Diisopropylethylamine → Boc-prolylproline methyl ester

HRID 2370886Notes

Reaction equation

HRID 2370886 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2733200methyl L-prolinate hydrochlorideHCID 27960291-Hydroxybenzotriazole hydrate

Product 1

HCID 14236281Boc-prolylproline methyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

METHOD 2 N-tert-butoxycarbonyl L-proline (3.04 g, 14.1 mmol) and L-proline methyl ester hydrochloride (2.34 g, 14.1 mmol) were dissolved in CH2Cl2 (25 mL). N,N-diisopropylethylamine (1.82 g, 14.1 mmol) was added and the solution cooled to 0° C. (icebath). HOBt hydrate (2.16 g, 14.1 mmol) and then EDC hydrochloride (2.97 g, 15.5 mmol) were added together with 15 mL CH2Cl2. The icebath was removed and the reaction mixture stirred for 16 h 15 min at room temperature. The reaction mixture was diluted with CH2Cl2 (60 mL) and the solution washed with 1M HCl(3×25 mL), 7.5% (w/w) K2CO3 solution (3×25 mL) and saturated brine (25 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a very pale yellow, almost clear oil, which was dried under high vacuum overnight. The compound (3.67 g, 79%) showed spectral characteristics in accordance with published data1; δH (200 MHz; d6-DMSO) 4.56-4.31 (2H, m, CαH(Pro1)/CαH(Pro2)), 3.78-3.28 (4H, m, CδH2(Pro1)/CδH2(Pro2)), 3.67 (3H, s, OCH3, rotomer 1), 3.65 (3H, s, OCH3, rotomer 2), 2.26-1.65 (8H, m, CH2), 1.40/1.34/1.22 (9H, s, (CH3)3, all rotomers); δC (75 MHz; CDCl3) 172.8, 172.5, 171.5, 171.0, 154.4, 153.6, 79.3, 58.5, 57.6, 57.5, 53.3, 52.0, 51.9, 46.7, 46.5, 46.3, 29.8, 28.9, 28.7, 28.6, 28.3, 28.2, 24.9, 24.8, 23.9, 23.4

Workup

  1. customThe icebath was removed
  2. additionThe reaction mixture was diluted with CH2Cl2 (60 mL)
  3. washthe solution washed with 1M HCl(3×25 mL), 7.5% (w/w) K2CO3 solution (3×25 mL) and saturated brine (25 mL)
  4. dry with materialThe solution was dried with anhydrous MgSO4
  5. customthe solvent evaporated

Sources & evidence

ORD record
ord-2eec2ddfcb2b403dad380cf1ef8a7032
Source dataset
uspto-grants-2014_04
Patent number
US08710008B2

Reaction notes

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