Gabapentin → HCID 21113516, compound

HRID 2360193Notes

Reaction equation

HRID 2360193 reaction equation
[CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][CH:29]([Cl:31])[CH3:30])=[O:27]>ClCCl>[Cl:31][CH:29]([O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])[CH3:30]

Participants

6

Reactant 4

HCID 3446GabapentinHCID 6397ChlorotrimethylsilaneHCID 8471Triethylamine2×HCID 5213051-Chloroethyl chloroformate

Product 1

HCID 21113516HCID 21113516, compoundYield 97.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) is added gabapentin (120.4 g, 0.704 mol) followed by triethylamine (294 mL, 2.11 mol). Chlorotrimethylsilane (178 mL, 1.40 mol) is slowly added while maintaining the reaction temperature below 15° C. and the resulting suspension is stirred for 30 min. 1-Chloroethyl chloroformate (100 g, 0.704 mol) is then added slowly while maintaining the temperature below 15° C. After the addition is complete, additional triethylamine (88 mL, 0.63 mol) is added and the resulting suspension is stirred at room temperature for 30 min. The resulting silyl ester is converted via acidic work-up to the corresponding acid by washing the reaction mixture with water (2×1 L), followed by 1N HCl (2×2 L) then brine (2×500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in vacuo, the crude product (190 g) is obtained as an orange oil and used in Step B without further purification. 1H NMR (CDCl3, 400 MHz): δ1.41-1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).

Workup

  1. temperaturewhile maintaining the reaction temperature below 15° C.
  2. temperaturewhile maintaining the temperature below 15° C
  3. additionAfter the addition
  4. stirringthe resulting suspension is stirred at room temperature for 30 min
  5. washby washing the reaction mixture with water (2×1 L)
  6. dry with materialAfter drying over anhydrous sodium sulfate and removal of the solvent in vacuo

Sources & evidence

ORD record
ord-70b49f10b48f478db92589e4f4328c32
Source dataset
uspto-grants-2014_04
Patent number
US08686034B2

Reaction notes

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