Structure of 848497-98-3
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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. : | 848497-98-3 |
Formula : | C5H12ClN |
M.W : | 121.61 |
SMILES Code : | CNC1CCC1.[H]Cl |
MDL No. : | MFCD11506003 |
InChI Key : | AZXFWSPGAJVTRL-UHFFFAOYSA-N |
Pubchem ID : | 50998946 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 33.8 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.03 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.51 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.56 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.14 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.06 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.48 |
Solubility | 4.03 mg/ml ; 0.0332 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.37 |
Solubility | 5.18 mg/ml ; 0.0426 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.09 |
Solubility | 9.91 mg/ml ; 0.0815 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 |
-5.97 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 |
2.0 |
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) |
1.0 |
* 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 |
---|---|---|
79% | With sodium acetate; sodium cyanoborohydride; In methanol; at 25℃; for 16h;4A molecular sieves; | 2-Oxo-cyclopentanecarboxylic acid ethyl ester (0.24 mL, 1.64 mmol) and C-<strong>[848497-98-3]cyclobutyl-methylamine hydrochloride</strong> (0.20 g, 1.64 mmol) were dissolved in methanol (8 mL). Sodium acetate (0.27 g, 3.28 mmol) was added followed by 4A powdered molecular sieves (0.20 g) and sodium cyanoborohydride (0.21 g, 3.28 mmol). The reaction was stirred at 25 0C for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The <n="189"/>organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, 2-(cyclobutylmethyl- amino)-cyclopentanecarboxylic acid ethyl ester (0.29 g, 1.30 mmol, 79%) as a clear oil. LC-MS (ESI) calcd for Ci3H23NO2 225.33, found 226.2 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Example 1 Step 1 (2S)-N-CYCLOBUTYL-N-METHYL-2- (TERT-BUTOXYCARBONYLAMINO)-2- cyclohexylacetamide N-Methylcyclobutylamine hydrochloride (159 mg) synthesized by the method described in Journal of Medicinal Chemistry, 1994, 37,3482 was dissolved in N, N-DIMETHYLFORMAMIDE (4 ml), and L- tert-butoxycarbonylcyclohexylglycine hydrate (159 mg), (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (676 mg) and diisopropylethylamine (0.453 ml) were added. The mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane : ethyl acetate=3: 1) to give the title compound. 1H-NMR (8PPM, CDC13) 1.13-1. 37 (5H, m), 1.42 (9H, s), 1.59-1. 71 (9H, m), 2.10-2. 29 (4H, m), 4.39-4. 55 (lH, m), 4.80-4. 90 (0. 4H, m), 5.25- 5.33 (0.6H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | Step 3 (S)- [ (N-CYCLOBUTYL-N-METHYLCARBAMOYL)- (4- oxocyclohexyl) methyl] carbamic acid tert-butyl ester A solution of (S)-2- (TERT-BUTOXYCARBONYLAMINO)-2- (4- oxocyclohexyl) acetic acid (29.47 g) obtained in Step 2 in N, N- DIMETHYLFORMAMIDE (150 ml) was COOLEDTO 0OC. N- hydrochloride (19. 1 G) SYNTHESIZED in accordance with the method described in Journal of Medicinal Chemistry, 1994,37, 3482, and diisopropylethylamine (35.07 ml) were added, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (59.84 g) was gradually added. After the completion of the addition, the mixture was allowed to warm to room temperature. Water (150 ml) was added and the mixture was extracted with a mixture of ethyl acetate-hexane. The organic layer was washed successively with 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 3) to give the title compound (23.5 g). H-NMR (8PPM, CDCL3) 1.23-2. 49 (24H, m), 2.88-3. 09 (3H, s), 4.30- 4.58 (lH, m), 4.58-4. 75 (0.6H, m), 4.76-4. 93 (0.4H, m), 5.26-5. 49 (lH, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Example 29 Step 1 (S)- [ (TRANS-4-AZIDOCYCLOHEXYL)- (N-CYCLOBUTYL-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (S)-N-TERT-BUTOXYCARBONYL- (TRANS-4-AZIDOCYCLOHEXYL) glycine (2.72 g) synthesized in accordance with the method described in W002/076450, <strong>[848497-98-3]N-methylcyclobutylamine hydrochloride</strong> (1.1 g) synthesized in accordance with the method described in Journal of Medicinal Chemistry, 1994,37, 3482, and triethylamine (3.17 ML) were dissolved in N, N-dimethylformamide (25 ml), and (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (5.2 g) was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate: hexane=2: 5-1: 2) to give the title compound (2.84 g). 1H-NMR (6PPM, CDCL3) 1.06-1. 37 (4H, m), 1.42 (9H, s), 1.45-1. 80 (5H, m), 1.97-2. 34 (6H, m), 2.92 (1. 8H, s), 2.99 (1. 2H, s), 3.13-3. 24 (lH, m), 4.36-4. 48 (lH, m), 4.51-4. 58 (0.6H, m), 4.78-4. 89 (0.4H, m), 5.26- 5.37 (lH, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Step 1. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(N-methyl-cyclobutylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (21) To a solution of compound 3 (150 mg, 0.29 mmol) in MeOH (4 mL) was added <strong>[848497-98-3]N-methylcyclobutylamine hydrochloride</strong> (105 mg, 0.90 mmol) and triethylamine (190 muL, 1.00 mmol). The reaction mixture was heated at 100 C. in a sealed tube for 15 h and cooled down to room temperature. An aqueous solution containing 30% NH4OH (1 mL) was added and the reaction mixture was heated at 100 C. in a sealed tube for 2 h, cooled down and concentrated. The residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90:10) to afford product 21 (90 mg, 0.25 mmol, 86%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Step 1 Into a 50-mL round-bottom flask, was placed (2R)-2-(4-bromophenyl)-2-[[(tert-butoxy)carbonyl]amino]acetic acid (1 g, 3.029 mmol, 1 equiv) in DMF (15 mL), to which was added diisopropylethylamine (1.57 g, 12.115 mmol, 4 equiv), <strong>[848497-98-3]N-methylcyclobutanamine hydrochloride</strong> (368 mg, 3.03 mmol, 1 equiv), and BOP (1.61 g, 3.63 mmol, 1.2 equiv) in sequence. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (4*30 mL), and the combined organic layer was washed with brine (2*10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1/1). This resulted in 1.1 g (91%) of tert-Butyl N-[(R)-(4-bromophenyl) [cyclobutyl(methyl)carbamoyl]methyl]carbamate as a yellow solid. |