Lithium Hydroxide → (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diol

HRID 1879374Notes

Reaction equation

HRID 1879374 reaction equation
[N+](C1C=CC(C([O:10][C@H:11]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][C@@:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[F:30])([OH:22])[CH2:13][CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C.O>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C@:14]1([OH:22])[CH2:13][CH2:12][C@@H:11]([OH:10])[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH2:15]1

Participants

6

Reactant 2

HCID 3939Lithium HydroxideHCID 58468003(6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-nitrobenzoate

Product 1

HCID 58467976(6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diolYield 86%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 250 mL round-bottom flask was dissolved (6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-nitrobenzoate (125 mg, 0.284 mmol) in tetrahydrofuran (2 mL) to give a colorless solution. Lithium hydroxide (0.568 mmol) was added, and the mixture was stirred at room temperature for 2 h. LCMS indicated complete conversion. It was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to a white solid. Purification by FCC up to 6% methanol/methylene chloride afforded the desired product as a white crystalline solid (71 mg, 86%). A few crystals were picked out and an x-ray structure was obtained to confirm the cis-diol stereochemistry. MS(ESI)[M+H+]=292.21; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.44 (d, J=4.58 Hz, 1H) 7.38-7.51 (m, 2H) 7.19 (dd, J=7.48, 5.04 Hz, 1H) 7.04-7.16 (m, 2H) 5.99 (br. s., 1H) 4.90 (dd, J=11.29, 2.14 Hz, 1H) 3.80-3.91 (m, 1H) 2.92 (dd, J=14.65, 2.14 Hz, 1H) 2.57-2.70 (m, 1H) 2.37 (br. s., 1H) 2.11 (ddd, J=14.19, 5.95, 3.97 Hz, 1H) 1.96-2.06 (m, 1H) 1.74-1.91 (m, 1H); 19F NMR (470 MHz, CHLOROFORM-d) δ ppm −138.91-−138.74 (m, 1F) −139.22-−139.06 (m, 1F); 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 160.64 (s, 1C) 152.00-150.10 (dd, J=21.42 and 254.52 Hz, 1C) 148.75-146.71 (dd, J=11.52 and 244.44 Hz, 1C) 145.55 (s, 3C) 139.91 (s, 3C) 138.44 (d, J=8.64 Hz, 1C) 129.37 (s, 1C) 123.89-124.57 (m, 2C) 122.48 (s, 3C) 120.84 (s, 1C) 116.22 (d, J=17.28 Hz, 2C) 71.79 (m, 3C) 71.70 (m, 4C) 44.30 (d, J=4.80 Hz, 2C) 39.65 (s, 1C) 31.29 (s, 2C).

Workup

  1. customto give a colorless solution
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with ethyl acetate
  4. washThe combined organic layers were washed with brine
  5. customdried
  6. concentrationconcentrated to a white solid
  7. customPurification by FCC up to 6% methanol/methylene chloride

Sources & evidence

ORD record
ord-01261de54e374ac58c1cc53afd28bf4b
Source dataset
uspto-grants-2012_11
Patent number
US08314117B2

Reaction notes

Loading…