Diisopropylethylamine → 4-{3-[5-Chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-4-ethylpiperidine-1-carboxylic acid tert-butyl ester

HRID 1986325Notes

Reaction equation

HRID 1986325 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.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH2:42])([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH:42][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)([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:25])([CH3:27])[CH3:26]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 688567424-(3-Aminopropyl)-4-ethylpiperidine-1-carboxylic acid tert-butyl esterHCID 866253512-(2,5-Dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide

Product 1

HCID 688568604-{3-[5-Chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-4-ethylpiperidine-1-carboxylic acid tert-butyl esterYield 66.7%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (180 mg, 0.494 mmol), 4-(3-aminopropyl)-4-ethylpiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.741 mmol) and diisopropylethylamine (128 mg, 0.988 mmol) in 1,4-dioxane (3 mL) is heated at 90° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with 3% 2 M NH3/MeOH in dichloromethane, to give 197 mg of 4-{3-[5-chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-4-ethylpiperidine-1-carboxylic acid tert-butyl ester. The intermediate is then subject to deprotection by dissolving the material (197 mg, 0.329 mmol) in MeOH (25 mL) and dichloromethane (12 mL) and bubbling anhydrous hydrogen chloride gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (184 mg, 98% yield). ES+(m/z) 498 (35Cl) and 500 (37Cl) [M(free base)+H].

Workup

  1. concentrationAt room temperature the mixture is concentrated
  2. customthe crude product is chromatographed on silica gel
  3. washeluting with 3% 2 M NH3/MeOH in dichloromethane

Sources & evidence

ORD record
ord-e12a7cdcb32a450da657240eaf76c33a
Source dataset
uspto-grants-2009_06
Patent number
US07547691B2

Reaction notes

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