Methanol → (4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-1'-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-N-[(3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide

HRID 470670Notes

Reaction equation

HRID 470670 reaction equation
C([N:3]([CH2:6][CH3:7])CC)C.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C@@:13]3([C:26]4([CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[N:25]4[C@@H:20]([C:21](=[O:46])[O:22][C@@H:23]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C@H:24]4C4C=CC=CC=4)[C@@H:19]3[C:47]3[CH:52]=[CH:51][N:50]=[C:49]([Cl:53])[C:48]=3[F:54])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[Cl-].[NH4+].[CH3:57][OH:58]>>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]3([C@@H:19]([C:47]4[CH:52]=[CH:51][N:50]=[C:49]([Cl:53])[C:48]=4[F:54])[C@H:20]([C:21]([NH:3][C@@H:6]4[CH2:7][CH2:12][C@@H:13]([CH2:14][OH:18])[O:58][CH2:57]4)=[O:46])[N:25]([C@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:23]([OH:22])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:26]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1

Participants

5

Reactant 4

HCID 887MethanolHCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 86672587(3'S,4'R,7'S,8'S,8a'R)-6''-chloro-8'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-dione

Product 1

HCID 86672589(4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-1'-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-N-[(3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamideYield 89%

Conditions

Temperature
50 °C

Procedure

The compound (131 mg, 1.00 mmol) obtained in Step 3 of Reference Example 2 and triethylamine (0.14 ml, 1.00 mmol) were added to a methanol (4 ml) solution of the compound (268 mg, 0.40 mmol) obtained in Step 1 of Example 16 and the resulting mixture was stirred at 50° C. for 5 days. After cooling, saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [chloroform:methanol=100:0→30:1 (v/v)] to give 288 mg (89%) of the title compound as a colorless amorphous solid.

Workup

  1. temperatureAfter cooling
  2. extractionfollowed by extraction with ethyl acetate
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated under reduced pressure
  6. customthe residue was purified by silica gel column chromatography [chloroform:methanol=100:0→30:1 (v/v)]

Sources & evidence

ORD record
ord-3040c5c8517843c19f75c09f90fdf5df
Source dataset
uspto-grants-2014_01
Patent number
US08629133B2

Reaction notes

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