“AN IMPROVED PROCESS FOR THE PREPARATION OF EBERCONAZOLE NITRATE”
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Eberconazole nitrate with high yield and purity.
BACKGROUND OF THE INVENTION
Eberconazole is an antifungal drug is clinically applied to skin fungal infection and is clinically used for skin fungal infection treatment of psoriasis, tinea manuum and pedis. It was approved for use in Spain (ES) and is sold under the trade name Ebernet® by Salvat in ES.
Eberconazole is chemically known as1-(2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-1H-Imidazole nitrate, represented by the following structure of formula (I).
Eberconazole nitrate (I) was first disclosed in EP 0,392,326 and it is prepared by reduction of 2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in presence of NaBH4/Methanol and further its treated with thionyl chloride in presence of dichloromethane (DCM) to produce 2, 4,5-trichloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, which is finally coupled with imidazole in presence of dimethylformamide and then nitric acid was added to give 1-(2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-1H-Imidazole nitrate i.e. Eberconazole nitrate (I), which is depicted in scheme-I given below:

WO 1999/021838 A1 discloses a process for the preparation of Eberconazole and intermediates, which comprises, the wittig condensation of 2-(Methoxycarbonyl)benzyl(triphenyl) phosphonium bromide (IX) with 3,5-dichorobenzaldehyde in presence of NaH in DMF to produce the compound of formula (VIII), which is hydrolyzed with NaOH in methanol to produce the corresponding free acid (VII). The hydrogenation of (VII) with H2 over Pd/C in ethanol affords the compound of formula (VI), which is cyclized to the compound of formula (V) by means of polyphosphoric acid. The reduction of compound (V) with NaBH4 yields the corresponding carbinol (IV), which is treated with SOCl2in dichloro methane to affording the chloride (III); finally the compound (III) is condensed with imidazole in reflux DMF to give 1-(2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-1H-Imidazole of formula (II), which is depicted in scheme-II given below:

Zhongguo Yaowu Huaxue Zazhi (2013), 23(5), 390-392 discloses an improved synthesis of Eberconazole nitrate, which comprises, the reaction of 3, 5-dichloro benzyl bromide (XI) with triphenylphosphine in toluene to produce the compound of formula (X), further it is treated with methyl o-formylbenzoate in presence of t-BuOK to produce the compound of formula (VIII), which on further reduced with H2 over Pd/C and add a NaOH solution to affords the compound of formula (VI), which is cyclized to the compound of formula (V) by means of thionyl chloride/ AlCl3 in DCM. The reduction of compound (V) with NaBH4 yields the corresponding carbinol (IV), which is treated with SOCl2 to affording the chloride (III); finally the compound (III) is condensed with imidazole in presence of dimethylformamide and then nitric acid was added to

give 1-(2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-1H-Imidazole nitrate of formula (I), which is depicted in scheme-III given below:
CN 104974092A discloses a novel synthesis of 1-(2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) imidazole, which comprises, the wittig condensation of 2-(Methoxycarbonyl) benzyl (triphenyl) phosphonium bromide (IX) with 3, 5-dichorobenzaldehyde in dichloro methane and then NaOH was added to produce the compound of formula (VII), The hydrogenation of (VII) with H2 over Pd/C in DCM affords the compound of formula (VI), which is cyclized to the compound of formula (V) by means of oxalyl chloride

in catalytic amount of DMF. The reduction of compound (V) with LiAlH4 in presence of THF yields the corresponding carbinol (IV), which is treated with DCM in presence of NaOH to affording the chloride (III); finally the compound (III) is condensed with imidazole in presence of sodium hydride and dichloro methane as solvent to give 1-(2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-1H-Imidazole of formula (II), which is depicted in scheme-IV given below:
In view of the above aforesaid methods available for Eberconazole nitrate, there is a need for simple and cost effective processes for the preparation of Eberconazole nitrate that provides improved efficiency per reaction volume in terms of yield and purity.

Hence, there is consequently a need for an improved method for the preparation of Eberconazole nitrate which does not involves the problems described above. So, the inventors of the present invention have developed improved processes for preparing Eberconazole nitrate towards as cost-effective, good yield and more purity.
SUMMARY OF THE INVENTION
The present invention is relates to an improved and cost-effective process for the preparation of Eberconazole nitrate (I).
In one aspect of the present invention provides an improved process for the preparation of 1-(2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)-1H-Imidazole nitrate of formula (I) comprising the steps of:
a) reacting 2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol with N,N-Carbonyldiimidazole in presence of organic solvent to obtain1-(2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-yl)imidazole (Eberconazole free base).
b) further Eberconazole free base is treated with nitric acid in presence of an alcoholor ether solvent to obtain a Eberconazole nitrate of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The main objective of the present invention is to provide an improved, simple and cost-effective process for the preparation of Eberconazole nitrate (I) with high purity and good yield on commercial scale, which is easily available and cheaper reagents.
In one embodiment of the present invention relates to an improved process for the preparation of Eberconazole nitrate of formula (I) comprises the steps of:
a) reacting 2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol with N,N-Carbonyldiimidazole in presence of organic solvent to obtain 1-(2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-yl)imidazole (Eberconazole free base).
b) further Eberconazole free base is treated with nitric acid in presence of an alcohol or ether solvent to obtain Eberconazole nitrate of formula (I).
According to an embodiment of the present invention, the reaction between 2, 4-dichloro-10, 11-dihydro-5H-dibenzo [a, d] [7] annulen-5-ol and N, N-Carbonyldiimidazole is carried out in the presence of organic solvent at reflux for 2 to 4 hrs till complies the reaction through HPLC; Further the reaction mixtures was cooled to room temperature, followed by cool water, brine solution, and ethyl acetate to separate the layers. The organic layer was distilled off to afford Eberconazole free base as a residue.

The residue was dissolved in a solvent mixture of isopropyl alcohol and isopropyl ether (IPA/IPE) and then 70% Nitric acid was added to isolate the solid precipitate of title compound was reached. After filtration of the resultant compound, the afford solid was recrystallized with isopropyl alcohol and isopropyl ether, further it was filtered and washed with IPA/IPE to obtain Eberconazole nitrate as a white solid.
According to the embodiment, the present invention further involves the Eberconazole free base is further treated with nitric acid in presence of alcohol/ether solvent to obtain Eberconazole nitrate using conventional methods known in the prior art. Wherein the alcohol solvent is selected from methanol, ethanol, isopropyl alcohol; ether solvent is selected from isopropyl ether or mixtures thereof.
According to an embodiment of the present invention, the reaction between 2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol and N,N-Carbonyldiimidazole is carried out in the presence of organic solvent to give 1-(2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-yl)imidazole; the reaction is completed within a shorter time span and provides good quantity of yield with high purity.
According to an embodiment, the organic solvent is selected from N, N- dimethylformamide, Ν, Ν-dimethyl acetamide, dimethyl sulfoxide or acetonitrile, preferably dimethylformamide.
According to the present invention, the compound of formula (I) or Eberconazole nitrate has a HPLC purity is not less than 99.5 %.
Advantages of the present invention:
1. The present invention is a simple, operation friendly and industrially applicable process.
2. The process is commercially viable and provides the compounds in high yield, which makes the process cost effective.
3. The reaction of the present invention is carried out in a shorter time span.
4. The present invention provides the compound of formula (I) with high purity and very less impurity profile.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Experimental procedure:
Example 1:
Preparation of Eberconazole Nitrate (I):
2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol 5.0 g (0.0179 mol) was reacted with N,N-Carbonyldiimidazole 2.90 g (0.0237 mmol) in 25 ml N,N-Dimethylformamide and refluxed for 2 hrs. If the reaction complies (checked by HPLC) and then cooled to room temperature, followed by 50 ml ice-water, 100 ml brine, and ethyl acetate (3x30 ml) to separate the layers. The organic layer was distilled off to afford Eberconazole free base as a residue.
The residue was dissolved in a solvent mixture of isopropyl alcohol and isopropyl ether (IPA/IPE) and then 70% Nitric acid was added to isolate the solid precipitate of desired compound. The resultant solid was filtered and washed with IPA/IPE to obtain Eberconazole nitrate as a white solid.
Yield: 5.4 g (77.10%)
Example 2:
Preparation of Eberconazole Nitrate (I):
2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol 5.0 g (0.0179 mol) was reacted with N,N-Carbonyldiimidazole 2.90 g (0.0237 mmol) in 25 ml N,N-Dimethyl acetamide and refluxed for 4 hrs. If the reaction complies (checked by HPLC) and then cooled to room temperature, followed by 50 ml ice-water, 100 ml brine, and ethyl acetate (3x30 ml) to separate the layers. The organic layer was distilled off to afford Eberconazole free base as a residue.
The residue was dissolved in a solvent mixture of isopropyl alcohol and isopropyl ether (IPA/IPE) and then 70% Nitric acid was added to isolate the solid precipitate of desired compound. The resultant solid was filtered and washed with IPA/IPE to obtain Eberconazole nitrate as a white solid.

Example 3:
Preparation of Eberconazole Nitrate (I):
2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol 5.0 g (0.0179 mol) was reacted with N,N-Carbonyldiimidazole 2.90 g (0.0237 mmol) in 25 ml dimethyl sulfoxide and refluxed for 4 hrs. If the reaction complies (checked by HPLC) and then cooled to room temperature, followed by 50 ml ice-water, 100 ml brine, and ethyl acetate (3x30 ml) to separate the layers. The organic layer was distilled off to afford Eberconazole free base as a residue.
The residue was dissolved in a solvent mixture of isopropyl alcohol and isopropyl ether (IPA/IPE) and then 70% Nitric acid was added to isolate the solid precipitate of desired compound. The resultant solid was filtered and washed with IPA/IPE to obtain Eberconazole nitrate as a white solid.
Yield: 5.4 g (77.10%)
Example 4:
Preparation of Eberconazole Nitrate (I):
2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol 5.0 g (0.0179 mol) was reacted with N,N-Carbonyldiimidazole 2.90 g (0.0237 mmol) in 25 ml acetonitrile and refluxed for 1 hr. If the reaction complies (checked by HPLC) and then cooled to room temperature, followed by 50 ml ice-water, 100 ml brine, and ethyl acetate (3x30 ml) to separate the layers. The organic layer was distilled off to afford Eberconazole free base as a residue.
The residue was dissolved in a solvent mixture of isopropyl alcohol and isopropyl ether (IPA/IPE) and then 70% Nitric acid was added to isolate the solid precipitate of desired compound. The resultant solid was filtered and washed with IPA/IPE to obtain Eberconazole nitrate as a white solid.
Yield: 6.0 g (86%)

WE CLAIM:
1) An improved process for the preparation of Eberconazole nitrate of formula (I) comprises the
steps of;
a) reacting 2,4-dichloro-10,ll-dihydro-5H-dibenzo[a,d][7]annulen-5-ol with N,N-Carbonyldimidazole in presence of organic solvent to obtain l-(2,4-dichloro-10,ll-dihydro-5H-dibenzo[a,d] cyclohepten-5-yl)imidazole (Eberconazole free base).
b) further Eberconazole free base is treated with nitric acid in presence of an alcohol or ether solvent to obtain Eberconazole nitrate of formula (I).
2) The process as claimed in claim 1, wherein organic solvent is selected from N, N-dimethylformamide, N, N-dimethyl acetamide, dimethyl sulfoxide or acetonitrile, preferably dimethylformamide.
3) The process as claimed in claim 1, where in alcohol solvent is selected from methanol, ethanol, isopropanol; ether solvent is selected from isopropyl ether or mixtures thereof

4) The process as claimed in claim 1, Eberconazole nitrate HPLC purity is not less than 99.5 %.