Trifluoroacetic acid--4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide (1/1) → N-[(E)-1-[4-[2-[3,5-bis[[(6aS)-2-methoxy-12-oxo-7,8,9,10-tetrahydro-6aH-pyrido[2,1-c][1,4]benzodiazepin-3-yl]oxymethyl]phenoxy]ethoxy]phenyl]ethylideneamino]-4-(2,5-dioxopyrrol-1-yl)butanamide

HRID 1968505Notes

Reaction equation

HRID 1968505 reaction equation
FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]1[CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19].[C:22]([C:25]1[CH:80]=[CH:79][C:28]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]([CH2:59][O:60][C:61]3[C:62]([O:77][CH3:78])=[CH:63][C:64]4[C:70](=[O:71])[N:69]5[CH2:72][CH2:73][CH2:74][CH2:75][C@@H:68]5[CH:67]=[N:66][C:65]=4[CH:76]=3)[CH:36]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:38]=2)=[CH:27][CH:26]=1)(=O)[CH3:23]>C(Cl)Cl>[CH3:78][O:77][C:62]1[C:61]([O:60][CH2:59][C:35]2[CH:34]=[C:33]([CH:38]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:36]=2)[O:32][CH2:31][CH2:30][O:29][C:28]2[CH:79]=[CH:80][C:25](/[C:22](=[N:21]/[NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:10]3[C:9](=[O:8])[CH:13]=[CH:12][C:11]3=[O:14])/[CH3:23])=[CH:26][CH:27]=2)=[CH:76][C:65]2[N:66]=[CH:67][C@@H:68]3[CH2:75][CH2:74][CH2:73][CH2:72][N:69]3[C:70](=[O:71])[C:64]=2[CH:63]=1

Participants

4

Reactant 2

HCID 68635864Trifluoroacetic acid--4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide (1/1)HCID 68635988(5Z,5'Z,6aR,6a'R)-3,3'-(5-(2-(4-Acetylphenoxy)ethoxy)-1,3-phenylene)bis(methylene)bis(oxy)bis(2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one)

Product 1

HCID 59440063N-[(E)-1-[4-[2-[3,5-bis[[(6aS)-2-methoxy-12-oxo-7,8,9,10-tetrahydro-6aH-pyrido[2,1-c][1,4]benzodiazepin-3-yl]oxymethyl]phenoxy]ethoxy]phenyl]ethylideneamino]-4-(2,5-dioxopyrrol-1-yl)butanamideYield 61.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide trifluroacetic acid salt (246) (3 mg, 0.0096 mmol), (5Z,5′Z,6aR,6a′R)-3,3′-(5-(2-(4-Acetylphenoxy)ethoxy)-1,3-phenylene)bis(methylene)bis(oxy)bis(2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one) (243) (7.5 mg, 0.0093 mmol) and 50 mg 4 Å molecular sieves was stirred in 2 ml of dry 5% HAc in DCM (one day earlier dried by 4 Å molecular sieves) for 2 h, neutralized with 0.5 ml of DIPEA, evaporated and purified on HPLC preparative C-18 column (Φ10 mm×200 mm column, flow rate 9 mL/min and a gradient solvent system going from 80:20 solvent A:B at time 0-5 min to 50:50 A:B at 15 min then to 30:70 A:B at 25 min until to 10:90 A:B at 30 min. Solvent A—water, solvent B—methanol/dioxane (2:1)) and lyophilized to afford a white solid 5.6 mg (61%) of the title compound. MS m/z+ 1066.3 (M+2CH3OH+Na).

Workup

  1. customearlier dried by 4 Å molecular sieves) for 2 h
  2. customevaporated
  3. custompurified on HPLC preparative C-18 column (Φ10 mm×200 mm column, flow rate 9 mL/min
  4. waitto 30:70 A:B at 25 min until to 10:90 A:B at 30 min

Sources & evidence

ORD record
ord-183ee710e8cf41c7ad15ab37fd589c48
Source dataset
uspto-grants-2013_04
Patent number
US08426402B2

Reaction notes

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