Structure of 1104083-23-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 1104083-23-9 |
Formula : | C9H17NO3 |
M.W : | 187.24 |
SMILES Code : | CC(C)(C)OC(=O)N1CC(C)(O)C1 |
MDL No. : | MFCD16037112 |
InChI Key : | DBJZEDYSQQXOOF-UHFFFAOYSA-N |
Pubchem ID : | 54751705 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.89 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 52.99 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.77 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.41 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.45 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.61 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.56 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.47 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.9 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.09 |
Solubility | 15.3 mg/ml ; 0.082 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.06 |
Solubility | 16.2 mg/ml ; 0.0864 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.75 |
Solubility | 33.4 mg/ml ; 0.178 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 |
-7.12 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) |
2.18 |
* 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 |
---|---|---|
87% | at 0 - 20℃; for 3 h; | Step a. tert-FJutyl 3-hydroxy-3-methylazetidine-l- carboxylate. Methyl magnesium bromide (3M in diethyl ether; 2.92 mL, 8.76 mmol) was added portionwise into a cold (0 °C) solution of tert-butyl 3-oxoazetidine-l-carboxylate (0.5 g, 2.92 mmol) and anhydrous THF (3 mL). The mixture was allowed to come to room temperature and stirred for 3 hours and carefully quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 1/1 ratio) to afford tert-butyl 3- hydroxy-3-methylazetidine-l-carboxylate as oil (480 mg, 87percent yield): XH NMR (500MHz, CDCk) δ ppm 3.87 (d, J= 9.0 Hz, 2H), 3.82 (d, J= 9.0, 2H), 2.46 (s, 1H), 1.51 (s, 3H), 1.44 (s, 9H). |
84% | Stage #1: at 0 - 20℃; for 19.75 h; Stage #2: With ammonium chloride In diethyl ether; water at 20℃; |
Step B: Preparation of 3-hvdroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester.; A solution of 1 -Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 ml_ anh Et2O was cooled to 0 0C and 3M MeMgBr in Et2O (10 ml_, 30 mmol) was added dropwise over 1 h. After 45 min, the reaction was allowed to warm to rt and stir an additional for 18h. Then Vi sat'd NH4CI (aq.) was added and the mixture extracted with EtOAc (2x). The combined organic layers were dried and the resulting semisolid was purified by RP HPLC (Agilent) to give the title compound as a white solid (3.2 g, 84percent). 1H NMR (CDCI3): 3.84 (q, J = 9.2 Hz, 4H), 1.97 (bs, 1 H), 1.52 (s, 3H), 1.44 (m, 9H). |
78.3% | at 0℃; for 1 h; Inert atmosphere | In an oven dried flask, tert-butyl 3-oxoazetidine-l-carboxylate (1.01 g,5.900 mmol) was dissolved in diethyl ether (0.2 M) and place under an atmosphere of N2. The reaction mixture was cooled to 0°C and treated dropwise with methylmagnesium bromide (2.07 mL, 6.195 mmol, 3.0 M). The reaction mixture was stirred at 0°C for 1 hour then quenched by pouring onto ice. The mixture was extracted with diethyl ether, washed with water and brine, dried over Na2S04, filtered, and concentrated in vacuo to provide tert- butyl 3-hydroxy-3-methylazetidine-l-carboxylate (865.3 mg, 4.621 mmol, 78.3percent yield). |
430 mg | at 20 - 35℃; for 1 h; | Methyl magnesium bromide (3.0M in Diethyl ether) (1.5 mL, 4.5 mmol) was added to cold (-10° C.) solution of tert-butyl 3-oxoazetidine-1-carboxylate (650 mg, 3.8 mmol) in THF (10 mL) and stirring was continued at 20-35° C. for 1 h. After which the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethylacetate. The organic layer separated was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using 60-120 silica gel and 50percent EtOAc in Hexane as eluent) to afford 430 mg of the title compound. 1H NMR (400 MHz, DMSO) δ ppm 5.56 (1H, s), 3.7-3.5 (4H, m), 1.4 (9H, s), 1.3 (3H, s). |
430 mg | at -10 - 35℃; for 1 h; | Methyl magnesium bromide (3.0M in Diethyl ether) (1.5 mL, 4.5 mmol) was added to cold (−10° C.) solution of tert-butyl 3-oxoazetidine-1-carboxylate (650 mg, 3.8 mmol) in THF (10 mL) and stifling was continued at 20-35° C. for 1 h. After which the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethylacetate. The organic layer separated was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using 60-120 silica gel and 50percent EtOAc in Hexane as eluent) to afford 430 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 5.56 (1H, s), 3.7-3.5 (4H, m), 1.4 (9H, s), 1.3 (3H, s) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: at 0℃; for 1 h; Stage #2: With water; ammonium chloride In tetrahydrofuran |
Step 1 In a dry round-bottomed flask, 1-Boc-3-azetidinone (0.70 g, 4.1 mmol) was dissolved in THF (20 mL). The solution was cooled to 0° C. and methylmagnesium chloride (3.0 M solution in THF, 2.0 mL, 6.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with 10 mL saturated NH4Cl, diluted with 5 mL water and extracted with 100 mL EtOAc (2*). The combined organic layers were washed with 10 mL water and 10 mL brine then combined, dried over sodium sulfate, filtered and concentrated to afford 757 mg (99percent) of 3-hydroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as an off-white solid. |
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