Hydrochloric Acid → (R)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid

HRID 1055034Notes

Reaction equation

HRID 1055034 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][C@@H:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][C:34]([OH:36])=[O:35].C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCCC1.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][C@@H:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][C:34]([OH:36])=[O:35])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 7010080(R)-3-Amino-4,4-dimethylpentanoic acidHCID 672853215-Chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine

Product 1

HCID 71251334(R)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
135 °C

Procedure

To a solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.100 g, 0.215 mmol: prepared in a similar manner as described below for Compound 25a in scheme 4) and (R)-3-amino-4,4-dimethylpentanoic acid, 2a, (0.031 g, 0.215 mmol) in tetrahydrofuran (1.66 mL) was added freshly ground Na2CO3 (0.068 g, 0.645 mmol) followed by acetonitrile (0.331 mL). The reaction mixture was heated to 135° C. for 30 minutes in a microwave reactor. The reaction mixture was slowly poured into 75 mL of 1N HCl. The pH of final solution was adjusted to 1. The aqueous was extracted with EtOAc (3×5 mL), washed with brine, dried over Na2SO4 and filtered to obtain a crude solid residue. The crude residue was purified via silica gel chromatography (0-10% MeOH—CH2Cl2 gradient) afforded 78 mg of the desired product 3a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.9 minutes (M+H) 546.22.

Workup

  1. extractionThe aqueous was extracted with EtOAc (3×5 mL)
  2. washwashed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. customto obtain a crude solid residue
  6. customThe crude residue was purified via silica gel chromatography (0-10% MeOH—CH2Cl2 gradient)

Sources & evidence

ORD record
ord-6257374491c5471493c78140f2b20f1a
Source dataset
uspto-grants-2016_07
Patent number
US09394302B2

Reaction notes

Loading…