Vinblastine → 4-Desacetylvinblastine

HRID 499966

Reaction equation

HRID 499966 reaction equation
[CH3:1][CH2:2][C@@:3]1([OH:59])[CH2:21][N:19]2[CH2:20][C@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:23]=[C:24]4[C@:32]56[C@@H:36]7[C@:37]([CH2:52][CH3:53])([C@@H:41]([O:48]C(C)=O)[C@:42]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@@H:31]5[N:30]([CH3:54])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[CH:38]=[CH:39][CH2:40][N:35]7[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1.CC[C@@]1(O)CN2C[C@H](C[C@](C(OC)=O)(C3C=C4[C@]56[C@@H]7[C@](CC)([C@@H](OC(C)=O)[C@](O)(C(OC)=O)[C@@H]5N(C)C4=CC=3OC)C=CCN7CC6)C3NC4C=CC=CC=4C=3CC2)C1.OS(O)(=O)=O>NN.C(O)C>[CH3:1][CH2:2][C@@:3]1([OH:59])[CH2:21][N:19]2[CH2:20][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:23]=[C:24]4[C:32]56[C@@H:31]([N:30]([CH3:54])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[C@@:42]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@H:41]([OH:48])[C@:37]3([CH2:52][CH3:53])[CH:38]=[CH:39][CH2:40][N:35]([C@H:36]53)[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1

Participants

4

Reactant 2

HCID 13342VinblastineHCID 5388983Vinblastine Sulfate

Product 1

HCID 1970264-Desacetylvinblastine

Reagents, catalysts & solvents 1

HCID 129679701Hydrazine-ethanolSolvent

Procedure

Vinca alkaloids such as vinblastine can be conjugated directly to aldehyde-bearing linkers following conversion to a hydrazide form as described by Brady et al. (J. Med. Chem., 45:4706-4715, 2002). Briefly, vinblastine sulfate is dissolved in 1:1 hydrazine/ethanol and heated to 60° C.-65° C. for 22 hours to yield desacetylvinblastine 3-carboxhydrazide (Table 2, DAVCH). Alternatively, amine-reactive forms of vinblastine may be generated in situ as described by Trouet et al. (U.S. Pat. No. 4,870,162) by (1) initially converting vinblastine sulfate to the desacetyl form (e.g. as described by Brady et al., reacting with 1:3 hydrazine/methanol at 20° C. for 20 hours), (2) reacting the resulting free base with approximately 2-fold excess succinic anhydride to generate the hemisuccinate (Table 2, DAVS), and (3) reacting with isobutyl chloroformate to form the reactive mixed anhydride.

Workup

  1. temperatureheated to 60° C.-65° C. for 22 hours

Sources & evidence

ORD record
ord-a46daf678c7e43fd939a5eee01069ad7
Source dataset
uspto-grants-2010_08
Patent number
US07767803B2

Linked notes

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