GABAPENTIN SALT"

FIELD OF THE INVENTION

The present invention relates to the field of chemistry for the preparation of gabapentin salt of formula (I). More particularly the present invention relates to a continuous process for preparation of gabapentin salt (I) by means of the Hofmann rearrangement reaction using pinch tube reactor in greener and commercially viable manner with safer conditions in high yield and high chemical purity.

(I)

wherein X is any alkali metal.

BACKGROUND OF THE INVENTION

Gabapentin, chemically also known as l-(aminomethyl)-l-cyclohexaneacetic acid, was disclosed first in U.S. Patent no. 4,024,175 (hereinafter referred to as US 175) by Warner-Lambert Co. It is a well-recognized drug used for treatment of epilepsy and other cerebral disorders.

Since the daily doses required are relatively high, the quantities produced annually worldwide are very considerable, more than 1000 tons. Hence there is a strong demand to develop highly-efficient and low-cost production processes, also given the need to contain the social costs of epilepsy treatment.

In literature there are several methods known for the synthesis and purification of gabapentin. Among the main synthetic strategies developed, the one based on the Hofmann re-arrangement of [l-(2-amino-2-oxoethyl)cyclohexyl] acetic acid which takes place via isocyanates. In this case, the acid amides are reacted with alkali metal hypohalites and after hydrolysis of the isocyanate formed by anionotripic rearrangement; the desired amine is formed with the elimination of carbon dioxide. This is the most common in industrial use and to afford the low production costs. Gabapentin (The Merck Index, XVI Ed., page 794, No. 4348),was described for the first time by Warner-Lambert Co. in the US 175 in 1977 and was subsequently described in numerous other patents involving the use of a batch technology. It is clear from the detailed description of the preparation of gabapentin based on this Hofmann re- arrangement reaction that a laborious management of the methods for bringing the reagents into contact and a careful control of the temperatures are needed to obtain high yields. In fact, the first problem consists in the exothermicity of the reaction, which makes temperature control troublesome and dependent on the scale on which the reaction is conducted.

The PCT patent application WO2002034709A1 gives a detailed description of the preparation of raw gabapentin based on the Hofmann re-arrangement reaction starting from two distinct aqueous solutions of 1,1-cyclohexanediacetic acid monoamide/sodium hydroxide (NaOH) and sodium hypochlorite/NaOH, the latter being prepared under vacuum and stirring. The Hofmann re-arrangement reaction is then conducted by adding the first solution to the second in 2.5 to 4 hours under a slight nitrogen flow, keeping an internal temperature of -5°C. The reaction mixture is maintained between -3°C and +5°C for two hours and then slowly brought up to 20°C in 2 to 3 hours and maintained at a temperature of 20°C to 25 °C for a further hour.

In another PCT patent application WO2003089403A1, in example 1, step 1 discloses the preparation of crude gabapentin by Hofmann re-arrangement that involves a solution of sodium hydroxide and hypochlorite at 0°C being mixed with an aqueous solution of [l-(2-amino-2-oxoethyl)cyclohexyl]acetic acid and NaOH at temperatures between 0°C and 10°C, and made to react for a period of approximately 2 to 3 hours.

Fundamentally, these methods of synthesis demand low temperatures and relatively long reaction times. Therefore, these procedures are difficult to implement, hardly reproducible and troublesome in industrial applications. Moreover, sodium hypochlorite is available at concentrations no higher than 14 to 15% by weight. The reaction accordingly takes place in highly diluted conditions, with relatively high reaction volumes. Large reaction volumes and reaction times of several hours give rise to a low yield and to the need to use systems of considerable dimensions to achieve the annual output required for an active ingredient in such widespread use. Hence, there is need to have a novel technology that, although it must treat diluted solutions, it can assure a high productivity potentially even using small-sized equipment in continuous mode.

The availability of a process for the synthesis of aliphatic amines, such as gabapentin, that is straightforward to manage on an industrial scale and capable of providing a pharmaceutical grade end-product is consequently a need that is strongly felt in the field.

The implementation of continuous flow processing is a key empowering technology for preparation of commercial drug compounds. It has capabilities to expand towards more efficient, reproducible and surplus manufacturing of drug in large quantities. The flow chemistry is emerging as an innovative synthesis concept for improving chemical synthesis to a powerful and widely applicable tool enabling the efficient multistep synthesis of numerous active pharmaceutical ingredients.

The PCT patent application no. WO2014167506A1 discloses a pinched pipe flow reactor to prevent back-mixing and to enhance heat transfer. The flow reactor comprising of plurality of fluidic components which helps to retain agility and re- configurability of the continuous chemical processes with improved mixing and heat transfer characteristics.

The European patent application no. EP2368872A1 discloses the method for the preparation of [(l-aminomethyl)cyclohexyl] acetic acid (gabapentin) using continuous reactor by Hofmann re-arrangement reaction of an alkaline aqueous solution of [l-(2-amino-2-oxoethyl)cyclohexyl] acetic acid with an alkaline aqueous solution of a hypohalogenite and further extraction of Gabapentin in zwitterionic form with a higher aliphatic alcohol C4-C7 from the reaction mixture. Gabapentin was obtained from the extracted alcoholic solution by filtering and/or by crystallization, after the solution has been anhydrified by azeotropically distilling the water. The continuous reaction was carried out in a plug flow reactor, tubular reactor, a cascade of agitated reactors or a combination of tubular and agitated reactors. However, the preparation process has disadvantages as the retention time of the reactant in continuous tubular reactor is high, moreover to reduce retention time of the reactant in continuous tubular reactor required special packing of polypropylene filler or the tubular reactor filled with glass beads. This additional requirement enhances the cost of production and requires the special arrangement in reactor. Further, this document is silent on the preparation of gabapentin salt using continuous process as well as use of pinch tube reactor for preparation of gabapentin salt.

The flow technology was introduced in the Indian patent application no. 1079/DEL/2013. The U.S. patent no. 7,018,591 discloses a tubular reactor integrated with heat exchange apparatus for conducting chemical reactions, whereas the U.S. patent no.5,779, 994 disclose a tubular reactor contains a plurality of parallel reaction tubes held between two tube plates in a cooling medium container. The reaction tubes are connected outside of the tube plates with 180° bends to form a tubular coil.

The U.S. patent no. 3,773,470 discloses the apparatus for continuous chemical reactions, especially polymerizations and copolymerizations particularly of olefins or diolefins. The U.S. patent no. 3,148,037 discloses repeating chemical reactor having better characteristics than individual batch mixing reactors and providing continuous flow feed and drain. The U.S. patent no. 7,871,579 discloses the tubular reactor with an insert for improving heat transfer characteristics of the tubular reactor.

Also, U.S. patent no. 4,763,727 discloses a panel heat exchanger that has a plate made of a heat conducting material and at least one pipe connected with it, this pipe having a meandering shape, and through which a heat exchange medium flow.

In another U.S. patent no. 6,920,917 provide an inexpensive double-pipe heat exchanger having high performance. It comprises an inner pipe and an outer pipe which constitute a double pipe without adding a heat-transfer facilitating material such as an inner fin. In the double -pipe heat exchanger having the inner pipe and the outer pipe, the outer pipe is dented from its outside toward its inside, thereby forming a plurality of projections which are dented toward the inner pipe. Examples of shapes of the projection are substantially conical shape, substantially truncated shape, substantially spherical surface shape, substantially cylindrical shape, substantially elliptic cylindrical shape and the like. The heat transfer performance is not deteriorated because a distance between the inner pipe and the outer pipe is substantially equally maintained by the projections of the outer pipe disposed around the inner pipe.

Despite of above drawback there is a need for an efficient system for carrying out processes in a simple, quick and reconfigurable manner. Further, there is a need in the art to provide a system devoid of inserts in the pipes/tubes, and yet retain the efficiency of the system. Also, a modular system, avoiding a tube-in-tube approach is preferred. Tube-in-tube is a typical heat exchanger. In tube-in-tube system the projections from outer tube side help to increase the turbulence thereby enhancing the heat transfer rates.

Using continuous reaction and extraction of gabapentin salt from the reaction product, the present invention entails a gabapentin salt production process with a high yield that demands no complex steps for its management on an industrial scale. With continuous process of present invention, it is also easy to automate, affording a considerable saving on production costs.

The object of the present invention is a process capable of providing an active ingredient gabapentin salt (GBP) in a continuous mode using novel pinch tube reactor with greater turbulence and superior agility. The said salt can be further converted into gabalactam with a high chemical yield and chemical purity suitable for the preparation of pharmaceutical products.

OBJECT OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of a compound of formula (I) in continuous mode, which is simple, economical, user-friendly, greener, safer and commercially viable.

Another objective of the present invention is to provide an improved process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention environment friendly as well.

Yet another objective of the present invention is to provide a continuous process for the preparation of a compound of formula (I) using pinch tube reactor or technology.

Yet another objective of the present invention is to provide an improved process for the preparation of a compound of formula (I) in a high yield with high chemical purity.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a continuous process for preparation of gabapentin salt of formula (I), wherein X is any alkali metal

NH coox

(I)

which comprises the steps of:

a) mixing and making to react an alkaline aqueous solution of [l-(2-amino-2- oxoethyl)cyclohexyl] acetic acid formula (II) with an alkaline aqueous solution of a hypohalogenite in a pinch tube reactor;

b) collecting a compound of formula (I).

The above process is illustrated in the following general synthetic scheme I.

Scheme I

(Π) (I) wherein X is any alkali metal. The process can be further commercially exploited for manufacturing of gabalactam followed by gabapentin.

BRIEF DESCRIPTION OF FIGURES

Figure 1 depicts the pinch tube reactor for continuous preparation of gabapentin salt;

Figure 2 depicts the flow diagram of experimental setup;

Figure 3 depicts the analysis of reaction mass after every 1 h plotted against % area analysis on primary Y axis and %w/w assay on secondary Y axis;

Figure 4 depicts the kinetic study of batch mode on basis of % area analysis (expansion of Figure 3);

Figure 5 depicts the analysis of reaction mass from different outlets corresponding to different residence time plotted against % area analysis on primary Y axis and %w/w assay on secondary Y axis; and

Figure 6 depicts the kinetic study of continuous mode on basis of % area analysis (expansion of Figure 5).

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly indicates otherwise.

The instant invention relates to a continuous process for preparation of gabapentin salt (I) by the Hofmann rearrangement reaction of an alkaline aqueous solution of [l-(2-amino-2-oxoethyl)cyclohexyl] acetic acid (CAM) formula (II) with an alkaline aqueous solution of a hypohalogenite in a pinch tube reactor as depicted in Figure 1.

(I) (Π) wherein X is any alkali metal.

In accordance with the objectives, wherein the present invention provides continuous process for the preparation of gabapentin salt (I) using said pinch tube reactor (PTR) which accomplished the green chemistry principles such as minimum energy consumption, avoids the use of hazardous substances and reduces the waste.

In an embodiment of the present invention, wherein group X is any alkali metal, preferably sodium, potassium; and most preferably sodium.

In an embodiment of the present invention, wherein the said hypohalogenite may be selected from the group consisting of sodium hypobromite (NaOBr), sodium hypochlorite (NaOCl), potassium hypobromite (KOBr), potassium hypochlorite (KOC1); and the like; and more preferably sodium hypobromite or sodium hypochlorite.

In an embodiment of the present invention, wherein the alkali may be selected from group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH)and the like; more preferably sodium hydroxide.

In another embodiment of the present invention, wherein the pinched tube reactor is used for continuous reaction. Pinched tube reactor is a tubular flow reactor comprising of a tube having pinched sections connected to each other by a non- pinched section. The figure 1 depicts the schematic presentation of the pinch tube reactor used in present invention.

The pinched tube reactor used for preparation of gabapentin salt in continuous mode, comprising two different pinched tubes, each one for mixing zone and reaction zone. The PTR is having helical configuration, with coil diameter 100mm. The internal diameter of the PTR is 4.00mm while outer diameter is 6.35mm. The length of mixing zone of PTR is 2000mm and the length of reaction zone is 3000mm. The angle between two alternate pinch axis is 90°.

Scheme II

(II) N-bromo intermediate (i)

In the present invention for preparation of gabapentin salt, raw materials, viz CAM and NaOBr are made to react inside high mass transfer effective pinched tube reactor as described above. The feed flow rates, temperature profile, length of reactor, are accordingly optimized to achieve the reaction mass specifications of CAM <0.2% w/w in less than 120 sees with NaOBnCAM mol equivalent 1.07: 1.

The CAM at 50°C temperature and NaOBr at 10°C temperature, are pumped inside the PTR. The reactor consists of two zones; zone 1 is mixing zone about 33% volume and reaction zone about 67% of volume. Zone 1 is immersed in water bath, maintained at 40°C and zone 2 is immersed in water bath, maintained at 55°C. The outlet of product is collected in collecting vessel.

The residence time (Tr) of reactor is about 120 sees and to stabilize the system, 10 to 15 min of stabilization time is provided. Further, the sample of reaction is drawn online in chilled conditions and submitted to analysis, for CAM content.

As soon as the sample passes the specification i.e. CAM content NMT 0.2% yield, experiment is started in which, the initial weights of reactants are noted. Experiment is continued for 1 h. At the end of 1 h, pumps are stopped. The final weights of reactants are noted. The weight of product collected in collecting vessel is noted. The reaction mass is taken forward for extraction to convert GBP salt to gabalactam. Once the yield experiment is completed, the reactor is cleaned using water from pump to avoid residue build up. The water is pumped for 15 to 20 min inside the reactor.

The reaction kinetics is study of speed or rate of chemical processes. Chemical kinetics includes investigations of different experimental variables such as nature of reactant, temperature, catalyst, pressure etc. which can influence the speed of a chemical reaction. Chemical kinetics is used in designing or modifying chemical reactors, for comparing batch and continuous processes and to optimize product yield, separate products efficiently, and eliminate hazardous by-products. Therefore, the comparative kinetic study of the batch mode and continuous process using pinch tube reactor for preparation of gabapentin salt is summarized below to better understand the technical advantages of the instant invention over batch mode operation.

Table 1 Data for analysis of reaction mass after every 1 h in batch method

The Hoffman reaction for preparation of gabapentin salt was carried out as per conventional process and analyzed reaction mass after every 1 h. The results are summarized in above table 1. In Figure 3, HPLC analysis of reaction mass after every 1 h plotted against % area analysis on primary Y axis and %w/w assay on secondary Y axis.

Figure 4 is the expansion of Figure 3, which clearly shows that reaction is completed after 8 h.

Following conclusions are made from above observations:

1. At 15°C (0 h) more than 99% CAM is converted to either to product GBP or N-bromo intermediate (N-Br).

2. Further 8 h required for complete conversion of N-Br intermediate to product GBP.

3. Area % for sodium carbonate (side product carbon dioxide) increases with time and attend steady state after 7 h.

4. Till 8 h GBP product increases and attends steady state (GBP 6.88 % w/w;

CAM- 0.13 % w/w; N-Br intermediate- 0.29 % Area)

Table 2: Data for analysis of reaction mass from continuous method

The Hoffman reaction for preparation of gabapentin salt of instant invention was carried out by a continuous process using pinch tube reactor. Samples were withdrawn from different outlets and analyzed by HPLC. The results are summarized in above table 2.

In Figure 5, HPLC analysis of reaction mass from different outlets corresponding different residence time has plotted against % area analysis on primary Y axis and %w/w assay on secondary Y axis.

Figure 6 is the expansion of Figure 5, which shows that reaction is completed after 10 min of residence time. Following conclusions are made from above observations:

1. More than 98% CAM gets converted to N-Br intermediate and GBP immediately.

2. After 10 min residence time, CAM and N-Br intermediate gets completely converted to GBP (GBP-7.58 % w/w; CAM- 0.15% w/w; N-Br intermediate- 0.10 % Area).

In conclusion, total 8 h of maintaining is required for completion of reaction in batch mode, whereas, in continuous mode reaction time is reduced to 10 min only. By considering addition and warm up time, time cycle for batch mode is 12 h, which is reduced to 10 min by continuous mode. Due to improvement in time cycle, the consumption of energy and total overall cost for manufacturing of gabalactam are lowered, hence the instant invention achieved the economical and greener benefits.

In another embodiment of the present invention, wherein all the crude compound may be used as such or may be purified by distillation or crystallization or by different techniques well understood by those skilled in the art.

The gabapentin salt is prepared with the process of instant invention may be further use for the preparation of gabalactam followed by gabapentin.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXAMPLES

Example 1: Preparation of gabapentin salt in a pinch tube reactor with a retention time of 2.0 minutes using 1.07 eq. of sodium hypobromite solution

A solution of 304.66g of [l-(2-amino-2-oxoethyl)cyclohexyl] acetic acid (CAM) in 541.33g of 11.31% aqueous sodium hydroxide and a solution of 2215g of 9.01% aqueous sodium hypobromite, were fed into pinch tube reactor made of stainless steel AISI 316L with an internal diameter of 4.00mm and a length of 5000mm (5 metre), in which constrictions are formed along the length of the tube by pinching the tube so that its walls are internally separated by less than one third of their original separation. The principal radial axis of each constriction being at an angle 90° to that of its neighbour, to leave a free volume of 70.59ml, and maintained at 40+2°C (first 2m part of pinch tube). The remaining 3m part of pinch tube was maintained at 55+2°C. The flow rates were l l.lmL/min for CAM solution and 28.3mL/min for hypobromite solution respectively, and the retention time was 2.0min. The product outlet from pinch tube was collected at atmospheric temperature. After reaching the stationary state, the collected solution contained 7.87% by weight of gabapentin(equivalent to 8.88% gabapentin salt), corresponding to a yield of 91.98%. The reaction mass was collected in three parts and confirmed reproducibility by HPLC analysis.

Example 2: Preparation of gabapentin salt in a pinch tube reactor with a retention time of 2.16 minutes using 1.2 eq. of sodium hypochlorite

A solution of 264.46g of [l-(2-amino-2-oxoethyl)cyclohexyl] acetic acid (CAM) in 460g of 12.72% aqueous sodium hydroxide and a solution of 1309g of 9.08% aqueous sodium hypochlorite, with 218.85g of 100% NaOH were fed into pinch tube reactor made of stainless steel AISI 316L with an internal diameter of 4.00 mm and a length of 7000 mm (7 m), in which constrictions were formed along the length of the tube by pinching the tube so that its walls were internally separated by less than one third of their original separation. The principal radial axis of each constriction being at an angle 90° to that of its neighbor, to leave a free volume of 98.8ml, and maintained at 25+ 2°C (first 2 m part of pinch tube). The2m part of pinch tube was kept at 35+2°C and remaining 3m at 55+2°C. The flow rates were 17.33g/min and 29.04 g/min, respectively, and the retention time was 2.16min. The product outlet from pinch tube was collected. After reaching the stationary state, the collected solution contained 9.84% by weight of gabapentin(equivalent to 11.11% gabapentin salt), corresponding to a yield of 91.46%. The reaction mass was collected in three parts and confirmed reproducibility by HPLC analysis. Abbreviations

Advantages of the present invention

1. The process of instant invention provides gabapentin salt in a high yield with high chemical purity.

2. The instant robust invention leads to low effluent generation, hence makes the process more environmental friendly, safer and thereby commercially viable.

3. The process of instant invention reduces the manufacturing cost. The process of instant invention has effectively less steps that result in shortening of reaction time and lowering of labour.

The process of present invention avoids the excess usage of reagent(s) and organic solvent(s) and thereby promotes green chemistry and ensure a cleaner surrounding by putting less load on environment.