4-Methylmorpholine → Fmoc-Lys(Alloc)-Glu(OtBu)-Arg(Pmc)-Val-Asp(OAllyl)-OBzl

HRID 414001Notes

Reaction equation

HRID 414001 reaction equation
[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)C2C1=CC=CC=2)=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9].C1CN([P+](ON2N=N[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:74][C@H:75]([C:85]([NH:87][C@H:88]([C:114]([NH:116][C@H:117]([C:121]([NH:123][C@H:124]([C:132]([O:134][CH2:135][C:136]1[CH:141]=[CH:140][CH:139]=[CH:138][CH:137]=1)=[O:133])[CH2:125][C:126](=[O:131])[O:127][CH2:128][CH:129]=[CH2:130])=[O:122])[CH:118]([CH3:120])[CH3:119])=[O:115])[CH2:89][CH2:90][CH2:91][NH:92][C:93](=[NH:113])[NH:94][S:95]([C:98]1[C:111]([CH3:112])=[C:109]([CH3:110])[C:108]2[O:107][C:104]([CH3:106])([CH3:105])[CH2:103][CH2:102][C:101]=2[C:99]=1[CH3:100])(=[O:97])=[O:96])=[O:86])[CH2:76][CH2:77][C:78](=[O:84])[O:79][C:80]([CH3:83])([CH3:82])[CH3:81]>C(#N)C>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:53]2[C:52](=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:32]2[C:33]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:18])[C@H:2]([C:14]([NH:74][C@H:75]([C:85]([NH:87][C@H:88]([C:114]([NH:116][C@H:117]([C:121]([NH:123][C@H:124]([C:132]([O:134][CH2:135][C:136]1[CH:137]=[CH:138][CH:139]=[CH:140][CH:141]=1)=[O:133])[CH2:125][C:126](=[O:131])[O:127][CH2:128][CH:129]=[CH2:130])=[O:122])[CH:118]([CH3:120])[CH3:119])=[O:115])[CH2:89][CH2:90][CH2:91][NH:92][C:93](=[NH:113])[NH:94][S:95]([C:98]1[C:111]([CH3:112])=[C:109]([CH3:110])[C:108]2[O:107][C:104]([CH3:106])([CH3:105])[CH2:103][CH2:102][C:101]=2[C:99]=1[CH3:100])(=[O:96])=[O:97])=[O:86])[CH2:76][CH2:77][C:78](=[O:84])[O:79][C:80]([CH3:81])([CH3:82])[CH3:83])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9]

Participants

6

Reactant 4

HCID 79724-Methylmorpholine2×HCID 2724699PyBOPHCID 11123257(2S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(((prop-2-en-1-yloxy)carbonyl)amino)hexanoic acidHCID 178459569Glu(OtBu)-Arg(Pmc)-Val-Asp(Allyl)-OBzl

Product 1

HCID 178459567Fmoc-Lys(Alloc)-Glu(OtBu)-Arg(Pmc)-Val-Asp(OAllyl)-OBzlYield 74.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
5 °C

Procedure

A suspension of Fmoc-Lys(Alloc) (4.2 g, 9.3 mmol) and benzotriazolyloxy-tris[pyrrolidino]-phosphonium hexafluoroacetate (PyBOP, 4.8 g, 9.3 mmol) in 69 mL acetonitrile at 5° C. is treated with N-methylmorpholine (0.94 g, 9.3 mmol), resulting in formation of a solution which is stirred at 5° C. for 30 minutes. A suspension of Glu(OtBu)-Arg(Pmc)-Val-Asp(Allyl)-OBzl (9 g, 9.3 mmole) in 52 mL acetonitrile is added, causing the reaction mixture to become cloudy white. N-methylmorpholine is added until the reaction mixture is at pH 7, then the mixture is allowed to warm to ambient temperature and stir for 1.33 hours. The mixture is filtered and the solid residue is washed with acetonitrile (2×40 mL) and dried overnight under vacuum with a nitrogen bleed to give 12.8 g of an off-white crusty solid which is triturated with 200 mL methyl-t-butyl ether, collected by filtration and dried under vacuum to afford 9.7 g of Fmoc-Lys(Alloc)-Glu(OtBu)-Arg(Pmc)-Val-Asp(OAllyl)-OBzl. (SEQ ID NO: 39) (Mcalc 1404.7; M+1obsvd 1406).

Workup

  1. customresulting in formation of a solution which
  2. additionis added
  3. temperatureto warm to ambient temperature
  4. stirringstir for 1.33 hours
  5. filtrationThe mixture is filtered
  6. washthe solid residue is washed with acetonitrile (2×40 mL)
  7. customdried overnight under vacuum with a nitrogen
  8. customto give 12.8 g of an off-white crusty solid which
  9. customis triturated with 200 mL methyl-t-butyl ether
  10. filtrationcollected by filtration
  11. customdried under vacuum

Sources & evidence

ORD record
ord-f95b68c7c7fd4944a1a1171bb79be862
Source dataset
uspto-grants-2003_05
Patent number
US06569993B1

Reaction notes

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