Structure of 383-50-6
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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. : | 383-50-6 |
Formula : | C9H11FO3S |
M.W : | 218.25 |
SMILES Code : | CC1=CC=C(C=C1)S(=O)(=O)OCCF |
MDL No. : | MFCD01658061 |
InChI Key : | XNRDLSNSMTUXBV-UHFFFAOYSA-N |
Pubchem ID : | 256019 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 50.44 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.75 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.38 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.79 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.17 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.77 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.27 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.37 |
Solubility | 0.923 mg/ml ; 0.00423 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.5 |
Solubility | 0.697 mg/ml ; 0.0032 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.55 |
Solubility | 0.0621 mg/ml ; 0.000284 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) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
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 |
-6.36 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 |
0.0 |
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) |
2.31 |
* 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 |
---|---|---|
41% | Sodium hydride (55% oiliness,140 mg, 3.2 mmols) was added to DMF (5 mL) solution oftert-butyl (3R)-3-hydroxypyrrolidine-1- carboxylate (501.2 mg, 2.7 mmols) and stirred at room temperature for 30 minutes, followed by addition of 2-fluoroethyl p-toluenesulfonate (1.17 g, 5.4 mmols) and further 24 hours' stirring at the same temperature. Ethyl acetate was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil FLASH 25 + M, ethyl acetate : hexane =1:10 → 2:8) to provide the title compound (253 mg, 41 %). | |
NaH 60% dispersion in mineral oil (3.3mmol) was slowly added to a stirring solution of hydroxyl amine (5a-f) (3.0mmol) in 6mL of DMF at room temp, and stirred for 30min. Compound 6 was then slowly added to reaction mixture, followed by an additional hour of stirring. A saturated NaHCO3 (aq) solution (40mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 2:5 EtOAc/hexanes gradient, to afford the desired Boc-protected O-alkylated fluoroethoxy compounds, identified by LCMS. The intermediate was then dissolved in CH2Cl2 (2mL), followed by dropwise addition of CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (7a-f) as oils used in the next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
NaH 60percent dispersion in mineral oil (3.3mmol) was slowly added to a stirring solution of hydroxyl amine (5a-f) (3.0mmol) in 6mL of DMF at room temp, and stirred for 30min. Compound 6 was then slowly added to reaction mixture, followed by an additional hour of stirring. A saturated NaHCO3 (aq) solution (40mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 2:5 EtOAc/hexanes gradient, to afford the desired Boc-protected O-alkylated fluoroethoxy compounds, identified by LCMS. The intermediate was then dissolved in CH2Cl2 (2mL), followed by dropwise addition of CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (7a-f) as oils used in the next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In acetonitrile; for 16h;Reflux; | 2-Iodopyridin-3-ol (30, 250 mg, 1.13 mmol, 1 eq) was suspended in CH3CN (20 mL). After addition of (2-fluoroethyl) tosylate (296 mg, 1.36 mmol, 1.2 eq) in CH3CN (5 mL) and K2CO3 (1.25 g, 9.04 mmol, 8 eq), the suspension was heated to reflux for 16 h. K2CO3 was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 4:1). Colorless solid, mp 75 C, yield 268 mg (1.00 mmol, 89 %). C7H7FINO (267.1). Rf = 0.39 (cyclohexane:ethyl acetate = 2:1). HPLC: 99.9 %, tR = 17.27 min. 1H NMR (600 MHz, CDCl3): δ [ppm] = 4.29 (dt, J = 26.9/4.1 Hz, 2H, OCH2CH2F), 4.83 (dt, J = 47.3/4.1 Hz, 2H, OCH2CH2F), 7.05 (dd, J = 8.1/1.5 Hz, 1H, 4-Hpyridine), 7.20 (dd, J = 8.2/4.6 Hz, 1H, 5-Hpyridine), 8.05 (dd, J = 4.5/1.5 Hz, 1H, 6-Hpyridine). 13C NMR (151 MHz, CDCl3): δ [ppm] = 68.9 (d, J = 21.0 Hz, 1C, OCH2CH2F), 81.7 (d, J = 172.1 Hz, 1C, OCH2CH2F), 112.5 (1C, C-2pyridine), 118.8 (1C, C-4pyridine), 123.6 (1C, C-5pyridine), 143.5 (1C, C-6pyridine), 154.6 (1C, C-3pyridine). IR: v[cm-1] = 3124, 3067 (=C-H), 2963, 2924, 2851 (C-Haliph.), 1558 (C=Carom.), 1439, 1420 (CH2 deform.), 1288, 1038 (C-O). Exact Mass (APCI): m/z = 267.9654 (calcd. 267.9629 for C7H8FINO [MH]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium carbonate; In acetonitrile; at 105℃; for 5.5h; | 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo [b]carbazole-3-carbonitrile (alectinib; 14.5 mg, 0.03 mmol, 1.0 eq.) was dissolvedin dry MeCN (2.0 mL) in a v-vial, and anhydrous K2CO3 (29 mg,0.21 mmol, 7 eq.) was added. To this mixture, fluoroethyl tosylate(21.8 mg, 0.1 mmol, 3.3 eq.) was added, and the reaction mixturewas heated at 105 C for 5.5 h. TLC showed that the mixture had a higher Rf spot (0.6 in 5% MeOH/CH2Cl2) at about 65% intensity ascompared with the starting material (0.5 in 5% MeOH/CH2Cl2). Themixture was filtered and concentrated under a stream of air, andthen the crude product was purified by flash chromatography onsilica gel and eluted with 3% MeOH/CH2Cl2 to obtain fluoroethylalectinib (compound 4; 10 mg, 63% yield) with 99% purity asassessed by analytical HPLC. 4: Rf 0.6 in 5% MeOH/CH2Cl2;1H NMR(DMSO-d6, 600 MHz) d: 8.49 (d, J 8.0, 1H), 8.29, (s, 1H), 8.01 (s,1H), 7.64 (d, J 8.0, 1H), 7.34 (s, 1H), 5.05, (d, JHF 24.1 Hz, 2H), 4.92(d, JHF 47.1 Hz, 2H), 3.61 (s, 5H), 3.23 (d, J 11.6 Hz, 2H), 2.79 (t,J 11.5 Hz, 2H), 2.73 (q, J 7.1 Hz, 2H), 2.33 (quintet, 1H), 2.49, 2H,1.93 (d, J 10.9, 2H), 1.85 (s, 6H), 1.75 (s, 1H), 1.61 (q, J 10.4 Hz,2H), 1.29 (t, J 7.2H, 3H). 1H NMR (CDCl3, 300 MHz) d: 8.75 (d,J 8.2 Hz, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.60 (d, J 6.9 Hz, 1H), 7.16(s, 1H), 4.93 (dt, J 24.6 Hz, 4.6 Hz, 2H), 4.82 (bs, 2H), 3.77 (t,J 4.4 Hz, 4H), 3.31 (d, J 10.7 Hz, 2H), 2.75 (m, 4H), 2.63 (t,J 4.6 Hz, 4H), 2.36 (m, 1H), 2.01 (d, J 11.3 Hz, 2H), 1.87 (s, 6H),1.73 (m, 2H), 1.33 (t, J 7.5 Hz, 3H). 13C NMR decoupled (CDCl3,150 MHz) d: 180.61, 156.85, 156.15, 147.71, 137.71, 136.89, 128.37,126.76, 125.89, 125.73, 123.43, 120.04, 115.92, 114.45, 114.44, 111.97,106.44, 81.92, 80.76, 67.33, 61.98, 52.18, 49.99, 45.94, 45.79, 37.59,29.53, 28.96, 23.20, 14.39. 19F NMR, decoupled (CDCl3, 300 MHz)d: 218.57 (s). HRMS: m/z [MH] calculated for C32H38FN4O2,529.2979; found, 529.2989. |
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