Triethylamine → Tert-butyl 2-((3-isobutyl-1-oxo-3-phenyl-1,3,4,5,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxamido)methyl)phenylcarbamate

HRID 1747730Notes

Reaction equation

HRID 1747730 reaction equation
Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].[CH2:36]([C:40]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH2:45][NH:46][CH2:47][CH2:48][C:43]=2[C:42](=[O:49])[O:41]1)[CH:37]([CH3:39])[CH3:38].FC1C=CC(C2(CC(C)C)C3CNCCC=3C(=O)O2)=CC=1>C1COCC1.ClCCl>[CH2:36]([C:40]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH2:45][N:46]([C:2]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:4])[CH2:47][CH2:48][C:43]=2[C:42](=[O:49])[O:41]1)[CH:37]([CH3:39])[CH3:38]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 2760955tert-Butyl [2-(aminomethyl)phenyl]carbamateHCID 896147743-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-oneHCID 896285953-(4-fluorophenyl)-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one

Product 1

HCID 117901096Tert-butyl 2-((3-isobutyl-1-oxo-3-phenyl-1,3,4,5,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxamido)methyl)phenylcarbamateYield 106.4%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To an ice-cold solution of triphosgene (36 mg, 0.123 mmol) and triethyl amine (75 mg, 0.737 mmol) in anhydrous THF (15 mL) was added tert-butyl 2-(aminomethyl)phenylcarbamate (100 mg, 0.369 mmol) in anhydrous THF (2 mL). The reaction mixture was stirred at 0° C. for 15 min., then warmed to room temperature and concentrated to dryness. The residue was re-dissolved in anhydrous dichloromethane (15 mL), a solution of 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (100 mg, 0.369 mmol) (prepared according to the methods described for 3-(4-fluorophenyl)-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one, Scheme 1) in anhydrous dichloromethane (2 mL) was added, and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes) to provide tert-butyl 2-((3-isobutyl-1-oxo-3-phenyl-1,3,4,5,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxamido)methyl)phenylcarbamate as a colorless oil (68 mg, 21% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.78-0.97 (m, 6H), 1.50-1.55 (m, 9H), 1.55-1.69 (m, 1H), 1.77 (dd, J=14.51, 7.35 Hz, 1H), 2.22-2.42 (m, 3H), 3.12-3.46 (m, 1H), 3.50-3.63 (m, 1H), 3.88 (d, J=18.84 Hz, 1H), 3.89-3.90 (m, 1H), 4.25-4.36 (m, 2H), 4.44 (d, J=18.84 Hz, 1H), 5.78 (d, J=5.65 Hz, 1H), 7.01 (dd, J=7.54, 1.13 Hz, 1H), 7.14-7.26 (m, 2H), 7.26-7.42 (m, 4H), 7.69 (d, J=8.29 Hz, 1H), 8.46-8.57 (m, 1H); MS m/z 542 (M+Na)+, 518 (M−H)−.

Workup

  1. temperaturewarmed to room temperature
  2. concentrationconcentrated to dryness
  3. dissolutionThe residue was re-dissolved in anhydrous dichloromethane (15 mL)
  4. additionwas added
  5. stirringthe mixture stirred at room temperature for 16 hours
  6. concentrationThe reaction mixture was concentrated
  7. custompurified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-17ae9565e9da4e0197126350beabc3ae
Source dataset
uspto-grants-2015_10
Patent number
US09150582B2

Reaction notes

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