Methanol → tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate

HRID 1396390ノート

反応式

HRID 1396390 の反応式
Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].CN1C(=O)CCC1.CO>ClCCl>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=1)(=[O:9])[NH2:10]

参加物

6

反応物 4

HCID 887MethanolHCID 13387N-methyl-2-pyrrolidoneHCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protectedHCID 866897466-Chloro-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide

生成物 1

HCID 86689747tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate収率 59.7%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

反応条件

温度
140 °C

実験手順

A pressure tube was charged with 6-chloro-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (310 mg, 1.00 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (429 mg, 2.00 mmol) and NMP (4 mL). The reaction mixture was stirred at 140° C. for 18 h, then the NMP was distilled using a Kugelrohr under high vacuum and at 120° C. to afford a brown viscous oil. The crude oil was dissolved in dichloromethane and methanol then adsorbed onto silica and purified by chromatography (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH, 40 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate as a brown viscous oil (291.3 mg). This was dissolved in dichloromethane (2 mL) and TFA (740 mg, 500 μL, 6.49 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The TFA and the dichloromethane were removed in vacuo and the residue obtained was purified by chromatography (Spherical silica 20-45 μm, 50 g, Versaflash from Supelco, eluting with 0.1:1.9:98 NH4OH:methanol:dichloromethane to 0.6:11.4:88 NH4OH:methanol:dichloromethane, 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (81 mg, 21%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (br. s., 1H), 8.34 (br. s., 1H), 7.59 (br. s., 1H), 7.46 (s, 1H), 7.35 (d, J=8.08 Hz, 1H), 6.70 (d, J=7.83 Hz, 1H), 6.57 (d, J=8.34 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.10 (br. s., 1H), 2.03 (br. s., 2H), 1.18-1.78 (m, 8H), 0.98-1.12 (m, 1H); LC-MS 388 [M+H]+.

後処理

  1. distillationthe NMP was distilled
  2. customat 120° C. to afford a brown viscous oil
  3. custompurified by chromatography (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH, 40 min)

出典と根拠

ORDレコード
ord-fdaedfa6d19b44cab6a2d1120c7cc78f
出典データセット
uspto-grants-2014_12
特許番号
US08901124B2

反応ノート

読み込み中…