Methyl chloroformate → 1-Piperidinecarboxylic acid, 3-[(R)-(3-chlorophenyl)[2-[(methoxycarbonyl)amino]ethoxy]methyl]-, 1,1-dimethylethyl ester, (3R)-

HRID 218375Notes

Reaction equation

HRID 218375 reaction equation
[NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1

Participants

6

Reactant 3

HCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 59598469(R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate

Product 1

HCID 595984981-Piperidinecarboxylic acid, 3-[(R)-(3-chlorophenyl)[2-[(methoxycarbonyl)amino]ethoxy]methyl]-, 1,1-dimethylethyl ester, (3R)-

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
2.5 °C

Procedure

To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (7.7 g, 21 mmol, HPLC=75%) and DMAP (1.27 g, 10 mmol, 0.5 eq) in dry CH2Cl2 (120 mL), Et3N (6.38 g, 8.45 mL, 63 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (8.1 mL, 104.5 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. The reaction was quenched with water (80 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (4.4 g, HPLC≧98%, the total yield for five steps is 41%).

Workup

  1. additionAfter addition
  2. customThe reaction was quenched with water (80 mL)
  3. extractionThe aqueous layer was extracted with CH2Cl2 (3×50 mL)
  4. washthe combined organic layers were washed with 10% citric acid (2×80 mL) and brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to the crude product, which
  8. customwas purified by preparative HPLC

Sources & evidence

ORD record
ord-073234ca44204ed4b2a28f6010e75d72
Source dataset
uspto-grants-2012_06
Patent number
US08198453B2

Reaction notes

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