WO2007036491A1

WO2007036491A1 - Method for the production of alpha-substituted carboxylic acids

Info

Publication number: WO2007036491A1
Application number: PCT/EP2006/066641
Authority: WO
Inventors: Eike Johannes Bergner; Klaus Ebel; Wolfgang Siegel; Andreas Pletsch
Original assignee: Basf Aktiengesellschaft
Priority date: 2005-09-30
Filing date: 2006-09-22
Publication date: 2007-04-05

Abstract

The invention relates to a method for producing carboxylic acids substituted in the 2-position by alkylating the respective dianions of the used carboxylic acid. The invention further relates to a method for producing the corresponding carboxylic acid derivatives, especially the corresponding carboxylic acid esters by esterifying the produced α-substituted carboxylic acids.

Description

Process for the preparation of α-substituted carboxylic acids

description

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 α-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. Depending on the choice of non-nucleophilic base used, complexing agents such as dimethylpropyleneurea (DMPU) or hexamethylphosphoric acid triamide (HMPT) are often added to the reaction mixture, which are not safe from a process engineering and toxicological point of view.

For the targeted one-step synthesis of α-substituted carboxylic acids, 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.

State of the art:

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. In addition, the conversion of a carboxylic acid into its dianion followed by allylation is described schematically.

P. Pfeffer et al. In J. Org. Chem. 1972, 451-459 describe a process for the preparation of α-alkyl carboxylic acids by formation of the carboxylic acid enolate dianion and subsequent alkylation in the presence of HMPT.

Object of the invention:

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.

DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The object has been achieved according to the invention by the provision of a process for preparing a carboxylic acid of the formula (I)

in which

R ^{1 is} hydrogen or unbranched, branched or cyclic C ¹ to C 6 alkyl and

R ^{2 is} unbranched or branched C 1 to C 6 alkyl or C 1 to C 6 alkenyl or

Benzyl, wherein said radicals one or more identical or different substituents selected from the group of substituents

Chlorine, bromine, iodine, alkoxy, thioalkyl, dialkylamino, diarylamino and aryl,

comprising the steps a) reaction of a carboxylic acid of the formula (II)

.OH _(M)

R ¹

O

in which

R ^{1 has} the same meaning as in formula (I),

with 1, 8 to 2.5 molar equivalents of at least one base and

b) reaction of the product obtained in step a) with a compound of the formula (III)

R ² - X (IM)

in which

R ^{2 has} the same meaning as in formula (I) and

X represents chlorine, bromine, iodine, triflate, tosylate or mesylate.

The process according to the invention enables the preparation of carboxylic acids of the formula (I)

R ¹

starting from carboxylic acids of the formula (M)

OH _(M)

R ¹

O

where the 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, where 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. The term 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,

1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclopentyl and cyclohexyl.

C2- to Cδ-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.

In the case of the radical R ² , the 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.

In this case, 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. The term thioalkyl is preferably a bonded via a sulfur, as described above d- to Cδ-alkyl radical. The term 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. The term aryl denotes in the context of the present invention an aryl radical having 6 to 14 carbon atoms, preferably optionally substituted phenyl. The term diarylamino is understood to mean an amino substituent having two identical or different aryl radicals.

As in the context of the present invention preferred 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 ° ^H <">

O

wherein the radical R ^{1 has} the same meaning as for the desired target compound of the formula (I). Preferably, R ¹ in formula (II) is unbranched or branched Cr to Ce-alkyl.

In accordance with 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. In principle, 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.

Within the scope of a further embodiment of the process according to the invention, it is also possible for the carboxylic acid of the formula (II) to be 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)

and then treat this with a strong base. 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. Preferably, after prior treatment with another base, 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)

MNR ³ R ⁴ (V),

where 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. Such 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.

To the prepared solution of the strong base is then usually added the selected starting compound of the formula (I), if desired in the form of a solution in one of the abovementioned solvents. 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. After 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.

According to 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)

in which the 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.

Accordingly, 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.

The reaction according to 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. After addition of the compound of the formula (III), 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. 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. Within the scope of a preferred embodiment of the process according to the invention, 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. In a preferred embodiment, the present invention relates to a process for the preparation of compounds of the formula (Ia)

wherein 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

a) reaction of a compound of the formula (IIa)

R1- ^0H (IIa)

O

wherein 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

b) reaction of the intermediate obtained in step a) with a compound of the formula (IIIa)

Z ^^^ Z (HIa)

wherein 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.

The α-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.

In addition, the 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. Such 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)

in which

R ¹ , R ² may have the meanings given in formula (I) and

X OR ⁵ , NR ⁶ R ⁷ , halogen, SR ⁵ or NHN R ⁶ R ⁷

in which

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

By preparing a carboxylic acid of the formula (I) according to the method described above and subsequent derivatization.

In a preferred embodiment, the present invention relates to processes for the preparation of carboxylic acid esters of the formula (VII)

R ¹

in which

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

comprising the steps

i) preparation of a carboxylic acid of formula (I) according to the method described above, and ii) esterification of the carboxylic acid of the formula (I) in the presence of an acid or Lewis acid and an alcohol of the formula (VIII)

R ⁵ OH (VIII).

In this case, 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. In this case, it is possible to avoid the self-condensation, which always occurs as a side reaction, when the corresponding esters or ester-enolates are used, which is particularly the case in the synthesis of more highly refined products, such as e.g. Pharmavorprodukte is of particular importance.

The following example is illustrative of the invention without in any way limiting it:

Example: Preparation of (4E) -5-chloro-2-isopropyl-4-pentenoic acid

28.0 g (0.28 mol) of diisopropylamine were dissolved in 100 ml of tetrahydrofuran in a flask under an inert gas atmosphere and cooled to -20 ° C. Then 118.9 g (0.28 mol) of a 15 wt .-% solution of n-butyllithium in n-hexane were added dropwise over 60 minutes. After dosing 60 min at -5 ° C was stirred. Thereafter, a solution of 14.2 g (0.14 mol) of 3-methylbutanoic acid in 40 ml of tetrahydrofuran was added dropwise within 30 min. After complete addition, the mixture was stirred at -20 ° C for 15 min. Thereafter, 15.5 g (94%, 0.34 mol) of trans-1, 3-dichloro propene were added dropwise over 20 min. The entire reaction mixture was after the addition of trans-1, 3-dichloropropene stirred for 3 h under slow warming to room temperature. Thereafter, 250 ml of 2N hydrochloric acid were added, the phases were separated and the aqueous phase was reextracted twice with 200 ml of methyl tert-butyl ether (MTBE). The combined organic extracts were dried over sodium sulfate and concentrated on a rotary evaporator. There were obtained 21, 5 g of crude product with a content of 56.3 wt .-% of the desired target compound. This corresponds to a yield of 49%.

Claims

claims:

1. Process for the preparation of a carboxylic acid of the formula (I)

in which

R ^{1 is} hydrogen or straight-chain, branched or cyclic C 1 - to C 6 -alkyl and

R ^{2 is} unbranched or branched C 1 - to C 6 -alkyl or C 1 - to C 6 -alkenyl or of benzyl, where the radicals mentioned have one or more identical or different substituents selected from the group of the substituents chlorine, bromine, iodine, Alkoxy, thioalkyl, dialkylamino, diarylamino and aryl,

comprising the steps

a) reaction of a carboxylic acid of the formula (II)

R ⁱ ^ r ^{OH (II)}

O

wherein R ^{1 has} the same meaning as in formula (I),

with 1, 8 to 2.5 molar equivalents of at least one base and

b) reacting the product obtained in step a) with a compound of

Formula (IM)

R ² - X (IM)

in which

R ^{2 has} the same meaning as in formula (I) and

X represents chlorine, bromine, iodine, triflate, tosylate or mesylate.

2. Process according to Claim 1 for the preparation of compounds of the formula (Ia)

in which

R ^{1 'may have} the same meanings as R ¹ in formula (I) and

Z means chlorine, bromine or iodine,

comprising the steps

a) reaction of a compound of the formula (IIa)

where R ^{1 'has} the same meaning as in formula (Ia),

with 1, 8 to 2.5 molar equivalents of at least one base and

b) reaction of the product obtained in step a) with a compound of the formula (IIIa)

Z - ^^^^ Z '(MIa)

in which

Z has the same meaning as in formula (Ia) and

Z 'may be the same or different from Z and is chlorine, bromine or iodine.

3. The method according to claim 2, characterized in that R ^{1 'is} isopropyl.

4. The method according to claim 2 or 3, characterized in that Z and Z 'are each chlorine.

5. The method according to any one of claims 1 to 4, characterized in that one uses as base a strong base.

6. The method according to any one of claims 1 to 4, characterized in that one carries out the reaction according to step a), that the carboxylic acid of formula (II) first by treatment with a base in the corresponding carboxylate of the formula (IV )

O (IV)

R ¹

O

transferred and then treated with a strong base.

7. The method according to any one of claims 1 to 6, characterized in that the strong base is a metalated dialkylamine of the formula (V)

MNR ³ R ⁴ (V),

in which

M lithium, sodium or potassium and

R ³ , R ^{4 are} identical or different and denote an unbranched, branched or cyclic C 1 - to C 6 -alkyl radical or a trialkylsilyl radical,

starts.

8. The method according to any one of claims 1 to 7, characterized in that one uses as strong base lithium diisoproylamide.

9. The method according to any one of claims 1 to 8, characterized in that it is carried out at a temperature in the range of -20 ° C to 0 ° C.

10. The method according to any one of claims 1 to 9, characterized in that one carries out step a) using 1, 9 to 2.2 mol equivalents of a strong base.

1 1. The method according to any one of claims 1 to 10, characterized in that one carries out step a) and / or step b) in the absence of complexing agents or cosolvents.

12. Process for the preparation of carboxylic acid derivatives of the formula (VI)

in which

R ¹ , R ² may have the meanings given in formula (I) and

X is OR ⁵ , NR ⁶ R ⁷ , halogen, SR ⁵ or NHNR ⁶ R ⁷

in which

R ^{5 is} a straight-chain, branched and / or cyclic C 1 to C 12

Alkyl radical or C7 to C12 aralkyl radical and

R ^6, R ⁷ are independently hydrogen or a linear, branched and / or cyclic d- to Ci2-alkyl or C7 to C12 aralkyl group mean

13. Process for the preparation of carboxylic acid esters of the formula (VII)

R ¹

in which

R ¹ , R ² may have the meanings given in formula (I) and

comprising the steps

i) preparation of a carboxylic acid of formula (I) according to the method described above, and Esterification of the carboxylic acid of the formula (I) in the presence of an acid or Lewis acid and an alcohol of the formula (VIII)

R ⁵ OH (VIII).