Diisopropylcarbodiimide → [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

HRID 1482257Notes

Reaction equation

HRID 1482257 reaction equation
[CH2:1]([S:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH3:2].C(=NC(C)C)=NC(C)C.[CH2:22]([C@@H:29]([C:86](=[O:150])[NH:87][CH2:88][C:89](=[O:149])[N:90]([CH3:148])[C@@H:91]([CH2:144][CH:145]([CH3:147])[CH3:146])[C:92](=[O:143])[N:93]([CH3:142])[C@@H:94]([CH:139]([CH3:141])[CH3:140])[C:95](=[O:138])[NH:96][C@@H:97]([CH2:131][C:132]1[CH:137]=[CH:136][CH:135]=[CH:134][CH:133]=1)[C:98](=[O:130])[NH:99][C@H:100]([C:105](=[O:129])[N:106]([CH3:128])[C@@H:107]([CH2:121][C:122]1[CH:127]=[CH:126][CH:125]=[CH:124][CH:123]=1)[C:108](=[O:120])[NH:109][C@@H:110]([CH3:119])[C:111](=[O:118])[N:112]1[CH2:117][CH2:116][CH2:115][CH2:114][CH2:113]1)[CH2:101][C:102](O)=[O:103])[N:30]([CH3:85])[C:31](=[O:84])[C@H:32]([C@H:62]([O:64][C:65]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[CH3:63])[NH:33][C:34](=[O:61])[C@H:35]([CH2:57][CH:58]([CH3:60])[CH3:59])[N:36]([CH3:56])[C:37](=[O:55])[C@H:38]([CH:52]([CH3:54])[CH3:53])[NH:39][C:40](=[O:51])[C@H:41]([CH3:50])[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:22]([C@@H:29]([C:86](=[O:150])[NH:87][CH2:88][C:89](=[O:149])[N:90]([CH3:148])[C@@H:91]([CH2:144][CH:145]([CH3:147])[CH3:146])[C:92](=[O:143])[N:93]([CH3:142])[C@@H:94]([CH:139]([CH3:141])[CH3:140])[C:95](=[O:138])[NH:96][C@@H:97]([CH2:131][C:132]1[CH:137]=[CH:136][CH:135]=[CH:134][CH:133]=1)[C:98](=[O:130])[NH:99][C@H:100]([C:105](=[O:129])[N:106]([CH3:128])[C@@H:107]([CH2:121][C:122]1[CH:123]=[CH:124][CH:125]=[CH:126][CH:127]=1)[C:108](=[O:120])[NH:109][C@@H:110]([CH3:119])[C:111](=[O:118])[N:112]1[CH2:117][CH2:116][CH2:115][CH2:114][CH2:113]1)[CH2:101][C:102]([O:12][C:6]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=1[S:4][S:3][CH2:1][CH3:2])=[O:103])[N:30]([CH3:85])[C:31](=[O:84])[C@H:32]([C@H:62]([O:64][C:65]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[CH3:63])[NH:33][C:34](=[O:61])[C@H:35]([CH2:57][CH:58]([CH3:60])[CH3:59])[N:36]([CH3:56])[C:37](=[O:55])[C@H:38]([CH:52]([CH3:54])[CH3:53])[NH:39][C:40](=[O:51])[C@H:41]([CH3:50])[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

6

Reactant 3

HCID 12734DiisopropylcarbodiimideHCID 896685262-(Ethyldisulfanyl)-6-methylphenolHCID 117735990(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-oic acid

Product 1

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-oxobutanoateYield 80%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

2-(Ethyldisulfanyl)-6-methylphenol separately synthesized according to a conventional method (J. AM. CHEM. SOC. 2009, 131, 5432-5437) (10.3 mg, 0.051 mmol), N,N′-methanediylidenebis(propan-2-amine) (8.0 ul, 0.051 mmol) and N,N-dimethylpyridin-4-amine (4.2 mg, 0.034 mmol) were added to a solution of (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-oic acid (Boc-Ala-Val-MeLeu-Thr(Trt)-MePhe-Gly-MeLeu-MeVal-Phe-Asp-MePhe-Ala-piperidine, 60.9 mg, 0.034 mmol) synthesized by peptide synthesis by the Fmoc method previously described using Boc amino acid in place of Fmoc amino acid at the N-terminal in dichloromethane (300 ul), and the mixture was stirred at room temperature overnight. The reaction solution was then concentrated under reduced pressure and purified by reverse phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford 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) (53.8 mg, 80%).

Workup

  1. concentrationThe reaction solution was then concentrated under reduced pressure
  2. custompurified by reverse phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100)

Sources & evidence

ORD record
ord-452d4f10fbc649eb9a411ddd1a39a591
Source dataset
uspto-grants-2016_08
Patent number
US09409952B2

Reaction notes

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