Hydrochloric Acid → Methyl 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carboxylate

HRID 626906Notes

Reaction equation

HRID 626906 reaction equation
Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]#N)[N:4]=1.[OH2:21].CC1C=CC([CH2:29][O:30]C(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CO.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]([O:30][CH3:29])=[O:21])[N:4]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 478568p-tolylmethyl N-(pyrazine-2-carbonylamino)carbamateHCID 574687094-Methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carbonitrile

Product 1

HCID 90015076Methyl 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carboxylateYield 94%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
80 °C

Procedure

Concentrated aq. hydrochloric acid (42 mL, 491.4 mmol) was added to a stirred suspension of 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carbonitrile [CAS: 951232-17-0] (8.3 g, 31.53 mmol) in methanol (248 mL). The stirred mixture was heated at block temperature of 80° C. for 20 h. The reaction mixture was cooled to ambient temperature, diluted with DCM (500 ml) and Na2CO3 solid was added with stirring. Water (500 ml) was added and the mixture transferred to a separating funnel and shaken (aqueous phase had pH10). The aq. phase was re-extracted with DCM (200 ml) and the combined organic layers were dried (Na2SO4) and evaporated to an oil which solidified, to give 7.6 g after drying. This was dissolved in DCM (30 ml) and the solution was applied to a 340 g silica cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc/iso-hexane from 0-75% to give methyl 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carboxylate (D29) (6.1 g, approximately 94% pure, contaminated with decarboxylated material);

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. additionwas added
  3. customthe mixture transferred to a separating funnel
  4. extractionThe aq. phase was re-extracted with DCM (200 ml)
  5. dry with materialthe combined organic layers were dried (Na2SO4)
  6. customevaporated to an oil which
  7. customto give 7.6 g
  8. customafter drying
  9. dissolutionThis was dissolved in DCM (30 ml)
  10. washwas then eluted on a Biotage SP4 system with a gradient of EtOAc/iso-hexane from 0-75%

Sources & evidence

ORD record
ord-5af05b864aa940ceaa4065926d01a251
Source dataset
uspto-grants-2016_04
Patent number
US09309254B2

Reaction notes

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