Diisopropylethylamine → N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-{(3R,4S,5S)-3-methoxy-1-[(2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(2-phenylethyl)amino]-3-thioxopropyl}pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

HRID 74737ノート

反応式

HRID 74737 の反応式
Cl.[CH3:2][O:3][C@@H:4]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)[C@@H:5]([CH3:17])[C:6](=[S:16])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]([CH3:68])[C@H:41]([C:45]([NH:47][C@H:48]([C:52]([N:54]([C@@H:56]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:57]([O:62][CH3:63])[CH2:58][C:59](O)=[O:60])[CH3:55])=[O:53])[CH:49]([CH3:51])[CH3:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]([CH3:68])[C@H:41]([C:45]([NH:47][C@H:48]([C:52]([N:54]([C@@H:56]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:57]([O:62][CH3:63])[CH2:58][C:59]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C@H:4]([O:3][CH3:2])[C@@H:5]([CH3:17])[C:6]([NH:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[S:16])=[O:60])[CH3:55])=[O:53])[CH:49]([CH3:51])[CH3:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1

参加物

7

反応物 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 60042710(5S,8S,11S,12R)-11-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5,8-diisopropyl-12-methoxy-4,10-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazatetradecan-14-oic acidHCID 131731847(2R,3R)-3-methoxy-2-methyl-N-(2-phenylethyl)-3-[(2S)-pyrrolidin-2-yl]propanethioamide, hydrochloride salt

生成物 1

HCID 86685728N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-{(3R,4S,5S)-3-methoxy-1-[(2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(2-phenylethyl)amino]-3-thioxopropyl}pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide収率 73.2%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒2 回

実験手順

To a mixture of #23 (337 mg, 0.983 mmol, 1 eq.) in dichloromethane (8 mL, 0.1 M) and N,N-dimethylformamide (1 mL) were added #8 (564 mg, 0.885 mmol, 0.9 eq.), diisopropylethylamine (383 mg, 2.95 mmol, 3 eq.) and HATU (472 mg, 1.18 mmol, 1.2 eq.). After 2 hours, the mixture was diluted with dichloromethane, washed sequentially with 0.1 M aqueous hydrochloric acid and with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (Method G) to give #35 (600 mg, 66%); LC-MS: m/z 926.6 [M+H+], retention time=1.16 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [9.94 (br t, J=5 Hz) and 10.16-10.23 (br m), total 1H], 7.90 (d, J=7.2 Hz, 2H), [7.71 (br d, J=7 Hz) and 8.06 (br d, J=8 Hz), total 1H], 7.60-7.65 (m, 2H), 7.41 (br dd, J=7, 7 Hz, 2H), 7.15-7.36 (m, 7H), 3.29 (s, 3H), 1.16-1.22 (m, 3H).

後処理

  1. washwashed sequentially with 0.1 M aqueous hydrochloric acid and with brine
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by reverse phase chromatography (Method G)

出典と根拠

ORDレコード
ord-4f08669084d74a36a65f13dd57085806
出典データセット
uspto-grants-2014_09
特許番号
US08828401B2

反応ノート

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