Tetrahydrofuran → HCID 69733822, compound

HRID 488356Notes

Reaction equation

HRID 488356 reaction equation
[C:1]1([CH2:7][O:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17](C([O-])=O)[CH2:16][CH2:15]3)=[O:10])C=CC=CC=1.[CH2:25]([Li])[CH2:26][CH2:27][CH3:28].[C:30]([O:35][CH2:36][C@@H:37]1O[CH2:38]1)(=[O:34])CCC.C1C[O:43][CH2:42]C1>>[OH:43][CH2:42][C@@H:7]1[O:8][C:9](=[O:10])[N:11]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:30]([O:35][CH2:36][C:37]2[CH:38]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:34])[CH2:16][CH2:15]3)[CH2:1]1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 2724536(2R)-Oxiran-2-ylmethyl butanoateHCID 22269647HCID 22269647, compoundHCID 178418339Butyllithium

Product 1

HCID 69733822HCID 69733822, compoundYield 69%

Conditions

Temperature
-78 °C

Procedure

A solution of 3,4-dihydro-6-[[(phenylmethoxy)carbonyl]amino]-2(1H)-isoquinolinecarboxylate (Step 2, 7.05 g, 16.93 mmol) in dry THF (85 mL) at −78° C. under N2 is treated with n-butyllithium (11.1 mL, 1.6M in hexanes, 17.77 mmol) dropwise over 10 mins. The resulting mixture is stirred at −78° C. for 45 mins and is then treated with (R)-(−)-glycidyl butyrate (2.52 mL, 17.77 mmol) dropwise. The resulting mixture is stirred at −78° C. for 30 mins and is then warmed to ambient temperature and stirred for an additional 20 hrs. The reaction is then quenched with saturated aqueous NH4Cl (25 mL), diluted with H2O (25 mL) and extracted with EtOAc (100 mL). The organic phase is washed with H2O (2×50 mL) and brine (25 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (350 g, 230-400 mesh), eluting with a gradient of MeOH/CH2Cl2 (1/99-3/97). Pooling and concentration of those fractions with an Rf=0.29 by TLC (MeOH/CHCl3, 5/95) provides 4.48 g (69%) of the title compound as an amorphous, white solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 7H), 7.11 (m, 1H), 5.19 (s, 2H), 4.75 (m, 1H), 4.63 (s, 2H), 4.00 (m, 3H), 3.75 (m, 3H), 2.86 (m, 2H) 1.65 (bs, 1H); MS (ESI+) for C21H22N2O5 m/z 383 (M+H)+; [α]25D=16° (c 0.52, chloroform).

Workup

  1. stirringThe resulting mixture is stirred at −78° C. for 30 mins
  2. temperatureis then warmed to ambient temperature
  3. stirringstirred for an additional 20 hrs
  4. customThe reaction is then quenched with saturated aqueous NH4Cl (25 mL)
  5. additiondiluted with H2O (25 mL)
  6. extractionextracted with EtOAc (100 mL)
  7. washThe organic phase is washed with H2O (2×50 mL) and brine (25 mL)
  8. dry with materialdried over anhydrous MgSO4
  9. concentrationconcentrated under reduced pressure
  10. customto give the crude product which
  11. customis then chromatographed on silica gel (350 g, 230-400 mesh)
  12. washeluting with a gradient of MeOH/CH2Cl2 (1/99-3/97)

Sources & evidence

ORD record
ord-d8afec967afc47ce99c200d67925c1f3
Source dataset
uspto-grants-2005_12
Patent number
US06972286B2

Reaction notes

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