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Methanol → 5-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

HRID 579317
Notes
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Reaction equation

HRID 579317 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([N:28]([CH3:39])[CH:29]3[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]3)=[N:25][N:24]=2)=[C:19]([Cl:40])[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.O.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.CS(C)=O>[Cl:40][C:19]1[CH:18]=[C:17]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[S:27][C:26]([N:28]([CH3:39])[CH:29]2[CH2:34][C:33]([CH3:35])([CH3:36])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]2)=[N:25][N:24]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 887MethanolHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 867271375-(4-Bromo-2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Product 1

HCID 867271385-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine
Yield 55.1%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (129 mg, 0.620 mmol) and 5-(4-bromo-2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (250 mg, 0.563 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (33 mg, 0.028 mmol), followed by a solution of Na2CO3 (179 mg, 1.69 mmol) in water (1 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 80° C. for an hour under microwave irradiation. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCO3(aq) (25 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a brown solid. The crude material was taken up in a 2:1 mixture of MeOH:DMSO (4.5 mL), passed through a syringe filter, and purified by UV-directed preparative HPLC under basic conditions (5 mM NH4OH), collecting at 335 nm to afford the title compound as a white solid (138 mg, 55% yield). LC-MS: Rt 0.90 min; MS m/z 445.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 8.02 (s, 1H), 7.99 (d, J=8.08 Hz, 1H), 7.84 (d, J=1.52 Hz, 1H), 7.67 (dd, J=8.08, 1.52 Hz, 1H), 4.36 (tt, J=12.44, 3.47 Hz, 1H), 3.88 (s, 3H), 3.01 (s, 3H), 1.62 (dd, J=11.87, 3.28 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.28 (br. s., 1H), 1.21 (s, 6H), 1.09 (s, 6H). LC-MS: Rt 1.84 mins; MS m/z 444.8 M+ [Method B].

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customsealed
  3. additionThe reaction mixture was diluted with EtOAc (50 mL)
  4. washwashed with saturated NaHCO3(aq) (25 mL)
  5. customThe organic phase was separated
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated in vacuo
  9. customto afford the crude product as a brown solid
  10. filtrationfilter
  11. custompurified by UV-directed preparative HPLC under basic conditions (5 mM NH4OH)
  12. customcollecting at 335 nm

Sources & evidence

ORD record
ord-3d33b13af65d4c41886f49ce7bdd668b
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09040712B2

Reaction notes

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