FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"An improved process for the preparation of
phenylalkylaminoethylsalicylamide
and intermediates thereof
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWAR1
(WEST), MUMBAI-400 102,
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

"AN IMPROVED PROCESS FOR THE PREPARATION OF
PHENYLALKYLAMINOETHYLSALICYLAMIDE
AND INTERMEDIATES THEREOF"
FIELD OF INVENTION
The present invention relates to a process for manufacturing of phenylalkylaminoethylsalicylamide and intermediates thereof.
BACKGROUND OF THE INVENTION
Labetalol, a phenylalkylaminoethylsalicylamide (CAS number: 36894-69-6) is a compound identified chemically as 2-hydroxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide described in US 4.012,444 has the structural formula:-

Labetalol hydrochloride (CAS number: 32780-64-6) is a compound identified chemically as 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide HCI having the structural formula:

Labetalol hydrochloride is a selective alpha-1-adrenergic blocking and non-selective beta-adrenergic receptor blocking agent, effective in the management of hypertension. Several types of synthesis are described in the literature for preparation of Labetalol and its pharmaceutically acceptable salts.

US 4,012,444 disclosed Labetalot hydrochloride, its preparation and US 4,066,755 disclosed its use in the treatment of hypertension. US 4,012,444 disclosed three methods for preparation of Labetalol hydrochloride as follows:
Method 1:

This method involved use of protected amine and comprises number of reaction steps. This reaction employs expensive Platinum (Pt) catalyst for reduction & produces Labetaiol hydrochloride in 12% yield only.
Method 2:

This method also uses protected amine and comprises number of reaction steps. It uses expensive Pt catalyst for reduction reaction, making it a costly reaction.


In this method, ester hydrochloride in ammonium hydroxide was allowed to stand for 8 hours at room temperature, removing the solvent under reduced pressure, neutralizing amine hydrochloride formed and then refluxing with 4-phenyl-2-butanone, reduction by hydrogen at room temperature and pressure, removing catalyst, extraction with solvent and removal of solvent to yield 5-[l-hydroxy-2-(l-methyl-3-phenylpropyl)aminoethyl] salicylamide. The reaction steps and reaction time makes the process tedious
These methods suffer from drawbacks of long synthetic route comprising numerous steps, expensive Pt catalyst for reduction, equipment requirements, long process cycle durations, low yield and high costs.
GB2149399 disclosed preparation of Labetalol hydrochloride by alkylation of non-benzylated or non protected amine as depicted in reaction scheme given below:


The process taught by '399 uses 5-Bromo salicylamide as one of the inputs. The process requires stringent conditions, longer durations and leads to formation of a bromo-Labetalol impurity having structure

Pharmacopoeial and 1CH specifications dictate that bromo-Labetalol impurity should be less than 0.05%. This is one of the critical process impurity. Once generated, this impurity is very difficult to remove from the final API. If the alkylation reaction is not controlled, it gives dimer as a main product whose
structure is given as below.

Thus there exist need to have an improved process that is free from drawbacks of prior art. Industry needs cheaper and a better process to prepare Labetelol that is free from bromo-Labetalol impurity & dimer.
OBJECT OF THE INVENTION
The object of the present invention to provide an improved process for the synthesis
of 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide HC1 that
overcomes the problems associated with prior art.
Another object of the invention is to provide a process for the preparation of Labetelol
free from Bromo impurity.
Yet another object of the invention is to provide a process for the preparation of
Labetelol that is free of dimer.

Yet another object of the present invention is to provide process for the synthesis of 5-Chloroacetyl salicylamide intermediate used for preparation of Labetalol HC1.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention, there is provided an improved process for the synthesis of 2-hydroxy-5-[1-hydroxy-2-[(4-phenyl-2-buty])amino]ethyl] benzamide hydrochloride comprising;
a) Reacting 5-Chloroacetyl salicylamide with l-phenyl-3-aminobutane in organic solvent followed by conc. HCI to produce 2-hydroxy-5-[N-(l-methyl-3-phenylpropyl) aminoacetyl]benzamide hydrochloride.
b) Reducing 2-hydroxy-5-[N-(l-methyl-3-phenylpropyl)aminoacetyl]benzamide hydrochloride of Formula (IV) in presence of NaOH and NaBH4 to produce 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)ammo]ethyl]benzamide (Labetalol free base) and
c) Reacting 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl] benzamide in organic solvent with dil. HCI to produce 2-hydroxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl] benzamide hydrochloride (Labetalol hydrochloride).
According to another aspect of the present invention, there is provided a process for synthesis of 5-Chloroacetyl salicylamide of Formula (II) comprising reacting 5-acetyl salicylamide of Formula (VI) in organic solvent with sulfuryl chloride,
DETAILED DESCRIPTION OF THE INVENTION:
The present invention addresses the need of an improved process for preparation of Labetalol hydrochloride. Term improved process meaning a faster process and/or a process that can be carried out under milder conditions and/or a process that provides good yields and/or a process that produces labetelol with improved impurity profile. Also the present invention provides a process for preparation of intermediate 5-chloroacetyl salicylamide used in the preparation of Labetalol hydrochloride.

Normally, when we compare the reactivity of alkyl halides, iodo compounds are more reactive than bromo compounds and bromo compounds are more reactive than chloro compounds. It is a matter of surprise that a chloro compound causes the reaction to be completed under milder conditions and the reaction is complete in shorter time. It was surprisingly found that use of 5-chloroacetyl salicylamide provides unexpected advantages. It was surprisingly noticed that when 5-chloroacetyl salicylamide is used the reaction can be carried out under normal room temperature conditions. Inventive step of the present invention lies in the use of 5-chloroacetyl salicylamide. It was surprisingly observed that when 5-chloroacetyl salicylamide was used, the reaction can be completed in much shorter time than time required for similar step in prior art. It was also surprisingly noticed that the reaction can be completed under much milder conditions than those used in the prior art. Use of 5-chloroacetyl salicylamide made the process faster, more economic and safer. Yet another surprise because of the use of 5-Chloroacetyl salicylamide was significant improvement in impurity profile of the Labetalol hydrochloride. Single maximum impurity obtained by this process is less than 0.05 %.
Novelty of the invention resides in the synthesis of 5-Chloroacetyl salicylamide and the use of 5-chloroacetyl salicylamide for the preparation of Labetalol hydrochloride. In one aspect, the present invention provides an improved process for the synthesis of 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide hydrochloride (Labetalol hydrochloride) of Formula (I) comprising:
a) Reacting 5-Chloroacetyl salicylamide of Formula (II) with l-phenyl-3-aminobutane of Formula (III) in organic solvent followed by cone. HC1 to produce 2-hydroxy-5-[N-(l-methyl-3-phenylpropyl) aminoacetyl] benzamide hydrochloride of Formula (IV).
b) Reducing 2-hydroxy-5-[N-(1-methyl-3-phenylpropyl)aminoacetyl] benzamide hydrochloride of Formula (IV) in presence of NaOH and NaBH4 to produce 2-hydroxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide (Labetalol free base) of Formula (V) and,
c) Reacting 2-hydro\y-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyI] benzamide of Formula (V) in organic solvent with dil. HC1 to produce 2-

hydroxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide hydrochloride (Labetaiol hydrochloride) of Formula (I).
Schematic representation for the synthesis of 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethy]]benzamide hydrochloride (Labetaiol hydrochloride) of Formula (I) is shown as follows:

In the above process 5-Chloroacetyl salicylamide was added to 1-phenyl-3-aminobutane of Formula (III) in organic solvent. Organic solvent is selected from polar aprotic solvents such as DMF, Dimethylacetamide and DMSO, preferably DMF. The reaction was maintained at room temperature for 3-4 hours. To this reaction mass, conc. HC1 was then added and reaction maintained till complete precipitation of 2-hydroxy-5-[N-(l-methyl-3-phenylpropyl)aminoacetyl] benzamide hydrochloride of Formula (IV). The product is filtered off and purified using ketonic solvent. Acetone being the preferred ketonic solvent. Yield = above 80 % and purity = above 96 %
NaOH was charged to round bottom flask containing 2-hydroxy-5-[N-(1-methyl-3-phenylpropyl) aminoacetyl] benzamide hydrochloride of Formula (IV) and water and the reaction mixture was stirred till clear solution was observed. NaBH4 was then added to the reaction mixture and reaction maintained till completion. Water and dil.HCl was then added to reaction mixture and product so obtained 2-hydroxy-5-[l-

hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide (Labetalol free base) is filtered off and dried in oven. Yield= above 85 % and purity - above 97 %
2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide so
obtained was charged in organic solvent and the reaction mass was heated. Dilute HCI was charged to reaction mass, heating was continued till clear solution was obtained. Organic solvent is selected from alcohols selected from methanol, ethanol, propanol; ketones selected from acetone, ethyl methyl ketone, butanone; water or mixtures thereof. Solvent used is preferably mixture of ethanol and water. To this clear solution charcoal was charged & filtered through hyflo bed. The filtrate was then cooled and dil. HCI was added till completion of reaction and product so obtained 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl] benzamide hydrochloride (Labetalol hydrochloride) is filtered off and dried in oven. Yield = above 70 % and purity = above 99.90 % (ICH quality)
In another aspect, the present invention provides process for synthesis of 5-Chloroacetyl salicylamide of Formula (II) comprising reacting 5-acetyl salicylamide of Formula (VI) in organic solvent with sulfuryl chloride.
Schematic representation for the synthesis of 5-Chloroacetyl salicylamide of Formula (II) is shown as follows:

In the above process sulfuryl chloride was added to 5-acetyl salicylamide dissolved in solvent at 10°C -30°C, more preferably 15°C -25°C. Solvent is selected from aliphatic solvents selected from alcohols selected from C1 to C4 carbon atoms such as methanol, ethanol, propanol; aromatic hydrocarbons selected from Toluene, xylene; aliphatic hydrocarbons such as cyclohexane; and halogenated solvents selected from dichloromethane, chloroform, carbon tetrachloride or mixtures thereof. Solvent used

is preferably mixture of methylene dichloride and methanol. Reaction was maintained till completion (2-6 hrs) and 5-ChloroacetyI salicylamide formed is separated by filtration and purified using ketonic solvent preferably acetone. Yield = above 90 % and purity = above 96 %.
When Compared with the prior art, the present invention has the following advantages:
• Simple preparation methods
• Suitable for industrial scale production
• The process requires few steps and is completed in shorter time than prior art process
• Reaction conditions are simpler
• Purity profile of the final product is enhanced
• Remarkable improvement in Impurity profile
The details of the invention, its objects and advantages are explained hereunder in greater detail by non-limiting exemplary illustrations. The examples are merely illustrative and do not limit the teaching of this invention and it would be obvious that various modifications or changes in the procedural steps by those skilled in the art without departing from the scope of the invention and shall be consequently encompassed within the ambit and spirit of this approach and scope thereof.
EXAMPLES
EXAMPLE 1: Preparation of 5-chloroacetyl salicylamide of Formula (II) In a Round Bottom Flask 700 ml of dichloromethane was charged. To this was added 100 gm of 5-acetyl salicylamide of Formula (VI) in 36 ml methanol. Temperature of reaction mass then maintained to 15°C-25°C in ice bath. To this 131.9 gm of sulfuryl chloride was added over the period of 1 to 2 hrs at temperature of 15-25°C and then maintained at 25°C-35°C for 2 hrs. 100 ml Water was then poured to reaction mixture at 25°C-35°C and then maintained for 30 minutes. Reaction product was filtered off and washed with dichloromethane. Wet product was then dissolved in acetone and temperature raised to 55°C-65°C for 1 hr. The reaction mass was then cooled to 25°C-

35°C and product obtained was filtered off, washed with acetone and dried in oven at 55°C-65°C (Yield = 104 gm, 87.4%, Purity 97.5%).
EXAMPLE 2: Preparation of 2-hydroxy-5-[N-(l-methyl-3-phenylpropyl) amino acetyl] benzamide hydrochloride of Formula (IV)
in a Round Bottom Flask 250 ml Dimethylformamide (DMF) was charged. To this was added 349 gm of l-phenyl-3-aminobutane of Formula (III) followed by 100 gm of 5-Chloroacetyl salicylamide of Formula (II) at 25°C-30°C. The reaction was then maintained for 2 hrs. 250 ml of conc. HC1 was added drop wise to reaction mixture at 25°C. Water (1000 ml) was then added to reaction mixture and maintained for 12-14 hours under stirring. The product obtained was filtered off and washed with water. Wet product was dissolved in 500 ml acetone and temperature raised to 55°C-60°C for 2 hrs. The reaction mass was then cooled to 20°C-25°C and product obtained was filtered off. washed with acetone and dried in oven at 60°C-65°C (Yield = 135gm, 79.41%, Purity = 99.47%).
EXAMPLE 3: Preparation of 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)aminoj ethyl]benzamide (Labetalol free base) of Formula (V)
350 ml Distilled water was charged in a Round Bottom Flask followed by 100 gm of 2-hydroxy-5-[N-(1-methyl-3-phenylpropyl) amino acetyl] benzamide hydrochloride of Formula (IV). A solution of 22.9 gm of NaOH in 70 ml of Distilled water was added to reaction mixture till clear. A solution of 10.5 gm sodium borohydride in 200ml 0.1N NaOH was added over a period of 4-5 hrs and maintained at 25°C-30°C for 10-12 hrs. Dil. HC1 was then poured in reaction mixture drop wise till pH of 9.5-10, solid observed. Reaction mixture was stirred for 2-3 hrs at 25°C-30°C, product then filtered off, washed with water and dried in oven (Yield = 85.5gm, 95%, Purity = 99.42 %).
EXAMPLE 4: Preparation of 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino] ethyl]benzamide hydrochloride (Labetalol hydrochloride) of Formula (I)

192 ml ethanol and 128 ml water was charged in a Round Bottom Flask. 80 gm of Labetalol free base was added to this mixture and the temperature was raised to 45°C-50°C. Dil. HC1 was added to the reaction mixture and stirred for 10-15 minutes.3.2 gm activated charcoal was then added and stirred reaction mixture for 45-60 minutes. Hot reaction mixture was filtered off on hyflo bed, washed with hot 160 ml ethanol-water mixture. Mother liquor cooled to 30°C-35°C and then dil. HC1 was added, solid observed. Reaction mixture maintained for 2-3 hrs at 10°C-15°C, filtered off the product, washed with chilled 160 ml ethanol-water mixture and dried in oven at 75°C-80°C (Yield = 68 gm, 72.27%, 99.95% purity).

CLAIMS:
We claim,
1) An improved process for the synthesis of 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-
2-butyl)amino]ethyl]benzamide hydrochloride (Labetalol hydrochloride) of
Formula (I) comprising:
a) Reacting 5-Chloroacetyl salicylamide of Formula (II) with l-phenyl-3-aminobutane of Formula (HI) in organic solvent at temperature range from -5°C to 45°C for 3 to 4 hours followed by conc. HC1 to produce 2-hydroxy-5-[N-(l-methyl-3-phenylpropyl) aminoacetyl]benzamide hydrochloride of Formula (IV).
b) Reducing 2-hydroxy-5-[N-(l-methyl-3-phenylpropyl)aminoacetyl] benzamide hydrochloride of Formula (IV) in presence of NaOH and NaBH4 to produce 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide of Formula (V) and
c) Reacting 2-hydroxy-5-[I-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl] benzamide of Formula (V) in organic solvent with dil. HC1 to produce 2-hydroxy-5-[l-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide hydrochloride of Formula (I).

2) The process as claimed in Claim 1 a), wherein organic solvent is selected from polar aprotic solvents selected from DMF, Dimethylacetamide and DMSO or mixture thereof, more preferable being DMF.
3) The process as claimed in Claim 1 a) wherein 5-Chloroacetyl salicylamide of Formula (II) is reacted with l-phenyl-3-aminobutane of Formula (III) in organic solvent at a temperature range of -5 C to 45 C, preferably at a temperature range of 10°C to 40 C, more preferably at a temperature range of 15°C to 35°C and most preferably at a temperature range of 20 C to 30°C.
4) The process as claimed in claim 1 c), wherein organic solvent is alcohols selected from methanol, ethanol, propanol; ketones selected from acetone, ethyl methyl ketone, butanone; water or mixture thereof, more preferably mixture of ethanol and water.
5) A process for synthesis of 5-Chloroacetyl salicylamide of Formula (II)
comprising

a. Reacting 5-acetyl salicylamide of Formula (VI) in organic solvent with
sulfuryl chloride to produce 5-Chloroacetyl salicylamide,
b. Optionally separating 5-Chloroacetyl salicylamide formed in step 5 a)
c. Optionally purifying 5-Chloroacetyl salicylamide separated in step 5b)
using suitable solvent.
6) The process for synthesis of 5-Chloroacetyl salicylamide of Formula (II) as claimed in claim 5 a) where 5-acetyl salicylamide of Formula (VI) is reacted with sulfuryl chloride in organic solvent at a temperature range of-5 C to 45 C, preferably at a temperature range of 10 C -30 C, more preferably at a temperature range of 15°C -25°C and most preferably at a temperature range of 15°C-20°C.
7) The process for synthesis of 5-Chloroacetyl salicylamide of Formula (II) as claimed in as claimed in Claim 5 a, where an organic solvent is selected from alcohols selected from C1 to C4 carbon atoms such as methanol, ethanol, propanol; aromatic hydrocarbons selected from Toluene, xylene; aliphatic hydrocarbons such as cyclohexane; and halogenated solvents selected from dichloromethane, chloroform, carbon tetrachloride or mixtures thereof.
8) The process for synthesis of 5-Chloroacetyl salicylamide of Formula (II) as claimed in as claimed in Claim 7 wherein the organic solvent is mixture of Dichloromethane and methanol.

9) The process for synthesis of 5-Chloroacetyl salicylamide of Formula (II) as claimed in as claimed in Claim 5 b wherein separation is carried out by filtration, extraction or combination thereof.
10) The process for synthesis of 5-Chloroacetyl salicylamide of Formula (II) as claimed in as claimed in Claim 5 c) where in purification is carried out using solvents ketones selected from acetone, ethyl methyl ketone, butanone; water or mixtures thereof, preferably acetone.