Structure of 155559-81-2
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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. : | 155559-81-2 |
Formula : | C7H4FNS2 |
M.W : | 185.24 |
SMILES Code : | FC1=CC2=C(SC(S)=N2)C=C1 |
MDL No. : | MFCD02181177 |
InChI Key : | JXMNNMYCHOHEDG-UHFFFAOYSA-N |
Pubchem ID : | 2774531 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 46.83 |
TPSA ? Topological Polar Surface Area: Calculated from |
79.93 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.19 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.52 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.14 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.21 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.85 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.78 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.18 |
Solubility | 0.122 mg/ml ; 0.000658 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.84 |
Solubility | 0.0265 mg/ml ; 0.000143 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.36 |
Solubility | 0.0809 mg/ml ; 0.000437 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) |
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 |
-5.64 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 |
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) |
2.11 |
* 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 |
---|---|---|
76.5% | In N,N-dimethyl-formamide; at 120℃; for 10h; | Step 1) Synthesis of 5-fluorobenzo [d] thiazole-2-thiol 2, 5-Difluoroaniline (1.00 g, 7.75 mmol) and potassium ethylxanthate (2.73 g, 17.05 mmol) were added into N, N-dimethylformamide (50 mL) in turn, the mixture was heated at 120 ? for 10 h. After the reaction is complete, the mixture was cooled to rt and diluted with water (100 mL) . The resulting mixture was adjusted with hydrochloric acid (1 M) to pH 4 to 5. Some solid precipitated, the mixture was filtered by suction. The solid was dried at 50 ? under a vacuum to give the title compound as a white solid (1.11 g, 76.5%) .MS (ESI, pos. ion) m/z: 185.00 [M+H] +; and1H NMR (DMSO-d6, 600 MHz) ? (ppm) : 13.98 (s, 1H) , 7.55 (d, J = 8.2 Hz, 1H) , 7.36~7.31 (m, 2H) . |
67% | In N,N-dimethyl-formamide; at 120℃; for 0.25h;microwave; | A mixture of 2,5-difluoro-phenylamine (129 mg, 1 mmol) and potassium o-ethyl dithiocarbonate (352 mg, 2.2 mmol) in DMF (5 mL) was heated to 120C for 15 min in microwave. The reaction mixture was cooled, diluted with 10 mL of ice water, and acidified with 3 mL of HCI solution (1 mol/L). Then the mixture was extracted with EtOAc (3 x 50 mL), washed with brine and dried over Na2SO/i. The dried organic layers were concentrated to give 5- fluorobenzo[d]thiazole-2-thiol (120 mg, 0.67 mmol, 67%). ESI-MS (M+l): 185 calc. for |
40% | In N,N-dimethyl-formamide; for 4h;Inert atmosphere; Heating; | General procedure: GP3-1: A solution of 2-halo substituted aniline (1.0 eq), potassium ethyl xanthate (1.2 eq or 2.2 eq,typically 2.2 eq) in 10 volume of anhydrous DMF was heated at 100 0Cor 120 0C for 4 hours under nitrogen. TLC monitored the progress ofreaction. After completion, the reaction mixture was cooled to room temperature,diluted with water (10 volume) and neutralized by 1 M HCl solution to pH 5. Theformed precipitate was collected by filtration, rinsed with water, firstlydried by rotavapor, and then dried by oil pump to afford 2-mercaptobenzothiazole.GP3-2: 2-mercaptobenzothiazole in 10 volume ofanhydrous DCM, was added by sulfuryl chloride (SO2Cl2, 1volume) under ice-cooled condition. The mixture was stirred at rt for 1 hour,which was monitored by TLC. After consumption of starting material, the mixturewas diluted by 30 volume of ether, following quenching carefully by addingwater. Stirring was kept for 1 hour to make sure the SO2Cl2was totally consumed and product was released. Organic layer was collected,neutralized by saturated NaHCO3, dried over Na2SO4and purified by silica gel chromatograph to give the pure product, which wasfinally characterized by LC-MS and NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sulfuryl dichloride; at 20 - 60℃; for 100.0h; | Sulfuryl chloride (0.3 mL, 4.41 mmol) was added neat to 5-fluoro-benzothiazole-2-thiol (680 mg, 3.67 mmol). The mixture was stirred at RT for 1 hour, and then heated to 60°C for 40 mins. The resulting solution was cooled to room temperature, and poured onto ice, extracted with EtOAc (3x50 mL), washed with brine and dried over Na2S04. The dried organic layers were concentrated to give 2-chloro-5-fluorobenzo[d]thiazole (520 mg, 2.75 mmol, 75percent). ESI-MS (M+l): 187 calc. for C7H5CIFN4S 186. |
51% | With sulfuryl dichloride; In dichloromethane; at 20℃; for 1.0h;Cooling with ice; | General procedure: GP3-1: A solution of 2-halo substituted aniline (1.0 eq), potassium ethyl xanthate (1.2 eq or 2.2 eq,typically 2.2 eq) in 10 volume of anhydrous DMF was heated at 100 0Cor 120 0C for 4 hours under nitrogen. TLC monitored the progress ofreaction. After completion, the reaction mixture was cooled to room temperature,diluted with water (10 volume) and neutralized by 1 M HCl solution to pH 5. Theformed precipitate was collected by filtration, rinsed with water, firstlydried by rotavapor, and then dried by oil pump to afford 2-mercaptobenzothiazole.GP3-2: 2-mercaptobenzothiazole in 10 volume ofanhydrous DCM, was added by sulfuryl chloride (SO2Cl2, 1volume) under ice-cooled condition. The mixture was stirred at rt for 1 hour,which was monitored by TLC. After consumption of starting material, the mixturewas diluted by 30 volume of ether, following quenching carefully by addingwater. Stirring was kept for 1 hour to make sure the SO2Cl2was totally consumed and product was released. Organic layer was collected,neutralized by saturated NaHCO3, dried over Na2SO4and purified by silica gel chromatograph to give the pure product, which wasfinally characterized by LC-MS and NMR. |
Sulfuryl chloride (50 muL, 0.65 mmol) was added neat to <strong>[155559-81-2]5-fluoro-1,3-benzothiazole-2-thiol</strong> (100 mg, 0.54 mmol). The mixture was stirred at ambient temperature for 1 h, then heated at 60° C. for 30 minutes. The resulting solution was cooled to rt, and poured onto ice. The title compound was collected by filtration, washed with water, and dried under vacuum. The solid obtained was used without further purification; LC-MS m/z 188.1 (MH+), ret. time 3.27 min. |
With thionyl chloride; N,N-dimethyl-formamide; for 3.0h; | Step 2) Synthesis of 2-chloro-5-fluorobenzo [d] thiazole To a 50 mL of reaction flask were added 5-fluorobenzo [d] thiazole-2-thiol (1.00 g, 5.40 mmol) , thionyl chloride (5 mL) and N, N-dimethylformamide (0.10 mL) . The mixture was refluxed for 3 h and cooled to rt. The mixture was concentrated in vacuo to give a product, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(ii) 2-Mercapto-5-fluorobenzthiazole yellow solid mp 125 C. (dec) (from 1,4-difluoro-2-nitrobenzene) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 40Preparation of7V,7V-dicyclopropyl-6-ethyl-4-(5-fluorobenzo[d]thiazol-2-ylamino)-l- methyl-l,6-dihydroimidazo [4,5-d] pyrrolo [2,3-b] pyridine-7-carboxamide 40A Preparation of 5-fluoro-2- methylthio)benzo|"d"lthiazole[00284] To a solution of <strong>[155559-81-2]5-fluoro-2-mercaptobenzothiazole</strong> (0.15 g, 0.810 mmol) in THF (8.10 niL) cooled to 0 C was added sodium hydride (0.036 g, 0.891 mmol). After stirring 10 min, iodomethane (0.076 mL, 1.215 mmol) was added and the reaction mixture was slowly warmed to room temperature over 2 h. The reaction was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 5-fluoro-2-(methylthio)benzo[d]thiazole (0.178 g, 110 % yield) was isolated as a white solid. Material was used without any further purification.[00285] MS (ESI) m/z 200.0 (M+H)[00286] 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.68 (dd, 1H, J= 8.81, 5.04 Hz), 7.56 (dd, 1H, J= 9.57, 2.52 Hz), 7.07 (td, 1H, J= 8.81, 2.52 Hz), 2.80 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 3h; | General procedure: A mixture of 4?-demethylepipodophyllotoxin (DMEP) (400mg 1mmol) and SH-containing building blocks in dichloromethane (15mL) at 0C was mixed with 1mL of TFA as the catalyst. After stirring the reaction mixture for 2-3hat room temperature and maximal conversion was reached (3h, monitored by TLC), the resultant mixture was washed with saturated NaHCO3 (20mL×2) and extracted with CH2Cl2 (45mL×2). The organic layer was dried over MgSO4, and the solvent was evaporated to give a crude residue, which was purified by flash column chromatography (petroleum ether: dichloromethane: ethyl acetate, 3:2:1) to afford the target compounds. The purity of compounds was determined by HPLC with a thermo-C18 (250mm×4.6mm, 5mum) column as the stationary phase and methanol-water (35:65) as the mobile phase at ambient temperature and a flow rate of 2.0mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere; | General procedure: GP3-1: A solution of 2-halo substituted aniline (1.0 eq), potassium ethyl xanthate (1.2 eq or 2.2 eq, typically 2.2 eq) In 10 volume of anhydrous DMF was heated at 100 C. or 120 C. for 4 hours under nitrogen. TLC monitored the progress of reaction. After completion, the reaction mixture was cooled to room temperature, diluted with water (10 volume) and neutralized by 1 M HCl solution to pH 5. The formed precipitate was collected by filtration, rinsed with water, firstly dried by rotavapor, and then dried by oil pump to afford 2-mercaptobenzothiazole.; 2-mercapto-7-fluorobenzothiazole The title compound was prepared according to GP3-1 using 2,3-difluoroaniline (3.0 g, 23.5 mmol), potassium ethyl xanthate (8.2 g, 51.0 mmol) and DMF (30 mL). Water was added to precipitate the product as off-white solid. (4.3 g, 100% yield) LC-MS (ESI): [M+1]+=185.77, tR=3.65 min. 1H NMR (400 MHz, d6-DMSO) delta 14.07 (s, 1H), 7.46 (td, J=8.2, 5.6 Hz, 1H), 7.23-7.16 (m, 2H). 13C NMR (101 MHz, d6-DMSO) delta 189.34, 154.34 (d, J=244.5 Hz), 143.52 (d, J=6.6 Hz), 129.13 (d, J=7.8 Hz), 115.67 (d, J=22.9 Hz), 110.14 (d, J=18.7 Hz), 108.94 (d, J=3.4 Hz). |
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