Thiophene-2-carbohydrazide → Tofimilast

HRID 2268146Notes

Reaction equation

HRID 2268146 reaction equation
[CH:1]1([N:6]2[C:10]3[C:11](OCC)=[N:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:27][NH2:28])=O>C(O)CCC>[CH:1]1([N:6]2[C:10]3[C:11]4[N:12]([C:25]([C:21]5[S:20][CH:24]=[CH:23][CH:22]=5)=[N:27][N:28]=4)[CH2:13][CH2:14][C:9]=3[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

4

Reactant 2

HCID 73098Thiophene-2-carbohydrazideHCID 98457511H-PYRAZOLO[3,4-C]PYRIDINE, 1-CYCLOPENTYL-7-ETHOXY-3-ETHYL-4,5-DIHYDRO-

Product 1

HCID 9896267Tofimilast

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

A solution of 1cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine (3.739 kg, 14.3 moles) and 2thiophenecarboxylic hydrazide (2.237 kg, 15.8 moles) were heated in a solution in 1-butanol (37 L) to ˜90° C. in a 50 gal tank for 48 hours. At this point, some 1-butanol was distilled off to remove water azeotropically. The reaction was concentrated to a low volume and 4 gallons of methylene chloride (4 gal, 15 L) was added. The organics were washed twice with 1 N HCl (8 gal, 30.3 L) and concentrated by distillation to low volume. Isopropanol (16 L) was added to the concentrate and the resulting slurry was cooled and granulated. The product was collected by filtration and vacuum oven dried at 40° C. The yield was 3.25 kg (67%) of a white solid; mp 126° C.

Workup

  1. distillationAt this point, some 1-butanol was distilled off
  2. customto remove water azeotropically
  3. concentrationThe reaction was concentrated to a low volume and 4 gallons of methylene chloride (4 gal, 15 L)
  4. additionwas added
  5. washThe organics were washed twice with 1 N HCl (8 gal, 30.3 L)
  6. concentrationconcentrated by distillation to low volume
  7. additionIsopropanol (16 L) was added to the
  8. concentrationconcentrate
  9. temperaturethe resulting slurry was cooled
  10. filtrationThe product was collected by filtration and vacuum oven
  11. customdried at 40° C

Sources & evidence

ORD record
ord-123c1ba390b146a79b3e0218c909ca3c
Source dataset
uspto-grants-2001_12
Patent number
US06326495B2

Reaction notes

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