DESC:FIELD OF THE INVENTION
[0001] The present invention relates to the field of pharmaceutical chemistry, particularly to the synthesis of optically active compounds. Specifically, it provides a novel process for the preparation of Arformoterol or its pharmaceutically acceptable salts through a single-step resolution method, utilizing chiral organic acids as resolving agents and organic solvents.

BACKGROUND OF THE INVENTION
[0002] Formoterol is a long-acting ß2 adrenoceptor agonist and has long duration action. Chemically termed as N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl) -1-methyl ethyl] amino] ethyl] phenyl] formamide. The structure of formoterol is as shown below,

[0003] Formoterol has two chiral centers, each of which can exist in two possible configurations. This gives rise to four diastereomers which have (R R), (S S), (R S) and (S R) configurations. The commercially available formoterol is a 50:50 mixture of the (R R) and (S S) enantiomers. (R R) – formoterol is an extremely potent full agonist at the ß2 adrenoceptor and is responsible for bronchodilation and has anti-inflammatory properties. On the other hand (S S) enantiomer has no bronchodilatory activity and is proinflammatory.
[0004] U.S. Patent No. 6268533 discloses a synthesis of Arformoterol Tartrate by the reaction of optically pure 4-benzyloxy-3-formamido styrene oxide with an optically pure 4-methoxy-a-methyl-N-(phenylmethyl) benzene ethanamine to give the penultimate precursor dibenzyl arformoterol followed by debenzylation and L-Tartrate salt thereof.

[0005] Patent No. WO 2009/147383 discloses a synthesis of Arformoterol or a salt thereof, the process comprising: reaction of optically pure 4-methoxy-a-methyl-N-(phenylmethyl) benzene ethanamine with 2-Bromo-4'-Benzyloxy-3'-nitroacetophenone to produce formula 4-Benzyloxy-3-nitro- a-[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amino] acetophenone followed by chiral reduction using R-methyloxazaborolidine to give 4-benzyloxy -3-nitro- a -[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl] benzyl alcohol followed by reduction of nitro group in presence of platinum and hydrogen gas to gives 3-amino -4-benzyloxy - a -[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl )aminomethyl] benzyl alcohol and preparation 4-benzyloxy -3-formylamino- a -[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl] benzyl alcohol using Formic acid and Acetic anhydride followed by debenzylation and Tartrate salt thereof.

[0006] ES 2005492 disclose another process for preparation of formoterol. More specifically, said document discloses the conversion of formoterol to arformoterol semifumarate in the presence of ethanol and fumaric acid. Further, process of this patent utilizes expensive chemical (crown ethers), hazardous reagents (hydrofluoric acid), and carcinogenic solvents (benzene). This process is not suitable for large scale operation as it leads to environmental and health problems.
[0007] US3994974 discloses reaction of phenacylbromo derivative with benzyl protected secondary amine to form a coupled keto derivative. The keto group is then reduced to the corresponding nitro alcohol using sodium borohydride. Further, the reduction of nitro group is performed using Iron and HCl to form amine derivative. The formylation of resulting amine derivative is carried out with acetic formic anhydride to give the dibenzylformoterol having all four isomers RR, RS, SS, and SR. The separation of RR and SS enantiomers is performed by converting the dibenzyl formoterol into its fumarate salt and selective crystallization from isopropyl alcohol. The purified dibenzyl formoterol base is liberated from its salt and is subjected to hydrogenation using palladium and charcoal to get Formoterol base. The base is then converted to its pharmaceutically acceptable fumarate salt. However, this process does not disclose stable dihydrate form, chemical and enantiomeric purity.
[0008] Therefore, there is an unmet need in the art to develop a more practical and efficient process for the synthesis of an optically active form of Formoterol i.e. Arformoterol or a pharmaceutically acceptable salt thereof.
[0009] Based on the above it is desired to address the above-mentioned disadvantages or other shortcomings or at least provide a useful alternative.

OBJECTIVES OF THE INVENTION
[0010] An object of the present invention is to provide a novel process for synthesizing optically pure (RR)-Formoterol (Arformoterol) or its pharmaceutically acceptable salts in a single step, utilizing chiral organic acids as resolving agents.
[0011] An object of the present invention is to achieve high enantiomeric purity (=98.5%) and chemical purity (=99.97%) of Arformoterol, making it suitable for therapeutic applications, particularly in the treatment of respiratory conditions such as asthma and COPD.
[0012] An object of the present invention is to simplify the synthesis process by resolving both chiral centers of Formoterol simultaneously, thereby reducing the complexity and time required compared to existing methods.
[0013] An object of the present invention is to provide a cost-effective and scalable process that eliminates the need for expensive reagents, hazardous chemicals, and carcinogenic solvents, making it suitable for large-scale industrial applications.
[0014] An object of the present invention is to develop an environmentally friendly process that minimizes the use of hazardous reagents and solvents, addressing environmental and health concerns associated with prior art methods.
[0015] An object of the present invention is to offer an integrated approach that includes both the synthesis of racemic Formoterol and the resolution of its enantiomers, enabling a streamlined and efficient pathway from precursor to final product.
[0016] An object of the present invention is to improve overall yield and quality of Arformoterol, ensuring better pharmaceutical performance and cost-efficiency for commercial production.

SUMMARY OF THE INVENTION
[0017] The present invention relates to a process for preparing optically pure (RR)-Formoterol (Arformoterol) or pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a single step process for the preparation Arformoterol from Formoterol {N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methyl ethyl] amino] ethyl] phenyl] formamide} base with a chiral organic acid.
[0018] In one aspect, a process for the synthesis of Arformoterol or pharmaceutically acceptable salt thereof is provided (scheme I).

SCHEME I

Said process comprises the following steps:
a) racemate Formoterol base and chiral resolving agent were added in an organic solvent at room temperature to form a mixture i.e. acid addition salt;
b) heating the above mixture at a suitable temperature for 15-30 mins to dissolve the mixture;
c) cooling the mixture and stirring the mixture for 12-24 hrs to obtain Arformoterol acid addition salt crystals;
d) isolating the Arformoterol acid addition salt crystals by filtration;
e) washing the isolated acid addition salt crystals with a solvent to yield crude Arformoterol acid addition salt; and
f) recrystallizing the crude Arformoterol acid addition salt in organic solvent or mixtures thereof to get desired enantiomeric purity.
[0019] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION
[0020] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0021] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0022] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0023] In some embodiments, numbers have been used for quantifying weights, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0024] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0025] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0026] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0027] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0028] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0029] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0030] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0031] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0032] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0033] The term "or", as used herein, is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
[0034] In one aspect, a process for the synthesis of Arformoterol or pharmaceutically acceptable salt thereof is provided (please see scheme I).

SCHEME I
Said process comprises the following steps:
a. racemate Formoterol and resolving agent were added in an organic solvent at room temperature to form a mixture;
b. heating the above mixture at a suitable temperature for 15-30 mins to dissolve the mixture;
c. cooling the mixture and stirring the mixture for 12-24 hrs at room temperature to obtain Arformoterol diastereomeric salt crystals;
d. isolating the Arformoterol diastereomeric salt crystals by filtration;
e. washing the isolated crystals with a solvent to yield crude Arformoterol; and
f. recrystallizing the crude Arformoterol diastereomeric salt in organic solvent or mixtures thereof to get desired enantiomeric purity.
[0035] In some embodiments of the present invention, the resolving agents are chiral organic acids.
[0036] In some embodiments of the present invention, the chiral resolving acids are selected from a group consisting of L-(+)-tartaric acid, D-(-)-tartaric acid, Dibenzoyl-L-tartaric acid, Dibenzoyl-D-tartaric acid, Di-p-toluoyl-L-tartaric acid, Di-p-toluoyl-D-tartaric acid, (R)-mandelic acid, (S)-mandelic acid, (R)-glutamic acid and (S)-glutamic acid.
[0037] In some embodiments of the present invention, the solvent in step (a) is the mixture of organic solvents in water.
[0038] In some embodiments of the present invention, the organic solvent is selected from a group consisting of isopropyl alcohol, ethanol, methanol, acetone and acetonitrile or combinations thereof.
[0039] In another embodiment of the present invention, the heating in step b is carried out at a temperature in the range of 50°C to 85°C.
[0040] In another embodiment of the present invention, the stirring in steps a and c is carried out at a temperature in the range of 10°C to 35°C.
[0041] In some embodiments of the present invention, the organic solvent in step (e) is selected from a group consisting of isopropyl alcohol, ethanol, methanol, acetone and acetonitrile or combinations thereof.
[0042] In some embodiments of the present invention, the recrystallization in step (f) is selected from a group consisting of water, isopropyl alcohol, ethanol, methanol, acetone and acetonitrile or combinations thereof.
[0043] As it would be apparent to a person skilled in the art, Racemate Formoterol base (RR, SS), may be synthesized from any of the many methods disclosed in the prior art. In some embodiments, Racemate Formoterol (RR, SS) may be procured form commercial sources.
[0044] In another embodiment, Racemate Formoterol (RR, SS) may be synthesized from the following process, comprising the steps of:
1. condensing N-benzyl-1-(4-methoxyphenyl) propane-2-amine with 2-Bromo-4-benzyloxy-3-nitroacetophenone in the presence of potassium carbonate to produce 2-(4-Methoxyphenyl)-1-methylethyl](phenylmethyl)amino]methyl]-3-nitro-4-(phenylmethoxy)- benzenone (Formula-I).
2. preparing 2-(4-Methoxyphenyl)-1-methylethyl(phenylmethyl)amino]methyl]-3-nitro-4-(phenylmethoxy) – benzene methanol (Formula II) by reduction of Formula-I using sodium borohydride in alcoholic solvent like methanol to give Formula II which have (R R), (S S), (R S) and (S R) configurations.
3. preparing Formula-III by nitro group reduction using Raney Nickel catalyst in Methanol to produce 3-Amino-a-[2-(4-Methoxyphenyl)-1-methylethyl] (phenylmethyl)amino] methyl]-4-(phenylmethoxy)-benzenemethanol which have (R R), (S S), (R S) and (S R) configurations, followed by diastereomers separation using L(+) Tartaric acid in Methanol which have (R R), (S S) configurations.
4. preparing Formula-IV by formylation using Ethyl formate and Formic acid to produce N-[5-[Hydroxy-2-[[methyl-2-(4 methoxyphenyl) ethyl] (phenylmethyl) aminoethyl]-2 (phenylmethoxy) phenyl]formamide which have (R R), (S S) configurations.
5. preparing Formula-V by debenzylation in presence of hydrogen gas and palladium carbon in Methanol to produce Formoterol N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl] amino] ethyl] phenyl] formamide which have (R R), (S S) configurations.
[0045] The process for the synthesis of Racemate Formoterol (RR, SS) is shown in scheme 2 below:

Scheme 2
[0046] In another embodiment of the present invention, the process for the separation of enantiomers from racemic mixture of Formoterol (RR SS) (Formula V) is carried out using chiral resolving acids in the mixture of organic solvent in water to gives RR enantiomer, which is RR-Formoterol (Formula VI) or a pharmaceutically acceptable salt thereof.

[0047] In yet another embodiment, the present invention relates to a novel single step process for the synthesis of Arformoterol, wherein Racemate Formoterol (RR, SS) is resolved using chiral acid in mixture of Acetone and water to produce pure R R-Formoterol (Arformoterol) or a pharmaceutically acceptable salt thereof.
[0048] In an embodiment, the present invention relates to a more practical and efficient process for the preparation of an optically active form of Formoterol i.e. Arformoterol or a pharmaceutically acceptable salt thereof. This method is particularly advantageous in comparison with known methods because it utilizes optically active Arformoterol readily available by simple resolution of RR, SS-Formoterol which is a novel synthesis. Also, the resolution of both chiral centers is conducted in a single step to get the desired R, R- isomer.
[0049] In another embodiment, the present invention is useful for the synthesis of Arformoterol in single step with better yields, highly cost effective and with superior quality commercially.
[0050] Accordingly, the present invention provides a simplified, cost-effective, and efficient solution for synthesizing optically pure Arformoterol, overcoming the challenges in the prior art. It demonstrates significant advantages in terms of environmental safety, scalability, and pharmaceutical quality. The method achieves high enantiomeric purity in a single step, addressing the unmet needs of the pharmaceutical industry for improved synthesis techniques.
[0051] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[0052] The present invention is further explained in the form of the following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.
[0053] Example 1: Process for the synthesis of Arformoterol Tartrate
N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl] amino] ethyl] phenyl] formamide (Formoterol) and L-(+)-tartaric acid were dissolved in hot Acetone, cooled to 10 to 35°C and kept under stirring at 10 to 35°C temperature for 14 to 20 hours/overnight. The diastereomeric crystals separated were collected by filtration having chiral purity (R, R)-isomer = 98.5%, (S, S) - isomer = 1.44%, Chemical purity = 99.97%, Melting point = 172°C, SOR = -28.39°.

[0054] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

ADVANTAGES OF THE PRESENT INVENTION
[0055] The present invention provides a novel process of preparing optically pure (RR)-Formoterol (Arformoterol) or pharmaceutically acceptable salt thereof.
[0056] The present invention provides a simple process for synthesis of optically pure Arformoterol or pharmaceutically acceptable salt thereof in single step from Formoterol.
[0057] The present invention provides a process which is highly cost effective and results in better yield.
[0058] The present invention provides a simple process, wherein both chiral centers of Formoterol are resolved in a single step to get the desired R, R- isomer.
,CLAIMS:1. A process for the synthesis of Arformoterol or pharmaceutically acceptable salt of Arformoterol with Scheme I:

SCHEME I

2. The process as claimed in claim 1, wherein said resolving agents are selected from chiral organic acids.
3. The process as claimed in claim 1, wherein said chiral organic acids are selected from a group consisting of L-(+)-tartaric acid, D-(-)-tartaric acid, Dibenzoyl-L-tartaric acid, Dibenzoyl-D-tartaric acid, Di-p-toluoyl-L-tartaric acid, Di-p-toluoyl-D-tartaric acid, (R)-mandelic acid, (S)-mandelic acid, (R)-glutamic acid and (S)-glutamic acid or a combination thereof.
4. The process as claimed in claim 1, wherein said solvent is organic solvent and selected from a group consisting of isopropyl alcohol, ethanol, methanol, acetone and acetonitrile or combinations thereof.
5. The process as claimed in claim 1, wherein said process comprises the steps of:
a. adding racemic Formoterol and a resolving agent in an organic solvent at room temperature to form a mixture;
b. heating the mixture to dissolve the components;
c. cooling the mixture and stirring it at a temperature of 10°C to 35°C for 12-24 hours to obtain Arformoterol diastereomeric salt crystals;
d. isolating the Arformoterol diastereomeric salt crystals by filtration;
e. washing the isolated crystals with an organic solvent to yield crude Arformoterol diastereomeric salt ; and
f. recrystallizing the crude Arformoterol diastereomeric salt in an organic solvent or a combination of solvents to achieve the desired enantiomeric purity of diastereomeric salt .The process as claimed in claim 1, wherein said solvent in step (a) is the mixture of organic solvents in water.
6. The process as claimed in claim 5, wherein said organic solvent in step (e) is selected from a group consisting of isopropyl alcohol, ethanol, methanol, acetone and acetonitrile or combinations thereof.
7. The process as claimed in claim 5, wherein said the recrystallization solvent in step (f) is selected from a group consisting of water, isopropyl alcohol, ethanol, methanol, acetone, ethyl acetate, isopropyl acetate and acetonitrile, propionitrile or combinations thereof.
8. A process for the separation of enantiomers from racemic mixture of Formoterol (RR SS) (Formula V) comprising the steps of mixing the chiral organic acids in organic solvent in water to gives RR enantiomer, wherein said RR-Formoterol (Formula VI) or a pharmaceutically acceptable salt thereof.