Structure of 190792-72-4
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| CAS No. : | 190792-72-4 |
| Formula : | C6H14ClNO |
| M.W : | 151.63 |
| SMILES Code : | Cl.N[C@H]1CCCC[C@H]1O |
| English Name : | (1R,2S)-2-Aminocyclohexanol hydrochloride |
| MDL No. : | MFCD11618002 |
| InChI Key : | LKKCSUHCVGCGFA-RIHPBJNCSA-N |
| Pubchem ID : | 12228413 |
| Num. heavy atoms | 9 |
| 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 | 39.68 |
| 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 |
0.74 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.05 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.57 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.39 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.55 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.25 |
| Solubility | 8.6 mg/ml ; 0.0567 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.29 |
| Solubility | 7.77 mg/ml ; 0.0512 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.1 |
| Solubility | 122.0 mg/ml ; 0.802 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 |
-6.7 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) |
1.97 |
* 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 |
|---|---|---|
| With hydrogenchloride; thionyl chloride 1) CHCl3, 0 deg C --> rt, 1 h, rt, 2 h; 2) reflux, 1 h; Yield given. Multistep reaction; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 18h; | 32 Example 32; 5-Fluoro-N-(1S,2R-2-hydroxy-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide; 1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE HYDROCHLORIDE (240mg, 1. 25MMOL) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (175mg, 0. 627MMOL), (1R, 2S)-2-AMINO-CYCLOHEXAN-1-OL HYDROCHLORIDE (100mg, 0. 627MOL), 1-HYDROXYBENZOTRIAZOLE (95MG, 0. 704MOL) and triethylamine (350µl, 2. 51mmol) in DIMETHYLFORMAMIDE (5ML) under nitrogen at room temperature. The reaction was stirred for 18h and partitioned between DIETHYLETHER (60M1) and water (60ml). The organic phase was removed and washed with water (30MOI), brine (30ml), dried over MGS04 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate : cyclohexane (10: 90 changing to 80: 20, by volume) to give 5-FLUORO-N- (1 S, 2R-2-HYDROXY-ACETYL-CYCLOHEXYL)-2- (3-METHYLSULFANYL- phenoxy) -nicotinamide (40mg) as an oil. 1H NMR (400MHZ, CDCI3) : (5= 8. 25-8.39 (2H, d + dd), 8.03-8. 05 (1H, d), 7.29-7. 38 (1H, t), 7.10-7. 18 (1H, d), 7.04 (1H, s), 6.92-6. 97 (1H, d), 4.17-4. 23 (1H, m), 3.98- 4.03 (1H, brs), 2.46 (3H, s), 2.04-2. 17 (1H, brs), 1.52-1. 80 (6H, 2xm), 1.38-1. 50 (2H, m) ppm. LRMS (electrospray) : M/Z [M+H] + 377, [M+NA] + 399, [M-H] + 375. Anal. Found C, 59.26 ; H, 5.57 ; N, 7.16. C19H21FN2O3S. 0. 4mol H20 requires C, 59.48 ; H, 5.73 ; N, 7.30%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12h; | 15 (IR, 2S) -2-Aminocyclohexanol hydrochloride (5.3 g) and triethylamine (15.1 ml) were dissolved in DMF (100 ml), and the solution was ice-cooled. Ethyl 3-bromo-2-isocyano-3- phenylacrylate (9.8 g) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (6.13 g) .1H-NMR (CDCl3) δ 1.10 (3H, t) , 1.21-1.37 (2H, m) , 1.38-1.52 (1H, m) , 1.60-1.79 (2H, m) , 1.80-1.97 (2H, m) , 2.22-2.37 (2H, m) , 3.76 (1H, dt), 4.04 (1H, br s) , 4.13 (2H, q) , 7.20-7.31 (2H, m) ,7.39-7.51 (3H, m) , 7.86 (1H, s) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 68% | With sodium hydrogencarbonate; In water; dimethyl sulfoxide; at 130℃; for 48h; | Example 282-Chloro-4-[[(lS,2R)-2-hydroxycyclohexyl] amino] -3 -methyl-benzonitrileA solution of 2-chloro-4-fluoro-3 -methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)- 2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130 C for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radialchromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+l). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With N-ethyl-N,N-diisopropylamine at 20℃; for 24h; | General Method C (nucleophilic substitutions of amines) To a solution of pyrazolo[l,5-a]pyrimidin-5-chlorine derivative (1 equiv) or 2- (methylsulfonyl)-8-arylpyrazolo[ 1,5-al [1,3 ,5ltriazin-4-amine (1.0 equiv) in THF, dioxane, DME, DMF or NMP was added amines or amine-HC1 (1-2 equiv) and DIPEA (1-3 equiv). The resulting mixture was stirred at rt for 24 h or more generally the reaction was heated in amicrowave reactor, an oil bath or a reaction block at temperatures from 35-130 °C for 2- 12 h. Solvent was removed in vacuo and the crude product was purified by flash chromatography. |
| 97% | With N-ethyl-N,N-diisopropylamine |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 10% | With N-ethyl-N,N-diisopropylamine In butan-1-ol at 150℃; for 72h; | 5 (1R,2S)-2-[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]amino}cyclohexanol 150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine and 168.7 mg (1.11 mmol) (1R,2S)-2-aminocyclohexanol hydrochloride (1:1) and 0.48 mL (2.78 mmol) N-ethyl-N-isopropylpropan-2-amine in 5.0 mL butan-1-ol were stirred 72 h at150°C. The solvent was removed. The residue was purified by HPLC to yield 19 mg (10%) product. LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos) m/z = 349 [M+H]+. 1H-NMR (600 MHz ,DMSO-d6), δ [ppm]= 1.40-1.52 (2H), 1.63-1.87 (6H), 3.88-3.94 (1H), 4.13-4.17 (1H), 4.70-4.74 (1H), 6.95-7.02 (2H), 7.27-7.31 (1H), 7.32-7.36 (1H), 7.52-7.54 (1H), 7.62-7.66 (1H), 7.68-7.72 (1H), 7.80-7.84 (1H), 7.93 (1H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 79% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 3h; Sealed tube; Microwave irradiation; | tert-butyl ( 3-bromo-5-( f(lS, 2R)-2-hvdroxycvclohexyl)amino)pyrazolo[l .5-a Jpyrimidin- 7-yl) ( yclopropylmethyQcarbamate To a solution of using tert-butyl (3-bromo-5-chloropyrazolo[l,5- a]pyrimidin-7-yl)(cyclopropylmethyl)carbamate (9.0 g, 22.5 mmol) in NMP (90 mL) was added (lR,2S)-2- aminocyclohexanol HCl (4.08 g, 27.0 mmol), and DIPEA (3.47 g, 25.1 mmol). The reaction was divided and sealed into six microwave vials. Each vial was microwaved for 3 h at 130 °C. Water and EtO Ac were added to separate the phases and the aqueous phase was extracted with EtO Ac. The combined organic extracts were dried over Na2S04, filtered and concentrated. The crude product was purified by flash chromatography (gradient: EtO Ac/hex 0-50%) using three columns in parallel to give the title compound as a beige solid (8.51 g, 79%). i NMR (400 MHz, CDCl3) δ ppm 7.80 (s, 1H), 6.08 (s, 1H), 5.33-5.19 (m, 1H), 4.26-4.14 (m, 1H), 4.13-4.06 (m, 1H), 3.61 (d, J = 7.3 Hz, 2H), 2.51 (br. s, 1H), 1.89-1.62 (m, 8H), 1.55-1.45 (m, 2H), 1.40 (s, 9H), 1.06-0.95 (m, 1H), 0.47-0.38 (m, 2H), 0.17-0.07 (m, 2H); MS ESI [M + H]+ 408.3, calcd for [C2iH3oBrN503 + H]+ 480.2. |
| 79% | With N-ethyl-N,N-diisopropylamine |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 43% | With N-ethyl-N,N-diisopropylamine In butan-1-ol at 110℃; for 100h; | 78.a (a) (1 R,2S)-2-(6-Chloro-4, 8-bis(methylamino)pyrimido[5 ,4-dj pyrimidin-2-ylamino) cyclohexanol (130) A mixture of 2,6-dichloro-N,N ‘ -dimethyl-pyrimido [5 ,4-dj pyrimidine-4, 8- diamine (88) (250 mg, 0.96 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (146 mg, 0.96 mmol) and N,N-diisopropylethylamine (319 tL, 1.92 mmol) in n-butanol (4 mL) washeated at 110°C for lOOh. The mixture was cooled, and a saturated NaHCO3 solution (20 mL) was added. The resulting suspension was extracted with EtOAc (3 x 3OmL). The combined organic extracts were washed with a brine solution (50 mL) and dried over solide anhydrous Na2SO4. The solvent was removed and the residue was purified by flash column chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/99) to afford (1 R,2S)-2-(6-chloro-4,8-bis(methylamino)pyrimido[5,4-djpyrimidin-2-ylamrno)cyclohexanol (130)(140 mg, 43% yield). 300 MHz ‘H NMR (CDC13, ppm): 6.63-6.52 (2H, m) 5.20 (1H, d, J7.1 Hz) 4.19-4.08 (1H, m) 4.06-3.98 (1H, m) 3.3-3.0 (1H, br s) 3.14 (3H, d, J=5.2 Hz) 3.05(3H, d, J=5.1 Hz) 1.84-1.57 (6H, m) 1.57-1.36 (2H, m). ESI-MS (m/z): 338, 340 [M+Hf’. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 49 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; | 103 6-(4-Chlorophenyl)-2-(3-fluorophenyl)-N-(cis-2-hydroxycyclohexyl)-3-oxo-2,3- dihydropyridazine-4-carboxamide A solution of 75 mg intermediate 17, 66 mg cis-2-amino-cyclohexanol hydrochloride (1 :1 ), 165 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: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5μ 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) to yield 49 mg 6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(cis-2-hydroxycyclohexyl)- 3-0X0-2, 3-dihydropyridazine-4-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm = 1.33 (m, 2 H), 1.46 - 1 .71 (m, 6 H), 3.77 (m, 1 H), 3.87 - 3.96 (m, 1 H), 4.87 (d, 1 H), 7.39 (tdd, 1 H), 7.51 - 7.66 (m, 5 H), 7.95 - 8.03 (m, 2 H), 8.66 (s, 1 H), 9.64 (d, 1 H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 41 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; | 106 2-(3-Fluorophenyl)-N-(cis-2-hydroxycyclohexyl)-6-(4-methoxyphenyl)-3-oxo-2,3- dihydropyridazine-4-carboxamide A solution of 100 mg intermediate 2-(3-fluorophenyl)-6-(4-methoxyphenyl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid, 82 mg cis-2-amino-cyclohexanol 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 (Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5μ 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) to yield 41 mg 2-(3-fluorophenyl)-N-(cis-2-hydroxycyclohexyl)-6-(4- methoxyphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm = 1.32 (m, 2 H), 1.48 - 1 .70 (m, 6 H), 3.77 (m, 1 H), 3.82 (s, 3 H), 3.91 (m, 1 H), 4.86 (d, 1 H), 7.04 - 7.1 1 (m, 2 H), 7.34 - 7.42 (m, 1 H), 7.50 - 7.56 (m, 1 H), 7.56 - 7.66 (m, 2 H), 7.87 - 7.93 (m, 2 H), 8.62 (s, 1 H), 9.69 (d, 1 H). |

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