WO2016207770A1

WO2016207770A1 - A process for the preparation of polyquaternium-1

Info

Publication number: WO2016207770A1
Application number: PCT/IB2016/053640
Authority: WO
Inventors: Hero Velladurai; Janardhana Rao Vascuri; Meenakshisunderam Sivakumaran; Tushar JANA; Vyshnavi DARIPALLI
Original assignee: Aurobindo Pharma Ltd
Current assignee: Aurobindo Pharma Ltd
Priority date: 2015-06-24
Filing date: 2016-06-18
Publication date: 2016-12-29
Anticipated expiration: 2017-12-24

Abstract

The present invention relates to a process for the preparation Polyquaternium-1 of formula (I).

Description

A PROCESS FOR THE PREPARATION OF POLYQUATERNIUM-l

This application claims the priority from our provisional Indian patent application number 3 166/CHE/2016 filed on June 24, 2015 which is incorporated herein by reference. FIELD OF THE INVENTION

The present invention relates to a process for the preparation Pol uaternium- l of formula (I).

Formula 1

BACKGROUND OF THE INVENTION

Polyquaternium- l (PQ1 ) is a polymeric quaternary ammonium anti-microbial agent that has been used, for example, in preserving ophthalmic compositions and disinfecting contact lenses, PQ1 is effective against bacteria, algae and fungi.

Polymeric quaternary ammonium compounds possess antimicrobial properties. Polyquaternium-l is an antimicrobial substance, and it is marketed under the trade name Polyquad® and Onamer® M. Polyquaternium-l may be used as a preservative in eye drops and as liquid artificial tear substitutes. It is also used as a disinfectant for contact lenses,

Polyquaternium- l for first time disclosed in US 3,93 1 ,319, US '319 patent discloses a method for the preparation of Polyquaternium- l by two step reaction. In. the two-step method, trans-l,4-dich!oro-2-butene is reacted with trans- 1 ,4- bis(dimethyiamino)-2-butene in the first step to obtain polymeric compound possess terminal chlorine atoms which is reacted with triethanolamine (known as end-capping) in aqueous medium to yield Poiyquaternium-l . US 4,027,020 disclose a method for the preparation of Polyquaternium-1 by one step reaction. In the one-step method, trans-1 ,4-bis(dimethylamino)-2-butene and triethanolamine are concomitantly mixed with trans- I,4-dichloro-2-butene in an aqueous solution. US 5,5 12,597 provides a one pot process for the preparation of polymeric quaternary ammonium, which is structurally similar to Polyquaternium- 1 , wherein after end-capping with Ν,Ν-dimethyiamine the polymer is precipitated from the reaction medium as a solid, In the above mentioned patents end-capping reaction is carried out in aqueous medium. Applicant has observed incomplete conversion when the end-capping reaction is conducted in aqueous medium which further results with formation of more polymeric impurities/degradation products which are difficult to separate from poiyquaternium-l . Moreover the obtained product is dark brown colour and difficult to improve the colour in conventional purification methods.

WO 2008/131013 suggests an improved method to synthetize polyquaternium- 1 , by on the one-step method, in which trans-l,4-bis(dimethylamino)-2-butene, triethanolamine and an acid are dissolved in water, thereafter trans- 1 ,4-dichloro-2- butene is added to the solution. Hydrochloric acid, sulfuric acid and phosphoric acid are mentioned as examples of suitable acids.

WO 2010/124225 describes a process for preparing polyquaternium-1 , which has a high average relative molecular weight of more than 28,000. The method described in WO 2010/124225 differs from that described in WO 2008/131013 merely by the fact that not the entire amounts of the triethanolamine and the acid were present in the initial reaction solution, and that the missing amounts were given into the reaction solution after the addition of trans- 1 ,4-dichioro-2-butene.

Applicant has observed that the usage of acid in the preparation of Polyquaternium-1 leads to the formation of triethanolamine acid salt which is precipitated along with the product and also removal of said salt from the product becomes difficult and makes the process is tedious.

WO 2013/1 89596 discloses a process for the preparation of polyquaternium-1 having purity approximately 95%, based on the one-step method using aprotic polar solvent. Since all the reactant, including the triethanolamine is added, in the initial stage applicant has observed that there is an inconsistency in polymerization stage and more impurities formation.

The reported literature for Po!yquaternium-I by one step method associated with certain disadvantages such as

i) impurities/degradation products are more in the final compound, which are difficult to remove;

ii) inconsistency in polymerization step;

iii) often fail to produce the desired molecular weight of po!yquaternium-1 ; and

iv) Incomplete end-capping reaction.

Considering the above said drawbacks in the preparation of Polyquaternium-1 and the importance of Polyquaternium-1 in the medical treatment, applicant diligently did research and succeeded with the preparation of Polyquaternium-1 having desired molecular weight and purity. OBJECTIVE OF INVENTION

An objective of the present invention is to provide a process for preparing Polyquaternium-l having desired molecular weight and purity. Another objective of the present invention is to provide a process for preparing

Polyquaternium- l , which is simple, industrially applicable and robust.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Pol uaternium-l of formula (I)

which comprises, treating 1 ,4-bis(dimethylamino)-2-butene-1 ,4-dichloro-2-butene co- polymer with triethanoiamine in presence of an alcoholic solvent.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, Polyquaternium-l can be obtained by treating 1,4-bis(dimethylamino)2-2bute1ne,- 4-dichloro-2-butene co-polymer with triethanoiamine in an alcoholic solvent.

In another embodiment of the present invention, the alcoholic solvent used in the second step is selected from the group comprising methanol, ethanol, isopropanoi, propanol, butanol and/or mixtures thereof. In still another embodiment of the present invention, the reaction is carried out temperature in the range of 35 - 100° C, preferably temperature in the range of 40 - 80° C and most preferably temperature in the range of 40 - 50° C. In yet another embodiment of the present invention, the product obtained is precipitated as per the teaching provided in the US 5,512,597.

In one embodiment of the present invention, the product obtained is optionally purified by carbon treatment. Accordingly the Polyquaternium- 1 precipitated is dissolved in any suitable solvent such as methanol, ethanol and/or mixtures thereof and subjected to carbon treatment, followed by isolated by conventional methods such as cooling or removing the solvent.

Accordingly the present invention provides a robust method for the preparation of Polyquaternium- 1 having high purity and further ali the terminal chlorine atoms are adequately end capped with triethanolamine.

In one more embodiment of the present invention, Polyquaternium-1 prepared according to the present invention having a number average molecular weight of 3000 to 35000 Daltons, preferably having a number average molecular weight of 3000 to 20000 Daltons and most preferably having a number average molecular weight of 6000 to 20000 Daltons. The purity of polyquaternium-1 is measured by using Gel Permeation Chromatography (GPC) analysis. Accordingly the present invention provides polyquaternium-1 with purity greater than 98%. in an embodiment of the present invention, polyquaternium-1 is prepared by two-step method in presence of alcoholic solvent for end capping reaction to obtain high purity, with consistent yields. In one more embodiment of the present invention, Polyquaternium-1 prepared according to the present invention having less polymeric impurities.

In one more embodiment of the present invention, the staring material 1 ,4- bis(dimethylamino)-2-butene- 1 ,4-dichioro-2-butene co-polymer (chloro intermediate) is prepared by conventional method such as coupling of 1 ,4-bis-dimethylamino-2- butene with 1 ,4-dichloro-2-butene, The said reaction is carried out in the presence of a solvent selected from the group comprising water, acetone, ethanol, isopropanol, acetonitrile, n-propanol, butanol and/or mixtures thereof.

Applicant has observed that the preparation of Polyquaternium- l by two step method only yields the compound with desired purity and molecular weight. Thus the process comprises i) 1 ,4-bis(dimethylamino)-2-butene- 1 ,4-dichloro-2-butene copolymer (chloro intermediate) is prepared by coupling of 1 ,4-bis-dimethylamino-2- butene with 1 ,4-dichloro-2-butene; and ii) chloro intermediate compound reacts with triethanolamine in an aicohoiic solvent to obtain Polyquaternium-l , The process for the preparation of Polyquaternium-l is represented below:

The embodiments of the present invention described above are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention in any manner whatsoever.

EXAMPLE- 1 : Preparation of Potyquaternium-1

To the suspension of 1 ,4-bis(dimethylamino)-2-butene-1 ,4-dichloro-2-butene co- polymer (10 g) in a mixture of isopropanol and ethanol, triethanolamine (10 g) was added. The reaction mass was heated to about 40-50° C and maintained at 40-50° C till completion of reaction. The progress of the reaction was monitored by ¹ H-NMR. After completion of reaction the solvent was removed under the reduced pressure. To residue, isopropanol (50 ml) was added and stirred. The solid obtained was filtered under nitrogen atmosphere. The wet solid was dissolved in methanol and subjected to carbon treatment, The filtrate was distilled under the reduced pressure. Isopropanol was added to the residue and stirred. The solid obtained was filtered under nitrogen atmosphere and dried. The solid was dissolved in water and excess water was distilled to get 40% aqueous solution of Polyquaternium-1 .

Purity (By GPC): > 98%

Number average molecular weight: About 1 1000 Daltons EXAMPLE-2: Preparation of Polyquaternium-l

To the suspension of 1 ,4-bis(dimethyiamino)-2-butene-1 ,4-dichloro-2-butene copolymer (10 g) in a mixture of isopropanol and methanol, triethanolamine (15 g) was added. The reaction mass was heated to about 70-80° C and maintained at 70-80° C till completion of reaction. After completion of reaction the solvent was removed under the reduced pressure. To residue, isopropanol (50 ml) was added and stirred. The solid obtained was filtered under nitrogen atmosphere. The wet solid was dissolved in methanol and subjected to carbon treatment. The filtrate was distilled under the reduced pressure. Isopropanol was added to the residue and stirred. The solid obtained was filtered under nitrogen atmosphere and dried. The solid was dissolved in water and excess water was distilled to get 40% aqueous solution of Poiyquaternium-1 .

Purity (By GPC): > 98%

Number average molecular weight: About 16000 Daltons

EXAMPLE-3: Preparation of Polyquaternium-l

To the suspension of 1 ,4-bis(dimethylamino)-2-butene- 1 ,4-dichioro-2-butene co- polymer ( 10 g) in isopropanol, triethanolamine (10 g) was added. The reaction mass was heated to about 40-50° C and maintained at 40-50° C till completion of reaction. The progress of the reaction was monitored by ¹H-NMR, After completion of reaction, the reaction mass was cooled and the solid obtained was filtered under nitrogen atmosphere. The wet solid was dissolved in methanol and subjected to carbon treatment. The filtrate was distilled under the reduced pressure. Isopropanol was added to the residue and stirred. The solid obtained was filtered under nitrogen atmosphere and dried. The solid was dissolved in water and excess water was distilled to get 40% aqueous solution of Polyquaternium-l .

Purity (By GPC): > 98%

Number average molecular weight: About 1 1000 Daltons EXAMPLE-4: Preparation of Polyquaternium-1

To the suspension of 1 ,4-bis(dimethy]amino)-2-butene-1 ,4-dichloro-2-butene copolymer (10 g) in isopropanol, triethanolamine( 12 g) was added. The reaction mass was heated to about 75-80° C and maintained at 75-80° C til! completion of reaction. The progress of the reaction was monitored by ¹H-NMR. After completion of reaction, isopropanol (50 ml) was added and the cooled to 25-30°C. The solid obtained was filtered under nitrogen atmosphere. The wet solid was dissolved in methanol and subjected to carbon treatment. The filtrate was distilled under the reduced pressure, isopropanol was added to the residue and stirred, The solid obtained was filtered under nitrogen atmosphere and dried.

Purity (By GPC): > 98%

Number average molecular weight: About 9000 Daltons EXAMPLE-5: Preparation of l,4-bis(dimethylamino)-2-butene-l,4-dichloro-2- butene co-polymer (chloro intermediate)

To acetone, trans- 1 ,4-bistdimethylamino-2-butene (100 gm) was added and heated the contents to 40-50°C followed by trans- 1 ,4-dich!oro~2-butene ( 106 g) was slowly added. The reaction mass was stirred at 40-50°C till completion of reaction. The progress of the reaction was monitored by ¹H-NMR. After completion of the reaction, the reaction mass was cooled to 25-30°C and stirred. The solid obtained was filtered, under nitrogen atmosphere and washed with acetone. The wet product dried under reduced pressure to obtain 1 ,4-bis(dimethyliminio)-2-butene-1 ,4-dichloro-2-butene copolymer. Yield: 95%

EXAMPLE-6: Preparation of 1 ,4-bis(dimethylamino)-2-butene-l,4-dichIoro-2- butene co-polymer (chioro intermediate)

To isopropanol, trans-1 ,4-bis(dimethylamino)-2-butene ( 100 gm) was added and heated the contents to 60-70°C followed by trans- 1 ,4-dichloro-2-butene ( 106 g) was slowly added. The reaction mass was stirred at 60-70°C till completion of reaction. The progress of the reaction was monitored by ¹H-NMR, After completion of the reaction, the reaction mass was cooled to 25-30°C. The solid obtained was filtered, under nitrogen atmosphere, and washed with acetone. The wet product dried under reduced pressure to obtain 1 ,4-bis(dimethylamino)-2-butene-1 ,4-dichloro-2-butene co-polymer. Yield: 90%.

Claims

We Claim:

1. A process for the preparation of Polyquaternium-l which comprises reacting

1 ,4-bis(dimethylamino)-2-butene- 1 ,4-dtchioro-2-butene co-polymer (chloro intermediate) with triethanolamine in an alcoholic solvent to provide Polyquaternium-l .

2. The process as claimed in claim 1 , wherein the alcoholic solvent in step (ii) is selected from methanol, ethanol, isopropanol, propanol, butanol and/or mixture thereof.

3. The process as claimed in claim I , wherein the reaction is carried out temperature range of 35- 100° C,

4. The process as claimed in claim 3, wherein the reaction is carried out temperature range of 40-50° C.

5. The process as claimed in claim 1 , wherein a weight ratio between 1 ,4- bis(dimethylamino)-2-butene-1 ,4-dichloro-2-butene co-polymer (chloro intermediate) and triethanolamine in the solution is 1 ;0.4 to 1 :3,

6. The process as claimed in claim 1 , wherein Polyquaternium-l , has an number average molecular weight of 3000 to 35000 daltons, preferably 6000 to 20000 daltons.

7. The process as claimed in claim 1 , wherein Polyquaternium- l has purity greater than 98%.