Triethylamine → 3-{2-[5-Chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-pyrrolidine-1-carboxylic acid benzyl ester

HRID 1986305Notes

Reaction equation

HRID 1986305 reaction equation
[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH:41][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 27564223-Aminoethyl-1-N-Cbz-pyrrolidineHCID 866253512-(2,5-Dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide

Product 1

HCID 688580123-{2-[5-Chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-pyrrolidine-1-carboxylic acid benzyl esterYield 57.9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.10 g, 0.27 mmol), racemic 3-(2-aminoethyl)-pyrrolidine-1-carboxylic acid benzyl ester (0.14 g, 0.55 mmol) and triethylamine (0.11 mL, 0.81 mmol) in 1,4-dioxane (1.5 mL) in a sealed reaction vessel is stirred at 90° C. overnight. The reaction is cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer is separated, dried over Na2SO4, filtered and concentrated. The crude solid is washed with ethyl acetate, dried under vacuum to provide 3-{2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-pyrrolidine-1-carboxylic acid benzyl ester as a white solid (90 mg, 56% yield). A stirred solution of this intermediate (16 mg, 0.028 mmol) in TFA (0.5 mL) and water (0.1 mL) is heated in a sealed tube at 100° C. for 20 minutes. At room temperature the mixture is concentrated and the residue is dissolved in methanol, passed through a SCX column, washed with methanol and 2 M NH3/methanol to give the crude product. It is further passed through a short pad of silica gel to afford the title compound as a solid (11 mg, 90% yield). ES+(m/z) 442 (35Cl) and 444 (37Cl) [M+H].

Workup

  1. customin a sealed reaction vessel
  2. temperatureThe reaction is cooled to room temperature
  3. custompartitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
  4. customthe organic layer is separated
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. washThe crude solid is washed with ethyl acetate
  9. customdried under vacuum

Sources & evidence

ORD record
ord-c84bc429b13640d9974d776123b3a55d
Source dataset
uspto-grants-2009_06
Patent number
US07547691B2

Reaction notes

Loading…