Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-09-07
2002-04-30
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
Reexamination Certificate
active
06380441
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing 3-hydroxybenzyl alcohol from 3-chloromethylphenyl chloroformate. 3-Hydroxybenzyl alcohol is a valuable intermediate for the preparation of pharmaceutical active compounds.
Various methods of preparing 3-hydroxybenzyl alcohol are known. These methods start from 3-hydroxybenzaldehyde, 3-hydroxybenzoic acid, or derivatives of these compounds. To convert them into 3-hydroxybenzyl alcohol, the starting compounds are reduced.
For example, 3-hydroxybenzoic acid can be reduced using lithium aluminum hydride, using organic aluminum or boron compounds, or by means of electrolysis to give 3-hydroxybenzyl alcohol. A similar reaction is the reduction of 3-hydroxybenzoic esters to 3-hydroxybenzyl alcohol, which can be carried out using aluminum hydrides or boron hydrides.
For the reduction of 3-hydroxybenzaldehyde to 3-hydroxybenzyl alcohol, it is possible to use the following reagents: lithium aluminum hydride, sodium borohydride, zinc borohydride, tin dichloride plus magnesium, sodium amalgam, or polymer-bound nicotinamide-adenine dinucleotide in the H form (NADH). This reaction can also be carried out as a catalytic hydrogenation, e.g., using Raney nickel catalysts or platinum catalysts. The catalytic reduction of benzyl ethers of 3-hydroxybenzyl alcohol is similar.
Further methods of forming 3-hydroxybenzyl alcohol are cleavage of (3-hydroxyphenyl)methyl formate and (3-hydroxyphenyl)methyl 2-nitrobenzenesulfenate. A disadvantage of all of these processes is that relatively expensive materials such as 3-hydroxybenzoic acid, 3-hydroxybenzaldehyde, or derivatives thereof have to be used as starting material. In addition, it is frequently necessary to employ reducing agents or catalytic hydrogenations, which are complicated or expensive.
There is therefore still a need for a process for preparing 3-hydroxybenzyl alcohol simply and inexpensively.
SUMMARY OF THE INVENTION
We have now found a process for preparing 3-hydroxybenzyl alcohol comprising
(a) subjecting 3-chloromethylphenyl chloroformate to an acidolysis with a carboxylic acid or a carboxylic acid salt, and
(b) carrying out an alcoholysis of the reaction product of the acidolysis step.
DETAILED DESCRIPTION OF THE INVENTION
The 3-chloromethylphenyl chloroformate to be used according to the invention is known from the literature. It can be obtained, for example, by phosgenation of m-cresol and subsequent side-chain chlorination of the resulting 3-methylphenyl chloroformate. As catalysts for the phosgenation, it is possible to use, for example, dimethylformamide and phosphorus compounds such as triphenylphosphine. Additives that can be used in the side-chain chlorination of the 3-methylphenyl chloroformate are, for example, pyridine, pyridine derivatives such as methylpyridines or chloropyridines, amides such as acetamide or benzamide, biuret, urea, cyclic lactams, urethanes, amines or polyamines such as urotropin, ethanolamine, or tetraethylenepentamine, phosphorus compounds such as phosphorus trichloride or phosphorus pentachloride, or sulfur compounds such as diaryl sulfides and diaryl disulfides.
As chlorinating agent in the side-chain chlorination of 3-methylphenyl chloroformate, it is possible to use, for example, chlorine or sulfuryl chloride.
The process of the invention is advantageously carried out using 3-chloromethylphenyl chloroformate containing less than 1% by weight of 3-methylphenyl chloroformate that has not been chlorinated in the side chain and less than 5% by weight of more highly chlorinated 3-bischloromethylphenyl chloroformate.
The 3-chloromethylphenyl chloroformate is, according to the invention, acidolyzed using a carboxylic acid or a carboxylic acid salt. The product of this reaction is the diester of 3-hydroxybenzyl alcohol with the carboxylic acid used.
According to the invention, a broad range of aliphatic, cycloaliphatic, and aromatic carboxylic acids can be used as carboxylic acid. Suitable aliphatic carboxylic acids are, for example, carboxylic acids having linear or branched alkyl radicals having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms. Examples that may be mentioned are formic acid, acetic acid, propionic acid, butyric acid, and 2-methylpropionic acid.
Suitable cycloaliphatic carboxylic acids are, for example, those having from 4 to 11 carbon atoms, preferably from 4 to 7 carbon atoms. Examples that may be mentioned are cyclopropanecarboxylic acid, cyclopentanecarboxylic acid, and cyclohexanecarboxylic acid.
Aromatic carboxylic acids that can be used are, for example, those having from 7 to 12 carbon atoms, preferably from 7 to 10 carbon atoms. An example that may be mentioned is benzoic acid.
The aliphatic and cycloaliphatic carboxylic acids may optionally bear, for example, from one to three additional substituents, for example, halogen atoms such as fluorine, chlorine, and/or bromine, preferably fluorine and/or chlorine.
The aromatic carboxylic acids can likewise bear, for example, from one to three substituents, for example, halogen atoms such as fluorine, chlorine, and/or bromine and/or C
1
-C
6
-alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, hexyl, and/or cyclohexyl.
As carboxylic acid salts, it is possible to use, for example, salts of alkali metals and alkaline earth metals and ammonium salts. Preference is given to alkali metal salts such as sodium salts and ammonium salts. The acid part of the carboxylic acid salts can correspond to the above-described aliphatic, cycloaliphatic, and aromatic carboxylic acids.
The amount of carboxylic acid and/or carboxylic acid salt to be used depends on the way in which the reactants 3-chloromethylphenyl chloroformate and carboxylic acid and/or carboxylic acid salt are brought into contact.
If for example, only one carboxylic acid is brought into contact with 3-chloromethylphenyl chloroformate, only the chloroformate group reacts with the carboxylic acid and the chloromethyl group remains largely unaltered. The chloromethyl group can then also be reacted by subsequent addition of carboxylic acid salt. The stoichiometrically required amounts of carboxylic acid and carboxylic acid salt are in this case each time 1 mol per mol of 3-chloromethylphenyl chloroformate. When liquid carboxylic acids are used, these can advantageously also serve as solvents for the acidolysis reaction, and in this case preference is thus given to using from 1 to 20 mol of carboxylic acid (particularly from 1 to 10 mol of carboxylic acid) and from 1 to 5 mol of carboxylic acid salt (particularly from 1 to 2 mol of carboxylic acid salt), in each case per mol of 3-chloromethylphenyl chloroformate.
If, for example, the carboxylic acid salt is brought directly into contact with 3-chloromethylphenyl chloroformate in the presence or absence of a carboxylic acid, 1 mol of carboxylic acid salt is consumed by the acidolysis of the chloroformate group and 1 mol is consumed by acidolysis of the chloromethyl group, so that in this case 2 mol of carboxylic acid salt are stoichiometrically required for complete acidolysis. In this case, preference is given to using from 2 to 5 mol of carboxylic acid salt (particularly from 2 to 3 mol of carboxylic acid salt) per 1 mol of 3-chloromethylphenyl chloroformate.
The carboxylic acid salt can either be used as such or can be prepared in situ from a carboxylic acid and a base. Suitable bases are, for example, alkali metal hydroxides and alkaline earth metal hydroxides, alkali metal carbonates and alkaline earth metal carbonates, and ammonia. Examples of suitable bases are NaOH, KOH, LiOH, Na
2
CO
3
, K
2
CO
3
, Mg(OH)
2
, Ca(OH)
2
, and/or NH
3
. Preference is given to adding carboxylic acid salt as such.
It is also possible to use mixtures of various carboxylic acids and various carboxylic acid salts. However, preference is given to using one carboxylic acid and one of its salts.
The reaction of 3-chloromethylphenyl chloroformate with the carboxylic acid and/or the carboxylic acid salt according to the invention can be carr
Diehl Herbert
Mais Franz-Josef
Bayer Aktiengesellschaft
Gil Joseph C.
Henderson Richard E. L.
Shippen Michael L.
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