Diisopropylethylamine → (S)-1-{(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2176214Notes

Reaction equation

HRID 2176214 reaction equation
[Cl:1][C:2]([Cl:19])([Cl:18])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:17])[C@@H:14]([NH2:16])[CH3:15])[NH:8]1)=[O:6].[C:20]([O:24][C:25]([N:27]([CH3:35])[C@@H:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:19][C:2]([Cl:1])([Cl:18])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:17])[C@@H:14]([NH:16][C:29](=[O:30])[C@@H:28]([N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH3:35])[CH:32]([CH3:34])[CH3:33])[CH3:15])[NH:8]1)=[O:6]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 7010608Boc-N-methyl-L-valineHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate MethanaminiumHCID 86706050(S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

Product 1

HCID 86706049(S)-1-{(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterYield 55.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of 1d (1.08 g, 2.5 mmol) in dichloromethane (35 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (682 mg, 0.55 mL, 3.1 mmol) was added and the reaction mixture was stirred at 0° C. for 45 min. N,N-diisopropylethylamine (1.29 g, 1.73 mL, 10 mmol) was added and the solvent was evaporated to afford crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol), which was used in the next step. A solution of crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol) in acetonitrile (30 mL) was stirred at 0° C. under nitrogen. (S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (635 mg, 2.75 mmol, obtained from Sigma-Aldrich Inc.) and N,N-diisopropylethylamine (1.29 g, 1.7 mL, 10 mmol) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.33 g, 3.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, hydrochloric acid (2 M), water, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 0:1 to afford the title compound (756 mg, 55%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.88 (d, J=6.5 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.28 (d, J=6.7 Hz, 3H), 1.49-1.54 (m, 9H), 1.65-2.30 (m, 5H), 2.82 (s, 3H), 2.82-2.94 (m, 1H), 3.62-4.18 (m, 3H), 4.30-4.45 (m, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.95 (d, J=12.0 Hz, 1H), 5.29-5.39 (m, 1H), 6.62-6.77 (m, 1H). LCMS (m/z) 545.2/547.1 [M+H], Tr=3.02 min.

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in ethyl acetate
  3. washThe solution was washed with water, hydrochloric acid (2 M), water, saturated sodium hydrogen carbonate solution, water and brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. customevaporated
  7. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-c4588b65785a4830864b510b4dcc9cc5
Source dataset
uspto-grants-2015_06
Patent number
US09062092B2

Reaction notes

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