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4-Methylmorpholine → (1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-3-(isoquinolin-1-yloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate

HRID 346964
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HRID 346964 반응식
[C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:9](O)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:33]([O:35][C:36]([C:38]1([NH:43][C:44]([CH:46]2[CH2:50][CH:49]([O:51][C:52]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:55]=[CH:54][N:53]=3)[CH2:48][NH:47]2)=[O:45])[CH2:40][CH:39]1[CH:41]=[CH2:42])=[O:37])[CH3:34].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:9]([N:47]1[C@H:46]([C:44]([NH:43][C@:38]2([C:36]([O:35][CH2:33][CH3:34])=[O:37])[CH2:40][C@H:39]2[CH:41]=[CH2:42])=[O:45])[CH2:50][C@@H:49]([O:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:55]=[CH:54][N:53]=2)[CH2:48]1)=[O:10])=[O:7])([CH3:2])([CH3:4])[CH3:3]
참가 물질실험 절차후처리출처 및 근거반응 노트

참가 물질

7

반응물 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21080146(S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acidHCID 1317262291-{[4-(Isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester, bis hydrochloride

생성물 1

HCID 86609033
(1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-3-(isoquinolin-1-yloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate
수율 71.1%

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 21226206Ethyl acetate hexane용매

실험 절차

(S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid (1.10 g, 2.40 mmol) dissolved in 20 mL of DCM was treated sequentially with 1-{[4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester, bis hydrochloride (1.27 g, 2.72 mmol), N-methyl morpholine (0.92 mL, 8.34 mmol), and HATU (PE biosystems)(1.28 g, 3.36 mmol). The reaction mixture was stirred at rt under N2 for 15 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give 2.0 g of the crude product. Flash chromatography (30% hexane/ethyl acetate) gave 1.4 g (70%) of (1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-3-(isoquinolin-1-yloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate as a purple solid. 1H NMR (CD3OD, 500 MHz) δ 1.23–1.31 (m, 9H), 1.46–1.52 (m, 4H), 1.59 (br s, 1H), 1.66 (br s, 1H), 1.74 (dd, J=7.93, 5.19 Hz, 1H), 2.00 (br s, 2H), 2.29 (q, J=8.95 Hz, 1H), 2.47 (m, 1H), 2.72 (m, 1H), 3.38–3.51 (m, 2H), 3.68 (m, 2H), 4.09–4.26 (m, 3H), 4.37 (d, J=11.29 Hz, 1H), 4.64 (m, 1H), 4.72 (m, 1H), 4.95 (d, J=10.99 Hz, 1H), 4.99 (dd, J=18.92, 1.53 Hz, 1H), 5.12 (d, J=10.68 Hz, 1H), 5.32 (d, J=17.40 Hz, 1H), 5.73–5.86 (m, 2H), 5.92 (s, 1H), 7.36 (m, 1H), 7.58 (m, 1H), 7.73 (m, 1H), 7.80–7.88 (m, 4H), 7.99 (m, 1H), 8.11 (m, 1H), 8.24 (d, J=8.24 Hz, 1H). LC-MS (Method D, retention time: 3.15 min), MS m/z 835 (M++1).

후처리

  1. concentrationconcentrated in vacuo
  2. customThe residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate)
  3. washThe organic phase was washed with sat. aq. NaHCO3
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customto give 2.0 g of the crude product

출처 및 근거

ORD 기록
ord-5b767170c4b74d2191043b68da88119c
출처 데이터셋
uspto-grants-2007_02
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US07173004B2

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