Field of the invention:
The present invention relates to an improved process for the preparation of ((2R,3R)-2-(2!4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-1 -(1H-1,2,4-triazol-1 -y !)butan-2-ol) compound of formula-1 and its salts thereof.
Background of the invention:
Efinaconazole is chemically known as ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-ly|)-l-(lH-l,2,4-triazol-l-yl) butan-2-ol) and is marketed by Valent pharmaceuticals under the brand name of Jublia® which is an azole antifungal indicated for the topical treatment of onychomycosis of the toenails due to Trichophyton rubrum and Trichophyton mentagrophytes.
US5620994A [herein after referred as US'994] patent first disclosed ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene- piperidin-1 yl)-1 -(1H-1,2,4-triazol-1 -yl) butan-2-ol) and its pharmaceutical Iy acceptable salts and process for their preparation.
Further US'994 patent discloses ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1 yl)-1 -(IH-1,2,4-triazol-1 -yt) butan-2-ol) as a solid and having melting point 86-87°C. The said patent did not disclose any other physical characteristic data of the said compound. Moreover, the process disclosed in US'994 patent provides the compound of formula-1 in lower yield with lesser purity. Hence the inventors of the present invention developed an improved process for the preparation of pure compound with higher yields.
US'994 & US8871942B2 patents discloses the process for the preparation of the compound of formula-1 comprising of reacting the (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[( 1H-1,2,4-triazole-1 -yI) methyljoxirane with 4-methylene piperidine.
Research disclosure database number 612036 discloses the crystalline forms-A, B &

C of ((2R,3R)-2-(2,4-difluoro pheny])-3-(4-methylene piperidin-1 yI)-1 -(1H-1,2,4-triazol-1 -
yl) butan-2-ol) and crystalline form-I of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-
methylenepiperidin-1 yl)-1 -(IH-1,2,4-triazol-1 -yl) butan-2-ol) p-toluenesulfonate.
The prior art processes discloses the coupling of oxirane compound with 4-methylene piperidine for the preparation of compound of formula-1, These processes required more steps and get less yield. The present inventors developed the process with lesser number of steps and provided improved yields.
Brief description of the invention:
i The first aspect of the present invention is to provide an improved process for the
preparation of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-1 -(IH-1,2,4-triazol-1-y I) butan-2-ol) compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-1 -(IH-1,2,4-triazol-1-yl) butan-2-ol) acid addition salt compound of general formula-la.
The third aspect of the present invention is to provide an improved process for the preparation of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-l -(1H-1,2,4-triazol-1-y I) butan-2-ol) compound of formula-1 and its salts thereof.
i Brief description of the Figures:
Figure 1: Illustrates the PXRD pattern of the compound of formula-1 obtained according to reference example.
Detailed description of the invention:
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-> dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl

ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, I, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) and the like; "alky] metals" such as n-butyl lithium and like; "metal hydrides" such as lithium hydride, sodium hydride, potassium hydride and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and "organic bases" selected from but not limited to methyl amine, ethyl amine, diisopropyl amine, diisopropylethyi amine (D1PEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), n-methyl pyridine (NMP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4;3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; or mixtures thereof.

The term "salts" or "acid addition salts" used in the present invention refers to acid addition salt which is formed by the addition of a suitable acid.
The term "suitable acid" used in the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic
i acids such as acetic acid, maleic acid, malic acid, oxalic acid, trifluoro acetic acid [TFA], methane sulfonic acid [MSA], p-toluene sulfonic acid [PTSA]; chiral acids such as S-(+) mandelic acid, R-(-) mandelic.acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (IR)-(-)-camphor sulfonic acid, (IS)-(+)-camphor sulfonic acid (IR)-(+)-bromocamphor-10-sulfonic acid, (lS)-(-)- bromocamphor-
> 10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaric acid monohydrate, (+)-Dibenzoyl-D-tartaric acid, (+)'-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataric acid, L(-)-' pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine etc., and like.
The term "Pure" refers to the compound having purity >97%, preferably >99%; more
i preferably >99.5% by HPLC and the term "stable" refers to the compound obtained according to the present invention is not converted into any other polymorphic forms & not converted to any degradation impurities.
The first aspect of the present invention provides an improved process for the preparation of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yI)-1 -(1H-1,2,4-
I triazol-1 -yI) butan-2-ol) compound of formula-1,
comprising of:
a) Treating the (2R,3R)-2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-d compound of formula-2 or its salts

wherein R is alkyl or aryl group;
in presence of a suitable base in a suitable solvent to provide the compound of general
formula-4,
wherein R= alkyl or aryl group;
reacting the compound of general formula-4 with 4-methylene piperidine compoun<
of formula-5 or its acid addition salts
in presence of a suitable base in a suitable solvent to provide the compound of formula-1, ) treating the compound of formula-1 obtained in step-b) in-situ with a suitable acid in a suitable solvent to provide the compound of general formula-la,

d) optionally purifying the compound of formula-la using a suitable solvent,
e) treating the obtained compound in step-c) or step-d) with a suitable base,
f) extracting the compound in a suitable solvent,
g) isolating the compound of formula-1,
h) optionally purifying the compound of formula-1 using the suitable solvent to get the
pure compound of formula-1. Wherein,
in step-a), step-b) & step-e) the suitable base is selected from organic or inorganic base;
in step-c) the suitable acid is selected from organic or inorganic acid;
in step-a) to h) a suitable solvent is selected from alcoholic solvents, ester solvents, hydrocarbon solvents, ketone solvents, ether solvents, nitrile solvents, polar aprotic solvents, chloro solvents, polar solvents and mixtures thereof;
in step-g) "isolating" refers to the obtaining the compound utilizing one or more of filtrations, filtration under vacuum, evaporation or distillation of solvent, decantation, centrifugation, drying or drying under vacuum. The product can also be isolated upon cooling at an ambient temperature.
The preferred embodiment of the present invention provides an improved process for the preparation of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-lyl)-l-(lH-1,2,4-triazol-l-yl) butan-2-ol) compound of formula-1, comprising of:
a) Treating the (2R,3R)-2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol
methane sulphonate compound of formula-2a

1 UllllUlU-id
with methanesulfonyl chloride compound of formula-3a
1 UIIJUIU-^IU
in presence of triethylamine in dichloromethane to provide the compound of formula-4a, "
rormula-4a ) reacting the compound of formula-4a with 4-methylene piperidine hydrochloride compound of formula-5a
Formula-5a in presence of a lithium hydroxide in the mixture of acetonitrile and water to provide the compound of formula-1,
treating the compound of fomula-1 in-situ with para-toluene sulfonic acid in isopropanol to provide the (^R^R^-^-difluorophenyO-S-^-methylenepiperidin-lyl)-l-(1H-l,2,4-triazol-l-yl)butan-2-ol) p-toluene sulfonate compound of formula-la(i),

d) purifying the compound of formula-la(i) using the mixture of isopropanol a methanol to get the pure compound of formula-la(i),
e) treating the compound of formula- la(i) with aqueous sodium hydroxide solution,
f) extracting the compound using ethyl acetate,
g) distilling off the solvent from the organic layer to provide the compound of formul 1,
h) purifying the compound using isopropanol and water to get the pure compound formula-1.
The second aspect of the present invention provides an improved process for t preparation of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-1 -(1H-1,2, triazol-1-yl) butan-2-ol) acid addition salt compound of general formula-la comprising of:
a) Treating the (2R)3R)-2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazot-l-yl)butane-2,3-di compound of formula-2 or its salts with the compound of general formula-3 presence of a suitable base in a suitable solvent to provide compound of gener formula-4,
b) reacting the compound of general formula:4 with 4-methylene piperidine compour of formula-5 or its acid addition salts in presence of a suitable base in a suitab solvent to get the compound of formula-1,
c) treating the compound of formula-1 in-situ with a suitable acid in a suitable solvent provide the compound of formula-la,
d) optionally purifying the compound of formula-1 a using the suitable solvent to g pure ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-1 -(1H-1,2,. triazol-l-yl) butan-2-ol) acid addition salt compound of general formula-1 a.
Wherein,

in step-a) & step-b) a suitable base is selected from organic or inorganic base; in step-a) to d) a suitable solvent is selected from alcoholic solvents, ester solvents, hydrocarbon solvents, ketone solvents, ether solvents, nitrile solvents, polar aprotic solvents, chloro solvents, polar solvents and mixtures thereof.
Preferred embodiment of the present invention provides an improved process for the preparation of ((2Rs3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-1 -(1H-1,2,4-triazol-1-yl) butan-2-ol) p-toluene sulfonate compound of formula-la(i) comprising of:
a) Treating the (2R,3R)-2-(2,4-difluorophenyl)-l-(lH-l)2)4-triazol-l-yl)butane-2J3-diol methane sulphonate compound of formula-2a with methane sulfonyl chloride compound of formula-3a in presence of triethylamine in dichloromethane to provide the compound of formula-4a,
b) reacting the compound of formula-4a with 4-methylene piperidine hydrochloride compound of formula-5a in presence of a lithium hydroxide in the mixture of acetonitrile and water to provide the compound of formula-l,
c) treating the compound of formula-l in-situ with p-toluene sulfonic acid in isopropanol to provide the ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-lyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol) p-toluene sulfonate compound of formula-la(i).
d) purifying the compound formula-la(i) using the mixture of isopropanol and methanol to provide pure ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-lyl)-l-(IH-l,2,4-triazol-l-yl)butan-2-ol) p-toluene sulfonate compound of formula-la(i).
The third aspect of the present invention provides an improved 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) compound of formula-l or its salts thereof, comprising of reacting the compound of general formula-4 with 4-methylene piperidine compound of general formula-5 or its acid addition salts in presence of a suitable base in a suitable solvent to provide the compound of formula-1,. optionally converting the compound of formula-l to its salts.
PXRD pattern of the compound of formula-l obtained according to the present

invention is matching with crystalline form-A of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidin-1 yl)-1 -(1H-1,2,4-triazol-1 -yl) butan-2-ol) and PXRD pattern of the compound of formula-la(i) is matching with crystalline form-I of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1 yl)-1 -(1H-1,2,4-triazol-l -yl)butan-2-ol) p-toluene sulfonate which are disclosed in Research disclosure database number 612036.
Further, 4-methylene piperidine hydrochloride compound of formula-5a used in the present invention is produced by the method described in US6054586 and (2R,3R)-2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol compound of formula-2 or its salts are prepared by the processes known in the prior art.
The compound of the formula-1 produced by the present invention can be further micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The present invention is represented in the following scheme:

The present inventors have repeated the process described in US5620994A and characterized the obtained solid by its PXRD pattern, further the same has been shown in figure-].
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Reference Example: Process for the preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-l-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol compound of formula-1 according to US5620994A
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(lH-i,2,4-triazole-l-yl) methyl] oxirane (20 gm) was dissolved in 128 gms of aqueous solution of 4-methylene piperidine and the obtained reaction mixture heated to 90-95°C, further stirred for 21 hours. Distilled off the reaction mixture under reduced pressure. The obtained residue was dissolved in isopropanol (159 ml) and there to was added the solution of p-toluensulphonic acid (15.14 gm) in isoprpopanol (56.85 ml). The obtained reaction mixture was allowed to stand for 1 hour at 25-30°C and over-night in refrigerator. Filtered the precipitated solid, washed with isopropanol and dried to get 19.4 gms of (2R,3R)-2-(2J4-difluorophenyl)-3-(4-methylenepiperidin-l-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol p-toluene sulfonate.
33 ml of ethyl ether was added to 15 gms of the above obtained p-toluene sulfonate salt al 25-30°C. IN aqueous solution was added to the reaction mixture and both the organic and aqueous layers were separated. The organic layer was dried with sodium sulphate and distilled off the solvent from the organic layer. 35 ml of n-hexane was added to the obtainec compound at 25-30°C and stirred for 30 minutes. Filtered the precipitated solid, washed witr n-hexane and dried to get the title compound. Yield: 6.4 gm. PXRD of the obtained compound was shown in figure-1.
Example-1: Preparation of (2R)-l-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2 yloxy)propan-l-one:

A mixture of tetrahydrofuran (500 ml) and magnesium turnings (13.8 gms) was stirred for 15 minutes at 25-30°C. Iodine (2 gm) was added to the reaction mixture at 25-30°C. 1-bromo-2,4-difluoro benzene (119 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. The reaction mixture was slowly cooled to -25 to -20°C. The solution of (R)-2-Hydroxy-1-(2R)-1-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one (100 gms) in tetrahydrofuran (100 ml) was slowly added to the reaction mixture at -25 to -20°C and stirred the reaction mixture for 30 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 0-5°C and neutralized the reaction mixture by using diluted acetic acid at the same temperature. Ethyl acetate was added to the reaction mixture and raised the temperature of the reaction mixture to 25-30°C. Both the aqueous and organic layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 110 gm.
Example-2: Preparation of (2R,3R)-2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol methane sulphonate compound of formula-2a: 1,2,4-triazole (32.56 gms) was slowly added to the mixture of dimethylformamide (440 ml) and trimethyl sulfoxonium iodide (103 gms) at 25-30°C and cooled the reaction mixture to 20-25°C. Sodium tertiary butoxide (88 gms) was slowly added to the reaction mixture at 20-25°C and stirred the reaction mixture for 30 minutes at 20-25°C. A solution of (2R)-l-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one (110 gms) in dimethyl formamide (100 ml) was slowly added to the reaction mixture at 20-25°C and stirred the reaction mixture for 1 hour at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 15 hours. Cooled the reaction mixture to 20-25°C and water was added to the reaction mixture. Ethyl acetate was added to the reaction mixture and stirred for 15 minutes at 20-25°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced

pressure and co-distilled with methanol. Methanol (550 ml) was added to the obtained compound and stirred for 15 minutes at 25-30°C. Para toluenesulfonic acid (65 gms) was added to the reaction mixture and stirred the reaction mixture for 4 hours at 25-30°C. Neutralized the reaction mixture using aqueous sodium hydroxide solution at 25-30°C and distilled off the reaction mixture under reduced pressure. Water was added to the obtained compound and stirred the reaction mixture for 15 minutes at 25-30°C. Ethyl acetate was added to the reaction mixture and stirred the reaction mixture for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water. Distilled off the solvent completely from organic layer under reduced pressure. Methanol (250 ml) was added to the obtained compound and stirred for 15 minutes at 25-30°C. Cooled the reaction mixture to 0-5°C. Methane sulphonic acid (22.44 gms) was slowly added to the reaction mixture at 0-5°C. Heated the reaction mixture to 60-65°C and stirred for 3 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. The obtained compound was cooled to 25-30°C and Ethyl acetate (100 ml) was added to the reaction mixture. The reaction mixture was further cooled to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 36 gms.
Example-3: Preparation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(lH-l,2,4-triazole-l-yl) butan-2-yl methanesulfonate compound of formula-4a: Triethylamine (41.4 gms) was added to the mixture of (2R,3R)-2-(2,4-difluorophenyl)-l-(lH-],2,4-triazol-]-yl)butane-2,3-diol methane sulphonate compound of formula-2a (50 gms) and dichloromethane (150 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and methane sulphonyl chloride (23.4 gms) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Water was added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from organic layer under reduced

pressure to get the title compound.
Yield: 45 gms.
Example-4: Preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methyIene piperidine-1-
yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol-4-methylbenzenesulphonate p-toluene sulfonate
compound of formula-la(i):
8.4 gms of lithium hydroxide was added to the solution of 4-methylene piperidine
hydrochloride compound of formula-5a (40 gms) in acetonitrile (210 ml) at 25-30°C and
stirred the reaction mixture for 10 minutes at the same temperature. (2R,3R)-3-(2,4-
difluorophenyl)-3-hydroxy-4-(lH-l,2,4-triazole-l-yl)butan-2-yl methane sulfonate compound
of formula-4a (40 gms) was added to the reaction mixture at 25-30°C. Heated the reaction
mixture to 85-90°C and stirred for 85 hours at the same temperature. Cooled the reaction
mixture to 25-30°C. Water followed by ethyl acetate were added to the reaction mixture and
stirred for 5 minutes at the same temperature. Both the organic and aqueous layers were
separated and the aqueous layer was extracted with ethyl acetate. Combined the organic
layers and washed with water followed by wijh aqueous sodium chloride solution. Distilled
off the solvent completely from organic layer under reduced pressure and co-distilled with
isopropanol. Isopropanol (240 ml) was added the obtained compound at 25-30°C and stirred
for 15 minutes at the same temperature. A solution of para-toluene sulphonic acid (19.2 gms)
in isopropanol (80 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 4
hours at the same temperature. Cooled the reaction mixture to 10-I5°C and stirred for 2
hours at the same temperature. Filtered the solid and washed with isopropanol. Methanol (48
ml) and isopropanol (480 ml) were added to the obtained wet compound at 25-30°C. Heated
the reaction mixture to 80-85°C and stirred for 45 minutes. The reaction mixture was slowly
cooled to 25-30°C. Filtered the precipitated solid, washed with isopropanol and dried to get
the title compound.
Yield: 24 gms; Melting point: 185-I95°C.
The PXRD pattern of the obtained compound of formula-la(i) is matching with the
crystalline form-I disclosed in Research disclosure database number 612036.
Example-5: Preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-l-
yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol compound of formula-1:

A mixture of water (40 ml), ethyl acetate (20 ml) and (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1 -yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol p-toluenesulfonate compound of formula-la(i) (10 gms) was stirred for 10 minutes at 25-30°C. The reaction mixture was basified by using aqueous sodium hydroxide solution. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water. Distilled off the solvent completely from organic layer under reduced pressure and co-distilled with isopropanol. Isopropanol (20 ml) was added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. Carbon was added to the reaction mixture and stirred for 15 minutes at 25-30°C. Filtered the reaction mixture through hyflo bed and washed with isopropanol. Filtrate was slowly added to water (40 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 4.4 gms; Melting point: 86-89°C. The PXRD pattern of the obtained compound of formula-1 is matching with the crystalline form-A disclosed in Research disclosure database number 612036.