Water → (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(2-(ethoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate

HRID 451998Notes

Reaction equation

HRID 451998 reaction equation
[NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Cl:26])[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.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C(Cl)Cl.CCN(CC)CC>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[C:23]([F:25])[CH:22]=1

Participants

6

Reactant 3

HCID 962WaterHCID 10928Ethyl chloroformateHCID 58017392(R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate

Product 1

HCID 58017379(R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(2-(ethoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylateYield 100%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Conditions

Temperature
2.5 °C

Procedure

To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (1.1 g, 2.85 mmol) in dry CH2Cl2 (20 mL), Et3N (2 mL) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of ethyl chloroformate (615 mg, 5.7 mmol) in dry CH2Cl2 (2 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at rt. Water (20 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(2-(ethoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.3 mg, 100%). 1H NMR (CD3OD, 400 MHz) δ 7.01 (d, 2H), 6.87 (d, 1H), 4.32 (m, 2H), 4.09 (m, 2H), 3.92 (m, 2H), 3.33 (m, 5H), 1.75 (s, 1H), 1.55 (m, 1H), 1.43 (s, 9H), 1.34 (m, 2H), 1.23 (t, 3H), 1.09 (t, 1H).

Workup

  1. additionAfter addition
  2. customto quench
  3. customthe reaction
  4. extractionThe aqueous layer was extracted with CH2Cl2 (3×20 mL)
  5. dry with materialthe combined organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-b06ee2f1c67b414bbc31c535c704805b
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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