DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PREPARATION OF SALTS OF POSACONAZOLE INTERMEDIATE

INTRODUCTION
Aspects of the present invention relate to salts of posaconazole intermediate and their use in preparation of posaconazole.
BACKGROUND
The triazole antifungal drug i.e., 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl) tetrahydro-5-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)-3 -furanyl]methoxy]phenyl]- 1 -piperazinyl] phenyl]-2-[( 1 S,2S)- 1 -ethyl-2-hydroxypropyl]-2,4-dihydro-3H- 1 ,2,4-triazol-3-one is commonly known as posaconazole,which is used against a wide range of fungal pathogens, including both yeast and molds and is represented by structure formula (I).

I
N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) is one of the key intermediate useful in the preparation of posaconazole.

II
Processes for the preparation of posaconazole and its intermediates have been disclosed in US 5661151 and US5625064.
There are several drawbacks associated with prior art processes which include tedious chromatography methods to isolate the required product which is not feasible at commercial scale and these processes involves the use of industrially less applicable solvents. The present invention relates to process for preparation and purification of posaconazole intermediate of formula (II) via acid addition salts.
SUMMARY
In the first embodiment of the present application provides a salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (III).

The second embodiment of the present invention provides process for preparation of substantially pure N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II)
which comprises;
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to suitable salt of formula (III) by treating with an inorganic or organic acid in the presence of a suitable solvent;
b) optionally isolating the compound of formula (III);
c) optionally purifying the compound of formula (III);
d) treating the compound of formula (III) with a suitable base in a suitable solvent to provide compound of formula (II);
e) optionally isolating and purifying compound of formula (II).
Third embodiment of the present invention provides the oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV).

Fourth embodiment of the present invention provides the process for preparation of oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV) which comprises:
a) reacting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) with oxalic acid in the presence of a suitable solvent to provide oxalate salt of formula (IV);

b) optionally isolating and purifying the oxalate salt of formula (IV).
Fifth embodiment of the present invention provides the process for preparation of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) which comprises
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to oxalate salt of formula (IV) by treating with oxalic acid in the presence of a suitable solvent;
b) optionally isolating and purifying the oxalate salt of formula (IV);
c) treating the oxalate salt of formula (IV) with a suitable base in a suitable solvent to provide compound of formula (II);
d) optionally purifying compound of formula (II).
Sixth embodiment of the present invention provides the process for preparation of posaconazole of formula (I) which comprises;
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to suitable salt of compound of formula (III) by treating with an inorganic or organic acid in the presence of a suitable solvent;
b) optionally isolating and purifying the salt of compound of formula (III);
c) treating salt of compound of formula (III) with a suitable base in a suitable solvent to provide compound of formula (II);
d) optionally isolating and purifying compound of formula (II);
e) converting compound of formula (II) to posaconazole.
Seventh embodiment of the present invention provides the use of oxalate salt of formula (IV) for the preparation of posaconazole of formula (I).
Eighth embodiment of the present invention provides a characteristic X-ray diffraction of oxalate salt of formula (IV).
Ninth embodiment of the present invention provides pharmaceutical compositions comprising posaconazole of formula (I) or its pharmaceutically acceptable salts prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates the PXRD pattern of oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV) obtained through example 1.
Figure 2: illustrates the PXRD pattern of oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV) obtained through example 3.
DETAILED DESCRIPTION
The first embodiment of the present application provides a salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (III)

The second embodiment of the present invention provides process for preparation of substantially pure N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) which comprises;
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to suitable salt of formula (III) by treating with an inorganic or organic acid in the presence of a suitable solvent;
b) optionally isolating the compound of formula (III);
c) optionally purifying the compound of formula (III);
d) treating the compound of formula (III) with a suitable base in a suitable solvent to provide compound of formula (II);
e) optionally isolating and purifying compound of formula (II).
Step (a) may be carried out by using one or more suitable organic or inorganic acid. Suitable organic acid that may be used in step (a) include, but are not limited to oxalic acid, tartaric acid, succinic acid, citric acid or the like. Suitable inorganic acid that may be used in step (a) include, but are not limited to hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid or the like.

Step (a) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (a) include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like or mixtures thereof.

Steps (b) and (c) which involves the isolation and purification of the salt of formula (III) can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
Step (d) may be carried out by using one or more suitable bases. Suitable base that may be used in step (d) include, but are not limited to alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like.
Step (d) may be carried out in the presence of one or more suitable solvents. Suitable solvent that may be used in step (d) include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; water or mixtures thereof.

Step (e) which involves the isolation and purification of the compound of formula (II) can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.

The temperature at which the above steps may be carried out in between about 0 °C and about 100 °C, preferably 10-50°C, based on the solvent or mixture of solvent used in particular step.
Third embodiment of the present invention provides the oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV)

Oxalic acid used in the present invention may be selected in the form of anhydrous or hydrate, preferably in the form of anhydrous.
Fourth embodiment of the present invention provides the process for preparation of oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV) which comprises
a) reacting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) with oxalic acid in the presence of a suitable solvent to provide oxalate salt of formula (IV);

b) optionally isolating and isolating the oxalate salt of formula (IV).
The reagents and solvents for steps (a) and (b) may be selected from one or more suitable reagents and solvents as described in step (a), (b) and (c) of the second aspect of the present invention.
The reaction mass containing compound of formula (II) may be used directly for the preparation of oxalate salt in step (a). Alternatively, the compound of formula (II) may be dissolved in a suitable solvent to prepare oxalate salt in step (a).
The process for preparation of compound of formula (II) may be followed according to known processes in the art. In one of the embodiment, the compound of formula (II) may be prepared starting from N-(2-(benzyloxy)propylidene)formohydrazide with ethyl magnesium bromide according to process known in the art.
The temperature at which the above steps may be carried out in between about -5 °C and about 100 °C, preferably at 0-50°C, based on the solvent or mixture of solvent used in particular step.
Fifth embodiment of the present invention provides the process for preparation of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) which comprises
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to oxalate salt of formula (IV) by treating with oxalic acid in the presence of a suitable solvent;
b) optionally isolating and purifying the oxalate salt of formula (IV);
c) treating the oxalate salt of formula (IV) with a suitable base in a suitable solvent to provide compound of formula (II);
d) optionally purifying compound of formula (II).
The reagents and solvents for steps(a), (b), (c) and (d) may be selected from one or more suitable reagents and solvents as described in step (a), (b), (c),(d) and (e) of the second aspect of the present invention.
The temperature at which the above steps may be carried out in between about -5 °C and about 100 °C, preferably 0-50°C, based on the solvent or mixture of solvent used in particular step.
Sixth embodiment of the present invention provides the process for preparation of posaconazole of formula (I) which comprises;
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to the suitable salt of compound of formula (III) by treating with an inorganic or organic acid in the presence of a suitable solvent;
b) optionally isolating and purifying the salt of compound of formula (III);
c) treating salt of compound of formula (III) with a suitable base in a suitable solvent to provide compound of formula (II);
d) optionally isolating and purifying compound of formula (II);
e) converting compound of formula (II) to posaconazole.
The reagents and solvents for steps(a), (b), (c), (d) may be selected from one or more suitable reagents and solvents as described in step (a), (b), (c), (d) and (e) of the second aspect of the present invention.
Compound of formula (II) may be converted to posaconazole according to methods known in the art.
The temperature at which the above steps may be carried out in between about -5 °C and about 100 °C, preferably 0-50°C, based on the solvent or mixture of solvent used in particular step.
Seventh embodiment of the present invention provides the use of oxalate salt of formula (IV) for the preparation of posaconazole of formula (I).
Eighth embodiment of the present invention provides a characteristic X-ray diffraction of oxalate salt of formula (IV) which is characterized by its PXRD having peaks at 6.18, 9.65, 13.65, 17.02, 18.50, 22.88, 23.61, 24.75, 26.82 and 27.84 about ± 0.2 degrees two theta as illustrated in figure-1 and figure-2.
N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) obtained through acid addition salt of the present invention is having better HPLC purity than the purity known in the prior art. The preparation of acid addition salts highly reduces the overall impurities including impurities arising from deformylation. The chemical purity of the compound of formula (II) obtained in the present invention is having more than 90.0%, preferably about 95% by HPLC method.
HPLC conditions for analysis of oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV)
Column : Agilent Eclipse Plus C-18 (250 mm x 4.6mm, 5.0µm)
Flow Rate : 1.0 mL/min.
Wavelength : 210 nm
Temperature : 45 oC
Load : 5 mL
Concentration : ~ 0.4 mg/mL
Diluents : Water: Acetonitrile (20:80)
Runtime : 40 minutes
Buffer preparation : Prepare 5mM Ammonium formate in 1000mL HPLC grade water and add 1 mL Formic Acid
Mobile phase-A : 100% Buffer.
Mobile phase-B : Methanol
Gradient programme:
Time % of Mobile Phase A % of Mobile Phase B
00.00 60 40
20.00 30 70
25.00 05 95
35.00 05 95
37.00 60 40
40.00 60 40

Ninth embodiment of the present invention provides pharmaceutical compositions comprising posaconazole of formula (I) or its pharmaceutically acceptable salts prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.
The process of the present invention is easy to handle, environment friendly, provides better yield and purity and it may also be practiced on industrial scale without any process issue.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6alcohols, or the like.
A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6ketones, 4-methyl-pentane-2-one or the like.
An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
EXAMPLES
Example 1: Preparation of oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide (IV)
Bis(trimethylsilyl)acetamide (98.5 g, 0.48 moles) was added to a solution of N-(2-(benzyloxy)propylidene)formohydrazide in toluene (1000 ml) and stirred at room temperature for 15-30 minutes. The reaction mixture was cooled to -5 to 0°C and ethyl magnesium bromide (1215 g, 1.2 moles) was added. The temperature of the reaction mixture was slowly raised to 20-25°C and maintained for 2-4 hours. The reaction mixture was added to 10% w/v ammonium chloride (1000 ml) at below 15°C and maintained for 15-30 minutes. The layers were separated and the aqueous layer was extracted with toluene (250 ml). The combined organic layer was washed with 10% w/v NaCl solution (500 ml) and toluene layer was distilled off till 10 % of the total volume remained in the flask. The reaction mixture was cooled to 0-5°C and oxalic acid (24 g, 0.025 moles) dissolved in methanol (50 ml) was added and maintained for 2-3 hours at 0-5°C. The solid was filtered, washed with toluene (50 ml) and dried under vacuum at 45°C to provide the title compound.
Yield: 38.3g (46.9%)
HPLC purity: 96%

Example 2: Purification of N-2-(benzyloxy)pentane-3-yl formylhydrazide via oxalate salt
Anhydrous oxalic acid (14.4 g, 0.16 moles) was added to methyl tertiary butyl ether (450 ml) and cooled to 0°C. Solution of N-2-(benzyloxy)pentane-3-yl formylhydrazide (II) (30.0 g, 0.145 moles) in methyl tertiary butyl ether (150 ml) was added to the reaction mixture drop wise at 0-5°C and stirred at 0-5°C for 2 hours. The precipitated salt was filtered and washed with chilled methyl tertiary butyl ether (90ml) and dried at room temperature for 1 hour. The resulting oxalate salt was added to methyl tertiary butyl ether (480 ml) and cooled to 0°C. Saturated bicarbonate solution (300 ml) was added to the reaction mixture at 0-5°C and stirred for one hour at 0-5°C. The layers were separated and the aqueous layer was extracted with methyl tertiary butyl ether (180 ml). The combined organic layers was washed with water followed by brine solution, dried over sodium sulfate and distilled under vacuum at below 45°C to give the title compound as a light yellow liquid.
Yield: 15.2g (44.22%)
HPLC purity: 90.92%

Example 3: Preparation of oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide (IV)
Bis(trimethylsilyl)acetamide (500 g, 2.46 moles) was added to a solution of N-(2-(benzyloxy)propylidene)formohydrazide (300 g, 1.45 moles) in toluene (6000 ml) and stirred at room temperature for 15-30 minutes. The reaction mixture was cooled to -5 to 0°C and ethyl magnesium bromide in THF (2M) (3600 ml) was added. The temperature of the reaction mixture was slowly raised to 20-25°C and maintained for 2-4 hours. The reaction mixture was added to 10% w/v ammonium chloride (6000 ml) at below 15°C and maintained for 15-30 minutes. The layers were separated and the aqueous layer was extracted with toluene (1500 ml). The combined organic layer was washed with 10% w/v NaCl solution (3000 ml) and toluene layer was distilled off till 10 % of the total volume remained in the flask. The reaction mixture was cooled to 0-5°C and anhydrous oxalic acid (144 g, 1.6 moles) dissolved in methanol (300 ml) was added and maintained for 2-3 hours at 0-5°C. The solid was filtered, washed with toluene (300 ml) and dried under vacuum at 45°C to provide the title compound.
Yield: 200 g (42.2%)
,CLAIMS:We Claim:
Claim 1: A salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (III)

Claim 2: A process for preparation of substantially pure N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II)
which comprises;
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to suitable salt of formula (III) by treating with an inorganic or organic acid in the presence of a suitable solvent;
b) optionally isolating the compound of formula (III);
c) optionally purifying the compound of formula (III);
d) treating the compound of formula (III) with a suitable base in a suitable solvent to provide compound of formula (II);
e) optionally isolating and purifying compound of formula (II).
Claim 3: The acid according to step a) of claim 2 is selected from oxalic acid, tartaric acid, succinic acid, citric acid, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid.
Claim 4: The solvent according to step a) of claim 2 is selected from ether solvents, aromatic hydrocarbon solvents, nitrile solvents, alcohol solvents ester solvents or the like or mixtures thereof.
Claim 5: The base according to step d) of claim 2 is selected from alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates.
Claim 6: The oxalate salt of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (IV).

Claim 7: The process for preparation of N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) which comprises;
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to oxalate salt of formula (IV) by treating with oxalic acid in the presence of a suitable solvent;
b) optionally isolating and purifying the oxalate salt of formula (IV);
c) treating the oxalate salt of formula (IV) with a suitable base in a suitable solvent to provide compound of formula (II);
d) optionally purifying compound of formula (II).
Claim 8: The process for preparation of posaconazole of formula (I) which comprises;
a) converting N-2-(benzyloxy)pentane-3-yl formylhydrazide of formula (II) to suitable salt of compound of formula (III) by treating with an inorganic or organic acid in the presence of a suitable solvent;
b) optionally isolating and purifying the salt of compound of formula (III);
c) treating salt of compound of formula (III) with a suitable base in a suitable solvent to provide compound of formula (II);
d) optionally isolating and purifying compound of formula (II);
e) converting compound of formula (II) to posaconazole.
Claim 9: Use of oxalate salt of formula (IV) for the preparation of posaconazole of formula (I).
Claim 10: Pharmaceutical compositions comprising posaconazole of formula (I) or its pharmaceutically acceptable salts prepared according to preceding claims together with one or more pharmaceutically acceptable excipient, carrier and diluents.