Field of the Invention
The present invention relates to the process for the preparation of a compound of Formula I.
O
CH3
Background of the Invention
The cyclohexanones or substituted cyclohexanones or appropriately substituted derivatives are
particularly valuable intermediates for the synthesis of highly purified final products or are themselves
final products of this type for the electronics industry, for plant protection and for the production of
pharmaceutically highly active substances. Production of the appropriate cyclohexanones on a large
industrial scale necessitates preparation which is as economical and environmentally compatible as
possible.
U.S. Patent No. 6,215,028 discloses a process for the preparation of cyclohexanones from the
corresponding phenols by partial hydrogenation followed by treatment with sulfonating agents to
provide corresponding cyclohexanone.
Japanese Patent Application No. 2004-256490 provides a method for isomerization of ciscyclohexylbenzene
derivative to a trans-cyclohexylbenzene derivative by treating a mixture of cis and
trans-cyclohexylbenzene derivatives with an acid selected from organic acids, inorganic acids and
lithium halides.
While working on present invention, the present inventors, surprisingly, found that
cyclohexanones of Formula I can be obtained in high yield and purity by treating the mixture of
compounds of Formula I, II and III with sodium bisulphite.
O
CH3
Formula I
3
HO
CH3
Formula II
HO
CH3
Formula III
Summary of the Invention
An aspect of the present invention provides a process for the preparation of a compound
of Formula I, comprising:
a) treating the reaction mixture comprising compounds of Formula I, II and III with sodium
bisulphite in the presence of an alcohol; and
b) isolating the compound of Formula I from step a).
O
CH3
Formula I
HO
CH3
Formula II
4
HO
CH3
Formula III
Detailed Description of the Invention
The present invention provides a process of preparation of a compound of formula I,
comprising:
a) treating the reaction mixture comprising compounds of Formula I, II and III with
sodium bisulphite in the presence of an alcohol,
b) isolating the compound of Formula I from step a).
O
CH3
Formula I
HO
CH3
Formula II
HO
CH3
Formula III
The alcohol is selected from the group comprising ethanol, methanol, isopropanol or a mixture
thereof.
5
The reaction mixture of step a) comprising the compounds of Formula I, II and III may be
prepared by hydrogenating the compound of formula (II) with sodium carbonate doped with Palladium-
Carbon (5%) in the presence of toluene at a temperature in the range of about 100°C to about 120°C
and at a pressure in the range of about 2 Kg/Cm2 to about 5 Kg/Cm2.
The compound of Formula II may be prepared by the method given in present application. The
yield of the compound of Formula II obtained by the process of present disclosure is greater than about
98%, preferably greater than about 99 %.
An adduct of Formula IV may be formed upon treatment of the reaction mixture comprising
compounds of Formula I, II and III with sodium bisulphite in the presence of an alcohol. The adduct of
Formula IV may be optionally isolated or carried further to step b) without isolation.
CH3
HO
NaO3S
Formula IV
The isolation of the compound of Formula I from step a) may be aided in the presence of a base,
preferably selected from sodium hydroxide and potassium hydroxide or mixture thereof at a
temperature in the range of about 10°C to about 40°C.
The isolation of the compound of Formula I from step a) is carried out by crystallization, recrystallization,
distillation, evaporation and decantation or mixture thereof.
The purity of compound of Formula I obtained by the process of present invention is greater
than about 98%, preferably greater than about 99 %.
The process of the present invention is suitable for production on industrial scale and the yield
of the product is much higher than the yield of prior art processes.
6
The term ‘about’ refers to variation of 10% on the higher and lower side of specified parameter.
Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the subject matter should not be limited to the description of the preferred embodiment contained therein.
Examples
Example: 1
Preparation of compound of Formula II (Trans-4-(4-propyl-cyclohexyl) phenol)
In a round bottom flask cis and trans 4-(4-propyl-cyclohexyl) phenol (20g) with 87.7 percent purity was taken and dichloromethane (225ml) was added to obtain a reaction mixture. The reaction mixture was stirred for 15 minutes to obtain a solution. The solution was cooled to 0°C and powdered aluminium chloride (14.6g) was added portion wise in 3 h. After addition, the temperature was maintained between 0 to 5°C for another 2 h. Reaction was monitored by gas chromatography. When the cis isomer was less than 8 percent with respect to the trans isomer of 4-propylcyclohexyl phenol, the solution was poured slowly into ice (200g). The organic layer was separated and the aqueous layer was extracted by dichloromethane. The organic layer was separated again. The organic layers were combined and was evaporated, recrystallized with cyclohexane to obtain Trans-4-(4-propyl-cyclohexyl)phenol
Yield: 13.1 g
Purity (%): 99
Example: 2
Preparation of a mixture of compound of Formula I, II and III (Trans-4-(4-propyl-cyclohexyl) cyclohexanone, Trans-4-(4-propyl-cyclohexyl)phenol and cis and trans isomer of 4-(4-propyl-cyclohexyl) cyclohexanol)
Trans-4-(4-propyl-cyclohexyl)phenol (10g) was charged into autoclave reactor and 5% Pd/C doped with sodium carbonate (1.3g) was added followed by toluene (89g), box up reactor, degassed with
7
hydrogen and maintained the hydrogen pressure between 3 to 5 kg/cm2. The reaction mixture was heated at 120°C for 5h. The reaction was terminated when product Trans-4-(4-propyl-cyclohexyl) cyclohexanone was at maximum selectivity (86%). The reaction mixture was cooled and filtered through sintered and was washed with toluene. Filtrate was evaporated under vacuum and a mixture of Trans-4-(4-propyl cyclohexyl) cyclohexanone, Trans-4-(4-propyl-cyclohexyl) phenol and cis and trans isomer of 4-(4-propyl-cyclohexyl) cyclohexanol (9.5g) was obtained. Desired product Trans-4-(4-propyl-cyclohexyl) cyclohexanone was isolated from the mixture through adduct formation with sodium hydrogen sulphite.
Example: 3
Preparation of compound of Formula I (Trans-4-(4-propyl-cyclohexyl) cyclohexanone)
Charged 9.9g of crude 4-(4-propylcyclohexyl) cyclohexanone dissolved in 78g of ethanol at 25o C into a round bottom flask. To it 5.5gm of sodium bisulphite dissolved in 10 ml of purified water was added drop wise for 15 min at 25°C. During addition white precipitate was formed and reaction mass was stirred at room temperature for 6 h for complete adduct formation. The solid formed was filtered through Buckner funnel and washed with 78g of ethanol. Dried the solid material in Buckner funnel under reduced pressure for 4h at 30oC, sodium hydrogen sulphite adduct of 4-(-4-propylcyclohexyl)cyclohexanone (13g) was obtained. The dried material was unloaded in a 250ml four necks round bottom flask equipped with thermo well, overhead stirrer and guard tube. Added 600ml of toluene at 25oC. Sodium hydroxide (2.6g) dissolved in purified water (20ml) was added drop wise into the reaction mass for 15 min at 10oC and the reaction mass was stirred for 10h until it becomes clear and the layers were separated. The upper toluene layer containing the desired product was kept aside and the lower aqueous layer was washed with fresh toluene (2x20 ml). Total toluene layer washed twice with purified water (50ml). Concentrate the total toluene layer under reduced pressure at 70oC for 5h to obtain the title compound..

We claim:
1. A process of preparation of a compound of formula I, comprising;
a) treating the reaction mixture comprising compounds of Formula I, II and III with
sodium bisulphite in the presence of an alcohol,
b) isolating the compound of Formula I from step a).
O
CH3
Formula I
HO
CH3
Formula II
HO
CH3
Formula III
2. The process of claim 1, wherein step a) alcohol is selected from the group comprising
ethanol, methanol, isopropanol or a mixture thereof.
3. The process of claim 1, wherein An adduct of Formula IV may be formed in step a) upon
treatment of the reaction mixture comprising compounds of Formula I, II and III with
sodium bisulphite in the presence of an alcohol.
CH3
HO
NaO3S
Formula IV
4. The process of claim 1, wherein isolation of compound of formula I is aided in the presence
9
of a base.
5. The process of claim 4, wherein the base is selected from sodium hydroxide and potassium hydroxide.
6. The process of claim 1, wherein step b) is carried out by crystallization, re-crystallization, distillation, evaporation and decantation or mixture thereof.