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[ CAS No. 86386-73-4 ] {[proInfo.proName]}

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Chemical Structure| 86386-73-4
Chemical Structure| 86386-73-4
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Product Details of [ 86386-73-4 ]

CAS No. :86386-73-4 MDL No. :MFCD00274549
Formula : C13H12F2N6O Boiling Point : -
Linear Structure Formula :- InChI Key :RFHAOTPXVQNOHP-UHFFFAOYSA-N
M.W :306.27 Pubchem ID :3365
Synonyms :
Fluconazole

Calculated chemistry of [ 86386-73-4 ]

Physicochemical Properties

Num. heavy atoms : 22
Num. arom. heavy atoms : 16
Fraction Csp3 : 0.23
Num. rotatable bonds : 5
Num. H-bond acceptors : 7.0
Num. H-bond donors : 1.0
Molar Refractivity : 70.71
TPSA : 81.65 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.92 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.41
Log Po/w (XLOGP3) : 0.35
Log Po/w (WLOGP) : 1.47
Log Po/w (MLOGP) : 1.47
Log Po/w (SILICOS-IT) : 0.71
Consensus Log Po/w : 0.88

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.17
Solubility : 2.08 mg/ml ; 0.0068 mol/l
Class : Soluble
Log S (Ali) : -1.63
Solubility : 7.2 mg/ml ; 0.0235 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.54
Solubility : 0.0883 mg/ml ; 0.000288 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.91

Safety of [ 86386-73-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 86386-73-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 86386-73-4 ]

[ 86386-73-4 ] Synthesis Path-Downstream   1~80

  • 1
  • [ 288-88-0 ]
  • [ 1774-47-6 ]
  • [ 86404-63-9 ]
  • [ 86386-73-4 ]
  • 3
  • [ 42768-45-6 ]
  • [ 86386-73-4 ]
  • O-2-bromovaleroylfluconazole [ No CAS ]
  • 4
  • [ 22118-12-3 ]
  • [ 86386-73-4 ]
  • O-2-bromobutyrylfluconazole [ No CAS ]
  • 5
  • [ 42768-46-7 ]
  • [ 86386-73-4 ]
  • O-2-bromohexanoylfluconazole [ No CAS ]
  • 6
  • [ 42768-44-5 ]
  • [ 86386-73-4 ]
  • O-2-bromooctanoylfluconazole [ No CAS ]
  • 7
  • [ 15949-84-5 ]
  • [ 86386-73-4 ]
  • O-11-bromoundecanoylfluconazole [ No CAS ]
  • 8
  • [ 59117-75-8 ]
  • [ 86386-73-4 ]
  • O-2-bromolauroylfluconazole [ No CAS ]
  • 9
  • [ 53411-22-6 ]
  • [ 86386-73-4 ]
  • O-2-bromomyristoylfluconazole [ No CAS ]
  • 10
  • [ 86386-73-4 ]
  • [ 194015-05-9 ]
  • 2-cyanoethyl-n-octyl fluconazole phosphate [ No CAS ]
  • 11
  • [ 86386-73-4 ]
  • diisopropyl-phosphoramidous acid methyl ester octyl ester [ No CAS ]
  • methyl-n-octyl fluconazole phosphate [ No CAS ]
  • 12
  • [ 86386-73-4 ]
  • diisopropyl-phosphoramidous acid methyl ester undec-10-enyl ester [ No CAS ]
  • methyl-ω-undecenyl fluconazole phosphate [ No CAS ]
  • 13
  • [ 86386-73-4 ]
  • diisopropyl-phosphoramidous acid methyl ester undecyl ester [ No CAS ]
  • methyl-undecanyl fluconazole phosphate [ No CAS ]
  • 14
  • [ 86386-73-4 ]
  • [ 125676-85-9 ]
  • [ 804566-93-6 ]
  • 15
  • [ 86386-73-4 ]
  • [ 804567-07-5 ]
  • [ 804566-94-7 ]
  • 16
  • [ 86386-73-4 ]
  • [ 804567-08-6 ]
  • [ 804566-95-8 ]
  • 17
  • [ 86386-73-4 ]
  • [ 198987-41-6 ]
  • [ 804566-96-9 ]
  • 18
  • [ 86386-73-4 ]
  • [ 804567-12-2 ]
  • 2-cyanoethyl 1-(β-D-2,3,4,6-tetra-O-acetylglucopyranosyl) fluconazole phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
(v) General procedure for the synthesis of carbohydrate phosphate triester derivatives of FLC (4a and 4b); Benzylamine (BNNH2) (163 LLL, 1.5 mmol) was added to a solution of ss-D-GLUCOSEPENTAACETATE (7a) or 2-acetamido-2-deoxy-1, 3,4, 6-tetra-O- ACETYL-P-D-GLUCOPYRANOSIDE (7b) (1 mmol) in THF (3 mL). After stirring overnight, the reaction mixture was diluted with cold, distilled water and extracted with DCM twice (2 x 5 ML). The combined organic phase was respectively washed with ice-cold diluted hydrochloric acid, saturated sodium bicarbonate (5 mL), brine (5 mL), and distilled water (5 mL). THECOMBINED EXTACTSWEREDRIED (MGSO4) ANDTHE SOLVENTWASREMOVEDIN vacuo. The syrup was dried in a vacuum overnight to afford 8a and 8b (Scheme 3). 2- Cyanoethyl N,N-diisopropylchlorophosphoramidite (236. 7 IL, 1 mmol) and diisopropyl ethylamine (174. 3 UL, 1 mmol) were added to a solution OF 8A or 8B (0.5 mmol) in dry DCM (2 mL). After stirring for 20 hours, the reaction mixture was extracted with EA (10 mL) and distilled water (10 mL). The organic phase was then washed with brine (10 mL) and dried (MGS04). The solvent was removed in vacuo and the syrup was dried under vacuum overnight to yield 9a and 9B (Scheme 3). FLC (100 MG, 0. 3 mmol) and 1H- tetrazol (42 mg, 0.6 mmol) were dissolved in dry DCM (1 mL) under a N2 atmosphere. The syrup (9a OR 9B) WAS DISSOLVED IN dry DCM (0.5 mL) and added to the reaction mixture. After stirring for 3 hours, the reaction mixture was cooled to 0 C and t-butyl hydroperoxide (0.15 mL) was added. After stirring for 1 hour, the reaction mixture was partitioned between EA (10 mL) and distilled water (10 mL). The organic layer was then washed with brine (10 mL) and dried (MGS04). The solvent was removed in vacuo. The syrup residue was purified using silica gel column chromatography, eluting with hexane- acetone from 2: 1 (v/v) to 1: 1 (v/v) to afford 4a or 4b (Scheme 3).
  • 19
  • [ 86386-73-4 ]
  • [ 804567-13-3 ]
  • 2-cyanoethyl 1-(2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl) fluconazole phosphate [ No CAS ]
  • 20
  • [ 86386-73-4 ]
  • [ 627-11-2 ]
  • O-2-chloroethyloxycarbonylfluconazole [ No CAS ]
  • 21
  • [ 86386-73-4 ]
  • [ 75-36-5 ]
  • O-acetylfluconazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
78.0% (ii) General procedure for the synthesis of carboxylic acid ester derivatives of FLC (la-h); Dry dimethyl formamide (DMF) (2 mL) was added to sodium hydride (48 mg, 40% immersion in oil, 1.2 mmol, prewashed with dry hexane) and the mixture was cooled to 0 C. A solution of FLC (300 mg, 1 mmol) in dry DMF was slowly added to this mixture. After stirring for 2 h at room temperature, the reaction mixture was cooled down again in an ice bath ; thereafter a solution of acyl chloride (1.5 mmol, freshly prepared by refluxing the corresponding carboxylic acid with thionyl chloride if not commercially available) in dry benzene was added dropwise during 30 min. The reaction mixture was stirred for a further period of 3 h at room temperature and poured into a separator funnel containing cold aqueous sodium bicarbonate (5%, 100 mL). The crude product was extracted with ethyl acetate (EA) (2 x 100 mL). The organic layers were combined, dried over magnesium sulfate (MGS04), and concentrated in vacuo. The residue, which consisted of one major product, was purified by a silica gel column chromatography using hexane/acetone (3: 1 v/v to 1 : 1 v/v) as eluting solvents to yield final products (Scheme 1).
  • 22
  • [ 86386-73-4 ]
  • [ 112-64-1 ]
  • tetradecanoic acid 1-(2,4-difluoro-phenyl)-2-[1,2,4]triazol-1-yl-1-[1,2,4]triazol-1-ylmethyl-ethyl ester [ No CAS ]
  • 23
  • [ 86386-73-4 ]
  • [ 7148-74-5 ]
  • O-2-bromopropionylfluconazole [ No CAS ]
  • 24
  • [ 86386-73-4 ]
  • [ 5538-51-2 ]
  • 2-acetoxy-benzoic acid 1-(2,4-difluoro-phenyl)-2-[1,2,4]triazol-1-yl-1-[1,2,4]triazol-1-ylmethyl-ethyl ester [ No CAS ]
  • 25
  • [ 288-88-0 ]
  • 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate [ No CAS ]
  • [ 86386-73-4 ]
  • 26
  • [ 86386-73-4 ]
  • [ 110-16-7 ]
  • C4H4O4*C13H12F2N6O [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethyl acetate;Heating / reflux; Fluconazole maleate:Maleic acid Co-crystal [00203] Fluconazole and maleic acid were dissolved in ethyl acetate with heat, then slowly evaporated. The co-crystal was characterized as a <strong>[86386-73-4]fluconazole</strong> maleate:maleic acid hydrate. [002Q4] Crystal data: (Bruker SMART-APEX CCD Diffractometer), monoclinic C2; a = 36.557(6) angstroms, b = 5.695(6) angstroms, c = 12.771(7) angstroms, beta = 94.530 degrees, Z = 4. [00205] IR spectroscopy (Nicolet Avatar 320 FTIR) showed peaks at: 3121, 3055, 1702, 1562, 1430, 1257, 1217, 915, 857, and 787 cm4. [00206] MEL-TEMP showed a melting point of about 84 degrees C for the <strong>[86386-73-4]fluconazole</strong> maleate:maleic acid co-crystal.
  • 27
  • 2',4'-Difluoro-2-(1H-1,2,4-triazol-1-yl)-acetophenone hydrochloride [ No CAS ]
  • [ 86386-73-4 ]
  • 28
  • [ 87820-35-7 ]
  • [ 86386-73-4 ]
  • 29
  • 1-(2,4-difluorophenacyl)-4-amino-(1H-1,2,4-triazolium) chloride [ No CAS ]
  • [ 86386-73-4 ]
YieldReaction ConditionsOperation in experiment
100% Example 21 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1, acetonitrile (20 ml), formic acid (4 ml; 98%) and trifluoroacetic acid (1.7 ml; 0.022 mole) were added and the reaction mixture was cooled to -5C. Then s-triazine (0.6 g; 0.0074 mole) was added and a yellow solution was obtained. The system was kept at -5C to -10C for 1 hour and then the temperature was allowed to increase to 15-20C and methylene chloride (20 ml) and a solution of water (10 ml) and NaCl (3 g) were added. The pH was 1.22. A 33% NaOH solution was added to pH 8.35 and then it was decanted. The aqueous phase was colourless and the organic phase was yellow. The aqueous phase was washed with methylene chloride (10 ml) and then again with methylene chloride (2 x 5 ml). Organic phases were then combined, dried with anhydrous sodium sulfate, filtered, washed with methylene chloride and evaporated on rotavapor in vacuo (bath temperature 40C). A beige product (1.53 g; yield 100%) was obtained. TLC (chloroform/methanol 15/2) showed that the product was pure (one stain).
98% Example 10 Synthesis of fluconazole It was proceeded as in Example 8. The reaction time was 50 minutes at 80-85C. A slightly coloured product (1.50 g; 98%) was obtained. TLC: chloroform/metanol 15/2, Rf 0.51. The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
98.7% Example 12 Synthesis of fluconazole It was proceeded as in Example 11. The reaction time was 2 hours 35 minutes at the temperature 20-25C. A slightly coloured product (1.51 g; 98.7%) was obtained. TLC: chloroform/metanol 15/2, Rf 0.51. The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
98% Example 13 Synthesis of fluconazole It was proceeded as in Example 11. The reaction time was 1 hour at the temperature 0-5C. A slightly coloured product (1.50 g; 98%) was obtained. TLC: chloroform/metanol 15/2, Rf 0.51 The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
98.7% Example 19 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1 methylene chloride (20 ml), formic acid (4 ml; 98%), trifluoroacetic acid (1.7 ml; 0.022 mole) and s-triazine (0.6 g; 0.0074 mole) were added. An orange solution (30C) was obtained. The reaction mixture was kept at 30C for 1 hour. TLC showed that the reaction was completed. A solution of water (10 ml) and NaCl (3 g) was added. The pH was 0.27. A 33% NaOH solution was added to pH 8 and then it was decanted. The aqueous phase was colourless and the organic phase was yellow. The aqueous phase was washed with methylene chloride (10 ml) and then again with methylene chloride (2 x 5 ml). Organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed with methylene chloride and evaporated on rotavapor in vacuo (bath temperature abot 40C). A beige solid (1.51 g; yield 98.7%) was obtained. The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
97.4% Example 7 Synthesis of fluconazole To a crude hydrazine compound (IV) from Example 1 (1.35 g; 0.005 mole) triazine (1.42 g; 0.017 mole; 97%) and acetic acid (10 ml) were added. A yellowish reaction mixture was heated at reflux temperature (116-118C) for 2 hours and 45 minutes. During this period the yellow reaction mixture became orange. The completion of the reaction was detected by TLC (chloroform/methanol 15/2). Acetic acid was evaporated at reduced pressure and at the bath temperature of 70-75C. Water (10 ml) and NaCl (3 g) were added to the orange residue after evaporation and methylene chloride (25 ml) was added. The pH of the aqueous phase was 2-3. The pH of the aqueous phase was adjusted to 7 with a 33% NaOH solution and then it was decanted. The aqueous phase was washed with methylene chloride (10 ml), the organic phases were combined and dried with anhydrous sodium sulfate. It was filtered, washed with methylene chloride and methylene chloride was evaporated at the temperature of 40C and at reduced pressure. A pink solid (1.49 g; 97.4%) was isolated. TLC: chloroform/metanol 15/2, Rf 0.51.
97.4% Example 20 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1, methylene chloride (40 ml), formic acid (4 ml; 98%) and trifluoroacetic acid (1.7 ml; 0.022 mole) were added and the reaction mixture was cooled to -5C. Then s-triazine (0.6 g; 0.0074 mole) was added and the reaction mixture was kept at -5C to -10C for 1 hour. Two phases were present, which means that the reaction took place in heterogenous phase. TLC showed that the reaction was completed. Then the temperature of the reaction mixture was increased to 15-20C and a solution of water (10 ml) and NaCl (3 g) was added. The pH was 0.01. A 33% NaOH solution was added to pH 8.15 and then it was decanted. The aqueous phase was colourless and the organic phase was pale yellow. The aqueous phase was washed with methylene chloride (10 ml) and then again with methylene chloride (2 x 5 ml). Organic phases were then combined, dried with anhydrous sodium sulfate, filtered, washed with methylene chloride and evaporated on rotavapor in vacuo (bath temperature 40C). A solid (1.49 g; yield 97.4%) was obtained. TLC (chloroform/methanol 15/2) showed that the product was very pure (one stain). The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
96.7% Example 17 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1, methylene chloride (10 ml), formic acid (4 ml; 98%), trifluoroacetic acid (1.7 ml; 0.022 mole) and s-triazine (0.6 g; 0.0074 mole) were added. An orange red solution was obtained. The reaction mixture was kept for 1 hour at 25C. TLC showed that the reaction was completed. Then a solution of water (10 ml) and NaCl (3 g) and methylene chloride (10 ml) were added. The pH was 0.05. A 33% NaOH solution was added to pH 8.14 and then it was decanted. The aqueous phase was colourless and the organic phase was yellow. The aqueous phase was washed with methylene chloride (10 ml) and then again with methylene chloride (2 x 5 ml). Organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed with methylene chloride and evaporated on rotavapor in vacua (bath temperature 40C). A beige product (1.48 g; yield 96.7%) was obtained. The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
96.7% Example 18 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1, methylene chloride (40 ml), formic acid (4 ml; 98%), trifluoroacetic acid (1.7 ml; 0.022 mole) and s-triazine (0.6 g; 0.0074 mole) were added. An orange emulsion (two phases) was obtained, which means that the reaction took place in heterogenous phase. The reaction mixture was heated at reflux (41C) and there were still two phases. Such reaction mixture was kept at reflux for 1 hour. TLC showed that the reaction was completed. Then the reaction mixture was cooled to room temperature and a solution of water (10 ml) and NaCl (3 g) was added. The pH was 0.17. A 33% NaOH solution was added to pH 8.45 and then it was decanted. The aqueous phase was colourless and the organic phase was almost colourless. The aqueous phase was washed with methylene chloride (10 ml) and then again with methylene chloride (2 x 5 ml). Organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed with methylene chloride and evaporated on rotavapor in vacuo (bath temperature 40C). A white solid (1.48 g; 96.7%) was obtained. TLC (chloroform/methanol 15/2) showed that the product was very pure (one stain). The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
95% Example 14 Synthesis of fluconazole It was proceeded as in Example 11. The reaction time was 90 minutes at the temperature 0-5C. A white product (1.46 g; 95%) was obtained. TLC: chloroform/metanol 15/2, Rf 0.51 The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
94.1% Example 9 Synthesis of fluconazole It was proceeded as in Example 8. The reaction time was 70 minutes at reflux temperature (100-101C). A slightly coloured product (1.44 g; 94.1%) was obtained. TLC: chloroform/metanol 15/2, Rf 0.51. The spectroscopic data (IR, 1H NMR, mass spectrum) corresponded to the title compound.
~ 74 - ~ 85% Step I: First Leaching of Crude Fluconazole: In a 2 L 4-necked round bottom flask, crude fluconazole (181 g; purity of about 93%), demineralized water (DM water)(905 ml), acetone (81.5 ml), and ethyl acetate (63.5 ml) were added at a temperature in the range of from about 25 C. to about 35 C. under stirring. The reaction mixture was then heated to a temperature in the range of from about 55 C. to about 60 C. and maintained for about 60 minutes. Cold water was circulated to the condenser. Next, the reaction mixture was brought to a temperature in the range of from about 25 C. to about 35 C. in about 60 minutes. This was followed by cooling to a temperature in the range of from about 5 C. to about 10 C. and maintained for about 60 minutes. The precipitated solid was filtered and washed with chilled demineralized water (36 ml). The wet cake weighs about 208 g, with a purity of about 98.96%. Step II: Second Leaching of Fluconazole: Into a 2 L 4-necked round bottom flask, the wet fluconazole product obtained from step I (208 g; purity of about 98% to about 99%), together with demineralized water (905 ml), acetone (81.5 ml), and ethyl acetate (63.5 ml) were added at a temperature in the range of from about 30 C. to about 35 C. under stirring. The reaction mixture was heated to a temperature in the range of from about 55 C. to about 60 C. and maintained for about 60 minutes. Cold water was circulated to the condenser. Next, the reaction mixture was brought to a temperature in the range of from about 25 C. to about 35 C. in about 60 minutes. This was followed by cooling to a temperature in the range of from about 5 C. to about 10 C. and maintained for about 60 minutes. The precipitated solid was filtered and washed with chilled demineralized water (36 ml). The wet cake weighs about 184 g, with a purity of about 99.45%. Step III: Acid/Base Treatment of Fluconazole: Into a 2 L 4-necked round bottom flask, the fluconazole product obtained from step II (184 g; purity of about 99.45%), together with demineralized water (543 ml), and concentrated hydrochloric acid (108 ml) were added under stirring at a temperature in the range of from about 25 C. to about 35 C. The reaction mixture was maintained under stirring for about 30 minutes. Toluene (about 100 ml) was added to the reaction mixture and stirred for about 30 minutes. The reaction mixture was then allowed to settle without stirring for about 30 minutes, which allows the layers to separate. The aqueous layer was extracted three times with toluene (100 ml×3). All organic layer washings were clubbed and kept aside for solvent recovery. The aqueous layer was decolorized with activated charcoal (18 g) at a temperature in the range of from about 55 C. to about 60 C. for about 60 minutes. The carbon treated aqueous layer was filtered through a Hyflow bed. The Hyflow bed was washed twice with demineralized water (45 ml×2). Again the washings were clubbed. The aqueous layer was charged into 2 L 4-necked flask. Citric acid (1 g), acetone (81.5 ml), ethyl acetate (81.5 ml), and methanol (18.1 ml) were added, and the mixture was heated to a temperature in the range of from about 50 C. to about 55 C. The pH of the reaction mixture was adjusted to be in the range of from about 6.8 to about 7.0 by slow addition of 15% liquor ammonia (128 ml) over about 60 minutes. The reaction mixture was maintained for about 30 minutes at a temperature in the range of from about 50 C. to about 55 C. The reaction mixture was then cooled to a temperature in the range of from about 25 C. to about 35 C. for about 30 minutes. The reaction mixture was further cooled to a temperature in the range of from about 5 C. to about 10 C. for about 30 minutes. The precipitated product was filtered and washed twice with chilled demineralized water (45 ml×2). The product was dried in a vacuum oven at a temperature in the range of from about 65 C. to about 70 C. until the moisture content was less than about 0.5%. The dried product is the pure fluconazole weighing about 154 g, with a yield of about 85% and purity greater than about 99.5%. All the individual impurities were below about 0.05%. EXAMPLE 2 Steps I through III of Example 1 were repeated in substantially the same manner, except that the amounts of solvents were changed as follows: Step I flask contents: DM water (900 ml), ethyl acetate (36.2 ml), acetone (81.5 ml) Step II flask contents: DM water (900 ml), ethyl acetate (36.2 ml), acetone (81.5 ml) Step III flask contents: DM water (543 ml), concentrated HCl (108 ml), acetone (81.5 ml), ethyl acetate (63.3 ml), methanol (18.1 ml) The dried product obtained in this example weighed about 145 g, which was a yield of about 80% and had a purity greater than about 99.5%, with all the individual impurities below about 0.05%. EXAMPLE 3 Example 2 was repeated in substantially the same manner, except that the amounts of solvents were changed as follows: Step I flask contents: DM water (900 ml), ethyl acetate (90.5 ...
Fluconazole (I): mp 138-140 C. 1 H-NMR (CDCl3) delta (ppm): 4.60 (ABq, 4H, JAB =14.3 Hz), 5.49 (s, 1H, OH), 6.76-6.82 (m, 2H), 7.41-7.45 (m, 1H), 7.86 (s, 2H), 8.06 (s, 2H);
COMPARATIVE EXAMPLE B Attempted Preparation of Fluconazole A mixture of the oxirane salt of formula II (1.68 g), where R is 2,4-difluorophenyl, and X is methanesulfonate anion, 4H-4-amino-1,2,4-triazol (840 mg) anhydrous potassium carbonate (2.27 g) in dimethylformamide (9 mL) was heated to 90 for 4.5 hrs, at which time it was cooled to 5 and concentrated hydrochloric acid (4 mL) was added. A solution of sodium nitrite (700 mg) in water (6 mL) was added dropwise, and the resulting solution allowed to warm to room temperature. Methylene chloride (12 mL) was added, the pH of the mixture adjusted to 10 with ammonium hydroxide, and the phases were separated. Chromatographic analysis of the organic phase revealed a complex product mixture that did not contain fluconazole.
COMPARATIVE EXAMPLE C Attempted Preparation of Fluconazole A suspension of epoxide salt II (50 mg,) aminotriazole V (25 mg) potassium carbonate (69 mg) in acetonitrile (3 mL) was heated to reflux for 21 hrs. Chromatographic examination of the reaction mixture indicated the presence only of starting materials.
1.35 g (29%) EXAMPLE 2 (The "Sulphate Process") Fluconazole A 3-necked flask, fitted with a mechanical stirrer, condenser, and addition funnel was charged with 6(4.00 g, 15.7 mmol) and ethanol-free chloroform (60 mL) under a nitrogen atmosphere. Stirring was initiated and powdered K2 CO3 (5.3 g, 32 mmol) was introduced in one portion. SO2 Cl2 (1.3 mL, 16 mmol) was added dropwise at 20 C. at a rate such that the internal temperature remained below 30 C. After the completion of the addition, the mixture was stirred at 20 C. for 15 minutes and then was heated to reflux for 2 hours. The chloroform was then removed by distillation and to the solid residue was added dry DMF (35 mL) at 0 C. followed by the sulphate 8. Solid 1,2,4-triazole, sodium derivative (4.8 g, 90%, 48 mmol) was added in portions maintaining the temperature below 5 C. The reaction suspension was allowed to reach room temperature and was then warmed to 65 C. for 5 hours during which time the evolution of an acidic gas was observed through the condenser. The reaction was cooled to 20 C. and treated with water (10 mL) and the DMF was distilled under reduced pressure. The aqueous residue was extracted with EtOAc (3*20 mL) and the combined extracts were dried (Na2 SO4) and evaporated. Crystallization of the residue afforded 1.35 g (29%) of fluconazole.
(4) Preparation of Fluconazole 34 g of TA, 57.87 g of potassium hydroxide, 118 g of trimethyl sulfoxonium iodide, and 100 g of TAAP were dissolved in 1,600 ml of water to obtain an aqueous solution. The aqueous solution was heated at 70 C. to react for 16 hours. Upon the completion of the reaction, the solution was adjusted with 4 N hydrochloric acid to a neutral pH and then extracted with acetyl acetate (800 ml*3). The organic layer was collected, dried with 30 g of anhydrous calcium dichloride, decolorized with 15 g of active charcoal, and finally filtered off solid residues. The filtrate was concentrated to afford 99.3 g of the crude product (yield 72%). The crude product was further recrystallized from 500 ml of a solvent mixture of acetyl acetate and n-hexane (2:1) to afford 66.3 g of the final productproduct in the form of white solid (yield 48%). 1 H-NMR data (CD3 OD delta values) of the product: delta 4.68 (4H, dd) delta 6.78 (1H, m) delta 6.97 (1H, m) delta 7.19 (1H, m) delta 7.81 (1H, s) delta 8.33 (1H, s)
Compounds which are particularly preferably used in the present invention include: 1,3-bis(1H-,2,4-triazol-1-yl) -2-bromo-2-(2,4-dichlorophenyl)-propane, 1,3-bis(1H-1,2,4-triazol-1-yl)-2-chloro-2-(2,4-dichlorophenyl)-propane, 1,3-bis(1H-1,2,4-triazol-1-yl)-2-(4-iodophenyl)propane-2-ol and 2,4-difluoro-alpha,alpha-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol
Example 22 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1, methylene chloride (40 ml), formic acid (4 ml; 98%) and trifluoroacetic acid (1.7 ml; 0.022 mole) were added and the reaction mixture was cooled to -5C. Two phases were obtained. Then s-triazine (0.8 g; 0.00987 mole) was added. A yellow emulsion (two phases) was obtained, which means that the reaction took place in heterogenous phase. The reaction mixture was kept at -5C to -10C for 1 hour, then the temperature was allowed to increase to 15-20C and a solution of water (10 ml) and NaCl (3 g) was added.
EXAMPLE 3 Alternate Preparation of Fluconazole A mixture of the oxirane of formula II' (410 mg), where R is 2,4-difluorophenyl, 4H-4-amino-1,2,4-triazole (284 mg), methanesulfonic acid (190 mg) in 2-propanol (1.5 mL) was heated to reflux for 4 hrs, after which the solvent was evaporated in vacuo. The residue was dissolved in water (6 mL), cooled at 5 and concentrated hydrochloric acid (1 mL) was added, followed by a solution of sodium nitrite (300 mg) in water (2 mL, dropwise). The resulting solution was allowed to warm to room temperature, methylene chloride (6 mL) was added, the pH adjusted to 10 with ammonium hydroxide, and the phases separated. The substantial presence of fluconazole in the organic phase was demonstrated by chromatographic means; however, the reaction mixture was more complex than that obtained by the preferred method of Example 2.
COMPARATIVE EXAMPLE B Attempted Preparation of Fluconazole A mixture of the oxirane salt of formula II (1.68 g), where R is 2,4-difluorophenyl, and X is methansulfonate anion, 4H-4-amino-1,2,4-triazol (840 mg), anhydrous potassium carbonate (2.27 g) in dimethylformamide (9 mL) was heated to 90 for 4.5 hrs, at which time it was cooled to 5 and concentrated hydrochloric acid (4 mL) was added. A solution of sodium nitrite (700 mg) in water (6 mL) was added dropwise, and the resulting solution allowed to warm to room temperature. Methylene chloride (12 mL) was added, the pH of the mixture adjusted to 10 with ammonium hydroxide, and the phases were separated. Chromatographic analysis of the organic phase revealed a complex product mixture that did not contain fluconazole.
COMPARATIVE EXAMPLE C Attempted Preparation of Fluconazole A suspension of epoxide salt II (50 mg,) aminotriazole V (25 mg) potasium carbonate (69 mg) in acetonitril (3 mL) was heated to reflux for 21 hrs. Chromatographic examination of the reaction mixture indicated the presence only of starting materials.
IF "YES?: Are you taking any of the following? a. Fluconazole b. Itraconazole c. Ketoconazole d. Voriconazole
, in which the chemical compound is a triazole derivative selected from the group consisting of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (Fluconazole); 1-{4-[[2-(2,4-dichlorophenyl)r-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-c-4-yl]methoxy]-phenyl}-4-isopropylpiperazine (Terconazole); (+-)-2-sec-butyl-4-[4-(4-{4-[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-(triazol-1ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazin-1-yl) phenyl]-2,4-dihydro-1,2,4-triazol-3-one (Itraconazole).
In a third preferred embodiment, the chemical compound having IKCa inhibitory activity for use according to the invention is a triazole derivative selected from the group consisting of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (Fluconazole); 1-{4-[[2-(2,4-dichlorophenyl)r-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-c-4-yl]methoxy]-phenyl}-4-isopropylpiperazine (Terconazole); (+-) -2-sec-butyl-4-[4-(4-{4-[(2R*, 4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4 triazol-1ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazin-1-yl)phenyl]-2,4-dihydro-1,2,4-triazol-3-one (Itraconazole).

  • 31
  • [ 86386-73-4 ]
  • [ 89429-50-5 ]
YieldReaction ConditionsOperation in experiment
48% 1) Synthesis OF FBR (LLA); A solution of 1.94 g of imidazole in 15 ml of dry acetonitrile at 0 C was treated with 1 ml of thionyl bromide and then with 1.63 g of 1, 3-bis (LU-1, 2, 4-TRIAZOL-1-YL)-2- (2, 4- DIFLUOROPHENYL)-PROPAN-2-OL (<strong>[86386-73-4]fluconazole</strong>). The resulting mixture was stirred for 2-3 hours. The residue obtained after evaporation of the solvent in vacuo was partitioned between methylene chloride (-100 mL) and cold 5% aqueous sodium bicarbonate (-100 mL), and the organic extract (-100 ml) was successively washed with aqueous sodium bicarbonate (50 mL), brine (50 mL) and dried (by anhydrous sodium sulfate). Removal of methylene chloride followed by flash chromatography of the residue on silica (100 g) and elution with 97% ethyl acetate/3% diethylamine yielded the title compound, which was c rystallised from ethyl acetate/hexane. Amorphous P OWDER ; Yield: 48% ;
  • 32
  • [ 86386-73-4 ]
  • [ 89429-55-0 ]
YieldReaction ConditionsOperation in experiment
65% 1) Synthesis of FCI (LLB); A solution of 1.94 g of imidazole in 15 ml of dry acetonitrile at 0 C was treated with 1 ml of thionyl chloride and then with 1.63 g of 1, 3-bis (1H-1, 2, 4-TRIAZOL-1-YL)-2- (2, 4- difluorophenyl) -propan-2-ol (<strong>[86386-73-4]fluconazole</strong>). The resulting mixture was stirred for 2-3 hours. The residue obtained after evaporation of the solvent in vacuo was partitioned between methylene chloride (-100 mL) and cold 5% aqueous sodium bicarbonate (-100 mL), and the organic extract (-100 ml) was successively washed with aqueous sodium bicarbonate (50 mL), brine (50 mL) and dried (by anhydrous sodium sulfate). Removal of methylene chloride followed by flash chromatography of the residue on silica (100 g) and elution with 97% ethyl acetate/3% diethylamine yielded the title compound, which WAS CRYSTALLISED FROM ethyl acetate/hexane. Amorphous powder ; Yield: 65%
  • 33
  • [ 7783-06-4 ]
  • [ 86386-73-4 ]
  • 2-(2.4-difluoro-phenyl)-1-(5-mercapto-1,2,4-triazol-1-yl)-3-(1,2,4-triazol-1-yl)-propan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; In tetrahydrofuran; hexane; STR612 At -20 C., a mixture of 1.53 g (5 mmol) of 2-(2,4-difluoro-phenyl)-1,3-bis-(1,2,4-triazol-1-yl)-propan-2-ol and 30 ml of absolute tetrahydrofuran is admixed with 4.4 ml (11 mmol) of n-butyl-lithium in hexane, and stirring is continued at 0 C. for 30 minutes. The reaction mixture is subsequently cooled to -70 C. admixed with stirring with 0.19 g (6 mmol) of sulphur powder and then stirred at -70 C. for 1 hour and subsequently at 0 C. for 2 hours. The resulting mixture is diluted with ethyl acetate and extracted repeatedly with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulphate and then concentrated under reduced pressure. The resulting crude product (2.3 g) is purified by silica gel chromatography using a mixture of ethyl acetate and ethanol=9:1 as mobile phase. In this manner, 1.0 g (59% of theory) of 2-(2.4-difluoro-phenyl)-1-(5-mercapto-1,2,4-triazol-1-yl)-3-(1,2,4-triazol-1-yl)-propan-2-ol is obtained in the form of a solid substance of melting point 187 C. GC/MS (ci): 339 (M+H+)
With n-butyllithium; In tetrahydrofuran; hexane; STR1099 At -20 C., a mixture of 1.53 g (5 mmol) of 2-(2,4-difluoro-phenyl)-1,3-bis-(1,2,4-triazol-1-yl)-propan-2-ol and 30 ml of absolute tetrahydrofuran is admixed with 4.4 ml (11 mmol) of n-butyl-lithium in hexane, and stirring is continued at 0 C. for 30 minutes. The reaction mixture is subsequently cooled to -70 C., admixed with stirring with 0.19 g (6 mmol) of sulphur powder and then stirred at -70 C. for 1 hour and subsequently at 0 C. for 2 hours. The resulting mixture is diluted with ethyl acetate and extracted repeatedly with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulphate and then concentrated under reduced pressure. The resulting crude product (2.3 g) is purified by silica gel chromatography using a mixture of ethyl acetate and ethanol=9:1 as mobile phase. In this manner, 1.0 g (59% of theory) of 2-(2,4-difluoro-phenyl)-1-(5-mercapto-1,2,4-triazol-1-yl)-3-(1,2,4-triazol-1-yl)-propan-2-ol is obtained in the form of a solid substance of melting point 187 C. GC/MS (ci): 339 (M+H+)
With n-butyllithium; In tetrahydrofuran; hexane; STR683 At -20 C., a mixture of 1.53 g (5 mmol) of 2-(2,4-difluoro-phenyl)-1,3-bis-(1,2,4-triazol-1-yl)-propan-2-ol and 30 ml of absolute tetrahydrofuran is admixed with 4.4 ml (11 mmol) of n-butyl-lithium in hexane and stirred at 0 C. for another 30 minutes. The reaction mixture is subsequently cooled to -70 C., admixed with stirring with 0.19 g (6 mmol) of sulphur powder and then stirred at -70 C. for 1 hour and then at 0 C. for 2 hours. The resulting mixture is diluted with ethyl acetate and extracted repeatedly with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulphate and then concentrated under reduced pressure. The resulting crude product (2.3 g) is purified by silica gel chromatography using a mixture of ethyl acetate and ethanol=9:1 as eluent. In this manner, 1.0 g (59% of theory) of 2-(2,4-difluoro-phenyl)-1-(5-mercapto-1,2,4-triazol-1-yl)-3-(1,2,4-triazol-1-yl)-propan-2-ol is obtained in the form of a solid substance of melting point 187 C. GC/MS(ci): 339 (M+H+)
With n-butyllithium; In tetrahydrofuran; hexane; STR327 At -20 C., a mixture of 1.53 g (5 mmol) of 2-(2,4-difluoro-phenyl)-1,3-bis-(1,2,4-triazol-1-yl)-propan-2-ol and 30 ml of absolute tetrahydrofuran is admixed with 4.4 ml (11 mmol) of n-butyl-lithium in hexane, and stirring is continued at 0 C. for 30 minutes. The reaction mixture is subsequently cooled to -70 C., admixed with stirring with 0.19 g (6 mmol) of sulphur powder and then stirred at -70 C. for 1 hour and subsequently at 0 C. for 2 hours. The resulting mixture is diluted with ethyl acetate and extracted repeatedly with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulphate and then concentrated under reduced pressure. The resulting crude product (2.3 g) is purified by silica gel chromatography using a mixture of ethyl acetate and ethanol=9:1 as mobile phase. In this manner, 1.0 g (59% of theory) of 2-(2,4-difluoro-phenyl)-1-(5-mercapto-1,2,4-triazol-1-yl)-3-(1,2,4-triazol-1-yl)-propan-2-ol is obtained in the form of a solid substance of melting point 187 C. GC/MS (ci): 339 (M+H+).

  • 34
  • (S,R)-2-(2,4-Difluorophenyl)-1,3-bis-(1H-1,2,4-triazol-1-yl)-2,3-epoxypropane [ No CAS ]
  • [ 86386-73-4 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; diisobutylaluminium hydride; In dichloromethane; A. From E epoxide (IV): The E epoxide (IV) (1.3 g, 4.28 mmol) was dissolved in dichloromethane (30 ml) under a nitrogen atmosphere and the solution was cooled to 0 C. Diisobutylaluminium hydride (DIBAL) (1M in CH2 Cl2, 4.7 ml, 4.7 mmol) was added via a syringe and the reaction was stirred at room temperature for 3 hours while adding 235 mL of the DIBAL solution twice after 1 and 2 hours. The reaction was quenched with 10% aqueous NaOH. The mixture was filtered to give a biphasic filtrate. The organic layer was separated, dried (MgSO4) and evaporated. The oil obtained was triturated with hexane/dichloromethane to give 0.98 g of fluconazole (I) as a yellowish solid which was recrystallyzed from isopropanol. The identity of the product was confirmed by comparing its IR, 13 C and 1 H NMR, UV spectra as well as TLC and HPLC chromatograms with those of the authentic material.
  • 35
  • [ 75-21-8 ]
  • [ 584-13-4 ]
  • [ 67-63-0 ]
  • [ 86386-73-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium nitrite; In dichloromethane; water; fluconazole; COMPARATIVE EXAMPLE A Attempted Preparation of Fluconazole A mixture of oxirane of formula II', where R is 2,4-difluorophenyl (500 mg) and n is 0, 4H-4-amino-1,2,4-triazole (176 mg) and 2-propanol (4 mL) was heated to reflux for 4 hrs. Following the solvent removal in vacuo the residue was dissolved in water (6 mL), cooled and concentrated hydrochloric acid (1.5 mL) was added, followed by a solution of sodium nitrite (300 mg) in water (2 mL dropwise). The resulting solution was allowed to warm to room temperature, methylene chloride (6 mL) was added, the pH of the mixture was adjusted to 10 with ammonium hydroxide, and the phases were separated. Chromatographic analysis of the organic phase revealed a complex product mixture in which fluconazole was only a minor component.
With hydrogenchloride; sodium nitrite; In dichloromethane; water; fluconazole; COMPARATIVE EXAMPLE A Attempted Preparation of Fluconazole A mixture of oxirane of formula II', where R is 2,4-difluorophenyl (500 mg) and n is 0, 4H-4-amino-1,2,4-triazole (176 mg) and 2-propanol (4 mL) was heated to reflux for 4 hrs. Following the solvent removal in vacuo, the residue was dissolved in water (6 mL), cooled and concentrated hydrochloric acid (1.5 mL) was added, followed by a solution of sodium nitrite (300 mg) in water (2 mL dropwise). The resulting solution was allowed to warm to room temperature, methylene chloride (6 mL) was added, the pH of the mixture was adjusted to 10 with ammonium hydroxide, and the phases were separated. Chromatographic analysis of the organic phase revealed a complex product mixture in which fluconazole was only a minor component.
  • 36
  • [ 288-88-0 ]
  • [ 86386-76-7 ]
  • [ 86386-73-4 ]
YieldReaction ConditionsOperation in experiment
68.1% With potassium carbonate; In acetonitrile; at 60℃; General procedure: A suspension of potassium carbonate (27.6 g, 0.20 mmol), 1H-1,2,4-triazole (9.8 g, 0.14 mol) and compound 3 (26.6 g, 0.14 mol) was stirred in acetonitrile (30 mL) at 60 C. After the reaction was completed (monitored by TLC, eluent, ethyl acetate/methanol, 15/1, V/V), the solvent was removed and the residue was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. After concentrating the filtrate, the crude product was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (15/1, V/V) to give compound 4 (25.9 g) as white solid. Yield: 83.1%
With potassium carbonate; In isopropyl alcohol; at 75℃; for 16h; 702 ml of isopropanol and 50 g of 1-[2-(2,4-difluorophenyl)-oxiranyl methyl]-1H-1,2,4-triazole obtained above was taken into a round bottom flask. 22.5 g of 1,2,4-triazole and 63.7 g of potassium carbonate were added to the above reaction mass under stirring. The reaction mass was heated to 75 C. The reaction mass was maintained at 75 C. for 16 hours. Reaction completion was checked using thin layer chromatography. After completion of the reaction, the reaction mass was cooled to 30 C. The reaction mass was then filtered and the filter bed was washed with 70 ml of isopropanol in two equal lots. The filtrate was taken into a separate round bottom flask and distilled at 65 C. To the residue obtained 140.5 ml of deionized water was added. The reaction mass was maintained at 66 C. for 30 minutes. The reaction mass was then cooled to 10 C. The separated solid was filtered and washed with 14 ml of deionized water. The wet material was taken into a separate round bottom flask and 267 ml of deionized water was added to it. The reaction mass was heated to 98 C. 2.25 g of carbon was charged into the reaction mass and maintained at 98 C. for 30 minutes. The reaction mass was filtered and the carbon bed was washed with 32.5 ml of deionized water. The filtrate was cooled to 12 C. and maintained for 45 minutes. The separated solid was filtered and washed with 32.5 ml of deionized water. The wet material was taken into another round bottom flask and 1220 ml of chloroform was added to it. The reaction mass was checked for clear dissolution. 1030 ml of water, 51.5 g of citric acid, and 103 g of sodium chloride were taken into a separate round bottom flask and stirred for 5 minutes. The chloroform layer obtained above was washed with the above solution in 3 equal lots. The organic layer was then subjected to distillation under a vacuum of 300 mm Hg at 45 C. 103 ml of water was charged to the residue obtained and heating given to 96 C. 1.2 g of carbon was added to the reaction mass and maintained at 96 C. for 30 minutes. The reaction mass was then filtered under hot conditions and the carbon bed was washed with 32.5 ml of deionized water. The filtrate was cooled to 10 C. and maintained for 1 hour. The separated compound was filtered and washed with 26 ml of chilled deionized water. The wet compound was dried in oven at 65 C. for 2 hours to yield 34 g of the title compound. Purity by HPLC: 99.98%
  • 37
  • [ 288-88-0 ]
  • [ 348-57-2 ]
  • [ 534-07-6 ]
  • [ 86386-74-5 ]
  • [ 86386-73-4 ]
YieldReaction ConditionsOperation in experiment
400 mg. (26%) With n-butyllithium; potassium carbonate; In N-methyl-acetamide; methanol; diethyl ether; hexane; dichloromethane; water; acetic acid; EXAMPLE 1 A solution consisting of 960 mg. (0.005 mole) of 1-bromo-2,4-difluorobenzene dissolved in 10 ml. of diethyl ether was stirred at -78 C., while 3.23 ml. of 1.55 M n-butyl lithium (0.005 mole) in n-hexane was slowly added thereto over a period of three minutes. After the addition was complete, the mixture was stirred for a further period of ten minutes and then a solution consisting of 630 mg. (0.005 mole) of 1,3-dichloroacetone dissolved in 10 ml. of diethyl ether was added dropwise to the stirred etheral mixture over a period of three minutes. After the latter addition was complete, the reaction mixture was stirred for a further period of 30 minutes of -78 C., while a solution consisting of 330 mg. of glacial acetic acid dissolved in 5 ml. of diethyl ether was slowly added thereto at 0 C., followed by the addition of 10 ml. of water. Upon completion of this step, the organic layer was separated and the aqueous phase was extracted once with fresh diethyl ether. The combined ethereal extracts were then dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was subsequently evaporated under reduced pressure to afford a pale yellow oil as the residual liquid. The latter material, which consisted essentially of pure 1,3-bischloro-2-(2,4-difluorophenyl)propane-2-ol, was dissolved in 20 ml. of dimethylformamide and used as such in the next reaction step. To the solution prepared above, 1.72 g. (0.025 mole) of 1,2,4-triazole and 2.07 g. (0.015 mole) of anhydrous potassium carbonate were added and the resulting mixture was heated at 70 C. for a period of 18 hours. The reaction mixture thus obtained was then poured into 100 ml. of water and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were then dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was subsequently evaporated under reduced pressure to give a gum. The latter material was then chromatographed on silica (270-400 mesh), using 3% methanol in methylene chloride as the eluant, to ultimately afford 400 mg. (26%) of pure 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol in the form of a white solid, m.p. 138-140 C. after recrystallization from ethyl acetate/n-hexane.
YieldReaction ConditionsOperation in experiment
Example 23 Synthesis of fluconazole To acetonitrile (12.5 ml) and epoxide (1.67 g, 0.005 mole) of the formula (II) in the form of methanesulfonate, hydrazine hydrate (0.61 ml, 0.0125 mole; 99%) was added. The reaction mixture was in three phases: two uncoloured phases and a suspension phase with a white solid. The reaction mixture was heated to the boiling point where only a two-phase system of two uncoloured phases was observed. The reaction mixture was heated at the boiling point for 3 hours when by TLC (chloroform/ methanol 15/2) the completion of reaction was established. The reaction mixture was cooled to room temperature and then methanesulfonic acid (0.2 ml) was added, the hydrazine methansulfonate formed was filtered and then washed with acetonitrile (30 ml).
  • 39
  • [ 101-05-3 ]
  • [ 86386-73-4 ]
YieldReaction ConditionsOperation in experiment
97.4% With formic acid; sodium chloride; In dichloromethane; water; Example 11 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1, triazine (1.42 g; 0.017 mole; 97%) and formic acid (10 ml; 98%) were added. The yellowish reaction mixture was heated to the temperature of 30C and then heated for 75 minutes at 30-35C. The yellow reaction mixture became orange and the completion of the reaction 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% NaOH solution and an uncoloured aqueous phase and a yellowish organic phase were decanted. The phases were separated, the aqueous phase was washed with methylene chloride (10 ml), organic phases were combined and dried with anhydrous sodium sulfate. It was filtered, the drying agent was washed with methylene chloride and the solvent was evaporated at the temperature of 40C and at reduced pressure. A white product (1.49 g; 97.4%) was isolated. TLC: chloroform/metanol 15/2, Rf 0.51.
96,7% With formic acid; sodium chloride; In dichloromethane; water; Example 8 Synthesis of fluconazole To the hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1 triazine (1.42 g; 0.017 mole; 97%) and formic acid (10 ml; 98%) were added. The obtained yellowish reaction mixture was heated at the reflux temperature (100-102C) for 40 minutes when the reaction mixture became orange, and the completion of the reaction was detected by TLC. Formic acid was evaporated at reduced pressure and at the bath temperature of 70-71C. Water (10 ml) and NaCl (3 g) and methylene chloride (25 ml) were added to the residue. The pH of the aqueous phase was 2-3. The pH of the solution was adjusted to 7 with a 33% NaOH solution and it was decanted. The organic phase was washed with methylene chloride (10 ml), the organic phases were combined and dried with anhydrous sodium sulfate. It was filtered, washed with methylene chloride and methylene chloride was evaporated at the temperature of 40C and at reduced pressure. A lightly coloured product (1.48 g; 96,7%) was isolated. TLC: chloroform/metanol 15/2, Rf 0.51.
95.4% Example 15 Synthesis of fluconazole It was proceeded as in Example 11. The reaction time was 1 hour at the temperature 0-5C. 97% triazine (0.7 g; 0.009 mole) was used. A slightly coloured product (1.46 g; 95.4%) was obtained. TLC: chloroform/metanol 15/2, Rf 0.51
  • 40
  • [ 290-87-9 ]
  • 2-(2,4-difluorophenyl)-1-hydrazino-3-(1H-1,2,4-triazol-1-yl)propan-2-ol [ No CAS ]
  • [ 86386-73-4 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hydroxide; formic acid; trifluoroacetic acid; In dichloromethane; water; Example 16 Synthesis of fluconazole To a hydrazine compound (IV) (1.35 g; 0.005 mole) from Example 1 methylene chloride (20 ml), trifluoroacetic acid (2 ml; 0.026 mole) and s-triazine (0.8 g; 0.00987 mole) were added. A two-phase system was heated to 37C and formic acid (4 ml; 98%) was added to obtain a yellow solution. The reaction mixture was kept for 1 hour at 35C. TLC showed that the reaction was completed. Then a solution of water (10 ml) and NACl (3 g) was added. The pH was 0.28. A 33% NaOH solution was added to pH 7.56 and then it was decanted. The aqueous phase was colourless and the organic phase was slightly pink. The aqueous phase was washed with methylene chloride (10 ml), organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed with methylene chloride and evaporated on rotavapor in vacuo (bath temperature 40C). A white product (1.39 g; yield 91%) was obtained. TLC (chloroform/methanol 15/2) showed that the product was very pure (one stain);
  • 41
  • [ 67-56-1 ]
  • iron(II) chloride tetrahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [dichlorobis(1-(2,4-difluorophenyl)-1,1-bis[(1H-1,2,4-triazol-1-yl)methyl]methanol)iron(II)]-methanol (1/2) [ No CAS ]
  • 42
  • [ 67-56-1 ]
  • copper(II) choride dihydrate [ No CAS ]
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • [ 68-12-2 ]
  • [bis(1-(2,4-difluorophenyl)-1,1-bis[(1H-1,2,4-triazol-1-yl)methyl]methanol)aquacopper(II)] sulfate-methanol-dimethylformamide-water (1/2/1/2) [ No CAS ]
  • 43
  • [ 67-56-1 ]
  • copper(II) choride dihydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [dichlorobis(1-(2,4-difluorophenyl)-1,1-bis[(1H-1,2,4-triazol-1-yl)methyl]methanol)copper(II)]-methanol (1/2) [ No CAS ]
  • 44
  • [ 67-56-1 ]
  • copper(ll) sulfate pentahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [ 68-12-2 ]
  • [bis(1-(2,4-difluorophenyl)-1,1-bis[(1H-1,2,4-triazol-1-yl)methyl]methanol)aquacopper(II)] sulfate-methanol-dimethylformamide-water (1/2/1/2) [ No CAS ]
  • 45
  • [ 7631-95-0 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • Ni2(α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol)4(H2O)4(Mo8O26)*6H2O [ No CAS ]
  • 46
  • [ 7631-95-0 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [Ni2(2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-ol)4(H2O)4][β-Mo8O26]*5H2O [ No CAS ]
  • 47
  • sodium molybdate [ No CAS ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • (fluconazole)4Ni2(MoO4)2*6H2O [ No CAS ]
  • 48
  • [ 67-56-1 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • (fluconazole)2NiCl2(methanol)*(methanol) [ No CAS ]
  • 49
  • iron(II) perchlorate hexahydrate [ No CAS ]
  • [ 1934-75-4 ]
  • [ 86386-73-4 ]
  • [Fe(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol)2(dicyanamide-H)2]n [ No CAS ]
  • 50
  • [ 1934-75-4 ]
  • [ 86386-73-4 ]
  • cobalt(II) perchlorate hexahydrate [ No CAS ]
  • [Co(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol)2(dicyanamide-H)2]n [ No CAS ]
  • 51
  • [ 7601-90-3 ]
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • zinc(II) oxide [ No CAS ]
  • Zn(α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol)2(ClO4)2*2H2O [ No CAS ]
  • 52
  • nickel(II) sulphate [ No CAS ]
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • [ 68-12-2 ]
  • (fluconazole)Ni(SO4)(N,N'-dimethylformamide)(H2O)*(N,N'-dimethylformamide) [ No CAS ]
  • 53
  • nickel(II) sulphate [ No CAS ]
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • (fluconazole)2Ni(H2O)2(SO4)*4H2O [ No CAS ]
  • 54
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • [ 7789-45-9 ]
  • Cu(α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol)2Br2*2H2O [ No CAS ]
  • 55
  • [ 7631-95-0 ]
  • [ 5970-45-6 ]
  • [ 86386-73-4 ]
  • [Zn2(2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-ol)4][β-Mo8O26]*4H2O [ No CAS ]
  • 56
  • [ 7631-95-0 ]
  • [ 6046-93-1 ]
  • [ 86386-73-4 ]
  • [Cu2(2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-ol)4][β-Mo8O26]*4H2O [ No CAS ]
  • 57
  • [ 7631-95-0 ]
  • cobalt(II) acetate dihydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [Co2(2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-ol)4(H2O)4][β-Mo8O26]*5H2O [ No CAS ]
  • 58
  • zinc(II) nitrate hexahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [ 68-12-2 ]
  • ([Zn(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol)2(H2O)2](NO3)2*2DMF)(n) [ No CAS ]
  • 59
  • [ 86386-73-4 ]
  • [ 68-12-2 ]
  • [ 7646-85-7 ]
  • [ 932711-78-9 ]
  • 60
  • copper(II) nitrate trihydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [Cu(1-(2,4-difluorophenyl)-1,1-bis[(1H-1,2,4-triazol-1-yl)methyl]ethanol)2(H2O)2](NO3)2 [ No CAS ]
  • 61
  • nickel(II) nitrate hexahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [ 942924-15-4 ]
  • 62
  • nickel(II) nitrate hexahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • (fluconazole)2Ni(NO3)2*H2O [ No CAS ]
  • 63
  • [ 67-56-1 ]
  • [ 6046-93-1 ]
  • [ 1934-75-4 ]
  • [ 86386-73-4 ]
  • [Cu3(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol-H)2(dicyanamide-H)4(CH3OH)2]n [ No CAS ]
  • 64
  • [ 333-20-0 ]
  • [ 86386-73-4 ]
  • copper(II) perchlorate [ No CAS ]
  • [(α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol)2 copper(II) (thiocyanate)2]n [ No CAS ]
  • 65
  • [ 333-20-0 ]
  • [ 86386-73-4 ]
  • [ 7758-99-8 ]
  • [(α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol)2 copper(II) (thiocyanate)2]n [ No CAS ]
  • 66
  • hexaammonium heptamolybdate tetrahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • silver nitrate [ No CAS ]
  • [Ag4(2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-ol)4][β-Mo8O26] [ No CAS ]
  • 67
  • [ 86386-73-4 ]
  • silver nitrate [ No CAS ]
  • silver(I)(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol) nitrate [ No CAS ]
  • 68
  • Zn(2+)*2SCN(1-)*3H2O=Zn(SCN)2*3H2O [ No CAS ]
  • [ 86386-73-4 ]
  • [[Zn(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol)2(SCN)2]](n) [ No CAS ]
  • 69
  • [ 5743-04-4 ]
  • [ 1934-75-4 ]
  • [ 86386-73-4 ]
  • [Cd(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol)2(dicyanamide-H)2]n [ No CAS ]
  • 70
  • manganese(II) perchlorate hexahydrate [ No CAS ]
  • [ 1934-75-4 ]
  • [ 86386-73-4 ]
  • [Mn(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol)2(dicyanamide-H)2]n [ No CAS ]
  • 71
  • zinc(II) nitrate hexahydrate [ No CAS ]
  • [ 1934-75-4 ]
  • [ 86386-73-4 ]
  • [Zn(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol)2(dicyanamide-H)2]n [ No CAS ]
  • 72
  • zinc(II) nitrate hexahydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [[Zn(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol)2(H2O)2](NO3)2](n) [ No CAS ]
  • 73
  • silver perchlorate [ No CAS ]
  • [ 86386-73-4 ]
  • silver(I) bis(2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol) perchlorate [ No CAS ]
  • 74
  • 12-molybdosilicic acid [ No CAS ]
  • copper(II) nitrate trihydrate [ No CAS ]
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • [Cu(II)4(1-(2,4-difluorophenyl)-1,1-bis[(1H-1,3,4-triazol-1-yl)methyl]methanolate)4(H2O)4(SiMo12O40)]*3H2O [ No CAS ]
  • 75
  • 12-molybdosilicic acid [ No CAS ]
  • copper(II) nitrate trihydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [Cu(I)4((1-(2,4-difluorophenyl)-1,1-bis(1H-1,2,4-triazol-1-yl)methyl)methanol)4(SiMo12O40)] [ No CAS ]
  • 76
  • dodecatungstosilic acid [ No CAS ]
  • copper(II) nitrate trihydrate [ No CAS ]
  • [ 7732-18-5 ]
  • [ 86386-73-4 ]
  • (CuC13H11OF2N6)2(2+)*6Cu(2+)*6C13H11OF2N6(1-)*2SiW12O40(4-)*8H2O=C104H104Cu8F16N48O96Si2W24 [ No CAS ]
  • 77
  • dodecatungstosilic acid [ No CAS ]
  • [ 7732-18-5 ]
  • [ 6046-93-1 ]
  • [ 86386-73-4 ]
  • [ 121-44-8 ]
  • [NHEt3]2[Cu(I)2((1-(2,4-difluorophenyl)-1,1-bis(1H-1,2,4-triazol-1-yl)methyl)methanol)2(SiW12O40)]*2H2O [ No CAS ]
  • 78
  • dodecatungstosilic acid [ No CAS ]
  • [ 7732-18-5 ]
  • [ 6046-93-1 ]
  • [ 86386-73-4 ]
  • [ 121-44-8 ]
  • [NHEt3]2[Cu(I)2((1-(2,4-difluorophenyl)-1,1-bis(1H-1,2,4-triazol-1-yl)methyl)methanol)2(SiW12O40)]*H2O [ No CAS ]
  • 79
  • dodecatungstosilic acid [ No CAS ]
  • copper(II) nitrate trihydrate [ No CAS ]
  • [ 86386-73-4 ]
  • [Cu(II)2(1-(2,4-difluorophenyl)-1,1-bis[(1H-1,3,4-triazol-1-yl)methyl]methanol)4(SiW12O40)]*3H2O [ No CAS ]
  • 80
  • 12-molybdosilicic acid [ No CAS ]
  • [ 7732-18-5 ]
  • [ 5970-45-6 ]
  • [ 86386-73-4 ]
  • [Zn(2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-ol)(H2O)3](2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-ol(+2H))(SiMo12O40)*3H2O [ No CAS ]
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