Synthesis of 2-chloromethyl-6-methylbenzoic ester
View Patent ↗A process is described for preparing compounds of formula (I) where R is H, optionally halogen-substituted alkyl, cycloalkyl, aryl, alkyl-aryl or heteroaryl, and, in alkyl and cycloalkyl, one or more CH 2 groups may be replaced by —O—. The compounds of the formula (I) are valuable intermediates in the synthesis of PPAR agonists.
1. A compound of formula (I)
wherein:
R is selected from the group consisting of H, C 1 –C 12 -alkyl, C 3 –C 8 -cycloalkyl, C 6 –C 12 -aryl, and C 1 –C 4 -alkyl-C 6 –C 12 -aryl, wherein, in the alkyl and cycloalkyl groups, one or more CH 2 groups may be replaced by —O—, and each of the alkyl, cycloalkyl and aryl groups may be independently substituted with halogen.
2. A compound of formula (I) as claimed in claim 1 in which
R is selected from the group consisting of C 1 –C 8 alkyl, C 3 –C 6 -cycloalkyl and C 1 –C 4 -alkyl-C 6 –C 12 -aryl, each of which may optionally be independently substituted with halogen and in which one or two CH 2 groups may be replaced by —O—.
3. A compound of formula (I) as claimed in claim 1 in which
R is C 1 –C 6 alkyl or C 1 –C 4 -alkyl-C 6 –C 12 -aryl, each of which may optionally be independently substituted with halogen and in which one CH 2 group may be replaced by —O—.
4. A compound of formula (I) as claimed in claim 1 in which
R is methyl, ethyl, propyl, i-propyl, t-butyl, phenyl, 2-methoxyethyl or benzyl.
5. A process for preparing a compound of formula (I) as claimed in claim 1 , which comprises
reacting a dimethylbenzoic ester of formula (II)
where R is as defined in claim 1 above
with a chlorinating reagent, optionally in an inert solvent, at a temperature above 40° C. and subsequently optionally purifying.
6. A process for preparing a compound of formula (C)
in which
R is selected from the group consisting of H, C 1 –C 12 -alkyl, C 3 –C 8 -cycloalkyl, C 6 –C 12 -aryl, and C 1 –C 4 -alkyl-C 6 –C 12 -aryl and, wherein, in the alkyl and cycloalkyl groups, one or more CH 2 groups may be replaced by —O— and the alkyl, cycloakyl and aryl groups may be independently substituted by halogen,
Y is —(CH 2 ) 3 —, 1,3-phenylene, or 1,3-cyclohexanediyl,
R′ is selected from H, F, Br, CF 3 , (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, and phenyl;
R″ is selected from H, (C 1 –C 6 )-alkyl, (C 1 –C 3 )-alkylphenyl, (C 5 –C 6 )-cycloalkyl, phenyl, and CF 3 ;
which comprises reacting a compound of the formula (C1)
where Y, R′ and R″ are each as defined above in this claim
with a compound of the formula (I)
where R is as defined above in this claim
in toluene, N-methyl-2-pyrrolidinon (NMP) or other aprotic solvents, in the presence of potassium tert-butoxide, at a temperature in the range of −78 to +50° C., and subsequently working up extractively and optionally crystallizing the end product.
7. The process for preparing the compounds of formula (C) as claimed in claim 6 , wherein the phenyl ring is substituted by R′ in the m- or p-position.