Sodium Hydroxide → (2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[3-chloro-6'-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4']bipyridinyl-3'-yl]-N-methyl-isobutyramide

HRID 547789Notes

Reaction equation

HRID 547789 reaction equation
[Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:17]=[C:18]([C:26]([CH3:47])([CH3:46])[C:27]([N:29]([C:31]2[CH:32]=[N:33][C:34]([N:38]3[CH2:42][C@H:41]([OH:43])[CH2:40][C@H:39]3[CH2:44][OH:45])=[CH:35][C:36]=2I)[CH3:30])=[O:28])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.[OH-].[Na+]>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[C:18]([C:26]([CH3:46])([CH3:47])[C:27]([N:29]([C:31]2[CH:32]=[N:33][C:34]([N:38]3[CH2:42][C@H:41]([OH:43])[CH2:40][C@H:39]3[CH2:44][OH:45])=[CH:35][C:36]=2[C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH3:30])=[O:28])[CH:17]=[C:16]([C:15]([F:49])([F:14])[F:48])[CH:21]=1

Participants

8

Reactant 4

HCID 14798Sodium HydroxideHCID 108476073-Chloro-2-iodopyridineHCID 86597685HCID 86597685, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 86597691(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[3-chloro-6'-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4']bipyridinyl-3'-yl]-N-methyl-isobutyramideYield 40%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent4×

Procedure

To a solution of 0.500 g (2.09 mmol) 3-chloro-2-iodo-pyridine in 6 ml tetrahydrofuran 1.04 ml (2.09 mmol) of a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran was added dropwise at −40° C. under an atmosphere of argon. After 30 min. 2.3 ml (4.2 mmol) of an anhydrous 1.8 M solution of zinc chloride in tetrahydrofuran was added slowly. The cooling bath was removed after completed addition, and the reaction mixture was stirred at room temperature for 90 min. A portion of 1.6 ml of this solution was added to a solution of 0.15 g (0.24 mmol) (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide and 14 mg (0.012 mmol) tetrakis(triphenylphosphine)palladium(0) in 1 ml tetrahydrofuran. The mixture was heated at 100° C. under microwave irradiation for 30 min. After cooling to room temperature a 0.5 M solution of sodium hydroxide was added, and the mixture was extracted with three portions of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 58 mg (40%) of the title compound as a light yellow solid.

Workup

  1. customThe cooling bath was removed
  2. additionaddition
  3. temperatureThe mixture was heated at 100° C. under microwave irradiation for 30 min
  4. additionwas added
  5. extractionthe mixture was extracted with three portions of dichloromethane
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-5f53f01459f1439fa63baa08dca285da
Source dataset
uspto-grants-2011_05
Patent number
US07939533B2

Reaction notes

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