Structure of 53871-08-2
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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. : | 53871-08-2 |
Formula : | C8H16ClNO2 |
M.W : | 193.67 |
SMILES Code : | O=C(C1CNC1)OC(C)(C)C.[H]Cl |
MDL No. : | MFCD20528798 |
InChI Key : | JROLDIFBZMRPMP-UHFFFAOYSA-N |
Pubchem ID : | 67346984 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.88 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 53.46 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.21 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.97 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.0 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.01 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.84 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.61 |
Solubility | 4.81 mg/ml ; 0.0248 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.61 |
Solubility | 4.73 mg/ml ; 0.0244 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.42 |
Solubility | 7.41 mg/ml ; 0.0383 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 |
-6.62 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) |
1.43 |
* 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 |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 1.83h; | 23 -B. tert-Butyl l-(3-chloro-4-cyanobenzyl)azetidine-3-carboxylate; [00260] A solution of 4-(bromomethyl)-2-chlorobenzonitrile (2.30 g, 9.66 mmol), tert-butyl azetidine-3-carboxylate, HCl (0.084 g, 0.434 mmol), and diisopropylethylamine (0.189 mL, 1.09 mmol) in dimethylformamide was stirred at 60 0C for 2.33 hrs. HPLC indicated a 83% complete reaction. Additional diisopropylethylamine (0.189 mL, 1.09 mmol) and tert-butyl azetidine-3-carboxylate, HCl (64 mg) were added and stirring at 60 0C was continued for 1.5 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a 10% aqueous solution of lithium chloride. The organic layer was collected, washed with a 10% aqueous solution of sodium bicarbonate (2x), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded tert-butyl l-(3-chloro-4-cyanobenzyl) azetidine-3-carboxylate (0.138 g) as a tan oil. The compound had an HPLC ret. time = 1.18 min. - Column: PHENOMENEX S5 4.6 x 30 mm (2 min.); Solvent A = 10% MeOH, 90% H2O, 0.1% TFA; Solvent B = 90% MeOH, 10% H2O, 0.1% TFA. MS M+1 = 307.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 1.0h; | 24-B. tert-Butyl l-(4-cyano-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate; [00267] A solution of 4-(bromomethyl)-2-(trifluoromethyl)benzonitrile (0.223 g, 0.843 mmol), tert-butyl azetidine-3-carboxylate, HCl (0.201 g, 0.927 mmol), and diisopropylethylamine (0.74 mL, 4.21 mmol) in dimethylformamide was stirred at 60 0C for 1 hr. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with a 10% aqueous solution of lithium chloride. The organic layer was collected, washed with a 10% aqueous solution of lithium chloride (2x), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded tert-butyl l-(4-cyano-3-(trifluoromethyl)benzyl)azetidine-3- carboxylate (0.268 g, 0.787 mmol, 93%) as a viscous tan oil. The compound had an HPLC ret. time = 1.26 min. - Column: PHENOMENEX S5 4.6 x 30 mm (2 min.); Solvent A = 10% MeOH, 90% H2O, 0.1% TFA; Solvent B = 90% MeOH, 10% H2O, 0.1% TFA. MS M+1 = 341.14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; at 20℃; | 21 -E. tert-Butyl l-(2-fluoro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4- oxadiazol-3-yl)benzyl)azetidine-3-carboxylate; [00248] To a mixture of 3-(4-(bromomethyl)-3-fluorophenyl)-5-(3-phenyl-4- (trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazole (0.080 g, 0.171 mmol) and tert-butyl azetidine-3-carboxylate, HCl salt (0.050 g, 0.256 mmol) at room temperature was added triethylamine (0.071 mL, 0.513 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 20% mixture of ethyl acetate in hexane provided tert-butyl l-(2-fluoro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.073 g, 0.134 mmol, 78 % yield) as a white solid. The compound had an HPLC ret. time = 3.07 min. - Column: CHROMOLITH SpeedROD 4.6 x 50 mm (4 min.); Solvent A = 10% MeOH, 90% H2O, 0.1% TFA; Solvent B = 90% MeOH, 10% H2O, 0.1% TFA. MS M+1 = 545.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 18.0h; | Prepared using General Procedure 7: To a stirred solution of (S)-3-(4-(5- bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido)propanoic acid (0.43 g, 0.93 mmol) in DMF (5 mL) at 0 C was added DIPEA (0.6 g, 4.6 mmol) followed bytert- butyl azetidine-3-carboxylate hydrochloride (0.22 g, 1.1 mmol). To the mixture was added HATU (0.88 g, 2.33 mmol). The reaction was allowed to stir at 0 C for 2h and then allowed to warm to RT for 16 h. Then the reaction mixture was diluted with saturated sodium bicarbonate solution (5 mL), water (5 mL) and EA (10 mL). The layers were separated and the aqueous layer was extracted with EA (2 x 10 mL). The combined organic layers were washed with IN hydrochloric acid, water, brine and then dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-40% EA/Hexanes) to afford 0.43 g (76%) of tert-butyl (S)-1-(3-(4- (5-bromopyrimidin-2-yl)phenyl)-2-(5-ethylthiophene-2-carboxamido) propanoyl) azetidine-3-carboxylate INT 73. LCMS-ESI (m/z) calculated for C28H31BrN4O4S : 599.5; found 601.3 [M+2]+, tR = 4.22 min (Method 25). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 4.0h; | Prepared using General Procedure 7: To a stirred solution of (S)-2- (((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoic acid (6.0 g, 12.2 mmol) in DMF (20 mL) at 0 C was added DIPEA (15.8 g, 122 mmol) followed by <strong>[53871-08-2]tert-butyl azetidine-3-carboxylate hydrochloride</strong> (2.85 g, 14.7 mmol). To the mixture was added HATU (14 g, 36 mmol) slowly in three portions with 30 minute intervals. The reaction was allowed to stir at 0 C for 2h and then allowed to warm to RT over 2h. Then the reaction mixture was diluted with saturated sodium bicarbonate solution (25 mL), water (25 mL) and EA (100 mL). The layers were separated and the aqueous layer was extracted with EA (2 x 100 mL). The combined organic layers were washed with water, brine and then dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-40% EA/Hexanes) to afford 4.6 g (60%) of lert- butyl (S)- 1 -(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2- yl)phenyl)propanoyl)azetidine-3-carboxylate. LCMS-ESI (m/z) calculated for C29H31BrN4O5: 595.5; found 596.6 [M+H]+, tR = 3.59 min (Method 16). |
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