Morpholine → 3-(4-Chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

HRID 500946Notes

Reaction equation

HRID 500946 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19]OCC1.CC[N:23](CC)CC.[Cl:28][C:29]1[CH:37]=[CH:36]C(C(Cl)=O)=[CH:31][C:30]=1[CH3:38]>C1C=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:23][N:15]=[C:20]([C:19]3[CH:36]=[CH:37][C:29]([Cl:28])=[C:30]([CH3:38])[CH:31]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

10

Reactant 4

HCID 8083MorpholineHCID 8471TriethylamineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 130583754-Chloro-3-methylbenzoyl chloride

Product 1

HCID 684601723-(4-Chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl esterYield 52.1%

Reagents, catalysts & solvents 5

HCID 6101p-Toluenesulfonic acidCatalystHCID 241BenzeneSolventHCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 55.8 g (0.28 mol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 25.7 g (0.29 mol) of morpholine in benzene (125 mL) was added a catalytic amount (˜0.25 g) of p-toluenesulfonic acid. The mixture was heated to reflux for 10 h under a Dean-Stark trap. The solvent was removed under reduced pressure to give a brown oil. The crude product was diluted with CH2Cl2 (400 mL), and 46.83 mL (0.34 mol) of Et3N was added. The mixture was cooled to 0° C., and a solution of 4-chloro-3-methyl-benzoyl chloride (0.35 mol) in CH2Cl2 (200 mL) was added slowly by dropping funnel over 2 h. The reaction mixture was poured over water (400 mL) and the CH2Cl2 layer was separated, dried (Na2SO4), and concentrated. The resulting oil was taken up in EtOH (400 mL) and treated with 35 mL of hydrazine at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 17 h, during which time a white precipitate formed. The volume of the reaction mixture was reduced to ˜150 mL, and Et2O (750 mL) was added. The suspension was stirred vigorously for 2 h and was filtered then washed with Et2O (2×200 mL) and dried under vacuum to afford 50.74 g (52% over 3 steps) of 3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester as a pale orange solid. MS (electrospray): exact mass calculated for C18H22ClN3O2, 347.1; m/z found, 348.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.26-7.43 (m, 4H), 4.65 (br s, 2H), 3.73 (br s, 2H), 2.77 (br s, 2H), 2.34 (s, 3H), 1.49 (s, 9H).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 10 h under a Dean-Stark trap
  3. customThe solvent was removed under reduced pressure
  4. customto give a brown oil
  5. additionwas added
  6. customover 2 h
  7. customthe CH2Cl2 layer was separated
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. additiontreated with 35 mL of hydrazine at 0° C
  11. temperatureto warm to room temperature
  12. customformed
  13. additionwas added
  14. stirringThe suspension was stirred vigorously for 2 h
  15. filtrationwas filtered
  16. washthen washed with Et2O (2×200 mL)
  17. customdried under vacuum

Sources & evidence

ORD record
ord-118ad51c3b444752b125fcefdc8d4d31
Source dataset
uspto-grants-2010_08
Patent number
US07772236B2

Reaction notes

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