Trifluoroacetic acid → [2-(ethyldisulfanyl)-6-methylphenyl] (3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methylbutanoyl]-methylamino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]-methylamino]-3-phenylpropanoyl]amino]acetyl]-methylamino]-4-methylpentanoyl]-methylamino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-4-[methyl-[(2S)-1-oxo-1-[[(2S)-1-oxo-1-piperidin-1-ylpropan-2-yl]amino]-3-phenylpropan-2-yl]amino]-4-oxobutanoate

HRID 1482258Notes

Reaction equation

HRID 1482258 reaction equation
FC(F)(F)C(O)=O.C([SiH](C(C)C)C(C)C)(C)C.[CH2:18]([C@@H:25]([C:82](=[O:157])[NH:83][CH2:84][C:85](=[O:156])[N:86]([CH3:155])[C@@H:87]([CH2:151][CH:152]([CH3:154])[CH3:153])[C:88](=[O:150])[N:89]([CH3:149])[C@@H:90]([CH:146]([CH3:148])[CH3:147])[C:91](=[O:145])[NH:92][C@@H:93]([CH2:138][C:139]1[CH:144]=[CH:143][CH:142]=[CH:141][CH:140]=1)[C:94](=[O:137])[NH:95][C@H:96]([C:112](=[O:136])[N:113]([CH3:135])[C@@H:114]([CH2:128][C:129]1[CH:134]=[CH:133][CH:132]=[CH:131][CH:130]=1)[C:115](=[O:127])[NH:116][C@@H:117]([CH3:126])[C:118](=[O:125])[N:119]1[CH2:124][CH2:123][CH2:122][CH2:121][CH2:120]1)[CH2:97][C:98]([O:100][C:101]1[C:106]([CH3:107])=[CH:105][CH:104]=[CH:103][C:102]=1[S:108][S:109][CH2:110][CH3:111])=[O:99])[N:26]([CH3:81])[C:27](=[O:80])[C@H:28]([C@H:58]([O:60]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:59])[NH:29][C:30](=[O:57])[C@H:31]([CH2:53][CH:54]([CH3:56])[CH3:55])[N:32]([CH3:52])[C:33](=[O:51])[C@H:34]([CH:48]([CH3:50])[CH3:49])[NH:35][C:36](=[O:47])[C@H:37]([CH3:46])[NH:38]C(=O)OC(C)(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[NH2:38][C@@H:37]([CH3:46])[C:36](=[O:47])[NH:35][C@@H:34]([CH:48]([CH3:50])[CH3:49])[C:33](=[O:51])[N:32]([CH3:52])[C@@H:31]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:30](=[O:57])[NH:29][C@@H:28]([C@H:58]([OH:60])[CH3:59])[C:27](=[O:80])[N:26]([CH3:81])[C@@H:25]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:82](=[O:157])[NH:83][CH2:84][C:85](=[O:156])[N:86]([CH3:155])[C@@H:87]([CH2:151][CH:152]([CH3:153])[CH3:154])[C:88](=[O:150])[N:89]([CH3:149])[C@@H:90]([CH:146]([CH3:147])[CH3:148])[C:91](=[O:145])[NH:92][C@@H:93]([CH2:138][C:139]1[CH:144]=[CH:143][CH:142]=[CH:141][CH:140]=1)[C:94](=[O:137])[NH:95][C@H:96]([C:112](=[O:136])[N:113]([CH3:135])[C@@H:114]([CH2:128][C:129]1[CH:134]=[CH:133][CH:132]=[CH:131][CH:130]=1)[C:115](=[O:127])[NH:116][C@@H:117]([CH3:126])[C:118](=[O:125])[N:119]1[CH2:120][CH2:121][CH2:122][CH2:123][CH2:124]1)[CH2:97][C:98]([O:100][C:101]1[C:106]([CH3:107])=[CH:105][CH:104]=[CH:103][C:102]=1[S:108][S:109][CH2:110][CH3:111])=[O:99]

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 138754Silane, tris(1-methylethyl)-HCID 131736694[2-(ethyldisulfanyl)-6-methylphenyl] (3S)-3-[[(2S)-2-[[(2S)-3-methyl-2-[methyl-[(2S)-4-methyl-2-[methyl-[2-[[(2S)-2-[methyl-[(2S,3R)-2-[[(2S)-4-methyl-2-[methyl-[(2S)-3-methyl-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]butanoyl]amino]pentanoyl]amino]-3-trityloxybutanoyl]amino]-3-phenylpropanoyl]amino]acetyl]amino]pentanoyl]amino]butanoyl]amino]-3-phenylpropanoyl]amino]-4-[methyl-[(2S)-1-oxo-1-[[(2S)-1-oxo-1-piperidin-1-ylpropan-2-yl]amino]-3-phenylpropan-2-yl]amino]-4-oxobutanoate

Product 1

HCID 131736695[2-(ethyldisulfanyl)-6-methylphenyl] (3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methylbutanoyl]-methylamino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]-methylamino]-3-phenylpropanoyl]amino]acetyl]-methylamino]-4-methylpentanoyl]-methylamino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-4-[methyl-[(2S)-1-oxo-1-[[(2S)-1-oxo-1-piperidin-1-ylpropan-2-yl]amino]-3-phenylpropan-2-yl]amino]-4-oxobutanoateYield 51.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Trifluoroacetic acid (300 ul) and triisopropylsilane (27.7 ul, 0.135 mmol) were added to a solution of 2-(ethyldisulfanyl)-6-methylphenyl (6S,9S,12S,15S,18S,24S,27S,30S,33S)-18,30-dibenzyl-12,24-diisobutyl-9,27-diisopropyl-2,2,6,11,17,23,26-heptamethyl-33-(methyl((S)-1-oxo-1-(((S)-1-oxo-1-(piperidin-1-yl)propan-2-yl)amino)-3-phenylpropan-2-yl)carbamoyl)-4,7,10,13,16,19,22,25,28,31-decaoxo-15-((R)-1-(trityloxy)ethyl)-3-oxa-5,8,11,14,17,20,23,26,29,32-decaazapentatriacontan-35-oate (Compound P-138) (53.0 mg, 27 umol) in dichloromethane (200 ul), and the mixture was stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure and purified by reverse phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution=70/30→0/100) to afford 2-(ethyldisulfanyl)-6-methylphenyl (3S,6S,9S,12S,18S,21S,24S,27S,30S)-30-amino-6,18-dibenzyl-21-((R)-1-hydroxyethyl)-12,24-diisobutyl-9,27-diisopropyl-10,13,19,25-tetramethyl-3-(methyl((S)-1-oxo-1-(((S)-1-oxo-1-(piperidin-1-yl)propan-2-yl)amino)-3-phenylpropan-2-yl)carbamoyl)-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazahentriacontan-1-oate (Compound P-139) (22.4 mg, 51%).

Workup

  1. concentrationThe reaction solution was then concentrated under reduced pressure
  2. custompurified by reverse phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution=70/30→0/100)

Sources & evidence

ORD record
ord-c19a168675404c0bb517c271a72f96e6
Source dataset
uspto-grants-2016_08
Patent number
US09409952B2

Reaction notes

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