Structure of 6936-47-6
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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. : | 6936-47-6 |
| Formula : | C6H14ClNO |
| M.W : | 151.63 |
| SMILES Code : | Cl[H].N[C@H]1CCCC[C@H]1O |
| English Name : | cis-2-Aminocyclohexanol hydrochloride |
| MDL No. : | MFCD00143981 |
| 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 |
|---|---|---|
| In 1-methyl-pyrrolidin-2-one at 140℃; for 0.166667h; Microwave oven; | 1 Example 1: (^^^^-^-(S^-Dimethoxy-phenyO-pyrazololi.S-alpyrimidin-S-ylamino]- cyclohexanol:5-Chloro-3-(3,4-dimethoxy-phenyl)-pyrazolo[1 ,5-a]pyrimidine (C) ( 25 mg; 0.086 mmol) and (as amino starting material) cis-2-aminocyclohexanol HCI (ACROS, F26585) (125 mg; 1.09 mMol) are suspended in NMP (0.5 mL) and stirred at 1400C for 10 min at 300 W in an Emry Optimizer (microwave oven from Personal Chemistry AB, Uppsala, Sweden). The reaction mixture is treated with water (2 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers are washed with a saturated NaHCO3 solution, water, then brine, and then dried (Na2SO4), and concentrated under reduced pressure. Purification is done by chromatography on a 4 g Redisep Sg-100 column (Teledyne ISCO, Inc., Lincoln, Nebraska, USA) eluting with CH2CI2/CH3OH 95:5 (v/v)), to obtain the title compound as beige crystals: MS(ESI+):m/z= 369.1 (M+H)+; HPLC: tRet = 5.33 minutes (System 1). |
| 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; | 35 Example 35; 5-Fluoro-N-(1R,2S-2-hydroxy-acetyl-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. 627MOL), (1S,2R)-2-amino-cyclohexan-1-ol hydrochloride (100mg, 0. 627MOL), 1-hydroxybenzotriazole (95mg, 0. 704MOL) and triethylamine (350, u1, 2. 51MMOL) in DIMETHYLFORMAMIDE (5ml) under nitrogen at room temperature. The reaction was stirred for 18h and partitioned between diethylether (60ml) and water (60ml). The organic phase was removed and washed with water (30ml), 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- (1R, 2S-2-HYDROXY-ACETYL-CYCLOHEXYL)-2- (3-METHYLSULFANYL- phenoxy) -nicotinamide (40mg) as an oil. 1H NMR (400MHZ, CD30D) : No.= 8.18-8. 22 (1H, dd), 8.08-8. 11 (1H, d), 7.31-7. 37 (1H, t), 7.13-7. 18 (1H, d), 7.12 (1H, s), 6.92-6. 98 (1H, d), 4.00-4. 08 (1H, m), 3.92-3. 98 (1 H, brs), 2.47 (3H, s), 1. 58-1. 80 (6H, 2xm), 1.35-1. 48 (2H, m) ppm. LRMS (ELECTROSPRAY) : m/z [2M+Na]+ 775, [M-H] + 375. Anal. Found C, 59.40 ; H, 5.62 ; N, 7.22. C19H21FN2O3S. 0. 4mol H20 requires C, 59.48 ; H, 5.73 ; N, 7. 30%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With triethylamine In hexane; dichloromethane; ethyl acetate | 2.A Step A: Step A: Cis-2-triphenylmethylaminocyclohexanol A mixture of cis-2-aminocyclohexanol hydrochloride (4.88 g; 32 mmol) (William S. Johnson and Elliot N. Schubert, J.A.C.S., Vol. 72, pp. 2187-2190 (1950), triphenylmethylchloride (10.7 g; 38.4 mmol) and triethylamine (16 ml; 115 mmol) in 250 ml methylene chloride are refluxed for 3 hrs. then stirred at room temperature overnight. The mixture is poured into H2 O and extracted with CH2 Cl2 (200 ml), dried (Na2 SO4) concentrated in vacuo and flash chromatographed using 9:1 7:1; hexane:EtOAc to obtain cis-2-triphenylmethylaminocyclohexanol which is used directly in the next step. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: cis-2-amino-cyclohexanol hydrochloride With sodium hydroxide In tetrahydrofuran; water at 20℃; for 1h; Stage #2: C15H7Cl2F6NO2 In tetrahydrofuran; water at 20℃; for 1h; | 4B.B.b 5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (1.5 g, 3.75 mmol) was dissolved in a mixture of THF (15 ml) and DMF (11.4 μl). To this solution was added with stirring oxalyl chloride (0.52 ml, 6.0 mmol), whereby at room temperature after 1 h the corresponding acid chloride was formed. (1R,2S)-2-Hydroxy-cyclohexyl-ammonium; chloride (608.9 mg, 4.02 mmol) was dissolved in a mixture of THF (6 ml) and water (6 ml). This solution was treated with NaOH 32% (1.74 ml, 18.8 mmol) and stirred at room temperature for 1 h. To this solution was added the above produced acid chloride and stirred at room temperature for 1 h. The reaction mixture was poured onto water (120 ml) and the formed precipitation filtered. The brown crystals were dissolved under reflux in ethanol (12 ml), cooled to room temperature, treated with water (10 ml) yielding after filtration and drying the title compound (1.62 g) as light grey crystals; MS (ISP) 497.1 (M+H)+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride; water for 1h; Reflux; | 4B.B.e (3aR,7aS)-2-Methyl-3a,4,5,6,7,7a-hexahydro-benzooxazol-3-ium; chloride (33 g, 159.7 mmol) were dissolved in a mixture of water (330 ml) and HCl (25%, 229 ml). The solution was heated to reflux for 1 h, cooled to room temperature, filtrated over speedex and the solvent evaporated. The residue was dissolved under reflux in ethanol (150 ml), filtered and the filtrate treated with TBME (300 ml). The formed crystals were filtered and dried to yield the title compound (14.2 g) as white crystals; MS (ISP) 116.1 (M+H)+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium carbonate In tetrahydrofuran; water at 0 - 20℃; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: (R)-2,2'-diphenyl-3,3'-biphenanthryl-4,4'-diyl phosphate; phenyl trimethylsilyl selenide / toluene / 1 h / 0 °C / Inert atmosphere 2: Phenylselenyl bromide; silver trifluoromethanesulfonate / dichloromethane / 24 h / 20 °C / Inert atmosphere 3: hydrogenchloride / water / 24 h / Reflux; Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: (R)-2,2'-diphenyl-3,3'-biphenanthryl-4,4'-diyl phosphate / toluene / 96 h / 20 °C / Inert atmosphere 2: Phenylselenyl bromide; silver trifluoromethanesulfonate / dichloromethane / 24 h / 20 °C / Inert atmosphere 3: hydrogenchloride / water / 24 h / Reflux; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With hydrogenchloride In water for 24h; Reflux; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 29% | With N-ethyl-N,N-diisopropylamine; at 180 - 190℃; for 6h;Microwave irradiation; | Example 242-Chloro-4-[[(lR,2S)-2-hydroxycyclohexyl]amino]-3-methyl-benzonitrileA mixture of <strong>[796600-15-2]2-chloro-4-fluoro-3-methyl-benzonitrile</strong> (500 mg, 2.95 mmol), diisopropylethylamine (1.29 mL, 7.37 mmol), and (lS,2R)-2-aminocyclohexanol hydrochloride (670 mg, 4.42 mmol, Acros) is microwaved using a CEM microwave at 190 C for 2 h and 180 C for 4 h. The mixture is diluted with dichloromethane and washed with 1 N HCl. The aqueous layer is extracted again with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2%methanol/dichloromethane. The isolated product is recrystallized with ether and hexane to yield the title compound as a white solid (231 mg, 29%). LC-ES/MS m/z 265.0 (M+1).The compounds in Table 8 below are prepared by essentially following the procedure described in Example 24, using the appropriate chiral amino-alcohol (commercially available) and <strong>[796600-15-2]2-chloro-4-fluoro-3-methyl-benzonitrile</strong>. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 300 mg | With dmap; sodium azide; trifluoromethylsulfonic anhydride In dichloromethane at 20℃; | 7 Sodium azide (2.43 g, 18.7 mmol) was dissolved in 7.6 mL water and stirred in ice bath. To it were added 8 mL DCM and then Tf20 (1.28 mL, 7.6 mmol).The mixture was stirred for 3 h in ice bath. The DCM phase was separated, and the aqueous phase was extracted with DCM twice. The combined DCM phase was washed with sat. NaHC03 and water, dried over MgS04. (lS,2R)-2-Aminocyclohexanol hydrochloride (302 mg, 2.0 mmol) was dissolved in 5 mL dry DCM and stirred at RT. To it were added DMAP (1.07 g, 8.8 mmol) and then the above- prepared TfN3/T)CM solution dropwise. The mixture was stirred for overnight. It was concentrated in vacuo and subjected to flash column to isolate (lS,2R)-2-azidocyclohexanol (300 mg, a clear oil). Proton NMR: (CDC13) δ 3.74 (1H, m), 3.59 (1H, m), 2.72 (1H, s), 1.83 (1H, m), 1.69-1.48 (5H, m), 1.27 (2H, m) ppm. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | Stage #1: 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: cis-2-amino-cyclohexanol hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 68% | In butan-1-ol | 80.a (a) (1 S,2R)-2-(6-Chloro-4, 8-bis(methylamino)pyrimido[5 ,4-dj pyrimidin-2-ylamino) cyclohexanol (134) 2,6-Dichloro-N,N’ -dimethyl-pyrimido [5 ,4-djpyrimidine-4, 8-diamine (88) (250 mg, 0.96 mmol) and (1S,2R)-2-aminocyclohexanol hydrochloride were reacted in n-butanol to afford (1 S,2R)-2-(6-chloro-4, 8-bis(methylamino)pyrimido [5 ,4-dj pyrimidin-2-ylamino) cyclohexanol (134) (221 mg, 68% yield). 300 MHz ‘H NMR (CDC13, ppm): 6.64-6.50 (2H, m) 5.20 (1H, d, J=7.3 Hz) 4.19-4.09 (1H, m) 4.05-3.98 (1H, m) 3.3-3.0 (1H, br s) 3.14 (3H,d, J=5.2 Hz) 3.05 (3H, d, J5.1 Hz) 1.84-1.36 (8H, m). ESI-MS (m/z): 338, 340 [M+Hf’. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | Stage #1: cis-2-amino-cyclohexanol hydrochloride With sodium carbonate In acetone at 0℃; Stage #2: acetic anhydride In acetone at 0 - 20℃; for 3h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: sodium carbonate / acetone / 0 °C 1.2: 3 h / 0 - 20 °C 2.1: Dess-Martin periodane / dichloromethane / 3 h / 20 °C |

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