Process for the preparation of hydroxybenzoic benzyl esters

Details Process for the preparation of hydroxybenzoic benzyl esters Process for the preparation of hydroxybenzoic benzyl esters

2002-04-05

2003-10-28

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C558S415000, C560S022000, C560S023000, C560S053000, C560S065000, C560S071000, C560S072000

Reexamination Certificate

active

06639093

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of hydroxybenzoic benzyl esters by reacting benzyl chloride with hydroxy-benzoic acid.
Benzyl salicylate is used as stabilizer in fragrance compositions and sunscreens. Benzyl salicylate and processes for its preparation are already known.
Thus, EP-A 117,502, for example, describes the preparation of benzyl salicylate by esterifying salicylic acid or transesterifying salicyclic esters with benzyl alcohol.
Benzyl salicylate can also be prepared by reacting alkali metal salicylates with benzyl chloride, optionally in the presence of phase transfer reagents (JP-A 63/218652, EP-A 534,817). A disadvantage is the formation of salts that must be disposed of and thus reduce the economic feasibility of these processes.
It was therefore the object to develop, starting from benzyl chloride, a process for the preparation of hydroxybenzoic benzyl esters that can be carried out under mild reaction conditions and leads to good yields in a cost-effective manner.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of hydroxybenzoic benzyl esters of the formula
in which R
1
to R
5
are identical or different and are hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-halogenoalkyl, C
1
-C
6
-halogenoalkoxy, CN, CO(C
1
-C
6
-alkyl), NO
2
, or halogen,
comprising reacting benzyl chlorides of the formula
in which R
1
, R
2
, and R
3
have the meanings given above for the hydroxybenzoic benzyl ester,
or mixtures of such benzyl chlorides and benzyl alcohols of the formula
in which R
1
, R
2
, and R
3
have the meanings given above for the hydroxybenzoic benzyl ester,
with hydroxybenzoic acids of the formula
in which R
4
and R
5
have the meanings given above, in the presence of one or more amides of the formula
R
6
CON R
7
R
8
in which
R
6
is hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, amino, C
1
-C
6
-alkyl-amino, C
1
-C
6
-cycloalkylamino, or C
1
-C
6
-dialkylamino, and
R
7
and R
8
are identical or different and are hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-cycloalkyl, C
1
-C
6
-alkoxy, C
1
-C
10
-aralkyl, or C
1
-C
12
-aryl,
or R
6
and R
7
together form a group (CH
2
)
n
or NR
9
(CH
2
)
n
,
in which
R
9
is hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-cycloalkyl, C
1
-C
10
-aralkyl, or C
1
-C
12
-aryl, and
n is 2 to 6.
DETAILED DESCRIPTION OF THE INVENTION
The process according to the invention can be carried out cost-effectively and under mild reaction conditions.
The radicals R
1
to R
5
generally have the following meanings:
Alkyl is generally a straight-chain or branched hydrocarbon radical having 1 to 6 (preferably 1 to 4, particularly preferably 1 or 2) carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, iso-pentyl, hexyl, and iso-hexyl. Preference is given to methyl, ethyl, propyl, iso-propyl, butyl, pentyl, and hexyl, and particular preference is given to methyl and ethyl.
Alkoxy generally means a straight-chain or branched alkoxy radical having 1 to 6 (preferably 1 to 4, particularly preferably 1 or 2) carbon atoms. Examples which may be mentioned are methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, pentoxy, iso-pentoxy, hexoxy, and iso-hexoxy. Preference is given to methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, pentoxy, and hexoxy, and particular preference is given to methoxy and ethoxy.
Halogenoalkyl generally means a straight-chain or branched hydrocarbon radical having 1 to 6 (preferably 1 to 4, particularly preferably 1 or 2) carbon atoms having 1 to 10 (preferably 1 to 8, particularly preferably having 1 to 5) halogen atoms. Examples that may be mentioned are chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, and hexafluorobutyl. Preference is given to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, and hexafluorobutyl, and particular preference is given to fluoromethyl and trifluoromethyl.
Halogenoalkoxy generally means a straight-chain or branched alkoxy radical having 1 to 6 (preferably 1 to 4, particularly preferably 1 or 2) carbon atoms having 1 to 10 (preferably 1 to 8, particularly preferably having 1 to 5) halogen atoms. Examples that may be mentioned are chloromethoxy, fluoro-methoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, fluoropropoxy, and hexafluorobutoxy. Preference is given to chloromethoxy, fluoromethoxy, trifluoromethoxy, fluoroethoxy, fluoropropoxy, and hexafluorobutoxy, and particular preference is given to fluoromethoxy and trifluoromethoxy.
Halogen generally means fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine, particularly fluorine or chlorine.
Very particularly preferred substituents for R
1
to R
5
are hydrogen, methyl, trifluoromethyl, methoxy, fluorine, or chlorine.
The process according to the invention can be used, for example, to prepare the following hydroxybenzoic benzyl esters: benzyl 2-hydroxy-benzoate (benzyl salicylate), benzyl 3-hydroxybenzoate, benzyl 4-hydroxy-benzoate, benzyl 3-chloro-2-hydroxybenzoate, benzyl 4-chloro-2-hydroxybenzoate, benzyl 5-chloro-2-hydroxybenzoate, benzyl 6-chloro-2-hydroxybenzoate, benzyl 3-bromo-2-hydroxybenzoate, benzyl 3-fluoro-2-hydroxybenzoate, benzyl 4-fluoro-2-hydroxybenzoate, benzyl 2-fluoro-3-hydroxybenzoate, benzyl 2-fluoro-4-hydroxybenzoate, benzyl 3-fluoro-2-hydroxybenzoate, benzyl 2-fluoro-5-hydroxybenzoate, benzyl 2-fluoro-6-hydroxybenzoate, benzyl 2-hydroxy-3-methylbenzoate, benzyl 2-hydroxy-4-methylbenzoate, benzyl 3-hydroxy-2-methylbenzoate, benzyl 4-hydroxy-2-methylbenzoate, benzyl 2-fluoro-6-hydroxy-4-methoxybenzoate, benzyl 3-trifluoromethyl-2-hydroxybenzoate, benzyl 4-trifluoromethyl-2-hydroxybenzoate, benzyl 2-trifluoromethyl-3-hydroxybenzoate, benzyl 2-fluoroethyl-4-hydroxybenzoate, and benzyl 4-fluorobutyl-2-hydroxybenzoate.
The benzyl chloride used in the process according to the invention is unsubstituted benzyl chloride or a substituted benzyl chloride. Particular preference is given to using unsubstituted benzyl chloride.
In the process according to the invention, it is possible to use benzyl chloride or benzyl chloride/benzyl alcohol mixtures such as are produced, for example, in the preparation of benzyl alcohol from benzyl chloride. The content of benzyl chloride in the mixture can be 50 to 100%, preferably 60 to 95%, particularly preferably 70 to 90%.
For the process according to the invention, the following hydroxy-benzoic acids may, for example, be mentioned: 2-hydroxybenzoic acid (salicylic acid), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 3-chloro-2-hydroxybenzoic acid, 4-chloro-2-hydroxybenzoic acid, 5-chloro-2-hydroxy-benzoic acid, 6-chloro-2-hydroxybenzoic acid, 3-bromo-2-hydroxybenzoic acid, 3-fluoro-2-hydroxybenzoic acid, 4-fluoro-2-hydroxybenzoic acid, 5-fluoro-2-hydroxybenzoic acid, 6-fluoro-2-hydroxybenzoic acid, 2-fluoro-3-hydroxybenzoic acid, 2-fluoro-4-hydroxybenzoic acid, 2-fluoro-5-hydroxy-benzoic acid, 2-fluoro-6-hydroxybenzoic acid, 2-hydroxy-3-methylbenzoic acid, 2-hydroxy-4-methylbenzoic acid, 3-hydroxy-2-methylbenzoic acid, 4-hydroxy-2-methylbenzoic acid, 6-hydroxy-2-fluoro-4-methoxybenzoic acid, 2-hydroxy-3-trifluoromethyl-benzoic acid, 2-hydroxy-4-trifluoromethyl-benzoic acid, 3-hydroxy-2-trifluoromethyl-benzoic acid, 4-hydroxy-2-fluoroethylbenzoic acid, 2-hydroxy-4-fluorobutyl-benzoic acid, 2-hydroxy-3-methoxybenzoic acid, 2-hydroxy-4-nitrobenzoic acid, 3-acetyl-2-hydroxy-benzoic acid, or 4-cyano-2-hydroxybenzoic acid.
Preference is given to hydroxybenzoic acids having 2 to 30 carbon atoms, particularly preferably 2 to 12 carbon atoms. Very particular preference is given to salicylic acids.
The process according to the invention is preferably carried out with removal of the hydrogen chloride formed. Removal of the hydrogen chloride by passing an inert gas through, such as, for example, nitrogen, is suitable.
In the process according to the invention, preference is given to using 0.1 to 50 mol of hydroxybenzoic acid (preferably 0.5 to 30 mol,

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