Reaktion #172788

ord-0ee1c699b9a24e7389f6ff25fa219f7d

Reaktionsgleichung

COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(NC(=O)CN6CCS(=O)(=O)CC6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
methyl 4-[(1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoate
O=C(O)C(F)(F)F
TFA
O.[Li+].[OH-]
lithium hydroxide monohydrate
→
CC(C)[C@@H]1CC[C@]2(NC(=O)CN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid
O=C(O)C(F)(F)F
TFA
Ausbeute 54.1%

Edukte

—
solution
COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(NC(=O)CN6CCS(=O)(=O)CC6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
methyl 4-[(1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoate
O=C(O)C(F)(F)F
TFA
O.[Li+].[OH-]
lithium hydroxide monohydrate

Reagenzien

Keine

Lösungsmittel

C1CCOC1
THF
O
H2O

Reaktionsbedingungen

Temperatur
75°CELSIUS
Detaillierte Bedingungen
See reaction.notes.procedure_details.

Aufarbeitung

  1. 1
    Einengenthe reaction was concentrated to dryness
  2. 2
    workup.DISSOLUTIONThe crude residue was dissolved in THF (1.2 mL)
  3. 3
    FiltrationThe solution was filtered
  4. 4
    Sonstigeinjected into reverse phase HPLC for purification

Vorschrift

To a solution of methyl 4-[(1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoate, TFA (33 mg, 0.040 mmol) in THF (Volume: 3 mL) was added a 0.753 molar solution of lithium hydroxide monohydrate (0.316 mL, 0.158 mmol) in H2O. The reaction mixture was heated to 75° C. After 5.5 h, the reaction was concentrated to dryness. The crude residue was dissolved in THF (1.2 mL), MeOH (0.3 mL) and 1N HCl (0.2 mL). The solution was filtered and injected into reverse phase HPLC for purification using HPLC method 3 to give 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, TFA (17.9 mg, 0.021 mmol, 54.1% yield) as a white solid. LCMS: m/z 707.6 (M+H+), retention time 2.030 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.93 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.13 (s, 1H), 5.31 (dd, J=1.5, 6.1 Hz, 1H), 3.26-3.22 (m, 5H), 3.21-3.15 (m, 4H), 2.66-2.59 (m, 1H), 2.37 (dd, J=6.7, 12.5 Hz, 1H), 2.17 (dd, J=6.4, 17.1 Hz, 1H), 1.99-1.91 (m, 1H), 1.80-1.70 (m, 4H), 1.67-1.57 (m, 2H), 1.57-1.45 (m, 9H), 1.44-1.39 (m, 1H), 1.39-1.26 (m, 3H), 1.18-1.11 (m, 2H), 1.09 (s, 3H), 1.04 (s, 6H), 0.96 (s, 3H), 0.95 (s, 3H), 0.91 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H).

Quelle

DOI: 10.6084/m9.figshare.5104873.v1Patent: US08846647B2uspto-grants-2014_09