2-Mercaptobenzoic Acid → 4-[(R)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide

HRID 237894Notes

Reaction equation

HRID 237894 reaction equation
C([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:12]2[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)C=C.C(O)(=O)C1C(=CC=CC=1)S>O1CCCC1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][C@H:6]1[CH2:5][NH:4][C@H:9]([CH3:10])[CH2:8][N:7]1[C@@H:11]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1

Participants

5

Reactant 2

HCID 54432-Mercaptobenzoic AcidHCID 119029rel-4-((R)-((2S,5R)-2,5-Dimethyl-4-(2-propen-1-yl)-1-piperazinyl)(3-hydroxyphenyl)methyl)-N,N-diethylbenzamide

Product 1

HCID 153522344-[(R)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamideYield 103.6%

Reagents, catalysts & solvents 2

HCID 821241,4-Bis(diphenylphosphino)butaneCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 4-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)-methyl]-N,N-diethylbenzamide (10.89 g, 25 mmol, from Method A) and thiosalicylic acid (4.63 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred with a catalyst solution prepared by dissolution of bis(dibenzylidineacetone)palladium (0.718 g, 1.25 mmol) and 1,4-bis(diphenylphosphino)butane (0.533 g, 1.25 mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen for 1.5 hours (J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270 (1995)). The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and aqueous sodium carbonate solution. The layers were separated and diethyl ether (250 mL) was added to the organic layer. This was extracted with 5% sodium carbonate solution (2×150 mL). The organic layer was diluted with pentane (500 mL) and extracted with 3 M hydrochloric acid (6×30 mL). The aqueous solution was adjusted to pH 9-10 with saturated aqueous sodium carbonate solution and extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide as a brittle pale yellow foam (10.24 g). The product showed a single peak on HPLC (Zorbax C-8, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 5 min; 1.0 mL/min; δobs=210 nm, Rt=19.24 min). Calc. for C24H33N3O2. 0.1 EtOAc. 0.4 CH2Cl2: % C, 67.96; H, 7.96; N, 9.59. Found: % C, 67.90; H, 8.03; N, 9.54. 1H NMR (CDCl3, 300 MHz): δ7.42 (d, J=8.1 Hz, 2H); 7.2 (d, J=8.3 Hz, 2H); 7.11 (t, J=7.8 Hz, 1H); 6.72 (d, J=8.1 Hz, 1H); 6.65 (s, 1H); 6.59 (d, J=7.6 Hz, 1H); 5.16 (s, 1H); 4.93 (v br s, 2H); 3.51 (br m, 2H); 3.27 (br m, 2H); 3.02-2.97 (m, 1H); 2.92 (d, J=10.5 Hz, 1H); 2.66 (br d, J=8.5 Hz, 2H); 2.60-2.45 (m, 1H); 1.84 (dd, J=11.3, 8.3 Hz, 1H); 1.27-1.15 (m, 3H); 1.10 (d, J=6.1 Hz, 3H overlapping with m, 3H); 1.02 (d, J=6.1 Hz, 3H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customthe residue was partitioned between ethyl acetate (150 mL) and aqueous sodium carbonate solution
  3. customThe layers were separated
  4. additiondiethyl ether (250 mL) was added to the organic layer
  5. extractionThis was extracted with 5% sodium carbonate solution (2×150 mL)
  6. additionThe organic layer was diluted with pentane (500 mL)
  7. extractionextracted with 3 M hydrochloric acid (6×30 mL)
  8. extractionextracted with methylene chloride (3×100 mL)
  9. dry with materialThe combined organic extracts were dried over anhydrous sodium sulfate
  10. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-c4b37a2c88b64c76be8020cfc0d5feb0
Source dataset
uspto-grants-2014_02
Patent number
US08642599B2

Reaction notes

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