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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
ノート
印刷プレビュー

反応式

HRID 346964 の反応式
[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]
参加物実験手順後処理出典と根拠反応ノート

参加物

7

反応物 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

生成物 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
収率 71.1%

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒HCID 21226206Ethyl acetate hexane溶媒

実験手順

(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).

後処理

  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

出典と根拠

ORDレコード
ord-5b767170c4b74d2191043b68da88119c
出典データセット
uspto-grants-2007_02
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US07173004B2

反応ノート

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