1-Hydroxybenzotriazole → (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-yl]-amide

HRID 19099Notes

Reaction equation

HRID 19099 reaction equation
OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:55][C:56]([F:66])([F:65])[CH2:57][CH2:58][C:59]1N=C(N)[S:61][N:60]=1>ClCCl>[F:55][C:56]([F:66])([F:65])[CH2:57][CH2:58][C:59]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:61][N:60]=1

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 44240794(S)-2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amideHCID 66898934HCID 66898934, compound

Product 1

HCID 57920096(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-yl]-amideYield 49.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 68 mg, 0.21 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol). The resulting solution was stirred for 5 min before 3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.25 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-yl]-amide (52 mg, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C21H22ClF3N4O3S [M+H]+ 503.1126, observed 503.1127; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.48 (br. s., 1H), 1.55-1.77 (m, 1H), 1.77-1.97 (m, 1H), 2.66-2.90 (m, 2H), 3.05 (t, J=6.9 Hz, 2H), 4.30 (d, J=18.4 Hz, 1H), 4.51 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 4.93-5.07 (m, 1H), 7.37 (td, J=8.0, 1.5 Hz, 1H), 7.47 (td, J=8.0, 1.5 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 7.66 (dd, J=8.0, 1.2 Hz, 1H), 13.38 (s, 1H).

Workup

  1. additionwas added
  2. washThe mixture was washed with saturated ammonium chloride (1 mL)
  3. customevaporated
  4. customthe crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which

Sources & evidence

ORD record
ord-8b5d329d074e4049914e0c2fad32866e
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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