4-Iodo-2-methylbut-1-ene → N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1-hydroxy-4-methylpent-4-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 1478765Notes

Reaction equation

HRID 1478765 reaction equation
I[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5].C([Li])(C)(C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]=[O:31])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N:21]2>C(OCC)C.O1CCCC1.[Cl-].[NH4+]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]([OH:31])[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:32][C:33](=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N:21]2

Participants

7

Reactant 3

HCID 102620764-Iodo-2-methylbut-1-eneHCID 89889275N-[(4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamideHCID 178418306HCID 178418306, compound

Product 1

HCID 90253491N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1-hydroxy-4-methylpent-4-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolvent3×HCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 4-iodo-2-methylbut-1-ene (942 mg, 4.8 mmol) in diethyl ether (5 mL) was added to a solution of tert-butyllithium (1.7 M in pentane, 5.65 mL, 9.6 mmol) in diethyl ether (15 mL) at −78° C. The reaction mixture was stirred at −78° C. for 35 minutes and then N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (400 mg, 0.96 mmol) in diethyl ether (5 mL) and tetrahydrofuran (4 mL) was added drop-wise over 10 minutes. The mixture was stirred at −78° C. for 15 minutes, then allowed to warm to 0° C. and stirred at 0° C. for 1 hour. The mixture was allowed to warm to room temperature, then stirred at room temperature for 15 minutes. The mixture was diluted with a saturated aqueous solution of ammonium chloride (35 mL) and extracted with ethyl acetate (3×35 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated to afford a yellow oil. Purification via silica gel chromatography (Gradient: 0% to 90% ethyl acetate in heptane) afforded the product as a white solid. Yield: 108 mg, 23%. LCMS m/z 487.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.22 (br d, J=6.8 Hz, 2H), 7.31-7.53 (m, 4H), 6.68-6.96 (m, 2H), 4.72-4.73 (m, 1H), 4.17 (d, J=12.5 Hz, 1H), 3.80-3.87 (m, 1H), 3.76 (br s, 1H), 3.61-3.65 (m, 1H), 3.56 (br d, J=8.2 Hz, 1H), 3.13 (br s, 1H), 3.03 (dd, J=12.7, 4.1 Hz, 1H), 2.68 (m, 1H), 2.0-2.29 (m, 4H), 1.74 (s, 3H), 1.59-1.69 (m, 2H).

Workup

  1. stirringThe mixture was stirred at −78° C. for 15 minutes
  2. temperatureto warm to 0° C.
  3. stirringstirred at 0° C. for 1 hour
  4. temperatureto warm to room temperature
  5. stirringstirred at room temperature for 15 minutes
  6. extractionextracted with ethyl acetate (3×35 mL)
  7. dry with materialThe combined ethyl acetate extracts were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto afford a yellow oil
  11. customPurification via silica gel chromatography (Gradient: 0% to 90% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-9008cfcbdc644bf8af50c4334823b9ff
Source dataset
uspto-grants-2016_08
Patent number
US09403846B2

Reaction notes

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