Triethylamine → Methyl 4-(4-(2-(1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate

HRID 1025514Notes

Reaction equation

HRID 1025514 reaction equation
[CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:31])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41]>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:31])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:26][CH2:27][N:28]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41])[CH2:29][CH:30]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 10608119Methyl 4-(chlorosulfonyl)butanoateHCID 674688385-Cyclopropyl-2-(4-(2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)pyrimidine

Product 1

HCID 67469130Methyl 4-(4-(2-(1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoateYield 36.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 5-cyclopropyl-2-(4-(2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)pyrimidine (90 mg, 0.216 mmol) and triethylamine (0.061 mL, 0.432 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (65 mg, 0.324 mmol). Upon completion of addition, the reaction mixture was warmed to room temperature, where it stirred for 3 h. After this time, the reaction mixture was diluted with CH2Cl2 (4 mL), and the resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min) to afford Compound 11H as a white solid (46 mg, 0.079 mmol, 36.7% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (s, 2 H), 7.06 (s, 1 H), 7.01-7.05 (m, 1 H), 6.60 (d, J=8.3 Hz, 1 H), 5.82 (ddd, J=3.2, 1.9, 1.7 Hz, 1 H), 4.65-4.78 (m, 2 H), 3.85-3.92 (m, 2 H), 3.60 (s, 3 H), 3.46 (t, J=5.8 Hz, 2 H), 3.08 (d, J=15.7 Hz, 1 H), 2.98 (dd, J=8.4, 6.7 Hz, 2 H), 2.65-2.78 (m, 3 H), 2.50 (d, J=1.7 Hz, 2 H), 2.44 (t, J=7.0 Hz, 2 H), 2.01-2.13 (m, 2 H), 1.76-1.87 (m, 2 H), 1.67-1.75 (m, 1 H), 1.56-1.65 (m, 1 H), 1.30 (s, 3 H), 1.15-1.28 (m, 2 H), 0.76-0.83 (m, 2 H), 0.45-0.51 (m, 2 H). LC/MS (m/z)=581 (M+H)+.

Workup

  1. additionUpon completion of addition
  2. washthe resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL)
  3. customThe organic layer was separated
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto yield a residue
  8. customThe residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min)

Sources & evidence

ORD record
ord-a05df3411d3b48d18ac1852dc4c67fd0
Source dataset
uspto-grants-2014_05
Patent number
US08729084B2

Reaction notes

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