Structure of 31775-67-4
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CAS No. : | 31775-67-4 |
Formula : | C5H12ClNO |
M.W : | 137.61 |
SMILES Code : | Cl[H].N[C@@H]1CCC[C@H]1O |
MDL No. : | MFCD02683551 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-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) |
1.79 |
* 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 |
---|---|---|
99% | To a solution of trans-2-azido-cyclopentanol (1.0 g, 7.87 mmol) in EtOAc, was added 10% Pd/C (0.5 g). The mixture was flushed with Ar, and then stirred on Parr apparatus at 40 psi for 2 h at 23. The mixture was filtered through celite and the celite was washed with EtOAc. The filtrate was acidified with 3 mL of 4N HCl in 1,4-dioxane, and a white solid was precipitated. The mixture was filtered and the solid was collected to give the desired product (0.76 g, 99%). 1H NMR (MeOD-d4): delta 4.09-4.04 (m, 1H), 3.29-3.25 (m, 1H), 2.18 (m, 1H), 2.03 (m, 1H), 1.83-1.80 (m, 2H), 1.65-1.58 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 20h; | N,N-diisopropylethylamine (1.269 mL, 7.27 mmol) was added to a stirred suspension of 2-aminocyclopentanol hydrochloride (1.00 g, 7.27 mmol) and di-t-butyl dicarbonate (1.687 mL, 7.27 mmol) in dichloromethane (45 mL). After 20 h at room temperature, the clear solution was concentrated. Silica gelchromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave tert-butyl trans- 2-hydroxycyclopentylcarbamate as white solid (1.23 g, 84% yield). XH NMR (400 MHz, chloroform-if) delta ppm 5.00 (1 H, br. s.), 3.99-4.29 (1 H, m), 3.81-3.93 (1 H, m), 3.53 (1 H, td, J=7.81, 5.72 Hz), 1.93-2.06 (1 H, m), 1.80-1.93 (1 H, m), 1.61-1.74 (1 H, m), 1.45-1.61 (2 H, m), 1.34 (9 H, s), 1.23-1.32 (1 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 80℃;Sealed tube; | Stepl[00186j To a solution of Intermediate 1 (150 mg, 0.73 mmol) in DMA (0.5 mL) was added <strong>[31775-67-4](±)-<strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong></strong> (111 mg, 0.80 mmol) and iPr2NEt(0.286 mL, 1.61 mmol), the reaction vessel was sealed and heated to 80 C overnight.The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated to give Intermediate 18 as the crude product (yield not determined). LC retention time 1.28 mm [L]. MS(E) m/z: 270 (MHj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.11 g | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | To a solution (5 mL) of 1-[4-(1H-pyrazol-1-yl)benzyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.1 g) prepared by referring to a document (Bioorganic and Medicinal Chemistry Letters, 2010, 20, 1334), (trans)-2-aminocyclopentanol hydrochloride (0.057 g) and triethylamine (0.12 mL) in DMF was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.16 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration and dried to give the title compound (0.11 g) as a pale-yellow solid. MS (ESI+): [M+H]+ 447.2 1H NMR (300MHz, DMSO-d6) delta 1.38-1.95 (5H, m), 2.02-2.18 (1H, m), 3.88-4.10 (2H, m), 5.86 (2H, d, J = 2.8 Hz), 6.47-6.56 (1H, m), 7.25 (2H, d, J = 8.5 Hz), 7.51 (1H, td, J = 8.0, 4.4 Hz), 7.59-7.69 (1H, m), 7.72 (1H, d, J = 1.7 Hz), 7.79 (2H, d, J = 8.5 Hz), 8.21 (1H, d, J = 7.9 Hz), 8.44 (1H, d, J = 2.5 Hz), 9.02 (1H, s), 9.89 (1H, d, J = 7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.0 g | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | To a solution of 1-(4-bromobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.83 g) known from a document (Journal of Medicinal Chemistry, 2007, 50, 5471) in DMF (20 mL) were added <strong>[31775-67-4](1,2-trans)-2-aminocyclopentanol hydrochloride</strong> (0.38 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.1 g) and triethylamine (0.80 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration and dried to give the title compound (1.0 g) as a pale-yellow solid. 1H NMR (300MHz, DMSO-d6) delta 1.37-1.94 (5H, m), 2.00-2.17 (1H, m), 3.88-4.10 (2H, m), 5.77 (2H, s), 5.86 (1H, s), 7.13-7.30 (2H, m), 7.44-7.97 (5H, m), 8.29-8.44 (1H, m), 9.08 (1H, s), 10.03 (1H, d, J = 7.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65 mg | To a solution of 1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (Intermediate 20), (110 mg) in DMF (2.1 mL) stirred at rt under nitrogen was added HATU (248 mg) and TEA (0.11 mL). This mixture was left to stir for 15 minutes and then <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (56.0 mg) was introduced. The reaction was left to stir overnight at room temperature, at which point LC-MS indicated completion. The reaction mixture was transferred to a separating flask and EtOAc and water were added. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, washed with brine and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane, followed by 0-15% MeOH/EtOAc) to give the desired product as a racemic mixture of trans isomers (65 mg). LCMS: m/z 354.57 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.64-1.91 (m, 4H) 1.97-2.15 (m, 1H) 2.17-2.35 (m, 1H) 4.05-4.22 (m, 2H) 5.29 (s, 2H) 6.93-7.22 (m, 5H) 7.59 (d, J=8.3 Hz, 1H) 8.09 (s, 1H) 8.48 (d, J=4.7 Hz, 1H) 9.11 (d, J=3.1 Hz, 1H) | |
65 mg | To a solution of 1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (Intermediate 20), (110 mg) in DMF (2.1 mL) stirred at rt under nitrogen was added HATU (248 mg) and TEA (0.11 mL). This mixture was left to stir for 15 minutes and then <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (56.0 mg) was introduced. The reaction was left to stir overnight at room temperature, at which point LC-MS indicated completion. The reaction mixture was transferred to a separating flask and EtOAc and water were added. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, washed with brine and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 0% to 100% EtOAc in hexane, followed by 0-15% MeOH/EtOAc) to give the desired product as a racemic mixture of trans isomers (65 mg). LCMS: m/z 354.57 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.64-1.91 (m, 4H) 1.97-2.15 (m, 1H) 2.17-2.35 (m, 1H) 4.05-4.22 (m, 2H) 5.29 (s, 2H) 6.93-7.22 (m, 5H) 7.59 (d, J=8.3 Hz, 1H) 8.09 (s, 1H) 8.48 (d, J=4.7 Hz, 1H) 9.11 (d, J=3.1 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
874 mg | With formic acid; at 100℃; | To a precooled solution of formaldehyde (25.5 mL) and formic acid (25.5 mL) was added (±)trans-2-aminocyclopentanol, hydrochloride (1.2 g). The solution was heated to 10000 overnight. After cooling, aq. HCI solution (6 M, 50 mL) was added. The solution was then concentrated to remove the excess formaldehyde and formic acid. The remaining solid wasrecrystalized from EA and ethanol. The residue was treated with aq. NaOH solution, extractedwith ether, dried over K2003 and concentrated to afford (±)trans-2-(dimethylamino)cyclopentanol (874 mg) as a light yellow oil. 1H-NMR (500 MHz, ODd3) 6 ppm4.06 (dd, J= 12.6, 5.5 Hz, 1H), 3.54 (s, 1H), 2.44-2.52 (m, 1H), 2.29 (s, 6H), 1.41-1.98 (m, 6H);MS(ES) m/z 130 (MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g | With triethylamine; In methanol; dichloromethane; for 72h;Reflux; | A mixture of methyl 5-bromo-3-chloro-2-hydroxy-4- methylbenzoate (2.90 g) , trans-2-aminocyclopentanolhydrochloride (2.84 g) and triethylamine (4.20 g) inmethanol/dichloromethane was stirred with heating under reflux for 3 days. The reaction mixture was concentrated, andpurified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (1.70 g) .1H NMR (400 MHz, CDC13) delta 1.65-1.95 (4H, m) , 2.02-2.10 (1H, m) , 2.25-2.35 (1H, m) , 2.55 (3H, s) , 3.55 (1H, brs), 4.02-4.12 (2H, m) , 6.45 (1H, brs), 7.51 (1H, s) . 1H was not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.9 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 29℃; for 16h; | A mixture of 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid (2.90 g) , <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (2.26 g) , WSC hydrochloride (3.17 g) , HOBt (2.23 g) , triethylamine (4.44 g) and dichloromethane (100 mL) was stirred at 29C for 16 hr. The reaction mixture was diluted with dichloromethane (100 mL) and washed with brine (200 mL) . The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (1.90 g) .XH NMR (400 MHz, CDC13) delta 1.50-1.93 (4H, m) , 2.01-2.13 (1H, m) , 2.20-2.32 (1H, m) , 3.66 (1H, brs) , 3.95-4.18 (5H, m) , 6.40 (1H, brs), 7.37 (1H, s) , 12.25 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.5 mg | With dmap; N-ethyl-N,N-diisopropylamine; 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 14.0h; | A solution of 75 mg intermediate 17, 60 mg cis-2-amino-cyclopentanol hydrochloride (1 :1 ), 165.5 mg HATU, 0.1 1 mL ethyldiisopropylamine and 1 .3 mg 4-dimethylaminopyridine in 2 mL of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: XBrigde C18 5mu 150x30mm; eluent B: water + 0.2 Vol-% aqueous ammonia (32%); eluent D: methanol; gradient: 3-7min 69-89% D; flow 50.0 mL/min; UV 254 nm) to yield 32.5 mg 6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(cis-2-hydroxycyclopentyl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide. 1H NMR (400 MHz, DMSO-d6) delta ppm = 1.45 - 1 .64 (m, 3 H), 1.69 - 1 .88 (m, 2 H), 1.90 - 2.05 (m, 1 H), 3.97 - 4.13 (m, 2 H), 5.03 (d, 1 H), 7.38 (tdd, 1 H), 7.50 - 7.71 (m, 5 H), 7.95 - 8.09 (m, 2 H), 8.66 (s, 1 H), 9.70 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With dmap; N-ethyl-N,N-diisopropylamine; 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℃; for 14h; | A solution of 100 mg intermediate 2-(3-fluorophenyl)-6-(4-methoxyphenyl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid, 74.3 mg trans-aminocyclopentanol hydrochloride (1 :1 ), 201 mg HATU, 0.14 mL ethyldiisopropylamine and 1.6 mg 4-dimethylaminopyridine in 2 mL of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC twice (Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5mu 100x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 mL/min; temperature: 25 C; DAD scan: 210-400 nm and Instrument: Waters Autopurificationsystem; column: Waters XBrigde C18 5mu 100x30mm; eluent A: water + 0.2 Vol-% aqueous ammonia (32%), eluent B: methanol; gradient: 0.00-0.50 min 32% B (25->70mL/min), 0.51-5.50 min 67-87% B (70mL/min), DAD scan: 210-400 nm) to yield 20 mg 2-(3-fluorophenyl)-N-(trans-2-hydroxycyclopentyl)-6-(4- methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide. 1H NMR (400 MHz, DMSO-d6) delta ppm = 1 .37 - 1.56 (m, 2 H), 1 .57 - 1 .76 (m, 2 H), 1 .76 - 1.88 (m, 1 H), 2.02 - 2.14 (m, 1 H), 3.82 (s, 3 H), 3.93 (quin, 1 H), 3.97 - 4.06 (m, 1 H), 4.94 (d, 1 H), 7.07 (d, 2 H), 7.37 (td, 1 H), 7.49 - 7.56 (m, 1 H), 7.56 - 7.66 (m, 2 H), 7.91 (d, 2 H), 8.60 (s, 1 H), 9.40 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | A solution of 3,4-dichlorobenzaldehyde (400 mg, 2.29 mmol, 1 eq) in methanol(8 mL) was treated with aminocyclopentanol hydrochloride (473 mg, 3.44 mmol, 1.5 eq) and triethylamine (0.5 cm3, 3.58 mmol,1.5 eq), and the mixture stirred at rt for 3 hr. Sodium triacetoxyborohydride (680 mg, 3.21 mmol, 1.4 eq) was then divided into two portions and added to the solution at half-hour intervals, and the solution was left to stir for 18 hr. The reaction mixture was quenched using NaOH (2M, 30 mL) and extracted with dichloromethane (30 mL). The aqueous layer was further extracted with dichloromethane (2 x 30 mL) and the combined organic layers were dried over magnesium sulfate, concentrated in vacuo and purified by column chromatographyeluting with dichloromethane: methanol (95:5) to yield the product as a pale pink solid (368 mg, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 mg | With dmap; N-ethyl-N,N-diisopropylamine; 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 14.0h; | A solution of 153 mg intermediate 2-(i -methyl-i H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-d ihyd ropyridazine-4-carboxylic acid, 112,3 mg cis-4- aminotetrahydro-3-furanol hydrochloride (1:1), 306 mg HATU, 0.28 mL ethyldiisopropylamine and 4 mg 4-dimethylaminopyridine in 3 mL of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: WatersAutopurification MS SingleQuad; Column: Waters XBrigde Ci8 Sp iOOx3Omm; eluent A: water+ 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 mm s-i 00% B; flow 70 mLlmin; temperature: 25C; DAD scan: 210-400 nm) to yield 120 mg N-[(cis)-4- hyd roxytetrahydrofuran-3-yl]-2-(i -methyl-i H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazine-4-carboxamide.1H NMR (400 MHz, DMSO-d6) 6 [ppm] = 3.48 (t, 1 H), 3.65 (dd, 1 H), 3.93 (s, 3 H), 3.94 - 3.98(m, 1 H), 4.01 (t, 1 H), 4.26 - 4.33 (m, 1 H), 4.34 - 4.44 (m, 1 H), 5.70 (d, 1 H), 7.53 (d, 2 H),8.12 (s, 1 H), 8.17 - 8.23 (m, 2 H), 8.56 (s, 1 H), 8.63 (s, 1 H), 9.90 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.17 g | With triethylamine; HATU; at 10 - 35℃; | 2-amino-5-bromo-N-(trans-2-hydroxycyclopentyl)-3,4-dimethylbenzamide A mixture of 2-amino-5-bromo-3,4-dimethylbenzoic acid (0.10 g), <strong>[31775-67-4]trans-2-aminocyclopentanol hydrochloride</strong> (0.06 g), triethylamine (0.10 g) and HATU (0.19 g) in DMF (2.0 mL) was stirred at room temperature overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.17 g). Further purification was not performed and the compound was used in the next step. MS: [M+H]+ 327.1, 329.1 |
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