Lithium Hydroxide → 2-[5-Chloro-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide

HRID 1986307Notes

Reaction equation

HRID 1986307 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:10]=3[CH:9]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[Li+].[OH-]>O1CCOCC1.ClCCl.CO>[Cl:20][C:5]1[C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:10]=3[CH:9]=2)=[N:7][C:2]([NH:36][CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]2)=[N:3][CH:4]=1

Participants

10

Reactant 6

HCID 3939Lithium HydroxideHCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 81531DiisopropylethylamineHCID 1514258tert-Butyl 4-(2-aminoethyl)piperidine-1-carboxylateHCID 866253572-(2,5-Dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid amide

Product 1

HCID 688566752-[5-Chloro-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amideYield 51.1%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
97 °C

Procedure

A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid amide (305 mg, 0.941 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (430 mg, 1.88 mmol) and diisopropylethylamine (0.492 mL, 2.82 mmol) in 1,4-dioxane (6 mL) is heated at 97° C. under a nitrogen atmosphere for 7 hours. At room temperature the mixture is concentrated in vacuo to give a crude solid and it is subjected to a subsequent deprotection reaction. The solid is suspended in dichloromethane (12 mL), followed by the successive addition of triethylsilane (0.9 mL) and TFA (4 mL). The resultant yellow solution is stirred for 2 hours. After concentration and subsequent chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 3-10%, the fractions containing the desired product are collected and concentrated to give a solid. The solid is dissolved in MeOH (20 mL) and dichloromethane (20 mL) with stirring and the solution is treated in portions with 0.5 N LiOH (14 mL) to form a suspension. Methanol and dichloromethane are concentrated at 45° C. to give a yellow suspension. After filtration and drying the title compound is obtained as a yellow solid (0.200 g, 51% yield). ES+(m/z) 416 (35Cl) and 418 (37Cl) [M+H].

Workup

  1. concentrationAt room temperature the mixture is concentrated in vacuo
  2. customto give a crude solid and it
  3. customis subjected to a subsequent deprotection reaction
  4. concentrationAfter concentration and subsequent chromatography on silica gel
  5. washeluting with 2.0 M NH3/MeOH in dichloromethane 3-10%
  6. additionthe fractions containing the desired product
  7. customare collected
  8. concentrationconcentrated
  9. customto give a solid
  10. customto form a suspension
  11. concentrationMethanol and dichloromethane are concentrated at 45° C.
  12. customto give a yellow suspension
  13. filtrationAfter filtration
  14. dry with materialdrying the title compound

Sources & evidence

ORD record
ord-bac718d170144bfc8bb685891cfaa0ca
Source dataset
uspto-grants-2009_06
Patent number
US07547691B2

Reaction notes

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