Diphosgene → 3-(3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanamido)-4-((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)-tetrahydro-2H-pyran-2-yloxy)benzyl 2-(3-(tert-butyldiphenylsilyloxy)propyl)oxazolidine-3-carboxylate

HRID 1045281Notes

Reaction equation

HRID 1045281 reaction equation
[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=2[NH:32][C:33](=[O:54])[CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][CH:41]2[C:53]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:47]3[C:42]2=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])[O:6]1)=[O:4].[O:55]=[C:56](Cl)OC(Cl)(Cl)Cl.[Si:63]([O:80][CH2:81][CH2:82][CH2:83][CH:84]1[NH:88][CH2:87][CH2:86][O:85]1)([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[Si:63]([O:80][CH2:81][CH2:82][CH2:83][CH:84]1[N:88]([C:56]([O:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C@H:7]3[C@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[O:6]3)=[C:25]([NH:32][C:33](=[O:54])[CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][CH:41]3[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=4[C:48]4[C:53]3=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:38])[CH:26]=2)=[O:55])[CH2:87][CH2:86][O:85]1)([C:76]([CH3:79])([CH3:77])[CH3:78])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1

Participants

4

Reactant 3

HCID 10426DiphosgeneHCID 598165432-(3-{[tert-Butyl(diphenyl)silyl]oxy}propyl)-1,3-oxazolidineHCID 59816548Me-triacetyl-beta-D-glucopyranuronate-Ph-CH2OH-Fmoc

Product 1

HCID 598165413-(3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanamido)-4-((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)-tetrahydro-2H-pyran-2-yloxy)benzyl 2-(3-(tert-butyldiphenylsilyloxy)propyl)oxazolidine-3-carboxylate

Procedure

The construction of the glucuronide-based linker unit with DPO (2) involved a different strategy (Scheme 4). Intermediate 11 was activated with diphosgene and then reacted with oxazoline 12 (prepared in 3 steps from 1,4-butane diol) to afford the desired oxazoline carbamate 13. Removal of the silyl protecting group with fluoride was followed by oxidation to give aldehyde 14. This compound was used in a reductive alkylation reaction with doxorubicin-HCl (15) to give the doxorubicin derivative 16. Lastly, the β-glucuronide protecting groups and Fmoc group were removed in a 2-step sequence with lithium hydroxide and piperidine, and the resulting primary amine was capped with 10 to give the desired β-glucuronide DPO linker 17.

Sources & evidence

ORD record
ord-39d9dec3e9be4ff8b66f542e98fbce72
Source dataset
uspto-grants-2013_10
Patent number
US08568728B2

Reaction notes

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