Hydrochloric Acid → N-[(4aR,6R,8aS)-8a-[5-(aminomethyl)-2,4-difluorophenyl]-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 68407Notes

Reaction equation

HRID 68407 reaction equation
Cl.O1CCOCC1.[C:8]([NH:16][C:17]1[S:18][CH2:19][C@@H:20]2[CH2:26][C@H:25]([CH2:27][F:28])[O:24][CH2:23][C@:21]2([C:29]2[C:30]([F:45])=[CH:31][C:32]([F:44])=[C:33]([CH:43]=2)[CH2:34][NH:35]C(=O)OC(C)(C)C)[N:22]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH2:35][CH2:34][C:33]1[C:32]([F:44])=[CH:31][C:30]([F:45])=[C:29]([C@:21]23[CH2:23][O:24][C@@H:25]([CH2:27][F:28])[CH2:26][C@H:20]2[CH2:19][S:18][C:17]([NH:16][C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:22]3)[CH:43]=1

Participants

4

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 86762646tert-butyl {5-[(4aR,6R,8aS)-2-(benzoylamino)-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzyl}carbamate

Product 1

HCID 86762645N-[(4aR,6R,8aS)-8a-[5-(aminomethyl)-2,4-difluorophenyl]-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamideYield 88.3%

Procedure

A solution of hydrogen chloride in dioxane (4.0 M, 10 mL, 41 mmol) was added to tert-butyl {5-[(4aR,6R,8aS)-2-(benzoylamino)-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzyl}carbamate (C25) (0.8277 g, 1.506 mmol) at room temperature. The reaction mixture was stirred overnight and then concentrated under reduced pressure to yield a brown solid. The solid was partitioned between a 1:1 solution of ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The organics were separated and the aqueous layer was extracted further with ethyl acetate (2×100 mL). The combined organics were then washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield the product as a brown solid (0.598 g), which was taken directly to the following step. LCMS m/z 450 [M+H+]. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.11-8.13 (m, 2H), 7.44-7.57 (m, 3H), 7.09 (dd, J=12.3, 9.6 Hz, 1H), 4.49-4.51 (m, 1H), 4.37-4.39 (m, 1H), 3.20-3.23 (m, 1H), 3.01 (dd, J=13.0, 4.2 Hz, 1H), 2.77 (dd, J=13.0, 2.8 Hz, 1H), 1.89 (m, 1H), 1.70 (ddd, J=13.4, 4.1, 2.2 Hz, 1H).

Workup

  1. concentrationconcentrated under reduced pressure
  2. customto yield a brown solid
  3. customThe solid was partitioned between a 1:1 solution of ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL)
  4. customThe organics were separated
  5. extractionthe aqueous layer was extracted further with ethyl acetate (2×100 mL)
  6. washThe combined organics were then washed with brine (200 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-721ea18439c248ad8cab1838d937a996
Source dataset
uspto-grants-2014_09
Patent number
US08822456B2

Reaction notes

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