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2-Chlorobenzaldehyde → 5-Chloromethyl-7-(2-chlorophenyl)-8a-methyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6,8-dicarboxylic acid 6-ethyl 8-methyl ester

HRID 1254
Notes
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Reaction equation

HRID 1254 reaction equation
[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:20][O:21][C:22](=[O:30])[CH:23]=[C:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>CO>[CH3:20][O:21][C:22]([CH:23]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH2:11][Cl:10])[N:26]2[CH2:27][CH2:28][O:29][C:24]12[CH3:25])=[O:30]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 69962-ChlorobenzaldehydeHCID 69484Ethyl 4-chloroacetoacetateHCID 854437083-(2-Hydroxyethylamino)-but-2-enoic acid methyl ester

Product 1

HCID 867521825-Chloromethyl-7-(2-chlorophenyl)-8a-methyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6,8-dicarboxylic acid 6-ethyl 8-methyl esterYield 17.6%

Reagents, catalysts & solvents 1

HCID 887
Methanol
Solvent

Procedure

A mixture of 2-chlorobenzaldehyde (XI, 57.0 g), ethyl 4-chloroacetoacetate (VIII, 69.3 g) and 3-(2-hydroxyethylamino)-but-2-enoic acid methyl ester (XXIII, 63.2 g) in methanol (800 mL) was stirred at room temperature for 48 h. Methanol was removed under reduced pressure and the residue dissolved in ethyl acetate (400 mL). The organic phase was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å) using a solvent mixture of hexane and ethyl acetate as eluent (95:5, 90:10, 85:15, 80:20, 70:30 and 60:40) as eluent afforded the title compound (XXIV 30.0 g). 1H-NMR (CDCl3) δ (ppm): 0.80 (t, 3H, J=6.9 Hz), 1.05 (s, 3H), 3.73 (s, 3H), 3.39 (s, 1H), 3.74-4.09 (m, 4H), 4.06 (q, 2H, J=6.9 Hz), 4.51 (d, 1H, J=11.5 Hz),4.63 (s, 1H), 5.40 (d, 1H, J=11.5 Hz), 7.12-7.40 (m, 4H); 13C-NMR (CDCl3) δ (ppm): 13.6, 25.7, 39.3, 39.7, 45.8, 51.0, 51.7, 59.5, 63.4, 90.5, 98.6, 126.3, 126.8, 129.6, 129.9, 133.6, 140.7, 149.5, 167.5, 171.8; HRMS: calc. for C20H23Cl2 NO2 427.0953 found 427.0939; Elemental Analysis (%): calc. (found) C 56.09 (56.12), H 5.41 (5.26), N 3.27 (3.07); m.p. 141.9°-142.8° C.; IR(KBr, cm-1): 1742, 1676, 1581, 1566.

Workup

  1. customMethanol was removed under reduced pressure
  2. dissolutionthe residue dissolved in ethyl acetate (400 mL)
  3. washThe organic phase was washed with brine
  4. dry with materialdried (sodium sulfate)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification of the residue by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å)
  8. additiona solvent mixture of hexane and ethyl acetate as eluent (95:5, 90:10, 85:15, 80:20, 70:30 and 60:40) as eluent

Sources & evidence

ORD record
ord-d1e2912f9b2444eeb1e5ad64e18d1404
Source dataset
uspto-grants-1998_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05723618

Reaction notes

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