Sodium Acetate → HCID 178469931, compound

HRID 1067392Notes

Reaction equation

HRID 1067392 reaction equation
[NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:21]=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+].C1(OC2(OC)C=CC=C(C=O)C2)CCCC1>CO.C(O)(=O)C.CO.C(Cl)Cl>[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:21][NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1

Participants

9

Reactant 5

HCID 517045Sodium AcetateHCID 27358933-Cyclopentyloxy-4-methoxybenzaldehyde3×HCID 5003444Sodium cyanoborohydrideHCID 21193735HCID 21193735, compoundHCID 178469928HCID 178469928, compound

Product 1

HCID 178469931HCID 178469931, compound

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolvent5×HCID 887MethanolSolvent2×HCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of ethyl 3-aminopyrazole 4-carboxylate (70 g, 0.45 mol) and 3-cyclopentyloxy-4-methoxybenzaldehyde (100 g, 0.45 mol) in methanol (400 mL) was treated with sodium cyanoborohydride (19.0 g, 0.30 mol) and sodium acetate (2.0 g, 0.024 mol) in a stirred reaction vessel equipped with pH stat attached to a syringe pump and a syringe filled with 3 N acetic acid in methanol. The pH stat was set to maintain pH 7. The acetic acid solution was added as the reaction proceeded. After 24 hours, 169 mL of acetic acid solution had been added and no aldehyde remained- in the reaction mixture by TLC (silica gel, 10% methanol/methylene chloride) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (19.0 g, 0.086 mol) was added to the reaction mixture. After 30 hours, a total of 216 mL of acetic acid solution had been added and 3-cyclopentyloxy-4-methoxybenzaldehyde (16 g, 0.072 mol) was added to the reaction mixture. After 48 hours, 263 mL of acetic acid solution had been added and additional 3-cyclopentyloxy-3-methoxybenzaldehyde (29 g, 0.13 mol) was added to the reaction mixture. After 76 hours, 320 mL of acetic acid solution had been consumed and the reaction mixture was evaporated under reduced pressure. The residue was partitioned between water (400 mL) and ethyl acetate (400 mL) and the ethyl acetate was evaporated under reduced pressure to give 240 g of crude product. The crude product was purified by flash chromatography over 900 g of flash chromatography silica gel and eluted with methanol-methylene chloride mixtures. Elution with pure methylene chloride afforded by-product 3-cyclopentyloxy-4-methoxybenzyl alcohol. Elution with 1-25% methanol-methylene chloride gave 91 g (42%) of nearly pure ethyl 3-(3-cyclopentyloxy-4-methoxybenzyl-amino)pyrazole-4-carboxylate. A portion of this ethyl 3-(3-cyclopentyloxy-4-methoxybenzylamino)pyrazole carboxylate (29 g) was recrystallized from methyl t-butyl ether to give 16.8 g of pure ethyl 3-(3-cyclopentyloxy-4-methoxybenzyl-amino) pyrazole-4-carboxylate, mp 102-104°.

Workup

  1. customequipped
  2. customattached to a syringe
  3. temperatureto maintain pH 7
  4. waitAfter 30 hours
  5. waitAfter 48 hours
  6. waitAfter 76 hours
  7. custom320 mL of acetic acid solution had been consumed
  8. customthe reaction mixture was evaporated under reduced pressure
  9. customThe residue was partitioned between water (400 mL) and ethyl acetate (400 mL)
  10. customthe ethyl acetate was evaporated under reduced pressure
  11. customto give 240 g of crude product
  12. customThe crude product was purified by flash chromatography over 900 g of flash chromatography silica gel
  13. washeluted with methanol-methylene chloride mixtures
  14. washElution with pure methylene chloride afforded by-product 3-cyclopentyloxy-4-methoxybenzyl alcohol
  15. washElution with 1-25% methanol-methylene chloride

Sources & evidence

ORD record
ord-a89be2c72d514b0d83722ac2ad3931a0
Source dataset
uspto-grants-2001_06
Patent number
US06248769B1

Reaction notes

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