Hydrochloric Acid → HCID 67365092, compound

HRID 2046942Notes

Reaction equation

HRID 2046942 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8](C([C@@H](NC(=O)CC3C4C=CC=CC=4C4C3=CC=CC=4)CC(C)C)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].C([O:50][C:51](=[O:67])[CH2:52][N:53]1[CH:57]=[C:56](B2OC(C)(C)C(C)(C)O2)[CH:55]=[N:54]1)C.[F-].[K+].[Li+].[OH-].Cl>C1COCC1.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.O1CCOCC1.O>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:56]3[CH:55]=[N:54][N:53]([CH2:52][C:51]([OH:67])=[O:50])[CH:57]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 14798Sodium HydroxideHCID 522689Potassium FluorideHCID 162183851-(Ethoxycarbonylmethyl)-1H-pyrazole-4-boronic acid pinacol esterHCID 67401017HCID 67401017, compound

Product 1

HCID 67365092HCID 67365092, compound

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
0 °C

Procedure

A mixture of N—((S)-1-{5-bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)-2-(9H-fluoren-9-yl)-acetamide (150.0 mg, 0.212 mmol) and aq 5M NaOH (0.42 mL, 1.1 mmol) in THF (5 mL) was cooled to 0° C. and stirred for 1 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel, extracting with DCM and water. The organic layer was concentrated in vacuo, and [4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]-acetic acid ethyl ester (89.1 mg, 0.318 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potassium fluoride (61.6 mg, 1.06 mmol) and 4:1 dioxane/H2O were added, and the mixture was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel and extracted with DCM and water. The organic layer was dry-loaded onto silica gel, and purified via column chromatography, eluting with 2% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in EtOH/H2O (8 mL), and LiOH (44.5 mg, 1.06 mmol) was added at 0° C. and stirred for 20 min. The pH of the solution was lowered to pH 5 by addition of 2M HCl, and the organic solvent was removed in vacuo. The material was transferred to a separatory funnel and extracted with DCM and brine. The organic layer was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.1 Hz, 3 H), 4.83 (s, 2 H), 5.29 (q, J=7.1 Hz, 1 H), 7.19 (t, J=8.6 Hz, 1 H), 7.36 (d, J=1.5 Hz, 1 H), 7.39-7.53 (m, 2 H), 7.57 (s, 1 H), 7.82 (s, 1H), 8.34 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 433.00 (100) [MH+]. HPLC: tR=3.53 min (ZQ3, polar—5 min).

Workup

  1. customThe organic solvent was removed in vacuo
  2. customthe material was transferred to a separatory funnel
  3. extractionextracting with DCM and water
  4. additionwere added
  5. temperaturethe mixture was heated to 90° C. for 2 h
  6. customThe organic solvent was removed in vacuo
  7. customthe material was transferred to a separatory funnel
  8. extractionextracted with DCM and water
  9. custompurified via column chromatography
  10. washeluting with 2% (7N NH3 in MeOH)/DCM
  11. additionThe fractions containing the pure product
  12. concentrationwere concentrated in vacuo
  13. dissolutionredissolved in EtOH/H2O (8 mL)
  14. stirringstirred for 20 min
  15. customthe organic solvent was removed in vacuo
  16. customThe material was transferred to a separatory funnel
  17. extractionextracted with DCM and brine
  18. concentrationThe organic layer was concentrated in vacuo

Sources & evidence

ORD record
ord-a7a2821f5844409f9379bb20c76c0f49
Source dataset
uspto-grants-2013_11
Patent number
US08592448B2

Reaction notes

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