Dichloromethane → 1'-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione

HRID 1665376Notes

Reaction equation

HRID 1665376 reaction equation
[NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1.Cl([O-])(=O)(=O)=O.[Li+].ClCCl>C(#N)C>[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 6932898(2S)-2-[(4-fluorophenoxy)methyl]oxiraneHCID 23665649Lithium perchlorateHCID 57661820Spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione

Product 1

HCID 236548721'-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dioneYield 46.8%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (1.0 g, 3.32 mmol) in acetonitrile (12.0 mL) was added (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.614 g, 3.65 mmol) followed by lithium perchlorate (0.388 g, 3.65 mmol). The reaction mixture was stirred at 80° C. for 2 hours. The reaction was cooled to room temperature and dichloromethane (100 mL) added to it. The reaction was then washed with water (100 mL). The organic layer was separated, washed with water, dried with sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography (SiO2, 80% EtOAc in dichloromethane to 100% EtOAc) to give the desired product as a purple solid (0.73 g, 45%). M.p.=174-175° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=1.6, 7.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.66 (dt, J=1.6, 7.6 Hz, 1H), 7.5 (dt, J=1.6, 7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.9-6.84 (m, 2H), 4.18-4.1 (m, 1H), 4.0-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.96 (s, 2H), 2.86-2.76 (m, 2H), 2.72-2.62 (m, 2H), 2.6-2.5 (m, 2H), 2.2-2.12 (m, 2H), 1.98-1.82 (m, 2H); LCMS: 470 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=30.54

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. washThe reaction was then washed with water (100 mL)
  3. customThe organic layer was separated
  4. washwashed with water
  5. dry with materialdried with sodium sulfate
  6. concentrationconcentrated under vacuum
  7. customThe crude product was purified by flash column chromatography (SiO2, 80% EtOAc in dichloromethane to 100% EtOAc)

Sources & evidence

ORD record
ord-409d947c7e724774a17185e1debe5d90
Source dataset
uspto-grants-2011_10
Patent number
US08039503B2

Reaction notes

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