CA2051281C - Process for the preparation of triazolyl isopropanols - Google Patents
Process for the preparation of triazolyl isopropanolsInfo
- Publication number
- CA2051281C CA2051281C CA 2051281 CA2051281A CA2051281C CA 2051281 C CA2051281 C CA 2051281C CA 2051281 CA2051281 CA 2051281 CA 2051281 A CA2051281 A CA 2051281A CA 2051281 C CA2051281 C CA 2051281C
- Authority
- CA
- Canada
- Prior art keywords
- preparation
- compound
- triazole
- reaction
- isopropanols
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preventing Corrosion Or Incrustation Of Metals (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
An improved method for the preparation of fluconazole is described, by reacting an halohydrinic intermediate with 4-amino-1,2,4-triazole compound of formula II
Description
PROOE SS FOR T~B PREPARATION OF TRIAZOLYL ISOPROPANOLS
The present invention refers to a process for the preparation of 2-(2,4-difluorophenyl)-1,3-bis-(lH,1,2,4-triazol-1-yl)-2-propanol, of formula I
0:~
F N~ I /G==~N
~ ~N - C~ 2 ~ C - C~2 - N ~ ( I ) ~~
I
The compound I, also known with the name of fluconazole, is an antimycotic drug, disclosed in GB
2099818.
The known processes for the preparation of compounds I are characterized by the opening of an epoxidic intermediate of formula FN\ ~ ~' ~ N - CH2 ~ C C~2 N ~ F
with 1,2,4-triazole.
This reaction, however, is not selective, and yields the isomer 2-(2,4-difluorophenyl),1-(lH,1,2,4-triazol-l-yl),3-(4H,1,2,4-triazol-4-yl),2-propanol.
It has now been found that the compound I may be selectively obtained by reacting an halohydrin of formula II
F \N - C~2--C--CH2--X
~ F (II) wherein X is fluorine, chlorine, bromine or iodine with 4-amino-1,2,4-triazole to give the compound III
OH
N - CH2 - C - C~.2 - N\ ~ N NH2 X~
~ F (III) wherein X is above defined which, by reaction with nitrous acid in aqueous or alcoholic-aqueous medium, yields the compounds I with high yields and purity.
The compound III is new and it is a further object of the invention, as an intermediate.
The compound II can be easily prepared (a) from 2,4-difluorobenzene, magnesium bromide, by reaction with 1,3-dichloroacetone (Synthesis 1983,647) and then with lH-1,2,4-triazole or (b) from ~-chloro-2,4-difluoro-acetophenone by reaction with (lH-1,2,4-triazole-1) methyl magnesium chloride (Synthesis 1983,647) or (c) from 1 [2 (2,4 difluorophenyl) 2,3-epoxypropyl]-lH-1,2,4-triazole by reaction with hydrohalogen acids.
The reaction between compound II and 4-amino-1,2,4-triazole is preferably carried out in inert solvents such as Cl-C5 alcohols, ketones, esters, ethers.
The following examples further illustrate the invention.
The present invention refers to a process for the preparation of 2-(2,4-difluorophenyl)-1,3-bis-(lH,1,2,4-triazol-1-yl)-2-propanol, of formula I
0:~
F N~ I /G==~N
~ ~N - C~ 2 ~ C - C~2 - N ~ ( I ) ~~
I
The compound I, also known with the name of fluconazole, is an antimycotic drug, disclosed in GB
2099818.
The known processes for the preparation of compounds I are characterized by the opening of an epoxidic intermediate of formula FN\ ~ ~' ~ N - CH2 ~ C C~2 N ~ F
with 1,2,4-triazole.
This reaction, however, is not selective, and yields the isomer 2-(2,4-difluorophenyl),1-(lH,1,2,4-triazol-l-yl),3-(4H,1,2,4-triazol-4-yl),2-propanol.
It has now been found that the compound I may be selectively obtained by reacting an halohydrin of formula II
F \N - C~2--C--CH2--X
~ F (II) wherein X is fluorine, chlorine, bromine or iodine with 4-amino-1,2,4-triazole to give the compound III
OH
N - CH2 - C - C~.2 - N\ ~ N NH2 X~
~ F (III) wherein X is above defined which, by reaction with nitrous acid in aqueous or alcoholic-aqueous medium, yields the compounds I with high yields and purity.
The compound III is new and it is a further object of the invention, as an intermediate.
The compound II can be easily prepared (a) from 2,4-difluorobenzene, magnesium bromide, by reaction with 1,3-dichloroacetone (Synthesis 1983,647) and then with lH-1,2,4-triazole or (b) from ~-chloro-2,4-difluoro-acetophenone by reaction with (lH-1,2,4-triazole-1) methyl magnesium chloride (Synthesis 1983,647) or (c) from 1 [2 (2,4 difluorophenyl) 2,3-epoxypropyl]-lH-1,2,4-triazole by reaction with hydrohalogen acids.
The reaction between compound II and 4-amino-1,2,4-triazole is preferably carried out in inert solvents such as Cl-C5 alcohols, ketones, esters, ethers.
The following examples further illustrate the invention.
2-(2,4-Difluorophenyl),l-(1~,1,2,4-triazol-1-yl),3-(4H,4-amino,1,2,4-triazonium-1-yl)2-propanol,bromide (III) 6.4 g of 2(2,4-difluorophenyl),l-bromo,3-(1~,1,2,4-triazol-1-yl)-2-propanol, are refluxed in 100 ml of isopropanol with 5.1 g of 4-amino-1,2,4-triazole for 8 hours. The reaction mixture is cooled to 0~C and the crystallized product is filtered. The crude wet product, so obtained, is refluxed with 50 ml of isopropanol, then refluxed, filtered and dried under vacuum at 40~C.
6.3 g (77.8~~) of the title product are obtained.
2-(2,4-Difluorophenyl),1,3-bis-(1~,1,2,4-triazol-1-yl)-2-propanol (I) 6.3 g of the product obtained in the Example 1 are dissolved in 60 ml of water and, cooling to 5~C, added with 1.8 g of concentrated hydrochloric acid. The solution is treated, at temperatures between 0 and 5~C, with a solution of 1.2 g of sodium nitrite in 6 ml of water. The reaction is continued at the same temperature for 30 minutes and then for at least 1 hour at 20~C. The so obtained solution is added with 500 mg of active charcoal and filtered. The so obtained clear solution is treated with concentrated ammonia up to p~
9 keeping the temperature at 20~C. When the product precipitation starts, the solution is cooled to 5~C for at least 5 ml of water. The obtained crude product is crystallized from 25 ml of isopropanol. The filtered product is washed with 5 ml of cold isopropanol, dried at 40~C under vacuum.
4.1 g (85.4Yo) of the title product, having the same elemental analysis, mass, IR and NMR spectrum as a product sample obtained accordin~ to Gs 2099818.
6.3 g (77.8~~) of the title product are obtained.
2-(2,4-Difluorophenyl),1,3-bis-(1~,1,2,4-triazol-1-yl)-2-propanol (I) 6.3 g of the product obtained in the Example 1 are dissolved in 60 ml of water and, cooling to 5~C, added with 1.8 g of concentrated hydrochloric acid. The solution is treated, at temperatures between 0 and 5~C, with a solution of 1.2 g of sodium nitrite in 6 ml of water. The reaction is continued at the same temperature for 30 minutes and then for at least 1 hour at 20~C. The so obtained solution is added with 500 mg of active charcoal and filtered. The so obtained clear solution is treated with concentrated ammonia up to p~
9 keeping the temperature at 20~C. When the product precipitation starts, the solution is cooled to 5~C for at least 5 ml of water. The obtained crude product is crystallized from 25 ml of isopropanol. The filtered product is washed with 5 ml of cold isopropanol, dried at 40~C under vacuum.
4.1 g (85.4Yo) of the title product, having the same elemental analysis, mass, IR and NMR spectrum as a product sample obtained accordin~ to Gs 2099818.
Claims (3)
1. A process for the preparation of the compound of formula I
which comprises the reaction of a compound of formula II
wherein X is fluorine, chlorine, bromine or iodine with 4-amino-1,2,4-triazole to give the compound of formula III
which is then reacted with nitrous acid.
which comprises the reaction of a compound of formula II
wherein X is fluorine, chlorine, bromine or iodine with 4-amino-1,2,4-triazole to give the compound of formula III
which is then reacted with nitrous acid.
2. A process according to claim 1 characterized in that a compound II wherein X is bromine is used.
3. Compound of formula III
wherein X is fluorine, chlorine, bromine or iodine.
wherein X is fluorine, chlorine, bromine or iodine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02058690A IT1249211B (en) | 1990-06-08 | 1990-06-08 | Process for the preparation of triazolyl isopropanols, in particular fluconazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2051281A1 CA2051281A1 (en) | 1993-03-14 |
| CA2051281C true CA2051281C (en) | 1998-07-07 |
Family
ID=11169192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2051281 Expired - Lifetime CA2051281C (en) | 1990-06-08 | 1991-09-13 | Process for the preparation of triazolyl isopropanols |
Country Status (5)
| Country | Link |
|---|---|
| AT (1) | AT400145B (en) |
| CA (1) | CA2051281C (en) |
| ES (1) | ES2026416A6 (en) |
| IT (1) | IT1249211B (en) |
| YU (1) | YU48331B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2049663B1 (en) * | 1992-10-13 | 1994-12-16 | Genesis Para La Investigacion | PROCEDURE FOR OBTAINING FLUCONAZOLE. |
| IL105200A (en) * | 1993-03-29 | 1997-03-18 | Teva Pharma | Regiospecific processes for the preparation of 1, 3-bis (1, 2, 4-triazol-1-yl)-propan- 2-ol derivatives |
| HU212424B (en) * | 1993-09-23 | 1996-06-28 | Richter Gedeon Vegyeszet | New propan-2-ol derivatives substituted with triazole or imidazole and process for producing them |
| SI9600165A (en) * | 1996-05-21 | 1997-12-31 | Krka Tovarna Zdravil D D Novo | Process for preparation of biological active derivative of 1,2,4- triazole and intermediates useful in this process |
| ES2252209T3 (en) * | 2001-03-23 | 2006-05-16 | Richter Gedeon Vegyeszeti Gyar R.T. | PROCESS TO PREPARE FLUCONAZOL AND ITS CRYSTAL MODIFICATIONS. |
| EA007326B1 (en) * | 2002-06-24 | 2006-08-25 | Басф Акциенгезельшафт | Method for the production of 1,2,4-triazolylmethyl-oxiranes |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR79307B (en) * | 1982-06-09 | 1984-10-22 | Pfizer | |
| ES8604940A1 (en) * | 1985-11-19 | 1986-03-01 | Inke Sa | 2-(Difluorophenyl) 1,3-bis(1H-triazolyl) propan-2-ol prepn. |
| ES8604939A1 (en) * | 1985-11-19 | 1986-03-01 | Inke Sa | 2-(Difluorophenyl) 1,3-bis (1H-triazolyl) propan-2-ol prepn. |
| ES8604938A1 (en) * | 1985-11-19 | 1986-03-01 | Inke Sa | 2-(Difluorophenyl)-1,3-bis(triazolyl) propan-2-ol prepn. |
| ES8605753A1 (en) * | 1985-12-06 | 1986-04-16 | Lazlo Int Sa | Di-triazolyl:methyl di:fluoro-phenyl carbinol prepn. |
-
1990
- 1990-06-08 IT IT02058690A patent/IT1249211B/en active IP Right Grant
- 1990-11-21 ES ES9002961A patent/ES2026416A6/en not_active Expired - Lifetime
-
1991
- 1991-06-05 AT AT113291A patent/AT400145B/en not_active IP Right Cessation
- 1991-06-06 YU YU101291A patent/YU48331B/en unknown
- 1991-09-13 CA CA 2051281 patent/CA2051281C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| IT9020586A0 (en) | 1990-06-07 |
| AT400145B (en) | 1995-10-25 |
| IT9020586A1 (en) | 1991-12-08 |
| YU48331B (en) | 1998-05-15 |
| ATA113291A (en) | 1995-02-15 |
| CA2051281A1 (en) | 1993-03-14 |
| ES2026416A6 (en) | 1992-04-16 |
| IT1249211B (en) | 1995-02-20 |
| YU101291A (en) | 1993-11-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |