# US 2014/0155632 A1 · Process for preparing aryl- and heteroarylacetic acid derivatives

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- Number: US 2014/0155632 A1
- Document ID: US20140155632A1
- Status: Published application
- Kind: A1
- Application number: 14/002,691
- Filed: 2012-02-27
- Published: 2014-06-05
- Earliest claimed: 2011-03-02
- Assignees: Bayer Intellectual Property GmbH
- Inventors: Thomas Himmler; Lukas J. Goossen; Felix Rudolphi; Bingrui Song
- Web page: https://patentgrep.com/patent/US20140155632A1

## CPC

- C07D 333/24: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07C 67/343: by increase in the number of carbon atoms
- C07C 201/12: by reactions not involving the formation of nitro groups
- C07C 253/30: by reactions not involving the formation of cyano groups
- C07C 319/20: by reactions not involving the formation of sulfide groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention relates to a process for preparing aryl- and heteroarylacetic acids and derivatives thereof by reaction of aryl or heteroaryl halides with malonic diesters in the presence of a palladium catalyst, of one or more bases and optionally of a phase transfer catalyst. This process enables the preparation of a multitude of functionalized aryl- and heteroarylacetic acids and derivatives thereof, especially also the preparation of arylacetic acids with sterically demanding substituents.

## Claims

### Claim 1

A process for preparing a compound of formula (III)
in which
Ar is a
group,
where
R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, halogen, optionally halogen-substituted C1-C6-alkyl, C1-C6-thioalkyl, thiophenyl, C1-C6-alkoxy, C6-C10-aryloxy, phenyl, —CO—C6-C10-aryl, —CO—C1-C3-alkyl, —COO—C1-C6-alkyl or —COO—C6-C10-aryl,
the Ar radical may additionally also be a heteroaromatic radical or
the Ar radical may also be 1- or 2-naphthyl,
and
R6 and R7 are each independently optionally substituted C1-C8-alkyl, phenyl, aryl, or NR8R9,
where R8 and R9 are the same or different and are each independently C1-C4-alkyl, or phenyl optionally substituted by optionally fluorine- or chlorine-substituted C1-C3-alkyl, by nitro, cyano or di-C1-C3-alkylamino, or together with the nitrogen atom to which they are bonded are a saturated or unsaturated, substituted or unsubstituted cycle,
wherein an aryl or heteroaryl halide of formula (I)
Ar—Hal (I)
in which
Hal is chlorine, bromine or iodine and
Ar is as defined above,
is reacted with a malonic ester of formula (II)
in the presence of a palladium catalyst, of a phosphine ligand and
A) of an inorganic base and of a phase transfer catalyst
or
B) of a mixture of inorganic bases, without using caesium carbonate or caesium bicarbonate, optionally using an organic solvent.

### Claim 2 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, where
Ar is 1- or 2-naphthyl, 3-thienyl or a
group,
where
R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, fluorine, optionally fluorine-substituted C1-C4-alkyl, C1-C4-thioalkyl, thiophenyl, C1-C4-alkoxy, C6-C10-aryloxy, phenyl, —CO—C6-C8-aryl, —CO—C1-C3-alkyl, —COO—C1-C4-alkyl or —COO—C6-C8-aryl,
Hal is chlorine, bromine or iodine,
R6 and le are the same or different and are each independently C1-C4-alkyl.

### Claim 3 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, where
Ar is 1- or 2-naphthyl, 3-thienyl or a
group,
where
R1, R2, R3, R4 and R5 are the same or different and are each independently hydrogen, amino, cyano, nitro, fluorine, methyl, methylthio, ethyl, i-propyl, n-propyl, CF3, C2F5, C3F7, methoxy, ethoxy, phenyl, —CO-phenyl, —CO-methyl, —CO-ethyl, —COO-methyl, —COO-ethyl or —COO-phenyl,
Hal is chlorine, bromine or iodine,
R6 and R7 are each independently methyl or ethyl.

### Claim 4 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, where
Ar is 1-naphthyl, 2-naphthyl, phenyl, 4-N,N-dimethylaminophenyl, 4-methylthiophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-ethylphenyl, 4-ethoxycarbonylphenyl, 3-thienyl.

### Claim 5 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, where
Ar is 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 4-cyanophenyl, 4-cyano-2-methylphenyl, 3-cyanophenyl, 4-ethoxycarbonylphenyl, 4-trifluoromethylphenyl, 4-acetylphenyl, 4-nitrophenyl, 4-benzoylphenyl.

### Claim 6 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, where
R6 and R7 are each ethyl.

### Claim 7 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the palladium catalyst used is bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or palladium acetate.

### Claim 8 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the phosphine ligand used is tri-tert-butylphosphine, tricyclohexylphosphine, tris(1-adamantyl)phosphine, n-butyldi(1-adamantyl)phosphine (cataCXium® A), benzyldi(1-adamantyl)phosphine (cataCXium® ABn), 2-(di-tert-butylphosphino)biphenyl (JohnPhos) or 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino.

### Claim 9 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the phosphine ligand used is tri(tert-butyl)phosphine.

### Claim 10 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the base used in process A) is potassium phosphate.

### Claim 11 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the bases used in process B) comprise a mixture of potassium carbonate and potassium bicarbonate.

### Claim 12 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the phase transfer catalyst used comprises a quaternary ammonium salt or phosphonium salt of formula (V)
in which
R13, R14, R15 and R16 are the same or different and are each independently C1-C28-alkyl, optionally branched C1-C28-alkyl, C6-C10-aryl, or benzyl,
A is N or P and
X is halogen, hydrogensulphate, sulphate, dihydrogenphosphate, hydrogenphosphate, phosphate or acetate.

### Claim 13 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the phase transfer catalyst used comprises a crown ether of formula (VI)
in which n is a number from 4 to 8
and the R17 to R20 radicals are each independently hydrogen, C1-C4-alkyl or phenyl, where two adjacent R radicals may also in each case together form a cyclic radical optionally comprising cyclopentyl, cyclohexyl or 1,2-phenylene.

### Claim 14 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein the phase transfer catalyst used is 18-crown-6.

### Claim 15 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein a malonic ester of formula (II) is used as a solvent in excess.

### Claim 16 (depends on 1)

The process for preparing a compound of formula (III) according to claim 1, wherein a temperature of from 100 to 180° C. is employed.