3-Hydroxy-2,2-dimethylpropionic acid → 3-hydroxy-2,2-dimethyl-N-(4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyl)propanamide

HRID 1499297Notes

Reaction equation

HRID 1499297 reaction equation
C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@H:6]3[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]3)[CH:26]=[CH:25][C:24]=2[CH3:27])=[CH:34][CH:33]=1)=[O:45]

Participants

6

Reactant 4

HCID 785483-Hydroxy-2,2-dimethylpropionic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 90177035(2S,3S,4R,5S,6R)-2-(3-(4-(4-aminobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

Product 1

HCID 901831103-hydroxy-2,2-dimethyl-N-(4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyl)propanamideYield 41.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-aminobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (19, 55 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.30 mmol) were combined in DMF (1 mL) and stirred for 4 hours at room temperature. The reaction quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in MeOH and treated with a few drops of NaOMe (25 wt % in MeOH) for 1 hour. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (C18 30×100 mm column, 5-40% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) to give the title compound 21 as a white solid (22 mg, 41% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 6.98-7.22 (m, 7 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1 H), 3.90-3.99 (m, 2 H), 3.49 (s, 2 H), 3.35-3.46 (m, 3 H), 3.19 (t, J=6.9 Hz, 2 H), 2.58 (t, J=7.5 Hz, 2 H), 2.18-2.23 (m, 3 H), 2.14 (s, 3 H), 1.60 (s, 2 H), 1.46-1.57 (m, 2 H), 1.11 (s, 6 H). MS (ES+) [M+H]+=532.

Workup

  1. customThe reaction quenched with saturated aqueous NaHCO3
  2. extractionextracted twice with EtOAc
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried with MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. dissolutionThe residue was dissolved in MeOH
  8. additiontreated with a few drops of NaOMe (25 wt % in MeOH) for 1 hour
  9. concentrationThe reaction was concentrated under vacuum
  10. customthe residue was purified by prep HPLC (C18 30×100 mm column, 5-40% CH3CN/10 mM aqueous ammonium formate, 45 mL/min)

Sources & evidence

ORD record
ord-943fcde0d0c64469a512fde2b0a9e01e
Source dataset
uspto-grants-2015_12
Patent number
US09200025B2

Reaction notes

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