1,2-Dichloroethane → HCID 69656217, compound

HRID 1058340Notes

Reaction equation

HRID 1058340 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]1[CH2:29][CH2:28][CH2:27][C@H:22]1[C:23]([O:25]C)=[O:24].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:21]1[CH2:29][CH2:28][CH2:27][C@H:22]1[C:23]([OH:25])=[O:24])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 181649HOAtHCID 2733200methyl L-prolinate hydrochlorideHCID 2734482Boc-3-(2-pyridyl)-Ala-OH

Product 1

HCID 69656217HCID 69656217, compoundYield 65.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1.0 g (3.8 mmol) N-(tert-butoxycarbonyl)-3-pyridin-2-yl-L-alanine in 7 ml DMF was added 0.62 g (3.8 mmol) methyl L-prolinate hydrochloride, 0.52 mL (3.8 mmol) triethylamine, 0.51 g (0.38 mmol) HOAt, and 1.1 g (5.7 mmol) EDC. After 3 h at room temperature, the reaction mixture was diluted with 300 ml EtOAc, washed with 200 ml each of saturated NaHCO3 solution, water, and ml brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by automated flash chromatography (ISCO combiflash, 70 g silica gel, linear gradient 50-100% EtOAc:hexane 30 min then 2-10% MeOH/EtOAc at 60 mL/min) afforded 0.9 g N-(tert-butoxycarbonyl)-3-pyridin-2-yl-L-alanyl-L-proline of which 0.44 g (1.2 mmol) was dissolved in 7 mL MeOH. To this was added 1.2 mL (1.2 mmol, 1M aqueous solution) LiOH and the reaction mixture stirred 6 hours, then another 0.12 mL (0.12 mmol, 1M aqueous solution) portion of LiOH was added and the reaction mixture stirred an additional 16 hrs before addition of 0.12 mL conc. HCl (1.44 mmol, 12M aqueous solution) was added and the reaction concentrated to a foam. 1H NMR (CD3OD, 400 MHz) δ 8.47 (m, 1H); 7.78 (m, 1H); 7.34 (m, 2H,); 4.31 (dd, 1H, J=4.21, 8.8 Hz); 3.78 (br m, 1H); 3.54 (br m, 1H); 3.17 (dd, 1H, J=6.23 and 13.5 Hz); 3.02 (m, 2H); 2.3-1.8 (br m, 4H); 1.35 (s, 9H); electrospray mass spectrum 364.

Workup

  1. washwashed with 200 ml each of saturated NaHCO3 solution, water, and ml brine
  2. dry with materialThe organic layer was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customPurification by automated flash chromatography (ISCO combiflash, 70 g silica gel, linear gradient 50-100% EtOAc

Sources & evidence

ORD record
ord-6bb81eec63314d98b167e0a5b3dd81f9
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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