WO1997044330A1 - Procedimiento para la preparacion de derivados biologicamente activos de 1,2,4-triazol e intermedios utiles en este procedimiento - Google Patents
Procedimiento para la preparacion de derivados biologicamente activos de 1,2,4-triazol e intermedios utiles en este procedimiento Download PDFInfo
- Publication number
- WO1997044330A1 WO1997044330A1 PCT/ES1996/000245 ES9600245W WO9744330A1 WO 1997044330 A1 WO1997044330 A1 WO 1997044330A1 ES 9600245 W ES9600245 W ES 9600245W WO 9744330 A1 WO9744330 A1 WO 9744330A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- formula
- compound
- hydrazine
- reaction
- Prior art date
Links
- 0 C=CN=C*=CN Chemical compound C=CN=C*=CN 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C241/02—Preparation of hydrazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/10—Hydrazines
- C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
- C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C243/18—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- 1, 2,4-triazole that has the common name of fluconazole, which is an important antifungal compound, from monosubstituted hydrazines and s-triazine. This antifungal compound is used in human medicine, veterinary medicine and agriculture.
- the synthesis routes of fluconazole are performed by opening the oxirane derivative (II) with 1, 2,4-triazole (Scheme 1 below) or by substituting the reactive groups with 1, 2,4-triazole in intermediate (III) , in both cases in a strongly alkaline medium.
- X represents halo, hydroxy, a hydroxysubstituted group
- an epoxide derivative is formed which, however, is not isolated during the reaction (Scheme 2 below).
- the first object of the invention is a process for the preparation of 2-
- R represents H, benzyl, triphenylmethyl and COOR 1 , where R 1 is alkyl or aryl, preferably tert-butyl or ethyl, and Z represents a triazole radical or a hydrazine radical optionally substituted by R of the above definition optionally in salt form, it is reacted with s-triazine of the formula
- organic solvents examples include ethanol, methanol, 1- and 2-propanol, ethers such as diethyl ether, dipropyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMSO, DMF, DMAA ( dimethyl acetamide), N-methylpyrrolidone.
- ethers such as diethyl ether, dipropyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, DMSO, DMF, DMAA ( dimethyl acetamide), N-methylpyrrolidone.
- an inorganic or organic acid such as formic acid, acetic acid, trifluoacetic acid, methanesulfonic acid, maleic acid, maleic acid, malic acid, chloroacetic acid, dichloroacetic acid, propanoic acid or paratoluenesulfonic acid, hydrochloric acid, sulfuric acid and nitric acid, preferably formic acid or trifluoacetic acid.
- Organic acid can also be used only as an organic solvent.
- the reaction temperature is between -60 ° C and the boiling point of the reaction mixture used.
- formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, malonic acid, maleic acid, malic acid, paratoluenesulfonic acid and also hydrochloric acid, sulfuric acid and nitric acid can be used.
- the compound (I) (fluconazole) is obtained in high yield (80-100%) according to the acid or solvent used, the reaction time, the reaction temperature and the pH of the reaction medium.
- the reactions carried out demonstrate that the conversion of the hydrazine compounds (IV) in the reaction with s-triazine to give the compound (I) is better and faster under strongly acidic reaction conditions, the compound (IV) being present in the form of salt, such as chloride, sulfate, acetate, format, methanesulfonate and others.
- the compound (IV) can be used in the form of a base or in the form of the above salts.
- the compounds of the formula (IV) are new and also represent an object of the invention. If used in the form of salts, these are salts with formic acid, acetic acid, trifluoacetic acid, sulfonic acid, methanesulfonic acid, malonic acid, maleic acid, malic acid and paratoluenesulfonic acid, as well as with hydrochloric acid, sulfuric acid, nitric acid .
- NH 2 NHR (V) in which R has the previous meaning The compound of the formula (V) can be used when R is hydrogen, in the form of hydrazine hydrate alone, hydrazine hydrate in water, hydrazine hydrate in organic solvents such as acetonitrile, or in a mixture of organic solvents and water, while that if R has the remaining meanings, other than hydrogen, it is used in an organic solvent.
- SUBSTITUTE SHEET (RULE 26) in which X represents halo, hydroxy or a substituted hydroxy group, a compound of the formula (IV) is obtained by substituting the group X with a hydrazine compound of the formula V. If in the compound of the formula (V) R represents hydrogen the substitution can be made with an excess of hydrazine hydrate or with hydrazine hydrate in a minimal excess in an organic solvent, preferably acetonitrile.
- an object of the invention is a process for the preparation of a compound of the formula (IV) in which Z is a triazole radical, characterized in that a) 2- (2,4-difluophenyl) -1 is reacted - (1 H-1, 2,4-triazol-1-yl) propane-2,3-epoxide of the formula (II)
- An object of the invention is also a process for the preparation of a compound of the formula (IV) in which Z is a hydrazine radical optionally substituted by R of the above meaning, characterized in that from 2- (2,4- difluophenyl) - 1,3-propane-disubstituted-2-ol of the formula (III)
- a compound of the formula (IV) is obtained by substituting the group X with the hydrazine compound of the formula (V).
- the starting compound of the formula (VIII) useful in variant b) of the process for the preparation of the compound of the formula (IV) in which Z is a triazole radical is also a new compound and represents one of The objects of the invention.
- An object of the invention is also a process for the preparation of
- VUI in which R 2 represents Cl, Br or I, characterized in that 1- (2,4-difluophenyl) -2- (1H-1, 2,4-triazolo-1-yl) ethane-1-one (Vil)
- IR (oily film): 3290, 3060, 3020, 2940, 1690, 1600, 1480, 1250, 1130, 945, 835.
- Example 8 The procedure was as in Example 8. The reaction time was 70 minutes at reflux temperature (100-101 ° C). A slightly colored product was obtained (1.44 g; 94.1%). TLC: chloroform / methanol 15/2, Rf 0.51.
- Example 8 The procedure was as in Example 8. The reaction time was 50 minutes at 80-85 ° C. A slightly colored product (1.50 g; 98%) was obtained. TLC: chloroform / methanol 15/2, Rf 0.51.
- Triazine (1.42 g; 0.017 mol; 97%) and formic acid (10 ml; 98%) were added to hydrazine compound (IV) (1.35 g; 0.005 mol) from Example 1.
- the yellowish reaction mixture was heated to the temperature of 30 ° C and then heated for 75 minutes at 30-35 ° C.
- the yellow reaction mixture was made orange and the reaction finish was detected by TLC (chloroform / methanol 15/2).
- Water (10 ml) and NaCl (3 g) and methylene chloride (25 ml) were added to the reaction mixture.
- the pH of the aqueous phase was 1.15.
- the pH of the solution was adjusted to 7 with a 33% solution of NaOH and a non-colored aqueous phase and a yellowish organic phase were decanted.
- the phases were separated, the aqueous phase was washed with methylene chloride (10 ml), the organic phases were combined and dried with anhydrous sodium sulfate.
- Example 12 Synthesis of fluconazole Proceed as in Example 11. The reaction time was 2 hours 35 minutes at the temperature of 20-25 ° C. A slightly colored product was obtained (1.51 g; 98.7%).
- Example 11 The procedure was as in Example 11. The reaction time was 1 hour at a temperature of 0-5 ° C. A slightly colored product was obtained (1.50 g; 98%).
- Example 11 The procedure was as in Example 11. The reaction time was 90 minutes at a temperature of 0-5 ° C. A white product was obtained (1.46 g; 95%). TLC: chloroform / methanol 15/2, Rf 0.51. The spectroscopic data (IR, 1 H NMR, mass spectrum) corresponded to the title compound.
- Example 11 The procedure was as in Example 11. The reaction time was 1 hour at a temperature of 0-5 ° C. 97% triazine (0.7 g; 0.009 mol) was used. A slightly colored product was obtained (1.46 g; 95.4%).
- the aqueous phase was colorless and the organic phase was slightly pink.
- the aqueous phase was washed with methylene chloride (10 ml), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed with methylene chloride and evaporated in a vacuum rotary evaporator (bath temperature 40 ° C). A white product was obtained (1.39 g; 91% yield).
- the aqueous phase was colorless and the organic phase was almost colorless.
- the aqueous phase was washed with methylene chloride (10 ml) and then again with methylene chloride (2 x 5 ml).
- the organic phases were combined, dried with anhydrous sodium sulfate, s'Itraron, washed with methylene chloride and evaporated in a vacuum rotary evaporator (bath temperature 40 ° C). A white solid was obtained (1.48 g; 96.7%).
- the reaction mixture was maintained at -5 ° C / -10 ° C for 1 hour and then the temperature was allowed to rise to 15-20 ° C and a solution of water (10 ml) and NaCl (3 g) was added. The pH was 0.57. A 33% NaOH solution at pH 8.29 was added and then decanted.
- the reaction mixture was cooled to room temperature and then methanesulfonic acid (0.2 ml) was added, the hydrazine methanesulfonate formed was filtered and then washed with acetonitrile (30 ml).
- the acetonitrile was evaporated on a rotary evaporator and 98% HCOOH (5 ml) and methylene chloride (5 ml) were added to the crude product.
- the system was cooled to 0 / -5 ° C and s-triazine (0.6 g, prepared according to the process disclosed in W. Kantlener et al., Synthesis, 1979, 690) was added to obtain a color solution yellow orange.
- Fluconazole methanesulfonate Fluconazole (1 g; 0.00327 mol) was mixed with methyl tert-butyl ether (10 ml) and a white suspension was obtained. Methanesulfonic acid (0.21 ml; 0.00327 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour, filtered and the solid precipitate was washed with methyl tert-butyl ether (2 x 5 mL). A white precipitate was isolated (1.30 g). Mp .: 77-80 ° C.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69628597T DE69628597T2 (de) | 1996-05-21 | 1996-12-20 | Verfahren zur herstellung biologisch aktiver derivate des 1,2,4-triazols und in diesem verfahren nuetzliche zwischenprodukte |
SI9630619T SI0967210T1 (en) | 1996-05-21 | 1996-12-20 | Process for preparing biologically active derivatives of 1,2,4-triazol and intermediaries useful in this process |
UA98126691A UA64712C2 (en) | 1996-05-21 | 1996-12-20 | A method for preparing biologically active derivative of 1,2,3-triazole and intermediate compounds used in this method |
EP96941664A EP0967210B1 (en) | 1996-05-21 | 1996-12-20 | Process for preparing biologically active derivatives of 1,2,4-triazol and intermediaries useful in this process |
AT96941664T ATE242221T1 (de) | 1996-05-21 | 1996-12-20 | Verfahren zur herstellung biologisch aktiver derivate des 1,2,4-triazols und in diesem verfahren nuetzliche zwischenprodukte |
AU10982/97A AU1098297A (en) | 1996-05-21 | 1996-12-20 | Process for preparing biologically active derivatives of 1,2,4-triazol and intermediaries useful in this process |
HU9903524A HU223570B1 (hu) | 1996-05-21 | 1996-12-20 | Eljárás 1,2,4-triazolszármazékok előállítására, intermedierjeik és előállításuk |
NO985408A NO985408L (no) | 1996-05-21 | 1998-11-20 | FremgangsmÕte for fremstilling av biologisk aktive derivater av 1,2,4,-triazol og anvendelige mellomprodukter i fremgangsmÕten |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SIP-9600165 | 1996-05-21 | ||
SI9600165A SI9600165A (en) | 1996-05-21 | 1996-05-21 | Process for preparation of biological active derivative of 1,2,4- triazole and intermediates useful in this process |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997044330A1 true WO1997044330A1 (es) | 1997-11-27 |
Family
ID=20431850
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/ES1996/000245 WO1997044330A1 (es) | 1996-05-21 | 1996-12-20 | Procedimiento para la preparacion de derivados biologicamente activos de 1,2,4-triazol e intermedios utiles en este procedimiento |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0967210B1 (es) |
KR (1) | KR20000015811A (es) |
AT (1) | ATE242221T1 (es) |
AU (1) | AU1098297A (es) |
DE (1) | DE69628597T2 (es) |
HR (1) | HRP970271A2 (es) |
HU (1) | HU223570B1 (es) |
NO (1) | NO985408L (es) |
RU (1) | RU2170736C2 (es) |
SI (1) | SI9600165A (es) |
UA (1) | UA64712C2 (es) |
WO (1) | WO1997044330A1 (es) |
YU (1) | YU19097A (es) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015058272A1 (pt) * | 2013-10-23 | 2015-04-30 | Iharabras S.A. Indústrias Químicas | Processo para a preparação seletiva de (1h-1,2,4-triazol-1-il)alcanóis, composto hidrazinil alcanol obtido por tal processo e seu uso. |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100327818B1 (ko) * | 1999-04-16 | 2002-03-09 | 윤재승 | 플루코나졸의 제조방법 |
KR100341688B1 (ko) * | 1999-04-16 | 2002-06-24 | 윤재승 | 플루코나졸의 제조방법 |
AU2002328176A1 (en) * | 2002-08-26 | 2004-03-11 | Ranbaxy Laboratories Limited | Azole derivatives as antifungal agents |
US9550752B2 (en) | 2013-04-12 | 2017-01-24 | Bayer Cropscience Aktiengesellschaft | Triazolinthione derivatives |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2099818A (en) * | 1981-06-06 | 1982-12-15 | Pfizer Ltd | Triazoles |
ES2026416A6 (es) * | 1990-06-08 | 1992-04-16 | Indusatriale Chimica S R L | Procedimiento para la preparacion de triazolil-isopropanol. |
WO1995007895A1 (en) * | 1993-09-13 | 1995-03-23 | Acic (Canada) Inc. | Methods for the manufacture of fluconazole and forms thereof, intermediates useful in the manufacture thereof, and combinations comprising fluconazole |
WO1995008543A1 (en) * | 1993-09-23 | 1995-03-30 | Richter Gedeon Vegyészeti Gyár Rt. | Novel substituted propane-2-ol derivatives |
WO1996004256A1 (en) * | 1994-08-02 | 1996-02-15 | Zeneca Limited | Process for preparing an antifungal azole with hydrazino and amidrazone intermediates |
WO1996004257A1 (en) * | 1994-08-02 | 1996-02-15 | Zeneca Limited | Crystalline form of an antifungal azole |
-
1996
- 1996-05-21 SI SI9600165A patent/SI9600165A/sl unknown
- 1996-12-20 AU AU10982/97A patent/AU1098297A/en not_active Abandoned
- 1996-12-20 WO PCT/ES1996/000245 patent/WO1997044330A1/es active IP Right Grant
- 1996-12-20 HU HU9903524A patent/HU223570B1/hu not_active IP Right Cessation
- 1996-12-20 EP EP96941664A patent/EP0967210B1/en not_active Expired - Lifetime
- 1996-12-20 KR KR1019980709360A patent/KR20000015811A/ko not_active Application Discontinuation
- 1996-12-20 RU RU98123117/04A patent/RU2170736C2/ru not_active IP Right Cessation
- 1996-12-20 UA UA98126691A patent/UA64712C2/uk unknown
- 1996-12-20 AT AT96941664T patent/ATE242221T1/de not_active IP Right Cessation
- 1996-12-20 DE DE69628597T patent/DE69628597T2/de not_active Expired - Fee Related
-
1997
- 1997-05-14 YU YU19097A patent/YU19097A/sh unknown
- 1997-05-20 HR HRP-9600165A patent/HRP970271A2/xx not_active Application Discontinuation
-
1998
- 1998-11-20 NO NO985408A patent/NO985408L/no not_active Application Discontinuation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2099818A (en) * | 1981-06-06 | 1982-12-15 | Pfizer Ltd | Triazoles |
ES2026416A6 (es) * | 1990-06-08 | 1992-04-16 | Indusatriale Chimica S R L | Procedimiento para la preparacion de triazolil-isopropanol. |
WO1995007895A1 (en) * | 1993-09-13 | 1995-03-23 | Acic (Canada) Inc. | Methods for the manufacture of fluconazole and forms thereof, intermediates useful in the manufacture thereof, and combinations comprising fluconazole |
WO1995008543A1 (en) * | 1993-09-23 | 1995-03-30 | Richter Gedeon Vegyészeti Gyár Rt. | Novel substituted propane-2-ol derivatives |
WO1996004256A1 (en) * | 1994-08-02 | 1996-02-15 | Zeneca Limited | Process for preparing an antifungal azole with hydrazino and amidrazone intermediates |
WO1996004257A1 (en) * | 1994-08-02 | 1996-02-15 | Zeneca Limited | Crystalline form of an antifungal azole |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015058272A1 (pt) * | 2013-10-23 | 2015-04-30 | Iharabras S.A. Indústrias Químicas | Processo para a preparação seletiva de (1h-1,2,4-triazol-1-il)alcanóis, composto hidrazinil alcanol obtido por tal processo e seu uso. |
Also Published As
Publication number | Publication date |
---|---|
DE69628597T2 (de) | 2004-04-22 |
ATE242221T1 (de) | 2003-06-15 |
YU19097A (sh) | 1999-09-27 |
HUP9903524A2 (hu) | 2000-02-28 |
KR20000015811A (ko) | 2000-03-15 |
AU1098297A (en) | 1997-12-09 |
DE69628597D1 (de) | 2003-07-10 |
EP0967210B1 (en) | 2003-06-04 |
SI9600165A (en) | 1997-12-31 |
HUP9903524A3 (en) | 2001-12-28 |
HU223570B1 (hu) | 2004-09-28 |
EP0967210A1 (en) | 1999-12-29 |
HRP970271A2 (en) | 1998-04-30 |
NO985408D0 (no) | 1998-11-20 |
RU2170736C2 (ru) | 2001-07-20 |
NO985408L (no) | 1999-01-20 |
UA64712C2 (en) | 2004-03-15 |
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