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WO2007036491A1 - Procede de production d'acides carboxyliques alpha-substitues - Google Patents

Procede de production d'acides carboxyliques alpha-substitues Download PDF

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Publication number
WO2007036491A1
WO2007036491A1 PCT/EP2006/066641 EP2006066641W WO2007036491A1 WO 2007036491 A1 WO2007036491 A1 WO 2007036491A1 EP 2006066641 W EP2006066641 W EP 2006066641W WO 2007036491 A1 WO2007036491 A1 WO 2007036491A1
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WO
WIPO (PCT)
Prior art keywords
formula
carboxylic acid
branched
alkyl
chlorine
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PCT/EP2006/066641
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German (de)
English (en)
Inventor
Eike Johannes Bergner
Klaus Ebel
Wolfgang Siegel
Andreas Pletsch
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Basf Aktiengesellschaft
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Filing date
Publication date
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Publication of WO2007036491A1 publication Critical patent/WO2007036491A1/fr

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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
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds

Definitions

  • the present invention relates to a process for the preparation of substituted in 2-position carboxylic acids by alkylation of the corresponding dianions of the carboxylic acid used.
  • the invention further relates to a process for the preparation of the corresponding carboxylic acid derivatives, especially the corresponding carboxylic esters by esterification of the produced ⁇ -substituted carboxylic acids.
  • Alkylation of carboxylic acid esters by deprotonation with strong bases and trapping of the metal enolate with electrophiles is an important transformation of organic synthetic chemistry.
  • Deprotonation is typically conducted at very low temperatures, often at -78 ° C. In order to avoid unwanted side reactions, especially the Claisen condensation, it is customarily allowed to warm up to room temperature only after addition of the electrophile, as described by W. Dai, for example. in J. Org. Chem. 1993, 58, 1900-1908.
  • DMPU dimethylpropyleneurea
  • HMPT hexamethylphosphoric acid triamide
  • the carboxylic acids selected as starting materials can also be converted into the corresponding dianions by addition of a sufficient amount of a strong base and then alkylated.
  • This synthesis variant is also carried out to obtain satisfactory yields, usually in the presence of complexing agents such as HMPT or DMPU.
  • 2-substituted isovaleric acids are in principle accessible in this way. They represent important intermediates for the production of active pharmaceutical ingredients.
  • WO 01/09079 discloses a process for the preparation of 2-alkyl-5-halogen-pent-4-enecarboxylic acids and their acid derivatives such as their esters by alkylation of the corresponding ester enolates with allyl halides.
  • the reaction of ethyl isovalerate with lithium diisopropylamide to give the corresponding ester enolate and subsequent reaction with trans-1,3-dichloropropene is described by way of example.
  • the reaction is carried out in the presence of potassium iodide and DMPU as cosolvent at -20 ° C.
  • US 4,492,799 discloses a process for the preparation of ethyl 4-chloro-2-isopropyl-4-pentenoate by deprotonation of ethyl isovalerate with lithium diisopropylpropamide and subsequent reaction with 2,3-dichloro-1-propene at temperatures from -78 ° C to -30 ° C C.
  • the target compound was obtained in a yield of 46% of theory receive.
  • the conversion of a carboxylic acid into its dianion followed by allylation is described schematically.
  • the object underlying the present invention was to provide a process for the one-stage preparation of 2-substituted carboxylic acids which can be carried out under conditions which are as advantageous as possible in the process, especially at advantageously realizable temperatures and avoiding undesired additives or solvents.
  • the formation of undesirable by-products should be avoided as far as possible.
  • R 1 is hydrogen or unbranched, branched or cyclic C 1 to C 6 alkyl
  • R 2 is unbranched or branched C 1 to C 6 alkyl or C 1 to C 6 alkenyl or
  • R 1 has the same meaning as in formula (I),
  • R 2 has the same meaning as in formula (I) and
  • X represents chlorine, bromine, iodine, triflate, tosylate or mesylate.
  • radical R 1 is hydrogen or straight-chain, branched or cyclic C 1 - to C 6 -alkyl and the radical R 2 is unbranched or branched C 1 - to C 6 -alkyl or C 2 - to C 6 -alkenyl or benzyl
  • the said Radicals may have one or more identical or different substituents selected from the group of the substituents chlorine, bromine, iodine, alkoxy, thioalkyl, dialkylamino, diarylamino and aryl.
  • C 1 to C 6 alkyl are to be understood as meaning alkyl radicals having 1 to 6 carbon atoms, such as, for example: methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3 Methylpentyl, 4-methylpentyl,
  • C2- to C ⁇ -alkenyl in the context of the present invention represents a mono- or polyethylenically unsaturated radical having 2 to 6 carbon atoms, such as, for example: ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
  • the radicals mentioned can, if possible, be present in each case in the cis or trans or the E or Z configuration with respect to the double bonds present.
  • radicals mentioned may contain one or more, usually 1 or 2, identical or different substituents selected from the group of the substituents chlorine, bromine, iodine, alkoxy, thioalkyl, dialkylamino, diarylamino and aryl, preferably chlorine , exhibit.
  • alkoxy is preferably a C 1 - to C 6 -alkyl radical bonded via an oxygen atom, as described above, particularly preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy or n-hexoxy.
  • thioalkyl is preferably a bonded via a sulfur, as described above d- to C ⁇ -alkyl radical.
  • dialkylamino is taken to mean amino substituents having two identical or different alkyl radicals, preferably as described above, to C 5 -alkyl radicals, for example dimethylamino or diethylamino.
  • aryl denotes in the context of the present invention an aryl radical having 6 to 14 carbon atoms, preferably optionally substituted phenyl.
  • diarylamino is understood to mean an amino substituent having two identical or different aryl radicals.
  • radicals R 1 may be mentioned: isopropyl, isobutyl, tert. Butyl, sec. Butyl, most preferably isopropyl.
  • Preferred radicals R 2 according to the invention are chlorine-substituted propenyl radicals, for example 3-chloropropen-1-yl, 2-chloropropen-1-yl, 1-chloropropen-3-yl, 2-chloropropene-3 Particularly preferred is trans-1-chloro-propen-3-yl.
  • the starting compounds to be used according to the invention are compounds of the formula (II)
  • R 1 has the same meaning as for the desired target compound of the formula (I).
  • R 1 in formula (II) is unbranched or branched Cr to Ce-alkyl.
  • step a) of the process according to the invention the starting compounds of the formula (I) are reacted with from about 1.8 to about 2.5 molar equivalents, preferably from about 1.9 to about 2.2 molar equivalents, more preferably about 2.0 mol equivalents (based on the amount of acid to be deprotonated of the formula (M)) base, preferably with the stated amounts of a strong base to.
  • the term strong base means those bases which are capable, ie strong enough, of converting a carboxylic acid into its corresponding dianion (ie into the enolate of the corresponding carboxylate), in particular those whose conjugated acid has a pK a value of about 26 or above, preferably about 30 or above, and more preferably having a pK a of from about 35 to about 50, especially to about 45, such as lithium alkyls such as methyllithium, butyl lithium, phenyllithium, alkali metals such as lithium, sodium or potassium, or amine bases such as, for example, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, lithium diisopropylamide, lithium diethylamide, lithium di-tert-butylamide, lithium di-adamantylamide, lithium 2,2,6,6-tetramethylethylpiperidide.
  • the carboxylic acid of the formula (II) is reacted according to step a) first by treatment with a base, preferably with about 0.8 to about 1.2 mol equivalents, more preferably with about 1 molar equivalent of a weak base capable of deprotonating a carboxylic acid group into the corresponding carboxylate of the formula (IV)
  • the amount of strong base to be used is expediently chosen so that the carboxylic acid used or the intermediate carboxylate of the formula (IV) is converted as completely as possible into the dianion, ie the enolate of the carboxylate.
  • about 0.8 to about 1.3 molar equivalents preferably from about 0.9 to about 1.1 molar equivalents, more preferably 1 molar equivalent of the selected strong base.
  • Preferred strong bases according to the invention are metallated dialkylamines of the formula (V)
  • M is lithium, sodium or potassium, preferably lithium and the radicals R 3 and R 4 are identical or different and are an unbranched, branched or cyclic C 1 to C 6 alkyl radical or a trialkylsilyl radical, for example trimethylsilyl.
  • metallated, preferably lithiated, dialkylamines can be prepared by methods known per se to the person skilled in the art, for example by treatment of a corresponding dialkylamine, such as, for example, diisopropylamine, diisobutylamine or isopropylcyclohexylamine, with a suitable lithium alkyl such as, for example,
  • Butyllithium, s-butyllithium, tert-butyllithium, n-hexyllithium, methyllithium or phenyl lithium Such processes are described in detail, for example, in "The Practice of the Organic Chemist", Gattermann, Wieland, newly edited by T. Wieland and W. Sucrow, 43rd ed., Berlin-New York, Walter de Gruyter Furthermore, solutions of such bases
  • a particularly preferred strong base according to the invention is lithium diisoproylamine (LDA).
  • the reaction according to step a) of the present invention is advantageously carried out by preparing a solution of the chosen strong base, preferably the chosen lithiated dialkylamine in a suitable solvent such as tetrahydrofuran, dioxane, dimethoxyethane or other cyclic or acyclic ethers. This is usually done at temperatures of about -80 ° C to about 0 ° C, preferably from about -60 ° C to about 0 ° C, more preferably about -40 ° C to about 0 ° C, and most preferably about -20 ° C to about 0 ° C by adding the selected organolithium reagent to the selected dialkylamine.
  • a suitable solvent such as tetrahydrofuran, dioxane, dimethoxyethane or other cyclic or acyclic ethers.
  • the selected starting compound of the formula (I) is then usually added to the prepared solution of the strong base.
  • the addition and the subsequent reaction of the carboxylic acid of the formula (I) with the selected strong base is preferably carried out at temperatures of about -20.degree. C. to about 0.degree.
  • a dropping time of usually about 10 minutes to about 1 hour the formation of the carboxylic acid dione is usually rapid, usually after about 2 hours, often after about 1 hour.
  • step b) of the process according to the invention the intermediate product or product mixture obtained in step a) is reacted with a compound of the formula (III) R 2 - X (III)
  • radical R 2 has the same meaning as in the target compound of the formula (I) and X is chlorine, bromine or iodine, triflate, tosylate or mesylate, preferably chlorine.
  • the compounds of the formula (III) are alkyl or alkenyl halides or triflates, mesylates or tosylates having up to 6 carbon atoms or benzyl halides or triflates, methylates or tosylates, each of which is further as described for the radical R 2 may have substituents.
  • Preferred compounds of the formula (III) according to the invention are allyl halides, in particular allyl halides such as, for example, allyl chloride, allyl bromide, 1,3-dichloropropene, 1,2-dichloropropene, 3-chloroallyl mesylate, 3-chloroallyl triflate, 3-chloroallyl tosylate, particularly preferably trans-1 , 3-dichloropropene.
  • allyl halides such as, for example, allyl chloride, allyl bromide, 1,3-dichloropropene, 1,2-dichloropropene, 3-chloroallyl mesylate, 3-chloroallyl triflate, 3-chloroallyl tosylate, particularly preferably trans-1 , 3-dichloropropene.
  • step b) is advantageously carried out by adding the selected compound of the formula (III) to the solution of the double-deprotonated carboxylic acid prepared in step a) preferably at a temperature of about -20.degree. C. to about 0.degree , It may be advantageous to use the selected compound of the formula (III) in a slight molar excess with respect to the carboxylic acid dianion or the starting compound of the formula (M), especially in a molar ratio of from about 1: 1 to about 2: 1 about 1.05 to 1 to about 1.3: 1.
  • the formation of the desired product of the formula (I) in the abovementioned temperature range is usually completed after about 1 to about 24 hours, often after about 3 to about 6 hours.
  • the products or product mixtures obtained can subsequently be worked up, isolated or further purified by methods known to those skilled in the art.
  • the reaction according to the invention in step b) can be successfully carried out while substantially avoiding complexing agents or co-solvents such as hexamethylphosphoric triamide (HMPT), dimethylpropylene urea (DMPU), tetramethylethylenediamine (TMEDA), pentamethyldiethylenetriamine, crown ethers, for example.
  • HMPT hexamethylphosphoric triamide
  • DMPU dimethylpropylene urea
  • TEDA tetramethylethylenediamine
  • pentamethyldiethylenetriamine crown ethers
  • B. 15-crown-5, DMF, potassium tert-butoxide can be performed.
  • the reaction is preferably carried out in the presence of up to about 0.25 equivalents, more preferably of up to 0.2 and more preferably of up to about 0.1 equivalents of the particular complexing agent, based on the molar amount of base used.
  • the reaction according to step a) and / or step b) is carried out without addition, ie in the absence of complexing agents or cosolvents, particularly preferably in the absence of HMPT.
  • the present invention relates to a process for the preparation of compounds of the formula (Ia)
  • R 1 ' may have the same meanings as R 1 in formula (I), preferably isopropyl and Z is chlorine, bromine or iodine, preferably chlorine, comprising the steps
  • R 1 has the same meaning as in formula (Ia), with 1, 8 to 2.5 mol equivalents of a base as described above and
  • Z has the same meaning as in formula (Ia) and Z 'may be the same or different from Z and chlorine, bromine or iodine, preferably chlorine.
  • ⁇ -substituted carboxylic acids of the formula (I) or (Ia) obtainable by the process according to the invention can in turn be esterified by methods known to the person skilled in the art, for example by acid catalysis in the presence of an alcohol.
  • carboxylic acids which can be prepared according to the invention are also suitable for the preparation of any further carboxylic acid derivatives such as, for example, carboxylic acid amides, hydrazides, azides, nitriles, orthoesters and carboxylic acid halides.
  • carboxylic acid derivatives such as, for example, carboxylic acid amides, hydrazides, azides, nitriles, orthoesters and carboxylic acid halides.
  • derivatizations are known to the person skilled in the art and are described, for example, in Organikum, Organisch-Chemisches Grundpraktikum, 20th Edition, Wiley-VCH Verlag Weinheim, Chapter 7.
  • the present invention therefore also relates to a process for the preparation of carboxylic acid derivatives of the formula (VI)
  • R 1 , R 2 may have the meanings given in formula (I) and
  • R 5 is a straight-chain, branched and / or cyclic C 1 - to C 12 -alkyl radical or C 7 - to C 12 -aralkyl radical and
  • R 6, R 7 are independently hydrogen or a straight-chain, branched and / or cyclic d- to Ci2-alkyl or C7 to C12 aralkyl group mean
  • the present invention relates to processes for the preparation of carboxylic acid esters of the formula (VII)
  • R 1 , R 2 may have the meanings given in formula (I) and
  • R 5 represents a straight-chain, branched and / or cyclic C 1 - to C 12 -alkyl radical or C 7 - to C 12 -aralkyl radical
  • C 1 - to C 12 -alkyl denotes a straight-chain or branched alkyl radical having 1 to 12 carbon atoms, for example as mentioned above for C 1 - to C 6 -alkyl and furthermore also heptyl, octyl, nonyl, decyl, dodecyl.
  • Cj- to C12-aralkyl is an attached via an alkyl radical having at least one carbon atom
  • Phenyl for example benzyl, 1-phenylethyl or 2-phenylethyl.
  • Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Accordingly, the process according to the invention provides attractive access to carboxylic acids substituted in the 2-position and their esters starting from the usually readily accessible unsubstituted carboxylic acids.
  • a particular advantage of the method according to the invention is that it can be carried out in procedurally and economically advantageous conditions, especially while avoiding low temperatures and while avoiding additional procedurally and toxicologically problematic reagents.

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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

La présente invention concerne un procédé de production d'acides carboxyliques substitués en position 2 par l'alkylation des dianions correspondants de l'acide carboxylique utilisé. Cette invention concerne également un procédé de production des dérivés d'acides carboxyliques correspondants, en particulier des esters d'acides carboxyliques correspondants par l'estérification des acides carboxyliques a-substitués produits.
PCT/EP2006/066641 2005-09-30 2006-09-22 Procede de production d'acides carboxyliques alpha-substitues WO2007036491A1 (fr)

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DE102005047450 2005-09-30

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047534A (en) * 1990-03-26 1991-09-10 Merrell Dow Pharmaceuticals Inc. Selective adenosine receptor agents
WO2001009079A1 (fr) * 1999-07-29 2001-02-08 Speedel Pharma Ag Acides alkyle-5-halogene-pent-4-ene-carboxyliques et leur preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047534A (en) * 1990-03-26 1991-09-10 Merrell Dow Pharmaceuticals Inc. Selective adenosine receptor agents
WO2001009079A1 (fr) * 1999-07-29 2001-02-08 Speedel Pharma Ag Acides alkyle-5-halogene-pent-4-ene-carboxyliques et leur preparation

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
KUEHNE M E ET AL: "STUDIES IN BIOMIMETIC ALKALOID SYNTHESES 8. TOTAL SYNTHESES OF THE 14 CARBON EPIMERIC HYDROXY VINCADIFFORMINES TABERSONINE A HYDROXYMETHYL-D NORVINCADIFFORMINE AND THE 20 CARBON EPIMERIC PANDOLINES", JOURNAL OF ORGANIC CHEMISTRY, vol. 47, no. 7, 1982, pages 1335 - 1343, XP002421004, ISSN: 0022-3263 *
MACPHEE J-A ET AL: "Steric effects in synthesis - steric limits to the alkylation of nitriles and carboxylic acids", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 36, no. 6, 1980, pages 775 - 777, XP002421050, ISSN: 0040-4020 *
NEVALAINEN M ET AL: "Total synthesis of nor-1,6-germacradien-5-ols", JOURNAL OF ORGANIC CHEMISTRY 08 MAR 2002 UNITED STATES, vol. 67, no. 5, 8 March 2002 (2002-03-08), pages 1554 - 1560, XP002421005, ISSN: 0022-3263 *
PADWA A ET AL: "LIGAND EFFECTS ON DIRHODIUM (II) CARBENE REACTIVITIES HIGHLY EFFECTIVE SWITCHING BETWEEN COMPETITIVE CARBENOID TRANSFORMATIONS", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, 1993, pages 8669 - 8680, XP000667320, ISSN: 0002-7863 *
PFEFFER P E ET AL: "Alpha-Anions of Carboxylic Acids", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 37, no. 3, 1972, pages 451 - 458, XP002421003, ISSN: 0022-3263 *

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