Triethylamine → (R)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid (5-chloro-2-fluoro-phenyl)-amide

HRID 655581Notes

Reaction equation

HRID 655581 reaction equation
Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([F:41])=[C:36]([N:38]=[C:39]=[O:40])[CH:37]=1>ClCCl>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([F:41])=[C:36]([NH:38][C:39]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:40])[CH:37]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 162280414-Chloro-1-fluoro-2-isocyanatobenzeneHCID 67080697(R)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride

Product 1

HCID 59149933(R)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid (5-chloro-2-fluoro-phenyl)-amideYield 53.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

0.022 g (purity: 76% corresponds to 0.04 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) was suspended in 1 ml dichloromethane. The reaction mixture was treated at room temperature with 0.031 ml (0.22 mmol, 5 eq.) of triethylamine and at 0° C. with 8 mg (0.05 mmol, 1.1 eq.) 5-chloro-2-fluorophenyl isocyanate. The solution was stirred overnight and warmed up to room temperature. The solution was evaporated. The crude product was purified by flash chromatography (20 g amine-silica, ethyl acetate/n-heptane 1:1, 4:1, 9:1, 100%, ethyl acetate/ethanol 95:5, 9:1) to give 0.010 g (48%) of the title compound as white solid. MS: 467.4 (MH+, Cl).

Workup

  1. customThe solution was evaporated
  2. customThe crude product was purified by flash chromatography (20 g amine-silica, ethyl acetate/n-heptane 1:1, 4:1, 9:1, 100%, ethyl acetate/ethanol 95:5, 9:1)

Sources & evidence

ORD record
ord-28f53583d23c4266a0b442488bb8823a
Source dataset
uspto-grants-2011_12
Patent number
US08071586B2

Reaction notes

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