Diethylamine → (R)-4-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(1-hydroxy-2-methoxycarbonyl-ethyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester

HRID 1915963Notes

Reaction equation

HRID 1915963 reaction equation
[CH3:1][O:2][C:3](=[O:53])[CH2:4][CH:5]([C:7]1([NH:10][C:11](=[O:52])[C@H:12]([NH:34][C:35](OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[O:36])[CH2:13][S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][CH2:8]1)[OH:6].C(NCC)C.C1CN([P+](ON2N=N[C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][C:77]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:92]([C:106]([O:108][CH2:109][CH:110]1C2C(=CC=CC=2)[C:116]2[C:111]1=[CH:112][CH:113]=[CH:114][CH:115]=2)=[O:107])[C@@H:93](C(O)=O)[CH2:94][CH2:95][C:96](=[O:102])[O:97][C:98]([CH3:101])([CH3:100])[CH3:99].C(N(C(C)C)CC)(C)C>CC#N.C(Cl)Cl>[C:98]([O:97][C:96](=[O:102])[CH2:95][CH2:94][C@@H:93]([NH:92][C:106]([O:108][CH2:109][CH:110]1[C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][C:77]=2[C:112]2[C:111]1=[CH:116][CH:115]=[CH:114][CH:113]=2)=[O:107])[C:35](=[O:36])[NH:34][C@@H:12]([C:11](=[O:52])[NH:10][C:7]1([CH:5]([OH:6])[CH2:4][C:3]([O:2][CH3:1])=[O:53])[CH2:9][CH2:8]1)[CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:101])([CH3:99])[CH3:100]

Participants

8

Reactant 5

HCID 8021DiethylamineHCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 7018822(2R)-5-(tert-butoxy)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-5-oxopentanoic acidHCID 670224183-{1-[(s)-2-(9h-Fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionylamino]-cyclopropyl}-3-hydroxy-propionic acid methyl ester

Product 1

HCID 87289761(R)-4-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(1-hydroxy-2-methoxycarbonyl-ethyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl esterYield 94%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To 4 (908 mg, 1.28 mmol) in MeCN (10 mL) was added diethylamine (1 mL, 10% v/v), and the reaction mixture was stirred for 2 h. The mixture was then concentrated in vacuo, MeCN (3×20 mL) was added, then removed in vacuo, and the crude amine was placed under high vacuum for 2 h. Subsequently, to a solution of PyBOP (705 mg, 1.35 mmol) and Fmoc-D-Glu(OtBu)-OH (577.8 mg, 1.36 mmol) in CH2Cl2 (15 mL) at 0° C. was added diisopropylethylamine (0.70 mL, 4.02 mmol) under Ar(g) and the mixture was stirred for 2 min. A solution of the crude amine derivative of 4 in MeCN (15 mL) was added, and the mixture was stirred at rt for 16 h, and the solvent was then removed in vacuo. Purification by flash column chromatography on silica (eluant 4:6-6:4 EtOAc/Hexane) gave 5 (1.099 g, 1.20 mmol, 94%) as a white solid: Rf 0.54 EtOAc/Hexane (6:4), and as a mixture of diastereoisomers not resolved by 1H NMR.

Workup

  1. concentrationThe mixture was then concentrated in vacuo, MeCN (3×20 mL)
  2. additionwas added
  3. customremoved in vacuo
  4. waitthe crude amine was placed under high vacuum for 2 h
  5. stirringthe mixture was stirred for 2 min
  6. stirringthe mixture was stirred at rt for 16 h
  7. customthe solvent was then removed in vacuo
  8. customPurification by flash column chromatography on silica (eluant 4:6-6:4 EtOAc/Hexane)

Sources & evidence

ORD record
ord-862f2a85e76c4c308d77f45d8b820332
Source dataset
uspto-grants-2013_12
Patent number
US08614193B2

Reaction notes

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