Structure of 1184919-69-4
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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. : | 1184919-69-4 |
Formula : | C5H12ClNO |
M.W : | 137.61 |
SMILES Code : | OC1CC(N)CC1.[H]Cl |
MDL No. : | MFCD16619116 |
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 | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 34.87 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.25 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 |
0.38 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.66 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.21 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.14 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.28 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.93 |
Solubility | 16.1 mg/ml ; 0.117 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.92 |
Solubility | 16.7 mg/ml ; 0.121 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
0.2 |
Solubility | 220.0 mg/ml ; 1.6 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 |
-6.87 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) |
1.84 |
* 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 |
---|---|---|
82% | With hydrogenchloride; In methanol; for 2.0h;Reflux; | A mixture of compound 4 (8.0 g, 34 mmol) in MeOH (100 mL) was added concentrated HCl (10 mL), and heated to reflux for 2 h. The mixture was concentrated in vacuo. The residue was dissolved with water and washed with EA. The aqueous phase was concentrated in vacuo to give the desired product with HCl salt (2.8 g, 82 %). lH NMR (400 MHz, CDC13): delta ppm: 4.33 (bs, 1H), 3.66 (bs, 1H), 2.08 - 2.16 (m, 2H), 1.74 -1.90 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine; In acetonitrile; at 20℃; for 2.0h; | To a solution of Compound 6 (626 mg, 1.72 mmol) and Compound 5 (174 mg, 1.72 mmol) in MeCN (7 mL) was added Et3N (260 mg, 2.58 mmol) at rt, and the mixture was stirred at rt for 2 h. The solution was concentrated in vacuo. The organic phase was concentrated in vacuo to give the crude product, which was purified by prep- HPLC to give the desired product (355 mg, 48%). H NMR (MeOD-d4 400MHz): 8.47-8.45(m, 1H), 8.230-8.22 (m, 1H), 7.98-7.96 (m, 1H), 7.62-7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.46-7.26(m, 1H), 4.13-4.10 (m, 1H), 3.72- 3.68 (m, 1H), 2.10-2.08 (m, 1H), 1.08-1.64 (m, 4H).1.64-1.43 (m, 1H). LCMS: 431.0 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2.0h; | Preparation of Intermediate A: Rac-3-aminopentanol hydrochloride (100 mg, 0.7267 mmol), dissolved in DCM (8 mL), was cooled to 0 C and then treated with triethylamine (140 pL, 1.018 mmol) followed by dropwise addition of o-phenylchlorothiocarbonate (1 10 pL, 0.7994 mmol). The reaction mixture was allowed to warm to rt over 2h and concentrated. The residue was purified by ISCO chromatography (EtOAc/hexanes) to give Intermediate A as yellow oil (45 mg, 26 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 100℃; for 4.0h; | Step 1: To a solution of <strong>[1184919-69-4]3-aminocyclopentanol hydrochloride</strong> (1.05 g, 7.63 mmol) and ethyl 4,6-dichloronicotinate (1.679 g, 7.63 mmol) in DMA (10 mL) was added DIPEA (6.66 mL, 38.2 mmol), then reaction mixture was heated at 100 C. for 4 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with cold water (2×50 mL) and brine solution (40 mL) then dried over Na2SO4. The filtrate was concentrated and the product was purified using silica gel eluting 40% ethyl acetate in hexane to afford ethyl 6-chloro-4-((3-hydroxycyclopentyl)amino)nicotinate (1.5 g, 5.27 mmol, 69% yield), which was taken for the next step without chiral separation. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.54 (br. s., 1H) 8.03-8.42 (m, 1H) 6.78 (d, J=9.54 Hz, 1H) 4.62-4.77 (m, 1H) 3.99-4.33 (m, 4H) 1.86-2.29 (m, 3H) 1.38-1.78 (m, 3H) 1.31 (td, J=7.03, 1.00 Hz, 3H); LCMS(M+H) 285.0. |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 100℃; for 4.0h; | To a solution of <strong>[1184919-69-4]3-aminocyclopentanol hydrochloride</strong> (1.05 g, 7.63 mmol) and ethyl 4,6-dichloronicotinate (1.679 g, 7.63 mmol) in DMA (10 mL) was added DIPEA (6.66 mL, 38.2 mmol), then reaction mixture was heated at 100 C for 4 hr. Water(5OmL) was added and the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with cold water (2 x 50 mL) and brine solution (40 mL) then dried over Na2SO4. The filtrate was concentrated and the product was purified using silica gel eluting 40% ethyl acetate in hexane to afford ethyl 6-chloro-4-((3- hydroxycyclopentyl)amino)nicotinate (1.5 g, 5.27 mmol, 69% yield), which was taken forthe next step without chiral separation. ?H NMR (400 MHz, DMSO-d6) oe ppm 8.54 (br.s., 1 H) 8.03-8.42 (m, 1 H) 6.78 (d, J=9.54 Hz, 1 H) 4.62-4.77 (m, 1 H) 3.99-4.33 (m, 4H) 1.86-2.29 (m, 3 H) 1.38-1.78 (m, 3 H) 1.31 (td, J=7.03, 1.00 Hz, 3 H); LCMS(M+H)285.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 30℃; for 48.0h; | A solution of 150 mg (0:21 mmol) of 4'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-[3-fluoro-4-(2H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-carboxylic acid 59 mg (0:43 mmol) of 3-aminocyclopentanolhydrochloride in 2.0 ml of dimethylformamide was treated with 0:11 ml (0.64 mmol) Nu, Nu-diisopropylethylamine and 163 mg (0:43 mmol) of N - [(dimethylamino) (3 / i- [l, 2,3] triazolo [4,5-b]pyridin-3-yloxy) methylidene] -N-methylmethanaminium hexafluorophosphate were added. It was stirred at 30 C for 48 h. The reaction mixture was chromatographically separated via HPLC(Method 11). The product-containing fractions were combined and lyophilized. This gave 29 mg(15% d. Th.) Of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 20℃; for 2.5h; | (XIX) Scheme XIX Intermediate 432: 3-(6-bromo-3-nitroquinolin-4-yl)aminocyclopentanol 1.69 g (5.9 mmol) of Compound 3 and 1.226 g (8.9 mmol) of <strong>[1184919-69-4]3-aminocyclopentanol hydrochloride</strong> (a mixture of cis and trans isomers) were dissolved in 20 ml of dichloromethane, added with 3.3 ml (23.6 mmol) of triethylamine, stirred at room temperature for 2.5 h to precipitate out solids, filtered, washed with a small amount of dichloromethane, and pumped to dryness to afford a yellow solid (2.154 g). Yield: 100%. LC-MS: 351.8, 353.8 [M+1]+, tR = 1.822 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2.0h; | A mixture of 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4, 3-e] [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yl) -2-phenylpropanoic acid (50 mg, 0.13 mmol) , <strong>[1184919-69-4]3-aminocyclopentan-1-ol hydrochloride</strong> (21 mg, 0.15 mmol) , HATU (57 mg, 0.15 mmol) and DIPEA (34 mg, 0.26 mmol) in DMF (5 mL) was stirred at rt for 2 hrs. The solution was added with water (5 mL) , extracted with ethyl acetate (10 mL) and washed with brine (10 mL) . The organic layer was dried, concentrated and purified by preparative TLC (EtOAc) to get the desired product (23 mg, 38%) . 1H NMR (400 MHz, DMSO-d6) delta 8.21 (d, J=12.0Hz, 1H) , 7.97 (br. s, 2H) , 7.95 (s, 1H) , 7.43-7.39 (m, 1H) , 7.32-7.24 (m, 4H) , 7.18-7.12 (m, 2H) , 6.74 (d, J=4.0Hz, 1H) , 4.47 (d, J=4.0Hz, 1H) , 4.18 (br. s, 1H) , 4.00 (s, 1H) , 2.27 (s, 3H) , 1.92-1.73 (m, 2H) , 1.67-1.59 (m, 2H) , 1.40-1.37 (m, 2H) ppm. MS: M/e 473 (M+1) + |
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