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CAS No. : | 131661-41-1 | MDL No. : | MFCD05664572 |
Formula : | C5H5N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SBHYNBAKHDSUKT-UHFFFAOYSA-N |
M.W : | 107.11 | Pubchem ID : | 1382043 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 28.27 |
TPSA : | 52.47 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) : | -6.72 cm/s |
Log Po/w (iLOGP) : | 0.72 |
Log Po/w (XLOGP3) : | 0.33 |
Log Po/w (WLOGP) : | 0.59 |
Log Po/w (MLOGP) : | -0.63 |
Log Po/w (SILICOS-IT) : | 1.36 |
Consensus Log Po/w : | 0.48 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.17 |
Solubility : | 7.17 mg/ml ; 0.0669 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.0 |
Solubility : | 10.8 mg/ml ; 0.101 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.64 |
Solubility : | 2.45 mg/ml ; 0.0229 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.53 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
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 |
---|---|---|
84% | With hydrazine hydrate at 25℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 14h; | 1 EXAMPLE 1 : 7V-(2-Chlorophenyl)-3-(3-methyl-lH-pyrazol-4-yl)-l,2,4-thiadiazol- 5-amine (Final Compound 1-3) tert-Butyl 4-cyano-3-methyl-lH-pyrazole-l-carboxylate According to Scheme 1 Step 1 : To a solution of 3-methyl-lH-pyrazol-4-carbonitrile (9.34 mmol, 1.00 g) in DCM (20 mL) were sequentially added DIEA (9.34 mmol, 1.60 mL), (BoC)2O (9.34 mmol, 2.04 g) and DMAP (0.93 mmol, 0.11 g). After stirring for 14 hours at room temperature, the reaction mixture was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with a saturated solution of NaηCC>3 and brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (85:15) as eluent to afford tert-butyl 4-cyano-3-methyl-lH-pyrazole-l-carboxylate (7.96 mmol, 1.65 g, 85%) as a white solid. LC (Zorbax SB-Ci8, 3.5μm, 4.6x50mm Column): RT = 3.72 min; MS m/z ES+= 108 (M+-BoC). |
85% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 14h; | 1 According to Scheme 1 Step 1: To a solution of 3-methyl-1H-pyrazol-4-carbonitrile (9.34 mmol, 1.00 g) in DCM (20 mL) were sequentially added DIEA (9.34 mmol, 1.60 mL), (Boc)2O (9.34 mmol, 2.04 g) and DMAP (0.93 mmol, 0.11 g). After stirring for 14 hours at room temperature, the reaction mixture was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with a saturated solution of NaHCO3 and brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (85:15) as eluent to afford tert-butyl 4-cyano-3-methyl-1H-pyrazole-1-carboxylate (7.96 mmol, 1.65 g, 85%) as a white solid.LC (Zorbax SB-C18, 3.5 μm, 4.6×50 mm Column): RT=3.72 min; MS m/z ES+=108 (M+-Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃; | 3 EXAMPLE 3: 3-(3-Methyl-lH-pyrazol-4-yl)-7V-(pyridin-2-yl)-l,2,4-thiadiazol-5- amine (Final Compound 1-5) l-(4-Methoxybenzyl)-3-methyl-lH-pyrazol-4-carbonitrile and l-(4-methoxybenzyl)-5- methyl-lH-pyrazol-4-carbonitrileAccording to Scheme 1 Step 1 : Triphenylphosphine (11 mmol, 2.9 g), (4- methoxyphenyl)methanol (10 mmol, 1.4 g) and di-tert-butylazodicarboxylate (11 mmol, 2.6 g) were added to a solution of 3-methyl-lH-pyrazol-4-carbonitrile (9.3 mmol, 1.0 g), in DCM (40 mL) at O0C. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with a saturated solution of NH4OH and brine. Then the organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90: 10) as eluent to yield a mixture of l-(4-methoxybenzyl)-3 -methyl- lH-pyrazol-4-carbonitrile and of l-(4- methoxybenzyl)-5-methyl-lH-pyrazol-4-carbonitrile (9.3 mmol, 2.1g, 100%). | |
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃; | 3 According to Scheme 1 Step 1: Triphenylphosphine (11 mmol, 2.9 g), (4-methoxyphenyl)methanol (10 mmol, 1.4 g) and di-tert-butylazodicarboxylate (11 mmol, 2.6 g) were added to a solution of 3-methyl-1H-pyrazol-4-carbonitrile (9.3 mmol, 1.0 g), in DCM (40 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with a saturated solution of NH4OH and brine. Then the organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to yield a mixture of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-carbonitrile and of 1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-4-carbonitrile (9.3 mmol, 2.1 g, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With hydrazine hydrate In ethanol at 0 - 10℃; for 1h; | Compound 257.3. 3-Methyl-lH-pyrazole-4-carbonitrile Compound 257.3. 3-Methyl-lH-pyrazole-4-carbonitrile. Into a 50-mL round- bottom flask, was placed a solution of (Z)-2-(ethoxymethylene)-3-oxobutanenitrile (compound 257.2, 5.00 g, 35.9 mmol) in ethanol (10 mL). The solution was cooled to 0 °C, then hydrazine monohydrate (2.09 mL, 43.1 mmol) was added and the reaction was stirred for 1 h at 10 °C. The reaction was diluted with water (10 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried ( a2S04), filtered and concentrated under reduced pressure. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1 : 10) as eluent to obtain the title compound as a yellow solid (2.0 g, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With N-iodo-succinimide In 1,2-dichloro-ethane at 150℃; for 1h; Microwave irradiation; | Compound 257.4. 5-Iodo-3-methyl-lH-pyrazole-4-carbonitrile. Into a 10-mL sealed tube, was placed a solution of 3 -methyl- lH-pyrazole-4-carbonitrile (compound 257.3, 2.0 g, 18.7 mmol) in DCE (6 mL). NIS (4.20 g, 18.7 mmol) was added to the reaction and the mixture was irradiated with microwave radiation for 1 h at 150 °C. The reaction was cooled, then carefully quenched with aqueous a2S203 (sat., 20 mL). The mixture was partitioned and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (5 x 30 mL), dried ( a2S04), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1 : 10) as eluent to obtain the title compound as a yellow solid (900 mg, 21%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrazine hydrate In ethanol at 20℃; for 1h; | Intermediate 123B: 3-ethyl-1H-pyrazole-4-carbonitrile General procedure: To a solution of Intermediate 123A (5.00 g, 32.60 mmol) in EtOH (50 mL) was added hydrazine hydrate (5.12 mL, 163 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with ice cold water (30 mL) and extracted with 10% MeOH:DCM (2 x 50 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 0-2% MeOH/DCM) to obtain Intermediate 123B (3.10 g, 78.00%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 - 1.32 (m, 3 H), 2.66 - 2.80 (m, 2 H), 4.09 - 4.19 (m, 1 H), 8.17 (s, 1 H). LCMS (Method-L): retention time 0.75 min, [M+H] 122.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-Fluorobenzyl bromide; 3-methyl-1H-pyrazole-4-carbonitrile With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Stage #2: di-<i>tert</i>-butyl dicarbonate With methanol; sodium tetrahydroborate; cobalt(II) chloride hexahydrate In N,N-dimethyl-formamide at 0℃; for 1h; | 1.2 3-Cyano-2-methylpyrazole and 1-(bromomethyl)-4-fluorobenzene (964.0 mg, 5.100 mmol) was taken into DMF (5 ml) and cooled to 0°C. Sodium hydride (240.0 mg, 6.000 mmol) was added to the reaction portionwise. The reaction was warmed to room temperature and stirred for 12 hrs. (Observed two regioisomers by LC/MS). The reaction was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine, dried over MgSO4and concentrated to give crude mixture which was purified by column chromatography (SiO2) eluting with a gradient of 0-50% ethyl acetate in hexane to provide inseparable regioisomers. ESMS(M+1)=216.14._The mixture of regioisomers from Step 1 (1-(4-fluorobenzyl)-3-methyl-1H-pyrazole-4-carbonitrile and 1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-4-carbonitrile (430.5 mg, 2.000 mmol), Boc2O (525 mg, 2.400 mmol), and dichlorocobalt hexahydrate (235.6 mg, 0.99 mmol) were taken into MeOH (5 mL) and cooled to 0°C. Sodium borohydride (940 mg, 1 mL, 24.8 mmol) was added to the mixture portion wise (the reaction turned black) and stirred for 1 hour. The reaction was evaporated in vacuo to afford a black solid. This was suspended in ethyl acetate (30 mL) and H2O (15 mL). The organic layer was collected and filtered to remove remaining solids. The filtrate was washed with brine and dried over MgSO4to provide the crude product that was purified by column chromatography (SiO2) eluting with a gradient of 0-50% ethyl acetate in hexane to give two peaks. The top spot was minor and the bottom spot was major. By H NMR and TLC, both spot were not separated cleanly so combined for next step (ratio: 1: 2.3).Top spot (ratio 1: 1.3):1H NMR (400 MHz, CDCl3)δ7.30 (d, J=69.7 Hz, 1H), 7.18-7.00 (m, 2H), 29.9 Hz, 2H), 6.96 (td, J=8.7, 6.6 Hz, 2H), 5.14 (d, J=4.53 (m, 1H), 4.92-(d, J=23.8 Hz, 3H), 4.07 (t, J=4.9 Hz, 2H), 2.16 (d, J=23.8 Hz, 3H), 1.41 (d, J=3.1 Hz, 9H).Bottom Spot (ratio 1:3):1H NMR (400 MHz, CDCl3)δ7.23 (s, 1H), 7.17 (ddd, J=8.1, 5.2, 2.5 Hz, 2H), 7.05-6.94 (m, 2H), 5.26-5.06 (m, 2H), 4.65 (s, 1H), 4.10 (d, J=5.1 Hz, 2H), 2.28-2.09 (m, 3H), 1.44 (q, J=2.5, 2.1 Hz, 10H). ESMS(M+1)=320.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 12h; | 1.1 Step 1: 1-(4-fluorobenzyl)-3-methyl-1H-pyrazole-4-carbonitrile and 1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-4-carbonitrile mmol) was taken into DMF (5 ml) and cooled to 0°C. Sodium hydride (240.0 mg, 6.000 mmol) was added to the reaction portionwise. The reaction was warmed to room temperature and stirred for 12 hrs. (Observed two regioisomers by LC/MS). The reaction was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine, dried over MgSO4and concentrated to give crude mixture which was purified by column chromatography (SiO2) eluting with a gradient of 0-50% ethyl acetate in hexane to provide inseparable regioisomers. ESMS(M+1)=216.14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-Fluorobenzyl bromide; 3-methyl-1H-pyrazole-4-carbonitrile With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Stage #2: With methanol; sodium tetrahydroborate; cobalt(II) chloride hexahydrate; di-<i>tert</i>-butyl dicarbonate In N,N-dimethyl-formamide at 0℃; for 1h; Stage #3: With hydrogenchloride In 1,4-dioxane at 20℃; for 3h; | 1.3 3-Cyano-2-methylpyrazole and 1-(bromomethyl)-4-fluorobenzene (964.0 mg, 5.100 mmol) was taken into DMF (5 ml) and cooled to 0°C. Sodium hydride (240.0 mg, 6.000 mmol) was added to the reaction portionwise. The reaction was warmed to room temperature and stirred for 12 hrs. (Observed two regioisomers by LC/MS). The reaction was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine, dried over MgSO4and concentrated to give crude mixture which was purified by column chromatography (SiO2) eluting with a gradient of 0-50% ethyl acetate in hexane to provide inseparable regioisomers. ESMS(M+1)=216.14._The mixture of regioisomers from Step 1 (1-(4-fluorobenzyl)-3-methyl-1H-pyrazole-4-carbonitrile and 1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-4-carbonitrile (430.5 mg, 2.000 mmol), Boc2O (525 mg, 2.400 mmol), and dichlorocobalt hexahydrate (235.6 mg, 0.99 mmol) were taken into MeOH (5 mL) and cooled to 0°C. Sodium borohydride (940 mg, 1 mL, 24.8 mmol) was added to the mixture portion wise (the reaction turned black) and stirred for 1 hour. The reaction was evaporated in vacuo to afford a black solid. This was suspended in ethyl acetate (30 mL) and H2O (15 mL). The organic layer was collected and filtered to remove remaining solids. The filtrate was washed with brine and dried over MgSO4to provide the crude product that was purified by column chromatography (SiO2) eluting with a gradient of 0-50% ethyl acetate in hexane to give two peaks. The top spot was minor and the bottom spot was major. By H NMR and TLC, both spot were not separated cleanly so combined for next step (ratio: 1: 2.3).Top spot (ratio 1: 1.3):1H NMR (400 MHz, CDCl3)δ7.30 (d, J=69.7 Hz, 1H), 7.18-7.00 (m, 2H), 29.9 Hz, 2H), 6.96 (td, J=8.7, 6.6 Hz, 2H), 5.14 (d, J=4.53 (m, 1H), 4.92-(d, J=23.8 Hz, 3H), 4.07 (t, J=4.9 Hz, 2H), 2.16 (d, J=23.8 Hz, 3H), 1.41 (d, J=3.1 Hz, 9H).Bottom Spot (ratio 1:3):1H NMR (400 MHz, CDCl3)δ7.23 (s, 1H), 7.17 (ddd, J=8.1, 5.2, 2.5 Hz, 2H), 7.05-6.94 (m, 2H), 5.26-5.06 (m, 2H), 4.65 (s, 1H), 4.10 (d, J=5.1 Hz, 2H), 2.28-2.09 (m, 3H), 1.44 (q, J=2.5, 2.1 Hz, 10H). ESMS(M+1)=320.09._The mixture of regioisomers from Step 2 (1 g, 3.26 mmol) were taken into 1,4-dioxane (2 mL). A solution of 4 M HCl (4 mL, 16 mmol) in dioxane was added to the solution and stirred at room temperature for 3 hours. Diethyl ether (10 mL) was added to the solution and a yellow precipitate formed. This was collected and dried to provide a mixture of regioisomers that were not separable.1H NMR (400 MHz, Methanol-d4)δ8.77 (s, 1H), 8.60-8.28 (m, 1H), 8.11 (td, J=5.9, 2.8 Hz, 1H), 7.95 (dddt, J=13.5, 8.7, 6.5, 2.6 Hz, 2H), 6.05 (dt, J=27.0, 2.4 Hz, 2H), 4.63 (dq, J=5.2, 2.7 Hz, 2H), 4.06-3.86 (m, 2H), 3.00 (dt, J=22.3, 1.8 Hz, 3H). ESMS(M+1)=220.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrazine hydrate; sodium hydrogencarbonate In water; toluene at 5℃; for 2h; | 2 Example 2 In a four-necked flask, put 98 g of a 10% aqueous solution of hydrazine hydrate,The percentage is the mass percentage of the mass of hydrazine hydrate relative to the total mass of the aqueous solution.2% sodium bicarbonate aqueous solution adjusts the pH of the reaction system to 8-9,The percentage is the mass percentage of the mass of sodium bicarbonate relative to the total mass of the aqueous solution, and the temperature is reduced to 5 ° C.75.7 g of the 2-((dimethylamino) methylene) -3-oxobutyronitrile toluene solution obtained in Example 1 was added dropwise,The temperature is controlled at <5 ° C. After dripping, stirring for 2hr, standing and layering,The organic layer was washed with 22.7 g of 10% hydrochloric acid, and the percentage was mass percentage.17.9 g of 3-methyl-4-cyano-1H-pyrazole was obtained in a yield of 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With potassium carbonate In tetrahydrofuran at 20℃; for 5h; | 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitr ile (38) 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitr ile (39) In accordance with Step 2 of Example 2, 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, accordingly, the products 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (38) (16.5 mg, white solid, yield: 19.5%) and 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (39) (9.5 mg, white solid, yield: 11%) were obtained. |
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