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 2168278Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2168278
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

Komponenten

4

Edukt 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

Produkt 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]benzamideAusbeute 88,3 %

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-d328b83cf130492987c96ded5b0a85c2
Quelldatensatz
uspto-grants-2015_06
Patentnummer
US09045498B2

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