Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-06-05
2002-10-08
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C564S375000, C568S814000, C568S649000, C568S428000
Reexamination Certificate
active
06462242
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing benzyl alcohols by formylation of aryl bromides to form benzaldehydes and reduction of the latter using a formate.
The formylation of aryl bromides by means of carbon monoxide in the presence of sodium formate and a palladium catalyst at atmospheric pressure is already known (Bull. Chem. Soc. Jpn., 67, 2329-2332, 1994). The corresponding benzaldehydes can in some cases be obtained in very good yields. However, no mention is made of the formation of benzyl alcohols.
Although various methods of synthesizing benzyl alcohols are known, there is no general route available which could advantageously be used for the industrial production of a wide variety of substituted benzyl alcohols. This is particularly true of the preparation of benzyl alcohols which bear fluorine substituents or fluorine-containing substituents on the aromatic ring.
For example, U.S. Pat. No. 4,118,561 teaches the preparation of 4-(trifluoromethoxy)benzoic alcohol by the reduction of 4-(trifluoromethoxy) benzoic acid using lithium alanate. In J. Med. Chem. 18, 1216, 1975, the reduction of 4-(trifluoromethoxy)benzoic acid using diborane is described. Carrying out reductions using lithium alanate or diborane on an industrial scale would require a considerable outlay in terms of safety measures.
Benzyl alcohols are used, inter alia, in the production of surface coatings and flavorings and can be used for the preparation of phenethylamines. Phenethylamines bearing fluorine substituents or fluorine-containing substituents such as 4-(trifluoromethoxy)-phenethylamine, are interesting intermediates in applications such as for agrochemicals (EP 00 665 225 or JP 08 291 149).
In view of the foregoing, there is a need for a simple and safe process for preparing benzyl alcohols having a widely variable substitution pattern, particularly those bearing fluorine substituents or fluorine-containing substituents.
DESCRIPTION OF THE INVENTION
We have now found a process for preparing benzyl alcohols of the formula (I)
in which R
1
, R
2
and R
3
are, in each case independently of one another, H, F, Cl, NO
2
, straight-chain or branched C
1
-C
12
-alkyl groups, phenyl groups, OH groups, O(CH
2
)
n
CH
3
groups wherein n=0-12, (CF
2
)
n
CF
3
in which n=0-2 or O(CX
2
)
n
CX
3
in which n =0-12, and X represents F and/or Cl. The process is characterized in that aryl bromides of the general formula (II),
wherein R
1
, R
2
, R
3
are as defined for formula (I), are reacted with carbon monoxide and a formate in the presence of a palladium catalyst to form benzaldehydes of the formula (III)
wherein R
1
, R
2
and R
3
are as defined for formula (I), in which the benzaldehydes of the formula (III) obtained in this way are reduced to the corresponding benzyl alcohols. The benzaldehydes of the formula (III) which are formed can, if desired, be isolated, purified and reduced in a second step.
In formulas (I), (II), (III) and (IV) R
1
is preferably in meta-position with respect to the CH
2
OH—, Br—, CHO— or CH
2
—CH
2
—NH
2
-group respectively.
The reduction to benzyl alcohols of the formula (I) can be carried out using formate in the presence of a palladium catalyst. Alternatively, the benzaldehyde formed can also be reduced by means of hydrogen in an autoclave at temperatures of at least about 60° C. from 60° C. to 120° C. and pressures of from 30 bar to 70 bar in the presence of a palladium catalyst to give the benzyl alcohol. Reduction with hydrogen is an interesting alternative, particularly when benzyl alcohols of the formula (1), in which at least one of the radicals R
1
, R
2
or R
3
is F, CF
3
, CF
2
CF
3
, CF
2
CF
2
CF
3
or O(CX
2
)
n
CX
3
, in which n=0-12 and X=F and/or Cl, are to be prepared, e.g., 4-trifluoromethoxy-benzyl alcohol.
However, the process of the invention is preferably carried out as a single-vessel reaction in which the benzaldehydes of the formula (III) formed in the first step are reacted directly, without intermediate work-up, with formate over a palladium catalyst to give benzyl alcohols of the formula (I). This procedure avoids purification steps at the benzaldehyde stage, which significantly reduces the complication of the synthesis in comparison with two-stage processes and thus makes this procedure very interesting for process-engineering and economic reasons.
The formate employed can be used, for example, in the form of the ammonium, lithium, potassium, sodium, caesium, calcium or barium salt or can be generated in situ, for example from triethylamine and formic acid. The use of potassium, sodium or ammonium formate is preferred.
To carry out the process of the invention, a palladium catalyst is used. Palladium is advantageously used in the oxidation state 0 or II. With respect to catalysts in which palladium is present in the oxidation state 0, it is possible to use complexes such as palladium complexes that have substituted or unsubstituted triphenylphosphine ligands. An example which may be mentioned is tetrakistriphenylphosphine-palladium (0).
Catalysts in which palladium is present in the oxidation state II can be used in the form of palladium (II) salts in combination with suitable free ligands or in the form of palladium(II) complexes.
Suitable palladium(II) complexes include compounds such as those of the general formula
L
2
PdX
2
or L
1
PdX
2
,
in which
L represents a phosphine bearing substituted or unsubstituted, branched or unbranched C
1
-C
10
-alkyl and/or substituted or unsubstituted C
6
-C
10
-aryl radicals,
L
1
represents a chelating ligand of the formula R
4
2
P(CH
2
)
n
PR
4
2
, in which R
4
=substituted or unsubstituted, branched or unbranched C
1
-C
10
-alkyl or substituted or unsubstituted C
6
-C
10
-aryl and n=1-4, and
X represents Cl, Br, I, acetate, dibenzylideneacetone and/or nitrate.
Examples of ligands L include PPh
3
, P(2—MeC
6
H4)
3
, P(
4
—MeC
6
H
4
)
3
, P(4—MeOC
6
H
4
)
3
, P(4—ClC
6
H
4
)
3
, P(cyclohexyl)
3
, PMe
2
Ph, PPh
2
Me, PPh
2
(CH(CH
3
)
2
), PEt
3
, PMe
3
, P(CH(CH
3
)
2
)
3
and P(C(CH
3
)
3
)
3
. Here, the two ligands L can, in each case, be selected independently of one another. However, it is advantageous for the two ligands L to be identical.
Examples of chelating ligands L
1
include (C
6
H
5
)
2
PCH
2
P(C
6
H
5
)
2
, (C
6
H
5
)
2
P(CH
2
)
2
P(C
6
H
5
)
2
, (C
6
H
5
)
2
P(CH
2
)
3
P(C
6
H
5
)
2
and 1,1′-bis(diphenylphosphino, ferrocene.
As palladium(II) salts in combination with free ligands L or L
1
, wherein L and L
1
are as defined above, it is possible to use, for example, palladium(II) halides, in particular, palladium(II) chloride, palladium(II) acetylacetonate, Pd(CN)
2
, Pd(CH
3
CN)Cl
2
, Pd(C
6
H
5
CN)Cl
2
, palladium(II) 1,1,1,5,5,5-hexafluoroacetylacetonate and palladium(II) acetate.
The process of the invention is advantageously carried out at temperatures of at least about 80° C., for example from about 80° C. to about 140° C., preferably at temperatures of from 105° C. to 115° C.
The reaction pressure is not critical. If the reaction is to be carried out at high temperatures using low-boiling solvents, an autoclave can be used. However, the reaction is advantageously carried out in a pressure range from at least about 1 bar, preferably from about 1 to 10 bar. In a preferred embodiment, carbon monoxide is passed into the reaction mixture in such a way that the reaction pressure is approximately atmospheric pressure (1 bar to 1.2 bar). Such reaction conditions place low demands on the pressure resistance of the reactor used. Accordingly, many reactors are suitable for carrying out the process of the invention.
If the aryl bromides used are liquid under the reaction conditions, the process of the invention can be carried out without addition of a solvent. However, it is advantageously carried out in a polar, aprotic, organic solvent, for example, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, pyridine, 1,3-dimethyl-imidazolidin-2-one, dimethyl sulfoxide, toluene, xylene, acetonitril
Marhold Albrecht
Neugebauer Torsten
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
Shippen Michael L.
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