Method for producing (2,4-dimethylbiphenyl-3-yl)acetic acids, the esters thereof and intermediate compounds
View Patent ↗The present invention relates to a novel process for preparing substituted and unsubstituted (2,4-dimethylbiphenyl-3-yl)acetic acids and their esters of the formula (I) using homogeneous and heterogeneous palladium catalysts, and also the intermediates 4-tert-butyl-2,6-dimethylphenylacetic acid and 4-tert-butyl-2,6-dimethylmandelic acid, and to processes for their preparation.
1. A process for preparing a compound of formula (I), characterized in that 1-tert-butyl-3,5-dimethylbenzene is reacted with a compound of formula (VI) to give a compound of the formula (V) which is subsequently reduced to a compound of formula (IV); the compound of formula (IV) is converted by removal of the tert-butyl radical into a compound of formula (III), and bromination of the compound of formula (III) gives a compound of formula (II) which, using a compound of formula (A) in the presence of a base and a palladium catalyst, optionally in a solvent, is converted into a biphenyl compound of formula (I):
in which
R represents hydrogen, C 1 -C 6 -alkyl or phenyl,
R′ represents hydrogen or C 1 -C 6 -alkyl,
R″ represents hydrogen or a radical R′CO,
R 2 represents hydrogen, halogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, cyano, or nitro,
n represents 0, 1, 2 or 3,
and
A is selected from the groups below:
(a) boronic acid of the formula (A-a), in which
m represents 2,
p represents 1,
Q represents a hydroxyl group, or the anhydrides, dimers and trimers formed therefrom, and
R 2 and n are as defined above,
(b) cyclic boronic esters of the formula (A-b), in which
m represents 2,
represents 1,
Q represents a C 1 -C 4 -alkoxy group, where the two Q substituents together with the boron atom to which they are attached via the oxygen atom form a 5- or 6-membered ring which is optionally substituted by C 1 -C 4 -alkyl, and
R 2 and n are as defined above,
(c) boronates of the formula (A-c), in which
m represents 3,
p represents 1,
Q represents hydroxy, fluorine, C 1 -C 4 -alkoxy or C 6 -C 10 -aryloxy and
where the negative charge of the boron ion is compensated by a cation, and
R 2 and n are as defined above,
(d) a diphenylboric acid of the formula (A-d), in which
m represents 1,
p represents 2,
Q represents hydroxy, C 1 -C 4 -alkoxy or C 6 -C 10 -aryloxy, and
R 2 and n are as defined above,
(e) a triarylborate salt of the formula (A-e), in which
m represents 0,
p represents 3, and
R 2 and n are as defined above,
(f) a difluoroborate salt of the borinic acid of the formula (A-f), in which
m represents 2,
p represents 2,
Q represents fluorine,
where the negative charge of the boron ion is compensated by a cation, and
R 2 and n are as defined above,
(g) a tetraarylborate salt of the formula (A-g), in which
m represents 0,
p represents 4,
where the negative charge of the boron anion is compensated by a cation, and
R 2 and n are as defined above.
2. The process as claimed in claim 1 , where
R represents hydrogen or C 1 -C 6 -alkyl,
R′ represents C 1 -C 6 -alkyl,
R″ represents hydrogen or a radical R′CO,
R 2 represents hydrogen, halogen or C 1 -C 4 -alkyl, and
n represents 0, 1, 2 or 3.
3. The process as claimed in claim 1 , where
R represents hydrogen or methyl,
R′ represents C 1 -C 6 -alkyl,
R″ represents hydrogen or a radical R′CO,
R 2 represents hydrogen or fluorine, and
n represents 0, 1, 2 or 3.
4. The process as claimed in claim 1 , where
R represents hydrogen,
R′ represents methyl,
R″ represents hydrogen or a radical R′CO,
R 2 represents fluorine, and
n represents 1.
5. A process for preparing a compound of formula (IV)
in which
R represents hydrogen, C 1 -C 6 -alkyl or phenyl,
characterized in that 4-tert-butyl-3,5-dimethylbenzene
is reacted with a compound of formula (VI)
OHC—COOR (VI)
in which R is as defined above,
in the presence of R′—COOH, where
R′ represents hydrogen or C 1 -C 6 -alkyl,
to give a compound of formula (V)
in which
R″ represents hydrogen or a radical R′CO, and R is, as defined above,
and the compound of formula (V) is then reduced.
6. A compound of formula (V)
in which
R represents hydrogen, C 1 -C 6 -alkyl or phenyl,
R″ represents hydrogen or a radical R′CO, and
R′ represents hydrogen or C 1 -C 6 -alkyl.
7. A process for preparing a compound of formula (III)
in which
R represents hydrogen, C 1 -C 6 -alkyl or phenyl,
comprising, removing the tert-butyl radical from a compound of formula (IV)
in which R is as defined above.
8. A process for preparing a compound of formula (II)
in which
R represents hydrogen, C 1 -C 6 -alkyl or phenyl,
comprising, brominating a compound of formula (III)
in which R is as defined above.
9. A process for preparing a compound of formula (I)
in which
R represents hydrogen, C 1 -C 6 -alkyl or phenyl,
R 2 represents hydrogen, halogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, cyano, or nitro
and
n represents 0, 1, 2 or 3,
comprising, reacting a compound of formula (II)
in which
R is as defined above, and
X represents halogen,
in the presence of a base and a palladium catalyst, optionally in a solvent, with a compound of formula (A)
where A is selected from the groups below:
(a) boronic acid of the formula (A-a), in which
m represents 2,
p represents 1,
Q represents a hydroxyl group, or the anhydrides, dimers and trimers formed therefrom, and
R 2 and n are as defined above,
(b) cyclic boronic esters of the formula (A-b), in which
m represents 2,
p represents 1,
Q represents a C 1 -C 4 -alkoxy group, where the two Q substituents together with the boron atom to which they are attached via the oxygen atom form a 5- or 6-membered ring which may be substituted by C 1 -C 4 -alkyl, and
R 2 and n are as defined above,
(c) boronates of the formula (A-c), in which
m represents 3,
p represents 1,
Q represents hydroxy, fluorine, C 1 -C 4 -alkoxy or C 6 -C 10 -aryloxy and
where the negative charge of the boron anion is compensated by a cation, and
R 2 and n are as defined above,
(d) a diphenylboric acid of the formula (A-d), in which
m represents 1,
p represents 2,
Q represents hydroxy, C 1 -C 4 -alkoxy or C 6 -C 10 -aryloxy, and
R 2 and n are as defined above,
(e) a triarylborate salt of the formula (A-e), in which
m represents 0,
p represents 3, and
R 2 and n are as defined above,
(f) a difluoroborate salt of the bonnie acid of the formula (A-f), in which
m represents 2,
p represents 2,
Q represents fluorine,
where the negative charge of the boron anion is compensated by a cation, and
R 2 and n have are as defined above,
(g) a tetraarylborate salt of the formula (A-g), in which
m represents 0,
p represents 4,
where the negative charge of the boron anion is compensated by a cation, and
R 2 and n are as defined above.