DESC:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

AN ECONOMICAL AND EFFICIENT INDUSTRIAL PROCESS FOR THE PREPARATION TRIAZOLONE INTERMEDIATE

AKTINOS Pharma Private Limited
4th and 5th floor, Sri Lakshmi Spaces, Plot no 7, Kavuri hills, Phase 1
Madhapur, Hyderabad, Telangana State, India- 500033

The following specification describes the invention and the manner in which it is to be performed
AN ECONOMICAL AND EFFICIENT INDUSTRIAL PROCESS FOR THE PREPARATION TRIAZOLONE INTERMEDIATE

FIELD OF THE INVENTION
The present invention relates to an economical and efficient industrial process for the preparation of triazolone intermediate having the formula I, useful in the synthesis of Itraconazole.

BACKGROUND OF THE INVENTION:

Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Cis-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl] methxoy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-l,2,4-triazol-3-one, commonly known as Itraconazole, a broad spectrum antifungal compound developed for oral, parental and topical use and it is disclosed in US4267179.

Itraconazole

US5998413 discloses the synthesis of Itraconazole and four stereo isomers thereof by condensing 2-(2,4-dichlororophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolane-4-methanol-4-methyl benzenesulfonate and 2,4-dihydro-4-[4-[4-[(4-Hydroxyphenyl)-1-piperzinyl]phenyl]2-(1-methylpropyl)-3H-1,2,4- triazol-3-one in the presence of sodium hydroxide and DMF.

Itraconazole is synthesized through the condensation of Key intermediates 4-[4-[4-(4-Hydroxyphenyl)piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (I) and Cis-[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl] methyl methanesulfonate (III).

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

In this literature, the demethylation of methoxy piperazine intermediate in 48% aqueous HBr is a time taking step, for example, it takes about 40-50 hrs and consumes large excess reagent to complete the reaction for example 4-5times with respect to starting material. In addition, the HBr vapours from the demethylation step pose serious health related hazards.

The cleavage of aromatic alkyl ethers is a versatile transformation in organic synthesis as it furnishes the widespread compound class of phenols and is therefore one useful member of the huge family of protecting and deprotecting reactions. It is therefore important to have suitable and efficient methods for the Deprotection of aromatic methyl ethers.
J. Org. Chem., 2002, 6406 discloses the use of thiophenol and 2-amino- thiophenol for demethylation of several methoxy naphthalenes and substituted phenyl methyl ethers.

WO2003/048104 A1 discloses the preparation of venlaflaxine using dodecanethiol and its sodium salt, as well as benzene thiol sodium salt as demethylating agent.

EP2394976A1 discloses a process for demethylating aromatic methyl ethers by reaction with 3-mercaptopropionic acid or salts thereof.

WO2011124190A2 discloses a method of producing 4-(2-(substituted)-1-(1-hydroxycyclohexyl)ethyl)phenols by o-demethylation of their methyl ethers by means of inodorous aromatic thiols.

Tetrahedron Letters, Vol. 23, p. 3611, 1982 discloses demethylation by pyridine hydrochloride requires extreme reaction conditions at high temperature (180-220 °C).

Regioselective cleavage of the ether bond by aluminium iodide (AlI3) in acetonitrile was described by Bhatt, M. V. and Babu, J. R. (Tetrahedron Letters, Vol. 25, p. 3497, 1984), and the same effect was found by Node, M. et al when they used aluminium chloride/sodium iodide reagent pair (Chem. Pharm. Bull., Vol. 31, p. 4178, 1983).

Synthetic Communications, 22(16), 2313-2327 (1992) discloses demethylation of opioid derivatives by using a methane sulfonic acid (MeSO3H)/methionine reagent pair. However, the high price of the methane sulfonic acid and that it was used in a 30-fold excess is not viable for industrial application.

Synthetic Communications, 40(12), 1765–1771 (2010) discloses demethylation of 6-(2,4-dimethoxybenzoyl)chromen-2-one and some other aryl methyl ethers using pyridinium bromide as demethylating agent and sulfolane as solvent.

A highly practical method for demethylation of aryl methyl ethers employing a long-chain odorless thiol has been developed by Junghyun Chae (Arch. Pharm. Res. 31, 305–309 (2008)). As per the conditions described in the literature, clean and fast conversions to the desired phenolic compounds have been achieved with a broad range of substrates.

To avoid problems arising from the penetrating odor, recently efforts have been made to improve the methods working with alkyl thiol and aryl thiol reagents to cleave the ether bond. According to Node's version (Node, M. et al: Tetrahedron Letters, Vol. 42, p. 9207, 2001), the penetrating EtSH could be replaced by the odorless 1-dodecanethiol (lauryl mercaptan) among others in the Fujita-method.

EP1831144B1 discloses a new process for the preparation of phenolic hydroxy-substituted compounds using thiourea/AlCl3 reagent pair.

The processes listed above have various difficulties at plant scale such as expensive reagents, extreme reaction conditions, low yield and intensive odor penetrating into the air.

Thus, there remains a need in the art to provide an efficient, industrially scalable process for the preparation of 4-[4-[4-(4-Hydroxyphenyl)piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (I), key intermediate for preparing Itraconazole which address the drawbacks of the prior art process.

OBJECTIVES OF THE INVENTION
The main objective of the present invention is to provide an efficient, eco- friendly and industrially scalable process for the preparation of 4-[4-[4-(4-Hydroxyphenyl)piperazin-1-yl]-phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Formula I).

Another objective of the present invention is to provide an efficient, eco-friendly and industrially scalable process for the preparation of 2-(Sec-Butyl)-4-(4-(4-(4-methoxyphenyl) piperazin-1-yl]- phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Formula II) using 1-(4-isocyanatophenyl)-4-(4-methoxyphenyl)piperazine (Formula V) and N'-sec-Butylformohydrazide (Formula Va).

Another objective of the present invention is to provide a process for the preparation of Itraconazole using compound of Formula (I) prepared according to the present invention.
SUMMARY OF THE INVENTION
An embodiment of the present invention provides a method for preparing a compound of Formula (I) from a compound of Formula (II) using Lewis acid in a chlorinated solvent in presence of aliphatic or aromatic thiol as below.

Another embodiment of the present invention provides an improved process for the preparation of compound of Formula (II),

Which comprises,
(a) reduction of Compound of Formula (VII) to compound of Formula (VI).

(b) conversion of compound of Formula (VI) obtained in step (a) without isolation into a compound of Formula (V) in situ.

(c) reaction of compound of Formula (V) obtained in step (b) without isolation with compound of Formula (Va) to a compound of Formula (II).

Another embodiment of the present invention provides a process for the preparation of Itraconazole by reaction of a compound of Formula (I) obtained according to the present invention with a compound of Formula (III),

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
Unless the context requires otherwise, throughout the specification, which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
In a preferred embodiment, the present invention relates to a process of preparation of the Itraconazole intermediate as provided in the following scheme,

According to the process of the present invention, the reaction is completed within 1-2 hours at room temperature or even at low temperature. The product obtained is isolated by quenching in aqueous hydrochloric acid followed by filtration.
In an embodiment of the present invention, the product formation in the process of the present invention is very clear and substantially free of impurities.
In aspects, conversion of compound of Formula (II) to compound of Formula (I) may carried out in presence of aliphatic or aromatic thiols in a suitable solvent. Aliphatic thiols used in the present reaction is selected from the group consisting of straight chain n-alkane thiols, branched chain alkane thiols, alkane thiols containing cyclic rings or dithiols and combinations thereof. The aliphatic thiols may contain 2 to 12 carbon atoms. The aliphatic thiols used includes, but not limited to ethanethiol, pentanethiol, heptanethiol, octanethiol, dodecanethiol, or tert. dodecanethiol. Aromatic thiols used in the present reaction includes but not limited to benzenethiol, 2-methyl-5-tert-butylbenzenethiol, 4-dodecylbenzenethiol, 4- dodecyloxybenzenethiol, 4-octyloxybenzenethiol, 4-heptylbenzenethiol and 4- tetramethylsilylbenzenethiol. Lewis acid used includes but not limited to aluminium halides, zinc halides and boron trifluoride. Specifically, lewis acid may be aluminium halides. Preferably, lewis acid may be aluminium chloride.
The reaction may be carried out at a temperature in the range of 0°C to 85° C. Preferably, in the range of 20°C to 85°C. More preferably, from 20°C to 35° C. The suitable solvents used may include, but not limited to dichloromethane, trichloromethane, tetrachloromethane, ethylene dichloride and like. Preferably, the solvent may be ethylene dichloride.

In yet another embodiment, the present invention further relates to a process of preparation of Itraconazole of formula (IV) by the reaction of a compound of Formula (I) obtained according to the present invention with a compound of Formula (III),

In aspects, conversion of compound of Formula (I) to compound of Formula (IV) by reaction with compound of Formula (III) may carried out in presence of a base in a suitable solvent. Bases used include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine and the like or mixtures thereof. Preferably, sodium hydroxide. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, DMA and water or a mixture thereof. Specifically, the solvent may be Toluene.

In another embodiment, the present invention also provides a process for the preparation of compound of formula II,

Which comprises,
(a) reduction of Compound of Formula (VII) to compound of Formula (VI).

(b) conversion of compound of Formula (VI) obtained in step (a) without isolation into a compound of Formula (V) in situ.

(c) reaction of compound of Formula (V) obtained in step (b) without isolation with compound of Formula (Va) to a compound of Formula (II).

In aspects, reduction of compound of Formula (VII) to compound of Formula (VI) may be carried out using suitable reducing reagents in suitable solvents. The reducing reagent used in step (a) includes but not limited to Hydrogen/ Raney nickel, Hydrogen/ Palladium on carbon, LiAlH4, Zinc and like. Preferably, may be Hydrogen/ Palladium on carbon. The solvents used include but not limited to group of dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile and like. Preferably, may be dimethylformamide.
In aspects, conversion of compound of Formula (VI) to compound of Formula (V) in step (b) may be carried out using triphosgene in presence of a suitable base and suitable solvent. Bases used include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine and the like or mixtures thereof. Preferably, may be triethylamine. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, DMA and water or a mixture thereof. Specifically, the solvent may be chloroform.
In aspects, conversion of compound of Formula (V) to compound of Formula (II) by reaction with compound of Formula (Va) in step (c) may be carried out using base in a suitable solvent. Bases used include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine and the like or mixtures thereof. Preferably, may be triethylamine. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, DMA and water or a mixture thereof. Specifically, the solvent may be Toluene.
While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.

Brief Manufacturing process:
Preparation of 4-[4-[4-(4-Hydroxyphenyl) piperazin-1-yl]-phenyl]-2-[(1RS)-1- methyl propyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (I):
Example 1:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2- [(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100 g) in dichloroethane (300 mL), anhydrous aluminium chloride (114 g) was charged followed by 1-octanethiol (84.3 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 25-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl at below 15°C. Then the reaction mixture was stirred for 30-60 minutes at 25-35°C. The solvent was distilled out completely at atmospheric pressure. To the reaction mixture water (400 mL) was added and stirred for 2-3 hours at 25-35°C. The material formed was filtered and washed with water. The wet material pH was adjusted with sodium carbonate solution to 9.0-9.5 and stirred for 60 minutes at 40-45°C. The solid material was filtered and dissolved using mixture of dichloromethane and methanol. The clear solution was treated with activated carbon (10 g) and distilled out the solvent completely. To the concentrated mass, dichloromethane (150 mL) was added and cooled to 0-5°C. The solid material was filtered and dried at 70-80°C. Yield: 80 g; HPLC purity: 99.58%.

Example 2:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2- [(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100g) in dichloroethane (300 mL), anhydrous aluminium chloride (114 g) was charged followed by 1-dodecanethiol (50 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 25-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl at below 15°C. The solvent was distilled out completely at atmospheric pressure. To the reaction mixture, water (400 mL) was added and stirred for 2-3 hours at 25-35°C. The material formed was filtered and washed with water. The wet material pH was adjusted with sodium carbonate solution to 9.0-9.5 and stirred for 60 minutes at 40-45°C. The solid material was filtered and dissolved using mixture of dichloromethane and methanol. The clear solution was treated with activated carbon (10 g) and the filtrate was concentrated. To the concentrated mass, dichloromethane (150 mL) was added and cooled to 0- 5°C. The solid material was filtered and dried at 70-80°C. Yield: 73.6 g; HPLC purity: 98.70%.

Example 3:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100 g) in dichloroethane (300 mL), anhydrous aluminium chloride (114 g) was charged followed by 1-Octanethiol (37 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 25-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl at below 15°C. The solvent was distilled out completely under vacuum. To the reaction mixture water (400 mL) was added and stirred for 2-3 hours at 25-35°C. The material formed was filtered and the wet material pH was adjusted with sodium carbonate solution to 9.0-9.5, stirred for 60 minutes at 40-45°C. The solid material was filtered and dissolved using dichloromethane-methanol mixture. The clear solution was treated with activated carbon (10 g) and distilled out the solvent completely. To the concentrated mass, dichloromethane (150 mL) was added and cooled to 0-5°C. The solid material was filtered and dried at 70-80°C.
Yield: 74 g; HPLC purity: 99.79%.

Example 4:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100 g) in dichloroethane (300 mL), anhydrous aluminium chloride (114 g) was charged followed by ethane thiol (17.20 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 25-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl and stirred for 30-60 minutes at 25-35°C. The solvent was distilled out completely at atmospheric pressure. To the reaction mixture water was added and stirred for 2-3 hours at 25-35°C. The material formed was filtered and washed with water. The wet material pH was adjusted with sodium carbonate solution to 9.0-9.5 and stirred for 60 minutes at 40-45°C. The solid material was filtered and dissolved using mixture of dichloromethane and methanol. The clear solution was treated with activated carbon (10 g) and distilled out the solvent completely. To the concentrated mass, dichloromethane (150 mL) was added and cooled to 0-5°C. The solid material was filtered and dried at 70-80°C.
Yield: 76 g; HPLC purity: 98.58%.

Example 5:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2- [(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100 g) in dichloroethane (300 mL), anhydrous aluminium chloride (114 g) was charged followed by thiophenol (27 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 25-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl and stirred for 30-60 minutes at 25-35°C. The solvent was distilled out completely. To the reaction mixture water (400 mL) was added and the material formed was filtered. The wet material pH was adjusted with sodium carbonate solution to 9.0-9.5 and stirred for 60 minutes at 40-45°C. The solid material was filtered and dissolved using mixture of dichloromethane and methanol. The resultant solution was treated with activated carbon (10 g) and distilled out the solvent completely. To the concentrated mass, dichloromethane (150 mL) was added and cooled to 0-5°C. The solid material was filtered and dried at 70-80°C.
Yield: 73.0 g; HPLC purity: 99.37%

Example 6:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2- [(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100g) in dichloroethane (300 mL), anhydrous Aluminium chloride (114 g) was charged followed by 1-Dodecanethiol (35 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 30-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl at below 15°C. The solvent was distilled out completely and water was charged. The reaction mass was stirred at 25-35°C and the product formed was filtered. The reaction mass pH was adjusted to 9.0-9.5 using sodium carbonate solution at 25-35°C. The reaction mass was heated to 40-45 °C and maintained for 1 hour at 40-45°C. The material was filtered and washed with pre-heated water. The wet material was charged into mixture of dichloromethane-methanol and stirred for 15-30 minutes. After charcoal treatment, the solvent was distilled out completely and dichloromethane (150 mL) was charged. The reaction mass was cooled to 0-5°C and stirred for 1-2 hours. The material was filtered and washed with pre-cooled dichloromethane. The material was dried for 8-10 hours at 70-80°C.
Yield: 75 g; HPLC purity: 99.56%.

Example 7:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2- [(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100 g) in dichloroethane (300 mL), anhydrous aluminium chloride (120 g) was charged followed by 1-Dodecanethiol (44 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 25-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl and stirred for 30-60 minutes at 25-35°C. The solvent was distilled out completely. To the reaction mixture water (400 mL) was added and the material formed was filtered. The wet material pH was adjusted with sodium carbonate solution to 9.0-9.5 and Chloroform (800 mL) was charged, stirred for 20 minutes at 50-60°C. Reaction mass was settled and aqueous layer was separated. The organic layer was treated with activated carbon (10 g) and 50% of solvent distilled out at atmospheric pressure. Resultant reaction mass was cooled to 0-5°C. The solid material was filtered and dried at 70-80°C.
Yield: 77.0 g; HPLC purity: 99.58%

Example 8:
To the mixture of 4-[4-[4-(4-Methoxyphenyl) piperazin-1-yl]-phenyl]-2- [(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100 g) in Chloroform (300 mL), anhydrous aluminium chloride (120 g) was charged followed by 1-Dodecanethiol (44 g) at below 15°C. The reaction mixture was stirred for 1-2hrs at 25-35°C. After completion of reaction, the reaction mixture was quenched into chilled dilute HCl and stirred for 30-60 minutes at 25-35°C. The solvent was distilled out completely. To the reaction mixture water (400 mL) was added and the material formed was filtered. The wet material pH was adjusted with sodium carbonate solution to 9.0-9.5 and Chloroform (800 mL) was charged, stirred for 20 minutes at 50-60°C. Reaction mass was settled and aqueous layer was separated. The organic layer was treated with activated carbon (10 g) and 50% of solvent distilled out at atmospheric pressure. Resultant reaction mass was cooled to 0-5°C. The solid material was filtered and dried at 70-80°C.
Yield: 77.0 g; HPLC purity: 99.52%

PREPARATION OF ITRACONAZOLE (IV)
To the mixture of 4-[4-[4-(4-Hydroxyphenyl)piperazin-1-yl]-phenyl]-2- [(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (100 g) and Cis-[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate (110 g) in toluene (700 mL ), TBAB (5 g) followed by 30% sodium hydroxide solution (100 mL) were added at 25-35°C. The reaction mixture was stirred at 90-100°C for 2 hours. After reaction completion, organic and aqueous layers were separated. To the top organic layer, methanol (150 mL) was charged at 60-65°C. The clear solution was treated with activated carbon (5 g) and filtered. The filtrate was concentrated and toluene-methanol (1:1, 300 mL) mixture was added. The resultant mixture was stirred at 50-55°C and cooled to -5 to 0°C. The product formed was filtered and washed with methanol (100 mL). The wet material was dried at 75-80°C under vacuum. Yield: 160 g; HPLC purity: 99.58%.

Preparation of 2-(Sec-Butyl)-4-(4-(4-(4-methoxyphenyl) piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (II):

Example 1:
The mixture of 1-(4-Methoxyphenyl)-4-(4-nitrophenyl)piperazine (100 g) and Dimethylformamide (500 mL) were stirred in pressure reactor for 10-15 minutes. The mixture of 10% Pd/C (0.4 g) and Dimethylformamide (50 mL) were added into the reaction mixture at 25-30 °C. The reaction mixture was heated to 40-45 °C and 4-6 Kg pressure of Hydrogen gas was applied to the reaction mixture up to consumption stopped at below 85 °C. Reaction mixture was stirred for 1-2 hours at below 85 °C. The progress of the reaction was monitored by TLC. After completion of reaction, Hydrogen gas pressure was released and applied 2.0 Kg of Nitrogen gas pressure at 80-85 °C. After releasing Nitrogen gas pressure, the reaction mixture was filtered through Hyflo bed and washed with hot Dimethylformamide (100 mL, 80-85 °C). The clear filtrate was concentrated under vacuum at below 85 °C. To the concentrated mass Toluene (650 mL) was added and stirred for 10-15 minutes at 25-30 °C. Triethylamine (49.5 g) was slowly added into the reaction mixture at 25-30 °C and stirred for 10-15 minutes. Triphosgene solution (56.7 g in 150 mL Toluene) was slowly added into the reaction mixture at 25-30 °C and stirred for 3-4 hours. The progress of the reaction was monitored by TLC. After completion of reaction, without isolating the product 1-(4-isocyanatophenyl)-4-(4-methoxyphenyl)piperazine, N'-sec-butylformohydrazide (51.3 g) was added into the reaction mixture at 25-30 °C and stirred for 10-15 minutes. Reaction mixture was heated to 80-85 °C and stirred for 2-3 hours. The reaction mixture was further heated to reflux temperature and stirred for 20-24 hours. Solvent was distilled out completely under vacuum at 70-75 °C and co-distilled with Chloroform (50 mL). Chloroform (650 mL) was charged into the concentrated mass and heated to 45-50 °C. Activated carbon (4.5 g) was charged into the reaction mixture at 45-50 °C and stirred for 20-30 minutes. Reaction mixture was filtered through Hyflo bed and washed with Chloroform (50 mL). Above filtrate was concentrated under vacuum at below 50 °C and co-distilled with Methanol (50 mL). Methanol (450 mL) was charged into the distillated crude and stirred for 50-60 minutes at 45-50 °C. Reaction mixture was cooled to 25-30 °C and stirred for 50-60 minutes. Product was filtered and wet material was washed with Methanol (50 mL). The wet material dried at 35-45 °C for 10-12 hours.
Yield: 91 g HPLC Purity: 98.23%

Example 2:
The mixture of 1-(4-Aminophenyl)-4-(4-methoxyphenyl)piperazine (100 g) and Toluene (700 mL) were stirred for 10-15 minutes at 25-30 °C. Triethylamine (55 g) was slowly added into the reaction mixture at 25-30 °C and stirred for 10-15 minutes. Triphosgene solution [63 g in Toluene (150 ml)] was slowly added into the reaction mixture at 25-30 °C and stirred for 3-4 hours. The progress of the reaction was monitored by TLC. After completion of reaction, N'-sec-butylformohydrazide (57 g) was added into the reaction mixture containing 1-(4-isocyanatophenyl)-4-(4-methoxyphenyl)piperazine at 25-30 °C and stirred for 10-15 minutes. Reaction mixture was heated to 80-85 °C and stirred for 2-3 hours. The reaction mixture was further heated to reflux temperature and stirred for 20-24 hours. Solvent was distilled out completely under vacuum at 70-75 °C and co-distilled with Chloroform (50 mL). Chloroform (700 mL) was charged into the concentrated mass and heated to 45-50 °C. Activated carbon (5 g) was charged into the reaction mixture at 45-50 °C and stirred for 20-30 minutes. Reaction mixture was filtered through Hyflo bed and washed with Chloroform (50 mL). Above filtrate was concentrated under vacuum at below 50 °C and co-distilled with Methanol (50 mL). Methanol (500 mL) was charged into the distillated crude and stirred for 50-60 minutes at 45-50 °C. Reaction mixture was cooled to 25-30 °C and stirred for 50-60 minutes. Product was filtered and wet material was washed with Methanol (50 mL). The wet material dried at 35-45 °C for 10-12 hours. Yield: 94.6 g HPLC Purity: 97.87%

N'-sec-Butylformohydrazide is prepared by the reaction of Formamide with Hydrazine hydrate followed by condensation with 2-Butanone and further reduction using sodium borohydride in alcohol medium.

Comparative Example 1:
Preparation of 2-(Sec-Butyl)-4-(4-(4-(4-methoxyphenyl) piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (II):
The mixture of 1-(4-Methoxyphenyl)-4-(4-nitrophenyl)piperazine and Dimethylformamide (500 mL) were stirred in pressure reactor for 10-15 minutes. The mixture of 10% Pd/C (0.4 g) and Dimethylformamide (50 mL) were added into the reaction mixture at 25-30 °C. The reaction mixture was heated to 40-45 °C and 4-6 Kg pressure of Hydrogen gas was applied to the reaction mixture up to consumption stopped at below 85 °C. Reaction mixture was stirred for 1-2 hours at below 85 °C. The progress of the reaction was monitored by TLC. After completion of reaction, Hydrogen gas pressure was released. The reaction mixture was filtered through Hyflo bed and washed with hot Dimethylformamide (100 mL, 80-85 °C). The clear filtrate was concentrated completely under vacuum at below 85 °C. Toluene (700 mL) was charged into the concentrated mass and cooled to 25-30 °C. Sodium bicarbonate (53.8 g) and Tetrabutylammonium bromide (4.5 g) was added into the reaction mixture at 25-30 °C. Phenyl chloroformate (76 g) was slowly added into the reaction mixture at 25-30 °C. Reaction mixture was stirred for 4-6 hours at 25-30 °C. The progress of the reaction was monitored by TLC. After completion of reaction, water (500 mL) was added into reaction mixture and heated to 45-50°C. The resultant mass was stirred for 1 hour at 45-50°C. The solid product was filtered and washed with preheated water (100 mL) followed by Methanol (200 ml). The wet material was dried at 65-70 °C for 10-12 hours.
Yield: 112 g; HPLC Purity: 97.53%

The mixture of Phenyl N-[4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl]carbamate (100 g), Toluene (700 mL), N'-sec-Butylformohydrazide (40 g) and Triethylamine (42 ml) were heated to reflux temperature and water was removed from reaction mixture by Azeotropic distillation. The reaction mixture was stirred for 15-18 hours at reflux temperature. The progress of the reaction was monitored by TLC. After completion of reaction, solvent was distilled out completely under vacuum at below 65-70 °C and co-distilled with Chloroform (100 mL). Chloroform (700 mL) was added to the reaction mixture at 25-30 °C and heated to 50-55 °C. Activated carbon (5g) and Concentrated HCl (3 mL) was added into the reaction mixture at 50-55 °C and stirred for 30-40 minutes. The reaction mixture was filtered through Hyflo bed and washed with Chloroform (50 mL). The filtrate solvent was distilled out at 50-55 °C under vacuum and co-distilled with Methanol (100 mL). Methanol (300 mL) was added to the resultant mixture at 50-55 °C and stirred for 50-60 minutes. The reaction mixture was further cooled to 25-30 °C and stirred for 30-40 minutes. The solid product was filtered and washed with methanol (50 mL). The wet material was dried at 50-55 °C for 8-10 hours to get 2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl) phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.
Yield: 81.0 g; HPLC Purity: 98.14%

The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

ADVANTAGES OF THE PRESENT INVENTION
The advantages of present invention using aluminium chloride/thiol in the process of preparation of compound, 4-[4-[4-(4-Hydroxyphenyl) piperazin-1- yl]-phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one of formula (I) are as follows.
(1) Very good yield and quality of product achieved.
(2) Less equivalent of thiol reagent is utilized for reaction completion.
(3) Easy operation and simple isolation of product using water.
(4) Recovery and reusability of solvent.
(5) Faster reaction and clean conversion at room temperature.

The advantages of present invention using intermediate V and Va in the process for the preparation of compound 2-(Sec-Butyl)-4-(4-(4-(4-methoxyphenyl) piperazine-1-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one of formula (II) are as follows,
(1) Very good yield and quality of product achieved.
(2) Isolation intermediate is avoided.
(3) Easy operation and simple isolation of product.
(4) No hazardous by-product formation.
(5) Faster reaction and clean conversion.

Dated this Apr, 05th 2023

Signature:
Dr. VURE PRASAD
Patent Agent Reg. No.: IN/PA-1636
,CLAIMS:We Claim:
1. A method for preparing Triazolone intermediate of formula (I), 4-[4-[4-(4- Hydroxyphenyl)piperazin-1-yl]-phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one comprising demethylation of a compound of formula (II) with Lewis acid and aliphatic or aromatic thiol in presence of solvent.

2. The method as claimed in claim 1, wherein the aliphatic thiol is selected from the group consisting of ethanethiol, pentanethiol, heptanethiol, octanethiol, dodecanethiol, and tert-dodecanethiol and aromatic thiol is selected from benzenethiol, 2-methyl-5-tert-butylbenzenethiol, 4-dodecylbenzenethiol, 4-dodecyloxybenzenethiol, 4-octyloxybenzene thiol, 4-heptylbenzenethiol, and 4-tetramethylsilylbenzenethiol.
3. The method as claimed in claim 1, wherein the Lewis acid is aluminium halide.
4. The method as claimed in claim 1, wherein the Lewis acid used is present in an amount stoichiometrically exceeding the amount of the aliphatic or aromatic thiol.
5. The method as claimed in claim 1, wherein the solvent is selected from the group consisting of dichloromethane, trichloromethane, tetrachloromethane, ethylene dichloride and toluene.
6. The method as claimed in claim 1, wherein the aliphatic or aromatic thiol is present in an amount of 0.5 to 2.0 equivalents with respect to the compound of formula (II).
7. A method for preparing Itraconazole comprising reaction of a compound of Formula (I) obtained according to the present invention with a compound of Formula (III).

8. A method for preparation of compound of Formula (II), 2-(Sec-butyl)-4-(4-(4-(4-methoxyphenyl) piperazine-1-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one comprising reaction of compound of Formula (V) with compound of Formula (Va) in presence of a base and solvent.

9. The method as claimed in claim 8, wherein base is triethylamine and solvent is toluene.

Dated this Apr, 05th 2023

Signature:
Dr. VURE PRASAD
Patent Agent Reg. No.: IN/PA-1636