Tetrahydrofuran → HCID 66884119, compound

HRID 2402980Notes

Reaction equation

HRID 2402980 reaction equation
[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([CH2:13][NH2:14])[N:10]=[N:9]2)=[CH:5][CH:4]=1.CO[C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28](CN)=CN=N2)=[CH:21][CH:20]=1.[CH:33]([C:35]1[CH:40]=CC([B:41]([OH:43])[OH:42])=C[CH:36]=1)=O.C([O:47][BH-:48](OC(=O)C)[O:49]C(=O)C)(=O)C.[Na+].COC1C=CC(CN2C=C(CNCC3C=CC(B(O)O)=CC=3)N=N2)=CC=1.COC1C=CC(CN2C(CNCC3C=CC(B(O)O)=CC=3)=CN=N2)=CC=1.[C:110](=O)([O-:112])[O-:111].[K+].[K+].[C:116](OC(OC(C)(C)C)=O)([O:118][C:119]([CH3:122])([CH3:121])[CH3:120])=[O:117].O1CCCC1>O.C(OCC)(=O)C>[C:119]([O:118][C:116]([N:14]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([B:41]([OH:43])[OH:42])=[CH:32][CH:31]=1)[CH2:13][C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[CH:12]=1)=[O:117])([CH3:122])([CH3:121])[CH3:120].[C:35]([O:112][C:110]([N:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([B:48]([OH:49])[OH:47])=[CH:32][CH:31]=1)[CH2:28][C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[N:9]=[N:10][CH:11]=1)=[O:111])([CH3:33])([CH3:36])[CH3:40]

Participants

13

Reactant 9

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 90495Di-tert-butyl dicarbonateHCID 5910734-Formylphenylboronic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 59488891HCID 59488891, compoundHCID 59488900916888-15-8HCID 59488919HCID 59488919, compoundHCID 66883848HCID 66883848, compound

Product 2

HCID 66884119HCID 66884119, compoundYield 97.3%HCID 66884224HCID 66884224, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of the regioisomeric C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and 1004, 20.06 g, 92.0 mmol) in tetrahydrofuran (THF, 300 mL) was treated with 4-formylphenylboronic acid (13.11 g, 87.4 mmol, 0.95 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (NaB(OAc)3H, 29.25 g, 138.0 mmol, 1.5 equiv) was then added to the reaction mixture in three portions over the period of 1.5 h at room temperature, and the resulting reaction mixture was stirred at room temperature for an additional 3.5 h. When TLC and HPLC/MS showed that the reductive amination reaction was complete, the reaction mixture, which contained a regioisomeric mixture of 4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid as the reductive amination products (1006 and 1007), was then treated with water (H2O, 200 mL). The resulting aqueous solution was subsequently treated with solid potassium carbonate (K2CO3, 38.0 g, 276 mmol, 3.0 equiv) and di-tert-butyl dicarbonate (BOC2O, 20.08 g, 92 mmol, 1.0 equiv) at room temperature and the reaction mixture was stirred at room temperature for 2 b. When TLC and HPLC/MS showed that the N—BOC protection reaction was complete, the reaction mixture was treated with ethyl acetate (EtOAc, 150 mL) and water (H2O, 100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with H2O (50 mL), 1.5 N aqueous HCl solution (2×100 mL), H2O (100 mL), and saturated aqueous NaCl solution (100 mL), dried over MgSO4, and concentrated in vacuo. The crude, 4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009, 38.45 g, 39.50 g, 97.3%) was obtained as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. This crude material was found to be essentially identical in every comparable aspect as the material obtained from Method A and was directly used in the subsequent reaction without further purification.

Workup

  1. customthe resulting reaction mixture
  2. customthe resulting reaction mixture
  3. stirringwas stirred at room temperature for an additional 3.5 h
  4. customWhen TLC and HPLC/MS showed that the reductive amination reaction
  5. stirringthe reaction mixture was stirred at room temperature for 2 b
  6. customThe two layers were separated
  7. extractionthe aqueous layer was extracted with ethyl acetate (50 mL)
  8. washThe combined organic extracts were washed with H2O (50 mL), 1.5 N aqueous HCl solution (2×100 mL), H2O (100 mL), and saturated aqueous NaCl solution (100 mL)
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-6b71f09b73e74c03be36e48d87f9e673
Source dataset
uspto-grants-2014_08
Patent number
US08796465B2

Reaction notes

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