WO2017168431A1 - Process for the preparation of salmeterol xinafoate - Google Patents

Process for the preparation of salmeterol xinafoate Download PDF

Info

Publication number
WO2017168431A1
WO2017168431A1 PCT/IN2016/000136 IN2016000136W WO2017168431A1 WO 2017168431 A1 WO2017168431 A1 WO 2017168431A1 IN 2016000136 W IN2016000136 W IN 2016000136W WO 2017168431 A1 WO2017168431 A1 WO 2017168431A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
salmeterol
methanol
solvent
Prior art date
Application number
PCT/IN2016/000136
Other languages
French (fr)
Inventor
Ponnaiah Ravi Dr.
Neela Praveen Kumar Dr.
Nageswara Rao Nimmakayala
Gopala Rao Chila
Ravinder Turka
Naga Vara Manga Devi Maddala
Original Assignee
Davuluri Ramamohan Rao
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Davuluri Ramamohan Rao filed Critical Davuluri Ramamohan Rao
Publication of WO2017168431A1 publication Critical patent/WO2017168431A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Definitions

  • the present invention relates to an improved process for the preparation of Salmeterol Xinafoate of Formu la (I).
  • Salmeterol Xinafoate is the racemic form of the l -hydroxy-2-naphthoic acid salt of Salmeterol. It
  • 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:
  • 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
  • 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.
  • the present invention provides an improved process for the preparation of Salmeterol Xinafoate of Formula (I)
  • the present invention provides an improved process for the preparation of compound of Formula D
  • 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:
  • 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.
  • Step 2 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:
  • 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.
  • 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.
  • 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.
  • a solvent selected from esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate.
  • the solvent used is ethylacetate.
  • 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.
  • 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.
  • a solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol and the like.
  • the solvent used is methanol.
  • the present invention provides an improved process for the preparation of Salmeterol Xinafoate of Formula (I)
  • the present invention provides an improved process for the preparation of Salmeterol Xinafoate of Formula (I), which comprises:
  • the present invention provides an improved process for the preparation of com ound of Formula D,
  • the present invention provides an improved process for the preparation of compound of Formula D,
  • Step I Preparation of 2-hydroxy-5-[[[6-(4-phenylbutoxy)hexylbenzyI]amino] acetyl] benzaldehyde (Formula 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)
  • 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).
  • Step 1 Preparation of Salmeterol Xinafoate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

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

Description

PROCESS FOR THE PREPARATION OF SALMETEROL XINAFOATE
Field of the Invention
The present invention relates to an improved process for the preparation of Salmeterol Xinafoate of Formu la (I).
Figure imgf000002_0001
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 p2-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:
Figure imgf000003_0001
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:
Figure imgf000003_0002
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:
Figure imgf000004_0001
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)
Figure imgf000005_0001
which comprises:
i) condensation of com ound of Formula A
Figure imgf000005_0002
with compound of Formula B,
Figure imgf000005_0003
in a solvent in the presence of a base to give compound of Formula C;
Figure imgf000006_0001
ii) reducing the compound of Formula C in a monophasic solvent with a reducing agent to obtain compound of Formula D;
Figure imgf000006_0002
iii) debenzylating compound of Formula D with hydrogen and a metal catalyst in a solvent to obtain Salmeterol of Formula I-l and
Figure imgf000006_0003
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
Figure imgf000006_0004
which com rises reducing the compound of Formula C
Figure imgf000007_0001
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:
Figure imgf000007_0002
Figure imgf000008_0001
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)
Figure imgf000010_0001
which comprises:
i) condensation of com ound of Formula A
Figure imgf000010_0002
with compound of Formula B,
Figure imgf000010_0003
in a solvent in the presence of a base to give compound of Formula C;
Figure imgf000011_0001
ii) reducing the compound of Formula C in a monophasic solvent with a reducing agent to obtain compound of Formula D;
Figure imgf000011_0002
iii) debenzylating compound of Formula D with hydrogen and a metal catalyst in a solvent to obtain Salmeterol of Formula 1-1 and
Figure imgf000011_0003
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),
Figure imgf000012_0001
which comprises:
i) condensation of compound of Formula A
Figure imgf000012_0002
with compound of Formula B
Figure imgf000012_0003
methylethylketone in the presence of diisopropylethylamine to give compound of Formula
Figure imgf000012_0004
ii) reducing the compound of Formula C in methanol solvent with sodium borohydride to obtain compound of Formula D;
Figure imgf000013_0001
iii) debenzylating the compound of Formula D with hydrogen and palladium on carbon in methanol to obtain Salmeterol of Formula I-l and
Figure imgf000013_0002
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,
Figure imgf000013_0003
which com rises reducing compound of Formula C
Figure imgf000013_0004
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,
Figure imgf000014_0001
which com rises reducing compound of Formula C
Figure imgf000014_0002
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 1st time TLC.
3. Purity of Salmeterol Xinafoate is > 99.5%.
4. Consistency in yields.

Claims

We Claim:
Figure imgf000018_0001
with compound of Formula B,
Figure imgf000018_0002
ii. reducing the compound of Formula C in a monophasic solvent with a reducing agent to obtain compound of Formula D;
Figure imgf000019_0001
iii.debenzylating compound of Formula D with hydrogen and a metal catalyst in a solvent to obtain Salmeterol of Formula I-l and
Figure imgf000019_0002
iv. converting the compound of Formula I-l to Salmeterol Xinafoate of Formula (I).
2. The process as claimed in (step i) of claim 1, wherein the base used in the condensation is diisopropylethylamine and the solvent used is methylethylketone.
3. The process as claimed in (step ii) of claim 1 , where in the reducing agent used for reduction of compound of Formula C to compound of Formula D is sodium borohydride.
4. The process as claimed in (step ii) of claim 1 , where in the solvent used for reduction is methanol.
5. The process as claimed in (step iii) of claim 1 , wherein the metal catalyst used for debenzylation of compound of Formula D to Salmeterol of Formula I-l is palladium on carbon.
6. The process as claimed in (step iii) of claim 1 , wherein the solvent used for debenzylation is methanol.
7. The process as claimed in (step iv) of claim 1 , wherein the solvent used for converting the Salmeterol of Formula 1-1 to Salmeterol Xinafoate of Formula (I) is methanol.
8. An im roved process for the preparation of compound of Formula D,
Figure imgf000020_0001
in a monophasic solvent with a reducing agent to obtain compound of Formula D.
9. The process as claimed in claim 8, where in the reducing agent used for reduction of compound of Formula C to compound of Formula D is sodium borohydride.
10. The process as claimed in claim 8, where in the solvent used for reduction is methanol.
PCT/IN2016/000136 2016-03-30 2016-05-26 Process for the preparation of salmeterol xinafoate WO2017168431A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN20164101105 2016-03-30
IN20164101105 2016-03-30

Publications (1)

Publication Number Publication Date
WO2017168431A1 true WO2017168431A1 (en) 2017-10-05

Family

ID=59963627

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2016/000136 WO2017168431A1 (en) 2016-03-30 2016-05-26 Process for the preparation of salmeterol xinafoate

Country Status (1)

Country Link
WO (1) WO2017168431A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8648214B2 (en) * 2005-10-17 2014-02-11 Generics [Uk] Limited Processes suitable for the preparation of salmeterol

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8648214B2 (en) * 2005-10-17 2014-02-11 Generics [Uk] Limited Processes suitable for the preparation of salmeterol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Contemporary Drug Synthesis", ISBN: 0-47 1 -2 1 480-9, article JIE-JACK LI ET AL., pages: 206 - 207 *

Similar Documents

Publication Publication Date Title
US5599994A (en) Amino acid-derived diaminopropanols
US9035061B2 (en) Process for preparing a biphenyl-2-ylcarbamic acid
CN101959870B (en) Preparation of morpholine derivatives
CA2884197C (en) Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof
US20110178326A1 (en) Unsaturated cinacalcet salts and processes for preparing cinacalcet hydrochloride
JP7685292B2 (en) Edoxaban key intermediate and its synthesis method
WO2013049605A1 (en) Processes for the preparation of an intermediate in the synthesis of eltrombopag
KR101308258B1 (en) A novel method of making Endoxifen
JP2006249095A (en) Amino acid-derived diaminopropanol
WO2005061446A2 (en) Processes for the preparation of aminoalkyl phenylcarbamates
CA2960473A1 (en) Processes for the preparation of tadalafil and intermediates thereof
US20180237386A1 (en) Process For Preparation Of Vortioxetine Hydrobromide
WO2017168431A1 (en) Process for the preparation of salmeterol xinafoate
EP2178864B1 (en) Process for the preparation of alfuzosin hydrochloride
WO1999052855A1 (en) A process for preparing chiral (s)-2,3-disubstituted-1-propylamine derivatives
TW500721B (en) Process for the preparation of 3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydor-2H-1-benzopyran-5-carboxamide
ES2957319T3 (en) Methods for producing (6S,15S)-3,8,13,18-tetraazalcosane-6,15-diol
EP0129383B1 (en) Process for the preparation of 3,4-di-isobutyryloxy-n-methyl-phenethylamine
US8629146B2 (en) Method for stereoselective synthesis of bicyclic heterocyclic compounds
JPS597709B2 (en) Novel morpholine derivative and its production method
JP2016511761A (en) Method for synthesizing 4-piperidin-4-yl-benzene-1,3-diol and salts thereof, and novel compound tert-butyl 4- (2,4-dihydroxy-phenyl) -4-hydroxy-piperidine-1-carboxylate
US20140256963A1 (en) Process for the preparation of aliskiren
KR101974388B1 (en) Alkyl diethylene triamine derivatives and a process of the preparation thereof
WO2025047770A1 (en) Method for producing deoxynyboquinone derivative
CN119176757A (en) Preparation method of mianserin hydrochloride intermediate and derivative thereof

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16896675

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 16896675

Country of ref document: EP

Kind code of ref document: A1