4-Formylbenzoic acid → Bavisant

HRID 604260Notes

Reaction equation

HRID 604260 reaction equation
[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(C1C=C[C:25]([C:26]([OH:28])=O)=CC=1)=O.S(Cl)(Cl)=O.[OH-].[Na+].Cl.Cl.[CH:39]1([N:42]2CCNCC2)C[CH2:40]1>C1(C)C=CC=CC=1.O.CN(C)C=O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH2:16][N:42]4[CH2:25][CH2:26][O:28][CH2:40][CH2:39]4)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1

Participants

9

Reactant 5

HCID 120884-Formylbenzoic acidHCID 14798Sodium Hydroxide2×HCID 24386Thionyl ChlorideHCID 212208121-Cyclopropylpiperazine dihydrochlorideHCID 592181834-(4-Cyclopropyl-piperazine-1-carbonyl)-benzaldehyde

Product 1

HCID 16061509BavisantYield 62%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

4-(4-Cyclopropyl-piperazine-1-carbonyl)-benzaldehyde. A mixture of 4-formyl-benzoic acid (54.4 g), toluene (500 mL), N,N-dimethylformamide (DMF) (3.6 mL), and thionyl chloride (30.4 mL) was heated at 60° C. for 2 h and then was cooled to 5° C. In a separate flask, a 5° C. mixture of NaOH (50.7 g), water (550 mL), and toluene (150 mL) was treated with 1-cyclopropyl-piperazine dihydrochloride (70.0 g) in portions while the temperature was maintained below 10° C. After the addition was complete, the mixture was cooled to 5° C. and treated with the crude acyl chloride solution prepared as above at a rate such that the temperature did not exceed 10° C. After the addition was complete, the mixture was allowed to warm to rt and was stirred overnight. The biphasic mixture was basified to pH ˜10 with 1 N NaOH (300 mL). The layers were separated and the aqueous layer was extracted with toluene (100 mL×2). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to give the title compound as pale yellow viscous oil (56.0 g, 62%). HPLC: RT=5.19 min. MS (ESI): mass calcd. for C15H18N2O2, 258.14; m/z found, 258.9 [M+H+]. 1H NMR (400 MHz, CDCl3): 10.1 (s, 1H), 7.94 (pseudo d, J=8.2 Hz, 2H), 7.56 (pseudo d, J=8.1 Hz, 2H), 3.77 (br s, 2H), 3.33 (br s, 2H), 2.71 (br s, 2H), 2.55 (br s, 2H), 1.66 (ddd, J=10.2, 6.6, 3.7 Hz, 1H), 0.52-0.46 (m, 2H), 0.45-0.40 (br s, 2H).

Workup

  1. temperaturewas cooled to 5° C
  2. temperaturewas maintained below 10° C
  3. additionAfter the addition
  4. temperaturethe mixture was cooled to 5° C.
  5. customdid not exceed 10° C
  6. additionAfter the addition
  7. temperatureto warm to rt
  8. customThe layers were separated
  9. extractionthe aqueous layer was extracted with toluene (100 mL×2)
  10. washThe combined organic layers were washed with brine (200 mL)
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-5ec5521021594e45bf3f2412eefacf84
Source dataset
uspto-grants-2011_03
Patent number
US07910582B2

Reaction notes

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