Structure of 169048-83-3
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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. : | 169048-83-3 |
Formula : | C4H6ClNO2 |
M.W : | 135.55 |
SMILES Code : | O=C1O[C@H](CCl)CN1 |
MDL No. : | MFCD08706410 |
InChI Key : | FNOZCEQRXKPZEZ-GSVOUGTGSA-N |
Pubchem ID : | 7058042 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 32.41 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.99 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.38 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.05 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.03 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.03 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.48 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.85 |
Solubility | 19.0 mg/ml ; 0.14 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.75 |
Solubility | 24.1 mg/ml ; 0.178 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.15 |
Solubility | 9.6 mg/ml ; 0.0708 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 |
No |
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 |
-6.86 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 |
2.0 |
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 |
1.0 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) |
2.41 |
* 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 |
---|---|---|
60% | With water; for 15.0h;Reflux; | Potassium cyanate (4.38 g) was dissolved in 220 ml of water, and (S)-epichlorohydrin was slowly added (2.50 g). The solution was stirred overnight (15 h) at reflux. The reaction mixture was then extracted with ethyl acetate (while still moderately warm) (5 x 200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the title compound as a wax (which upon standing overnight in vacuo became an off-white solid) (2.18 g, 60%). |
41% | With magnesium sulfate; In water; at 100℃; for 5.0h; | (S)-Epichlorohydrin [(S)-5, 390 muL, 4.99 mmol] and MgSO4 (1.2 g,10 mmol) were added to a solution of potassium cyanate(KOCN, 811 mg, 10 mmol) in H2O (5 mL). After stirring at100C for 5 h, the reaction mixture was diluted with H2O(5 mL) and then extracted with EtOAc (3×20 mL). The combinedextract was washed with brine (20 mL), dried, andconcentrated in vacuo to give a residue (304 mg). Chromatographyon a silica gel column with n-hexane-EtOAc (1 : 2) asthe eluent gave (S)-6 (275.7 mg, 41%) as a colorless powder.1H-NMR (300 MHz, CDCl3) delta: 6.37 (1H, br s, NH), 4.92-4.81(1H, m), 3.76 (1H, td, J=9.2, 0.7 Hz), 3.72-3.70 (2H, m), 3.54(1H, ddd, J=9.2, 5.9, 0.9 Hz).20) HR-EI-MS m/z 135.0087 [M]+(Calcd for C4H6ClNO2: 135.0087). [alpha]D25 +10.0 (c=1.0, CHCl3). |
In water; for 19.0h;Reflux; | To a solution of (2S)-2-(chloromethyl)oxirane (0.813 g, 8.79 mmol) in water (70 mL) was added potassium cyanate (1.43 g, 17.63 mmol) at room temperature and the resulting mixture was refluxed with stirring for 19 h. The reaction mixture was allowed to cool to room temperature and extracted with ethyl acetate (50 mL, three times). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated by evaporation to yield (5S)-5-(chloromethyl)-1,3-oxazolidin-2-one along with ethyl acetate as colorless oil (87% in ethyl acetate, 0.242 g, 18%,). 1H NMR (270 MHz, CDCl3) delta: 3.52-3.58 (1H, m), 3.63-3.80 (3H, m), 4.81-4.91 (1H, m), 5.56 (1H, br s). MS (ESI+) m/z: 136, 138 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 12.0h; | A mixture of (5S)-5-(chloromethyl)-l,3-oxazolidin-2-one (2.15 g, INTERMEDIATE 4), 2- bromo-5-chloropyridine (3.05 g), cesium carbonate (20.67 g), bispalladium tribenzylideneacetone (2.18 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.07 g) in 16 ml of dioxane was stirred at 850C for 12 h. The sample was then cooled to room temperature, and purified was purified via column chromatography (2x) on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volumes), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (2.44 g, 61%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃; for 2.5h; | General procedure: To the solution of 4-amino-6-{7-chloro-3-oxatricyclo[7.3.1.05,13]trideca-1(13),5,7,9,11-pentaen-8-yl}-1,3,5-triazine-2-thiol (17, 399 mg, 1.21 mmol) and N-(2-chloroethyl)methanesulfonamide (381 mg, 2.41 mmol) in N,N-dimethylformamide (20 mL) was added N-ethyldiisopropylamine (631 muL, 3.14 mmol) at room temperature. The resulting mixture was stirred for 2.5 h at 70 C. After cooling to room temperature, the mixture was extracted between ethylacetate and water. The organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated by evaporation and the resulting residue was purified by preparative HPLC to give the title compound 62%, a light brown solid). H NMR (400 MHz, DMSO-d6) delta: 3.26 (1H, dd, J = 6.6, 8.8 Hz), 3.38 (1H, dd, J = 14.0, 6.0 Hz), 3.47 (1H, dd, J = 14.0, 6.0 Hz), 3.57 (1H, dd, J = 8.8, 8.8 Hz), 4.79-4. 87 (1H, m), 5.05 (2H, s), 5.06 (2H, s), 7.35 (1H, d, J = 7.1 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.45 (1H, s), 7.53 (1H, dd, J = 8.8, 7.1 Hz), 7.57 (1H, s), 7.91 (2H, s). MS (ESI+) m/z: 430, 432 [M+H]+. HRMS (ESI+) m/z: [M+H]+ calcd for C19H1735ClN5O3S, 430.07351; found, 430.07277, [M+H]+ calcd for C19H1737ClN5O3S, 432.07056; found, 432.06954. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With magnesium sulfate; In water; at 100℃; for 5.0h; | (R)-Epichlorohydrin [(R)-5, 390 muL, 4.99 mmol] and MgSO4(1.2 g, 10 mmol) were added to a solution of KOCN (811 mg,10 mmol) in H2O (5 mL). After stirring at 100C for 5 h, thereaction mixture was diluted with H2O (5 mL) and then extractedwith EtOAc (3×20 mL). The combined extract waswashed with brine (20 mL), dried, and concentrated in vacuo to give a residue (320 mg). Chromatography on a silica gelcolumn with n-hexane-EtOAc (1 : 2) as the eluent gave (R)-6(272.8 mg, 40%) as a colorless powder. 1H-NMR (300 MHz,CDCl3) delta: 6.37 (1H, br s, NH), 4.92-4.81 (1H, m), 3.76 (1H,td, J=9.2, 0.7 Hz), 3.72-3.70 (2H, m), 3.54 (1H, ddd, J=9.2,5.9, 0.9 Hz).20) HR-EI-MS m/z 135.0086 [M]+ (Calcd forC4H6ClNO2: 135.0087). [alpha]D25 -9.9 (c=1.0, CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.75h; | (S)-6(21.7 mg, 160 mumol) in N,N-dimethylformamide (DMF)(4.0 mL) was added to a solution of 4 (43.5 mg, 123 mumol).K2CO3 (204 mg, 1.48 mmol) was added, and the reactionmixture was stirred at 140C for 45 min. The mixture wasfiltered, and the filtrate was diluted with H2O (5 mL) and thenextracted with CHCl3 (3×30 mL). The combined extract waswashed with brine (20 mL), dried, and concentrated in vacuoto give a residue (60 mg). Chromatography on a silica gel columnwith n-hexane-EtOAc (1 : 2-1 : 1) as the eluent gave (S)-1(26.8 mg, 48%) as a colorless powder. 1H-NMR (400 MHz,CDCl3) delta: 7.35 (2H, s), 5.79 (1H, br), 5.02 (1H, ddt, J=8.7, 6.2,5.0 Hz), 4.82 (1H, br), 4.20 (2H, d, J=5.0 Hz), 3.91 (1H, dd,J=8.7, 6.2 Hz), 3.82 (1H, t, J=8.7 Hz), 3.67 (3H, s), 3.39 (2H, q,J=6.7 Hz), 2.74 (2H, t, J=6.7 Hz). HR-FAB-MS m/z 450.9498[M+H]+ (Calcd for C14H17Br2N2O5: 450.9504). [alpha]D25 +21.4(c=0.1, MeOH). |
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