WO2017098520A1 - Process for the preparation of labetalol hydrochloride - Google Patents

Process for the preparation of labetalol hydrochloride Download PDF

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Publication number
WO2017098520A1
WO2017098520A1 PCT/IN2016/000135 IN2016000135W WO2017098520A1 WO 2017098520 A1 WO2017098520 A1 WO 2017098520A1 IN 2016000135 W IN2016000135 W IN 2016000135W WO 2017098520 A1 WO2017098520 A1 WO 2017098520A1
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WIPO (PCT)
Prior art keywords
formula
hydroxy
labetalol hydrochloride
benzamide
hydrochloride
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Application number
PCT/IN2016/000135
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French (fr)
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WO2017098520A8 (en
Inventor
Ponnaiah Ravi
Neela Praveen Kumar
Nimmakayala Nageswara RAO
Narayana Venugopala RAO
Polepally NAGARJUNA
Marthala Venkata SUBBAREDDY
Turka RAVINDER
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prscDAVALURI RAMAMOHAN RAO
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Priority to IN6885CH2015 priority Critical
Priority to IN6885/CHE/2015 priority
Application filed by prscDAVALURI RAMAMOHAN RAO filed Critical prscDAVALURI RAMAMOHAN RAO
Publication of WO2017098520A1 publication Critical patent/WO2017098520A1/en
Publication of WO2017098520A8 publication Critical patent/WO2017098520A8/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/14Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/12Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Abstract

The present invention relates to process for the preparation of Labetalol Hydrochloride which gives higher yield and purity.

Description

^'PROCESS FOR THE PREPARATION OF LABETALOL HYDROCHLORIDE

FIELD OF THE INVENTION

The present invention relates to process for the preparation of 5-[l-hydroxy-2-(l-methyl-3- phenylpropyl)aminoethyl] salicylamide hydrochloride having formula (I). The compound of formula (I) has adopted name "Labetalol Hydrochloride".

Figure imgf000002_0001

.HC1

BACK GROUND OF THE INVENTION

Labetalol Hydrochloride is disclosed in US4012444, assigned to Allen & Hanburys Limited. It is used for the treatment of hypertension.

The process for preparation of Labetalol Hydrochloride of formula (I) is disclosed in US4012444, GB2149399 and GB2952931. Process disclosed in these patent references results in lower yield and purity.

Therefore, it would be desirable to have a process for the preparation of Labetalol Hydrochloride of formula (I) which gives higher yield and purity.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for the preparation of Labetalol Hydrochloride of formula (I)

which comprises:

a) reacting l -methyl-3-

Figure imgf000002_0002
with 5-(bromoacetyl)-2-hydroxy benzamide of formula (B)

Figure imgf000003_0001

in the presence of solvent to give 2-hydroxy-5-{[(l -methy-3-phenylpropyl)amino]acetyl}benzamide of formula (C);

Figure imgf000003_0002

b) reducing 2-hydroxy-5-{ [(l-methy-3-phenylpropyl)amino]acetyl}benzamide of formula (C) with sodium borohydrate in the presence of base and solvent to give 2-Hydroxy-5-{ l -hydroxy"2-[(l-methyl- 3-phenylpropyl)amino]ethyl}benzamide of formula (D);

Figure imgf000003_0003

c) adding water and toluene to the above reaction mixture; d) stirring for the period of 30 minutes and separate the resulting aqueous layer; e) adding concentrated hydrochloride to the above obtained aqueous layer at room temperature for the period of 2 hours to give crude Labetalol Hydrochloride of formula (I); f) dissolving the above obtained crude Labetalol Hydrochloride of formula (I) in methanol, followed by recrystallization using isopropyl alcohol to obtain pure Labetalol Hydrochloride of formula (I).

In another aspect, the present invention provides process for the preparation of Labetalol Hydrochloride of formula (I) which is highly pure. In another aspect, the present invention provides process for the preparation of Labetaiol Hydrochloride of formula (I) which results in higher yield.

In another aspect, the present invention provides process for the preparation of Labetaiol HCl of formula (I); which is simple, convenient, economical and environmental friendly.

DETAILED DESCRIPTION

Accordingly, the aration of Labetaiol Hydrochloride of

Figure imgf000004_0001

Scheme -I illustrates the process for preparation of Labetaiol Hydrochloride of formula (I).

Figure imgf000004_0002

30% NaOH

Step - Sodium borohydride

Figure imgf000004_0003

Pure Labetaiol Hydrochloride (I)

Scheme - I In step- 1 of the preparation, 4-phenylbutan-2-amine of formula (A) is treated with 5-(bromoacetyl)-2- hydroxybenzamide of formula (B) in the presence of solvent to obtain 2-Hydroxy-5-{[( l -methyl-3- phenylpropyl)amino]acetyl}benzamide of formula (C). The solvent used in the reaction is selected from the group consisting of methanol, ethanol, propanol, isopropanol or butanol, preferably using methanol. The reaction temperature may range from 25 °C to 35 °C and preferably at room temperature. The duration of the reaction may be in the range of 0.5 hour to 1.5 hours, preferably for a period of 1 hour.

In step-2 of preparation, the above obtained 2-Hydroxy-5-{ [( l -methyl-3-phenyl propyl)amino] acetyl }benzamide of formula (C) is reduced with sodiumborohydrate in the presence of solvent and base to obtain 2-Hydroxy-5-{ l -hydroxy-2-[(l-methyl-3-phenyl propyl)amino]ethyl}benzamide of formula (D). The solvent used in the reaction is selected from the group consisting of methanol, ethanol, propanol, isopropanol or butanol, preferably using methanol. The base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide or potassium hydroxide and preferably using sodium hydroxide. The reaction temperature may range from 25 °C - 35 °C and preferably at room temperature. The duration of the reaction may range from 1 .5 hours to 2.5 hours and preferably for a period of 2 hours.

In step-3 of the preparation, add toluene and water mixture to the above obtained 2-Hydroxy-5-{ l - hydroxy-2-[( l -methyl-3-phenyl propyl)amino]ethyl}benzamide of formula (D), stir for 30 minutes and separate the aqueous layer. Add concentrated HC1 to the aqueous layer to give crude Labetalol Hydrochloride of formula (I). The reaction temperature may range from 25 °C - 35 °C and preferably at room temperature. The duration of the reaction may range from 1.5 hours to 2.5 hours and preferably for a period of 2 hours.

In step-4 of the preparation, dissolve the above obtained crude Labetalol Hydrochloride of formula (I) in methanol and stir for 30 minutes, followed by recrystallization using isopropyl alcohol to obtain pure Labetalol Hydrochloride of formula (I). The reaction temperature may range from 25 °C - 35 °C and preferably at room temperature. The duration of the reaction may range from 1 hour to 1 .5 hours and preferably for a period of 1 hour.

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.

EXAMPLES:

Example: Process for the preparation of Labetalol Hydrochloride

Step - 1 : Process for the preparation of crude Labetalol Hydrochloride To the round bottom flask having methanol (500 mL) is charge 4-phenylbutan-2-amine (288.76 grams) at room temperature. Charged 5-Bromo acetylsalcylamide (100 grams) lot wise at room temperature and maintain for 1 hour. Reaction mass cooled to 1 -20 °C. Charge 30% sodium hydroxide ( 100 mL) solution at 15-20 °C. Stir the contents for 30 minutes at 15-20 °C. Slowly added sodium borohydride (26 grams) lot wise at 15-25 °C. Raise the temperature to room temperature and maintain for 2 hours. Charge purified water (500 mL) and stir for 30 minutes at room temperature. Charge toluene (400 mL) and stir for 30 minutes. Separate the aqueous layer and kept toluene layer aside. Charge toluene (300 mL) to aqueous layer and stir for 30 minutes. Separate the aqueous layer and kept toluene layer aside. Charge toluene (300 mL) to aqueous layer and stir for 30 minutes. Separate the aqueous layer and kept toluene layer aside. All toluene layer combined and sent for the recovery of amine compound. Aqueous layer was taken in to another round bottom flask. Slowly adjusted the pH below 2 with hydrochloric acid at room temperature. Stir for 2 hours at room temperature. Cool to 5-10 °C and stirred for 1 hour. Filtered the compound and washed with purified water (200 mL). The obtained wet compound was taken into another round bottom flask and charge ethyl acetate (500 mL). Heated to 45-50 °C and stirred for 1 hour. Cooled to room temperature and stirred for 2 hours. Filtered the compound and washed with ethyl acetate (100 ml). Dry the material at 85-90 °C in hot air oven to obtain crude Labetalol hydrochloride. Yield 68%.

Ή - NMR (DMSO-d6): 1.35 - 1.31 (3 H, t), 1.84 - 1.75(1 H, m), 2.19 - 2.10 (l H,m), 2.77 - 2.50(2H, m), 3.38 - 3.08(3H, br), 4.93 - 4.90(1 H, t), 6.14 - 6.12( 1 H, t), 6.93 - 6.90 (1 H, d), 7.33 - 7.17(1 H, m), 7.47 - 7.44 ( 1 H, d), 7.94 (2H, s), 8.64 - 8.53(amine, br), 9.24 - 9.17 ( 1 H, br);

Mass (m/z+ 1): 329.40.

Step - 2: Process for the preparation Labetaiol Hydrochloride

To the round bottom flask having methanol (1000 mL) charge crude Labetalol Hydrochloride ((100 grams) at room temperature. Stirred for dissolution at room temperature. Charged activated carbon (5 grams) and stirred for 30 minutes at room temperature. Filtered the reaction mass through buchner funnel followed by micron filter and wash with methanol ( 100 mL). Filtrate was taken in to round bottom flask and distilled off methanol maximum extent under vacuum (600-700 mm of Hg at below 50 °C). Cooled the contents to 25-35 °C and charge isopropyl alcohol (500 mL) at room temperature and maintain the content for 1 hour at room temperature. Cool the contents to 0-5 °C and maintained the content for 1 hour at 0-5 °C. Filtered the compound and washed with isopropyl alcohol (200 mL). Dried the under vacuum at 85 - 95 °C to obtain Labetalol Hydrochloride. Yield: 90%.

Ή - NMR (DMSO-d6): 1.35 - 1.31 (3H, t), 1.84 to 1 .75( 1 H, m), 2.19 - 2.10 (l H,m), 2.77 - 2.50(2H, m), 3.38 - 3.08(3H, br), 4.93 - 4.90(1H, t), 6.14 - 6.12( 1 H, t), 6.93 - 6.90 (1 H, d), 7.33 -7.17(1 H, m), 7.47 - 7.44 (lH, d), 7.94 (2H, s), 8.64 - 8.53(amine, br), 9.24 - 9.17 (l H, br);

Mass (m/z +1 ): 329.40. ADVANTAGES OF THE PRESENT INVENTION

1. It is a simple and cost effective process.

2. Toluene and water washing removes all the unreacted starting material (4-phenylbutan-2-amine) which yields highly pure Labetalol Hydrochloride.

3. The starting raw material (4-phenylbutan-2-amine) which is recovered from the toluene layer can be used for the preparation of Labetalol Hydrochloride. ,

Claims

We claim:
1. A process for the preparation of Labetalol Hydrochloride of formula (I)
Figure imgf000008_0001
.HC1
which comprises:
a) reacting l -methyl-3-phenyl propylamine of formula (A)
Figure imgf000008_0002
with 5-(brpmoacetyl)-2-hydroxy benzamide of formula (B)
Figure imgf000008_0003
in the presence of solvent to give 2-hydroxy-5-{ [(l -methy-3-phenylpropyl)amino]acetyl}benzamide of formula (C);
Figure imgf000008_0004
b) reducing 2-hydroxy-5-{[(l -methy-3-phenylpropyl)amino]acetyl}benzamide of formula (C) with sodium borohydrate in the presence of base and solvent to give 2-Hydroxy-5-{ 1 -hydroxy"2-[(l -methyl- 3-phenylpropyl)amino]ethyl}benzamide of formula (D);
Figure imgf000009_0001
c) adding water and toluene to the above reaction mixture; d) stirring for the period of 30 minutes and separate the resulting the aqueous layer; e) adding concentrated hydrochloride to the above obtained aqueous layer at room temperature for the period of 2 hours to give crude Labetalol Hydrochloride of formula (I); f) dissolving the above obtained crude Labetalol Hydrochloride of formula (I) in methanol, followed by recrystallization using isopropyl alcohol to obtain pure Labetalol Hydrochloride of formula (I).
2. The process according to claim 1 , wherein said solvent used in step (a) and (b) is selected from the group consisting of methanol, ethanol, propanol or butanol.
3. The process according to claim 2, wherein said solvent used in step (a) and (b) is methanol.
4. The process according to claim 1 , wherein said base used in step (b) is selected from the group consisting of lithium hydroxide, sodium hydroxide or potassium hydroxide.
5. The process according to claim 4, wherein said base used in step (b) is sodium hydroxide.
PCT/IN2016/000135 2015-12-09 2016-05-26 Process for the preparation of labetalol hydrochloride WO2017098520A1 (en)

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IN6885CH2015 2015-12-09
IN6885/CHE/2015 2015-12-09

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WO2017098520A8 WO2017098520A8 (en) 2019-03-28

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2552427B1 (en) * 1983-09-27 1988-03-25 Scharper Spa New process for the preparation of hydroxy-2 (hydroxy-1 ((1 methyl-3-phenylpropyl) amino) -2 ethyl) -5 benzamide and therapeutic compositions based on compound obtained according to this new process

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2552427B1 (en) * 1983-09-27 1988-03-25 Scharper Spa New process for the preparation of hydroxy-2 (hydroxy-1 ((1 methyl-3-phenylpropyl) amino) -2 ethyl) -5 benzamide and therapeutic compositions based on compound obtained according to this new process

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