Water → HCID 178436719, compound

HRID 1192723Notes

Reaction equation

HRID 1192723 reaction equation
CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[Cl:22][C:23]1[C:28]([C:29]#[CH:30])=[C:27](/[N:31]=[N:32]/[N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[C:25]([C:45](=[O:47])[CH3:46])[CH:24]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>[Cl:22][C:23]1[C:28]([C:29]#[CH:30])=[C:27](/[N:31]=[N:32]/[N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)[C:26]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[C:25]([C@H:45]([OH:47])[CH3:46])[CH:24]=1

Participants

8

Reactant 4

HCID 962Water5×HCID 11430Potassium CarbonateHCID 2734713(3aS)-1-methyl-3,3-diphenyl-hexahydropyrrolo(1,2-c)(1,3,2)oxazaboroleHCID 178436713HCID 178436713, compound

Product 1

HCID 178436719HCID 178436719, compoundYield 126.4%

Reagents, catalysts & solvents 3

HCID 311Citric AcidSolvent2×HCID 313Hydrochloric AcidSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-20 °C

Procedure

A solution of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (280 g, 1.0 mol) in tetrahydrofuran (2.8 L) at room temperature under an atmosphere of nitrogen was treated with 1.0 M borane-THF complex in THF (1.2 L, 1.2 mol) in small portions, stirred for 15 minutes, and then cooled to −20° C. The reaction mixture was treated with a solution of 1-{4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-yl}ethanone (380 g, 1.0 mol) in anhydrous tetrahydrofuran (3.0 L) dropwise over 60 min with the internal temperature rising from −20 to −12° C. The flask that contained the ketone was rinsed with tetrahydrofuran (500 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at −12 to −10° C. for 30 minutes. The reaction mixture was quenched with water (440 mL, 24 mol) at −10° C. over 10 minutes (temperature rose to 0° C.), warmed to room temperature, treated with 10% potassium carbonate in water (3.0 L, 2.1 mol), and stirred for 20 minutes. The organic layer was separated, diluted with ethyl acetate (2 L) and hexanes (0.5 L) and washed with 0.5 M citric acid in water (3.0 L, 1.5 mol), 1.0 M hydrogen chloride in water (3.0 L, 3.0 mol), and 0.5 M citric acid in water (3.0 L, 1.5 mol). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (470 g, theoretical 380 g). The main impurities were the alcohol with triazene moiety removed and the hydrolyzed ligand. The product had ˜91 ee %. This material was used directly in the next step without further purification.

Workup

  1. customrising from −20 to −12° C
  2. washwas rinsed with tetrahydrofuran (500 mL)
  3. additionadded dropwise to the reaction mixture
  4. stirringThe reaction mixture was stirred at −12 to −10° C. for 30 minutes
  5. temperaturewarmed to room temperature
  6. stirringstirred for 20 minutes
  7. customThe organic layer was separated
  8. additiondiluted with ethyl acetate (2 L) and hexanes (0.5 L)
  9. washThe organic layer was washed with brine
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-c8b193fe15af4e57acd7e2f8723b47fd
Source dataset
uspto-grants-2014_03
Patent number
US08680108B2

Reaction notes

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