Hydrochloric Acid → Piclamilast

HRID 1870339Notes

Reaction equation

HRID 1870339 reaction equation
[H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O1CCCC1.ClCCl>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:19]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 898884-Amino-3,5-dichloropyridineHCID 27946003-(Cyclopentyloxy)-4-methoxybenzoyl chloride

Product 1

HCID 154575Piclamilast

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
10 °C

Procedure

A suspension of sodium hydride (60% dispersion in oil; 2.2 g) in dry tetrahydrofuran (25 mL) at 15-20° C. is treated portionwise with a solution of 4-amino-3,5-dichloropyridine (4.5 g; that is prepared as described in Reference Example 5) in dry tetrahydrofuran (40 mL), with cooling. The mixture is stirred for a further 30 minutes, and then it is cooled to 10° C. and treated with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.4 g) in dry tetrahydrofuran (40 mL), dropwise, during 45 minutes at 10° C. The mixture is stirred at 10° C. for 30 minutes and is then treated with dilute hydrochloric acid (50 mL; 1 N), followed by dichloromethane (75 mL). The layers are separated and the aqueous layer is washed with a further quantity of dichloromethane (25 mL). The combined organic layers are washed with water (50 mL), with saturated aqueous sodium bicarbonate solution (100 mL), and with water (50 mL), dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized from isopropanol, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (7.0 g).

Workup

  1. customthat is prepared
  2. temperaturewith cooling
  3. waitdropwise, during 45 minutes at 10° C
  4. stirringThe mixture is stirred at 10° C. for 30 minutes
  5. customThe layers are separated
  6. washthe aqueous layer is washed with a further quantity of dichloromethane (25 mL)
  7. washThe combined organic layers are washed with water (50 mL), with saturated aqueous sodium bicarbonate solution (100 mL)
  8. dry with materialwith water (50 mL), dried over magnesium sulfate
  9. customevaporated to dryness
  10. customThe resulting residue is recrystallized from isopropanol

Sources & evidence

ORD record
ord-08d37031a25a4cff880b9fbdcb069ed5
Source dataset
uspto-grants-2000_08
Patent number
US06096768

Reaction notes

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