An improved process for the preparation of highly pure Isoproterenol and its pharmaceutical acceptable salts thereof.

Priority

This application claims the benefit to the provisional application No. 2529/CHE/2015, filed on May 20th , 2015 entitled "An improved process for the preparation of highly pure Isoproterenol & its pharmaceutical^ acceptable salts thereof the contents of which incorporated by reference herein.

Field of the Invention

The present invention relates to an improved process for the preparation of pure Isoproterenol of Formula (I) and its pharmaceutically acceptable salts thereof

wherein A=acid, selected from the group of inorganic acids like hydrochloric acid, hydrobromic acid, or organic acids comprising acetic acid, trifluoroacetic acid, tartaric acid, oxalic acid,fumaric acid, succinic acid, maleic acid, benzoic acid, para toluene sulphonic acid and methanesulfonic acid.

Specifically, the present invention relates to process for the preparation of Isoproterenol and its pharmaceutically acceptable salts thereof through acid addition salt of acetophenone intermediate of formula (II).


• wherein A'=acid, same as defined above for A.

The present invention also provides an improved and an industrially advantageous process for preparation of pure crystalline Isoproterenol hydrochloride and its pharmaceutically acceptable salts, wherein the level of impurities and residual solvents are present in specified limits as per ICH guidelines.

Back ground of the Invention

Isoproterenol is Chemically known as 3,4-Dihydroxy-a-[(isopropylamino)methyl] benzyl alcohol. Isoproterenol is a non-selective beta-adrenergic agonist and used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma.

US2308232 discloses Isoproterenol and its process for the preparation thereof. The process for the preparation of Isoproterenol sulphate as described in the '232 patent can be represented by the below Scheme-1.

As represented in Scheme-1, Isoproterenol sulphate is prepared by the reaction of 3,4-dihydroxy-w-chlorine acetophenone with aqueous isopropylamine solution in the presence of ethyl alcohol and neutralizing with diluted sulphuric acid followed by recrystallization from alcohol to give 3,4-dihydroxy-w-isopropylaminoacetophenone sulphate, which upon hydrogenation with palladium chlorine, carbon in methyl alcohol and water produces Isoproterenol sulphate.

The complete process as described in '232 patent is very complex, using of sulfuric acid is not recommended which is difficult to handle at large scale manufacturing. And the '232 patent is silent about the purity of the final compound. Further, the '232 patent is not disclosed or described regarding preparation process of Isopreterenol hydrochloride and its purity. The patent is also silent on product appearance, purity and crystalline nature.

Isoproterenol and its pharmaceutical^ acceptable salts prepared by the prior art process is having high level of impurities. Especially, the major disadvantage of the prior art process is formation of the completely reduced impurity of compound of formula (la). Removal of this impurity is not possible by simple purification techniques known in the art. Hence, there is need to develop an alternate process to prepare highly pure Isoproterenol and its pharmaceutical^ acceptable salts thereof suitable for pharmaceutical formulation.

or pharmaceutical^ acceptable salts thereof.
Object of the Invention

The main object of the present invention is to provide an improved process for the preparation of highly pure (>99.7%) Isoproterenol and pharmaceutical^ acceptable salts thereof using acid addition salts of Intermediate.

Another object of the present invention is to provide a process for the preparation of acid addition salt of an intermediate compound of Isoproterenol.

One more object of the present invention is to provide crystalline forms of Isoproterenol and pharmaceutically acceptable salts thereof.

Yet another object of the present invention is to provide an improved, industrially advantageous, efficient process for the preparation of crystalline forms of Isoproterenol and pharmaceutical^ acceptable salts thereof.

Summary of the invention

The main aspect of the present invention is to provide a process for the preparation of highly pure (>99.7%) Isoproterenol of formula (I) and its pharmaceutically acceptable salts thereof,

wherein A=acid, as defined above through acid addition salt of acetophenone intermediate of formula (II).

wherein A'=acid, as defined above

Drawings

Sheet (1 of 4)
Shows the PXRD values of formula (II)

Sheet (2 of 4)
Shows the IR values of formula (II)
.Sheet (3 .of 4)
Shows the PXRD values of formula (I)

Sheet (4 of 4)
Shows the IR values of formula (I)

Detailed Description of the Invention

Accordingly, the first aspect of the present invention is to provide an improved and efficient process for the preparation of highly pure (>99.7%) Isoproterenol of formula (I) and its pharmaceutically acceptable salts thereof,

wherein A=acid/ as defined above through acid addition salt of acetophenone intermediate of formula (II).


wherein A'=acid, as defined above

The second aspect of the present invention provides a process for the preparation of compound of Formula (II).

According to another aspect of the present invention provides a process for the purification of Isoproterenol and pharmaceutically acceptable salts thereof, which comprises of re-crystallization/ salt exchange process of compound

According to one other embodiment, the present invention provides a process for the preparation of Isoproterenol and pharmaceutically acceptable salts comprises the steps of:
a) reacting 3,4-dihydroxy-w-chlorine acetophenone of compound of Formula (IV),

with isopropyl amine in presence of a suitable solvent to form 3,4-dihydroxy-w-isoprpylamino acetophenone of formula (III);


b) converting the compound of formula (III) of step a) to its acid addition salt of compound
of formula (II) by reacting with a suitable acid;

c) hydrogenating the compound of formula (II) of step b) by a suitable method in the
presence of a suitable solvent to form Isoproterenol and pharmaceutical^ acceptable salts
thereof of formula (I);


d) isolating Isoproterenol and pharmaceutical^ acceptable salts thereof of compound formula (I) as obtained by step c) by conventional method to obtain crystalline Isoproterenol and pharmaceutical^ acceptable salts thereof of formula (I) and
e) optionally purifying the crystalline Isoproterenol and pharmaceutical^ acceptable salts thereof of compound of formula (I) obtained by step d).

According to one aspect of the present invention the above reaction steps, step a) and step b) performed in a single step without isolation of compound of formula (III) as obtained by step a).
According to one aspect of the present invention the above reaction steps, step a) the suitable solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl formamide, ethyl acetate, dichloromethane and toluene. Preferably an alcohol solvent was used. More preferably methanol used.

According to one aspect of the present invention the above reaction steps, step b) the acid is selected from hydrochloric acid, hydrobromic acid, or organic acids comprising acetic acid, trifluoroacetic acid, tartaric acid, oxalic acid,fumaric acid, succinic acid, maleic acid, benzoic acid, para toluene sulphonic acid and methanesulfonic acid. And more preferably hydrochloric acid used.

According to one aspect of the present invention the above reaction steps, step c) hydrogenating catalyst selected from nickel, platinum, palladium etc. More preferably palladium on carbon used

According to another aspect of the present invention, the acid moieties A' & A compounds of formula (II) and (I) respectively are may be same or different.

According to another aspect of the present invention, Isoproterenol and pharmaceutical^ acceptable salts thereof of compound formula (I) obtained from compound of formula (II) where if A' ¥" A, by acid exchange technique by a suitable method.

According to one more embodiment, the present invention provides a process for the preparation of Isoproterenol and pharmaceutically acceptable salts comprises the steps of:
a) reacting 3,4-dihydroxy-w-chlorine acetophenone of compound of Formula (IV),

with isopropyl amine in presence of a suitable solvent to form 3,4-dihydroxy-w-isoprpylamino acetophenone of formula (III);

b) converting the compound of (III) of step a) to its acid addition salt of compound of
formula (II) by reacting with a suitable acid;


c) reacting acid addition salt of compound of formula (II) of step b) with a base in a suitable solvent to form highly pure free base of compound of formula (II);
d) hydrogenating the free base of compound of formula (II) as obtained by step c) by a suitable method in the presence of a suitable solvent to form Isoproterenol and pharmaceutically acceptable salts thereof of formula (I);
e) isolating Isoproterenol and pharmaceutically acceptable salts thereof of compound formula (I) as obtained by step d) by conventional method to obtain crystalline Isoproterenol and pharmaceutically acceptable salts thereof of formula (I) and
f) optionally purifying the crystalline Isoproterenol and pharmaceutically acceptable salts thereof of compound of formula (I) obtained by step e).

According to another aspect of the present invention, a process for the preparation of Isoproterenol and pharmaceutically acceptable salts thereof of compound formula (I) can be represented by the following synthetic scheme-2.

According to another embodiment, the present invention provides crystalline forms of Isoproterenol and pharmaceutical^ acceptable salts thereof.
According to another embodiment, the present invention provides a method of purification of Isoproterenol and pharmaceutically acceptable salts thereof by a crystallization method from organic solvents.

According to another embodiment, the present invention provides crystalline forms of free base of compound of formula (II).

According to one more embodiment, the present invention provides crystalline forms of compound of formula (II), specifically crystalline form of compound of formula (II) wherein the salt is hydrochloride salt.

Yet another embodiment, the present invention provides crystalline form of hydrochloride salt of compound of formula (II) characterized by a powder X-ray diffraction pattern having peaks at 20 values comprising at about 3.7, 6.5, 8.2,9.4, 10.2, 11.7,14.2, 16.3, 17.2, 18, 18.4, 19.3, 19.9,
20.1, 21.1, 22.3, 23.5, 24.2, 27.0, 28.1, 29.4, 30.2 and 32.1.

Yet another embodiment, the present invention provides crystalline form of hydrochloride salt of compound of formula (II) characterized by a Raman spectrum having peaks at values of about 3317 cm'1, 2992 cm"1, 2978 cm"1, 2817 cm"1.

Yet another embodiment, the present invention provides crystalline form of hydrochloride salt of Isoproterenol of formula (I) characterized by a powder X-ray diffraction pattern having peaks at 26 values comprising at about 3.6, 4.0, 6.6, 9.4, 11.5, 12.4, 13.4, 14.8, 17.0, 18.4, 18.9,20.4,
22.2, 23.0, 24.7, 25.0, 26.0, 27.3, 29.4, 29.9 and 30.5.

Yet another embodiment, the present invention provides crystalline form of hydrochloride salt of Isoproterenol of formula (I) characterized by a Raman spectrum having peaks at values of about 3162 cm"1, 3101 cm"1, 2970 cm*1, 2814 cm"1, 2794 cm"1

Yet another embodiment, the present invention provides an improved, industrially advantageous and efficient process for the preparation of crystalline forms of Isoproterenol and pharmaceutical^ acceptable salts thereof.

Yet another embodiment, the present invention provides an improved process for the preparation of highly pure Isoproterenol and pharmaceutical^ acceptable salts thereof, where the levels of impurities are below 0.3%.

In the present invention, the formation of the completely reduced impurity of compound of formula (la) limit is less than 0.3%.

According to one more embodiment, the present invention provides a process for the preparation of crystalline forms of Isoproterenol and pharmaceutical^ acceptable salts thereof.

The Following examples are illustrative of the present inventions and are not intended to limit
the inventions.

EXAMPLES:

Charged 2-chloro-l-(3,4-di hydroxyphenyl)ethan-l-one (lOOg; 0.5359moles) into the clean and dry round bottom Flask under nitrogen atmosphere at 25- 35°C, to this methanol was added and stirred the Mass at Room temperature. Isopropyl amine (101 ml; 1.179moles) was added drop wise to the above reaction mass at 25- 35°C and then temperature was maintained at 35- 45°C. The reaction mass maintained at 60-65°C for 3-4 hrs. Reaction was monitored by thin layer chromatography. After reaction completed, reaction mass was cooled and filtered through Silica gel bukner funnel. The wet cake was washed with methanol and dried under vaccum at below 40°C. The dried compound was taken in another

clean and dry round bottom Flask, to this methanol was added at 25-35°C. Hydrochloride gas was purged for 45-60 min. Methyl tert-butyl ether (MTBE) was added and stirred for 30-40 min at 0 -5°C. Then filtered the mass and dried under suction. The dried compound was taken into another flask, to this Methanol was added at room temperature slowly heated to 50-55°C to obtained clear solution, then cooled to 25-35°C, to this Methyl tert-butyl ether (MTBE) was added and stirred for 3-4 hrs (solid formation observed). Filtered through Buckner funnel bed washed with Methyl tert-butyl ether (MTBE) and suck dried for 30-40min to get the pure compound of formula (II)
The compound of formula (II) Purity is 99.89%

Formula (II) characterized by a powder X-ray diffraction pattern having peaks at 29 values comprising at about 3.7, 6.5, 8.2, 9.4, 10.2, 11.7,14.2, 16.3, 17.2, 18, 18.4, 19.3, 19.9,20.1,21.1, 22.3, 23.5, 24.2, 27.0, 28.1, 29.4, 30.2 and 32.1.

Formula (II) characterized by a Raman spectrum having peaks at values of about 3317 cm"1, 2992 cm"1, 2978 cm"1, 2817 cm"1.

The above obtained compound formula (II) (lOg; 0.040moles) was charged into a clean and dry round bottom Flask at 25 -35°C, Methanol was added to the reaction mass at Room temperature. To the mixture added (50%wet) 10% Pd/C (0.5 g) at 25-35°C and stirred for 6-7 hrs under hydrogen atmosphere at 25 -35°C. Reaction was monitored by thin layer chromatography. After reaction completed, the mass . was filtered and wet cake washed with methanol. To the obtained filtrate, charcoal was added and stirred for 30-40 min and then filtered and the filtrate distilled under reduced pressure at below 40°C. To the residue methanol was added at 25-35°C and stirred for 10-15 min and added Methyl tert-butyl ether (MTBE) and the mass was stirred for 3-4 hours at 25-35°C. Filtered the solid compound and washed with Methyl tert-butyl ether (MTBE) and dried under vacuum oven at 60-65°C to get compound of formula (I).

Example: 3

Crystallization of Formula (I)

In a clean and dry RBFlask Methanol was added to the example 2 compound at room - temperature slowly heated-to 50-55°C to obtained clear„soJution, to this Acetone was added at same temperature then cooled to 25-35°C stirred for 6-8 hrs (solid formation observed). Filtered the solid through Buckner funnel bed wash with Acetone and suck dried for 30-40min to obtained pure crystalline compound of Formula (I)

The Crystalline compound of Formula (I) Purity is 99.89%

Crystalline form of hydrochloride salt of Isoproterenol of formula (I) characterized by a powder X-ray diffraction pattern having peaks at 26 values comprising at about 3.6, 4.0, 6.6, 9.4, 11.5, 12.4, 13.4, 14.8,-17.0, 18.4, 18.9, 20.4, 22.2, 23.0, 24.7, 25.0, 26.0, 27.3, 29.4, 29.9 and 30.5.

Crystalline form of hydrochloride salt of Isoproterenol of formula (I) characterized by a Raman spectrum having peaks at values of about 3162 cm"1, 3101 cm"1, 2970 cm"1, 2814 cm"1, 2794 cm"1

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CLAIMS:

1. A process for the preparation of Isoproterenol and pharmaceutical^ acceptable salts of Formula (I) comprising:

wherein A=acid, selected from the group of inorganic acids like hydrochloric acid, hydrobromic acid, or organic acids comprising acetic acid, trifluoroacetic acid, tartaric acid, oxalic acid,fumaric acid, succinic acid, maleic acid, benzoic acid, para toluene sulphonic acid and methanesulfonic acid.
a) reacting 3,4-dihydroxy-w-chlorine acetophenone of compound of Formula (IV),

with isopropyl amine in presence of a suitable solvent to form 3,4-dihydroxy-w-isoprpylamino acetophenone of formula (III);

b) converting the compound of (III) of step a) to its acid addition salt of compound of
formula (II) by reacting with a suitable acid;


c) optionally reacting acid addition salt of compound of formula (II) of step b) with a base in a suitable solvent to form highly pure free base of compound of formula (II);
d) hydrogenating the compound of formula (II) of step b) or step c) by a suitable method in the presence of a suitable solvent to form Isoproterenol and pharmaceutically acceptable salts thereof of formula (I);
e) isolating Isoproterenol and pharmaceutically acceptable salts thereof of compound formula (I) as obtained by step d) by conventional method to obtain crystalline Isoproterenol and pharmaceutically acceptable salts thereof of formula (I)

2. A process of claim 1, wherein the suitable solvent used in Step a) is selected from methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, dimethyl formamide, ethyl acetate, dichloromethane and toluene. Preferably an alcohol solvent was used. More preferably methanol..
3. A process of claim 1, wherein the acid is used in Step b) is selected from hydrochloric acid, hydrobromic acid, or organic acids comprising acetic acid, trifluoroacetic acid, tartaric acid, oxalic acid,fumaric acid, succinic acid, maleic acid, benzoic acid, para toluene.sulphonic acid and methanesulfonic acid. And more preferably hydrochloric acid.
4. A process of claim 1, wherein the hydrogenating catalyst used in Step d) is selected from nickel, platinum, palladium etc and preferably palladium on carbon.

5. A process of claim 1, wherein the crystallization process of compound of Formula (I), crystallization process the solvent used in step e) is selected from alcohols, ketones, organic ethers and their mixtures thereof.
6. Crystalline form of hydrochloride salt of compound of formula (II) characterized by a powder X-ray diffraction pattern having peaks at 20 values comprising at about 3.7, 6.5, 8.2,9.4, 10.2, 11.7,14.2, 16.3, 17.2, 18, 18.4, 19.3, 19.9,20.1,21.1,22.3,23.5,24.2,27.0, 28.1, 29.4, 30.2 and 32.1.
7. Crystalline form of hydrochloride salt of Isoproterenol of formula (I) characterized by a powder X-ray diffraction pattern having peaks at 29 values comprising at about 3.6, 4.0, 6.6,9.4, 11.5, 12.4, 13.4, 14.8, 17.0, 18.4, 18.9,20.4, 22,2,23.0,24.7,25.0,26.0,27.3, 29.4, 29.9 and 30.5.
8. The compound of Formula (I), wherein the impurity compound of formula (la) is less
than 0.3%.