Methanol → HCID 16730263, compound

HRID 895657Notes

Reaction equation

HRID 895657 reaction equation
[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:23]4=[C:24]([CH2:31][CH3:32])[C:25]([C:27]([O:29]C)=[O:28])=[CH:26][N:22]4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:23]4=[C:24]([CH2:31][CH3:32])[C:25]([C:27]([OH:29])=[O:28])=[CH:26][N:22]4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 887MethanolHCID 168937Lithium hydroxide, monohydrateHCID 22379831HCID 22379831, compound

Product 1

HCID 16730263HCID 16730263, compoundYield 59%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Methyl 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (51.3 g, 0.12 mol) was dissolved in THF (750 mL) and the solution added to a 2 L round bottomed flask equipped with a reflux condenser. Methanol (250 mL) was then added to the flask followed by a solution of lithium hydroxide monohydrate (60.8 g, 1.45 mol) in water (300 mL). The reaction was then heated to reflux for 20 hrs. HPLC analysis of the mixture after this time indicated that the reaction was complete. The reaction was then cooled and the mixture concentrated under reduced pressure. Water (200 mL) was then added to the residue and the resulting solution extracted with ethyl acetate (2×100 mL). Hydrochloric acid (2N) was then added to the aqueous solution until a pH of 3-4 was obtained. This resulted in the formation of a thick white precipitate, which was filtered off. The filter cake was then slurried in ethyl ether (1 L), re-filtered and dried, affording 29.2 g of 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid. The filtrate was combined with the original ethyl acetate extract and the solvents removed under reduced pressure. Purification of the residue by trituration with a 2:1 mixture of ether and ethyl acetate (500 mL) followed by filtration and drying, afforded a further 13.4 g of the desired acid. The combined total yield of 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid was 42.6 g (86%) and the material had an HPLC purity of 98.2%.

Workup

  1. additionthe solution added to a 2 L round bottomed flask
  2. customequipped with a reflux condenser
  3. temperatureThe reaction was then heated
  4. temperatureto reflux for 20 hrs
  5. temperatureThe reaction was then cooled
  6. concentrationthe mixture concentrated under reduced pressure
  7. additionWater (200 mL) was then added to the residue
  8. extractionthe resulting solution extracted with ethyl acetate (2×100 mL)
  9. additionHydrochloric acid (2N) was then added to the aqueous solution until a pH of 3-4
  10. customwas obtained
  11. customThis resulted in the formation of a thick white precipitate, which
  12. filtrationwas filtered off
  13. filtrationre-filtered
  14. customdried

Sources & evidence

ORD record
ord-acfe86cc6dc94f7e9af9a5092e9a577c
Source dataset
uspto-grants-2005_07
Patent number
US06916815B2

Reaction notes

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