FORM 2
THE PATENTS ACT 1970
(Act 39 of l970)
and
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"PROCESS FOR THE PREPARATION OF ARFORMOTEROL OR SALT THEREOF"
Glenmark Pharmaceuticals Limited;
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered office at
Glenmark House. HDO - Corporate 81dg: Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai -400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

PRIORITY
This application claims the benefit of Indian Provisional Application No. 1762/MUM/2013. filed on May 17, 2013, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of arformoterol L-(+)- tartrate. More specifically the present invention relates to a novel process for the preparation of arformoterol L-(+)- tartrate via arformoterol D-(-)-tartrate. BACKGROUND OF THE INVENTION
Arformoterol tartrate is the United States Adopted Name (USAN) for (R,R) formotero! L-tartrate. The chemical name for arformoterol tartrate is formamide. N-[2-hydimy-5-[(IR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-(2R,3R)-2,3dihydroxybutanedioate (1:1 salt), and is represented by formula (la):

Arformoterol tartrate is currently marketed in the United States under the trade name BROVANA®. BROVANA® (arformoterol tartrate) inhalation Solution is supplied as 2 mL of arformoterol tartrate solution packaged in 2.1 niL unit-dose, low-density polyethylene (LDPE) unit-dose vials. Each unit-dose vial contains 15 mcg of arformoterol (equivalent to 22 meg of arformoterol tartrate) in a sterile, isotonic saline solution, pH-adjusted to 5.0 with citric acid and sodium citrate.
United Stares Patent No. 6,472.563 discloses polymorphic form A. B and C of arfomoterol L-(+)-tartrate. The specification recites that the product described in the art, United States Patent No. 6,268,533 as it initially crystallizes, contains four identified chemical impurities and no matter how many times the product is recryslallized the resultant polymorph A contains al least 0.5% of impurities. Further the specification of US:563 discloses that conditions of recrystallizarion may result in partial hydrolysis and lead to the formation of impurities and that it may be possible that some degradation occurs and impurities are introduced in the recrystallization process.
For the development of an active pharmaceutical ingredient two factors are important namely the impurity profile of the active pharmaceutical ingredient and the polymorphic Form that is to be targeted. The known art discloses that crystallization conditions and method of isolation of Arformoterol L-(+)- tartrate

may lead to varied polymorphic Forms A. B, C or mix lures thereof with different levels of impurities', compounds of Formula A, B, C and/or D.

The art discloses thai polymorphic Form B of Arformoterol L-(+)- tartrate can be obtained in a crude state only and attempts to improve the chemical purity of Form B by altering the temperature and ratios of solvents leads to interconversion to polymorphic Form C. The temperature and the ratios of solvents used are not only critical for removal of chemical impurities but important for crystal morphology also. Tints when optimization of chemical purity of Arformoterol L-(+)- tartrate occurs, the polymorphic Form B does not remain same and is converted to Form C. Thus the state of art does not disclose a process for the preparation of Arformoterol L-(+)-tartrate in polymorphic Form B and substantially free of impurities, compounds of Formula A. B, C. D and/or E.

The process of conversion of crude arformoterol to arformoterol L-(+)- tartrate, in the an entails use of specific solvent systems to meet the desired standards of chemical, chira! and polymorphic Form purity but is still unable to obtain polymorphic Form B in desired chemical purity and uncontaminated with other polymorphic Forms.
We have also found that when crude arformoterol base is subjected to reaction with L (+) tartaric acid in a solvent the arformoterol L-(+)- tartrate cannot be obtained in desired polymorphic Form B and chemical purity and is contaminated with other polymorphic forms. Further, when crude arformoterol base with impurities, compounds of Formula A. B, C, D and/or E is subjected to reaction with L (+)tartaric acid in aqueous tetrahydrofuran system, to improve the chemical and chira! purity, the arformoterol L-(+)-

tartrate cannot be obtained in desired chemical purity and polymorphic Form B and is usually contaminated with other polymorphic forms.
Therefore, there is a need for an improved process for the preparation of arformoterol L-(+)- tartrate in desired single polymorphic Form B, unconiaminaied with other polymorphic Forms A and C and substantially free of impurities, compounds of Formula A. B. C, D and/or E. The need in the art is to provide a reliable and reproducible process to prepare consistently the desired polymorphic Form B of arformoterol L-(+)- tartrate having a chemical purity of at least 99% and a chiral purity of at least 99% without using chromatographic purification techniques.
The present invention provides a process which is simple, ecofriendly. inexpensive, reproducible, robust and well suited on commercial scale and circumvents the likely formation of isomeric and other process-related impurities: while ensuring a target polymorphic form of arformoterol tartrate product with optimum yield and polymorphic and chemical purity.
In the process of the present invention, the crude arformolerol is reacted with D-(-)-tartaric acid to form arformoterol D-(-)-tartrate. which is then reacted with a base and L-(+)-tartaric acid to provide high purity arformoterol L-(+)- tartrate. Surprisingly, we have found that the present process via arformoterol D-(-)-tartrate affords high purity arformoterol l--(+)- tartrate, substantially free of impurities, compounds of Formula A, B, C, D and/or IE and in desired polymorphic Form 13. in contrast to the known method of conversion of crude arformoterol to arformolerol L-(+)- tartrate by reacting it with L-(+)-tartaric acid.
Brief Description of The Accompanying Figures
Fig. 1: PXRD pattern of arformoterol D-(-)-tartrate, compound of formula II, according to example 4.
Fig 2: Differential scanning calorimetry endotherm of arformoterol D-(-)-lartrate. compound of formula II according to example 4. Fig. 3: PXRD pattern of arformoterol L-(+)- tartrate, compound of formula la, according to example 6, Fig 4: Differential scanning calorimetry endotherm of arformoterol L-(+)-t art rate, compound of formula la. according to example 6. SUMMARY OF INVENTION
The present invention provides a process for the preparation of arformoterol L-(+)- tartrate, a compound of Formula la,



comprising: a) reacting crude arformoterol. a compound of Formula 1

with D-(-)-tartaric acid to form arformoterol D-(-)-tartrate. a compound of formula II; and

wherein the level of compounds of formula A or B. is less than 0.15%w/w relative to the amount of arformoterol L-(+)- tartrate as determined by HPLC.
b) reacting the arformoterol D-(-)-taiirate. the compound of formula II. with a base and L-(+)-tartaric
acid, to form arformoterol L-(+)- tartrate, compound of Formula la.
DETAILED DESCRIPTION OF INVENTION
The present invention provides a process for (he preparation of arformoterol L-(+)- tartrate, a compound
of Formula la.


wherein the level of compounds of formula A ;B. C . D or E is less (ban 0.15% wAv relative to the amount of arformoterol L-(+)- tartrate as determined by HPLC
a) reacting crude arformoterol. a compound of Formula I with D-(-)-tartaric acid to form arformoterol D-(-)-tartrate, a compound of formula li: and

b) reacting the arformoterol D-(-)-tartratc. the compound of formula II, with a base and L-(+)-tartaric acid, to form arformoterol L-(+)- tartrate, compound of Formula la.
The present invention provides a process for the preparation of arformoterol L-(+)- tartrate, a compound of Formula la,

wherein the level of compounds of formula A or B, is less than 0.15%w/w relative to the amount of arformoterol L-(+)- tartrate as determined by HPLC

comprising: a) reacting crude arformoterol. a compound of Formula I with D-(-)-iaitaric acid to form arformoterol D-(-)-tartrate, a compound ofibnnula II; and


b) reacting the arformoterol D-(-)-tartrate. the compound of formula II. with a base and L-(+)-tar(aric acid, lo form arformoterol L-(+)- tartrate, compound of Formula la,
In one embodiment, of the process of the present invention, the crude arformoterol. compound of formula I is obtained by a process comprising hydrogenating a compound of formula III in a solvent system.

The hydrogenation of compound of formula III may be carried out using metal catalysts such as platinum, palladium, nickel, rhodium or ruthenium supported on solid supports like calcium carbonate, alumina, barium sulfate, silica or activated charcoal carbon. The hydrogenation of compound of formula III may be carried out in the presence of hydrogen or hydrogen transfer reagents selected from formic acid, salts of formic acid, phosphonic acid, hydrazine, where hydrogen is preferred.The hydrogenation of compound of formula 111 may be carried out in a solvent system selected from alcohols, esters and the like.
The alcohols may be selected from the group consisting of methanol, ethanol, propanol. isopropanol, n-butanol, sec. butanol and the like.The esters solvent may be selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like.
In one embodiment, the crude arformoterol is obtained by hydrogenation of compound of formula 111. and subjecting the reaction mass to nitration to remove the catalyst to obtain the crude arformoterol in the filtrate.
In one embodiment, the crude arformoterol present in the filtrate may be used for further reaction with D-(-)-tartaric acid, without isolating it from the filtrate.
In one embodiment, the crude arformoterol present in the filtrate may be isolated in a solid form or as a residue by removal of the solvent by evaporation or distillation. The isolated solid crude arformoterol may be then subjected to reaction with D-(-)-1artaric acid
In one embodiment, of the process of the presem invention the crude arformoterol was obtained by a process comprising hydrogenating the compound of formula III with Pd/C in a solvent system followed by filtration.

In one embodiment the "'crude arformoterol" means arformoterol having n chemical purity of 50-99.5% as determined by HPLC.
The reaction of crude arformoterol with D-(-)-tartaric acid 10 form arformoterol D-(-)-tartrate, a compound of formula II, may be carried out in a solvent system selected from the group consisting of alcohols, hydrocarbons, halogenated hydrocarbons, ethers, esters, water or mixtures thereof.
The alcohols may be selected from the group consisting of methanol, ethanol. propanol. isopropanol, n-butanol, sec. butanol and the like, The hydrocarbons may be selected from the group consisting of pentane, n-hexane, heptane, eyclohexane, petroleum ether, benzene, toluene, m-.o-.or p-xylenc and the like. The halogenated hydrocarbons may be selected from the group consisting of dichloromethane (MDC), 1, 2-dichloroethane and the like. The ethers may be selected from the group consisting of diethyl ether, di-isopropyl ether, tetrahydrofuran, 1.4-dioxane, telrahydropyran and the like.The esters solvent may be selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like.
The D-(-)-iar(aric acid may he added directly to crude arformoterol in a solvent system or an aqueous solution of D-(-)-tartaric acid may be added to crude arformoterol in a solvent system.
In one embodiment; a solution of D-(-)-tartaric acid in water is added to crude arformoterol present in a mixture of alcohol and hydrocarbon solvent system. Preferably isopropyl alcohol and toluene mixture.
(n one embodiment, the reaction of crude arformoterol with D-(-)-tartaric acid to form arformoterol D-(-)-tartrate is carried out in isopropanol and toluene system to obtain arformoterol D-(-)-tartratc.ln one embodiment, a solution of D-(-)-tartaric acid in water is added to crude arformoterol present in a mixture of ethanol and isopropanol solvent system to obtain arformoterol D-(-)-tartrafe.
In one embodiment, the reaction of crude arformoterol with D-(-)-tartaric acid to form arformoterol !>(-)-tartrate is carried out in ethanol-isopropanol (70:30) system to obtain arformoterol D-(-)-tartrate.
In one embodiment, the arformoterol D-(-)-tartraie. compound of formula 11. is subjected to purification, prior to reacting with L-(+)-tartaric acid.
The purification may be carried out by crystallization of arformoterol D-(-)-tarlrate, compound of formula II in a solvent system comprising ether, alcohol, ketone, hydrocarbon, halogenated hydrocarbon, water or mixture thereof.

The ether solvent may be selected from the group consisting, of letrahvdrofuran. tetrahvdropvran. 1, 4 dioxane and the like. Preferably tetrahydrofuran.
The alcohol solvent may be selected from the group consisting of methanol, eihanol, propanol. isopropanol. isobutanol. 2-butanol and the like.The ketone solvent may be selected from the group consisting of acetone, methyl ethyl ketone, ethyl methyl ketone and the like.The hydrocarbon solvent may be selected from the group consisting of n-pentane, n-hexane, heptane, cyclohexane. petroleum ether. benzene, toluene, m-.o-.or p-xyiene and the like. The halogenaied hydrocarbon solvent may be selected from the group consisting of dichloromethane (MDC). 1. 2-dichloroethane and the like.
In one embodiment, (he arformoterol D-tarlrate compound of formula II is subjected to purification by crystallization in a solvent system comprising ether and water.
In one embodiment, the present invention provides a process for preparation of arformoterol D-(-)-tartraie having a chemical purity of at least 95% as determined by HPLC comprising subjecting the arformoterol D-(-)-tanrate a compound of formula II to purification by crystallization with tetrahydrofuran and water.
In one embodiment, the present invention provides a process for the preparation of arformoterol D-{-)-tartrate in a chemical purity of at least 95% as determined by HPLC by a process comprising:
a) adding tetrahydrofuran to arformoterol D-(-)-tartrale to form a mixture:
b) refluxing the mixture;
c) adding water to the refluxing mixture to form a clear solution:
d) adding tetrahydrofuran to the clear solution: and
e) cooling the solution of step (d) to obtain arformoterol D-(-)-tartrate in a chemical purity of at least 95% as determined by HPLC
In one embodiment in step a) tetrahydrofuran was added to arformoterol D-(-)-tartrate at room temperature. In step b) the mixture of arformoterol D-(-)-tarirate and tetrahydrofuran was re fluxed at about 60-80° C; In step e) water was added slowly at the temperature in the range of about 60-80 C followed by stjrring for a period of 10 -40 minutes to form a clear homogeneous solution.In step d) tetrahydrofuran was added slowly to the clear homogeneous solution in step c; al the temperature in the range of about 60-80° C; and In step e) the clear solution of step d was cooled with stirring to room temperature for a period of about 3-8 hours.
The purification process of arformoterol D-(-)-tartrate may be carried out once or repeatedly to 'increase the chemical and chiral purity of arformoterol D-(-)-tartrate to the desired level.

In one embodiment, the present invention provides arformoterol D-(-)-tartrate in a chemical purity of at least 99% and chiral purity of least 99% as determined by HPLC after repeaiedlv purifying it by purification as described above.
The crude arformotero I D-{-)-tartrale obtained when subjected to purification by recrystallization from aqueous lelrahydrofuran system, results in arformotero! D-(-)-tarlrale of chemical purity of at least 99% and a chiral purity of at least 99% as determined by HPLC. The conversion of highly pure arformoterol D-(-)-larlrale with L-(+)-tartaric acid in presence of a base results in arformoterol L-(+)- tartrate in single polymorphic Form, more specifically Form (3 with a high degree ofchemical and chiral purity.
In step b, the conversion of arformoterol D-(-)-tartralc, to arformoterol L-(+)- tartrate is carried out with a
base and L-(+)-tartaric acid.
The base may be selected from an inorganic base or an organic base.
The inorganic base may be selected from the group consisting of alkali metal hydroxides such as sodium
hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like,metal carbonates_such
as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate and the like;
metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkoxides such as
sodium methoxide, potassium methoxide. sodium lerubutoxide. potassium tert-butoxide and the like or
aqueous mixture thereof. Preferably, sodium bicarbonate.The organic base may be selected from trielhyl
amine, trimethyl amine, diisopropyl ethylamine, dimethyl amino pyridine, picoltne. dimethyl amino
pyridine and pyridine.
In one embodiment the conversion of arformoterol D-(-)-tartrate, to arformoterol L-(+)- tartrate is carried out with a base and L-(+)-tartaric acid and a solvent.
The solvent may be selected from the group consisting of ester, hydrocarbon, halogenated hydrocarbon, water or mixture thereof.
The esters solvent may be selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like. Preferably, ethyl acetate.The hydrocarbon solvent may be selected from the group consisting of n-pentane. n-hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, m-.o-.or p-xylenc and the like.The halogenated hydrocarbon solvent may be selected from the group consisting of dichlorometane (MDC). I. 2-dichloroethane and the like.
In one embodiment, in step b) the arformoterol D-(-)-tartra(e. base and L-(+)-(artaric acid are added simultaneously.

In one embodiment, in step b) the arformoterol D-(-)-iar(rate, the compound of formula II is reacted with a base to obtain arformoterol. followed by reacting the arformoterol with L-(+)-tartaric acid lo form arformoterol L-(+)- tartrate.
The reaction of arformoterol D-(-)-tartrate. the compound of formula II with a base produces arformoterol, compound of Formula I which can be isolated from the reaction mixture before reacting it with L-(+)-tartaric acid. Alternatively the L-(+)-lartaric acid is added to the reaction mass containing arformoterol in-situ to obtain arformoterol L-(+)- tartrate.
[n one embodiment, the arformoterol D-(-)-lnrtra(e. (lie compound of formula 11 is reacted with a base to produce arformoterol. the compound of formula 1. which is not isolated from the reaction mixture and is reacted in-silu with L-(+)- tartaric acid. In one embodiment, the arformoterol D-(-)-tartrate. the compound of formula If is reacted with a base to produce arformoterol, which is isolated as a residue or solid. The isolated solid or residue of arformoterol thus obtained is then reacted with L-(+)-tartaric acid.
In one embodiment, the conversion of arformoterol D-(-)-tartrate. to arformoterol L-(+)- tartrate is carried out by reacting arformoterol D-(-)-tartrale with a base to obtain arformoterol which is isolated from the reaction mixture as a residue and treated with L-(+)-tanaric acid to obtain arformoterol L-(+)- tartrate, a compound of Formula la.In one embodiment, the present invention provides a process for preparation of arformoterol L-(+)- tartrate, a compound of Formula la, comprising reacting the arformoterol D-(-)-tartraie, the compound of formula II with a base and L-(+)-tartaric acid.
In one embodiment, in step b) the arformoterol D-(-)-tartrate. the compound of formula I! is reacted with a base to obtain arformoterol, followed by reacting the arformoterol with L-(+)-(artaric acid in a mixture of toluene and isopropanol to form arformoterol L-(+)- tartrate
In one embodiment, the isopropanol and toluene are used in the ratio of 8:2 v/v. In one embodiment, an aqueous solution of L-(+)-tartaric acid is used.In one embodiment, the aqueous solution ofL-(+)-tartaric acid is used in a proportion such that isopropanol: toluene: water is in the ratio of 8:2:1 v/v, for 1 part by weight of arformoterol D-(-)-tartrate.
In one embodiment, the present invention provides a process for preparation of arformoterol L-(+)-tartrate, a compound of Formula la, in polymorphic Form 13. comprising reacting the arformoterol D-(-)-tarlrate. the compound of formula II with a base and L-(+)-tartaric acid, in a mixture of toluene and isopropanol.

In one embodiment, the present invention provides a process for preparation of arforrnoterol L-(+)-lartrale, a compound of Formula la. characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 8.69, 17.44. 20.63. 21.96. 22.74 ± 0.2 degrees 2 theta, comprising reacting the arformoterol D-(-)-tartrate. the compound of formula II with a base and L-(+)-tartaric acid, in a mixture of toluene and isopropanol.ln one embodiment, the present invention provides a process for preparation of arforrnoterol L-(+)- tartrate, a compound of formula la. in polymorphic Form B. wherein the aqueous solution of L-(+)-lartaric acid is used in a proportion such that isopropanol: toluene: water is in the ratio of 8:2:1 v/v, for i part by weight of arforrnoterol D-(-)-tartratc.
Advantageously in one embodiment, the implementation of the process of the present invention provides polymorphic Form B. of arforrnoterol L-(+)- tartrate, a compound of Formula la. reproducibly without contamination of polymorphic Form C and polymorphic Form A and in desired chemical and chiral purity. The arforrnoterol L-(+)- tartrate, obtained by the process of the present invention has a chemical purity of at least 99% and a chiral purity of at least 99% without using chromatographic purification techniques.
Purification of arforrnoterol L-(+)- tartrate. Form B by methods known in the art where crude arforrnoterol L-(+)- tartrate. Form B slurry obtained was heated at 45 -50°C for removal of impurities leads to Form C of arforrnoterol L-(+)- tartrate which on further crystallization from aqueous isopropyi alcohol leads to Form A. The process of the present invention provides for isolation of Form B without isolation or formation of Form A and Form C during the overall purification process.
The present invention provides use of arforrnoterol D-(-)-tartra!e. compound of formula If. in the process for preparation of arforrnoterol L-(+)- tartrate, compound of Formula la.
The present invention provides use of arforrnoterol D-(-)-tar(raie. compound of formula II. in the process for preparation of arformorerol L-(+)- tartrate, compound of Formula la 'in crystalline polymorphic Form B.The present invention provides use of arforrnoterol D-(-)-larlrate. compound of formula II. in the process for preparation of arforrnoterol L-(+)- tartrate, compound of Formula la in crystalline polymorphic Form B, wherein the level of compounds of formula A or B. is less than 0.15% w/w relative to the amount of arforrnoterol L-(+)- tartrate as determined by HPLC.
In one embodiment, the present invention provides arforrnoterol D-(-)-tarlrate, compound of formula II characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 3.82. 15.44 and 17.79 ± 0.2 degrees 2 theta.

In one embodiment, the present invention provides arformoterol L-(+)- tartrate, a compound of Formula la, wherein the level of compounds of formula A or B, is less than 0.15%w/\v relative to the amount of arformoterol L-(+)- tartrate as determined by HPLC in crystalline polymorphic Form B. In one embodiment, the present invention provides arformolerol L-(+)- tartrate, a compound of Formula la. wherein the level of compounds of formula A or B. is less than 0.I5%w/w relative to the amount of arformoterol L-(+)- tartrate as determined by HPLC in crystalline polymorphic Form B and a chiral purity of at least 99%.
In one embodiment, the present invention provides arformoterol L-(+)- tartrate, a compound of Formula la. wherein the level of compounds of formula A or B. is less than O.I5%w/w relative to the amount of arformoterol L-(+)- tartrate as determined by HPLC in crystalline polymorphic Form B and wherein the level of polymorphic Form A and /or C is less than 1%.
In one embodiment, the present invention provides a process for preparation of arformoterol having chemical purity of at least 99% as determined by HPLC, comprising reacting arformoterol D-(-)-tartrate with a base. The base may be selected as described supra.
In one embodiment, the present invention provides a process for the preparation of a compound of Formula III, comprising: reacting a compound of Formula IV. with a compound of Formula V

to form a compound of Formula III.
In one embodiment the present invention provides a process for the preparation of arformoterol L-(+)-tartrate, a compound of Formula la.


substantially fvca of one or more of the compounds of formula A. B. C. D and E as determined by HPLC comprising:
(a) adding leirahydrofuran to arformoterol L-(+)-tartrate to form a mixture;
(b) refluxing the mixture;
(c) adding water to the refluxing mixture to form a clear solution;
(d) adding telrabydrofuran to the clear solution; and
(e) cooling the solution of step (d) to obtain arformoteral L-(+)-tartrale in a chemical purity of at least 95% as determined by HPLC
In one embodiment the present invention provides novel polymorphic form of arformoterol L-(+)-lartrate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 6.63. 16.20. 18.74. 19.86, 22.97, 23.64±0.2 degrees 2 theta.
In one embodiment the present invention provides novel polymorphic form of arformoterol L-(+)-tartrate characterized by Differential Scanning Calorimetric (DSC) thermogram having an endotherm at about I28.4°±1°C, 174.82±1°C, 180.26±1°C and exotherm at about 137.21±1°C.
In one embodiment, the present invention provides arformoterol L-(+)- tartrate, a compound of formula
la. obtained by the processes herein described, having a D90 particle size of about 35 microns. D>o particle
size of about 16 microns and D10 particle size of about 6 microns.
In one embodiment, the present invention provides micronized arformoterol L-(+)- tartrate, a compound
of formula la. obtained by the processes herein described, having a D90 particle size of about 7 microns,
D50 particle size of about 4 microns and D10 particle size of about 2 microns.
In one embodiment the present invention provides arformoterol L-(+)- tartrate, a compound of formula
la. having bulk density of 0.159 g/cc.
In one embodiment the present invention provides arformoterol L-(+)- tartrate, a compound of formula
la. having taped density of 0.271 g/cc.
In one embodiment the present invention provides arformoterol L-(+)- tartrate, a compound of formula
la. having specific surface area of about 8.44 m /g.
In one embodiment the present invention provides arformoterol L-(+)- lartrale, a compound of formula
la, having Hausner ratio of 1.70.
Jn one embodiment the present invention provides arformoterol L-(+)- tartrate, a compound of formula
la. having aspect ratio of 1.12 10 2.47

Instrumental settings for XRPD : The measurements were performed on Philips X-Ray Diffraetometer model XPERT-PRO (PANalytical) Detector: X'celerator j 1] using Cu lamp with type and wavelength of the X-ray radiation: K-α, 1.54060[A], K-α2 1.5444[A].
instrumental settings for DSC: The DSC thermogram was measured by a Differential Scanning Calorimeter (DSC 822. Mettler Toledo) at a scan rale of 10 C per minute in the temperature range of range is "25°C to 350°C",The DSC module was calibrated with Indium and zinc standard.
Related substances by HPLC:
Reagents and Solvents:
Water (Milli Q or equivalent); Acetonitrile (KPLC grade):Sodium dihydrogen phosphate (AR grade) Di-sodium hydrogen phosphate (AR grade): Potassium dihydrogen phosphate (AR grade) Ortho phosphoric acid (AR grade) Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and Integrator software or equivalent. Column: Inertsil C8: 250 ' 4.6 mm. 5.0 m or equivalent: Mobile phase: A=Buffcr, B= Acetonitrile
(Gradient Program)
Buffer: 3.75 gm of Sodium dihydrogen phosphate in 1000 mL water, pH adjusted to 3.0 with dilute
ortho phosphoric acid solution. Filter through 0.45u filter paper and degas.Diluent: Solution A:
Acetonitrile (84:16 v/v)
Solution A: 6.1 g Potassium dihydrogen phosphate + 1.03 g Di-sodium hydrogen phosphate to 1000 mL.
pH adjusted to 6.0 with dilute ortho phosphoric acid solution. Filter through 0.45u filter paper and degas.
Flow Rate: 1.0 mL/minule; Detection wavelength: UV 214 nm Column temperature: 25
°C Injection volume: 20 mL ; Run time: 55 minutes

Gradient Program:
Time (minute) A (%) B (%)
0.01 84 16
10 84 16
37 30 70
40 84 16
55 84 16
Preparation of Reference solution:

Weigh accurately about 25 mg of Arformolerol tartrate reference standard and transfer if into a 50 mL
volumetric flask. Add 30 mL of diluent and .sonicate to dissolve. Make up to the mark with diluent & mix.
further dilute 1 mL to 200 mL with diluent.
Preparation of Test solution: (Prepare in duplicate)
Weigh accurately about 25 mg of test sample and transfer it into a 50 mL volumetric flask. Add 30 mL of
diluent and sonicate to dissolve. Make up to the mark with diluent & mix.
Procedure:
Inject the blank, six replicate injections of reference solution and (lien inject each of test solution. Record the chromatograms for all injections. System Suitability:
The relative standard deviation (RSD) lor peak area responses and retention lime of six replicate injections of reference solution should not be more than 5.0%. It is observed that Arformolerol tartrate is eluted at retention time of about 16 minutes.
Area of Individual Weight of Std in
Impurity in test solution reference solution 1 25

The following examples are provided to enable one skilled in the art to praclice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of (he invention as defined in the features and advantages.

Examples
Example I: Preparation of'N-{2-(benzyloxy)-5-|(2R)-oxiran-2-yl]henyl)formamide, compound of formula IV.
a) Synthesis of |(1R)-l-|4-(l)enzyloxy)-3-nitrophenyl]-2-l)romoclhanol|
Mctho98%; Chiral Purity: >98%

b) Synthesis of |(1R)-l-|3-amino-4-(l)enxyloxy)phenyl]-2-bromoethanol}
To solution of 0.40 kg of [(lR)-l-[4-(benzy!oxy)-3-nitrophcnyIJ-2-bromoethanol] and 4 litre of acetic acid, 0.31 7 Kg of iron powder was charged to the reaction mass at about 25-30° C. Further the reaction mass was stirred at about 25-30° C for about 5-6 hours. The reaction mass was quenched in 20 litre ice cold water and stirred for about 15-20 minutes. 4 litre of ethyl acetate was charged to the reaction mass and stirred further for about 25-30 minutes for extraction. The ethyl acetate layer was separated from the aqueous layer and additionally the aqueous layer was extracted with ethyl acetate twice. The combined ethyl acetate layers were washed with salurated sodium bicarbonate solution followed by water and brine. Finally the organic layer was dried over sodium sulphate and filtered through hyflobed. The ethyl acetate layer was concentrated under vacuum. To the residue obtained was added 1.2 litre of ethyl acetate and temperature was raised to about 50-55°C to get clear solution. To this clear solution. 3.6 litre of hexane was added slowly. The reaction mass was cooled to about 25-30°C and maintained for about 2 hours and the solid obtained was filtered and washed with I litre hexane. The product obtained was dried at about 30-35° C for about 8 hours under vacuum to yield 0.32 Kg titled compound.
c) Synthesis of |N-{2-(benzyloxy)-5-[(lR)-2-bromo-l-hydroxyethyl|phenyl} formamide|
Method-1: To a 1 litre four necked flask with nitrogen, 0.304 kg of acetic anhydride was charged. Subsequently 0.274 kg of formic acid was added slowly al about 0-5° C and maintained for about 30-45 minutes. Meanwhile in another flask 0.32 kg of (lR)-l-[3-amino-4-(benzyloxy)pbenyl]-2-bromoetha»ol was charged followed by 3.2 litre telrahydrofuran under nitrogen blanketing. The reaction mass was then cooled to about 0-5° C. Above prepared solution of acetic anhydride /formic acid was added to the above reaction mass at about 0-5° C within about 20-30 minutes. The reaction mass was stirred and maintained al about 0-5° C for further 60 minutes. After completion of reaction the solvent was evaporated under vaccum completely at about 35°C. To this residue. 0.64 litre of ethyl acetate was added and distilled the reaction mass to remove the entrapped solvent and the process was repeated. To this residue, 0.64 litre of ethyl acetate: was added, and stirred at about 50-55° C for about 20-30 minutes followed by addition of 0.96 litre of cyclohexane. The reaction mass was cooled to about 25-30° C and maintained for about 1 hour. The product was filtered and washed with 0.32 litre of cyclohexane and subsequently dried at about 35-40° C for about 8 hours under vacuum to yield 0.27 kg of the titled compound.
Method-11: To the solution of 1gm (1 R)-1 -[3-amino-4-(benzyloxy)pheny]]-2-bromoethanol and 0.17gm of formic acid in 10 ml toluene was added sulfated tungstate (10 wt %) and heated in an oil bath at about 70°C. The reaction mass was cooled to about 25-30°C. followed by addition of toluene under stirring. The insoluble catalyst was filtered on hyflo and washed with toluene. The combined organic layer (both

filtrate and washings) were washed with water, dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to get ().8gm of the tilled compound.
Method-Ill: To the solution of !gm (lR-1-[3-amino-4-(benzyloxy)phenyl]-2-bromoethanol and 0.17g of formic acid in 10 nil letrahydrofuran was added sulfated tungstate (10 wt %) and healed in an oil hath at about 70°C and the progress of the reaction was monitored by TLC. The reaction mass was cooled to about 25-30°C, the insoluble catalyst was filtered and washed with letrahydrofuran. The tetrahydrofuran was evaporated under vacuum and residue was extracted with ethyl acetate. Further this organic layer was washed with water, dried over anhydrous sodium sulphate and the solvent was concentrated under reduced pressure to yield 0.78 gm of the titled compound.
(I) Preparation of N-{2-(benzyloxy)-5-|(2R)-oxiran-2-yI|phenyl}fonnamide, compound of formula FV. A 20 litre four neck assembly with nitrotien was arranged. 1 kg of N-{2-(bcnzyloxy)-5-[(IR)-2-bromo-l-hydroxyethyl]phenyl}lbrmamide was charged followed by addition of 5 litre of tetrahydrofuran and 5 litre of methanol to the reaction mass. 0.591 kg of potassium carbonate was added to the reaction mass. The reaction mass was stirred and maintained at about 25-30° C for about 2 hours. The completion of the reaction was monitored by HPLC. After completion of the reaction the organic volatiles were distilled out completely under vacuum. 10 litre of toluene was charged to the reaction mass and the reaction mass was stirred at about 25-30° C for further about I hour. The reaction mass was filtered through hyflo and the bed washed with toluene. The toluene layer was then concentrated lo get the oily residue under vacuum, To this obtained residue 10 litre toluene/n-heptane mixture (1:1) was added and the mixture was refluxed at about S0-110° C. The reaction mass was then cooled slowly to about 25-30° C and stirred for about 2-3 hours when product precipitated out. The product was filtered and washed with I litre mixture of toluene and n-heptane and dried for about 10 hours under vacuum at about 35-40° C to yield 0.60 kg of titled compound. Purity: >95%; SOR: 5.1 ° and Melting Point: 79 Co 80° C
Example 2: Preparation of [(2R)-N-l)benzyl-1-(4-methoxyphenyl)propan-2-amine|, compound of formula V.
a) Synthesis of [/V-l)enzyl-1-(4-mcthoxyphcnyl)propan-2-amiue Mandalatc sale|
To a clean and dry 10 litre autoclave. 5 litres of methanol and 1 kg of l-(p-methoxyphenyl)-2-propanone was charged. To this 0.650 kg of benzyl amine was added at about 25-30° C. The temperature of the reaction mass was slowly raised to about 40-45° C and maintained for about 2 hours. The reaction temperature was then lowered to 25-30°C and 1 gm of platinum dioxide catalyst was charged to the autoclave and about 6-8 kg hydrogen pressure was applied. The reaction was maintained at about 6-8 kg hydrogen pressure for about 3-4 hours. The progress of the reaction was monitored by HPLC. After

completion of reaction, the reaction mass was filtered through hyflo bed and subsequently washed with methanol. The filtrate was collected and transferred to another 10 litre RBF. 0.950 kg L-(+)-mandelic acid was added to the reaction mass under stirring. The reaction temperature was then raised to about 70-75° C and maintained for about 30-45 minutes. The reaction mass was slowly cooled to about 25-30° C to precipitate out the product. The product obtained was filtered, washed with methanol and dried at about 45-50° C for about 6-8 hours to yield 1.4 kg ofihe tilled compound.
Purification: To a 5 litre four neck assembly. 1 Kg of A;-benzyl-l-(4-methoxyphenyl)propan-2-amine mandalate sail was charged followed by 3 litres of methanol at about 25-30° C. The reaction temperature was raised to reflux. The reaction mass was maintained at about 65-70° C. for about 25-30 minutes and then slowly cooled to about 25-30° C and maintained for about I hour with stirring. The product was filtered, washed with methanol. The wet cake was dried for about 1 hour at about 45-50° C for about 6-8 hours. Purification can be repeated to achieve the desired chiral purity. Chiral Purity>98%: Chemical Purity: >99%.
b) Synthesis of |(2R)-N-benzyl-1-(4-me(ho.vyphenyl)propan-2-amine|
To a 10 litre four neck assembly 10 litre of water and 1 kg of N-benzyl-1-(4-metho\yphenyl)propan-2-amine mandalate salt was charged followed by 8 litre of methylene dichloride. To this 0,8 litre of 20% sodium hydroxide solution was slowly charged a! about 25-30° C to adjust pH>12.The reaction mass was maintained for next 2 hours. The organic layer was separated from aqueous layer and the aqueous layer was extracted with methylene dichloride. The total organic layer was combined and washed with water followed by washing with brine solution. Methylene dichloride layer was charged to the flask and subsequently 1.5 kg Neutral alumina was added and stirred for about 2 hours. The methylene dichloride layer was filtered to remove neutral alumina and concentrated completely under vaccum to yield 0.6 kg of title compound. Chiral Purity; >98%; Chemical Purity: >98%.
Example 3: Preparation ofcompound of formula III.
A 2 litre assembly was arranged and 80.9 gm of N-{2-(benzyloxy)-5-[(2R)-oxiran-2-yl]phenyl}formamide (compound of formula IV) and 72.S gm of (2R)-N-benzyl-l-(4-mcthoxyphenyl)propan-2-aminc (compound of formula V) were added sequentially. The temperature of the reaction mass was slowly raised to aboul 90-1 10° C and maintained at that temperature for about 12 hours with stirring. Subsequently the reaction mass was cooled to about 25-30° C to obtain compound of Formula III. Example 4: Preparation of arformotcrol D-(-)-tartra1c compound of formula II

Method-1: To a clean and dry 2 litre Autoclave, 100 gm of compound of formula III was charged followed by addition of 750 ml isopropyl alcohol and 5 gm of 10% Pd/C. 3-3.5 kg of hydrogen pressure was applied to the reaction mass and the reaction mass was maintained at about 35-36° C and 3.5 kg pressure for about 10-12 hours. The progress of the reaction was monitored by HPLC. After the completion of reaction, the mass was filtered through hyllobcd and the bed was washed with 50 ml isopropy! alcohol. The total filtrate was combined and charged to a 2 litre four necked flask followed by addition of 200 ml of toluene under nitrogen. To this reaction mass D-{-)-tartaric acid solution was added slowly (Prepared by using 34.3 gm D-(-)-tartaric acid in 100 ml water) at about 25-30° C. Subsequently the reaction mass was stirred and maintained al about 25-30° C for aboui 3 hours. The salt precipitated out was filtered and washed wish isopropy! alcohol and dried at about 40-45°C under vacuum for about 6-8 hours to yield 70 gm titled compound. Chemical Purity: >90%,
Mcthod-II: To a clean and dry 2 litre Autoclave, 100 gm of compound of formula III was taken in 1050 ml ethanol: isopropyl alcohol mixture (7:3 ratio) and 7.5 gm of 10% Pd on C (50%wet). 4-4.5 kg of hydrogen pressure was slowly applied to the reaction mass. The temperature was raised to about 50-55°C and maintained for about 3-4 hours. The reaction mass was filtered through hyflo bed and washed with 50 ml isopropyl alcohol. The filtrate was combined and charged lo a flask followed by addition of D-(-)-lartaric acid solution. (Prepared by using 34.3 gm D-(-)-tartaric acid in 100 ml water) at about 25-30° C. The reaction mass was stirred and maintained for about 25-30° C for about 3 hours. The product obtained was filtered and washed with isopropyl alcohol and dried at about 40-45°C under vacuum for about 6-8 hours to yield 70gm titled compound. Chemical Purity: >90%.
Purification: To a clean 2 litre. 4-neck flask 525 ml of tetrahydrofuran was charged followed by addition of 65 gm of the crude compound of formula 11a at about 25-30° C. The reaction temperature was slowly raised to reflux at about 65-70° C and DM water was added slowly till clear solution was observed. The homogenous reaction mass was stirred for about 15-20 minutes and then 790 ml of tetrahydrofuran was slowly added to the reaction mass. The reaction mass was then allowed to cool naturally and stirring continued for further about 5-6 hours at about 25-30° C. The product precipitated out was filtered and washed with tetrahydrofuran. The we! product was then dried al aboui 30-35° C under vacuum for aboui 6-8 hours. The same purification procedure was repeated two more times till required purity was achieved. Chemical Puvky: >99.5%
Data of pure arrformoterol D-(-)-tartrate

Chemical purity: 99.76%: Formula A = 0.15%; Formula B =0.02%: Chiral purify: 99.76%: SOR= -44o (C-0.61% in water): Melting point: 186.10° C by DSC; 1R: 34S9, 3445. 3370. 3003. 2987, 2958. 2889. 2837.2754. 1735. 1677.
XRD Table of arformoterol D-(-)-tartrate

Peak Number °2Th. Intensity
1 3.82 19.47
2 15.44
100
3 17.79 11.97
4 18.13 4.57
5 19.28 7.53
6 22.83 9.69
7 23.91 6.20
8 24.41 5.87
9 25.52 10.34
10 27.07 5.31
1 1 30.98 4.99
12 34.99 7.35
13 36.25 4.52
14 38.98 9.53
Example 5: Preparation of arformotcrol L-(+)-tartrate. compound ol'formula la.
To a clean 5 L 4-neck flask 2 L , DM water was charged followed by addition of 100 gm of arformoterol D-(-)-tarlrate at 25-30° C. Subsequently 1 L of ethyl acetate was charged to the solution followed by slow addition of H5 gm of sodium bicarbonate. 200 gm of sodittm chloride was added to me reaction mass and the reaction mass was stirred for about 30 minutes and two layers were separated. The aqueous layer was then extracted twice with 500 ml ethyl acetate. The combined organic layer was then dried over sodium sulphate. The organic layer was distilled off completely under vacuum followed by codistillation twice of 300 ml isopropanol each. The residue was then degassed for about one hour and

dissolved in 800 ml of isopropanol and followed by addition of 200 ml of toluene. In 2L flask subsequently Aq. L-(+)-Tartaric acid solution (36.43 gm of L-(+)-tartaric acid dissolved in 100 ml of DM water) was added slowly to the reaction mass under stirring. After complete addition, the stirring was continued for 3 hours at about 25-30° C. The precipitated product was filtered and the wet cake was washed with 200 ml isopropyl alcohol and dried at about 40-45° C under vacuum for about 6-8 hours. Further dried product was micronized to yield 65gm of Arformolerol L(+)tartrate.
Data of arlormoterol L- (+)- Tartrate:
Chemical purily: 99,65% Formula A = 0.09%; Formula B = below detection limit; Chiral purity: 100%: SOR=-28.6°(C=0.6I% in water); Melting point: 178.54° C by DSC; IR; 3840, 3736, 3459, 3398. 3317: 3103, 2985. 2938, 2843: 2738, 2536. 1660.
XRD Tabic of arformoterol L-(+)-Tartrate

Peak Number 2-Theta Intensity Peak Number 2-Thcta Intensity
1 4.32 11.77 9 21.96 46.S8
8.69 100 10 22.74 44.62
12.26 18.44 11 25.29 19.05
4 13.85 18.79 12 25.65 17.05
5 16.45 14.41 13 26.05 15.63
6 17.44 94.36 14 26.29 22.21
7 19.38 30.40 15 26.62 13.55
8 20.63 74,72 16 28.57 12.54
16 28.57 12,54
Example 6: Preparation of';irfornioterol L(+) Tartrate, compound of formula la.
Method I: To a clean and dry 2 L Autoclave, 100 gin of compound of formula III was added, followed by addition of 750 ml isopropyl alcohol and 7.5 gin 10% Pd o^ C. 3-3.5 kg hydrogen pressure was applied to the reaction mass and the react ion mass was maintained at about 35-36° C and 3.5 kg pressure for about 10-12 hours. The reaction mass was llltered through hyflo and washed with 50 ml isopropyl alcohol. The llhrate was collected and charged to a 2 L flask followed by addition of 200 mi of toluene under nitrogen blanketing. To this reaction mass L-(+)-tartaric acid solution prepared by using 34.3 gm of L-(-r-)-Tartaric

acid in 100 ml water was added at about 25-30° C. The reaction mass was stirred and maintained tor about 25-30° C far about 3 hours. The reaction mass was filtered and the wet cake was washed with 100 ml isopropyl alcohol. The wet cake was suck dried for about one hour. The crude material was dried at about 35-40°C under vacuum for about 6-8 hours to yield 68gm tilled compound. Chemical Purity; 97.33% Method II: To a clean and dry 2 L Autoclave. 100 gm of compound of formula III was added, followed by addition of 750 ml isopropyl alcohol and 7.5 gm 10% Pd on C. 3-3.5 kg hydrogen pressure was applied to the reaction mass and the reaction mass maintained at about 35-36° C and 3.5 Kg pressure for about 10-12 hours. The reaction mass was filtered through hyflo and washed with 50 ml isopropyl alcohol. The total nitrates were combined and the organic volatiles were removed under reduced pressure. To this residue was added 900 ml of tetrahydrofuran followed by slow addition of L-(+)-tarlaric acid solution ( 34.3 gm of L-(-f)-tartaric acid in 30 ml water) at about 25-30o C. The reaction mass was stirred and maintained for about 25-30° C for about 3 hours. The reaction mass was filtered and the wet cake was washed with 100 ml tetrahydrofuran. The crude material was dried at about 35-40°C under vacuum for about 6-8 hours (o yield 60gm of titled compound.
Purification: To a clean 2 litre 4-neck flask 520 ml of tetrahydrofuran was charged followed by addition of 65 gm of the crude arformoterol L-(+)-Tartrate at about 25-30° C. The reaction temperature was raised to reflux at about 65-70° C and DM water was added slowly till clear solution was observed. The reaction mass was stirred for about 15-20 minutes under hot condition and then 780 ml of tetrahydrofuran was added to the reaction mass. The reaction mass was then allowed to cool and stirring continued for about 5-6 hours at about 25-30° C. The precipitated salt was filtered, washed with tetrahydrofuran and dried at about 30-35° C under vacuum for about 6-8 hours. Same purification process can be repeated to achieve the desired chemical and chiral purity. Data of pure L-(+)-tartralc: Chemical purity: 99.88%; Chiral purity: 100 %; SOR= -29.2 °(C=0.6I% in water)DSC: Endotherm at 128.4° C. 174.82° C. 180.26° C and exothermal I37.2I°C. IR: 3854, 3490. 3358. 3076. 2976: 1660. 1597
XRD of arformoterol L-(+)-larfrafe:

Peak Number 2-Thela intensity Peak Number 2-Thela Intensity
] 6.63 90.57 14 17.92 42.91
2 7.64 12.09 15 18.74 100
9,26 16.12 16 19.86 80.62
4 10.81 10.92 17 20.28 42.54

5
11.44 12.18 IR 21.77 45.16
6 12.65 33.07 19 22.97 85.40
7 13.22 29,12 20 23.64 75.78
8 13.83 12.85 21 24.44 38.19
9 14.36 12.43 22 25.08 24.53
10 15.30 11.95 23 26.56 25.60
11 16.20 41.20 24 34.86 10.68
12 16.67 19.06 25 36.30 11.22
13 17,25 32.02
Comparative Example: Preparation ol'arformoterol L-(+)-tartrate, compound of formula la
To a clean and dry 2 L Autoclave. 30 gm of compound of formula Hi was added, followed by addition of 248 ml isopropyl alcohol, 62 ml toluene and 10% Pd on C with 3-4 kg hydrogen pressure. The reaction mass was filtered through hyflo bed and aqueous L-tartaric acid solution (9.32 gm of L-tartaric acid dissolved in 46.5 ml of water) was added to reaction mass and maintained for 1-2 hour. The reaction mass was cooled to 10-15°C and further maintained for 2 hours. The precipitated arformoterol L-(+)-tartrate was filtered and washed with about 50 ml of lPA-To!uenc mix (8:2) and dried under vacuum at 35-40°C to form 2! gm of arformoterol L(+) tartrate. Chemical Purity: 95.88% by HPLC.

Impurity Area percentage
Formula A 3.49%
Formula B 0.04%
Formula D 0.05%
Formula E 0.22%

We claim
!. A process for the preparation of arformoterol L-(+)- tartrate, a compound of Formula la.

wherein the level of compounds of formula A or B, is less than 0.15% w/w relative 1o the amount of arformoterol L-(+)- tartrate as determined by HPLC,

comprising: a) reacting crude arformoterol. a compound of Formula )

with D-(-)-tartaric acid to form arformoterol D-(-Vtartrate, a compound of formula II: and

b) reacting the arformoterol D-(-)-tartrnle, the compound of formula 11. with a base and L-(+)-tartaric acid, to form arformoterol I--(+)- tartrate. compound of Formula la.

2. The process as claimed in claim 1. wherein arformoterol D(-)-tarlrate a compound of formula II. is subjected to purification.
3. The process as claimed in claim 2. wherein arformoterol D-(-)-tartrate a compound of formula II, is subjected to purification by crystallization in a solvent system
4. The process as claimed in claim 3, wherein the solvent system comprises ether and water.
5. The process as claimed in claim I. wherein arformoterol D-{-)-tarlrate. a compound of formula II has a chemical purity of at least 95% as determined by HPLC.
6. The process as claimed in claim I. wherein in step b) the arformoterol D-(-)-tartraie. the compound of formula IE is reacted with a base to obtain arformoterol. followed bv reacting life nrformotcrol with L-(+)-(artaric acid in a mixture of toluene and isopropanol to form arformoterol L-{+)- tartrate.
7. The process as claimed in claim 6. wherein the isopropanol and toluene are used in the ratio of 8:2 v/v.
8. The process as claimed in claim 6. wherein an aqueous solution of L-(+)-tariaric acid is used.
9. The process as claimed in claim 8. wherein the aqueous solution of L-(-t-)-iariaric acid is used in a proportion such that isopropanol: toluene: water is in the ratio of 8:2:1 v/v. for I part b> weight oY arformoterol D-(-)-tartrate.
10. The process as claimed in claim 6 or 9, wherein the arformoterol L-(+)- tartrate, a compound of
Formula (a, is isolated in crystalline polymorphic Form B.