Benzamide → N-[(3S,4R)-3-Hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-chroman-4-yl]-4,5-dimethoxy-2-nitrobenzamide

HRID 483754Notes

Reaction equation

HRID 483754 reaction equation
[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]([C:7]([O:9]C)=O)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[OH-].[K+].S(Cl)(Cl)=O.[NH2:24][C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][C:36]([F:39])([F:38])[F:37])[CH:33]=2)[O:28][C:27]([CH3:41])([CH3:40])[C@H:26]1[OH:42].C(N(CC)CC)C.C(N)(=O)C1C=CC=CC=1>O.C1C=CC=CC=1.ClCCl.CO.C1C=CC=CC=1>[OH:42][C@H:26]1[C@H:25]([NH:24][C:7](=[O:9])[C:6]2[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][C:36]([F:39])([F:37])[F:38])[CH:33]=2)[O:28][C:27]1([CH3:41])[CH3:40]

Participants

11

Reactant 6

HCID 2331BenzamideHCID 8471TriethylamineHCID 14797Potassium HydroxideHCID 24386Thionyl ChlorideHCID 117867Benzoic acid, 4,5-dimethoxy-2-nitro-, methyl esterHCID 15020328(3S,4R)-4-Amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol

Product 1

HCID 67754048N-[(3S,4R)-3-Hydroxy-2,2-dimethyl-6-(trifluoromethoxy)-chroman-4-yl]-4,5-dimethoxy-2-nitrobenzamideYield 56.3%

Reagents, catalysts & solvents 4

HCID 241BenzeneSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 21927730Benzene methanolSolvent

Procedure

Methyl 4,5-dimethoxy-2-nitrobenzoate (4.8 g, 20 mmol) was hydrolyzed to the corresponding carboxylic acid by refluxing overnight with KOH (1.6 g, 40 mmol) in 1:1 methanol/benzene (100 mL). The mixture was concentrated to give the crude carboxylate, dissolved in H2O, and precipitated as 4,5-dimethoxy-2-nitrobenzoic acid with 2N HCl. This acid (2.27 g, 10 mmol) was then converted to the corresponding acid chloride by refluxing in benzene (30 mL) with thionyl chloride (1.66 g, 14 mmol) for 1 hour. The crude mixture was concentrated in vacuo and diluted with dichloromethane (10 mL). This solution was added to a cooled solution of (3S,4R)-4amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol (2.75 g, 10 mmol), triethylamine (1.39 mL, 10 mmol) and dichloromethane (25 mL). The crude benzamide was worked-up in a method similar to that in Example 1 and chromatographed (1:1 hexanes/ethyl acetate) to afford 2.74 g (56%) of white solid: m.p. 97°-100° C.; 1H NMR (DMSO-d6): δ 9.00 (s, 1H), 7.62 (s, 1H), 7.39 (d, 1H), 7.25 (s, 1H), 7.16 (d, 1H), 6.86 (d, 1H), 5.86 (d, 1H), 4.96 (br t, 1H), 3,91 (s, 3H), 3.89 (s, 3H), 3.64 (dd, 1H), 1.43 (s, 3H), 1.20 (s, 3H).

Workup

  1. concentrationThe mixture was concentrated
  2. customto give the crude carboxylate
  3. customprecipitated as 4,5-dimethoxy-2-nitrobenzoic acid with 2N HCl
  4. concentrationThe crude mixture was concentrated in vacuo
  5. additiondiluted with dichloromethane (10 mL)
  6. customchromatographed (1:1 hexanes/ethyl acetate)

Sources & evidence

ORD record
ord-5e6ffb004322492fbd1e01a51bbb65f6
Source dataset
uspto-grants-1993_07
Patent number
US05225566

Reaction notes

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