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Structure of 103883-30-3
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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. : | 103883-30-3 |
Formula : | C6H13NO2 |
M.W : | 131.17 |
SMILES Code : | NC[C@H]1OC(C)(C)OC1 |
MDL No. : | MFCD02262087 |
InChI Key : | HXOYWCSTHVTLOW-RXMQYKEDSA-N |
Pubchem ID : | 10154073 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3259 |
Packing Group: | Ⅲ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 33.76 |
TPSA ? Topological Polar Surface Area: Calculated from |
44.48 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.85 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.45 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.1 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.26 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.6 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.37 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.3 |
Solubility | 65.2 mg/ml ; 0.497 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.02 |
Solubility | 126.0 mg/ml ; 0.959 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.73 |
Solubility | 24.3 mg/ml ; 0.185 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 |
-7.42 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) |
2.88 |
* 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 |
---|---|---|
With triethylamine; In dichloromethane; | Part A; To a solution of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (22.00 g, 76.52 mmol) indichloromethane (250 mL) was added triethylamine (16.0 mL, 115 mmol) followed by thedropwise addition of a solution of 4/?-(-)-(2,2-dimethyl)-l,3-dioxolane-4-methananiine(1 1 .04 g, 84.16 mmol) in dichloromethane (200 mL). The reaction was monitored byTLC, and after the starting material was consumed, the reaction mixture was transferred toa separatory funnel and washed with water (200 mL) and brine (200 mL), dried overNa2SC>4, filtered, and concentrated. The resulting yellow residue was triturated with water(200 mL) and the solid was collected by filtration and dried. The solid was sonicated indiethyl ether (100 mL) and isolated by filtration. The solid was dried under vacuum at 40°C to yield 7-bromo-A^-[(4JR)-2,2-dimethyl-l,3-dioxolan-4-yl]methyl}-3-nitroquinolin-4-amine (25.84 g) as a yellow solid, mp 136-137 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 20.0℃; | Example 48A 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- methylchroman-2-yl)-N-(((i?)-2,2-dimethyl-l,3-dioxolan-4-yl)methyl)benzamide In a 4 mL vial, 300 of a stock solution containing the product from Example 16 (0.13 M, 0.039 mmol, 1.0 equivalent) and diispropylethylamine (0.39 M, 0.12 mmol, 3.0 equivalents) in dimethyl acetamide was added to a stock solution containing 2-(3H-[l,2,3]triazolo[4,5- b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (0.15 M in dimethyl acetamide, 300 mu, 0.046 mmol, 1.2 equivalents). A stock solution of (i?)-(2,2-dimethyl-l,3- dioxolan-4-yl)methanamine (0.40 M in dimethyl acetamide, 145 mu, 0.058 mmol, 1.5 equivalents) was added and the reaction was stirred at room temperature until complete as determined by LC. The material was loaded directly into a Gilson GX-271 autosampler and purified using preparative LC method TFA8 to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20.0℃; for 1.0h; | Example 137A N-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-fluoro-2,4-dinitroaniline A solution of 1,5-difluoro-2,4-dinitrobenzene (0.778 g, 3.81 mmol) and N,N-diisopropylethylamine (0.732 mL, 4.19 mmol) in tetrahydrofuran (38 mL) was treated dropwise with a solution of <strong>[103883-30-3](R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine</strong> (0.500 g, 3.81 mmol) in tetrahydrofuran (38 mL). The reaction was stirred at room temperature for 1 hour. Volatiles were then removed in vacuo, and the crude material was then partitioned between ethyl acetate (150 mL) and water (100 mL). The organic layer was washed with water (2*50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10 to 70percent ethyl acetate-heptanes, eluent) to afford the title compound as a yellow oil (0.989 g, 82percent). 1H NMR (400 MHz, CDCl3) delta 9.15 (d, J=8.0 Hz, 1H), 8.78 (s, 1H), 6.67 (d, J=13.3 Hz, 1H), 4.48 (qd, J=5.8, 3.7 Hz, 1H), 4.24-4.07 (m, 1H), 3.81 (dd, J=8.7, 5.7 Hz, 1H), 3.58 (ddd, J=13.4, 4.9, 3.8 Hz, 1H), 3.42 (dt, J=13.3, 5.5 Hz, 1H), 1.52 (s, 3H), 1.40 (s, 3H). MS (DCI+) m/z 333.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20.0℃; for 16.0h; | 10300] In a typical run, (R)-2-amino-3-mercapto-3-meth- ylbutanoic acid (0.25 g, 1.68 mmol, 1 eq) and 1-(2,2- difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane-1 -carboxylic acid (0.45 g, 1.85 mmol, 1.1 eq) were taken up in DMF (10 mE) and HATU (0.83 g, 2.18 mmol, 1.3 eq) was added, followed by Et3N (0.508 g, 5.03 mmol, 3 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. The following morning, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by preparative HPEC afford (R)-2-(1 -(2,2- difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamido)-3-mercapto-3-methylbutanoic acid (0.368 g, 59percentyield) as a white solid. This material (0.368 g, 0.987 mmol, 1 eq) and (R)-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methan- amine (0.155 g, 1.2 mmol, 1.1 eq) were taken up in DMF (5 mE) and HATU (0.487 g, 1.28 mmol, 1.3 eq) was added, followed by Et3N (0.299 g, 2.96 mmol, 3 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. The following morning, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated and concentrated under reduced pressure. The resulting residue was purified by preparative HPEC to afford 1 -(2,2-difluorobenzo[d] [1 ,3]dioxol-5-yl)-N-((R)- 1 -((((R)2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl)amino)-3-mercapto-3-methyl-i -oxobutan-2-yl)cyclopropane-1 -carboxamide(0.27 g, 56percent yield) as a colorless oil. This material (0.27 g, 0.556 mmol, 1 eq) was taken up in DMF (2 mE) along with tert-butyl N-((4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4,7, 10,13, 16,1 9-hexaenoyl)-S-(pyridin-2-ylthio)-E-cysteinate (0.365 g, 0.611 mmol, 1.1 eq) and methanol (2 mE) was added. tert-butyl N-((4Z,7Z, 1 OZ, 13Z, 1 6Z, 1 9Z)-Docosa-4,7, 10,13, 16,1 9-hexaenoyl)-S-(pyridin-2-ylthio)-E-cysteinate, in turn, was prepared according to the procedures outlined in example 3. The resulting reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative HPEC to afford tert-butyl S?(((R)-3-(i-(2,2- difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane-i -carboxamido)-4-((((R)-2,2-dimethyl-i ,3-dioxolan-4-yl)methyl) amino)-2-methyl-4-oxobutan-2-yl)thio)-N-((4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4,7, 10,13,16,1 9-hexaenoyl)-E-cysteinate (0.22 g, 40.8percent yield) as a colorless oil. This material (0.22 g, 0.467 mmol, 1 eq) was taken up in CH2C12 (5 mE) and TFA (1 mE) was added. The resulting reaction mixture was stirred at room temperature for 4 hour and then concentrated under reduced pressure. The resulting residue was purified by preparative HPEC to afford S?(()-3-(i -(2,2-difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane- 1-car- boxamido)-4-(((R)-2,3-dihydroxypropyl)amino)-2-methyl- 4-oxobutan-2-yl)thio)-N-((4Z,7Z, 1 OZ, 13Z, 1 6Z, 1 9Z)- docosa-4,7, 10,13,16,1 9-hexaenoyl)-E-cysteine (0.02 g, 10percent yield) as a colorless oil. MS, calculated for CH59F2N3O9S2: 875.37; found 876 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.5% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18.0h;Inert atmosphere; Cooling with ice; | A solution of 2-((2-fluoro-4-iodophenyl)amino)- 1-methyl- 1H-pyrrolo[2,3 - b]pyridine-3-carbonyl chloride (See Example 2, 937 mg, 2.18 mmol) in dry THF (4 mL) under N2 was cooled in an ice-water bath while stirring. The reaction mixture was treated with a solution of <strong>[103883-30-3](R)-(-)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine</strong> (256 mg, 1.95 mmol) and diisopropylethylamine (0.33 mL, 1.95 mmol) in dry THF (5 mL) and stirred for 18 h. Reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (Silica 40 g, 20-80percent EtOAc in hexane) to give the product (442 mg, 3 8.5percent) as an off-white solid which was used in subsequent steps without further purification. UPLC-MS (Acidic Method, 2 mm): rt 1.10 mi m/z 525.0 [M+H]t ?HNIVIR (400 IVIHz, DMSO-d6) ppm 8.83 (s, 1H), 8.32 - 8.36 (m, 1H), 8.27 - 8.32 (m, 1H), 7.62 - 7.68 (m, 1H), 7.55 -7.62 (m, 1H), 7.31 -7.37 (m, 1H), 7.21 -7.27 (m, 1H), 6.40 -6.47 (m, 1H), 4.05 -4.09 (m, 1H), 3.84 - 3.89 (m, 1H), 3.57 - 3.62 (m, 1H), 3.54 (s, 3H), 3.37 - 3.38 (m, 2H), 1.26 (s, 3H), 1.22 (s, 3H). |
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