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4-Methylmorpholine → Z-Asp(OtBu)-Leu-Lys(Boc)-Glu(OtBu)-Lys(Boc)-Lys(Boc)-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu

HRID 462874
Notes
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Reaction equation

HRID 462874 reaction equation
[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:44]([NH:46][C@H:47]([C:57]([NH:59][C@H:60]([C:64]([NH:66][C@H:67]([C:71]([NH:73][C@H:74]([C:84]([NH:86][C@H:87]([C:97]([NH:99][C@H:100]([C:102]([NH:104][C@H:105]([C:115]([NH:117][C@H:118]([C:123]([O:125][C:126]([CH3:129])([CH3:128])[CH3:127])=[O:124])[CH2:119][C:120](=[O:122])[NH2:121])=[O:116])[CH2:106][CH2:107][C:108](=[O:114])[O:109][C:110]([CH3:113])([CH3:112])[CH3:111])=[O:103])[CH3:101])=[O:98])[CH2:88][CH2:89][C:90](=[O:96])[O:91][C:92]([CH3:95])([CH3:94])[CH3:93])=[O:85])[CH2:75][CH2:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:72])[CH:68]([CH3:70])[CH3:69])=[O:65])[CH:61]([CH3:63])[CH3:62])=[O:58])[CH2:48][CH2:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:130]([O:137][C:138]([NH:140][C@H:141]([C:150]([NH:152][C@H:153]([C:158]([NH:160][C@H:161]([C:174]([OH:176])=O)[CH2:162][CH2:163][CH2:164][CH2:165][NH:166][C:167]([O:169][C:170]([CH3:173])([CH3:172])[CH3:171])=[O:168])=[O:159])[CH2:154][CH:155]([CH3:157])[CH3:156])=[O:151])[CH:142](C(C)(C)C)[C:143](=[O:145])[OH:144])=[O:139])C1C=CC=CC=1.[CH:177]1[CH:178]=[CH:179][C:180]2N(O)N=N[C:181]=2[CH:182]=1.C1CCC(N=C=N[CH:196]2[CH2:201][CH2:200]CCC2)CC1.[CH3:202]N1CCOCC1>CC(O)=O.CO.C(Cl)(Cl)Cl.O.CS(C)=O.CN(C=O)C>[NH:140]([C:138]([O:137][CH2:130][C:181]1[CH:180]=[CH:179][CH:178]=[CH:177][CH:182]=1)=[O:139])[C@H:141]([C:150]([NH:152][C@H:153]([C:158]([NH:160][C@H:161]([C:174]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:44]([NH:46][C@H:47]([C:57]([NH:59][C@H:60]([C:64]([NH:66][C@H:67]([C:71]([NH:73][C@H:74]([C:84]([NH:86][C@H:87]([C:97]([NH:99][C@H:100]([C:102]([NH:104][C@H:105]([C:115]([NH:117][C@H:118]([C:123]([O:125][C:126]([CH3:127])([CH3:128])[CH3:129])=[O:124])[CH2:119][C:120](=[O:122])[NH2:121])=[O:116])[CH2:106][CH2:107][C:108](=[O:114])[O:109][C:110]([CH3:113])([CH3:112])[CH3:111])=[O:103])[CH3:101])=[O:98])[CH2:88][CH2:89][C:90](=[O:96])[O:91][C:92]([CH3:93])([CH3:94])[CH3:95])=[O:85])[CH2:75][CH2:76][C:77](=[O:83])[O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:72])[CH:68]([CH3:70])[CH3:69])=[O:65])[CH:61]([CH3:63])[CH3:62])=[O:58])[CH2:48][CH2:49][C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:176])[CH2:162][CH2:163][CH2:164][CH2:165][NH:166][C:167]([O:169][C:170]([CH3:171])([CH3:172])[CH3:173])=[O:168])=[O:159])[CH2:154][CH:155]([CH3:157])[CH3:156])=[O:151])[CH2:142][C:143](=[O:145])[O:144][C:201]([CH3:200])([CH3:196])[CH3:202]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

12

Reactant 5

HCID 79724-MethylmorpholineHCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 13501922H-Glu(OtBu)-Lys(Boc)-Lys(Boc)-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBuHCID 131714165N-Benzyloxycarbonyl-beta-tert-butyl-L-aspartyl-L-leucyl-Nepsilon-tert-butyloxycarbonyl-L-lysine

Product 1

HCID 16162891Z-Asp(OtBu)-Leu-Lys(Boc)-Glu(OtBu)-Lys(Boc)-Lys(Boc)-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu

Reagents, catalysts & solvents 6

HCID 176Acetic AcidSolvent2×HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolvent2×HCID 962WaterSolventHCID 6212ChloroformSolvent2×HCID 6228DimethylformamideSolvent

Procedure

The DMF:DMSO-containing solution of H-Glu(OtBu)-Lys(Boc)-Lys(Boc)-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu (~23 mmol) from step (d) was combined with Z-Asp(OtBu)-Leu-Lys(Boc)-OH (IV, 18.6 g, 28.0 mmol, 1.2 eq.) and HOBt (10.62 g, 69.0 mmol, 3.0 eq.) added and the solution cooled to 0°. DCC (7.87 g, 38.0 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 (~17 mL). Stirring proceeded for 1 h at 0° and 23 h at 25°. The resultant reaction mixture was poured into H2O (10 L) and stirred for 1.5 h. The product was collected by filtration, washed with H2O (5 L), dried and washed with MeOH using the centrifuge to separate the 2 layers. When all the dicyclohexylurea was removed the product was pooled and dried in vacuo to give 44.56 g (77.9%); mp >330°; [α] D25 -11.56° (c 1, TFE); Rf 0.16 (CHCl3 :MeOH:AcOH; 80-5-1); Rf 0.36 (CHCl3 :MeOH:TFE:AcOH; 85-10-2.5-1).

Workup

  1. additionadded
  2. temperaturethe solution cooled to 0°
  3. custom(mechanical) reaction mixture
  4. stirringStirring
  5. customThe resultant reaction mixture
  6. stirringstirred for 1.5 h
  7. filtrationThe product was collected by filtration
  8. washwashed with H2O (5 L)
  9. customdried
  10. washwashed with MeOH using the centrifuge
  11. customto separate the 2 layers
  12. customWhen all the dicyclohexylurea was removed the product
  13. customdried in vacuo
  14. customto give 44.56 g (77.9%)

Sources & evidence

ORD record
ord-3de57346c34146479c4336a663dc9ce7
Source dataset
uspto-grants-1985_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US04517119

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes