Structure of 871014-19-6
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CAS No. : | 871014-19-6 |
Formula : | C9H18N2O2 |
M.W : | 186.25 |
SMILES Code : | O=C(OC(C)(C)C)N[C@H]1C[C@H](N)C1 |
MDL No. : | MFCD09040641 |
InChI Key : | OPDOEOOBYOABCJ-UHFFFAOYSA-N |
Pubchem ID : | 16228707 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.89 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 50.48 |
TPSA ? Topological Polar Surface Area: Calculated from |
64.35 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.23 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.61 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.0 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.56 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.06 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.89 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.12 |
Solubility | 14.3 mg/ml ; 0.0767 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.54 |
Solubility | 5.43 mg/ml ; 0.0291 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.12 |
Solubility | 14.1 mg/ml ; 0.0755 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) |
No |
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 |
-7.0 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) |
2.92 |
* 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 |
---|---|---|
81% | With dmap; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 110℃; for 2h; | Tert-butyl(trans-3-aminocyclobutyl)carbamate (1.48 g, 7.95 mmol), 2-chlorobenzothiazole (1.6 ml, 12.93 mmol), 4-dimethylaminopyridine (0.051 g, 0.417 mmol), and diisopropylethylamine (3.0 ml, 17.25 mmol) were suspended in dry dimethylsulfoxide (5 mL) under nitrogen. The mixture was heated at 110 C. for 2 hours then cooled to room temperature. Then, the mixture was partitioned between 30% saturated ammonium chloride (300 mL) and ethyl acetate (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was triturated with 1:1 dichloromethane:hexane (50 mL total) at 40 C. The mixture was filtered through a sintered glass frit and the solids washed with additional 1:1 dichloromethane:hexane (10 mL) before drying under high vacuum to give tert-butyl(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl) carbamate (2.063 g, 6.46 mmol, 81% yield) as an off white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.5% | With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 2h; | Tert-butyl(trans-3-aminocyclobutyl)carbamate (1.38 g, 7.41 mmol), 2-chloro-3-nitropyridine (1.25 g, 7.88 mmol) and potassium carbonate (0.655 ml, 10.85 mmol) were combined in dry dimethylsulfoxide (20 mL) and heated at 110 C. After 2 hours the reaction was cooled and partitioned between ethyl acetate (300 mL) and water (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired tert-butyl(trans-3-((3-nitropyridin-2-yl)amino)cyclobutyl)carbamate (1.45 g, 4.70 mmol, 63.5% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.4% | With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; sodium t-butanolate; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | A microwave vial containing a mixture of ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2-methylpropanoate (2.08 g, 7.57 mmol), tert-butyl(trans-3-aminocyclobutyl)carbamate (1.551 g, 8.33 mmol), tris(dibenzylideneacetone) dipalladium (0) (0.520 g, 0.568 mmol), dicyclohexyl(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine (0.731 g, 1.363 mmol) and sodium tert-butoxide (2.317 ml, 18.93 mmol) in dioxane (15 mL) was purged with argon and capped. The reaction mixture was heated at 100 C. for 3 hours, cooled, and partitioned between water (200 mL) and ethyl actate (200 mL). The organic was isolated and concentrated under reduced pressure. Purification using the ISCO eluting with 0-70% EtOAc/hexane to give the desired product tert-butyl(trans-3-(5,5-dimethyl-2-(methylthio)-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate (0.9 g, 2.378 mmol, 31.4% yield). m/z: 379.2 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.4% | With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2?,4?,6?-tri-1-propyl-1,1?-biphenyl][2-(2-aminoethyl)phenyl]palladium(II); sodium t-butanolate; In 1,4-dioxane; at 50℃; for 0.5h;Inert atmosphere; | Methyl (2-chloro-5-fluoropyridin-3-yl)(methyl)carbamate (intermediate 37, 0.343 g, 1.569 mmol), tert-butyl(trans-3-aminocyclobutyl)carbamate (0.292 g, 1.569 mmol), BrettPhos Precatalyst (0.125 g, 0.157 mmol), and sodium tert-butoxide (0.377 g, 3.92 mmol) were mixed in 1,4-dioxane (2 mL) under an argon atmosphere. The reaction mixture was heated to 50 C. and stirred for 30 min. The reaction mixture was diluted with water and extracted once with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield tert-butyl(trans-3-(6-fluoro-1-methyl-2-oxo-1 h-imidazo[4,5-b]pyridin-3(2h)-yl)cyclobutyl)carbamate (0.250 g, 0.743 mmol, 47.4% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 2h; | A mixture of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.099 g, 0.533 mmol), 2-chloro-6-fluoro-1,3-benzothiazole (0.100 g, 0.533 mmol) and diisopropylethylamine (0.185 ml, 1.066 mmol) in DMSO (0.5 mL) contained in a microwave vial was capped and heated to 120 C. for 2 hrs. The mixture was diluted with water and extracted with EtOAc. EtOAc extract was concentrated to give crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate. To the crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate was added hydrogen chloride, 4N in 1,4-dioxane (10 ml, 40.0 mmol) and the resulting solution stirred at room temperature for 2 h and concentrated to afford crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride. The crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride was added to mixture of methyl (2-chloropyridin-3-yl)(methyl)carbamate, INTERMEDIATE 40, (0.107 g, 0.533 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2?-4?-6?-triisopropyl-1,1?-biphenyl)]2-(2-aminoethyl)Ph)Pd(II) (0.021 g, 0.027 mmol), and sodium tert-butoxide (0.261 ml, 2.132 mmol) in dioxane (10 mL). The mixture was stirred at 100 C. for 2 h and concentrated. The residue was diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO on silica gel column eluting with 0-80% EtOAc/hexanes to give the title compound 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.092 g, 0.249 mmol, 46.7% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) delta: ppm 8.07 (dd, J=5.18, 1.27 Hz, 1H), 7.49 (dd, J=8.90, 4.79 Hz, 1H), 7.32 (dd, J=8.12, 2.64 Hz, 1H), 7.17 (dd, J=7.73, 1.27 Hz, 1H), 6.97-7.07 (m, 2H), 5.90 (br. s., 1H), 5.33-5.50 (m, 1H), 4.48-4.74 (m, 1H), 3.48-3.67 (m, 2H), 3.43 (s, 3H), 2.34-2.63 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.6% | With caesium carbonate; In dimethyl sulfoxide; at 70℃; | Tert-butyl(trans-3-aminocyclobutyl)carbamate (0.150 g, 0.805 mmol) and intermediate 5 (0.120 g, 0.703 mmol) were dissolved in dry dimethylsulfoxide (3 mL) and cesium carbonate (0.123 ml, 1.535 mmol) was added. The reaction was heated at 70 C. After minutes the reaction was cooled and partitioned between water (100 mL) and ethyl acetate (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired tert-butyl(trans-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclobutyl)carbamate (0.150 g, 0.468 mmol, 66.6% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 2-(1H-9-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 21h; | 2-(2-Chloropyridin-3-yl)-2-methylpropanoic acid hydrochloride (intermediate 25, 992 mg, 4.20 mmol), tert-butyl(trans-3-aminocyclobutyl)carbamate (939 mg, 5.04 mmol), hatu (2077 mg, 5.46 mmol) and triethylamine (2.4 ml, 16.81 mmol) were dissolved in dichloromethane (8.4 mL). The reaction mixture was stirred at room temperature for 21 hours then diluted with water and extracted with dichloromethane. The organic was washed with saturated ammonium chloride and dried over magnesium sulfate. Evaporation under reduced pressure and purification using silica chromatography (0% to 100% ethyl acetate in hexane gradient) gave tert-butyl(trans-3-(2-(2-chloropyridin-3-yl)-2-methylpropanamido)cyclobutyl)carbamate (1327 mg, 3.61 mmol, 86% yield) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 24h; | To a solution of N-(6-bromopyridin-2-yl)-2-chloroacetamide (349a) (0.55 g, 2.204 mmol, prepared according to the procedure reported by Chenard, Bertand L. and Wu, Xinyuan; in PCT Int. Appl., 2016044792, 24 Mar 201 6) in THF (10 mL) was added DIPEA (0.578 mL, 3.31 mmol), tert-butyl (/ram)-3-aminocyclobutylcarbamate (0.452 g, 2.425 mmol) and stirred at 60 C for 24h. Mixture was poured into sat. NaHCCb solution (60 ml) and resultant suspension was extracted with EtOAc (2 x 80 ml). The combined organics were washed with brine, dried, filtered, concentrated and purified by flash column chromatography [silica gel 24 g, EtOAc in hexanes as eluents 0 to 100%] to afford tert-butyl ((iras)-3-((2-((6- bromopyridin-2-yl)amino)-2-oxoethyl)amino)cyclobutyl)carbamate (349b) (0.43 g, 49 % yield) as off-white solid; NMR (300 MHz, VMSO-de) delta 10.45 (s, 1H), 8.10 (dd, J = 8.1, 0.7 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.35 (dd, J = 7.7, 0.7 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 4.09 - 3.93 (m, 1H), 3.27 - 3.14 (m, 3H), 2.03 - 1.89 (m, 4H), 1.36 (s, 9H); MS (ES+): 421.3, 423.3 (M+Na), MS (ES-): 397.3, 399.3 (M-l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Step 1: tert-Butyl ((trans)-3-(6-chloropyrazine-2-carboxamido)cyclobutyl)carbamate A stirred solution of 6-chloropyrazine-2-carboxylic acid (0.25 g, 1.58 mmol) in DMF (3 mL) was added with DIPEA (0.42 mL, 2.37 mmol) and HATU (0.72 g, 1.9 mmol). The reaction mixture was stirred at room temperature for 20 minutes. A solution of <strong>[871014-19-6]tert-butyl (trans-3-aminocyclobutyl)carbamate</strong> (0.32 g, 1.74 mmol) in DMF (3 mL) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and was washed sequentially with saturated aqueous sodium hydrogen carbonate (*2) and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated at reduced pressure to afford the title compound (0.530 g, 93%). 1H NMR (400 MHz, DMSO-d6); delta 9.18 (d, J=7.5 Hz, 1H), 9.11 (s, 1H), 9.01 (s, 1H), 7.30 (d, J=7.0 Hz, 1H), 4.54-4.49 (m, 1H), 4.08-4.01 (m, 1H), 2.70 (s, 1H), 2.48-2.39 (m, 2H), 2.27-2.19 (m, 2H), 1.40 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | To a solution of 1.6 (200 mg, 0.548 mmol), tert-butyl (1r,3r)-3- aminocyclobutylcarbamate (122 mg, 0.658 mmol), HOBt (248 mg, 1.096 mmol) and TEA (166 mg, 1.644 mmol) in DCM (10 mL) was added EDCI (210 mg, 1.096 mmol) portion wise under ice-water bath. The reaction mixture was then stirred at RT for 16 h. Upon completion, the reaction mass was diluted with DCM (50 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The crude product was purified on prep-TLC using 9% MeOH/DCM to afford 12a.1 (190 mg, 65.0% yield) as white solid. LCMS (ESI+) m/z = 534 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
800 mg | A solution of <strong>[871014-19-6]tert-butyl N-[(trans)-3-aminocyclobutyl]carbamate</strong> (545 mg, 2.78 mmol) and methyl (3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate (820 mg, 2.78 mmol) in DCM (30 mL) was stirred for 1 h at 25 C. Sodium triacetoxyborohydride (807 mg, 3.62 mmol) was added in two portions, and the resulting mixture was stirred for additional 14 h at 25 C. The reaction was quenched by the addition of water/ice (30 mL). The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was treated with DMF (5 mL). The solids were collected by filtration, washed with MeOH (3 x 10 mL) and dried in an oven to afford benzyl N-[(3S)-5-oxo-l-[(trans)-3-[[(tert- butoxy)carbonyl]amino]cyclobutyl]pyrrolidin-3-yl]carbamate as a white solid (800 mg). LCMS (ES, m/z) 404 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Into a 100 mL round-bottom flask was placed 5-bromothiazole-2-carboxylic acid (300 mg, 1.41 mmol), N,N-dimethylformamide (5 mL), tert-butyl N-[(trans)-3- aminocyclobutyl]carbamate (270 mg, 1.42 mmol), N,N-diisopropylethylamine (560 mg, 4.33 mmol) and HATU (661 mg, 1.74 mmol). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was poured into water (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-TLC (eluting with 1 : 1 ethyl acetate/petroleum ether) to afford tert-butyl ((trans)-3-(5-bromothiazole-2- carboxamido)cyclobutyl)carbamate as a yellow solid. LC-MS (ESI) m/z 320.0, 322.0 [M+H-tBu]+ |