Novel Process for the Manufacturing of amino acid amide hydrochloride
Field of the Invention
The present invention relates to a process for the manufacture of (S)-2-aminobutanamide hydrochloride represented by the formula (II), which is useful as an intermediate for preparing the drug compound levetiracetam of formula (I).
Background of the Invention
The present invention relates to a cost-effective process for the manufacture of intermediate, (S)-2-Aminobutanamide hydrochloride of a compound of formula (II), useful for preparing levetiracetam formula (I)
Preparation of levetiracetam using (S)-2-aminobutanamide hydrochloride (II) described in the example of US4696 943, US4943639, and US4837223.
US7531673 describes a method of preparation (S)-2-aminobutyramide hydrochloride (II) in the example, by reacting (S)-2-aminobutyric acid hydrochloride (III) with Thionyl Chloride in methanol to form (S)-methyl-2-aminobutanoate hydrochloride (IV) followed by the introduction of ammonia gas in isopropanol as represented in the scheme-1.

As the process disclosed in Scheme-1, the preparation process involves hydrochloride salt of (S)-2-amino butanoic acid as the key starting material. Further, the above process requires isopropanol and hydrogen chloride, thus, this process leads to an increase in production cost and a long manufacturing cycle with low yield.
CN110698379 describes a method of preparation (S)-2-aminobutyramide hydrochloride (II), by the reaction of (S)-2-amino butanoic acid (I-A) with Thionyl Chloride in methanol to form an intermediate compound (S)-methyl 2-aminobutanoate hydrochloride (IV) followed by reacting with ammonia and Isopropanol-HCl in presence of a catalyst Oleic acid to form (S)-2-aminobutyramide hydrochloride (II). Further, the obtained crude compound (II) is treated with ethyl acetate at 50°C for2hrs, to get a pure compound of formula (II).

As the process disclosed in Scheme-2, the process requires a catalyst (oleic
acid) and an additional step with the use of ethyl acetate treatment to get a pure
compound of formula (II). Thus, this process is not suitable for industrial-scale
manufacture of the compound of formula (II).
It is clear from the above described prior art, the taught processes are involved
multiple steps, and higher process cycle time with low yields, Thus the said
manufacturing processes are not economically viable for large-scale
production.
Therefore, there is a need for a simple cost-effective process to manufacture
high purity Intermediate (S)-2-aminobutanamide hydrochloride (II)

Objects of the Invention
The primary object of the invention is to provide a cost-effective single stream process suitable for the large-scale manufacture of the compound of formula
(»).
Another object of the present invention is to provide an efficient, operationally
simple process, which does not require the isolation of intermediates
Yet another object of the present invention is to provide a process for the
manufacture of a highly pure compound of formula (II).
Summary of the Invention
The present invention provides an alternate simple, one-pot synthetic route for
the larger-scale manufacture of (S)-2-aminobutanamide hydrochloride (II)
comprising steps of; reacting the (S)-2-amino butanoic acid represented by
formula( I-A) with Thionyl Chloride using lower alcoholic solvent without any
catalyst to get the compound of formula (IV) which is treated with ammonia
and subsequently treated with Aqueous hydrochloric acid to furnish compound
of formula (II) as represented by scheme-3.

Detailed Description of the Invention
The primary aspect of the present invention is to provide a cost-effective single stream process for the manufacture of (S)-2-aminobutanamide hydrochloride » (II), a key intermediate for the preparation of levetiracetam (I), comprises: a) Esterification of (S)-2-aminobutanoic acid (1-A).
With Thionyl Chloride and Lower alcohol to form a compound of formula (IV) (in-situ)
b) Subjecting the obtained compound of formula (IV) in step (a), in an Ammonolysis reaction using gaseous Ammonia in an alcoholic solvent, followed by treatment with Con.HCl to get title product (S)-2-aminobutanamide hydrochloride (II) as represented by Scheme-3.
In one aspect of the present invention is the selection ester of (S)-2-amino butanoic acid hydrochloride of formula (IV), wherein R is selected from a group consisting of methyl, ethyl, propyl, 2-propyl, and butyl, more preferably

from a group consisting of methyl, ethyl, and 2-propyl; and most preferably
R=methyl or ethyl.
In another aspect of the present invention is the selection of the lower alcohol
solvent in step (a) is selected from a group consisting of methanol, ethanol, 1-
propanol, 2-propanol, 1-butanol, 2-butanol; and most preferably methanol or
ethanol.
The third aspect of the present invention is the temperature range for the step (a) reaction is selected from 30 to 75°C, more preferably 40°C to 70°C, and most preferably 50 to 60°C.
The fourth aspect of the present invention is the selection of the alcoholic
solvent in step (b) is selected from a group consisting of methanol, ethanol, l-
propanol, 2-propanol, 1-butanol, 2-butanol; and most preferably methanol or
ethanol.
The fifth aspect of the present invention is the use of Con.HO after completion
of ammonolysis reaction in step (b).
The pH of the completed reaction mixture is preferably adjusted to less than 2, more preferably in the range of 1.0 to 1.3
Step (a) and (b) of the process of the present invention is preferably conducted at a temperature range of 30 to 90°C, more preferably from 50° to 70° C, and most preferably from 30 to 60°C. Advantageously, the reaction temperature is ranging from 55 to 60° C.
The process according to the invention enables the production of a compound of formula (II) having a high optical purity
The process may enables large-scale production of a compound of formula (II) having a high chemical purity.

The process further enables the production of a compound of formula (II) with less impurities. Examples
Reference is now made to the following examples, which together with the i above descriptions; illustrate the invention in a non-limiting fashion. Expcriment-1: Preparation of (S)-2-aminobutanamide hydrochloride (II)
Methanol (1400mL), (S)-2-amino butanoic acid (200g, l.Omol), and Thionyl Chloride (249.6g, 1.08 mol) are charged into a reaction flask at 25-30°C. The reaction mass temperature is raised to reflux temperature (50 to 60°C) and stirred for about 8 hours. The progress of the reaction is monitored by HPLC, after the complete conversion of (S)-2-amino butanoic acid (l-A) to (S)-methyl 2-aminobutanoate hydrochloride (IV), methanol is distilled off completely under reduced pressure at 50°C. To the residue, methanol is added and stirred for 30 minutes and the resulted mother liquor is placed in an autoclave and pressurized with dry ammonia gas (50-55 PSI) for 24 hours at 40-45°C. The resulted reaction mixture is cooled to 25-30°C, inorganic salts are filtered out and methanol has been distilled from the mixture. Isoprop.anol (600ml) is charged followed by the introduction of the con.HCl (70 ml) and the reaction temperature is raised from 50 to 55°C and continued the stirring fori -2 hrs. The pH of the reaction mixture is maintained in the range of 1.0 to 1.3. After completion of the reaction, the formed solid (S)-2-aminobutanamide hydrochloride (II) is filtered, washed with IPA, and dried. Yield I.04w/w, purity 99% by HPLC.

Experinient-2:
Preparation of (S)-2-aminobutanamide hydrochloride (II)
Ethanol (l400mL), (S)-2-amino butanoic acid (200g, l.Omol), and Thionyl Chloride (249.6g, 1.08 mol) are charged into a reaction flask at 25 to 30 °C. The reaction mass temperature is raised to reflux temperature (50 to 60°C) and stirred for about 8 hours. The progress of the reaction is monitored by HPLC, after the complete conversion of (S)-2-amino butanoic acid (I-A) to (S)-ethyl 2-aminobutanoate hydrochloride (IV), methanol is distilled off completely under reduced pressure at 50°C. To the residue, methanol is added and stirred for 30 minutes and the resulted mother liquor is placed in an autoclave and pressurized with dry ammonia gas (50-55 PSI) for 24 hours at 40-45°C. The resulted reaction mixture is cooled to 25-30°C, inorganic salts are filtered out and methanol has been distilled from the mixture, then isopropanol (600ml) is charged followed by the introduction of the con. HC1 (70 ml) and the reaction temperature is raised from 50 to 55°C and continued the stirring fori-2 hrs. The pH of the reaction mixture is maintained in the range of 1.0 to 1.3. After completion of the reaction, the formed solid (S)-2-aminobutanamide hydrochloride (II) is filtered, washed with IPA, and dried. Yield :0.95 w/vv, Purity 98.37 % by HPLC.
Levetiracetam (I) can be prepared from the compound of formula (S)-2-aminobutanamide hydrochloride (II) by the known process as represented in the following examples.

Example-3:
Preparation of Levetiracetam from (S)-2-aminobutanamide hydrochloride (II) (reported in US 7531673)
50 grams of (S)-2-aminobutyramide hydrochloride is suspended in 500 niL of dichloromethane at room temperature, then cooled to temperatures between -5 and 0°C. 81.2 grains of potassium hydroxide and 23.3 grams' of tetrabutylammonium bromide are added to the reaction mixture. 66.4-grams of 4-chlorobutyryl chloride is added at the same temperatures. After completion of the reaction, solids are removed by filtration; the solution pH is adjusted to 7 to 7.5 with acetic acid, and dichloromethane is partially evaporated by the" application of a vacuum. 150-ml of ethyl acetate is added to precipitate the product, which is isolated by filtration and washed with ethyl acetate and then with acetone; the product has a chiral purity of 99.8 percent by high-performance liquid chromatography. The final product is purified by crystallization from ethyl acetate.

We Claim:
1. A process for the preparation of (S)-2-aminobutanamide hydrochloride of Formula (II),
Wherein said process comprises the steps of:
a) esterification of (S)-2-aminobutanoic acid (l-A).
with Thionyl Chloride and in the presence of lower alcohol to form an in-situ compound of the formula represented by the formula (IV)
R= ethyl or methyl

b) subjecting the resulting reaction solution of step (a) to an ammonolysis process with an ammonia source in a suitable organic solvent followed by treating with Con.HCI to form a high purity compound of formula (II).
2. The process as claimed in claim-1, wherein the reagent in step (a) is selected from the group consisting of Thionyl Chloride, phosphorus dichloride, phosphorus pentachloride, and phosgene.
3. The process according to claim 2, wherein the reagent is Thionyl Chloride
4. The process according to claim I, wherein the source of ammonia in step (b) is chosen from gaseous ammonia, ammonium chloride, and ammonium acetate,
5. The process according to claim 4, wherein the source of ammonia is gaseous ammonia.
6. The process according to claim I, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol.
7. The process according to claim 4, wherein the alcoholic solvent is methanol.
8. The process as claimed in claim-1, wherein the organic solvent in step b) is selected from the group consisting of methanol, butanol, and isopropanol
9. The process according to claim 8, wherein the alcoholic solvent is methanol or isopropanol.

10. The process as claimed in claim 1, wherein the said process comprises maintaining the reaction at a temperature between 50 to 55°C.
11. The process as claimed in claim 1, wherein the pH is adjusted to in the range of I to 1.3.