2-(Dicyclohexylphosphino)biphenyl → [8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine

HRID 451577Notes

Reaction equation

HRID 451577 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F:26][C:27]([F:56])([F:55])[C:28]1[CH:29]=[C:30]([C:38]2[C:39]3[N:40]([N:44]=[C:45]([NH:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH:49]4[F:54])[N:46]=3)[CH:41]=[CH:42][CH:43]=2)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.Cl[C:58]1[S:62][N:61]=[C:60]([CH3:63])[N:59]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:56][C:27]([F:26])([F:55])[C:28]1[CH:29]=[C:30]([C:38]2[C:39]3[N:40]([N:44]=[C:45]([NH:47][CH:48]4[CH2:53][CH2:52][N:51]([C:58]5[S:62][N:61]=[C:60]([CH3:63])[N:59]=5)[CH2:50][CH:49]4[F:54])[N:46]=3)[CH:41]=[CH:42][CH:43]=2)[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1

Participants

7

Reactant 4

HCID 27342162-(Dicyclohexylphosphino)biphenyl2×HCID 129191595-Chloro-3-methyl-1,2,4-thiadiazole2×HCID 23676156Sodium t-butoxideHCID 866567258-(3,5-bis(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

Product 1

HCID 76775942[8-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 312751,4-DioxaneSolvent3×

Conditions

Temperature
150 °C

Procedure

A degassed solution of palladium(II) acetate (2.73 mg, 12.2 μmol) and 2-(dicyclohexylphosphino)biphenyl (8.52 mg, 24.3 μmol) in dioxane (1 mL) was stirred for 10 minutes at room temperature, then added to a solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (68 mg, 152 μmol), 5-chloro-3-methyl-1,2,4-thiadiazole (24.5 mg, 182 μmol) and sodium tert-butoxide (21.9 mg, 228 μmol) in dioxane (2 mL). Through the solution was bubbled argon for 5 minutes, then heated to 150° C. in the microwave for 45 minutes. Again a degassed solution of palladium(II) acetate (3.1 mg, 13.8 mmol) and 2-(dicyclohexylphosphino)biphenyl (9.69 mg, 27.6 μmol) in dioxane (1 mL) was added, followed by 5-chloro-3-methyl-1,2,4-thiadiazole (24.5 mg, 182 μmol) and heated for further 45 minutes to 150° C. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as colorless oil (30 mg, 36%) as a mixture of cis- and trans-isomers.

Workup

  1. customThrough the solution was bubbled argon for 5 minutes
  2. temperatureheated for further 45 minutes to 150° C
  3. customThe crude material was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane)

Sources & evidence

ORD record
ord-64a9dfbd21064e2fbbf1ca3c1e5244d1
Source dataset
uspto-grants-2013_07
Patent number
US08486967B2

Reaction notes

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