Phosgene → WAY127093B racemate

HRID 1612945Notes

Reaction equation

HRID 1612945 reaction equation
[C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:34]3[N:38]([CH3:39])[NH:37][C:36](=[O:40])[CH2:35]3)[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:34]3[CH2:35][C:36](=[O:40])[N:37]([C:1]([NH:19][CH2:18][C:14]4[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=4)=[O:2])[N:38]3[CH3:39])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24]1

Participants

6

Reactant 4

HCID 6371PhosgeneHCID 8471Triethylamine2×HCID 310183-PyridinemethanamineHCID 197927655-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone

Product 1

HCID 19792796WAY127093B racemate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-15 °C

Procedure

To a -15° C. solution of phosgene (4.50 mmol, 2.30 mL; 1.9M solution in toluene) in dry tetrahydrofuran (8 mL) is added neat triethylamine (4.50 mmol, 0.450 g; 0.620 mL) and the resulting suspension is stirred at -15° C. for 10 minutes. To this suspension is added 3-picolylamine (4.50 mmol, 0.490 g; 0.460 mL) and triethylamine (4.50 mmol, 0.450 g; 0.620 mL) in dry tetrahydrofuran (10 mL) in one portion and the reaction mixture is stirred at -15° C. for 30 minutes. Subsequently, 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (3.0 mmol, 0.870 g) in dry tetrahydrofuran (7 mL) is added at -15° C. and the reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with water (20 mL), the volatiles removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer is dried (Na2SO4) and concentrated in vacuo to give a tan solid. This material is purified by flash chromatography (SiO2 :1) 50% ethyl acetate/hexane; 2) 100% ethyl acetate; 3) 5% methanol/ethyl acetate) to give a mixture of starting material and product which is triturated with ether. The title compound is isolated as a white solid (0.158 g; 12%). Also isolated is a mixture of starting pyridazone and title compound (0.511 g). 1H-NMR (DMSO-d6, 400 MHz) δ8.45 (m, 3H); 7.65 (dt, 1H, J=8.0, 1.6 Hz); 7.22 (ddd, 1H, J=8.0, 5.0, 0.7 Hz); 6.94 (d, 1H, J=2.0 Hz); 6.88 (d, 1H, J=8.0 Hz); 6.82 (dd, 1H, J=8.0, 2.0 Hz); 4.63 (m, 1H); 4.38 (m, 3H); 3.70 (s, 3H); 3.65 (m, 1H); 2.74 (s, 3H); 2.65 (m, 1H); 1.79 (m, 2H); 1.63 (m, 4H); 1.49 (m, 2H). IR (KBr, cm-1) 3420, 3320, 2950, 1730, 1715, 1530, 1515, 1235, 1135.

Workup

  1. stirringthe reaction mixture is stirred at -15° C. for 30 minutes
  2. temperatureto warm to room temperature overnight
  3. customThe reaction is quenched with water (20 mL)
  4. customthe volatiles removed in vacuo
  5. customthe residue partitioned between ethyl acetate (150 mL) and water (150 mL)
  6. dry with materialThe organic layer is dried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customto give a tan solid
  9. customThis material is purified by flash chromatography (SiO2 :1) 50% ethyl acetate/hexane
  10. custom3) 5% methanol/ethyl acetate) to give
  11. additiona mixture of starting material and product which
  12. customis triturated with ether

Sources & evidence

ORD record
ord-b2e0ff8677dd47e6bf9d4c5d9b5902ee
Source dataset
uspto-grants-1993_03
Patent number
US05191084

Reaction notes

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