Pyridine → N-(((1S,3'R,4'S,5'S,6'R)-5-chloro-6-(4-ethylbenzyl)-3',4',5'-trihydroxy-3',4',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,2'-pyran]-6'-yl)methyl)pivalamide

HRID 1716966Notes

Reaction equation

HRID 1716966 reaction equation
[NH2:1][CH2:2][C@H:3]1[O:8][C@@:7]2([C:16]3[C:11](=[CH:12][C:13]([Cl:26])=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=4)[CH:15]=3)[CH2:10][O:9]2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].N1C=CC=CC=1.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@:7]1([C@H:6]([OH:27])[C@@H:5]([OH:28])[C@H:4]([OH:29])[C@@H:3]([CH2:2][NH:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[O:8]1)[O:9][CH2:10]2

Participants

6

Reactant 3

HCID 1049PyridineHCID 62493Pivaloyl chlorideHCID 59013483(1S,3'R,4'S,5'S,6'R)-6'-(aminomethyl)-5-chloro-6-(4-ethylbenzyl)-3',4',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,2'-pyran]-3',4',5'-triol

Product 1

HCID 59013471N-(((1S,3'R,4'S,5'S,6'R)-5-chloro-6-(4-ethylbenzyl)-3',4',5'-trihydroxy-3',4',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,2'-pyran]-6'-yl)methyl)pivalamideYield 28.7%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a stirred solution of (1S,3′R,4′S,5′S,6′R)-6′-(aminomethyl)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (20 mg, 0.047 mmol) and 0.04 mL of pyridine in 1 mL of dichloromethane was added of pivaloyl chloride (60 μL, 0.05 mmol) and 3 mg of 4-dimethylaminopyridine. After being stirred for 2 h at ambient temperature, the reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 M hydrochloric acid and concentrated. The residue was dissolved in 1 mL of methanol and cooled in an ice bath. After addition of 0.3 mL of 4 M potassium hydroxide solution, the mixture was stirred for 2 h at ambient temperature. The reaction mixture was then neutralized with 1 M hydrochloric acid and concentrated. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated and dried over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6.8 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.37 (s, 1H), 7.16 (s, 1H), 7.10 (s, 4H), 5.07 (s, 2H), 4.12 (d, J=15.8 Hz, 1H), 4.04 (d, J=15.8 Hz, 1H), 3.82-3.59 (m, 3H), 3.45-3.39 (m, 2H), 3.43 (dd, J=9.9, 8.4 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H), 1.11 (s, 9H); MS ESI (m/z) 504 (M+1)+, calc. 503.

Workup

  1. washwashed with 1 M hydrochloric acid
  2. concentrationconcentrated
  3. dissolutionThe residue was dissolved in 1 mL of methanol
  4. temperaturecooled in an ice bath
  5. additionAfter addition of 0.3 mL of 4 M potassium hydroxide solution
  6. stirringthe mixture was stirred for 2 h at ambient temperature
  7. concentrationconcentrated
  8. customThe residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate
  9. customthe organic layer was separated
  10. dry with materialdried over sodium sulfate
  11. concentrationConcentration under reduced pressure
  12. customprovided the crude product, which
  13. customwas purified by preparative TLC

Sources & evidence

ORD record
ord-575f6a02bc3c40149a89f2c7d16a810f
Source dataset
uspto-grants-2010_09
Patent number
US07803778B2

Reaction notes

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