DESC:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION

“PROCESS FOR THE PREPARATION OF EFINACONAZOLE”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO – Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai – 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention
The present invention relates to process of preparation of efinaconazole.
Background of the invention
Efinaconazole which is chemically known as (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is represented by a compound of formula I,

Efinaconazole marketed as JUBLIA® is a topical solution, 10% and is indicated for the topical treatment of onchomycosis of toenail (s) due to trichophyton rubrum and trichophyton mentagrophytes.
Various synthetic processes for preparation of efinaconazole are known in the art. The present invention provides a novel process for preparation of efinaconazole which provides a better purity profile and which can be easily performed on industrial scale.
Summary Of The Invention
The present invention provides a process for the preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [efinaconazole], a compound of formula I, comprising :

(a) reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l)methyl]oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof to obtain crude efinaconazole;
II III
(b) reacting the crude efinaconazole obtained from step ‘a’ with an acid selected from the group consisting of an inorganic acid, an organic carboxylic acid and an optically active acid to obtain reaction mixture containing acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;
(c) separating acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the reaction mixture; and
(d) converting the acid addition salt of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the present invention provides Di-toluoyl-D-tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VII or Di-toluoyl-L-tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound VIII.

In one embodiment, the present invention provides a process for the preparation of D- di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or L-di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol comprising reacting crude efinaconazole with D-di-toluoyl tartaric acid or with L di-toluoyl tartaric acid to obtain D- di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VII or L- di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VIII.
In one embodiment, the present invention provides a process for the preparation of (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, the compound of formula I comprising reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l)methyl] oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof in the presence of a Lewis acid.
In one embodiment, the present invention provides a method for preparing efinaconazole, or salt thereof, suitable for pharmaceutical use, comprising steps of:
(a) providing a batch of efinaconazole or a salt thereof;
(b)assessing the purity of said batch of efinaconazole or salt thereof, by using at least one compound selected from the group consisting of IX, X, II, V and VI as a reference marker to determine the level of the reference marker compound ; and
(c) selecting the batch of efinaconazole only if the percentage of the reference marker compound is less than 0.15% w/w as determined by HPLC

wherein in compound IX when i) R is 2,4-difluoro, G is selected from the group consisting of hydroxy, 4-methylenepiperidine-N-oxide and amino; ii) when G is 4-methylenepiperidine, R is selected from the group consisting of 4-fluorine and H.
In one embodiment, the present invention provides a method of assessing the purity of efinaconazole and pharmaceutical compositions thereof comprising steps of:
(a) providing a standard solution of at least one of the reference marker compound selected from the group consisting of IX, X, II, V and VI ; and

(b) using the solution as a reference marker to determine the level of the compound referece marker compound.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1: XRD pattern of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol according to example 6b.
Fig 2: XRD pattern of Di-L-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol according to example 6a.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) [efinaconazole], a compound of formula I comprising:
(a) reacting (2R,3S) -2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l)methyl]oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof to obtain crude efinaconazole;
II III
(b) reacting the crude efinaconazole obtained from step ‘a’ with an acid selected from the group consisting of an inorganic acid, an organic carboxylic acid and an optically active acid to obtain a reactio mixt containing an acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;
(c) separating the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the reaction mixture; and
converting the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the term ‘crude efinaconazole’ refers to efinaconazole obtained by reacting compound of formula II with compound of formula III or a salt thereof.
In one embodiment, the term ‘crude efinaconazole’ is defined as a substance wherein the content of impurities is greater than 0.5% w/w with respect to efinaconazole as determined by HPLC.
In one embodiment, the term ‘crude efinaconazole’ is defined as a substance wherein the content of chemical impurities is greater than 0.5% w/w with respect to efinaconazole as determined by HPLC.
In one embodiment, crude efinaconazole is defined as a substance wherein the content of (2S, 3S) isomer of efinaconazole, a compound of formula IV, and/or (2R,3S) isomer of efinaconazole, a compound of formula V and /or (2S,3R) isomer of efinaconazole, a compound of formula VI, is greater than 0.5% w/w with respect to efinaconazole as determined by HPLC.

In one embodiment, the content of (2S, 3S) isomer of efinaconazole, a compound of formula IV and/or (2R, 3S) isomer of efinaconazole, a compound of formula V and /or (2S, 3R) isomer of efinaconazole, a compound of formula VI, in the efinaconazole obtained by the above process is less than 0.5% w/w with respect to efinaconazole as determined by HPLC.
In one embodiment, in step ‘a’ of the above process the reaction of compound of formula II with the compound of formula III or a salt thereof is carried out in presence of a Lewis acid. The Lewis acid may be selected from the group consisting of lithium bromide, boron trifluoride etherate, zinc chloride, ferric chloride, aluminium chloride, lithium perchlorate and stannic chloride, copper(II) trifluoromethanesulfonate, zinc acetate, zinc trifluoromethanesulfonate. Preferably, the Lewis acid is lithium bromide.
In one embodiment, in step ‘a’ of the above process the reaction of compound of formula II with compound of formula III or a salt thereof is carried out in presence of a solvent.
In one embodiment, in step ‘a’ of the above process the reaction of compound of formula II with the compound of formula III or a salt thereof is carried out in presence of a Lewis acid in a suitable solvent to obtain crude efinaconazole. The solvent may be selected from the group consisting of chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride; ethers such as diethyl ether, methyl tertiary butyl ether, di-isopropyl ether, tetrahydrofuran ; nitriles such as acetonitrile, propionitrile; esters such as ethyl acetate, butyl acetate, isopropyl acetate; hydrocarbonssuch as, cyclohexane, toluene, xylene, hexane; alcohols such as methanol, ethanol, butanol, isopropanol, n-propanol; sulfoxides such as dimethyl sulfoxide; amides such as dimethyl formamide, dimethyl acetamide; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; water and or mixtures thereof. Preferably, the solvent is toluene.
In one embodiment, in step ‘a’ of the above process the reaction of compound of formula II with the compound of formula III or a salt thereof is carried out in presence of a phase transfer catalyst. The phase transfer catalyst may be selected from the group consisting of benzyltrimethylammonium chloride, hexadecyltributyl phosphonium bromide, tetrabutyl ammonium hydrogen sulphate, tetrabutylammonium bromide, methyltrioctyl ammonium chloride, crown ethers, polyethylene glycols.
In one embodiment, in step ‘a’ of the above process the reaction of compound of formula II with the compound of formula III is carried out in presence of a Lewis acid and a phase transfer catalyst in a suitable solvent to obtain crude efinaconazole.
In one embodiment, in step ‘a’ of the above process the reaction of compound of formula II with the compound of formula III is carried out in presence of a Lewis acid in a suitable solvent to obtain crude efinaconazole wherein the 4-methylenepiperidine is obtained by reacting a salt of 4-methylenepiperidine with a base. Suitable base may be selected from the group consisting of organic bases or inorganic bases. Inorganic bases may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; carbonate such as of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxide such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like. Organic bases may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, ?,?-dimethylaniline, pyridine, 2-bromopyridine, 4-dimethylaminopyridine, Di- tert-butyl pyridine, 2,6-Di-tert-butyl-4-methylpyridine, N- methylmorpholine, 2,6-Lutidine, imidazole.
In one embodiment, the crude efinaconazole obtained by the reaction of compound of formula II with the compound of formula III may be purified from a solvent selected from group consisting of chlorinated solvents like methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride; ethers like diethyl ether, methyl tertiary butyl ether, di-isopropyl ether, tetrahydrofuran ; nitriles like acetonitrile, propionitrile; esters like ethyl acetate, butyl acetate, isopropyl acetate; hydrocarbon like, cyclohexane, toluene, xylene, hexane; alcohols such as methanol, ethanol, butanol, isopropanol, n-propanol; sulfoxides like dimethyl sulfoxide; amides like dimethyl formamide, dimethyl acetamide; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; water and or mixtures thereof.
In one embodiment, in step ‘b’ of the above process the crude efinaconazole obtained from step ‘a’ is reacted with an acid selected from the group consisting of an inorganic acid, an organic carboxylic acid and an optically active acid to obtain an acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
The inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or mixture thereof; the organic carboxylic acid is selected from group consisting of acetic acid, trifluoroacetic acid, propionic acid, butyric acid, acrylic acid, methacrylic acid, crotonic acid, pyruvic acid, maleic acid, oxalic acid and dihydroxyfumaric acid; optically active acid is selected from group consisting of mandelic acid, tartaric acid, camphor sulfonic acid, dibenzoyltartaric acid, di-p-toluoyl tartaric acid, glutamic acid, malic acid, aspartic acid, mucic acid, pyruglutamic acid, glucoronic acid, camphoric acid, gluconic acid, lactic acid, pantothenic acid, phenylpropionic acid, N-acetylphenylalanine, diacetyl tartaricacid, tosylglutamic acid, camphanic acid.
In step ‘b’ of above process crude efinaconazole obtained from step ‘a’ is reacted with optically active acid to obtain acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, in step ‘b’ of the above process the crude efinaconazole is reacted with Di-toluoyl-L-tartaric acid to obtain reaction mixture containing Di-toluoyl-L-tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities, isomers of efinaconazole or salt thereof.
In one embodiment, step ‘c’ of the above process involves separating the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the mixture containing the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and isomers of efinaconazole or salt thereof.
In one embodiment, the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is separated from the reaction mixture containing the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and isomers of efinaconazole or salt thereof based on their difference in solubility in the reaction mixture.
In one embodiment, the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is selectively separated from the from the reaction mixture containing the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and isomers of efinaconazole or salt thereof by addition of a suitable anti-solvent.
In one embodiment, the separation is effected by the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol being soluble in a suitable solvent and the impurities and isomers of efinaconazole or salt thereof being insoluble in the solvent.
In one embodiment, the separation is effected by the acid addition salt of (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol being insoluble in a suitable solvent and the impurities and isomers of efinaconazole or salt thereof being soluble in the solvent.
In one embodiment, the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is selectively separated from the reaction mixture containing the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and isomers of efinaconzole or salt thereof comprising:
(i) removing solvent from the reaction mixture containing the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and isomers of efinaconazole or salt and thereof; and
(ii) optionally, adding a second solvent to step ‘(i)’.
In one embodiment, in step (i) of the above process involves partial or complete removal of the solvent from the reaction mixture containing the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and isomers of efinaconazole or salt thereof.
In one embodiment, the removal of solvent is carried out by methods selected from the group consisting of filtration, distillation, evaporation, centrifugation, spray drying and freeze drying.
In one embodiment, step (ii) of the above process involves optional addition of a second solvent to the reaction mixture containing acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and isomers of efinaconazole or salt thereof.
The addition of a second solvent is carried out optionally, if the solvent is completely removed in the above step (i).
The second solvent may be selected from, but is not limited to alcohols such as methanol, ethanol, n-propanol, 2-propanol; esters such as ethyl acetate, butyl acetate, isopropyl acetate; hydrocarbons such as hexane, heptane, toluene, cyclohexane, xylene; ethers such as diethyl ether, di-isopropyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; water or mixtures thereof.
In one embodiment, the Di-toluoyl-L-tartaric salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) is separated from the reaction mixture containing Di-toluoyl-L-tartaric salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, impurities and the isomers of efinaconazole or salt thereof by method of filtration.
In one embodiment, the present invention provides a process for the preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [efinaconazole], comprising converting Di-toluoyl-L-tartaric salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VIII to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the present invention provides a process for the preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [efinaconazole], comprising converting Di-toluoyl-D-tartaric salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VII to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
The Di-toluoyl-L-tartaric salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) obtained may be optionally purified or recrystallized in a solvent.
In one embodiment, the purification or recrystallization may be carried out in a suitable solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, water or mixtures thereof. Preferably recrystallized from mixture of ethanol-water.
In one embodiment, step ‘d’ of the above process involves converting the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is subjected to basification to obtain (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
Base may be selected from the group consisting of organic or inorganic base. Inorganic bases may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; carbonate such as of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxide such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like. Organic bases may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, ?, ?-dimethylaniline, pyridine and the like.
In one embodiment, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is isolated by methods known in the art such as extraction, centrifugation, filtration and the like.
In one embodiment, in step ‘d’ of the above process the D - di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or L- di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is converted to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol by treating with potassium carbonate. The (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1, 2, 4-triazol-1-yl) butan-2-ol obtained is isolated by extracting from reaction mixture using a suitable solvent.
Solvent may be selected from the group consisting of chlorinated solvents like methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride; ethers such as diethyl ether, methyl tertiary butyl ether, di-isopropyl ether, tetrahydrofuran ; nitriles such as acetonitrile, propionitrile; esters such as ethyl acetate, butyl acetate, isopropyl acetate; hydrocarbon such as, cyclohexane, toluene, xylene, hexane; alcohols such as methanol, ethanol, butanol, isopropanol, n-propanol; amides such as dimethyl formamide, dimethyl acetamide; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; water and or mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [efinaconazole], a compound of formula I comprising :
a) reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l) methyl] oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof, in the presence of a lewis acid to obtain crude efinaconazole;
II III
(a) reacting the crude efinaconazole obtained from step ‘a’ with an acid selected from the group consisting of an inorganic acid, an organic carboxylic acid and an optically active acid to obtain a reaction mixture containing an acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;
(b) separating the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the reaction mixture; and
converting the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the present invention provides Di-toluoyl-D- tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, compound of formula VII or Di-toluoyl-L-tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VIII.

In one embodiment, the present invention provides a process for the preparation of D- di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or L-di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol comprising reacting the crude efinaconazole with D-di-toluoyl tartaric acid, or with L -di-toluoyl tartaric acid to obtain D-di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or L- di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the present invention provides a process for the preparation of D or L di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol comprising reacting the crude efinaconazole with a solution of D- di-toluoyl tartaric acid or L-di-toluoyl tartaric acid in a solvent to obtain D- di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or L-di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, crude efinaconazole may be purified in a suitable solvent prior to the reaction with an acid to form the acid addition salt thereof.
In one embodiment, crude efinaconazole is reacted with Di-toluoyl-L-tartaric acid to obtain Di-toluoyl-L-tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, D or L di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol may be purified in a solvent.
In one embodiment, the present invention provides a process for the preparation of crystalline (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, the compound of formula I comprising:
a) treating (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, with a solvent to obtain a reaction mixture;
b) optionally adding an anti-solvent; and
c) isolating (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the above step a) or step b), wherein the solvent is selected from the group consisting of C1-C5 alcohol, nitrile, water, sulfoxides, hydrocarbons, esters, ethers, amides, chlorinated hydrocarbon and mixtures thereof.
In one embodiment, the step a) of the above process involves treating ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol), with a solvent to obtain a reaction mixture. The solvent C1-C5 alcohol may be selected from the group consisting of methanol, ethanol, butanol, isopropanol, n-propanol; nitriles may be selected from the group consisting acetonitrile, propionitrile; water; sulfoxides such as dimethyl sulfoxide; hydrocarbons such as, cyclohexane, toluene, xylene, hexane; esters such as ethyl acetate, butyl acetate, isopropyl acetate; ethers such as diethyl ether, methyl tertiary butyl ether, di-isopropyl ether, tetrahydrofuran; amides such as dimethyl formamide, dimethyl acetamide; chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride; and or mixtures thereof.
In one embodiment, in step b) of the above process an anti-solvent is added to the reaction mixture of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol in a solvent. The anti-solvent may be selected from the group consisting of water, hydrocarbons such as, cyclohexane, toluene, xylene, hexane; alcohols such as methanol, ethanol, butanol, isopropanol, n-propanol.
In one embodiment, in step c) of the above process (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is isolated from the reaction mixture of step a) or step b) by methods known in the art such as extraction, filtration, centrifugation and the like.
In one embodiment, the present invention provides crystalline salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the present invention provides crystalline D-di-toluoyl-tartaric salt of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or L-di-toluoyl-tartaric salt of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
In one embodiment, the present invention provides crystalline L-di-toluoyl-tartaric salt of (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1, 2, 4-triazol-1-yl)butan-2-ol.
In one embodiment, the present invention provides crystalline Di-toluoyl-L-tartaric salt of (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1, 2, 4-triazol-1-yl)butan-2-ol characterized by X-ray Diffraction (XRD) spectrum having peak reflections at 5.6,9.2,13.9,16.9 and 18.6 ±0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline Di-toluoyl-L-tartaric salt of (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1, 2, 4-triazol-1-yl)butan-2-ol characterized by 1HNMR having peaks at 0.751, 0.772, 2.248, 2.401, 2.459, 2.851, 2.867, 2.885, 3.163, 3.186, 4.636, 4.790, 4.839, 4.868, 4.915, 5.829, 6.887, 6.916, 6.936, 7.079, 7.111, 7.142, 7.300, 7.329,7.355, 7.381,7.407, 7.683, 7.893, 7.919, and 8.311 (300 MHz, DMSO d6).
In one embodiment, the present invention provides a process for the preparation of (2R, 3R)-2 (2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, the compound of formula I.
I
comprising reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l)methyl] oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof in the presence of a Lewis acid.
In one embodiment, the present invention provides a process for the preparation of ((2R, 3R)-2 (2, 4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (I), comprising reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l)methyl] oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof in the presence of a lewis acid and a phase transfer catalyst.
In one embodiment, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is crystallized from a mixture of aqueous alcohol to obtain crystalline efinaconazole. The ratio of alcohol to water may be 6:4 or 7:3. The alcohol may be selected from the group consisting of C1-C5 alcohol such as methanol, ethanol, propanol, isobutanol, isopropanol and the like.
In one embodiment, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is crystallized from a mixture of ethanol and water to obtain crystalline efinaconazole.
In one embodiment, the present invention provides crystalline efinaconazole characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 7.6, 14.9, 15.3, 16.6 and 18.8 ±0.2 degrees 2 theta and is in accordance with Fig. 1.
In one embodiment, the present invention provides efinaconazole wherein the content of (2S, 3S) isomer of efinaconazole, compound of formula IV or (2R, 3S) isomer of efinaconazole compound of formula V or (2S, 3R) isomer of efinaconazole, compound of formula VI is less than 0.5% w/w with respect to efinaconazole as determined by HPLC.
In one embodiment, the present invention provides a hydrate or an amorphous or an alcohol solvate of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, wherein solvate may be methanol, ethanol or isopropanol.
In one embodiment, the present invention provides pharmaceutical compositions comprising efinaconazole or salt thereof obtained by the processes herein described, having D50 and D90 particle size less than about 150 µ, preferably less than about 100 µ, more preferably less than about 50µ, still more preferably less than about 20 µ, still more preferably less than about 15 microns and most preferably less than about 10µ.
In one embodiment, the present invention provides efinaconazole or salt obtained by the processes herein described having D90 particle size of less than about 16 µ and D50 particle size of less than about 8 µ. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in art to bring solid state efinaconazole or salt into any of the foregoing desired particle size range.
In one embodiment, the present invention provides a method for preparing efinaconazole, or salt thereof, suitable for pharmaceutical use,comprising the steps of:
a) providing a batch of efinaconazole or a salt thereof;
b) assessing the purity of said batch of efinaconazole or salt thereof, by using at least one compound selected from the group consisting of IX, X, II, V and VI as a reference marker to determine the level of the reference marker compound ; and
c) selecting the batch of efinaconazole only if the percentage of the reference marker compound is less than 0.15% w/w as determined by HPLC

wherein in compound IX when i) R is 2,4-difluoro, G is selected from the group consisting of hydroxy, 4-methylenepiperidine-N-oxide and amino; ii) when G is 4-methylenepiperidine, R is selected from the group consisting of 4-fluoro and H.
In one embodiment, the compound of formula IX is as shown below below,

In one embodiment, the present invention provides a method of assessing the purity of efinaconazole and pharmaceutical compositions thereof comprising the steps of:
(a) providing a standard solution of at least one of the reference marker compound selected from the group consisting of IX, X, II, V and VI ; and

(b) using the solution as a reference marker to determine the level of the reference marker compound.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

Examples:
Example 1: Preparation of (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol: A suspension of 4-methylene-piperidine hydrochloride (1.59gm) in ethanol(2.5ml), lithium carbonate(1.47gm) was added at about 25-30°C. Aqueous lithium bromide(0.84gm) was added to this and stirred. To this 1-{[2-(2,4-dimethylphenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole(0.5gm) was added and heated to reflux. On completion, the reaction mass was concentrated and to residue ethyl acetate and water added. The organic layer was concentrated and residue stirred in n-heptane at 5-10°C. The precipitated solid was filtered, dried to obtain (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.
Example 2: The experiment 1 was repeated in water as a solvent instead of ethanol.
Ex 3: Experiment 1 was repeated with K2CO3 as base instead of lithium carbonate.
Example 4: Preparation of (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol:To a suspension of 4-methylene-piperidine hydrochloride(1.59gm) in dichloromethane(15ml), powdered potassium hydroxide(0.66gm) were added and stirred. The reaction mixture was filtered. The filtrate was concentrated under vacuum to obtain oil. To the obtained oil methanol(2.5ml) was added followed by addition of lithium carbonate(1.47gm) and aqueous lithium bromide(0.84gm) solution to obtain a reaction mixture. To this reaction mixture 1-{[2-(2,4-dimethylphenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole(0.5gm) was added and heated to reflux. On completion of the reaction, the reaction mass was concentrated under vacuum to obtain a residue. The residue was treated with a mixture of ethyl acetate(5ml) and water(5ml). The layers were separated and ethyl acetate layer was concentrated under vacuum. The obtained residue was taken in n-heptane and stirred for about 3 hrs at about 5-10°C. The precipitated solid was filtered and dried under vacuum to obtain (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.
Ex 5: Preparation of (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol: To a suspension of 4-methylene-piperidine hydrochloride(0.79gm) in dichloromethane(15ml), powdered potassium hydroxide(0.55gm) and water(10ml) were added. The reaction mixture was stirred and layers were separated. The organic layer was concentrated under vacuum at 40°C to get oil. The oil was dissolved in acetonitrile followed by addition of lithium bromide (0.519gm), 1-{[2-(2,4-dimethylphenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole(0.5gm) at about 25°C. The reaction mass refluxed. On completion of the reaction, the reaction mass was concentrated. The residue was taken in ethyl acetate and water and stirred for about 30 min organic layer concentrated and residue taken in n-heptane stirred for about 3 hrs at about 5-10°C. The precipitated solid was filtered, dried under vacuum to obtain 0.4gm (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.
Example 6a: Preparation of L-di-toluoyl-tartaric acid salt of (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol; Powdered potassium hydroxide (5.5 gm) was added to 4-methylene-piperidine hydrochloride (7.9gm) in dichloromethane (80ml), stirred. The reaction mixture was filtered and the filtrate concentrated under vacuum at about 35°-40° C. The obtained oil was dissolved in toluene (100 ml) followed by addition of lithium bromide (5.19 gm), 1-{[2-(2,4-dimethylphenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole (5gm,) and tetrabutylammonium bromide (0.5 gm). The reaction mass was heated to 85°C for 15-20 hrs. The reaction mass was cooled to 25-30°C and water added. The toluene layer was concentrated under vacuum to obtain residue. To this residue, Di-p-toluoyl-L-tartaric acid (9.98 gm) in ethanol was added at 70°C. The reaction mixture was stirred and then cooled to 20-25°C and again stirred for 3 Hrs. The precipitated solid was filtered. This solid was taken in a mixture of ethanol:water (7:3) and heated to 75°C to get clear solution. The reaction mixture was cooled to 20-25°C and stirred for 3Hrs. The precipitated solid was filtered and dried.
XRD of L-di-toluoyl tartaric acid salt of 2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Example 6b) Preparation of (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol: The solid obtained in example 6a) was taken in a dichloromethane and an aq solution of potassium carbonate was added to basify to a pH of 8-9. The aq layer was extracted with dichloromethane, washed with water and concentrated. To this a mixture of ethanol: water (7:3) mixture and cooled to 0°C. The precipitated solid was filtered and dried under vacuum to afford (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.(HPLC purity=99.96%).
XRD:2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Example 7 : Preparation of (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol: To a suspension of 4-methylene-piperidine hydrochloride (7.9 gm) in dichloromethane (80 ml) was added powdered potassium hydroxide (5.5 gm) and stirred. The reaction mixture was filtered and the filtrate was concentrated. The obtained oil was dissolved in toluene(100ml) and to it lithium bromide (5.19 gm) and 1-{[2-(2,4-dimethylphenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole (5 gm) was added at about 25°C. The reaction mass was heated to 85°C for 20 hrs. The reaction mass was cooled to 25-30°C then added water. The toluene layer was concen to obtain a residue to which Para-toluene-sulphonic acid monohydrate (4.9 gm) and isopropyl alcohol (20ml) were added and it was heated to 70°C. The reaction mixture was cooled to 20-25°C. The precipitated solid was filtered, dissolved in dichloromethane and aq potassium carbonate (5 gm) was added.The MDC layer was concen under vacuum to get a residue. The residue was taken in a mixture of ethanol:water (7:3) mixture and cooled to 0°C to get precipitate. The precipitated solid was filtered and dried under vacuum to obtain (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.(HPLC purity=98.70%)
Example 8: Preparation of (2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (comparative example): In an RBF, (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazole-1-yl)methyl]oxirane (17.59gm) was dissolved in an aqueous solution of 4-methylenepiperidine (113 g, content 61%) and the obtained solution was refluxed at 90°C. The reaction did not proceed to completion even after 48 Hrs. The excess of 4-methylenepiperidine was removed under vacuum, and the residue was dissolved in isopropyl alcohol and thereto was added p-toluenesulfonic acid monohydrate (13.32 g ) dissolved in isopropyl alcohol. The obtained mixture was allowed to stand for 1 hour at 45-50°C and thereafter overnight at 20-25°C, but no crystal precipitated.
,CLAIMS:We Claim:
1] A process for the preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [efinaconazole], a compound of formula I, comprising:
I
(a) reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l)methyl]oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof to obtain crude efinaconazole;
II III
(b) reacting the crude efinaconazole obtained from step ‘a’ with an acid selected from the group consisting of an inorganic acid, an organic carboxylic acid and an optically active acid to obtain a reaction mixture containing an acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;
(c) separating the acid addition salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the reaction mixture; and
(d) converting the acid addition salt of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) to (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
2] The process as claimed in claim 1, wherein the content of (2S, 3S) isomer of efinaconazole, compound of formula IV and/or (2R,3S) isomer of efinaconazole, compound of formula V and /or (2S,3R) isomer of efinaconazole, compound of formula IV

IV V VI
is less than 0.5% w/w with respect to efinaconazole as determined by HPLC.
3] The process as claimed in claim 1 wherein the step ‘a’ is carried out in presence of a Lewis acid.
4] The process as claimed in claim 1 wherein the step ‘a’ is carried out in presence of a phase transfer catalyst.
5] Di-toluoyl-D-tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VII or Di-toluoyl-L-tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound of formula VIII


6] A process for the preparation of D or L di-toluoyl tartaric acid salt of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol comprising the step of reacting crude efinaconazole with D or L di-toluoyl tartaric acid to obtain D or L di-toluoyl tartaric acid salt of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
7] The process as claimed in claim 7, comprising converting L di-toluoyl tartaric acid salt of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or D- di-toluoyl tartaric acid salt of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol to (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
8] A process for the preparation of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, the compound of formula I, comprising the step of reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-y- l) methyl] oxirane, a compound of formula II, with 4-methylenepiperidine, a compound of formula III or salt thereof in the presence of a Lewis acid.
9] A method for preparing efinaconazole, or salt thereof, suitable for pharmaceutical use, comprising the steps of:
a) providing a batch of efinaconazole or a salt thereof;
b) assessing the purity of said batch of efinaconazole or salt thereof, by using at least one compound selected from the group consisting of IX, X, II, V and VI as a reference marker to determine the level of the reference marker compound ; and
c) selecting the batch of efinaconazole only if the percentage of the reference marker compound is less than 0.15% w/w as determined by HPLC

wherein in compound IX when i) R is 2,4-difluoro, G is selected from the group consisting of hydroxy, 4-methylenepiperidine-N-oxideand amino; ii) when G is 4-methylenepiperidine, R is selected from the group consisting of 4-fluoro and H.
10] A method of assessing the purity of efinaconazole and pharmaceutical compositions thereof comprising the steps of:
(a) providing a standard solution of at least one of the reference marker compound selected from the group consisting of IX, X, II, V and VI; and

(b) using the solution as a reference marker to determine the level of the reference marker compound.