Diisopropylamine → methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate

HRID 1469407Notes

Reaction equation

HRID 1469407 reaction equation
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][C@H:45]([CH2:50][C:51]#[CH:52])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])[CH3:39].C(NC(C)C)(C)C>C(N(CC)CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([C:52]#[C:51][CH2:50][C@@H:45]([NH:44][C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[C:46]([O:48][CH3:49])=[O:47])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

9

Reactant 3

HCID 7912DiisopropylamineHCID 12149490(R)-2-(Boc-amino)-4-pentynoic acid methyl ester2×HCID 235027842-(3,5-Bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyrid-3-yl)-N,2-dimethylpropanamide

Product 1

HCID 57965578methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoateYield 168.5%

Reagents, catalysts & solvents 5

HCID 11776TriphenylphosphineCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 8471TriethylamineSolvent

Procedure

A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577, 1.05 g, 1.97 mmol), methyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 11, 1.343 g, 5.91 mmol), Pd(PPh3)2Cl2 (69 mg, 0.098 mmol), copper(I) iodide (19 mg, 0.100 mmol) and triphenylphoshine (52 mg, 0.198 mmol) in triethylamine (2 ml)/diisopropylamine (8 ml) was heated at 100° C. under microwave irradiation for 30 min. This reaction was carried out three times always using the amounts of reagents reported above. The reaction mixtures were combined and evaporated to dryness. The final reaction crude was taken-up in water (50 ml) and extracted with DCM (3×50 ml). The organic phases were collected, dried over sodium sulphate and concentrated. Purification on Si (SP1, 65M column) with Cyclohexane/EtOAc [from Cyclohexane 100 to Cyclohexane/EtOAc 70/30 in 4CV and then Cyclohexane/EtOAc 70/30] elution afforded the title compound (2.4 g, 3.32 mmol, 56.1% yield) as a yellow-brown solid. UPLC: Rt 1.02 min, m/z 724 [M+H+]. Chiral analysis, chromatographic conditions: [Column Chiralpak AD-H (25×0.46 cm); mobile phase: n-hexane/Ethanol 70/30% v/v; Flow rate 0.8 ml/min; DAD 210-340 nm, CD 250] Rt 13.43 min, 99.2% e.e.

Workup

  1. customThe reaction mixtures
  2. customevaporated to dryness
  3. customThe final reaction crude
  4. extractionextracted with DCM (3×50 ml)
  5. customThe organic phases were collected
  6. dry with materialdried over sodium sulphate
  7. concentrationconcentrated
  8. customPurification on Si (SP1, 65M column) with Cyclohexane/EtOAc [from Cyclohexane 100 to Cyclohexane/EtOAc 70/30 in 4CV and then Cyclohexane/EtOAc 70/30]
  9. washelution

Sources & evidence

ORD record
ord-875a1de041ac49898eb53ba979bd7128
Source dataset
uspto-grants-2015_04
Patent number
US09006271B2

Reaction notes

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