(r)-2-(Thiazol-2-yl)but-3-yn-2-ol → (2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-(methoxymethyl)-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

HRID 1398709Notes

Reaction equation

HRID 1398709 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][CH3:12])[N:7]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C@:26]([OH:30])([C:28]#[CH:29])[CH3:27]>N1CCCCC1.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.[Cu]I>[NH2:19][C:15]1[N:16]=[CH:17][N:18]=[C:13]([N:7]2[C:6]3[CH:20]=[C:2]([C:29]#[C:28][C@:26]([C:22]4[S:21][CH:25]=[CH:24][N:23]=4)([OH:30])[CH3:27])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][O:11][CH3:12])[N:14]=1

Participants

6

Reactant 2

HCID 58221813(r)-2-(Thiazol-2-yl)but-3-yn-2-olHCID 681816384-[6-bromo-2-(methoxymethyl)-1H-1,3-benzodiazol-1-yl]-1,3,5-triazin-2-amine

Product 1

HCID 68181662(2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-(methoxymethyl)-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst2×HCID 8082PiperidineSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 4-[6-bromo-2-(methoxymethyl)-1H-1,3-benzodiazol-1-yl]-1,3,5-triazin-2-amine (150 mg at 86% purity, 0.38 mmol) in piperidine (3 mL) was introduced tetrakis(triphenylphosphine)palladium(0) (22.2 mg, 0.02 mmol), copper(I) iodide (7.3 mg, 0.04 mmol) and (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol (118 mg, 0.77 mmol). The reaction was warmed to 70° C. for 1 hr. After cooling to RT, additional tetrakis(triphenylphosphine)palladium(0) (22.2 mg, 0.02 mmol) was introduced and the reaction mixture warmed to 70° C. for a further 1 hr. The reaction mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography (DCM containing a 0-3% gradient of methanol) to furnish the title compound as a brown oil: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 5.10 (2H, s), 7.06 (1H, br. s.), 7.31-7.40 (1H, m), 7.64-7.73 (2H, m), 7.75-7.80 (1H, m), 8.02 (1H, br. s.), 8.08 (1H, br. s.), 8.30 (1H, s), 8.40-8.45 (1H, m), 8.65 (1H, s); LC-MS: m/z=+408.00 (M+H)+.

Workup

  1. temperatureAfter cooling to RT
  2. temperaturethe reaction mixture warmed to 70° C. for a further 1 hr
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. customthe residue purified by silica gel flash chromatography (DCM containing a 0-3% gradient of methanol)

Sources & evidence

ORD record
ord-3fb38dd08efa427bbca71aab39544d9d
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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