Claims:
1. A process for preparation of Posaconazole comprising;
a) Reacting intermediate compound of formula A (wherein L is a leaving group selected from 4-Chlorobenzene sulfonyl or 4-Nitrobenzene sulfonyl or p-Toluenesulfonyl) with intermediate compound of formula B in presence of an alkali and Polar aprotic solvent to obtain Benzyl posaconazole and

b) Debenzylating the Benzyl posaconazole using Pd/C in methanol to obtain Posaconazole.
2. The process as claimed in claim 1, wherein the Polar aprotic solvent is selected from the group consisting of Dimethylsufoxide and Dimethyl formamide.
3. The process as claimed in claim 1, wherein theintermediate compound of formula A is selected from the group consisting of [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate; [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-chlorobenzene sulfonate and [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-p-toluene sulfonate.
4. The process as claimed in claim 1, wherein theintermediate compound of formula Ais[(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate.
5. The process as claimed in claim 1, wherein the intermediate compound of formula A is prepared by a process comprising;
a) Reacting 1,3-Difluorobenzene with Succinic anhydride under Friedel craft conditions to obtain 4-(2,4-Difluorophenyl)-4-oxobutanoic acid (A-3);
b) Subjecting the 4-(2,4-Difluorophenyl)-4-oxobutanoic acid (A-3) to a Wittig reaction with Diphenyl methyl phosphonium bromide to obtain 4-(2,4-Difluorophenyl)-pent-4-enoic acid (A-4);
c) Reacting the 4-(2,4-Difluorophenyl)-pent-4-enoic acid with R(-)-4-Phenyl-2-oxazolidone in presence of a base to obtain (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one (A-5);
d) Reacting the (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one with Trioxane followed by iodination to isolate (4S)-3-{[(5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one (A-7);
e) Reducing the (4S)-3-{[(5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one (A-7) with Lithium borohydride to obtain [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8);
f) Tritylating the [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8) to obtain (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan(A-9) followed by reaction with 1H-1,2,4 –triazole in presence of a base to obtain 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy)methyl)furan-2-yl) methyl)-1H-1,2,4-triazole (A-10);
g) Detritylating the 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole (A-10) to obtain [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11);
h) Reacting the [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11) with 4-Chlorobenzene sulfonyl chloride or 4-Nitrobenzene sulfonyl chloride or p-Toluenesulfonyl chloride in presence of a base to obtain respective salts of [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A).

6. The process as claimed in claim 5, wherein the solvents used in the Wittig reaction are selected from aromatic hydrocarbons like Xylene, Toluene, and Mixed Xylenes.
7. The process as claimed in claim 5, wherein the base used in step c) is selected from the group consisting of tertiary bases like Triethyl amine, Pyridine, Hunig’s base.
8. The process as claimed in claim 5, wherein the R(-)-4-Phenyl-2-oxazolidone is recovered after isolating the product [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8) from mother liquor.
9. The process as claimed in claim 5, wherein the tritylation reaction is carried out in presence of alkali and alkaline earth metal carbonates.
10. The process as claimed in claim 5, wherein the trityl alcohol is recovered after isolating the product, [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol from the reaction mass.
11. The process as claimed in claim 1, wherein the intermediate compound of formula B is prepared by a process which comprises:
a) Reacting S-Methyl lactate with a secondary base to obtain the corresponding amide (B-3);
b) O-benzylating the amide (B-3) followed by subjecting to Grignard reaction with Ethyl magnesium bromide to obtain (2S)-2-(Benzyloxy)pentan-3-one (B-5);
c) Reducing the (2S)-2-(Benzyloxy)pentan-3-one with Lithium borohydride to obtain (2S)-2-(Benzyloxy)pentan-3-ol (B-6);
d) O-sulfonylating the (2S)-2-(Benzyloxy)pentan-3-ol B-6 by reacting with sulfonylating agent to obtain corresponding O-Sulphonyloxy derivative (B-7);
e) Reacting the O-Sulphonyloxy derivative (B-7) with Hydrazine to obtain [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazide (B-8);
f) Resolving the [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine (B-8) with Dibenzoyl D-tartaric acid to obtain [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine salt of (2S,3S)-2,3-bis(benzoyloxy)succinic acid (B-9);
g) Formylating the [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine salt of (2S,3S)-2,3-bis(benzoyloxy)succinic acid using Ethyl formate to obtain N'-[(1S,2S)-2-(Benzyloxy)-1-ethylpropyl]formic hydrazide (B-10); and
h) Reacting N'-[(1S,2S)-2-(Benzyloxy)-1-ethylpropyl]formic hydrazide with Phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl) phenylcarbamate to obtain 2-[(1S,2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl]phenyl]-3H-1,2,4-triazol-3-one (intermediate compound B).
12. The process as claimed in claim 11, wherein, the secondary base used in step a) is selected from the group consisting of Pyrrolidine, Piperidine and Morpholine.
13. The process as claimed in claim 11, wherein, the amides in step a) is selected from the group consisting of (S)-2-Hydroxy-1-morpholinopropan-1-one; (2S)-1-Oxo-1-pyrrolidin-1-ylpropan-2-ol and (2S)-1-Oxo-1-piperidin-1-ylpropan-2-ol.
14. The process as claimed in claim 11, wherein, the O-benzylated amides in step b) may be selected from the group consisting of 1-[(2S)-2-(Benzyloxy)propanoyl]pyrrolidine; (S)-2-(Benzyloxy)-1-morpholinopropan-1-one and 1-[(2S)-2-(Benzyloxy)propanoyl]piperidine.
15. The process as claimed in claim 11, wherein, the O-Sulphonyloxy derivative in step d) is selected from the group consisting of (2S)-2-(Benzyloxy)-1-ethylpropyl-4-chlorobenzene sulfonate; (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate; and 2-(Benzyloxy)-1-ethylpropyl-4-methylbenzene sulfonate.
16. The process as claimed in claim 15, wherein, the O-Sulphonyloxy derivative is(2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate.
17. The process as claimed in claim 11, wherein, the formylation reaction of step h) is carried out in presence of alcoholic solvents like Methanol, Ethanol or Isopropanol.
18. [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate of formula A

19. (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate of formula B-7

Description:Technical field:
The present invention relates to an improved process for the manufacture of Posaconazole, an anti-fungal agent belonging to the category of substituted TetrahydrofuranTriazole compound. The present invention further relates to preparation of formula A and formula B, the key intermediates in the preparation of Posaconazole.

Background and prior art:
Posaconazole was first reported in WO 9517407 (US 5661151) by Schering Corporation, having the following structural formula.

US Patent 5,403,937 discloses a process for the preparation of intermediate (A) shown above where L = p-Tolyl. The process involves use of n-Butyl lithium during the preparation of Oxazolidinone lithium salt, which is very expensive and extremely flammableand also involves column chromatography purificationof the intermediates at each stage of the process. This drawback makes it unsuitable for commercial manufacture of intermediate A and its use in the preparation of Posaconazole.PCT/US92/0898l further discloses processes for thesynthesis of substituted Tetrahydrofuran azoleantifungals via a Tosylate intermediate of the formula A. This process is inefficient and requires a costly chiral epoxidation to introduce the proper stereochemistry in the molecule. It was therefore desirable to develop a chiral synthesis of this key intermediate which does not suffer the shortcomings of the prior art process.

US Patent application 2016/0237066 claims an improved process for the above intermediate A and its use in the preparation of Posaconazole. This process uses potassium t-Butoxide and costly reagents like R-Phenyl oxazolidinone and solvents like Dimethyl sulphoxide which are not easily recoverable from the reaction medium. The process also involves tedious workup, leading to handling loses and lower yield.

In the absence of any robust process reported in the prior art, there felt a need by the present inventors for an improved process by providing simple workup techniques leading to higher yield or higher purity at every step in the production of intermediate of formula A. Further, it was also felt necessary to provide a process for the recovery and reuse of the R-Phenyl oxazolidinone, an expensive starting material in the manufacture of intermediate compound of formula A, which becomes an objective of the invention.

The process for preparation of intermediate compound of formula Bwasdisclosed in US5625064. US9102664 discloses another process for preparation of intermediate compound of formula B, viz., 2-[(1S,2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl]phenyl]-3H-1,2,4-triazol-3-one. Both the processes suffer from the drawback of poor yields. For instance, the process according to US 9102664 (example 14) gives the product in an approximateyield of 32%.

Therefore, the other objective of the present invention is to provide a cost-effective and commercially viable process for the preparation of intermediate compound of formula B, viz., 2-[(1S,2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl]phenyl]-3H-1,2,4-triazol-3-onewith increased yields and also by avoiding the excessive use of costly reagents like 4-Dimethylaminopyridine.

A further objective of the present invention to provide a commercially viable process for the production of Posaconazole by reacting the intermediate compounds of formula A and B.

Summary of the invention
With the above objectives, the present invention provides a process for preparation of key intermediates of compounds of formula A and formula B in high yields and purity and its further reaction to provide Posaconazole with high yields and purity.
Accordingly, in one aspect, the invention provides process for preparation of intermediate compound of formula A, which process comprises;
a) Reacting 1,3-Difluorobenzene with Succinic anhydride under Friedel craft conditions to obtain 4-(2,4-Difluorophenyl)-4-oxobutanoic acid (A-3);
b) Subjecting the 4-(2,4-Difluorophenyl)-4-oxobutanoic acid (A-3) to a Wittig reaction with Diphenyl methyl phosphonium bromide to obtain 4-(2,4-Difluorophenyl)-pent-4-enoic acid (A-4);
c) Reacting the 4-(2,4-Difluorophenyl)-pent-4-enoic acid with R(-)-4-Phenyl-2-oxazolidone in presence of a base to obtain (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one(A-5);
d) Reacting the (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one with Trioxane followed by iodination to isolate (4S)-3-{[(5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one (A-7);
e) Reducing the (4S)-3-{[(5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one (A-7) with Lithium borohydride to obtain [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8);
f) Tritylating the [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8) to obtain (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan(A-9)followed by reaction with 1,2,4–triazole in presence of a base to obtain 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole (A-10);
g) De-tritylating the 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole(A-10) to obtain [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11);
h) Reacting the [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11) with 4-Chlorobenzene sulfonyl chloride or 4-Nitrobenzene sulfonyl chloride or p-Toluenesulfonyl chloride in presence of a base to obtain respective salts of [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A).

According toanother aspect, the invention provides process for preparation of intermediate compound of formula B, which process comprises;
a) Reacting S-Methyl lactate with a secondary base to obtain the corresponding amide B-3;
b) O-Benzylating the amide B-3 followed by subjecting to Grignard reactionwith Ethyl magnesium bromideto obtain Benzyloxy ketone B-5;
c) Reducing the Benzyloxy ketone with Lithium borohydride to obtain B-6;
d) O-sulfonylating the product B-6by reacting with sulfonylating agent to obtain O-Sulphonyloxy derivative B-7;
e) Reacting the O-Sulphonyloxy derivativeB-7 with Hydrazine to obtain hydrazide compound B-8;
f) Resolving the hydrazide compound B-8 with Dibenzoyl D-tartaric acid to obtain chiral Hydrazide B-9;
g) Formylating the chiral Hydrazide using Ethyl formateto obtainFormyl hydrazide B-10; and
h) Reacting the formylhydrazide(B-10) with Phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenylcarbamate(B-11) to obtain 2-[(1S,2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl]phenyl]-3H-1,2,4-triazol-3-one (IntermediateB).

In yet another aspect, the invention provides a process for preparation of Posaconazole which process comprises;
a) Reacting intermediate (A) (where L is leaving group selected from 4-Chlorobenzene sulfonyl; 4-Nitrobenzene sulfonyl or p-Toluenesulfonyl) with intermediate (B) to obtain Benzyl posaconazole and
b) Debenzylating the Benzyl posaconazole using Pd/C.

Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

Accordingly, the present invention provides a process for preparation of key intermediates of compounds of formula A and formula B in high yields and purity and its further reaction to provide Posaconazole with high yields and purity.
Accordingly, in one embodiment, the invention provides process for preparation of intermediate compound of formula A, which process comprises;
a) Reacting 1,3-Difluorobenzene with Succinic anhydride under Friedel craft conditions to obtain 4-(2,4-Difluorophenyl)-4-oxobutanoic acid (A-3);
b) Subjecting the 4-(2,4-Difluorophenyl)-4-oxobutanoic acid (A-3) to a Wittig reaction with Methyl triphenyl phosphonium bromide to obtain 4-(2,4-Difluorophenyl)-pent-4-enoic acid (A-4);
c) Reacting the 4-(2,4-Difluorophenyl)-pent-4-enoic acid with R(-)-4-Phenyl-2-oxazolidone in presence of a base to obtain (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one (A-5);
d) Reacting the (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one with Trioxane followed by iodination to isolate (4S)-3-{[(5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one (A-7);
e) Reducing the (4S)-3-{[(5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one (A-7) with Lithium borohydride to obtain [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8);
f) Tritylating the [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8) to obtain (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan(A-9) followed by reaction with 1H-1,2,4 –triazole in presence of a base to obtain 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole (A-10);
g) Detritylating the 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole (A-10) to obtain [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11);
h) Reacting the [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11) with 4-Chlorobenzene sulfonyl chloride or 4-Nitrobenzene sulfonyl chloride or p-Toluenesulfonyl chloride in presence of a base to obtain respective salts of [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A).

The solvents used in the Wittig reaction are selected from Aromatic hydrocarbons like Xylene, Toluene, and Mixed Xylenes etc. In a preferred embodiment, the solvent is toluene.

The reaction of 4-(2,4-Difluorophenyl)-pent-4-enoic acid (A-4)with R(-)-4-Phenyl-2-oxazolidone to obtain (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one (A-5)is carried out without using Dimethyl amino pyridine. Instead the present invention usetertiary bases like Triethyl amine, Pyridine, Hunig’s base etc. In a preferred embodiment, the base selected is Pyridine.

In step (e), the product, [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol(A-8) obtained is sufficiently pure and is easily isolated without resorting to column chromatography.After isolating the product [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8), the mother liquor is distilled and then recovered R(-)-4-Phenyl-2-oxazolidone by the addition of suitable solvent to the residue.

The resultant product, [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (A-8) is tritylatedto obtain (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan(A-9)and then reacted with 1, 2,4 triazoleto obtain 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole(A-10). The tritylation reaction can becarried out easily using inorganic carbonates instead of Potassium/Sodium tert-butoxide. The inorganic carbonates are selected from alkali and alkaline earth metal corbonates. Preferably the reaction is carried out using Potassium carbonate.

The product, 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole (A-10)thus obtained is detritylated to obtain [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11). The Tritylalcoholthus released is recovered and reused in the subsequent batch.The [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (A-11) thus obtained is reacted with 4-Chlorobenzene sulfonyl chloride or 4-Nitrobenzene sulfonyl chloride or p-Toluenesulfonyl chloride to obtain respective salts of [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (compound of formula-A).In a preferred embodiment, the reagent is 4-Nitrobenzene sulfonyl chloride.

Accordingly, the salts of [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol(compound of formula A) are selected from the group consisting of [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate; [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-chlorobenzene sulfonate and [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-p-toluene sulfonate.

According to another embodiment, the invention provides hitherto unreported novel intermediate compound of formula A, viz. [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate of formula A, which is characterized by IR and NMR, as shown in example 31.

The isolation procedure and work up in each step has been improved to obtain the compound of formula A in significantly higher yields of 85% on theory against 44% of the methods reported in prior arts. The process for preparation of intermediate compound of formula A is shown in scheme A below:
Scheme A

According to another embodiment, the invention provides process for preparation of intermediate compound of formula B, which process comprises;
a) Reacting S-Methyl lactate with a secondary base to obtain the corresponding amide (B-3);
b) O-benzylating the amide (B-3)to obtain O-benzylated amides (B-4) followed by subjecting the O-benzylated amides to Grignard reaction with Ethyl magnesium bromide to obtain (2S)-2-(Benzyloxy)pentan-3-one(B-5);
c) Reducing the (2S)-2-(Benzyloxy)pentan-3-one(B-5)with Lithium borohydride to obtain (2S)-2-(Benzyloxy)pentan-3-ol (B-6);
d) O-sulfonylating the (2S)-2-(Benzyloxy)pentan-3-ol (B-6) by reacting with sulfonylating agent to obtain corresponding O-Sulphonyloxy derivative (B-7);
e) Reacting the O-Sulphonyloxy derivative (B-7) with Hydrazine to obtain [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazide (B-8);
f) Resolving the [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine (B-8) with Dibenzoyl D-tartaric acid to obtain [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine salt of (2S,3S)-2,3-bis(benzoyloxy)succinic acid (B-9);
g) Formylating the [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine salt of (2S,3S)-2,3-bis(benzoyloxy)succinic acid using Ethyl formate to obtain N'-[(1S,2S)-2-(Benzyloxy)-1-ethylpropyl]formic hydrazide (B-10); and
h) Reacting N'-[(1S,2S)-2-(Benzyloxy)-1-ethylpropyl]formic hydrazide with Phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl) phenylcarbamate to obtain 2-[(1S,2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl]phenyl]-3H-1,2,4-triazol-3-one (B).

The secondary base used in step a) is selected from the group consisting of Pyrrolidine, Piperidine, Morpholine etc. Preferably, the secondary base can be used in the order of Morpholine, Pyrrolidine and Piperidine to obtain the corresponding amides such as (S)-2-Hydroxy-1-morpholinopropan-1-one( example 2); (2S)-1-Oxo-1-pyrrolidin-1-ylpropan-2-ol(example 1) and (2S)-1-Oxo-1-pyrrolidin-1-ylpropan-2-ol.
The O-benzylated amides may be selected from the group consisting of 1-[(2S)-2-(Benzyloxy)propanoyl]pyrrolidine (example-3);(S)-2-(Benzyloxy)-1-morpholinopropan-1-one (example-4) and 1-[(2S)-2-(Benzyloxy)propanoyl]piperidine.

The sulfonylating agent as used step d) is selected from the group consisting of 4-Chlorobenzene sulfonyl chloride or 4-Nitrobenzene sulfonyl chloride or p-Toluenesulfonyl chloride. In one preferred embodiment, the sulfonylating agent is 4-Nitrobenzene sulfonyl chloride.The important feature of this reaction is that the use of expensive Dimethyl amino pyridine is avoided.

The O-Sulphonyloxy derivative (B-7) is selected from the group consisting of (2S)-2-(Benzyloxy)-1-ethylpropyl-4-chlorobenzene sulfonate (example-8); (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate(example-10); and 2-(Benzyloxy)-1-ethylpropyl-4-methylbenzene sulfonate.

In additional aspect, the invention provides novelO-Sulphonyloxy derivative, viz., (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate of formula B-7 as shown below, which is further characterized by NMR, as provided under example 11.

The formylation reaction of step h) is carried out in presence of alcoholic solvents like Methanol, Ethanol or Isopropanol, preferably, the alcoholic solvent is Methanol.
The process for preparation of compound of formula B is briefly depicted in scheme B:

SchemeB:

In yet another embodiment, the invention provides a process for preparation of Posaconazole which process comprises;
a) Reacting intermediate compound of formula A(where in L is a leaving group selected from 4-Chlorobenzene sulfonyl or 4-Nitrobenzene sulfonyl or p-Toluenesulfonyl with intermediate compound of formula B in presence of a Base and Polar aprotic solvent to obtain Benzyl posaconazole; and
b) Debenzylating the Benzyl posaconazole using Pd/C to obtain Posaconazole.

The Polar aprotic solvent is selected from the group consisting of Dimethylsufoxide and Dimethyl formamide.

The intermediate compound of formula A is selected from the group consisting of [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate; [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-chlorobenzene sulfonate and [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-p-toluene sulfonate.

In a preferred embodiment, the intermediate compound of formula A is[(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate.

The process for preparation of Posaconazole in accordance with the invention is shown in scheme C.

Scheme C

Other features and embodiments of the invention will become apparent by the following examples which are given for illustration of the invention rather than limiting its intended scope. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.

Example-1:
Process for preparation of (2S)-1-Oxo-1-pyrrolidin-1-ylpropan-2-ol:
S-Methyl lactate (1 kg) was added to the flask at room temperature followed by the slow addition of N-Pyrrolidine (1 kg) for 30 min. The reaction mixture was slowly heated to 80-850C and maintained for 3 hrs. After completion of the reaction N-Pyrrolidine was completely distilled out under vacuum at 850C.
Crude: 1.3 kg; G.C: 92%

Example-2:
Process for preparation of (S)-2-Hydroxy-1-morpholinopropan-1-one:
S-Methyl lactate (1 kg) was added to the flask at the temperature 25-300C. Morpholine (1 kg) was slowly added and stirred for 15 min. The reaction mixture was heated slowly to 90-950C and maintained for 15-20 hrs. After completion of the reaction, Morpholine was distilled out under vacuum at 80-850C.
Crude: 1.40 kg; G.C: 95%;

Example-3:
Process for preparation of 1-[(2S)-2-(Benzyloxy)propanoyl]pyrrolidine:
Toluene (6 lit) was added to the RB flask at the room temperature under Nitrogen media along with sodium hydroxide (0.605 kg). Benzoyl chloride (0.9 kg) was added slowly and stirred for 10 min. Then (2S)-1-Oxo-1-pyrrolidin-1-ylpropan-2-ol of (1 kg) was slowly added for about 1 hr. The reaction mixture was heated to 80-850C and maintained for 2 hrs and cooled to room temperature, water (8 lit) was added slowly and allowed to stir for 10 min. Aqueous layer and Toluene layer were separated and aqueous layer was extracted with 1 lit of Toluene. Then aqueous layer and organic layer were separated and organic layer pH was adjusted to 2.0 with solution of Hydrochloric acid in water. Organic layer was separated and washed with brine solution and dried over Sodium sulphate and distilled under vacuum at below 600C.
Crude: 1.4 kg; Purity: 96%;

Example-4:
Process for preparation of (S)-2-(Benzyloxy)-1-morpholinopropan-1-one:
Sodium hydroxide (0.6 kg) was added to the Flask containing Toluene (6 lit) at room temperature under nitrogen media followed by the addition of Benzoyl chloride (0.9 kg) and stirred for 10 min. Then (S)-2-Hydroxy-1-morpholinopropan-1-one (1 kg) was slowly added for 1 hr and then heated to 90-950C and maintained for 9-11 hrs and cooled to room temperature. Then water (8 lit) was slowly added for 2 hrs, aqueous layer and Toluene layer were separated and aqueous layer was extracted with Toluene (1 lit). Then again aqueous layer and Toluene layer were separated and the total Toluene layer was washed with solution of hydrochloric acid (0.08 lit) in Water (1 lit). Then again aqueous layer and Toluene layer were separated and the total Toluene layer was washed with Water (1 lit). Again aqueous layer and Toluene layer were separated and the total Toluene layer was washed with mixture of 0.1 kg of Sodium chloride and Water (1 lit). Aqueous layer and Toluene layerwere separated and the toluene layer was dried over Sodium sulfate (0.2 kg) and distilled toluene layer under vaccum 50°C.
Crude: 1.40 kg; Purity: 97%;

Example-5:
Process for preparation of (2S)-2-(Benzyloxy)pentan-3-one:
Ethyl bromide (0.09 kg) was added to the mixture of magnesium (0.3 kg) and Tetrahydrofuran (0.85 lit) in RB flask at room temperature under Nitrogen media. After the reaction was initiated then the temperature was automatically raised to 60-650C and Ethyl bromide (1.6 kg) in Tetrahydrofuran (4 lit) was added to the reaction mixture and maintained for 1 hr. Then it was cooled to room temperature and stirred for 15 min. Then it was again cooled to the temperature of 0-50C and slowly 1-[(2S)-2-(Benzyloxy)propanoyl]pyrrolidine (1 kg) along with 2 lit of Tetrahydrofuran were charged and maintained for 1 hr and the reaction mixture was kept aside. Ice (7 kg) and Hydrochloric acid (1.75 lit) were charged into another Flask and it was cooled to 0-50C, and this reaction mixture was added to above reaction mixture slowly for 1-2 hrs. Stirred for 15 min and reaction mass was extracted with Dichloromethane (2.5 lit).Organic layer was separated and washed with the solution of Sodium chloride (0.3 kg) in Water (3 lit). This step of separation and washing was repeated once. Aqueous layer and organic layer were separated and organic layer was dried over sodium sulphate, which was distilled under vacuum at below 500C and make sure that the percentage of Dichloromethane must be nil.
Crude: 0.85 kg; Purity: 87%;

Example-6:
Process for preparation of (R)-2-(Benzyloxy)hexan-3-one:
Ethyl bromide (0.09 kg) was added to the solution of Magnesium (0.3 kg) in Tetrahydrofuran (0.85 lit) at Room temperature under Nitrogen media. Reaction initiation was observed and the Temperature was automatically raised to 60-650C and mixture of Ethyl bromide (1.6 kg) and of Tetrahydrofuran (4 lit) was added to the reaction mixture and maintained for 1 hr. Then it was cooled to Room temperature and stirred for 15 min. Then it was again cooled to the temperature of 0-50C and slowly (S)-2-(Benzyloxy)-1-morpholinopropan-1-one (1 kg) along with Tetrahydrofuran (2 lit) were charged and maintained for 1 hr, and the reaction mixture was kept aside. Ice (7 kg) and Hydrochloric acid (1.75 lit) were added to another Flask and it was cooled to 0-50C, and this reaction mixture was added to above reaction mixture slowly for 1-2 hrs. Stirred for 15 min and reaction mass was extracted with Dichloromethane (2.5 lit).Organic layer was separated and washed with the mixture of Sodium chloride (0.3 kg) and Water (3 lit). This step of separation and washing was repeated once. Aqueous layer and organic layer were separated and organic layer was dried over sodium sulphate, which was distilled under vacuum at below 500C and make sure that the percentage of Dichloromethane must be nil.
Crude: 0.89 kg; Purity: 89%;

Example-7:
Process for preparation of (2S)-2-(Benzyloxy) pentan-3-ol:
Tetrahydrofuran (5 lit) and Sodium borohydride (0.32 kg) were added to the flask at room temperature under Nitrogen media and maintained for 30 min followed by the addition of Lithium bromide (0.75 kg). This addition leads to automatic temperature rise to 500C and maintained for 15 hrs without any cooling. Zinc bromide (0.02 kg) was added at room temperature and then cooled to -70C to -20C. (2S)-2-(Benzyloxy) pentan-3-one (1 kg) was added slowly for 1-2 hrs and maintain at 0-50C for 1 hr and 10 lit of water was slowly added and pH was adjusted to 2.0 with 50% HCl. Temperature was raised to 30-350C then reaction mass was extracted with Dichloromethane Aqueous layer and organic layer were separated and organic layer was added and stirred for 10 min. Dichloromethane layer was washed with Water (3 lit). Aqueous layer and organic layer were separated and organic layer washed with brine solution. After washing, organic layer was separated and dried with Sodium sulphate (0.2 kg), distilled under vacuum at below 500C.
Crude: 0.8 kg; HPLC: 76%

Example-8:
Process for preparation of (2S)-2-(Benzyloxy)-1-ethylpropyl-4-chlorobenzene sulfonate:
Dichloromethane (6.9 lit) and (2S)-2-(Benzyloxy)pentan-3-ol (1 kg) were added to the Flask along with 4-Dimethylaminopyridine (240 gm) at Room temperature. The mass was then cooled to 0-50C and 4-Chlorobenzene sulfonyl chloride (1.42 kg) was added slowly for 10 min and Triethylamine (2.43 kg) was added slowly for 1 hr. Then the temperature was raised to 30-350C and maintained for 12 hrs and then cooled to room temperature. Water (5 lit) was added and stirred for 30 min. aqueous layer and organic layer was separated and aqueous layer was extracted with Dichloromethane (2.5 lit). Then total Dichloromethane layer was washed with solution of HCL (550 ml) in Water (5 lit). Dichloromethane layer was again washed with solution containing Sodium carbonate (250 gm) and Water (5 lit). Dichloromethane layer was washed with brine solution and then dried over Sodium sulphate and distilled under vacuum at below 500C.
Crude: 1.75 kg; HPLC: 89%

Example-9:
Process for preparation of (2S)-2-(Benzyloxy)-1-ethylpropyl-4-chlorobenzene sulfonate (New Procedure):
Dichloromethane (6.95 lit) and (2S)-2-(Benzyloxy)pentan-3-ol (1 kg) were added to the flask along with 4-Dimethylaminopyridine (240 gm) at room temperature. The reaction mass was then cooled to 0-50C and 4-Chlorobenzene sulfonyl chloride (1.42 kg) was added slowly for 10 min and Pyridine (2.43 kg) was slowly added for 1 hr. Then the temperature was raised to 30-350C and maintained for 12 hrs and then cooled to room temperature. Water (5 lit) was added and stirred for 30 min. aqueous layer and organic layer were separated and aqueous layer was extracted with Dichloromethane (2.5 lit). Then total Dichloromethane layer was washed with solution of HCL (550 ml) in Water (5 lit). Dichloromethane layer was again washed with solution contains Sodium carbonate (250 gm) and Water (5 lit) and then dried over Sodium sulphate and distilled under vacuum at below 500C.
Crude: 1.75 kg; HPLC: 89%;

Example-10:
Process for preparation of (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate:
Dichloromethane (6.95 lit) and (2S)-2-(Benzyloxy) pentan-3-ol (1 kg) were added to the Flask at room temperature. The mass was then cooled to 0-50C and 4-Nitrobenzene sulfonyl chloride (1.42 kg) was slowly added for 10 min and Triethylamine (1.575 kg) slowly added for 2 hrs. Then the temperature was raised to 30-350C and maintained for 12 hrs and then cooled to Room temperature. Water (5 lit) was added and stirred for 30 min. Aqueous layer and organic layer was separated and aqueous layer was extracted with Dichloromethane (2.5 lit). Then total Dichloromethane layer was washed with solution of HCL (550 ml) in Water (5 lit). Dichloromethane layer was again washed with solution containing Sodium carbonate (250 gm) and Water (5 lit) and then dried over Sodium sulphate and distilled under vacuum at below 500C.
Crude: 1.7 kg; HPLC: 94%
Example-11:
Process for preparation of (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate:
Dichloromethane (6.95 lit) and (2S)-2-(Benzyloxy)pentan-3-ol (1 kg) were added to the flask at room temperature. The mass was then cooled to 0-50C and 4-Nitrobenzene sulfonyl chloride (1.42 kg) was slowly added for 10 min and also Pyridine (1.575 kg) was slowly addedfor 2 hrs. Then the temperature was raised to 30-350C and maintained for 12 hrs. Water (5 lit) was added and stirred for 30 min. Aqueous layer and organic layer was separated and aqueous layer was extracted with Dichloromethane (2.5 lit). Then total Dichloromethane layer was washed with solution of HCL (550 ml) in Water (5 lit) and washed with solution containing Sodium carbonate (250 gm) and Water (5 lit). Dichloromethane layer was washed with brine solution and then dried over Sodium sulphate and distilled under vacuum at below 500C.
Crude: 1.7 kg; HPLC: 94%
IR Spectrum of Compound (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate: Sample has characteristic peaks at 3105 cm-1, 3021 cm-1, 2934 cm-1, 2877 cm-1, 2386 cm-1, 2113 cm-1, 1606 cm-1, 1529 cm-1, 1453 cm-1, 1311 cm-1, 1182 cm-1, 1027 cm-1, 915 cm-1, 738 cm-1, 558 cm-1.
1H NMR (CDCl3) of Compound (2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzene sulfonate: ?? 8.00-7.95 (m, 2H), ??7.88-7.85 (m, 1H), ?? 7.23-7.13 (m, 4H), ??7.06-7.04 (m, 1H), ??4.69-4.67 (m, 1H), ??4.25-4.23 (d, 2H), ??3.53-3.46 (m, 1H), ??1.79-1.48 (m, 2H), ?? 1.03-1.01 (d, 3H), ?? 0.89-0.81 (t, 3H).

Example-12:
Process for preparation of [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine salt of (2S,3S)-2,3-bis(benzoyloxy)succinic acid:
(2S)-2-(Benzyloxy)-1-ethylpropyl-4-chlorobenzenesulfonate (1 kg) was added to the flask along with Ethanol (1.5 lit) at 25-300C. Hydrazine hydrate (2.75 lit) was slowly added for 1 hr and the temperature was raised to 65-700C and maintained for 12 hrs and then cooled to 25-300C and to 10-150C. Water (2.2 lit) was added to the reaction mixture, organic layer and aqueous layer were separated, organic layer was washed with Water (1.8 lit) and brine solution. The resultant reaction mixture was added to another Flask containing Dibenzoyl D-tartaric acid (0.8 kg) and Methyl T-butyl ether (3 lit) at room temperature, maintained for 1 hr, filtered and washed with Methyl T-butyl ether (0.5 lit) and material was dried at 40-450C.
Crude: 0.5 kg; HPLC: 89%

Example-13:
Process for preparation of [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine salt of (2S,3S)-2,3-bis(benzoyloxy)succinic acid:
(2S)-2-(Benzyloxy)-1-ethylpropyl-4-nitrobenzenesulfonate (1 kg) was added to the flask along with Ethanol (1.5 lit) at 25-300C. Hydrazine hydrate (2.75 lit) was slowly added for 1 hr and the temperature was raised to 65-700C and maintained for 12 hrs and then cooled to 25-300C and to 10-150C. Water (2.2 lit) was added to the reaction mixture, organic layer and aqueous layer were separated, aqueous layer was kept aside and organic layer was washed with Water (1.8 lit). Again organic layer and aqueous layer were separated and organic layer was washed with solution with the brine solution. Again organic layer and aqueous layer were separated and organic layer was dried over sodium sulphate and was kept aside under 10-150C. Dibenzoyl D-tartaric acid (0.8 kg) and Methyl T-butyl ether (3 lit) was taken into another flask at 25-300C. The organic layer which was kept aside was added into the flask. Kept aside aqueous layer was extracted with Methyl T-butyl ether (1.8 lit) at 10-150C. Organic layer and aqueous layer were separated, aqueous layer was kept aside and organic layer was washed with the brine solution. Organic layer and aqueous layer were separated, and organic layer was dried with Sodium sulphate and was added into the Reaction mixture at 25-300C. Kept aside aqueous layer was extracted with Methyl T-butyl ether (1 lit) at 10-150C. Organic layer and aqueous layer were separated, and organic layer was washed with brine solution. Organic layer and aqueous layer were separated at 10-150C, organic layer was dried with Sodium sulphate and was added to the Reaction mixture and maintained at 25-300C for 1 hr, filtered and Filter washed with Methyl T-butyl ether (0.5 lit) and the material was transferred to another Flask along with Methyl T-butyl ether (4 lit), heated to temperature 40-450C and maintained for 1 hr. Then the reaction mass was cooled to 25-300C and again cooled to 10-150C and maintained for 30 min, Filter and the material was washed with Methyl T-butyl ether (1 lit) and material was dried at 40-450C.
Crude: 0.55 kg; HPLC: 89%

Example-14:
Process for preparation of N'-[(1S,2S)-2-(Benzyloxy)-1-ethylpropyl]formic hydrazide:
Methanol (4 lit) and [(2S)-2-(Benzyloxy)-1-ethylpropyl]hydrazine salt of (2S,3S)-2,3-bis(benzoyloxy) succinic acid (1 kg) were added to the flask at room temperature. Temperature was raised to 50-550C, then Ethyl formate (6 lit) was added to the reaction mixture slowly and maintained for 4 hrs. After completion of reaction cooled to room temperature. Water (5 lit) and Dichloromethane (5 lit) were added to the mass and cooled to 0-50CpH was adjusted to 9.0-9.5 with 20% Sodium carbonate (0.6 kg) in Water (3 lit). Then the temperature was raised to room temperature and stirred for 10 min. Aqueous layer and Dichloromethane layers were separated organic layer was washed with Water (3 lit)and brine solution. Organic layer was separated and dried with Sodium sulphate and distilled completely under vacuum at below 500C.
Out Put: 0.38 kg; HPLC: 89%.

Example-15:
Process for preparation of 2-[(1S2S)-1-Ethyl-2-benzyloxy propyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl]phenyl]-3H-1,2,4-triazol-3-one:
N'-[(1S,2S)-2-(Benzyloxy)-1-ethylpropyl]formic hydrazide (1 kg) and 1,4-Dioxane (5 lit) were added to the flask at room temperature along with Phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenylcarbamate (1.4 kg). The reaction mass was heated to 90-950C and Triethylamine (0.89 lit) was slowly added and stirred for 1 hr and maintained for 12-18 hrs. TLC was checked for intermediate and cooled to Room temperature and Dichloromethane (20 lit) was charged and filter through the Hyflow bed and washed with Dichloromethane (5 lit). Water (4 lit) was added and stirred for 10 min. Aqueous layer and Organic layer were separated and organic layer was washed with brine solution. Organic layer was separated and dried with Sodium sulphate and distilled completely under vacuum at below 500C and co-distilled with Toluene (1 lit) and Isopropyl alcohol (1 lit). Isopropyl alcohol (2.5 lit) was added to the crude and maintained at 65-700C for 1 hr, then cooled to Room temperature, stirred for 30 min and cooled to 10-150C, and then filtered and washed with Isopropyl alcohol (0.5 lit).
Out Put: 0.89 kg; HPLC: 97%.

Example-16:
Process for preparation of 4-(2,4-Difluorophenyl)-4-oxobutanoic acid:
1, 3-Difluorobenzene (1 kg) was added to the flask along with Succinic anhydride (0.95 kg) and Dichloromethane (8 lit) at room temperature and cooled to 0-50C under Nitrogen media. Aluminium chloride (1 kg) was slowly added in lot wise and maintained for 15 min at 0-50C. This process was repeated for 2 times until yellow colour changes to brown colour. Then the temperature was raised to 35-400C, pink colour appears and maintained for 3-4 hrs and cooled to room temperature. The reaction mass was then added to another flask containing ice (10 kg) below 200C. Hydrochloric acid (1 lit) was added and stirred for 30 min, followed by the addition of Dichloromethane (5 lit) and stirred for 30 min. aqueous layer and Dichloromethane layers were separated at 30-350C. Then Dichloromethane layer was washed with brine solution. Aqueous layer and Dichloromethane layers were separated at same temperature and Dichloromethane layer was dried over Sodium sulfate (0.2 kg) and distilled under vacuum at below 500C. Toluene (3 lit) was added to the Resulting crude, then heated to 75-800C and maintained for dissolution. The reaction mass was cooled to room temperature and stirred for 30 min and then again cooled to 10-150C and maintained for 1 hr, filtered and finally washed with Toluene (0.5 lit).
Output: 1.35 kg; HPLC: 99%.

Example-17:
Process for preparation of 4-(2,4-Difluorophenyl)-pent-4-enoic acid:
Toluene (10 lit) was added to the flask along with 4-(2,4-Difluoro phenyl)-4-oxobutanoic acid (1 kg) and Methyl Triphenyl phosphonium bromide (2.2 kg) at room temperature under Nitrogen media. The reaction mass was cooled to 10-150C. Sodium t-but oxide (1.12 kg) was added and heated to 60-650C and maintained for 5 hrs. Then it was cooled to 100C. After the addition of water (10 lit), temperature was raised to 300C. Toluene layer and aqueous layer were separated. Aqueous layer was washed with Dichloromethane (5 lit) and stirred for 15 min. aqueous layer was separated and cooled to 0-50C. The pH of the reaction mass was adjusted to 2.0-3.0 with Hydrochloric acid solution and maintained for 1 hr. The resultant material was then filtered, washed with Water (0.3 lit) and dried at 40-450C. The resultant crude was purified with n-Hexane (1.9 lit) and stirred for 1 hr at room temperature and dried at 40-450C.
Output: 0.95 kg; HPLC: 98%.

Example-18:
Process for preparation of (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one :
4-(2,4-Difluorophenyl)-pent-4-enoic acid (1 kg) was added to the Flask containing Dichloromethane (3 lit) under Nitrogen media at room temperature. 4-Dimethylaminopyridine (60 gm) and R-(-)-4-Phenyl-2-oxazolidinone (770 gm) were added and stirred for 15 min. N,N'-Dicyclohexylcarbodiimide (1.07 kg) solution was slowly added at 10-150C for 5-6 hrs. Temperature was raised to room temperature and maintained for 5-6 hrs. The resultant Bi-product was filtered and washed with Dichloromethane (2 lit) and transferred to another flask. Dichloromethane (3 lit) was added and stirred for 30 min at room temperature, filtered and washed with Dichloromethane (1 lit). The resultant Dichloromethane layer was washed with solution of Hydrochloric acid (0.46 lit) in Water (0.5 lit). This process of washing was repeated for 2 more times. The total Dichloromethane layer was then dried over Sodium sulfate and distilled under vacuum completely at below 500C. Co-distilled with Methanol (0.5 lit) at room temperature, heated to 40-450C and maintained for 2 hrs. Finally the reaction mass was filtered and washed with Methanol (2 lit) and dried.
Output: 1.3 kg; HPLC: 98.4%.

Example-19:
Process for preparation of (4S)-3-[(2R)-4-(2,4-Difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl]-4-phenyl-1,3-oxazolidin-2-one:
(4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one (1 kg) was added to the Flask containing Dichloromethane (10 lit) at room temperature under Nitrogen media and cooled to -100C to -150C. Slowly Titanium tetrachloride (0.33 lit) and Dichloromethane (0.5 lit) was added at same temperature for 45 min. Diisopropyl ethylamine (0.46 kg) was slowly added for 45 min and followed by the slow addition of 1,3,5-Trioxane and Dichloromethane (1.5 lit) for 60 min at -100C to -150C. Temperature was raised to 20°C and maintained for 15 min. Ammonium chloride (1 kg) and Water (9 lit) was added to another Flask, stirred for 10 min and cooled to 10-150C. The above reaction mass was added to ammonium chloride solution below 100C, stirred for 15 min. Aqueous layer and Dichloromethane layer were separated where Dichloromethane layer was washed with Water (2.5 lit) and brine solution. This process was again repeated for one more time and Dichloromethane layer was separated anddried over Sodium sulfate and added to another Flask, cooled to 10-150C under Nitrogen media. Solution of Iodine (1.78 kg) in Tetrahydrofuran (2.5 lit) was added for 1 hr and maintained for 1 hr at same temperature and quench the reaction mass with solution of Sodium thiosulfate (3 kg) in water (12 lit). Aqueous layer and organic layer were separated and organic layer was washed with brine solution. Organic layer was dried over Sodium sulfate and distilled under vacuum at 450C and further co-distilled with Methanol (1 lit). To the resultant crude, Methanol (5 lit) was added and heated to 60-650C, stirred for 1 hr, cooled to Room temperature, stirred for 3 hrs and then again cooled to 5-100C and maintained for 1 hr. Finally washed with Methanol (0.15 lit) and dried the material at 50-550C.
Output: 0.82 kg; HPLC: 96.4%.

Example-20:
Process for preparation of[(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol:
Tetrahydrofuran (5 lit) and Sodium borohydride (0.32 kg) were added to the flask and stirred for 30 min at room temperature. Lithium bromide (0.8 kg) was added and stirred for overnight at room temperature and cooled to 0-50C. (4S)-3-{[(5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl }-4-phenyl-1,3-oxazolidin-2-one (1 kg) and Tetrahydrofuran (5 lit) were slowly added to the reaction mixture and stirred for 30 min at same temperature under Nitrogen media. Chilled water (6.6 lit) was slowly added. The reaction mass was extracted with Dichloromethane (3.3 lit).The Dichloromethane layer was separated and washed with the brine solution and dried on sodium suphate.The resultant Dichloromethane layer was distilled under vacuum at 400C. Then Diisopropyl ether (1.5 lit) was added into resultant crude and cooled to 10-150C, filtered the Solid (Recovery of R-Phenyl oxazolidinone) and washed with Diisopropyl ether (0.3 lit).Distilled the Diisopropyl ether filtrate under vacuum at 400C to get [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanolas a syrup of about650 gm.
HPLC purity is about: 80%; Recovery R-Phenyl oxazolidinone Wt: 0.19Kg

Example-21:
Process for preparation of (4S)-3-[4-(2,4-Difluorophenyl)-pent-4-enoyl]-4-phenyl-oxazolidin-2-one using the recoverered R-(-)-4-Phenyl-2-oxazolidinone
Dichloromethane (0.7 lit) was added to the Flask under Nitrogen media at room temperature followed by the addition of 4-(2,4-Difluorophenyl)-pent-4-enoic acid (0.24 kg), 4-Dimethylaminopyridine (60 gm) and above recovered R-(-)-4-Phenyl-2-oxazolidinone (0.19 Kg) (From example-20) were added and stirred for 15 min. Solution of N,N'-Dicyclohexylcarbodiimide (0.265 kg) was slowly added at 10-150C for 5-6 hrs. Temperature was then raised to room temperature and maintained for 5-6 hrs. The resultant Bi-product was filtered and washed with Dichloromethane (0.5 lit) and transferred to another Flask. Dichloromethane (0.7 lit) was added and stirred for 30 min at room temperature, filtered and washed with Dichloromethane (0.250 lit). The resultant Dichloromethane layer was washed with Hydrochloric acid and water. The total Dichloromethane layer was then dried over Sodium sulfate and distilled under vacuum completely at below 500C. Co-distilled with Methanol (0.12 lit) at room temperature, heated to 40-450C and maintained for 2 hrs. Filtered and washed with Methanol (0.5 lit) and dried to get the title compound.
Output: 1.28 kg; HPLC: 98.2%.

Example-22:
Process for preparation of (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan:
Dichloromethane (2.5 lit) and [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (1 kg) was added to the flask at room temperature and cooled to 10-150C. Triethylamine (1 kg) was added and followed by the slow addition of Trityl chloride (1 kg) and Dichloromethane (2.5 lit) for 2 hrs. Temperature was raised to room temperature and maintained for 4 hrs. After completion of reaction water (5 lit) was added and stirred for 15 min and allowed to settle for 15 min. Dichloromethane layer was separated and washed with water (5 lit) and brine solution Aqueous layer and Dichloromethane layers were separated and Dichloromethane layer was dried over Sodium sulfate, distilled under vacuum below 450C and co-distilled with Methanol (0.2 lit). Methanol (8 lit) was added to the reaction mixture and temperature raised to 60-650C, maintained for 1 hr and cooled to 35-400C. The resultant mass was filtered and washed with Methanol (0.2 lit) and dried at 50-550C.
Output: 1.30 kg; HPLC: 99%.

Example-23:
Process for preparation of 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole
Dimethyl formamide (5 lit) was charged into the flask along with 1,2,4 –Triazole (0.28 kg) and 4-Dimethyl amino pyridine (0.02 kg) and Sodium t-butoxide (1 kg) at room temperature and maintained for 3 hrs. (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan was added into the reaction mixture and heated to temperature 110-1150C and maintained for 12 hrs. The reaction was cooled to room temperature after completion. Then Water (8 lit) was added slowly for 3 hrs and maintained for 1 hr, Filtered and washed with water (0.5 lit).
Yield: 0.65Kg; Purity: 97%.

Example-24:
Process for preparation of 1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole:
Dimethyl formamide (5 lit) was charged into the Flask along with 1,2,4-Triazole (0.28 kg) and Potassium carbonate (1 kg) at room temperature and maintained for 3 hrs. (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl) furan was added into the reaction mixture and heated to temperature 110-1150C and maintained for 12 hrs. The reaction was cooled to room temperature after completion. Then water (8 lit) was added slowly for 3 hrs and maintained for 1 hr, Filtered and washed with water (0.5 lit).
Yield: 0.8KG; Purity: 98%.

Example-25:
Process for preparation of [(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol:
1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy) methyl)furan-2-yl) methyl)-1H-1,2,4-triazole (1 kg) and Acetone (3 lit) was added to the flask at room temperature, then cooled to 10-150Cand Hydrochloric acid (1 lit) was slowly added for 1 hr and maintained at same temperature for 2 hrs. Water (3 lit) was added slowly to the reaction mass for 30 min. Filtered and washed with water (1 lit). The resultant mass was Trityl alcohol (Recovery).The filtrate was washed with Dichloromethane. Aqueous layer and Dichloromethane layer were separated and aqueous layer was cooled to 0-50C and pH was adjusted to 8.0-9.0 with 50% Sodium hydroxide solution, Dichloromethane (3 lit) was charged and stir for 10mins. Aqueous layer and dichloromethane layer were separated and aqueous layer was extracted with dichloromethane (1 lit). Aqueous layer and organic layer were separated and the both organic layers were washed with brine solution. Aqueous layer and organic layer were separated and organic layer was dried over Sodium sulphate and distilled under vacuum at 450C to get the title compound.
Output: 0.55 kg; HPLC: 99%; Recovery: Trityl alcohol

Example-26:
Trityl alcohol is converted to trityl chloride and used in the manufacturing of (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan (Example-6).

Example-27:
Process for preparation of (3R,5R)-2-(2,4-Difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan:
Dichloromethane (2.5 lit) and [(3R,5R)-5-(2,4-Difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (1 kg) was added to the flask at room temperature and cooled to 10-150C. Triethylamine (1 kg) was added and followed by slow addition of above recovered Trityl chloride (1 kg) and Dichloromethane (2.5 lit) for 2 hrs. Temperature was raised to room temperature and maintained for 4 hrs. And water (5 lit) was added, stirred for 15 min and allowed to settle for 15 min. Aqueous layer and Dichloromethane layers were separated and to the Dichloromethane layer, Water (5 lit) was added, stirred for 15 min and allowed to settle for 15 min. Aqueous layer and Dichloromethane layers were separated and to the Dichloromethane layer brine solution washing was given and stirred for 15 min and allowed to settle for 15 min. Aqueous layer and Dichloromethane layers were separated and Dichloromethane layer was dried with Sodium sulfate, distilled under vacuum below 450C and co-distilled with Methanol (0.2 lit). Methanol (8 lit) was added to the reaction mixture and temperature raised to 60-650C, maintained for 1 hr and cooled to 35-400C. The resultant mass was filtered and washed with Methanol (0.2 lit) and dried at 50-550C.
Output: 1.25 kg; HPLC: 99%.

Example-28:
Process for preparation of [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-chlorobenzenesulfonate:
[(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (1 kg) was added to the Flask along with Dichloromethane (7 lit) at room temperature and stirred to dissolve. Then 4-Chloro benzene sulfonyl chloride (1.5 kg) was added and stirred to dissolve, then cooled to 10-150C. Then Pyridine (2.5 lit) was slowly added for 1hr and then the temperature was raised to room temperature and maintained for 5 hrs. Water (5 lit) was added and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was dried over Sodium sulphate and distilled under vacuum at below 500C and co-distilled with Isopropyl alcohol (1 lit). Mixture of Isopropyl alcohol (4 lit) and Water (3 lit) was added into reaction mass and heated to temperature of 70-750C and maintained up to material dissolved, then cooled to Room temperature and maintained for 2 hr. Filtered the product and washed with mixture of Isopropyl alcohol and Water.
Yield: 1.32Kg; HPLC: 99%.

Example-29:
Process for preparation of [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-chlorobenzene sulfonate:
[(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (1 kg) was charged along with Dichloromethane (7 lit) at room temperature and stirred to dissolve. Then 4-Chloro benzene sulfonyl chloride (0.9 kg) was charged and the reaction mixture was cooled to 10-150C. Then slowly Triethylamine (1.06 kg) was added for 30 min and the temperature was raised to room temperature and maintained for 5 hrs. Water (5 lit) was added and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was dried over Sodium sulphate and distilled under vacuum at below 500C and co-distilled with Isopropyl alcohol (1 lit). Mixture of Isopropyl alcohol (4 lit) and Water (3 lit) was added into reaction mass and heated to temperature of 70-750C and maintained up to material dissolved, then cooled to Room temperature and maintained for 2 hr. Filtered the product and washed with mixture of Isopropyl alcohol and Water.
Yield: 1.3Kg; HPLC: 99%.

Example-30:
Process for preparation of [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate:
[(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (1 kg) was taken in RB flask along with Dichloromethane at room temperature and stirred to dissolve. Then 4-Nitro benzene sulfonyl chloride (1.5 kg) was added and stirred to dissolve, then cooled to 10-150C. Then Pyridine (2.5 lit) was slowly added for 1 hr and then the temperature was raised to room temperature and maintained for 5 hrs. Water (5 lit) was added and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was washed with Water (5 lit) and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was washed with the solution of Sodium chloride and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was dried over Sodium sulphate and distilled under vacuum at below 500C and Co-distilled with Isopropyl alcohol (1 lit). Isopropyl alcohol (4 lit) and Water (3 lit) was added into Reaction mass and heated to temperature of 70-750C and maintained up to material dissolved, then cooled to Room temperature and maintained for 1 hr. Filtered and washed with mixture of Isopropyl alcohol and Water.
Yield: 1.25Kg; HPLC: 99%.

Example-31:
Process for preparation of [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate:
[(3R,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methanol (1 kg) was taken in a RB flask along with Dichloromethane at room temperature and stirred to dissolve. Then 4-Nitro benzene sulfonyl chloride (1.5 kg) was added and stirred to dissolve, then cooled to 10-150C. Then Triethylamine (2.5 lit) was added slowly for 1 hr and then the temperature was raised to room temperature and maintained for 5 hrs. TLC was checked and Water (5 lit) was added and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was washed with Water (5 lit) and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was washed with Sodium chloride solution and stirred for 15 min. Then Dichloromethane layer and aqueous layer were separated and Dichloromethane layer was dried over Sodium sulphate and distilled under vacuum at below 500C and Co-distilled with Isopropyl alcohol (1 lit). Isopropyl alcohol (4 lit) and Water (3 lit) was added into Reaction mass and heated to temperature of 70-750C and maintained up to material dissolved, then cooled to Room temperature and maintained for 1 hr. Filtered the solid and washed with mixture of Isopropyl alcohol and Water.
Yield: 1.22Kg; HPLC: 99%.
IR Spectrum of Compound [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate:
Sample has characteristic peaks at 3124 cm-1, 2957 cm-1, 2895 cm-1, 1617 cm-1, 1498 cm-1, 1461 cm-1, 1314 cm-1, 1257 cm-1, 7093 cm-1, 1009 cm-1, 746 cm-1, 6721 cm-1, 611 cm-1, 543 cm-1,
1H NMR (DMSO) of Compound [(3S,5R)-5-(2,4-Difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate:
Sample has characteristic peaks at ?? 8.483-8.461 (dd, 2H), ?? -8.263 (s, 1H), ??8.187-8.164 (dd 2H), ??7.742 (s, 1H), ??7.278-7.179 (m, 2H), ??6.980-6.953 (m, 1H), ??4.496 (s, 2H), ??4.058-4.018 (q, 2H), ?? 3.950-3.873 (m, 1H), ?? 3.581-3.542 (q, 1H), ?? 2.465-2.393 (m, 1H), 2.321-2.262 (m, 1H), ?? 2.015-1.994 (q, 1H).

Example-32:
Process for preparation of 4-(4-(4-(4-(((3R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)-tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-(benzyloxy)pentan-3-yl)-2H-1,2,4-triazol-3(4H)-one:
2-[(1S2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl] phenyl]-3H-1,2,4-triazol-3-one (1 kg) was added to the Flask along with Dimethylsulfoxide (8 lit) at room temperature and stirred for 15 min. Solution of Sodium hydroxide (0.15 kg) in Water (0.3 lit) was added at same temperature and maintained for 1 hr. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)-tetrahydrofuran-3-yl)methyl-4-methylbenzene sulfonate (1.2 kg) was added and maintained for 4-5 hrs. Water (10 lit) was added to the reaction mixture and stirred for 15 min. Ethyl acetate (7.5 lit) was added and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and aqueous layer was extracted with Ethyl acetate (3 lit). Aqueous layer and Ethyl acetate layer were separated and total aqueous layer was washed with Water (5 lit) and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and Ethyl acetate layer was washed with brine solution. Aqueous layer and Ethyl acetate layer were separated and Ethyl acetate layer was dried over Sodium sulfate and distilled under vacuum at below 500C. The resultant crude was treated with Isopropyl alcohol (10 lit) and heated to 75-800C, maintained for material dissolved and treated with activated Carbon (0.05 kg) and maintained for 1 hr. The material was filtered through the Hyflow bed and washed with Isopropyl alcohol (1 lit). The resultant mass was cooled to room temperature, maintained for 2 hrs, filtered the solid and washed with Isopropyl alcohol (1 lit).
Yield: 1.3Kg; HPLC: 98.6%.

Example-33:
Process for preparation of 4-(4-(4-(4-(((3R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)-tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-(benzyloxy)pentan-3-yl)-2H-1,2,4-triazol-3(4H)-one:
2-[(1S2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl] phenyl]-3H-1,2,4-triazol-3-one (1 kg) was added to the flask along with Dimethylsulfoxide (8 lit) at room temperature and stirred for 15 min. Solution of Sodium hydroxide (0.15 kg) in Water (0.3 lit) was added at same temperature and maintained for 1 hr. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl) methyl)-5-(2,4-difluorophenyl)-tetrahydrofuran-3-yl)methyl-4-chlorobenzene sulfonate (1.2 kg) was added and maintained for 4-5 hrs. Water (10 lit) was added to the reaction mixture and stirred for 15 min. Ethyl acetate (7.5 lit) was added and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and aqueous layer was extracted with Ethyl acetate (3 lit). Aqueous layer and Ethyl acetate layer were separated and total aqueous layer was washed with Water (5 lit) and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and aqueous layer was washed with brine solution and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and Ethyl acetate layer was dried with Sodium sulfate and distilled under vacuum at below 500C. The resultant crude was treated with Isopropyl alcohol (10 lit) and heated to 75-800C, maintained for material dissolved and charged with activated Carbon (0.05 kg) and maintained for 1 hr. The material was filtered through the Hyflow bed and washed with Isopropyl alcohol (1 lit). The resultant mass was cooled to room temperature, maintained for 2 hrs, filtered the solid and washed with Isopropyl alcohol (1 lit).
Yield: 1.28Kg; HPLC: 98%.

Example-34:
Process for preparation of 4-(4-(4-(4-(((3R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)-tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-(benzyloxy)pentan-3-yl)-2H-1,2,4-triazol-3(4H)-one:
2-[(1S2S)-1-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperozinyl] phenyl]-3H-1,2,4-triazol-3-one (1 kg) was added to the Flask along with Dimethylsulfoxide (8 lit) at room temperature and stirred for 15 min. Solution of Sodium hydroxide (0.15 kg) in Water (0.3 lit) was added and maintained for 1 hr and ((3S,5R)-5-((1H-1,2,4-triazol-1-yl) methyl)-5-(2,4-difluorophenyl)-tetrahydrofuran-3-yl)methyl-4-nitrobenzene sulfonate (1.2 kg) was added and maintained for 4-5 hrs. Water (10 lit) was added to the reaction mixture and stirred for 15 min. Ethyl acetate (7.5 lit) was added and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and aqueous layer was extracted with Ethyl acetate (3 lit). Aqueous layer and Ethyl acetate layer were separated and total Ethyl acetate layer was washed with Water (5 lit) and brine solution. Ethyl acetate layer was dried with Sodium sulfate and distilled under vacuum at below 500C. The resultant crude was treated with Isopropyl alcohol (10 lit) and heated to 75-800C. The resultant mass was cooled to room temperature, maintained for 2 hrs, filtered the solid and washed with Isopropyl alcohol (1 lit).
Yield: 1.3Kg; HPLC: 98.46%.

Example-35:
Process for preparation of Posaconazole:
4-(4-(4-(4-(((3R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)-tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-(benzyloxy)pentan-3-yl)-2H-1,2,4-triazol-3(4H)-one (1 kg) was added to the flask along with Methanol (7 lit), followed by the addition of 10% Pd / C (0.24 kg) and Hydrochloric acid (1.78 lit) at room temperature. Hydrogen gas (5 kg) was applied and temperature was raised to 500C. The resultant material was cooled to room temperature, filtered through the Hyflow bed and washed with Methanol (1 lit). The resultant filtration mass was cooled to 0-50C and pH was adjusted to 7.0-7.5 with 16% Sodium hydroxide solution, maintained for 2 hrs and filtered the solid and washed with Methanol.

The resultant material was added to the Flask along with Methanol (10 lit) and heated to 60-650C and maintained for 1 hr. Activated Carbon was added, stirred for 30 min and filtered through Hyflow bed and washed with methanol (1 lit). The resultant mass was cooled to room temperature and maintained for 1-2 hrs, filtered the solid and washed with Methanol (1 lit) to get the title compound.
Yield: 0.68Kg; HPLC: 99.4%.