L-Pyroglutamic Acid → Z-Glu(OtBu)-Lys(Boc)-Lys(Boc)-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu

HRID 462872Notes

Reaction equation

HRID 462872 reaction equation
[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:57]([NH:59][C@H:60]([C:70]([NH:72][C@H:73]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:74][C:75](=[O:77])[NH2:76])=[O:71])[CH2:61][CH2:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:58])[CH3:56])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:40])[CH2:30][CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:85]([O:92][C:93]([NH:95][C@H:96]([C:106]([NH:108][C@H:109]([C:122]([NH:124][C@H:125]([C:138]([OH:140])=O)[CH2:126][CH2:127][CH2:128][CH2:129][NH:130][C:131]([O:133][C:134]([CH3:137])([CH3:136])[CH3:135])=[O:132])=[O:123])[CH2:110][CH2:111][CH2:112][CH2:113][NH:114][C:115]([O:117][C:118]([CH3:121])([CH3:120])[CH3:119])=[O:116])=[O:107])[CH2:97][CH:98](C(C)(C)C)[C:99](=[O:101])[OH:100])=[O:94])[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1.C1C=C[C:144]2N(O)N=N[C:145]=2[CH:146]=1.[CH2:151]1CCC(N=C=NC2CCCCC2)CC1.CN1CCOCC1.N1C(=O)CC[C@H]1C(O)=O>CC(O)=O.CO.C(Cl)(Cl)Cl.O.CCCCO.CS(C)=O.CN(C=O)C>[NH:95]([C:93]([O:92][CH2:85][C:86]1[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=1)=[O:94])[C@H:96]([C:106]([NH:108][C@H:109]([C:122]([NH:124][C@H:125]([C:138]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:57]([NH:59][C@H:60]([C:70]([NH:72][C@H:73]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:74][C:75](=[O:77])[NH2:76])=[O:71])[CH2:61][CH2:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:58])[CH3:56])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:40])[CH2:30][CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:140])[CH2:126][CH2:127][CH2:128][CH2:129][NH:130][C:131]([O:133][C:134]([CH3:136])([CH3:135])[CH3:137])=[O:132])=[O:123])[CH2:110][CH2:111][CH2:112][CH2:113][NH:114][C:115]([O:117][C:118]([CH3:119])([CH3:120])[CH3:121])=[O:116])=[O:107])[CH2:97][CH2:98][C:99](=[O:101])[O:100][C:145]([CH3:144])([CH3:146])[CH3:151]

Participants

14

Reactant 6

HCID 7405L-Pyroglutamic AcidHCID 79724-MethylmorpholineHCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 13501920H-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu2×HCID 131714220N-Benzyloxycarbonyl-gamma-t-butyl-L-glutamyl-Nepsilon-t-butyloxycarbonyl-L-lysyl-Nepsilon-t-butyloxycarbonyl-L-lysine

Product 1

HCID 16162889Z-Glu(OtBu)-Lys(Boc)-Lys(Boc)-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu

Reagents, catalysts & solvents 7

HCID 176Acetic AcidSolvent2×HCID 2631-ButanolSolventHCID 679Dimethyl SulfoxideSolvent2×HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6212ChloroformSolventHCID 6228DimethylformamideSolvent

Procedure

The DMF:DMSO-containing solution of H-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu (~32 mmol) from (b) was combined with Z-Glu(OtBu)-Lys(Boc)-Lys(Boc)-OH (III, 36.8 g, 46 mmol, 1.44 eq.) and HOBt (14.7 g, 96 mmol, 3 eq.) added and the solution cooled to 0°. DCC (10.9 g, 52 mmol, 1.65 eq.) was added to the cold stirring (mechanical) reaction mixture and the pH was maintained at 7.5-8.0 by addition of N-methylmorpholine (21 mL). Stirring proceeded for 2 h at 0° and 21 h at 25°. The resultant gelatenous reaction mixture was poured into H2O (9.0 L) and stirred for 4 h. The product was collected by filtration, washed with H2O (8×500 mL), dried and washed with MeOH using the centrifuge to separate the 2 phases. When all the dicyclohexylurea was removed the product was combined and dried in vacuo to give 45.22 g (71.5%); mp 312° dec; [ α]D25 -18.20° (c 1, DMSO); [α]D25 -13.27° (c 1, TFE); Rf 0.81 (n-BuOH:AcOH:Pyr:H2O; 15-3-10-12); Rf 0.52 (CHCl3 :MeOH:AcOH; 85-10-5).

Workup

  1. additionadded
  2. temperaturethe solution cooled to 0°
  3. custom(mechanical) reaction mixture
  4. stirringStirring
  5. stirringstirred for 4 h
  6. filtrationThe product was collected by filtration
  7. washwashed with H2O (8×500 mL)
  8. customdried
  9. washwashed with MeOH using the centrifuge
  10. customto separate the 2 phases
  11. customWhen all the dicyclohexylurea was removed the product
  12. customdried in vacuo
  13. customto give 45.22 g (71.5%)

Sources & evidence

ORD record
ord-8d13e6dadc334b9eb3723c19e223565e
Source dataset
uspto-grants-1985_05
Patent number
US04517119

Reaction notes

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