Lithium Hydroxide → Racemic 2-[5-Methyl-2-(3-piperidin-3-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide

HRID 1986328Notes

Reaction equation

HRID 1986328 reaction equation
[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[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.C(OC([N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:32]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>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:40][CH2:39][CH2:38][CH2:37][CH:33]5[CH2:34][CH2:35][CH2:36][NH:31][CH2:32]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1

Participants

9

Reactant 6

HCID 3939Lithium HydroxideHCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 81531DiisopropylethylamineHCID 68857542tert-Butyl 3-(3-aminopropyl)piperidine-1-carboxylateHCID 866253772-(2-Chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide

Product 1

HCID 68857359Racemic 2-[5-Methyl-2-(3-piperidin-3-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamideYield 25%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.50 g, 1.5 mmol), racemic 3-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.88 g, 3.6 mmol) and diisopropylethylamine (0.47 g, 3.6 mmol) in 1,4-dioxane (7 mL) is heated at 90° C. under a nitrogen atmosphere for 48 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 1-10%, the intermediate is obtained as a solid. The solid is suspended in dichloromethane (3 mL), followed by the successive addition of triethylsilane (0.50 mL) and TFA (3 mL), the resultant yellow solution is stirred for 16 hours. After concentration a wet solid is obtained. It is treated with 2 N LiOH, with sonication, until pH reaches 12. The mixture is filtered and the solid is dried before it is subjected to chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 10-20%, to give the title compound as a yellow solid (160 mg, 25% yield). ES+(m/z) 450 [M+H].

Workup

  1. concentrationAfter concentration and subsequent chromatography on silica gel
  2. washeluting with 2 M NH3/MeOH in dichloromethane 1-10%
  3. customthe intermediate is obtained as a solid
  4. concentrationAfter concentration a wet solid
  5. customis obtained
  6. filtrationThe mixture is filtered
  7. customthe solid is dried before it
  8. washeluting with 2 M NH3/MeOH in dichloromethane 10-20%

Sources & evidence

ORD record
ord-cc79490746f24f5b881d064a596ba0f1
Source dataset
uspto-grants-2009_06
Patent number
US07547691B2

Reaction notes

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