DESC:Technical field
The present invention relates to a novel and improved process for obtaining Betaxolol or its pharmaceutical salt.

Background and prior art
Betaxolol hydrochloride, chemically known as 1-[4-[2-(cyclopropylmethoxy) ethyl]phenoxy]-3-(propan-2-ylamino)propan-2-ol, hydrochloride is a cardioselective beta-adrenergic receptor blocking agent, in a sterile isotonic solution.

The chemical structure of Betaxolol is presented below:

Betaxolol is first disclosed in CA1072981. According to the teachings of this patent, Betaxolol is prepared by a reaction which involves cyclopropanation of p-benzyloxy phenethyl alcohol, followed by debenzylation and epoxidation and further reaction with isopropyl amine to give Betaxolol which is further crystallized to give the base by using ether in column chromatography.

The above process discloses purification by column chromatography; however, purification using column chromatography is difficult to carry out on industrial scale. Moreover, the process CA’981 has drawbacks resulting in inconsistent quality of the active pharmaceutical ingredient. The process disclosed in CA’981 is depicted below as in scheme A.

Scheme A

There are various other processes are reported for preparation and purification of Betaxolol and intermediates thereof in various articles and patent/patent applications.

US4760182 (A) and GB2187190 (B) discloses a process of preparation of Betaxolol by first reacting p-hydroxyphenethyl alcohol, with epichlorohydrin followed by isopropylamine, to prepare the required secondary amine-hydroxy side chain. Then the secondary amine-alcohol group is protected by reaction with a suitable aldehyde such as benzaldehyde to form an oxazolidine ring protectant. The oxazolidine ring protectant is removed by simple acid hydrolysis to give Betaxolol, which on further reaction with HCl in presence of isopropanol gives hydrochloride salt of Betaxolol.

US7019172 (B2) discloses a process for preparation of Betaxolol by selective benzylation of 2-[4-hydroxyphenyl-ethanol] with benzyl halide in the presence of base and an organic solvent to obtain 2-[4-benzyloxyphenyl ethanol]; which on further condensing with an allyl halide in the presence of a base and an organic solvent gives 1-(2-allyloxyethyl)-4-benzyloxybenzene; this is followed by cyclopropanation to obtain the 1-benzyloxy-4-(2-cyclopropyl methoxy-ethyl)-benzene; which is de-protected by hydrogenation to obtain 4-(2-cyclopropylmethoxyethyl)-phenol. S(-)-Betaxolol is further obtained by O-Alkylation of the 4-(2-cyclopropylmethoxyethyl)-phenol with R-(-)-epichlorohydrin in the presence of alkali gives a mixture of compounds, the mixture on further reaction with isopropylamine gives S-(-)-Betaxolol which is either reacted with an alcoholic hydrochloride to give Betaxolol hydrochloride or with an organic acid such as maleaic acid in organic solvent to give S-(-)-Betaxolol maleate salt.

Journal of Medicinal Chemistry, 1987, Vol. 30, No. 6 1003-1011, 1987 describes a process of preparation of Betaxolol by reacting cyclopropylmethoxy ethyl phenol in presence of NaOH and epichlorohydrin at ambient temperature to give crude l-[4-[(cyclopropylmethoxy)-ethyl]phenoxy]-2,3-epoxypropane which is further reacted with isopropylamine that is heated under reflux for 48 h. The mixture was then evaporated under reduced pressure to afford Betaxolol base which was further converted into its hydrochloride and crystallized from acetone to give Betaxolol.

Another method of preparation of Betaxolol disclosed in Synthetic Communications, 41: 2468–2474, 2011 is as depicted below in Scheme

Scheme B
Therefore, there remains a need in the art to provide an improved process for the preparation of Betaxolol that controls the generation of hazardous chemicals such as hydrogen gas & chemical waste by avoiding hazardous and pyrophoric reagents such as sodium hydride thereby maintaining environment friendly green chemistry. There also remains a further need in the art that avoids tedious purifications of intermediates and the final product, i.e., Betaxolol such as chromatographic methods reported in the prior arts which are cumbersome to carry out on large scale and does not give consistent quality of the active pharmaceutical ingredient.

It is therefore an object of the present invention to provide a process for purification of Betaxolol via formation of an organic acid salt of Betaxolol and further conversion into Betaxolol free base thereby leading to a better and consistent quality of Betaxolol base.

Summary of the invention
In accordance with the above objective, the present invention provides a process for preparation of Betaxolol base with high purity, which comprises:

a) Condensing Phenyl para hydroxy phenyl ethanol with epichlorohydrine in an organic solvent to obtain 2-(4-(oxiran-2-ylmethoxy)phenyl)ethan-1-ol;
b) Coupling of the 2-(4-(oxiran-2-ylmethoxy)phenyl)ethan-1-ol with cyclopropyl methyl bromide in presence of a suitable base to obtain 2-((4-(2-(cyclopropylmethoxy)ethyl)phenoxy)methyl)oxirane;
c) Solvolysing the 2-((4-(2-(cyclopropylmethoxy)ethyl)phenoxy)methyl)oxirane with isopropyl amine to give crude Betaxolol Base;
d) Reacting the crude Betaxolol Base with Sorbic acid in an organic solvent to obtain Betaxolol Sorbate salt;
e) Optionally purifying the Sorbate salt of Betaxolol with an organic solvent;
f) Treating the Betaxolol Sorbate salt with aqueous ammonia/alkali hydroxide solution followed by extraction into an organic solvent to yield pure Betaxolol base and
g) Treating the Betaxolol base with aqueous HCl solution in an organic solvent to obtain Betaxolol hydrochloride.

The present process uses non-hazardous reagents. The purification of Betaxolol formation of organic acid salt of Betaxolol and on further treatment with a base to obtain Betaxolol with high purity circumvent the tedious column chromatographic purifications reported in earlier processes. The purification process of Betaxalol as disclosed in the present invention industrially viable and can be carried out efficiently on a large scale as it also reduces the undesired impurities /byproducts thereby giving a better quality of Betaxolol base. The process of the present invention consistently gives better quality of Betaxolol base as per ICH guidelines.

In an additional aspect, the invention further provides a process for purification of Betaxolol which process comprises treating Betaxolol with sorbic acid to obtain Betaxolol sorbate and neutralizing the Betaxolol sorbate to obtain pure Betaxolol.

Thus the present invention further encompasses the novel salt of Betaxolol, i.e, Betaxolol sorbate of formula I.

Formula I

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention describes a novel and improved process for preparation of Betaxolol base with high purity which comprises;

a) Condensing Phenyl para hydroxy phenyl ethanol with epichlorohydrine in an organic solvent to obtain 2-(4-(oxiran-2-ylmethoxy)phenyl)ethan-1-ol;
b) Coupling of the 2-(4-(oxiran-2-ylmethoxy)phenyl)ethan-1-ol with cyclopropyl methyl bromide in presence of a suitable base to obtain 2-((4-(2-(cyclopropylmethoxy)ethyl)phenoxy)methyl)oxirane;
c) Solvolysing the 2-((4-(2-(cyclopropylmethoxy)ethyl)phenoxy)methyl)oxirane with isopropyl amine to give crude Betaxolol Base;
d) Reacting the crude Betaxolol Base with Sorbic acid in an organic solvent to obtain Betaxolol Sorbate salt;
e) Optionally purifying the Sorbate salt of Betaxolol with an organic solvent;
f) Treating the Betaxolol Sorbate salt with aqueous ammonia/alkali hydroxide solution followed by extraction into an organic solvent to yield pure Betaxolol base and
g) Treating the Betaxolol base with aqueous HCl solution in an organic solvent to obtain Betaxolol hydrochloride.

The reaction of step a) can be conducted at room temperature to reflux temperature of the solvent.

In the present invention, the reaction of step b) is carried out in presence of Potassium tert. butoxide as a suitable base at a temperature range of 5 to 15°C.

The organic solvent in step a) and step d) to g) is selected from ketones such as acetone, halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, hydrocarbons such as toluene and nitriles such as acetonitrile.

The process steps of c) to g) can be conveniently carried out at room temperature to reflux temperature of the solvent.

In an additional aspect, the invention further provides a process for purification of Betaxolol which process comprises treating Betaxolol with sorbic acid to obtain Betaxolol sorbate and neutralizing the Betaxolol sorbate to obtain pure Betaxolol.
Accordingly, the present invention provides process for purification of Betaxolol which process comprises;
a) Reacting the crude Betaxolol Base with Sorbic acid in an organic solvent to obtain Betaxolol Sorbate salt;
b) Optionally purifying the Sorbate salt of Betaxolol with an organic solvent; and
c) Treating the Betaxolol Sorbate salt with aqueous ammonia/alkali hydroxide solution followed by extraction into an organic solvent to yield pure Betaxolol base.

Thus the present invention further encompasses the novel salt of Betaxolol, i.e, Betaxolol sorbate of formula I.

Formula I

The process of the present invention is outlined in Scheme 1:
Scheme 1
Since the present process uses non-hazardous reagents; it provides a less toxic, environmental friendly and convenient process for obtaining pure Betaxolol. The purification by column chromatography reported in earlier processes is cumbersome and does not give consistent quality of the active pharmaceutical ingredient whereas, the purification by formation of organic acid salt of Betaxolol makes it more industrially viable on large scale and also reduces the undesired impurities thereby giving a better quality of Betaxolol base. The process of the present invention consistently gives better quality of Betaxolol base and the quality meets the requirement of ICH guidelines.

The present invention is exemplified by the following examples which are provided for illustration only and, should not be construed to limit the scope of the invention.

EXAMPLES:
Preparation of stage-I: 2-(4-(oxiran-2-ylmethoxy) phenyl)ethan-1-ol
4-Hydroxy phenyl ethanol (200 g, 1.45 mole)) was treated with Epichlorohydrin (401 g, 4.34 mole) & Potassium Carbonate (401 gm, 2.9 mole) in Acetone (800 ml) at reflux temperature for 4 hrs. The completion of reaction was monitored by TLC. After completion of reaction, insoluble salts were filtered and washed with Acetone (2 x 200 ml), acetone was distilled off to get product / intermediate.

Wt. 274.2 gm
[Yield: 97.46%molar] Mass: [M-18] : 177.08

Preparation of stage-II: 2-((4-(2-(cyclopropylmethoxy) ethyl)phenoxy)methyl) oxirane
2-(4-(oxiran-2-ylmethoxy) phenyl) ethan-1-ol (103 g, 0.53 mole) was dissolved in N,N-Dimethylacetamide (515 ml) . This solution was treated with Cyclopropyl methyl bromide (79 gm, 0.58 mole) and Potassium tert butoxide (66.28 gm, 0.58 mole) at 5-15°C. The completion of reaction was monitored by TLC. After completion, the reaction mass was quenched into water & product extracted in Ethyl acetate (800 ml). Solvent was removed by distillation to get oily intermediate.
Wt. of oil ; 130.29g
[Yield: 98.77%molar] Mass: [M+1] : 249.19

Preparation of stage-III; Betaxolol Base
2-((4-(2-(cyclopropylmethoxy) ethyl)phenoxy)methyl) oxirane (130 gm, 0.52 mole) was treated with Isopropyl amine (197 gm) at room temperature. The completion of reaction was monitored by TLC. After completion of reaction, excess isopropyl amine was distilled out. Oily residue was stripped out with Toluene (130 ml) to get crude Betaxolol base.
Wt. of base: 83.23 g
Yield: 51%
HPLC Purity>90%
[Yield: 51.0%molar] Mass: [M+1] : 308.14

Purification of Betaxolol base:
Betaxolol base (25 g, 0.08 mole) was dissolved in Acetone (125 ml) treated with Sorbic acid (7.3 gm, 0.065 mole) at room temperature for one hour. Sorbate salt thus obtained was filtered and washed with Acetone (25 ml). Betaxolol Sorbate was treated with Sodium hydroxide & product extracted in Toluene. After distillation of Toluene, Betaxolol pure base was obtained. Purity by HPLC: 97.54%
Wt.: 16 g
Yield: 64 %

Preparation of Betaxolol Hydrochloride:
Betaxolol purified base (16 gm) was dissolved in Acetone (80 ml) and treated with aqueous HCl at 25-30°. White solid precipitate of the product obtained was filtered and dried at 50-55°C.
Wt. of Betaxolol Hydrochloride: 15 g , Purity by HPLC: 99.5%
,CLAIMS:1. A process for obtaining Betaxolol base with high purity which comprises,,
a) Condensing Phenyl para hydroxy phenyl ethanol with epichlorohydrine in an organic solvent to obtain 2-(4-(oxiran-2-ylmethoxy)phenyl)ethan-1-ol;
b) Coupling of the 2-(4-(oxiran-2-ylmethoxy)phenyl)ethan-1-ol with cyclopropyl methyl bromide in presence of a suitable base to obtain 2-((4-(2-(cyclopropylmethoxy)ethyl)phenoxy)methyl)oxirane;
c) Solvolysing the 2-((4-(2-(cyclopropylmethoxy)ethyl)phenoxy)methyl)oxirane with isopropyl amine to give crude Betaxolol Base;
d) Reacting the crude Betaxolol Base with Sorbic acid in an organic solvent to obtain Betaxolol Sorbate salt;
e) Optionally purifying the Sorbate salt of Betaxolol with an organic solvent;
f) Treating the Betaxolol Sorbate salt with aqueous ammonia/alkali hydroxide solution followed by extraction into an organic solvent to yield pure Betaxolol base and
g) Treating the Betaxolol base with aqueous HCl solution in an organic solvent to obtain Betaxolol hydrochloride.

2. The process as claimed in claim 1 wherein, the suitable base in step b) is carried out in presence of Potassium tert butoxide as a suitable base at a temperature range of 5 to 15°C.

3. The process as claimed in claim 1 wherein, the organic solvent in step a) and step d) to g) is selected from ketones such as acetone, halogenated hydrocarbons such as methylenedichloride, ethylene dichloride, hydrocarbons such as toluene and nitriles such as acetonitrile.
4. The process as claimed in claim 1 wherein, the reaction of step a) is conducted at room temperature to reflux temperature of the solvent.

5. The process as claimed in claim 1 wherein, the process steps of c) to g) are carried out at room temperature to reflux temperature of the solvent.

6. A process for purification of Betaxolol which process comprises treating Betaxolol with sorbic acid to obtain Betaxolol sorbate and neutralizing the Betaxolol sorbate to obtain pure Betaxolol.

7. The process for purification of Betaxolol as claimed in claim 6, wherein, the process comprises;
a) Reacting the crude Betaxolol Base with Sorbic acid in an organic solvent to obtain Betaxolol Sorbate salt;
b) Optionally purifying the Sorbate salt of Betaxolol with an organic solvent; and
c) Treating the Betaxolol Sorbate salt with aqueous ammonia/alkali hydroxide solution followed by extraction into an organic solvent to yield pure Betaxolol base.

8. The process for purification of Betaxolol as claimed in claim 7, wherein, the organic solvent in step a) to step c) is selected from ketones such as acetone, halogenated hydrocarbons such as methylenedichloride, ethylene dichloride, hydrocarbons such as toluene and nitriles such as acetonitrile.

9. The process as claimed in claim 7, wherein, the process steps of a) to c) are carried out at room temperature to reflux temperature of the solvent.

10. Betaxolol sorbate of formula I

Formula I