Dimethylformamide → 5-[3,3-Dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid

HRID 1046440Notes

Reaction equation

HRID 1046440 reaction equation
[CH3:1][C:2]([CH3:13])([C:11]#[CH:12])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.C[O:15][C:16]([C:18]1[S:19][C:20](I)=[CH:21][C:22]=1[N:23]([CH:33]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]1)[C:24]([CH:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])=[O:17].C([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])C.[CH3:48]N(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>[CH3:1][C:2]([CH3:13])([CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:11]#[C:12][C:20]1[S:19][C:18]([C:16]([OH:15])=[O:17])=[C:22]([N:23]([C:24]([CH:26]2[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])[CH:33]2[CH2:34][CH2:35][CH:36]([O:39][C:46]3[CH:47]=[CH:48][CH:45]=[CH:44][N:43]=3)[CH2:37][CH2:38]2)[CH:21]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 249893473-[(4-Hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxHCID 581139252-(2,2-Dimethyl-but-3-ynyloxy)-tetrahydro-pyran

Product 1

HCID 509061505-[3,3-Dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acidYield 69%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalyst

Procedure

A solution of 2-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-pyran (147 mg, 0.806 mmol), 3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (326 mg, 0.645 mmol) and triethylamine (1.0 mL, 7.17 mmol) in DMF (1.0 mL) was degassed for 10 minutes with nitrogen. PdCl2(PPh3)2 (20 mg, 0.028 mmol) and CuI (5.0 mg, 0.026 mmol) was added and the resulting mixture was degassed with nitrogen for an additional 5 minutes after which the reaction was in a 60° C. oil bath and heated for 4 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 orange-brown foam. Purification by flash column chromatography on silica gel using 20% hexanes in ethyl acetate provided the desired product (251 mg, 69%) 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 in a 60° C.
  3. temperatureheated for 4 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 orange-brown foam
  11. customPurification by flash column chromatography on silica gel using 20% hexanes in ethyl acetate

Sources & evidence

ORD record
ord-f483f1aeda5b47aeab0d55957f26b993
Source dataset
uspto-grants-2013_10
Patent number
US08569302B2

Reaction notes

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