Structure of 127199-54-6
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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. : | 127199-54-6 |
Formula : | C10H20N2O2 |
M.W : | 200.28 |
SMILES Code : | O=C(OC(C)(C)C)N[C@@H]1CNC[C@@H]1C |
MDL No. : | MFCD18432662 |
InChI Key : | BKITXDSDJGOXPN-JGVFFNPUSA-N |
Pubchem ID : | 11138119 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.9 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 59.3 |
TPSA ? Topological Polar Surface Area: Calculated from |
50.36 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.4 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.13 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.74 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.86 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.64 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.15 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.53 |
Solubility | 5.92 mg/ml ; 0.0295 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.78 |
Solubility | 3.31 mg/ml ; 0.0165 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.92 |
Solubility | 2.39 mg/ml ; 0.0119 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) |
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 |
-6.72 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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.97 |
* 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 |
---|---|---|
palladium on charcoal; In methanol; hydrogen; | (3S,4S)-3-(tert-Butoxycarbonyl)amino-4-methylpyrrolidine A mixture of 60.0 g of (3S,4S)-1-benzyl-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine, 6.00 g of 5% palladium on charcoal, and 500 ml of methanol was hydrogenated in an autoclave under 5 kgf/cm2 hydrogen pressure at 40 C. for 3 hours. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. The product was recrystallized from n-hexane to give 38.0 g of colorless needles, m.p. 83-85 C. NMR spectrum delta(CDCl3) ppm: 0.97 (3H, d, J=7 Hz), 1.45 (9H, s), 2.20-2.30 (1H, m), 2.44-2.53 (1H, m), 2.70 (1H, dd, J=11.5, 4.5 Hz), 3.15 (1H, dd, J=11, 7.5 Hz), 3.20-3.30 (1H, m), 4.05-4.20 (1H, m), 4.62 (1H, br-s) | |
With potassium hydroxide; ammonium formate;palladium charcoal; In methanol; water; | Example 29 Synthesis of 3(S)-[(t-butoxycarbonyl)amino]-4(S)-methylpyrrolidine Into 60 ml of methanol were dissolved 5.27 g of 1-benzyl-3(S)-[(t-butoxycarbonyl)amino]-4(S)-methylpyrrolidine, and, after 12 ml of water containing 0.28 g of suspended 10% palladium charcoal and 4.57 g of dissolved ammonium formate was added, the mixture was refluxed for 1 hour at 80C. The catalyst in reaction liquor was filtered off and the filtrate was concentrated. After 12.0 g of potassium hydroxide was added to the residue, water and ether were added to extract. The ether layer was separated, washed with saturated saline solution, dried over anhydrous Glauber's salt, and then concentrated. The residue thus obtained was recrystallized from n-hexane to obtain 3.19 g of aimed product as white needle-like crystals. Melting point: 84-85C Specific rotation: [alpha] [20/D ] = +18.9 (c=1.47, chloroform) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-ethyl-N,N-diisopropylamine; In methanol; water; dimethyl sulfoxide; | 5-Amino-7-[(3S,4S)-3-tert-butoxycarbonylamino-4-methyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid A mixture of 1.01 g of ?5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid-O3,O4!difluoroborate, 0.71 g of (3S,4S)-3-tert-butoxycarbonylamino-4-methylpyrrolidine, 0.51 ml of N,N-diisopropylethylamine, and 4.04 ml of dimethylsulfoxide was stirred at outer temperature of 30 C. for 64 hours. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed successively with water and brine, and then dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, methylene chloride: methanol=100:1), and crystals obtained were washed with diethyl ether to give 0.58 g of yellowish orange crystals. A mixture of 0.58 g of the crystals obtained, 0.58 ml of triethylamine, 11.6 ml of methanol, and 5.8 ml of 1,2-dichloroethane was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and then, the residue was added with water and crystals precipitated were collected by filtration. The crystals were washed with water to give 0.52 g of yellow crystals. The crystals were recrystallized from acetone-diisopropyl ether to give yellow crystals, m.p. 178.5-180 C. Specific rotation [alpha]D20 -141.9 (c=0.1, CHCl3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; citric acid; In chloroform; water; acetonitrile; | Example 34 Synthesis of 7-[3(S)amino-4(S)-methyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxyic acid hydrochloride To 20 ml of acetonitrile were added 2.00 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, 2.15 g of 3(S)-[(t-butoxycarbonyl)amino]-4(S)-methyl-pyrrolidine and 1.09 g of DBU, and the mixture was refluxed for 7 hours at 100C. The reaction liquor was concentrated and the residue was dissolved into 100 ml of chloroform, which was washed with 10% aqueous solution of citric acid, water and saturated saline solution in this order, dried over anhydrous Glauber's salt, and then concentrated. The residue was purified through silica gel column (elution solvent, chloroform:methanol: concentrated aqueous ammonia=20:5:1) to obtain 3.06 g of 7-[3(S)-[(t-butoxycarbonyl)amino]-4(S)-methyl-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | [Referential Example 25] Ethyl 4-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoate A solution of (3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine (1.80 g, 8.97 mmol), ethyl 3-methyl-2,4,5-trifluorobenzoate (2.18 g, 10.0 mmol), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (2.24 mL, 15 mmol) in dimethyl sulfoxide (20 mL) was stirred under a nitrogen atmosphere at an external temperature of 60C for 70 hours. The temperature of the mixture was cooled to room temperature. The resultant mixture was poured to a 10% aqueous citric acid solution, followed by extraction with ethyl acetate (200 mL * 3), washing by water (200 mL), saturated aqueous sodium hydrogencarbonate (150 mL), and saturated brine (150 mL), and dried over anhydrous sodium magnesium. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (n-hexane: ethyl acetate = 6:1), to thereby yield the title compound as colorless crystals (2.51 g, 70.2%). 1H-NMR(400MHz, CDCl3)delta ppm:1.07(3H,d, J=7.0Hz),1.38(3H,t, J=7.OHz),1.47(9H,s),2.20(3H, d,J=2.5Hz),2.50-2.57(1H,m),3.06-3.12(1H,m), 3.16(1H,dd,J=3.0,10.0Hz),3.39-3.44(1H,m),3.73-3.77(1H,m), 4.27-4.33(1H,m),9.36(2H,q,J=7.0Hz), 4.71(1H,br),7.42(1H,dd,J=7.0,13.0Hz). MS (ESI)m/z:399 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.1% | [Referential Example 22] (3S,4S)-3-(tert-Butoxycarbonyl)amino-4-methylpyrrolidine A suspension of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-(phenylsulfanil)methylpyrrolidine (7.97 g, 18.01 mmol) and Raney nickel (R100) (50 mL) in ethanol (150 mL) was stirred in a hydrogen atmosphere under an ordinary pressure at an external temperature of 50C for 18 hours. The temperature of the resultant mixture was cooled to room temperature. Thereafter, insoluble matter was removed through filtration by use of Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (100 mL), and a 10% palladium carbon catalyst (2.0 g) was added to the solution, followed by stirring in a hydrogen atmosphere under an ordinary pressure at room temperature for 3 hours. After insoluble matter was removed through filtration by use of Celite, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether. The solution was washed by a 1 mol/L aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure, to thereby yield the title compound as colorless crystals (2.602 g, 72.1%). 1H-NMR(400MHz,CDCl3)delta ppm:0.97(3H,d,J=7.0Hz),1.45(9H,s),1.79(1H,br),2.21-2.28(1H,m),2.48(1H,dd,J=8.5,10.5),2.70(1H,dd,J=4.5,11.0Hz),3. 15(1H,dd,J=8.0,10.5Hz),3.25(1H,dd,J=6.5,11.0Hz),4.10(1H,br),4.63(1H,br). IR(ATR)nu cm-1:3365,3217,2956,1678,1520,1365,1244,1167, 1061,906,627. MS(FAB)m/z(%):201(93,M++1),145(100,M+-55),101(8,M+-99). HRMS(FAB)m/z:Calcd for C10H21O2N2:201.1603.Found:201.1602. |
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