FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
An improved process for the preparation of Terbinafine hydrochloride
2. APPLICANT (S)
(a) NAME: Dr. Manne Satyanarayana Reddy
(b) NATIONALITY': Indian.
(c) ADDRESS
Dr. Manne Satyanarayana Reddy MSN Laboratories Limited, Factory: Sy.No:317 & 323, Rudraram (Vil), Patancheru (Mdl), MEDAK (Dist), Andhra pradesh - 502329 India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which
it is to be performed.
4. CLAIMS (not applicable for provisional specification. Claims should start with the
preamble "I/We claim" on separate page)
5. DATE AND SIGNATURE (to be given at the end of last page of specification)
6. ABSTRACT OF THE INVENTION (to be given along with complete specification
on separate page)

Terbinafine, particularly in the form of the hydrochloride acid addition salt form, is known from e.g., EP 24587. It belongs to the class of allylamine antimycotics. It is commercially available under the trademark LamisilR. 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, terbinafine is a good antifungal agent used preferably against mycosis caused by dermathophytons on the skin and on the nail. Terbinafine 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 terbinafine may be related to the accumulation of squalene, which at high concentrations may be toxic to the fungus. The spectrum of activity of terbinafine in vitro embraces all dermatophytes of the genera Trichophyton, Epidermophyton and Microsporum.
Background of the Invention
Many processes for the preparation of Terbinafine hydrochloride has been developed and published. Few of the relevant processes discussed below.
US Patent No. 4755534 disclosed the process for the preparation of 6,6-dimethyl-hept-l-ene-4-yne-3-ol by reaction of 3,3-dimethyl-l-butyne with acrolein using n-butyllithium. The drawbacks of this process is usage of n-butyllithium is not preferable at commercial scale, which is highly pyrophoric and highly sensitive to air and moisture and transportation is also a big problem.
US Patent No. 6689913 published in 2004 describes a process which comprises reaction of 2-pivaloylfuran with hydrazide compounds to give hydrazone derivative. This
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hydrazone derivative on reaction with secondary amine and further reduction with sodiumborohydride and converting the base with hydrochloric acid gives Terbinafine HC1. The yields are very low, ranging from 15-40%. The process, is lengthy and not economical.
US Patent No. 6515181 describes a process which involves reaction of secondary amine of the formula (VII) with (E) 1,3-dichloropropene to give vinyl chloride of the formula (VIII). The vinyl chloride of formula (VIII) is converted to Terbinafine HC1 on reaction with tertiary butyl acetylene and copper iodide. The production of vinyl chloride of the formula (VIII) is expensive due to the use of expensive (E) 1,3-dichloropropene.

The process described in WO 01/28976 involving the reaction of 6,6-dimethyl-hept-l-ene-4-yne-3-ol with hydrochloric acid and subsequent reaction of mixture (cis/trans) 1-chloro 6,6-dimethyl-hept-2-ene-4-yne in methyl isobutyl ketone with secondary amine of the formula (VII) to give Terbinafine which is converted to its hydrochloride salt in methylisobutyl ketone. The yields reported are low (42-50%) hence process is not economical.
US Patent No. 6570044 describes the preparation of 6,6-dimethyl-hept-l-ene-4-yne-3-ol by reaction of ethylmagnesiumbromide with tertiarybutylacetylene and further reaction of tertiarybutylacetylide formed with acrolein. The preparation of grignard reagent ethylmagnesium bromide is done using a mixture of toluene and tetrahydrofuran and also the further reactions. The mixture of toluene and tetrahydrofuran give insoluble grignard reagent hence the yield is low.
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Apart from all the above problems, another major drawback of the prior art processes is that all the above processes for the preparation of Terbinafine hydrochloride leads to the formation of Genotoxic impurity of formula (II). This impurity (Genotoxic Impurity) derives from the original synthesis process that used acrolein and PCI5. This Impurity 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 L5178Y mouse lymphoma cells under the test conditions when standard mutagenicity criteria were applied in these studies.
So there is a need to develop a process which avoids all the above said problems.
Extenstive process research has been carried out to find out the origin of the Genotoxic impurity and to minimize or to avoid the formation of so called impurity in the reaction itself. Attempts were made to minimize the Genotoxic impurity by purifying the Terbinafine hydrochloride and found that the impurity percentage was not come down to the required level. Attempts were made to minimize the impurity level by distillation of Terbinafine free base and found that the impurity is more than 10 ppm, but as Terbinafine is a Nitrogen containing molecule, distillation is not preferable at industrial scale, because it forms N-Oxide which may be explosive while distillation. 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-dimethyM-chlorohept-2-ene-4-yne by distillation we found that the impurity level has come down to little extent at Terbinfine hydrochloride. So distillation of 6,6-dimethyl-l-chlorohept-2-ene-4-yne has not given good results with respect to this impurity. Further we went back to the earlier stage and more focused on that particular compound 6,6-dimethyl-l-heptene-4-yne-3-ol, distilled the 6,6-dimethyl-l-heptene-4-yne-3-ol and moved further two stages and prepared Terbinafine and found that the Genotoxic impurity was not detected. This clearly indicating that the source for the
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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 the structure. We thought it may be due to the acrolein compound which is used at grignard reaction and found that the origin for the formation of corresponding derivative of said Genotoxic impurity is at grignard reaction, and it has not been identified at this stage. As corresponding derivative of Genetoxic impurity was not detected at this stage (i.e., grignard reaction) and it is being converting into corresponding derivative of Genotoxic impurity in the next step and finally converting to the Genotoxic impurity at Terbinafine stage and it was analyzed by HPLC method.
After identifying the source of the impurity, our extensive process work has been carried out to arrest the formation of corresponding derivative of Genotoxic impurity at source itself. The main factors which influences the formation of corresponding derivative of Genotoxic impurity 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-butyllithium 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 depends on mole ratio of magnesium metal used for the preparation of ethyl magnesium bromide. The results are
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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.
* l Magnesium metal is used for the preparation of ethylmagnesium 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.
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Objective of the present invention
The main objective of the present invention is to provide a process for the preparation of Terbinafine hydrochloride of formula (I) which is substantially free from Genotoxic impurity of formula (II).
The another objective of the present invention is to provide a process for the preparation of Terbinafine which avoiding all the above said problems.
Yet another objective of the present invention is to provide a process for the preparation of Terbinafine which is eco-friendly, easy to scale up and cost effective process.
Disadvantages of the prior art processes
Ø 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.
Ø 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.
Ø Usage of hazardous phosphorous oxychloride in step 2 of the process leads to
high volumes of effluent.
Ø Usage of tetrahydrofuran as a single solvent in grignard reaction leads to thick
mass of grignard complex formation, which needs very slow addition of
acrolein this ultimately needs more time.
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Brief description of the Invention
The present invention relates to an improved process for the preparation of Terbinafine and its pharmaceutically acceptable salts, preferably hydrochloride, which is chemically known as (E)-N - (6, 6 - Dimethyl -2- hepten -4 yn -yl) - N-methyl -1-naphthalene Methanamine Hydrochloride compound of formula (I).
The present invention comprises of the following steps
a) Reacting 3,3-dimethylbutyne compound of formula (III) with acrolein compound of
formula (IV) in presence of proton-extracting agent selected from the group
consisting of an organometallic compound like grignard reagent in a suitable solvents
like ether solvents or chloro solvents or mixture of solvents gives the compound of
formula (V).
b) Treating the compound of formula (V) obtained from step (a) with an acid in a
suitable solvent gives the compound of formula (VI).
c) Reacting the compound of formula (VI) obtained from step (b) with the compound of
formula (VII) in presence of an alkali base and in a suitable polar solvent gives the
compound of formula (I).
d) Purifying the above obtained compound of formula (I) from step (c) using suitable
solvent selected from nitrile solvents, ester solvents, keto solvents, preferably nitrile
solvents more preferably acetonitrile.
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The another embodiment of the present invention is to provide a process for the preparation of Terbinafme Hydrochloride.
Which comprises of
a) Reacting the compound of formula (VI) with the compound of formula (VII) in
presence of an alkali base and in a suitable polar solvent gives the compound of
formula (I).
b) Isolating the compound of formula (I) using a solvent selected from keto solvents,
ester solvents and nitrile solvents, preferably keto solvents.
The process of the present invention is simple, cost effective environment friendly and commercially suitable over the prior art references.
Advantages over prior art processes
> Present invention provides the process for the preparation of Terbinafme
hydrochloride substantially free from Genotoxic impurity (i.e., below 5 ppm).
> Present invention avoids the usage of hazardous phosphorous oxychloride.
> Present invention avoids the usage of highly pyrophoric n-butyllithium.
> Present invention avoids using dimethyl formamide as a solvent.
> Cost effective process.
> Reduction of cycle time.
> Environment friendly and easy scale-up.
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Detailed description of the Invention
The present invention relates to an improved process for the preparation of Terbinafine and its pharmaceutically acceptable salts, preferably hydrochloride, which is chemically known as (E)-N - (6, 6 - Dimethyl -2- hepten -4 yn -yl) - N-methyl -1- naphthalene Methanamine Hydrochloride compound of formula (I).
The present invention comprises of the following steps
a) Reacting 3,3-dimethylbutyne compound of formula (III) with acrolein compound of formula (IV) in presence of proton-extracting agent selected from the group consisting of an organometallic compound like grignard reagent like ethyl magnesium bromide in a suitable solvents like ether solvents like tetrahydrofiiran 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 -50°C to -5°C, preferably at a temperature of about -45 to -35°C gives the compound of formula (V).
b) Treating the compound of formula (V) obtained from step (a) with an acid like hydrochloric acid or hydrobromic acid in a suitable solvent selected from nitrile
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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 (VI).
c) Reacting the compound of formula (VI) obtained from step (b) with the compound of
formula (VII) in presence of an mild alkali base like sodium cacbonate, potassium
carbonate, sodium bicarbonate, preferably sodium carbonate and in a suitable polar
solvent like dimethyl formamide, dimethyl acetamide, water, preferably water at a
temperature of about 35-95°C, preferably at a temperature of about 75°C gives the
compound of formula (I).
d) Purifying the above obtained compound of formula (I) from step (c) using suitable
solvent selected from nitrile solvents, ester solvents, keto solvents, preferably nitrile
solvents more preferably acetonitrile.
The another embodiment of the present invention is to provide a process for the preparation of Terbinafine Hydrochloride.
Which comprises of
a) Reacting the compound of formula (VI) with the compound of formula (VII) in
presence of an mild alkali base like sodium cacbonate, potassium carbonate, sodium
bicarbonate, preferably sodium carbonate and in a suitable polar solvent like dimethyl
formamide, dimethyl acetamide, 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 (I) 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.
Related substances by HPLC of Terbinafine hydrochloride is carried out to find out the level of Genotoxic impurity using a liquid chromatograph is equipped with variable wavelength Detector and integrator, Xterra RP18, 150x4.6 mm ID, 3.5p, or
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equivalent column, 1.0 ml/min flow rate at 280 nm, 20^1 injection 16 minutes run time and dilluent 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)
Brief description of the drawings :
• Figure-1 - HPLC Chromatograph of Terbinafine hydrochloride with 100 ppm
solution of Genotoxic Impurity.
• Figure-2 - HPLC Chromatograph of Terbinafine hydrochloride multiplot with
different injection ID's.
• Figure-3 - HPLC Chromatograph of Terbinafine hydrochloride.
• Figure-4 - HPLC Chromatograph of Terbinafine hydrochloride.
The present invention schematically represents as follows.
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The process described in the present invention were 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-dimethyM-heptene-4-yne-3-ol
Slowly added 83 grams of ethyl bromide at ambient temperature to a heterogeneous solution of 150 ml of tetrahydrofuran, 12.5 grams of magnesium and catalytic amount of Iodine. Stirred for 90 minutes at 45-65°C. Cooled the mass to -10°C and added 250 ml of methylene chloride. Slowly added 50 grams of 3,3-dimethylbutyne. Stirred for 90 minutes at -10°C. Cooled the mass farther to -30°C and acrolein slowly added to the mass. Stirred the reaction mixture at -30°C for 2.0 hours. Reaction mixture decomposed into chilled water. Separated the organic phase and aqueous phase. Extracted the aqueous phase twice with methylene chloride. Organic phase washed with water. Concentrated the organic phase below 50°C under reduced pressure to get title compound as a residue.
Yield: 75 grams
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Example-2
Preparation of 6,6-dimethyI-l-chIorohept-2-ene-4-yne
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 for 4 hours at 0-10°C. Further stirred the reaction mixture at ambient temperature for 5 hours. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with hexanes. Washed the hexanes layer with water and concentrated to get the title compound as a residue. Yield: 65 grams
Example-3
Preparation of (E)-N - (6,6 - Dimethyl -2- hepten -4 yn -yl) - N-methyl -1-naphthalene Methanamine Hydrochloride (Terbinafine hydrochloride)
60 gr of sodium carbonate is added to a solution of N-methyl naphthylmethyl amine (75 gr) and water (450 ml) at ambient temperature. Stirred the mass for 45 minutes at ambient temperature. Cooled the mixture to 10-15°C and slowly added 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 25-35°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 10-15°C. Slowly added hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 50°C. Hexanes added to the obtained crude and decanted thrice. Isolated the compound using acetone. The obtained compound purified using acetonitrile as a solvent.
Yield 75 gr.
ExampIe-4
Preparation of (E)-N - (6,6 - Dimethyl -2- hepten -4 yn -yl) - N-methyl -1-naphthalene Methanamine Hydrochloride (Terbinafine hydrochloride)
60 gr of sodium carbonate is added to a solution of N-methyl naphthylmethyl amine (75 gr) and water (450 ml) at ambient temperature. Stirred the mass for 45 minutes at ambient temperature. Cooled the mixture to 10-15°C and slowly added 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 25-35°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 10-15°C. Slowly added hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 50°C. Isolated the compound using acetone. The obtained compound purified using acetonitrile as a solvent.yield 75 gr.