Di-tert-butyl Iminodicarboxylate → {4-[3,5-Bis-({4-[tert-butoxycarbonyl-(4-tert-butoxycarbonylamino-butyl)-amino]butylamino}-methyl)-benzylamino]-butyl}-(4-tert-butoxycarbonylamino-butyl)-carbamic acid tert-butyl ester

HRID 1503089Notes

Reaction equation

HRID 1503089 reaction equation
[CH:1]([C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[C:5]([CH:11]=O)[CH:4]=1)=[O:2].[C:13]([O:17][C:18](=[O:37])[N:19]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH3:16])([CH3:15])[CH3:14].[BH4-].[Na+].[C:40]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(OC(C)(C)C)=O>CO.C(Cl)Cl.CO.C(Cl)Cl>[NH4+:19].[OH-:2].[C:13]([O:17][C:18](=[O:37])[N:19]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][CH2:9][C:7]1[CH:6]=[C:5]([CH2:11][NH:36][CH2:35][CH2:34][CH2:33][CH2:32][N:19]([C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:4]=[C:3]([CH2:1][NH:36][CH2:35][CH2:34][CH2:33][CH2:32][N:19]([C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:37])[CH2:20][CH2:21][CH2:22][CH2:40][NH:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH:8]=1)[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])([CH3:15])([CH3:14])[CH3:16]

Participants

9

Reactant 4

HCID 279800Di-tert-butyl IminodicarboxylateHCID 2747968Benzene-1,3,5-tricarboxaldehydeHCID 4311764Sodium borohydrideHCID 86761292(4-Amino-butyl)-(4-tert-butoxycarbonylamino-butyl)-carbamic acid tert-butyl ester

Product 2

HCID 14923Ammonium HydroxideYield 1%HCID 24807263{4-[3,5-Bis-({4-[tert-butoxycarbonyl-(4-tert-butoxycarbonylamino-butyl)-amino]butylamino}-methyl)-benzylamino]-butyl}-(4-tert-butoxycarbonylamino-butyl)-carbamic acid tert-butyl esterYield 40%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

1,3,5-Triformyl benzene 16 (32 mg, 0.197 mmol) was dissolved in 25% MeOH/CH2Cl2 (5 mL). A solution of Boc-protected homospermidine 12 (265 mg, 0.738 mmol) was added via an addition funnel. The reaction mixture was stirred overnight under a N2 atmosphere. Loss of starting material was monitored via 1H NMR and the disappearance of the aldehyde proton at 10.21 ppm. Upon conversion of the starting material, the solvent was removed in vacuo and the crude material was redissolved in a solution of 50% MeOH/CH2Cl2. To this new solution was added NaBH4 (83 mg, 2.19 mmol) at 0° C. The solution was stirred overnight under a N2 atmosphere. The solvents were removed under reduced pressure. The aqueous layer was extracted 3 times in CH2Cl2 and saturated Na2CO3. The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated. Crude material was dissolved in dry THF (10 mL) and allowed to stir for 20 minutes at 0° C. Solid 2-(tert-butoxycarbonyloyimino)-2-phenylacetonitrile (Boc-On, 51 mg, 0.206 mmol) was added to change the Rf value of the starting diBoc amine and the solution was allowed to stir for 2 hours at 0° C. Upon completion the solvents were removed under reduced pressure. Residue was redissolved in CH2Cl2 and the aqueous layer was extracted 3 times in CH2Cl2 and saturated Na2CO3. The organic layers were separated, dried over anhydrous Na2SO4, filtered, and concentrated. Flash column chromatography (92% CH2Cl2, 7% MeOH, 1% NH4OH Rf=0.40) afforded 17 (94 mg, 0.079 mmol, 40%). 1H NMR (CDCl3): δ 7.16 (s, 3H), 4.72 (s, 3H), 3.78 (s, 6H), 3.18 (m, 18H), 2.64 (t, 6H), 1.69-1.19 (m, 78H).

Workup

  1. additionwas added via an addition funnel
  2. customUpon conversion of the starting material, the solvent was removed in vacuo
  3. dissolutionthe crude material was redissolved in a solution of 50% MeOH/CH2Cl2
  4. stirringThe solution was stirred overnight under a N2 atmosphere
  5. customThe solvents were removed under reduced pressure
  6. extractionThe aqueous layer was extracted 3 times in CH2Cl2
  7. dry with materialdried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. dissolutionCrude material was dissolved in dry THF (10 mL)
  11. stirringto stir for 20 minutes at 0° C
  12. stirringto stir for 2 hours at 0° C
  13. customUpon completion the solvents were removed under reduced pressure
  14. dissolutionResidue was redissolved in CH2Cl2
  15. extractionthe aqueous layer was extracted 3 times in CH2Cl2
  16. customThe organic layers were separated
  17. dry with materialdried over anhydrous Na2SO4
  18. filtrationfiltered
  19. concentrationconcentrated

Sources & evidence

ORD record
ord-c79c7a81fe5c499ab1116bcc7b38153a
Source dataset
uspto-grants-2015_12
Patent number
US09212131B2

Reaction notes

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