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 74737노트

반응식

HRID 74737 반응식
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

참가 물질

7

반응물 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

생성물 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-valinamide수율 73.2%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매2회

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-4f08669084d74a36a65f13dd57085806
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08828401B2

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