Process for the preparation of triazole antifungal drug, its intermediates and polymorphs thereof

1. A process for the preparation of triazole derivative compound of Formula-1

comprising:

a) reacting a compound of Formula-16

with ethyl magnesium halide in the presence of bis(trimethylsilyl)acetamide in a solvent to provide a compound of Formula-17,

b) reacting the compound of Formula-17 in-situ with a compound of Formula-19

in the presence of a base in a solvent to provide a compound of Formula-20,

c) condensing the compound of Formula-20 with a compound of Formula-10

in the presence of a base in a polar aprotic solvent to provide a compound of Formula-21,

d) debenzylating the compound of Formula-21 with Pd/C under hydrogen pressure in the presence of mineral acid in an alcoholic solvent to provide the compound of Formula-1; and

e) optionally, purifying the compound of Formula-1 obtained in step-(d) from a solvent to provide pure compound of Formula-1.

2. The process according to claim 1 , wherein:

in step (a), the solvent is methyl tertiary butyl ether, tetrahydrofuran, diethyl ether, methyl tert-butyl ether or dioxane;

in step (b), the base is an organic base and the solvent is ether solvent selected from tetrahydrofuran, dioxane, tertiarybutylmethyl ether or diethyl ether;

in step (c), the base is an inorganic base and the polar aprotic solvent is selected from dimethylformamide, dimethylacetamide or dimethylsulfoxide;

in step (d), the mineral acid is hydrochloric acid, hydroiodic acid or sulfuric acid and the alcoholic solvent is methanol, ethanol, isopropanol or butanol; and

in step (e), the solvent is an alcoholic solvent.

3. The process according to claim 1 , wherein the process for the preparation of the compound of Formula-10 comprises:

i) hydrolyzing a compound of Formula-6

in presence of a base and hydrogen peroxide in a solvent to provide a compound of Formula-7,

ii)reducing the compound of Formula-7 with a reducing agent in a solvent to provide a compound of Formula-8,

iii) reacting the compound of Formula-8 with 1,2,4-triazole in presence of a base in a solvent to provide a compound of Formula-9,

iv) reacting the compound of Formula-9 in-situ with tosyl chloride in presence of a base in a solvent to provide the compound of Formula-10.

4. The process according to claim 3 , wherein:

in step (i), the base is an inorganic base; and the solvent is selected from ether solvents, ester solvents or ketone solvents;

in step (ii), the reducing agent is selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithiumborohydride, NaBH 3 CN, sodiumborohydride/BF 3 -etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminiumchloride, sodiumborohydride/iodine or 9-BBN; and the solvent is selected from ether solvents, ester solvents or ketone solvents;

in step (iii), the base is an organic base selected from triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine or diisopropylethyl amine, or an inorganic base selected from alkali metal carbonates, alkali metal hydroxide, alkali metal bicarbonates, or alkali metal alkoxides; and the solvent is selected from polar aprotic solvents, chloro solvents, ester solvents, or ketone solvents; and

in step (iv), the base is selected from an organic base selected from triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine or diisopropylethyl amine; and the solvent is selected from chloro solvents, alcoholic solvents, or hydrocarbon solvents.

5. The process according to claim 3 , wherein the process for the preparation of the compound of Formula-7

comprises:

A) reacting a compound of Formula-2

with a compound of Formula-3

in presence of an activating agent and a base in a solvent to provide a compound of Formula-4,

B) hydroxymethylating the compound of Formula-4 with 1,3,5-trioxane in presence of a base and a catalyst in a solvent to provide a compound of Formula-5,

C) cyclizing the compound of Formula-5 in-situ in presence of iodine and a base in a solvent to provide a compound of Formula-6,

D) hydrolyzing the compound of Formula-6 in presence of an aqueous base and hydrogen peroxide in a solvent to provide the compound of Formula-7.

6. The process according to claim 5 , wherein:

in step (A), the activating agent is selected from thionyl chloride, oxalyl chloride, pivaloyl chloride, carbonylditriazole, oxalylditriazole, POCl 3 , PCl 3 , PCl 5 or SO 2 Cl 2 ; the organic base is selected from triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine or diisopropylethyl amine and the solvent is selected from chloro solvents, ester solvents, ketone solvents, polar aprotic solvents or alcoholic solvents or mixture thereof;

in step (B), the base is an organic base; the catalyst is titanium tetrachloride; and the solvent is selected from chloro solvent, ketone solvents, ester solvents, ether solvents or alcoholic solvents;

in step (C), the base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, or alkali metal bicarbonates; and the solvent is selected from ether solvents, chloro solvents, alcoholic solvents or ester solvents or a mixture thereof; and

in step (D), the base is an organic base or an inorganic base; and the solvent is selected from ether solvents, ester solvents, ketone solvents or hydrocarbon solvents.

7. The process according to claim 5 , wherein the amount of hydrogen peroxide used in step (D) is between 1.0-2.0 moles per one mole of compound of Formula-6.

8. The process according to claim 1 , wherein the process for the preparation of the compound of Formula-19 comprises reacting a compound of Formula-18

with phenylchloroformate in the absence of a base in a solvent selected from polar aprotic solvents, chloro solvents, ester solvents, ketone solvents, alcoholic solvents or ether solvents to provide the compound of Formula-19.

9. The process according to claim 1 , wherein step (c) further comprises:

i) condensing the compound of Formula-20 with the compound of Formula-10 in the presence of an aqueous base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, or alkali metal bicarbonates in a solvent selected from polar aprotic solvents, chloro solvents, ester solvents, or ether solvents to provide the compound of Formula-21;

ii) quenching the reaction mixture with water; and

iii) neutralizing the reaction mixture with an acid to provide amorphous compound of Formula-21.

10. The process according to claim 1 , wherein the process for the preparation of the compound of Formula-16 comprises:

i) reacting racemic methyl lactate with benzyl chloride in the presence of an alkali metal alkoxide in a solvent selected from polar aprotic solvents, ester solvents, chloro solvents or alcoholic solvents to provide a compound of Formula-12

ii) hydrolyzing the compound of Formula-12 in-situ with an alkali metal hydroxide in a solvent selected from hydrocarbon solvents, ester solvents, or alcoholic solvents to provide a compound of Formula-13

iii) resolving the compound of Formula-13 in-situ with (S)-1-phenylethanamine in a solvent selected from hydrocarbon solvents, chloro solvents or ester solvents to provide a compound of Formula-13a

iv) reacting the compound of Formula-13a with methanol in presence of thionyl chloride in a polar aprotic solvent to provide a compound of Formula-14

v) reducing the compound of Formula-14 with DIBAL-H in toluene to provide a compound of Formula-15

vi) reacting the compound of Formula-15 in-situ with formyl hydrazine in methanol to provide the compound of Formula-16.

11. The process according to claim 1 , wherein the compound of Formula-1 is in the form of:

a) isopropanol solvate compound of Formula-1 characterized by its powder X-ray diffractogram having peaks at about 3.5, 6.9, 7.6, 9.8, 14.1, 14.4, 15.0, 15.7, 17.7, 19.3, 19.9, 20.3, 22.2, 22.9, 23.1 and 25.4±0.2 degrees of two-theta;

b) crystalline form-S compound of Formula-1 characterized by its powder X-ray diffractogram having peaks at about 7.19, 7.95, 10.20, 13.91, 15.38, 16.05, 16.69, 17.32, 17. 77, 18.95, 19.29, 19.83, 20.20, 21.32, 21.67, 23.44, 24.70, 25.93, 26.64 and 27.79.±0.2 degrees of two theta; or

c) crystalline form-N compound of Formula-1 characterized by its powder X-ray diffractogram having peaks at about 7.92, 10.17, 10.86, 11.26, 12.98, 13.86, 17.72, 18.66, 22.62, 24.65, 25.84 and 28.52±0.2 degrees of two theta.

12. The process according to claim 11 , wherein the compound of Formula-1 is in the form of the isopropanol solvate compound of Formula-1 and is prepared by a process comprising:

i) dissolving the compound of Formula-1 in isopropanol by heating to reflux temperature;

ii) filtering the reaction mixture;

iii) cooling the reaction mixture;

iv) stirring the reaction mixture;

v) filtering the solid and washing with isopropanol; and

vi) drying the solid to get crystalline isopropanol solvate of compound of Formula-1.

13. The process according to claim 11 , wherein the compound of Formula-1 is in the form of crystalline form-S compound of Formula-1 and is prepared by a process comprising:

i) debenzylating the compound of Formula-21 with Pd/C under hydrogen pressure in the presence of mineral acid in an alcoholic solvent to provide the compound of Formula-1 in accordance with step (d);

ii) filtering the reaction mixture;

iii) adding an organic solvent to the reaction mixture;

iv) cooling the reaction mixture to 10 to 15° C.;

v) adjusting pH of the reaction mixture;

vi) adding purified water to the reaction mixture;

vii) stirring the reaction mixture; and

viii) filtering the solid and washing with purified water to get crystalline form-S of compound of Formula-1.

14. The process according to claim 13 , wherein:

in step (i), the mineral acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid and the alcoholic solvent is methanol, ethanol, or isopropanol; and

in step (iii), the organic solvent is a ketone solvent.

15. The process according to claim 11 , wherein the compound of Formula-1 is in the form of crystalline form-N compound of Formula-1 and is prepared by a process comprising:

i) dissolving the compound of Formula-1 in acetone;

ii) heating the reaction mixture to reflux;

iii) filtering the reaction mixture;

iv) adding purified water to the filtrate;

v) stirring the reaction mixture; and

vi) filtering the solid and washing with purified water to get crystalline form-N of compound of Formula-1.

16. The process according to claim 1 , wherein the compound of Formula-21 is in amorphous form.

17. The process according to claim 1 , wherein the compound of Formula-21 is characterized by its powder X-ray diffractogram having peaks at about 3.90, 5.86, 7.82, 9.82, 11.79, 12.59, 13.38, 13.74, 16.24, 16.95, 17.83, 18.90, 20.09, 21.49, 22.89, 24.93, 26.53, 27.56, 28.73, 29.88 and 34.20±0.2 degrees of two theta.

18. The process according to claim 1 , further comprising:

i) dissolving the compound of Formula-1 in a solvent selected from chloro solvents, ketone solvents, ester solvents, ether solvents, or alcoholic solvents;

ii) filtering the reaction mixture;

iii) adding filtrate to a non-polar solvent;

iv) stirring the reaction mixture; and

v) filtering the solid and then drying to get amorphous form of compound of Formula-1.

19. The process according to claim 18 , comprising:

i) dissolving the compound of Formula-1 in dichloromethane;

ii) filtering the reaction mixture;

iii)adding filtrate to n-pentane;

iv)stirring the reaction mixture; and

v) filtering the solid and then drying to get amorphous form of compound of Formula-1.

20. The process according to claim 1 , further comprising:

i) debenzylating the compound of Formula-21 with Pd/C under hydrogen pressure in presence of hydrochloric acid in methanol;

ii) filtering the reaction mixture and adding acetone to the filtrate;

iii) cooling the reaction mixture and adjusting the pH of the reaction mixture;

iv) adding water to the reaction mixture;

v) filtering the precipitated solid;

vi) adding acetone to the solid obtained in step (v) and heating the reaction mixture;

vii) filtering the reaction mixture;

viii) adding water to the filtrate and stirring the reaction mixture;

ix) filtering the precipitated solid;

x) optionally, purifying the solid obtained in step (ix);

xi) adding dichloromethane to the solid;

xii) slowly adding the mixture obtained in step (xi) to n-pentane;

xiii) stirring the reaction mixture; and

xiv) filtering the solid and then drying to get amorphous form of compound of Formula-1.