Diisopropylethylamine → (9R,11S, 14S,20E)-14-cyclohexyl-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),3,5,20,22,24-heptaene-11-carboxamide

HRID 1879268Notes

Reaction equation

HRID 1879268 reaction equation
[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.[CH:41]1([C@@H:47]2[NH:71][CH2:70][CH2:69][CH2:68][CH2:67][CH:66]=[CH:65][C:64]3[CH:72]=[C:60]([CH:61]=[CH:62][CH:63]=3)[C:59]3=[CH:73][C:55](=[CH:56][CH:57]=[CH:58]3)[CH2:54][O:53][C@H:52]3[CH2:74][N:49]([C@H:50]([C:75](O)=[O:76])[CH2:51]3)[C:48]2=[O:78])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:41]1([C@@H:47]2[NH:71][CH2:70][CH2:69][CH2:68][CH2:67][CH:66]=[CH:65][C:64]3[CH:72]=[C:60]([CH:61]=[CH:62][CH:63]=3)[C:59]3=[CH:73][C:55](=[CH:56][CH:57]=[CH:58]3)[CH2:54][O:53][C@H:52]3[CH2:74][N:49]([C@H:50]([C:75]([NH:16][C@:11]4([C:9]([NH:8][S:5]([CH:2]5[CH2:4][CH2:3]5)(=[O:7])=[O:6])=[O:10])[CH2:13][C@H:12]4[CH:14]=[CH2:15])=[O:76])[CH2:51]3)[C:48]2=[O:78])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1

Participants

6

Reactant 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 58005172(9R,11S,14S,20E)-14-cyclohexyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,20,22,24-heptaene-11-carboxylic acidHCID 86637110[(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]azanium chloride

Product 1

HCID 86637111(9R,11S, 14S,20E)-14-cyclohexyl-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),3,5,20,22,24-heptaene-11-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

48 (1.2 eq.) and HATU (1.2 eq.) were added to a 0.12M solution of (9R,11S,14S,20E)-14-cyclohexyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,20,22,24-heptaene-11-carboxylic acid 111 in DMF containing DIPEA (4.0 eq.). The reaction mixture was stirred at RT overnight then it was concentrated to dryness and the residue was dissolved in DMSO and purified by RP-HPLC (stationary phase: column WATERSXBRIDGE 19×150 mm, 5 μm; mobile phase: MeCN/H2O buffered with 0.1% TFA from 50% to 90% of MeCN in 14 min., run time 18 min.). Fractions containing the pure compound were combined and freeze dried to afford compound 146 (TFA salt) as an off white solid (4.0% over 3 steps). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 10.73 (s, 1H), 8.83 (s, 1H), 8.80-8.68 (m, 1H), 8.58-8.42 (m, 1H), 7.92 (s, 2H), 7.68 (d, J 7.6, 1H), 7.62 (d, J 7.6, 1H), 7.51-7.40 (m, 2H), 7.29 (t, J 8.1, 2H), 6.58 (d, J 15.7, 1H), 6.49-6.37 (m, 1H), 5.68-5.54 (m, 1H), 5.27 (d, J 16.9, 1H), 5.16 (d, J 11.6, 1H), 4.74 (d, J 11.9, 1H), 4.60 (d, J 11.9, 1H), 4.50-4.33 (m, 3H), 4.19 (d, J 11.1, 1H), 3.86 (dd, J 11.1, 3.8, 1H), 3.18-2.91 (m, 3H), 2.60-2.46 (m, partially obscured by residual DMSO-d6, 1H), 2.43-2.24 (m, 2H), 2.19 (q, J 8.8, 1H), 2.09-1.97 (m, 1H), 1.92-1.65 (m, 9H), 1.64-1.52 (m, 1H), 1.38-1.02 (m, 11H). MS (ES) m/z 729 (M+H)+.

Workup

  1. concentrationit was concentrated to dryness
  2. dissolutionthe residue was dissolved in DMSO
  3. custompurified by RP-HPLC (stationary phase: column WATERSXBRIDGE 19×150 mm, 5 μm; mobile phase: MeCN/H2O buffered with 0.1% TFA from 50% to 90% of MeCN in 14 min., run time 18 min.)
  4. additionFractions containing the pure compound
  5. customfreeze dried

Sources & evidence

ORD record
ord-9a0f03f80c034965930a9f809f8898e4
Source dataset
uspto-grants-2012_11
Patent number
US08314062B2

Reaction notes

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