Water → HCID 58017407, compound

HRID 451993Notes

Reaction equation

HRID 451993 reaction equation
[NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[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.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[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]=[CH:23][C:22]=1[F:25]

Participants

7

Reactant 4

HCID 962WaterHCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 58017391HCID 58017391, compound

Product 1

HCID 58017407HCID 58017407, compoundYield 4.3%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
2.5 °C

Procedure

To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-4-fluorophenyl)methyl)piperidine-1-carboxylate (1 g, 2.6 mmol) and DMAP (79 mg, 0.62 mmol) in dry CH2Cl2 (20 mL), Et3N (657 mg, 6.5 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (1.22 g, 13 mmol, 5 eq) 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 product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (50 mg, yield 4.3%). 1H NMR (CDCl3, 400 MHz) δ 7.27 (m, 1H), 7.12 (m, 2H), 4.30 (s, 1H), 3.91 (d, 2H), 3.66 (s, 3H), 3.10-3.40 (m, 5H), 2.90 (m, 1H), 1.75 (s, 1H), 1.55 (d, 1H), 1.46 (s, 9H), 1.33 (m, 2H), 1.04 (m, 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
  8. customto give the crude product, which
  9. customwas purified by preparative HPLC

Sources & evidence

ORD record
ord-20ed0571a754482ba3837aa6ef19c2b7
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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