Hydrochloric Acid → HCID 136377178, compound

HRID 1027288Notes

Reaction equation

HRID 1027288 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH3:25])[CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)=[CH:10][CH:9]=2)=[C:4]([F:26])[CH:3]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:29])C.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)(=O)C.C(OC(=O)C)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH3:25])[CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]3)=[CH:10][CH:9]=2)=[C:6]([OH:29])[CH:7]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 24477Sodium ThiosulfateHCID 76724Iodobenzene diacetateHCID 86710714HCID 86710714, compound

Product 1

HCID 136377178HCID 136377178, compoundYield 37.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 176Acetic AcidSolventHCID 7918Acetic AnhydrideSolvent

Conditions

Temperature
40 °C

Procedure

6-(4-Chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (50 mg, 0.13 mmol), PhI(OAc)2(60 mg, 0.19 mmol), and Pd(OAc)2(8.9 mg, 0.013 mmol) were dissolved in a mixture of acetic acid (0.6 mL) and acetic anhydride (0.6 mL). The mixture was stirred at 40° C. overnight. A solution of sodium thiosulfate was added and the mixture was stirred for 8 days at RT. A solution of potassium carbonate was added and the reaction pH was adjusted to 10. The aqueous phase was extracted (2×) with dichloromethane and methanol (9:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase preparative HPLC (10 to 30% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). The appropriate fractions containing product were free based by catch and release using SiliaBond Propylsulphonic Acid® (4 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (3/1 mL). 1 M aqueous HCl (3 equivalents) was added, and the volatiles were concentrated in vacuo to afford the hydrochloride salt of 5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol as a yellow solid (19 mg, 33%). LCMS Rt=0.57 min [Method Q]; [M+H]: 393.2; 1H NMR (400 MHz, MeOD) δ 8.21 (d, J=10.0 Hz, 1H), 7.99 (d, J=10.0 Hz, 1H), 6.99 (dd, J=10.0, 2.0 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H), 5.09 (bs, 1H), 3.18 (s, 3H), 1.98-2.12 (m, 4H), 1.65 (s, 6H), 1.57 (s, 6H).

Workup

  1. stirringthe mixture was stirred for 8 days at RT
  2. extractionThe aqueous phase was extracted (2×) with dichloromethane and methanol (9:1)
  3. dry with materialThe combined organic phases were dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude material was purified via reverse phase preparative HPLC (10 to 30% acetonitrile in water, 0.1% trifluoroacetic acid as modifier)
  7. additionThe appropriate fractions containing product
  8. concentrationThe solvent was concentrated in vacuo
  9. concentrationthe volatiles were concentrated in vacuo

Sources & evidence

ORD record
ord-db7dbfc629e24fe9862737f91c348b83
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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