Structure of 944804-88-0
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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. : | 944804-88-0 |
Formula : | C8H11BrN2O2S |
M.W : | 279.15 |
SMILES Code : | BrC1=CSC(=N1)NC(OC(C)(C)C)=O |
MDL No. : | MFCD11111844 |
InChI Key : | OVRIFGLINJVMLO-UHFFFAOYSA-N |
Pubchem ID : | 45117837 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 60.06 |
TPSA ? Topological Polar Surface Area: Calculated from |
79.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.47 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.88 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.06 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.4 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.48 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.46 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.39 |
Solubility | 0.115 mg/ml ; 0.000412 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.21 |
Solubility | 0.0173 mg/ml ; 0.0000619 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.1 |
Solubility | 0.224 mg/ml ; 0.000804 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 |
-5.96 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 |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.99 |
* 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 |
---|---|---|
100% | With lithium diisopropyl amide; In tetrahydrofuran; hexane; water; at 20℃; for 12.25h; | Diisopropylamine (2.3 mL, 16 mmol) was taken up in 30 mL of THF and chilled to 0 C. Butyllithium, 2.5M in hexane (6.4 mL, 16 mmol), was added to the reaction mixture, and the mixture was stirred for 20 minutes. tert-Butyl 5-bromothiazol-2-ylcarbamate (1.5 g, 5.4 mmol) was then added slowly in 8 mL of THF. After 15 minutes, approximately 2 mL of water was added, and the mixture was warmed to room temperature and stirred for 12 hours. The mixture was diluted with 30 mL of 1/2 saturated aqueous NH4Cl and transferred to a separatory funnel. The mixture was extracted twice with 5 mL of EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl 4-bromothiazol-2-ylcarbamate (1.5 g, 100% yield) as a brown solid. |
100% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at 20℃; | t-Butyl 4-bromothiazol-2-ylcarbamate: Diisopropylamine (2.3 mL, 16 mmol, Aldrich) was taken up in 30 mL of THF, and the mixture was chilled to 0 0C. Butyllithium (2.5 M in hexane (6.4 mL, 16 mmol, Aldrich)) was added to the reaction mixture, and the mixture was stirred for 20 minutes. tert-Butyl 5-bromothiazol-2- ylcarbamate (1.5 g, 5.4 mmol, prepared as shown in Scheme 2) was then added slowly in 8 mL of THF. After 15 minutes, approximately 2 mL of water was added, and the mixture was warmed to room temperature and stirred for 12 hours. The mixture was diluted with 30 mL of 1/2 saturated aqueous NH4Cl and transferred to a separatory funnel. The mixture was extracted twice with 5 mL of EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl 4-bromothiazol-2-ylcarbamate (1.5 g, 100 %) as a brown solid |
96% | With lithium diisopropyl amide; In tetrahydrofuran; hexanes; water; at 0 - 7℃; for 0.6h; | 4.3 Synthesis of tert-butyl (4-bromo-1,3-thiazol-2-yl)carbamate (507) Tetrahydrofuran (160 mL) and N,N-diisopropylamine (14 mL, 97 mmol) were combined in a 3-neck 500 mL RBF equipped with a stirbar, septum, and an internal temperature probe. The resulting solution was cooled to 0.8 C., and n-butyllithium in hexanes (2.50 M, 38 mL, 95 mmol) was added slowly over ca. 5 min to produce a light yellow solution (Tint max=10 C.), which was stirred and allowed to re-cool to near 0 C. A solution of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate, 506 (8.74 g, 31.3 mmol) in tetrahydrofuran (30.0 mL) was added dropwise to the above solution over 16 min (Tit varied from 0.9 C. to a maximum of 7 C.). The now deep brown reaction mixture was stirred for 15 min before being quenched with water (13 mL), and stirred for an additional 5 minutes. Aqueous saturated NH4Cl (250 mL) and ethyl acetate (250 mL) were added, and the layers were separated. The aqueous was extracted with ethyl acetate, and the combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel with ethyl acetate, and elute through a plug of silica gel with 2 liters of 9:1 hex:EtOAc The eluent was collected, and the solvents were removed to give 507 (8.41 g, 96%) as a colorless solid. Data for 507: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1 H), 7.24 (s, 1 H), and 1.48 (s, 9 H) ppm. 13C NMR (400 MHz, CDCl3) d 160.6, 152.7 (br), 119.8, 110.6, 81.7, and 27.9 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2C=CH2+), 223.1 (100, M79Br-(CH3)2C=CH2+). |
96% | Tetrahydrofuran (160 mL) and N,N-diisopropylamine (14 mL, 97 mmol) were combined in a 3-neck 500 mL RBF equipped with a stirbar, septum, and an internal temperature probe. The resulting solution was cooled to 0.8 C., and n-butyllithium in hexanes (2.50 M, 38 mL, 95 mmol) was added slowly over ca. 5 min to produce a light yellow solution (Tint max=10 C.), which was stirred and allowed to re-cool to near 0 C. A solution of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate, 506 (8.74 g, 31.3 mmol) in tetrahydrofuran (30.0 mL) was added dropwise to the above solution over 16 min (Tint varied from 0.9 C. to a maximum of 7 C.). The now deep brown reaction mixture was stirred for 15 min before being quenched with water (13 mL), and stirred for an additional 5 minutes. Aqueous saturated NH4Cl (250 mL) and ethyl acetate (250 mL) were added, and the layers were separated. The aqueous was extracted with ethyl acetate, and the combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel with ethyl acetate, and elute through a plug of silica gel with 2 liters of 9:1 hex:EtOAc The eluent was collected, and the solvents were removed to give 507 (8.41 g, 96%) as a colorless solid. Data for 507: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1H), 7.24 (s, 1H), and 1.48 (s, 9H) ppm. 13C NMR (400 MHz, CDCl3) d 160.6, 152.7 (br), 119.8, 110.6, 81.7, and 27.9 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2CCH2+), 223.1 (100, M79Br-(CH3)2CCH2+). | |
78% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; | To a solution of 158 diisopropylamine (64mL, 446mmol) in 154 THF (100mL) was added dropwise 159 n-BuLi (2.5M, 173mL) under N2 atmosphere at 0C. After that a solution of 156 47 (40g, 143.9mmol) in THF (400mL) was added dropwise at 0C. The reaction mixture was stirred at the same temperature for 2h, and then quenched with sat. 160 NH4Cl (500mL) and extracted with ethyl acetate (3×300mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na2SO4. The organic layers were evaporated to dryness and the crude product was purified by silica gel flash chromatography (eluting with ethyl acetate in 74 petroleum ether 1-30%) to give the 20 title compound 48 as a white solid (31.2g, yield=78%). 1H NMR (400MHz, CDCl3) delta 8.05 (br, 1H), 6.78 (s, 1H), 1.56 (s, 9H); LC/MS (ESI, m/z) 222.98 [M+H-56]+. |
77.5% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; | A solution of diisopropylamine (64 ml, 446 mmol) in 200 mL of tetrahydrofuran was added to a dry three-neck bottle, which was protected under nitrogen, and cooled to 0 C, and then n-butyllithium (2.5M, 173ml, 431.7mmol) was added. The reaction was conducted for 1 hour after addition was completed. A solution of <strong>[405939-39-1]tert-butyl 5-bromothiazol-2-ylcarbamate</strong> in 400 mL of tetrahydrofuran was added dropwise at 0 C, and the reaction was conducted for 2 hours after addition was completed. TLC showed the reaction was completed. At 0 C, the reaction was quenched by slow addition of ice water (5 mL), stirred for 30 min, then saturated ammonium chloride (500mL) aqueous solution was added, and separated. The aqueous layer was extracted with dichloromethane (2 × 300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was recrystallized with petroleum ether : ethyl acetate = 30:1 to give 31g of tert-butyl 4-bromothiazol-2-ylcarbamate as a white solid, yield 77.5%, MS(ESI): m/z 278.98 (M + H)+. |
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