Structure of 78208-72-7
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CAS No. : | 78208-72-7 |
Formula : | C9H14N2O2 |
M.W : | 182.22 |
SMILES Code : | O=C(C1=CC(C(C)C)=NN1)OCC |
MDL No. : | MFCD03232642 |
InChI Key : | ILTUMWMASHHTOQ-UHFFFAOYSA-N |
Pubchem ID : | 6422484 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.56 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 49.25 |
TPSA ? Topological Polar Surface Area: Calculated from |
54.98 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.99 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.93 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.71 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.98 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.05 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.73 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.21 |
Solubility | 1.13 mg/ml ; 0.00622 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.71 |
Solubility | 0.356 mg/ml ; 0.00196 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.54 |
Solubility | 0.527 mg/ml ; 0.00289 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.04 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.3 |
* 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 |
---|---|---|
88% | With sodium hydroxide; In ethanol; water; at 20℃; for 3h; | To a mixture of compound 14-4 (2.2 g, i2 mmol) in a mixed solvent of ethanol (10 mL) and water (5 mL) was added NaOH (1.9 g, 48 mmol). The mixture was stirred at rt for 3 hours. After the reaction was complete, the mixture was adjusted with hydrochloric acid (1 M) to pH 2 and concentrated in vacuo to remove ethanol. The mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaC1 solution, and dried over anhydrous Na2504 and concentrated in vacuo to give product 14-5 as a white solid (1.64 g, 88percent). |
With sodium hydroxide; water; In 1,4-dioxane; at 50℃; for 3h; | <strong>[78208-72-7]5-isopropyl-1H-pyrazol-3-carboxylic acid ethyl ester</strong> (18.9 g, 104 mmol) and 1M NaOH solution (260 mL, 259 mmol) were dissolved in 1,4-dioxane (300 mL), the reaction was heated to 50° C. under nitrogen and stirred for 3 h. The reaction mixture was cooled, adjusted to pH 2 using concentrated hydrochloric acid and the solvent was removed under reduced pressure. The residual solid was azeotroped with toluene (2.x.30 mL), dissolved in ethyl acetate (500 mL) and washed with water. The aqueous phase was removed, extracted with ethyl acetate (2.x.200 mL) and the combined organic extracts were dried over MgSO4. The solvent was removed under reduced pressure and the residue was azeotroped with dichloromethane (2.x.50 mL) to give the title product (14.7 g) as a white solid; 1H NMR (400 MHz, DMSO-D6): delta 12.50-13.30 (bs, 2H), 6.42 (s, 1H), 2.84-2.94 (quin, 1H), 1.15-1.19 (d, 6H) ppm; LRMS (electrospray): m/z [M-H]+ 153. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With hydrazine hydrate; In ethanol; at 75℃; for 1h;Inert atmosphere; | A mixture of compound 14-3 (1 g, 5.37 mmol) and hydrazine hydrate (10.7 mmol, 9.64 mol/L) in ethanol (20 mL) was stirred at 75 °C under N2 for 1 hour. After the reaction was complete, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE : EtOAc (V: V) = 2 : ito afford a pale yellow solid 14-4 (0.55 g, 56percent). MS (ESI, pos.ion) m/z: i83.i[M+1] and 1HNIVIR (600 MFIz, CDC13): (5 11.37 (b, iH), 6.63 (s, iH), 4.40?4.37 (m, 2H), 3.07?3.05 (m, iH), 1.43?1.40 (m, 3H), 1.39?1.30 (m, 6H) ppm. |
54% | With hydrazine hydrate; acetic acid; In ethanol; for 12h; | a) Ethyl 5-isopropyl-lH-pyrazole-3-carboxylate To a solution of ethyl 4-methyl-3-oxopentanoate (4 g, 21.6 mmol, CAS: 7152-15-0) in ethanol (100 mL), was added acetic acid (1.9 g, 32.4 mmol) and hydrazine monohydrate (1.7 g, 0.032 mol, CAS: 7803-57-8). The reaction mixture was stirred for 12 hours until LCMS analysis indicated the completion of the reaction. The reaction solution was concentrated under reduced pressure and diluted with water. The mixture was extracted twice with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine(40 mL), dried over Na2S04, filtered through thin silica pad, and concentrated under vacuum to give ethyl 5-isopropyl-lH-pyrazole-3- carboxylate (2.1 g, 54percent yield) as a yellow oil. MS (ESI): 183.2 (M+H)+. |
With hydrazine; In ethanol; water; at 20℃; for 18h; | Hydrazine hydrate (6.6 mL, 134 mmol) was added to a solution of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (23.8 g, 188 mmol) in ethanol (100 mL) at RT under nitrogen. The reaction was allowed to proceed at RT for 18 h, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and water (300 mL) and the aqueous phase was removed. The organic phase was washed with water (2.x.200 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane:ethyl acetate (4:1 changing to 2:1, by volume) to give the title product (18.9 g) as a white solid; 1H NMR (400 MHz, CDCl3): delta 10.80-10.95 (bs, 1H), 6.61 (s, 1H), 4.33-4.40 (quart, 2H), 2.98-3.08 (quin, 1H), 1.35-1.41 (t, 3H), 1.24-1.32 (d, 6H) ppm; LRMS (electrospray): m/z [M-H]+ 181. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 18h; | A mixture of <strong>[78208-72-7]ethyl 5-isopropyl-1H-pyrazole-3-carboxylate</strong> (Chem. and Pharm. Bull. 1984; 32(4);1568) (509 mg, 2.8 mmol), 2-(2-bromoethoxy)tetrahydro-2-pyran (732 mg, 3.5 mmol) and potassium carbonate (483 mg, 3.5 mmol) in 1-methyl-2-pyrrolidinone (5 ml) was stirred at 80° C. for 18 hours. The cooled mixture was poured into ethyl acetate and washed with water and brine, then dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (20:80 to 40:60) to afford the title compound of preparation 34 as a clear oil, 663 mg. [0469] 1HNMR (CDCl3, 400 MHz) delta: 1.25 (d, 6H), 1.37 (t, 3H), 1.44-1.71 (m, 6H), 2.97 (m, 1H), 3.42 (m, 1H), 3.54 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H), 4.32 (q, 2H), 4.54 (t, 1H), 4.68 (m, 1H), 4.76 (m, 1H), 6.64 (s, 1H). [0470] LRMS: m/z ACPI+ 311 [MH]+ [0471] Further elution provided the title compound of preparation 35, 242 mg. [0472] 1HNMR (CDCl3, 400 MHz) delta: 1.25 (d, 6H), 1.38 (t, 3H), 1.46-1.72 (m, 6H), 3.15 (m, 1H), 3.45 (m, 1H), 3.65 (m, 1H), 3.81 (m, 1H), 4.10 (m, 1H), 4.34 (m, 2H), 4.39 (m, 2H), 4.49 (t, 1H), 6.57 (s, 1H). [0473] LRMS: m/z ACPI+ 311 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With sulfuric acid; for 3h;Heating / reflux; | Preparation 6 5-ISOPROPYL-1 H-PVRAZOLE-3-CARBOXYLIC acid ethyl ester 5-ISOPROPYL-1 H-PYRAZOLE-3-CARBOXYLIC acid (WO 03/035065, page. 485, example 17b) (1. 00G, 6. 49mmol) was dissolved in a mixture of concentrated sulphuric acid (1.5mL) and ethanol (25mL) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was cooled, poured into water, basified with 0. 88 ammonia then extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield the title product, 514mg (43percent). 1HNMR (CDCI3, 400MHZ) : 1.30 (d, 6H), 1.38 (t, 3H), 3.64 (m, 1H), 4.38 (m, 2H), 6.63 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 18h; | Preparation 14 5-ISOPROPYL-1-R2- (TETRAHVDRO-PVRAN-2-YLOXV)-ETHYLL-1 H-PYRAZOLE-3-CARBOXYLID ethyl ester The ester of preparation 6 (509mg, 2. 8MMOL), 2- (2-bromoethoxy) tetrahydro-2H- pyran (732mg, 3. 5MMOL) and potassium carbonate (483mg, 3. 5MMOL) were dissolved in 1-methyl-2-pyrrolidinone (5mL) and the reaction mixture heated to 80°C for 18 hours. The reaction mixture was cooled, poured into ethyl acetate, washed with water (x 2) and brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate 80: 20 to 60: 40 to yield the title product, 663mg (76percent). HNMR (CD3, 400MHZ) : 1.25 (d, 6H), 1.37 (t, 3H), 1.44-1. 71 (m, 6H), 2.97 (m, 1 H), 3.42 (m, 1 H), 3.54 (m, 1 H), 3.75 (m, 1 H), 4.00 (m, 1 H), 4.32 (m, 2H), 4.54 (t, 1 H), 4.68 (m, 1 H), 4.76 (m, 1 H), 6.64 (s, 1 H). MS ES+ M/Z 227 [MH] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 2 5-Isopropyl-1H-pyrazol-3-carboxylic Acid Ethyl Ester Hydrazine hydrate (6.6 ml, 134 mmol) was added to a solution of the product from Preparation 1 (23.8 g, 188 mmol) in ethanol (100 ml) at room temperature under nitrogen. The reaction was allowed to proceed at room temperature for 18 h, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (300 ml) and water (300 ml) and the aqueous phase was removed. The organic phase was washed with water (2*200 ml), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluding with a solvent gradient of pentane:ethyl acetate (4:1 changing to 2:1, by volume) to give the title product (18.9 g) as a white solid; 1H NMR (400 MHz, CDCl3): delta=10.80-10.95 (1H, brs), 6.61 (1H, s), 4.33-4.40 (2H, quart), 2.98-3.08 (1H, quin), 1.35-1.41 (3H, t), 1.24-1.32 (6H, d) ppm; LRMS (electrospray): m/z [M-H]+181. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 3 5-Isopropyl-1H-pyrazol-3-carboxylic Acid The product from preparation 2 (18.9 g, 104 mmol) and 1M NaOH solution (260 ml, 259 mmol) were dissolved in 1,4-dioxan (300 ml), the reaction was heated to 50° C. under nitrogen and stirred for 3 h. The reaction mixture was cooled, adjusted to pH 2 using concentrated hydrochloric acid and the solvent was removed under reduced pressure. The residual solid was azeotroped with toluene (2*30 ml), dissolved in ethyl acetate (500 ml) and washed with water (200 ml). The aqueous phase was removed, extracted with ethyl acetate (2*200 ml) and the combined organic extracts were dried over MgSO4. The solvent was removed under reduced pressure and the residue was azeotroped with dichloromethane (2*50 ml) to give the title product (14.7 g) as a white solid; 1H NMR (400 MHz, DMSO-D6): delta=12.50-13.30 (2H, brs), 6.42 (1H, s), 2.84-2.94 (1H, quin), 1.15-1.19 (6H, d) ppm; LRMS (electrospray): m/z [M-H]+153. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54%; 20% | NaH (1.23 g, 31.15 mmol) was dissolved in DMF (200 mL) under 2 atmosphere at 0 °C. To this solution was added <strong>[78208-72-7]ethyl 5-isopropylpyrazole-3-carboxylate</strong> (5.16 g, 28.33 mmol) in DMF (50 mL) over 10 min at 0 °C. After the addition, the r.m. was stirred for 10 min at 0 °C and then at r.t. for 40 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (4.5 mL, 31.15 mmol) was subsequently added and the mixture was stirred at r.t. for 3 h. After this time the rm was quenched by addition of EtOH at 0 °C. Water was added to the mixture and the water layer was extracted with EtOAc. The organic layer was then washed with brine, dried (MgS04), filtered and concentrated in vacuo. The resulting crude was purified by flash column chromatography (silica; heptanes/EtOAc 100/0 to 60/40) to afford intermediate 42 (4.05 g, 54percent) and regioisomer intermediate 43 (1.52 g, 20percent). | |
54%; 20% | NaH (1.23 g, 31.15 mmol) was dissolved in DMF (200 mL) under N2 atmosphere at 0° C. To this solution was added <strong>[78208-72-7]ethyl 5-isopropylpyrazole-3-carboxylate</strong> (5.16 g, 28.33 mmol) in DMF (50 mL) over 10 min at 0° C. After the addition, the r.m. was stirred for 10 min at 0° C. and then at r.t. for 40 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (4.5 mL, 31.15 mmol) was subsequently added and the mixture was stirred at r.t. for 3 h. After this time the rm was quenched by addition of EtOH at 0° C. Water was added to the mixture and the water layer was extracted with EtOAc. The organic layer was then washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting crude was purified by flash column chromatography (silica; heptanes/EtOAc 100/0 to 60/40) to afford intermediate 42 (4.05 g, 54percent) and regioisomer intermediate 43 (1.52 g, 20percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 12h; | b) Ethyl 5-isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylate To a solution of ethyl 5-isopropyl-lH-pyrazole-3-carboxylate (1 g, 5.5 mmol) in DMF (10 mL), were added 2,2,2-trifluoroethyl iodide (1.7 g, 8.3 mmol, CAS: 353-83-3) and Cs2C03 (2.1 g, 11 mmol). The reaction mixture was stirred at 50°C for 12 hours. Then the reaction solution was concentrated under reduced pressure and diluted with water. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered through a thin silica pad, and concentrated under vacuum. The crude product was purified by silica gel chromatography to give ethyl 5-isopropyl-2-(2,2,2- trifluoroethyl)pyrazole-3-carboxylate (500 mg, 36percent yield) as a white solid. MS (ESI): 265.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With Selectfluor; In acetonitrile; at 0 - 70℃; for 15h; | b) Ethyl 4-fluoro-5-isopropyl- 1 H-pyrazole-3-carboxylateTo a solution of <strong>[78208-72-7]ethyl 5-isopropyl-1H-pyrazole-3-carboxylate</strong> (5.0 g, 0.027 mmol) in CH3CN(300 mL) was added Selectfluor (12.65 g, 35.67 mmol, CAS: 14068 1-55-6) at 0°C. The solutionwas stilTed at 70°C for 15 hours and cooled to room temperature afterwards. Volatiles were removed under reduced pressure. The residue was diluted with aqueous HC1 (3N, 200 mL) and extracted with CH2C12 (100 mLx2). The organic layer was washed with brine, dried over Na2504, and concentrated under reduced pressure. Purification by flash chromatography (silica gel,CH2C12/MeOH = 200/1 100/1 by vol) gave ethyl 4-fluoro-5-isopropyl-1H-pyrazole-3- carboxylate (900 mg, 17percent yield) as a yellow oil.MS (ESI): 201.1 ([M+H]j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | a) Ethyl 5-isopropyl- 1 H-pyrazole-3-carboxylateTo a solution of CH3CH2ONa (23 g, 0.34 mol) in anhydrous EtOH (500 mL) were added diethyl oxalate (50 g, 0.34 mol, CAS: 95-92-1) and 3-methyl-2-butanone (29 g, 0.34 mol, CAS: 563-80- 4) at 0°C. The solution was stuffed at 50°C overnight. The mixture was cooled to O-5°C, and acetic acid (20.4 g, 0.34 mol) was added, followed by hydrazine monohydrate (17.2 g, 0.34 mol,CAS: 7803-57-8). The mixture was stirred at 30°C overnight and cooled to room temperature afterwards. Volatiles were removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (500 mL) and extracted with ethyl acetate (1 L). The organic layer was washed with brine and concentrated under reduced pressure to give the desired crude product. Purification by flash chromatography (silica gel, CH2C12/MeOH = 200/1-80/1 by vol)gave crude ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (30 g, 48percent yield) as a yellow solid. MS (ESI): 183.1 ([M+H]j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of ethyl 5-ethyl-1H-pyrazole-3-carboxylate (32.0 mg, 0.190 mmol) in DMF (0.4 mL) was added sodium hydride (7.0 mg, 0.17 mmol, 60percent oil suspension) at 0 oC. After being stirred at room temperature for 10 minutes, a solution of 7-(bromomethyl)-5-chloro-2-phenylpyrazolo[1,5-a]pyridine (50.0 mg, 0.155 mmol) in DMF (0.4 mL) was added to the mixture at 0 oC. After being stirred at 0 oC for 1 h, saturated aq. ammonium chloride was added to the mixture. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, and then dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (Hexane:AcOEt = 4:1) to give the title compound 28c as a yellow oil (34.0 mg, 52percent). |
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