IT9020586A1 - PROCESS FOR THE PREPARATION OF TRIAZOLYL ISOPROPANOLS IN PARTICULAR FLUCONAZOLE - Google Patents
PROCESS FOR THE PREPARATION OF TRIAZOLYL ISOPROPANOLS IN PARTICULAR FLUCONAZOLEInfo
- Publication number
- IT9020586A1 IT9020586A1 IT020586A IT2058690A IT9020586A1 IT 9020586 A1 IT9020586 A1 IT 9020586A1 IT 020586 A IT020586 A IT 020586A IT 2058690 A IT2058690 A IT 2058690A IT 9020586 A1 IT9020586 A1 IT 9020586A1
- Authority
- IT
- Italy
- Prior art keywords
- compound
- preparation
- isopropanols
- triazolyl
- reaction
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 5
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 title description 2
- 229960004884 fluconazole Drugs 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 229960004592 isopropanol Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- FMCUPJKTGNBGEC-UHFFFAOYSA-N 1,2,4-triazol-4-amine Chemical compound NN1C=NN=C1 FMCUPJKTGNBGEC-UHFFFAOYSA-N 0.000 description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 2
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- PXNMFQMREJNQQT-UHFFFAOYSA-N 1-(chloromethyl)-1,2,4-triazole Chemical compound ClCN1C=NC=N1 PXNMFQMREJNQQT-UHFFFAOYSA-N 0.000 description 1
- UIXQTZYZQHYHRL-UHFFFAOYSA-N 1-[[2-(2,4-difluorophenyl)oxiran-2-yl]methyl]-1,2,4-triazole Chemical compound FC1=CC(F)=CC=C1C1(CN2N=CN=C2)OC1 UIXQTZYZQHYHRL-UHFFFAOYSA-N 0.000 description 1
- MGHBDQZXPCTTIH-UHFFFAOYSA-N 1-bromo-2,4-difluorobenzene Chemical compound FC1=CC=C(Br)C(F)=C1 MGHBDQZXPCTTIH-UHFFFAOYSA-N 0.000 description 1
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- -1 alcohol ketones Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000003944 halohydrins Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Preventing Corrosion Or Incrustation Of Metals (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: "PROCESSO PER LA PREPARAZIONE DI TRIAZOLIL ISOPROPANOLI IN PARTICOLAR E FL UCONAZOLO " Description of the industrial invention entitled: "PROCESS FOR THE PREPARATION OF TRIAZOLYL ISOPROPANOLS IN PARTICULAR AND FL UCONAZOLE"
La presente invenzione ha per oggetto un procedimento per la preparazione del The present invention relates to a process for the preparation of
-2-propanolo, di formula (I) -2-propanol, of formula (I)
Il composto (I), noto anche col nome comue fluconazolo, è un farmaco ad attività antimicotica, descritto nel brevetto britannico n. Compound (I), also known by the common name fluconazole, is a drug with antifungal activity, described in the British patent n.
2.099.818. 2,099,818.
I procedimenti per la preparazione del composto (I) finora noti sono caratterizzati dall'apertura di un intermedio epossidico di formula The processes for the preparation of the compound (I) known up to now are characterized by the opening of an epoxy intermediate of formula
con 1,2,4-triazolo. with 1,2,4-triazole.
Questa reazione, tuttavia, non è selettiva, e dà luogo alla formazione dell'isomero This reaction, however, is not selective, and results in the formation of the isomer
Si è ora trovato che il composto I può essere ottenuto, selettivamente per reazione di un 'alogenoidrina di formula II It has now been found that compound I can be obtained selectively by reaction of a halohydrin of formula II
dove X è fluoro, cloro, bromo o iodio con 4-ammino -l,2,4-triazolo a dare il composto III where X is fluorine, chlorine, bromine or iodine with 4-amino-1, 2,4-triazole to give compound III
dove X è come sopra definito, che, per reazione con acido nitroso in ambiente acquoso o acquoso-alcolico porta a composto I in elevate rese e purezza. Il composto III è nuovo ed è oggetto dell'invenzione a titolo di intermedio. where X is as defined above, which, by reaction with nitrous acid in an aqueous or aqueous-alcoholic environment, leads to compound I in high yields and purity. Compound III is new and is the subject of the invention as an intermediate.
Il composto II è facilmente ottenibile da l-bromo-2,4-difluorobenzene per reazione con 1,3-dicloroacetone e quindi con 1H-1,2,4-triazolo eppure da -difluoro-acetofenone per reazione con 1-clorometil-1H--1,2,4-triazolo (Synthesis 1983, 647) oppure ancora da 1-(2-(2,4-difluorofenil)-2,3-epossipropil)-1H-1,2 ,4-triazolo per reazione con acidi alogenidrici. Compound II is easily obtainable from 1-bromo-2,4-difluorobenzene by reaction with 1,3-dichloroacetone and therefore with 1H-1,2,4-triazole and from -difluoro-acetophenone by reaction with 1-chloromethyl-1H --1,2,4-triazole (Synthesis 1983, 647) or 1- (2- (2,4-difluorophenyl) -2,3-epoxypropyl) -1H-1,2, 4-triazole by reaction with halogenhydric acids.
La reazione fra composto II e 4-ammino -l,2,4-triazolo viene preferibilmente condotta in solventi inerti quali alcoli chetoni, esteri, eteri. The reaction between compound II and 4-amino -1, 2,4-triazole is preferably carried out in inert solvents such as alcohol ketones, esters, ethers.
I seguenti esempi illustrano ulteriormente l'invenzione. The following examples further illustrate the invention.
Esempio 1 Example 1
2-(2,4-difluorofenil),1-(IH,1,2,4-triazol-l-il ),3-(4H,4-amino,1,2,4-triazonio-l-il)2-propanolo,bromuro (III). 2- (2,4-difluorophenyl), 1- (1H, 1,2,4-triazol-1-yl), 3- (4H, 4-amino, 1,2,4-triazonium-1-yl) 2 -propanol, bromide (III).
6,4 g di 2(2,4-difluorofenil),1-bromo,3-(IH,1,2,4-triazol-l-il)-2-propanolo, vengano fatti reagire a riflusso in 100 ml di alcool isopropilico con 5,1 g di 4-amino,1,2,4-triazolo per 8 ore. Si raffredda la miscela di reazione a 0°C e si filtra il prodotto che cristallizza. Il prodotto grezzo umido, così ottenuto, viene trattato a riflusso con 50 ml di alcool isopropilico, quindi raffreddato, filtrato ed essiccato sotto vuoto a 40°C. 6.4 g of 2 (2,4-difluorophenyl), 1-bromine, 3- (1H, 1,2,4-triazol-1-yl) -2-propanol, are refluxed in 100 ml of alcohol isopropyl with 5.1 g of 4-amino, 1,2,4-triazole for 8 hours. The reaction mixture is cooled to 0 ° C and the product which crystallizes is filtered. The wet crude product thus obtained is treated by reflux with 50 ml of isopropyl alcohol, then cooled, filtered and dried under vacuum at 40 ° C.
Si ottengono 6,3 g (77,8% d.t.) di prodotto del titolo. 6.3 g (77.8% of theory) of the title product are obtained.
Esempio 2 Example 2
2-(2,4-difluorofenil) ,l,3-bis-(lH,l,2,4-triazol-l-il)-2-propanolo (I). 2- (2,4-difluorophenyl), 1,3-bis- (1H, 1,2-triazol-1-yl) -2-propanol (I).
6,3 g di prodotto ottenuto all'esempio 1 vengono disciolti in 60 ml di acqua e, raffreddando a 5°C, addizionati di 1,8 g di acido cloridrico concentrato. La soluzione è trattata, a temperatura tra 0°C e 5°C, con una soluzione di 1,2 g di sodio nitrito in 6 ml di acqua. Si prosegue la reazione alla stessa temperatura per 30 minuti e poi per ancora 1 ora a 20°C. La soluzione così ottenuta è addizionata di 500 mg di carbone attivo e filtrata. La soluzione limpida così ottenuta è trattata oon ammoniaca concentrata fino a pH 9 mantenendo a 20°C. Quando la precipitazione del prodotto è iniziata si raffredda a 5°C per almeno 2 ore. Si filtra il precipitato che è lavato sul filtro ccn 5 ml di acqua. Il grezzo ottenuto viene cristallizzato da 25 mi di alcool isopropilico. Il prodotto filtrato è lavato con 5 mi di alcool isopropilico freddo, essiccato a 40°C sotto vuoto. 6.3 g of product obtained in 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 a temperature between 0 ° C 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 another hour at 20 ° C. The solution thus obtained is added with 500 mg of activated carbon and filtered. The clear solution thus obtained is treated with concentrated ammonia up to pH 9 while maintaining at 20 ° C. When the precipitation of the product has started it is cooled to 5 ° C for at least 2 hours. The precipitate is filtered and washed on the filter with 5 ml of water. The crude obtained is crystallized from 25 ml of isopropyl alcohol. The filtered product is washed with 5 ml of cold isopropyl alcohol, dried at 40 ° C under vacuum.
Si ottengono 4,1 g (85,4 d.t.) di prodotto del titolo, identico per analisi centesimale, massa, spettro IR e NMR ad un canpione di prodotto ottenuto secondo il brevetto britannico 2.099.818. 4.1 g (85.4 d.t.) of title product are obtained, identical by centesimal analysis, mass, IR and NMR spectrum to a sample of product obtained according to British patent 2,099,818.
Claims (3)
Priority Applications (5)
| 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 |
| ES9002961A ES2026416A6 (en) | 1990-06-08 | 1990-11-21 | Procedure for the preparation of triazolil-isopropanol. (Machine-translation by Google Translate, not legally binding) |
| AT113291A AT400145B (en) | 1990-06-08 | 1991-06-05 | METHOD FOR PRODUCING TRIAZOLYL ISOPROPANOLS |
| YU101291A YU48331B (en) | 1990-06-08 | 1991-06-06 | PROCEDURE FOR OBTAINING TRIAZOLYL-ISOPROPANOL |
| CA 2051281 CA2051281C (en) | 1990-06-08 | 1991-09-13 | Process for the preparation of triazolyl isopropanols |
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 (3)
| Publication Number | Publication Date |
|---|---|
| IT9020586A0 IT9020586A0 (en) | 1990-06-07 |
| IT9020586A1 true IT9020586A1 (en) | 1991-12-08 |
| IT1249211B IT1249211B (en) | 1995-02-20 |
Family
ID=11169192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02058690A IT1249211B (en) | 1990-06-08 | 1990-06-08 | Process for the preparation of triazolyl isopropanols, in particular fluconazole |
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 |
| CZ304213B6 (en) * | 2001-03-23 | 2014-01-08 | Richter Gedeon Vegyészeti Gyár Rt. | Process for preparing monohydrate and crystalline modifications of fluconazole |
| WO2004000835A1 (en) | 2002-06-24 | 2003-12-31 | Basf Aktiengesellschaft | 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. |
| ES8604938A1 (en) * | 1985-11-19 | 1986-03-01 | Inke Sa | 2-(Difluorophenyl)-1,3-bis(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. |
| 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 |
|---|---|
| YU48331B (en) | 1998-05-15 |
| YU101291A (en) | 1993-11-16 |
| AT400145B (en) | 1995-10-25 |
| IT9020586A0 (en) | 1990-06-07 |
| IT1249211B (en) | 1995-02-20 |
| CA2051281C (en) | 1998-07-07 |
| ES2026416A6 (en) | 1992-04-16 |
| ATA113291A (en) | 1995-02-15 |
| CA2051281A1 (en) | 1993-03-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 0001 | Granted | ||
| TA | Fee payment date (situation as of event date), data collected since 19931001 |
Effective date: 19970626 |