Triphenylphosphine → (R)-tert-butyl 3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate

HRID 2365879Notes

Reaction equation

HRID 2365879 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][C:3]=1[F:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:56][S:57][C:58]1[N:63]=[C:62]([C:64]2[CH:69]=[CH:68][NH:67][C:66](=[O:70])[CH:65]=2)[CH:61]=[CH:60][N:59]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:67]2[CH:68]=[CH:69][C:64]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]([S:57][CH3:56])[N:63]=3)=[CH:65][C:66]2=[O:70])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][C:3]=1[F:22].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:67]2[CH:68]=[CH:69][C:64]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]([S:57][CH3:56])[N:63]=3)=[CH:65][C:66]2=[O:70])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][C:3]=1[F:22]

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 717270054-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-oneHCID 86696732HCID 86696732, compound

Product 2

HCID 86696733(R)-tert-butyl 3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylateHCID 86696734(R)-tert-butyl 3-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

(3R)-tert-Butyl 3-((4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (640 mg, 1.943 mmol) was dissolved in DCM (4.9 mL, 0.2M) under nitrogen, treated with triphenylphosphine (637.0 mg, 2.429 mmol) and cooled to 0° C. Diisopropyl azodicarboxylate (478.2 μL, 2.429 mmol) was added by syringe. After 5 minutes, the mixture was warmed to room temperature and stirred for 10 minutes prior to being treated with 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (213 mg, 0.9714 mmol). The mixture was then stirred at room temperature for 16 hours. After concentration by rotovap and high vacuum, the mixture was loaded onto a C18 reverse phase column and eluted with a gradient of 5% acetonitrile to 100% acetonitrile in water. The mixture of diastereomers isolated were then loaded onto an SP1 samplet and purified by silica gel chromatography using a 20% to 80% gradient of MTBE in dichloromethane. Fractions containing each diastereomer were isolated and concentrated to afford (R)-tert-butyl 3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate from the higher rf spot and (R)-tert-butyl 3-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate as the lower rf spot, both as oils (54 mg, 10% yield and 48 mg, 9% yield respectively).

Workup

  1. temperaturethe mixture was warmed to room temperature
  2. stirringThe mixture was then stirred at room temperature for 16 hours
  3. concentrationAfter concentration by rotovap and high vacuum
  4. washeluted with a gradient of 5% acetonitrile to 100% acetonitrile in water
  5. additionThe mixture of diastereomers
  6. customisolated
  7. custompurified by silica gel chromatography
  8. additionFractions containing each diastereomer
  9. customwere isolated
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-859c751eec824e198d186b019a07dd38
Source dataset
uspto-grants-2014_04
Patent number
US08697715B2

Reaction notes

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