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Synthesis of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one

IP.com Disclosure Number: IPCOM000250387D
Publication Date: 2017-Jul-10
Document File: 5 page(s) / 477K

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Synthesis of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-

yl)butoxy)quinolin-2(1H)-one

7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (referred to as

Compound A) has the following structure:

Compound A is obtained by a process as shown in the scheme below:

Two intermediates involves in the synthesis of Compound A: 1-(benzo[b]thiophen-4-

yl)piperazine diyhdrochloride (referred to as Compound III) and 7-(4-

chlorobutoxy)quinolin-2(1H)-one (referred to as Compound IV).

Compound III starts with a reaction between 4-bromobenzo[b]thiophene (referred to

as Compound I) and tert-butyl piperazine-1-carboxylate to give tert-butyl 4-

(benzo[b]thiophen-4-yl) piperazine-1-carboxylate (referred to as Compound II).

Next, removal of the Boc moiety upon acidic conditions gives 1-(benzo[b]thiophen-4-

yl)piperazine dihydrochloride salt (referred to as Compound III).

In parallel, a synthesis of Compound IV involves cyclization and de-methylation of

N-(3-methoxyphenyl)cinnamamide (referred to as Compound VI) to give 7-

hydroxyquinolin-2(1H)-one (referred to as Compound V). Next, a condensation with

1-bromo-4-chlorobutane gives 7-(4-chlorobutoxy)quinolin-2(1H)-one (referred to as

Compound IV).

Eventually, Compound III reacts with Compound IV upon heating and alkaline

conditions to give Compound A.

Synthesis of intermediate 1-(benzo[b]thiophen-4-yl)piperazine diyhdrochloride

(referred to as Compound III)

Step 1:Preparation of tert-butyl 4-(benzo[b]thiophen-4-yl) piperazine-1-carboxylate

[Compound II]

To a 1L reactor equipped with Dean Stark apparatus, condenser and a mechanical

stirrer were added 10% Pd/C (50% wet, 1 g) and Toluene (200 ml). The moisture was

removed from the sample by distillation as an azeotrope with toluene upon heating (Tj

=Tjacket~128 °C). Then, the mixture was cooled to Tj~75 o C and dean stark apparatus

was removed. The reactor was loaded with racemic BINAP [(±)-2,2′-

Bis(diphenylphosphino)-1,1′-binaphthalene] (0.44 gr, 0.71 mmol), tert-butyl

piperazine-1-carboxylate (22.7 g, 0.14 mol), NatOBu [sodium tert-butoxide] (18 g,

0.19 mol) and 4-bromobenzo[b]thiophene (Compound I, 20 gr, 0.09 mol). The

reaction mixture was stirred at 100 °C for 3 hours until full consumption of 4-

bromobenzo[b]thiophen (Compound I) was obtained. Then, the reaction mixture was

cooled to Tr (temperature in the reaction)=40±5 °C followed by addition of 5% citric

acid (200 ml) and stirred at this temperature for about 30 minutes. Next, water was

added (60 ml) followed by mechanical filtration under vacuum (Tr=40±5 °C). The

separated organic phase was introduced to the further step as toluenic solution of tert-

butyl 4-(benzo[b]thiophen-4-yl)piperazine-1-carboxylate (Compound II).

Step 2: Preparation of 1-(benzo[b]thiophen-4-yl)piperazine dihydrochloride salt

[Compound III]

2-iso-Propanole (200 ml) was added to a stirred toluenic solution of tert-butyl 4-

(benzo[b]thiophen-4-yl)piperazine-1-carboxylate (Compound II, from the previous

step) at Tr=40...