Structure of 99839-16-4
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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. : | 99839-16-4 |
Formula : | C6H9NOS |
M.W : | 143.21 |
SMILES Code : | CC1=C(C)N=C(CO)S1 |
MDL No. : | MFCD12198452 |
InChI Key : | NNZZUYMCPDVPQA-UHFFFAOYSA-N |
Pubchem ID : | 20402108 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 38.17 |
TPSA ? Topological Polar Surface Area: Calculated from |
61.36 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.61 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.9 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.1 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.09 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.75 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.25 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.64 |
Solubility | 3.28 mg/ml ; 0.0229 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.77 |
Solubility | 2.41 mg/ml ; 0.0168 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.87 |
Solubility | 1.91 mg/ml ; 0.0134 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 |
-6.53 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) |
2.47 |
* 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 |
---|---|---|
38% | Under argon, sodium hydride (60%, 3.1 mg, 0.08 mmol) was added to a solution of (4,5-dimethyl-1,3-thiazol-2-yl)methanol (16.2 mg, 0.11 mmol) in anhydrous THF (1 mL). The reaction mixture was stirred at room temperature for 20 minutes, then 3-chloro-5-(2,6-dimethoxyphenyl)-1,2,4-triazine (10 mg, 0.04 mmol, prepared as in example 41) was added and the resulting mixture was stirred overnight at 70C. An aqueous ammonium chloride solution was added and the mixture was extracted with diethyl ether and ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. Purification by preparative TLC (silica gel, dichloromethane/methanol 95/5) afforded 5-(2,6-dimethoxyphenyl)-3-[(4,5-dimethyl-1,3-thiazol-2-yl)methoxy]-1,2,4-triazine (5.4 mg, 38%) as a pale yellow oil. ESI-MS m/z 359 (M+H)+. 1H NMR (CDCl3), δ (ppm): 8.99 (s, 1H), 7.40 (t, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 2H), 5.80 (s, 2H), 3.76 (s, 6H), 2.36 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; | Step 3: Methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl ester To a stirred solution of (4,5-dimethyl-thiazol-2-yl)-methanol (200 mg, 1.4 mmol) and Et3N (478 mg, 4.2 mmol) in DCM (20 mL) was added MsCl (424 mL, 4.2 mmol) in dropwise at 0 C. After the additional, the mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched by water (15 mL), extracted with DCM (3 x 10 mL). The combined organic phase was dried over Na2S04, filtered and concentrated in vacuum to give the crude product methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl eesstteerr (250 mg, 100% yield): lR NMR (400 MHz, CDC13) δ 5.21 (s, 2H), 3.67 (s, 3H), 2.88 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2 g | With methanol; sodium tetrahydroborate; at 40℃; | Step 2: (4,5-Dimethyl-thiazol-2-yl)-methanol To a solution of 4,5-Dimethyl-thiazole (2.6 g, 18.4 mmol) in MeOH (40 mL) was added NaBH4 (1.4 g, 36.8 mmol) in portions while the temperature was below 40 C, and the mixture was stirred overnight. After TLC showed the start material was disappeared, the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over Na2S04j filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the pure product (4,5-dimethyl-thiazol-2-yl)-methanol (2 g, 77% yield): lR NMR (400 MHz, CDC13) δ 4.76 (s, 2H), 2.25-2.21 (m, 6H); ES-LCMS m/z 144.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.5% | To a solution of<strong>[99839-16-4](4,5-dimethylthiazol-2-yl)methanol</strong> (20.95 mg, 0.146 mmol) in THF (1) at 0 C was added NaH (5.85 mg, 0.146 mmol) and the resulting mixture was stirred for 10 mi (S)-Isopropyl 2-(6-(bromomethyl)-4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4- fluorophenethoxy)phenyl)-2-methylpyridin-3 -yl)-2-(tert-butoxy)acetate (50 mg, 0.073 mmol) in THF (0.5 mL) was then added and the mixture was stirred for 4 h. At this pointLCMS indicated completion of reaction. Mixture was then concentrated and treated with iON NaOH (0.073 mL, 0.731 mmol) in ethanol (1 mL) at 80 C for 4 h. Mixture was then cooled and purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin- 1 -yl)-6-(((4, 5 -dimethylthiazol-2-yl)methoxy)methyl)-5 -(4-(4- fluorophenethoxy)phenyl)-2-methylpyridin-3 -yl)acetic acid (18.3 mg, 0.026 mmol, 35.5% yield). ‘H NMR (500MHz, DMSO-d6) ö 7.43 - 7.32 (m, 2H), 7.23 (d, J=8.4 Hz, 1H),7.14 (t, J=8.8 Hz, 2H), 7.09 -6.98 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 5.82 (br. s., 1H), 4.54-4.35 (m, 2H), 4.30-4.15 (m, 3H), 4.12 (d, J=9.9 Hz, 1H), 3.05 (t, J=6.6 Hz, 2H), 2.85 -2.77 (m, 1H), 2.48 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 1.97- 1.87 (m, 1H), 1.50 (br. s.,1H), 1.38- 1.23 (m, 1H), 1.19(d,J12.iHz, 1H), 1.12(s,9H), 1.02(d,J11.7Hz, 1H),0.85 (br. s., 3H), 0.61 (br. s., 3H). LCMS (M+H) = 704.2. |
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