Triphenylphosphine → (1r)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonyl-propyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide

HRID 853966Notes

Reaction equation

HRID 853966 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([C@H:45]([N:49]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[NH:59][C:60]([CH:62]3[CH2:64][CH2:63]3)=[O:61])[CH2:50]2)[CH2:46][CH2:47]O)[CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH3:35].[CH3:65][S-].[Na+].O[O:69][S:70]([O-:72])=O.[K+]>C1COCC1.CO.O>[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([C@H:45]([N:49]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[NH:59][C:60]([CH:62]3[CH2:64][CH2:63]3)=[O:61])[CH2:50]2)[CH2:46][CH2:47][S:70]([CH3:65])(=[O:72])=[O:69])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH3:35]

Participants

9

Reactant 5

HCID 11776TriphenylphosphineHCID 4378561Sodium methanethiolateHCID 5363146Diisopropyl azodicarboxylateHCID 9845251(1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideHCID 23707502Potassium hydroxy sulfite

Product 1

HCID 10413135(1r)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonyl-propyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amideYield 5%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of triphenyl phosphine (0.63 g, 2.4 mmol) in THF (10 mL) was added DIAD (0.47 mL, 2.4 mmol) at 0° C. After 10 min, (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.93 mL, 2.2 mmol) was added as solid. After 5 min, sodium thiomethoxide (180 mg, 2.6 mmol) was added. After 20 min, the cold bath was removed and the mixture was stirred at room temperature for 1.5 hrs. To the mixture was added water (15 mL), methanol (15 mL), and oxone (5.4 g, 8.8 mmol) and kept for 16 h. The mixture was extracted with methylene chloride (100 mL) and water (50 mL). The organic layer was dried over MgSO4. The solvent was removed in vacuo to give a solid. The solid was purified with prep HPLC to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (50 mg, 5% yield): mp, 148-150° C.; 1H NMR (CDCl3) δ 0.89-0.94 (m, 2H, CH2), 1.10-1.13 (m, 2H, CH2), 1.46 (t, J=7 Hz, 3H, CH3), 1.65-1.73 (m, 1H, CH), 2.60-2.69 (m, 2H, CH2), 2.96 (s, 3H, CH3), 3.02-3.22 (m, 2H, CH2), 3.87 (s, 3H, CH3), 3.99 (d, J=17 Hz, 1H, NCHH), 4.07 (q, J=7 Hz, 2H, CH2), 4.30 (d, J=17 Hz, 1H, NCHH), 5.48 (t, J=8 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.46 (t, J=8 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.49 (s, 1H, NH); 3C NMR (CDCl3) δ 8.30, 14.75, 16.19, 23.78, 41.24, 45.95, 51.99, 53.01, 56.00, 64.65, 111.60, 112.37, 116.88, 117.00, 117.89, 119.46, 129.82, 133.52, 138.09, 141.29, 148.87, 149.55, 169.79, 172.66; Anal Calcd for C25H30N2O6S1: C, 61.71; H, 6.21; N, 5.76. Found: C, 61.33; H, 6.19; N, 5.59.

Workup

  1. waitAfter 5 min
  2. waitAfter 20 min
  3. customthe cold bath was removed
  4. waitkept for 16 h
  5. extractionThe mixture was extracted with methylene chloride (100 mL) and water (50 mL)
  6. dry with materialThe organic layer was dried over MgSO4
  7. customThe solvent was removed in vacuo
  8. customto give a solid
  9. customThe solid was purified with prep HPLC

Sources & evidence

ORD record
ord-1fef471fffeb4d83825d82c411401b7b
Source dataset
uspto-grants-2007_08
Patent number
US07256210B2

Reaction notes

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