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CAS No. : | 22179-78-8 | MDL No. : | MFCD00216571 |
Formula : | C7H7FN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 154.14 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 38.49 |
TPSA : | 56.11 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.6 cm/s |
Log Po/w (iLOGP) : | 1.53 |
Log Po/w (XLOGP3) : | 0.9 |
Log Po/w (WLOGP) : | 1.55 |
Log Po/w (MLOGP) : | 1.97 |
Log Po/w (SILICOS-IT) : | 0.99 |
Consensus Log Po/w : | 1.39 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.63 |
Solubility : | 3.58 mg/ml ; 0.0232 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.66 |
Solubility : | 3.35 mg/ml ; 0.0217 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.23 |
Solubility : | 0.906 mg/ml ; 0.00587 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.42 |
Signal Word: | Danger | Class: | 8,6.1 |
Precautionary Statements: | P273-P280-P301+P310-P305+P351+P338-P310-P501 | UN#: | 2923 |
Hazard Statements: | H301-H314-H410 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In acetone at 25℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 0.5h; Inert atmosphere; | |
With 1,1'-carbonyldiimidazole 1.) DMF, 30 min, 2.) DMF, 25 deg C, 4 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydroxylamine In ethanol; water monomer Reflux; | |
96% | With hydroxyamino hydrochloride In water monomer; isopropanol at 100℃; for 0.0833333h; | |
89.57% | With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol at 85℃; for 4h; | 603.1 1. Synthesis of 4-fluoro-N-hydroxybenzene-1-carboximidamide 1. Synthesis of 4-fluoro-N-hydroxybenzene-1-carboximidamide Into a 250-mL round-bottom flask, was placed 4-fluorobenzonitrile (5.00 g, 41.28 mmol, 1 equiv), hydroxylamine hydrochloride (14.0 g, 201.47 mmol, 4.880 equiv), ethanol (150 mL) and N-ethyl-N-isopropylpropan-2-amine (27.0 g, 208.90 mmol, 5.060 equiv). The resulting mixture was stirred for 4 hours at 85° C. in an oil bath. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with methanol: ethyl acetate (1:10). This resulted in 5.70 g (89.57%) of 4-fluoro-N-hydroxybenzene-1-carboximidamide as a white solid. LC-MS (ES+): m/z 155.30 [MH]+, tR=0.60 min (2.00 minute run). |
89% | With hydroxyamino hydrochloride; potassium carbonate In ethanol at 20℃; for 16h; Inert atmosphere; | 8.1 First step: Preparation of 4-fluoro-N-hydroxybenzimide To a solution of Example 8-1 (4-fluorobenzonitrile) (0.500g, 4.13mmol) in ethanol (5mL) at room temperature was added hydroxylamine hydrochloride (0.427g, 6.19mmol) and potassium carbonate (1.14g, 8.26mmol). The reaction was stirred at room temperature for 16h. The reaction solution was concentrated, diluted with water, acidified with dilute hydrochloric acid, and extracted with DCM. The organic layer was dried and concentrated to obtain Example 8-2 (0.450 g, yield: 89%). |
87% | With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer for 1.5h; Reflux; | 4-Fluoro-N'-hydroxybenzimidamide (2b). A solution of 4-fluorobenzonitrile (2.42 g, 0.02 mol), hydroxylamine hydrochloride (5.56 g, 0.08 mol), sodium carbonate (4.24 g, 0.04 mol), water (50 mL) and ethanol (100 mL) was refluxed for 1.5 h. The reaction was allowed to cool and the ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 × 10 mL), the combined organic fractions were dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to afford 4-fluorobenzamidoxime (2b, 2.68 g, 87% yield) as a white solid, mp 97-99 °C (lit. 98-99 °C).1 1H NMR (DMSO-d6): δ 9.68 (s, 1H, OH), 7.74-7.70 (m, 2H, Ar), 7.22-7.17 (m, 2H, Ar), 5.88 (s, 2H, NH2). 13C{1H} NMR (DMSO-d6): δ 162.6 (d, J= 245.4 Hz), 150.2, 129.8 (d, J = 3.0 Hz), 127.6 (d, J = 8.4 Hz), 115.0 (d, J = 21.5 Hz). 19F NMR (DMF): δ -114.11. HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C7H8FN2O 155.0621; Found 155.0619. |
84.1% | With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer at 70℃; for 8h; | |
75.3% | With hydroxyamino hydrochloride; sodium hydroxide In ethanol; water monomer Reflux; | |
71% | With hydroxyamino hydrochloride; triethylamine In methanol at 20℃; Reflux; | 6 5.1.1. General procedure for the synthesis of N'-hydroxybenzimidamides 2a-2k General procedure: A solution of the appropriate cyanophenyl 1a-1k (0.1 mol), hydroxylamine hydrochloride (0.2 mol), and TEA (0.2 mol) in methanol was left under stirring at room temperature for 1 h, then heated under reflux until the disappearance of the starting materials (TLC analysis). After cooling, the solvent was evaporated to dryness under reduced pressure to give the crude, which was dissolved in ethyl acetate (400 mL) and washed with brine (3 100 mL) and dried with Na2SO4. The ethyl acetate was evaporated under reduced pressure to yield the compounds 2a-2k. |
71% | With hydroxyamino hydrochloride; triethylamine In methanol at 20 - 65℃; | 8 5.1.1 General procedure for the synthesis of N'-hydroxybenzimidamides 2a-2j General procedure: A solution of the appropriate cyanophenyl 1a-1j (0.1mol), hydroxylamine hydrochloride (0.2 mol), and TEA (0.2 mol) in methanol was stirred at room temperature for 1 h, then heated under reflux until the disappearance of the starting materials (TLC analysis). After cooling, the solvent was evaporated to dryness under reduced pressure to give the crude, which was dissolved in ethyl acetate (400 mL) and washed with brine (3×100 mL) and dried with Na2SO4. Ethyl acetate was evaporated under reduced pressure to yield the compounds 2a-2j. |
68% | With hydroxyamino hydrochloride; potassium carbonate In methanol for 6h; Reflux; | General procedure for the synthesis of N-hydroxy benzimidamide(amidoxime) (17): General procedure: A 1.3 g of a solution of 4-chorobenzonitrile (16v, 9.69 mmol, 1 equivalent) was dissolved in 50 mL of methanol. To this 2 g of K2CO3 (14.53 mmol, 1.5 equiv) was added and mixed properly. The reaction mixture was cooled at 0 °C, and 1.35 g of hydroxylamine hydrochloride (19.38 mmol, 2 equiv) was added in portion-wise. After completion of the addition, it was refluxed for 6 hr.Then evaporated the solvent and excess of water was added to afford the precipitate of the desired product which was filtered and dried. |
68.2% | With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer for 24h; Reflux; | |
66.5% | With hydroxyamino hydrochloride; potassium carbonate In ethanol at 20℃; for 12.5h; Reflux; | 4.1.1. Synthesis of the compound 2 series. General procedure: Hydroxylamine hydrochloride (200 mmol) and K2CO3(200 mmol) were dissolved in 200 mL of alcohol and stirred for30 min at room temperature. The corresponding nitriles (75 mmol)1 were added and the reaction mixture was heated to reflux for12 h. After filtration of inorganic salts, the solvent was evaporatedunder reduced pressure. The products 2 were purified by columnchromatography (petroleum ether/acetone, 2:1, v/v). |
66% | With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol for 6h; Reflux; | Preparation of amidoximes 1a-o. General procedure [1]. General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). |
63% | With hydroxyamino hydrochloride; sodium hydroxide In ethanol for 3h; Reflux; | 34.2 Step 2: 4-Fluoro-N’-hydroxybenzimidamide Step 2: 4-Fluoro-N'-hydroxybenzimidamide To a stirred solution of 4-fluorobenzonitrile (10 g, 82.5 mmol) in EtOH (71 mL) was added NH2OH.HCl (6.42 g, 92.1 mmol), followed by NaOH pellets (3.69 g, 92.1 mmol). The resulting reaction mixture was then heated at reflux for 3 h. The reaction progress was monitored by TLC using solvent system EtOAc:Hexane (1 : 1). After completion of reaction the solvent was evaporated under reduced pressure and the minimum amount of water (ca. 30 mL) was added to the residue. The mixture was extracted with dichloromethane (3 x 300 mL), dried over a2S04, and concentrated under vacuum. The crude compound obtained was recrystallized from hot toluene to obtain 8.0 g (63%) of 4-fluoro-N-hydroxybenzimidamide as a colorless solid. XH NMR (400 MHz, DMSO-d6): δ 9.6 (s, 1H), 7.07-7.67 (m, 2H), 7.18 (t, 2H, J=8.8Hz), 5.80 (br s, 2H); LC-MS m/z calculated for [M+H]+ 155.05, found 155.1. |
60% | With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer Reflux; | |
56.5% | With hydroxyamino hydrochloride; potassium carbonate In ethanol Reflux; | |
55% | With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer for 8h; Reflux; | |
51% | With hydroxyamino hydrochloride; anhydrous sodium carbonate In methanol; water monomer at 120℃; for 12h; Schlenk technique; Inert atmosphere; | |
With hydroxylamine In ethanol Heating; | ||
With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 150℃; for 0.2h; | ||
With hydroxyamino hydrochloride; anhydrous sodium carbonate In methanol; water monomer at 70℃; for 1h; | ||
With hydroxylamine monohydrate at 150℃; for 0.666667h; | ||
With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol Reflux; | ||
With hydroxylamine | ||
With hydroxyamino hydrochloride; anhydrous sodium carbonate In methanol; water monomer for 4h; Reflux; | ||
With hydroxyamino hydrochloride In ethanol; water monomer at 65℃; | 51; 52 Preparation of BB8: 4-Fluoro-N-hydroxy-benzamidine; To a solution of the 4-fluoro-benzonitrile (10.0 g, 52.9 mmol) in ethanol (200 mL), the solution of NH2OH-HCl (4.0 g, 58.2 mmmol) in H20 (4 mL) was added dropwise. The mixture was stirred vigorously at about 65 °C and stood overnight. The analysis by TLC indicated the complete consumption of starting material. The solution was concentrated to remove the solvent. The residue was dissolved in DCM and washed with water, brine, dried over Na2S04 and concentrated in vacuum to afford 4-Fluoro-N-hydroxy-benzamidine as pale- yellow solid (BB8). | |
With hydroxyamino 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]+. |
|
0.45 g | With hydroxyamino hydrochloride; potassium carbonate In ethanol at 20℃; | 18 4-Fluoro-N-hydroxybenzimidamide To a solution of 4-fluorobenzonitrile (0.500 g, 4.13 mmol) in ethanol (3 mL) was added hydroxyl amine HCl (0.427g, 6.19 mmol) and potassium carbonate (1.14g, 8.26 mmol). The reaction mass was stirred at RT for 15-17 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water, acidified with dilute HCl and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.450 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.84 (br s, 2H), 7.17-7.27 (m, 2H), 7.68-7.73 (m, 2H), 9.64 (br s, 1H); MS (m/z): 155.13 (M+H)+. |
With hydroxyamino hydrochloride; triethylamine In ethanol; water monomer 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. | |
With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol for 6h; Reflux; | ||
With hydroxyamino hydrochloride In ethanol for 8h; Reflux; | ||
With hydroxylamine; glacial 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. | |
With hydroxylamine for 4h; Reflux; | ||
With hydroxyamino hydrochloride; sodium hydroxide In ethanol; water monomer for 4h; Reflux; | General procedure for the synthesis of N'-hydroxy-4-substituted benzimidamide (2). General procedure: To the solution of NaOH (5.93 g, 0.15 mol) in water (20 mL) and ethanol (120 mL), hydroxylamine hydrochloride (10.33 g, 0.15 mol) was added in one portion at room temperature. The resulting mixture was then stirred for 10 min, followed by the addition of 4-substituted cyanobenzene (1, 0.12 mol) and then heated to reflux for 4 h. After cooled to room temperature, the reaction mixture was evaporated in vacuo to remove ethanol. The obtained slurry was dissolved in ethyl acetate and filtered. The filtrate was collected, dried over anhydrous Na2SO4, and then concentrated to give corresponding compound 2, which was used in next step without any purification. | |
With hydroxylamine In ethanol; water monomer for 3h; Reflux; Inert atmosphere; | ||
With hydroxyamino hydrochloride; anhydrous sodium carbonate | ||
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol for 4h; Reflux; | 3.1.2. Synthesis of Carboxamidine 7 General procedure: To a solution of nitrile 6 (3.3 mmol, 1.0 equiv) in EtOH (15 mL) was added hydroxylamine hydrochloride (4.0 mmol, 1.2 equiv) and NaHCO3 (6.6 mmol, 2.0 equiv). The mixture was refluxed for 4 h. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate (3 x 30 mL), washed with brine (1 x 30 mL), driedover anhydrous MgSO4, and concentrated. The residue was subjected to silica gel chromatography with EtOAc/MeOH (9:1) to make carboxamidine 7. | |
With hydroxylamine In ethanol; water monomer Reflux; | ||
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol Sonication; | ||
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol for 4h; | ||
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol at 80℃; | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol; water monomer 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. | |
With hydroxylamine In ethanol; water monomer for 3h; Reflux; | ||
With hydroxylamine In acetonitrile for 3h; Reflux; | ||
With hydroxylamine | ||
With hydroxyamino hydrochloride; sodium hydroxide In ethanol; water monomer at 40℃; for 16h; | 6; 61 A-16: A mixture of 4-fluorobenzonitrile (500 mg, 4.13 mmol), hydroxylamine hydrochloride (860.66 mg, 12.39 mmol) and NaOH (495.42 mg, 12.39 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated to remove most of EtOH, then diluted with EhO (15 mL). The mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over NaiSCL, filtered and concentrated to give the crude product (300 mg) as a solid. NMR (400MHz, CDCh) dH = 8.70 (s, 1H), 7.74 - 7.56 (m, 2H), 7.19 - 6.98 (m, 2H), 4.88 (s, 2H). | |
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol; water monomer at 20℃; | ||
With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol Reflux; | ||
With hydroxyamino hydrochloride; triethylamine In ethanol at 80℃; | General procedure for the preparation of benzamidoxime derivatives General procedure: The mixture of benzonitrile(1.0 mmol), Et3N (2.0 mmol) and NH2OHHCl (1.0 mmol)was heated in solvent ethanol (2 mL) at 80 C for the stipulated period. After completionof the reaction as monitored by TLC, the reaction mixture was added to ice waterand the product was filtered off, washed with water (22 ml) and dried to afford corresponding benzamidoxime derivatives | |
With hydroxyamino 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. | |
With hydroxyamino hydrochloride; potassium hydroxide In methanol at 20℃; Alkaline conditions; | ||
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol at 20℃; Reflux; | General procedure for synthesis of N-hydroxybenzamidine (5a-e) General procedure: To a solution of ethanol, added Na2CO3 (1.5 mol) followed by charged benzonitrile (0.20 mol) and hydroxylamine hydrochloride (1.5 mol) at ambient temperature the reaction mixture was slowly heat to refluxed for 5-6 h. (reaction progress was monitored by TLC). After completion of the reaction solvent was distilled under vacuum below 45 C, to the residue added ice cold water and stirred to get fine crystals and filtered to get a desired product (5a-e). | |
With hydroxyamino hydrochloride; sodium hydroxide In ethanol Reflux; | Synthesis of intermediates 1 General procedure: Hydroxylamine hydrochloride (4.0 g, 58.2 mmol) was addedto 30mL of EtOH in a 100mL three-necked bottle. About50% aqueous solution of sodium hydroxide (2.2 g,58.2 mmol) was then dropped into the reaction mixture atroom temperature. Benzonitrile (5.0 g, 48.5 mmol) or benzonitrilewith different substituents in ethanol (20 mL) was furtheradded to the above mixture. The mixture was heated toreflux and monitored with thin-layer chromatography(TLC). The precipitated product was removed by suction,and the filtrate was concentrated under reduced pressure. The residue was diluted with 20mL ethyl acetate, washedwith saturated brine and dried with anhydrous sodium sulfateto get intermediates 1, yield 80.0%92.0%. | |
With hydroxylamine In ethanol; water monomer at 70℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;benzotriazol-1-ol; In 1,4-dioxane; at 20℃; for 4h;Heating / reflux; | Example 60 (4-Fluoro-phenyl)- {2- [3- (4-fluoro-phenyl)- [1, 2,4] oxadiazol-5-yl]-morpholin-4-yl}- methanone; 60 (A) 2- [3- (4-Fluoro-phenyl)- [1, 2,4] oxadiazol-5-yl] -morpholine-4- carboxylic acid tert-butyl ester A mixture of (R, S)-N-Boc-2-carboxymorpholine (0.5 g, 2.16 mmol), N- hydroxy-4-fluoro-benzamidine (0.333 g, 2.16 mmol), EDCI. HC1 (0.621g, 3.24 mmol), HOBT (0.292 g, 2.16 mmol) and anhydrous triethylamine (605 mL, 4.32 mmol) in dioxane (7 mL) was stirred overnight at room temperature, under nitrogen atmosphere. The mixture was then refluxed for 4h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (15 mL) and water (15 mL) and the phases were separated. The organic layer was washed with NaOH IN (15 mL) and brine, dried over sodium sulphate and evaporated under reduced pressure. The crude was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 9/1) to afford 325 mg (yield: 43%) of 2- [3- (4-fluoro-phenyl)- [1, 2,4] oxadiazol-5-yl] - morpholine-4-carboxylic acid tert-butyl ester as a white oil. LCMS (Tr): 7.51 min (Method A); MS (ES+) gave m/z: 350. 1. 1H-NMR (CDC13, 300 MHz), 8 (ppm) : 8. 11 (dd, 2H) ; 7.16 (dd, 2H) ; 4.83 (dd, 1H) ; 4.27 (m br, 1H) ; 4.09 (m, 1H); 3.87 (m, 1H); 3.74 (ddd, 1H); 3.41 (m br, 1H); 3.23 (ddd, 1H) ; 1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In diethylene glycol dimethyl ether at 20 - 110℃; | R)-1- (3- (4-Fluorophenyl)-1, 2, 4-oxadiazol-5-yl)-2- (7-methyl-2- ( (2- (trimethylsilyl) ethoxy) methyl)-2H-indazol-5-yl) ethyl 4- (2-oxo-1, 2- dihydroquinolin-3-yl) piperidine-1-carboxylate; A stirred solution of (R)-3- (7-methyl-2- ( (2- (trimethylsilyl) ethoxy) methyl)-2H-indazol-5-yl)-2- (4- (2-oxo-1, 2- dihydroquinolin-3-yl) piperidine-1-carbonyloxy) propanoic acid (22.4 mg, 0. 0370mmol) in anhydrous diglyme (2 mL) was treated with 4- fluorobenzamidoxime (5.3 mg, 0.0389mmol) and 1- [3- (dimethylamino) propyl] 3- ethylcarbodiimide hydrochloride (7.5 mg, 0.0389 mmol) to at room temperature. The mixture was stirred overnight. The stirred mixture was then heated to 110° C overnight. After cooling to room temperature, the solvent was removed in vacuo and the crude product was purified using preparative HPLC to afford a tan gum (16.2 mg, 61%).'H-NMR (CDC13, 400 MHz) 8 8.8. 06 (bs, 2H), 7.88 (s, 1H), 7.69-7. 46 (m, 2H), 7.40 (s, 1H), 7.35-7. 20 (m, 2H), 7.18-7. 07 (m, 2H), 7.07 (s, 1H), 6.19-6. 15 (m, 1H), 5.79 (s, 2H), 4.40-4. 20 (m, 2H), 3.55-3. 40 (m, 4H), 3.20- 2.83 (m, 4H), 2.70 (s, 3H), 2.72-2. 35 (m, 2H), 2.08-1. 9 (m, 2H), 0.90-0. 77 (m, 2H), -0.11 (s, 9H). Mass spec. 723.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane at 20 - 100℃; for 43h; | 9.9(D) . 9(D) 2-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-yn )pyridine; A mixture of commercially available 4-fluoro-N'-hydroxybenzamidine (220 mg, 1.4 mmol), 5- (pyridin-2-yl)pent-4-ynoic (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HC1 (400 mg, 2.1 mmol) in dioxane (4.5mL) was stirred at R. T for 7H, The reaction mixture was then heated at 100°C for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, IN NaOH and water. The organic layer was dried over Na2S04, filtred and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH : 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4- fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1=ynyl)pyridine (Yield : 25%) as a yellow oil. LCMS (RT) : 3.99min; MS (ES+) gave m/z : 294.1 ¹NMR (CDC13), No. (ppm) : 8.64 (s, H), 8.10 (m, 2H), 7.68 (t, H), 7.41 (d, H), 7.27 (d, H), 7.21-7.14 (m, 2H), 3.32 (t, 2H), 3.07 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.3 mg (4.8%) | With pyridine; thionyl chloride; In benzene; | b) 5-(3-Bromo-furan-2-yl)-3-(4-fluoro-phenyl)-[1,2,4]-oxadiazole To a mixture of <strong>[14903-90-3]3-bromo-furan-2-carboxylic acid</strong> (0.700 g, 3.66 mmol) in anhydrous benzene (9 mL) was added thionyl chloride (0.9 mL) and the reaction mixture was heated at 60 C. for 6 h. The reaction mixture was concentrated to dryness (an oil) and then co-evaporated with hexane several times to yield a semi-solid. To the semi-solid was added 4-fluoro-benzamidoxime (0.147 g, 0.955 mmol) and pyridine (2 mL) and the solution was refluxed for 12 h. After cooling to room temperature, the solution was poured over water, and extracted by ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The compound was purified by column chromatography (3:1, hexane:ethyl acetate) and further purified by chromatography (3:1, hexane:ethyl acetate) to yield 14.3 mg (4.8%) of yellowish powder. 1H NMR (Acetone-d6): 8.21 (m, 2H), 8.07 (d, J=1.8 Hz, 1H), 7.39 (t, 2H), 7.03 (d, J=2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hypochlorite; triethylamine; In dichloromethane; at 20℃; for 3h; | Example 27; 3-(4-Fluoro-phenyl)-5-methyl-4,5-dihvdro-isoxazole-5-carboxylic acid (4- cvano-3-trifluoromethyl-phenyl)-amide; Compound No.95; EPO <DP n="91"/> 4-Fluorobenzamidoxime (1.39 g, 10 mmol) was mixed with triethylamine (200 mg, 2.0 mmol) and NaOCI (4%, 15 ml, 1.48 g, 10 mmol) in CH2CI2 (25 ml). N-(4-(Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (508 mg, 2.0 mmol) was added into the mixture and the mixture was then stirred for 3 hrs at room temperature. The reaction mixture was quenched by NaHCO3, and then extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield a crude product. Purification of the crude product on column (Hexane: ethyl acetate, 2:1 , Rf= 0.45) yielded the title compound as a white solid.1H NMR (CDCI3) delta 9.15 (s, 1 H), 8.15 (s, 1 H), 7.85 (dd, J=4.5 Hz, 0.2 Hz, 2H), 7.60 (m, 2H), 7.05 (m, 2H), 3.75 (dd, J=17.4Hz, 2.0 Hz, 2 H), 1.75 (s, 3H).MS (m/z): MH+ (392) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]pentanoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 4h; Stage #2: 4-fluoro-benzamidoxime In N,N-dimethyl-formamide at 85℃; for 22h; | 10 Example 10; 3-ButvM-l4-r3-(4-fluorophenylM.2.4-oxadiazol-5-vϖbutyl"}-8-(trifluoromethyl)-3J-dihvdro-1 H-purine-2,6-dione; 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]pentanoic acid(0.301g, O.δmmol) and CDI (0.153g, 0.94mmol) were dissolved in anhydrous dimethylformamide (10ml). After stirring the solution under nitrogen for 4h at room temperature 4-fluorobenzamido>cime (0.135g, 0.88mmol) was added and the solution heated at 850C for 22h. The reaction m ixture was concentrated in vacuo, taken up in ethyl acetate and washed with brine (2x20ml) and 0.1 N HCI. The organic phase was dried (MgSO4) and concentrated in vacuo to give the required product as a pale yellow oil which crystallised on standing. This material was freeze dried from dioxan to give the title compound as a cream lyophilate (0.225g, 57%). LC/MS: m/z 495 [MH]+, RT 3.77 rnin1H NMR (CDCI3) δH 0.97 (3H, t, J = 7Hz), 1.27 (2H, m), 1.77 (2H1 m), 1.87 (2H, m,), 1 .97 (2H, m), 3.02 (2H, t, J = 7Hz), 4.17 (4H, m,), 7.15 (2H, m, J = 9Hz), 8.04 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In 1,4-dioxane; at 20℃;Heating / reflux; | l (B) 5-[3-(4-Fluoro-phenyl)-[l,2,4]oxadiazol-5-yl]-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl esterA mixture of 5,6-dihydro-2H-pyridine-l,3-dicarboxylic acid 1-tert-butyl ester (3.66 mmol), 4-fluoro-N-hydroxy-benzamidine (0.565 g, 3.66 mmol), HOBT (0.495 g, 3.66 mmol), EDCLHCl (1.052 g, 5.49 mmol) and dry triethylamine (0.77 mL, 5.49 mmol) in dry dioxane (40 mL) was kept under stirring at ambient temperature for a week-end, under nitrogen atmosphere. The reaction mixture was then refluxed for 6h and the solvent was evaporated under reduced pressure. The residue was diluted with water (40 mL) and ethyl acetate (40 mL), the phases were separated and the organic layer was washed sequentially with water (40 mL, twice), IN NaOH (40 mL, twice) and with brine. The organic layer was dried over sodium sulphate and the solvent was removed under vacuum to give 1.3 g of a brown oil, that was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 8:2). 5-[3-(4-Fluoro-phenyl)- [l,2,4]oxadiazol-5-yl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester was obtained as a white solid (1.0 g).Yield: 79%; LCMS (RT): 7.05 min (Method C); MS (ES+) gave m/z: 345.9, 289.9; 1H-NMR (CDCl3), delta (ppm): 8.10 (dd, 2H); 7.22 (m, IH); 7.16 (dd, 2H); 4.41 (m, 2H); 3.60 (t, 2H); 2.44 (m, 2H); 1.51 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine for 3h; Heating / reflux; | 75 3-(4-fluorophenyl)-5-(pyridin-3-yl)-1 ,2,4-oxadiazole 4-Fluoro-N'-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.47 (t, J= 6.8 Hz, 2 H), 7.74-7.70 (m, 1 H), 8.20-8.15 (m, 2 H), 8.58-8.54 (m, 1 H), 8.91 -8.89 (dd, J= 1 .7, 1 .7 Hz, 1 H), 9.35 (d, J= 1 .4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+. | |
With pyridine for 3h; Reflux; | 75 4-Fluoro-N'-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-J6) δ 7.47 (t, J= 6.8 Hz, 2 H), 7.74-7.70 (m, 1 H), 8.20-8.15 (m, 2 H), 8.58-8.54 (m, 1 H), 8.91-8.89 (dd, J= 1.7,1.7 Hz, 1 H), 9.35 (d, J= 1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere; Reflux; | |
50% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20 - 60℃; for 2h; | 10 3 -(4-Fluorophenyl)-1,2,4-oxadiazol-5 (4H)-one 4-Fluoro-N'-hydroxybenzene-1-carboximidamide () (24.0 g) was dissolved in tetrahydrofuran (300 mL), N,N-diisopropylethylamine (54.2 mL) was added thereto, and a solution of triphosgene (18.5 g) in tetrahydrofuran (50 mL) was added dropwise thereto. The mixture was stirred at room temperature for 1 hour and further stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residues were dissolved in dichloromethane and extracted 3 times with a 1 M sodium hydroxide aqueous solution. The combined water layers were acidified with 1 M hydrochloric acid, and the precipitated solid was collected by filtration, washed with water, and dried at 50°C under reduced pressure, thereby obtaining 13.9 g (yield: 50%) of the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a suspension of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (3.9 g, 18.2 mmol) in 60 mL of dichloromethane was added N,N'-carbonyldiimidazole (4.4 g, 27.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then 4-fluoro-N'-hydroxybenzimidamide (5.0 g, 32.4 mmol) was added, followed by stirring at room temperature for 8 h. After this time, the mixture was concentrated in vacuo, diluted in 40 mL of toluene and stirred at reflux for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with 100 mL of ethyl acetate and washed with 30 mL of brine. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The resulting crude material was purified by flash chromatography over 330 g of silica gel (elution with 0-20% ethyl acetate in hexanes) to afford compound 17A (3.0 g, 9.1 mmol, 50%) as a white solid. LCMS (m/z)=331 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.0833333h; Stage #2: 4-fluoro-benzamidoxime In dichloromethane at 20℃; for 0.75h; Stage #3: With pyridine In toluene at 100℃; for 2h; | 177 4-[[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile Example 177 4-[[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile To a suspension of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine, Example 129B (0.050 g, 0.153 mmol) in CH2Cl2 (1.5 mL) was added EDCl (0.033 g, 0.169 mmol). After 5 min, 4-fluorobenzamidoxime (0.025 g, 0.161 mmol) was added and stirred at rt for 45 min. The mixture was concentrated and toluene (2 mL) and pyridine (0.5 mL) were added to the residue. The heterogeneous mixture was heated at 100° C. for 2 h. Upon cooling, the mixture was partitioned between EtOAc and 0.5N HCl. The organic phase was washed twice with 0.5N HCl, once with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc-hexanes gradient), followed by a second chromatography (10-100% CH2Cl2-hexanes gradient) to give the title compound (0.053 g, 78% yield): MS (ES) m/z 445 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: Z-Lys(Boc)-OH With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 1h; Stage #2: 4-fluoro-benzamidoxime With pyridine for 3h; Heating / reflux; | 292a.1 Example 292a; (S)-benzyl 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-5-(sulfamoylamino)pentyl-carbamate (338a) Step 1: (S)-tert-butyl 5-(benzyloxycarbonylamino)-5-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)pentylcarbamate (337a) The reaction was done following the procedure of S. Borg et al. (J. Org. Chem. 1995 60 3112-3120). The formation of the symmetric anhydride of (S)-2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)hexanoic acid was done by adding DCC (0.136 g, 0.657 mmol) to a 0° C. solution of (S)-2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)hexanoic acid (0.500 g, 1.314 mmol) in dichloromethane (5 mL). After 1 hour the resulting dicyclohexyl urea was filtered off and the filtrate concentrated to a white foam then it was redissolved in pyridine (5 mL) and a solution of the 4-fluoro-N'-hydroxybenzimidamide (0.125 g, 0.81 mmol) in pyridine (1 mL) was added. The reaction was then heated to reflux for 3 hours, pyridine was removed by under reduced pressure and the residue dissolved in ethyl acetate. It was then washed with 5% citric acid (aqueous), NaHCO3 (sat'd), brine, dried over anhydrous sodium sulfate, and then filtered and concentrated. The crude was then purified by silica gel chromatography (Biotage 12M, 20 to 50% ethyl acetate in hexanes) to give 337a (0.136 g, 42%) as a white white solid. LRMS (ESI): (calc) 498.2 (found) 521.3 (MNa)+. |
Stage #1: 4-fluoro-benzamidoxime; Z-Lys(Boc)-OH With dicyclohexyl-carbodiimide In dichloromethane Stage #2: With pyridine Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In N,N-dimethyl-formamide at 120℃; for 0.166667h; Sealed tube; Microwave irradiation; | General procedure for synthesis of 1,2,4-oxadiazole (2a-i) General procedure: To a solution of arylamidoximes 1a-i (1 mmol) in DMF (0.5 mL) dicyclohexylcarbodiimideDDC (1.5 or 2.0 mmol) was added. The mixture was irradiated in a closed vesselat 120 C and 150W for a specific time. The reaction was monitored each 5 min usingTLC (hexane:ethyl acetate 7:3). After it cooled, the residue was evaporated underreduced pressure. The crude material was purified using column chromatography on silicagel (eluents, hexane:EtOAc gradient from 8:2 to 7:3) to give the products 2a-i. |
at 150℃; for 3h; Molecular sieve; Neat (no solvent); | ||
In N,N-dimethyl-formamide for 0.166667h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.2% | Stage #1: 4-fluoro-benzamidoxime; chloroacetyl chloride In chloroform at 0℃; Stage #2: With triethylamine In chloroform at 20℃; | |
With potassium carbonate In acetone at 20℃; for 12h; | 13 5.1.12 General procedure for the synthesis of 5-(chloromethyl)-3-aryl -1,2,4-oxadiazoles 4a-4j General procedure: Potassium carbonate (13.8 g, 0.10 mol) was added to a solution of N′-hydroxybenzimidamides 2a-2j (0.10 mol) in dry acetone (250 mL). Chloroacetyl chloride (9.68 mL, 13.56 g, 0.12 mol) was added dropwise over a period of 1 h to the stirred reaction mixture, and the reaction was allowed to stir overnight at room temperature. Solvent was then removed under reduced pressure to give the product. This solid was dissolved in ethyl acetate (400 mL) and was partitioned once with water (100 mL). The organic layer was then washed with water (3×100 mL), brine (3×100 mL), dried over Na2SO4, and concentrated under reduced pressure to give the O-acyl products 3a-3j. The O-acyl adducts 3a-3j were added to 200 mL of toluene and were heated to reflux for 5 h. Removal of the solvent under reduced pressure gave the crude products, which were chromatographed on silica gel using ethyl acetate/petroleum ether as an eluent to afford the products 4a-4j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In benzene for 10h; Reflux; | 4.2.1.1. 5-(Chloromethyl)-3-phenyl-1,2,4-oxadiazole (3a) General procedure: A solution of chloroacetyl chloride (0.813 g, 7.2 mmol) in benzene (10 mL) was added dropwise to a solution of benzamidoxime (2a) (2.448 g, 18.0 mmol) in benzene (100 mL) and the mixture was heated under reflux for 10 h. The reaction was monitored by TLC. The reaction mixture was concentrated in vacuo, and the crude residue was purified by flash column chromatography (FCC) using n-hexane:ethyl acetate (2:1) mixture to give(3a) as a white solid (1.245 g, 89%). |
80% | In toluene at 50 - 110℃; for 24h; | 3-Aryl-5-(chloromethyl)-1,2,4-oxadiazoles 3a-3e(general procedure). General procedure: A flask equipped with a refluxcondenser was charged with 10 mmol of amidoxime2a-2e dissolved in 15 mL of toluene, the solution washeated to 50°C, and 15 mmol of chloroacetyl chloridewas added at 50°C. The mixture was stirred at 100-110°C for 24 h until the initial amidoxime disappeared(TLC), the solvent was distilled off under reducedpressure, and the residue was purified by flash chromatographyusing methylene chloride as eluent. |
66% | With N-ethyl-N,N-diisopropylamine In 1,1-dichloroethane at 0℃; Reflux; |
With triethylamine In benzene for 5h; Inert atmosphere; Reflux; | ||
In toluene at 0℃; for 4.25h; Reflux; | General procedure for the synthesis of 5-chloromethyl-3-aryl-1,2,4-oxadiazole (3). General procedure: To a solution of intermediate 2 (70.4 mmol) and toluene (30 mL) under stirring below 0 °C, was added dropwise the solution of chloroacetyl chloride (7.70 g, 68.1 mmol) in toluene (40 mL). The resultant mixture was stirred at 0 °C for 15 min and then heated to reflux for 4 h, the reaction was cooled and quenched by water (50 mL). Separated water phase was then extracted by toluene (3 × 40 mL). The combined organic layers were washed with brine (3 × 40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give product 3, which was used in next step without any purification. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane | ||
In benzene Reflux; | ||
With triethylamine In benzene Reflux; | ||
In toluene for 11h; Cooling with ice; Reflux; | Synthesis of intermediates 2 from 1 General procedure: Chloroacetyl chloride (6.6 g, 48.5 mmol) was added dropwise into the mixture of the intermediate 1 (5.5 g, 48.5 mmol)and 20mL of toluene in an ice bath, stirred for 1 h, and refluxed for 10 h at room temperature. When completed,removed the solvent, dichloromethane (20 mL) and brine(20 mL) were added to the residue. The collected organiclayer was dried and further purified to afford 2 by columnchromatography (ethyl acetate:petroleum ether 20:1) witha yield of 74.0-82.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole In dichloromethane for 12h; | 64.1 To a solution of (lS,3R)-3-(methoxycarbonyi)-l,2,2-trimethylcyclopentanecarbxylic acid (1 g, 9.35 mmol) in dichloromethane, carbonyldiimidazole(1.51 g, 9.34 mmol), 4- fluoroN'-hydroxybenzene carboximidamide(0.791 g, 5.14 mmol) were added and stirred for 12 h. After the completion of the reaction an aqueous NH4CI and dichloromethane was added. The organic layer separated, dried and concentrated. The residue obtained was dissolved in toluene and refluxed for 24 hours. The volatiles were removed under high vaccum, crude compound purified by column. Yield: 0.8 g; 1H NMR (400MHz, CDCl3) δ ppm: 0.64(s, 3H), 1.28(s, 3H), 1.36(s, 3H), 1.58-1.60(m, IH), 1.95-2.09(m, IH), 2.35-2.49(m, IH), 2.85-3.00(m, 2H), 3.75(s, 3H), 7.14-7.26(m, 2H), 8.07-8.1 l(m, 2H). m/z(M+H): 333.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole In dichloromethane; toluene at 20℃; for 48h; | 48.1 A solution of intermediate 6 (0.5 g, 1.84 mmol), carbonyldiimidazole (0.59g, 3.68 mmol) and 4-fluoro-N-hydroxybenzenecarboximidamide (0.284 g, 1.84 mmol) in dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was concentrated; toluene was added and refluxed of another 24 hours. Toluene was removed under reduced pressure, crude mixture purified by column using ethyl acetate 5% in hexane. 1H NMR (400MHz, CDCl3) δ ppm: 0.8 l(s, 3H)5 1.21(m, 3H), 1.44(s, 9H), 1.57(s, 3H)5 2.08-2.2(m, 4H), 3.3-3.37(m, IH), 7.13-7.26(m, 2H), 8.09-8.12(m, 2H. m/z(M+H-100): 290.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4,5-Dimethoxy-3-nitrobenzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: 4-fluoro-benzamidoxime In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide for 24h; Reflux; | General procedure for synthesis of 1 (2) Acid 8 (142.2 mg, 0.5 mmol) and CDI (Carbonyl diimidazole) (97.3 mg, 0.6 mmol) were dissolved in 3.0 mL of DMF and stirred at room temperature. After 30 min, amidoxime 7a (99.7 mg, 0.6 mmol) was added and the reaction mixture was heated under reflux for about 24 h (monitored by TLC). Then the mixture was poured into water (20.0 mL), extracted by CHCl3 (3X15.0mL), and the combined organic solvent was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica-gel chromatography to give a white solid product 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; | 1 Add 4-fluorobenzamidoxime (4.61 g, 29.93 mmol) to a 1M solution of potassium t-butoxide (27.6 mL, 27.63 mmol) in tetrahydrofuran. Add methyl 3-tert-butyl-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3-a]pyridine-7-carboxylate (6.07 g, 23.02 mmol) and stir overnight at room temperature. Dissolve the reaction in a 1 : 1 mixture of 50% saturated aqueous sodium bicarbonate and ethyl acetate. Separate layers and extract the aqueous layer with additional ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography (silica gel), eluting with first 25-100% ethyl acetate : hexane and then 5% methanol in ethyl acetate. Recrystallize fromdichloromethane and hexane to afford the title compound as a white solid (3.96 g). Mass spectrum (m/z): 342(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 16h; | 1 Add dropwise potassium tert-butoxide 1M in tetrahydrofuran (2.08 Kg, 2.08 mol) to a solution of ethyl 3-tert43Utyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyridine-7- carboxylate (455 g, 1.81 mol) and 4-fluorobenzamidoxime (320 g, 2.08 mol) in tetrahydrofuran (1 1 L) at room temperature. Stir the reaction mixture for 16 hours. Pour the mixture over a solution of saturated sodium bicarbonate (6 L) and add brine (3 x 2 L).Separate phases and extract aqueous phase with ethyl acetate (3 x 1 L). Combine organics, dry over magnesium sulfate, filter, and concentrate to dryness under reduced pressure. Purify the resulting residue by silica gel chromatography eluting with ethyl acetate to ethyl acetate : methanol (9: 1) to provide the title compound as a white solid(330 g). Mass spectrum (m/z): 342(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-cyano-4-(4-fluoro-piperidin-1-yl)-benzoic acid With trichloroacetonitrile; triphenylphosphine In tetrahydrofuran at 100℃; for 0.0833333h; Inert atmosphere; microwave irradiation; Stage #2: 4-fluoro-benzamidoxime With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 150℃; for 0.25h; microwave irradiation; Inert atmosphere; | 51; 52 Preparation of 5-[3-(4-Fluoro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-fluoro-piperidin-l-yl)- benzonitrile:; A solution of the 3-cyano-4-(4-fluoro-piperidin-l-yl)-benzoic acid BB6 (0.5 g x 18, 2 mmol) and CCI3CN (0.44 g x 18, 3 mmol) in dry THF (15 mL) was prepared and to this the Ph3P (1.58 g*18, 6 mmol) was added under protection of nitrogen at about 25 °C. The mixture was reacted in microwave add to abbreviation list at about 100 °C for about 5 min, then a solution of 4-fluoro- -hydroxy-benzamidine BB8 (0.34 g x 18, 2.2 mmol) and DIEA (0.52 g x 18, 4 mmol) was added. The mixture was reacted in MW at about 150 °C for about 15 min.The analysis by TLC showed the formation of desired product, which was purified by silica gel column chromatograph to afford 5-[3-(4-fluoro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4- fluoro-piperidin-l-yl)-benzonitrile as white solid (BB9). 1H NMR (400 MHz, DMSO) δ ppm 8.31 (1H, m), 8.19 - 8.17 (1H, m), 8.08 - 8.05 (2H, m), 7.41 - 7.36 (2H, m), 7.32 - 7.30 (1H, m), 4.97 - 4.85 (1H, m), 3.50 - 3.35 (4H, m), 2.07 - 1.91 (2H, m) and 1.89 - 1.85 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydrogencarbonate In ethanol at 60℃; for 2h; regioselective reaction; | Synthesis of chromeno [4, 3-d] pyrimidine 3-oxide derivatives (3a-n) General procedure: A solution of 4-chloro-3-formyl coumarin (1 mmol), hydroxybenzimidamide (1 mmol) and sodium bicarbonate (1 equivalent) in 5ml EtOH was heated at 60°C for 2h. After completion of the reaction the precipitate obtained was filtered and washed thoroughly with water and re-crystallized from ethanol to afford pure products 3a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (S)-1-(3-chloro-2-methylbenzoyl)piperidine-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 4-fluoro-benzamidoxime In 1,4-dioxane Inert atmosphere; | 8 4.2.4 General method of condensation and cyclization for 14a-h General procedure: A solution of 17 (0.55 g, 2.0 mmol) in dry 1,4-dioxane (20 mL) at room temperature was charged with HOBt (0.27 g, 2.0 mmol), DIPEA (3.0 mmol) and EDCI·HCl (0.58 g, 3.0 mmol). After 30 min, an amide oxime 19a-h (2.0 mmol) was added and the mixture was stirred until 17 had completely disappeared as monitored by LC-MS analysis. Then, the reaction mixture was refluxed overnight. After the solvent was removed, the solid residue was partitioned between EtOAc and water (1:1, 60 mL). The organic layer was separated, washed with water (15 mL) and 1 N NaOH (15 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (hexane/EtOAc = 2:1) provided target oxadiazole (14a-h) in 11-32% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: 4-fluoro-benzamidoxime With sodium hydride In tetrahydrofuran at 50℃; for 0.25h; Inert atmosphere; Stage #2: ethyl 2-hydroxy-2-(pyridin-4-yl)propanoate In tetrahydrofuran at 50℃; for 1h; | 34.3 Step 3: 1 -(3 -(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5 -yl)-l -(pyridin-4-yl)ethanol Step 3 : 1 -(3 -(4-Fluorophenyl)- 1 ,2,4-oxadiazol-5 -yl)- 1 -(pyridin-4-yl)ethanol Sodium hydride (60%, 6.00 g, 150 mmol) was taken up in THF (250 mL) under nitrogen atmosphere, and then a solution of 4-fluoro-N'-hydroxybenzimidamide (Step 2; 23.22 g, 150 mmol) in THF (250 mL) was added. The resulting reaction mixture was heated at 50°C for 15 min, and then a solution of ethyl 2-hydroxy-2- (pyridin-4-yl)propanoate (Step 1 ; 25 g, 120 mmol) in THF (250 mL) was added. The mixture was stirred for 1 hr at 50°C. The progress of reaction was monitored by TLC using solvent system EtOAc:Hexane (7:3). After completion of reaction, the solvent was concentrated to one third of the total volume. The crude mixture was poured into ice water and extracted with EtOAc (3 x 500 mL). The combined organic extract was dried over Na2S04 and concentrated under vacuum. The crude residue was washed with water several times to obtain a solid which was then washed with hexane (100 mL) followed by 50 mL of chilled ether to obtain 14 g (38%) of l-(3-(4- fluorophenyl)-l,2,4-oxadiazol-5-yl)-l-(pyridin-4-yl)ethanol as a colorless solid. HPLC purity: 99.4%; ¾ NMR (400 MHz, DMSO-d6): δ 8.58 (d, 2H, J=5.6Hz), 8.06- 8.03 (m, 2H), 7.51 (d, 2H, J=6.4Hz), 7.39 (t, 2H, J=8.8Hz), 7.09 (s, 1H), 1.96 (s, 3H); LC-MS m/z calculated for [M+H]+ 286.09, found 286.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With 2-hydroxy-4-methylbenzenesulfonic acid; zinc(II) chloride In N,N-dimethyl-formamide at 80℃; for 18h; | 2 5-[1-(2,4-dichlorophenoxy )ethyl ]-3-( 4-fluorophenyl)-1,2,4-oxadiazole (MBX-2667) To a solution of2-(2,4-dichlorophenoxy)propanenitrile (0.20 g, 0.93 mmol) in DMF (3 mL)were added 4-fluorobenzamidoxime (0.14 g, 0.93 mmol, 1.0 eq), p-toluenesulfonic acidhydrate (53 mg, 0.30 mmol, 0.3 eq), and ZnCh (38 mg, 0.30 mmol, 0.3 eq). The mixture washeated to 80 oc for 18 h, then cooled to room temperature and diluted with water (30 mL).The aqueous mixture was extracted with DCM (3 x 20 mL), dried over MgS04, filtered, and concentrated to residue. The crude material was purified by flash chromatography on silicagel ( 40 g) with a gradient of ethyl acetate/hexanes (0-30%). The product-containing fractionswere pooled and evaporated to provide 25 mg (8% yield) of white solid: 1H-NMR [300 MHz,CDCb]: d 8.11-8.05 (m, 2H), 7.40 (d, IH), 7.21-7.13 (m, 3H), 6.96 (d, 1H), 5.55 (q, 1H),1.92 (d, 3H); LCMS: 352.9 [M+1]; mp: 77-81°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.025 g | With zinc(II) chloride In N,N-dimethyl-formamide at 100℃; Inert atmosphere; | 30 3-(2-Chloro-6-fluorophenyl)-1-(4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5-yl)phenyl)-1H- 1 ,2,4-triazol-5(4H)-one To a solution of 4-fluoro-N-hydroxybenzimidamide (Intermediate- 18, 0.073 g, 0.47 mmol) in dry DMF (3 mL) under nitrogen atmosphere was added 4-(3-(2-chloro-6- fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (step-4 of Intermediate- 17, 0.100 g, 0.31 mmol) and ZnCl2 (0.0087 g, 0.06 mmol). The reaction mass was heated at 100°C for 8-10 h. The reaction mass was quenched with water, extracted in DCM and column purified to afford 0.025 g of desired product. 1HNMR (DMSO-d6): δ 7.02 (br s, 1Η), 7.33 (t, 1Η), 7.45-7.54 (m, 2Η), 7.61 (d, 1Η), 7.70 (m, 1Η), 7.83 (t, 1Η), 8.09-8.17 (m, 2Η), 8.26-8.30 (m, 2Η), 12.81 (br s, 1H).MS (m/z): 452.05 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.29 g | With N,N-dimethyl-formamide at 120℃; for 0.5h; | 2.2.1 Preparation of 3,5-bis(4-fluorophenyl)-1,2,4-oxadiazole (pFmOXD) General procedure: 4-fluorobenzoic acid (2.80g, 20.0mmol) and sulfurous dichloride (4.76g, 2.92ml, 40.0mmol) were added in a 100ml flask, then the mixture was stirred at room temperature for 10min, 76°C refluxed for 30min, stirred at 80°C for 3h. Redundant sulfurous dichloride was removed by reduced pressure distillation, then 4-fluorobenzoyl chloride was achieved. Then 4-fluoro-N′-hydroxybenzimidamide (3.00g, 19.46mmol) afforded before and 20ml DMF were added into the flask, and heated to 120°C stirred for 30min. After cooling to room temperature, the reaction mixture was dumped into ice water and filtered, washed with water. The crude material was purified by column chromatography with 1:3 (v/v) dichloromethane/petroleum ether as the eluent to give a white solid (4.29g). 83.2% yield. 1H NMR (400MHz, CDCl3) δ (ppm): 8.23-8.21(m, 2H), 8.19-8.15(m, 2H), 7.27-7.18(m, 4H). 13C NMR (CDCl3) δ (ppm): 174.91, 168.21, 166.81, 165.91, 164.27, 163.41, 132.87, 130.68, 130.59, 129.74, 129.65, 123.08, 120.62, 116.43, 116.19, 115.97, 115.61. MS (EI): m/z 258.29 [M+]. Anal. calcd for C14H8F2N2O (%):C 65.12, H 3.12, N 10.85; found: C 64.32, H 3.23, N 10.39. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethanol at 80℃; for 48h; | 1.2.6.6.iii Step Hi) [00325] TEA (0.383 mL, 2.75 mmol, 3 eq.) was added to a solution of the above prepared methylthiourea (300 mg, 0.917 mmol, 1 eq.) in 10 mL of EtOH, followed by 4-fluorobenzamidoxime (283 mg, 1.833 mmol, 2 eq.), then the reaction mixture was stirred at 80°C over 2 days. The reaction mixture was quenched by addition of a saturated NaHCOs solution (100 mL) and extracted with 20 mL of DCM three times. The organic phases were combined, dried over Na2S04 and concentrated in vacuo. The residue was purified by chromatography on silica gel (elution with DCM/MeOH: 100/0 to 95/5) to afford Intermediate Gen-5-ae. [00326] LC-MS: MW (calcd): 415 (79Br), 417 (81Br); m/z (obsd): 416 (79Br M+l), 418 (81Br M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 20℃; Combinatorial reaction / High throughput screening (HTS); | 4.1.2. Synthesis of the compound 3 series General procedure: Compounds in series 2 (20 mmol) were dissolved in 50 mL ofdistilled methanol under anhydrous conditions. 1.2 equiv of dimethylacetylenedicarboxylate(24 mmol) was added drop-wise withexternal cooling. The reaction mixture was stirred for 14 h at roomtemperature and then concentrated under vacuum. Brown oil (3)was obtained, which was used for the next step without furtherpurification. | |
In methanol at 0 - 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine at 20℃; for 0.5h; Reflux; | 21 5.1.16. General procedure for the synthesis of methyl 7-(3-aryl-1,2,4-oxadiazol-5-yl)heptanoate 4a-4k General procedure: To a solution of N'-Hydroxybenzimidamides 2a-2k (36 mmol) in dry pyridine (15 mL) was added methyl 8-chloro-8-oxooctanoate 3 (44 mmol) by dripping at room temperature over a period of 0.5 h. Then the mixture was heated to reflux for 3-6 h. After cooling to room temperature, the mixture was added ethyl acetate (100 mL) and was partitioned once with water (50 mL). The organic layer was then washed with 2 M HCl solution (2 50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude products, which were chromatographed on silica gel using ethyl acetate/petroleum ether as an eluent to afford the products 4a-4k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 1-bromomethyl-4-bromobenzene With potassium carbonate; dimethyl sulfoxide at 110℃; for 4h; Stage #2: 4-fluoro-benzamidoxime With dimethyl sulfoxide at 110℃; for 4h; | Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles derivatives 3a-h;general procedure General procedure: A mixture of benzyl bromide 1 (1 mmol) and K2CO3 (1.5 mmol) in dimethyl sulfoxide (DMSO) (1 mL) was stirred for 4 h at 110 °C. Then, benzamidoxime 2 (1 mmol) were added to the reaction mixture and stirring was continued at 110 °C for 4 h. The reaction mixture was cooled to room temperature and H2O (3 mL) was added. The precipitate was filtered, washed with H2O (2 mL) and dried. The crude products were purified by column chromatography using diethyl ether/ethyl acetate(5:1) as an eluent to give pure 3,5-diphenyl-1,2,4-oxadiazole 3a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tributyl-amine; tetraethylammonium chloride In N,N-dimethyl-formamide at 150℃; for 11h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tributyl-amine; tetraethylammonium chloride In N,N-dimethyl-formamide at 150℃; for 11h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-nitrobenzoic acid With 1,2-dichloro-ethane In acetone at 20℃; for 0.5h; Stage #2: 4-fluoro-benzamidoxime In acetone at 20℃; for 12h; | Typical proceduresfor the synthesis of O-acylamidoximes1a-w General procedure: a) To a mixture of the carboxylic acid (5 mmol) in acetone (20 mL) was added EDC (5.5 mmol). The reaction mixture was stirred at room temperature for 30 min, then the amidoxime (5 mmol) was added. The resulting mixture was stirred at room temperature for 12 h. Acetone was evaporated at reduced pressure and to the residue was added water (100 mL). The resulting precipitate was filtered off, washed with water (50 ml) and dried under vacuum at rt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With TEA In acetone at 0 - 20℃; for 12h; | Typical proceduresfor the synthesis of O-acylamidoximes1a-w General procedure: b) To a 0 °C mixture of amidoxime (5 mmol) and TEA (5.5 mmol) in acetone (20 mL) was added the acyl chloride (5.5 mmol). The reaction mixture was stirred at room temperature for 12 h. Acetone was evaporated at reduced pressure and to the residue was added water (100 mL). The resulting precipitate was filtered off, washed with water (50 ml) and dried under vacuum at rt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In neat (no solvent); at 100℃; for 6h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In neat (no solvent); at 100℃; for 6h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Stage #1: 7-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene; N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 90℃; for 1.5h; Stage #2: 4-fluoro-benzamidoxime In N,N-dimethyl-formamide at 110℃; for 5h; | 140A Example 140A 7rt-butyl 4-{3-[3-(4-fluorophenyl)-l,2,4-oxadiazol-5-yl]-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidin- 7-yl}piperidine-l-carboxylate To a solution of compound 7-[l-(tert-butoxycarbonyl)piperidin-4-yl]-5-oxo-4,5-dihydropyrazolo[l,5- a]pyrimidine-3-carboxylic acid (150 mg, 0.41 mmol) in 3 ml dimethylformamide was added 1,1 '- carbonyldiimidazole (134 mg, 0.83 mmol), DBU (148 mg, 0.97 mmol) and N,N-Diisopropylethylamin (107 mg, 0.83 mmol) and then the reaction mixture was stirred 1.5 h at 90 °C. After this time 4-fluoro- N'-hydroxybenzenecarboximidamide (127 mg, 0.83 mmol) was added and the mixture was stirred for 5 h at 110 °C. After cooling to RT, the mixture was diluted in 2 ml acetonitrile and purified by preparative HPLC (water/acetonitrile, 0.1% formic acid). After evaporation of acetonitrile from collected fractions the resulting solid in the aqueous fraction was filtered and dried overnight under vacuum to yield the title compound (33 mg, 16% of theory). LC-MS (method IB): RT = 1.19 min, m z = 481 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In tetrahydrofuran for 8h; Inert atmosphere; Reflux; | 8.2 Second step: Preparation of 5-(bromomethyl)-3-(4-fluorophenyl)-1,2,4-oxadiazole To a solution of Example 8-2 (308 mg, 2 mmol) in tetrahydrofuran (10 mL) was added bromoacetyl bromide (0.19 mL, 2.2 mmol) at room temperature. The mixture was heated to reflux and stirred for 8h. After cooling, the reaction solution was concentrated and purified by a flash silica gel column (petroleum ether/ethyl acetate=4/1) to obtain Example 8-3 (290 mg, yield: 57%). |
Stage #1: 4-fluoro-benzamidoxime; 2-Bromoacetyl bromide Stage #2: In toluene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In diethylene glycol dimethyl ether at 50 - 110℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 3Å molecular sieve In 1,2-dichloro-ethane at 20 - 70℃; for 35h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: indole-3-acetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.5h; Stage #2: 4-fluoro-benzamidoxime In dichloromethane for 2h; | 3.1.3. Synthesis of Carboxamidine 9 General procedure: To a solution of 3-indoleacetic acid (3.6 mmol, 1.0 equiv) in CH2Cl2 (20 mL), DIPEA (4.7 mmol,1.3 equiv) and HATU (3.6 mmol, 1.0 equiv) were added, and the reaction mixture was stirred for 30 min, then carboxamidine 7 (3.6 mmol, 1.0 equiv) dissolved in CH2Cl2 (10 mL) was added and stirred for 2 h. The mixture was filtered and the residue was washed with CH2Cl2, after which the solution was combined and concentrated. The residue was subjected to silica gel chromatography with petroleum ether/EtOAc (2:1) to give carboxamidine 9. |
Stage #1: indole-3-acetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.5h; Stage #2: 4-fluoro-benzamidoxime In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.59% | With acetic acid at 120℃; for 16h; | 603.2 2. Synthesis of 3-(4-fluorophenyl)-5-methyl-1,2,4-oxadiazole 2. Synthesis of 3-(4-fluorophenyl)-5-methyl-1,2,4-oxadiazole Into a 100-mL round-bottom flask, was placed 4-fluoro-N-hydroxybenzene-1-carboximidamide (5.70 g, 36.98 mmol, 1.0 equiv), acetyl acetate (54.1 g, 529.93 mmol, 14.3 equiv) and acetic acid (5 mL). The resulting solution was stirred for 16 hours at 120° C. in an oil bath. The reaction was then quenched by the addition of 150 mL of water. The pH value of the solution was adjusted to 7 with NaHCO3 solution. The resulting solution was extracted with ethyl acetate (30 mL*2) and the organic layers combined. The resulting mixture was washed with brine (30 mL*2). The mixture was dried over with anhydrous sodium sulfate and the solid was filtered out. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 6.10 g (92.59%) of 3-(4-fluorophenyl)-5-methyl-1,2,4-oxadiazole as a white solid. LC-MS (ES+): m/z 178.95 [MH]+, tR=1.18 min (2.00 minute run). |
at 130℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate; titanium(IV) oxide In tetrachloromethane; water at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydride; titanium(IV) oxide In tetrahydrofuran at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | 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%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | In acetone at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; 1,10-Phenanthroline; iodine; iron(II) chloride In chlorobenzene at 120℃; for 8h; | 2. General procedure for the synthesis of (2,4-diphenyl-1H-imidazol-5-yl)(phenyl)methanone 3ab General procedure: The reactions were carried out in a round-bottom sidearm flask (10 mL). 1a (0.2 mmol), 2b (0.4 mmol), FeCl2 (10 mol%), 1,10-phen (10 mol%), I2 (60 mol%), DMAP (1 eq) and PhCl (1 mL) were added to the flask with magnetic stirring bar. The resulting mixture was stirred at 120 °C for 8 h. After cooling to room temperature, the mixture was filtered and extracted with ethyl acetate (3×10 mL). Then the filtrate was concentrated under reduced pressure in order to get the crude product, which was further purified by silica gel chromatography (petroleum/ethyl acetate = 10/1 as eluent) to obtain product 3ab. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1,10-Phenanthroline; iron(III) chloride hexahydrate; potassium carbonate In toluene at 120℃; for 10h; | 2. General procedure for the synthesis of 2,4,6-triphenylpyrimidine 4ab General procedure: The reactions were carried out in a round-bottom sidearm flask (10 mL). 1a (0.2 mmol), 2b (0.4 mmol), FeCl3.6H2O (10 mol%), 1,10-phen (10 mol%), K2CO3 (2 eq) and Toluene (2 mL) were added to the flask with magnetic stirring bar. The resulting mixture was stirred at 120 °C for 10 h. After cooling to room temperature, the mixture was filtered and extracted with ethyl acetate (3×10 mL). Then the filtrate was concentrated under reduced pressure in order to get the crude product, which was further purified by silica gel chromatography (petroleum/ethyl acetate = 50/1 as eluent) to obtain product 4ab. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In dichloromethane at 20℃; for 4h; | General procedure for Synthesis of N,N-dimethyl-1,2,4-oxadiazol-5-amine derivatives (3a to 3t) General procedure: 0.002 mol amidoximes and 0.008 mol triethylamine dissolved in 10 ml dichloromethane. The solution was then instilled to 10 ml dichloromethane containing 0.004 mol Vilsmeier salt and stirred for 4 h . The whole progress was monitored by TLC and evaporated the solvent then followed by column chromatography column chromatography to get terminated material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 20h; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
118.3 mg | With fluorosulfonyl fluoride; triethylamine In dichloromethane at 20℃; for 2h; Schlenk technique; | |
With fluorosulfonyl fluoride; triethylamine In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 4-fluoro-benzamidoxime; (S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Stage #2: In 1,4-dioxane at 100℃; | General procedure B: Synthesis of compounds 137-157 General procedure: (4-Chlorophenyl)carbamoyl)-L-proline (115) (1.0 equiv), corresponding benzamidoxime (116-136) (1.0 equiv), EDCI (1.1 equiv), and HOAT (1.1 equiv) were dissolved in DCM (0.3 M) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Dioxane was added into the residue and the reaction mixture was heated at 100 °C overnight. After completion, the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed twice with water and once with brine. The combined organic layer was dried over MgSO4 and then evaporated under reduced pressure. The corresponding product was separated using silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride; 4-fluoro-benzamidoxime In dimethyl sulfoxide at 20℃; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; diastereoselective reaction; | Synthesis and characterization of 1,2,4-oxadiazoles-5-yl-acrylic acids 4a-o General procedure: To a solution of amidoxime 1 (1 mmol) in dry DMSO (1 mL) exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride 2 (182 mg, 1.1 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Then powdered NaOH (92 mg, 2.3 mmol) was rapidly added. After addition, the reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was diluted with CF3COOH (0.46 mL, 6 mmol) and stirred at 60-70 °C for 1 h. After cooling to the room temperature was diluted with cold water (5 mL), the precipitate was filtered, was with cold water (2 x 2 mL) and dried in air at 50 °C. The crude compound was recristallizated from Et2O or chromatographed on silica gel using CH2Cl2/MeOH (1 : 0.05) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 20℃; for 2h; | Methyl 3-[(amino(4-fluorophenyl)methylene)amino]oxy}acrylate (3b). An oven dried round bottom flask was loaded with methyl propiolate (1.01 g, 12 mmol) and DCM (40 mL), then 4-fluorobenzamidoxime (2b, 1.85 g, 12 mmol) and DABCO (0.14 g, 1.2 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through silica gel, which was additionally washed with DCM (300 mL). The combined organic fractions were evaporated under reduced pressure to afford the desired O-vinylamidoxime (3b, 2.14 g, 75% yield, E/Z = 9/1) as a pale yellow solid, mp 83-85 °C. 1H NMR (CDCl3) for E-isomer: δ 7.92 (d, J = 12.3 Hz, 1H, CH=CH), 7.68-7.64 (m, 2H, Ar), 7.13-7.09 (m, 2H, Ar), 5.71 (d, J = 12.3 Hz,1H, CH=CH), 5.08 (br s, 2H, NH2), 3.70 (s, 3H, Me); for Z-isomer: δ 7.68-7.64 (m, 2H, Ar, overlapped with the signal of E-isomer), 7.36 (d, J = 7.1 Hz, 1H), 7.13-7.09 (m, 2H, Ar, overlapped with the signal of E-isomer), 5.29 (br s, 2H, NH2), 4.92 (d, J = 7.1 Hz, 1H, CH=CH), 3.70 (s, 3H, Me, overlapped with the signal of E-isomer). 13C{1H} NMR (CDCl3) for E-isomer: δ 168.5, 164.4 (d, J = 251.2 Hz), 161.7, 154.5, 128.5 (d, J = 8.7 Hz), 127.1 (d, J = 3.2 Hz), 116.0 (d, J = 22.0 Hz), 96.4, 51.2. 19F NMR (DMF): δ -111.35. HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C11H12FN2O3 239.0832; Found 239.0827. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | Stage #1: 4-fluoro-benzamidoxime; propynoic acid methyl ester With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 80℃; for 0.25h; Microwave irradiation; Inert atmosphere; Stage #2: at 240℃; for 0.0333333h; Microwave irradiation; | General Procedure B: General procedure: An oven dried microwave vial was loaded with the desired amidoxime 2 (0.66 mmol) and DABCO (7.4 mg, 0.066 mmol), then methyl propiolate (55 mg, 0.66 mmol) in dry N,N-dimethylformamide (3 mL) was added under a nitrogen atmosphere. The reaction mixture was subjected to a two-stage microwave irradiation sequence (Stage 1: 80 °C, 15 min /Stage 2: 240 °C, 2 min). The mixture was concentrated under reduced pressure, the residue dissolved in ethyl acetate (20 mL), washed with water (2×10 mL) and dried over anhydrous Na2SO4. The residue after solvent evaporation was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to afford the desired imidazole 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 4-fluoro-benzamidoxime; (E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)acetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile for 1h; Stage #2: In toluene for 3h; Reflux; Stage #3: With lithium hydroxide monohydrate In tetrahydrofuran; water for 2h; | 4. General procedure for the synthesis of (E)-3-(4-((3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)phenyl)acrylic acid (9): General procedure: E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)acetic acid (15) (2 g, 8.47 mmol, 1 equiv) and hydroxybenzotriazole (HOBt) (1.44 g,8.47 mmol, 1 equiv) were slurried in dry acetonitrile (20 mL). Addition of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) (1.6 g, 8.47 mmol) to this mixture was done at room temperature. To this solution, 4-chloro-N-hydroxybenzimidamide (17v,1.45 g, 8.47 mmol, 1 equiv) was added and stirred for 1 h. The solvent evaporated to afford the intermediate product and to this toluene was added and refluxed for 3 h. The reaction mixture was partitioned with ethyl acetate and aqueous bicarbonate solution. Then dried the organic layer and concentrated to afford the crude product which was purified by recrystallization in DCM to afford the desired product. Later 1 g of crude product was directly hydrolyzed by dissolving in 20 mL of THF and a suspension of LiOH·H2O (0.12 g, 2.97 mmol, 1.1 equiv) in THF:water (6 mL, 1:1, v/v) was added and then stirred for 2 hr. TLC was analyzed , then the lithium salt of carboxylic acid was converted to the corresponding acid by neutralizing with dil. HCl (1 N). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In toluene at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1h; | General procedure for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and aldehydes in the superbasic system NaOH/DMSO. General procedure: A 10-mL flask was charged with 1 mmol of amidoxime which was dissolved in 1.5 mL of DMSO, and2.2 mmol of aldehyde 2 and 0.05 mmol (2 mg) ofpowdered sodium hydroxide were added each in oneportion. The mixture was stirred for 1 h, 1.75 mol(70 mg) of powdered sodium hydroxide was added,and the mixture was stirred for 21 h more. After completionof the reaction (TLC), the resulting suspensionwas diluted with 7 mL of distilled water, and theprecipitate was filtered off and washed with 2 mL ofwater. If a tarry material was formed, the supernatantwas separated by decanting, and the residue waswashed with three 2-4-mL portions of water. Theproducts were purified by chromatography usingacetone-toluene-petroleum ether (5:3:5) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.74 mg | Stage #1: 2-[(5-cyclopropyl-2-methylpyrazole-3-carbonyl)amino]propanoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 15℃; for 1h; Stage #2: 4-fluoro-benzamidoxime In N,N-dimethyl-formamide at 110℃; for 16h; | 6 8: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3- carbonyl)amino]propanoic acid (150 mg, 0.63 mmol) and CDI (112.77 mg, 0.70 mmol) in DMF (10 mL) was stirred at 15 °C for 1 hour and then 4-fluoro-N'-hydroxy-benzamidine (97.45 mg, 0.63 mmol) was added. The reaction mixture was then stirred at 110 °C for 16 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Agela DuraShell (150 mm x 25 mm, 5 pm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 40-80% B over 8.5 minutes) to give the product (40.74 mg, 114.60 pmol, 18% yield) as an oil. *H NMR (400MHz, CDCI3) 5H = 8.15 - 8.00 (m, 2H), 7.23 - 7.13 (m, 2H), 6.53 (d, 1H), 6.30 (s, 1H), 5.65 - 5.51 (m, 1H), 4.10 (s, 3H), 1.98 - 1.87 (m, 1H), 1.74 (d, 3H), 1.03 - 0.88 (m, 2H), 0.81 - 0.68 (m, 2H). LCMS Rt = 1.15 min in 2 min chromatography, 10-80AB, MS ESI calcd. for C18H19FN5O2 [M+H]+ 356.1, found 356.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
257 mg | Stage #1: L-N-Boc-Ala With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 25℃; for 1h; Stage #2: 4-fluoro-benzamidoxime In N,N-dimethyl-formamide at 70℃; for 16h; | 61 A-126: A mixture of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (736.52 mg, 3.89 mmol) and CDI (694.3 mg, 4.28 mmol) in DMF (10 mL) was stirred at 25 °C for 1 hour and then 4-fluoro-N'-hydroxy-benzamidine (600 mg, 3.89 mmol) was added. The reaction mixture was then stirred at 70 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by chromatography flash column on silica gel (EtOAc in PE = 0% to 40%) to give the product (257 mg, 0.80 mmol, 21% yield) as a solid. LCMS Rt = 0.90 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C11H11FN3O3 [M+H-/-Bu]+ 252.1, found 252.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.7% | Stage #1: 1‐(4‐methoxybenzyl)‐6‐[(4‐methoxybenzyl)oxy]‐3‐(trifluoromethyl)‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-fluoro-benzamidoxime In N,N-dimethyl-formamide at 20℃; for 120h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 4-fluoro-benzamidoxime; chloroformic acid ethyl ester With triethylamine In dichloromethane at 0 - 20℃; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
146 mg | With sodium hydroxide at 25℃; for 1h; | 2 Example 2: Add 122 mg of p-methoxybenzoic acid, 6 mL of acetonitrile, 200 mg of triethylamine, and 120 mg of methyl propiolate into a 100 mL eggplant-shaped flask equipped with a magnetic stirrer, and react for 30 min at 25°C.Add 188 mg of 4-fluoro-N-hydroxybenzamidine, 60 mg of sodium hydroxide, and react at 25°C for 60 min. After the reaction, 50 mL of water was added and filtered.The filter cake was washed with 5 mL of water. 3-(4-fluorophenyl)-5-phenyl-1,2,4-oxadiazole is obtained. 146mg.The yield was 53%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine In acetonitrile at 0 - 20℃; for 1.5h; | Synthesis of O-acylamidoximes 4a-i (General method) General procedure: A solution of acyl chloride 3- (6.37 mmol) inanhydrous MeCN (15 ml) at 0°C was added dropwise to a stirred mixture of amidoxime 1-f (6.37 mmol) and Et3N (0.64 ml, 6.37 mmol) in anhydrous MeCN (15 ml). The reaction mixture was stirred under the same conditions for30 min, then stirred for 1 h at 20°C and poured into cold water (150 ml), the white precipitate that formed was filtered off, washed with H2O, and dried at 80-90°. The product was crystallized from MeOH or EtOH. 4-Fluoro-N'-[(3-nitro-1H-pyrazol-5-yl)carbonyl]oxy}-phenylcarboxyimidamide (4a). Yield 1.14 g (61%),mp 226-228°C. IR spectrum, ν, cm-1: 3507, 3409, 3142,3046, 2942, 2839, 2756, 1735, 1629, 1607, 1570, 1538,1518, 1463, 1420, 1400, 1329, 1247, 1227, 1188, 1159,1098, 1003, 917, 849, 829, 754, 570, 480. 1H NMRspectrum, δ, ppm (J, Hz): 7.98 (1H, s, H-4 pyrazole); 7.81(2H, d, J = 7.4, H Ar); 7.33 (2H, d, J = 7.4, H Ar); 7.25(2H, br. s, NH2). 13C NMR spectrum, δ, ppm (J, Hz): 163.4(d, 1JCF = 246.6); 156.3; 155.5; 135.3; 129.4 (d, 3JCF = 8.9);127.0; 115.5 (d, 2JCF = 21.6); 104.6. Found, m/z: 294.0628[M+H]+. C11H9FN5O4. Calculated, m/z: 294.0633. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In water at 80℃; for 1h; | General procedure for the preparation of product 3a-3j General procedure: The mixture of amidoximes (1.0 mmol) and isothiocyanate (1.0 mmol) in water (2.0 mL)was stirred magnetically at 80 C for the stipulated period (1 (amidoximes) and 2 (isothiocyanates)both are organic compounds, they are soluble in the aqueous medium atheating conditions).After completion of the reaction as monitored by TLC, the reaction mixture wascooled to room temperature, excess water (30 mL) was added and extracted with ethyl acetate (230 mL) and the combined organic layer was washed with brine (30 mL),dried over Na2SO4 and solvent was evaporated under reduced pressure to get crude.Crude was purified by silica gel column chromatography using hexane and ethylacetate(10:1) as eluent to afford corresponding products 3a-3j |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With Imidazole hydrochloride In N,N-dimethyl-formamide at 120℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With Imidazole hydrochloride In neat (no solvent) at 100℃; for 6h; | 2.2. General procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles 3a-3r, 4a-4d, 5a-5c and 6a-6c. General procedure: A round-bottom flask was charged with benzamidoxime 1a (0.5 g, 3.67 mmol, 1.0 equiv.), N,N-dimethylacetamide (1 ml, excess), and imidazole hydrochloride (2.5 equiv.). The mixture was stirred at 100 °C for 6 hours. Reaction was monitored by TLC. When the reaction reached completion, a saturated solution of NaCl (20 ml) was added. After extraction of aqueous phase with ethyl acetate (3×50 mL), the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuum with silica gel added. The residue was separated by chromatography (petroleum ether/ethyl acetate 150:1) to obtain the desired product 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide; sodium carbonate at 110℃; for 13h; | [1,2,4]Triazolo[4,3-a]pyridines 3a-3l and 3,5-disubstituted 1,2,4-oxadiazoles 5a-5h (general procedure). General procedure: A 50-mL round-bottom flask was charged witha mixture of styrene 2a-2m (0.23 g), 2-hydrazinylpyridine(1) or benzamidoxime 4a or 4b (0.20 g), TBAI(1 equiv), TBHP (10 equiv), and Na2CO3 (1 equiv),and the mixture was stirred at 110 (oil bath) for 13 h.After completion of the reaction (TLC), the mixturewas cooled to room temperature, treated with water(10 mL), and extracted with ethyl acetate. The organicextract was dried over anhydrous Na2SO4, the solventwas evaporated under reduced pressure, and the crudeproduct was purified by column chromatography on100-200 mesh silica gel using hexane-ethyl acetate aseluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: (1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; Stage #2: 4-fluoro-N'-hydroxybenzimidamide In dichloromethane at 20℃; | General method of the synthesis of O-acylamidoximes 5a-t. General procedure: (+)-Ketopinic acid 4 (300 mg, 1.65 mmol, 1.0 eq.) and N,N'-carbonyldiimidazole (CDI) (320 mg, 1.98 mmol, 1.2 eq.) were dissolved in CH2Cl2 (10 ml), and the solution was stirred at room temperature for 3-5 h in the air atmosphere. Then, the corresponding amidoximes 2a-t (1.98 mmol, 1.2 eq.) were added to the solution and stirred at room temperature for 8-10 h in the air atmosphere until complete conversion of the starting acid 4 (the progress of the reaction was monitored by TLC; eluent was CHCl3). Then, the solution was concentrated to a minimum volume on a rotary evaporator and purified by column chromatography (SiO2, CHCl3). As a result, the target compounds 5a-t were obtained in 40-90% yields as white powders. |
55% | Stage #1: (1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; Stage #2: 4-fluoro-N'-hydroxybenzimidamide In dichloromethane at 20℃; | General method of the synthesis of O-acylamidoximes 5a-t. General procedure: (+)-Ketopinic acid 4 (300 mg, 1.65 mmol, 1.0 eq.) and N,N'-carbonyldiimidazole (CDI) (320 mg, 1.98 mmol, 1.2 eq.) were dissolved in CH2Cl2 (10 ml), and the solution was stirred at room temperature for 3-5 h in the air atmosphere. Then, the corresponding amidoximes 2a-t (1.98 mmol, 1.2 eq.) were added to the solution and stirred at room temperature for 8-10 h in the air atmosphere until complete conversion of the starting acid 4 (the progress of the reaction was monitored by TLC; eluent was CHCl3). Then, the solution was concentrated to a minimum volume on a rotary evaporator and purified by column chromatography (SiO2, CHCl3). As a result, the target compounds 5a-t were obtained in 40-90% yields as white powders. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; zinc(II) chloride In N,N-dimethyl-formamide at 80℃; for 12h; | 24 (Example 24) (24g) (-)-Methyl (4R∗,8R∗)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate (-)-Methyl (4R∗,8R∗)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate Methyl (4R∗,8R∗)-10-cyano-2-[(methylcarbamoyl)amino]-4,7,8,9-tetrahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-6(5H)-carboxylate (150 mg) of Example 24 (24f) was dissolved in N,N-dimethylformamide (2 mL), 4-fluoro-N'-hydroxybenzen-1-carboximidamide () (89.4 mg), zinc chloride (12.2 mg), and a tosylic acid monohydrate (15.4 mg) were sequentially added thereto at room temperature, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was purified by high performance liquid chromatography [column: Waters Xbridge; mobile phase: acetonitrile/10 mM ammonium hydrogen carbonate aqueous solution = 21/79 to 51/49 (V/V)], thereby obtaining 31.4 mg (yield: 15%) of the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In dimethyl sulfoxide at 20℃; | General procedure for synthesis of 5-(5-aryl-1-phenyl1H-pyrazol-3-yl)-3-aryl-1,2,4-oxadiazole (6a-o) General procedure: A solution of N′-hydroxy substituted benzimidamide (5a-e) (0.01 mol) NaOH (0.01 mol) and 5-aryl-1-phenyl-1H-pyrazole-3-carboxylate (3a-c) (0.011 mol) in DMSO (5 mL) was stirred for 2-4 h at ambient temperature. After the completion reaction (reaction progress was monitored by TLC), the reaction mixture was quenched in water and extracted with ethyl acetate (3 × 25 mL). The combined organic layer was dried over anhydrous sodium sulphate and distilled on rotary evaporator. The crude product was purified on column chromatography using ethyl acetate: hexane (3:7) as eluent furnished 5-(5-aryl-1-phenyl-1H-pyrazol3-yl)-3-aryl-1,2,4-oxadiazole (6a-o) (yield: 60-70%) (Table-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In dimethyl sulfoxide at 20℃; | General procedure for synthesis of 5-(5-aryl-1-phenyl1H-pyrazol-3-yl)-3-aryl-1,2,4-oxadiazole (6a-o) General procedure: A solution of N′-hydroxy substituted benzimidamide (5a-e) (0.01 mol) NaOH (0.01 mol) and 5-aryl-1-phenyl-1H-pyrazole-3-carboxylate (3a-c) (0.011 mol) in DMSO (5 mL) was stirred for 2-4 h at ambient temperature. After the completion reaction (reaction progress was monitored by TLC), the reaction mixture was quenched in water and extracted with ethyl acetate (3 × 25 mL). The combined organic layer was dried over anhydrous sodium sulphate and distilled on rotary evaporator. The crude product was purified on column chromatography using ethyl acetate: hexane (3:7) as eluent furnished 5-(5-aryl-1-phenyl-1H-pyrazol3-yl)-3-aryl-1,2,4-oxadiazole (6a-o) (yield: 60-70%) (Table-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In dimethyl sulfoxide at 20℃; | General procedure for synthesis of 5-(5-aryl-1-phenyl1H-pyrazol-3-yl)-3-aryl-1,2,4-oxadiazole (6a-o) General procedure: A solution of N′-hydroxy substituted benzimidamide (5a-e) (0.01 mol) NaOH (0.01 mol) and 5-aryl-1-phenyl-1H-pyrazole-3-carboxylate (3a-c) (0.011 mol) in DMSO (5 mL) was stirred for 2-4 h at ambient temperature. After the completion reaction (reaction progress was monitored by TLC), the reaction mixture was quenched in water and extracted with ethyl acetate (3 × 25 mL). The combined organic layer was dried over anhydrous sodium sulphate and distilled on rotary evaporator. The crude product was purified on column chromatography using ethyl acetate: hexane (3:7) as eluent furnished 5-(5-aryl-1-phenyl-1H-pyrazol3-yl)-3-aryl-1,2,4-oxadiazole (6a-o) (yield: 60-70%) (Table-1). |
Tags: 22179-78-8 synthesis path| 22179-78-8 SDS| 22179-78-8 COA| 22179-78-8 purity| 22179-78-8 application| 22179-78-8 NMR| 22179-78-8 COA| 22179-78-8 structure
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P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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