3-Aminobenzoic Acid → Ammonia methanol

HRID 2370949Notes

Reaction equation

HRID 2370949 reaction equation
Cl.ClC1N=C(NC2CC(C)(C)NC(C)(C)C2)C(F)=C[N:4]=1.[CH:21]1([C:24]2[C:29]([N:30]3[CH:34]=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH2:35])=[C:26]([F:36])[CH:25]=2)[CH2:23][CH2:22]1.N1C=NN=N1.Cl[C:43]1[N:48]=[C:47]([NH:49][CH:50]2[CH2:55][C:54]([CH3:57])([CH3:56])[NH:53][C:52]([CH3:59])([CH3:58])[CH2:51]2)[C:46]([F:60])=[CH:45][N:44]=1.NC1C=C(C=CC=1)[C:65](O)=[O:66].N1C=CC=NC=1>CC(O)C>[NH3:4].[CH3:65][OH:66].[CH:21]1([C:24]2[C:29]([N:30]3[CH:34]=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH:35][C:43]3[N:48]=[C:47]([NH:49][CH:50]4[CH2:51][C:52]([CH3:58])([CH3:59])[NH:53][C:54]([CH3:57])([CH3:56])[CH2:55]4)[C:46]([F:60])=[CH:45][N:44]=3)=[C:26]([F:36])[CH:25]=2)[CH2:23][CH2:22]1

Participants

9

Reactant 6

HCID 74193-Aminobenzoic AcidHCID 9260PyrimidineHCID 58065786HCID 58065786, compoundHCID 59442725HCID 59442725, compoundHCID 86653878HCID 86653878, compoundHCID 178418441HCID 178418441, compound

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 56644100HCID 56644100, compound

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine hydrochloride (6.68 g, 20.68 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (6.80 g, 31.02 mmol, 1.5 equiv), and PTSA monohydrate (3.15 g, 16.54 mmol, 0.8 equiv) in IPA (200 mL) were heated to 70° C. for 4 days. LCMS indicated 2-4% of the cleaved tetrazole product and 7-9% unreacted 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine. After cooling the reaction mixture to ambient temperature, 3-amino benzoic acid (8.51 g, 62.04 mmol, 3 equiv) was added and heated to 70° C. for overnight to scavenge the unreacted pyrimidine. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The residue was taken in ice-cold water and EtOAc then adjusted to ca. pH 12-14 with 1N NaOH (300 mL). The aqueous and organic layers were partitioned, and the organic layer washed with 1N NaOH (2×300 mL). The aqueous layer was extracted with EtOAc (1×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and the solvent removed under vacuum. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 96:4 using 1% 2M NH3/MeOH increments to provide the desired product which was triturated with EtOAc/hexane to give the title compound (5.16 g, 53%) as a solid.

Workup

  1. temperatureAfter cooling the reaction mixture to ambient temperature
  2. temperatureheated to 70° C. for overnight
  3. temperatureAfter cooling to ambient temperature
  4. concentrationthe crude mixture was concentrated to dryness
  5. customThe aqueous and organic layers were partitioned
  6. washthe organic layer washed with 1N NaOH (2×300 mL)
  7. extractionThe aqueous layer was extracted with EtOAc (1×150 mL)
  8. dry with materialThe combined organic extracts were dried (Na2SO4)
  9. filtrationfiltered
  10. customthe solvent removed under vacuum
  11. customThe crude product was purified by flash chromatography
  12. washeluted with DCM

Sources & evidence

ORD record
ord-83f95e61ebe04fbb8b900c478585a459
Source dataset
uspto-grants-2014_04
Patent number
US08710223B2

Reaction notes

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