(R)-tert-butyl 4-(((S)-5-((tert-butoxycarbonyl)amino)-6-(cyanomethoxy)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate → (4R)-tert-butyl 4-(((55)-6-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)oxy)-5-((tert-butoxycarbonyl)amino)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate
Reaction equation
C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@H:68]([C:88](OCC#N)=[O:89])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]1[CH2:80][S:79][CH2:78][N:77]1[C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[O:75])=[O:66])([CH3:63])([CH3:62])[CH3:61]>O.O1CCCC1>[NH2:58][C:55]1[CH:56]=[CH:57][N:52]([C@@H:26]2[O:25][C@H:24]([CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]3[C@@H:39]([O:40][C:88](=[O:89])[C@@H:68]([NH:67][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:66])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]4[CH2:80][S:79][CH2:78][N:77]4[C:81]([O:83][C:84]([CH3:86])([CH3:87])[CH3:85])=[O:82])=[O:75])[C@@H:38]([OH:41])[C@H:37]([N:42]4[CH:50]=[N:49][C:48]5[C:43]4=[N:44][CH:45]=[N:46][C:47]=5[NH2:51])[O:36]3)([OH:32])=[O:31])[CH2:27]2)[C:53](=[O:59])[N:54]=1Participants
Reactant 2
HCID 89668744(R)-tert-butyl 4-(((S)-5-((tert-butoxycarbonyl)amino)-6-(cyanomethoxy)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate
HCID 117735960((2R,3S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt2×Product 1
Reagents, catalysts & solvents 2
Procedure
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (50 mg, 0.079 mmol) in water (0.5 mL) and a solution of (R)-tert-butyl 4-(((S)-5-((tert-butoxycarbonyl)amino)-6-(cyanomethoxy)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk83) (118 mg, 0.236 mmol) in tetrahydrofuran (0.5 mL) were added to buffer A (40 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (water/acetonitrile solution) to afford a crude purified product of (4R)-tert-butyl 4-(((5S)-6-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)oxy)-5-((tert-butoxycarbonyl)amino)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk84) (80 mg).
Workup
- customthe resulting residue was purified by reverse-phase silica gel column chromatography (water/acetonitrile solution)
- customto afford a crude
- custompurified product of (4R)-tert-butyl 4-(((5S)-6-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)oxy)-5-((tert-butoxycarbonyl)amino)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk84) (80 mg)
Sources & evidence
- ORD record
- ord-5d0f0c8f68c04e5483f72de433a8c678
- Source dataset
- uspto-grants-2016_08
- Patent number
- US09409952B2
Reaction notes
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