Diisopropylethylamine → (9R,11S, 14S)-14-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxamide

HRID 1879262Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1879262
[Cl-].[CH:2]1([S:5]([NH:8][C:9]([C@@:11]2([NH3+:16])[CH2:13][C@H:12]2[CH:14]=[CH2:15])=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([C@@H:45]1[NH:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][C:62]2[CH:70]=[C:58]([CH:59]=[CH:60][CH:61]=2)[C:57]2=[CH:71][C:53](=[CH:54][CH:55]=[CH:56]2)[CH2:52][O:51][C@H:50]2[CH2:72][N:47]([C@H:48]([C:73](O)=[O:74])[CH2:49]2)[C:46]1=[O:76])([CH3:44])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([C@@H:45]1[NH:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][C:62]2[CH:70]=[C:58]([CH:59]=[CH:60][CH:61]=2)[C:57]2=[CH:71][C:53](=[CH:54][CH:55]=[CH:56]2)[CH2:52][O:51][C@H:50]2[CH2:72][N:47]([C@H:48]([C:73]([NH:16][C@:11]3([C:9]([NH:8][S:5]([CH:2]4[CH2:4][CH2:3]4)(=[O:7])=[O:6])=[O:10])[CH2:13][C@H:12]3[CH:14]=[CH2:15])=[O:74])[CH2:49]2)[C:46]1=[O:76])([CH3:44])([CH3:42])[CH3:43]

Komponenten

6

Edukt 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 58005162(9R,11S,14S)-14-tert-butyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.1 9,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxylic acidHCID 86637110[(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]azanium chloride

Produkt 1

HCID 86637109(9R,11S, 14S)-14-tert-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride 48 (prepared as described in WO 03/099274) (1.2 eq.) and HATU (1.2 eq.) were added to a 0.1M solution of (9R,11S,14S)-14-tert-butyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxylic acid 105 in DMF containing DIPEA (4.0 eq.). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness, dissolved in DMSO and purified by RP-HPLC (stationary phase: column WATERS XTERRA C18, 5 μm, 19×150. Mobile phase: MeCN/H2O buffered with 0.1% TFA from 30% to 90% of MeCN in 14 minutes, run time 18 minutes). Fractions containing the pure compound were combined and freeze dried to afford compound 142 (TFA salt) as an off white solid (30% over 4 steps). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 10.65 (s, 1H), 8.89 (s, 1H), 8.65-8.49 (bs, 1H), 8.25-8.11 (bs, 1H), 7.62-7.56 (m, 2H), 7.51-7.38 (m, 4H), 7.31 (d, J 7.3, 1H), 7.24 (d, J 7.3, 1H), 5.69-5.53 (m, 1H), 5.24 (d, J 17.2, 1H), 5.14 (d, J 11.9, 1H), 4.71 (d, J 12.4, 1H), 4.61 (d, J 12.4, 1H), 4.31 (bt, 1H), 4.37 (bs, 1H), 4.16 (d, J 8.8, 1H), 4.04 (d, J 11.9, 1H), 3.79 (dd, J 11.5, 3.9, 1H), 3.00-2.91 (m, 1H), 2.91-2.81 (m, 1H), 2.80-2.68 (m, 2H), 2.22 (q, J 17.5, 8.8, 1H), 2.02-1.91 (m, 1H), 1.83-1.69 (m, 2H), 1.68-1.56 (m, 2H), 1.41-1.24 (m, 5H), 1.22-1.02 (m, 13H), 0.91 (t, J 7.3, 4H). MS (ES+) m/z 705 (M+H)+.

Aufarbeitung

  1. concentrationThe reaction mixture was concentrated to dryness
  2. dissolutiondissolved in DMSO
  3. custompurified by RP-HPLC (stationary phase: column WATERS XTERRA C18, 5 μm, 19×150. Mobile phase: MeCN/H2O buffered with 0.1% TFA from 30% to 90% of MeCN in 14 minutes, run time 18 minutes)
  4. additionFractions containing the pure compound
  5. customfreeze dried

Quellen und Nachweise

ORD-Eintrag
ord-95a3615cfb4644f59f0b6b3def1b9c2f
Quelldatensatz
uspto-grants-2012_11
Patentnummer
US08314062B2

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