Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-28
2003-10-21
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S602000
Reexamination Certificate
active
06635772
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing chroman-carboxylic acid and a novel intermediate useful for the synthesis of chroman-carboxylic acid. The chroman-carboxylic acid is useful as, for example, a starting material of pharmaceutical products (WO99/32475) showing &bgr;
3
-adrenoreceptor activity, a starting material of pharmaceutical products (EP 0 115 142) having &agr;
2
-antagonism, and a starting material for the synthesis of a fungicide (U.S. Pat. No. 4,745,114).
BACKGROUND OF THE INVENTION
As a production method of chroman-carboxylic acid, there are conventionally known (1) a method comprising obtaining 4-oxochromene-carboxylic acid from diethyl oxalate and 2-hydroxyacetophenone, and hydrogenating this 4-oxochromene-carboxylic acid (JP-A-59-130286), and (2) a method comprising obtaining phenoxylactone from bromobutyrolactone and phenol, and reducing the phenoxylactone (J. Med. Chem., vol. 14, pp. 758-766 (1971)). In addition, EP 0 891 974 discloses a production method of a chroman compound, which comprises reacting a phenol compound wherein at least one ortho position relative to a phenolic hydroxyl group is not substituted, a formaldehyde and an alcohol to give an alkoxymethylated phenol compound, and reacting the obtained alkoxymethylated phenol compound with a compound having a carbon-carbon double bond but without, in a molecule, a hydroxyl group or an electron withdrawing group directly bonded to a carbon atom constituting the carbon-carbon double bond.
However, the above-mentioned method (1) uses a large amount of acid and base, as well as poisonous oxalic acid ester, and the method (2) uses expensive bromobutyrolactone. Neither of them is an industrially advantageous method.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a method for producing chroman-carboxylic acid smoothly and easily in a high yield with high industrial productivity from an easily obtainable starting material or an economical starting material.
According to the present invention, there has now been found that, by reacting an easily obtainable and economical dialkylphenol compound, a formaldehyde and an alcohol in the presence of a secondary amine and an acid, an alkoxymethylated phenol compound, wherein the ortho position relative to the phenolic hydroxyl group is alkoxymethylated, can be obtained (Step 1); by reacting the obtained alkoxymethylated phenol compound with an ester having a carbon-carbon double bond at a temperature of not less than 100° C., a dialkylchroman carboxylic acid ester can be obtained (Step 2); by hydrolyzing the obtained dialkylchroman carboxylic acid ester, a dialkylchroman-carboxylic acid can be obtained (Step 3); and by reacting the obtained dialkylchroman-carboxylic acid with an aromatic hydrocarbon in the presence of a Lewis acid, chroman-carboxylic acid can be obtained smoothly in a high yield (Step 4).
It has been also found that, by reacting, in Step 2, an alkoxymethylated phenol compound and an ester having a carbon-carbon double bond in the presence of an acid, the reaction can be accelerated.
It has been further found that a specific synthetic intermediate in the production method of chroman-carboxylic acid, which comprises the above-mentioned 4 reaction steps, is a novel compound.
That is, the present invention provides a method for producing a chroman-carboxylic acid of the formula (II)
wherein R
3
is a hydrogen atom or an alkyl group [hereinafter to be referred to as chroman-carboxylic acid (II)], which method comprises reacting a dialkylchroman-carboxylic acid of the formula (I)
wherein R
1
and R
2
are each independently an alkyl group and R
3
is as defined above [hereinafter to be referred to as dialkylchroman-carboxylic acid (I)] with an aromatic hydrocarbon in the presence of a Lewis acid.
The present invention also provides a method for producing a chroman-carboxylic acid (II), which method comprises reacting a dialkylphenol compound of the formula
wherein R
1
and R
2
are as defined above [hereinafter to be referred to as dialkylphenol compound (III)], a formaldehyde and an alcohol in the presence of a secondary amine and an acid to give an alkoxymethylated phenol compound of the formula (IV)
wherein R
1
and R
2
are as defined above and R
4
is an alkoxyl group [hereinafter to be referred to as alkoxymethylated phenol compound (IV)]; reacting the obtained alkoxymethylated phenol compound (IV) with an ester of the formula (V)
wherein R
3
is as defined above and R
5
is an alkyl group or an aralkyl group, having a carbon-carbon double bond [hereinafter to be referred to as unsaturated ester (V)] at a temperature of not less than 100° C. to give a dialkylchroman carboxylic acid ester of the formula (VI)
wherein R
1
, R
2
, R
3
and R
5
are as defined above [hereinafter to be referred to as dialkylchroman carboxylic acid ester (VI)]; hydrolyzing the obtained dialkylchroman carboxylic acid ester (VI) to give a dialkylchroman-carboxylic acid (I); and reacting the obtained dialkylchroman-carboxylic acid (I) with an aromatic hydrocarbon in the presence of a Lewis acid.
The present invention also provides dialkylchroman-carboxylic acid (I) and an alkoxymethylated phenol compound (IV).
The present invention further provides a method for producing dialkylchroman-carboxylic acid (I), which method comprising reacting dialkylphenol compound (III), a formaldehyde and an alcohol in the presence of a secondary amine and an acid to give alkoxymethylated phenol compound (IV); reacting the obtained alkoxymethylated phenol compound (IV) with unsaturated ester (V) at a temperature of not less than 100° C. to give dialkylchroman carboxylic acid ester (VI); and hydrolyzing the obtained dialkylchroman carboxylic acid ester (VI).
DETAILED DESCRIPTION OF THE INVENTION
In the above-mentioned formulas, the alkyl group represented by R
1
, R
2
, R
3
and R
5
is preferably straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, hexyl group, 2-ethylhexyl group, octyl group and the like. The alkoxyl group represented by R
4
is preferably alkoxyl group having 1 to 8 carbon atoms, such as methoxy group, ethoxy group, 1-propoxy group, 1-butoxy group, 1-hexanoxy group, 1-octanoxy group, 2-ethyl-1-hexanoxy group, 2-propoxy group, 2-butoxy group, cyclohexanoxy group, 2-hydroxy-1-ethoxy group, 4-hydroxy-1-butoxy group, 6-hydroxy-1-hexanoxy group, benzyloxy group, phenethyloxy group and the like. The aralkyl group represented by R
5
is preferably aralkyl group wherein the aryl moiety has 6 to 14 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, such as benzyl group, phenethyl group and the like.
In the above-mentioned Step 1, dialkylphenol compound (III), a formaldehyde and an alcohol are reacted in the presence of a secondary amine and an acid to give alkoxymethylated phenol compound (IV). This alkoxymethylated phenol compound (IV) is novel and is provided for the first time by the present invention.
Examples of formaldehyde include linear polymers of formalin such as formalin, paraformaldehyde and the like; cyclic acetal oligomers such as trioxane, tetraoxane and the like; and the like. These formaldehydes may be used solely or in combination of two or more thereof.
Examples of alcohol include saturated aliphatic primary alcohols such as methanol, ethanol, 1-propanol, 1-butanol, 1-hexanol, 1-octanol, 2-ethyl-1-hexanol and the like; saturated aliphatic secondary alcohols such as 2-propanol, 2-butanol, cyclohexanol and the like; saturated aliphatic diols such as ethylene glycol, 1,4-butanediol, hexylenediol and the like; aralkyl alcohols such as benzyl alcohol, phenethyl alcohol and the like; and the like. These alcohols may be used solely or in combination of two or more thereof. The alkoxyl group at R
4
in the above-mentioned formula (IV) is derived from the aforementioned alcohol.
The above-men
Hayashibara Tatsuhiko
Sato Junko
Torihara Masahiro
Covington Raymond
Kuraray Co. Ltd.
Rotman Alan L.
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