2-Mercaptobenzoic Acid → 4-((alpha-s)-alpha-((2s,5r)-2,5-Dimethyl-1-piperazinyl)benzyl)-n,n-diethylbenzamide

HRID 538258Notes

Reaction equation

HRID 538258 reaction equation
C([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:6]([CH3:31])[CH2:5]1)C=C.C(O)(=O)C1C(=CC=CC=1)S.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:31][C@H:6]1[CH2:5][NH:4][C@H:9]([CH3:10])[CH2:8][N:7]1[C@H:11]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:29][CH:30]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

5

Reactant 3

HCID 54432-Mercaptobenzoic AcidHCID 821241,4-Bis(diphenylphosphino)butaneHCID 66048784-[(S)-[(2S,5R)-2,5-Dimethyl-4-(2-propenyl)-1-piperazinyl]phenylmethyl]-N,N-diethylbenzamide

Product 1

HCID 102158644-((alpha-s)-alpha-((2s,5r)-2,5-Dimethyl-1-piperazinyl)benzyl)-n,n-diethylbenzamideYield 45.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

The compound of Example 1 was de-allylated by the method of Genet [J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270 (1995)] as follows. A solution of 4-((alpha-S)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (Example 1, 8.392 g, 20 mmol) and thiosalicylic acid (3.70 g, 24 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred under nitrogen for 3 h at room temperature with a catalyst solution prepared by dissolution of bis(dibenzylidineacetone)palladium (575 mg, 1.0 mmol) and 1,4-bis(diphenylphosphino)butane (426 mg, 1.0 mmol) in tetrahydrofuran (10 mL). The reaction mixture was evaporated to dryness, the residue dissolved in a mixture of ethyl acetate/ether (1:3, 300 mL) and extracted with 5% sodium carbonate solution (2×300 mL). The organic layer was diluted with two volumes of pentane and extracted with 3M-hydrochloric acid (6×50 mL). The aqueous solution was filtered to remove suspended solid and the pH adjusted to 12 with 5-M NaOH. The resulting oily suspension was extracted with methylene chloride (2×125 mL) and the combined organic extracts dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate to yield fine white needles of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (3.46 g). The product showed a single spot on thin layer chromatography (silica gel, EM60F264, 4% NH4OH/10% EtOH in ethyl acetate, Rf=0.47). 1H NMR (CDCl3, 600 MHz); δ 0.93 (d, J=6.3 Hz, 3H); 1.12 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H); 1.24 (br m, 3H); 1.55 (dd, J=9.7, 11.3 Hz, 1H, partially obscured by br m, 2H); 2.33 (m, 1H); 2.68 (m, 2H); 2.89 (m, 1H); 2.92 (dd, J=12.1, 3.1 Hz, 1H); 3.29 (br m, 2H); 3.54 (br m, 2H); 5.38 (s, 1H); 7.14 (m, 2H); 7.30 (m, 3H); 7.35 (m, 2H); 7.46 (d, J=7.8 Hz, 2H).

Workup

  1. customThe reaction mixture was evaporated to dryness
  2. dissolutionthe residue dissolved in a mixture of ethyl acetate/ether (1:3, 300 mL)
  3. extractionextracted with 5% sodium carbonate solution (2×300 mL)
  4. additionThe organic layer was diluted with two volumes of pentane
  5. extractionextracted with 3M-hydrochloric acid (6×50 mL)
  6. filtrationThe aqueous solution was filtered
  7. customto remove
  8. extractionThe resulting oily suspension was extracted with methylene chloride (2×125 mL)
  9. dry with materialthe combined organic extracts dried over anhydrous sodium sulfate
  10. customevaporated to dryness
  11. customThe residue was crystallized from ethyl acetate

Sources & evidence

ORD record
ord-db68b830b0ce4a6d9cf16265e7add65e
Source dataset
uspto-grants-2014_10
Patent number
US08865721B2

Reaction notes

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