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CAS No. : | 3619-17-8 | MDL No. : | MFCD00025122 |
Formula : | C4H10N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PLNNJQXIITYYTN-UHFFFAOYSA-N |
M.W : | 102.14 | Pubchem ID : | 19239 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 27.05 |
TPSA : | 55.12 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.37 cm/s |
Log Po/w (iLOGP) : | 1.04 |
Log Po/w (XLOGP3) : | -0.63 |
Log Po/w (WLOGP) : | -0.37 |
Log Po/w (MLOGP) : | 0.01 |
Log Po/w (SILICOS-IT) : | -0.9 |
Consensus Log Po/w : | -0.17 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.06 |
Solubility : | 116.0 mg/ml ; 1.14 mol/l |
Class : | Highly soluble |
Log S (Ali) : | -0.05 |
Solubility : | 90.0 mg/ml ; 0.881 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.27 |
Solubility : | 55.0 mg/ml ; 0.538 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 4.1 |
Precautionary Statements: | P210-P240-P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362-P370+P378-P403+P233-P501 | UN#: | 1325 |
Hazard Statements: | H228-H302-H315-H319-H335 | 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 |
---|---|---|
65.6% | With hydrazine hydrate In ethanol for 7 h; Reflux | Ethyl isobutyrate (58.0 g, 0.5 mol) reacted with excess50percent hydrazine hydrate (110 mL) under reflux for 7 h. Thesolvent was removed by distillation under vacuum, and thecrude product was purified by recrystallisation using ethanolto yield isobutyrohydrazide (3). Yield: 65.6percent. |
61% | With hydrazine hydrate In ethanol for 4 h; Reflux | A mixture of compound 24-3 (20 g, 172.18 mmol) and hydrazine hydrate (20 mL, 514.5mmol, 25.73 mol/L) in ethanol (30 mL) was refluxed for 4 hours. After the reaction wascomplete, the mixture was cooled to rt and concentrated in vacuo to afford a white solid 24-4(10.7 g, 61percent). MS (ESI, pos.ion) m/z: 103[M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With hydrazine In methanol at 60℃; Heating / reflux | A7. General Method for the Synthesis of 2-Aminooxadiazoles; Step 1. Isobutyric Hydrazide; A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60° C. for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, 10percent), which was used in the next step without further purification. |
10% | With hydrazine In methanol at 60℃; for 336 h; Heating / reflux | A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60 °C for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, 10percent), which was used inb the next step withour further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Inert atmosphere; Reflux; | |
With ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.6% | With hydrazine hydrate In ethanol for 7h; Reflux; | Ethyl isobutyrate (58.0 g, 0.5 mol) reacted with excess50% hydrazine hydrate (110 mL) under reflux for 7 h. Thesolvent was removed by distillation under vacuum, and thecrude product was purified by recrystallisation using ethanolto yield isobutyrohydrazide (3). Yield: 65.6%. |
61% | With hydrazine hydrate In ethanol for 4h; Reflux; | 24 preparation of compound 24-4 A mixture of compound 24-3 (20 g, 172.18 mmol) and hydrazine hydrate (20 mL, 514.5mmol, 25.73 mol/L) in ethanol (30 mL) was refluxed for 4 hours. After the reaction wascomplete, the mixture was cooled to rt and concentrated in vacuo to afford a white solid 24-4(10.7 g, 61%). MS (ESI, pos.ion) m/z: 103[M+1]. |
With hydrazine |
With hydrazine hydrate | ||
With hydrazine In ethanol for 3h; Heating; | ||
With hydrazine hydrate Yield given; | ||
90 % Turnov. | With hydrazine hydrate In ethanol for 5h; Heating; | |
With hydrazine hydrate In butan-1-ol at 80℃; for 5h; | 12.1 First, 2.40 g of ethyl isobutyrate, 10 mL of 1-butanol, and 1.05 g of hydrazine monohydrate (ΝΗ2ΝΗ2·Η2θ) were put in a 100 mL three-neck flask, and heated and stirred at 80 °C for 5 hours to be reacted. Then, 5.0 g of N-[(ethylsulfanyl)(4-fluorophenyl)methylidene]-2,6-dimethylaniline was added to this mixed solution, and heated and stirred at 130 °C for 22 hours to be reacted. Further, 0.96 g of isobutyric acid hydrazide was added to this mixed solution, and heated and stirred at 130 °C for 15 hours to be reacted. After the reaction, 1-butanol was distilled off under a reduced pressure. The resulting residue was purified by silica gel column chromatography. Ethyl acetate was used as a developing solvent. The resulting fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of toluene and hexane, so that4-(2,6-dimethylphenyl)-3-(4-fluorophenyl)-5-isopropyl-4H-l,2,4-triazole (abbreviation: HiPrFptz-dmp) was prepared (a white solid, yield: 11 %). The synthetic scheme of Step 1 is shown by (a-11). | |
With hydrazine hydrate for 15h; Reflux; | 112.1 Ethylisobutyrate (5g, 0.043 mol) and hydrazine monohydrate (3.2g, 0.065 mol) were heated to reflux for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was treated with toluene(3 x 100ml) to azeotrope hydrazine in excess. The crude residue was used for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol | ||
With potassium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 53h; Heating / reflux; | A.A7.2 Step 2. 2-Amino-5-isopropyl oxadiazole; To a mixture of isobutyric hydrazide (0.093 g), KHCO3 (0.102 g), and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 g). The resulting mixture was heated at the reflux temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH2Cl2 (5 mL). The organic layer washed with water (2×10 mL), dried (MgSO4) and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 ((M+H)+). | |
With potassium hydrogencarbonate In 1,4-dioxane; water at 20℃; Reflux; | A7.2 Step 2. 2-Amino-5-isopropyl oxadiazole To a mixture of isobutyric hydrazide (0.093 g), KHCO3 (0.102 g), and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 g). The resulting mixture was heated at the reflux temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH2Cl2 (5 mL). The organic layer was washed with water (2*10 mL), dried (MgSO4) and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 ((M+H)+). |
With potassium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 48h; Heating / reflux; | A.A7.2 To a mixture of isobutyric hydrazide (0.093 g), KHCO3 (0.102 g), and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 g). The resulting mixture was heated at the reflux temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH2Cl2 (5 mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO4) and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 ((M+H)+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol Heating; | ||
In ethanol for 4h; Reflux; | ||
In dimethyl sulfoxide at 25℃; for 1h; | 2. General procedure for the synthesis of 2-amino-1,3,4-oxadiazole derivatives (3a-p, 4a-h) General procedure: A solution of benzoylhydrazine (0.20 g, 1.5 mmol) and phenylisothiocyanate (0.20 g, 1.5 mmol) in DMSO (3 mL) was stirred atroom temperature for 1 h. Then, KHSO4 (1.19 g, 8.75 mmol) wasdirectly added to the stirred solution at the room temperature andreacted for another 6 h. After the completion of the reactionmonitored by TLC, the solution was diluted with 30 mL water, andthe resulting precipitate was separated by filtration or extractedwith EA, concentrated and dried. The residue was purified by columnchromatography on silica gel with petroleum ether/ethyl acetateto afford the target product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate In water for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol at 70℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With benzoic acid In tetrahydrofuran for 12h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane | |
90% | With triethylamine; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | |
0.26 g | With triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With acetic acid In methanol at 25℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In various solvent(s) at 160℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In various solvent(s) at 160℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With hydrazine hydrate for 5h; Heating; | |
10% | With hydrazine In methanol at 60℃; Heating / reflux; | A.A7.1 A7. General Method for the Synthesis of 2-Aminooxadiazoles; Step 1. Isobutyric Hydrazide; A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60° C. for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, 10%), which was used in the next step without further purification. |
10% | With hydrazine In methanol at 60℃; for 336h; Heating / reflux; | A.A7.1 A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60 °C for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, 10%), which was used inb the next step withour further purification. |
With hydrazine hydrate for 28h; Heating; | ||
With hydrazine hydrate | ||
With hydrazine In methanol at 60℃; Reflux; | A7.1 Step 1. Isobutyric Hydrazide: A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60° C. for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, 10%), which was used in the next step withour further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With diphenyl ether-biphenyl eutectic at 155℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With diphenyl ether-biphenyl eutectic at 155℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With diphenyl ether-biphenyl eutectic at 155℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With diphenyl ether-biphenyl eutectic at 155℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester; isobutyric acid hydrazide With triethylamine In dichloromethane at 18 - 25℃; for 18h; Stage #2: With trichlorophosphate In acetonitrile at 80℃; for 16h; Stage #3: With sodium hydrogencarbonate In water; ethyl acetate; acetonitrile | Then, isobutyrohydrazide (0.30 g, 2.95 mmol) was added to a mixture of this oil, triethylamine (0.75 mL, 5.37 mmol) and DCM (10 mL) , and the mixture was stirred for 18 h at room temperature. The mixture was washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo. A mixture of the residue, phosphorus oxychloride (0.28 mL, 2.95 mmol) and CH3CN (10 mL) was stirred at 800C for 16 h.After cooling, the mixture was diluted with AcOEt, washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo. The residue was purified by chromatography on silica (hexanes/AcOEt 2/1) to give trans- methyl 4- (5-isopropyl-l, 3, 4-oxadiazol-2- yl) cyclohexanecarboxylate (0.40 g, 60%) as colorless crystals: 1H NMR (400 MHz, CDCl3) δ 1-37 (6H, d, J = 7.2 Hz), 1.50-1.70 (4H, m), 2.08-2.18 (2H, m) , 2.18-2.28 (2H, m) , 2.37 (IH, m) , 2.85 (IH, m) , 3.15 (IH, m) , 3.69 (3H, s) ; m/z (APCI pos) 253.1 (100%) [M+H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester; isobutyric acid hydrazide With triethylamine In dichloromethane at 18 - 25℃; for 18h; Stage #2: With Lawessons reagent In toluene at 100℃; for 16h; | Isobutyrohydrazide (0.30 g, 2.95 mmol) was added to a mixture of the oil, triethylamine (0..75 mL, 5.37 mmol) and DCM (10 mL) , and the mixture was stirred for 18 h at room temperature. The mixture was washed with water and brine, dried and concentrated in vacuo. To the residue, in toluene (10 mL) , was added Lawesson's reagent (0.65 g, 1.61 mmol) and the mixture was stirred at 1000C for 16 h. After- cooling, the mixture was diluted with AcOEt, washed with saturated aqueous NaHCC>3 and brine, dried and concentrated in vacuo. The residue was purified by chromatography on silica (hexanes/AcOEt 2/1) to give trans-methyl 4- (5-isopropyl-l, 3, 4-thiadiazol-2- yl) cyclohexanecarboxylate {0.23 g, 32%) as colorless crystals: 1H NMR (400 MHz, CDCl3) δ 1 • 42 (6H, d, J = 6.8 Hz), 1.52-1.68 (4H, m) , 2.06-2.20 (2H, m) , 2.20-2.32 (2H, m) , 2.38 (IH, m) , 3.11 (IH, m) , 3.43 (IH, m) , 3.69 (3H, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 18 - 25℃; for 16h; | A mixture of 5- (methoxycarbonyl) picolinic acid (0.50 g, 2.62 mmol), isobutyrohydrazide (0.30 g, 2.88 mmol), EDAC-HCl (0.75 g, 3.93 mmol), HOBt-H2O (0.60 g, 3.93 mmol) and triethylamine (0.73 mL, 5.24 mmol) in CH3CN (20 mL) was stirred for 16 h at room temperature. The mixture was diluted with AcOEt, washed successively with IN HCl, saturated aqueous NaHCtheta3 and brine, dried and concentrated in vacuo to give methyl 6- (N' -isobutyrylhydrazinocarbonyl) nicotinate (0.51 g, 73 %) as yellow solid. 1H NMR (400MHz, CDCl3) delta 1.27 (6H, d, J=6.8 Hz), 2.57 (IH, m) , 3.99 (3H, s), 8.22 (IH, d, J=8.0 Hz), 8.38-8.50 (2H, m) , 9.17 (IH, d, J=2.0 Hz), 10.29 (IH, s); m/z <n="199"/>(APCI pos) 266.0 (100 %) (M+H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at 20℃; for 24h; | tert-butyl[3-(N'-isobutyryl-hydrazino)-3-oxo-propyl]-carbamate 25.00 g (132 mmol) 3-tert-butoxycarbonylamino-propionic acid, 13.50 g (132 mmol) isobutyric acid hydrazide, 50.91 g (159 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 50 ml diisopropylethylamine are stirred in 500 ml of tetrahydrofuran/dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is extracted with ethyl acetate and 10% potassium hydrogen carbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallised from toluene/isopropylether. |
46% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at 20℃; for 24h; | tert-butyl[3-(N'-isobutyryl-hydrazino)-3-oxo-propyl]-carbamate 25.00 g (132 mmol) 3-tert-butoxycarbonylamino-propionic acid, 13.50 g (132 mmol) isobutyric acid hydrazide, 50.91 g (159 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 50 ml diisopropylethylamine are stirred in 500 ml of tetrahydrofuran/dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is extracted with ethyl acetate and 10% potassium hydrogen carbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallised from toluene/isopropylether. Yield: 16.55 g (46% of theoretical) |
46% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at 20℃; for 24h; | tert-butyl [3-(N'-isobutyryl-hydrazino)-3-oxo-propyl]-carbamate 25.00 g (132 mmol) 3-tert-butoxycarbonylamino-propionic acid, 13.50 g (132 mmol) isobutyric acid hydrazide, 50.91 g (159 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 50 ml diisopropylethylamine are stirred in 500 ml of tetrahydrofuran/dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is extracted with ethyl acetate and 10% potassium hydrogen carbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallised from toluene/isopropylether. Yield: 16.55 g (46% of theoretical) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | In various solvent(s) at 160℃; for 0.5h; | |
27% | Stage #1: 2,4-dichloro-N-ethyl-1,8-naphthyridine-3-carboxamide; isobutyric acid hydrazide With diphenyl ether-biphenyl eutectic at 160℃; for 0.5h; Stage #2: With sodium carbonate In dichloromethane; water at 20℃; for 0.5h; | 5.1.4 N-substituted-5-chloro-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 6a,c,d and N-substituted-5-hydroxy-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 7a,c,d General procedure: A mixture of 8.0mmol of 5a (2.05g) or 5c (2.27g) or 5d (2.27g), 12.0mmol (1.23g) of isobutyrohydrazide and 10mL of Dowtherm A was stirred at 160°C for 30min. After cooling, 10% aqueous Na2CO3 (50mL) and CH2Cl2 (50mL) were added and the mixture was further stirred at room temperature for 30min. After discarding some insoluble impurities by filtration, the mixture was transferred in a separatory funnel, then the organic layer was collected and the aqueous one was exhaustively extracted with CH2Cl2. The combined extracts were dried (anhydrous Na2SO4) then evaporated to dryness at reduced pressure, and the residue was chromatographed on a silica gel column eluting first with CH2Cl2 to remove Dowtherm A. Then the column was eluted with the mixture CH2Cl2-EtOAc (1:1), affording small amounts of the 5-hydroxyderivatives 7; the subsequent elution with the mixture CH2Cl2-EtOAc-acetone (2:1:1) gave the desired compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 50℃; for 0.5h; | 8.1 Step 1 5-(3-Isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4'-methyl-biphenyl-3-carboxylic acid methyl ester The isobutyric acid hydrazide used in this example was prepared from isobutyric acid chloride and hydrazine hydrate following the procedure of Org. Synth. Vol. 81 p. 254 (2005). Isobutyric acid hydrazide (55 mg, 5.34 mmol) and 1,1-dimethoxy-ethyl)-dimethyl-amine (774 mg, 5.81 mmol) were added to 6 mL CH3CN and the mixture was heated to 50° C. and stirred for 30 minutes. 5-Amino-4'-methyl-biphenyl-3-carboxylic acid methyl ester (1.0 g, 4.15 mmol) was added, followed by 6 mL of acetic acid. The reaction mixture was heated to 120° C. and stirred for five hours, then cooled to room temperature. Solvent was removed under reduced pressure and the residue was purified via flash chromatography to give 400 mg (30%) of 5-(3-Isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4'-methyl-biphenyl-3-carboxylic acid methyl ester as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C36H43N3O7S; isobutyric acid hydrazide With 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 0℃; Stage #2: With triphenylphosphine In carbon tetrabromide; 1,2-dichloro-ethane at 20℃; | CycIoprop[*nindolo[2,l-«H2]benzazepine-5-carboxamide, 8-cyclohexyl- l,lfl,2,12^-tetrahydro-ll-methoxy-l«-[[4-[5-(l-methylethyl)-l,3,4-oxadiazol-2- ylj-l-piperidinyljcarbonyll-λ'-tCl-methylethyOsulfonyl]-. To a solution of the acid (35.1 mg, 0.053 mmol) in 1 ,2-dichloroethane (1 mL) at 0 0C was added 1,1'- carbonyldiimidazole (9.45 mg, 58.3 umol). After 30 min, isobutyrohydrazide (5,41 nig, 53 umol) was added. The coupling was allowed to proceed at 0 0C for 45 min, and then CBr4 (35.2 mg, 106 umol) and Ph3P (27.8 mg, 106 umol) were added in one portion. The mixture was stirred at room temperature overnight. The product was purified by preparation HPLC; MH+ = 728.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 2,4-dichloro-N-ethyl-N-methyl-1,8-naphthyridine-3-carboxamide; isobutyric acid hydrazide In diphenylether; biphenyl at 160℃; for 0.5h; Stage #2: With sodium carbonate In diphenylether; biphenyl; dichloromethane; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: (2,4-dichloro-1,8-naphthyridin-3-yl)-(4-methyl-1-piperazinyl)-methanone; isobutyric acid hydrazide In diphenylether; biphenyl at 160℃; for 0.5h; Stage #2: With sodium carbonate In diphenylether; biphenyl; dichloromethane; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); (R)-(-)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; sodium hydrogencarbonate In N,N-dimethyl-formamide at 100℃; for 60h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: (1R,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid; isobutyric acid hydrazide With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran at 120℃; for 0.25h; microwave irradiation; | 12 Example 12Preparation of Compounds 16 and 17To a solution of Compound 2C (150 mg, 0.56 mmoi) in 5 ml_ DMF was added isobutyric acid hydrazide (152 mg, 1.48 mmoi), DIPEA (0.26 mi, 1.48 mmol) then HATU (563 mg, 1.48 mmol). The resulting reaction was allowed to stir at room temperature for 4 hours, after which time it was diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo and the residue obtained was taken up in 5 mL THF and PS-BEMP (2.2 mmo. base/g, 1.3g, 2.8 mmol). To the resulting solution was added p-toluenesulfonyl chloride (130 mg, 0.67 mmol) and the resulting reaction was heated to 120 °C under microwave irradiation for 15 minutes. After cooling to room temperature the reaction mixture was filtered through celite and the collected solid was washed three times with ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue was purified using flash coiumn chromatography (10-20% acetone in hexanes) to provide Compound 16A (120 mg, 63% yleld).Compound 16A was converted to Compounds 16 and 17 using the method described in Example 2. LCMS: 501 (M+H)*. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In 1,1-dichloroethane at 20℃; for 16h; | 28 To a solution of 1-(5-(2-phenyl-5-(trifluoromethyl)oxazole-4- carboxamido)pyridin-2-yl)piperidine-4-carboxylic acid (46 mg, 0.10 mmol) in dichloroethane (2 ml.) was added isobutyrohydrazide (15.3 mg, 0.15 mmol), triethylamine (31 mg, 0.31 mmol) and Mukaiyama resin (Varian Polymer Lab.. 0.20 mmol). The reaction mixture was agitated at room temperature for 16 h. Trisamine resin (Argonaut Tech. Inc., 0.40 mmol) and isocyanate resin (Argonaut Tech. Inc., 0.60 mmol) were added. The reaction mixture was agitated at room temperature for 16 h. The reaction mixture was filtered. The organic solvent was evaporated under reduced pressure to yield the desired N-(6-(4-(2-isobutyrylhydrazinecarbonyl)piperidin-1 -yl)pyridin-3-yl)-2-phenyl-5- (trifluoromethyl)oxazole-4-carboxamide (54) (53 mg, 0.097 mmol) which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In toluene at 60 - 70℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | In butan-1-ol at 130℃; for 26.5h; | 20.4 N-[(3-bromophenyl)(ethylsulfanyl)methylidene]-2,6-dimethylaniline that was prepared in Step 3 described above and 50 mL of 1-butanol were put in a 100 mL three-neck flask, and stirred. Further, 2.72 g of isobutyric acid hydrazide was added to this mixed solution, and heated and refluxed at 130 °C for 14 hours. After that, 1.36 g of isobutyric acid hydrazide was further added, and heated and refluxed at 130 °C for 12.5 hours. After the reflux, 1-butanol was distilled off to give a residue. This residue was purified by silica gel column chromatography. Ethyl acetate was used as a developing solvent. The resulting fraction was condensed to give a solid. This solid was recrystallized from a mixed solvent of ethyl acetate and hexane, so that 3-(3-bromophenyl)-5-isopropyl-4-(2,6-dimethylphenyl)-4H-l,2,4-triazole was prepared (white powder, yield: 16 %). The synthetic scheme of Step 4 is shown by (d-17). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol at 130℃; for 22h; | 12.1 First, 2.40 g of ethyl isobutyrate, 10 mL of 1-butanol, and 1.05 g of hydrazine monohydrate (ΝΗ2ΝΗ2·Η2θ) were put in a 100 mL three-neck flask, and heated and stirred at 80 °C for 5 hours to be reacted. Then, 5.0 g of N-[(ethylsulfanyl)(4-fluorophenyl)methylidene]-2,6-dimethylaniline was added to this mixed solution, and heated and stirred at 130 °C for 22 hours to be reacted. Further, 0.96 g of isobutyric acid hydrazide was added to this mixed solution, and heated and stirred at 130 °C for 15 hours to be reacted. After the reaction, 1-butanol was distilled off under a reduced pressure. The resulting residue was purified by silica gel column chromatography. Ethyl acetate was used as a developing solvent. The resulting fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of toluene and hexane, so that4-(2,6-dimethylphenyl)-3-(4-fluorophenyl)-5-isopropyl-4H-l,2,4-triazole (abbreviation: HiPrFptz-dmp) was prepared (a white solid, yield: 11 %). The synthetic scheme of Step 1 is shown by (a-11). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | In xylene at 150℃; for 0.25h; Microwave irradiation; | 112.2 A suspension of tert-butyl (1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1 H-pyrido[2,3- b][1 ,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (150 mg, 0.308 mmol) andisobutyrohydrazide (28mg, 0.308 mmol) in p-xylene (1.5 ml) was heated to 150°C for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (28 mg, 17%). LCMS (Method D): RT = 1.497 min, M+1 = 538. NMR (500 MHz, CDCI3) δ 7.85 (1 H, s), 7.36-7.31 (5H, m), 7.28 (2H, m), 7.24- 7.19 (2H, m), 5.56 (2H, s), 3.46- 3.36 (1 H, m), 2.57-2.39 (4H, m), 2.13-2.02 (1 H, m), 1.88-1.76 (1 H, m), 1.57- 1.53 (6H, d), 1.44-1.29 (9H, bs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 46.1 Step 1.(2R,5S)-6-(benzyloxy)-N'-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (194) Step 1. (2R,5S)-6-(benzyloxy)-N'-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (194) To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added 2-methylpropanehydrazide 193 (0.14 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N'-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 194 (0.30 g, 92.6%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.12 (6H, m), 1.60 (1H, m), 1.94 (2H, m), 2.29 (1H, m), 2.47 (1H, q, J=6.8 Hz), 3.06 (1H, d, J=12.0 Hz), 3.18 (1H, d, J=11.6 Hz), 3.30 (1H, s), 3.99 (1H, d, J=7.2 Hz), 4.90 (1H, d, J=10.8 Hz), 5.04 (1H, d, J=11.2 Hz), 7.40 (5H, m), 8.07 (1H, br s), 8.61 (1H, br s). |
92.6% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 46.1 (2R,5S)-6-(benzyloxy)-N’-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added 2-methylpropanehydrazide 193 (0.14 g, 1.35 mmol,), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N'-(2-methylpropanoyl)-7-oxo-1 ,6- diazabicyclo[3.2.1]octane-2-carbohydrazide 194 (0.30 g, 92.6%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.12 (6H, m), 1.60 (1 H, m), 1.94 (2H, m), 2.29 (1 H, m), 2.47 (1 H, q, J = 6.8 Hz), 3.06 (1 H, d, J = 12.0 Hz), 3.18 (1 H, d, J = 11.6 Hz), 3.30 (1 H, s), 3.99 (1 H, d, J = 7.2 Hz ), 4.90 (1 H, d, J = 10.8 Hz), 5.04 (1 H, d, J = 11.2 Hz), 7.40 (5H, m), 8.07 (1 H, br s), 8.61 (1 H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In dichloromethane at 20℃; for 3h; | To a solution of isobtrtyrie acid h dr te (353 mg, 1.50 mmoi) and M (0.58 mL, 4,16 mmoi) in CftCL (3 mL) was added a solution of com ound (510 mg, 1.00 mmoi) m CC (5.0 mL}. The teaetion mixture was stirred at room temperatare for 3 h The reaction mixture was then extracted with EtOAc and washed with 1 HQ am brine. The organic extracts were dried over 0*. filtered, and concentrated. The residue was purified by flash chromatography (silica gel 0% to 100% EtOAc m liexsmes) to give compound 4 (525 mg. 91%) as a white solid; m 576.4 (M ?). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol for 4h; Reflux; | General procedure: To a stirred solution of aryl isothiocyanate (4) (0.02 mol)in ethanol (20 mL), the isobutyrohydrazide (3) (2.0 g, 0.02mol) in hot ethanol (20 mL) was added dropwise. Afterrefluxing for 4 h, the mixture was cooled down, and theresidue 5 was separated by filtering off the solution in vacuo.To a solution of the residue 5 in ethanol (20 mL), 2N sodiumhydroxide solution (20 mL) was added. After 4h of stirringunder refluxing, the mixture was cooled and diluted with icewater. Concentrated hydrochloric acid was used to adjust pHto 6, and the precipitated solid was collected, washed withwater. The crude product was further purified by recrystallisationfrom ethanol to obtain compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol for 4h; Reflux; | General procedure: To a stirred solution of aryl isothiocyanate (4) (0.02 mol)in ethanol (20 mL), the isobutyrohydrazide (3) (2.0 g, 0.02mol) in hot ethanol (20 mL) was added dropwise. Afterrefluxing for 4 h, the mixture was cooled down, and theresidue 5 was separated by filtering off the solution in vacuo.To a solution of the residue 5 in ethanol (20 mL), 2N sodiumhydroxide solution (20 mL) was added. After 4h of stirringunder refluxing, the mixture was cooled and diluted with icewater. Concentrated hydrochloric acid was used to adjust pHto 6, and the precipitated solid was collected, washed withwater. The crude product was further purified by recrystallisationfrom ethanol to obtain compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol for 4h; Reflux; | General procedure: To a stirred solution of aryl isothiocyanate (4) (0.02 mol)in ethanol (20 mL), the isobutyrohydrazide (3) (2.0 g, 0.02mol) in hot ethanol (20 mL) was added dropwise. Afterrefluxing for 4 h, the mixture was cooled down, and theresidue 5 was separated by filtering off the solution in vacuo.To a solution of the residue 5 in ethanol (20 mL), 2N sodiumhydroxide solution (20 mL) was added. After 4h of stirringunder refluxing, the mixture was cooled and diluted with icewater. Concentrated hydrochloric acid was used to adjust pHto 6, and the precipitated solid was collected, washed withwater. The crude product was further purified by recrystallisationfrom ethanol to obtain compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium methylate In methanol at 20℃; chemoselective reaction; | N′-(7-Amino-5H-pyrrolo[3,4-b]pyrazin-5-ylidene)carbohydrazides 3a-m; General Procedure General procedure: To a stirred solution of the respective acid hydrazide (3.5 mmol) in anhydrous MeOH (30 mL) was added NaOMe (0.35 mL, 1 N solution in MeOH). After 5 min, pyrazine-2,3-dicarbonitrile (1; 0.46 g,3.5 mmol) was added in one portion and the stirring was continued for 0.5-1.5 h at r.t. The precipitate formed was collected by filtration, washed with hexane (5 mL), recrystallized from MeOH or EtOH, and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium methylate In methanol Reflux; chemoselective reaction; | N′-(3-Amino-1H-pyrrolo[3,4-b]quinoxalin-1-ylidene)carbohydrazides 4a-k; General Procedure General procedure: Quinoxaline-2,3-dicarbonitrile (2; 0.63 g, 3.5 mmol) was dissolved by heating in anhydrous MeOH (30 mL) and the corresponding acidhydrazide (3.5 mmol) and NaOMe (0.35 mL, 1 N solution in MeOH) were added. The resulting mixture was refluxed with stirring for 4-6 h. After cooling, the precipitate formed was collected by filtration and washed with MeOH (5 mL). Recrystallization fromMeOH, EtOH, or DMF afforded 4a-k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | With potassium hydroxide In methanol; water at 60℃; for 10h; | 6 Preparation of Intermediate Using Dimethylcarbonate(DMC)/KOH 102 g (1.0 mole) of Iso-butyric acid hydrazide, 300 ml of methanol and 0.15 mole of KOH (45% aqueous solution) were mixed in a four-neck flask reactor equipped with a reflux condenser, and 100 g (1.05 equivalent) of dimethylcarbonate (DMC) was slowly added thereto with strong stirring. Then, a reaction temperature was maintained for 10 hours up to 60° C. and the reaction was completed. After the reaction was completed, the reactant was cooled up to room temperature. Methanol used as the reaction solvent and methanol produced as a side-product was concentrated by vacuum-evaporation to be crystallized. After the obtained solid was filtered, the obtained cake was washed with water twice and dried. The obtained solid was a hydrazine carboxylic acid 132 g (yield 82.5%) having a purity of 98.5 area% by GC as a light yellow solid and an intermediate, which was possible to be directly used in a next reaction without additional purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide In dichloromethane; water at 10 - 20℃; Dean-Stark; | 1 Preparation of Intermediate Using Methylchloroformate (MCF)/NaOH/MC EXAMPLE 1 Preparation of Intermediate Using Methylchloroformate (MCF)/NaOH/MC 204 g (2.0 mole) of Iso-butyric acid hydrazide, methylene chloride (MC) 600 ml and 170 g (2.1 mole) of 50% of NaOH aqueous solution were mixed in a four-neck flask reactor equipped with a Dean-Stark trap. The obtained mixture was cooled at a temperature of 10° C. or less and 190 g (1.0 equivalent) of methylchloroformate (MCF) was slowly added thereto for 3 to 5 hours while controlling temperature with strong stirring. When the addition was completed, a reaction temperature was maintained by controlling it from 10° C. up to room temperature and the reaction was complete. After the reaction was completed, the stirring was stopped, followed by layer-separation, thereby separating an organic layer (MC) positioned in a lower portion of the flask reactor, and the separated organic layer was washed twice with water 600 ml. Then, the obtained organic layer was concentrated to obtain a hydrazine carboxylic acid 314 g (yield 98%) having a purity of 99 area % by GC as an intermediate, which was possible to be directly used in a next reaction without additional purification. |
98% | With sodium hydroxide In dichloromethane; water at 10 - 20℃; Dean-Stark; | 1 Preparation of Intermediate using Methyl Chloroformate (MCF)/NaOH/MC 204 g (2.0 mole) of isobutyric acid hydrazide, 600 ml of methylene chloride (MC) and 170 g (2.1 mole) of 50% NaOH aqueous solution were mixed in a four-neck flask reactor equipped with a Dean-Stark trap. The obtained mixture was cooled to 10° C. or less and 190 g (1.0 equivalent) of methyl chloroformate (MCF) was slowly added to the mixture over 3 to 5 hours with strong stirring while slowly controlling temperature. Afier completion of addition, the resulting material was maintained at a reaction temperature ranging from 10° C. to room temperature to complete the reaction. Afier completion of the reaction, stirring was stopped, followed by layer separation to separate an organic layer (MC) placed at a lower portion of the flask reactor. The separated organic layer was washed with 600 ml of water twice. Then, the obtained organic layer was concentrated, whereby 314 g (yield: 98%) of hydrazine carboxylic acid (purity: 99.54 area% by HPLC) was obtained as an intermediate. The obtained intermediate could be directly used in subsequent reaction without additional purification and had a melting point of 81°C. to 89°C. FIG. 1 is a graph depicting H-NMR data of a product obtained in Example 1, and it could be seen that the analysis data was the same as data of a standard product (hydrazine carboxylic acid). The following shows NMR data thereof: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With trichlorophosphate; at 100℃; for 18h; | 5-Bromo-3-(5-isopropyl-[l,3,4]oxadiazol-2-yl)-pyridin-2-ylamine: To a solution of 2-amino-5-bromo-nicotinic acid (1.0 g, 4.60 mmol) in POCl3 (20 mL) was added isobutyric acid hydrazide (705 mg, 6.912 mmol) at RT. The reaction temperature was slowly heated to 100° C and stirred for 18 h. The solvent was evaporated under reduced pressure, the residue was basified with saturated cold sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3 X 50 mL), organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 40percent EtOAc in petroleum ether to afford the title compound as a yellow solid. Yield: 650 mg (50percent) 1HNMR (DMSO-dg, 400 MHz, TMS) delta: 8.28-8.27 (IH, d), 8.18-8.17 (IH, d), 7.45 (2H, br, s), 3.32-3.24 (IH, m), 1.38-1.37 (6H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Stage #1: 1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid; isobutyric acid hydrazide With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20 - 27℃; for 5h; Stage #2: With Burgess Reagent at 80℃; for 120h; | 15 Route eTypical procedure for the preparation of oxadiazoles via Intermediate 1 asexemplified by the preparation of Example 15, ethyl 4-(4-(5-isopropyl-1,3,4- oxadiazol-2-yl)piperidin- 1-yl)azepane-1-carboxylate 1 -(1 -(Ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (200 mg, assumed 0.67 mmol), HATU (178 mg, 0.74 mmol), isobutyramidoxime (68.5 mg, 0.670 mmol) andDIPEA (128 tl, 0.74 mmol) in DMF (4 mL) were stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo. Burgess reagent (259 mg, 1.09 mmol) was added and the reaction was heated at 80°C for 3 days. A second amount of Burgess Reagent (164 mg, 0.69 mmol) was added and heating was continued at 80°C for 1 day. A further portion of Burgess Reagent (100 mg, 0.42 mmol) was added and heating was continued at 80°C for 1 day. The reaction mixture was concentrated in vacuo and theresidue was purified by reverse phase column chromatography acidic 10 mm [reverse phase HPLC (XSELECT CSH Prep 5 tm, 19 x 50 mm, 28 mL per mm, gradient 5% MeCN in 0.1 HCOOH in water (30 secs), 5% to 40% (over 7 mm) then 95% MeCN in 0.1 HCOOH in water (1 mm) then 5% MeCN in 0.1 HCOOH in water (1.5 min)j. The residue was dissolved in DCM (10 mL) and washed with sat. NaHCO3 sol. (2 x 2 mL). The phaseswere separated using a phase separation cartridge and the organic layer was concentrated in vacuo. The product was loaded onto a column of SCX (1 g) in 5% AcOH in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford ethyl 4-(4-(5-isopropyl- 1,3 ,4-oxadiazol-2-yl)piperidin- 1 -yl)azepane- 1 -carboxylate (21.7 mg, 4% yield) as a brownoil. The data for the title compound are in Table 2 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 27% 2: 3.9% | Stage #1: 2,4-dichloro-N-methyl-1,8-naphthyridine-3-carboxamide; isobutyric acid hydrazide With diphenyl ether-biphenyl eutectic at 160℃; for 0.5h; Stage #2: With sodium carbonate In dichloromethane; water at 20℃; for 0.5h; | 5.1.4 N-substituted-5-chloro-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 6a,c,d and N-substituted-5-hydroxy-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 7a,c,d General procedure: A mixture of 8.0mmol of 5a (2.05g) or 5c (2.27g) or 5d (2.27g), 12.0mmol (1.23g) of isobutyrohydrazide and 10mL of Dowtherm A was stirred at 160°C for 30min. After cooling, 10% aqueous Na2CO3 (50mL) and CH2Cl2 (50mL) were added and the mixture was further stirred at room temperature for 30min. After discarding some insoluble impurities by filtration, the mixture was transferred in a separatory funnel, then the organic layer was collected and the aqueous one was exhaustively extracted with CH2Cl2. The combined extracts were dried (anhydrous Na2SO4) then evaporated to dryness at reduced pressure, and the residue was chromatographed on a silica gel column eluting first with CH2Cl2 to remove Dowtherm A. Then the column was eluted with the mixture CH2Cl2-EtOAc (1:1), affording small amounts of the 5-hydroxyderivatives 7; the subsequent elution with the mixture CH2Cl2-EtOAc-acetone (2:1:1) gave the desired compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 45% 2: 4.4% | Stage #1: 2,4-dichloro-N-propyl-1,8-naphthyridine-3-carboxamide; isobutyric acid hydrazide With diphenyl ether-biphenyl eutectic at 160℃; for 0.5h; Stage #2: With sodium carbonate In dichloromethane; water at 20℃; for 0.5h; | 5.1.4 N-substituted-5-chloro-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 6a,c,d and N-substituted-5-hydroxy-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 7a,c,d General procedure: A mixture of 8.0mmol of 5a (2.05g) or 5c (2.27g) or 5d (2.27g), 12.0mmol (1.23g) of isobutyrohydrazide and 10mL of Dowtherm A was stirred at 160°C for 30min. After cooling, 10% aqueous Na2CO3 (50mL) and CH2Cl2 (50mL) were added and the mixture was further stirred at room temperature for 30min. After discarding some insoluble impurities by filtration, the mixture was transferred in a separatory funnel, then the organic layer was collected and the aqueous one was exhaustively extracted with CH2Cl2. The combined extracts were dried (anhydrous Na2SO4) then evaporated to dryness at reduced pressure, and the residue was chromatographed on a silica gel column eluting first with CH2Cl2 to remove Dowtherm A. Then the column was eluted with the mixture CH2Cl2-EtOAc (1:1), affording small amounts of the 5-hydroxyderivatives 7; the subsequent elution with the mixture CH2Cl2-EtOAc-acetone (2:1:1) gave the desired compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 39% 2: 4.4% | Stage #1: 2,4-Dichloro-N-isopropyl-1,8-naphthyridine-3-carboxamide; isobutyric acid hydrazide With diphenyl ether-biphenyl eutectic at 160℃; for 0.5h; Stage #2: With sodium carbonate In dichloromethane; water at 20℃; for 0.5h; | 5.1.4 N-substituted-5-chloro-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 6a,c,d and N-substituted-5-hydroxy-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 7a,c,d General procedure: A mixture of 8.0mmol of 5a (2.05g) or 5c (2.27g) or 5d (2.27g), 12.0mmol (1.23g) of isobutyrohydrazide and 10mL of Dowtherm A was stirred at 160°C for 30min. After cooling, 10% aqueous Na2CO3 (50mL) and CH2Cl2 (50mL) were added and the mixture was further stirred at room temperature for 30min. After discarding some insoluble impurities by filtration, the mixture was transferred in a separatory funnel, then the organic layer was collected and the aqueous one was exhaustively extracted with CH2Cl2. The combined extracts were dried (anhydrous Na2SO4) then evaporated to dryness at reduced pressure, and the residue was chromatographed on a silica gel column eluting first with CH2Cl2 to remove Dowtherm A. Then the column was eluted with the mixture CH2Cl2-EtOAc (1:1), affording small amounts of the 5-hydroxyderivatives 7; the subsequent elution with the mixture CH2Cl2-EtOAc-acetone (2:1:1) gave the desired compounds 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With phosphotungstic acid In N,N-dimethyl-formamide at 60℃; for 4h; | 3.6.1. Brevenal Derivatives General procedure: In a typical reaction, brevenal was dissolved in DMF and the hydrazide (2 eq) was added, followed by addition of a catalytic amount of tungstophosphoric acid. The reaction mixture was heated at 60 °C for 4 h. The solvents were evaporated under vacuum and the residue was taken up in methanol. The mixture was filtered through a 0.2 μm nylon filter and subjected to purification by HPLC. Desired products were positively identified by HRMS mass spectrometry and NMR. Spectroscopic data collected for all compounds can be found in the supplementary data document. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane at 90℃; for 9h; | 3.4 Step4:Ethyl-2-r2-(methoxymethyl)-6-(trifluoromethyl)-3-pyridyll-2-q- methylpropanoylhydrazono)acetate Ethyl 2-[2-(methoxymethyl)-6-(trifluoromethyl)-3-pyridyl]-2-oxo-acetate (1.50g mmol) is dissolved in dioxane (50.0mL) and heated to 90°C. 2- methylpropanehydrazide (0.552g) is added portion wise and the mixture stirred for 9 hours. The reaction mixture is concentrated in vacuo and the residue suspended in 15.0mL diethylether. The resulting solid is collected by filtration to give the clean product as a white solid (420. Omg). lR NMR (400 MHz, Chloroform) δ ppm = 1.22 (br. s., 6 H) 1.33 (t, J=6.91 Hz, 3 H) 3.32 (s, 3 H) 3.54 (br. s., 1 H) 4.33 (q, J=6.97 Hz, 2 H) 4.55 (s, 2 H) 7.68 - 7.78 (m, 2 H) 8.08 (br. s., 1 H) The filtrate is concentrated and liquid- loaded onto a silica cartridge using iso-hexane: ethyl acetate as the solvent system. The fractions containing the product are combined, added to the solid previously collected and concentrated in vacuo to yield ethyl (2E)-2-[2-(methoxymethyl)-6-(trifluoromethyl)-3-pyridyl]-2-(2- methylpropanoylhydrazono)acetate (0.430 g, 1.15 mmol, 22.2% yield) as a white solid. NMR indicates the presence of the two regioisomers. lR NMR (400 MHz, Chloroform) δ ppm = 1.21 (d, J=6.60 Hz, 6 H) 1.33 (t, J=7.09 Hz, 3 H) 3.31 (s, 3 H) 3.53 (br. s., 1 H) 4.27 - 4.38 (m, 2 H) 4.54 (s, 2 H) 7.68 - 7.78 (m, 2 H) 8.15 (br. s., 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; | A Part A. N'-isobutyryl-3-nitrobenzohydrazide To a solution of isobutyric acid hydrazide (1.101 g, 10.78 mmol) in dichloromethane (80 mL) containing N,N-diisopropylethylamine (1.882 mL, 10.78 mmol) at room temperature under nitrogen was added 3-nitrobenzoyl chloride (2.00 g, 10.78 mmol). The reaction mixture was stirred for 30 minutes at room temperature. The product crashed out as a white solid. The reaction mixture was filtered through a Buchner funnel and the solid was washed with cold hexanes then dried under high vaccum overnight to afford N"-isobutyryl-3-nitrobenzohydrazide (2.09 g, 77% yield). LCMS (ESI) m/e 252 [(M+H)+, calcd for C11H14N3O4 252.1]. |
77% | With N-ethyl-N,N-diisopropylamine at 20℃; for 0.5h; Inert atmosphere; | A Part A. N'-Isobutyryl-3-nitrobenzohydrazide Part A. N'-Isobutyryl-3-nitrobenzohydrazide To a solution of isobutyric acid hydrazide (1.101 g, 10.78 mmol) in dichloromethane (80 mL) containing N,N-diisopropylethylamine (1.882 mL, 10.78 mmol) at room temperature under nitrogen was added 3-nitrobenzoyl chloride (2.00 g, 10.78 mmol). The reaction mixture was stirred for 30 minutes at room temperature. The product crashed out as a white solid. The reaction mixture was filtered through a Buchner funnel and the solid was washed with cold hexanes then dried under high vacuum overnight to afford A/"-isobutyiyl-3-nitrobenzohydrazide (2.09 g, 77% yield). LCMS (ESI) m/e 252 [(M+H)+, calcd for C11H14N3O4 252.1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In acetonitrile at 82℃; |
Yield | Reaction Conditions | Operation in experiment |
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72% | In acetonitrile at 82℃; |
Yield | Reaction Conditions | Operation in experiment |
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77% | In ethanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: ethyl 2-ethoxy-2-iminoacetate hydrochloride; isobutyric acid hydrazide In ethanol at 20℃; Stage #2: With sodium hydrogencarbonate In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 50℃; for 0.5h; | A Step A: 4-Iodo-N-isobutyrylbenzohydrazide N-Methylmorpholine (1.77 mL, 16.1 mmol) was added to a stirring solution of 4- iodobenzoic acid (1.00 g, 4.03 mmol), isobutyric acid hydrazide (495 mg, 4.84 mmol), EDC (1.35 g, 7.06 mmol), and HO At (0.274 g, 2.02 mmol) in DMF (8.1 mL) and the resulting mixture allowed to stir at 50 °C for 30 min. The reaction mixture was cooled to ambient temperature and excess water added. The resulting solids were filtered and washed with water. The substrate was dried under high vacuum with heat to give the title compound. LC-MS m/z found = 333.3 [M+l]+. | |
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h; | A Step A: 4-Iodo-N'-(2-methoxy-2-methylpropanoyl)benzohydrazide N-Methylmorpholine (1.68 mL, 15.3 mmol) was added to a stirring solution of 4- iodobenzohydrazide (1.00 g, 3.82 mmol), 2-methoxy-2-methylpropanoic acid (0.541 g, 4.58 mmol), EDC (1.28 g, 6.68 mmol), and HOAt (0.260 g, 1.91 mmol) in DMF (13.0 mL). The resulting mixture was stirred at ambient temperature for 1 h. Excess water was added and the resulting solids filtered and washed with water. The substrate was dried under high vacuum with heat to give the title compound. LC-MS m/z found = 363.1 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 25℃; for 14.5h; | A Step A: 4-Bromo-N-isobutyrylbenzohydrazide To a solution of 4-bromobenzoic acid (20.1 g, 100 mmol) in DMF (150 mL) was added HOBt (14.9 g, 110 mmol), EDC (21.1 g, 110 mmol) and TEA (20.9 mL, 150 mmol). The mixture was stirred at 25 °C for 0.5 h, and then isobutyrohydrazide (11.22 g, 110 mmol) was added. The mixture was stirred at 25 °C for 14 h, and then diluted with EtOAc and washed with H20 (2x). The organics were dried over Na2S04, and concentrated in vacuo. The residue was washed with DCM (3x) and dried to afford the title compound; LC-MS* m/z: 285.0, 287.0 [M+l]+; 1H NMR (DMSO-dtf 300 MHz): δ 10.41 (s, 1H), 9.87 (s, 1H), 7.81 (d, J= 8.4Hz, 2H), 7.72 (d, J= 8.4Hz, 2H), 2.46-2.50 (m, 1H), 1.07 (d, J= 6.9Hz, 6H). | |
Stage #1: 4-Bromobenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: isobutyric acid hydrazide In N,N-dimethyl-formamide at 25℃; for 14h; | A13.A 4-Bromo-N'-isobutyrylbenzohydrazide To a solution of 4-bromobenzoic acid (20.1 g, 100 mmol) in DMF (150 mL) was added HOBt (14.9 g, 1 10 mmol), EDC (21.1 g, 1 10 mmol) and Et3N (20.9 mL, 150 mmol). The mixture was stirred at 25 °C for 0.5 h, and then isopropylhydrazide (1 1.2 g, 1 10 mmol) was added. The reaction mixture was stirred at 25 °C for 14 h, and then diluted with EtOAc (300 mL) and washed with H20 (100 mL x 2). The organic phase was dried over Na2S04, and concentrated. The residue was washed with CH2C12(20 mL x 3) and dried to afford the title compound as a white solid. MS (ESI) m/z = 285.0, 287.0 [M + 1 ]. NMR (300 MHz, DMSO- d6): 8 10.41 (s, 1H), 9.87 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 2.46-2.50 (m, 1H), 1.07 (d, J = 6.9 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 23℃; for 1.0h; | N-Methylmorpholine (1.65 mL, 15.0 mmol) was added to a solution of 2-f uoro- 4-iodobenzoic acid (1.0 g, 3.7 mmol), isobutyrohydrazide, (0.44 g, 4.3 mmol), EDC (1.3 g, 6.6 mmol), and HO At (0.26 g, 1.9 mmol) in DMF (7.5 mL). The resulting mixture was stirred at 23 C for 1 h. Excess ice water was added. The resulting solids were filtered, washed with water, then diethyl ether, and dried under high vacuum to give the title compound. MS m/z = 351.0 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium carbonate; sodium hydroxide In methanol at 15 - 20℃; for 1h; | 5 Preparation of Intermediate Using Ethyl Chloroformate (ECF)/NaOH 30 g of isobutyric acid hydrazide, 300 ml of methanol and 34.3 g of Na2CO3 were mixed in a four-neck flask reactor equipped with a reflux condenser, followed by strong stirring and adjustment of the temperature to 15° C. to 20° C. Then, 33.5 g (1.05 equivalents) of ethyl chloroformate (ECF) was added to the mixture over 1 hour while maintaining the reaction temperature at 15° C. to 20° C., together with confirming the reaction completion. Afier completion of the reaction, unreacted Na2CO3 and NaC1 were removed through filtration. Then, the solid obtained by concentration of the remaining liquid at reduced pressure was a pale yellow solid, and hydrazine carboxylic acid (purity: 98.39 area % by HPLC) was obtained substantially in a quantitative yield of 99% as an intermediate (V-2). The obtained intermediate could be directly used in subsequent reaction without additional purification. FIG. 2 is a graph depicting H-NMR data of a product obtained in Example 5, and it could be seen that the analysis data was the same as data of a standard product (hydrazine carboxylic acid). The following shows NMR data thereof: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate In methanol at 15 - 20℃; | 6 Preparation of Intermediate Using Isopropyl Chloroformate (IPCF) 30 g of isobutyric acid hydrazide, 240 ml of methanol and 34.3 g of Na2CO3 were mixed in a four-neck flask reactor equipped with a reflux condenser. Then, 37.8 g (1.05 equivalents) of isopropyl chioroformate (IPCF) was added to the mixture over 1 hour while maintaining the reaction temperature at 15° C. to 20° C., together with confirming the reaction completion. Afier completion of the reaction, NaC1 produced as a side product and unreacted Na2CO3 were removed through filtration. Then, a product (V-3) was obtained substantially in a quantitative yield through concentration of the remaining liquid at reduced pressure and had a purity of 98.13% by HPLC. FIG. 3 is a graph depicting H-NMR data of the product obtained in Example 6, and it could be seen that the analysis data was the same as data of a standard product (hydrazine carboxylic acid). The following shows NMR data of the obtained product:10055] ‘H-NMR(MeOD 400 MHz, dppm)1.31, 1.148 (d, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-butyl 3-(methylthio)-2-phenyl-5,6-dihydropyrazine-1(2H)-carboxylate; isobutyric acid hydrazide In butan-1-ol at 155℃; for 3h; Stage #2: With di-<i>tert</i>-butyl dicarbonate In butan-1-ol at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorobenzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; water at 20℃; for 1h; Stage #2: isobutyric acid hydrazide In dichloromethane; water for 18h; | 4.1 (Step 4-1) Preparation of 4-(3-(l -(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy) -2,6-difluoro-N'-isobutyrylbenzohydrazide (Step 4-1) Preparation of 4-(3-(l -(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy) -2,6-difluoro-N'-isobutyrylbenzohydrazide 4-(3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl-propoxy)-2,6-difluorobenzoic acid synthesized in the above step 3-2 of Preparation Example 3> was dissolved in dichloromethane (4 ml), and then EDC(70.9 mg, 0.37 mmol) and HOBt-H20(56.7 mg, 0.37 mmol) were added thereto. After activating at room temperature for 1 hour, isobutyrohydrazide (37.8 mg, 0.37 mmol) was dropped thereto, and stirring was carried out for 18 hours. After completion of the reaction, the reactant was filtered through celite, and then concentrated under reduced pressure to obtain the desired form of the compound, 4-(3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluoro-N'-isobutyrylbenzohydra zide in a yield of 88%. [M+l]+=490.3 m/z(ESI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine In dichloromethane at 20℃; Cooling with ice; | 24 preparation of compound 24-6 To a solution of compound 24-4 (3.0 g, 29 mmol) in DCM (40 mL) was added triethylamine (4 mL, 29 mmol) in an ice bath, and then compound 24-5 (4.0 g, 29 mmol) was added dropwise slowly. After the addition, the mixture was stirred at rt overnight. After the reaction was complete, the mixture was diluted with EtOAc (100 mL) and filtered to remove salt. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE : EtOAc (V: V) = 5 : 1 to afford compound 24-6 as a white solid (5.8 g, 99%). MS (ESI, pos.ion) m/z: 203 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With urea hydrogen peroxide adduct; potassium carbonate; potassium iodide In 1,2-dimethoxyethane; water at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With hydrazine hydrate; sodium hydroxide In water at -5 - 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.7% | In 1,4-dioxane at 100℃; for 20h; | 31.2 Step 2. Preparation of (S)-methyl 3-(8-chloro-1-isopropyl-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate (Compound 29s) (S)-Methyl 3-(7-chloro-2-((dimorpholinophosphoryl)oxy)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate (compound 31b) was dissolved in dioxane, and isobutyrohydrazide (854 mg, 8.37 mmol) was added. The mixture was heated to 100° C. and stirred for 20 h. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water for three times, dried and concentrated. The residue was purified through preparative TLC to obtain (S)-methyl 3-(8-chloro-1-isopropyl-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl) propanoate (compound 29s, 114 mg, yield 8.7%). MS m/z (ESI): 468 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ: 8.56-8.54 (m, 1H), 8.10-8.08 (m, 1H), 7.98-7.93 (m, 1H), 7.88-7.81 (m, 2H), 7.53-7.49 (m, 2H), 4.30-4.26 (m, 1H), 3.63 (s, 3H), 3.45-3.38 (m, 1H), 2.78-2.50 (m, 4H), 1.47-1.45 (m, 3H), 0.91-0.89 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum oxide; hydrazine hydrate In 5,5-dimethyl-1,3-cyclohexadiene Reflux; | Ex-2.1 (1) Synthesis of Compound I(b) 44.1 g (0.50 mol) of isobutyric acid was sequentially added to a 500 mL four-necked flask.80% hydrazine hydrate 46.8g (0.75mol), active Al2O3 5g, xylene 100mL, start stirring, warm reflux reductive, to anhydrous dehydration, cooling to remove active Al2O3, the obtained isobutyryl hydrazine xylene solution to be taken next. | |
With hydrazine hydrate In butan-1-ol at 20℃; Reflux; | 1; 2; 3; 4; 5; 6; 7; 8 Example 3 44.5 g (0.50 mol) of isobutyric acid and 133.5 g of n-butanol were placed at room temperature.In a 500 mL reaction flask, start stirring and slowly add dropwise32.9g (0.525mol)80% hydrazine hydrate. After the dropwise addition is completed, the temperature is raised to reflux and dehydrated.When the 23 mL of water is removed, the heating is turned off.The water bath is cooled to 10~15 °C,Product 1 was obtained.Slowly pass 52.5g (0.525mol) phosgene at 1015°C,It took 2 hours and continued to incubate at this temperature for 3 hours to give product 2.Thereafter, 31.3 g (0.50 mol) of 80% hydrazine hydrate and 10.7 g (0.1 mol) of sodium carbonate were charged, and the mixture was heated to reflux at 95 to 100 ° C for 3 hours.The reaction is over. The layer was allowed to stand and the upper n-butanol was separated.The lower aqueous phase continues to cool down to 20 to 40 ° C.Adjust the pH to 6~7 with 30% hydrochloric acid, then continue to cool down to 0~5 °C, and continue stirring at this temperature for half an hour, suction filtration, a small amount of water washing,Drying gave product 3 (yield 85.3%, purity 99.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene at 90 - 100℃; for 2h; | 2.3 (3) Synthesis of compound III(b) At room temperature, the above two isobutyryl hydrazideThe toluene solution is slowly added dropwise to isothiocyanateThe reaction system of ethyl ester, after the end of the addition,Slowly raise the temperature to 90-100 ° C, stir for 2 h, cool to room temperature, the liquid phase detection content is 94.5%, the yield is 82.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 10 - 15℃; for 5h; Reflux; Irradiation; | 1; 2; 3; 4; 5; 6; 7; 8 Example 3 44.5 g (0.50 mol) of isobutyric acid and 133.5 g of n-butanol were placed at room temperature.In a 500 mL reaction flask, start stirring and slowly add dropwise32.9g (0.525mol)80% hydrazine hydrate. After the dropwise addition is completed, the temperature is raised to reflux and dehydrated.When the 23 mL of water is removed, the heating is turned off.The water bath is cooled to 10~15 °C,Product 1 was obtained.Slowly pass 52.5g (0.525mol) phosgene at 1015°C,It took 2 hours and continued to incubate at this temperature for 3 hours to give product 2.Thereafter, 31.3 g (0.50 mol) of 80% hydrazine hydrate and 10.7 g (0.1 mol) of sodium carbonate were charged, and the mixture was heated to reflux at 95 to 100 ° C for 3 hours.The reaction is over. The layer was allowed to stand and the upper n-butanol was separated.The lower aqueous phase continues to cool down to 20 to 40 ° C.Adjust the pH to 6~7 with 30% hydrochloric acid, then continue to cool down to 0~5 °C, and continue stirring at this temperature for half an hour, suction filtration, a small amount of water washing,Drying gave product 3 (yield 85.3%, purity 99.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethylsulfoxide-d6 at 90℃; for 16h; | 4.1.4. General procedure 2 - synthesis of selected acylhydrazones General procedure: After analysis of the reaction mixture screening, several acylhydrazoneswere selected for larger-scale synthesis and purification.The required hydrazides (14.7-35.0 mg, 0.0932-0.138mmol)were weighed into 0.5mL Eppendorf tubes. To indole aldehyde 1(285mg, 1.13mmol), was added DMSO-d6 (1.885 mL, 600mM).Then, the aldehyde stock solution was added to each hydrazide,resulting in 1.05 equivalents of hydrazidewith respect to aldehyde.The Eppendorf tubes were mixed, shortly centrifuged and thenplaced in a pre-heated 90 °C aluminum heating block overnight.The yellow solutions were allowed to cool down to room temperature,mixed, shortly centrifuged and then added dropwise toice-cold demi water (1500 mL). After mixing, the suspensions werecentrifuged at 12.5 103 g at 5 °C for 10 min. The pale yellowaqueous DMSO layer was removed and in order to remove theremaining DMSO, the solids were washed with ice-cold demiwater (2 1200 mL; including mixing, sonication and centrifugation).Then, the remaining hydrazide was removed by washing thesolids with ice-cold absolute EtOH (3 1.2mL, same procedure aswith water). The solids were dried under high-vacuum until nomore weight loss was observed, resulting in product (yield62-92%) with purity 95% as confirmed by qHNMR (see supportinginformation) [14]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
222 mg | In 1,4-dioxane; 2-methoxy-ethanol at 175℃; for 0.5h; Inert atmosphere; Schlenk technique; Microwave irradiation; | 3.1 General procedure (GP) General procedure: In an oven-dried Schlenk flask with magnetic stirring bar and screw cap were placed glyoxylicacid 1 (1.00 mmol) and dry 1,4-dioxane (2.5 mL) under argon (for experimental details seeTable S4). Then, oxalyl chloride (0.09 mL, 1.00 mmol) was added dropwise at roomtemperature (external water bath) and the reaction mixture was stirred at 50 °C (preheated oilbath) for 4 h. After the mixture had cooled to room temperature CuI (10 mg, 0.05 mmol), alkyne2 (1.00 mmol), and dry triethylamine (0.42 mL, 3.00 mmol) were successively added. Stirringat room temperature (external water bath) was continued for 15 h. Then, hydrazide 3(1.20 mmol) and 2-methoxyethanol (1.0 mL) were added and the reaction mixture was stirredat 175 °C (preheated oil bath) for 30 min. After complete conversion (monitored by TLC) andcooling to room temperature deionized water (5 mL) was added and the mixture was extractedwith dichloromethane (4 × 5 mL). The combined organic phases were dried with anhydroussodium sulfate and the solvents were removed in vacuo. The crude product was adsorbed oncelite and purified by flash chromatography on silica gel (petrolether 40-60 °C/ethyl acetate)to give analytically pure 1,5-diacyl-5-hydroxypyrazolines 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane at 85℃; | Synthesis of 5-isopropyl-3H-[1 ,3,4]oxadiazol-2-one (BB-8-5) CDI (1228 mg, 7.34 mmol) was added to a soln. of isobutyric acid hydrazide (500 mg, 4.9 mmol) in anh. dioxane (21 mL) and the rxn mixture was heated at 85°C and stirred ON. Dioxane was evaporated off and the residue was partitioned between water and EtOAc. The org. phase was washed with brine (1x), dried over MgS04 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc. LC-MS: tR=0.49 min, [M+MeCN+H]+: 170.27 1H NMR (400 MHz, DMSO-d6) 5: 12.05 (m, 1 H), 2.86 (m, 1 H), 1.19 (d, J = 6.9 Hz, 6 H) | |
In 1,4-dioxane at 85℃; for 18h; | Method B (Cvclisation) General procedure: A soln. of the appropriate hydrazide (1 eq) and CDI (1.5 eq) in anh. Dioxane (4.2 mL/mmol) was heated to 85°C and stirred for 18h. The solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and H2O. The org. phase was washed with brine, dried over MgSCh and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 5.d 5- ( (1R, 5S) -1- (2, 5-difluorophenyl) -2-azabicyclo [3.1.0] hexan-2-yl) -N'-isobutyrylp yrazolo [1, 5-a] pyrimidine-3-carbohydrazide (5d) A mixture of isobutyrohydrazide (5c) (233 mg, 1.68 mmol) , 5- ( (1R, 5S) -1- (2, 5-difluorophenyl) -2-azabicyclo [3.1.0] hexan-2-yl) pyrazolo [1, 5-a] pyrimidine-3-carboxylic acid (5b) (300 mg, 0.842 mmol) , DIPEA (435 mg, 3.37 mmol) and HATU (480 mg, 1.26 mmol) in DMF (10 mL) was stirred at RT for overnight. The reaction was quenched with water and extracted with EtOAc. The extracts were washed with brine, dried over Na 2SO 4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE /EtOAc (1: 1) to give the title compound 5- ( (1R, 5S) -1- (2, 5-difluorophenyl) -2-azabicyclo [3.1.0] hexan-2-yl) -N'-isobutyrylpyrazolo [1, 5-a] pyrimidine-3-carbohydrazide (5d) . MS-ESI (m/z) : 441 [M + 1] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | Stage #1: carbon disulfide; isobutyric acid hydrazide With potassium hydroxide In methanol at 0 - 5℃; for 1h; Stage #2: 1,1,2-trifluoro-4-bromobut-1-ene In methanol at 0 - 20℃; for 3h; | 2.a a) Preparation of 3.4.4-trifluoro-3-butenyl 2-isobutyryldithiocarbazate I Compound having general formula (XVIa)l 6.5 ml (107.7 mmoles) of carbon disulfide were slowly added dropwise to a solution of 10.00 g of isobutyryl hydrazide (97.9 mmoles) and 10.98 g of potassium hydroxide (195.8 mmoles) in methanol (60 ml), maintaining the temperature at a value of 0 to 5°C. After an hour at this temperature, a yellowish suspension was obtained to which 12.5 ml (107.7 mmoles) of 4-bromo- 1,1,2- trifluorobutene were added dropwise on an ice bath at about 0°C. After an hour, the reaction mixture was allowed to return to room temperature, as the turbidity gradually increases due to the formation of KBr and is produced and left under stirring at this temperature for 2 hours. After LC-MS control, the alcohol solvent was removed by rotary evaporation at reduced pressure and the aqueous phase was extracted with dichloro methane 3 times. The combined organic phases were washed with a saturated solution of sodium chloride, anhydrified on sodium sulfate, filtered and evaporated to give 26 g of the desired product, used without further purification in the next step. Yield: 92.8% LC-MS: M = 285 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 0℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With acetic acid In ethanol for 4.5h; Reflux; | 2.4 Synthesis of the ligand (1) Isobutyrohydrazide was synthesized from ethyl isobutyrate and hydrazine hydrate as described in a previously reported method [67]. Diacetyl monoxime (1mmol, 0.102g) and seven drops of glacial acetic acid were added to a solution of isobutyrohydrazide (1mmol, 0.102g) in absolute ethanol (25mL). The reaction mixture was stirred while refluxing for 4.5h. The transparent crystals formed from the mixture after a few days were collected by filtration, washed with cold diethyl ether and then dried in air producing a yield of 70%. An elemental analysis of CHN (C8H15N3O2: 185.12gmol-1) calculated the following percentages: C:52.01 (51.88), H:8.00 (8.16), N:22.82 (22.69). The 1H NMR (400MHz, DMSO-d6, 298K, δ/ppm) results showed: 11.48/11.44 (E/Z isomer; s, 1H); 10.32/10.22 (E/Z isomer; s, 1H); 3.32/2.71 (E/Zisomer; m, 1H); 1.96 (E/Z isomer; s, 3H), 2.02/2.05 (E/Zisomer; s, 3H), 1.06 (E/Zisomer; d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate at 0 - 20℃; for 16h; | Intermediate 772A: tert-butyl (2S,5R)-4-(1-(4-fluorophenyl)-2-(2-isobutyrylhydrazineyl)- 2-oxoethyl)-2,5-dimethylpiperazine-1-carboxylate To a stirred solution of 2-((2R,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin- 1-yl)-2-(4-fluorophenyl)acetic acid (500 mg, 1.37 mmol) in EtOAc (6 mL) were added isobutyrohydrazide (139mg, 1.36 mmol), Et3N (0.38 mL, 2.73 mmol) followed by 1- propanephosphonicanhydride (1042 mg, 1.64 mmol) at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The reaction mixture was extracted with ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to give tert-butyl (2S,5R)-4-(1-(4-fluorophenyl)-2- (2-isobutyrylhydrazineyl)-2-oxoethyl)-2,5-dimethylpiperazine-1-carboxylate (0.55 g, 1.22 mmol, 89 % yield). LCMS: m/z, 451.5 (M+H); rt 1.64 min. (LCMS Method: Column: Waters Acquity UPLC BEH C18 (2.1 x 50 mm) 1.7 mm, Mobile phase A: 10 mM ammonium acetate:acetonitrile (95:5); Mobile phase B: 10 mM ammonium (2298) acetate:acetonitrile (5:95), Gradient = 20-100 % B over 2 minute, then a 0.3 minute hold at 100 % B; Temperature: 50 °C; Flow rate: 0.7 mL/min; Detection: UV at 220 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 g | With triethylamine | 2 Step 2: 2-Bromo-/V-isobutyrylisonicotinohydrazide Triethylamine (28 mL, 199.59 mmol) was added to a mixture of 2- bromoisonicotinoyl chloride (22 g), isobutyrohydrazide (10.19 g, 99.80 mmol), and CH2CI2 (130 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 10 min, warmed to rt slowly, stirred for 2 h, concentrated, and then purified by silica gel chromatography (petroleum ether/ethyl acetate= 1/50-1/30) to give 2-bromo-/V-isobutyrylisonicotinohydrazide (25 g) as a yellow solid. LCMS: 286.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 1-propanephosphonic acid cyclic anhydride; triethylamine In N,N-dimethyl-formamide at 20℃; for 5h; | 2-amino-5-bromo-N'-(2-methylpropanoyl)pyridine-3-carbohydrazide To a mixture of 2-amino-5-bromopyridine-3-carboxylic acid (8.85 g, 40.8 mmol), 2- methylpropanehydrazide (5.00 g, 49.0 mmol), and triethylamine (23 ml, 160 mmol) in DMF (30 ml) at rt was added dropwise a solution of T3P (71 ml, 50 % purity, 120 mmol). The reaction was then stirred at rt for 5 h. Subsequently, it was diluted with water and ethyl acetate and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate / tert- butyl methyl ether and the precipitate was collected by suction filtration to yield 7.87 g (99 % purity, 63 % yield) of the title compound.LC-MS (method 1): Rt= 0.85 min; MS (ESIpos): m/z = 301, 303 [M+H]+-NMR (400 MHz, DMSO-d6) d [ppm]: 1.07 (d, 6H), 7.21 (s, 2H), 8.12 (d, 1H), 8.20 (d, 1H), 9.84 (s, 1H), 10.29 (br s, 1H). |
63% | With 1-propanephosphonic acid cyclic anhydride; triethylamine In N,N-dimethyl-formamide at 20℃; for 5h; | 2-Amino-5-bromo-N'-(2-methylpropanoyl)pyridine-3-carbohydrazide To a mixture of 2-amino-5-bromopyridine-3-carboxylic acid (8.85 g, 40.8 mmol), 2- methylpropanehydrazide (5.00 g, 49.0 mmol), and triethylamine (23 ml, 160 mmol) in DMF (30 ml) at rt was added dropwise a solution of T3P (71 ml, 50 % purity, 120 mmol). The reaction was then stirred at rt for 5 h. Subsequently, it was diluted with water and ethyl acetate and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate / tert-butyl methyl ether and the precipitate was collected by suction filtration to yield 7.87 g (99 % purity, 63 % yield) of the title compound. LC-MS (method 1): Rt = 0.85 min; MS (ESIpos): m/z = 301, 303 [M+H]+ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.07 (d, 6H), 7.21 (s, 2H), 8.12 (d, 1H), 8.20 (d, 1H), 9.84 (s, 1H), 10.29 (br s, 1H). |
63% | With 1-propanephosphonic acid cyclic anhydride; triethylamine In N,N-dimethyl-formamide at 20℃; for 5h; | 2-Amino-5-bromo-N'-(2-methylpropanoyl)pyridine-3-carbohydrazide To a mixture of 2-amino-5-bromopyridine-3-carboxylic acid (8.85 g, 40.8 mmol), 2- methylpropanehydrazide (5.00 g, 49.0 mmol), and triethylamine (23 ml, 160 mmol) in DMF (30 ml) at rt was added dropwise a solution of T3P (71 ml, 50 % purity, 120 mmol). The reaction was then stirred at rt for 5 h. Subsequently, it was diluted with water and ethyl acetate and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate / tert-butyl methyl ether and the precipitate was collected by suction filtration to yield 7.87 g (99 % purity, 63 % yield) of the title compound. LC-MS (method 1): Rt = 0.85 min; MS (ESIpos): m/z = 301, 303 [M+H]+ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.07 (d, 6H), 7.21 (s, 2H), 8.12 (d, 1H), 8.20 (d, 1H), 9.84 (s, 1H), 10.29 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.76% | With ammonium hydroxide In ethanol at 50℃; for 1h; | 61 1-(6-chloro-1-hydroxy-2,3,1-benzodiazaborinin-2-yl)-2-methyl- propan- 1-one To a solution of (4-chloro-2-formyl-phenyl)boronic acid (200 mg, 1.08 mmol, 1 eq) and 2-methylpropanehydrazide (111 mg, 1.08 mmol, 1 eq) in EtOH (5 mL) was added NH3.H2O (1.95 mmol, 301 µL, 25% purity, 1.8 eq) dropwise at room temperature, the resulting mixture was stirred at 50oC for 1 h. The reaction mixture was concentrated in vacuo to give crude product, which was triturated with H2O (6 mL)/acetonitrile (2 mL) (v:v=3:1) at room temperature to afford 1-(6-chloro-1-hydroxy-2,3,1-benzodiazaborinin-2-yl)-2-methyl-propan- 1-one (100 mg, 388 µmol, 35.76% yield, 97.15% purity) as a white solid.1H NMR (DMSO-d6, 400 MHz) d 8.19 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.62-7.60 (m, 1H), 7.57-7.55 (m, 1H), 3.81- 3.78 (m, 1H).1.01 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). MS (ESI): mass calcd. For C11H12BClN2O2250.07, m/z found 267.1 [M+18-H]-. HPLC: 97.15% (220 nm), 97.02% (254 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium hydroxide In ethanol for 6h; Reflux; | 4.2. General procedure for the synthesis of 1,3,4-oxadiazol-2-thiones (2a-j) General procedure: The appropriate hydrazide (10 mmol) was dissolved in absoluteethanol (50 mL) in a 100 mL three-neck bottom flask. Potassiumhydroxide (1.3 equiv) was then added to the solution followed bythe slowly addition of excess carbon disulfide (1.1 equiv). This reactionmixture was properly stirred and refluxed for 6 h. Themixture was evaporated under reduced pressure followed by theaddition of distilled water (10 mL) and acidified with dilute hydrochloricacid (6 N) to pH 1e2 with precipitated formation. It was then filtered and washed with cold ethanol. The pure products 2d-iwere purified by precipitation from their solution with NaOH inwater, after adding hydrochloric acid to adjust pH 1e2. The product2a and 2j had good solubility in water, 2b and 2c were both liquidsat room temperature, these four species must be extracted withethyl acetate and then concentrated to get the product.Particularly, the aldehyde group of formohydrazide was sensitiveto heat, so for the synthesis of 1,3,4-oxadiazole-2-thione (2j),the reaction mixture must be quickly filtered at room temperaturebefore the addition of distilled water and the acidification to formprecipitated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In ethanol at 20℃; for 2h; | 4.3. General procedure for the synthesis of 1,3,4-thiadiazol-2-thiones (4a-j) General procedure: The appropriate hydrazide (10 mmol) was dissolved in absoluteethanol (50 mL) in a 100 mL three-neck bottom flask. Potassiumhydroxide (1.5 equiv) was then added to the solution followed bythe slowly addition of excess carbon disulfide (1.3 equiv). This reactionmixture was properly stirred at room temperature for 2 h.The mixture was filtered and washed with cold ethanol, and thenslowly added into concentrated sulfuric acid (10 mL) at 0e5 C withvigorous stirring. After 1 h, the reaction mixture was poured intoice to form precipitated. It was then filtered and washed with coldethanol. The pure products 4a and 4c-i were purified by precipitationfrom their solution with NaOH in water, after adding hydrochloricacid to adjust pH 1e2. The product 4bwas liquid at roomtemperature, which must be extracted with ethyl acetate and thenconcentrated to get the product.Particularly, the aldehyde group of formohydrazide was sensitiveto air, so for the synthesis of 1,3,4-thiadiazole-2-thione (4j), thereaction mixture must be quickly filtered at room temperature andthen added into concentrated sulfuric acid. The significantly loweryields of 2j and 4j were mainly caused by side reaction of aldehydegroup, which should be suppressed in further research. | |
With potassium hydroxide In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With acetic acid In methanol for 4.5h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In water; dimethyl sulfoxide at 20℃; |
Tags: 3619-17-8 synthesis path| 3619-17-8 SDS| 3619-17-8 COA| 3619-17-8 purity| 3619-17-8 application| 3619-17-8 NMR| 3619-17-8 COA| 3619-17-8 structure
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