1,1'-Carbonyldiimidazole → HCID 72712668, compound

HRID 1809477Notes

Reaction equation

HRID 1809477 reaction equation
[C:1]([NH:18][NH2:19])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].Cl.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1.CCN(C(C)C)C(C)C.[NH2:42][C@H:43]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46].Cl>C1COCC1.CN(C=O)C>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[NH:19][C:26]([NH:42][C@H:43]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:27]

Participants

7

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 12451443tert-butyl (2S)-2-amino-4-methylpentanoate hydrochlorideHCID 23080809HCID 23080809, compound

Product 1

HCID 72712668HCID 72712668, compoundYield 99%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Fmoc-Phe and Fmoc-Orn(Mtt) were introduced into 4 g (0.55 mmol/g) of Rink Amide MBHA resin commercially available to prepare Fmoc-Orn(Mtt)-Phe-Rink Amide MBHA resin, and 50 mL of TFA/TIS/DCM (1/5/94) was added to the resin. The mixture was then shaken for 50 minutes. After washing the resin, 40 mL of DCM and 2.27 g of N-methyl-N,N′-bis-Boc-1-guanylpyrazole prepared in EXAMPLE 5 were added to the resin. DIEA was added to the mixture to adjust pH of the solution to 9. The mixture was shaken for 15 hours to give 4.74 g of Fmoc-Arg(Boc2,Me)Phe-Rink Amide MBHA resin. Separately, 145 mg of Fmoc-NHNH2HCl was suspended in 10 mL of THF. Under ice cooling, 89 mg of CDI and 87 mL of DIEA were added to the suspension, followed by stirring at room temperature for an hour. Under ice cooling, a solution of 224 mg of H-Leu-OBut HCl in 5 mL of DMF was added to the mixture. While reverting to room temperature, the mixture was stirred for 18 hours. After the solvent was distilled off, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aq. solution, satd. NaHCO3 aq. solution and then satd. NaCl aq. solution. After drying over Na2SO4, the solvent was concentrated. Purification by flush column chromatography gave 230 mg of Fmoc-AzaGly-Leu-OBut (yield 99%). To 187 mg of the product, 10 mL of TFA/H2O (9/1) was added, followed by stirring for an hour. After the solvent was distilled off, the residue was dissolved in AcOEt and the solution was washed with satd. NaCl aq. solution. After drying over Na2SO4, the solvent was concentrated and diethyl ether was added to give 143 mg of Fmoc-AzaGly-Leu-OH as precipitates (yield 87%). To Trt-Phe-AzaGly-Leu-Arg(Boc2,Me)Phe-Rink Amide MBHA resin (SEQ ID NO: 222) prepared by introducing the resulting Fmoc-AzaGly-Leu-OH and Trt-Phe into Fmoc-Arg(Boc2,Me)Phe-Rink Amide MBHA resin, 50 mL of TFA/TIS/DCM (1/5/94) was added and the mixture was shaken for 50 minutes. After the resin was washed and neutralized, Fmoc-Ser(But) and then Fmoc-Asn(Trt) were introduced into the resin. Using 80.3 mg of the resulting Fmoc-Asn(Trt)Ser(But)Phe-AzaGly-LeuArg(Boc2,Me)Phe-Rink Amide MBHA resin (SEQ ID NO: 223), the peptide chain was extended to give 97.2 mg of H-D-Tyr(But)Asn(Trt)Trp(Boc)Asn(Trt)Ser(But)Phe-AzaGly-LeuArg(Boc2,Me)Phe-Rink Amide MBHA resin. To the resin obtained, 1 mL of TFA/PhSMe/m-cresol/H2O/TIS/EDT (80/5/5/5/2.5/2.5) was added, and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for washing. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Linear density gradient elution (60 minutes) was then performed with eluants A/B:76/24-66/34 using: 0.1% TFA in water and eluant B: 0.1% TFA-containing acetonitrile on preparative HPLC using YMC SH-343-5 S-5, 120A column (20×250 mm). The fractions containing the product were collected and lyophilized to give 11.7 mg of white powders.

Workup

  1. customWhile reverting to room temperature
  2. stirringthe mixture was stirred for 18 hours
  3. distillationAfter the solvent was distilled off
  4. dissolutionthe residue was dissolved in AcOEt
  5. washthe solution was washed with 1N HCl aq. solution
  6. dry with materialAfter drying over Na2SO4
  7. concentrationthe solvent was concentrated
  8. customPurification
  9. customby flush column chromatography

Sources & evidence

ORD record
ord-01939dc12c504e7aae5fac97d59f89d0
Source dataset
uspto-grants-2013_01
Patent number
US08361968B2

Reaction notes

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