Pivalic acid → (R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

HRID 2402387Notes

Reaction equation

HRID 2402387 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]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=[C:29]([CH3:44])[CH:28]=1.[OH:45][C@:46]1([C:60]2[S:61][CH:62]=[CH:63][N:64]=2)[CH2:55][CH2:54][CH2:53][C:52]2[CH:51]=[C:50]([C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:48][C:47]1=2.[F-].[Cs+].C(O)(=O)C(C)(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:45][C@:46]1([C:60]2[S:61][C:62]([C:27]3[CH:28]=[C:29]([CH3:44])[CH:30]=[C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=4)[N:32]=3)=[CH:63][N:64]=2)[CH2:55][CH2:54][CH2:53][C:52]2[CH:51]=[C:50]([C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:48][C:47]1=2

Participants

8

Reactant 5

HCID 6417Pivalic acidHCID 25953Cesium fluorideHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneHCID 70977548(R)-methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylateHCID 866807956-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine

Product 1

HCID 86680803(R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylateYield 80.2%

Reagents, catalysts & solvents 2

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

Procedure

A suspension of butyl di-1-adamantylphosphine (5.95 g, 16.59 mmol) and Pd(OAc)2 (1.862 g, 8.29 mmol) in 1,4-dioxane (100 mL) was stirred under nitrogen for 10 minutes and a yellow slurry was formed. 6-Bromo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (17.39 g, 52.4 mmol), (R)-methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (enantiomer 2, 12 g, 41.5 mmol), cesium fluoride (18.90 g, 124 mmol), pivalic acid (7.22 mL, 62.2 mmol) and 1,4-dioxane (50 mL) were then added. The reaction mixture was vacuum purged with nitrogen 3 times and then heated to reflux under nitrogen for 20 hours. The reaction was cooled to rt and filtered through Celite®, washing through with EtOAc. The organic filtrate was washed sequentially with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 40% ethyl acetate in hexanes to afford the (R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a pale yellow solid (18 g, 80% yield). MS ESI calcd for C27H23F3N4O3S [M+H]+ 541, found 541. 1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.63 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.36 (s, 1H), 7.23-7.17 (m, 2H), 7.09 (s, 1H), 6.63 (s, 1H), 3.82 (s, 3H), 2.92-2.85 (m, 2H), 2.33-2.30 (m, 4H), 2.15-2.09 (m, 1H), 2.02-1.88 (m, 2H) ppm.

Workup

  1. customa yellow slurry was formed
  2. custompurged with nitrogen 3 times
  3. temperatureheated
  4. temperatureto reflux under nitrogen for 20 hours
  5. filtrationfiltered through Celite®
  6. washwashing through with EtOAc
  7. washThe organic filtrate was washed sequentially with water and brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by silica gel column chromatography
  11. washeluting with 40% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-ebc39afe5d70468a8807c38eca3f4a13
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

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