Ethyl Acetate → 7-{2-[2-(tert-Butyldimethylsilanyloxy)ethoxy]thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl ester

HRID 1096873Notes

Reaction equation

HRID 1096873 reaction equation
[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:22][O:23][C:24]([C:26]1[CH:27]2[N:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:31]([CH2:32][C:33]=1OS(C(F)(F)F)(=O)=O)[CH2:30][N:29]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28]2)=[O:25].CCOC(C)=O>C1COCC1.[NH4+].[Cl-].[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:27]2[N:42]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH:31]([CH2:32][C:33]=1[C:14]1[S:13][C:12]([O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[N:16][CH:15]=1)[CH2:30][N:29]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28]2)=[O:25]

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 667842562-[2-(Tert-butyldimethylsilanyloxy)ethoxy]thiazoleHCID 866370767-Trifluoromethanesulfonyloxy-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl esterHCID 178418339Butyllithium

Product 1

HCID 866370757-{2-[2-(tert-Butyldimethylsilanyloxy)ethoxy]thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl esterYield 99.2%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

A sol. of 2-[2-(tert-butyldimethylsilanyloxy)ethoxy]thiazole (3.75 g; 14.46 mmol) in THF (72 mL) was cooled to −78° C. BuLi (1.6M in hexane, 9.5 mL; 15.2 mmol) was added dropwise over 5 min. After completion of the addition, the resulting solution was stirred further at −78° C. for 1 h. ZnCl2 (1.0 M in THF; 16.7 mL, 16.7 mmol) was added dropwise over 5 min, and the reaction mixture was allowed to warm up to rt, and stirred for 1.5 h. A sol. of compound Y (3.84 g; 7.23 mmol) in THF (5 mL) was added, followed by Pd(PPh3)4 (0.25 g; 0.22 mmol). The resulting sol. was stirred at 50° C. for 45 min. The reaction mixture was cooled to rt, and EtOAc (80 mL) was added. The mixture was then poured in sat. aq. NH4Cl (150 mL). The phases were shaken, separated and the aq. phase was extracted with EtOAc (2×150 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30/70) yielded the title compound (4.59 g, 99%). LC-MS: tR=1.20 min; ES+: 640.31.

Workup

  1. additionAfter completion of the addition
  2. temperatureto warm up to rt
  3. stirringstirred for 1.5 h
  4. stirringThe resulting sol. was stirred at 50° C. for 45 min
  5. temperatureThe reaction mixture was cooled to rt
  6. stirringThe phases were shaken
  7. customseparated
  8. extractionthe aq. phase was extracted with EtOAc (2×150 mL)
  9. dry with materialextracts were dried over MgSO4
  10. filtrationfiltered
  11. customthe solvents were removed under reduced pressure
  12. customPurification of the residue by FC (EtOAc/heptane 30/70)

Sources & evidence

ORD record
ord-44378af22a4c452e9c0d3b33dfcd9fff
Source dataset
uspto-grants-2012_03
Patent number
US08138340B2

Reaction notes

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