methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate → tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate

HRID 1779171Notes

Reaction equation

HRID 1779171 reaction equation
[F:1][C:2]([F:55])([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]([C:25](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)SC1=O)=[O:26])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:56][C@@H:57]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]#[C:72][CH3:73])=[CH:65][CH:64]=1)[C:58]([O:60][CH3:61])=[O:59]>ClCCl>[CH2:70]([O:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][C@H:57]([NH:56][C:25]([C@@H:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:55])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:12]([OH:24])([CH2:20][CH2:21][O:22][CH3:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:26])[C:58]([O:60][CH3:61])=[O:59])=[CH:68][CH:67]=1)[C:71]#[C:72][CH3:73]

Participants

4

Reactant 2

HCID 58239373methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionateHCID 90060173tert-Butyl (E)-(2S,3S)-12,12-difluoro-2-hydroxy-3-((S)-4-isopropyl-2-oxo-5,5-diphenyl-thiazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-nonadec-4-enoate

Product 1

HCID 118260122tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoateYield 80%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
45 °C

Procedure

tert-Butyl (E)-(2S,3S)-12,12-difluoro-2-hydroxy-3-((S)-4-isopropyl-2-oxo-5,5-diphenyl-thiazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552816; 38.8 mg, 0.0494 mmol) synthesized in Steps B1 to B6 and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (18.3 mg, 0.074 mmol) were dissolved in dichloromethane, and the solvent was distilled off under reduced pressure. The obtained mixture was stirred at 45° C. for 4 days, cooled to room temperature, and then extracted by adding ethyl acetate and water. The organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled out of the filtrate under reduced pressure and the residue was purified with SP1 (SiO2 cartridge, 25% ethyl acetate/n-hexane, Rf=0.1) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 6804236; 28.9 mg, 80% yield).

Workup

  1. distillationthe solvent was distilled off under reduced pressure
  2. temperaturecooled to room temperature
  3. extractionextracted
  4. additionby adding ethyl acetate and water
  5. washThe organic layer was washed with a saturated brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. distillationThe solvent was distilled out of the filtrate under reduced pressure
  9. customthe residue was purified with SP1 (SiO2 cartridge, 25% ethyl acetate/n-hexane, Rf=0.1)

Sources & evidence

ORD record
ord-a0e14b1483cc4692a045a1c5234a742c
Source dataset
uspto-grants-2016_02
Patent number
US09266853B2

Reaction notes

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