3-Hydrazino-6,7-dihydro-5h-benzo[6,7]cyclohepta[1,2-c]pyridazine → (R)-1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-C]pyridazin-3-YL)-N3-(7-(pyrrolidin-1-YL)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-YL)-1H-1,2,4-triazole-3,5-diamine

HRID 1749340Notes

Reaction equation

HRID 1749340 reaction equation
[C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][C@H:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11][C:10]=2[CH:21]=1)#[N:2].[C:29]([N:31]=[C:32](OC1C=CC=CC=1)[NH:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][CH2:42][C@@H:41]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:40][CH2:39][C:38]=2[CH:49]=1)#[N:30].[NH:57]([C:59]1[N:64]=[N:63][C:62]2[C:65]3[CH:73]=[CH:72][CH:71]=[CH:70][C:66]=3[CH2:67][CH2:68][CH2:69][C:61]=2[CH:60]=1)[NH2:58]>>[N:63]1[C:62]2[C:65]3[CH:73]=[CH:72][CH:71]=[CH:70][C:66]=3[CH2:67][CH2:68][CH2:69][C:61]=2[CH:60]=[C:59]([N:57]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[CH2:15][CH2:14][C@H:13]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH2:12][CH2:11][C:10]=4[CH:21]=3)=[N:58]2)[N:64]=1.[N:63]1[C:62]2[C:65]3[CH:73]=[CH:72][CH:71]=[CH:70][C:66]=3[CH2:67][CH2:68][CH2:69][C:61]=2[CH:60]=[C:59]([N:57]2[C:29]([NH2:30])=[N:31][C:32]([NH:33][C:34]3[CH:35]=[CH:36][C:37]4[CH2:43][CH2:42][C@@H:41]([N:44]5[CH2:45][CH2:46][CH2:47][CH2:48]5)[CH2:40][CH2:39][C:38]=4[CH:49]=3)=[N:58]2)[N:64]=1

Participants

5

Reactant 3

HCID 592955463-Hydrazino-6,7-dihydro-5h-benzo[6,7]cyclohepta[1,2-c]pyridazineHCID 178512232HCID 178512232, compoundHCID 178512233HCID 178512233, compound

Product 2

HCID 25126770(R)-1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-C]pyridazin-3-YL)-N3-(7-(pyrrolidin-1-YL)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-YL)-1H-1,2,4-triazole-3,5-diamineHCID 46215462Bemcentinib

Procedure

Phenyl (S)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate and phenyl (R)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate were treated with 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine in a similar manner as described above in Synthetic Example 2 to yield 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine and 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine. For example, a suspension of a single enantiomer of phenyl N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamimidate (0.06 g, 0.16 mmol) and 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (0.036 g, 0.16 mmol) in 1 mL of IPA was stirred at 90° C. for 18 h. After cooling to ambient temperature, the solvent was evaporated and the residue was purified by HPLC to provide enantiomerically pure 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine as a yellow solid (0.04 g, 50%). 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.94 (s, 1H), 7.85 (br s, 2H), 7.72 (m, 1H), 7.46 (m, 3H), 7.37 (m, 2H), 7.06 (m, 1H), 3.46 (m, 4H), 3.12 (m, 2H), 2.72 (m, 4H), 2.61 (m, 3H), 2.25 (m, 5H), 2.09-1.82 (m, 5H) ppm; MS (ES) 507 (M+H).

Sources & evidence

ORD record
ord-09edf794ac38409a807f00c8d2f488ce
Source dataset
uspto-grants-2015_10
Patent number
US09156820B2

Reaction notes

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