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WO2020202130A2 - Improved process for the preparation of indacaterol maleate - Google Patents

Improved process for the preparation of indacaterol maleate Download PDF

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Publication number
WO2020202130A2
WO2020202130A2 PCT/IB2020/054812 IB2020054812W WO2020202130A2 WO 2020202130 A2 WO2020202130 A2 WO 2020202130A2 IB 2020054812 W IB2020054812 W IB 2020054812W WO 2020202130 A2 WO2020202130 A2 WO 2020202130A2
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formula
compound
solvent
preparation
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WO2020202130A3 (en
Inventor
Mahender Rao Siripragada
Krishnaiah PENDYAM
Sudheer Kumar KALLEPALLY
Sathya Nagendra Kumar LAKKADASU
Venkata Naidu Gottapu
Sriramachandra Murthy Patnala
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Neuland Laboratories Ltd
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Neuland Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof

Definitions

  • the present invention relates to an improved process for the preparation of Indacaterol Maleate having the structural Formula (I).
  • the present invention also relates to an improved process for the preparation of benzyl intermediate of Formula IV.
  • Indacaterol is marketed as maleate salt. It is chemically known as (R)-5-[2-(5,6-diethylindan-2- ylamino)-l-hydroxyethyl]-8-hydroxy-lFl-quinolin-2-one maleate and is represented by the structural Formula-I:
  • Indacaterol is a selective long acting inhaled P ⁇ -adrcncrgic agonist indicated for long-term, once- daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
  • COPD chronic obstructive pulmonary disease
  • the drug is marketed by Sunovion Pharmaceuticals Inc under the brand name ARCAPTA NEOHALER® in US.
  • the present invention provides a cost effective, novel and an efficient process for the preparation of Indacaterol Maleate by using Formula-IV.
  • the present invention provides an improved process for the preparation of Indacaterol Maleate of Formula-I.
  • the present invention provides an improved process for the preparation of benzyl intermediate compound of Formula IV
  • the present invention provides an improved process for the preparation of Indacaterol maleate of compound of Formula-I.
  • the main embodiment of the present invention provides an improved process for the preparation of Indacaterol maleate of formula (I) as shown in the Scheme-I given below.
  • step- a condensation of compound of Formula-II with compound of formula-III in presence of a water and base, followed by treatment with hydrochloric acid to obtain compound of Formula- IV;
  • the base used in step -a is selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, 1 ,4-diazabicyclo [2.2.2]octane (DABCO), 4- dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide.
  • DIPEA diisopropylethylamine
  • DABCO 1 ,4-diazabicyclo [2.2.2]octane
  • DMAP 4- dimethylaminopyridine
  • sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide Preferably sodium hydroxide is used.
  • the reaction temperature may range from 80-110°C and preferably at a temperature in the range from 90-100°C.
  • the duration of the reaction may range from 10-14 hours, preferably for a period of 11-12 hours.
  • step- b conversion of compound of Formula-IV in the presence of malic acid and solvent to obtain compound of Formula-V.
  • the solvent used in step-b is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate, isopropyl acetate or mixtures thereof.
  • methylene chloride or isopropanol is used.
  • the reaction temperature may range from 40-60°C and preferably at a temperature in the range from 50-60°C.
  • the duration of the reaction may range from 1-4 hours, preferably for a period of 2-3 hours.
  • step-c deprotecting the compound of Formula-V in the presence of palladium on carbon, acetic acid and solvent to obtain compound of Formula- VI.
  • the solvent used in step-c is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate, isopropyl acetate or mixtures thereof.
  • methanol is used.
  • the reaction temperature may range from 10-30°C and preferably at a temperature in the range from 25-30°C.
  • the duration of the reaction may range from 1-6 hours, preferably for a period of 2-4 hours.
  • step-d conversion of the compound of Formula- VI in the presence of maleic acid in solvent or mixture of solvents to obtain Indacaterol maleate of Formula-I.
  • the solvent used in step-d is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate, isopropyl acetate or mixtures thereof.
  • the mixture of methylene chloride and methanol is used.
  • the reaction temperature may range from 15-35 °C and preferably at a temperature in the range from 25-30°C.
  • the duration of the reaction may range from 0-4 hours, preferably for a period of 1-2 hours.
  • the present invention provides a process for the preparation of 8- phenyImethoxy-5- [(R)-2-(5,6-diethyIindan-2-yIamino) -1 -hydroxy ethyl] -lH-quinoIin-2-one hydrochloride compound of FormuIa-IV, as shown in the Scheme-II given below
  • step- a condensation of compound of Formula-II with compound of formula-III in presence of a water and base, followed by treatment with hydrochloric acid to obtain compound of Formula- IV;
  • the base used for the condensation in step -a is selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, 1 ,4-diazabicyclo [2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, or potassium hydroxide.
  • DMAP dimethylaminopyridine
  • sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, or potassium hydroxide Preferably sodium hydroxide is used.
  • the reaction temperature may range from 80-110°C and preferably at a temperature in the range from 90-100°C.
  • the duration of the reaction may range from 8-14 hours, preferably for a period of 10-12 hours.
  • Example-1 Compound obtained in Example-1 (100 grams) was added to a mixture of chloroform (900 mL), and imidazole (72.77 grams), tert-butyldimethylsilyl chloride (TBDMS-C1) solution were added at 25-30 °C and refluxed for 10 hours. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 15-20 °C, washed with 5% HC1 solution and distilled under vacuum at 45-50 °C to obtain a residue. The residue was mixed cyclohexane (500 mL) and stirred for 1 hour at 25-30 °C. The resultant solid was filtered, washed with cyclohexane and dried at 60-65 °C for 5 hours to get the title compound.
  • TDMS-C1 tert-butyldimethylsilyl chloride
  • Example-3 To a mixture of water (300 mL) and dichloromethane (800 mL) and compound obtained in Example-3 (100 grams) was added and the pH was adjusted to 9.0-9.5 with sodium carbonate solution. The organic layer thus separated was distilled under vacuum at 40-45 °C to get a residue, charge methanol (900 mL) and Acetic acid (100 mL) to benzyl Indacaterol free base followed by Palladium-Carbon (10.0 grams) was added and then maintained for 4 hours at 25-30 °C with a hydrogen pressure of 0.01 - 0.02 Kg /cm for 4.0 hours at 25-30 °C. The progress of the reaction was monitored by HPLC.
  • the catalyst was filtered, washed with methanol (100 mL) and filtrate was distilled under vacuum at 50-55 °C to get a residue.
  • methanol 200 mL
  • ethyl acetate 600 mL
  • the formed solid was filtered, washed with ethyl acetate (10 mL) and dried at 60-65 °C for 5 hours to get the title compound.
  • Example - 4 A mixture of methanol, MDC (200 mL) and Indacaterol Acetate compound obtained in Example - 4 (25 grams) was stirred for 10-15 min at 25-30 °C, to get clear solution and treated carbon treatment separate the carbon by filtration and wash with 25 mL of MDC and Methanol add maleic acid (6.5 grams) in to filtrate and maintain the contents for 1.0 hour at 25-30 °C.
  • the present invention is carried out in the presence of water (step -a) without using any other solvents.
  • the present invention is economically significant and eco-friendly.
  • the present invention is carried out in a shorter time period when compared to the prior-art process.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An improved process for the preparation of Indacaterol Maleate having the structural formula (I). The present invention also relates to an improved process for the preparation of benzyl intermediate of Formula IV. The present invention provides improved process for the preparation of benzyl intermediate of formula-IV using water as a reaction solvent which is eco-friendly.

Description

Field of The Invention
The present invention relates to an improved process for the preparation of Indacaterol Maleate having the structural Formula (I).
Figure imgf000003_0001
Formula-I
The present invention also relates to an improved process for the preparation of benzyl intermediate of Formula IV.
Figure imgf000003_0002
Background of The Invention
Indacaterol is marketed as maleate salt. It is chemically known as (R)-5-[2-(5,6-diethylindan-2- ylamino)-l-hydroxyethyl]-8-hydroxy-lFl-quinolin-2-one maleate and is represented by the structural Formula-I:
Figure imgf000004_0001
Formula-I
Indacaterol is a selective long acting inhaled P^-adrcncrgic agonist indicated for long-term, once- daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. The drug is marketed by Sunovion Pharmaceuticals Inc under the brand name ARCAPTA NEOHALER® in US.
Indacaterol maleate was first time disclosed in US 6878721 by Novartis.
The process for the preparation Indacaterol Maleate by using Formula-IV is already disclosed in US 9682935.
Figure imgf000004_0002
The process for the preparation in this patent is not economically feasible. Hence there exists a need to develop a economically significant process for the preparation of Indacaterol Maleate. Summary of The Invention
The present invention provides a cost effective, novel and an efficient process for the preparation of Indacaterol Maleate by using Formula-IV.
In one aspect the present invention provides an improved process for the preparation of Indacaterol Maleate of Formula-I.
Figure imgf000005_0001
Formula -I
which comprises:
a) condensation of compound of Formula-II
Figure imgf000005_0002
with compound of Formula-Ill
Figure imgf000005_0003
Formula -HI
in the presence of water and base, followed by treatment with hydrochloric acid to obtain compound of Formula-IV ;
Figure imgf000006_0001
Formula -IV
b) converting compound of Formula-IV to compound of Formula V
Figure imgf000006_0002
Formula -V
in the presence of malic acid and solvent to obtain compound of Formula-V ; c) deprotecting the compound of Formula-V
Figure imgf000006_0003
in the presence of palladium on carbon, acetic acid and solvent to obtain compound of Formula- VI; d) converting compound of Formula- VI in the presence of maleic acid and solvent to obtain compound of Formula-I.
In another aspect, the present invention provides an improved process for the preparation of benzyl intermediate compound of Formula IV
Figure imgf000007_0001
which comprises:
a) condensation of compound of Formula-II
Figure imgf000007_0002
with compound of Formula-Ill
Figure imgf000007_0003
Formula -III
in the presence of water and base, followed by treatment with hydrochloric acid to obtain compound of Formula-IV. Detailed Description of The Invention
Accordingly, the present invention provides an improved process for the preparation of Indacaterol maleate of compound of Formula-I.
The main embodiment of the present invention provides an improved process for the preparation of Indacaterol maleate of formula (I) as shown in the Scheme-I given below.
Figure imgf000008_0001
Formula- VI rormula -I
Scheme-I
In step- a, condensation of compound of Formula-II with compound of formula-III in presence of a water and base, followed by treatment with hydrochloric acid to obtain compound of Formula- IV;
The base used in step -a is selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, 1 ,4-diazabicyclo [2.2.2]octane (DABCO), 4- dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide. Preferably sodium hydroxide is used. The reaction temperature may range from 80-110°C and preferably at a temperature in the range from 90-100°C. The duration of the reaction may range from 10-14 hours, preferably for a period of 11-12 hours.
In step- b, conversion of compound of Formula-IV in the presence of malic acid and solvent to obtain compound of Formula-V.
The solvent used in step-b is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate, isopropyl acetate or mixtures thereof. Preferably methylene chloride or isopropanol is used.
The reaction temperature may range from 40-60°C and preferably at a temperature in the range from 50-60°C. The duration of the reaction may range from 1-4 hours, preferably for a period of 2-3 hours.
In step-c, deprotecting the compound of Formula-V in the presence of palladium on carbon, acetic acid and solvent to obtain compound of Formula- VI.
The solvent used in step-c is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate, isopropyl acetate or mixtures thereof. Preferably methanol is used.
The reaction temperature may range from 10-30°C and preferably at a temperature in the range from 25-30°C. The duration of the reaction may range from 1-6 hours, preferably for a period of 2-4 hours.
In step-d, conversion of the compound of Formula- VI in the presence of maleic acid in solvent or mixture of solvents to obtain Indacaterol maleate of Formula-I.
The solvent used in step-d is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate, isopropyl acetate or mixtures thereof. Preferably the mixture of methylene chloride and methanol is used.
The reaction temperature may range from 15-35 °C and preferably at a temperature in the range from 25-30°C. The duration of the reaction may range from 0-4 hours, preferably for a period of 1-2 hours.
In yet another embodiment, the present invention provides a process for the preparation of 8- phenyImethoxy-5- [(R)-2-(5,6-diethyIindan-2-yIamino) -1 -hydroxy ethyl] -lH-quinoIin-2-one hydrochloride compound of FormuIa-IV, as shown in the Scheme-II given below
Figure imgf000010_0001
Scheme-II
In step- a, condensation of compound of Formula-II with compound of formula-III in presence of a water and base, followed by treatment with hydrochloric acid to obtain compound of Formula- IV;
The base used for the condensation in step -a is selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, 1 ,4-diazabicyclo [2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, or potassium hydroxide. Preferably sodium hydroxide is used. The reaction temperature may range from 80-110°C and preferably at a temperature in the range from 90-100°C. The duration of the reaction may range from 8-14 hours, preferably for a period of 10-12 hours.
EXPERIMENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Example-1:
Synthesis of (R)-8-(benzyloxy)-5-(2-bromo-l-hydroxyethyl) quinolin-2(lH)-one
To a mixture of tetrahydrofuran (1400 mL) and 8-(Benzyloxy)-5-(2-bromoacetyl) quinolin- 2(lH)-one (100 grams), R-methyl CBS (Corey-Bakshi-Shibata) (7.5 grams) catalyst was slowly added at 25-30 °C under nitrogen atmosphere and cooled to 0-5 °C, followed by the addition of Boron Dimethyl Sulfide (BMS) complex (24.3 grams) at 0-10 °C. The reaction mass was stirred for 1-2 hours at 0-10 °C. The progress of the reaction was monitored by HPLC. After the completion of the reaction, methanol (100 mL) was slowly added to the reaction mass for 30 minutes and stirred for 15 minutes at 0-10 °C. The contents were distilled under vacuum at a temperature of 40-45 °C and cooled to 25-30 °C. The cooled reaction mixture was slowly added to hydrochloric acid solution at 25-30 °C and stirred for 1-2 hours at the same temperature. The resulted solid was filtered, washed with water (300 mL) and dried at 65-70 °C for 8 hours to get the title compound.
Yield: 95%.
Example-2:
Synthesis of (/?)-8-(Benzyloxy)-5-[2-bromo-l-[(tert-butyldimethylsilyl) oxy] ethyl] quinolin- 2(1//) -one
Compound obtained in Example-1 (100 grams) was added to a mixture of chloroform (900 mL), and imidazole (72.77 grams), tert-butyldimethylsilyl chloride (TBDMS-C1) solution were added at 25-30 °C and refluxed for 10 hours. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 15-20 °C, washed with 5% HC1 solution and distilled under vacuum at 45-50 °C to obtain a residue. The residue was mixed cyclohexane (500 mL) and stirred for 1 hour at 25-30 °C. The resultant solid was filtered, washed with cyclohexane and dried at 60-65 °C for 5 hours to get the title compound.
Yield: 85%. Example-3:
Synthesis of 8-phenylmethoxy-5-[(7?)-2-(5,6-diethylindan-2-ylamino)-l-hydroxyethyl]-l/7- quinolin-2-one maleate
Part-A
5,6-Diethyl-2-amino indane hydrochloride (83.0 grams) was added to a mixture of purified water (750 mL), NaOH (37.0 grams) and compound obtained in Example-2 (150 grams) and heated to 95-100 °C. The reaction mixture was maintained for 12 hours at 95-100 °C till the completion of the reaction. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 10 to 30 °C, followed by the addition of Concentrated. HC1 (300 mL) and the reaction mixture was stirred for 6 hours at a temperature of 20-30 °C, the progress of the reaction was monitored by HPLC. The isolated solid was filtered, washed with water (150 mL), wet compound 125 grams.
Part-B
To the product obtained in the aforementioned Part-A, water (450 mL) and dichloromethane (1200 mL) was added and the pH was adjusted to 9.0-9.5 with sodium carbonate solution. The organic layer thus separated was distilled under vacuum at 40-45 °C to get a residue. The obtained residue was mixed with isopropyl alcohol (750 mL) and acetic acid (150 mL) and the contents were heated to 45-50 °C. Maleic acid (53.5 grams) added to the contents at 45-50 °C and heated to Reflux temperature for 1 hour. The contents were than cooled to 25-30 °C and stirred for 2.0 hours at the same temperature. The resultant solid was filtered, washed with isopropyl alcohol (150 mL) and dried at 55-60 °C for 8 hours get the title compound.
Yield: 85%.
Example-4
Synthesis of (R)-5-[2-(5,6-Diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-lH- quinolin-2-one acetate (Indacaterol Acetate).
To a mixture of water (300 mL) and dichloromethane (800 mL) and compound obtained in Example-3 (100 grams) was added and the pH was adjusted to 9.0-9.5 with sodium carbonate solution. The organic layer thus separated was distilled under vacuum at 40-45 °C to get a residue, charge methanol (900 mL) and Acetic acid (100 mL) to benzyl Indacaterol free base followed by Palladium-Carbon (10.0 grams) was added and then maintained for 4 hours at 25-30 °C with a hydrogen pressure of 0.01 - 0.02 Kg /cm for 4.0 hours at 25-30 °C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the catalyst was filtered, washed with methanol (100 mL) and filtrate was distilled under vacuum at 50-55 °C to get a residue. To add methanol (200 mL). Heat the content to 60-65 °C, add ethyl acetate (600 mL) at 60-65 °C and maintain the content for 2.0 hours at 60-70 °C. cool the contents to 25-30 °C. The formed solid was filtered, washed with ethyl acetate (10 mL) and dried at 60-65 °C for 5 hours to get the title compound.
Yield: 88.5%.
Example-5
Synthesis of (R)-5-[2-(5,6-Diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-lH- quinolin-2-one maleate (Indacaterol Maleate).
A mixture of methanol, MDC (200 mL) and Indacaterol Acetate compound obtained in Example - 4 (25 grams) was stirred for 10-15 min at 25-30 °C, to get clear solution and treated carbon treatment separate the carbon by filtration and wash with 25 mL of MDC and Methanol add maleic acid (6.5 grams) in to filtrate and maintain the contents for 1.0 hour at 25-30 °C. The resultant solid was filtered, washed with methanol (25 mL) and dried at 60-65 °C under vacuum for 10 hours to get the final compound of 5-[(R)-2-(5, 6-diethyl- indan-2-ylamino) -1-hydroxy- ethyl] -hydroxy-(IH)-quinolin-2-one maleate.
Yield: with 92.5 %.
'NMR (400MHz, DMSO): d 10. 54 (s, 2H),8. 93 (br, 2H), 8. 17 8.13 (d, 1H, J = 12Hz), 7.19 7.17 (d, 1H, J = 8 Hz), 7. 03 7.0 (m, 3H), 6.62 6.59 (d, 1H, J = 8Hz), 6. 20 (s, 1H), 6. 02 (s, 2H), 5. 3 (d, 1H, J = 8 Hz), 4. 06 (t, 1H, J. = 8Hz), 3. 3 -3 20 (m, 3H), 3 .20 - 3. 04 (m, 3H), 2. 57 (q, 4H, J = 8 Hz), 1. 13 (t, 6H, J = 8Hz).
Advantages of the present invention:
> The present invention is carried out in the presence of water (step -a) without using any other solvents.
> The present invention is economically significant and eco-friendly.
> Also the present invention is carried out in a shorter time period when compared to the prior-art process.

Claims

We Claim:
1. Improved process for the preparation of Indacaterol Maleate of Formula-I.
Figure imgf000015_0001
Formula -I
which comprises:
a) condensation of compound of Formula-II
Figure imgf000015_0002
with compound of Formula-Ill
Figure imgf000015_0003
Formula -III
in the presence of water and base, followed by treatment with hydrochloric acid to obtain compound of Formula-IV ;
Figure imgf000016_0001
Formula -IV
b) converting compound of Formula-IV
Figure imgf000016_0002
Formula -V
in the presence of malic acid and solvent to obtain compound of Formula-V ;
c) deprotecting the compound of Formula-V
Figure imgf000016_0003
in the presence of palladium on carbon, acetic acid and solvent to obtain compound of Formula- VI; d) converting compound of Formula- VI in the presence of maleic acid in solvent to get compound of Formula-I.
2. Improved process for the preparation of benzyl intermediate compound of Formula IV
Figure imgf000017_0001
which comprises:
a) condensation of compound of Formula-II
Figure imgf000017_0002
with compound of Formula-Ill
Figure imgf000017_0003
Formula -PI
in the presence of water and base, followed by treatment with hydrochloric acid to obtain compound of Formula-IV.
3. The process as claimed in claim 1, wherein the said base is selected from group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, 1 ,4-diazabicyclo [2.2.2]octane
(DABCO), 4-dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide or potassium hydroxide.
4. The process as claimed in claim 2, wherein the said base is selected from group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, 1 ,4-diazabicyclo [2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide or potassium hydroxide.
5. The process as claimed in claim 1, wherein the solvent is selected from group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, dichloromethane, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate or isopropyl acetate.
6. The process as claimed in claim 2, wherein the solvent is selected from group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, dichloromethane, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate or isopropyl acetate
7. The process as claimed in claim 1 wherein the solvent used in step-d is selected from group consisting of methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, diethyl ether, diisopropyl ether, chloroform, dichloromethane, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate, isopropyl acetate or mixtures thereof.
PCT/IB2020/054812 2019-04-04 2020-05-21 Improved process for the preparation of indacaterol maleate Ceased WO2020202130A2 (en)

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