Triethylamine → 5-[3,3-Dimethyl-4-(tetrahydro-furan-3-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester

HRID 1046446Notes

Reaction equation

HRID 1046446 reaction equation
[CH3:1][C:2]([CH3:12])([C:10]#[CH:11])[CH2:3][O:4][CH:5]1[CH2:9][CH2:8][O:7][CH2:6]1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19](I)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16].C(N(CC)CC)C>CN(C=O)C.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>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:11]#[C:10][C:2]([CH3:12])([CH3:1])[CH2:3][O:4][CH:5]2[CH2:9][CH2:8][O:7][CH2:6]2)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:33][CH2:34][CH:35]([OH:38])[CH2:36][CH2:37]1)[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16]

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 249893473-[(4-Hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxHCID 581138943-(2,2-Dimethyl-but-3-ynyloxy)-tetrahydro-furan

Product 1

HCID 581141645-[3,3-Dimethyl-4-(tetrahydro-furan-3-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl esterYield 75.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

A solution of 3-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-furan (169 mg, 1.00 mmol), 3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (404 mg, 0.80 mmol) and triethylamine (1.2 mL, 8.61 mmol) in DMF (1.2 mL) was degassed for 10 minutes with nitrogen. PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuI (6.0 mg, 0.031 mmol) was added and the resulting mixture was degassed with nitrogen for an additional 5 minutes after which the reaction was placed in a 65° C. oil bath and heated for 2.5 h. The reaction was cooled and partitioned between ethyl acetate and sat. NaHCO3. The organic layer was separated, washed with 5% LiCl, brine, dried over Na2SO4 and concentrated to give a dark brown foam. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes then 5% methanol in ethyl acetate provided 5-[3,3-dimethyl-4-(tetrahydro-furan-3-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (331 mg, 75%) as a pale yellow foam.

Workup

  1. customthe resulting mixture was degassed with nitrogen for an additional 5 minutes after which the reaction
  2. customwas placed in a 65° C.
  3. temperatureheated for 2.5 h
  4. temperatureThe reaction was cooled
  5. custompartitioned between ethyl acetate and sat. NaHCO3
  6. customThe organic layer was separated
  7. washwashed with 5% LiCl, brine
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customto give a dark brown foam
  11. customPurification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-c45a278d4ef94792b7101171a4e22211
Source dataset
uspto-grants-2013_10
Patent number
US08569302B2

Reaction notes

Loading…