Diethylamine → [(1-{(S)-2-[(R)-2-((E)-(S)-3-Hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-3-phenyl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester

HRID 1915975Notes

Reaction equation

HRID 1915975 reaction equation
[CH3:1][O:2][C:3](=[O:65])[CH2:4][NH:5][C:6]([C:8]1([NH:11][C:12](=[O:64])[C@H:13]([NH:35][C:36](=[O:63])[C@H:37]([NH:45][C:46](OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[O:47])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:14][S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].N([CH2:69][CH3:70])CC.[OH:71][C@H:72](/[CH:77]=[CH:78]/[CH2:79][CH2:80][S:81][C:82](C1C=CC=CC=1)([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[CH2:73]C(O)=O.[CH2:101]1[CH2:105]N([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:103][CH2:102]1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:65])[CH2:4][NH:5][C:6]([C:8]1([NH:11][C:12](=[O:64])[C@H:13]([NH:35][C:36](=[O:63])[C@H:37]([NH:45][C:46](=[O:47])[CH2:73][C@H:72]([OH:71])/[CH:77]=[CH:78]/[CH2:79][CH2:80][S:81][C:82]([C:70]2[CH:69]=[CH:103][CH:102]=[CH:101][CH:105]=2)([C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)[C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:14][S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][CH2:10]1)=[O:7]

Participants

8

Reactant 5

HCID 8021DiethylamineHCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 11711429(S,E)-3-Hydroxy-7-(tritylthio)hept-4-enoic acidHCID 58256993[(1-{(S)-2-[(R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenyl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester

Product 1

HCID 58257064[(1-{(S)-2-[(R)-2-((E)-(S)-3-Hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-3-phenyl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl esterYield 87%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2 (294 mg, 0.33 mmol, 1 eq) in MeCN (7 mL) was added Et2NH (0.7 mL, 10% v/v) dropwise at rt under Ar(g). The solution was stirred at rt for 2 h, then the solvent was removed in vacuo. The excess of amine was co-evaporated with MeCN (3×5 mL), then with a 1:5 mixture of CH2Cl2/hexane (5 mL). A white solid was obtained and the flask was dried under high vacuum for 2 h. To a solution of β-hydroxy acid 3 (145 mg, 0.35 mmol, 1.1 eq) in MeCN (5 mL) at 0° C. was added PyBOP (189 mg, 0.36 mmol, 1.1 eq) and N-ethyldiisopropylamine (143 μL, 0.83 mmol, 2.5 eq) under Ar(g). The crude amine, dissolved in CH2Cl2 (5 mL) was added to the mixture dropwise. The reaction mixture was then left to warm to rt overnight. The mixture was then concentrated in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (2:3→0:1) to yield 4 as a white solid (305 mg, 87%).

Workup

  1. customthe solvent was removed in vacuo
  2. additionwith a 1:5 mixture of CH2Cl2/hexane (5 mL)
  3. customA white solid was obtained
  4. customthe flask was dried under high vacuum for 2 h
  5. additionwas added to the mixture dropwise
  6. waitThe reaction mixture was then left
  7. temperatureto warm to rt overnight
  8. concentrationThe mixture was then concentrated in vacuo
  9. customthe residue was further purified by silica gel column chromatography with hexane/EtOAc (2:3→0:1)

Sources & evidence

ORD record
ord-d71b3f4f917e4517ba992015504827df
Source dataset
uspto-grants-2013_12
Patent number
US08614193B2

Reaction notes

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