WO2007096904A2

WO2007096904A2 - Improved process for the preparation of terbinafine hydrochloride and novel crystalline form of terbinafine

Info

Publication number: WO2007096904A2
Application number: PCT/IN2007/000068
Authority: WO
Inventors: Manne Satyanarayana Reddy; Karamala Rama Subba Reddy
Original assignee: Manne Satyanarayana Reddy; Karamala Rama Subba Reddy
Priority date: 2006-02-23
Filing date: 2007-02-21
Publication date: 2007-08-30
Also published as: WO2007096904A3

Abstract

Improved process for the preparation of Terbinafme Hydrochloride compound of formula (I): substantially free of Genotoxic impurity compound of formula (II) and Novel crystalline form of Terbinafine.

Description

Improved Process for the Preparation of Terbinafine Hydrochloride and

Novel Crystalline Form of Terbinafine Field of the Invention

The present invention relates to an improved process for the preparation of Terbinafine hydrochloride compound of formula- 1 substantially free of (E)-4[4,4- Dimethylpentyn-(E)-ylidene]-N¹,N⁵-dimethyl-N¹,N⁵-bisnaphthalene-l-yl methyl -pent-2- en-1,5 diamine represented by the compound of formula-2.

Furthermore, the present invention relates to a novel crystalline form of Terbinafine and process for the preparation of Terbinafine base substantially free of (E)-4[4,4- Dimethylpentyn-(E)-ylidene] -N¹ ,N⁵-dimethyl-N¹ ,N⁵-bisnaphthalene- 1 -yl methyl -pent-2- en-1,5 diamine compound of formula-2.

Formula —1

Formula-2

Terbinafine particularly in the form of hydrochloride acid addition salt form commercially available under the brand name of LAMISIL®. Terbinafine hydrochloride belongs to the class of allylamine antimycotics. It is effective upon both topical and oral administration, in a wide range of fungal infections. Terbinafine is particularly useful against dermatophytes, contagious fungi that invade dead tissues of the skin or its appendages such as stratum corneum, nail and hair.

The impurity compound of formula-2 was evaluated for potential mutagenic activity at the thymidine kinase (tk) locus of L5178Y mouse lymphoma cells, and it was demonstrated that the impurity induced an increase in the mutant frequencies under all test conditions, at acceptable levels of cytotoxicity, and a statistically significant dose-response relationship was seen after linear trend analysis. It was thus concluded that the impurity is a mutagen at the thymidine kinase locus of L5178 Y mouse lymphoma cells under the test conditions when standard mutagenicity criteria were applied in these studies which is referred in Chimia 50 (1996) : 154-156 by Beutler et al. Herein after referred as

"Genotoxic impurity"

Terbinafme represents a significant advance in antifungal therapy based on its potent fungicidal action in vitro and rapid clinical efficacy in various dermatophyte infections when given orally as well as topically. It is a potent inhibitor of ergosterol biosynthesis, it blocks the action of squalene epoxidase, thus inhibiting the transformation of squalene to squalene epoxide. Although ergosterol synthesis is only partially inhibited, cell growth is completely arrested. This suggests that the fungicidal effect of Terbinafme may be related to the accumulation of squalene, which at high concentrations may be toxic to the fungus.

Background of the Invention

Terbinafme and process for its preparation is first disclosed in US Patent No.

4755534, which comprises of reacting 6,6-dimethyl-hept-l-ene-4-yne-3-ol with 3,3-dimethyl-l-butyne and acrolein using n-butyllithium. The drawback of this process is usage of n-butyllithium, which is not preferable at commercial scale, which is highly pyrophoric, highly sensitive to air and moisture and transportation is also a big problem.

US Patent No. 6689913 describes a process for the preparation of Terbinafme hydrochloride, which comprises reaction of 2-pivaloylfuran with hydrazide compounds to give hydrazone derivative. This hydrazone derivative on reaction with secondary amine and further reduction with sodium borohydride and converting the base with hydrochloric acid gives Terbinafme HCl. The yields are very low, ranging from 15-40%. The process is lengthy and not economical.

US Patent No. 6515181 describes a process for the preparation of Terbinafme, which involves reaction of secondary amine of the formula- 11 with (E)l,3-dichloropropene to give vinyl chloride of the formula- 12. The vinyl chloride of formula-9 is converted to Terbinafme HCl on reaction with tertiary butyl acetylene and copper iodide. The production of vinyl chloride of the formula -9 is expensive due to the use of expensive (E) 1,3-dichloropropene.

U yne-3-ol reaction

reagent ethymiagnesium bromide has been prepared using a mixture of toluene and tetrahydrofuran. The mixture of toluene and tetrahydrofuran gives insoluble grignard reagent hence the yield is low.

The EP patent 0341048 broadly disclosed the process for the preparation of 6,6- dimethylhept-l-en-4-yn-3-ol by condensation of acrolien compound of general formula (VIII) and acetylene compound of general formula (IX) by using a base such as alkyllithiums (e.g. n-butyllithium), phenyllithiums, alkylmagnesium halides (e.g. ethylmagnesium bromide), alkali metal hydrides (e.g. lithium hydride, sodium hydride, potassium hydride), alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide), alkali metals (e.g. lithium, sodium, potassium), etc.

In Swiss Patent No. CH 678 527, the hydrochloride salt of N-methyl-1- naphthylmethyl amine (III) is reacted with a 14% excess of a 3:1 trans/cis isomer mixture of l-bromo-6,6-dimethyl-2-hepten-4-yne (IVa) in a 30% aqueous sodium hydroxide solution at a temperature of between about 100 to 105°C for three hours.

The International publication WO 01/28976 described the process for the preparation of Terbinafine hydrochloride, which involves the reaction of 6,6-dimethyl- hept-l-ene-4-yne-3-ol with hydrochloric acid and subsequent reaction of

(cis/trans) 1-chloro 6,6-dimethyl-hept-2-ene-4-yne in an aqueous methyl isobutyl ketone with secondary amine of the formula-8 to give Terbinafme which is converted to its hydrochloride salt in methyl isobutyl ketone. The yields reported are low (42-50%) hence process is not economical.

The international publication WO 2006/089746 described the process for the purification of Terbinafine from non-metal contaminants which involves the short path distillation of Terbinafine crude form to remove the non-metal contaminants. This distillation process is not recommendable for commercial scale up.

The international publication WO 2005/121155 described the process for the preparation of Terbinafine and its analogues using metal catalyst like Ni(II) salts or its complexes.

The international publication WO 2005/110968 described the process for the preparation of Terbinafine hydrochloride from 6,6-dimethyl-hept-l-ene-4-yne-3-ol without isolating any intermediates.

The international publication WO 2005/058794 described the process for the preparation of Terbinafine intermediate compound of N-methyl-N(l-naphthylmethyl)-6,6- dimethyl-2-hydroxyheptan-4-ynyl- 1 -amine.

Apart from all the above problems, another major drawback of the prior art processes is that all the above processes for the preparation of Terbinafme hydrochloride leads to the formation of Genotoxic impurity compound of formula-2. This impurity

(Genotoxic Impurity) derives from the original synthetic process which uses acrolein and

PCl₅. So there is a need to develop a process which avoids all the above said problems. Extensive process research has been carried out to find out the origin and/or to minimize and/or to avoid the formation of Genotoxic impurity. Attempts were made to minimize the Genotoxic impurity by purifying the Terbinafine hydrochloride and found that the impurity percentage was reduced to the required level. Attempts were made to minimize the impurity level by high vacuum distillation of Terbinafine free base and found that the impurity is more than 10 ppm, but as Terbinafine is a Nitrogen containing molecule, high vacuum distillation is not preferable at industrial scale, because it forms N-Oxide which may explode while distillation. Hence the purification of Terbinafine and its hydrochloride has not served the purpose. Then our research work has been carried out to identify the source of the Genotoxic impurity, for this we have taken one of the key starting material of Terbinafine which is 6,6-dimethyl-l-chlorohept-2-ene-4-yne and focused on preparation and purification of the same. Purifying the key starting material 6,6-dimethyl-l-chlorohept-2-ene-4-yne by distillation and found that the Genotoxic impurity level is reduced to little extent at Terbinafine hydrochloride. So distillation of 6,6-dimethyl~l-chlorohept-2-ene-4-yne has not given good results with respect to this impurity.

Further studied on earlier stage compound 6,6-dimethyl-l-heptene-4-yne-3-ol, which is a liquid, purified this liquid by fractional distillation. The fractional distilled compound of formula-6 further converted into Terbinafine hydrochloride as per the scheme- 1 and found that the Genotoxic impurity was not detected in the obtained Terbinafine hydrochloride. This clearly indicating that the source for the formation of corresponding derivative of Genotoxic impurity is at the preparation of 6,6-dimethyl-l- heptene-4-yne-3-ol. In addition to this, structural formula of Genotoxic impurity is clearly indicating that the additional 3 -carbon chain is present in addition to the structure of Terbinafine, which may be due to the acrolein compound used at Grignard reaction. The above data concludes that the origin for the formation of corresponding derivative of Genotoxic impurity is at Grignard reaction (i.e., preparation of compound of formula-6 in scheme- 1) and which is identified as compound of formula-9. Identification of the corresponding peak for particular impurity is little difficult by gas chromatography analysis of the compound of formula-6 containing the compound of formula-9 in ppm level and also other impurities in smaller level. Due to that, inventors converted the compound of formula-6 with compound of formula-9 to compound of formula-7 and compound of formula- 10. Which are further reacted with compound of formula-8 gives Terbinafine hydrochloride compound of formula- 1 along with Genotoxic impurity compound of formula-2, which is schematically represented in scheme-2. The Genotoxic impurity in Terbinafine is identified by HPLC method which is already published by the innovator.

After identifying the source of the impurity, our extensive process work has been carried out to arrest the formation of compound of formula-9 at source itself. The main factors which influences the formation of compound of formula-9 at Grignard reaction are as follows

> The reaction medium (i.e., solvent)

> The basicity of the reaction mixture > Temperature of the reaction mixture

Usage of n-butyl lithium in a solvent like tetrahydrofuran for the preparation of 6,6-dimethyl-hept-l-ene-4-yne-3-ol leads to formation of Genotoxic impurity in Terbinafine hydrochloride. The same reaction is carried out using Grignard reagent in a solvent like tetrahydrofuran and observed the formation of Genotoxic impurity level at Terbinafine hydrochloride. Incorporation of methylene chloride solvent with the combination of tetrahydrofuran for the preparation of 6,6-dimethyl-hept-l-ene-4-yne-3-ol leads to formation of very minimum level of Genotoxic impurity in Terbinafine hydrochloride has been observed. Incorporation of methylene chloride in reaction medium reduces the formation of Genotoxic impurity as well as reducing the time cycle of the reaction. Basicity, the another parameter of the reaction mixture which depends on mole ratio of magnesium metal used for the preparation of ethyl magnesium bromide. The results are negative while using 1.0 mole equivalent or more than 1.0 mole equivalent with respect to 3,3-dimethylbutyne. The suitable quantity of magnesium metal is preferably less than 1.0 mole, more preferably 0.85 moles. Various temperatures of the reaction has been studied and the suitable temperature is -50°C to -5°C. The impact of HPLC Purity of Terbinafine Hydrochloride (level of Genotoxic impurity by ppm) with different reaction (Grignard reaction) conditions is tabulated below. The obtained compound of Grignard reaction has been consumed in the synthesis of Terbinafine and analyzed the Terbinafine Hydrochloride sample to know the Genotoxic impurity level.

Magnesium metal is used for the preparation of ethyl magnesium bromide reagent.

^{* 2} The corresponding material has been consumed for the preparation of Terbinafine

Hydrochloride and analyzed to find out the Genotoxic impurity level.

^{• 3} The HPLC Chromatograph of Terbinafine Hydrochloride which is prepared from the corresponding experiment.

US Patent No. 4755534 discloses the Terbinafine base as an oily residue compound. The said patent isolated the Terbinafine as a hydrochloride salt. It is also disclosed either free base form or a chemotherapeutically acceptable acid addition salt can be used in the treatment of mammals .

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Terbinafine, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behaviors different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermo gravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms. ₍

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

There is a need in the art for the improved process for the preparation of Terbinafine hydrochloride.

Disadvantages of the prior art processes

• Formation of Genotoxic impurity level is about 400 ppm has been observed in Terbinafine hydrochloride while conducting the grignard reaction using tetrahydrofuran as a single solvent at a temperature of -10°C to +10°C. • Formation of Genotoxic impurity level is about 20 ppm has been observed in

Terbinafine hydrochloride while conducting the grignard reaction using tetrahydrofuran as a single solvent at a temperature of -20°C to -30°C.

• Usage of hazardous phosphorous oxy chloride in step 2 of the process leads to high volumes of effluent. • Usage of tetrahydrofuran as a single solvent in Grignard reaction leads to the formation of thick mass of Grignard complex, which needs very slow addition of acrolein this ultimately needs more time. Brief description of the Invention

Accordingly, the present invention is to provide an improved process for the preparation of Terbinafine hydrochloride compound of formula- 1 substantially free of Genotoxic impurity compound of formula-2 and a novel crystalline form of Terbinafine and process for the preparation of crystalline Terbinafine base substantially free of Genotoxic impurity compound of formula-2.

Formula— 1

First aspect of the present invention is to provide an improved process for the preparation of Terbinafine hydrochloride compound of formula- 1 substantially free of Genotoxic impurity compound of formula-2, which comprises of the following steps,

a) Reacting 3,3-dimethylbutyne compound of formula-4 with acrolein compound of formula-5 in presence of proton-extracting agent selected from the group consisting of an organometalic compound like grignard reagent in a suitable solvents like ether solvents or chloro solvents or mixture of solvents gives the compound of formula-6 free of compound of formula-9, b) Treating the compound of formula-6 obtained from step (a) with an acid in a suitable solvent gives the compound of formula-7, c) Reacting the compound of formula-7 obtained from step (b) with the compound of formula-8 in presence of an alkali base and in a suitable polar solvent gives the compound of formula- 1 , d) Purifying the above obtained compound of formula- 1 from step (c) using suitable solvent selected from nitrile solvents, ester solvents, keto solvents, preferably nitrile solvents more preferably acetonitrile. The second aspect of the present invention is to provide an improved process for the preparation of Terbinafme Hydrochloride compound of formula- 1, which comprises of the following steps a) Reacting the compound of formula-7 free of compound of formula- 10 with the compound of formula-8 in presence of an alkali base and in a suitable polar solvent gives the compound of formula- 1, b) Isolating the compound of formula- 1 using a solvent selected from keto solvents, ester solvents and nitrile solvents, preferably keto solvents.

The third aspect of the present invention is to provide a novel crystalline form of

Terbinafine compound of formula-3, herein defined as Form-I, characterized by X-ray powder diffraction peaks at about 9.5, 15.7,18.0,19.2, 21.9 and 24.2 ± 0.2 degrees two- theta.

The fourth aspect of the present invention is to provide a process for preparing

Crystalline Form-I of Terbinafme compound of formula-3, which comprises of the following steps a) Reacting the compound of formula-7 free of compound of formula- 10 with naphthalene compound of formula-8 in presence of an alkali base in a suitable polar solvent, b) Isolating the crystalline Form-I of Terbinafine by using suitable solvent.

The fifth aspect of the present invention is to provide a process for preparing Crystalline Form-I of Terbinafine compound of formula-3, which comprises of the following steps a) Dissolving the Terbinafme acid addition salts such as hydrochloride prepared as per the process described in the first and second aspect of the present invention, in a suitable polar solvents or mixtures thereof, b) Adjusting the pH of the reaction mixture to basic, c) Extracting with suitable water immiscible solvent, d) Distilling off the solvent under reduced pressure, e) Adding a suitable solvent, f) Cooling the reaction mixture, g) Isolating the product by filtration, h) Drying the material to get the crystalline Forai-I of Terbinafme.

Crystalline Form-I of Terbinafme prepared by the fourth and fifth aspect of the present invention substantially free of Genotoxic impurity compound of formula-2.

Crystalline Terbinafme as provided by the present invention can in turn be prepared from salts of Terbinafme such as Terbinafme hydrochloride or any other suitable salt or directly from the reaction as described in one of the embodiment of the present invention.

The preparation of crystalline Terbinafme according to the present invention is advantageous, as it is free flowing solid with high purity and can be used directly for formulation as an active pharmaceutical ingredient.

This crystalline Terbinafme can be employed as a useful intermediate in the preparation of high pure pharmaceutically acceptable salts of Terbinafine, in particular Terbinafme hydrochloride and its hydrates. Pharmaceutically acceptable salts of Terbinafine prepared from crystalline Terbinafme can exhibit beneficial properties, for example, Terbinafine hydrochloride prepared from crystalline Terbinafine as provided by the present invention is more resistant/stable than Terbinafine hydrochloride prepared by conventional methods known in the prior art.

Advantages over prior art processes

• Present invention provides the process for the preparation of Terbinafine hydrochloride substantially free of Genotoxic impurity (i.e., below 5 ppm).

• Present invention avoids the usage of hazardous phosphorous oxy chloride.

• Present invention avoids the usage of highly pyrophoric n-butyllithium. • Provides an novel crystalline form of Terbinafine base

• Cost effective process.

• Reduction of cycle time.

• Environment friendly and easy scale-up. Brief description of the drawings:

Figure-1: HPLC Chromatograph of Terbinafme hydrochloride with 100 ppm solution of

Genotoxic Impurity.

Figure-2: HPLC Chromatograph of Terbinafme hydrochloride multiplot with different injection ID's.

Figure-3: HPLC Chromatograph of Terbinafme hydrochloride. Figure-4: HPLC Chromatograph of Terbinafme hydrochloride. Figure-5: Illustrates the powder X-ray diffraction pattern of Crystalline Form-I of

Terbinafme. Figure-6: Illustrates the IR spectrum of Crystalline Form-I of Terbinafine. Figure-7: Illustrates the DSC of Crystalline Form-I of Terbinafine.

Detailed description of the Invention

The present invention relates to an improved process for the preparation of

Terbinafine hydrochloride compound of formula- 1 substantially free of Genotoxic impurity compound of formula-2 and also relates to a novel crystalline form of Terbinafine base and process for preparing the same. Terbinafine hydrochloride chemically known as N- [(2E)-6,6-Dimethyl-2-hepten-4-ynyl] -N-methyl- 1 -naphthalenemethanamine hydrochloride compound represented as formula- 1 ,

Formula- 1

First aspect of the present invention is to provide an improved process for the preparation of Terbinafme hydrochloride compound of formula- 1 substantially free of Genotoxic impurity compound of formula-2, which comprises of the following steps a) Reacting 3,3-dimethylbutyne compound of formula-4 with acrolein compound of formula-5 in presence of proton-extracting agent selected from the group consisting of an organometalic compound like grignard reagent like ethyl magnesium bromide in a suitable solvents like ether solvents like tetrahydrofuran or chloro solvents like methylene chloride, chloroform or mixture of solvents like tetrahydrofuran and methylene chloride, preferably mixture of tetrahydrofuran and methylene chloride at a temperature of about -50⁰C to -5⁰C, preferably at a temperature of about -45 to -35°C gives the compound of formula-6 free of compound of formula-9, b) Treating the compound of formula-6 obtained from step (a) with an acid like hydrochloric acid or hydrobromic acid in a suitable solvent selected from nitrile solvents like acetonitrile at a temperature of about 0-40°C, preferably at a temperature of about 10-25°C gives the compound of formula-7, c) Reacting the compound of formula-7 obtained from step (b) with the compound of formula-8 in presence of a mild alkali base like sodium carbonate, potassium carbonate, sodium bicarbonate, preferably sodium carbonate and in a suitable polar solvents like dimethyl formamide, dimethyl acetamide, dimethylsulfoxide and water and/or mixtures thereof at a temperature of about 35-95°C, preferably at a temperature of about 75 °C gives the compound of formula- 1, d) Purifying the above obtained compound of formula- 1 from step (c) using suitable solvent selected from nitrile solvents, ester solvents, keto solvents, preferably nitrile solvents more preferably acetonitrile.

The second aspect of the present invention is to provide an improved process for the preparation of Terbinafine Hydrochloride compound of formula- 1 substantially free of Genotoxic impurity compound of formula-2, which comprises of the following steps a) Reacting the compound of formula-7 free of compound of formula- 10 with the compound of formula-8 in presence of a mild alkali base like sodium carbonate, potassium carbonate, sodium bicarbonate, preferably sodium carbonate and in a suitable polar solvents like dimethyl formamide, dimethyl acetamide, dimethylsulfoxide and water, preferably water at a temperature of about 35-95°C, preferably at a temperature of about 75 °C, b) Isolating the compound of formula- 1 from step (a) using a solvent selected from keto solvents like acetone methylisobutyl ketone, ester solvents like ethyl acetate, methyl acetate and nitrile solvents like acetonitrile, preferably keto solvents, more preferably acetone.

The third aspect of the present invention is to provide a novel crystalline Form-I of Terbinafine. Terbinafine chemically known as N-[(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N- methyl-1-naphthalenemethanamine compound can be represented as Formula -3,

Formula -3

Novel crystalline Form-I of Terbinafine compound of formula-3 of the present invention is characterized by XRD pattern as illustrated in Fig.l, its IR spectrum as illustrated in Fig.2 and its DSC as illustrated in Fig.3.

Terbinafine crystalline Form-I in accordance with the present invention is characterized by X-ray powder diffraction peaks at about 9.5, 15.7, 18.0, 19.2, 21.9 and 24.2 ± 0.2 degrees two-theta.

Terbinafine crystalline Form-I in accordance with the present invention is characterized by Infrared spectrum peaks at about 3043, 2968, 1631, 1598, 1455, 960, 794 and 775 cm^'1.

Terbinafine crystalline Form-I in accordance with the present invention is characterized by endotherm at about 40.8°C by differential scanning calorimetry ("DSC").

The fourth aspect of the present invention is to provide a process for the preparation of Crystalline Form-I of Terbinafine compound of formula-3, which comprising the following steps a) Reacting the compound of formula-7 free of compound of formula- 10

CH₃

H₃C-C-C≡C— CH=CH-CH₂ Cl CH₃

Formula-7 with naphthalene methylamine compound of formula-8

Formula-8 in presence of a mild alkali base like sodium carbonate, potassium carbonate, sodium bicarbonate, preferably sodium carbonate, in a suitable polar solvent like dimethyl formamide, dimethyl acetamide, dimethylsulfoxide and water, preferably water at a temperature of about 35-95°C, preferably at a temperature of about 75°C, b) Isolating the crystalline Form-I of Terbinafine compound of formula-3 by using the solvent selected from the group like alcohols such as methanol, ethanol and isopropanol, ketones like acetone, methylisobutylketone, methylethylketone, esters like ethyl acetate and isopropyl acetate, nitriles like acetonitrile.

The fifth aspect of the present invention is to provide a novel process for the preparation of Crystalline Form-I of Terbinafine compound of formula-3, which comprises of the following steps, a) Dissolving the Terbinafine acid addition salts such as hydrochloride prepared as per the process described in the first and second aspect of the present invention, in a suitable polar solvent like water or chlorosolvent like methylene chloride or mixtures thereof preferably mixture of water and methylene chloride, b) Adjusting the pH of the reaction mixture to 7.5-8 with an aqueous sodium carbonate solution at 5-30⁰C, preferably at 10-25⁰C and most preferably at 15-2O⁰C, c) Extracting the aqueous layer with suitable chloro solvents like methylene chloride, chloroform preferably methylene chloride, d) Removing the solvent by evaporation, e) Adding a suitable solvent selected from alcohols like methanol, ethanol and isopropanol, ketones like acetone, methylisobutylketone, methylethylketone, esters like ethyl acetate and isopropyl acetate, nitriles like acetonitrile. f) Cooling the reaction mixture, g) Isolating the product by filtration, h) Drying the material to afford Form-I of Terbinafme.

The crystalline Form-1 of Terbinafme compound of formula-3 obtained as per the fourth and fifth aspect substantially free of Genotoxic impurity compound of formula-2.

Detection of Genotoxic impurity is preferably effected using an analytical method sensitive to concentrations below the conventional quantitation limit of about 0.05%w/w

(500ppm) usually achieved with conventional detection method such as reversed-phase high pressure liquid chromatography, preferably down to quantitation limit of around

0.0001% w/w (lppm), such as RP-HPLC with UV detection.

Genotoxic impurity detection has been carried out using High pressure liquid chromatograph is equipped with variable wavelength Detector and integrator, Xterra RP 18, 150x4.6 mm ID, 3.5μ or equivalent column, 1.0 ml/min flow rate at 280 nm, 20μl injection 16 minutes run time, sample concentration is 40 mg/ml and diluents is 8:2 of Acetonitrile and water. Mobile phase A (1000:1 v/v ratio of water and triethylamine), Mobile phase B (1000: 1 v/v ratio of acetonitrile and triethylamine)

The Resolution of Genotoxic impurity with Terbinafme is shown in Figure- 1.

FI-IR spectrum of Terbinafme was recorded on Thermo model Nicolet-380 as KBr pellet.

The thermal analysis of Terbinafme was carried out on Waters DSC Q- 10 model differential scanning calorimeter. The present invention schematically represented as follows. Scheme-1:

Scheme-2:

Formula-7 Formula-10 of (E,E) and (E,Z) Isomers

Formula-l FormuIa-2, (E,E) Isomer Formula-2a, (E,Z) Isomer The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples

Example-1: Preparation of 6,6-dimethyl-l-heptene-4-yne-3-ol compound of formuIa-6

Slowly added 83 grams of ethyl bromide to a heterogeneous solution of 150 ml of tetrahydrofuran, 12.5 grams of magnesium and catalytic amount of Iodine at ambient temperature. Stirred the reaction mixture for 90 minutes at 45-65°C. Cooled the reaction mixture to -10°C and added 250 ml of methylene chloride followed by 50 grams of 3,3-dimethylbutyne. Stirred the reaction mixture for 90 minutes at -10°C. Cooled the reaction mixture further to -30°C and slowly added 34 grams of acrolein to the reaction mixture. Stirred the reaction mixture at -30°C for 2 hours. Reaction mixture decomposed with chilled water. Separated the organic phase and aqueous phase. Extracted the aqueous phase twice with methylene chloride. Washed organic phase with water. Concentrated the organic phase at below 5O⁰C under reduced pressure to get title compound as a residue. Yield: 75 grams

Example-2: Preparation of 6,6-dimethyl-l-chlorohept-2-ene-4-yne compound of formula-7

Slowly added 240 ml of hydrochloric acid to a solution of 60 grams of 6,6-dimethyl-l-heptene-4-yne-3-ol and 240 ml of acetonitrile at 0-10°C. Stirred the reaction mixture for 4 hours at 0-10°C. Further stirred the reaction mixture at an ambient temperature for 5 hours. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with hexanes. Washed the hexane layer with water and concentrated to get the title compound as a residue. Yield: 65 grams Example-3: Preparation of Terbinafine hydrochloride compound of formula- 1

60 grams of sodium carbonate is added to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water and 100 ml of dimethyl formamide at an ambient temperature. Stirred the reaction mixture for 45 minutes at ambient temperature. Cooled the mixture to 10-15°C and slowly added 34 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne. Heated the reaction mixture to 70-75⁰C and stirred for 6 hours. Cooled the reaction mixture to 25-35⁰C. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed the organic phase thrice with water. Separated the organic phase and added water then cooled to 10-15⁰C. Slowly added 160.5 ml of hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 50⁰C. Hexanes added to the obtained crude and decanted thrice. Isolated the title compound using acetone. The obtained compound purified using acetonitrile as a solvent. Yield 75 grams.

Example-4: Preparation of Terbinafine hydrochloride compound of formula- 1

60 grams of sodium carbonate is added to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water and 100 ml of dimethylformamide at an ambient temperature. Stirred the reaction mixture for 45 minutes at ambient temperature. Cooled the mixture to 10-15⁰C and slowly added 112.5 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne. Heated the reaction mixture to 70-75⁰C and stirred for 6 hours. Cooled the reaction mixture to 25-35°C. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed the organic phase thrice with water. Separated the organic phase and added water then cooled to 10-15⁰C. Slowly added 160.5 ml hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 50⁰C. Isolated the compound using acetone. The obtained compound purified using acetonitrile as a solvent. Yield 75 grams Example-5: Preparation of Terbinafine hydrochloride compound of formula- 1

60 grams of sodium carbonate is added to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water at an ambient temperature. Stirred the reaction mixture for 45 minutes at ambient temperature. Cooled the mixture to 10-15°C and slowly added 112.5 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne. Heated the reaction mixture to 70-75°C and stirred for 6 hours. Cooled the reaction mixture to 25-35⁰C. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed the organic phase thrice with water. Separated the organic phase and added water then cooled to 10-15°C. Slowly added 160.5 ml hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 5O⁰C. Isolated the compound using acetone. The obtained compound purified using acetonitrile as a solvent. Yield 75 grams

Example-6: Preparation of crystalline Form-I of Terbinafine compound of formula-3 Added 60 grams of sodium carbonate to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water and at an ambient temperature. Stirred the reaction mixture for 45 minutes at an ambient temperature. Cooled the reaction mixture to 10-15⁰C. Added 112.5 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne to the above reaction mixture at 10-15°C. Heated the reaction mixture to 70-75⁰C. Stirred the reaction mixture for 6 hours at 70-75⁰C. Cooled the reaction mixture to 25-35°C. Quenched the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed thrice with water. Separated the organic phase. Distilled the organic phase completely under reduced pressure at below 50⁰C. Added 50 ml of isopropyl alcohol to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 50⁰C. Cooled the reaction mixture to 25-35⁰C. Added 180 ml of isopropyl alcohol to the above reaction mixture and heated to reflux. Stirred the reaction mixture at reflux for 20 minutes. Cooled the reaction mixture to 0-5⁰C. Stirred the reaction mixture for 60 minutes at 0-5⁰C. Filtered the precipitated solid and washed with chilled isopropyl alcohol. Dried the material to get the crystalline Form-I of Terbinafme. Yield: 74 grams

Example-7: Preparation of crystalline Form-I of Terbinafine compound of formula-3

Added 60 grams of sodium carbonate to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water and of dimethylformamide at an ambient temperature. Stirred the reaction mixture for 45 minutes at an ambient temperature. Cooled the reaction mixture to 10-15°C. Added 112.5 grams of 6,6-dimethyl- l-chlorohept-2-ene-4-yne to the above reaction mixture at 10-15°C. Heated the reaction mixture to 70-75°C. Stirred the reaction mixture for 6 hours at 70-75°C. Cooled the reaction mixture to 25-35°C. Quenched the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed thrice with water. Separated the organic phase. Distilled the organic phase completely under reduced pressure at below 5O⁰C. Added 50 ml of ethyl acetate to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 60°C. Cooled the reaction mixture to 25-35°C. Added 180 ml of ethyl acetate to the above reaction mixture and heated to reflux. Stirred the reaction mixture at reflux for 20 minutes. Cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 60 minutes at 0-5°C. Filtered the precipitated solid and washed with chilled ethyl acetate. Dried the material to get the crystalline Form-I of Terbinafine. Yield: 72 grams

ExampIe-8: Preparation of crystalline Form-I of Terbinafine compound of formula-3 Added 60 grams of sodium carbonate to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water and 100 ml of dimethyl formamide at an ambient temperature. Stirred the reaction mixture for 45 minutes at an ambient temperature. Cooled the reaction mixture to 10-15⁰C. Added 112.5 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne to the above reaction mixture at 10-15⁰C. Heated the reaction mixture to 70-75°C. Stirred the reaction mixture for 6 hours at 70-75⁰C. Cooled the reaction mixture to 25-35⁰C. Quenched the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed thrice with water. Separated the organic phase. Distilled the organic phase completely under reduced pressure at below 50°C. Added 50 ml of acetone to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 60°C. Cooled the reaction mixture to 25-35°C. Added 180 ml of acetone to the above reaction mixture and heated to reflux. Stirred the reaction mixture at reflux for 20 minutes. Cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 60 minutes at 0-5°C. Filtered the precipitated solid and washed with chilled acetone. Dried the material to get the crystalline Form-I of Terbinafme. Yield: 73 grams

Example-9: Preparation of Form-I of Terbinafme compound of formula-3 from Terbinafine hydrochloride

Dissolved the 200 grams of Terbinafine hydrochloride in 600 ml of D.M water and 500 ml of methylene chloride at 25-35°C. Stirred the reaction mixture for 15 minutes at

25-35°C. Cooled the reaction mixture to 15-20⁰C. Adjusted the pH of the reaction to 7.9 with sodium carbonate solution. Separated the organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Washed the organic layer with water. Dried the organic layer with sodium sulphate. Distilled the solvent from organic layer completely at below 50°C under reduced pressure. Added 100ml of isopropyl alcohol to the above reaction mixture and distilled the solvent completely under reduced pressure at below

60°C. Cooled the reaction mixture to 25-35°C. Added 360 ml of isopropyl alcohol to the above reaction mixture. Heated to reflux and stirred the reaction mixture for 20 minutes at reflux. Cooled the reaction mixture to 0-5⁰C. Stirred the reaction mixture for 60 minutes at 0-5°C. Filtered the precipitated solid and washed with chilled isopropyl alcohol. Dried the obtained solid at 30-35⁰C to get form-I of Terbinafine.

Yield: 152 grams

M.R: 40°C

Claims

We Claim:

1. An improved Process for the preparation of Terbinafine hydrochloride compound of formula-1 substantially free from (E)-4[4,4-Dimethylpentyn-(E)-ylidene]-N¹,N⁵- dimethyl-N¹,N⁵-bisnaphthalene-l-yl methyl-pent-2-en-l,5 diamine - "Genotoxic impurity" compound of formula-2,

Formula -1

Formula-2

Which comprises of the following steps,

a) Reacting 3,3-dimethylbutyne compound of formula-4 with acrolein compound of formula-5 in presence of proton-extracting agent selected from the group consisting of an organometalic compound like grignard reagent like ethyl magnesium bromide in a suitable solvents like ether solvents like tetrahydrofuran or chloro solvents like methylene chloride or mixtures thereof, preferably mixture of tetrahydrofuran and methylene chloride at a temperature of about -50°C to -5°C, preferably at a temperature of about -45 to -35⁰C gives the compound of formula-6 free of compound of formula-9, b) Treating the compound of formula-6 obtained from step (a) with an acid like hydrochloric acid or hydrobromic acid in a suitable solvent selected from nitrile solvents like acetonitrile at a temperature of about 0-40⁰C, preferably at a temperature of about 10-25°C gives the compound of formula-7, c) Reacting the compound of formula-7 obtained from step (b) with the compound of formula- 8 in presence of a mild alkali base like sodium carbonate, potassium carbonate, sodium bicarbonate, preferably sodium carbonate and in a suitable polar solvent like dimethyl formamide, dimethyl acetamide, dimethylsulfoxide and water and/or mixtures thereof at a temperature of about 35-95°C, preferably at a temperature of about 75°C gives the compound of formula-1, d) Purifying the compound of formula-1 obtained from step (c) using suitable solvent selected from nitrile solvents, ester solvents, keto solvents, preferably nitrile solvents more preferably acetonitrile.

2. The process according to claim Ia) where in the solvent is a mixture of tetrahydrofuran and methylene chloride.

3. The process according to claim 2 wherein the ratio of methylene chloride in a mixture of solvent is at least about 1% to 95%.

4. The process according to claim 2 wherein the ratio of methylene chloride in a mixture of solvent is at least about 5% to 75%.

5. Reaction temperature according to claim Ia) is -45 to -35°C.

6. The mole ratio of magnesium according to claim Ia) is below 1.0 mole, preferably 0.85 moles.

7. Usage of hydrochloric acid without co-solvent for the preparation of 6,6-dimethyl-l- chlorohept-2-ene-4-yne.

8. Terbinafine Hydrochloride is substantially free of Genotoxic impurity compound of formula-2 according to claim 1 is below 10 ppm level.

9. Terbinafine Hydrochloride is substantially free of Genotoxic impurity compound of formula-2 according to claim 1 is below 5 ppm level, more preferably below 2 ppm level.

10. The usage of methylene chloride as a co-solvent in Grignard reaction to minimize the formation of corresponding derivative of Genotoxic Impurity compound of formula-2.

11. An improved process for the preparation of Terbinafine hydrochloride compound of formula- 1 substantially free of Genotoxic impurity compound of formula-2 comprises of the following steps a) Reacting the compound of formula-7 free of compound of formula- 10, with the compound of formula- 8 in presence of an mild alkali base like sodium carbonate, potassium carbonate, sodium bicarbonate, preferably sodium carbonate and in a suitable polar solvent like water at a temperature of about 35-95°C, preferably at a temperature of about 75°C, b)- Isolating the compound of formula- 1 from step (a) using a suitable solvent selected from keto solvents like acetone, methyl isobutyl ketone, ester solvents like ethyl acetate, methyl acetate and nitrile solvents like acetonitrile, preferably keto solvents, more preferably acetone.

12. The solvent according to claim 11 a) is water.

13. A Crystalline Form-I of Terbinafine compound of formula-3.

Formula-3

14. The crystalline Form-I of Terbinafme according to claim 13, is characterized by

X-ray power diffraction pattern having peaks at about 9.5, 15.7, 18.0, 19.2, 21.9 and 24.2 degrees two-theta± 0.2 degrees two-theta.

15. The crystalline Form-I of Terbinafme according to claim 13, is characterized by

IR spectrum having peaks at about 3043, 2968, 1631, 1598, 1455, 960, 794 and 775 cm^" .

16. The crystalline Form-I of Terbinafme according to claim 13, having an X-ray powder diffraction pattern substantially as shown in Figure-5.

17. The crystalline Form-I of Terbinafme according to claim 13, having an Infrared absorption spectrum substantially as shown in Figure-6.

18. The crystalline Form-I of Terbinafine according to claim 13, having DSC substantially as shown in Figure-7.

19. Process for the preparation of Crystalline Form-I of Terbinafine base compound of formula-3 comprises of the following, a) Reacting the compound of formula-7 free of compound of formula- 10

CH₃

H₃C-C-C≡C— CH=CH-CH₂ Cl CH₃

Formula-7 with naphthalene compound of formula-8

Formula-8 in presence of mild base like sodium carbonate, potassium carbonate, sodium bicarbonate, preferably sodium carbonate and in a suitable polar solvents like dimethyl formamide, dimethyl acetamide, dimethylsulfoxide and water, preferably water at a temperature of about 35-95°C, preferably at a temperature of about 75°C, b) Isolating the crystalline Form-I of Terbinafine by using a solvent selected from alcohols like methanol, ethanol and isopropanol, ketones like acetone, methylisobutylketone, methylethylketone, esters like ethyl acetate and isopropyl acetate, nitriles like acetonitrile.

20. The crystalline Terbinafine prepared according to claim 19 is free of Genotoxic impurity compound of formula-2.

21. The process according to claim 19 b) wherein the solvent used for isolation is selected from alcohols like methanol, ethanol and isopropyl alcohol and ketones like acetone, methylisobutylketone, methylethylketone, esters like ethyl acetate, isopropyl acetate, nitriles like acetonitrile.

22. A process for the preparation of Crystalline Form-I of Terbinafine compound of formula-3 comprises of the following; a) Dissolving the Terbinafine acid addition salts such as hydrochloride prepared as per the process described in the first and second aspect of the present invention, in a suitable polar solvent like water or chloro solvent like methylene chloride or mixtures thereof preferably mixture of water and methylene chloride, b) Adjusting the pH of the reaction mixture to 7.5-8 with aqueous sodium carbonate solution at 5-30°C, preferably at 10-25°C and most preferably at 15-2O⁰C, c) Extracting the aqueous layer with suitable chloro solvents like methylene chloride, chloroform preferably methylene chloride, d) Removing the solvent by evaporation, e) Adding a suitable solvent selected from alcohols like methanol, ethanol and isopropanol, ketones like acetone, methylisobutylketone, methylethylketone, esters like ethyl acetate and isopropyl acetate, nitriles like acetonitrile. f) Cooling the reaction mixture, g) Isolating the product by filtration, h) Drying the material to afford Form-I of Terbinafme.

23. The process according to claim 22 e), wherein the solvents used is selected from alcohols like methanol, ethanol and isopropanol, ketones like acetone, methylisobutylketone, methylethylketone, esters like ethyl acetate and isopropyl acetate, nitriles like acetonitrile.