and / or amine N-oxide has a sufficient basicity to catalyze the oxidation of the optically active aldehyde in optically active carboxylic acid. 9. A process for producing an optically active carboxylic acid whose process comprises: (1) reacting a prochiral or chiral compound with carbon monoxide and hydrogen in the presence of an optically active complex metal catalyst-coordinating group to produce an optically active aldehyde; and (2) oxidizing the optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide which is selected from the group consisting of a substituted or unsubstituted alkylamine N-alkylamine oxide, aromatic amine, aromatic amine N-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof, to produce the optically active carboxylic acid wherein the amine catalyst and / or amine N-oxide has a basicity sufficient to catalyze the oxidation of the optically active aldehyde in optically active carboxylic acid. The process of claim 9, wherein the complex catalyst of optically active metal-co-polymer group comprises a metal that is selected from a Group VIII, Group IB, Group VIB and Group VA formed complex of a metal. optically active coordinating group that has the formula: wherein each W is the same or different and is phosphorus, arsenic or antimony, each X is the same or different and is oxygen, nitrogen or a covalent bond linking W and Y, and is a substituted or unsubstituted hydrocarbon residue, each Z is the same or different and is a substituted or unsubstituted hydrocarbon residue or the Z-substituents linked to W can be connected together to form a cyclic substituted or unsubstituted hydrocarbon residue, and m is a value equal to the free valence of Y, with the except that at least one of Y and Z is optically active. The process of claim 9, wherein the prochiral or chiral compound is selected from p-isobutylstyrene, 2-vinyl-6-methoxynaphthalene, 3-ethenyl phenyl ketone, 2-thienylketone 4-ethenylphenyl, 4-ethenyl-2. -fluorobiphenyl, 4- (1, 3-dihydro-l-oxo-2H-isoindol-2-yl) styrene, 2-ethenyl-5-benzoylthiophene, 3-ethenylphenyl phenyl ether, propenylbenzene, isobutyl-4-propenylbenzene, phenyl vinyl ester and vinyl chloride. The process of claim 9, wherein the optically active aldehyde is selected from S-2- (p-isobutyl-phenyl) propionaldehyde, S-2- (6-methoxy-2-naphthyl) propionaldehyde, S-2- (3-benzoylphenyl) -propionaldehyde, S-2- (p-thienoylphenyl) -propionaldehyde, S-2- (3-fluoro-4-phenyl) phenylpropionaldehyde, S-2- [4- (1,3-dihydro-l) -oxo-2H-isoindol-2-yl) phenyl] propionaldehyde, S-2- (3-phenoxy (propionaldehyde, S-2-phenylbutylaldehyde, S-2- (4-isobutylphenyl) butylaldehyde, S-2-phenoxypropionaldehyde, S -2-chloropropionaldehyde, R-2- (3-benzoylphenyl) propionaldehyde and R-2- (3-fluoro-4-phenyl) phenylpropionaldehyde 1

3. The process of claim 9, wherein the peracid is selected from peracetic acid, Performamic acid, perpropionic acid and perbenzoic acid 1

4. The process of claim 9, wherein the amine catalyst and / or amine N-oxide is selected from 2,6-lutidine N-oxide, 5-ethyl-2. -methylpyridine, 5-ethyl-2-methylpyridine N-oxide, N-oxide of 4-methoxypyridine and 2,5-lutidine N-oxide. The process of claim 9, wherein the optically active carboxylic acid comprises S-2- (p-isobutyl-phenyl) propionic acid, S-2- (6-methoxy-2-naphthiDpropionic acid, S-2- acid (3-benzoylphenyl) -propionic, S-2- (p-thienoylphenyl) -propionic acid, S-2- (3-fluoro-4-phenyl) phenylpropionic acid, S-2- [4- (1, 3- dihydro-l-oxo-2H-isoindol-2-yl) phenyl] propionic, S-2- (3-phenoxy) (propionic, S-2-phenylbutyric acid, S-2- (4-isobutylphenyl) butyric acid, acid S-2-phenoxypropionic, S-2-chloropropionic acid, R-2- (3-benzoylphenyl) propionic acid or R-2- (3-fluoro-4-phenyl) phenylpropionic acid 16. A process for producing a carboxylic acid optically active whose process comprises: (1) reacting a chiral or prochiral organic compound - - olefinically unsaturated as carbon oxide and hydrogen in the presence of an optically active rhodium complex catalyst and a coordinating group for producing an optically active aldehyde; and (2) oxidizing the optically active aldehyde with a peracid in the presence of an amine catalyst and / or amine N-oxide which is selected from the group consisting of a substituted or unsubstituted alkylamine N-alkylamine oxide, aromatic amine, Aromatic amine n-oxide, heterocyclic amine, heterocyclic amine N-oxide and mixtures thereof, to produce the optically active carboxylic acid, wherein the amine catalyst and / or amine N-oxide has a sufficient basicity to catalyze Oxidation of the optically active aldehyde in optically active carboxylic acid. The process of claim 16, wherein the optically active rhodium complex catalyst and coordinating group comprises a rhodium formed in complex with the optically active coordinating group having the formula: where each W is the same or different and is phosphorus, arsenic or antimony, each X is the same or different and is oxygen, nitrogen or a covalent bond linking W and Y, Y is a substituted or unsubstituted hydrocarbon residue, each Z is the same or different and is a substiuid or unsubstituted hydrocarbon residue or Z-linked substituents W can be connected together to form an unsubstituted substituted cyclic hydrocarbon residue and in m it is a value equal to the free valence of Y, with the proviso that at least one of Y and z is optically active. 18. The process of claim 17, wherein the optically active coordinating group is (2R, R) -di [2, 2'-í3,3'-di-tert-butyl-5,5'-dimethoxy-1, 1-bi phenyl)] 2, -pentyl diphosphite. The process of claim 17, wherein the optically active rhodium complex catalyst and coordinating group comprises rhodium complexed with an optically active coordinating group having the selected form of: wherein W, Y, Z and m are as defined in claim 16, and Y'1 is the same or different and is hydrogen or a substituted or unsubstituted hydrocarbon residue. The process of claim 16, wherein the amine catalyst and / or amine N-oxide is selected from 2,6-lutidine N-oxide, 5-ethyl-2-methylpyridine, 5- N-oxide ethyl-2-methylpyridine, 4-methoxypyridine N-oxide and 2,5-lutidine N-oxide.