Ammonium Chloride → 7-{2-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]thiazol-5-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl ester

HRID 1096876Notes

Reaction equation

HRID 1096876 reaction equation
[Cl:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([Cl:18])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Li]CCCC.[CH3:24][O:25][C:26]([C:28]1[CH:29]2[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:33]([CH2:34][C:35]=1OS(C(F)(F)F)(=O)=O)[CH2:32][N:31]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:30]2)=[O:27].[NH4+].[Cl-]>C1COCC1.[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.CCOC(C)=O>[CH3:24][O:25][C:26]([C:28]1[CH:29]2[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])[CH:33]([CH2:34][C:35]=1[C:10]1[S:9][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]3[C:13]([Cl:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:2]=3[Cl:1])=[N:12][CH:11]=1)[CH2:32][N:31]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:30]2)=[O:27]

Participants

9

Reactant 4

HCID 25517Ammonium ChlorideHCID 667835842-[2-(2,6-Dichloro-4-methylphenoxy)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 866370797-{2-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]thiazol-5-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl esterYield 93%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

A cooled (−78° C.) sol. of 2-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]thiazole (3.11 g, 10.2 mmol) in anhydrous THF (90 mL) was treated dropwise with BuLi (1.6 M in hexane; 7.00 mL; 11.2 mmol). After additional stirring at −78° C. for 1 h, ZnCl2 (1M in THF, 12.3 mL, 12.3 mmol) was added dropwise, and the resulting reaction mixture was allowed to warm up to rt for 1.5 h. A sol. of compound Y (4.34 g, 8.18 mmol) and Pd(PPh3)4 (284 mg, 0.246 mmol) in THF (20 mL) was added and the resulting mixture was heated to 50° C. for 1 h. The mixture was cooled to 0° C., and aq. sat. NH4Cl (30 mL) was added. EtOAc (200 mL) was added, and this mixture was successively washed with aq. sat. NH4Cl (150 mL) and brine (150 mL). The org. phase was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc, 3:2) yielded the title compound as a pale yellow solid (5.21 g, 93%). LC-MS: tR=1.19 min, ES+: 684.16.

Workup

  1. customthe resulting reaction mixture
  2. temperatureto warm up to rt for 1.5 h
  3. temperaturethe resulting mixture was heated to 50° C. for 1 h
  4. temperatureThe mixture was cooled to 0° C.
  5. washthis mixture was successively washed with aq. sat. NH4Cl (150 mL) and brine (150 mL)
  6. dry with materialphase was dried over MgSO4
  7. filtrationfiltered
  8. customthe solvents were removed under reduced pressure
  9. customPurification of the crude by FC (heptane/EtOAc, 3:2)

Sources & evidence

ORD record
ord-a109ce989a2c4a0aac3a1cd66419feda
Source dataset
uspto-grants-2012_03
Patent number
US08138340B2

Reaction notes

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