DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201741026086 filed on July 21, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides an improved process for the preparation of polyallylamine or its salts having an average molecular weight not less than 15,000 Daltons and a Poly Dispersity Index of not more than 5, and purification of the same thereof.

BACKGROUND OF THE INVENTION

The polyallylamine hydrochloride is the key starting material for the preparation of colesevelam hydrochloride, sevelamer and other polyallylamine derivatives. Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide and used in the adjunctive therapy to diet and exercise for the reduction of elevated LDL cholesterol in patients with primary hypercholesterolemia. Colesevelam is marketed in USA as Welchol.

The process for preparing a monoallylamine polymer of high polymerization degree in high yield by radically polymerizing monoallylamine under conditions of easy industrial applicability using 2,2’-azobis-[2-imidazolinyl)propane] dihydrochloride is first disclosed in the US Patent No. 4,569,979. The monoallylamine was converted to its hydrochloride before the reaction. The 2,2’-azobis-[2-imidazolinyl)propane]dihydrochloride, the radical initiator was added to monoallylamine hydrochloride in nitrogen atmosphere at 60°C for 40 hours till the formation of polyallylamine hydrochloride. The polyallylamine hydrochloride prepared by this method had an average molecular weight of about 11,000 as measured by equilibrium precipitation method in 3.5 M aqueous sodium chloride solution.

The US Patent Application No. 20130123433 discloses the preparation of polyallylamine hydrochloride having average molecular weight ranging from 10,000 to 50,000 Daltons by the addition of aqueous solution of 2,2’-azobis-[2-imidazolinyl)propane] dihydrochloride in two lots into aqueous monoallylamine hydrochloride solution.

The US Patent No. 6,303,723 discloses the preparation of polyallylamine hydrochloride from the monoallylamine hydrochloride by the addition of aqueous solution of 2,2’-azobis-[2-imidazolinyl)propane] dihydrochloride in one time or multiple times in the process. The average molecular weight of the resulting polyallylamine hydrochloride by the process disclosed in this patent is about 33,000 Daltons.

The existing methods to produce polyallylamine hydrochloride are difficult and involve costly handling and cleanup procedures particularly in a commercial batch.

Therefore, there is a need to develop an improved process for the preparation of polyallylamine hydrochloride having specific range of average molecular weight, which is simple and efficient in large scale.

OBJECT OF THE INVENTION

The object of the invention is to provide an improved process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons, and a Poly Dispersity Index of not more than 5.

SUMMARY OF THE INVENTION

Accordingly, there is provided an improved process for the preparation of polyallylamine or its salts thereof.

In one aspect of the invention, there is provided an improved process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons, and a Poly Dispersity Index of not more than 5, said process comprising the steps of:
(i) adding an aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to one molar equivalent of allylamine;
(ii) maintaining the reaction mixture formed in step (i) for about 24 hours;
(iii) repeating the steps of:
a) adding of the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to the obtained reaction mixture and
b) maintaining the reaction mixture of step (a) for about 24 hours,
for two to four times; and
(iv) optionally purifying the reaction mass obtained from step (iii) to yield solid polyallylamine hydrochloride.

In some embodiment of the invention, the polyallylamine hydrochloride prepared according to the above described process has an average molecular weight of more than 35000 Daltons

In some embodiment of the invention, the polyallylamine hydrochloride prepared according to the invention has Poly Dispersity Index of not more than 3.

In some embodiment of the invention, there is provided a process for the preparation of polyallylamine hydrochloride wherein the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride is added to the mixture of allylamine and concentrated hydrochloric acid.

In another embodiment of the invention, in the above described process for the preparation of polyallylamine hydrochloride the reaction mixture obtained in step (i) or step (iii)(a) is heated to temperature of about 55 ± 5°C.

In yet another embodiment of the invention, in the above described process for the preparation of polyallylamine hydrochloride the reaction mass obtained in step (iii) is purified by washing with methanol

In some other embodiment of the invention, the above described process for the preparation of polyallylamine hydrochloride is carried under inert atmosphere.

In another aspect of the invention, there is provided a process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons and a Poly Dispersity Index of not more than 5, said process comprising the steps of:

(i) adding an aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to a mixture of one molar equivalent of allylamine and concentrated hydrochloric acid;
(ii) heating the reaction mixture obtained in step (i) to temperature of about 55 ± 5°C.
(iii) maintaining the reaction mixture of step (ii) for about 24 hours;
(iv) repeating the steps of:
a) adding of the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to the obtained reaction mixture at temperature of about 55 ± 5°C, and
b) maintaining the reaction mixture of step (a) for about 24 hours,
for two to four times;
(v) cooling the reaction mass obtained in step (iv) to about 25 ± 5°C;
(vi) washing the reaction mass obtained from step (v) with methanol; and
(vii) isolating solid polyallylamine hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have surprisingly found an improved process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons, preferably more than 20,000 Daltons and a Poly Dispersity Index of not more than 5, which is efficient and is amenable for large scale production.

In one aspect of the invention, there is provided a process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons, preferably more than 20,000 Daltons and a Poly Dispersity Index of not more than 5, said process comprising the steps of:

(i) adding an aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to one molar equivalent of allylamine;
(ii) maintaining the reaction mixture formed in step (i) for about 24 hours;
(iii) repeating the steps of:
a) adding of the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to the obtained reaction mixture and
b) maintaining the reaction mixture of step (a) for about 24 hours,
for two to four times; and
(iv) optionally purifying the reaction mass obtained from step (iii) to yield solid polyallylamine hydrochloride.

The polyallylamine hydrochloride prepared by according to the present invention have many uses including the preparation of colesevelam hydrochloride, sevelamer hydrochloride and sevelamer carbonate.

As used herein an “allylamine” is an compound in which one or more allyl groups are covalently bonded to an amino nitrogen atom. The amino nitrogen can be primary, secondary, tertiary or quarternary nitrogen atom. Thus, allylamine compounds include, for example allylamine, diallylamine, triallylamine and tetraallyl ammonium.

The process for the preparation of polyallylamine hydrochloride may be carried out in a suitable polar solvent. Suitable solvents include, for example water, inorganic acids or its aqueous solutions, organic acids or its aqueous solutions, aqueous solution of water miscible organic solvents such as dimethylsulfoxide, dimethylformamide, acetone and the like. Preferably the polar solvent is acidic.

In the present invention, the allylamine salt can be added to the polar reaction solvent or can be prepared in situ by dissolving the free base of the allylamine in reaction solvent that contains a sufficient quantity of acid to convert the free base into an acid addition salt. In some embodiment of the invention, there is provided a process for the preparation of the polyallylamine hydrochloride wherein the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride is added to the mixture of allylamine and concentrated hydrochloric acid.

The polymerization of allylamine compounds is inhibited by oxygen. Thus in a preferred embodiment, the oxygen content of the reaction solvent is reduced. Suitable methods for reducing the oxygen content of an aqueous solution are known in the art and include for example bubbling an inert gas through the solution and maintained the solution under reduced pressure. Preferably, the reaction mixture is maintained under an inert atmosphere after the oxygen content is reduced. In some other embodiment of the invention, the above described process for the preparation of polyallylamine hydrochloride is carried under inert atmosphere.

The polymerization reaction is maintained at suitable temperature for an amount of time suitable for polymerization to occur. For example, the reaction can be maintained at a temperature of about 50°C to about 100°C, preferably 50°C to 60°C. Preferably the reaction is maintained at the desired temperature which is sufficient to allow conversion of about 80% or more allylamine into polymers. In some embodiments, the reaction mixture obtained in step (i) or step (iii)(a) of the above described process for the preparation polyallylamine hydrochloride is heated to temperature of about 55 ± 5°C.

Polymers produced in accordance with the process of the invention can be recovered using any suitable method, such as precipitation and/or filtration.

The preferable mode of present invention provides a process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons, preferably more than 20,000 Daltons, more preferably more than 35,000 Daltons and a Poly Dispersity Index of not more than 5 more preferably Poly Dispersity Index is not more than 3.

In some embodiment of the invention, the polyallylamine hydrochloride prepared according to the above described process has an average molecular weight of more than 35000 Daltons. In some other embodiment of the invention, the polyallylamine hydrochloride prepared according to the invention has Poly Dispersity Index of not more than 3.

The addition of the aqueous solution 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to one molar equivalent of allylamine to the reaction mixture includes addition of 0.003 molar equivalents of 2,2’-azobis-2-amidinopropane dihydrochloride to one molar equivalent of allylamine to the reaction mixture.

The polyallylamine hydrochloride prepared according to the invented process is purified according to the know techniques of purification. In some embodiment of the invention, the polyallylamine hydrochloride prepared is purified by washing with methanol. In some embodiment of the invention, in the process for preparation of polyallylamine hydrochloride as described above the reaction mass obtained in step (iii) is purified by washing with methanol. In some other embodiment of the invention, polyallylamine hydrochloride prepared is purified by multiple washings with methanol.

In another aspect of the invention, there is provided a process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons and a Poly Dispersity Index of not more than 5, said process comprising the steps of:

(i) adding an aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to a mixture of one molar equivalent of allylamine and concentrated hydrochloric acid;
(ii) heating the reaction mixture obtained in step (i) to temperature of about 55 ± 5°C;
(iii) maintaining the reaction mixture of step (ii) for about 24 hours;
(iv) repeating the steps of:
a) adding of the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to the obtained reaction mixture at temperature of about 55 ± 5°C, and
b) maintaining the reaction mixture of step (a) for about 24 hours,
for two to four times;
(v) cooling the reaction mass obtained in step (iv) to about 25 ± 5°C;
(vi) washing the reaction mass obtained from step (v) with methanol; and
(vii) isolating solid polyallylamine hydrochloride.

In some embodiment of the invention, there is provided a process for the preparation of polyallylamine hydrochloride having improved yield and purity. In some embodiment of the invention, the polyallylamine hydrochloride prepared according to invention has high yield and purity.
The present invention is described by the following examples, which are for illustrative purpose only and should not be construed as to limit the scope of the invention in any manner.

EXAMPLES

Example-1: Preparation of polyallylamine hydrochloride:

Allylamine (300 g) was slowly added to concentrated hydrochloric acid (558 ml), then stirred for 10 minutes. A solution of 2,2’-azobis-2-amidinopropane dihydrochloride (6 g) in water (13.5 ml) was added to the mixture at 25°C ± 5°C. After addition the reaction mixture was heated to 55°C ± 5°C and maintained for 24 hours. The addition of the solution of 2,2’-azobis-2-amidinopropane dihydrochloride (6 g) in water (13.5 ml) to the reaction mixture at 55°C ± 5°C and maintenance at the same temperature for 24 hours were consecutively done three times. The progress of the reaction was monitored by Gel Permeation Chromatography. After completion of the reaction, the reaction mass was cooled to 25°C ± 5°C. The reaction mass was mixed with methanol (6000 ml) at 25°C ± 5°C and stirred for 2 hours at the same temperature. The resulted solid was filtered in nitrogen atmosphere and washed with methanol (300 ml). The washed solid was mixed with methanol (3000 ml) and stirred for 12 hours. The resultant solid was filtered, washed with methanol (300 ml) and dried. % Yield: 77.90%; Average molecular weight: 26116; Poly Dispersity Index: 2.3
,CLAIMS:
1) A process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons and a Poly Dispersity Index of not more than 5, said process comprising the steps of:
(i) adding an aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to one molar equivalent of allylamine;
(ii) maintaining the reaction mixture of step (i) for about 24 hours;
(iii) repeating the steps of:
a) adding of the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to the obtained reaction mixture and
b) maintaining the reaction mixture of step (a) for about 24 hours,
for two to four times; and
(iv) optionally purifying the reaction mass obtained from step (iii) to yield solid polyallylamine hydrochloride.

2) The process as claimed in claim 1, wherein said molecular weight is preferably more than 35000 Daltons.

3) The process as claimed in claim 1, wherein said Poly Dispersity Index is preferably not more than 3.

4) The process as claimed in claim 1, wherein the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride is added to the mixture of allylamine and concentrated hydrochloric acid.

5) The process as claimed in claim 1, wherein the reaction mixture obtained in step (i) or step (iii)(a) is heated to temperature of about 55 ± 5°C.

6) The process as claimed in claim 1, wherein the reaction mass obtained in step (iii) is purified by washing with methanol.
7) The process as claimed in claim 1, wherein the reaction is carried under inert atmosphere.

8) A process for the preparation of polyallylamine hydrochloride having an average molecular weight not less than 15,000 Daltons and a Poly Dispersity Index of not more than 5, said process comprising the steps of:
(i) adding an aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to a mixture of one molar equivalent of allylamine and concentrated hydrochloric acid;
(ii) heating the reaction mixture obtained in step (i) to temperature of about 55 ± 5°C;
(iii) maintaining the reaction mixture of step (ii) for about 24 hours;
(iv) repeating the steps of:
a) adding of the aqueous solution of 2,2’-azobis-2-amidinopropane dihydrochloride of about 0.004 molar equivalents to the obtained reaction mixture at temperature of about 55 ± 5°C, and
b) maintaining the reaction mixture of step (a) for about 24 hours,
for two to four times;
(v) cooling the reaction mass obtained in step (iv) to about 25 ± 5°C;
(vi) washing the reaction mass obtained from step (v) with methanol; and
(vii) isolating solid polyallylamine hydrochloride.