PROCESS FOR PREPARING alpha -KETO-CARBOXYLIC ACIDS

Abstract: A process for preparing alpha -keto-carboxylic acids by reacting an organohalide in a liquid solvent medium with carbon monoxide at elevated temperature and elevated pressure in the presence of a catalytic amount of a metal carbonyl compound and an alkali metal inorganic base or an alkaline earth metal inorganic base characterized by utilizing as the organohalide a compound of the formula: RX, wherein X represents a halogen atom and R is a primary or secondary alkyl group; a primary arylalkyl group having two or more carbon atoms in the alkyl portion thereof bonded to the halogen atom; or a primary or secondary aryloxyalkyl group.

Description: PROCESS FOR PREPARING α-KBTO-CARBQXYLIC ACIDS The presenC invention relates to a process for Che carbonylation of certain organohalides to form α-keto-carboxylic acids. More particularly, the inven- tion relates to a process for Che carbonylation of cer¬ tain organohalides to form alkyl α-keto-carboxylic acids, β-substituted- -keto acids, arylalkylpyruvic acids and aryloxyalkylpyruvic acids. The practical value of such acids is that they can be used as intermediates in the preparation of α-amino-acids, β-substituted-α-amino-acids and other chemical products. Further, certain of the arylalkyl¬ pyruvic acids have been found to be useful as hypoglycemics. The preparation of α-keto-carboxylic acids and their derivatives has been the subject of a large number of investigations. According to Rodd, The Chemistry of Carbon Compounds (1952 edition), Vol. 1, pages 227-229, the following methods of preparation are available: gentle oxidation of -hydroxyacids containing a secondary hydroxyl group, or by the enzyma¬ tic deamination of -amino acids; hydrolysis of an acyl cyanide; hydrolysis of α-oximino-esters from glycidic acid esters on treatment with benzene satura¬ ted with boron trifluoride; from α,β-dibromocarboxylic acids by forming a piperidine addition compound followed by hydrolysis; from α-keto-acetals by ultraviolet irradiation in the presence of N-bromosuccinimide; from α-bromomethylketones by boiling with selenium dioxide in absolute methanol or ethanol; from carboxylic acid esters by oxidation with selenium dioxide; permanganate oxidation of vinyl ketones; from carboxylic acid esters by condensation with oxalic ester followed by decarboxylation; from aldehydes via 5-alkylidene-2-thio-oxazo- lid-4-ones or by reaction with methyl methoxy- acetate; hydrolysis of the reaction product of Grignard reagents on diethyl-oxa ic ester; oxidation of α-hydroxyacid esters containing - two β-hydrogen atoms by N-bromosuccinimide in carbon tetτachloride to β-bromo-α-keto-acid esters; and by the action of alkali on the di ethanesul- phonates and ditoluene-p_-sulphonates of .α » β-dihydroxycarboxylic acids. Methods for preparing arylpyruvic acids also are known. For example., U.S. Pat. No. 4,152,352 discloses the preparation of an arylpyruvic acid by reacting an arylmethyl halide in a liquid solvent medium with carbon monoxide at pressures of 5 to 200 bars in the presence of a catalytic amount of a metal carbonyl compound and an alkaline earth metal inorganic base. Further, U.K. Patent Application 2,025,478A discloses that alkali metal salts of an arylpyruvic acid can be prepared by reacting an arylmethyl halide, carbon monoxide and an alkali metal base in the presence of a metal carbonyl compound as catalyst and in the presence of an alcohol or cyclic ether as solvent. The cobalt-catalyzed carbonylation of secondary benzyl halides to give either monocarbonyl or double carbonyl insertion or coupling of organohalides is reported by E. Francalanci e_t al_. , Journal of Electro- analytical Chemistry, 1982, pp. 59-70. It has now been found that certain α-keto-car- boxylic acids can be prepared by reacting an organo- halide in a liquid solvent medium with carbon monoxide at elevated temperature and elevated pressure in the presence of a catalytic amount of a metal carbonyl com¬ pound and an alkali metal inorganic base or an alkaline earth metal inorganic base characterized by utilizing as the organohalide a compound of the formula: RX wherein X represents a halogen atom and R is a primary or secondary alkyl group; a primary arylalkyl group having two or more carbon atoms in the alkyl portion thereof bonded to the halogen atom; or a primary or secondary aryloxyalkyl group. Alpha-keto-carbox lic acid products which can be prepared by the process of the present invention include alkyl ct-keto-carboxylic acids of Che general formula: 00 III! RCC-OH in which R represents a linear alkyl radical having up to at least 20 carbon atoms; β-substituted-α-keto-carboxylic acids of the general formula: in which R-, and 2 are the same or different and are alkyl radicals which can be either straight chain or branched having from 1 to 18 carbon atoms; arylalkylpyruvic acids of the general formula: (R) n -A-(CH 2 ) m CH 2 C0C00H in which: A represents an aromatic hydrocarbon radical containing 1 benzene ring or 2 condensed benzene rings, each R, which may be the same or different, represents hydrogen or a linear or branched alkyl radi¬ cal with up to 4 carbon atoms which is unsubstituted or substituted by a nitro group or by an alkoxy group con¬ taining 1 to 4 carbon atoms, or an alkoxy group contain¬ ing 1 Co 4 carbon aComs, or a halogeno, niCrile, nitro or alkylcarbonyloxy group, n is 0 or an integer from 1-3 when A contains one benzene ring, and n is 0 or an integer from 1-5 when A contains two condensed benzene rings and m is 1-20; and aryloxyalkylpyruvic acids of the general f ormula : (R) n - -0 (C ' 2 ) m -CR π H-C0C00H In which : A represents an aromatic hydrocarbon radical containing 1 benzene ring or 2 condensed benzene rings, and R, R'-and R", which may be the same or different, represent hydrogen or linear or branched alkyl radicals having up to about 6 carbon atoms, and n is 0 or an integer from 1-5 when A contains one benzene ring, and n is 0 or an integer from 1-7 when A contains two condensed benzene rings and m is 0-20. The particular α-keto-carboxylic acid which is produced by the instant process depends, of course, upon the particular organohalide starting material used in the reaction. For example, the aforedescribed alk l- ct-keto-carboxylic acids are prepared by carbonylating a primary alkyl halide of the formula: RX wherein R Is a linear alkyl radical having from 1 to about 20 carbon atoms and X is halogen. Specific alkyl halides used to produce the corresponding alkyl-α-keto- carboxylic acids are primary alkyl halides having from 1 to 20 carbon atoms, although higher alkyl halides can be used, if desired. Alkyl flourides and alkyl iodides may be used, but it is preferable to use alkyl halides of the "middle halogens"--i.e. , alkyl chlorides and alkyl bromides. Specific examples of preferred alkyl halides include the onochlorides and the monobromides of methane, propane, butane, -pentane, hexane, heptane, octane, nonane, and other hydrocarbons having up to about 20 carbon atoms. The β-substituted-α-keto-carboxylic acids produced by the present process are prepared by car- bonylating secondary alkyl halides of the general formula: wherein R, and ~ are the same or different and are alkyl radicals which can be either straight chain or branched having from 1 to 18 carbon atoms each and X represents halogen. Alkyl halides suitable for use in the preparation of the β-substituted-α-keto-car- boxylic acid products of the present invention are secondary alkyl halides having from 3 to 36 carbon atoms, although higher alkyl halides can be used, if desired. Preferred alkyl flourides and alkyl iodides may be used, but it is preferable to use alkyl halides of the "middle halogen"--i.e. , alkyl chlorides and alkyl bromides. Among the alkyl radicals which may be em¬ ployed in the secondary halides include, for example, methyl, ethyl, propyl, butyl, amyl, and the like, up to and including those containing 18 carbon atoms and their corresponding branched chain isomers. Methods for preparing alkyl halides are well known to the art. The arylalkylpyruvic acid products of the present invention are produced by carbonylating an arylalkyl halide of the general formula: (R) n -A-(CH 2 ) m CH 2 X wherein X represents halogen, A represents an aromatic hydrocarbon radical containing 1 benzene ring or 2 con¬ densed benzene rings; each R, which may be the same or different, represents hydrogen or a linear or branched alkyl radical with 1 to 4 carbon atoms which is unsub- stituted or substituted by a nitro group or an alkoxy group containing 1 to 4 carbon atoms, or a halogeno, nitrile, nitro or alkylcarbonyloxy group; and n is 0 or an integer from 1-3 when A contains one benzene ring, and n is 0 or an integer from 1-5 when A contains two condensed benzene rings and m is 1-20. Specific examples of halides which can be used in the preparation of the arylalkylpyruvic acids of the present invention include: phenethyl bromide or chloride; 2-(o-methylphenyl)ethyl bromide or chloride; 2-(m-methylphenyl)ethyl bromide or chloride; 2-(p-methylphenyl)ethyl bromide or chloride; 2-(2' ,6' -dimethylphenyl)ethyl bromide or chloride; 2-(3' ,5'-dimethylphenyl)ethyl bromide or chloride; 2-(2' ,4'- imethylphenyl)ethyl bromide or chloride; 2-(3' ,4' -dimethylphenyl)ethyl bromide or chloride; 2-(2' ,3'-dimethylphenyl)ethyl bromide or chloride; 2-(2' ,5'-dimethylρhenyl)ethyl bromide or chloride; l-(2'-bromoethyDnaphthalene; and the like. The aryloxyalkylpyruvic acid products of the present invention are prepared by carbonylat.ing an aryloxyalkyl halide of the general formula: OMPI (R) n -A-0 (CR ' ) -CR"H-X wherein X is halogen and A represents an aromatic hydro¬ carbon radical containing 1 benzene ring or 2 condensed benzene rings, and R, R 1 and R rι , which may be the same or different, represent hydrogen or linear or branched alkyl radicals having up to about 6 carbon atoms, and n is 0 or an integer f om 1-5 when A contains one. benzene ring, and n is 0 or an integer from 1-7 when A contains two condensed benzene rings and is 0-20. Specific examples of halides which can be used to produce aryloxyalkylpyruvic acids made by the present process include: 2-phenoxyethyl bromide; 3-phenoxypropyl bromide; 4-phenoxybutyl bromide; 5-phenoxypentyl bromide; 6-phenoxyhexyl bromide; 7-phenoxyheptyl bromide; 8-phenoxyoctyl bromide; 2-(2-naphthoxy) ethyl bromide; 3-(2-naphthoxy) butyl bromide; 5-(2-naphthoxy) pentyl bromide; and the like. The reaction is carried out in Che presence of a mixture of water and alcohol as a reaction medium in which the carbonylation of the organohalide takes place. Preferably, the alcohols employed for the reaction may be straight-chain, branched or cyclic, and preferably contain from 1 to 6 carbon atoms. Methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert- butanol, and tert-amyl alcohol may be mentioned as examples. Cyclic ethers, such as tetrahydrofuran, also may be used. A particularly preferred solvent alcohol is tert-butanol. Mixtures containing 10% to 90% by weight of water and 90% to 10% by weight of alcohol generally are used. Preferred mixtures contain 30% to 80% by weight water and 70% to 207 β by weight alcohol. The reaction takes place in the presence of a basic substance suitably an alkali metal hydroxide or an alkaline earth metal hydroxide employing a metal carbonyl compound. Although not wishing to be bound by theory, it is believed that the organohalide reactant undergoes a reaction with the carbon monoxide and basic substance whereby a salt of the α-keto carboxylic acid is formed from which the acid is isolated after acidi¬ fication in a known manner. Specific examples of suitable basic agents which can be used in the practice of the process include: LiOH, NaOH, KOH, RbOH, Ca(0H) 2 , Ba(0H) 2 and Mg(0H) 2< The LiOH and Ca(0H) 2 are particularly preferred. Yields of alkyl α-keto-carboxylic acids of up to approximately 84% can be obtained using Ca(0H) 2 as the basic substance and a solvent medium of tert-butanol and water. Yields of β-substituted-α-ketb-carboxylic acids of up to approximately 46% can be obtained using Ca(0H) 2 as the basic substance and a solvent medium of tert-butanol and water. Yields of arylalkylpyruvic acids of up to approximately 90% can be obtained using Ca(0H) 2 as the basic substance and a solvent medium of tert-butanol and water. Yields of up to approxi¬ mately 74% of arylalkylpyruvic acid^ can be achieved when LiOE Is used as the basic agent in a tert-butanol- water system and yields of aryloxyalkylpyruvic acids of up to approximately 50% can be obtained using Ca(0H) as the basic substance and a solvent medium of tert- butanol and water. Optionally, lithium iodide and/or bis(l,2-di- phenylphosphino)ethane can be employed in the instant process as co-catalysts for producing the alkyl α-keto- carboxylic acid products of the present invention. Although experiments thus far have failed to define the exact role these two agents play in the overall process of the present invention, in some instances their presence appears to exert a yield enhancing effect on the reaction. For example, using lithium iodide and bis(l, 2-diphenylphosphino) ethane as co-catalysts in the biscarbonylation of n-butyl bromide with lithium hydroxide as base and dicobalt-ocCacarbonyl as catalyst, a 62% yield of 2-oxohexanoic acid was obtained at 70-80°C. and 800 psig CO pressure after four hours of reaction. The same reaction carried out for sixteen hours, however, in the absence of lithium iodide and bis(l,2-diphenylphosphino)ethane, only produced a 36% yield of 2-oxohexanoic acid. In contrast, however, an 83.7% yield of n-pentylpyruvic acid was obtained by the biscarbonylation of n-hexylbromide using calcium hydroxide as base, dicobaltoctacarbonyl as catalyst and no lithium iodide or bis (1,2-diphenylphosphino)ethane at reaction conditions similar to those aforedescribed. When used in the present process, only small amounts of from about .01 to 1 mole percent each of lithium iodide and bis(l,2-diphenylphosphino)ethane are employed. The amount of basic agent used can vary within wide limits. In general, the molar ratio of the alkali metal or alkaline earth metal base to organohalide reactant is from 10:1 to 1:1, preferably from 6:1 to 2:1. In the process described herein, it is preferred to use metal carbonyl compounds as carbonylation cata- lysts. These catalysts include particularly metal car- bonyls such as iron pentacarbonyl, dicobalt-octacarbonyl OMP ^ and nickel-tetracarbonyl, or their salts such as, for example, the potassium or sodium salts thereof. Di- cobalt-octacarbonyl is very particularly suited. These catalysts can be added to the medium in the solid state or in the form of solutions in the solvent used for the carbonylation reaction. The weight ratio of the metal carbonyl compound to the organohalide reactant is pre¬ ferably from 1:1 to 1:300 and more preferably from 1:10 to 1:100. The concentration of the organohalide used in the reaction solvent is not critical and can vary within wide limits. Thus, it can be between 1 and 307«. by weight, based on the weight of the solvent, however, it Is possible to go outside of these limits without disadvantage. The present process is advantageously carried out by bringing the mixture consisting of Che organo¬ halide reactant, the metal carbonyl catalyst and the alkali metal base or the alkaline earth metal base, suspended in the mixture of water and alcohol, into contact, under nitrogen, in a suitable pressure-resis¬ tant reactor equipped with a stirrer, with a large ex¬ cess of carbon monoxide -(amount greater than 2 moles of carbon monoxide per mole of organohalide reactant) introduced at the desired pressure and temperature, in accordance with techniques suitable for bringing about the reaction between a liquid phase and a gas phase. The carbonylation reaction is carried out at a temperature in the range of from 30°C. to 150°C. , preferably from 50°C. to 100°C, over a period of time of from 3 to 60 hours, typically 3 to 20 hours. In general, the reaction Cakes place aC elevaCed carbon monoxide pressures which may range from 300 psig Co 3000 psig. Preferably, Che reaccion Cakes place aC a pressure in Che range of 300 psig Co 1000 psig. The carbon monoxide may contain or be mixed with an inert gas, such as nitrogen. On completion of the reaction, the product mix¬ ture is filtered, resulting in the alkali metal salt or the alkaline earth metal salt of the α-keto-carboxylic acid product being separated from the liquid reaction components as the main solid component. The filtrate contains the remainder of the alkali metal salt or the alkaline earth metal salt of the α-keto-carboxylic acid, and, where unbranched alcohols are used, esters in addition to unreacted organohalide as well s acid and alcohol products from the starting organohalide reactant. In a further process step, the metal salt of the α-keto-carboxylic acid is acidified with a dilute acid, such as hydrochloric acid, so as to displace the α-keto- carboxylic acid from its alkali metal salt or its alka¬ line earth metal salt. The solution obtained is OMPI extracted with a suitable solvent, for example, an ether such as diethyl eCher, and Che organic exCract thus obtained is purified by conventioned acid-base work-up. The final residue consists of highly pure α-keto-carboxylic acid. If desired, lower alkyl esters of the α-keto— carboxylic acid products of the present invention can be prepared by esterifying the α-keto-carboxylic acid product according to conventional esterification tech- niques employing lower aliphatic alkanol and acid cata¬ lysts such as, for example, B 3 , B 3 HC1, BF., MeOH, BF Et 2 0 or diazo ethane at suitable reaction conditions. The following examples illustrate the invention. Example 1 6.8 g (50 mmoles) of n-butyl bromide, 700 mg ( 2 mmoles) of Co 2 (C0)g, 6.0 g (150 mmoles) of NaOH, 30 ml t-BuOH, 80 m s of H 2 0 and 50 mg of bis(l,2- diphenylphosphino)ethane and 560 mg (3 mmoles) of Lil were stirred at 96°C. and under 800 psig CO pressure for 18 hours. The reaction mixture was cooled, acidified with excess HC1, and extracted with Et 2 0 to give a crude oily residue which was made basic with excess NaOH solution (checked with pH paper). The basic aqueous solution was washed with a little of Et 2 0, acidifed with H.C1 (checked with pH paper), and extracted again with Et 2 0 to give 70% of a mixture of acids. H NMR showed that the mixture contained 50% valeric acid and 20% 2-oxohexanoic acid. 13C NMR confirmed these structural assignments. Example 2 6.8 g (50 mmoles) of n-butyl bromide, 4.8 g (200 mmoles) of LiOH, 30 Ls of t-BuOH, 80 mLs of H 2 0, - 00 mg (^2 mmoles) of Co 2 (C0)g, 560 mg (^3 mmoles) of Lil, 56 mg (0.1 mole) of bis(l,2-diphenylphos- phino)ethane were stirred in a 300 ml autoclave at 70-80°C. under 800 psig CO pressure for 4 hours. Simi¬ lar workup as in Example 1 gave a 62.2% yield of 2-oxo¬ hexanoic acid and an 8% yield of valeric acid based on H NMR spectrum of the mixture. Example 3 6.8 g (50 mmoles) of n-butyl bromide, 7.4 g (100 mmoles) of Ca(OH) 2 , ^700 mg (^2 mmoles) of Co 2 (C0)g, 560 g (3 mmoles) of Lil, 50 mg (0.1 mmole) of bis(l,2-di-pheπylphosphino)ethane, 30 mLs t-BuOH, and 80 mLs of HLO were stirred at 90°C. and under 800 psig CO pressure for 18 hours. The reaction mixture was cooled to room temperature and filtered; the crude cake was rinsed with a small amounC of Et 2 0, acidified with excess HC1 (checked by pH paper) and extracted with t 2 0 to give a 50.2% isolated yield of 2-oxohexanoic acid. In a similar manner, several other runs were carried out. The results of such experiments which were conducted at different reaction conditions and employed different reactants are given in the following table. TABLE I Preparation of Alkyl A PHA-Keto-carboxyl ic Acid by Reaction of Alkyl Halide With Carbon Monoxide in the Presence of Metal Carbonyl, Base and Solvent Example n-CijHgBR Base / Solvent Co 2<CO) 8 CO Temp. Time R4COCO2H R5CO2H R OH No. (mmoles) mnoles/ mLs (m noles) (psig) (0°C.) (hours) % Yield % Yield % Yield 4 50 Li Oil t-BuOH (30) 2 900 90 16 36 27 N/A (200) «2θ (80) 5d) 50 Ca( 011)2 t-BuOil (30) 2 900 90 15 56 N/A N/A (130) 112" (00) 1 6 50 Ca(OH)2 t-BuOII (30) 2 850-970 80 22.5- 80.6 3.8 1.6 (100) « θ (70) 1 7 50 Ca ( Oil ) 2 t-BuOH (30) 2 050-980 120 23 62.8 23.5 2.1 (100) H 2 0 (70) 8 50 Ca(OH) 2 t-BuOIl (30) 2 850-950 80 22.5 54.9 35.3 1.3 (55) ' H 2 0 (70) 9 50 LiOli t-BuOH (30) 2 850-860 77 18 62.8- 30.6 0 (200) H 2 0 (70) TABLE I (continued) Preparation of Alky) ALPilA-Keto-carboxyl ic Acid by Reaction of Alkyl Halide With Carboη Monoxide in the presence of Metal Carbonyl, Base and Solvent example n-CβHnB Base / Solvent 02C :o) 8 CO Temp. Time 6COCO2H R7CO2H R 6 OH No, (mmoles) mmoles/ mLs (mmo les) (psig) (0°C.) (hours) % Yield i Yield % Yield 10 50 Li Oil t-BuOII (30) 2 850-870 60 20 0(2) 0 0 (200) H2θ (70) 11 50 Li Oil t-BuOH (30) 2 820 60 16 74.5 15.1 0 (200) H2θ (70) 1 12 50 Ca ( Oil ) 2 t-BuOH (70) 2 040-890 80 17 83.7 8.2 trace (100) ll2θ (30) 13 50 ca(on) 2 i-propyl (30) 2 820-860 80 16 0(3) 0 0 Q (100) H2θ (70) 14 50 Cή( 011)2 i-propyl (30) 2 050-970 80 17 45.0 24.2 9.7 (100) II 20 (70) 15 50 Ca(0H)2 TUP (30) 2 850-970 80 17 68.2 18.0 2.7 (100) 112 (70) TABLE I (continued) Preparation of Alkyl ALPHA-Keto-Carboxyl ic Acid by Reaction of Alkyl Halide With Carbon Monoxide in the Presence of Metal Carbonyl, Base and Solvent Example n-Cl2H25B R Base / Solvent Co2(C0) β CO Temp, Time R12COCO2H Rj3C0 2 H Rl2θH No. (mmoles) mmoles/ mLs (mmoles) (psig) (0"C.) (hours) % Yield % Yield t Yield 16 50 Li Oil t-BuOll (30) 900 70 16 35 23 30 (200) H2θ (70) <1 ) 0.1 ramole bis( 1 ,2-diphenylphosρhino)ethane present ( 2 ) reactor contents spilled ( 3 ) reactor contents spilled I tvi Examp le 17 Preparation of Isopropylglyoxylic Acid from 2-Bromopropane A mixture of 6.2 g (50 mmoles) of 2-bromopropane 5 and 70 mLs of t-BuOH was charged into a 300 ml auto¬ clave. Next, 0.682 g (2 mmoles) of Gθ2(C0)g was added to the mixture under CO after which a mixture of 7.4 g (100 mmoles) of lime and 30 mLs of I ^ O was added to the mixture. After pressuring to 850 psig, CO was 0 added to the reaction mixture and the mixture was heated to 96°C. (^1 hour) and held at that temperature for 19 hours. The CO uptake was not stopped and total of 70 psi CO was reacted. The pH value of the reaction mixture was 10. After centrifugation, the solid was -5 rinsed once with a 20 ml portion of a 50:50 t-butanol/- water solution and then acidified with 150 mLs of HC1 solution containing 'v-100 -nmoles of HC1. The free acid was extracted from the aqueous solution with diethyl ether (2 x L20 mLs). The combined undried ethereal 0 solution was evaporated to give a 46% yield of crude isopropylglyoxylic acid based on proton NMR data with internal standard» Example 18 9.25 g (50 mmoles) of phenethyl bromide, 30 mLs 5 of t-BuOH, 700 mg (^2 mmoles) of Co 2 (C0)g, 80 mLs of ϋ O, 4.8 g (200 mmoles) of LiOH were stirred in a 300 ml autoclave for 24 hours at 70°C. and under 300 psig CO pressure. The reaction mixture was cooled to room temperature, then filtered. The crude cake was rinsed with 20 mLs of Et 2 0 to give a pale yellow solid which was acidified in cooled HCl solution (check by pH paper) and extracted with Et2θ. The neutral impuri¬ ties in the filtrate were extracted with Et 2 0 and discarded; any acidic material left in the acidified filtrate (pH = 2 by adding HCl) was extracted with E 2 0 (3 x 30 mLs) . Approximately 74% isolated yield of benzylpyruvic acid identified by both H NMR and C NMR was obtained from the combined Et 2 0 solution. Example 19 Under 900 psig CO pressure after 15 hours reac¬ tion, 9.3 g (50 mmoles) of phenethyl bromide, 10 g (130 mmoles) of Ca(0H) 2> 30 mLs t-BuOH, 80 mLs H 2 0, 700 mg (2 mmoles) of Co 2 (C0)„ were stirred in a 300 ml autoclave at 84°C. The reaction mixture was then cooled and filtered. The calcium salt of benzylpyruvic acid was acidified with excess HCl and extracted with Et 2 0 (2 x 120 mLs) to give 90% isolated yield of benzylpyruvic acid. Example 20 90 mg (0.5 mmoles) of benzylpyruvic acid obtained by the procedure set forth in Example 18, 150 mg (1.1 mmoles) of BF~ Et 2 0 in 5 mLs of EtOH were stirred in a 25 ml flask at reflux temperature for 130 minutes. The reaction mixture was evaporated to oily residue. Then, 25 mLs of CH 2 C1 2 was added; the organic solu¬ tion washed with H 2 0 (3 x 15 mLs) , dried over MgSO, and evaporated to give 64% (GC area %) yield of benzyl- pyruvic acid ester ( ΈL NMR and 13 C NMR) . In a similar manner, several other runs were carried out. The results are set forth in the following table. TABLE II Preparation Of Benzylpyruvic Acid By Reaction of Phenethyl Bromide With Carbon Monoxide in the Presence of Metal Carbonyl, Base and Solvent Phenethyl Example Bromide No. (mciolea) Base / solvent mmoles/ mLs Co 2 (Cθ) 8 ( mnoles) f«° Λ » ^2£\ ime . B^ylpyruvic 21 50 ... fti;ιu siei Li Oil t-BuOIl (30) (200) 2 H 20 (80) 300 70 24 50% 22 50 LiOH t-BuOH (30) (200) 2 ll2θ (50) 300 70 20 66% 23 50 NaOH t-BuOH (30) (200) 2 »2θ (B0) 300 70 60 16% 24 5P LiOH t-BuOH (30) (100) 2 H 0 (80) 300 80 17 20% 25 50 LiOH t-BuOII (30) (200) 2 1120 (80) 300 90-100 3 57% (salt) 26 50 LiOH t-BuOII (30) (150) 2 II 20 (80) 300 90-100 3 38% (salt) 27 50 Ca(OII) 2 t-BuOH (30) (100) j| 2 0 (80) 300 90 24 0% TABLE II (continued) Preparation Of Benzylpyruvic Acid By Reaction Of Phenethyl Bromide With Carbon Monoxide in the presence of Metal Carbonyl, Base and Solvent. Phenethyl uκample Bromide Base / Solvent Co 2 (CO)B CO Temp. Time Benzylpyruvic NO. (mmoles) mmoles/ mLs (mmoles) (psig) (hours) Acid ϊiel d 2U 50 NaOII t-BuOH (50) 2 950 60 20 trace (250) H 0 (110) 29 50 NaOH t-BuOII (50) 2 900 90 20 0% (250) II 2 o (110) 30 25 Li 01] t-BuOII (30) 2 950 70 4 35% (100) ll 2 0 (80) 31 50 Lion fc-Buθll (30) 2 950 80-90 3 47% (salt) r- j (200) 1120 (00) 32 50 Ca(OH)2 t-BuOH (30) 2 900 • 96 60 77% (130) 11 2 0 (80) 33 50 CHl 011)2 t-BuOll (30) 2 600 84 24 6.6% (130) II 2 (00) 34 50 ca ( on )2 t-BuOII (30) 2 540 96 β 67.4% (130) ll2 (80) A comparison between Example No. 24 and Example No. 22 in the table indicates that at approximately the same reaction conditions a reduction in the amount of LiOH used in the reaction has an adverse effect on the yield of benzylpyruvic acid by reducing the yield from about 667o in Example No. 22 to about 20% in Example No. 24. Reference to Example No. 23 indicates that NaOH is a less reactive base than either LiOH or Ca(OH) 2 af¬ fording only a 16% yield of benzylpyruvic acid. A com- pa ison between Example No. 27 and Example No. 32 demonstrates the effect a reduction in pressure has on the yield of benzylpyruvic acid when Ca(0H)2 is used as the basic agent. At similar reaction conditions > the yield of acid dropped from approximately 77% in Example No. 32 (900 psig) to 0% in Example No. 27 (300 psig). The lack of product in Example Nos. 28 and 29 cannot be explained other than to say that a lack of product was not consistent with the overall results obtained and might perhaps be attributed to leakage in the reaction system * Example 35 13.4 g (50.48 mmoles) of 4-phenoxybutyl bromide, 70 mLs of t-butanol, 1.0 g (2.92 mmoles) of Co 2 (C0)g, 30 mLs of H 2 0, and 17.31 g (234 mmoles) of Ca(0H) 2 were charged to a 300 ml autoclave and stirred for 9 hours at 90°C. under approximately 1000 psig CO pressure. The reaction mixture then was cooled to room temperature and filtered. The crude cake was rinsed with 100 mLs of a solution comprised of 50 mLs of water and 50 mLs of t-butanol, to give 28.7 g of an off-white solid. The solid product was acidified with 10% HCl with cool¬ ing, extracted with diethyl ether and dried over MgSO, . The solvent was evaporated therefrom to give 7.65 g (62% yield) of crude reaction product. Analysis of the crude product by H- NMR, gas chromotography and mass spectroscopy showed that the product contained 6-phenoxy-2-oxo-hexanoic acid of 78% purity. Major impurities in the crude product were identified as 5-phenoxy pentanoic acid (10%) and 6-phenoxy-2-hydroxy hexaτioic acid (12%) .

Claims: CLAIMS : 1. A process for preparing .-keto-carboxylic acids which comprises reacting an organohalide in a liquid solvent medium with carbon monoxide at elevated temperature and elevated pressure in the presence of a catalytic amount of metal carbonyl compound and an alkali metal inorganic base or an alkaline earth metal inorganic base wherein the organohalide is a compound having the formula: RX wherein X represents a halogen atom and R is a primary or secondary alkyl group, a primary arylalkyl group having two or more carbon atoms in the alkyl portion thereof bonded to the halogen atom, or a primary or secondary aryloxyalkyl group. 2. The process as claimed in Claim 1 in which said organohalide is a primary alkyl halide selected from the onochloride or monobromide of methane, propane, butane, pentane, hexane, heptane, octane, nonane, decane, undecane and dodecene. 3. The process as claimed in Claim lin which said organohalide is a secondary alkyl halide having the formula: -UMJ-j wherein R-, and R 2 are the same or different and are alkyl radicals which can be either straight chain or branched having from 1 to about 18 carbon atoms each and X is halogen. 4, The process as claimed in Claim 1 in which said organohalide is an arylalkyl halide having the formula: (R) π -A-(CH 2 ) m CH 2 X wherein X is halogen and A is an aromatic hydrocarbon radical containing 1 benzene ring or 2 condensed benzene rings; each R, which may be the same or different, represents hydrogen or a linear or branched alkyl radi¬ cal with up to 4 carbon atoms which is unsubstituted or substituted by a nitro group or an alkoxy group con¬ taining 1 to 4 carbon atoms, or a halogeno, nitrile, nitro or alkylcarbonyloxy group, n is 0 or an integer from 1-3 when A contains one benzene ring, and n is 0 or an integer from 1-5 when A contains two condensed benzene rings; and m is 1-20. 5. The process as claimed in Claim 1 in which said organohalide is an aryloxyalkyl halide of the general formula: (R) n -A-0(CR' 2 ) m -CR"H-X wherein: A represents an aromatic hydrocarbon radical containing 1 benzene ring or 2 condensed benzene rings; R, R' and R" may be the same or different, and are selected from hydrogen and linear or branched alkyl radicals having up to about 6 carbon atoms; n is 0 or an integer from 1-5 when A contains one benzene ring, and n is 0 or an integer from 1-7 when A contains two condensed benzene rings; - is 0-20; and X represents halogen. 6. The process as claimed in Claim 1 in which said α-keto-carboxylic acid is an arylalkylpyruvic acid. 7. The process as claimed in Claim 1 in which said α-keto-carboxylic acid is an aryloxyalkylpyruvic acid. OMPI 8. The process as claimed in Claim 1 in which the carbon monoxide pressure is from 300 to 3000 psig. 9. The process as claimed in Claim 1 in which the reaction is carried out at a temperature of from 30°C, to 150°C. 10. The process as claimed in Claim 1 in which the inorganic base is selected from LiOH, NaOH, OH, RbOH, Ca(0H) 2 , Ba(0H) 2 or Mg(0H) 2 . 11. The process as claimed in Claim 1 in which the metal carbonyl catalyst compound is iron penta¬ carbonyl, dicobalt-octacarbonyl, or nickel-tetra- carbonyl. 12. The process as claimed in Claim 11 in which the metal carbonyl is dicobalt-octacarbonyl. 13. The process as claimed in Claim 1 in which the liquid solvent medium is a mixture, of water and alcohol. 14. The process as claimed in Claim 13 in which the alcohol is tert-butanol. 15. The process as claimed in Claim 13 in which the alcohol is isopropanol. 16. The process as claimed in Claim 1 in which lithium iodide is present in the reaction. 17. The process as claimed in Claim 16 in which bis(1,2-diphenylphosphino)ethane is present in the reaction.

Inventors: LEE JOHN YUCHU, WOLFRAM JOACHIM WILHELM, LEE, JOHN, YUCHU, WOLFRAM, JOACHIM, WILHELM
Applicants: ETHYL CORP, ETHYL CORPORATION
Application year: 1983
Main classification: C07C51
IPC codes: C07C51