FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]

1. TITLE OF THE INVENTION: AN IMPROVED PROCESS
2. APPLICANT (S)
(a) Name : Emcure Pharmaceuticals Ltd.
(b) Nationality : India
(c) Address : R&D Center II, 12/2 F - II Block, M.I.D.C. Pimpri,
Pune - 411018, Maharashtra
3. PREAMBLE TO THE DESCRIPTION

PROVISION COMPLETE
The following specification describes the The following specification particularly Invention describes the invention and the manner in
which it is to be performed

4. DESCRIPTION (Description starts from next page.)
5. CLAIMS (not applicable for provisional specification.)
6. DATE AND SIGNATURE (to be given at the end of the last page of specification)
7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page)
Note: -
*Repeat boxes in case of more than one entry
*To be signed by the applicants) or by the authorized registered patent agent.
*Name of the applicants should be given in full, family name in the beginning
*Complete address of the applicant should be given stating the postal index
no./code, state and country.
*Strike out the column which is/are not applicable.
AN IMPROVED PROCESS
FIELD OF INVENTION:
The present invention relates to an improved, simple, safe and commercially viable process for the preparation of optically active enantiomer of benzene dimethanol derivative. The current embodiment also discloses a process for making the same by making use of safe reducing agent.
BACKROUND OF THE INVENTION:
Albuterol (1), chemically known as alpha'- [[(1,1 dimethylethyl)amino]methyl]-4-hydroxy-l,3-benzenedimethanol, is a beta-adrenergic stimulant used as a bronchodilator. Albuterol is used to prevent and treat wheezing, shortness of breath and troubled breathing caused by asthma, chronic bronchitis, emphysema, and other lung diseases.
It is well known fact that in the drug having a chiral center, one of the enantiomer of racemic pair is frequently more effective than the other in the treatment of any medical conditions. Studies have shown that the levorotatory R-isomer of albuterol, known as levalbuterol is more potent than the dextrorotatory S-isomer of albuterol. Also, levalbuterol is more effective and less toxic than albuterol (Ref: US 5545745).
Levalbuterol of formula (I-a) is marketed in the form of its hydrochloride salt, under the tradename "Xopenex" (Ref: http://www.accessdata. fda.gov/scripts/cder/drugsatfda/ mdex.cfm?fuseaction=Search.Overview&DrupName=XOPENEX).

1) The synthesis of R-isomer of albuterol was first disclosed in Journal of Medicinal
Chemistry, 1971, 14(9), 895-896 by Hartley et al. However, this process requires use of expensive starting materials. Further, this process involves at least 6 independent steps resulting in producing low overall yields. More importantly the reduction of the ester precursor of R-albuterol is carried out by using lithium aluminum hydride, which has following disadvantages. The lithium aluminum hydride reagent used for reduction is corrosive to eyes, skin, nose and throat. Product contact with the body results in burns. Lithium aluminum hydride is pyrophoric and results in hazards during addition. Further, it makes the process costly. The reactions conditions used while using lithium aluminum hydride are critical making the workup of the reaction critical. Lithium aluminum hydride is very much moisture sensitive, which catches fire very easily during the reactions. Lithium Aluminum hydride is sensitive to static discharge (Flash point is -17°C), reacts violently with water so requires cryogenic temperature conditions.

Scheme I: Method as disclosed in US 5,442,118 for preparation of (R>Albuterol.
US 5, 442, 118 assigned to Sepracor, discloses a method for the preparation of levalbuterol by the above Scheme I. The starting material used was commercially available as methyl, 5-acetylsalicylate (H), which on oxidation in DMSO, in presence of 2 equivalents of HBr gave arylglyoxal (HI). The arylglyoxal on further treatment with tertiary butyl amine gave the iminoketone (IV). The iminoketone on reduction with three equivalents of borane reducing agent along with catalyst was converted to the amino diol (I-a). The stereochemistry of the aminodiol obtained as a product depends upon the optically active catalyst used e.g. the (R) isomer of albuterol was prepared by making use of the R-catalyst prepared from D-proline.
This process has several disadvantages, which limits its scope on an industrial scale, they are,
a) the borane reducing agent used i.e. borane methyl sulphide complex makes the process more costly,

b) further, the catalyst used to bring about the enantiomeric selectivity is also having a higher cost,
c) to increase the enatioselectivity, a slow addition of the iminoketone is required which increases the time cycle of the reaction,
d) the borane reducing agent used is highly flammable with flash point of 18°C and is harmful on contact with skin and
e) it has a strong obnoxious odour, which is irritating.

Scheme II: Method as disclosed in US 5,545,745 for preparation of (R)-Albuterol
US 5,545,745 is a patent, which discloses a method for producing (R) and (S) albuterol according to the Scheme II. The process disclosed in the Scheme II makes use of a precursor, for making (R) salbutamol, which is obtained by making use of (+)-di-toluyl-D-tartaric acid and (+) -di-benzoyl-D-tartaric acid. The compound (VIII) is reduced to substantially optically pure alpha- [[(1,1-dimethylethyl) amino] methyl]-4-(phenylmethoxy)-l,3-benzenedimethanol (DC) by treatment with 2 to 3 equivalents of

borane-THF solution (BH3-THF) in a suitable solvent, such as tetrahydrofuran (THF). Further compound (IX) is debenzylated to give optically pure albuterol (I-a).
However, there are certain limitations associated with this process e.g. the BH3. THF used
has following disadvantages:
a) It is highly flammable with flash point -21.7°C, diluted in THF.
b) It has an unpleasant odor.
c) It is a strong skin irritant.
d) Reacts violently with water, moist air, alcohols, acids etc.
e) Its vapours may cause flash fire.
f) It may cause liver and kidney effects.
g) Evolves flammable and toxic diborane gas.

Scheme HI: Method as disclosed in US 5,399,765 for preparation of (R)-Albuterol
US 5,399,765 is a patent which discloses a process for making optically pure albuterol as disclosed in Scheme III. Methyl 5-acetyl salicylate (II), is oxidized in presence of DMSO in the presence of aqueous HBr to give arylglyoxal (III), which is treated with t-butylamine to give the alpha-iminoketone (IV). The alpha imino ketone (IV) is further reduced to give the racemic compound i.e. (X). Alternatively, the compound of formula

(X) is also prepared directly from the corresponding alpha-iminoketone (TV) by the catalytic reductive amination with t-butylamine in the presence of heterogeneous noble-metal catalysts such as Pd/C, Pt/C or PtO2. The precursor (X) is resolved with a chiral acid such as (-) or (+) di-p-toluyltartaric acid. Thus, by using (+) -di-p-toluyl tartaric acid, R isomer (VI) is obtained. The compound was further reduced to levalbuterol (I-a) using BH3-Me2S.
However, there are many disadvantages associated with this process. The use of the resolving agent makes the process costly. Apart from the other disadvantages the reducing agent also creates the limitations. The availability of the borane reagent also used, for the process, is difficult. The borane methyl sulphide complex used, has^ following disadvantages:
1) The reagent is highly flammable.
2) It is harmful on the contact with skin.
3) The borane methyl sulphide complex on contact with water liberates high flammable gases.
4) It is skin irritant and causes burns on skin.
5) It liberates the toxic gas causing inhalation hazard.

Scheme IV: Method as disclosed in US 20040054215 for preparation of (R)-Albuterol.
US 20040054215 is a patent application, which discloses a process for making optically pure (R) and / or (S) salbutamol or pharmaceutically acceptable salts thereof, which comprises obtaining the respective enantiomer of salbutamol in substantially optically pure form. The racemic 4-benzyl albuterol ester (VIII) is converted to the desired optically active tartaric acid salt, which is further converted to the free base. The said free base (VIII) is reduced using lithium aluminum hydride to give respective 4-benzyl albuterol. The (R) or (S) 4-benzyl albuterol free base is de-benzylated in order to give (R) or (S) salbutamol.
However, this process has certain disadvantages. The lithium aluminum hydride used in the reduction is corrosive to eyes, skin, nose and throat. Product contact with the body results in burns. It is very destructive of mucous membranes. Lithium Aluminum Hydride is a solid, which is pyrophoric which results in hazards during addition. Lithium aluminum hydride is very much moisture sensitive, which catches fire very easily during the reactions. Further, it makes me process costly. It violently reacts with water liberating

hydrogen. Thus, the reactions conditions for lithium aluminum hydride are critical making the work up of the reaction critical. Further, the molecular weight of lithium aluminum hydride is 38, which is low. Hence, for carrying out the small scale reactions it becomes critical to weigh the appropriate amount of the said reducing agent, which is moisture sensitive.
Hence, there remains a need to develop a process for preparation of optically active Albuterol, which makes use of safe reducing reagents, which is cost effective and which is industrially feasible, easy to handle, easy to store, easily available, less hazardous, easy to add, easy to workup and convenient to measure the quantities.
OBJECT OF THE INVENTION:
First object of the invention is to develop a process for the preparation of optically active albuterol using the safe reducing agent.
Second object of the invention is to develop a process for the preparation of optically active albuterol, which makes use of the reducing agent, which is cost effective, easily available and industrially feasible.
Third object of the invention is to develop a process for the preparation of optically active albuterol using the reducing agent, which is less hazardous, less unstable to moisture, less pyrophoric and less toxic to skin and stable at ambient temperature.
Fourth object of the invention is to develop a process for the preparation of optically active albuterol using the reducing agent, which is easy to handle, easy to store, convenient to measure and easy to work up.

SUMMARY OF THE INVENTION:
According to the present invention, die optically active albuterol is obtained using the process, wherein the reducing agent used is Vitride. Thus, use of Vitride as a reducing agent makes die process less hazardous, cost effective, safe, easy and industrial friendly.

DETAILED DESCRIPTION OF THE INVENTION:
The levalbuterol is prepared as per the scheme (V) disclosed below.

Scheme V: Emcnre's scheme for the preparation of Levalbuterol.
The present embodiment describes the process for the preparation of Levalbuterol as per the reaction sequence in Scheme V.
The reaction sequence includes the conversion of Schiff s base (XII) to the amino alcohol
(VII) by reducing the Setoffs base with NaBR,.
The R group in (XII) is lower alkyl (Ci to C*) or aryl such as phenyl, toluyl etc.


Scheme V: Emcure's scheme for the preparation of Levalbuterol.
The present embodiment describes the process for the preparation of Levalbuterol as per the reaction sequence in Scheme V.
The reaction sequence includes the conversion of Schiff’s base (XII) to the amino alcohol
(VII) by reducing the Setoffs base with NaBH4,.
The R group in (XII) is lower alkyl (C1 to C6) or aryl such as phenyl, toluyl etc.

The racemic amino alcohol is further converted to the optically active amino alcohol salt
XIII) using (D) (-) dibenzoyl tartaric acid (DBTA). The optically active dibenzoyl
tartaric acid salt (DBTA) of (XIII) formed is converted to the free base (VIII) by
basifying (XIII) with base.
The base is selected from the group comprising of hydroxides of alkali or alkaline earth
metals. The preferred alkali earth metal is Na, K, Li etc. The more preferred alkali is
sodium. Thus, using sodium hydroxide the desirable salt is obtained.
The free base is further subjected to the reduction by making use of Vitride to reduce the
ester group to the alcohol. The levalbuterol (I-a) is formed by debenzylation of (IX) by
carrying out hydrogenation using Pd/C.
The current embodiment makes use of Vitride as reducing agent, which makes the process advantageous in following ways:
1) Vitride is a safe reducing agent as compared to the other strong reducing agents.
2) It is easy to handle.
3) It can be stored easily at ambient temperature.
4) It has a high molecular weight. Hence, while carrying out the small scale reactions the weighing can be done easily.
5) It is less pyrophoric as compared to the other reducing agents like LiAH4 and Borane reducing agents. Vitride is stable upto 170°C.
6) It has less toxic effects on the skin and body.
7) Making use of Vitride as a reducing agent makes the overall process cost effective and industrially feasible.
8) Vitride reducing agent is easily available.
9) The work up conditions, while making use of Vitride are not so stringent as compared to other reducing agents.
10) Vitride is comparatively less moisture sensitive.
The invention is described in detail here below with respect to the following examples, which are provided merely for illustration and are not intended to restrict the scope of the

invention in any manner. Any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention.

EXAMPLES:
Example 1: Preparation of Racemic amino alcohol (VII)
Methanol (7 liters) was charged in a round bottom flask. Schiff’s base (XII) (1.00 kg)
(2.83 moles) was added with stirring. The reaction mixture was cooled to 15-20°C. Sodium borohydride (0.130 kg) (3.43 moles) was added at 25-30°C. After completion of the reaction, 6.0 liters of methanol was distilled out and ammonium chloride solution was added drop wise. The reaction mixture was washed with cold water, dried and finally washed with methanol. The solid was dried completely.
Yield: 0.930-0.950 kg
Example 2: Resolution of Racemic amino alcohol (VII) to (R)-amino alcohol DBTA Salt (XIII)
Methanol (20 liters) was charged in a round bottom flask. Racemic amino alcohol (VIII)
(1.0Kg) (2.80 moles) was added to it. D (-) Di-benzoyl-tartaric acid (0.5012kg) (1.399
moles) was dissolved in methanol (2.0 liters) and added to the reaction mixture. The
reaction mixture was filtered and washed with methanol. The wet cake was heated to
reflux in methanol for 1hour. The reaction mixture was gradually cooled, filtered and
dried.
Yield: 0.52-0.55 kg
Example 3: Preparation of (R)-benzyl levalbuterol (IX)
Water (7 liters) was charged in a round bottom flask. Sodium hydroxide (93.28g) (2.33 moles) was added with stirring. (R)-amino alcohol DBTA salt (1.0 kg) (0.93 moles) (XIII) was charged and stirred for 1-2 hours. The solid was filtered after the completion of the reaction and washed with water. The solid was dried to get compound (VIII). Toluene (7.01iters) was charged to another clean reactor. R-amino alcohol free base (VIE) was charged at 25-30°C. Vitride (1.076 kg diluted in 1.0 litres toluene) (3.731 moles) was added. After the completion of reaction aqueous ammonium chloride solution was added. The toluene layer was separated, cooled and filtered. The solid was dried.
Yield: 0.51-0.55 kg.

Example 4: Preparation of Levalbuterol (I-a)
(R)-Benzyl salbutamol (IX) (1 kg) (3.039 moles) was dissolved in 7.5 liters isopropanol in hydrogenation vessel. 10% Pd/C (40 gm) was charged to the same. The vessel was pressurized with hydrogen up to 100 psi. After completion of the reaction, the vessel was depressurized and flushed with nitrogen. The reaction mixture was filtered through hyflow bed and washed with isopropanol. The filtrate was transferred to a clean round bottom flask and was chilled to 10°C. Hydrochloric acid was charged in iso propyl alcohol to the reaction mixture till the pH of the mass became acidic. The mixture was stirred for 1 hour below 10°C and washed with acetone.
Yield: 0.78-08 kg.

WE CLAIM
1) A process for the preparation of (R) salbutamol, comprising the steps of:
a) reducing iminoketone (XII) to amine (VII) using NaBH4 wherein R is lower alkyl or aryl,

b) resolving racemic amino alcohol (VII) to (R) isomer salt (XIII) using D (-) dibenzoyl tartaric acid,

c) converting the salt (XIII) to its base (VIII) using sodium hydroxide,

d) reducing the ester (VIII) to the corresponding alcohol (IX) using Vitride and,

e) debenzylating the alcohol (IX) to (R) salbutamol (I-a).

2) A process according to claim 1, wherein reduction of the ester (VIII) to alcohol (DC) is carried out by Vitride.
3) A process according to claims 1 and 2, wherein R is lower alkyl (C1-C6) or aryl group viz. phenyl or toluyl.
4) A process according to claim 3, where in preferable R group is lower allyl group (C1-C6).
5) A process for preparing optically pure (R) salbutamol substantially as described in foregoing examples.

ABSTRACT
The present invention provides the procedure for the preparation of optically active albuterol, wherein the reducing agent used is Vitride. Thus, use of Vitride as a reducing agent makes the process less hazardous, cost effective, safe, easy and industrial friendly.