Acetic Acid → 3-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl} benzoic acid

HRID 2249468Notes

Reaction equation

HRID 2249468 reaction equation
[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@@H:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.[C:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([OH:32])=[O:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:17]([N:16]([CH2:19][CH3:20])[C:14]([C:13]1[CH:21]=[CH:22][C:10]([C@H:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[N:3]2[C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:36][C:35]3[CH:34]=[C:33]([CH:40]=[CH:39][CH:38]=3)[C:30]([OH:32])=[O:31])[C@H:5]([CH3:8])[CH2:4]2)=[CH:11][CH:12]=1)=[O:15])[CH3:18]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 120773-CarboxybenzaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 153522344-[(R)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide

Product 1

HCID 596395093-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl} benzoic acidYield 46.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

The 4-[(R)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (2.50 g, 6.32 mmol) and 3-carboxybenzaldehyde (1.90 g, 12.64 mmol) were placed in a 250 mL flask with 60 mL of tetrahydrofuran and 0.80 mL (13.91 mmol) of acetic acid. The reaction was stirred at room temperature for 20 minutes, and sodium triacetoxyborohydride (2.68 g, 12.64 mmol) was added portionwise. The reaction solution became very turbid and was sealed under mntrogen and stirred overnight. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (60 mL) and 3M HCl (12 mL). The organic layer was extracted with a further 5×12 mL 3M HCl. The combined aqueous extracts were adjusted to pH 4.5-5 with 0.5 M NaOH solution and solid Na2CO3 The resulting gel was collected by filtration, dissolved in 30 mL of 0.5 M NaOH solution, and extracted with 20 mL of EtOAc/Et2O twice to remove impurities. 1M HCl was added dropwise to the aqueous solution to the precipitation point at pH 4.5-5. The resulting white gel was collected by filtration and washed with a small volume of cold water. The 3-{(2R,5S)-4-[(R)-(4-diethylcarbamoylphenyl)-(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoic acid was dried in a vacuum oven (30 mmHg, 40° C.) to give 1.55 g of white solid. 1 H NMR (300 MHz, d6-DMSO): δ 0.99-1.20 (m, 12H); 1.89-2.05 (m, 2H); 2.48-2.65 (m, 5H); 3.06-3.57 (m, 5H); 3.78-3.83 (d, J=12.5 Hz, 1H); 4.94 (s, 1H); 6.63-6.84 (m, 3H); 7.09-7.91 (m, 9H); 9.36 (s, 1H).

Workup

  1. customwas sealed under mntrogen
  2. stirringstirred overnight
  3. customThe reaction mixture was evaporated to dryness
  4. custompartitioned between ethyl acetate (60 mL) and 3M HCl (12 mL)
  5. extractionThe organic layer was extracted with a further 5×12 mL 3M HCl
  6. filtrationwas collected by filtration
  7. dissolutiondissolved in 30 mL of 0.5 M NaOH solution
  8. extractionextracted with 20 mL of EtOAc/Et2O twice
  9. customto remove impurities
  10. addition1M HCl was added dropwise to the aqueous solution to the precipitation point at pH 4.5-5
  11. filtrationThe resulting white gel was collected by filtration
  12. washwashed with a small volume of cold water
  13. dry with materialThe 3-{(2R,5S)-4-[(R)-(4-diethylcarbamoylphenyl)-(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoic acid was dried in a vacuum oven (30 mmHg, 40° C.)

Sources & evidence

ORD record
ord-40b65533983a4ebd95c71f4a1ad61961
Source dataset
uspto-grants-2008_01
Patent number
US07314880B2

Reaction notes

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