Acetic Acid → Ard-353

HRID 2249465Notes

Reaction equation

HRID 2249465 reaction equation
C(O)(=O)C.[CH3:5][C@H:6]1[CH2:11][NH:10][C@H:9]([CH3:12])[CH2:8][N:7]1[C@@H:13]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.[C:34]([C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1)([OH:36])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:21]([N:20]([CH2:23][CH3:24])[C:18]([C:17]1[CH:25]=[CH:26][C:14]([C@H:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[N:7]2[C@@H:6]([CH3:5])[CH2:11][N:10]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[C@H:9]([CH3:12])[CH2:8]2)=[CH:15][CH:16]=1)=[O:19])[CH3:22]

Participants

6

Reactant 4

HCID 176Acetic Acid2×HCID 120884-Formylbenzoic acid2×HCID 5049666Sodium triacetoxyborohydride2×HCID 153522344-[(R)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide

Product 1

HCID 9958625Ard-353Yield 88.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Glacial acetic acid (0.635 mL, 11.1 mmol) was added to a solution of 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (1.98 g, 5 mmol) and 4-carboxybenzaldehyde (1.50 g, 10 mmol) in anhydrous tetrahydrofuran (35 mL. While stirring briskly, sodium triacetoxyborohydride (2.12 g, 10 mmol) was added in 50-100 mg portions, allowing effervescence to subside after each addition. The reaction was monitored for absence of starting material by HPLC. After stirring at room temperature for 16 hours, more 4-carboxybenzaldehyde (0.75 g, 5 mmol), acetic acid (0.318 mL, 5 mmol), and sodium triacetoxyborohydride (1.06 g, 5 mmol) was added. After stirring an additional 4 hours, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and 3 M hydrochloric acid (10 mL). The layers were separated and the organic layer was extracted again with 3 M hydrochloric acid (5×10 mL). The aqueous solution was adjusted to pH 4.5-5 with saturated aqueous sodium carbonate solution and extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 4-{(2R, 5S)-4-[(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinyl-methyl}benzoic acid as a brittle white foam (2.34 g). The product showed a single peak on HPLC (Zorbax RX-C8, 4.6 mm×25 cm, 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; λobs=210 nm, Rt=13.75 min).

Workup

  1. additionafter each addition
  2. stirringAfter stirring at room temperature for 16 hours
  3. stirringAfter stirring an additional 4 hours
  4. concentrationthe reaction mixture was concentrated under reduced pressure
  5. customthe residue was partitioned between ethyl acetate (50 mL) and 3 M hydrochloric acid (10 mL)
  6. customThe layers were separated
  7. extractionthe organic layer was extracted again with 3 M hydrochloric acid (5×10 mL)
  8. extractionextracted with methylene chloride (3×50 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-fa3f7e4ae6584713a32a284a523b1cd4
Source dataset
uspto-grants-2008_01
Patent number
US07314880B2

Reaction notes

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