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

HRID 271757노트

반응식

HRID 271757 반응식
[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]

참가 물질

10

반응물 4

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

생성물 1

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

시약·촉매·용매 5

HCID 6101p-Toluenesulfonic acid촉매HCID 241Benzene용매HCID 962Water용매HCID 3283Diethyl Ether용매HCID 6344Dichloromethane용매2회

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온도
0 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-f95348194c2e40229624ef1ba55d661f
출처 데이터셋
uspto-grants-2008_11
특허 번호
US07452890B2

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