Acetic Acid → 1-{3-[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

HRID 132921Notes

Reaction equation

HRID 132921 reaction equation
C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:57][CH2:58]C=O)[N:45]=[C:46]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)[C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:57][CH2:58][CH2:6][N:8]3[CH2:9][CH2:10][N:11]([C:14]4[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:23])[CH2:12][CH2:13]3)[N:45]=[C:46]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:51][CH:52]=3)[C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 587677041-Boc-4-(2-chloro-6-nitrophenyl)piperazineHCID 865848181-(3-Oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

Product 1

HCID 684630981-{3-[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl esterYield 92%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (940 mg, 2.75 mmol) in 10 mL of CH2Cl2 was treated with 5 mL of trifluoroacetic acid and stirred at 25° C. for 1 h. The volatiles were then removed. The residue was taken up in CH2Cl2 (60 mL) and KOH (4 N, 20 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The yellow oil was dissolved in CH2Cl2 and added into the 996 mg (2.35 mmol) of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester. The yellow solution was treated with glacial acetic acid (0.8 mL, 6 eq) and stirred at 25° C. for 1 h. NaBH(OAc)3 (1.5 g, 7.05 mmol) was added and stirred under nitrogen for 2 h. Then saturated NaHCO3 (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Column chromatography (silica, 2-5% MeOH/CH2Cl2) afforded 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester as a white solid (1.40 g, 92%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C31H36ClF3N6O4, 648.24; m/z found 649.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.69 (d, J=8.2 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.37 (m, 4H), 7.02 (t, J=8.2 Hz, 1H), 4.58 (br s, 2H), 4.04 (t, J=6.7 Hz, 2H), 3.73-3.65 (m, 2H), 3.05-2.95 (m, 4H), 2.71 (t, J=5.6 Hz, 2H), 2.50-2.35 (m, 4H), 2.30 (t, J=6.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.41 (s, 9H).

Workup

  1. customThe volatiles were then removed
  2. customThe organic layer was separated
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. dissolutionThe yellow oil was dissolved in CH2Cl2
  6. stirringstirred at 25° C. for 1 h
  7. stirringstirred under nitrogen for 2 h
  8. stirringstirred for 30 min
  9. customthe layers were separated
  10. extractionThe organic extract
  11. washwas washed with brine
  12. dry with materialdried over Na2SO4
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-a77fad4b940f406f96b85c5b4d87672a
Source dataset
uspto-grants-2008_06
Patent number
US07388011B2

Reaction notes

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