Structure of 147751-16-4
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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. : | 147751-16-4 |
Formula : | C6H13NO4S |
M.W : | 195.24 |
SMILES Code : | CC(C)(C)OC(=O)NS(C)(=O)=O |
MDL No. : | MFCD13194912 |
Boiling Point : | No data available |
InChI Key : | GAIZFMKSOHADOV-UHFFFAOYSA-N |
Pubchem ID : | 10081367 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.83 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 44.43 |
TPSA ? Topological Polar Surface Area: Calculated from |
80.85 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.34 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.55 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.27 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.76 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.47 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.1 |
Solubility | 15.5 mg/ml ; 0.0792 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.77 |
Solubility | 3.33 mg/ml ; 0.0171 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.15 |
Solubility | 13.9 mg/ml ; 0.0711 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 |
-7.14 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) |
2.37 |
* 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 |
---|---|---|
25% | n-BuLi (10.2 mL, 1 M in hexane, 10.2 mmol) was added to a solution of diisopropylamine (1.7 mL, 10.2 mmol) in THF (20 mL) at -78 C, and the resulting mixture was stirred for 10 minutes at -78 C and then 30 minutes at -5 C. The reaction mixture was again cooled to -78 C, then a solution of B1 (1.0 g, 5.1 mmol) in THF (10 mL) was added dropwise to this reaction mixture (maintaining the reaction mixture temperature at -78 C) and the stirring was continued for 20 minutes. A solution of propylene oxide (0.47 mL, 6.7 mmol) in THF (15 mL) was added dropwise to this reaction mixture at -78 C and stirring was continued for 30 minutes. The reaction mixture was slowly warmed to room temperature and stirring was continued for 16 h. The mixture was poured onto an ice-cold saturated aqueous NH4CI solution. The resulting precipitate was dissolved by addition of water, and the mixture was acidified with 1 N HCI to pH = 3. The aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2S04, concentrated to get residue which was chromatographed on silica gel (230 - 400 mesh) using diethyl ether as eluent to obtain B2 as a colorless oil (0.3 g. 25%). Rf: 0.3 (Et20). LCMS m/z = 252.1 (M - 1 ) | |
25% | To a 100 mL 3-necked rmmd bottom flask purged with and maintained under an inertatmosphere of nitrogen was added a solution of diisopropy lamine (1.03 g, 10.18 mmoL 2.00equiv.) in tetrahydrofuran (20 mL), the solution was cooled to -78C. A 2.5M solution ofn-1 0 BuLi in THF (4.1 mL, 2.00 equiv .) was added dropwise with stirring during a 10 min period.The rnixture was stirred for another 10 min at this temperature. A solution ofteli-butyl Nmethanesulfonylcarbamate216b (1 g, 5.12 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL)-vvas added drop wise with stirring at -78C during a l 0 min period. Tile reaction wascontinued for 20 min. Then, a solution of2-methyloxirane (298 mg, 5.13 mmol, 1.00 equiv.)15 in tetrahydrofuran (10 mL) 1v·as added dropwise with stirring at -78C in a 15 rnin period.The reaction wa.s continued f()r 30min at this low temperature. Cooling bath was removed,and the reaction mixture was stirred at room temperature overnight. The mixture was cooledin an ice/salt bath, quenched by the addition of 40 mL of a saturated NH4Cl aqueous solution.The pH value of the solution vas adjusted to 3 using a 2M hydrogen chloride aqueous20 solution. Tile aqueous rnixture wa<; extracted with ethyl acetate (1 00 mL x 2), and thecombined organic extracts w·ere washed w·ith brine (100 mL x 3), dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purified by silica gel colunmchromatography eluting with ethyl acetate/petroleum ether (1:2) to furnish tert-hutyl N-[(3-hydroxybutane)sulfonyl]carbamate 216c (320 mg, 25%) as a light yellow oil | |
17 g | To a solution of diisopropylamine (15.54 g, 163.66 mmol) in THF (150 mL) was added n- BuLi (61.5 mL, 153.75 mmol, 2.5 M in hexane) at -78 C. The mixture was stirred at -78 C for 20 mins. Then a solution of tert-butyl methylsulfonylcarbamate (compound I-13a, 15.0 g, 76.8 mmol) in THF (150 mL) was added to the above mixture drop- wise over a period of 20 mins. The mixture was stirred at -50 C for 30 mins, followed by addition of a solution of propylene oxide (5.58 g, 96.03 mmol, 6.72 mL) in THF (90 mL) over 30 mins at -78 C. The mixture was allowed to warm up to rt and stirred for 15 hrs. The mixture was poured into aqueous NH4C1 solution (210 mL). The resulting precipitate was collected and dissolved with water, followed by acidification with 2 M HC1 to pH=3. The resulting aqueous mixture was extracted with DCM (100 mL) for 5 times. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography to give compound I-13b (17 g) as a colorless oil. MS obsd. (ESI+) [(M+H)+] : 254 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | n-BuLi (2.5 M in hexane, 19 mL, 47.7 mmol, 3.1 equiv) was added dropwise to freshly distilled (i-Pr)2NEt (8.30 mL, 50.7 mmol, 3.30 equiv) in THF (50 mL) at 0 C. The mixture was stirred for 30 minutes, then N-Boc-methylsulfonamide (3.00 g, 15.3 mmol, 1 equiv) in THF (50 mL) was added and the reaction stirred for a further 1 hour at 0 C. Next, methyl 2-methoxymethoxybenzoate (3.00 g, 16.9 mmol, 1.1 equiv) in THF (10 mL) was added and the reaction was stirred for 3 hours at 0 C. The reaction mixture was quenched with saturated aq NaCl (50 mL) and 0.5 M aq NaH2PO4 (50 mL) and extracted with EtOAc (3×50 mL) and the combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (30:70 EtOAc/hexane) afforded the title compound (3.93 g, 71%) as a white solid: mp 128-129 C.; Rf 0.7 (70:30 EtOAc/hexane); 1H NMR (600 MHz, CDCl3) delta 1.48 (s, 9H), 3.52 (s, 3H), 5.11 (s, 2H), 5.31 (s, 2H), 7.07 (t, J=7.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.38 (br s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) delta 28.0, 56.8, 61.6, 84.4, 94.8, 115.0, 122.0, 126.3, 130.9, 135.4, 149.6, 156.9, 188.9; HRMS (ESI+) calcd for C15H21NNaO7S [M+Na]+ 382.0931, found 382.0908 (error 6.0 ppm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In N,N-dimethyl acetamide; at 55℃; for 16h;Product distribution / selectivity; | Part F. Preparation of N-tert-butyl ester-N-(4-benzylsulfanyl-5-nitro-thiophen-3-ylmethyI> methanesulfonamide.; Method A:; The product from Part E (32.46 g, 108.27 mmol) was dissolved in dimethyl acetamide (162 mL) and to the solution was added N-tert-butyl ester- methanesulfonamide (22.3 g, 114.22 mmol) and potassium carbonate (10.51 g, 76.04 mmol). The resulting solution was heated to 55 0C for 16 h. To the cooled reaction mixture was added ethyl acetate (444 mL) and the solution was washed with a 7% aqueous sodium chloride (3 x 444 mL) solution. The solvent was removed under vacuum and the residue was dissolved in ethanol. The product crystallized and was isolated by filtration and washed with cold ethanol to provide 39 g (80%) of N-tert-butyl ester-N-(4-benzylsulfanyl-5-nitro-thiophen-3-ylmethyl)- methanesulfonamide as a light yellow solid. 1H-NMR(DMSOd6) delta 1.42 (9H, s), 3.41 (3H, s), 4.19 (2H, s), 4.63 (2H, s), 7.1-7.3 (5H, m), 7.62 (IH, s); 13C-NMR (DMSOd6) delta 27.50J9.24, 41.76, 44.99, 84.09, 126.92, 127.40, 127.93, 128.26, 131.33, 136.21, 141.48, 150.16, 150.81; DCI-MS 476 (M+ 18). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With diethylazodicarboxylate; trimethylphosphane; In tetrahydrofuran; toluene; at 25℃; for 3.5h; | Boc-N-methanesulfonamide (11.0 g, 56.3 mmol), trimethylphosphine (56.1 mL of a 1.0 M solution in tetrahydrofuran, 56.1 mmol), and a 40 wt. % solution of diethyl azodicarboxylate in toluene (25.6 mL, 56.0 mmol) were added sequentially to a solution of (4-benzylsulfanyl-5-nitro-thiophen-3-yl)-methanol (10.52 g, 37.4 mmol) in tetrahydrofuran (300 mL) at 25 C. The mixture was stirred for 3.5 h at 25 C., and then was concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 mum; 20% ethyl acetate in hexanes) afforded the desired product, Boc-N-(4-benzylsulfanyl-5-nitro-thiophen-3-ylmethyl)-methanesulfonamide (9.79 g, 21.3 mmol, 57%), as a dark brown oil. 1H NMR (400 MHz, CDCl3) delta: 1.50 (9H, s), 3.29 (3H, s), 4.19 (2H, s), 4.68 (2H, s), 7.15-7.18 (2H, m), 7.22-7.25 (3H, m), 7.40 (1H, s). |
Method B:; To a solution of N-Boc methanesulfonamide (12.00 g, 61.5 mmole) and IM of trimethylphosphine (61.5 mL, 61.5 mmole) in THF was added (4-benzylsulfanyl-5-nitro-thiophen-3-yl)- methanol (11.5 g, 40.9 mmole) in 135 mL THF over 15 min at ~ 25 0C. The resulting solution was stirred at - 25 0C for ~ 10 min., and 26.7 g of 40% DEAD solution in toluene (26.7 g, 61.4 mmole) added slowly over ~ 10 min (slightly exothermic, water bath cooling). The reaction mixture was stirred at ~ 25 0C overnight or until the starting material was consumed as indicated by HPLC. The reaction mixture was concentrated to dryness, and ethyl acetate (200 mL) and 5% nuaHCtheta3 aq. Solution (200 mL) added. The upper organic was washed with 5% NaHCO3 (200 mLx2), and 25% brine (200 mL). The organic was dried over MgSO4, filtered. The filtrate was concentrated to ~ 50-60 mL volume (some solid), diluted with heptane (50 mL). The solid was filtered off, rinsed with ethyl acetate: heptane (1:1, 20 mL). The filtrate was concentrated to ~ 40 mL volume, chromatographed om a silica gel column (250 g), eluting with heptane :acetone (4:1). The main fractions of product were pooled, and concentrated to dryness to yield an oil (18.0 g), which was crystallized from abs ethanol to give 14.1 g product of N-tert-butyl ester- N-(4-benzylsulfanyl-5-nitro-thiophen-3-ylmethyl)-methanesulfonamide as a light yellow solid. |
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