Lithium Hydroxide → HCID 24762809, compound

HRID 1013848Notes

Reaction equation

HRID 1013848 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18](S(C(F)(F)F)(=O)=O)[N:17]=[CH:16][C:15]2=3)[C:10]1=[O:30].ClC1C=C(OS(C(F)(F)F)(=O)=O)C=C(Cl)C=1C[C@@H]1CCN(C2CCCC3C2=CN(S(C(F)(F)F)(=O)=O)N=3)C1=O.[F:79][C:80]1[CH:85]=[CH:84][C:83](B(O)O)=[CH:82][CH:81]=1.C(=O)([O-])[O-].[Na+].[Na+].[Li+].[OH-]>C1COCC1.O.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:83]2[CH:84]=[CH:85][C:80]([F:79])=[CH:81][CH:82]=2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][CH2:20][C:19]3[NH:18][N:17]=[CH:16][C:15]2=3)[C:10]1=[O:30]

Participants

10

Reactant 5

HCID 3939Lithium HydroxideHCID 10340Sodium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 86629990HCID 86629990, compoundHCID 86629991HCID 86629991, compound

Product 1

HCID 24762809HCID 24762809, compound

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
80 °C

Procedure

A mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-pyrrolidin-3-ylmethyl]-phenyl ester and trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)-pyrrolidin-3-ylmethyl]-phenyl ester, Preparation 73, (0.49 g, 0.76 mmol), 4-fluorophenylboronic acid (0.13 g, 0.91 mmol), sodium carbonate (0.24 g, 2.28 mmol) in THF (20 mL) and water (6 mL) is brought to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.044 g, 0.038 mmol). Raise the reaction temperature to 80° C. and stir the reaction for 1 hour. Cool the reaction, dilute with ethyl acetate and wash with water and brine. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product (0.45 g). Dissolve in THF (5 mL) and LiOH (2 N, 5 mL) and stir at room temperature for 1 hour. Quench the reaction with HCl (1N, 8 mL) and dilute with ethyl acetate and washed with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 50% ethyl acetate in hexanes to 100% ethyl acetate to afford 0.25 g of the title product. MS (m/z): 458 (M+). Separate the two component mixture into individual enantiomers via preparative chiral chromatography (Chiralpak AD, 5×15 cm, 60/40 ethanol/heptane/0.2% DMEA, flow=40 mL/min, 260 nm). The analytical conditions are as follows: Chiralpak AD-H, 4.6×150 mm, 60/40 ethanol/heptane/0.2% DMEA, flow=0.6 mL/min, 260 nm.

Workup

  1. customis brought to 60° C
  2. customthe reaction for 1 hour
  3. temperatureCool
  4. customthe reaction
  5. washwash with water and brine
  6. dry with materialDry the organic layer (Na2SO4)
  7. customremove the solvent in vacuo
  8. customto afford crude product (0.45 g)
  9. customQuench
  10. customthe reaction with HCl (1N, 8 mL)
  11. washwashed with water
  12. dry with materialDry the organic layer (Na2SO4)
  13. customremove the solvent in vacuo
  14. customto afford crude product
  15. custompurify on silica gel column with 50% ethyl acetate in hexanes to 100% ethyl acetate

Sources & evidence

ORD record
ord-a4de3db67e8647768c9f83d7fa2b73f4
Source dataset
uspto-grants-2011_07
Patent number
US07981918B2

Reaction notes

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