(S)-tert-Butyl (3-chloro-2-hydroxypropyl)carbamate → (-)-phenylmethyl 7-[(5S)-5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

HRID 488376Notes

Reaction equation

HRID 488376 reaction equation
C1(C[O:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)=O)C=CC=CC=1.Cl[CH2:33][C@@H:34]([OH:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].O(C(C)(C)C)[Li]>CN(C=O)C>[CH3:40][C:39]([CH3:42])([O:38][C:37]([NH:36][CH2:35][C@@H:34]1[O:44][C:9](=[O:8])[N:11]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)[CH2:33]1)=[O:43])[CH3:41]

Participants

5

Reactant 3

HCID 11195158(S)-tert-Butyl (3-chloro-2-hydroxypropyl)carbamateHCID 22269646phenylmethyl 3,4-dihydro-7-[[(phenylmethoxy)carbonyl]amino]-2(1H)-isoquinolinecarboxylateHCID 178506942HCID 178506942, compound

Product 1

HCID 69734605(-)-phenylmethyl 7-[(5S)-5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylateYield 80%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of phenylmethyl 3,4-dihydro-7-[[(phenylmethoxy)carbonyl]amino]-2(1H)-isoquinolinecarboxylate (Step 3, 5.12 g, 12.29 mmol) and tert-butyl (2S)-3-chloro-2-hydroxypropylcarbamate (which can be prepared according to U.S. patent application, serial No. 60/241122, 3.22 g, 15.36 mmol) in dry DMF (5.6 mL) at 0° C. under N2 is treated with LiOtBu (1M in THF, 29.5 mL, 29.5 mmol) dropwise over 5 mins. The cooling bath is removed, and the resulting mixture is stirred at ambient temperature for 18 hrs, quenched with saturated aqueous NH4Cl (25 mL), diluted with H2O (25 mL) and extracted with EtOAc (50 mL). The EtOAc phase is then washed with H2O (2×50 mL) and brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of EtOAc/heptane (25/75-50/50). Those fractions with an Rf=0.20 by TLC (EtOAc/hexane, 50/50) are pooled and concentrated to give 4.69 g (80%) of the title compound as a white solid, mp 135-137° C. [α]25D=−27° (c 1.00, DMSO).

Workup

  1. customThe cooling bath is removed
  2. customquenched with saturated aqueous NH4Cl (25 mL)
  3. additiondiluted with H2O (25 mL)
  4. extractionextracted with EtOAc (50 mL)
  5. washThe EtOAc phase is then washed with H2O (2×50 mL) and brine (25 mL)
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated under reduced pressure
  8. customthe residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge
  9. washeluting with a gradient of EtOAc/heptane (25/75-50/50)
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-d1b37533946b42d0813109602b156558
Source dataset
uspto-grants-2005_12
Patent number
US06972286B2

Reaction notes

Loading…