Triphenylphosphine → (3r)-Thioacetic acid s-[3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propyl] ester

HRID 1797238Notes

Reaction equation

HRID 1797238 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH2:17]2)[CH2:13][CH2:14]O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([OH:54])(=[S:53])[CH3:52].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO>[CH:29]1([C:27]([NH:26][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[C:24](=[O:25])[N:16]([C@@H:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH2:13][CH2:14][S:53][C:51](=[O:54])[CH3:52])[CH2:17]3)=[O:28])[CH2:31][CH2:30]1

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 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 178418634HCID 178418634, compound

Product 1

HCID 87540694(3r)-Thioacetic acid s-[3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propyl] esterYield 81.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (5.7 g, 13 mmol), triphenyl phosphine (7.1 g, 2.4 mmol) and thioacetic acid (2.2 mL, 31 mmol) in THF (50 mL) was added a solution of DIAD (5.5 mL, 28 mmol) in THF (50 mL) at room temperature. After 4 hrs, methanol (5 mL) was added to the solution. The solvent was removed in vacuo. The residue was purified with Chromatography to give (3R)-thioacetic acid S-[3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propyl]ester (5.1 g, 79% yield). To a solution of (3R)-thioacetic acid S-[3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propyl]ester (5.0 g, 10 mmol) and methyl iodide (0.8 mL, 13 mmol) in methanol (40 mL) was added a solution of sodium hydroxide (5N, 4.2 mL, 21 mmol) at room temperature. After 2 hrs, to the mixture was added water (40 mL), methylene chloride (20 mL), and oxone (18 g, 29 mmol) and kept for 1.5 hrs. The mixture was extracted with methylene chloride (100 mL) and water (50 mL). The organic layer was washed with Na2S2O3 (10% 50 mL), brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with chromatography (Silica Gel) to give (3R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfinyl-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (320 mg, 6% yield): mp, 122–125° C.; 1H NMR (CDCl3) δ 0.86–0.93 (m, 2H, CH2), 1.08–1.14 (m, 2H, CH2), 1.45 (t, J=7 Hz, 3H, CH3), 1.63–1.72 (m, 1H, CH), 2.58 and 2.59 (2s, 3H, CH3), 2.60–2.82 (m, 4H, CH2CH2), 3.86 (s, 3H, CH3), 3.97 (d, J=17 Hz, 1H, NCHH), 4.06 (q, J=7 Hz, 2H, CH2), 4.31 and 4.35 (2 sets of d, J=17 Hz, 1H, NCHH), 5.50–5.59 (m, 1H, NCH), 6.84–7.02 (m, 4H, Ar), 7.41–7.48 (m, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH); 13C NMR (CDCl3) δ 8.28, 14.76, 16.18, 24.28, 24.76, 38.95, 45.71, 45.89, 51.22, 51.42, 53.07, 53.63, 55.99, 64.64, 111.54, 112.49, 116.89, 117.19, 117.80, 119.54, 130.38, 130.48, 133.37, 138.04, 141.36, 148.77, 149.40, 169.79, 169.82, 172.66; Anal Calcd for C25H30N2O5S+0.8 H2O: C, 61.93; H, 6.57; N, 5.78; H2O, 2.97. Found: C, 61.63; H, 6.62; N, 5.61; H2O, 2.19.

Workup

  1. customThe solvent was removed in vacuo
  2. customThe residue was purified with Chromatography

Sources & evidence

ORD record
ord-afd1b2c5d91545868d2603c08cd0fffb
Source dataset
uspto-grants-2006_04
Patent number
US07034052B2

Reaction notes

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