Chlorotrimethylsilane → 6-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid

HRID 1277799Notes

Reaction equation

HRID 1277799 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([N:33]1[CH2:40][CH:39]([OH:41])[CH2:38][C@H:34]1[C:35](O)=[O:36])(=[O:32])[CH3:31].CN1CCOCC1.ClC(OC)=O>C(O)(C)C.C(O)(=O)C.ClCCl>[C:30]([N:33]1[CH2:40][CH:39]([OH:41])[CH2:38][C@H:34]1[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:36])(=[O:32])[CH3:31]

Participants

10

Reactant 6

HCID 6397ChlorotrimethylsilaneHCID 6586Methyl chloroformateHCID 79724-MethylmorpholineHCID 8471TriethylamineHCID 2729005(2S)-1-acetyl-4-hydroxypyrrolidine-2-carboxylic acidHCID 129189566-(4-Aminophenyl)-1,2-dihydro-2-oxonicotinic acid

Product 1

HCID 130021066-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acidYield 84.8%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent5×

Procedure

A suspension of 172.5 g (0.75 mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 312 ml (2.23 mol) of triethylamine, and 11.8 L of dichloromethane was stirred at 10° and 290 ml (2.28 mol) of chlorotrimethylsilane is slowly added. The resulting mixture was stirred overnight at room temperature. A mixture of 273 g (1.58 mol) of N-acetyl-4-hydroxy-L-proline and 3.5 L of dichloromethane was stirred at -15° and 177.5 ml (1.61 mol) of N-methylmorpholine was added during a 20 min period followed by 250 ml of dichloromethane. The mixture was stirred at -13° for 15 min and 125.5 ml (1.62 mol) of methyl chloroformate was added over a 25 min period at -14° followed by 150 ml of dichloromethane. The mixture was stirred at -15° for 40 min and the above silylated nicotinic acid was added over a period of 60 min at -17° followed by 500 ml of dichloromethane. The mixture was stirred for 1 hr and 40 min as the temperature rose to 1°. The mixture was stirred overnight with ice bath cooling as the temperature rose to 16° and 135 ml of glacial acetic acid was added followed by 135 ml of isopropanol. The reaction mixture was concentrated to 4 L under reduced pressure and the solid filtered, washed with dichloromethane and dried to give 245 g of 6-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.

Workup

  1. stirringThe resulting mixture was stirred overnight at room temperature
  2. stirringwas stirred at -15°
  3. stirringThe mixture was stirred at -13° for 15 min
  4. stirringThe mixture was stirred at -15° for 40 min
  5. stirringThe mixture was stirred for 1 hr and 40 min as the temperature
  6. customrose to 1°
  7. stirringThe mixture was stirred overnight with ice bath
  8. temperaturecooling as the temperature
  9. customrose to 16°
  10. concentrationThe reaction mixture was concentrated to 4 L under reduced pressure
  11. filtrationthe solid filtered
  12. washwashed with dichloromethane
  13. customdried

Sources & evidence

ORD record
ord-17e9d956c1474f18a10b1d2231c9edfa
Source dataset
uspto-grants-1981_07
Patent number
US04278681

Reaction notes

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