| 75% |
With hydroxylamine hydrochloride; sodium carbonate In ethanol; water at 55℃; for 0.5h; Sonication; |
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With hydroxylamine; acetic acid at 100℃; for 0.0166667h; microwave irradiation; |
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With hydroxylamine hydrochloride; sodium hydrogencarbonate In methanol Reflux; |
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With hydroxylamine In water |
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With hydroxylamine; potassium carbonate In ethanol; water at 120℃; for 0.666667h; sealed microwave vial; |
i-3e.A
Preparation of i-3 eStep A; Preparation of 3-bromo-iV-hydroχybenzenecarboximidamide (i-3 a)Hydroxylamine (1.00 mL of a 50% aqueous solution, 16.3 mmol) was added to a solution of 3-bromobenzonitrile (750 mg, 4.12 mmol) and potassium carbonate (1.00 mg, 7.24 μmol) in EtOH (3.00 mL). The resulting mixture was heated to 120 °C in a sealed microwave vial for 40 min. After cooling to rt, the reaction mixture was concentrated in vacuo to afford the title compound I1Ia. m/z (ES) 215 (MH)+. |
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With hydroxylamine hydrochloride; triethylamine In ethanol at 70℃; for 48h; Inert atmosphere; |
1 4.3.1
N'-Hydroxybenzimidamide (22)
General procedure: Triethylamine (42 mL, 0.3 mol) was added to a solution of benzonitrile (21, 10.3 g, 0.1 mol), hydroxylamine hydrochloride (20.9 g, 0.3 mol) and ethanol (150 mL) and stirred for 12 h at 75 °C. The reaction mixture was cooled to room temperature and evaporated to dryness, extracted with DCM (300 mL)/water (100 mL). The organic layer dried with MgSO4, filtered and evaporated to dryness yielding the desired product 22 as a primrose yellow liquid (10.6 g, yield 78%). 1H NMR (300 MHz, DMSO-d6): δ = 9.59 (s, 1H), 7.62-7.67 (m, 2H), 7.32-7.37 (m, 3H), 5.77 (s, 2H); LC/MS (ESI): m/z 137 [M + H]+. |
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With hydroxylamine hydrochloride; triethylamine In ethanol; water at 75℃; for 12h; |
1
General procedure: 4-Fluorobenzonitrile (3.33 g, 27.47 mmol), hydroxylamine hydrochloride (4.20 g, 60.44 mmol) and triethylamine (6.40 g, 8.77 ml, 63.37 mmol) were dissolved by 40 ml ethanol and 2 ml water in a 100 ml flask, then the mixture was heated to 75 °C for 12 h. After cooled to room temperature added 65 ml water in the solution, then evaporated the ethanol in the solution with a rotary evaporator to get white powder precipitated out. Dried the white powder 4-fluoro-N'-hydroxybenzimidamide after filtered, then they can be used directly in the next step. |
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With hydroxylamine hydrochloride; triethylamine In ethanol; water at 75℃; for 12h; |
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With hydroxylamine; acetic acid at 100℃; for 0.5h; |
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With hydroxylamine; acetic acid In neat (no solvent) at 150℃; for 0.666667h; |
Synthesis of compounds 7a-l; general procedure
General procedure: A mixture of the appropriate nitrile (4, 2 mmol), hydroxylamine50% (0.132 g, 2 mmol), and a catalytic amount of AcOH was stirredat 150 C for 40 min. After nearly complete conversion to thecorresponding amidoxime, as was indicated by TLC monitoring, theappropriate 2,2-dialkoxyacetate (6, 2 mmol) and K2CO3 (0.276 g,2 mmol) were added to the reaction mixture which was stirred at100 C for further 6 h. After completion of the reaction as indicatedby TLC, the reaction mixture was cooled to room temperature andthe residue was purified by column chromatography using n-hexane-EtOAc (6:1) as eluent. The solvent was removed, and the product was obtained. |
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With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol; water at 20℃; for 20h; |
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With hydroxylamine In ethanol; water for 3h; Reflux; Inert atmosphere; |
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| 292.6 mg |
With hydroxylamine hydrochloride; sodium hydrogencarbonate In methanol at 65℃; for 3h; Sealed tube; Microwave irradiation; |
209.209a 209a) 3-Bromo-N'-hydroxybenzimi
209a) 3-Bromo-N'-hydroxybenzimi To a solution of 3-bromobenzonitrile in methanol was added hydroxylamine hydrochloride and sodium bicarbonate. The reaction mixture was heated to 65 °C for 3 h in a sealed microwave vessel. The reaction mixture was concentrated. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 x 5mL). The combined organic layer was dried over MgS04, filtered and concentrated to afford the title compound (292.6 mg, 1 .361 mmol, 124 % yield). LC-MS m/z 214.9 (M+H)+, 0.16 min (ret. time). |
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With hydroxylamine hydrochloride; potassium hydroxide In methanol at 60℃; |
Step 1: Preparation of amidoxime intemediates 22a-o
General procedure: A 1.0 M solution of hydroxylamine hydrochloride in MeOH (2.0eq) and a 1.0 M solution of KOH in MeOH (2.0 eq) were combined at 0°C and stirred for ~30 min (slowly warming from 0°C to rt). The potassium chloride salt formed was removed by filtration. The filtrate was added to the nitrile 21 [1.0 eq; the corresponding nitrile was either purchased from commercial source (analogs 21a-l and 21o), or synthesized starting from a commercial nitrile, which was further modified via a Suzuki coupling reaction using established methods (21m-n)] and the mixture was heated at 60°C for 17-24h. MeOH was removed under vacuum and the residue was diluted with EtOAc, washed with brine, and the organic layer was concentrated. The product 22 was typically obtained in quantitative yield and >90% purity, and was used in the next step without further purification. |
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With hydroxylamine hydrochloride; sodium carbonate In ethanol Sonication; |
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With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 50 - 60℃; for 8h; |
General procedure for Synthesis of amidoxime derivatives(1a to 1p)
General procedure: 0.01mol nitrile dissolved in 10 ml ethanol. After that, 0.011 mol hydroxylamine hydrochloride, 10 ml water and 1.23g sodium acetate was added as followed, stirred in room temperature for 0.5 h then refluxed in 50-60 for 8 h. The ethanol was mostly evaporated in vacuum and then the aqueous residue was extracted with CH2Cl2 three times. The combined organic layer was dried over MgSO4 and evaporated to dryness to afford the desired product. |
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With hydroxylamine In ethanol; water for 3h; Reflux; |
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With hydroxylamine In acetonitrile for 3h; Reflux; |
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| 10 g |
With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol at 70℃; for 16h; |
131 Synthesis of 3-bromo-N'-hydroxybenzimidamide (A-242)
To a solution of 3-bromobenzonitrile (10 g, 55.25 mmol) in ethanol (200 mL) was added hydroxylamine hydrochloride (11.45 g, 164.82 mmol) followed by DIPEA (29.25 mL, 164.82 mmol). The reaction mixture was heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated. The mixture was treated with water (100 mL) and extracted with ethyl acetate (2 x 150 mL). The organic layer was washed with brine (40 mL), dried over NaiSCL and concentrated to afford compound A-242 (10 g). It was used for the next step without further purification. |
| 1.05g |
With hydroxylamine hydrochloride; sodium hydrogencarbonate In methanol at 70℃; for 1h; |
141.a Example 141 (S)-2-(3-([1,1′-Biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonitrile
Step a. To a solution of 3-bromobenzonitrile (1.00 g, 5.49 mmol) in MeOH (10 ml) was added NaHCO3 (1.840 g, 22.0 mmol) followed by NH2OH.HCl (0.750 g, 11.0 mmol) at rt. The reaction mixture was heated at 70° C. for 1 h. The resulting reaction mixture was concentrated under vacuum. The obtained residue was diluted with ice cold water (50 ml). The resulting precipitates were collected by filtration and washed with water (25 ml). The resulting solid material was dried under high vacuum yielding 3-bromo-N′-hydroxybenzimidamide (1.050 g, 4.88 mmol). This material was used directly for the next step without further purification. LCMS: Method C, 1.386, MS: ES+215.10, 217.10 |
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With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol; water at 20℃; |
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With hydroxylamine hydrochloride; triethylamine In ethanol at 60℃; |
2.1. General procedure for the synthesis of amidoximes 1a-1r
General procedure: A mixture of benzonitrile (10 g, 97.0 mmol, 1.0 equiv.), hydroxylamine hydrochloride (145.5 mmol, 1.5 equiv.), triethylamine (145.5 mmol, 1.5 equiv.) in ethanol (100 ml) was stirred in a 250ml three-necked round-bottom flask at 60 °C for 6 hours. Reaction was monitored by TLC. When the reaction reached completion, reaction mixture was concentrated in vacuum with silica gel added. The residue was put on flash chromatography column (petroleum ether/ethyl acetate) to isolate the amidoxime 1, further purified via recrystallization. |
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