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 400415ノート

反応式

HRID 400415 の反応式
[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

参加物

5

反応物 3

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

生成物 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

実験手順

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).

出典と根拠

ORDレコード
ord-70abc5d63e314c0ab0a609f5291b2d79
出典データセット
uspto-grants-2014_06
特許番号
US08741898B2

反応ノート

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