HCID 178431693, compound → HCID 178431677, compound

HRID 339889Notes

Reaction equation

HRID 339889 reaction equation
[C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:43])[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[N:17][S:16]2(=[O:42])=[O:41])=[CH:11][CH:10]=1>C1COCC1.C(OCCCC)CCC.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:9]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]=[CH:11][C:12]([C:15]2([CH3:43])[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:25][CH2:26][OH:27])=[N:17][S:16]2(=[O:41])=[O:42])=[CH:13][CH:14]=1

Participants

7

Reactant 2

HCID 178431693HCID 178431693, compoundHCID 178506676HCID 178506676, compound

Product 1

HCID 178431677HCID 178431677, compound

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent2×HCID 8909Butyl etherSolvent

Procedure

Under inert gas, 5.52 ml of a 0.5 N zinc chloride solution in THF were cooled to −75° C., and 1.02 ml of a 1.8 N phenyllithium solution in dibutyl ether was added dropwise. The reaction solution was allowed to come to room temperature and stirred for 30 minutes. Then this solution was added to a solution of 110 mg of [5-(4-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine and 8 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium in 3 ml of THF. After stirring at 60° C. for 75 minutes, the reaction solution was concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 2 ml of methanol, 0.2 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated by rotary evaporation and the residue was extracted with 20 ml of dichloromethane and 10 ml of water, and the aqueous phase was washed once again with 10 ml of dichloromethane. The combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation, and the crude product was purified further in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (39.7 mg) with a molecular weight of 478.6 g/mol (C27H30N2O4S); MS (ESI): m/e=479 (M+H+).

Workup

  1. customto come to room temperature
  2. stirringAfter stirring at 60° C. for 75 minutes
  3. concentrationthe reaction solution was concentrated by rotary evaporation
  4. dissolutionthe residue was dissolved in 2 ml of methanol
  5. addition0.2 ml of concentrated hydrochloric acid was added
  6. stirringthe mixture was stirred at room temperature for 1.5 hours
  7. concentrationThe reaction solution was concentrated by rotary evaporation
  8. extractionthe residue was extracted with 20 ml of dichloromethane and 10 ml of water
  9. washthe aqueous phase was washed once again with 10 ml of dichloromethane
  10. customThe combined organic phases were dried
  11. concentrationconcentrated by rotary evaporation
  12. customThe residue was purified by means of normal phase chromatography
  13. concentrationconcentrated by rotary evaporation
  14. customthe crude product was purified further in a purification laboratory by means of preparative HPLC
  15. customthe acetonitrile was removed under reduced pressure
  16. extractionextracted with dichloromethane
  17. dry with materialThe organic phase was dried over MgSO4
  18. concentrationconcentrated by rotary evaporation
  19. additionthe residue was taken up again in a mixture of acetonitrile and water

Sources & evidence

ORD record
ord-919daf424d4e446f97bc5b0597c014c3
Source dataset
uspto-grants-2014_11
Patent number
US08895547B2

Reaction notes

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