Triethylamine → HIV-RT inhibitor 1

HRID 513889Notes

Reaction equation

HRID 513889 reaction equation
Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH:5]=O.[Cl:8][C:9]1[CH:59]=[CH:58][C:12]([CH2:13][NH:14][CH2:15][C@@H:16]([C@:18]23[CH2:53][C:52](=[O:54])[C:51]([CH:55]([CH3:57])[CH3:56])=[C:19]2[C@@H:20]2[C@@:33]([CH3:36])([CH2:34][CH2:35]3)[C@@:32]3([CH3:37])[C@@H:23]([C@:24]4([CH3:50])[C@@H:29]([CH2:30][CH2:31]3)[C:28]([CH3:39])([CH3:38])[C@@H:27]([O:40][C:41](=[O:49])[CH2:42][C:43]([CH3:48])([CH3:47])[C:44]([OH:46])=[O:45])[CH2:26][CH2:25]4)[CH2:22][CH2:21]2)[OH:17])=[CH:11][CH:10]=1.CCN(CC)CC.C([BH3-])#N.[Na+]>CO.C(Cl)Cl.CCOC(C)=O.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[CH2:15][C@@H:16]([C@:18]23[CH2:53][C:52](=[O:54])[C:51]([CH:55]([CH3:56])[CH3:57])=[C:19]2[C@@H:20]2[C@@:33]([CH3:36])([CH2:34][CH2:35]3)[C@@:32]3([CH3:37])[C@@H:23]([C@:24]4([CH3:50])[C@@H:29]([CH2:30][CH2:31]3)[C:28]([CH3:38])([CH3:39])[C@@H:27]([O:40][C:41](=[O:49])[CH2:42][C:43]([CH3:47])([CH3:48])[C:44]([OH:46])=[O:45])[CH2:26][CH2:25]4)[CH2:22][CH2:21]2)[OH:17])=[CH:58][CH:59]=1

Participants

9

Reactant 4

HCID 8471TriethylamineHCID 5003444Sodium cyanoborohydrideHCID 13908802(Dimethylamino)acetaldehyde--hydrogen chloride (1/1)HCID 86690378HCID 86690378, compound

Product 1

HCID 71580991HIV-RT inhibitor 1Yield 67.9%

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (6.75 g, 54.6 mmol) in methanol (20 mL) was added 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, Trifluoroacetic acid salt (46) (9.5 g, 10.92 mmol). The pH was adjusted to 7-8 with Et3N. The reaction mixture was stirred at rt for 2 h. Sodium cyanoborohydride (0.686 g, 10.92 mmol) was then added and the mixture was stirred at rt overnight. After the reaction was complete, water (15 mL) and EtOAc (15 mL) were added, and then the organic phase was removed and concentrated under reduced pressure. The product was extracted with EtOAc (80 mLx3), the combined organic phase was washed with brine, dried, and concentrated. The product was purified by flash chromatography (DCM:EtOAc=2:1 to 1:1, then DCM:MeOH=100:1 to 20:1) to give 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (51) (6 g, 7.41 mmol, 67.9% yield) as white solid. Multiple batches of this material (were combined 95 g), dissolved in 600 mL of dichloromethane and washed with NaHCO3 (400 mL*3) and the organic phase was dried over Na2SO4, filtered and concentrated. The solids were washed with a mixture of EtOAc: petroleum ether (600 mL), and filtered followed by lyophilization to provide the final title compound 62 g as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ=7.47-7.29 (m, 4H), 4.48 (dd, J=5.8, 10.3 Hz, 1H), 4.15-4.04 (m, 1H), 3.80 (d, J=13.8 Hz, 1H), 3.57 (d, J=14.1 Hz, 1H), 3.21-2.82 (m, 5H), 2.72-2.41 (m, 9H), 2.37-2.05 (m, 4H), 2.05-0.74 (m, 45H);

Workup

  1. stirringthe mixture was stirred at rt overnight
  2. customthe organic phase was removed
  3. concentrationconcentrated under reduced pressure
  4. extractionThe product was extracted with EtOAc (80 mLx3)
  5. washthe combined organic phase was washed with brine
  6. customdried
  7. concentrationconcentrated
  8. customThe product was purified by flash chromatography (DCM

Sources & evidence

ORD record
ord-02ac53cb1363427a90adea7cc1047652
Source dataset
uspto-grants-2015_08
Patent number
US09102685B2

Reaction notes

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