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Crystalline forms of intermediates related to 7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one synthesis 7-(

IP.com Disclosure Number: IPCOM000244628D
Publication Date: 2015-Dec-30
Document File: 4 page(s) / 464K

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Crystalline forms of intermediates related to 7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one synthesis

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:

Intermediates involved in synthesis of Compound A are 7-(4-chlorobutoxy)quinolin- 2(1H)-one (referred to as Compound B), 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride (referred to as Compound C) and 1-(benzo[b]thiophen-4-yl)piperazine (referred to as Compound D).

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

Preparation of crystalline 7-(4-chlorobutoxy)quinolin-2(1H)-one [Compound B]

A reaction mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (Compound I, 0.02 mol), 1-bromo-4-chlorobutane (0.12 mol), potassium carbonate (0.04 eq.) and DMF (10 ml) was stirred and heated to 50o C. After the reaction was completed, water was added and the obtained precipitation was collected by filtration followed by washings with water and MTBE and drying to give 7-(4-chlorobutoxy)-3,4-dihydroquinolin- 2(1H)-one (Compound II).


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Next, a reaction mixture of 7-(4-chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one (Compound II) (0.015 mol), DDQ (0.018 eq.) and dioxane (20 ml) was stirred and heated to 40o C. After the reaction was completed, it was added to aqueous solution of sodium sulfite. Then, the reaction mixture was filtered, washed and dried. The resulting product was crystallized from DMF/water (5v/5v) upon heating at 50o C to give crystalline compound B.

The obtained crystalline product was characterized by XRPD. The XRPD pattern is presented in the following figure:

Sample ID: Analyst: Uri, Sample name: BRX 15011501T083-1A (BRX-1 CL)+SI, Temp: 25.0°C
Date: 09/06/15 13:04 Step : 0.050° Integration Time: 1.000 sec
Range: 2.000 - 40.000° Cont. Scan Rate: 3.000 [°/min]

°2theta

Main XRD peak positions of crystalline 7-(4-chlorobutoxy)quinolin-2(1H)-oneare:
10.9, 11.4, 12.2, 12.8, 15.3, 15.7, 16.7, 17.8, 18.7, 19.7, 20.2, 21.1, 22.3, 23.0, 23.7,
24.5, 24.9, 25.4, 26.4, 26.8, 27.5 and 29.3 ±0.2 °2θ.

Compound C was obtained according the described procedure in Org. Process Res. Dev. 2015, 19, 555-558. Next, the resulting product was purified by slurry in dichloromethane (10 volumes per gram of the crude) at 40 °C over a period of 1h followed by hot vacuum filtration. The isolated product was washed with dichloromethane (2 volumes per gram of the crude) and dried in vacuum oven at 50 °C for ~20 hrs t...