Hydrochloric Acid → (2R)-2-[(2-chloropyrimidin-4-yl)amino]-2-methylbutanoic acid

HRID 1894937Notes

Reaction equation

HRID 1894937 reaction equation
C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C@:9]([C:13]([OH:15])=[O:14])([CH3:12])[CH2:10][CH3:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.Cl>O.C(O)(C)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:8][C@:9]([CH3:12])([CH2:10][CH3:11])[C:13]([OH:15])=[O:14])[CH:20]=[CH:19][N:18]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 775312,4-DichloropyrimidineHCID 17998883(R)-2-Amino-2-methylbutanoic acid hydrochloride

Product 1

HCID 72164990(2R)-2-[(2-chloropyrimidin-4-yl)amino]-2-methylbutanoic acidYield 89.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
87.5 °C

Procedure

To a solution of K2CO3 (526.2 mg, 3.80 mmol) in water (1.6 mL, 6 volume) was added isovaline-HCl (292.4 mg, 1.90 mmol). The resulting solution was stirred for 10 minutes. A solution of [14C] enriched 2,4-dichloropyrimidine (11a**) (0.261 g, 90 mCi) in isopropanol (5.2 mL, 20 volume) was added dropwise at room temperature, and the resulting mixture was heated at 85-90° C. for 18 hours. The mixture was then concentrated to 4 volumes, then 1N NaOH (6 mL) and isopropyl acetate (6 mL) were added. The aqueous phase was separated and the organic phase was extracted with 1N NaOH (6 mL×2). The combined aqueous layer was acidified to pH=3.0-3.5 using 6N HCl (aq). The resulting solution was extracted with isopropyl acetate (15 mL×3). The collected organic layer was concentrated to 3-4 volumes, then 1N HCl etherate (1.73 mL, 1.73 mmol) was added drop wise at 0° C. and stirred for 15 minutes. The organic solvent was decanted and the solid was washed with isopropyl acetate (5 mL×2). The solid was dried under vacuum and obtained 360 mg of (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**) with 70% radiochemical purity by instant imager to provide (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**).

Workup

  1. concentrationThe mixture was then concentrated to 4 volumes
  2. addition1N NaOH (6 mL) and isopropyl acetate (6 mL) were added
  3. customThe aqueous phase was separated
  4. extractionthe organic phase was extracted with 1N NaOH (6 mL×2)
  5. extractionThe resulting solution was extracted with isopropyl acetate (15 mL×3)
  6. concentrationThe collected organic layer was concentrated to 3-4 volumes
  7. stirringstirred for 15 minutes
  8. customThe organic solvent was decanted
  9. washthe solid was washed with isopropyl acetate (5 mL×2)
  10. customThe solid was dried under vacuum

Sources & evidence

ORD record
ord-5e9fded0930b497da2d65917deeda293
Source dataset
uspto-grants-2013_08
Patent number
US08513414B2

Reaction notes

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