Field of the Invention

The present invention relates to an improved process for the preparation of Salmeterol Xinafoate of Formu la (I).

Background of the Invention

Salmeterol Xinafoate is the racemic form of the l -hydroxy-2-naphthoic acid salt of Salmeterol. It

1

has the chemical name 4-hydroxy-a -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3- benzenedimethanol, l-hydroxy-2-naphthalencarboxylate.

Salmeterol Xinafoate is a Long-acting p ₂ -adrenergic agonist (LABA). It is used for the treatment of asthma and in the prevention of bronchospasm. Salmeterol Xinafoate is commercialized under the brand name of SEREVENT ^® .

Salmeterol was first described and claimed in U.S. Pat. No. 4,992,474 A. This patent describes a specific method for producing Salmeterol by the reaction of 4-phenyl-l-butanol of Formula 1 with 1 ,6-dibromohexane of Formula 2 in the presence of sodium hydride (NaH) in tetrahydrofuran (THF) to give the ether derivative [4-[(6-bromohexyl)oxy]butyl]benzene of Formula 3, which is then condensed with 5-(2-amino-l-hydroxyethyl)-2-hydroxybenzyl alcohol of Formula 4 in the presence of potassium iodide ( I) and triethylamine in hot dimethylfumarate (DMF) to give Salmeterol of Formula 1-1. The process is shown in the scheme I given below:

Scheme I

ES 2065269 B l describes a process for the preparation of Salmeterol by reacting 6-(4- phenylbutoxy)]hexyl]benzylamine of Formula 6 with salicylaldehyde derivative of Formula 5 followed by, catalytic hydrogenation of the obtained compound of Formula 7 to give Salmeterol of

Formula I-l. The process is shown in the scheme II given below:

Scheme II US 8,648,214 B2 discloses a process for preparing Salmeterol or a salt or solvate thereof, comprising the steps of reacting an amine compound of Formula 9 with an aldehyde compound of Formula 8 to obtain compound of Formula 10; followed by reducing the compound of Formula 10 to alcohol compound of Formula 11 in a biphasic solvent system and finally deprotecting the alcohol compound of Formula 11 to obtain Salmeterol of Formula 1-1. The process is shown in the scheme III given below:

wherein X is a leaving group and Pg is a protecting group

Scheme III

The processes described in the above patents are lengthy, cumbersome and results in low yield and purity.

Therefore, there is need of providing an improved process for the preparation of Salmeterol Xinafoate, which is simple, eco-friendly, inexpensive, reproducible and well suited for commercial scale up. Objective of the Invention

The main objective of the present invention is to provide cost effective and commercially viable process for the preparation of Salmeterol Xinafoate. Another objective of the present invention is to provide a process for the preparation of Salmeterol Xinafoate which employs less expensive, easily available and environment friendly reagents.

Summary of the Invention

Accordingly, the present invention provides an improved process for the preparation of Salmeterol Xinafoate of Formula (I)

which comprises:

i) condensation of com ound of Formula A with compound of Formula B,

in a solvent in the presence of a base to give compound of Formula C;

ii) reducing the compound of Formula C in a monophasic solvent with a reducing agent to obtain compound of Formula D;

iii) debenzylating compound of Formula D with hydrogen and a metal catalyst in a solvent to obtain Salmeterol of Formula I-l and

iv) converting the compound of Formula I-l to Salmeterol Xinafoate of Formula (I).

In another aspect, the present invention provides an improved process for the preparation of compound of Formula D

which com rises reducing the compound of Formula C

in a monophasic solvent with a reducing agent to obtain compound of Formula D.

Detailed Description of the Invention

The main embodiment, of the present invention provides an improved process for the preparation of Salmeterol Xinafoate of Formula (I) as shown in the scheme IV given below:

Scheme IV

Step 1:

Condensation of compound of Formula A with compound of Formula B in a solvent in the presence of a base to give compound of Formula C.

The solvent used for condensation is selected from alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol and the like; preferably the solvent used is methanol. The base used for condensation is selected from amines such as triethylamine or diisopropylethylamine. Preferably the base used is diisopropylethylamine (DfPEA). The condensation reaction temperature may range from 0 °C to 15 °C and preferably at a temperature in the range from 5 °C to 10 °C. The duration of the reaction may range from 10 hours to 20 hours, preferably for a period of 15 hours.

After the completion of the reaction, the reaction mass is quenched into water and extracted with n-heptane. The n-heptane layer (which contains the compound of Formula C) is further extracted with methanol before proceeding to step-2 to give compound of Formula C in methanol. Step 2:

Reduction of compound of Formula C in methanol with reducing agent to give compound of Formula D. The reducing agent used for reduction of compound of Formula C to compound of Formula D is selected from sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, sodium bis(2-methoxyethoxy)aluminum hydride. Preferably the reducing agent used is sodium borohydride. The reduction reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25 °C to 30 °C. The duration of the reaction may range from 7 hours to 9 hours, preferably for a period of 8 hours.

Step 3:

Debenzylation of compound of Formula D with hydrogen and a metal catalyst in a solvent to give Salmeterol free base of Formula 1-1.

The debenzylating agent is selected from platinum, platinum oxide, palladium, Raney nickel or rhodium, on a support, such as charcoal or mixtures thereof. Preferably debenzylation is carried out by using palladium on carbon. The solvent used is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol and the like. Preferably the solvent used is methanol. The reaction temperature may range from 20 °C to 30 °C and preferably at a temperature in the range from 25 °C to 28 °C. The duration of the reaction may range from 1 hour to 2 hours, preferably for a period of 1 .5 hours. Salmeterol free base of Formula 1-1 is subjected to purification using a solvent selected from esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate. Preferably the solvent used is ethylacetate.

Step 4:

Xinafoate salt formation of Salmeterol in a solvent using l -hydroxy-2-napthoic acid to give Salmeterol Xinafoate of Formula (I).

The solvent used for salt formation is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol and the like. Preferably the solvent used is methanol. The reaction temperature may range from 20 °C to 30 °C and preferably at a temperature in the range from 25 °C to 30 °C. The duration of the reaction may range from 1 hour to 2 hours, preferably for a period of 1 .5 hours.

Salmeterol Xinafoate of Formula (I) is subjected to purification using a solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol and the like. Preferably the solvent used is methanol. in a preferred embodiment, the present invention provides an improved process for the preparation of Salmeterol Xinafoate of Formula (I)

which comprises:

i) condensation of com ound of Formula A with compound of Formula B,

in a solvent in the presence of a base to give compound of Formula C;

ii) reducing the compound of Formula C in a monophasic solvent with a reducing agent to obtain compound of Formula D;

iii) debenzylating compound of Formula D with hydrogen and a metal catalyst in a solvent to obtain Salmeterol of Formula 1-1 and

iv) converting the compound of Formula 1-1 to Salmeterol Xinafoate of Formula (I).

In a most preferred embodiment, the present invention provides an improved process for the preparation of Salmeterol Xinafoate of Formula (I), which comprises:

i) condensation of compound of Formula A

with compound of Formula B

methylethylketone in the presence of diisopropylethylamine to give compound of Formula

ii) reducing the compound of Formula C in methanol solvent with sodium borohydride to obtain compound of Formula D;

iii) debenzylating the compound of Formula D with hydrogen and palladium on carbon in methanol to obtain Salmeterol of Formula I-l and

iv) converting the compound of Formula I-l to Salmeterol Xinafoate of Formula (I).

In another preferred embodiment, the present invention provides an improved process for the preparation of com ound of Formula D,

which com rises reducing compound of Formula C

in a monophasic solvent with a reducing agent to obtain compound of Formula D. In another most preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula D,

which com rises reducing compound of Formula C

in methanol with sodium borohydride to obtain compound of Formula D.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale.

Examples

Example-1: Preparation of Salmeterol free base of Formula 1-1

Step I: Preparation of 2-hydroxy-5-[[[6-(4-phenylbutoxy)hexylbenzyI]amino] acetyl] benzaldehyde (Formula C):

Mixture of Methylethylketone (1250 mL), benzyl amine derivative (146.66 grams) were taken in round bottom flask and stirred for 1 5 minutes at 25-30 °C. Cooled the reaction mixture to 0 °C and diisopropylethylarnine (DIPEA) (66.66 grams) was added. Bromo acetyl derivative (100 grams) was added lot wise in 2 hours intervals at 0-5 °C. Raised the reaction mixture temperature to 5- 10 °C and stirred for 15 hours. After the completion of the reaction by High Performance Liquid Chromatography (HPLC), the reaction mixture was quenched into purified water (7833 mL) at 20±3 °C. n-Heptane (1000 mL) and vacuum ( 166 grams) were added into reaction mixture at 20±3 °C. Separated the organic layer and washed with purified water (500 mL) and vacuum salt (42.6 grams) at 25-30 °C. Filtered the organic (n-Heptane) layer through (hyflo 25 g with n-Heptane 250 mL) hyflo bed and washed with n-Heptane (333.33 mL). Dried the filtrate over sodium sulphate (83.33 grams) at 25-30 °C. Filtered the sodium sulphate and washed with n-Heptane (125 mL). Extracted the filtrate with methanol (1666.66 mL) at -5 to 0 °C. Separated the n-heptane layer from the methanol ic layer at -5 to 0 °C.

Step 2: Preparation of 4-hydroxy-a'-[[[6-(4-phenylbutoxy)hexyl]benzyIamino]methyl]- l,3- ben- zenedimethanol (Formula D - Benzyl Salmeterol)

Cooled the methanolic layer obtained in Step 1 to -5 °C and sodium borohydride (1 10 grams) was added slowly at -5 °C to 10 °C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30 °C and stirred for 8.0 hours under nitrogen atmosphere. After the completion of the reaction by HPLC, heated the reaction mixture to 30-35 °C. Washed the reaction mixture with n-Heptane (2x833.33 mL) at 30-35 °C. Cooled the methanolic layer to 0-10 °C and purified water (4166.66 mL) was added followed by adjusting the pH to 2-3 with hydrochloric acid at below 10 °C. Distilled the methanol completely under vacuum at below 40 °C. Cooled the reaction mixture to 15-20 °C and Ethylacetate (2333.33 mL) was added followed by adjusting the pH to 7.3-7.7 with saturated sodium bicarbonate solution. Heated the reaction mixture to 25-30 °C, separated the aqueous layer and extracted with Ethylacetate (833.33 mL). The combined ethylacetate layers were washed with purified water (500 mL). Dried the ethylacetate layer over sodium sulphate (83.33 grams), filtered and washed with Ethyl acetate (166.66 mL). Concentrated the filtrate under vacuum at 45 °C to obtain compound of Formula D (Benzyl Salmeterol) as oily residue. Step 3: Preparation of Salmeterol free base (Formula 1-1)

Mixture of methanol (1833 mL) and Benzyl salmeterol compound of Formula D oily residue obtained in Step 2 were taken in hydrogenator at 25 °C under nitrogen atmosphere. Palladium on carbon (33.33 g 20%) was added into the reaction mixture and hydrogen gas was purged at 8-10 psi hydrogen pressure at 25±2 °C. Maintained the reaction mixture for 1 hour 10 minutes at the same temperature. After completion of reaction by Thin layer chromatography (TLC), the reaction mixture was filtered and washed with methanol (166.66 mL). Concentrated the filtrate under vacumm at below 45 °C and co-distilled with thrice Ethylacetate (3x 1000 mL). Ethylacetate (1000 mL) was added into reaction mixture and stirred for dissolution. Cooled the reaction mixture to - 5±2 °C and stirred for 2 hours. Salmeterol base (83 mgrams) was added into reaction mixture and stirred for 10-30 hours at -5±2 °C. Filtered the product and washed with chilled Ethylacetate (83.33 mL). Dried the product in vacuum tray dryer for 8 hours at 40-45 °C to obtain 57 grams of Salmeterol free base.

Step 4: Purification of Salmeterol free base (Formula 1-1)

Salmeterol base (57 grams) and Ethylacetate (456 mL) were taken in round bottom flask. Heated the reaction mixture to 40-45 °C and stirred for 30 min. Cooled the reaction mixture to 0±2 °C and stirred for 1 hour. Filtered the product and washed with chilled ethylacetate (22.8 mL). Wet compound (65 grams) and Ethylacetate (456 mL) were taken in round bottom flask. Heated the reaction mixture to 40-45 °C and stirred for 30 min. Cooled the reaction mixture to 0±2 °C and stirred for 1 hour. Filtered the product and washed with chilled ethylacetate (22.8 mL). Dried the product in vacuum tray dryer for 12 hours at 40-45 °C to obtain pure Salmeterol base (45 grams). Ί INMR (DMSO, 300 MHz): 1.26-1.62 (m, 12H), 2.49-2.59 (m, 6H), 3.28-3.36 (m 4H), 4.46-4.51 (m, 3H), 5.03, (br s l H), 6.67-6.70 (d I ), 6.96-6.99 (dd l H), 7.13-7.18 (m 3H), 7.24-7.28 (m 3H). MS: m/z = 416 [M+H] ⁺ . Example-2: Preparation of Salmeterol Xinafoate

Step 1 : Preparation of Salmeterol Xinafoate

Mixture of Salmeterol base (30 grams) and methanol (150 mL) were taken in round bottom flask and stirred for clear solution at 25-30 °C. Activated carbon (3.0 grams) was added and stirred for 30 minutes at 25-30 °C. Filtered the reaction mixture through hyflo bed and washed with methanol (30 mL). l -hydroxy-2-napthoic acid ( 13.59 grams) was added to the filtrate at 30±2 °C. Stirred the reaction mixture for 1.0 hour at 30±2 °C and cooled to 18-22 °C. Stirred the reaction mixture for 2.0 hours and the product was filtered, slurry washed with chilled methanol (60 mL). Dried the product in vacuum tray dryer for 12 hours at 40-45 °C to obtain of Salmeterol Xinafoate (36 grams). Step 2: Purification of Salmeterol Xinafoate

Mixture o Salmeterol Xinafoate (25 grams) and methanol (150 mL) were taken in round bottom flask and heated at 45-50 °C to get clear solution. Activated carbon (Norit Darco G60) (1.25 grams) was added and stirred for 15 minutes at 45-50 °C. Filtered the reaction mixture was through hyflow bed and washed with methanol (8.33 mL). The filtrate was taken into round bottom flask and heated at 45-50 °C to get clear solution. Cooled the reaction mixture slowly to 20±2 °C and stirred for 4.0 hours. Filtered the precipitated product and slurry washed with chilled methanol (25 mL). Dried the product in vacuum tray dryer for 12 hours at 40-45 °C to obtain pure Salmeterol Xinafoate (20.75 gram's).

,'HNMR (DMSO, 300 MHz): 1.29-1.64 (m, 12H), 2.50-2.58 (m, 2H), 2.91-3.10 (m 4H), 3.27-3.34 (m, 4H), 4.5 (s 2H), 4.83-4.87 (d 2H), 5.05 (br s I H), 6.13 (br s 1 H), 6.77-6.79 (d 1H), 7.02-7.08 (m 2H), 7.13-7.18 (m 3H), 7.23-7.28 (m 3H), 7.36-7.40 (m 2H), 7.43-7.48 (m I H), 7.70-7.79 (m 2H), 8.19-8.22 (d I H), 8.82 (br s IH), 9.52 (br s IH).

MS: m/z = 416 [M+H] ⁺ .

Advantages of the present invention:

1. Extraction of compound of Formula C in n-heptane layer to methanol ic layer improved the purity of the compound of Formula C as the impurities were removed in the n-Heptane layer.

2. Reduction reaction completed with 1 ^st time TLC.

3. Purity of Salmeterol Xinafoate is > 99.5%.

4. Consistency in yields.