WO2011121594A1 - A process for the preparation of itraconazole - Google Patents
A process for the preparation of itraconazole Download PDFInfo
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- WO2011121594A1 WO2011121594A1 PCT/IN2010/000218 IN2010000218W WO2011121594A1 WO 2011121594 A1 WO2011121594 A1 WO 2011121594A1 IN 2010000218 W IN2010000218 W IN 2010000218W WO 2011121594 A1 WO2011121594 A1 WO 2011121594A1
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- triazol
- phenyl
- methylpropyl
- dihydro
- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
Definitions
- the present invention is related to a preparation and purification of Cis- 4-[4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3-dioxolan-4-yl]methxoy] phenyl]-l-piperazinyl]phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one of formula (I) commonly known as Itraconazole.
- formula (I) commonly known as 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-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 surprisingly 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.
- the Principal aspect of the present invention is to provide a process for the preparation of pure Itraconazole of formula I comprising:
- 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-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-l,2,4-triazol-l- ylmethyl)-l ,3-dioxolan-4-yl]methxoy]phenyl]- 1 -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.
- the solvent for the above purification is a mixture of dimethylformamide, acetone and methanol.
- the starting material 2,4-dihydro-4-[4-[4- [(4-hydroxyphenyl)-l-piperzinyl]phenyl]2-(l-methylpropyl)-3H-l,2,4-triazol-3-one of formula III is optionally purified in the presence of methanol and dimethylformamide ( DMF ) to obtain pure compound of formula III having HPLC purity more than 98.5%.
- DMF dimethylformamide
- 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.
- Example 1 Purification of 2,4-dihvdro-4-f4-[4-f(4-hvdroxyphenylM-piperzinyll phenyll 2-(l-methylpropyl)-3H-1.2.4-triazol-3-one
- Example 2 Cis- 4- ⁇ 4-14- ⁇ 4- ⁇ 2-(2.4- ⁇ chlorophenvn-2-riH-1.2.4-triazol-l-ylmetlivn- l,3-dioxolan-4-yllmethxoylplienyll-l-piperazinyllphenyll-2,4-dihvdro-2-(l- methylpropyn-3H-1.2.4-triazol-3-one
- the reaction was charged into methanol (1000 mL) cooled to 5-10 °C, stirred for 1 hour at 5-10 °C and filtered and sucked to obtain wet mass.
- the obtained compound was first crystalised in methanol and then by DM water and again in methanol.
- the mixture was cooled to 0-5 °C and maintained for one hour.
- the product was filtered and washed with chilled methanol ( 150 mL ).
- the obtained wet mateial was dissolved in methanol (390 mL) and toluene (390 mL) at reflux temperature.
- the activated carbon (10 g) was charged and maintained for 15 minutes at reflux, filtered in hot condition and washed with methanol ( 50 mL) and toulene ( 30 mL), cooled the filterate to 20 °C and maintained for 5 hours at 20-25 °C.
- the product was filtered and washed with methanol (100 mL) and dried at 100- 105 °C till constant weight . 126.5 g of purity : >99.5% is achieved.
Abstract
The present invention encompasses a process for the 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) to obtain a specifically desired four possible sterioisomer.
Description
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-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3-dioxolan-4-yl]methxoy] phenyl]-l-piperazinyl]phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,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-( 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 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-l-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 surprisingly 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-(l-methylpropyl)-3H-l,2,4-triazol-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-(l H- 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- 1 -ylmethyl)- 1 ,3-dioxolan-4-yl]methxoy]phenyl]- 1 -piperazinyl]phenyl] -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-( 1 H- 1 ,2,4-triazol- 1 - ylmemyl)-l,3-dioxolan-4-yl]metlixoy]phenyl]-l-piperazmyl]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:
Cis - Itraconazole
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]- 1 -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- 1,2,4- 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, potassium 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)-l-piperzinyl]phenyl]2-(l-methylpropyl)-3H-l,2,4-triazol-3-one of formula III is optionally purified in the presence of methanol and dimethylformamide ( DMF ) to obtain pure compound 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 (+)-[2R-[2a, 4a, 4(S)]]
2 (-)-[2S-[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-[4-f(4-hvdroxyphenylM-piperzinyll phenyll 2-(l-methylpropyl)-3H-1.2.4-triazol-3-one
2,4-Dmydro-4-[4-[4-[(4-hydroxyphenyl)-l-piperzinyl]phenyl]2-(l-methylpropyl)-3H- l,2,4-triazol-3-one ( 500 g ) in methanol (2000 mL) and dimethyl formamide (1500 mL) was dissolved at reflux temperature and activated carbon ( 50 g ) was added into it and maintained 0.5 hr. The content was filtered in hot condition, washed the carbon bed with hot methanol ( 250 mL ), cooled the filterate to 25-30 °C and further cooled the contents to 0-5 °C and maintained for 2 hours. The product was filtered and sucked well to obtain a mass. This process was repeated twice and finally the obtained wet mass was dissolved in methanol ( 1000 mL) and stirred for 0.5 hours at reflux. The content was cooled to 25 - 30 °C for 0.5 hours, filtered, sucked well and dried at 95-100 °C till the constant weight. 327.0 g of purity 99% is obtained.
Example 2: Cis- 4- Γ4-14- Γ4- Γ2-(2.4-Ρί chlorophenvn-2-riH-1.2.4-triazol-l-ylmetlivn- l,3-dioxolan-4-yllmethxoylplienyll-l-piperazinyllphenyll-2,4-dihvdro-2-(l- methylpropyn-3H-1.2.4-triazol-3-one
2,4-Dihydro-4-[4-[4-[(4-hydroxyphenyl)-l-piperzinyl]phenyl]2-(l-methylpropyl)- 3H-l,2,4-triazol-3-one (lOOg) obtained above and and 2-(2,4-dichlororophenyl)-2-(lH- l,2,4-triazol-l-yl-methyl)-l,3-dioxolane-4-methanol 4 methyl sulfonate ( 124.6 g) were
heated at 60-65 C in dimethylsulfoxide (460 mL) and potassium hydroxide powder (25 g) and stirred 3 hours at 60-65 °C. The reaction was charged into methanol (1000 mL) cooled to 5-10 °C, stirred for 1 hour at 5-10 °C and filtered and sucked to obtain wet mass. The obtained compound was first crystalised in methanol and then by DM water and again in methanol.
Wet weight 209.5 g , Dry weight 166.7 g.
Example 3;
triazol-l-ylmethvn-l,3-dioxolan-4-yllmethxoylphenyll-l-piperazinyllphenyll-2.4- dihvdro-2-(l-methylpropyD-3H-1.2.4-triazol-3-one.
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 ( 150 g ) was refluxed in the mixture of dimethylformamide (315 mL), methanol (315 mL), and acetone (315 mL ) for 0.5 hours. The mixture was cooled to 0-5 °C and maintained for one hour. The product was filtered and washed with chilled methanol ( 150 mL ). The obtained wet mateial was dissolved in methanol (390 mL) and toluene (390 mL) at reflux temperature. The activated carbon (10 g) was charged and maintained for 15 minutes at reflux, filtered in hot condition and washed with methanol ( 50 mL) and toulene ( 30 mL), cooled the filterate to 20 °C and maintained for 5 hours at 20-25 °C. The product was filtered and washed with methanol (100 mL) and dried at 100- 105 °C till constant weight . 126.5 g of purity : >99.5% is achieved.
The chiral analysis by HPLC of above obtained compound gives the following results:
1st isomer : 26.29%
2nd isomer : 24.82%
3rd isomer : 23.98
4th isomer : 24.91%
Claims
1. A process for the preparation of Itraconazole formula ( I )
which c 
a) purification of the crude intermediate 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-l- piperzinyl]phenyl]2-(l-methylpropyl)-3H-l,2,4-triazol-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-( 1 H- 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 ΠΙ 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 -piperazinyl]phenyl] -2,4- dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one of formula (IV); and
II
c) purification of crude cis-4-[4-[4-[4-[[2-(2,4-Di chlorophenyl)-2-(lH-l,2,4-triazol-l- ylmethyl)- 1 ,3 -dioxolan-4-yi]methxoy]phenyi] - 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.
2. A process according to claim 1 wherein, 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)-l-piperzinyl]phenyl]2-(l-methylpropyl)-3H-l,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-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 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-(l-methylpropyl)-3H-l,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-l,2,4-triazol-l-ylmethyl)- 1 ,3-dioxolan-4-yl]methxoy]phenyl] - 1 -piperazinyljphenyl] -2,4-dihydro-2-( 1 - 1 methylpropyl)-3H-l,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.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293642A (en) * | 2018-09-29 | 2019-02-01 | 北京莱瑞森医药科技有限公司 | A kind of polishing purification method of Itraconazole |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267179A (en) * | 1978-06-23 | 1981-05-12 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
| WO2005116011A1 (en) * | 2004-05-28 | 2005-12-08 | Hetero Drugs Limited | A novel stereoselective synthesis of benzimidazole sulfoxides |
-
2010
- 2010-04-01 WO PCT/IN2010/000218 patent/WO2011121594A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267179A (en) * | 1978-06-23 | 1981-05-12 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
| WO2005116011A1 (en) * | 2004-05-28 | 2005-12-08 | Hetero Drugs Limited | A novel stereoselective synthesis of benzimidazole sulfoxides |
Non-Patent Citations (1)
| Title |
|---|
| BELL ET AL.: "Triazole Antifungals", THE ART OF DRUG SYNTHESIS, 2007, pages 1 - 276 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293642A (en) * | 2018-09-29 | 2019-02-01 | 北京莱瑞森医药科技有限公司 | A kind of polishing purification method of Itraconazole |
| CN109293642B (en) * | 2018-09-29 | 2020-07-03 | 北京莱瑞森医药科技有限公司 | Refining and purifying method of itraconazole |
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