Acetic Acid → Apremilast, (+-)-

HRID 1050730Notes

Reaction equation

HRID 1050730 reaction equation
C(N[C@H](C(O)=O)CC(C)C)(=O)C.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C@H:24]([NH2:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14].[C:31]([NH:34][C:35]1[CH:45]=[CH:44][CH:43]=[C:37]2[C:38]([O:40][C:41](=O)[C:36]=12)=[O:39])(=[O:33])[CH3:32].C(O)(=O)C.C=CCl>CCO>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:24]([N:30]2[C:41](=[O:40])[C:36]3[C:37](=[CH:43][CH:44]=[CH:45][C:35]=3[NH:34][C:31](=[O:33])[CH3:32])[C:38]2=[O:39])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 6338Vinyl ChlorideHCID 2261213-Acetamidophthalic AnhydrideHCID 66648136L-Leucine, N-acetyl-, compd. with (alphaS)-3-ethoxy-4-methoxy-alpha-((methylsulfonyl)methyl)benzenemethanamine (1:1)

Product 1

HCID 10151715Apremilast, (+-)-Yield 75%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50° C. After the solvent was removed in vacuum, the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqueous NaHCO3 (250 mL×2), and brine (250 mL×2), and then dried over anhydrous sodium sulfate. After the solvent was evaporated in vacuum, the residue was recrystallized from a binary solvent containing a mixture of ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuum at 60° C. to a constant weight, affording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 @pH 0.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). The product in CDCl3 was characterized by a 1H NMR spectrum showing the following chemical shifts (6 in ppm): 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). The product in DMSO-d6 was characterized by a 13C NMR spectrum showing the following chemical shifts (δ in ppm): 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

Workup

  1. customA 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer
  2. temperatureThe mixture was refluxed over night
  3. temperaturecooled to <50° C
  4. customAfter the solvent was removed in vacuum
  5. dissolutionthe residue was dissolved in ethyl acetate
  6. washThe resulting solution was washed with water (250 mL×2), saturated aqueous NaHCO3 (250 mL×2), and brine (250 mL×2)
  7. dry with materialdried over anhydrous sodium sulfate
  8. customAfter the solvent was evaporated in vacuum
  9. customthe residue was recrystallized from a binary solvent
  10. additioncontaining
  11. additiona mixture of ethanol (150 mL) and acetone (75 mL)
  12. customThe solid was isolated by vacuum filtration
  13. washwashed with ethanol (100 mL×2)
  14. customThe product was dried in vacuum at 60° C. to a constant weight
  15. customaffording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee
  16. custom25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%)

Sources & evidence

ORD record
ord-080b41c41f36480a8f9a062f8b59db23
Source dataset
uspto-grants-2016_07
Patent number
US09387195B2

Reaction notes

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