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WO1984002699A1 - PROCEDE DE PREPARATION D'ACIDES alpha-CETO-CARBOXYLIQUES - Google Patents

PROCEDE DE PREPARATION D'ACIDES alpha-CETO-CARBOXYLIQUES Download PDF

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Publication number
WO1984002699A1
WO1984002699A1 PCT/US1983/001814 US8301814W WO8402699A1 WO 1984002699 A1 WO1984002699 A1 WO 1984002699A1 US 8301814 W US8301814 W US 8301814W WO 8402699 A1 WO8402699 A1 WO 8402699A1
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Prior art keywords
organohalide
keto
carbon atoms
alkyl
acid
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Application number
PCT/US1983/001814
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English (en)
Inventor
John Yuchu Lee
Joachim Wilhelm Wolfram
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Ethyl Corp
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Ethyl Corp
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Filing date
Publication date
Priority claimed from US06/457,520 external-priority patent/US4492798A/en
Priority claimed from US06/529,570 external-priority patent/US4532345A/en
Application filed by Ethyl Corp filed Critical Ethyl Corp
Publication of WO1984002699A1 publication Critical patent/WO1984002699A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/10—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide

Definitions

  • the present invention relates to a process for the carbonylation of certain organohalides to form ⁇ -keto-carboxylic acids. More particularly, the invention relates to a process for the carbonylation of certain organohalides to form alkyl ⁇ -keto-carboxylic acids, ⁇ -substituted- ⁇ -keto acids, arylalkylpyruvic acids and aryloxyalkylpyruvic acids.
  • 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.
  • 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.
  • ⁇ -keto-carboxylic acids can be prepared 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:
  • 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-carboxylic acid products which can be prepared by the process of the present invention include alkyl ⁇ -keto-carboxylic acids of the general formula:
  • R represents a linear alkyl radical having up to at least 20 carbon atoms; ⁇ -substituted- ⁇ -keto-carboxylic acids of the general formula:
  • R 1 and R 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:
  • 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 radical with up to 4 carbon atoms which is unsubstituted or substituted by a nitro group or by an alkoxy group containing 1 to 4 carbon atoms, or an alkoxy group containing 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; and aryloxyalkylpyruvic acids of the general f ormula :
  • A represents an aromatic hydrocarbon radical containing 1 benzene ring or 2 condensed benzene rings
  • 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.
  • ⁇ -keto-carboxylic acid which is produced by the instant process depends, of course, upon the particular organohalide starting material used in the reaction.
  • the aforedescribed alkyl- ⁇ -keto-carboxylic acids are prepared by carbonylating a primary alkyl halide of the formula:
  • R I 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- ⁇ -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.
  • preferred alkyl halides include the monochlorides and the monobromides of methane, propane, butane, pentane, hexane, heptane, octane, nonane, and other hydrocarbons having up to about 20 carbon atoms.
  • the ⁇ -substituted- ⁇ -keto-carboxylic acids produced by the present process are prepared by carbonylating secondary alkyl halides of the general formula:
  • R 1 and R 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 each and X represents halogen.
  • Alkyl halides suitable for use in the preparation of the ⁇ -substituted- ⁇ -keto-carboxylic 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.
  • alkyl radicals which may be employed 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.
  • arylalkylpyruvic acid products of the present invention are produced by carbonylating an arylalkyl halide of the general formula:
  • X represents halogen
  • 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 radical with 1 to 4 carbon atoms which is unsubstituted or substituted by a nitro group or an alkoxy group containing 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.
  • aryloxyalkylpyruvic acid products of the present invention are prepared by carbonylating an aryloxyalkyl halide of the general formula: (R) n -A-O (CR ' 2 ) m -CR"H-X
  • X is halogen and A represents an aromatic hydrocarbon radical containing 1 benzene ring or 2 condensed benzene rings
  • 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.
  • Specific examples of halides which can be used to produce aryloxyalkylpyruvic acids made by the present process include:
  • the reaction is carried out in the presence of a mixture of water and alcohol as a reaction medium in which the carbonylation of the organohalide takes place.
  • 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.
  • a basic substance suitably an alkali metal hydroxide or an alkaline earth metal hydroxide employing a metal carbonyl compound.
  • a basic substance suitably an alkali metal hydroxide or an alkaline earth metal hydroxide employing a metal carbonyl compound.
  • suitable basic agents which can be used in the practice of the process include: LiOH, NaOH, KOH, RbOH, Ca(OH) 2 , Ba(OH) 2 and Mg(OH) 2 .
  • the LiOH and Ca(OH) 2 are particularly preferred. Yields of alkyl ⁇ -keto-carboxylic acids of up to approximately 84% can be obtained using Ca(OH) 2 as the basic substance and a solvent medium of tert-butanol and water.
  • Yields of ⁇ -substituted- ⁇ -ketb-carboxylic acids of up to approximately 46% can be obtained using Ca(OH) 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(OH) 2 as the basic substance and a solvent medium of tert-butanol and water.
  • Yields of up to approximately 74% of arylalkylpyruvic acid can be achieved when LiOH 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(OH) 2 as the basic substance and a solvent medium of tert-butanol and water.
  • lithium iodide and/or bis(1,2-diphenylphosphino)ethane can be employed in the instant process as co-catalysts for producing the alkyl ⁇ -keto-carboxylic acid products of the present invention.
  • 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.
  • 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.
  • lithium iodide and bis(1,2-diphenylphosphino)ethane are employed.
  • the amount of basic agent used can vary within wide limits.
  • 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.
  • metal carbonyl compounds as carbonylation catalysts.
  • These catalysts include particularly metal carbonyls such as iron pentacarbonyl, dicobalt-octacarbonyl and nickel-tetracarbonyl, or their salts such as, for example, the potassium or sodium salts thereof. Dicobalt-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 preferably 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 30% 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 the organohalide 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-resistant reactor equipped with a stirrer, with a large excess 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.
  • the reaction takes place at elevated carbon monoxide pressures which may range from 300 psig to 3000 psig.
  • the reaccion takes place at a pressure in the range of 300 psig to 1000 psig.
  • the carbon monoxide may contain or be mixed with an inert gas, such as nitrogen.
  • the product mixture is filtered, resulting in the alkali metal salt or the alkaline earth metal salt of the ⁇ -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 ⁇ -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.
  • the metal salt of the ⁇ -keto-carboxylic acid is acidified with a dilute acid, such as hydrochloric acid, so as to displace the ⁇ -keto-carboxylic acid from its alkali metal salt or its alkaline earth metal salt.
  • a dilute acid such as hydrochloric acid
  • the solution obtained is extracted with a suitable solvent, for example, an ether such as diethyl ether, and the organic extract thus obtained is purified by conventioned acid-base work-up.
  • the final residue consists of highly pure ⁇ -keto-carboxylic acid.
  • lower alkyl esters of the ⁇ -keto-carboxylic acid products of the present invention can be prepared by esterifying the ⁇ -keto-carboxylic acid product according to conventional esterification techniques employing lower aliphatic alkanol and acid catalysts such as, for example, BF 3 , BF 3 HCl, BF 3 MeOH, BF 3 Et 2 O or diazomethane at suitable reaction conditions.
  • lower aliphatic alkanol and acid catalysts such as, for example, BF 3 , BF 3 HCl, BF 3 MeOH, BF 3 Et 2 O or diazomethane at suitable reaction conditions.
  • Example 18 9.25 g (50 mmoles) of phenethyl bromide, 30 mLs of t-BuOH, 700 mg ( ⁇ 2 mmoles) of Co 2 (C0) 8, 80 mLs of H 2 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 O to give a pale yellow solid which was acidified in cooled HCl solution (check by pH paper) and extracted with Et 2 O.
  • 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 3 Et 2 O 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 Cl 2 was added; the organic solution washed with H 2 O (3 x 15 mLs), dried over MgSO 4 and evaporated to give 64% (GC area %) yield of benzylpyruvic acid ester ( 1 H NMR and 13 C NMR) .
  • Example No. 24 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 66% 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 affording only a 16% yield of benzylpyruvic acid.
  • a comparison between Example No. 27 and Example No. 32 demonstrates the effect a reduction in pressure has on the yield of benzylpyruvic acid when Ca(OH) 2 is used as the basic agent. At similar reaction conditions, the yield of acid dropped from approximately 77% in Example No.
  • Example No. 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 (CO) 8 , 30 mLs of H 2 O, and 17.31 g (234 mmoles) of Ca(OH) 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.
  • 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 hexanoic acid (12%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de préparation d'acides alpha-céto-carboxyliques par la réaction d'un organo-halogénure dans un milieu solvant liquide avec de l'oxyde de carbone à température et pression élevées en présence d'une quantité catalytique d'un composé de carbonyle métallique et d'une base inorganique de métal alcalin ou d'une base inorganique de métal alcalino-terreux, caractérisé par l'utilisation en tant qu'organo-halogénure d'un composé de formule RX, dans laquelle X représente un atome d'halogène et R est un groupe alkyle primaire ou secondaire, un groupe arylalkyle primaire possèdant deux ou plusieurs atomes de carbone dans sa partie alkyle liée à l'atome d'halogène, ou bien un groupe d'aryloxy-alkyle primaire ou secondaire.
PCT/US1983/001814 1983-01-13 1983-11-15 PROCEDE DE PREPARATION D'ACIDES alpha-CETO-CARBOXYLIQUES Ceased WO1984002699A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/457,520 US4492798A (en) 1982-03-01 1983-01-13 Process for preparing arylalkylpyruvic acids
US06/529,570 US4532345A (en) 1983-09-06 1983-09-06 Process for preparing aryloxyalkylpyruvic acids

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WO1984002699A1 true WO1984002699A1 (fr) 1984-07-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3605882A1 (de) * 1985-02-27 1986-08-28 Director-General Of Agency Of Industrial Science And Technology, Tokio/Tokyo Verfahren zur herstellung von (alpha)-ketosaeuren
US4981619A (en) * 1985-11-27 1991-01-01 Rhone Poulenc Specialities Chimiques Process for preparing alpha-hydroxy acids

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4152352A (en) * 1975-01-09 1979-05-01 Rhone-Poulenc Industries Process for the carbonylation of aralkylhalides
US4334089A (en) * 1979-10-31 1982-06-08 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Substituted oxocarboxylic acids, processes for their preparation, their use and medicaments containing them
US4351952A (en) * 1980-07-01 1982-09-28 Montedison S.P.A. Process for preparing phenyl pyruvic acids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2828041C2 (de) * 1978-06-26 1984-05-10 Dynamit Nobel Ag, 5210 Troisdorf Verfahren zur Herstellung von Arylbrenztraubensäuren

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4152352A (en) * 1975-01-09 1979-05-01 Rhone-Poulenc Industries Process for the carbonylation of aralkylhalides
US4334089A (en) * 1979-10-31 1982-06-08 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Substituted oxocarboxylic acids, processes for their preparation, their use and medicaments containing them
US4351952A (en) * 1980-07-01 1982-09-28 Montedison S.P.A. Process for preparing phenyl pyruvic acids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0134216A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3605882A1 (de) * 1985-02-27 1986-08-28 Director-General Of Agency Of Industrial Science And Technology, Tokio/Tokyo Verfahren zur herstellung von (alpha)-ketosaeuren
US4820823A (en) * 1985-02-27 1989-04-11 Director-General Of Agency Of Industrial Science And Technology Process of producing α-keto acids
US4981619A (en) * 1985-11-27 1991-01-01 Rhone Poulenc Specialities Chimiques Process for preparing alpha-hydroxy acids

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Publication number Publication date
EP0134216A1 (fr) 1985-03-20
EP0134216A4 (fr) 1985-07-01

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