Acetic Acid → [5-(1-Cyclobutyl-piperidin-4-yloxy)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-methanone

HRID 494009Notes

Reaction equation

HRID 494009 reaction equation
[O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:26]([CH3:28])[CH3:27])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C.[CH2:34]1[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:34]1([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[N:11]([CH:26]([CH3:27])[CH3:28])[C:10]([C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:29])[CH2:3][CH2:4]3)=[O:9])=[CH:18]4)[CH2:21][CH2:22]2)[CH2:37][CH2:36][CH2:35]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 9250CyclobutaneHCID 5049666Sodium triacetoxyborohydrideHCID 67073486(1,1-Dioxo-1lambda6-thiomorpholin-4-yl)-[1-isopropyl-5-(piperidin-4-yloxy)-1H-indol-2-yl]-methanone

Product 1

HCID 16739610[5-(1-Cyclobutyl-piperidin-4-yloxy)-1-isopropyl-1H-indol-2-yl]-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-methanoneYield 32.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
55 °C

Procedure

To a mixture of (1,1-dioxo-1λ6-thiomorpholin-4-yl)-[1-isopropyl-5-(piperidin-4-yloxy)-1H-indol-2-yl]-methanone (268 mg, 1.0 eq.) in acetic acid (115 mg, 3.0 eq.) was added a solution of cyclobutane (90 mg, 2.0 eq.) in tetrahydrofuran (8 mL). The mixture was stirred for 2 h at 55° C. Then the mixture was cooled to room temperature and sodium triacetoxyborohydride (279 mg, 2.0 eq.) was added. The reaction mixture was stirred overnight at 65° C. The residue was partitioned between water and ethyl acetate. The organic layer was washed with a sodium hydrogenocarbonate aqueous solution, dried over sodium sulfate, filtered and dried in vacuo. Then the residue was purified on silica eluting with a gradient of dichloromethane/methanol to yield 97 mg (32%) of the desired product as off-white oil. MS (m/e): 474.5 (MH+, 100%).

Workup

  1. temperatureThen the mixture was cooled to room temperature
  2. stirringThe reaction mixture was stirred overnight at 65° C
  3. customThe residue was partitioned between water and ethyl acetate
  4. washThe organic layer was washed with a sodium hydrogenocarbonate aqueous solution
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. customdried in vacuo
  8. customThen the residue was purified on silica eluting with a gradient of dichloromethane/methanol

Sources & evidence

ORD record
ord-0d7aca292b214bc9ad651dbd983c79f7
Source dataset
uspto-grants-2009_05
Patent number
US07538101B2

Reaction notes

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