DESC:Field of The Invention
The present invention relates to an industrially viable process for manufacturing of 2-aminobutyramide of formula (I) by continuous flow technology.

2-aminobutyramide of formula (I) is used as an intermediate in the synthesis of Levetiracetam.

Background of The Invention
2-aminobutyramide of formula (I) is used as an intermediate in the synthesis of Levetiracetam and Brivaracetam.

Levetiracetam and Brivaracetam are blockbuster drugs and their sales are increasing day to day based on information available on Newport, the sales of the Levetiracetam is 2108.3M with increase of sales by 11% and the Brivaracetam 162.7M with increase of sales by 97%. Hence, there is a need to develop a cost-effective process with higher yield and purity.

The method for the preparation of 2-aminobutyronitrile is disclosed in Tetrahedron Vol 44, issue 14, pages 4431-46, 1988 which involves reaction of propionaldehyde with sodium cyanide, ammonium chloride and water to obtain 2-aminobutyronitrile with lower yield (38%). The above process is shown in the scheme-1 given below:

The above process involves the higher operational expenditure with very lower yield and purity.

Another method for preparation of 2-aminobutyramide is reported in CN101928229, which involves reaction of n-propionaldehyde with sodium cyanide, ammonium chloride and water to obtain 2-aminobutyronitrile which is further hydrolysis by using 10% sodium hydroxide alkaline solution to obtain 2-aminobutyramide. Reaction time is 24 hours to 48 hours.

The above process involves the higher operational expenditure with lower yield and purity.

Another method for preparation of 2-aminobutyramide is also reported in CN106083642, which involves reaction of n-propionaldehyde with hydrogen cyanide, ammonium chloride, ammonia and water to obtain 2-aminobutyronitrile which is further hydrolysis by using sodium hydroxide and water to obtain 2-aminobutyramide. Reaction time is 24 hours to 36 hours.

The above process involves the higher operational expenditure with lower yield and purity.

The prior-art processes reported for the preparation of 2-aminobutyramide is having higher operational expenditure with lower yield and purity.

In order to overcome the above said problems it is necessary to develop a process with lower operational expenditure, higher yield and higher purity.

Brief Description of The Drawings
Figure-I illustrates an experimental set-up of a process continuous flow technology for stage-1 of the reaction.
Figure-II illustrates an experimental set-up of a process continuous flow technology of stage-2 of the reaction.

Summary of The Invention
In one aspect, the present invention relates to an improved process for the preparation of 2-aminobutyramide by continuous flow technology.

In another aspect, the present invention relates to Strecker reaction of 1-propionaldehyde of Formula (A) to obtain 2-aminobutyronitrile of Formula (B)

followed by hydrolysis of compound of Formula (B) in presence of base to obtain 2-aminobutyramide of compound of Formula (I)

wherein the process comprises the steps of:
i. charging water, ammonium chloride, ammonium hydroxide and sodium cyanide (Strecker reaction) in feed 1 reactor and stirred to obtain clear cyanide solution;
ii. charging propionaldehyde in feed 2 reactor;
iii. pumping solutions of feed 1 and feed 2 to tubular reactor (residence time 1 minute) and maintained the temperature at 80-85°C;
iv. collect the reaction mass in feed 3 reactor;
v. charging water and base in feed 4 reactor, stirred to get clear solution;
vi. pumping solutions of Strecker reaction mass (feed 3 reactor) and caustic solution (feed 4 reactor) to tubular reactor (residence time 1 minute) and maintained the temperature at 80-85°C;
vii. collect the reaction mass from outlet of tubular reactor.

In yet another aspect, the present invention provides 2-aminobutyramide of formula (I) with lower operational expenditure, higher yield and higher purity.

Detailed Description of The Invention

Accordingly, the present invention is to provide a process for the preparation of 2-aminobutyramide compound of Formula (I) by continuous flow technology.

Scheme-I illustrates the process for the preparation of 2-aminobutyramide compound of formula I.

Step (i):
In step (i), reacting propionaldehyde compound of Formula (A) in presence of reagents and solvents to obtain 2-aminobutyronitrile compound of Formula (B), the reagents used in the reaction are selected from sodium cyanide, potassium cyanide, ammonium hydroxide preferably sodium cyanide and ammonium hydroxide, the solvents used are selected from ammonium chloride and water. The reaction time is 1 minute and the reaction temperature is 80-85°C.

Step (ii):
In step (ii), hydrolysing 2-aminobutyronitrile compound of Formula (B) in the presence of base by using water to obtain compound of Formula (I), the base used in the reaction is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction time is 1 minute and the reaction temperature is 80-85°C.

Procedure for continuous flow technology.
In feed 1 reactor charge water, ammonium chloride, ammonium hydroxide and sodium cyanide and stir to obtain clear cyanide solution; In feed 2 reactor take propionaldehyde; Pump solutions of feed 1 and feed 2 through tubular reactor (residence time 1 minute) using pump 1 and pump 2 and maintained the temperature at 80-85°C; After completion of feed solutions switch off pump 1 & 2. Submit sample of reaction mass (feed 3 reactor) for gas chromatography to check the absence of Propionaldehyde; In feed 4 reactor charge water and base stir to get clear solution; Charge this caustic solution to above obtained Strecker reaction mass (feed 3 reactor). Place tubular reactor and maintained the temperature at 80-85°C; pump solutions of feed through tubular reactor (residence time 1 minute) using pump. Collect the reaction mass from outlet of tubular reactor; Submit sample of reaction mass for gas chromatography to check the absence of 2-aminobutyro nitrile.

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: Preparation of 2-aminobutyramide (Formula I)
Step (i): Preparation of 2-aminobutyronitrile
Prepare solution of feed 1 & 2. In feed 1 reactor charge 125 mL of water, 50.65 grams of ammonium chloride, 110 mL of ammonium hydroxide and 40.75 grams of sodium cyanide and stir to obtain clear (Total solution 306.6 mL /315.8 grams) cyanide solution. In feed 2 reactor take propionaldehyde. Pump solutions of feed 1 at 13.7 mL/minutes and feed 2 at 2.3 mL/minutes through tubular reactor (residence time 1 minute) using pump 1 and pump 2 and maintained the temperature at 80-85°C. Collect the reaction mass from outlet of tubular reactor. After completion of feed solutions switch off pump 1 & 2. Submit sample of reaction mass (feed 3 reactor) for gas chromatography to check the absence of Propionaldehyde.

Step (ii): Preparation of 2-aminobutyramide (Formula I)
Prepare solution of feed 4 reactor: Charge 34 mL of water and 13.8 grams of sodium hydroxide stir to get clear solution. Charge this caustic solution to above obtained Strecker reaction mass (feed 3 reactor). Place tubular reactor (volume of 16 mL) and maintained the temperature at 80-85°C. Pump solutions of feed at 16 mL/minute through tubular reactor (residence time 1 minute) using pump. Collect the reaction mass from outlet of tubular reactor. After completion of feed solution switch off pump 1 & 2. Submit sample of reaction mass for gas chromatography to check the absence of 2-Aminobutyronitrile.

Example 2:
Differences between the batch process and continuous flow technology (the present invention) in step (i)
The below differences are observed between the batch process and continuous flow technology (the present invention). More purity and yields are reported in continuous flow technology with less time consumption (1 minute).

Strecker Reaction (step - i)
Batch Process:
Experiment
Number Reaction Temperature (°C) Result by Gas chromatography
Propanal
(Not more than 0.5%) Dimer
Impurity
7 hours Residence time
1. 5 -10 0.29 86.60 6.60
2. 5 -10 0.28 86.27 7.08
3. 5 -10 0.37 87.05 6.81

Continuous Flow technology (present invention) [21 mL Flow reactor (3mm dia.)]:
Experiment
Number Reaction Temperature (°C) Result by Gas chromatography
Propanal
(Not more than 0.5%) Dimer
Impurity
1minute Residence time
1. 75 0.50 85.50 1.90
2. 75 ND 90.00 0.02
3. 75 ND 89.45 0.02

Example 3:
Differences between the batch process and continuous flow technology (present invention) in step (ii)
Hydrolysis reaction (Step – ii)
Batch Process:
Experiment
Number Reaction Temperature (°C) Result by Gas chromatography
8 hours Residence time
1. 25-30 84.30

2. 25-30 83.95

Continuous Flow technology (present invention) [21 mL Flow reactor (3mm dia.)]:
Experiment
Number Reaction Temperature (°C) Result by Gas chromatography
1minute Residence time
1. 85 90.56

2. 85 93.311

Advantages of the invention:
1. The present invention results in the preparation of 2-aminobutyramide of formula (I) with lower operational expenditure, higher yield, purity and consistency in the quality of the product.
2. The present invention also results in the lower percentage of dimer impurity, better selectivity, lesser bi-product formation.
,CLAIMS:

1. An improved process for the preparation of 2-aminobutyramide by continuous flow technology which involves Strecker reaction of 1-propionaldehyde of Formula (A) to obtain 2-aminobutyronitrile of Formula (B)

followed by hydrolysis of compound of Formula (B) in presence of base to obtain 2-aminobutyramide of compound of Formula (I)

wherein the process comprises the steps of:
i) charging water, ammonium chloride, ammonium hydroxide and sodium cyanide in feed 1 reactor and stirred to obtain clear cyanide solution;
ii) charging propionaldehyde in feed 2 reactor;
iii) pumping solutions of feed 1 and feed 2 to tubular reactor (residence time 1 minute) and maintained the temperature at 80-85°C;
iv) collect the reaction mass in feed 3 reactor;
v) charging water and base in feed 4 reactor, stirred to get clear solution;
vi) pumping solutions of Strecker reaction mass (feed 3 reactor) and caustic solution (feed 4 reactor) to tubular reactor (residence time 1 minute) and maintained the temperature at 80-85°C;
vii) collect the reaction mass from outlet of tubular reactor.

2. The process as claimed in claim 1, wherein the reaction time in steps (iii) and (vi) is 1 minute.