A PROCESS FOR THE PREPARATION OF ITRACONAZOLE

TECHNICAL FIELD OF THE INVENTION

The present invention is related to a preparation and purification of 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-1,2,4-triazol-3-one of formula (I) commonly known as Itraconazole.

BACKGROUND OF THE INVENTION

Cis-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(lH-l,2,4-triazol-1-ylmethyl)-l,3-dioxolan-4-yl]methxoy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1 -methylpropyl)-3H-l,2,4-triazol-3-one of Formula (I), commonly known as Itraconazole is a broad spectrum antifungal compound developed for oral, parental and topical use and its disclosed in US4267179.

US5998413 discloses the synthesis of Itraconazole and four stereo isomers thereof by condensing 2-(2,4-dichlororophenyl)-2-(lH-l,2,4-triazol-1-yl-methyl)-l,3-dioxolane-4-methanol-4-methyl benzenesulfonate (ester) 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. This patent also disclosed the purification of Itraconazole in methanol. The present inventors found that the above process gives a specific enantiomeric ratio of the four possible stereoisomeric cis forms, which is not suitable for the pharmaceutical formulation. After the extensive experimentation, the present inventors sxuprisingly found a process which gives approximately 1:1:1:1 ratio of the four possible stereoisomeric cis forms, which is highly suitable for the pharmaceutical formulation.

SUMMARY OF THE INVENTION

The Principal aspect of the present invention is to provide a process for the preparation of pure Itraconazole of formula I comprising:

a) purification of the crude intermediate 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-l-piperzinyl]phenyl]2-(1-methylpropyl)-3H-1,2,4-triazol-3-one of formula III in the presence of methanol and dimethylformamide (DMF) to obtain pwre formula III;

b) condensing 2-(2,4-dichlororophenyl)-2-( 1H-1,2,4-triazol-1 -yl-methyl)-1,3-dioxolane-4-methanol-4-methyl sulfonate of formula 11 with 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-l-piperzinyl]phenyl]2-(l-methylpropyl)-3H-l,2,4-triazol-3-one of formula III to obtain crude cis- 4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-1,2,4-triazol-1 -ylmethyl)-1,3-dioxolan-4-yl]methxoy]phenyl]-1 -piperazinyljphenyl] -2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one of formula (IV); and

c) purification of crude cis-4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-( 1H-1,2,4-triazol-1 -ylmethyl)-l,3-dioxolan-4-yl]methxoy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one in the presence of mixture of dimethylformamide, acetone and methanol to obtain relatively pure Itraconazole of formula I.
This process can be represented by the below scheme:

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the primary aspect of the invention is to provide a process for the preparation of Itraconazole of formula I having the four possible stereoisomeric cis forms, each in the range of 22-27 %, preferably the four isomer are in approximately 1:1:1:1 ratio. This desired isomeric ratio of four stereoisomeric cis forms is obtained by the purification of crude itraconazole i.e cis- 4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methxoy]phenyl]-l-piperazinyl]phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one of formula IV in the presence of a mixture of solvents. The solvents for this purification is selected dipolar aprotic solvent, ketonic sovent and alcoholic solvent.

Preferably the solvent for the above purification is a mixture of dimethylformamide, acetone and methanol.

In an embodiment of the condensation of 2-(2,4-dichlororophenyl)-2-(lH-l,2,4-
triazol-l-yl-methyl)-l,3-dioxolane-4-methanol-4-methyl sulfonate and 2,4-dihydro-4-[4-[4- [(4-hydroxyphenyl)-1 -piperzinyl]phenyl]2-( 1 -methylpropyl)-3H-1,2,4-triazol-3 -one is carried out in presence of a dipolar aprotic solvents such as Dimethyl sulfoxide, N,N dimethylformamide, N,N-dimethyl acetamide and the like, preferably Dimethyl sulfoxide and a base selected from the group consisting of potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassiimi carbonate, potassium bicarbonate, potassium tert-butoxide, triethyl amine, diisopropyl amine and the like; preferably Potassium hydroxide. The condensation reaction is usually conducted at a temperature of about 40°C to 80°C, preferably, the temperature is maintained during reaction is about 60°C to about 65 °C for a period of 3 hours.

In further embodiment of the invention the starting material 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1 -piperzinyl]phenyl]2-( 1 -methylpropyl)-3H-1,2,4-triazol-3-one of formula III is optionally purified in the presence of methanol and dimethylformamide ( DMF) to obtain pure compoimd of formula III having HPLC purity more than 98.5%.

In yet another embodiment of the present invention, the purifcation of 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1 -piperzinyl]phenyl]2-( 1 -methylpropyl)-3H-1,2,4-triazol-3-one of formula III is carried out using Dimethyl formamide, Activated carbon and alcoholic solvent selected from the ethanol, isopropanol, methanol, and the like, preferably methanol, at the reflux temperature of the mixture of solvents.

In yet another embodiment of the invention the four possible sterioisomer of cis -Itraconazole are;
1 (+H2R-[2a,4a,4(S)]]
2 (-H2S-[2a,4a,4(S)]]
3 (-)-[2S-[2a,4a,4(R)]]
4 (+)-[2R-[2a,4a,4(R)]]
The examples are provided below to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples:
Example 1: Purification of 2.4-dihvdro-4-f4-f4-[(4-hv99.5% is achieved.

The chiral analysis by HPLC of above obtained compound gives the following results: 1'' isomer : 26.29% 2 isomer : 24.82% y'isomer : 23.98 4 isomer : 24.91%

We Claim:

1. A process for the preparation of Itraconazole formula (I)
which comprises:
a) purification of the crude intermediate 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperzinyl]phenyl]2-(1-methylpropyl)-3H-1,2,4-tria2ol-3-one of formula III in the presence of methanol and dimethylformamide (DMF ) to obtain pure formula III;

b) condensing 2-(2,4-dichlororophenyl)-2-(lH-1,2,4-triazol-1-yl-methyl)-1,3-dioxolane-4-methanol-4-methyl sulfonate of formula II with 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1 -piperzinyl]phenyl]2-( 1 -methylpropyl)-3H-1,2,4-triazol-3-one of formula III to obtain crude cis- 4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-1,2,4-triazol-l-ylmethyl)-1,3-dioxolan-4-yl]methxoy]phenyl]-1-piperazinyl]phenyl] -2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one of formula (IV); and

c) purification of crude cis-4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-l,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methxoy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2- (1-methylpropyl)-3H-1,2,4-triazol-3-one in the presence of mixture of dimethylformamide, acetone and methanol to obtain relatively pure Itraconazole of formula I.

2. A process according to claim 1 wherein, the condensation of 2-(2,4-dichlororophenyl)-2- (lH-1,2,4-triazol-1-yl-methyl)-l,3-dioxolane-4-methanol-4-methyl sulfonate and 2,4- dihydro-4-[4-[4-[(4-hydroxyphenyl)-1 -piperzinyl]phenyl]2-( 1 -methylpropyl)-3H-1,2,4- triazol-3-one is carried out in presence of a dipolar aprotic solvents selected from the groupe consisting of Dimethyl sulfoxide, N,N dimethylformamide, N,N-dimethyl acetamide Dimethyl sulfoxide and a base selected from the group consisting of potassium

hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, triethyl amine, diisopropyl amine.

3. A process according to claim 1 wherein, the condensation of 2-(2,4-dichlororophenyl)-2-(lH-1,2,4-triazol-1-yl-methyl)-1,3-dioxolane-4-methanol-4-methyl sulfonate and 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1 -piperzinyl]phenyl]2-( 1 -methylpropyl)-3H-1,2,4-triazol-3-one is carried out in presence of dimethylsulfoxide and a base potassium hydroxide.

4. A process according to claim 1 wherein, the mixture of solvent for the purification in step (c) is selected from dipolar aprotic solvent, ketonic solvent and alcoholic solvent.

5. A process according to claim 1 wherein, the mixture of solvent for the purification in step (c) comprises dimethylformamide, methanol, and acetone.

6. A process for the purification of cis-4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-1,2,4-triazol-1 -ylmethyl)-1,3 -dioxolan-4-yl]methxoy]phenyl] -1 -piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one in the presence of a mixture of solvents to obtain Itraconazole having four- possible stereoisomeric cis forms, each in the range of 22-27%.

7. A process for the pufication according to claim 6 where the four possible stereoisomeric cis forms of cis-4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-1,2,4-triazol-1-yhneftiyl)-1,3-dioxolan-4-yl]methxoy]phenyl]-1 -piperazinyl]phenyl]-2,4-dihydro-2-( 1 -methylpropyl)-3H-1,2,4-triazol-3-one is obtained in 1:1:1:1 ratio,

8. A process according to claim 6 wherein, the mixture of solvent is selected from dipolar aprotic solvent, ketonic solvent and alcoholic solvent.

9. A process according to claim 6 wherein, the mixture of solvent comprises dimethylformamide, methanol, and acetone.