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

HRID 579345Notes

Reaction equation

HRID 579345 reaction equation
[NH:1]1[C:5](B(O)O)=[CH:4][CH:3]=[N:2]1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[N:18][N:17]=2)=[C:12]([O:33][CH3:34])[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:34][O:33][C:12]1[CH:11]=[C:10]([C:5]2[NH:1][N:2]=[CH:3][CH:4]=2)[CH:15]=[CH:14][C:13]=1[C:16]1[S:20][C:19]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:28])([CH3:29])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:18][N:17]=1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 112519791H-Pyrazole-5-boronic acidHCID 867271675-(4-Chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Product 1

HCID 867271685-(2-Methoxy-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amineYield 23.1%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred suspension of (1H-pyrazol-5-yl)boronic acid (14 mg, 0.139 mmol) and 5-(4-chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (50 mg, 0.127 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (40 mg, 0.380 mmol) in water (0.25 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. under microwave irradiation for 30 minutes, then again at 145° C. Additional catalyst and boronate were added and the mixture was heated for an additional 30 minutes under microwave irradiation at an increased temperature of 160° C. The reaction mixture was diluted with DCM (20 mL), washed with saturated NaHCO3(aq) (10 mL) and the organic phase was separated and concentrated in vacuo to afford the crude product as an oily residue. The crude material was purified by mass directed preparative HPLC under basic conditions (NH4OH midified) to afford the title compound as a white solid (12.5 mg, 23% yield). LC-MS: Rt 0.81 min; MS m/z 427.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 8.12 (d, J=8.08 Hz, 1H), 7.82 (br. s., 1H), 7.60 (s, 1H), 7.54 (d, J=6.06 Hz, 1H), 6.84 (d, J=2.02 Hz, 1H), 4.31-4.41 (m, 1H), 4.01 (s, 3H), 2.99 (s, 3H), 1.61 (dd, J=12.13, 3.54 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H).

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customsealed
  3. customagain at 145° C
  4. additionAdditional catalyst and boronate were added
  5. temperaturethe mixture was heated for an additional 30 minutes under microwave irradiation at an increased temperature of 160° C
  6. additionThe reaction mixture was diluted with DCM (20 mL)
  7. washwashed with saturated NaHCO3(aq) (10 mL)
  8. customthe organic phase was separated
  9. concentrationconcentrated in vacuo
  10. customto afford the crude product as an oily residue
  11. customThe crude material was purified by mass

Sources & evidence

ORD record
ord-cf1e7a16a93349c187794da870fc5fa3
Source dataset
uspto-grants-2015_05
Patent number
US09040712B2

Reaction notes

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