Cyclopropane → tert-butyl N-[(4aR,11bR)-10-[[5-(cyclopropylmethoxy)pyrazine-2-carbonyl]amino]-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]carbamate

HRID 627755Notes

Reaction equation

HRID 627755 reaction equation
C1CC1.[H-].[Na+].Cl[C:7]1[N:8]=[CH:9][C:10]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]3[O:42][CH2:41][CH2:40][C@H:23]4[S:24](=[O:39])(=[O:38])[C:25]([CH3:37])([CH3:36])[C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:27][C@:22]4([CH3:43])[C:20]=3[CH:21]=2)=[O:14])=[N:11][CH:12]=1.[Cl-].[NH4+].[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1>>[CH:46]1([CH2:50][O:49][C:7]2[N:8]=[CH:9][C:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]4[O:42][CH2:41][CH2:40][C@H:23]5[S:24](=[O:39])(=[O:38])[C:25]([CH3:37])([CH3:36])[C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:27][C@:22]5([CH3:43])[C:20]=4[CH:21]=3)=[O:14])=[N:11][CH:12]=2)[CH2:47][CH2:48]1

Participants

6

Reactant 5

HCID 6351CyclopropaneHCID 8028Tetrahydrofuran2×HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 86728168tert-butyl ((4aR,11bR)-10-(5-chloropyrazine-2-carboxamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate

Product 1

HCID 86728167tert-butyl N-[(4aR,11bR)-10-[[5-(cyclopropylmethoxy)pyrazine-2-carbonyl]amino]-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]carbamateYield 83%

Procedure

A solution of hydroxymethyl)cyclopropane (0.10 mL, 1.20 mmol) in THF (1.4 mL) was cooled to 0° C. and treated with sodium hydride (60% wt; 36.1 mg, 0.90 mmol). The reaction was stirred for 30 minutes and then a solution of tert-butyl N-[(4aR,11bR)-10-[(5-chloropyrazine-2-carbonyl)amino]-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]carbamate (113 mg, 0.20 mmol) in 1 mL of THF was added. The reaction was stirred at ambient temperature for 1 hour. The reaction was treated with aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was concentrated. The resulting crude was purified by column chromatography, eluting with 10-50% ethyl acetate/heptane to afford the title compound (100 mg, 0.17 mmol, 83%) as an off-white solid. MS m/z=600.2 (M+H).

Workup

  1. stirringThe reaction was stirred at ambient temperature for 1 hour
  2. extractionextracted with ethyl acetate
  3. concentrationThe organic portion was concentrated
  4. customThe resulting crude was purified by column chromatography
  5. washeluting with 10-50% ethyl acetate/heptane

Sources & evidence

ORD record
ord-521ee8e1106e412297524df301ef7a8b
Source dataset
uspto-grants-2016_04
Patent number
US09309263B2

Reaction notes

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