DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(SECTION 10)

A NOVEL PROCESS FOR THE PREPARATION OF ITRACONAZOLE AND INTERMEDIATES OF ITRACONAZOLE

We, AKTINOS PHARMA PRIVATE LIMITED
a company incorporated under the companies act, 1956 having address at 4th & 5th Floor, Sri Lakshmi Spaces, Plot No. 7, Phase-I, Kavuri Hills, Madhapur, Hyderabad- 500033, Telangana, India.

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of triazole antifungal agents or its pharmaceutically acceptable salts.

The present invention particularly relates to novel process for the preparation of Itraconazole or its pharmaceutically acceptable salts.

The present invention also relates to the novel process for the preparation of intermediate compound of Formula (II)
Formula (II),
and compound of Formula (III)
Formula (III)

BACKGROUND OF THE INVENTION
SPORANOX® is the brand name for Itraconazole; Itraconazole is a synthetic triazole antifungal agent, which is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural Formula (I):
Formula (I)
The chemical name of Itraconazole is (±)-cis-4-[4-[4-[4[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one.

Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

US Patent 4,267,179 of Janssen Pharmaceutica discloses a broad spectrum antifungal compound developed for oral, parental and topical use of Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-?2-1,2,4­triazoline-5-one of Formula (I) of Itraconazole.

WO 98/21204 discloses (Method-1) the reaction of 2-Ar-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl reactive ester (IV) such as methylsulfonyloxy,4-methylphenylsulfonyloxy or halo with hydroxy phenyl piperazine compound (III) by O-alkylation reaction. The reaction is carried out in solvent like dimethylformamide and an appropriate base like metal hydride or metal carbonate.

EP 0 539 938 A1 (Method-2) discloses the preparation of semi carbazide of formula (V) and cyclizing to required triazolone with formamidine salt to obtain final product, Itraconazole.

In the above methods, crucial N-alkylation reaction was performed on piperazine moieties of compound VI or VII with 4-halo nitrobenzene in the presence of metal hydride, hydroxide or carbonate in appropriate solvent to obtain Cis-Itraconazole I or intermediate 2-(4-(4-(1-(sec-butyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-yl)-5-methoxybenzene (II), followed by a series of 5-6 chemical manipulations as shown hereunder to obtain Itraconazole.

CN 101775009 B discloses synthetic method for Itraconazole. A compound of formula II, an antioxidant, an inorganic base were reacted at 30 °C - 60 ° C for 20-40 minutes, the compound of Formula I is added at 50 °C-110 °C and the reaction was continued for 3-5 hours. The molar ratio of the compound of formula II with compound of formula I is 1: 1.1~1.5; the reaction solvent is selected from DMF, DMA, DMSO or HMPT; and said antioxidant is selected from hydrazine hydrate, a salt thereof, or of BHT or mercaptoethanol; and inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride. The reaction scheme is given below:

IN 2198/CHE/2012 discloses a process for preparation of Itraconazole comprising compound of Formula C with compound of Formula B in presence of a base and phase transfer catalyst (PTC) in a solvent.

Journal of Medicinal Chemistry, 1984, Vol 27, No. 07, page 894-900 discloses aqueous hydro bromic acid or acetic acid and hydrobromic acid mixture to de-methylate corresponding methoxy compound II to prepare hydroxy phenyl piperazine derivative III.

The drawbacks in the above methods are:

First, exploiting the electron withdrawing nature of nitro group substituted para to halo group, which makes the halide labile for N-alkylation on piperazine moiety, followed by building sec-butyl substituted triazolone ring after several chemical steps. Usually all these steps are performed in-situ without isolating intermediates. Nitro reduction step in these reaction sequences is difficult due to solubility problems of starting material and temperature of reaction, use of Raney Ni or Pd-C, which are pyrophoric in nature.
Second, demethylation of methoxy piperazine intermediate in 48% aqueous HBr, is a time taking for example takes about 40-50 hrs and is to be used large excess reagent to complete the reaction for example 4-5times with respect to starting material and HBr vapours pose health related hazards.

In order to avoid the above said problems, the present inventors advantageously and surprisingly found that, readily and inexpensively available 4-halo substituted anilines can be converted to 4-halo triazolone and thus formed triazolone can be coupled with piperazine amine by employing 0.01-10 mole% palladium catalysed carbon nitrogen bond forming process commonly known as Buchwald-Hartwig amination reaction in good yields and with high purity and in a shorter time.

Secondly, the inventors after extensive experimentation with several de-methylating reagents now surprisingly found that demethylation of methoxy piperazine intermediate can be achieved by using pyridinium hydrochloride. This melt based demethylation serves as an efficient and scalable synthetic method to accomplish this transformation within 8-10 hrs.

Thus, the inventors put focussed efforts in an attempt to develop a new and alternative process for Cis-Itraconazole from either readily available staring material or modifying the reagents used in the reaction.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide a novel process for the preparation of triazole antifungal agent or its pharmaceutically acceptable salts.

Another objective of the present invention is to provide novel process for the preparation of Itraconazole or its pharmaceutically acceptable salts.

Yet another objective of the present invention is to provide novel process for the preparation of intermediate compound of Formula (II) and compound of Formula (III).

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel process for the preparation of Itraconazole of Formula (I)
Formula (I)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is alkyl, a protecting group or ; using a catalyst, and an optional base in presence of a suitable solvent.

Another aspect of the present invention is to provide a novel process for the preparation of Itraconazole of Formula (I)
Formula (I)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is as defined above, with compound of Formula (VII)
Formula (VII)
wherein R is alkyl or protecting group; to give compound of Formula (II),

ii) optionally de-alkylating of compound of Formula (II)
Formula (II)
wherein R is alkyl or protecting group to give compound of Formula (III)
Formula (III), and followed by
iii) condensing with compound of Formula (X)
Formula (X)
to obtain Itraconazole compound of Formula (I).

Yet another aspect of the present invention is to provide a novel process for the preparation of Itraconazole of Formula (I)
Formula (I)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or a protecting group, by using suitable palladium complex and an optional base in presence of a suitable solvent to afford compound of Formula (II);
Formula (II)
ii) de-alkylating of compound of Formula (II) using HBr or HBr in acetic acid or pyridinium hydrohalide to give compound of Formula (III)
Formula (III), and
iii) condensing compound of Formula (X)
Formula (X)
with compound of Formula (III) using an optional base in presence of a suitable solvent to obtain Itraconazole compound of Formula (I).

Yet another aspect of the present invention is to provide process for the preparation of compound of Formula (III)
Formula (III),
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or protecting group, by using suitable palladium complex, and an optional base in presence of a suitable solvent to afford compound of Formula (II);
Formula (II)
ii) de-alkylating compound of Formula (II) to give compound of Formula (III) or its salts.

Yet another aspect of the present invention is to provide a novel process for preparation of compound of Formula (II)
Formula (II)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or protecting group, by using suitable palladium complex, and an optional base in presence of a suitable solvent to give compound of Formula (II) or its salts.

Yet another aspect of the present invention is to provide an alternative process for the preparation of Itraconazole comprising the steps of:
i) coupling the compound of Formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is ; using a catalyst and an optional base in presence of a suitable solvent to obtain Itraconazole of Formula (I); and
Formula (I)
ii) optionally purifying the obtained Itraconazole in dimethylformamide and alcoholic solvent.

DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the palladium-catalysed coupling of amines with aryl halide for preparation of Cis-Itraconazole or intermediates for preparation of Itraconazole. This amination reaction requires a catalytic system containing four components to efficiently generate the desired C-N bond between piperazine moiety and aryl carbon. A palladium precursor/complex, typically stabilized in the solution by an appropriate ligand that also raises the electron density at the metal to facilitate oxidative addition and provide sufficient bulkiness to accelerate reductive elimination.

Halide group in the pyridinium hydrohalide is may be bromo, chloro, fluoro or iodo group.

A base is required to deprotonate the amine substrate either before or after coordination to the palladium centre. At time, reaction nature may be heterogeneous due to solubility of base or substrates, thus solvent plays an important role than in other transition metal mediated processes. Temperature of the reaction is also a significant parameter and influence the activity of ligand or reactivity of the coupling partners. Further parameters like ratio of ligand to palladium or catalyst loadings have to be taken into consideration.

Preheating of palladium precursor, ligand and base in solvent prior to the introduction of substrates can have beneficial effects on reproducibility.

Palladium catalyst used in the present invention for performing coupling reaction can be palladium (0) or palladium (II) catalysts or precursors, which are reducible if necessary insitu to the corresponding, zero oxidation state most often by the amine in the presence of phosphine and base. Thus palladium precursors are selected form tris-(dibenzylidineacetone)dipalladium(0), Pd2(dba)3, di-(dibenzylidine acetone) palladium (0), Pd(dba)2. Release of dba during the catalysis can have an effect on the performance of the reaction. Other palladium salts/precursors like Palladium acetate, Pd(OAc)2, tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), dichlorobis(triphenylphosphine) palladium, PdCl2(Ph3), allyl palladium(II)chloride [(allyl)PdCl2], palladium(II) acetylacetonate, Pd(acac)2 or palladium (II)chloride, PdCl2, Dichloro [9,9,dimethyl-4,5-bis (diphenyl phospheno)xanthene]palladium (II), dichloro[bis(diphenylphosphenyl) ether]palladium II or mixture of catalysts, for example Pd(OAc)2 and Pd2(dba)3 also can be employed.

The palladium catalyst used in the process of the invention is in the range of 0.01 mol% to 10mol%, preferably from 0.2-5 mole%.

Catalyst system may contain phosphine ligand. When ligand is added, ligand may be selected from P(o-Tol)3, P(t-Bu)3, PPh3, PCy3 chelating bisphosphines like BINAP, DPPF, DPPP, DtBPF, DPPE, XantPhos DPEPhos, triaminophosphines, biphenylbased pyrole, pyrazole ligands, N-arylindole ligands or adamantyl substituted alkyl phosphine. Phosphines may be either racemic or chiral wherever applicable. Exemplary ligands include BippyPhos, MorDalPhos and IPr-HCl.

Precatalysts can be used for the rapid generation of active catalyst in the reaction mixture. Such Precatalysts include palladium ligand complexes bearing phosphines or N-heterocyclic carbenes. A variety of palladacycles, pyridine containing palladium complexes and p-allyl palladium complexes e.g., [(tBuBrettPhos)Pd(allyl)]OTf, [(BrettPhos) Pd(crotyl)]OTf, (PtBu3)Pd(crotyl)Cl, {[P(tBu)3]PdBr}2, [P(t-Bu)3]Pd, Pd(BINAP)Cl2, Pd(DPE-Phos)Cl2, Pd(Xantphos)Cl2, Pd(allyl)(Sphos)Cl, Pd(crotyl)(Sphos)Cl, rapidly activate under the commonly used reaction conditions to release a catalytically active species. Compared to the traditional approach involving the separate addition of ligand and palladium precursor to the reaction mixture, the use of palladium precatalysts simplifies the reaction setup and, in some cases, allows for significantly lower temperatures and or catalysts loadings to be employed. The ligand used in the process is in the range of 0.01% to 10 mol%.

Bases which are used in the process of the present invention are alkali metal and alkaline earth metal hydroxides, carbonates, bicarbonates, alcoholates, acetates, silazides, primary, seconday and tertiary amines like sodium tertiarybutoxide (t-BuONa), potassium tertiary n-butoxide(t-BuOK), lithium hexamethyl disilazane (LiHMDS), cesium carbonate(Cs2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), sodium methoxide (NaOMe), sodium hydroxide (NaOH), potassium hydroxide (KOH) and sodium tertiary amyloxide (t-AmONa), trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, or tri-tert-butylamine, tert-butyldimethylamine.

In the process of the present invention, 1-5 moles of base was used with respect to amine compound, preferably 1-3 moles, based on the aromatic piperazine compound.

Solvents suitable for performing process of this step is selected from ethers such as dimethyl ether, diethyl ether, diethylene glycol dimethyl ether, di isopropyl ether, methoxy ethanol, di-tertiary butyl ether, cylic ethers such as THF, dioxane, hydrocarbons such as hexane, iso-hexane, heptane, cyclohexane, benzene, toluene, xylene, higher alcohols not completely miscible with water such as 1-butanol, 2-butanol, tertiary butanol, amyl alcohol, ketones such as isobutyl methyl ketone, amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, nitriles such as acetonitrile, butyronitrile, water miscible sulfoxide like DMSO and mixtures thereof.

To carry out the process of the present invention the piperazine compound and aromatic halogen compound, the base, catalytic amount of palladium compound, phosphorous ligand is added to a solvent and stirred at a temperature from -20 to 200°C., preferably from 30-170°C, for a period of half an hour to 70 hours, preferably 0.5 hour to 24 hours.

The work-up is carried out by known methods with which those skilled in the art are familiar, for example, product can be filtered or water may be added and extracted with solvent.
To avoid contamination of palladium, reaction mixture at the end of the reaction to be added with sufficient complexing ligand and all the palladium to be drawn into the aqueous phase.

Palladium can be removed by chromatography method or by precipitation, for example as sulphide.

The water soluble, typically phosphorous containing ligand is completely removed from the product purely by separation of aqueous and organic phases.

Further workup after phase separation can be done, by removal of solvent, the crude product freed of solvent can be obtained. Subsequently, product can be further purified by crystallization, distillation or chromatography techniques.

In second aspect of this process of the invention, demethylation of 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol -3-one in step-b can be performed in pyridine hydrochloride. Wherein, pyridine hydrochloride salt may be prepared by the method reported in literature (J.Chem.Edu 1955, 39). Pyridinium hydrochloride (Py.HCl) liquifies fairly at high temperature, reaction proceed smoothly to completion within 4-12 hours, the temperature of reaction is about 110-200 °C, preferably 160-200 °C, more preferably 180-200 °C. Pyridinium hydrochloride is about 2-8 equivalents, preferably 3-6 equivalents. The workup was carried out by cooling the reaction mass followed by addition of water. The product was further purified.

Alternatively, the de-methylated product also can be obtained by performing reaction in aqueous HBr or HBr in acetic acid medium conventionally by the methods known in the prior art. ( J.Heterocyclic.chem.,27,2063,(1990); Journal of Med.Chem. 1984,27, 894 -900). In the process of the present invention, condensation reaction in step-c was carried out by the methods published in the prior art (Journal of Med.Chem.1984, 27, 894 -900).

According to the present invention, in one more embodiment, the metal catalyst used for coupling is selected from copper, nickel, manganese complexes such as Ni (COD)2, (Ph3P)2Ni (1-nap)Cl, (dppf)Ni(O-tolyl)Cl, Ni(dppe)Cl2, [(TMEDA)Ni(o-toyl)Cl), NiCl2(dppf), NiCl2(dme), Ni2.glyme, (BINAP)Ni (?2- NC-Ph), [Bis (triphenyl phosphine)](o-tolyl chloro nickel, [1,1’-Bis(diphenyl phosphino)ferrocene] (o-tolyl) chloro nickel .

Copper catalysts include copper salt like copper (I) halide, copper acetate and a ligand like BINOL, BINAP, alkene diols, alkene diamines, cyclic diamines, substituted diamines and cyclic beta lactones.

When manganese catalyst is used, it may be a manganese salt or complexes such as manganese pincer complexes, which include MLlstein, Beller, Boncella, Kempe, Kirchner complexes.

Synthetic procedures for preparation of intermediates required for this coupling steps are well known in the literature.

According to the process of the invention Cis-Itraconazole obtained in the above process, optionally is purified. Solvents for purification are chosen from dimethylformamide and an alcoholic solvent such as methanol, ethanol, propanol, isopropanol, mixture of these solvents or aqueous mixtures. Optionally a third solvent like acetone can also be used. Volumes used for purification may be 2 to 10 volumes with respect to crude product. Temperature in purification step may be at reflux temperature of the solvent or mixture of solvents or by heating the solvent at below reflux temperature or at room temperature.

The compounds of this invention include all stereo isomers and optical isomers of compounds of formula I (e.g., R and S enantiomers) as well as racemic, diastereomeric and other mixtures of such isomers.

In a preferred embodiment, the present invention provides a novel process for the preparation of Itraconazole of Formula (I)
Formula (I)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is alkyl, a protecting group or ; using a catalyst, and an optional base in presence of a suitable solvent.

In yet another embodiment, the present invention is to provide a novel process for the preparation of Itraconazole of Formula (I)
Formula (I)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is as defined above, with compound of Formula (VII)
Formula (VII)
wherein R is alkyl, a protecting group; to give compound of Formula (II),

ii) optionally de-alkylating of compound of Formula (II)
Formula (II)
wherein R is alkyl or protecting group to give compound of Formula (III)
Formula (III),
and followed by
iii) condensing with compound of Formula (X)
Formula (X)
to obtain Itraconazole compound of Formula (I).

In yet another embodiment, the present invention is to provide a novel process for preparation of Itraconazole of Formula (I)
Formula (I)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or a protecting group, by using suitable palladium complex, and an optional base in presence of a suitable solvent to afford compound of Formula (II);
Formula (II)
ii) de-alkylating of compound of Formula (II) using HBr or HBr in acetic acid or pyridinium hydrochloride to give compound of Formula (III),
Formula (III), and
iii) condensing compound of Formula (X)
Formula (X)
with compound of Formula (III) using an optional base in presence of a suitable solvent to obtain Itraconazole of Formula (I).

In yet another embodiment, the present invention is to provide process for the preparation of compound of Formula (III)
Formula (III),
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or protecting group, by using suitable palladium complex, and an optional base in presence of a suitable solvent to afford compound of Formula (II); and
Formula (II)
ii) de-alkylating compound of Formula (II) to give compound of Formula (III) or its salts.

In yet another embodiment, the present invention is to provide a novel process for preparation of compound of Formula (II)
Formula (II)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or protecting group, by using suitable palladium complex, and an optional base in presence of a suitable solvent to give compound of Formula (II) or its salts.

In yet another embodiment, the present invention is to provide an alternative process for the preparation of Itraconazole comprising the steps of:

i) coupling the compound of Formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is ; using a catalyst and an optional base in presence of a suitable solvent to obtain Itraconazole of Formula (I); and
Formula (I)
ii) optionally purifying the obtained Itraconazole in dimethylformamide and alcoholic
solvent.

The examples are provided below to illustrate particular aspects of the disclosure.

EXAMPLES
Example 1: Synthesis of Cis-Itraconazole:
Step-a: 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
1-(4-methoxyphenyl)piperazine (5g, 0.026 mol.), 4-(4-bromophenyl)-2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (7.7g, 0.026mol.), Sodium tertiary butoxide (3.5 g, 0.0364mol.), Pd(dba)3 (0.12g, 0.00013mol), BINAP (0.24g, 0.00039mol) and toluene (50 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was refluxed for 12 hours. 4-bromocompound was not consumed as determined by TLC. The reaction mixture was allowed to cool to room temperature. To the reaction mixture, methanol and water were added. The black whitish product formed was filtered (300 mg).
Step-b: 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
To a four necked round bottom flask equipped with a condenser, thermometer lead, and overhead stirring apparatus was charged 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20 g, 0.049mol.) followed by pyridinium hydrochloride (28.2g, 0.245mol). The resultant mixture of the two solids was heated to 180-190 °C and reaction progress was monitored by TLC. After completion of the reaction, reaction mixture was cooled and water was added slowly. The reaction mixture was stirred for 1 hour and the Crude product obtained was filtered. The wet solid was taken in to water adjusted pH to 7-8, stirred for 1 hour and filtered. The product was dried to afford the title compound (16 g).
Step c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one:
2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10 g) obtained in step-b and (2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methyl methane sulfonate (12.46 g) were heated at 60-65 °C in dimethyl sulfoxide (46 mL) and potassium hydroxide powder (2.5 g) and stirred 3 hours. The reaction mixture was charged into methanol (100 mL), cooled to 5-10 °C and filtered the product (14.5g).

Example 2: Synthesis of Cis-Itraconazole:
Step-a: 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl) piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
1-(4-methoxyphenyl)piperazine (5g, 0.026 mol), 4-(4-bromophenyl)- 2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6.5g, 0.0221mol.), Sodium tertiary butoxide (3.75g, 0.039mol.), Pd(dba)3 (0.5g, 0.00052mol.), BINAP (1.0g, 0.00156mol.) and toluene (50 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-bromocompound was consumed as determined by TLC. The reaction mixture was then allowed to cool to room temperature, taken up in methylene dichloride and methanol mixture. The reaction mixture was filtered on celite bed and concentrated the solvents under reduced pressure. Residue was added with water and methylene di chloride. The organic layer was separated, washed with water and concentrated. The product (6.5g) was isolated from methanol and compared with standard.
Step-b: 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
To a four necked round bottom flask equipped with a condenser, thermometer lead, and overhead stirring apparatus was charged 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20 g, 0.049mol.) and refluxed with 48% hydro bromic acid (100 mL). The progress of reaction was monitored by TLC. After completion of the reaction; reaction mixture was cooled, filtered to remove black solids and concentrated under vacuum. The brown gummy residue obtained was dissolved in chloroform at 80 °C, cooled and filtered the product (13 g).
Step-c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one (Cis-Itraconazole):
A suspension of sodium hydride (60% mineral oil) (1.2g) in dimethyl sulfoxide (50 mL) and 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6 g) obtained in step-b was stirred for 1 hour. After the addition of (2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methyl methane sulfonate (10 g) the stirred mixture was warmed to 60 °C for 5 hours. The black solution was diluted with water and extracted with methylene dichloride (3x60 mL). The extract was dried (magnesium sulphate) and the solvent removed, in vacuum. Residue triturated in methanol to obtain the product (4.5 g).

Example 3: Synthesis of Cis-Itraconazole:
Step-a): 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one :
1-(4-methoxy phenyl) piperazine (5g, 0.026 mol.), 4-(4-bromophenyl)- 2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6.5g, 0.0221mol.), Sodium tertiary butoxide (3.75g, 0.039mol.), Pd(dba)3 (0.25g, 0.00027mol.) and BINAP (0.5g, 0.0008mol.) and toluene (50 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-bromocompound was consumed as determined by TLC. The reaction mixture was then allowed to cool to room temperature, taken up in methylene dichloride and methanol mixture. The reaction mixture was filtered on celite bed and concentrated the solvents under reduced pressure. Residue was added water and methylene di chloride. Separated the organic layer and washed with water and concentrated. The product (6 g) was isolated from methanol and compared with standard.
Step-b): 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
To a four necked round bottom flask equipped with a condenser, thermometer lead, and overhead stirring apparatus was charged 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20g, 0.049mol.) followed by pyridinium hydrochloride (28.2g, 0.245mol.). The resulting mixture of the two solids was heated to 180-190 °C and reaction progress was monitored by TLC. After completion of the reaction, reaction mixture was cooled and water was added slowly and stirred for 1 hour. Crude product was filtered and again taken in to water adjusted pH 7-8, stirred for 1 hour and filtered the product and dried to afford the title compound (16g).
Step c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one:
2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10 g) obtained in step-b and (2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methyl methane sulfonate (12.46 g) were heated at 60-65 °C in dimethyl sulfoxide (46 mL) and potassium hydroxide powder(2.5 g). The reaction mixture was stirred for 3 hours and charged into methanol (100 mL). The reaction mixture was further cooled to 5-10 °C and filtered the product (14.5g).

Example 4: Synthesis of Cis-Itraconazole:
Step-a): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one:
1-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine (5g), 4-(4-bromophenyl)-2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (4.5g), Sodium tertiary butoxide (3.75g), Pd(dba)3 (0.5g), BINAP (1.0 g) and toluene (50 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-bromocompound was consumed as determined by TLC. The reaction mixture was then allowed to cool to room temperature, taken up in methylene dichloride and methanol mixture. The reaction mixture was filtered on celite bed and concentrated the solvents under reduced pressure. The obtained residue was added with water and methylene di chloride. The organic layer was separated and washed with water. The organic layer was concentrated under vacuum. The product (3.5g) was isolated from methanol and compared with standard.
Step-b) Purification of Cis-Itraconazole:
Crude (10g) prepared as above was taken in DMF (20 mL) and methanol (20 mL) mixture and refluxed for a half an hour and cooled to 25-30 °C. Then the mixture was stirred and filtered the product and washed with methanol.

Example 5: Synthesis of Cis-Itraconazole:
Step-a): 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
1-(4-methoxy phenyl) piperazine (1g, 0.0052 mol), 4-(4-bromophenyl)- 2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.3g, 0.0044mol), Sodium tertiary butoxide (0.75g, 0.0078mol), Dichloro [9,9,dimethyl-4,5-bis (diphenyl phospheno)xanthene]palladium (II) (0.0787g, 0.000104 mol) and toluene (10m L) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-bromocompound was consumed as determined by TLC and product spot was matched with standard compound by TLC.
Step b): 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
The titled compound was synthesised by a method similar to that used in the preparation Step (b) of Examples 1-3.
Step c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one (Cis-Itraconazole):
The titled compound was synthesised by a method similar to that used in the preparation Step (c) of Examples 1-3.
Example 6: Synthesis of Cis-Itraconazole:
Step-a): 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl) piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
1-(4-methoxy phenyl) piperazine (1g, 0.0052 mol), 4-(4-chlorophenyl)-2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.1g, 0.0044mol), Sodium tertiary butoxide (0.75g, 0.0078mol), Dichloro[9,9,dimethyl-4,5-bis (diphenyl phospheno)xanthene] palladium (II) (0.157g, 0.000208 mol) and toluene (10 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-chloro compound was consumed as determined by TLC and product spot was matched with standard compound by TLC.
Step-b): 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
The titled compound was synthesised by a method similar to that used in the preparation Step (b) of Examples 1-3.Step-c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one (Cis-Itraconazole)
The titled compound was synthesised by a method similar to that used in the preparation Step (c) of Examples 1-3.

Example 7: Synthesis of Cis-Itraconazole:
Step a): 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl) piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
1-(4-methoxy phenyl) piperazine (1g, 0.0052 mol), 4-(4-bromophenyl)- 2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.3g, 0.0044mol), Sodium tertiary butoxide (0.75g, 0.0078mol), dichloro[bis(diphenylphosphenyl)ether]palladium II (0.0745g, 0.000104 mol) and toluene (10 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-bromo compound was consumed as determined by TLC and product spot was matched with standard compound by TLC
Step-b): 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
The titled compound was synthesised by a method similar to that used in the preparation Step (b) of Examples 1-3.
Step c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one (Cis-Itraconazole)
The titled compound was synthesised by a method similar to that used in the preparation Step (c) of Examples 1-3.
Example 8: Synthesis of Cis-Itraconazole:
Step-a): 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl) piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
1-(4-methoxy phenyl) piperazine (1g, 0.0052 mol), 4-(4-bromophenyl)- 2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.3g, 0.0044mol), Sodium tertiary butoxide (0.75g, 0.0078mol), PdCl2 (S)-BINAP (0.416g, 0.00052mol) and toluene (10 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-bromo compound was consumed as determined by TLC. The reaction mixture was then allowed to cool to room temperature, taken up in methylene dichloride and methanol mixture. The reaction mixture was filtered on celite bed and concentrated the solvents under reduced pressure. Residue was added with water and methylene di chloride. The organic layer was separated and washed with water and concentrated under vacuum. The product was isolated (0.88 g) from methanol and compared with standard.
Step-b): 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
The titled compound was synthesised by a method similar to that used in the preparation Step (b) of Examples 1-3.Step c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy] phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one (Cis-Itraconazole):
The titled compound was synthesised by a method similar to that used in the preparation Step (c) of Examples 1-3.
Example 9: Synthesis of Cis-Itraconazole:
Step-a): 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
1-(4-methoxyphenyl)piperazine (2g, 0.0052 mol), 4-(4-chlorophenyl)-2-(sec-butyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.6g, 0.00884mol), Sodium tertiary butoxide (1.5g, 0.0156mol), Pd(dba)3 (0.25g,0.00273 mol) and toluene (10 mL) were added to oven-dried, clean flask under nitrogen atmosphere. The reaction mixture was then heated to 90-95 °C until the 4-bromocompound was consumed as determined by TLC. The reaction mixture was then cooled to room temperature and taken up in methylene dichloride-methanol mixture. The reaction mixture was filtered on celite bed and concentrated the solvents under reduced pressure. The residue obtained was added with water and methylene di chloride. The organic layer was separated and washed with water and concentrated. The product was isolated by column chromatography using 10 % ethyl acetate in hexane followed by 12 %.
Step-b): 2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one:
The titled compound was synthesised by a method similar to that used in the preparation Step (b) of Examples 1-3.Step-c): Cis -(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-?2-1,2,4­triazoline-5-one (Cis-Itraconazole):
The titled compound was synthesised by a method similar to that used in the preparation Step (c) of Examples 1-3
,CLAIMS:We Claim:
1. Novel process for the preparation of Itraconazole of Formula (I)
Formula (I)
comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is alkyl, a protecting group or ; using a catalyst, and an optional base in presence of a suitable solvent.

2. The process for the preparation of Itraconazole as claimed in claim 1, wherein the process comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is as defined above, with compound of Formula (VII)
Formula (VII)
wherein R is alkyl or protecting group; to give compound of Formula (II),

ii) optionally de-alkylating of compound of Formula (II)
Formula (II)
wherein R is alkyl or protecting group to give compound of Formula (III)
Formula (III), and
followed by
iii) condensing with the compound of Formula (X)
Formula (X)
to obtain Itraconazole of Formula (I).

3. The process for the preparation of Itraconazole as claimed in in claim 2, wherein the process comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or a protecting group, by using suitable palladium complex, and an optional base in presence of a suitable solvent to afford compound of Formula (II);
Formula (II)
ii) de-alkylating of compound of Formula (II) using HBr or HBr in acetic acid or pyridinium hydrohalide to give compound of Formula (III)
Formula (III), and
iii) condensing the compound of Formula (X)
Formula (X)
with compound of Formula (III) using an optional base in presence of a suitable solvent to obtain Itraconazole of Formula (I).

4. The process for the preparation of Itraconazole as claimed in in claim 3, wherein the halide group in the pyridinium hydrohalide is bromo, chloro, fluoro or iodo group.

5. A process for the preparation of intermediate compound of Formula (III)
Formula (III),
as used in claim 2, wherein the process comprising the steps of:
i) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or protecting group, by using suitable palladium complex, using an optional base in presence a suitable solvent to afford compound of Formula (II);
Formula (II)
ii) de-alkylating compound of Formula (II) to give compound of Formula (III) or its salts.

6. A process for the preparation of compound of Formula (II)
Formula (II)
as used in claim 2, wherein the process comprising the steps of:
ii) coupling the compound of formula (IX)
Formula (IX)
wherein X is halogen, with compound of Formula (VII)
Formula (VII)
wherein R is an alkyl or protecting group; by using suitable palladium complex, using an optional base in presence of a suitable solvent to give compound of Formula (II) or its salts.

7. The process for the preparation of Itraconazole of Formula (I) as claimed in Claim 1, wherein the process comprising the steps of:
i) coupling the compound of Formula (IX)
Formula (IX)
wherein X is halogen; with compound of Formula (VII)
Formula (VII)
wherein R is ; using a catalyst and an optional base in presence of a suitable solvent to obtain Itraconazole of Formula (I); and
ii) optionally purifying the obtained Itraconazole in dimethylformamide and alcoholic solvent.

8. The process as claimed in claims 3-7, wherein the catalyst used for performing coupling reaction is palladium (0) or palladium (II) catalysts or precursors are selected form tris-(dibenzylidineacetone)dipalladium(0), Pd2(dba)3, di-(dibenzylidine acetone) palladium (0), Pd(dba)2. Palladium acetate, Pd(OAc)2, tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), dichlorobis(triphenylphosphine) palladium, PdCl2(Ph3), allyl palladium(II)chloride [(allyl)PdCl2], palladium(II) acetylacetonate, Pd(acac)2 or palladium (II)chloride, PdCl2, Dichloro [9,9,dimethyl-4,5-bis (diphenyl phospheno)xanthene]palladium (II), dichloro[bis(diphenylphosphenyl) ether]palladium II, Pd(OAc)2 and Pd2(dba)3; metal catalyst selected from copper, nickel, manganese complexes such as Ni (COD)2, (Ph3P)2Ni (1-nap)Cl, (dppf)Ni(O-tolyl)Cl, Ni(dppe)Cl2, [(TMEDA)Ni(o-toyl)Cl), NiCl2(dppf), NiCl2(dme), Ni2.glyme, (BINAP)Ni (?2- NC-Ph), [Bis (triphenyl phosphine)](o-tolyl chloro nickel, [1,1’-Bis(diphenyl phosphino)ferrocene] (o-tolyl) chloro nickel; copper catalysts include copper salt like copper (I) halide, copper acetate and a ligand like BINOL, BINAP, alkene diols, alkene diamines, cyclic diamines, substituted diamines and cyclic beta lactones; manganese catalyst is used, it may be a manganese salt or complexes such as manganese pincer complexes, which include MLlstein, Beller, Boncella, Kempe, Kirchner complexes or mixture of catalysts .

9. The process as claimed claims 1-7, wherein the catalyst system in any of the claims may contain phosphine ligand, wherein the ligand is selected from P(o-Tol)3, P(t-Bu)3, PPh3, PCy3, BINAP, DPPF, DPPP, DtBPF, DPPE, XantPhos DPEPhos, triaminophosphines, biphenylbased pyrole, pyrazole ligands, N-arylindole ligands or adamantyl substituted alkyl phosphine, racemic or chiral phosphines, BippyPhos, MorDalPhos and IPr-HCl.

10. The process as claimed claims 1-7, wherein the solvents used is selected from dimethyl ether, diethyl ether, diethylene glycol dimethyl ether, di isopropyl ether, methoxy ethanol, di-tertiary butyl ether, THF, dioxane, hexane, iso-hexane, heptane, cyclohexane, benzene, toluene, xylene, 1-butanol, 2-butanol, tertiary butanol, amyl alcohol, isobutyl methyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidine, acetonitrile, butyronitrile, DMSO and mixtures thereof.

11. The process as claimed claims 1-7, wherein the base used is selected from alkali metal and alkaline earth metal hydroxides, carbonates, bicarbonates, alcoholates, acetates, silazides, primary, seconday and tertiary amines, sodium tertiarybutoxide (t-BuONa), potassium tertiary n-butoxide(t-BuOK), lithium hexamethyl disilazane (LiHMDS), cesium carbonate(Cs2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), sodium methoxide (NaOMe), sodium hydroxide (NaOH), potassium hydroxide (KOH) and sodium tertiary amyloxide (t-AmONa) trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, or tri-tert-butylamine, tert-butyldimethylamine.

12. The process as claimed in claim 7, wherein the solvents used in the purification is dimethylformamide or an alcoholic solvent selected from methanol, ethanol, propanol, isopropanol, acetone mixture of these solvents or aqueous mixtures.

Dated this Third (03rd) day of April, 2019

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883