Trimethylsilylacetylene → N-({1-[4-(5-Ethynyl-2-oxo-2H-pyridin-1yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide

HRID 2188555Notes

Reaction equation

HRID 2188555 reaction equation
I[C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.[C:36]([Si](C)(C)C)#[CH:37].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:36]([C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1)#[CH:37]

Participants

7

Reactant 3

HCID 66111TrimethylsilylacetyleneHCID 2724141Tetrabutylammonium FluorideHCID 49764697N-({1-[4-(5-Iodo-2-oxo-2H-pyridin-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide

Product 1

HCID 49764698N-({1-[4-(5-Ethynyl-2-oxo-2H-pyridin-1yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

N-({1-[4-(5-Iodo-2-oxo-2H-pyridin-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 8, Step C, 450 mg, 0.75 mmol), ethynyl-trimethyl-silane (Fluka, 100 mg, 1.02 mmol), Pd(Ph3P)2Cl2 (Aldrich, 0.02 mmol), CuI (Aldrich, 0.02 mmol) and TEA (1 mL) were mixed in THF (6 mL) at room temperature under argon. The reaction was stirred overnight. The solid was filtered off and the residue was partitioned between water and a chloroform/IPA “cocktail” (˜3:1, v/v). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was treated with TBAF (Aldrich, 1.0 N in THF, 2 mL) for 30 min. at room temperature. The solvent was removed and the residue was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as yellow solid.

Workup

  1. filtrationThe solid was filtered off
  2. customthe residue was partitioned between water
  3. dry with materialThe organic layer was dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give the crude product, which
  7. customThe solvent was removed
  8. customthe residue was then purified by a CombiFlash® system

Sources & evidence

ORD record
ord-4a6c9822e9a74685ad7d0f1a76e2f782
Source dataset
uspto-grants-2012_12
Patent number
US08324186B2

Reaction notes

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