Diisopropylethylamine → 2-[5-Methyl-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide

HRID 1986310Notes

Reaction equation

COC1C=CC(C([NH:18][C:19]([C:21]2[C:29]3[CH:28]=[C:27]([C:30]4[C:35]([CH3:36])=[CH:34][N:33]=[C:32](Cl)[N:31]=4)[S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])C2C=CC(OC)=CC=2)=CC=1.C(OC([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:36][C:35]1[C:30]([C:27]2[S:26][C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:19]([NH2:18])=[O:20])[C:29]=3[CH:28]=2)=[N:31][C:32]([NH:54][CH2:53][CH2:52][CH2:51][CH:48]2[CH2:49][CH2:50][NH:45][CH2:46][CH2:47]2)=[N:33][CH:34]=1

Participants

Conditions

Temperature: 97 °C

Procedure

A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid [bis-(4-methoxyphenyl)-methyl]-amide (1.14 g, 2.15 mmol), 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (1.04 g, 4.30 mmol) and diisopropylethylamine (1.12 mL, 6.45 mmol) in 1,4-dioxane (10 mL) is heated at 97° C. under a nitrogen atmosphere for 3 days. After concentration and subsequent chromatography on silica gel, eluting with MeOH in dichloromethane 0-2%, the desired product is obtained as a solid. The solid is suspended in dichloromethane (20 mL), followed by the successive addition of triethylsilane (1.5 mL) and TFA (5 mL). The resultant yellow solution is stirred for 2 hours. After concentration the solid is dissolved with stirring in MeOH (30 mL) and dichloromethane (30 mL) and the solution is treated in portions with 1.0 N LiOH (15 mL) to form a suspension. The suspension is concentrated at 45° C. under atmospheric pressure for 30 minutes, then methanol and dichloromethane are evaporated off in vacuo. The suspension is filtered and the yellow solid is dried under vacuum at 45° C. to provide the title compound (0.890 g, 100% yield). ES+(m/z) 410 [M+H].

Workup

concentrationAfter concentration and subsequent chromatography on silica gel
washeluting with MeOH in dichloromethane 0-2%

Sources & evidence

ORD record: ord-d23f1ccf450f475e9b9115d08775a6c9
Source dataset: uspto-grants-2009_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07547691B2

Reaction notes

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