Tetrahydrofuran → 3-Hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (1-naphthalen-1-yl-ethyl)-amide

HRID 919011Notes

Reaction equation

HRID 919011 reaction equation
[OH:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[C:12](C)[C:5]=2[O:4]1.[CH2:17]1COCC1.[C:22]1([C@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC>O.CCOCC>[C:22]1([CH:32]([NH:34][C:14]([C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:3]([CH2:2][OH:1])([CH3:17])[O:4][C:5]=3[CH:12]=2)=[O:16])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2724264(+)-1-(1-Naphthyl)ethylamineHCID 687762923-Hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid

Product 1

HCID 1317348813-Hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (1-naphthalen-1-yl-ethyl)-amide

Reagents, catalysts & solvents 2

HCID 962WaterCatalystHCID 3283Diethyl EtherSolvent

Procedure

To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid (2.00 g, 8.92 mmol), THF (45 mL), (R)-(+)-1-(1-naphthyl)ethylamine (2.23 mL, 8.92 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.53 g, 9.81 mmol). This mixture was stirred at room temperature for 36 hours. A few drops of water were added and the mixture stirred for 5 minutes. The reaction was diluted with ether and washed once with 1N HCl, once with saturated sodium bicarbonate(aq), once again with 1N HCl, dried over magnesium sulfate, filtered and evaporated to provide 3-hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (1-naphthalen-1-yl-ethyl)-amide. Crystals of acceptable purity for x-ray crystallography were obtained by subliming the material twice under vacuum at 60° C. This x-ray analysis established the regiochemistry and the absolute stereochemistry of the compounds as shown, since the configuration of the naphthylethylamine stereocenter is known and not subject to racemization under the conditions of synthesis. 1H NMR (300 MHz, CD3COCD3) δ (ppm): 1.71 (d, 3H), 2.22 (s, 3H), 3.80 (m, 2H), 4.06 (m, 1H), 4.23 (m, 2H), 4.32 (m, 1H), 6.09 (m, 1H), 6.65 (d, 1H), 6.87 (d, 1H), 7.55 (m, 3H), 7.69 (m, 2H), 7.83 (d, 1H), 7.94 (d, 1H), 8.35 (d, 1H); TLC Rf=0.12 (1:1 ethyl acetate/hexane).

Workup

  1. customTo a round bottom flask equipped
  2. stirringThis mixture was stirred at room temperature for 36 hours
  3. stirringthe mixture stirred for 5 minutes
  4. washwashed once with 1N HCl, once with saturated sodium bicarbonate(aq), once again with 1N HCl
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated

Sources & evidence

ORD record
ord-64ac94af505242fc9243ff430bea3b12
Source dataset
uspto-grants-2016_03
Patent number
US09272986B2

Reaction notes

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