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Chemical Structure| 327056-58-6
Chemical Structure| 327056-58-6
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CAS No. :327056-58-6 MDL No. :
Formula : C6H6FN3O Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 155.13 Pubchem ID :-
Synonyms :

Safety of [ 327056-58-6 ]

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Application In Synthesis of [ 327056-58-6 ]

* 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 [ 327056-58-6 ]

[ 327056-58-6 ] Synthesis Path-Downstream   1~13

  • 1
  • [ 176548-70-2 ]
  • [ 79-37-8 ]
  • [ 327056-58-6 ]
  • [ 453566-50-2 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In N-methyl-acetamide; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1H-imidazol-4-yl)phenyl) -1,2,4-oxadiazole A mixture of <strong>[176548-70-2]3-Bromo-5-fluorobenzoic acid</strong> (0.41 g, 1.87 mmol) in dichloromethane (5 mL) was treated with oxalyl chloride (2.8 ml, 5.60 mmol, 2M dichloromethane) and 3 drops of N,N-dimethylformamide. The mixture was stirred 4 hours at room temperature. The solvent and excess reagent were removed in-vacuo. The residue was treated with 5-Fluoro-2-pyridylamidoxime (0.29 g, 1.87 mmol) and triethylamine (0.78 ml, 5.60 mmol) in dichloromethane (5 mL). The mixture was then heated in dimethylformamide (5 mL) at 120 C., overnight. Standard work up followed by purification on silica gel using 20% ethyl acetate in hexanes afforded 3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (150 mg).
  • 2
  • [ 176548-70-2 ]
  • [ 327056-58-6 ]
  • [ 453566-50-2 ]
YieldReaction ConditionsOperation in experiment
218 mg (45%) In N-methyl-acetamide; water; 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole Using the general procedure for the preparation of acid chlorides, 3-fluoro-5-bromobenzoyl chloride was prepared 3-fluoro-5-bromobenzoic acid (350 mg, 1.598 mmol). The acid chloride was treated 5-fluoropyrid-2-ylamidoxime (223 mg, 1.438 mmol) in dimethylformamide (5 mL) and the mixture heated in sealed tube at 130 C. for 16 hours. After cooling, the reaction was treated with water and the solid collected by filtration. Recrystallization from ethanol afforded 218 mg (45%) of 3-(5-fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), delta (ppm): 8.70 (d, 1H), 8.28 (s, 1H), 8.27 (dd, 1H), 7.93 (td, 1H), 7.61 (td, 1H), 7.53 (td, 1H).
  • 3
  • [ 84923-71-7 ]
  • [ 79-37-8 ]
  • [ 327056-58-6 ]
  • 3-(5-Fluoro-pyrid-2-yl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
75 mg (25.3%) With triethylamine; In N-methyl-acetamide; dichloromethane; N,N-dimethyl-formamide; 3-(5-Fluoro-pyrid-2-yl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole A mixture of <strong>[84923-71-7]5-cyano-2-methoxybenzoic acid</strong> (1.77mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane) and 1 drops of N,N-dimethylformamide. The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 5-fluoropyrid-2-ylamidoxime (155 mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (10 mL). The mixture was then heated in dimethylformamide (1 mL) for 3 hours at 120 C. Standard work up, afforded 75 mg (25.3%) of 3-(5-Fluoro-pyrid-2-yl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole. 1H NMR (CDCl3), delta (ppm): 8.69 (d, 1H), 8.59 (d, 1H), 8.26 (dd, 1H), 7.85 (dd, 1H), 7.60 (m, 1H), 7.19 (d, 1H), 4.10 (s, 3H).
  • 4
  • [ 79-37-8 ]
  • [ 453565-91-8 ]
  • [ 453565-92-9 ]
  • [ 327056-58-6 ]
  • [ 453567-18-5 ]
YieldReaction ConditionsOperation in experiment
14.9 mg (19.6%) With triethylamine In <i>N</i>-methyl-acetamide; dichloromethane 5 5-(3-Cyano-5-trifluoromethoxyphenyl)-3-(5-fluoro-pyrid-2-yl) -1,2,4-oxadiazole 5-(3-Cyano-5-trifluoromethoxyphenyl)-3-(5-fluoro-pyrid-2-yl) -1,2,4-oxadiazole A mixture of 3-cyano-5-trifluoromethoxybenzoic acid, which contained 3-[imino(methoxy)methyl]-5-trifluoromethoxybenzoic acid (3:1, 50 mg, 0.2165 mmoles) in dichloromethane (1 mL) was treated with 2M oxalyl chloride (0.433 ml, 0.866 mmol, dichloromethane). The mixture was stirred 3 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 5-fluoropyrid-2-ylamidoxime (33.6 mg, 0.216 mmol) and triethylamine (87 mg, 0.866 mmol) in dichloromethane (1 mL). The mixture was then heated in dimethylformamide (0.5 mL) for 3 hours at 120° C. Standard work up, purified by prep HPLC (C18 column, CH3CN:H2O=60:40), afforded 14.9 mg (19.6%) of 5-(3-cyano-5-trifluoromethoxyphenyl)-3-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.72 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.25 (m, 1H), 7.78 (s, 1H), 7.61 (m, 1H).
  • 5
  • [ 79-37-8 ]
  • [ 176548-72-4 ]
  • [ 327056-58-6 ]
  • [ 453567-38-9 ]
YieldReaction ConditionsOperation in experiment
13% With triethylamine; In N-methyl-acetamide; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-methoxyphenyl)-1,2,4-oxadiazole A mixture of <strong>[176548-72-4]3-Fluoro-5-methoxybenzoic acid</strong> (0.20 g, 1.18 mmol) in dichloromethane (2.5 mL) was treated with oxalyl chloride (1.76 ml, 3.53 mmol, 2M dichloromethane) and 3 drops of N,N-dimethylformamide. The mixture was stirred 4 hours at room temperature. The solvent and excess reagent were removed in-vacuo. The residue was treated with 5-Fluoro-2-pyridylamidoxime (182 mg, 1.18 mmol) and triethylamine (0.49 ml, 3.53 mmol) in dichloromethane (2.5 mL). The mixture was then heated in dimethylformamide (2.5 mL) at 120 C., overnight. Standard work up followed by purification on silica gel using 20% ethyl acetate in hexanes afforded the title compound (43.1 mg, 13%) as a light yellow solid. 1H-NMR (CDCl3), delta (ppm): 8.69 (d, 1H), 8.26 (dd, 2H), 7.60 (m, 3H), 6.87 (m, 1H).
  • 6
  • [ 79-37-8 ]
  • [ 25026-64-6 ]
  • [ 327056-58-6 ]
  • [ 453566-63-7 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; N,N-dimethyl-formamide; 3-(5-Fluoropyrid-2-yl)-5-(3-fluoro-5-chlorophenyl)-1,2,4-oxadiazole Using the general procedure for the preparation of acid chlorides, 3-chloro-5-fluorobenzoyl chloride is prepared from <strong>[25026-64-6]3-chloro-5-fluorobenzoic acid</strong> using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N,N-dimethylformamide. Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 5-fluoropyrid-2-ylamidoxime followed by heating in N,N-dimethylformamide overnight at 110 C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, and trituration, affords purified 3-(5-fluororopyrid-2-yl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole.
  • 7
  • [ 79-37-8 ]
  • [ 327056-58-6 ]
  • [ 78621-81-5 ]
  • [ 453567-46-9 ]
YieldReaction ConditionsOperation in experiment
15% With triethylamine; In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; (a) 3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole To a mixture of 3-cyano-5-methylbenzoic acid (80 mg, 0.5 mmol), oxalyl chloride (1 mls, 2M solution in CH2Cl2, 2 mmol) in CH2Cl2 (5 ml) was added a few drops of DMF (one pipette drops) and the mixture was stirred at room temperature for 3 h. The solvent was then removed in vacuo. The residue was then dissolved in CH2Cl2 (5 ml) followed by the addition of 5-Fluoro-2-pyridyl amidoxime (78 mg, 0.5 mmol) and Et3N (0.2 ml) and stirring was continued for a further 1 h. Removal of the solvent in vacuo gave the crude residue which was dissolved in DMF (5 ml). The resulting solution was heated to 120 C. overnight after which the solvent was removed in vacuo and the residue was trituated with 20% ethylacetate/hexane giving the product as a white solid (21 mg, 15% yield). 1H-NMR(CDCl3) : 8.70 (d, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.28 (dd, 1H), 7.70 (s, 1H), 7.60 (dt, 1H), 2.50 (s, 3H).
  • 8
  • [ 327056-62-2 ]
  • [ 327056-58-6 ]
YieldReaction ConditionsOperation in experiment
98.42% With hydroxyamino hydrochloride; In methanol; at 20℃; for 10h; To the solution of cyano compound (2) (10 g, 0.082 mol) was dissolved in 250 ml methyl alcohol to this added hydroxylamine hydrochloride (NH2OH.HCI) (8.52 g, 0.123 mol) in presence of TEA (12.44 g, 0.123 mol) and then the reaction mixture was stirred at RT for 10 h. Reaction was monitored by thin layer chromatography, under reduced pressure solvent was removed. Obtained residue was further dissolved in methylene dichloride (DCM) solvent and washed with water. By using separating funnel the organic layer was separated, again which is washed with the brine solution, separated organic layer was dried with anhydrous Na2SO4 and concentrated to get title compound (3). (0053) Colour: Off White crystalline solid; M.p.: 190-191 C; Yield: 98.42 %; *H-NMR (400 MHz, CDCI3, 5 ppm): 8.55 (d, 1H, .7=2,8 Hz, Ar-H), 7.89-7.92 (m, 1H, Ar-H), 7.72-7 ,77(m, 1H, Ar-H), 5.84(s, 2H, NH2); 13C NMR (100 MHz, CDCI3, 5 ppm): 163.1(1C, C=N-OH), 158.4(1C, Ar-H), 150.3(lC, Ar-H) 134.0(lC, Ar-C), 121.6(1C, Ar-C), 12O.6(1C, Ar-C); MS (m/z): 156.1 (M+); Anal, calcd. for C6H6FN3O: C, 46.45 ; H, 3.90; N, 27.09%; Found: C, 46.28; H, 3.92; N, 27.21%.
98.42% With hydroxyamino hydrochloride; In methanol; at 20℃; for 10h; To the solution of cyano compound (2) (10 g, 0.082 mol) was dissolved in 250 ml methyl alcohol to this added hydroxylamine hydrochloride (NH2OH.HCI) (8.52 g, 0.123 mol) in presence of TEA (12.44 g, 0.123 mol) and then the reaction mixture was stirred at RT for 10 h. Reaction was monitored by thin layer chromatography, under reduced pressure solvent was removed. Obtained residue was further dissolved in methylene dichloride (DCM) solvent and washed with water. By using separating funnel the organic layer was separated, again which is washed with the brine solution, separated organic layer was dried with anhydrous Na2SO4 and concentrated to get title compound (3). (0053) Colour: Off White crystalline solid; M.p.: 190-191 C; Yield: 98.42 %; *H-NMR (400 MHz, CDCI3, 5 ppm): 8.55 (d, 1H, .7=2,8 Hz, Ar-H), 7.89-7.92 (m, 1H, Ar-H), 7.72-7 ,77(m, 1H, Ar-H), 5.84(s, 2H, NH2); 13C NMR (100 MHz, CDCI3, 5 ppm): 163.1(1C, C=N-OH), 158.4(1C, Ar-H), 150.3(lC, Ar-H) 134.0(lC, Ar-C), 121.6(1C, Ar-C), 12O.6(1C, Ar-C); MS (m/z): 156.1 (M+); Anal, calcd. for C6H6FN3O: C, 46.45 ; H, 3.90; N, 27.09%; Found: C, 46.28; H, 3.92; N, 27.21%.
80% With hydroxyamino hydrochloride; sodium hydroxide; In ethanol; water monomer; at 80℃; for 1h; 5-Fluoropyridine-2-carbonitrile 4b (2.9 g, 23.8 mmol) 2 was treated with hydroxylamine (1M, 40 mL) (prepared from 1:1 mixture of hydroxylamine hydrochloride and sodium hydroxide in 1:1 water and ethanol) at 80C for 1h. The solvent was half evaporated and the precipitate was washed with 1:1 water:ethanol (100 mL) and water (100 mL x 2). After drying, 2.93 g (80% yield) of the title compound was obtained. 1H NMR (270 MHz, CDCl3) δ ppm: 8.41 (d, 1H), 7.94 (dd,1H), 7.44 (ddd,1H), 6.62 (br s,1H), 5.58 (br s, 2H). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.88 (s, 1 H), 8.54 (d, J=2.7 Hz, 1 H), 7.91 (dd, J=9.0, 4.7 Hz, 1 H), ), 7.73 (td, J=8.8, 2.8 Hz, 1 H), 5.79 (br. s., 2 H)
330 mg (61%) With sodium hydroxide; hydroxyamino hydrochloride; In ethanol; Using the general procedure for the synthesis of amidoximes, <strong>[327056-62-2]2-cyano-5-fluoropyridine</strong> (425 mg, 3.48 mmol), 5M hydroxylamine hydrochloride (0.79 ml, 3.95 mmol) in ethanol (5 mL), and 10N sodium hydroxide (0.398 mL, 3.98 mmol) were heated at reflux for 24 hours. Standard work up afforded 330 mg (61%) of 5-fluoropyrid-2-ylamidoxime.
With hydroxyamino hydrochloride; anhydrous sodium carbonate; In methanol; for 24h; EXAMPLE 10; Example 10 utilized a 5-fluoro-2-hydroxyamidinylpyridine as an intermediate to obtain the desired product. To a mixture of 5-amino-2-cyanopyridine (100 g, 840 rnmol) cooled to -1O0C was added HF-pyridine (50OmL, 70%v/v). Sodium nitrite (91g, 1.32mol) was added in portions. The reaction was then stirred at -100C for 45 minutes, room temperature for 30 minutes, and 800C for 90 minutes. Upon completion, the reaction was cooled to room temperature and quenched with ice/water. The aqueous solution was extracted with CH2Cl2, dried over magnesium sulfate and concentrated. The fluoropyridine (4Og, 328mmol) was treated with sodium carbonate (82g, 773mmol) and hydroxylamine- hydrochloride (45g, 652mmol) in methanol (30OmL). The reaction was allowed to stir for 24h and upon completion, the reaction was concentrated in vacuo, diluted with water, filtered and dried under vacuum.Example 10 was generated under similaτ reaction conditions described in the examples above and shown in Schemes 4 and 5. 1H NMR (DMSOd6, 500 MHz) δ 12.0 (s, IH), 8.79(s, IH), 8.23 (m, IH), 8.14 (m, IH), 7.97 (m, IH), 7.64 (m, IH), 7.26 (m, IH), 4.64 (m, IH), 3.56 (m, 2H); LCMS m/z 394 (M+Na).
With hydroxylamine; In methanol; at 20℃; for 48h; To a suspension of 5-amino-2-cyano pyridine (20-0 g, 0.168 mol) in HF-pyridine (100 g) in an Erlenmeyer flask cooled to 0 C. was added sodium nitrite (17.4 g, 0.251 mol) in four portions. After 45 min at 0 C. the reaction mixture was stirred at room temperature for 30 min and then heated to 80 C. for 90 min. The reaction mixture was quenched by pouring into an ice/water mixture. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the fluoropyridine nitrile as an orange solid. To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.131 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.157 mmol, 50% by wt). After stirring the reaction mixture at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxyamidine as a yellow solid. To a suspension of this amidine intermediate (5.32 g, 34.32 mmol) in anhydrous pyridine (10 mL) was added 4-chloro-4-oxo-methyl butyrate (5 mL, 41.18 mmol). The resulting reaction mixture was heated at 120 C. for 2 h. The mixture was cooled to RT and concentrated. The residue was dissolved in ethyl acetate and washed with 1N HCl, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a dark brown solid. This material was purified by Biotage using 25%-60% ethyl acetate-hexanes gradient to give the heterobiaryl intermediate as a light yellow solid. To a solution of this ester intermediate (900 mg, 3.58 mmol) in dioxane (3 mL) was added ammonium hydroxide (3 mL) and the mixture was allowed to stir at room temperature for 12 hours. Upon completion, the mixture was concentrated, and the amide was purified via flash chromatography (Biotage 40M). To the amide (0.25 g, 1.0 mmol) in a degassed solution of dioxane (7 mL) was added the corresponding triflate (0.92 g, 2.1 mmol), cesium carbonate (1.0 g, 3.0 mmol), xantphos ligand (0.1 g, 0.2 mmol), and Pd2(dba)3 catalyst (0.09 g, 0.1 mmol), and the reaction mixture was heated to 75 C. for 6 hours. The mixture was cooled, filtered, concentrated in vacuo, and purified via flash chromatography (Biotage 40 M). To the desired cycloalkene (0.26 g, 0.5 mmol) in THF/H2O (1:1) was added sodium hydroxide (0.06 g, 1.5 mmol). The biphasic reaction mixture was allowed to stir for 12 hours at room temperature. The mixture was concentrated in vacuo and purified by reverse phase HPLC (Gilson) to afford the desired product Example 43. 1H NMR (DMSO-d6, 500 MHz) δ 11.46 (s, 1H), 8.76 (s, 1H), 8.12 (m, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 6.87 (m, 1H), 3.43 (m, 2H), 3.26 (m, 2H), 2.89 (m, 2H), 2.18 (m, 1H), 2.11 (m, 2H) 1.88, (m, 1H), 1.30 (m, 3H); LCMS m/z 527 (M+Na).
With hydroxylamine; In methanol; at 20℃; for 48h; To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.131 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.157 mmol, 50% by wt). After stirring the reaction at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxy amidine as a yellow solid.
With hydroxylamine; In ethanol; water monomer; for 1h;Reflux; General procedure: 50 % Aq. Hydroxylamine (1.05 mmole) was added to a solution of nitrile (10, 1.0 mmole)in ethanol (10 vol) at room temperature. Reflux the reaction mass for 1 hr (TLC monitored).After completion of reaction, cooled to room temperature and concentrated under reducedpressure to get the corresponding amidoxime (7a-m) as a white to yellow colored solidwhich was used directly in the next step without further purification.
With hydroxylamine; In ethanol; water monomer;Reflux; General procedure: To a stirred solution of nitrile (1.0 mmol.) in ethanol (10 vol), Hydroxylamine (1.05 mmol.) (50% aqueous solution) was added and refluxed. After completion of the reaction, as indicated by TLC, the reaction mixture was concentrated to get the corresponding amidoxime.
With hydroxylamine; In ethanol; water monomer;Reflux; General procedure: To a stirred solution of nitrile (1.0 mmol.) in ethanol (10 vol), Hydroxylamine (1.05 mmol.) (50% aqueous solution) was added and refluxed. After completion of the reaction, as indicated by TLC, the reaction mixture was concentrated to get the corresponding amidoxime.

  • 9
  • [ 327056-58-6 ]
  • [ 28186-62-1 ]
  • [ 1261570-88-0 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; N,N-dimethyl-formamide; 3-(5-Fluoro-2-pyridyl)-5-(3-cyano-5-trifluoromethylphenyl)-1,2,4-oxadiazole In a similar fashion, 3-iodo-5-trifluoromethylbenzoyl chloride was prepared from 3-iodo 5-trifluoromethylbenzoic acid (118.2 mg, 0.374 mmol). To a solution of the acid chloride in dichloromethane (2 mL), 5-fluoropyridylamidoxime (124.4 mg, 0.3861 mmol) was added. The solution was stirred at room temperature for 10 minutes and then concentrated in vacuo. DMF (8 mL) was added to the residue and the resulting solution was stirred at 120 C. for 16 h under argon.
  • 10
  • MSproduct RT [ No CAS ]
  • [ 327056-58-6 ]
  • [ 171243-30-4 ]
  • 3-(5-fluoro-pyridin-2-yl)-5-(3-fluoro-5-trifluoromethylphenyl)-1,2,4-oxadiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
In hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-trifluoromethylphenyl)-1,2,4-oxadiazole 3-Fluoro-5-trifluoromethylbenzoyl chloride (0.10 mL, 0.65 mmol) was added to a solution of 5-fluoropyridylamidoxime (102.9 mg, 0.66 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature for 10 minutes and then concentrated in vacuo. DMF (4 mL) was added to the residue and the resulting solution was stirred at 120 C. for 16 h under argon. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo. Flash chromatography on silica gel (10%-20% ethyl acetate in hexane) yielded 131.1 mg (62.5%, GC/MSproduct RT 7.34 min, 96% pure) of 3-(5-fluoro-2-pyridyl) -5-(3-fluoro-5-trifluoromethylphenyl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.70 (d, 1H), 8.38 (s, 1H), 8.28 (dd, 1H), 8.17 (d, 1H), 7.60 (dt, 2H).
  • 11
  • [ 327056-62-2 ]
  • [ 327056-58-6 ]
YieldReaction ConditionsOperation in experiment
37.7% With hydroxylamine hydrochloride; potassium carbonate; In ethanol; for 12h;Reflux; General procedure: 2-cyanopyridine (2.5g, 24.01mmol) was dissolved in EtOH (60mL) treated with K2CO3 (5.97g; 43.22mmol; 1.8 equiv) and H2NOH·HCl (3.0g; 43.22mmol; 1.8 equiv) and heated to reflux for 12h. The mixture was diluted with diethyl ether when it was cooled to room temperature. The product was collected by filtration, washed with water, and dried under an infrared lamp. The compound was used without further purification. Yield: 1.5g (45.5%).
With hydroxylamine; In methanol; at 20℃; for 48h; EXAMPLE 17As shown in Scheme 6 a suspension of 5-amino-2-cyano pyridine (20.0 g, 0.168 mol) in HF-pyridine (100 g) in an Erlenmeyer flask cooled to O0C was added sodium nitrite (17.4 g, 0.25 mol) in four portions. After 45 min at O0C the reaction mixture was stirred at room temperature for 30 min and then heated to 8O0C for 90 min. The reaction mixture was quenched by pouring into ice/water mixture. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the fluoropyridine as an orange solid.To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.13 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.16 mmol, 50% by wt). After stirring the reaction mixture at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxy amidine as a yellow solid.To a suspension of this amidine intermediate (5.32 g, 34.3 mmol) in anhydrous pyridine (10 mL) was added 4-chloro-4-oxo-methyl butyrate (5 mL, 41.2 mmol). The resulting reaction mixture was heated at 12O0C for 2 h. The mixture was cooled to RT and concentrated. The residue was dissolved in ethyl acetate and washed with IN HCl, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a dark brown solid. This material was purified by Biotage using 25%-60% ethyl acetate-hexanes gradient to give the heterobiaryl intermediate as a light yellow solid.To a solution of this ester intermediate (900 mg, 3.58 mmol) in THF (4 mL) was added methanol (2 mL) followed by 5N NaOH (1 mL). After 30 min, the reaction mixture was EPO <DP n="41"/>neutralized by the addition of IN HCl (5 mL). The reaction mixture was concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a light yellow solid of the carboxylic acid.EXAMPLE 17 was prepared by reaction of the carboxylic acid described above and the intermediate prepared for EXAMPLE 2. 1H NMR (DMSOd6, 500 MHz) δ 10.95 (br s, IH), 8.75 (d, IH), 8.12 (dd, IH), 7.95-7.91 (m, IH) .50 (t, 2H), 3.31 (t, 2H), 3.03 (d, IH), 2.32- 2.21 (m, 3H), 1.75 (br s, 2H), 1.26-1.24 (m, lH)m 0.99 (d, 3H); LCMS m/z 372 (M+l).
With hydroxylamine; In ethanol; acetic acid butyl ester; water; N,N-dimethyl-formamide; at 25℃; for 1h;Product distribution / selectivity; Examples; Example 1. Using zinc cyanide as cyanide source; 2-Bromo-5-fluoropyridine (280.43 mmol; 49.80 g; commercially available from Asymchem), zinc (11.27 mmol; 739.20 mg), zinc acetate (8.45 mmol; 1.55 g), 1,1'- bis(diphenylphosphino)ferrocene DPPF) (845.09 μmol; 483.00 mg), tris(dibenzylideneacetone)dipalladium(0) (281.74 μmol; 258.00 mg) were charged to an inerted reactor and dimethylformamide (98.00 mL; 92.64 g) warmed to 1050C was added. Zinc cyanide (155.49 mmol; 18.58 g) was added in 5 portions of equal size while keeping the temperature at 100+/-5C. The reaction mixture was cooled to ambient temperature and butyl acetate (175.00 mL; 154.14 g) was added. Ethylenediaminetetraacetic acid tetrasodium salt tetrahydrate (Na-EDTA) (259.10 mmol; 117.88 g) dissolved in water (300.00 mL) was added and the mixture was stirred for 1 hour. The mixture was clear filtered and the filter was rinsed with butyl acetate (25.00 mL; 22.02 g). The phases were allowed to separate and the aqueous phase was discarded. Ethanol (78.00 mL; 61.72 g) was added and hydroxylamine (309.74 mmol; 17.79 mL; 19.19g) was charged during 1 hour using a syringe pump. The precipitated product was isolated by filtration, washed with butyl acetate (10OmL) and dried under vacuum at 400C, obtaining 5-Fluoro-N-hydroxy-pyridine-2-carboxamidine, 180.58 mmol; 28.24 g in 64.40% yield.
With hydroxylamine; In 1-methyl-pyrrolidin-2-one; ethanol; acetic acid butyl ester; water; at 25℃; for 1h;Product distribution / selectivity; Example 2. Using acetone cyanohydrin as cyanide source and palladium2(dba)3 as palladium source and sodium carbonate as base; 2-Bromo-5-fluoropyridine (281.84 mmol; 50.00 g), sodium carbonate (154.86 mmol; 16.43 g), sodium acetate (22.57 μmol; 1.87 mg), l,r-bis(diphenylphosphino)ferτocene (DPPF) (839.84 μmol; 480.00 mg), tris(dibenzylideneacetone)dipalladium(0) (287.75 μmol; 310.00 mg), butyl acetate (50.00 mL; 44.04 g) and N-methylpyrrolidone (50.00 mL; 51.45 g) was mixed under nitrogen and was heated to 1050C. Acetone cyanohydrin (295.58 mmol; 27.34 mL; 25.41 g) was charged during 2 hours using a syringe pump. The mixture was cooled to ambient temperature and water (200.00 mL) was charged. The mixture was clear filtered and butyl acetate (150.00 mL; 132.12 g) was added, the phases were allowed to separate and the aqueous phase was discarded. Ethanol (80.00 mL; 63.30 g) was added and hydroxylamine (281.84 mmol; 17.10 mL; 18.43 g) was charged during 1 hour using a syringe pump. The precipitated product was isolated by filtration, washed with butyl acetate (10OmL) and dried under vacuum at 400C, obtaining 5-Fluoro-N-hydroxy-pyridine- 2-carboxamidine, 238.96 mmol; 37.37 g in 84.79% yield.
With hydroxylamine; In ethanol; acetic acid butyl ester; water; at 25℃; for 1h;Product distribution / selectivity; Example 3. Using acetone cyanohydrin as cyanide source with palladium acetate as palladium source and triethanolamine as base; 2-Bromo-5-fluoropyridine (50.02g. 281.95 mmol), palladium acetate (129 mg, 565 μmol), 1,1 '-bis(diphenylphosphino)ferrocene (DPPF) (847 mg, 847 μmol), sodium acetate (1.87 g, 22.6 mmol), triethanolamine (43 ml, 312 mmol) and n-butyl acetate (100 ml) was mixed under nitrogen and heated to 1050C and acetone cyanohydrine (27.37 ml, 295.91 mmol) was added during 2 hours using a syringe pump. The resulting slurry was sampled for conversion control (result: 100% conversion) and was then cooled to O0C. The solids (triethanolamine hydrobromide) were removed by filtration, the reaction vessel and the salt was washed with cold n-butyl acetate (2x50 ml) and the washing liquor was pulled off from the salt and was combined with the mother liquor which was then washed with water (200 ml) and the water phase was discarded. To the mother liquor containing 5-Fluoro- pyridine-2-carbonitrile was added ethanol (78 ml) and hydroxylamine 50% aq. (21.87 ml, 310.15 mmol) was added during 1 hour at ambient temperature using a syringe pump. The resulting slurry was cooled to 00C and the product was isolated by filtration, was washed with cold n-butyl acetate (100 ml), the mother liquor was pulled off and the product was dried at 400C under reduced pressure obtaining 5-Fluoro-N-hydroxy-pyridine-2- carboxamidine 37.88g in 85.9% yield.

  • 12
  • [ 327056-74-6 ]
  • [ 327056-58-6 ]
  • [3H]-AZD 9272 [ No CAS ]
YieldReaction ConditionsOperation in experiment
24% 3-Fluoro-5-cyanobenzoic acid 6s (1.0 g, 6 mmol) 3 was treated with a solution of oxalyl chloride (12 mL of 2.5 M in dichloromethane, 30 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. Excess oxalyl chloride was removed in vacuo. The formed acid chloride (1.1 g, 6 mmol) was re-dissolved in pyridine (5 mL), followed by addition of 5b (0.93 g, 6 mmol) in a sealed tube and heated at 175 C for 4 hours. After cooling and dilution with dichloromethane, the organic solution was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, followed by silica gel chromatography using a gradient of 20% to 50% ethyl acetate in hexane. Additional recrystallization from 2-propanol afforded 0.41 g (24%) of the title compound. GC/MS(EI) m/z (rel. int.): 284 (M+, 100), 285 (16), 253 (2), 138 (99), 120 (23), 108 (16), 96 (25), 82 (15), 57 (11). LC/MS(ES+) m/z 285 [M+H]+. 1H NMR (400 MHz, CDCl3) d ppm 7.60 - 7.66 (m, 2 H), 8.21 - 8.30 (m, 2 H), 8.41 (s, 1 H), 8.72 (d, J=3.03 Hz, 1 H).
  • 13
  • [ 327056-58-6 ]
  • [ 455-86-7 ]
  • 5-(3,4-difluorophenyl)-3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
44.3% General procedure: 3,4-difluorobenzoic acid (0.46g, 2.92mmol, 1.0 equiv) was dissolved in DMF (3.0mL) treated with carbonyldiimidazole (0.48g, 2.92mmol, 1.0 equiv) and stirred at room temperature for 1h. 45 (0.4g, 2.92mmol, 1.0 equiv) was added in the mixed solution and another 3mL DMF was added in the system. Then the temperature was increased to 110C and stirring was continued for 12-18h. After cooling, the mixture was diluted by means of water and saturated aqueous NaHCO3 solution. The generated solid product was collected by filtration and washed with saturated aqueous NaHCO3 solution. Yield: 0.345g (45.6%).
Same Skeleton Products
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