Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2000-02-28
2001-10-09
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06300512
ABSTRACT:
The present invention concerns a new process for production of a 1-(3-cyclopentyloxy-4-alkoxyphenyl)-4-oxocyclohexanecarbonitrile starting from 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediacid dialkyl ester.
1-(3-cyclopentyloxy-4-alkoxyphenyl)-4-oxocyclohexanecarbonitrile, abbreviated CMC below, is used in the manufacture of pharmaceuticals, for example in the production of phenylcyclohexane-1-ylcarboxylic acid derivatives, which inhibit the production of tumor necrosis factor (WO 95/24381).
There are several known processes for production of CMC. For example, WO 95/24381 describes a 4-stage procedure for production of CMC that begins with 3-cyclopentyloxy-4-methoxybenzaldehyde. In this procedure, 3-cyclopentyloxy-4-methoxybenzaldehyde is converted into 3-cyclopentyloxy-4-methoxyphenylacetonitrile, which with Triton-B and methyl acrylate is turned into the 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediacid dimethyl ester. The latter, in the presence of a strong base, is then cyclized into 5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxocyclohexanecarboxylic acid methyl ester, which upon dissolution in dimethyl sulfoxide is decarboxylated to form CMC. With this procedure, CMC is obtained through a quite involved process with several changes of solvent at a yield of approximately 60% relative to 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediacid dimethyl ester, which is abbreviated as CMD below. The two disadvantages of this procedure are the mediocre yield and the use of dimethyl sulfoxide (DMSO) in an environment in which the solvent is inclined to thermal decomposition.
The goal of the present invention was to provide a simpler process for the production of CMC in which the desired product is isolated with good yields.
This goal is achieved with the process according to claim
1
. According to the invention, the process is carried out such that CMD, of the general formula
wherein R
1
, R
2
and R
3
represent C
1-5
-alkyl groups, is cyclized in the presence of a base to a 5-cyano-5-(3-cyclopentyloxy-4-alkoxyphenyl)-2-oxocyclohexanecarboxylic acid alkyl ester, abbreviated CMOM below, of the general formula
wherein R
1
and R
2
have the given meaning, the compound of the general formula III is neutralized with an alkali metal hydrogen carbonate, and is then decarboxylated in the presence of an alkali metal carbonate to form the end product of formula I.
C
1-5
-alkyl can be defined below as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and pentyl.
An alkali metal hydride or an alkoxide [1] may be used as base. Examples of alkoxides that can be used include alkali metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide, sodium or potassium propoxide, or sodium or potassium butoxide. Sodium hydride, for example, may be used as the alkali metal hydride.
Sodium or potassium hydrogen carbonate may be used as the alkali metal hydrogen carbonate.
It is expedient to carry out the cyclization of the CMD to the CMOM at a temperature of 20 to 100° C., preferably from 50 to 70° C. The decarboxylation of the CMOM to the CMC is efficiently conducted at a temperature of 20 to 100° C., preferably from 70 to 90° C.
It is expedient to carry out the decarboxylation under weakly basic conditions, preferably between pH 8 and pH 12.
Polar solvents such as ether may be used as the solvent for the cyclization and decarboxylation. Dioxane, diethyl ether, dibutyl ether, anisole, tetrahydrofuran or mono-, di-, tri- or polyethyleneglycol ether, such as 1,2-dimethoxyethane may be used as the ether.
The production of the educt, the CMD of general formula II, is known in principle from PCT WO 93/19 750. It is expedient to produce the CMD of general formula II such that in a first stage, an isovanillin derivative of the general formula
wherein R
1
has the given meaning, is reacted with a halogen cyclopentane to form a 3-cyclopentyloxy-4-methoxybenzaldehyde of the general formula
wherein R
1
has the given meaning.
It is expedient to conduct the conversion in the first stage in the presence of an alkali metal or earth alkaline metal carbonate. Sodium or potassium carbonate may be used as the alkali metal carbonate and magnesium or calcium carbonate may be used as the earth alkaline metal carbonate.
Fluoro-, chloro-, bromo- or iodocyclopentane may be used as the halogen cyclopentane.
The conversion in the first stage is efficiently conducted in a polar solvent. Examples of polar solvents that may be used include dimethylformamide (DMF) or a C
1-4
-alcohol such as methanol, ethanol, propanol or butanol. Methanol is preferable.
The conversion in the first stage is effectively conducted at a temperature of 100 to 130° C., preferably 110 to 125° C.
In the second stage, the 3-cyclopentyloxy-4-methoxybenzaldehyde is reduced to the (3-cyclopentyloxy-4-methoxyphenyl)methanol of the general formula
The reduction is efficiently conducted with sodium or potassium borohydride.
It is expedient to carry out the reduction in the second stage at a temperature of −10 to 90° C., preferably 0 to 25° C.
The reduction is usually conducted in an atmosphere of inert gas. The same solvents used in the first stage may be used here.
In the third stage, the (3-cyclopentyloxy-4-methoxyphenyl)methanol is halogenated to a 4-(halogenmethyl-2-cyclopentyloxy-1-alkoxy)benzene of the formula
Hydrogen chloride or bromide, especially an aqueous solution of hydrogen chloride or bromide, may be used as the halogenation agent. Hydrogen chloride is preferable.
It is expedient to conduct the halogenation in an atmosphere of inert gas in a hydrocarbon solvent. Toluene, xylol or benzene may be used as the hydrocarbon.
It is expedient to conduct the halogenation at a temperature of 0 to 50° C., preferably 10 to 25° C.
In the fourth stage, the (halogenmethyl-2-cyclopentyloxy-1-alkoxy)benzene is converted into a (3-cyclopentyloxy-4-alkoxyphenyl)acetonitrile of the general formula
wherein R
1
has the given meaning.
The conversion in the fourth stage is effectively conducted in an atmosphere of inert gas and in a polar solvent. The same solvents used in the first and the second stages may be used as the polar solvent.
The fourth stage is usually carried out with an alkali metal cyanide such as sodium or potassium cyanide.
The conversion in the forth stage is effectively carried out at a temperature of 10 to 100° C., preferably 20 to 50° C.
In the fifth stage, the (3-cyclopentyloxy-4-alkoxyphenyl)acetonitrile is combined with an alkyl acrylate to form the CMD of the general formula
Methyl, ethyl, propyl or butyl acrylate may be used as the alkyl acrylate.
The conversion in the fifth stage is effectively carried out in the presence of a base, as for example in the presence of a non-ionic tenside such as Triton B.
The conversion in the fifth stage may be conducted in a polar solvent. Acetonitrile and DMF are suitable polar solvents.
The conversion in the fifth stage is effectively conducted at a temperature of 0 to 60° C., preferably 20 to 40° C.
The inventive process for production of CMC of the general formula I is simple to carry out due to the few required solvent changes and delivers the desired product at a yield of 70 to 80%.
REFERENCES:
patent: WO 93 19750 (1993-10-01), None
Kazuo Haga et al. “Condensations of 1,4-Cyclohexanediones and Secondary Aromatic Amines. The Formation of Alkyldiarylamines and Triarylamines”, Bulletin of the Chemical Society of Japam, vol. 57, No. 6, pp. 1586-1590, Jun. 1984.
Kanagy James M.
Kinzig Charles M.
Lonza AG
McKane Joseph K.
Murray Joseph
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