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Sodium Hydroxide → HCID 87304286, compound

HRID 1951688
Notes
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Reaction equation

HRID 1951688 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.C[O:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][O:46]C)[NH:41]1.[OH-].[Na+].B(Br)(Br)Br>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.ClCCl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[OH:38][CH2:39][C@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][OH:46])[N:41]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1.[OH:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][OH:46])[N:41]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 4

HCID 14798Sodium HydroxideHCID 25134Boron tribromideHCID 7019262(S,S)-(+)-2,5-Bis(methoxymethyl)pyrrolidineHCID 235027842-(3,5-Bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyrid-3-yl)-N,2-dimethylpropanamide

Product 2

HCID 87304286HCID 87304286, compoundYield 2%
HCID 87304714
HCID 87304714, compound
Yield 2%

Reagents, catalysts & solvents 4

HCID 5974Hexadecyltrimethylammonium BromideCatalystHCID 178418851HCID 178418851, compoundCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
90 °C

Procedure

A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. over night. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.09 g of the crude coupling product. This material was dissolved in 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 M solution of boron tribromide in dichloromethane at 0° C. After 15 min. the reaction was quenched by the addition of water, followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 7 mg (2%) of (2R,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid and 6 mg (2%) of (2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid.

Workup

  1. customwas degassed by two freeze-thaw cycles
  2. temperatureAfter cooling to room temperature the mixture
  3. additionwas diluted with water
  4. extractionextracted with three portions of tert-butyl methyl ether
  5. dry with materialThe combined organic layers were dried over sodium sulphate
  6. concentrationconcentrated in vacuo
  7. customFlash column chromatography gave 0.09 g of the crude coupling product
  8. customAfter 15 min. the reaction was quenched by the addition of water
  9. extractionfollowed by extraction with three portions of dichloromethane
  10. dry with materialThe combined organic layers were dried over sodium sulphate
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-7f98eddfb3b94a8c8200f17cb5e323ad
Source dataset
uspto-grants-2013_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08404708B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes