Acetyl chloride → 1-tert-butyl 2-methyl (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate

HRID 61499Notes

Reaction equation

HRID 61499 reaction equation
[C:1](Cl)(=[O:3])[CH3:2].Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1.CN1CCOCC1>C(#N)C>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 79724-MethylmorpholineHCID 866214931-tert-butyl 2-methyl(1S,2S,4R)-4-(piperidin-4-yloxy)cyclohexane-1,2-dicarboxylate hydrochloride

Product 1

HCID 865982671-tert-butyl 2-methyl (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

A solution of acetyl chloride (24 uL, 0.00033 mol) in 0.5 ml of ACN was added to a solution of 1-tert-butyl 2-methyl(1S,2S,4R)-4-(piperidin-4-yloxy)cyclohexane-1,2-dicarboxylate hydrochloride made above (50 mg, 0.0001 mol) and 4-methylmorpholine (44 uL, 0.00040 mol) in acetonitrile (1.5 mL, 0.029 mol) at 22 Celsius. It was stirred at rt for 30 min, then quenched with Water, extracted with EA, and concentrated to give 1-tert-butyl 2-methyl(1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate. 2 ml of TFA was added in 1-tert-butyl 2-methyl(1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate (0.1 mmol, 0.0001 mol) in dichloromethane (2 ml). It was stirred at rt overnight and concentrated to give the corresponding TFA salt for next step. Benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (49 mg, 0.00011 mol) was added To a solution of (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]-2-(methoxycarbonyl)cyclohexanecarboxylic acid made above (0.1 mmol, 0.0001 mol) and 1-phenylpiperazine (17 uL, 0.00011 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) at rt. After 5 min, N,N-diisopropylethylamine (52 uL, 0.00030 mol) was added at 0 Celsius. It was stirred at rt overnight. The reaction was chromatographed by combiflash (ethyl acetate in hexanes: 100%).

Workup

  1. customquenched with Water
  2. extractionextracted with EA
  3. concentrationconcentrated

Sources & evidence

ORD record
ord-25ce6adfbe3b4dd0b81727a51239513b
Source dataset
uspto-grants-2016_09
Patent number
US09440958B2

Reaction notes

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