Brivaracetam, ((2S)-2-((4R)-2-oxo-4-n-propyl-1 -pyrrolidinyl) butanamide (I), is anti-epileptic that was first disclosed in WO 01/62726.

A method of synthesis is equally disclosed in WO 01/62726, said method involves the following two steps.

5-hydroxy-4-propyl-furan-2-one (373) could be obtained according to Bourguignon et al in the Journal of Organic Chemistry (1981 ), 46(24), 4889. The above method thus comprises

• a reductive amination step using S-2-aminobutyramide yielding the

unsaturated intermediate compound (III), as well as

• a hydrogenolysis step using NH ₄ COOH yielding the diastereomers (la) & (lb).

An improved method for manufacturing brivaracetam is disclosed in WO 2005/028435, consisting of the following steps : Step 1 : Obtention of 5-hydroxy-4-n-propyl-furan-2-one through condensation of valeraldehyde with glyoxylic acid :

Step 2 : Obtention of (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide and (2S)- 2-((4S)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide

(lb) (la

Said step 2 combines the reductive amination step as well as the hydrogenolysis step disclosed in WO 01/62726 in a one-pot reaction. The individual diastereomers obtained therefrom may then be separated, e.g. through chiral MCC.

Importantly, the methods disclosed in the art are performed in the batch process mode. The batch process is a single- or multi-stage process in which a certain quantity of inputs (starting materials, solvents, catalysts, energy, etc.) are fed into the chemical reaction unit (of the entire reaction) under conditions suitable for obtaining the desired reaction

(temperature, pressure, required time, etc.). With the batch process, within the reactor and at any given period of time, various actions may be initiated in the wake of which a concentration of reactants and products varies so long as the reaction progresses. At the conclusion of the process the mixture is removed from the reactor and it then subjected to a suitable separation or purification steps (either physical or chemical) to reach the required degree of purity.

In the batch process, so long as the batch has not undergone the entire series of actions, there is no possibility of preparing a further batch. The batch process can be undertaken in one reactor in which all the actions are carried out one after the other, or in a series of reactors in each of which a different stage of the process is carried out. The quality of the end product may be controlled by the addition of appropriate separation stages between the various other stages as required. Reactants that do not react, being then separated from the reaction mixture, may be returned for a further reaction (usually after they have undergone a purification step), thus maximizing yield.

The continuous flow process, on the other hand, is one in which inputs are fed into the system at a constant rate and at predefined ratios (starting materials, solvents, catalysts, energy, etc.), and at the same time, a permanent extraction of outputs (final products) is performed (products, by-products, energy, etc.). In an integrated continuous flow process a series of reaction steps are performed in separate but connected flow reactors that are individually and sequentially fed and evacuated in such a way that continuous flow of starting products, intermediate and final products in the integrated system is achieved. Such method is characterized by a constant process taking place in each section (flow reactor) of the integrated facility and during the time of its action a constant process takes place. Thus, the concentration of reactants and products at every location in the system is in a durable state and control of the process is done by maintaining these concentrations. Each of the production methods (batch/continuous) has its own characteristics. In the batch process, the shift from one stage to the next is carried out in series and so the overall time of the process is, in fact, the sum of the times required for the various stages, and it is relatively extensive.

In the continuous process, all the stages are carried out simultaneously (although possibly in different parts of a system), and so the overall time required for the process is shortened. In contrast, the required volume of the tanks for a specific batch process is greater than that required for a parallel continuous process.

For example, if a batch process takes one hour and the required output is one cubic meter per hour, a reactor whose volume is one cubic meter will be required, which is huge compared to the requirements related to the continuous mode. Hence, due to volume of the reaction systems required for the batch process the capital investment regarding equipment is more significant. Furthermore, batch installations generally tend to require more manpower whereas a continuous process installation may be operated automatically under computer control. Today, milli or micro-structured devices offer greatly enhanced mixing and heating capabilities compared to the batch process, leading to improved product profiles and higher yields. Thus, micro-reactors might be regarded as the chemist's round-bottomed flask of the 21 st century. Micro-reactors are generally operated in a continuous flow mode. With a reactor volume of less than some milliliters (up to some liters), flow chemistry allows the scale-independent synthesis from g to kg amounts in a single day. The small reactor volume facilitates the safe and easy handling of hazardous or instable materials and highly exothermic reactions. Fast and easy parameter screening makes micro-reactor technology an ideal tool for process development.

In general, the initial investment for continuous process plants tend to be less significant compared to batch installations, due to the size of batch reactors which are bigger, even if the automated control systems is more important. The overall Capex spending shows though a clear advantage for the continuous approach. For final products required in large quantities and to be manufactured throughout a 12-month period, the continuous process would be first choice. On the other hand, final products required in small amounts, or alternatively, for which the annual demand varies, the batch process is the preferred approach by many but not for all companies. The objective of the present invention consists in the provision of a more economical approach for preparing brivaracetam; ideally such process would be more cost-effective, produce less waste products and would be safe from a chemical engineering point of view.

SUMMARY OF THE INVENTION

The present invention relates to a new method for the preparation of brivaracetam, said method comprises an integrated continuous flow process for reactions wherein a

succession of connected (integrated) flow reactors are used to perform a series of reaction steps to yield the final product. Today , the work-up is done in classical batch equipment. It is a mixed process with continuous reactions and batch workup.

FIGURES

Figure 1 A shows a flow-chart, illustrating one embodiment of how to run an integrated, continuous flow with batch workup of the method according to the present invention.

Figure 1 B shows flow-charts illustrating by example step 1 of the present invention, where glyoxylic acid (1 .2 eq) at a temperature of 70°C and valeraldehyde acid (1 eq) are both added into a flow reactor to get hydroxyfuranone to be used in the process set out in Figure 1 A. First case, the reaction is done in only one reactor or to improve the yield we can add a second reactor to transform Form E into hydroxyfuranone in the second reactor using different operating conditions.

Figure 1 C shows a flow-chart, illustrating by example step 2 of the present invention, which is composed with 3 consecutive reactions. Figure 1 D: shows the continuous gas/liquid/solid reactors used for hydrogenation reaction

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an integrated, continuous flow method for the preparation of brivaracetam for reactions with batch system for work-up. Said method comprises three major chemical synthetic steps, performed in a succession of flow reactors that are connected in such a way to give an integrated flow manufacturing system with batch work-up.

One aspect of the invention consists in the fact that 3 steps - set out in WO 2005/ 028435 - starting from valeraldehyde and glyoxylic acid leading to the diasteromers (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide (lb) and (2S)-2-((4S)-2-oxo-4- n-propyl-1 -pyrrolidinyl)-butanamide (la) are performed in an integrated continuous flow process, whereby each step is performed in several flow reactors. All flow reactors are connected with batch equipment to get the right purity before introducing the flow in the next following continuous reaction step. The method thus comprises the following 3 steps :

Step 1 : Synthesis of 5-hydroxy-4-n-propyl-furan-2-one (II) :

Step 1 would typically be run, essentially without the use of any solvent, in one embodiment and without any catalyst at all (Neat reaction) in another embodiment.

Xeq 5-hydroxy-4-propylfuran-2-one The ratio of the glyoxylic acid / valeraldehyde mixture would be typically about 1 .1 /1 , up to 1.5/1 and preferably between 1 .2/1 and 1.3/1 . The residence time of said mixture in the reactor x _s is typically anywhere between 1 and 20 minutes, preferably about 2-10 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between 140 and 270°, preferably between 180-250° and even more preferably between 180-230°C. For example, if the temperature is T=180°C ,the ratio must be 1.2 with a residence time = 10mn to get a yield close to 92%. But if the temperature is T=230°C , the ratio must be 1.3 with a residence time = 2mn to get a yield of hydroxyfuranone close to 88% and form E close to 9% that we can transform later to hydroxyfuranone by using a classical acid such as Acetic acid, boric acid.

Optionally, a purification within said flow reactor may be performed after step 1 is completed, e.g.

· by liquid/liquid extraction with n-heptane and DIPE (diisopropyl ether)

• with reactive distillation

• with a molecular sieve 3A to remove H ₂ 0

• with charcoal to remove other impurities.

The conversion rate of valeraldehyde obtained is typically between 90-100 %, preferably up to 100%. The overall yield for 5-hydroxy-4-n-propyl-furan-2-one is about 85-93%.

The synthetic productivity achieved may be about 21 kg/L/h (by comparison, the productivity obtained through a batch process is about 0.0013kg/L/h, which is 18000 times lower). Step 2 : Synthesis of (2S)-4,5-dehydro-(2-oxo-4-n-propyl-1 -pyrrolidinyl)-2-butanamide (III):

5-hydroxy-4-n-propyl S-aminobutyramide

furan-2-one base

Step 2 comprises the condensation of S-aminobutyric amide with 5-hydroxy-4-n-propyl- furan-2-one (II) in ethanol obtained from step 1 , at temperatures ranging from 30-50°C, preferably at 40°C during 5 minutes, followed by addition of a mixture of NaBH ₄ / NH ₃ at a temperature of 30-50°C, preferably about 40°C, during up to 10 minutes

(preferably 5 minutes) and after addition of AcOH where the temperature of reaction should be kept between 80-120°C and preferably at a temperature of 105°C for about 7-12 minutes, preferably for about 9 minutes. Thereafter, still in this same flow reactor of the integrated continuous flow system, the lactam is extracted through addition of either of the following solvents EtOAc, i-PrOAc MIPK, t-BuOAc or mixtures thereof. A specific embodiment is the use of EtOAc which may also help to remove salts. Such extraction is typically performed at room temperature (20-25°C)..

Thus, to summarize, regarding Step 2, 3 consecutive reactions are achieved in one single flow in 3 different types of continuous reactors :

First reaction : condensation of S-ABA free base on hydroxyfuranone in ethanol.

Second reaction : Imine formation: addition of a mixture of NaBH ₄ /NH ₃ (0.1 M)

Third reaction : to finish the cyclisation to get unsaturated lactam by addition of AcOH/H ₂ 0 AcOH= 2.55 eq

The overall yield for the 3 consecutive reactions in Step 2 is up to 96% in a continuous process that takes less than 30mn.

Step 3 : Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide (lb) through catalytic reduction

(la) (lb)

The catalytic reduction is performed in a solvent, typically in water using the Pd/C catalyst system ("Catalyst"; which are commercially available) or Pd/CaC0 ₃ . The hydrogen pressure is usually adjusted at below about 20 bar, preferably below 15, more preferably below 10 bar.

In specific embodiments, the following catalytic systems ("Catalyst") are used

• Pd/C; with the addition of citric acid;

• Pd/C catalyst with the addition of citric acid, whereby the Pd/C catalyst is pre- treated / impregnated with TTT;

• Pd/CaC0 ₃ with the addition of HCI;

TTT stands for triazine trithiol trisodium and has the following structure :

The catalytic reduction using Pd/C catalyst with the addition of citric acid, whereby the Pd/C catalyst is pre-treated / impregnated with TTT provides for specifically high diasteroselective purities. The above synthetic conditions allow stereoselectivity in favor of brivaracetam ranging from 77-88% (d.e) which is a marked improvement over the methods used so far.

In order to obtain essentially pure brivaracetam diastereomer ( (lb) > 98% d.e), a chromatographic separation may be performed. The chromatographic separation of the two diastereoisomers (la) and (lb) obtained in step 3 is performed using of

(CHIRALPAK AD 20 μηη) chiral stationary phase and a 45/55 (volume/volume) mixture of n-heptane and ethanol as eluent at a temperature of 25 ± 2°C. The crude (2S)-2- ((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)-butanamide (lb) thus obtained is recrystallised in isopropylacetate, yielding pure (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide (lb).

All the reactors in step 3 described in figure 1 D, are performed in flow reactors connected to each other in such a way to provide an integrated system. There are many configurations of such connected reactor system, that a person skilled in the art is aware of. To solve the issues of reaction control, stirring, product and solvent feed and gas-liquid transfer, a continuous flow reactor is preferred. This reactor consist in several (about 5) separately controlled CSTR reactors in series. Each reactor is equipped with a Rushton self-gas-inducing agitator affording a very high gas-liquid transfer and a filter at the outlet to prevent the catalyst from leaving the each reactor. The reaction conditions (stirrer speed, Hydrogen pressure, internal temperature, etc ..) in each reactor could be set and monitored separately, allowing the reactor to fit the need. Moreover, as the last reactor of the series would only afford the last percent of conversion, it would be possible to bypass a reactor for maintenance or catalyst replacement while having the entire system ongoing with only a conversion loss of 1 % - thus allowing the catalyst to be replaced without stopping the process. The advantages of this continuous reactor system are:

• The temperature used in each module of reactor can be adapted at the kinetic rate of reaction

• The type and the load of catalyst can be different in each reactor.

· Gas liquid mass transfer is very important due to the self gas-inducing agitator Rushton.

• The load of catalyst can be discharged and charged in a quick time without

stopping the evolution f reaction.

EXAMPLES

Step 1 : Example 1

Pure glyoxilic acid monohydrate was continuously introduced at T=90°C in a plug flow reactor at a flowrate equal to 0.53ml/mn ( density = 1 .4 at T=90°C) with a flowrate of pure valeraldehyde equal to 0.71 ml/mn ( Density = 0,81 at T=25°C) in order to get a ratio glyoxylic acid / valeraldehyde = 1.2. The residence time in the reactor is 5mn at T= 180°C. This reaction is done without any solvent and catalyst: it is a neat reaction The volume of reactor, made of Hastelloy C is close to 6.2ml. We obtained a yield of hydroxyfuranone equal to 88% with 5.5% of Form E, either a potential yield close to 93% before the workup. Afterwards, we purified said crude product by classical batch technology to remove water, and by-products by several extractions with n-heptane and IPAC (Isopropyl Acetate).

Step 1 : Example 2

Pure glyoxilic acid monohydrate was continuously introduced at T=90°C at a flowrate equal to1.37ml/mn (density = 1.4 at T=90°C) with a flowrate of pure valeraldehyde equal to 1 .71 l/mn (density = 0,81 at T=25°C) in order to get a molar ratio glyoxylic acid / valeraldehyde = 1 .3. The residence time in the reactor is 2mn at T= 230°C

We obtained a yield of hydroxyfuranone equal to 88% with 9% of Form E, either a potential yield close to 97% before the workup. Then this mixture coming out this first reactor, is continuously introduced in a second reactor at T= 180°C during 5 mn with acetic acid (20%) in order to transform a part of Form E into hydroxyfuranone, to get a global yield close to 92% before the workup. Afterwards, we purified the crude product by classical batch technology to remove water, and by-products by several extractions with n-heptane and IPAC (Isopropyl Acetate). Step 2 : Example 3

For obtaining the (2S)-4,5-dehydro-(2-oxo-4-n-propyl-1 -pyrrolidinyl)-2-butanamide (III) from 5-hydroxy-4-n-propyl-furan-2-one (II), 3 consecutive reactions are to be performed:

- S-ABA condensation with hydoxyfuranone for obtaining an imine

Reduction and cyclization of the imine with NaBH ₄

Triggering the cyclization with AcOH

S-ABA free base in EtOH solvent (0.4mol/l) and (dried) hydroxyfuranone ( coming from step 1 ) are introduced separately and in continuous plug flow the reactor with a molar ratio S-ABA free base /Hydroxyfuranone equal to 1.2. The temperature in the first plug flow reactor is 40°C and the residence time is 5mn. The mixture coming out from this first reactor is introduced continuously in well mixed reactor in which it is added continuously NaBH4 (0.4 eq of Hydroxyfuranone) with NH3 at 0.1 M. The residence time in the reactor is 10mn at T=40°C. Then the mixture is introduced continuously in a third plug-flow reactor with a flow rate of AcOH (2.55eq of hydroxyfuranone) whose the residence time is 9mn at T=105°C. The global yield is 96% before the workup.

The purification of crude lactam is done by several extractions, for example by EtOAc , MEK, or l-PrOAc in batch way.

Step 3:Example 4

In the reactor N°1 (see figure 1 D) it has been introduced 100ml of aqueous solution at 20 wt% of 714 and 10 wt% of citric acid with 5%w/w of Pd/C at T= 60°C. When the mixture is reached T= 60°C in the reactor N°1 under P _H2 = 20 bar, a continuous flow rate composed with an aqueous solution at 20 wt% of unsaturated (2S)-4,5-dehydro-(2- oxo-4-n-propyl-1 -pyrrolidinyl)-2-butanamide (III) (from the step 2) and 10wt% of citric acid, have been introduced in the first reactor N°1 at fixed rate at 9ml/mn. The solution coming out the reactor N°1 at the same flowrate, is introduced into the reactor N°2 and then the mixture coming out from reactor N°2 is introduced in the reactor N°3 and so on.

In the reactor N°1 , when we reach the steady state, after 40mn, we have a global conversion of lactam close to 50% with

d.e.= ((lb) - (la) / (lb) + (la)) = 60%

either (lb) =80% and (la) = 20% with a TT= 50%

The reaction is finished in the other following reactors Step 3 : Example 5:

In the reactor N°1 (see figure 1 D) it has been introduced 100ml of aqueous solution with 9g of (lb) , 3g of (la) , 8 g of lactam and 10g of citric acid with 1 g of Pd/C Sigma 75990 (10%w% Pd). When the mixture is reached T= 60°C in the reactor N°1 under 20 bar , it have been introduced in the reactor N°1 in continuous way, an aqueous solution composed with 77% of water 15.3% wt% of unsaturated lactam and 7.7 wt% of citric acid at fixed rate at 2.5 ml/mn in the reactor N°1 . The solution coming out the reactor N°1 at the same flowrate, is introduced into the reactor N°2 and then the mixture coming out from reactor N°2 is introduced in the reactor N°3 and so on during all the time of experiment over several hours. We can observe that we got the stationary state after 80mn and we keep the right activity over several hours.

In the reactor N°1 , when we reach the steady state, we have a global conversion of lactam close to 65% with a constant concentration of (lb) in the mixture close to 60% The reaction is finished in the other following reactors.