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 1879262노트

반응식

HRID 1879262 반응식
[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]

참가 물질

6

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 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

생성물 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

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

실험 절차

(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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-95a3615cfb4644f59f0b6b3def1b9c2f
출처 데이터셋
uspto-grants-2012_11
특허 번호
US08314062B2

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