1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide

HRID 19057Notes

Reaction equation

HRID 19057 reaction equation
[Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)[C:8](=[O:19])[CH:7]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:45][C:46]1([CH3:58])[O:50][C@H:49]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)[CH2:48][O:47]1>ClCCl>[CH3:45][C:46]1([CH3:58])[O:50][C@H:49]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH:57][C:12](=[O:14])[C@@H:11]([N:9]3[CH2:10][C:6]([O:5][C:4]4[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=4[F:23])=[CH:7][C:8]3=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:53]2)[CH2:48][O:47]1

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 59344941(R)-1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-amineHCID 66895188(S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

Product 1

HCID 66899479(S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amideYield 49%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.75 g, 2.20 mmol) in dichloromethane (39 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.42 mL, 2.40 mmol) and 1-hydroxybenzotriazole (0.31 g, 2.29 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.53 g, 2.68 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.56 g, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C25H30N4O5FCl [M+H]+ 521.1962, observed 521.1963; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.46 (br. s., 1H), 1.51-1.65 (m, 1H), 1.71-1.82 (m, 1H), 3.74 (dd, J=8.5, 5.8 Hz, 1H), 4.01 (dd, J=8.2, 6.3 Hz, 1H), 4.04-4.18 (m, 2H), 4.25 (d, J=18.5 Hz, 1H), 4.35 (dq, J=6.0, 5.8 Hz, 1H), 4.61 (d, J=18.5 Hz, 1H), 4.89 (dd, J=10.9, 4.7 Hz, 1H), 5.03 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.33 (td, J=8.3, 1.3 Hz, 1H), 7.50-7.60 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).

Workup

  1. stirringThe reaction mixture was stirred at 25° C. for 18 h
  2. washwas washed with a saturated aqueous ammonium chloride solution (2×50 mL)
  3. dry with materiala saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate
  4. filtrationfiltered
  5. washrinsed with dichloromethane
  6. concentrationconcentrated in vacuo
  7. customPurification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-3e3c8b50dd8b4bf8b20bdc0739a88b05
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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