Cesium carbonate → (3-Carbamoyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yloxy)-acetic acid methyl ester

HRID 1527573Notes

Reaction equation

HRID 1527573 reaction equation
[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CS(C)=O>[CH3:46][O:45][C:43](=[O:44])[CH2:42][O:26][C:23]1[CH:24]=[C:25]2[C:20]([C:19]([C:27](=[O:28])[NH2:29])=[CH:18][N:17]2[CH2:16][C:15]([N:10]2[CH2:11][C@H:12]([F:14])[CH2:13][C@H:9]2[C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[C:3]=2[F:34])=[O:30])=[CH:21][CH:22]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 60984Methyl bromoacetateHCID 68283145HCID 68283145, compound

Product 1

HCID 68283320(3-Carbamoyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yloxy)-acetic acid methyl ester

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

A solution of 1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-hydroxy-1H-indole-3-carboxylic acid amide Example 578 (140 mg, 0.285 mmol) in DMSO (3 mL) was treated with Cs2CO3 (0.28 g, 0.85 mmol). The mixture was stirred at RT for 5 min, followed by addition of methyl 2-bromoacetate (0.039 mL, 0.428 mmol) and stirring at RT for 4 h. The mixture was partitioned between water and CH2Cl2, and the organic phase was washed twice with brine (the combined aqueous washings were filtered and the solid thus obtained was dried in vacuo to give an aliquot of the title compound), dried (phase separator) and concentrated under reduced pressure. Purification by preparative HPLC (SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified fractions the title compound as a white solid. MS: 563 [M+H]+; tR (HPLC conditions c): 4.17 min.

Workup

  1. stirringstirring at RT for 4 h
  2. customThe mixture was partitioned between water and CH2Cl2
  3. washthe organic phase was washed twice with brine (the combined aqueous washings
  4. filtrationwere filtered
  5. customthe solid thus obtained
  6. customwas dried in vacuo

Sources & evidence

ORD record
ord-1ea71285de464dc5985b71d00cbc3a92
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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