Specification
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"IMPROVED PROCESS FOR THE PREPARATION OF
BLONANSERIN"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Indian companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad 380015, Gujarat, India.
The following specification particularly describes the nature of the invention and the manner in which it is performed:
FIELD OF INVENTION
The present invention provides an improved process for preparation of Blonanserin
using a novel intermediate as well as process for the purification of the same. BACKGROUND OF THE INVENTION
Blonanserin is a novel antipsychotic agent having both dopamine D2 and serotonine 5-HT2 receptor antagonist properties. 2-(l-piperazinyl)-4-phenylcycloalkanopyridine derivatives such as the compound with the generic name Blonanserin was Chemically known as 2-(4-Ethyl-l-piperazinyl)-4-(4-fluoropheny!)-5,6,7,8,9J0-hexahydro-cycloocta[b]pyridine has the structural formula as shown in formula (I)
F Formula (I)
US 5021421, is the product patent for Blonanserin. This patent describes several molecules, which are 2-(l-piperazinyl)-4-phenylcycloalkanopyridine derivatives. Among these molecules is disclosed Blonanserin. Here, various synthetic schemes for preparation of the molecules disclosed and their intermediates are mentioned. Particularly, preparation of Blonanserin and its dimaleate, dihydrochloride, fumarate and citrate is mentioned in Example 1.
US Patent No. 5021421 describes a process for the preparation of Blonanserin as shown in below scheme 1.
BLONASERIN (I)
Scheme- 1
US 5021421 disclose a process for the preparation of Blonanserin, involves the step-(a), the preparation of 4-(4-Fluorophenyl)-5,6,7,8,9J10-hexahydro-lH-cycloocta[b]pyridin-2-one formula (IV) by condensation of formula (II) and formula (II) using polyphosphoric acid. The use of polyphosphoric acid has been observed very tedious during the quenching of reaction mixture in water due to high degree of viscosity of reaction mixture even at high temperature.
As disclosed in scheme-I step-(b), the compound of formula (IV) is reacted with a phenyl phosphonic acid dichloride to obtain compound of the formula (V). Step-(c) involves the reaction of the formula (V) with N-ethylpiperazine is carried out in the presence of a basic substance and temperature is usually in the range of 40 to 200 °C.
However, the disadvantages of using a chloro (halo group), mesylate, tosylate as leaving groups resulted in the formation of undesired impurities and a very slow conversion was found in our hand. The document (US 5021421) stated nothing about the purity and yield of compound formula I obtained through this process. However it was observed that use of any of these leaving group leads to the formation of compound of formula (IV) as major impurity in the further process. So, a robust process for the preparation of compound of formula (V) and compound of formula (I) has been required, which must be smooth and easy to operate at commercial scale production.
The present application disclosed the condensation of N-ethylpiperazine with Trifluoromethanesulfonic acid 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]-pyridin-2-yl ester of formula (VI) resulting very fast and clean condensation.
Thus, there remains a need for developing a process which overcomes one or more of the deficiencies of the prior art and thereby develop an improved process for preparing Blonanserin which gives better yields and improved purity and also make it industrial applicable. We herein disclose an improved process for preparing Blonanserin wherein impurity formation is substantially reduced and thereby obtained pure final product. One of the major drawback with using polyphosphoric acid during intermediate formation was overcome by present invention, which involves the dilution of polyphosphoric acid with orthophosphoric acid (85%) and thereby improving the viscosity of reaction mass. Second drawback is that when using a chloro (halo group), mesylate, tosylate as leaving groups resulted in the formation of undesired impurities and a very slow conversion. This problem was also overcome by the process of the present invention, which involves the use of triflate leaving group instead of a chloro (halo group), mesylate, tosylate. OBJECTS OF THE INVENTION
It is an object of the present invention to provide an improved and industrially suitable process for preparing Blonanserin using novel intermediate.
In an embodiment is provided a novel intermediate Trifluoromethanesulfonic acid 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycIoocta[b]-pyridin-2-yl ester of formula (VI). In another embodiment is provided a process for the purification of Blonanserin. The above and other embodiments are further described in the following paragraphs. DETAILED DESCRIPTION
The improved process for preparing Blonanserin of formula (I) is described in the following scheme 2:
.0
CN
Step-(b)
o
Formula (II)
Formula (III)
PPA, H3PO4 Step-(a)
Formula (IV)
Documents
Application Documents
| # |
Name |
Date |
| 1 |
3025-MUM-2009- AFR.pdf |
2022-10-28 |
| 1 |
3025-mum-2009-general power of attorney.pdf |
2018-08-10 |
| 2 |
3025-mum-2009-form 5.pdf |
2018-08-10 |
| 2 |
3025-MUM-2009-AbandonedLetter.pdf |
2018-08-10 |
| 3 |
3025-mum-2009-form 3.pdf |
2018-08-10 |
| 4 |
3025-mum-2009-form 2.pdf |
2018-08-10 |
| 4 |
3025-mum-2009-abstract.pdf |
2018-08-10 |
| 6 |
3025-mum-2009-form 2(title page).pdf |
2018-08-10 |
| 6 |
3025-mum-2009-claims.pdf |
2018-08-10 |
| 7 |
3025-MUM-2009-FORM 18(9-12-2013).pdf |
2018-08-10 |
| 7 |
3025-MUM-2009-CORRESPONDENCE(7-5-2010).pdf |
2018-08-10 |
| 8 |
3025-mum-2009-form 1.pdf |
2018-08-10 |
| 8 |
3025-MUM-2009-CORRESPONDENCE(9-12-2013).pdf |
2018-08-10 |
| 9 |
3025-MUM-2009-FORM 1(7-5-2010).pdf |
2018-08-10 |
| 9 |
3025-mum-2009-correspondence.pdf |
2018-08-10 |
| 10 |
3025-mum-2009-description(complete).pdf |
2018-08-10 |
| 10 |
3025-MUM-2009-FER.pdf |
2018-08-10 |
| 11 |
3025-mum-2009-description(complete).pdf |
2018-08-10 |
| 11 |
3025-MUM-2009-FER.pdf |
2018-08-10 |
| 12 |
3025-mum-2009-correspondence.pdf |
2018-08-10 |
| 12 |
3025-MUM-2009-FORM 1(7-5-2010).pdf |
2018-08-10 |
| 13 |
3025-MUM-2009-CORRESPONDENCE(9-12-2013).pdf |
2018-08-10 |
| 13 |
3025-mum-2009-form 1.pdf |
2018-08-10 |
| 14 |
3025-MUM-2009-CORRESPONDENCE(7-5-2010).pdf |
2018-08-10 |
| 14 |
3025-MUM-2009-FORM 18(9-12-2013).pdf |
2018-08-10 |
| 15 |
3025-mum-2009-claims.pdf |
2018-08-10 |
| 15 |
3025-mum-2009-form 2(title page).pdf |
2018-08-10 |
| 17 |
3025-mum-2009-abstract.pdf |
2018-08-10 |
| 17 |
3025-mum-2009-form 2.pdf |
2018-08-10 |
| 18 |
3025-mum-2009-form 3.pdf |
2018-08-10 |
| 19 |
3025-mum-2009-form 5.pdf |
2018-08-10 |
| 19 |
3025-MUM-2009-AbandonedLetter.pdf |
2018-08-10 |
| 20 |
3025-mum-2009-general power of attorney.pdf |
2018-08-10 |
| 20 |
3025-MUM-2009- AFR.pdf |
2022-10-28 |
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