4-Aminopyridine → 2-Methyl-1-(2-(pyridin-4-ylamino)-4'-(trifluoromethyl)-4,5'-bipyrimidin-2'-ylamino)propan-2-ol

HRID 1397171Notes

Reaction equation

HRID 1397171 reaction equation
OC(C)(C)CNC(N)=N.[NH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][C:28]([OH:51])([CH3:50])[CH2:29][NH:30][C:31]1[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[C:34]([C:41]2[CH:46]=[CH:45][N:44]=[C:43](S(C)=O)[N:42]=2)=[CH:33][N:32]=1>C1COCC1>[CH3:50][C:28]([OH:51])([CH3:27])[CH2:29][NH:30][C:31]1[N:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[C:34]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:42]=2)=[CH:33][N:32]=1

Participants

6

Reactant 4

HCID 17274-AminopyridineHCID 2733832Lithium HexamethyldisilazideHCID 867055912-Methyl-1-(2-(methylsulfinyl)-4'-(trifluoromethyl)-4,5'-bipyrimidin-2'-ylamino)propan-2-olHCID 178459320HCID 178459320, compound

Product 1

HCID 679836022-Methyl-1-(2-(pyridin-4-ylamino)-4'-(trifluoromethyl)-4,5'-bipyrimidin-2'-ylamino)propan-2-olYield 30%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

This compound was synthesized in an analogous manner to 22 utilizing 1-(2-hydroxy-2-methylpropyl)guanidine in step 3. To a solution of 4-aminopyridine (80 mg, 0.852 mmol) in THF (426 μl) cooled at −78° C. under nitrogen, LiHMDS (852 μl, 0.852 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 2-methyl-1-(2-(methylsulfinyl)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol (80 mg, 0.213 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for 1 hour. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a pale yellow solid (25.7 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (s, 6 H) 3.40 (br. s., 2 H) 4.51 (s, 1 H) 7.13 (d, J=5.05 Hz, 1 H) 7.76 (s, 2 H) 8.01 (br. s., 1 H) 8.34 (d, J=5.56 Hz, 2 H) 8.66 (d, J=4.93 Hz, 1 H) 10.19 (s, 1 H). HRMS (ES+) for C18H18F3N7O.H+ [MH+]: calcd, 406.1603. found, 406.1612. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.95 minutes over 7.75 minutes.

Workup

  1. temperatureTo the reaction mixture cooled back to −78° C.
  2. temperaturethe reaction mixture was warmed up to rt
  3. stirringwas stirred for 1 hour
  4. customThe crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes]

Sources & evidence

ORD record
ord-73cb03f74cfc476fad9e8ca7222c2def
Source dataset
uspto-grants-2014_12
Patent number
US08901147B2

Reaction notes

Loading…