Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2001-01-30
2001-09-11
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C558S426000, C568S442000
Reexamination Certificate
active
06288262
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an advantageous process for the preparation of 2-methoxyethoxy-benzenes from corresponding phenols and to novel 2-methoxyethoxy-benzyl cyanides.
BACKGROUND OF THE INVENTION
Alkoxybenzyl cyanides, such as 4-(2-methoxyethoxy)-benzyl cyanide, are active ingredient intermediates which make a series of subsequent products, such as the corresponding phenylacetic acids, amides and amines, accessible. For 2-(4-(2-methoxyethoxy)-phenyl)-ethylamine, which is readily obtainable from 4-(2-methoxyethoxy)-benzyl cyanide, uses as a building block in the synthesis of pharmacologically effective substances are known (WO 98/37079). However, the synthesis of this amine has hitherto not been described in the literature. The 4-(2-methoxyethoxy)-benzyl cyanide according to the invention permits simple access to this synthesis building block.
It is known that 3- and 4-(2-methoxyethoxy)-benzaldehyde can be prepared by boiling at reflux 3- or 4-hydroxybenzaldehyde respectively with 2-chloroethyl methyl ether in dimethylformamide in the presence of potassium carbonate. This gives yields of 60.5 and 75.5% of theory respectively (see J. Med. Chem. 25, 440 (1982) method B). A disadvantage is firstly the at times unsatisfactory yield and, secondly, the use of a costly strong polar solvent, which requires considerable expenditure with respect to industrial hygiene and cannot be completely recycled.
In a process for the preparation of 2-methoxyethoxy-benzene (referred to there as 1-methyl-4-phenyl-ethylene glycol), phenol is reacted with 2-bromoethyl methyl ether in acetonitrile, also a costly strong polar solvent, in the presence of potassium carbonate by boiling at reflux (see Can. J. Chem. 73, 572 (1995)). In addition to the expenditure for the provision of the bromine compound and the disadvantages arising by virtue of the use of acetonitrile (which are similar to those in the case of the use of dimethylformamide), the yield achieved of only 26% is entirely unsatisfactory.
There is therefore still a need for a process for the preparation of 2-methoxyethoxybenzenes which produces the desired products in good yields in a simple and cost-effective manner.
DESCRIPTION OF THE INVENTION
We have now found a process for the preparation of 2-methoxyethoxy-benzenes from the corresponding phenol compounds by reaction with 2-chloroethyl methyl ether, which is wherein the process is carried out without the addition of a strong polar solvent at temperatures above 95° C. and under pressure.
Phenol compounds which can be used are, for example, those of the formula (I)
in which
X is H, an alkali metal or a half-equivalent of an alkaline earth metal and
R is H, CHO, CH
2
CN, CN, NO
2
, C
1
-C
10
-alkyl, C
1
-C
10
-alkoxy, (CH
2
)
x
—OH where x is 1 to 5, halogen or halogeno-C
1
-C
10
-alkyl.
In formula (D, the radical R is preferably in the ortho- or para-position, in particular in the para-position, relative to the OX group.
In formula (I), X is preferably H, Na or K.
If, in formula (I) X is H, the process according to the invention is carried out in the presence of a base, otherwise the presence of a base is not obligatory, but advantageous. Examples of suitable bases are hydrides, hydroxides, oxides, alkoxides, hydrogen-carbonates and carbonates of alkali metals and alkaline earth metals. Preference is given to potassium carbonate and sodium carbonate.
If the process is carried out in the presence of bases, 0.5 to 10 equivalents preferably 0.9 to 2 equivalents, of one or more bases can, for example, be used per mole of phenol compound of the formula (I). In formula (I), R is preferably H, CHO, CH
2
CN or CF
3
.
2-Chloroethyl methyl ether can be used, for example, in amounts of from 1 to 50 mol per mole of phenol compound. This amount is preferably 2 to 20 mol.
An essential feature of the process according to the invention is that no strong polar solvent is used. Strong polar solvents, for example, comprise amides such as dimethyl formamide, dimethylacetamide and N-methyl-pyrrolidone, sulfones such as dimethylsulfon, sulfoxides such as dimethylsulfoxide, cyclic sulfones such as tetramethylene sulfene and nitrites such as benzonitrile and acetonitrile. Examples of solvents which might be present in the process of the invention can be an excess of 2-chloroethyl methyl ether or weakly polar and no polar solvents such as toluene, xylenes, chlorobenzene and dichlorobenzenes. An excess of 2-chloroethyl methyl ether is preferred.
The process according to the invention can, for example, be carried out at temperatures in the range 95 to 300° C. Preference is given to carrying out the reaction at 100 to 200° C., in particular at 130 to 170° C.
A further essential feature of the process according to the invention is that it is carried out under pressure. The pressure can, for example, be in the range 1 to 60 bar.
The process is preferably carried out in a sealed vessel at the pressure which is automatically established at the respective reaction temperature. At the particularly preferred reaction temperatures, pressures below 10 bar, frequently below 6 bar, arise.
The reaction of the phenol compounds with the 2-chloroethyl methyl ether is generally complete after 3 to 20 hours. It is of course advantageous to stir the mixture during the reaction.
The reaction mixture present after the process according to the invention has been carried out can be worked up, for example, by cooling it, removing the solid constituents of the reaction mixture (essentially chlorides and in some instances bases) e.g. by filtration, and, from the filtrate, obtaining firstly optionally present excessive 2-chloroethyl methyl ether and/or solvents and then the prepared 2-methoxyethoxybenzenes, e.g. by fractional distillation. The separated-off 2-chloroethyl methyl ether is of high purity, meaning that it can be recycled completely and repeatedly.
It is possible for the prepared 2-methoxyethyl-benzene in some cases still to comprise small amounts of unreacted phenol compound. If desired, these can be removed, e.g. by dilution with an inert solvent, e.g. toluene, and extraction with a strong base, e.g. aqueous sodium hydroxide solution.
The 2-methoxyethoxy-benzenes to be prepared according to the invention correspond, for example, to the formula (II)
in which
R has the meaning given in the case of formula (I).
The process according to the invention has a number of advantages. For example, the yields and purities of the 2-methoxyethoxy-benzenes which may be obtained are high. The yield is often around 90% of theory and often considerably greater than in accordance with the prior art. The purity of the 2-methoxyethoxy-benzenes obtained is frequently 98% and can reach almost 100%. Costly solvents which require high expenditure in terms of industrial hygiene and which cannot be completely recycled, such as dimethylformamide, are not required. To carry out the process according to the invention, stirred reactors designed for pressures of from 1 to 60 bar suffice. The reaction times are generally shorter than in the case of known processes.
These advantages are surprising since the process according to the invention is carried out at similarly high temperatures as in accordance with the prior art. However, here as well as there, secondary reactions must be expected at similar temperatures, which adversely affect the yield and purity of the prepared products, in particular where phenol compounds of the formula (I) where R does not equal H are used. Surprisingly, in the case of the process according to the invention, the yields and purities are better. In addition, it had not been predicted that the omission of the strongly polar solvent hitherto regarded as necessary would not have a negative effect.
The present invention further relates to novel 2-methoxyethoxy-benzyl cyanides of the formula (III)
in which the CH
2
CN group is arranged in the ortho- or para-position relative to the 2-methoxyethoxy group.
The preparation and use of these novel compounds has been described above. The novel compounds enrich
Dreisbach Claus
Giffels Guido
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
McKane Joseph K.
Murray Joseph
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