Trifluoroacetic acid → (2S,5S)-(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 2-amino-6-((((4-azidobenzyl)oxy)carbonyl)amino)-5-(methyldisulfanyl)hexanoate

HRID 1482323Notes

Reaction equation

HRID 1482323 reaction equation
FC(F)(F)C(O)=O.[N:8]([C:11]1[CH:81]=[CH:80][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C@H:21]([S:77][S:78][CH3:79])[CH2:22][CH2:23][C@@H:24]([NH:69]C(OC(C)(C)C)=O)[C:25]([O:27][C@H:28]2[C@@H:32]([OH:33])[C@@H:31]([N:34]3[CH:42]=[N:41][C:40]4[C:35]3=[N:36][CH:37]=[N:38][C:39]=4[NH2:43])[O:30][C@H:29]2[CH2:44][O:45][P:46]([O:49][C@H:50]2[CH2:54][C@H:53]([N:55]3[CH:60]=[CH:59][C:58]([NH2:61])=[N:57][C:56]3=[O:62])[O:52][C@@H:51]2[CH2:63][O:64][P:65]([OH:68])([OH:67])=[O:66])([OH:48])=[O:47])=[O:26])=[O:18])=[CH:13][CH:12]=1)=[N+:9]=[N-:10]>ClCCl>[NH2:69][C@H:24]([CH2:23][CH2:22][C@@H:21]([S:77][S:78][CH3:79])[CH2:20][NH:19][C:17]([O:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:8]=[N+:9]=[N-:10])=[CH:81][CH:80]=1)=[O:18])[C:25]([O:27][C@H:28]1[C@@H:32]([OH:33])[C@@H:31]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:43])[O:30][C@H:29]1[CH2:44][O:45][P:46]([O:49][C@H:50]1[CH2:54][C@H:53]([N:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[N:57][C:56]2=[O:62])[O:52][C@@H:51]1[CH2:63][O:64][P:65]([OH:68])([OH:67])=[O:66])([OH:48])=[O:47])=[O:26].[NH2:69][C@H:24]([CH2:23][CH2:22][C@@H:21]([S:77][S:78][CH3:79])[CH2:20][NH2:19])[C:25]([O:27][C@H:28]1[C@@H:32]([OH:33])[C@@H:31]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:43])[O:30][C@H:29]1[CH2:44][O:45][P:46]([O:49][C@H:50]1[CH2:54][C@H:53]([N:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[N:57][C:56]2=[O:62])[O:52][C@@H:51]1[CH2:63][O:64][P:65]([OH:67])([OH:68])=[O:66])([OH:48])=[O:47])=[O:26]

Participants

5

Reactant 2

HCID 6422Trifluoroacetic acidHCID 117736185(2S,5S)-(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 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate

Product 2

HCID 117735972(2S,5S)-(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 2-amino-6-((((4-azidobenzyl)oxy)carbonyl)amino)-5-(methyldisulfanyl)hexanoateYield 25%HCID 117736103(2S,5S)-(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 2,6-diamino-5-(methyldisulfanyl)hexanoateYield 14%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A 10% solution of trifluoroacetic acid in dichloromethane (0.24 mL) was added to a solution of (2S,5S)-(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 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk10) (14.0 mg, 0.013 mmol) in dichloromethane (0.2 mL), and the mixture was stirred at room temperature for 30 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S,5S)-(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 2-amino-6-((((4-azidobenzyl)oxy)carbonyl)amino)-5-(methyldisulfanyl)hexanoate (Lys(5S-SSMe)(Acbz)-pdCpA) (Compound tk11) (3.2 mg, 25%) and (2S,5S)-(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 2,6-diamino-5-(methyldisulfanyl)hexanoate (Lys(5S-SSMe)-pdCpA) (Compound tk12) (1.5 mg, 14%).

Workup

  1. concentrationconcentration under reduced pressure
  2. customthe resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution)

Sources & evidence

ORD record
ord-6075360ef4914399b834a0489e40dff1
Source dataset
uspto-grants-2016_08
Patent number
US09409952B2

Reaction notes

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