Hydrochloric Acid → 2-Cyclopropyl-6-hydroxypyrimidine-4-carboxylic acid

HRID 218298

Reaction equation

HRID 218298 reaction equation
[Na].[C:2]([O:12]CC)(=[O:11])[CH2:3][C:4]([C:6]([O:8]CC)=O)=O.[OH-].[Na+].Cl.[CH:18]1([C:21](=[NH:23])[NH2:22])[CH2:20][CH2:19]1.Cl>O.C(O)C>[CH:18]1([C:21]2[NH:23][C:6](=[O:8])[CH:4]=[C:3]([C:2]([OH:12])=[O:11])[N:22]=2)[CH2:20][CH2:19]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium Hydroxide2×HCID 2781916Cyclopropanecarboximidamide hydrochlorideHCID 57351814Diethyl 2-oxosuccinate,sodium salt

Product 1

HCID 1355475272-Cyclopropyl-6-hydroxypyrimidine-4-carboxylic acidYield 87.3%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
27.5 °C

Procedure

A 500-mL jacketed reactor equipped with a pH meter, temperature probe and metering addition funnel was charged with denatured ethanol (contained 5% 2-propanol, 30 mL) and water (150 mL). The reaction mixture was stirred while diethyl oxalacetate sodium salt (70 g, 0.33 mol) was added over 10 minutes. A solution of 25% aqueous NaOH (14 g, 56 mL, 0.35 mol) was metered into the stirring vortex over 1 h while maintaining the temperature in a range of 25 to 30 ° C. The reaction mixture was stirred for an additional 30 minutes at 30 ° C., and cyclopropanecarboximidamide monohydrochloride (32 wt % solution in water, 32 g, 0.267 mol) was added. A solution of 25% aqueous NaOH (31 g, 0.19 mol) was added at a temperature ranging from 30 to 35 ° C. over about 1 h so as to maintain the pH in the range of 10.5-11.5. Then the resulting orange mixture was gradually heated to 60 ° C. over a period of 1 h and held at the same temperature for additional 30 minutes. The reaction mixture was cooled to 45-50 ° C., and hydrochloric acid (37 wt. % in water, 50 mL, 0.60 mol) was added over 1 h at about 45 ° C. (CAUTION: foaming) until the pH reached to about 1.5. The reaction mixture was cooled to 5 ° C. and filtered. The resulting wet cake was washed with water (3×20 mL), suction-dried, and dried in a vacuum-oven at 70 ° C. for 16 h to afford 42 g (85% yield) of the title compound as a beige solid (97% purity by HPLC assay) decomposing at 235-236 ° C.

Workup

  1. customequipped with a pH meter, temperature probe and metering addition funnel
  2. additionwas added over 10 minutes
  3. waitranging from 30 to 35 ° C. over about 1 h
  4. temperatureso as to maintain the pH in the range of 10.5-11.5
  5. temperatureThen the resulting orange mixture was gradually heated to 60 ° C. over a period of 1 h
  6. waitheld at the same temperature for additional 30 minutes
  7. temperatureThe reaction mixture was cooled to 45-50 ° C.
  8. temperatureThe reaction mixture was cooled to 5 ° C.
  9. filtrationfiltered
  10. washThe resulting wet cake was washed with water (3×20 mL)
  11. customsuction-dried
  12. customdried in a vacuum-oven at 70 ° C. for 16 h

Sources & evidence

ORD record
ord-c23bf50a9d83425fa0fc6e6d632bbc94
Source dataset
uspto-grants-2012_06
Patent number
US08198442B2

Linked notes

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