Pivalic acid → HCID 70977363, compound

HRID 2402405Notes

Reaction equation

HRID 2402405 reaction equation
C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Br[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=[C:29]([CH3:42])[CH:28]=1.[OH:43][C:44]1([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH2:53][CH2:52][CH2:51][C:50]2[CH:49]=[C:48]([C:54]([O:56][CH3:57])=[O:55])[CH:47]=[CH:46][C:45]1=2.[F-].[Cs+].C(O)(=O)C(C)(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:43][C:44]1([C:58]2[S:59][C:60]([C:27]3[CH:28]=[C:29]([CH3:42])[CH:30]=[C:31]([NH:33][C:34]4[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][N:35]=4)[N:32]=3)=[CH:61][N:62]=2)[CH2:53][CH2:52][CH2:51][C:50]2[CH:49]=[C:48]([C:54]([O:56][CH3:57])=[O:55])[CH:47]=[CH:46][C:45]1=2

Participants

8

Reactant 5

HCID 6417Pivalic acidHCID 25953Cesium fluorideHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneHCID 70977307HCID 70977307, compoundHCID 86680797HCID 86680797, compound

Product 1

HCID 70977363HCID 70977363, compoundYield 52%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent2×

Procedure

To a solution of Pd(OAc)2 (45 mg, 0.2 mmol) in 1,4-dioxane (20 mL) was added butyldi-1-adamantylphosphine (143 mg, 0.4 mmol) and the mixture was stirred at under nitrogen for 10 minutes, during which time a yellow slurry developed. Then 6-bromo-N-(4-methoxypyridin-2-yl)-4-methylpyridin-2-amine (410 mg, 1.4 mmol), methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (289 mg, 1 mmol), CsF (456 mg, 3 mmol), pivalic acid (153 mg, 1.5 mmol) and 1,4-dioxane (10 mL) were added. The reaction mixture was vacuum-purged with N2 and then heated to reflux under N2 for 20 hours. After cooling to rt, the reaction was filtered through Celite®, and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a solvent system of 2:1 petroleum ether/EtOAc to afford racemic methyl 5-hydroxy-5-(5-(6-((4-methoxypyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (160 mg, 52% total), which was resolved by supercritical fluid chromatography using a Chiralpak AS-H 150*4.6 mm I.D., 5 um column and a mobile phase of 5 to 40% MeOH (0.05% diethylamine) in CO2 with a flow rate 3 mL/min at a wavelength 220 nm to give two enantiomers. MS ESI calcd for C27H26N4O4S [M+H]+ 503. found 503.

Workup

  1. customThe reaction mixture was vacuum-purged with N2
  2. temperatureheated
  3. temperatureto reflux under N2 for 20 hours
  4. filtrationthe reaction was filtered through Celite®
  5. washthe organic layer was washed with water and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-09fd3b562efe4258b5377913c5a128a3
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

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