Claims:1. An improved process for the preparation of Amorolfine base compound of formula-I and its hydrochloride salt Amorolfine HCl of formula-Ia, comprising the steps of:

(a) reacting a benzaldehyde compound of formula-II with a propinaldehyde compound of formula-III to obtain a-methyl cinnamaldehyde compound of formula-IV;

(b) reacting a-Methylcinnamaldehyde compound of Formula-IV obtained in step (a) with Cis 2,6-dimethyl morpholine compound of formula-V to obtain Bepromoline base compound followed by treating with ethyl acetate solution of hydrochloric acid (HCl) to obtain Bepromoline hydrochloride compound of formula-VI;

(c) reacting Bepromoline hydrochloride compound of formula-VI obtained in step (b), with 3-methyl-2-butanol compound of formula VII in presence of a catalyst at -20 to 0°C to obtain Amorolfine base compound of formula-I;

(d) optionally, treating Amorolfine base compound of formula-I obtained in step (c) with hydrochloric acid (HCl) in presence of isopropyl alcohol to obtain highly pure Amorolfine HCl compound of formula-Ia.

2. The process as claimed in claim 1, wherein the reaction of step (b) is carried out in presence of palladium catalyst (Pd/C) and simple hydrogen gas (H2).

3. The process as claimed in claim 1, wherein the reaction of step (b) is carried out in a solvent selected from the group consisting of Non-polar organic solvents comprising Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether, Polar aprotic organic solvents comprising Tetrahydrofuran, Ethyl acetate Dimethylformamide, Acetonitrile and Dimethyl sulfoxide, Polar protic organic solvents comprising Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water.

4. The process as claimed in claim 3, wherein the solvent is toluene.

5. The process as claimed in claim 1, wherein the reaction of step (c) is carried out in a solvent selected from the group consisting of Non-polar organic solvents comprising Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether, Polar aprotic organic solvents comprising Tetrahydrofuran, Ethyl acetate Dimethylformamide, Acetonitrile and Dimethyl sulfoxide, Polar protic organic solvents comprising Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water.

6. The process as claimed in claim 5, wherein the solvent is dichloromethane (DCM).

7. The process as claimed in claim 1, wherein the catalyst in step-(c) is selected from the group consisting of sulphuric acid, hydrochloric acid, nitric acid and phosphoric acid.

8. The process as claimed in claim 7, wherein the catalyst is sulphuric acid.

9. The process as claimed in claim 1, wherein the HPLC purity of the Amorolfine HCl obtained from the process is more than 99.6% or more.

10. The process as claimed in claim 1, wherein the Fenpoprimorph (FPM) impurity in the Amorolfine HCl obtained from the process is 0.15% or less.

11. A process for preparation of Amorolfine Base (AMF Base) compound of formula-I, comprising the step of reacting a Bepromoline hydrochloride compound of formula-VI with 3-methyl-2-butanol compound of formula VII in presence of a catalyst at -20 to 0°C to obtain Amorolfine base compound of formula-I.

12. The process as claimed in claim 11, wherein the reaction is carried out in a solvent selected from the group consisting of Non-polar organic solvents comprising Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether, Polar aprotic organic solvents comprising Tetrahydrofuran, Ethyl acetate Dimethylformamide, Acetonitrile and Dimethyl sulfoxide, Polar protic organic solvents comprising Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water.

13. The process as claimed in claim 12, wherein the solvent is dichloromethane (DCM).

14. The process as claimed in claim 11, wherein the catalyst is selected from the group consisting of sulphuric acid, hydrochloric acid, nitric acid and phosphoric acid.

15. The process as claimed in claim 14, wherein the catalyst is sulphuric acid.

16. The process as claimed in claim 11, wherein the Amorolfine Base (AMF Base) obtained from the process is further treated with hydrochloric acid (HCl) in presence of isopropyl alcohol to obtain highly pure Amorolfine HCl salt.

17. The process as claimed in claim 16, wherein Amorolfine HCl salt obtained by the process has HPLC purity 99.6% or more and Fenpropimorph (FPM) impurity 0.15% or less .
, Description:FIELD OF INVENTION
The invention relates to a process for the preparation of antifungal morpholine compound Amorolfine base of Formula-I and/or its pharmaceutically acceptable hydrochloride salt of Formula-Ia. More particularly, the invention relates to an improved process for the preparation of Amorolfine Base which is further converted into the Active Pharmaceutical Ingredient (API) Amorolfine Hydrochloride. The Amorolfine Hydrochloride obtained by the process has high purity (HPLC) of 99.6% or more and reduced impurities like Fenpropimorph (tert butyl impurity) to as low as 0.15% or less and starting material impurity as low as 0.15% or less.

Formula-I Formula-Ia

BACKGROUND OF THE INVENTION
Amorolfine (AMF Base), chemically Cis-(2R,6S)-2,6-dimethyl-4-{2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl}morpholine and structurally represented by morpholine compound of formula-I below, is usually used as an Active Pharmaceutical Ingredient (API) in its pharmaceutically acceptable hydrochloride salt form. Amorolfine Hydrochloride (AMF HCl), chemically Cis-(2R, 6S)-2,6-dimethyl-4-{2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl}morpholine hydro-chloride and structurally represented by morpholine compound of formula-Ia below is fungicidal, generally used as an API in topical antimycotic compositions.

Formula-I Formula-Ia
Amorolfine Base (AMF Base) Amorolfine Hydrochloride (AMF HCl)

Many processes for the synthesis of Amorolfine Base (AMF Base, Formula-I) and AMF HCl (Formula-Ia) have been reported so far in prior arts; however achieving highly pure API with minimum amount of impurities with a simplified process still remains a need.

In the prior art processes it has been seen that during the synthesis of AMF Base and/or AMF HCl, the final product(s) contain impurities such as Bepromoline (BPM) Base/HCl, Fenpropimorph (FPM) Base/HCl and/or trans-isomers. For the pharmaceutical use, purity of the API is very crucial and impurity level should always be within the recommended regulatory standards. In order to achieve purity of the API within specified levels, the API obtained by a process is further purified by an additional process leading to increase in time, cost and use of chemicals leading the process industrially unviable.

Impurity Fenpropimorph HCl (FPM HCl) as presented in formula-X below is a principal impurity which remains present in the final product AMF HCl during the synthesis by the prior art processes.

Fenpropimorph HCl
Formula-X
(Tert-butyl Impurity)

In the prior art processes for synthesis of AMF HCl, purification of AMF Base is done before proceeding to next step of conversion of AMF Base to AMF HCl. This purification of AMF Base is necessary to minimise FPM HCl impurity in the final product. Conventionally, the purification is done by use of techniques such as reduced pressure distillation which is difficult to perform at large scale and also increases the cost of synthesis. Alternatively chromatographic method is applied to remove impurity FPM HCl to purify final product AMF HCl.

Hoffmann-La Roche in the prior art patent publication FR 2,463,767 (EP0024334 or CA1128943) describes multiple processes for the synthesis of AMF Base of formula-I and its HCl salt of formula-Ia. Particularly in the process variant (c) of the said prior art AMF Base is synthesized through Friedel Crafts Alkylation by reacting Bepromoline (BPM) with a compound of general formula-a as shown below (please refer page-3 of CA1128943):

BPM Formula-a Formula-I (AMF Base)

In the above said synthetic method Sulfuric acid is chosen as a preferred catalyst. The temperature at said alkylation step is not critical but generally mentioned as 0°C to 50°C, preferably between 18-20°C (page-6 of CA1128943). Preferred compound of general formula-a yielding carbonium ions are corresponding tertiary alcohols such as 2-methyl-2-butanol or tertiary alkyl halides such as 2-chloro-2-methyl-butane (page-7 of CA1128943). Example-3 of this prior art patent publication describes detailed procedure taking 2-methyl-2-butanol as formula-a for synthesis of AMF Base wherein in the process to BPM, methylene chloride is added drop wise at -5°C, then conc. sulphuric acid and 2-methyl-2-butanol are added. The solution is then treated with water while cooling with ice and the aqueous phase is extracted several times with methylene chloride and subsequently with water, dried, evaporated and the oily AMF Base is distilled at low-pressure distillation (vacuo) with a boiling point of 120°C /0.1 Torr.

Gladerma S.A. in International Patent Publication WO2007012983 describes a process for synthesis of AMF Base by contacting Bepromoline HCl with FeCl3 as catalyst and then adding 2-chloro-2-methylbutane as shown below:

The halogen in 2-halogeno-2-methylbutane is selected from Br, Cl, I or F. The above method after above said steps further comprises one or more steps to for obtaining AMF Base wherein the further steps includes Distillation. Example 2 and Example 3 of this prior art respectively describes the synthesis of crude AMF Base and distillation of crude AMF Base.

This method produces crude AMF Base with a yield of 90%, which after distillation produces 67% AMF Base distilled.
This prior art document mentions FPM as a problematic by-product and difficult to remove from the final product. To decrease the quantity of FPM in final product, the above reaction is performed at low temperature, preferably at -50 °C. Further this prior art mentions that purification of crude AMF Base by distillation is a necessary step (Example-3 of this prior art) to obtain purified AMF Base final product which is performed at 0.1-4.0 mbar at temperature 140-180°C and thus produces 67% AMF Base after distillation. Thus there is a need of additional distillation step in order to get highly pure AMF Base, which is not an industrially economical process at large scale production. After this additional distillation step, the purified AMF Base is then treated with HCl gas to produce AMF HCl with 77% yield. Crystallization with ethanol is performed to reduce the impurities in end product. Impurities BPM, FPM and Trans Isomers present in different final products produced by the process of this prior art are as presented below-

Though the quantity of all impurities as mentioned above are within the limit of required specifications, this is achieved only after performing the reaction at -50°C, performing additional step of distillation and also crystallization with ethanol. Before distillation, for AMF Base and AMF HCl crude, the amount of BPM, FPM and Trans-Isomers are much higher than the acceptable specified ranges and hence the distillation is essential in the said prior art process.

Synteco S.P.A. in the International Publication WO2010094739 emphasized that purification need to be performed at the AMF base stage and describes the pressure reduced distillation step as only efficient method being performed at the AMF Base production stage in above prior art WO2007012983, which is difficult at large scale; and came up with a purification process (reverse phase preparative high performances liquid chromatography (prep-HPLC)) to produce AMF HCl with HPLC purity grade more than 99.5%. In this process also the AMF HCl is prepared by two steps as follows:
(i) Obtaining crude AMF Base by
- Reaction of BPM HCl with 2-chloro-2-methylbutane using Friedel Crafts catalyst FeCl3 or AlCl3, or
- 2-methyl-2-butanol using conc. sulphuric acid as the Friedel Crafts catalyst; and
(ii) then the crude AMF Base as obtained in above step is treated with HCl.
Thus from the above described prior arts processes it is clear that the impurities such as BPM, FPM or trans isomers are difficult to reduce during the production stage and for its control reduced temperature such as -50 °C, additional distillation and further HPLC purification steps are being required to limit the level of impurities within specified level pharmaceutically acceptable.

Since these additional steps to get highly purified end products with higher yield are industrially not cost effective and time consuming, further there is a need of a simplified process for the production of AMF Base as well as AMF HCl with purity level more than 99.5% with higher products yields without use of further distillation step and/or HPLC purification and extremely low temperature such as -50 °C.

The inventors of the present invention are able to develop an improved process for the synthesis of AMF Base (formula-I) as well as AMF HCl (formula-Ia), which neither requires further in-process reduced pressure distillation step at the stage of AMF Base preparation to improve purity of final AMF HCl nor requires final HPLC purification process to achieve highly pure AMF HCl. The process reduces the amounts of impurities formation in the final product.

OBJECT OF THE INVENTION

The primary object of the invention is to provide an improved, simplified cost-effective, time efficient and industrially viable process for the synthesis of highly pure Amorolfine base (AMF Base).
Another object of the invention is to provide an improved, simplified cost-effective, time efficient and industrially viable process for the synthesis of highly pure Amorolfine Hydrochloride (AMF HCl).

A further object of the invention is to provide an improved process for the preparation of highly pure AMF HCl with reduced tert-butyl impurity (FPM) without use of additional reduced pressure distillation or HPLC purification steps.

Yet a further object of the invention is to provide an improved process for the preparation of AMF HCl with purity level of 99.6% (HPLC) or more.

Another object of the invention is to provide an improved process for the preparation of AMF HCl with Fenpropimorph (tert butyl impurity) to as low as 0.15% or less and starting material impurity also as low as 0.15% or less.

SUMMARY OF THE INVENTION
Accordingly the present invention provides an improved process for the preparation of antifungal compound Amorolfine Base (AMF Base, Formula-I) and/or its pharmaceutically acceptable hydrochloride salt Amorolfine hydrochloride (AMF HCl, Formula-Ia) with high purity and high yield, wherein the process minimizes process impurities such as FPM, trans isomers.

Formula-I Formula-Ia

In one aspect, the present invention provides an improved process for the preparation of Amorolfine base (AMF Base, formula-I) and/or its hydrochloride salt compound of formula Ia (AMF HCl), comprising the steps of:

(a) reacting a benzaldehyde compound of formula-II with a propinaldehyde compound of formula-III to obtain a-methyl cinnamaldehyde compound of formula-IV;

(b) reacting a-Methylcinnamaldehyde compound of Formula-IV obtained in step (a) above, with Cis 2,6-dimethyl morpholine compound of formula-V in presence of a catalyst in combination with a hydrogenating reagent and in presence of a solvent to initially obtain Bepromoline base compound of formula-VI (base), followed by further treating with ethyl acetate solution of hydrochloric acid (HCl) to obtain Bepromoline hydrochloride compound of formula-VI;

(c) reacting Bepromoline hydrochloride compound of formula-VI obtained in step (b) above, with 3-methyl-2-butanol compound of formula VII in presence of a catalyst at -20 to 0°C to obtain AMF base compound of formula-I, wherein the solutions compounds of formula-VI and formula-VII are prepared in a solvent;

(d) optionally, treating AMF Base compound of formula-I obtained in step (c) above, with hydrochloric acid (HCl) in presence of solvent isopropyl alcohol (IPA) to obtain highly pure AMF HCl compound of formula-Ia.

The catalytic hydrogenation (step-b) is carried out by using palladium catalyst (Pd/C) with combination of hydrogenating reagents like ammonium formate, ammonium acetate or simple hydrogen gas (H2). The solvent in step-(b) may be selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water etc. Preferably the said hydrogenating reagent in step-(b) is simple hydrogen gas; and the said solvent in step-(b) is toluene.

The said solvent in step-(c) may be selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate, Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water etc. The said solvent in step-(c) for preparing solutions of both compounds of formula-VI and formula-VII is dichloromethane (DCM) wherein the said solution of 3-methyl 2-butanol (formula-VII) is added drop wise to the mixture comprising compound of formula-VI at temperature range -20 to 0 °C.

The said catalyst in step-(c) may be selected from acid catalysts such as sulphuric acid, hydrochloric acid, nitric acid and phosphoric acid etc. Preferably the said catalyst in step-(c) is sulphuric acid (H2SO4), which is added drop wise to the solution of formula-VI at temperature range -20 to 0 °C.

The said solvent in step-(d) is isopropyl alcohol (IPA).

In one preferred embodiment, the above said process for preparation of Amorolfine base (AMF Base) compound of formula-I or its hydrochloride salt compound (AMF HCl) of formula-Ia, comprises the following steps:

(a) reacting a benzaldehyde compound of formula-II with a propinaldehyde compound of formula-III in presence of NaOH and a mixture of water/MeOH to obtain a-methylcinnamaldehyde compound of formula-IV;
(b) reacting a-Methylcinnamaldehyde compound of Formula-IV obtained in step (a) above, with Cis 2,6-dimethyl morpholine compound of formula-V in presence of catalyst Pd/C under nitrogen, hydrogen gas and toluene to initially obtain Bepromoline base of formula-VI (base), followed by further treating with ethyl acetate solution of hydrochloric acid (HCl) to obtain Bepromoline hydrochloride of formula-VI;
(c) reacting solution of Bepromoline hydrochloride of formula-VI obtained in step (b) above, with solution of 3-methyl-2-butanol compound of formula VII in presence of sulphuric acid (H2SO4) at a temperature range of -20 to 0°C to obtain AMF base compound of formula-I, wherein the solution of compounds of formula-VI and formula-VII are prepared by solvent dichloromethane (DCM);
(d) optionally, treating AMF Base compound of formula-I obtained in step (c) above, with HCl in presence of solvent isopropanol (IPA) to obtain highly pure AMF HCl compound of formula-Ia.

The process provides AMF HCl with purity (HPLC) 99.6% or more and reduces amounts of Fenpoprimorph (FPM) impurity and limits FPM to 0.15% or less without use of additional reduced pressure distillation or HPLC purification steps.

In another aspect, the present invention provides a process for the preparation of Amorolfine Base (AMF base, formula-I), wherein the said process comprises the following reaction step-(a):
(a) reacting Bepromoline hydrochloride compound of formula-VI with 3-methyl-2-butanol compound of formula VII to obtain AMF base compound of formula-I.

In a further aspect, the present invention provides a process for the preparation of Amorolfine HCl (AMF HCl, formula-Ia) wherein the process comprises reacting Bepromoline hydrochloride compound of formula-VI with 3-methyl-2-butanol compound of formula VII to obtain AMF base compound of formula-I followed by treatment with HCl to produce highly pure AMF HCl compound of formula-Ia.

The above reaction proceeds in presence of a solvent selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water etc.; preferably DCM and in presence of a catalyst selected from acid catalysts such as sulphuric acid, hydrochloric acid, nitric acid and phosphoric acid etc; preferably sulphuric acid (H2SO4).

In another embodiment, the invention provides a process of using 3-methyl-2-butanol compound of formula-VII for preparations of AMF Base compound of formula-I and AMF HCl compound of formula-Ia.
(Formula-VII)

DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention relates to an improved process for the preparation of antifungal compound Amorolfine Base (AMF Base, Formula-I) and its pharmaceutically acceptable hydrochloride salt Amorolfine hydrochloride (AMF HCl, Formula-Ia) with high purity and high yield, wherein the process minimizes process impurities such as FPM, starting material and trans isomers; and does not require additional steps for purification such as reduced pressure distillation at the stage of AMF Base production and HPLC methods for the purification of AMF HCl; and hence the process is cost-effective, time efficient and easy to perform at industrial scale. The HPLC purity of final product AMF HCl as obtained by the present process is 99.6% or more comprising significantly reduced amount of FPM impurity (0.15% or less). The present process also avoids extreme low temperature such as -50°C which is used in prior arts in order to avoid and minimize FPM impurity at the stage of AMF Base production.

Formula-I Formula-Ia

The synthetic Scheme-1 below represents process steps of the present invention comprising process stage-I to stage-III for the synthesis of AMF Base. The AMF base as produced by stages-I to III may be further converted to its hydrochloride salt by treatment with HCl. Process stage-I to stage-IV represents the synthesis of AMF HCl.

In the first aspect, the present invention provides a process for the preparation of AMF Base (formula-I) and subsequently AMF HCl (formula-Ia) from fromula-I comprising the steps of:
(a) reacting a benzaldehyde compound of formula-II with a propinaldehyde compound of formula-III to obtain a-methyl cinnamaldehyde compound of formula-IV;

(b) reacting a-Methylcinnamaldehyde compound of Formula-IV obtained in above step (a) with Cis 2,6-dimethyl morpholine compound of formula-V in presence of a catalyst in combination with a hydrogenating reagent and in presence of a solvent to initially obtain Bepromoline base compound of formula-VI (base) followed by further treating with hydrochloric acid (HCl) to obtain Bepromoline hydrochloride compound of formula-VI;

(c) reacting Bepromoline hydrochloride compound of formula-VI obtained in step (b) above, with 3-methyl-2-butanol compound of formula VII in presence of a catalyst at a temperature range of -20 to 0°C to obtain AMF base compound of formula-I, wherein the solution of compounds of formula-VI and formula-VII are prepared in a solvent;

(d) optionally, treating AMF Base compound of formula-I obtained in step (c) above, with HCl in presence of a solvent to obtain highly pure AMF HCl compound of formula-Ia.

The above process provides AMF HCl with a HPLC purity level of 99.6% or more and comprises tert butyl impurity (FPM) 0.15% or less.

The details of the process stages I-IV as shown in the above synthetic Scheme-1 and steps (a) to (d) of above process are further elaborated in following paragraphs.

Stage-I (step-a): Preparation of alpha a-Methylcinnamaldehyde (Formula-IV)
In this step-(a), benzaldehyde compound of formula-II reacts with propinaldehyde compound of formula-III to produce a-methyl cinnamaldehyde compound of formula-IV.

This particular process step is known in the art and can be prepared accordingly by known process. The detailed process of this known step (a) is as described in example-1 of the present invention as presented in below paragraph.

Stage-II (step-b): Preparation of Bepromoline HCl (Formula-VI)
Stage-II comprises the process step of reaction of a-Methylcinnamaldehyde compound of Formula-IV as formed in above stage-I, with Cis 2,6-dimethyl morpholine compound of formula-V in presence of a catalyst, hydrogenating reagent and a solvent to initially give Bepromoline base compound, which on further treatment with hydrochloric acid in presence of a solvent provides Bepromoline hydrochloride compound of formula-VI.

In step-(b) the catalytic hydrogenation is carried out by using palladium catalyst (Pd/C) with combination of hydrogenating reagents like ammonium formate, ammonium acetate and simple hydrogen gas (H2). Preferably the said hydrogenating reagent in step-(b) is simple hydrogen gas. Catalyst is palladium catalyst (Pd/C) which is added to the reaction mixture under nitrogen. Pressure is applied through hydrogen gas. Generally pressure of hydrogen applied is 5.0 kg/cm2 followed by stirring for 10 to 20 hrs, preferably it is stirred for 12-15 hrs.

The solvent in step-(b) may be selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water. Preferably the solvent selected in step (b) is toluene.

After completion of the reaction, applied hydrogen pressure is released and catalyst is filtered followed by distillation of the solvent under reduced pressure to obtain the residue Bepromoline base.

Step-(b) further comprises treatment of the Bepromoline base compound thus obtained above with HCl in presence of a solvent is to convert the base to Bepromoline HCl compound of formula-VI. The solvent used in this conversion of Bepromoline base to Bepromoline HCl may be selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water. Preferably solvent ethyl acetate is used during conversion of Bepromoline base to Bepromoline HCl. Solution of HCl in ethyl acetete is added drop wise below temperature of 45 °C.

After further follow up, the solid can be separated, filtered and washed with a solvent ethyl acetate. The obtained product may be recrystallized from a solvent to obtain highly pure Bepromoline HCl compound of formula-VI. The recrystallizing solvent may be selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate, Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water. Preferably the recrystallizing solvent in step (b) is ethyl acetate.

In one preferred embodiment of the invention, the stage-II (step-b) comprises reaction of compound of Formula-IV with compound of formula-V in solvent toluene, in presence of catalyst Pd/C under nitrogen and then hydrogen pressure is applied and stirred for 12-15 hrs, to initially obtain Bepromoline base compound, which on further treatment with solution of hydrochloric acid in ethyl acetate provides Bepromoline hydrochloride compound of formula-VI, which is washed and recrystalized with ethyl acetate to obtain pure compound of formula-VI.

In a preferred embodiment, the above step-(b) of the process produces Bepromoline HCl with HPLC purity level of 99.94% comprising 0.06% of Trans-isomers.

Stage-III (step-c): Preparation of Amorolfine Base (Formula-I)
Stage-III of the process comprises preparation of Amorolfine base compound of formula- I from compound of formula-VI thus obtained in stage-II (step-b).

In this stage, solution of compound of formula-VI in a solvent reacts with solution of 3-methyl-2-butanol compound of formula VII in presence of a catalyst at a temperature range of -20 to 0°C.

The solvent for preparing above said solutions of compounds of formula-VI and formula-VII in step-(c) may be selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate, Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water etc. Preferably the solvent for preparing solutions of both compounds of formula-VI and formula-VII is DCM.

The catalyst in step-(c) may be selected from acid catalysts such as sulphuric acid, hydrochloric acid, nitric acid and phosphoric acid etc, preferably the catalyst selected and used is in step-(c) is sulphuric acid (H2SO4). The catalyst is added drop wise to the solution of compound of formula-VI at temperature -20 to 0°C over a period of 40-50 min.

After this, temperature is raised to -10°C before addition of solution of compound of formula-VII to the above formed mixture of compound of formula-VI and catalyst; followed by addition of solution of compound of formula-VII. The solution of 3-methyl 2-butanol (formula-VII) is added drop wise to the reaction mixture at temperature range -20 to 0°C over period of 8.0 hrs.

Then after completion of reaction, the mass is cooled by cold water followed by stirring at 20-25°C and bottom organic layer is separated. Then solution of sodium hydroxide in DM water is added to the organic layer drop wise at room temperature. The organic layer is separated and is washed with aqueous sodium hydroxide solution fallowed by water. Then dried and concentrated under reduced pressure to obtain crude Amorolfine base (formula-I).

In a preferred embodiment of the invention the step-(c) comprises reaction of solution of compound of formula-VI in DCM with solution of 3-methyl-2-butanol compound of formula VII in DCM in presence of catalyst sulphuric acid (H2SO4) at a temperature range of -20 to 0 °C.

In the prior art processes using 2-methyl-2-butanol and/or 2-chloro-2-methylbutane, the AMF Base produced requires reduced pressure distillation process in order to minimize the FPM impurity. Performing distillation under reduced pressure is difficult for large scale production, time consuming and industrially not economical as it increases the time and labour.

Further prior art processes at this stage of AMF base production require extreme low temperature such as -40 to -60°C, preferably -50°C to minimize the FPM impurity. Performing reaction at such extreme low temperature is a difficult task and is usually not feasible for large scale industrial production.

The inventors of the present invention now able to provide a solution of above mentioned problems of prior art processes by the process step as described in step-(c) of the present invention and thus avoids above mentioned disadvantageous step or process conditions of prior arts such as reduced pressure distillation process and extremely low temperature such as -50°C to reduce and minimize FPM impurity at this stage of production of AMF Base.

The present process at this stage-III does not require distillation or purification of crude AMF Base. The crude AMF Base thus obtained by the process step-(c) of the present invention subsequently proceeds to next step (d) without purification. Thereby the difficulty, extra time, labour and cost as incurred by the prior art process has been avoided by the inventors of the present invention by the process as described above in step-(c) and results in a simplified process producing highly pure AMF HCl with minimal amount of FPM impurity in next step.

Stage-IV (step-d): Conversion of Amorolfine Base to Amorolfine HCl (Formula-Ia)

In this stage-IV, to a solution of crude Amorolfine base compound of formula-I formed in stage-III above, IPA.HCL is added drop wise at below 40 °C followed by cooling the mass to 0-5 °C and stirring for 4-5 hrs at same temperature to obtain final AMF HCl compound of Formula-Ia. The solution of AMF Base can be prepared by using solvent isopropanol (IPA). Solid formed is separated, filtered and washed with chilled IPA.

Purification is performed by recrystllizing the isolated compound from alcoholic solvent such as methanol, ethanol, isopropanol (IPA), butanol etc. to get pure Amorolfine hydrochloride (AMF HCl). Preferably solvent IPA is used for recrystallization to obtain highly pure AMF HCl.

In a preferred embodiment the present process at this final stage produces highly pure AMF HCl (99.6% or more HPLC) and limits the tert-butyl impurity to 0.15% or less.

In the second aspect, the present invention provides a process for the preparation of AMF base compound of formula-I comprising the following step of reaction in the process:
(a) reacting Bepromoline hydrochloride compound of formula-VI with 3-methyl-2-butanol compound of formula VII in presence of a solvent and a catalyst at a temperature range of -20 to 0 °C to obtain AMF base compound of formula-I.

In the third aspect, the present invention provides a process for the preparation of AMF HCl compound of formula-Ia comprising the following step of reaction in the process:

(a) reacting Bepromoline hydrochloride compound of formula-VI with 3-methyl-2-butanol compound of formula VII in presence of a solvent and a catalyst at a temperature range of -20 to 0 °C to obtain AMF base compound of formula-I followed by treatment with HCl in presence of IPA to produce highly pure AMF HCl compound of formula-Ia.

The final product as obtained by the above process of third aspect, after recrytsallization AMF HCl produced is of purity (HPLC) level of 99.6% or more with FPM impurity content 0.15% or less.
In any of the above mentioned second and third aspects, the solvent solution of formula-VI in a solvent reacts with solution of 3-methyl-2-butanol compound of formula VII in presence of a catalyst at a temperature range of -20 to 0 °C. The solvent for preparing above said solutions of compounds of formula-VI and formula-VII may be selected from Non-polar organic solvents such as Hexane, Cyclohexane, Benzene, 1,4-Dioxane, toluene, Chloroform, dichloromethane (DCM) and Diethyl ether; Polar aprotic organic solvents such as Tetrahydrofuran, Ethyl acetate, Dimethylformamide, Acetonitrile and Dimethyl sulfoxide; Polar protic organic solvents such as Isopropanol, n-Propanol, Ethanol, Methanol, Acetic acid and Water etc. Preferably the solvent for preparing solutions of both compounds of formula-VI and formula-VII is DCM. The catalyst may be selected from acid catalysts such as sulphuric acid, hydrochloric acid, nitric acid and phosphoric acid etc,; preferably the catalyst selected and used is sulphuric acid (H2SO4). Preferably the catalyst H2SO4 is added drop wise to the solution of formula-VI at temperature -20 to 0 °C over a period of 40-50 min, preferably at -20 to -16 °C. The solution of 3-methyl 2-butanol of formula-VII is added drop wise to the reaction mixture at -20 to 0 °C over period of 8.0 hrs.

In a preferred embodiment of the invention any of the above said processes of second and third aspects, the process comprises reaction of solution of formula-VI in DCM with solution of 3-methyl-2-butanol compound of formula VII in DCM in presence of catalyst sulphuric acid (H2SO4) at a temperature range of -20 to 0°C.

In the fourth aspect, the present invention further provides use of the reagent 3-methyl-2-butanol compound of formula-VII in the process for preparation of AMF Base of formula-I and AMF HCl of formula-Ia.

(Formula-VII)
Without limiting the scope of the present invention, the process of the present invention is further explained by the way of following examples.

EXAMPLES
Example 1: Synthesis of a-methyl cinnamaldehyde (Formula-IV)

Formula-II Formula-III Formula-IV

To a solution of Sodium hydroxide (39.2 g) in mixture of water (785 ml) and methanol (785 ml), benzaldehyde (formula-II) (500 gm) was added at 25-30 °C. Then reaction mass was heated to 50 °C and propinaldehyde (formula-III) (136.6 g) was added drop wise at same temperature over period of 5-6 hrs. Total reaction mass was stirred for 1.0 hr at same temperature. After completion of the reaction, the reaction mass was cooled to 25-30 °C and the pH was adjusted to 7.0-7.5 with acetic acid. Then the bottom organic layer was separated and the aqueous layer was again extracted with 200 mL of DCM. Combined organic layer was dried with sodium sulphate and distilled out completely under vacuum to get crude residue (Weight of the residue 570 gm). Crude residue was purified by high vacuum distillation. In fraction-I the excess benzaldehyde was recovered and in fraction-II, 260 gm of a-methyl cinnamaldehyde (formula-IV) was collected.

Example 2: Synthesis of Bepromoline HCl (formula-VI)

Formula-IV Formula-V Formula-VI

To a solution of a-methyl cinnamaldehyde (200 gm) (formula-IV as obtained in Example-1 and Cis 2,6-dimethyl morpholine (formula-V) (173.3 gm) in Toluene (1.6 lit) 7.0 gm of 5% Pd/C (7.0 g) was added under nitrogen in 5.0 lit autoclave at RT. Then 5.0 kg/cm2 hydrogen pressure was applied and stirred for 12-15 hrs at the same temperature. Reaction was monitored by TLC. After completion of the reaction, hydrogen pressure was released and the catalyst was filtered through hyfow bed. Toluene was distilled out completely under reduced pressure to get the residue (Bepromoline Base). Weight of the residue was 290 gm.

Above residue was dissolved in 391 mL of ethyl acetate at RT. 309 ml of 18% HCl in Ethyl acetate was added drop wise below 45 °C into 3.0lit RBF. After completion of the addition, total reaction mass stirred for 2.0 hrs at 25-30 °C. Solid separated was filtered and washed with 150 ml Ethyl acetate. Wet compound was recrystllized from ethyl acetate to get pure material (Bepromoline HCl (formula-VI)).

Dry weight 155 gm (purity by HPLC 99.94%, Trans: 0.01 & 0.05 %).

Example 3: Amorolfine hydrochloride (AMF HCl, formula-Ia)

1.Preparation of AMF Base (formula-I):
To a solution of 100 gm of Bepromoline HCl (formula-VI as obtained in Example-2) in 1500 mL of DCM, 404 gm of sulfuric acid was added drop wise at -20 to -16 °C over period of 40-50 min. Then reaction mass temperature was raised to -10 °C and then the solution of 3-methyl 2-butanol in DCM (49.7 gm dissolved in 800 mL DCM) was added drop wise at -12 to -16 °C over period of 8.0 hrs. After completion of the addition, the reaction mass was quenched into 1.5 lit of cold water and stirred for 30 min at 20-25 °C and the bottom organic layer was separated. Mean while lye solution was prepared by dissolving 50 gm sodium hydroxide in 500 ml DM water in another flask and was added to the above organic layer drop wise at room temperature. Combined layer stirred for 30 min and separated the bottom organic layer. Organic layer was again washed with 500 ml of 10 % aqueous sodium hydroxide solution fallowed by 2×500 ml of water. Dried the organic layer over the anhydrous sodium sulphate and concentrated under reduced pressure to get 72 gm of crude Amorolfine base (AMF Base, formula-I).

2.Preparation of AMF HCl (formula-Ia):
Above obtained crude Amorolfine base was dissolved in 144 mL of isopropanol and then 49 mL of 22% IPA.HCl was added drop wise below 40 °C. Then reaction mass was gradually cooled to 0-5 °C and stirred for 4-5 hrs at same temperature. Solid separated was filtered, washed with chilled IPA. Wet compound was recrystllized from isopropanol to get pure Amorolfine hydrochloride (AMF HCl, formula-Ia).

Dry weight of the compound 60 gm (purity by HPLC: 99.78%, tert butyl impurity: 0.051%, Starting Material: 0.028%).