Triethylamine → 6-Ethyl-2-[3-(6-fluoronaphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

HRID 1483211

Reaction equation

HRID 1483211 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](C(O)=O)[CH:6]=[CH:5]2.C([N:17]([CH2:20]C)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:23]C1C=CC=CC=1.[NH2:41][C:42]1[S:52][C:45]2[CH2:46][N:47]([CH2:50][CH3:51])[CH2:48][CH2:49][C:44]=2[C:43]=1[C:53]([NH2:55])=[O:54]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:50]([N:47]1[CH2:48][CH2:49][C:44]2[C:43]([C:53]([NH2:55])=[O:54])=[C:42]([NH:41][C:20]([NH:17][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[CH:8]=3)=[O:23])[S:52][C:45]=2[CH2:46]1)[CH3:51]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 123414Diphenylphosphoryl azideHCID 6144392-Amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamideHCID 27827886-Fluoro-2-naphthoic acid

Product 1

HCID 1182697006-Ethyl-2-[3-(6-fluoronaphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamideYield 22%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred mixture of 6-fluoro-2-naphthoic acid (G1, 0.951 g, 5.00 mmol), triethylamine (0.759 g, 7.50 mmol) in anhydrous toluene (40 mL) was added diphenyl phosphorazidate (1.51 g, 5.50 mmol). After addition, the reaction mixture was heated at 80° C. for 2 h and then cooled to room temperature. The resulting solution was added to another stirred solution of compound F4 (1.13 g, 5.00 mmol) in anhydrous tetrahydrofuran (50 mL). After addition, the resulting mixture was heated at 80° C. for another 2 h. After this time, the reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (60 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85) to afford compound G2 as an off-white solid (451 mg, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.27 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.91 (dd, J=10.8 and 5.7 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.64-6.70 (m, 5H), 3.47 (s, 2H), 2.78 (d, J=5.1 Hz, 2H), 2.66 (d, J=5.1 Hz, 2H), 2.55-2.49 (m, 2H), 1.08 (t, J=7.0 Hz, 3H). MS (M+H) 413.

Workup

  1. additionAfter addition
  2. temperaturecooled to room temperature
  3. additionAfter addition
  4. temperaturethe resulting mixture was heated at 80° C. for another 2 h
  5. temperatureAfter this time, the reaction mixture was cooled to room temperature
  6. customquenched with saturated aqueous sodium bicarbonate (60 mL)
  7. extractionextracted with ethyl acetate (3×100 mL)
  8. dry with materialThe combined organic extracts were dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85)

Sources & evidence

ORD record
ord-abcd82fd2efd45838ddf252bc4d8f693
Source dataset
uspto-grants-2016_08
Patent number
US09416141B2

Linked notes

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