Pivalic acid → (R)-methyl 5-hydroxy-5-(5-(6-((4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

HRID 2402395Notes

Reaction equation

HRID 2402395 reaction equation
Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[N:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:19]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:29])[CH:3]=1.[OH:30][C@:31]1([C:45]2[S:46][CH:47]=[CH:48][N:49]=2)[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]([O:43][CH3:44])=[O:42])[CH:34]=[CH:33][C:32]1=2.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.[F-].[Cs+].C(O)(=O)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:30][C@:31]1([C:45]2[S:46][C:47]([C:2]3[CH:3]=[C:4]([CH3:29])[CH:5]=[C:6]([NH:8][C:9]4[CH:14]=[C:13]([C:15]5[N:16]=[N:17][N:18]([CH2:20][C:21]6[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=6)[CH:19]=5)[CH:12]=[CH:11][N:10]=4)[N:7]=3)=[CH:48][N:49]=2)[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]([O:43][CH3:44])=[O:42])[CH:34]=[CH:33][C:32]1=2

Participants

7

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 866808016-bromo-N-(4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-4-methylpyridin-2-amine

Product 1

HCID 86680804(R)-methyl 5-hydroxy-5-(5-(6-((4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylateYield 34%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
100 °C

Procedure

To microwave vial were added 6-bromo-N-(4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-4-methylpyridin-2-amine (247 mg, 0.547 mmol), (R)-methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (158 mg, 0.547 mmol), butyldi-1-adamantylphosphine (78 mg, 0.219 mmol), CsF (249 mg, 1.64 mmol), pivalic acid (95 μl, 0.821 mmol), and Pd(OAc)2 (24.6 mg, 0.109 mmol). The reaction was vacuum and purged with argon 3 times, then degassed 1,4-Dioxane (2.0 mL) was added and the reaction was heated to 100° C. for 16 h. The reaction was cooled to rt and diluted with EtOAc (20 mL). The reaction was filtered, concentrated and purified by silica gel chromatography using a gradient solvent system of 30-100% EtOAc/Hexanes. The product-containing fractions were collected and concentrated to give (R)-methyl 5-hydroxy-5-(5-(6-((4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (121 mg, 34%) as a white foam. MS ESI calcd for C36H33N7O4S [M+H]+ 660, found 660.

Workup

  1. custompurged with argon 3 times
  2. additiondegassed 1,4-Dioxane (2.0 mL) was added
  3. temperatureThe reaction was cooled to rt
  4. additiondiluted with EtOAc (20 mL)
  5. filtrationThe reaction was filtered
  6. concentrationconcentrated
  7. custompurified by silica gel chromatography
  8. customThe product-containing fractions were collected
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-ec15c21d5de543b5976318b2867e98bb
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

Loading…