Dimethyl Sulfoxide → HCID 60115377, compound

HRID 1622938Notes

Reaction equation

HRID 1622938 reaction equation
[CH3:1][C:2]([N:5]([C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[CH:15]=[O:16])[C:6](=[O:8])[O-:7])([CH3:4])[CH3:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:27][CH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].C(N(CC)CC)C.CC(N([C@H]1CCCC[C@H]1CNCC(C)C)C(=O)[O-])(C)C>ClCCl.O>[CH3:4][C:2]([N:5]([C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[CH:15]=[O:16])[C:6](=[O:7])[O-:8])([CH3:1])[CH3:3].[CH:28]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:27]

Participants

10

Reactant 6

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 54488680Carbamic acid, [(1S,2R)-2-(hydroxymethyl)cyclohexyl]-, 1,1-dimethylethyl esterHCID 131731663HCID 131731663, compoundHCID 131731664HCID 131731664, compound

Product 2

HCID 60115377HCID 60115377, compoundHCID 131731663HCID 131731663, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

racemic-1,1-Dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate, racemic-[(1R,2S,5S)-2-Amino-5-phenylcyclohexyl]methanol hydrochloride (800 mg, 4.82 mmol) was dissolved in MeOH (40 mL) and bis(1,1-dimethylethyl)dicarbonate (1.16 g, 5.30 mmol) and triethylamine (4 mL, 28.92 mmol) were added and the mixture was stirred 18 hours at ambient temperature. The solvents were removed tinder reduced pressure, ethyl acetate and aqueous saturated sodium bicarbonate were added and the product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and the solvents were removed under reduced pressure. Purification by silica gel chromatography (9:1 hexanes:ethyl acetate to ethyl acetate gradient elution) gave 1,1-dimethylethyl racemic-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (934 mg, 85%) as a white solid. 1H NMR (CDCl3) δ 4.87 (m, 1H), 4.03-3.95 (m, 2H), 3.26 (m, 1H), 3.15 (m, 1H), 1.73-1.48 (m, 5H), 1.38 (s, 9H), 1.27-1.15 (m, 3H), 0.887 (m, 1H). b) racemic-1,1-Dimethylethyl[(1S,2R)-2-Formylcyclohexyl]carbamate. To a solution of dimethylsulfoxide (0.2 mL, 2.88 mmol) in dichloromethane (3 mL) at 78° C. was added oxalyl chloride (0.72 mL, 1.44 mmol) dropwise. The mixture was stirred minutes and racemic-1,1-dimethylethyl [(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (220 mg, 0.961 mmol) in dichlormethane was added dropwise and stirred 10 minutes. Triethylamine (0.53 mL, 3.84 mmol) was added slowly and the reaction was stirred at −78° C. for one hour and allowed to warm to ambient temperature. Water was added and product was extracted with dichloromethane. The combined organics were washed with brine and dried over sodium sulfate. Removal of solvents under reduced pressure afforded racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (223 mg, quantitative) as a yellow oil, 1H NMR (CDCl3) δ 9.61 (s, 1H), 5.19 (m, 1H), 3.88 (m, 1H), 2.61 (m, 1H), 1.85 (m, 1H), 1.63-1.49 (m, 4H), 1.37-1.16 (m, 12H), c) racemic-1,1-dimethylethyl((1S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclohexyl)carbamate, racemic-1,1-Dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (223 mg, 0.982 mmol) was dissolved in dichloroethane and 2-methylpropyl)amine (0.15 mL, 1.47 mmol) and sodium triacetoxyborohydride (290 mg, 1.37 mmol) were added and the reaction was stirred at ambient temperature for 18 hours. Aqueous sodium bicarbonate was added and the product was extracted with dichloromethane. The combined extracts were dried over sodium sulfate and the solvents were removed under reduced pressure. Purification by silica gel chromatography (dichloromethane to 1% ammonium hydroxide 19% methanol 80% dichloromethane gradient elution) afforded racemic-1,1-dimethylethyl((1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclohexyl)carbamate (112 mg, 40%) as a clear colorless oil. 3H NMR (CDCl3) δ 6.06 (br s, 1H), 3.76 (br s, 1H), 2.63 (m, 1H), 2.43-2.37 (m, 2H), 2.25 (m, 1H), 1.81 (m, 1H), 1.71-1.59 (m, 3H), 1.44-1.32 (m, 14H), 1.27-1.19 (m, 2H), 0.866 (m, 6H). d) racemic-(1S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclohexanamine hydrochloride.

Workup

  1. stirringstirred 10 minutes
  2. stirringthe reaction was stirred at −78° C. for one hour
  3. extractionproduct was extracted with dichloromethane
  4. washThe combined organics were washed with brine
  5. dry with materialdried over sodium sulfate
  6. customRemoval of solvents under reduced pressure

Sources & evidence

ORD record
ord-683475d2af364b0bb92d1ef996add723
Source dataset
uspto-grants-2014_07
Patent number
US08778943B2

Reaction notes

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