WO2023012822A1 - Continuous process for preparation of pregabalin - Google Patents
Continuous process for preparation of pregabalin Download PDFInfo
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- WO2023012822A1 WO2023012822A1 PCT/IN2022/050691 IN2022050691W WO2023012822A1 WO 2023012822 A1 WO2023012822 A1 WO 2023012822A1 IN 2022050691 W IN2022050691 W IN 2022050691W WO 2023012822 A1 WO2023012822 A1 WO 2023012822A1
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- pregabalin
- sodium
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- carbamoylmethyl
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 43
- 229960001233 pregabalin Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000010924 continuous production Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims description 51
- 230000008569 process Effects 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 239000011541 reaction mixture Substances 0.000 claims description 20
- NPDKTSLVWGFPQG-SSDOTTSWSA-N (3r)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-SSDOTTSWSA-N 0.000 claims description 19
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 18
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 15
- 230000003534 oscillatory effect Effects 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- 238000007872 degassing Methods 0.000 claims description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 5
- 230000032683 aging Effects 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 5
- 230000033001 locomotion Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000010926 purge Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 12
- 238000002156 mixing Methods 0.000 description 10
- 230000010355 oscillation Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000011143 downstream manufacturing Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108090000489 Carboxy-Lyases Proteins 0.000 description 1
- 108091022930 Glutamate decarboxylase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000573 anti-seizure effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
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- 238000010586 diagram Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000005111 flow chemistry technique Methods 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000003621 hammer milling Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
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- 238000011084 recovery Methods 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B55/00—Racemisation; Complete or partial inversion
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a continuous process for the preparation of Pregabalin of formula (I), reaction is carried out in an Oscillating Baffled Reactor. NH2COOHCH3CH3Formula (I)
Description
CONTINUOUS PROCESS FOR PREPARATION OF PREGAB ALIN
FIELD OF THE INVENTION
The present invention relates to a continuous process for the preparation of pregabalin of formula (I), wherein the reaction is carried out in an Oscillating Baffled Reactor.
Formula (I)
BACKGROUND OF THE INVENTION
Pregabalin is chemically described as (S)-3-(aminomethyl)-5-methylhexanoic acid having structure of formula (I). Pregabalin (LYRICA™) is known to treat several central nervous system disorders that include epilepsy, neuropathic pain, anxiety and social phobia.
Pregabalin (S-isomer) has been found to activate GAD (L-glutamic acid decarboxylase) in a dose dependent manner and promote production of GABA (gamma-amino butyric acid), one of the major inhibitory neurotransmitters of brain. The discovery of anti-seizure activity was first disclosed in US Patent No. 5,563,175. Pregabalin (S-isomer) and its preparation are disclosed in product patent US Patent No. 6,197,819.
Several patents and published patent applications for example U.S. Pat. No.
5,616,793, WO 2006/122258, WO 2006/122255 and WO 2006/121557 disclose a
more convenient preparation of pregabalin by means of a Hofmann rearrangement of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid ((R)-CMH).
Another US Patent No. 8,071,808 disclose preparation of pregabalin by means of a Hofmann rearrangement of (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid with sodium hypochlorite at a temperature about 50 to 70°C.
Considering the importance of pregabalin in the pharmaceutical field, there is still the need of an efficient improved process, particularly of an efficient continuous process for the preparation pregabalin in large volumes with reduced time, and improved quality and thus making the process more commercially viable with lower operating overhead costs.
Continuous flow chemistry is becoming prevalent as both academic and industrial researchers seek to improve upon traditional batch processes. In particular, the pharmaceutical industry has made strides to incorporate continuous flow methods to chemical synthesis and processing due to the potential for process intensification. These advantages lead to more efficient processes and the potential for improved process control and automation resulting in high performance in terms of product quality, yield, consistency, productivity, waste production, and overall cost.
Oscillating Baffled Reactor (OBR) is one of such continuous intensified process equipment, which creates intense Gas- Liquid and Liquid-Liquid mixing to overcome mass transfer resistances. Its typical characteristics of up stroke & down stroke hydrodynamics motion, creates bubble cavitation and provides very efficient mixing for fast chemical reactions. It also provides high interfacial area of contact for effective heat transfer and mass transfer for exothermic processes. Oscillatory baffled reactors (OBRs) are tubular devices that provide a platform for continuous process development near to a plug flow conditions even under laminar flow
conditions. Reactor contents are oscillated via reciprocating action of a plunger pump relative to internal perforated stationary baffles, equi-spaced periodically along the length of reactor. Vortex formation creates a novel mixing mechanism that is power-efficient, uniform even under low shear and enhances mass and heat transfer. These mixing attributes have proven successful for the development and intensification of various industrial continuous chemical processes.
SUMMARY OF THE INVENTION
In an aspect, the present invention relates to process for the preparation of pregabalin of formula (I) comprises the use of Oscillating Baffled Reactor to provides continuous process for the preparation of pregabalin of formula (I).
Formula (I)
In another aspect, the present invention relates to process for the preparation of pregabalin comprises reacting (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid ((R)-CMH) solution with sodium hypohalite solution wherein the reaction is carried out in an Oscillating Baffled Reactor.
In still another aspect, the present invention provides process for the preparation of pregabalin of formula (I) using Oscillating Baffled Reactor (OBR) that comprises a vertical reactor column (tube) with one or more inlet and outlet; one or more perforated baffles within the reactor column (tube); and an oscillatory means which during use provides oscillatory flow of a fluid relative to the stationary baffle.
In one another aspect the process is carried out using single column or multiple columns in of Oscillating Baffled Reactor in a continuous manner.
In yet another aspect, the present invention comprises a process for preparing pregabalin comprising contacting or administering a solution (R)-(— )-3- (carbamoylmethyl)-5-methylhexanoic acid as a first flowing stream with solution of sodium hypochlorite as a second flowing stream; subjecting both contacted streams to oscillatory motion in an oscillating baffled reactor or a series of oscillating baffled reactors.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure- 1 is an illustration of continuous process flow diagram for Oscillating Baffled Reactor.
DETAILED DESCRIPTION OF PRESENT INVENTION
Oscillatory Baffled Reactor (OBR) in general comprising a cylindrical reactor vessel having high height to diameter ratio, supply means to supply a simultaneously continuous feed of aqueous medium through the reactor vessel; and oscillation means to oscillate liquid within the reactor vessel with definite stroke length and frequency; said reactor vessel comprising two inlets; an outlet; a plurality of perforated stationary baffles; and at least one port for the introduction of process components and/or initiators. Oscillation can be applied to a flow reactor using various oscillatory devices, such as piston- bellow, plunger, diaphragm, or peristaltic pumps. The symmetrical oscillation generates vortices, leading to improved radial mixing. The geometrical parameters, Baffles orientation, design and physical dimensions, are important for OBR design includes but not limited to baffle diameter, baffle thickness, baffle spacing, size and number of perforations, length/height ratio of reactor, heat transfer area etc. Provision of an external utility jacket and/or internal spiral coil within OBR offers high interfacial area of contact
per unit volume of contents (‘a’-m2/m3), and also enhance baffling effects for turbulence.
Oscillatory Baffled Reactors (OBR) has been used to provide a reactor which promotes mixing without the use of rotating stirrers to create turbulent flow within the reactor. The liquid or multiphase fluid is typically oscillated in the axial direction by means of a reciprocating diaphragms or bellows or pistons or plungers, at one or at both ends of the column, developing an efficient mixing mechanism, where fluid moves from the walls to the center of the column (tube) with its intensity controlled by the oscillation frequency and amplitude. The formation and dissipation of eddies, in these reactors, has proved to result into significant enhancement in chemical reaction and unit operation such as heat transfer and mass transfer compared to conventional stirred tank batch reactor.
In an embodiment, the continuous manufacturing of pregabalin is carried out by feeding of sodium hypochlorite solution & (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid ((R)-CMH) solution to the bottom of OBR column at a controlled flow rate.
In an embodiment, the Oscillatory Baffled Reactor comprising a vertical reactor column (tube) with one or more inlet and outlet; one or more perforated baffles within the reactor column (tube); and an oscillatory means which, during use, provides oscillatory flow of a fluid relative to the stationary baffle.
The reaction is conducted in a single OBR or multiple OBR columns kept in series manner to control the reaction, ageing process and downstream process such as degassing which includes removal of dissolved gases formed during the reaction such as ‘carbon dioxide’. The reaction is conducted in the first OBR at a temperature in the range of 0 to 80°C, preferably 0 to 45°C and the residence time of reactants in the first OBR varies 30-150 minutes, preferably 30-60 minutes and then reaction
mass overflowed to second OBR to allow the reaction ageing to complete at a temperature in the range of 0 to 80°C, preferably 20 to 45°C and the residence time in the second OBR varies 30-150 minutes, preferably 30-60 minutes. An optional third OBR may be employed for further down streaming processes such as degassing etc. Alternatively the entire reaction can be carried out in single OBR by carefully adjusting or varying the reaction temperature, flow rates, residence time or oscillation speed.
The flow rate and reactor dimensions are properly controlled and selected in order to obtain an optimal residence time of the reaction mixture in the reactor with the aim of completing the reaction.
In an embodiment, the oscillatory movement (Sinusoidal Flow Pattern) in the flow reactor is provided using a reciprocating piston. The upward and downward or back and forth strokes motion using piston generates oscillation to the reaction mass for efficient mixing. The oscillation frequency ranges from 30 -150 strokes per minutes, preferably in the range of 60-120 strokes.
In one embodiment, the solution of (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid ((R)-CMH) is prepared by dissolving (R)-CMH in water optionally under alkaline condition preferably in aqueous sodium hydroxide solution in first batch reactor and aqueous solution of sodium hypochlorite in second batch reactor.
The preparation of above two solutions of input materials to form feed stream of materials may be carried out in advance in a separate stirred batch reactors, micro mixers, in upstream mixing zones and like.
In an embodiment, the input materials namely ‘sodium hypochlorite solution’ & ‘(R)-CMH solution’ are then introduced in pre-chilled conditions into Oscillating
Baffled Reactor individually or as mixtures. For example, two streams A and B can be continuously introduced into the OBR reactor and continuously mixed therein so that the reaction takes place instantaneously.
In an embodiment, the first and second flowing stream separately and simultaneously passed into Oscillating Baffled Reactor having a temperature in the range of 0 to 80°C, preferably 0 to 45 °C and flow rate between 5 to 50 ml per minute so as to have a residence time between 30-150 minutes.
The desired temperature of reaction contents can be carefully controlled by using chilled water into OBR Jackets and/or internal spiral coils.
The process further involves maintaining (ageing) and degassing of reaction mixture using same or multiple Oscillating Baffled Reactor columns having a temperature in the range of 0 to 80°C, preferably 20 to 45°C and flow rate between 5 to 50 ml per minute so as to have a residence time between 30-150 minutes.
In further embodiment, the process further involves ageing of reaction mixture followed by degassing operation to remove residual dissolved gases and subsequently neutralizing the reaction mixture with cone. HC1 to precipitate technical grade pregabalin.
The downstream process after degassing the reaction mass involves isolation of pregabalin, which is done by adjusting the reaction mass pH to 6.0 to 8.5 , by using an acid such as HC1, sulphuric acid and the like, preferably by using an automated pH controller. Preferably the said operation is done in a continuous stirred tanker (CSTR) or OBR column, which allows the precipitated aqueous slurry to gets overflow from precipitator (CSTR) or OBR column and enters on the top of continuous pusher or peeler or basket type centrifuge, where product wet cake of pregabalin and filtrate are separated in a continuous mode of operation, further
filtered cake is dried to obtain pregabalin in batch mode. The pregabahn thus obtained is optionally purified.
In another embodiment, the present invention also provides process of preparing pregabalin by insitu preparation of sodium hypochlorite which involves direct purging or injecting of chlorine gas using Venturi device to the solution of (R)(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, sodium hydroxide and water in OBR reactor.
In another aspect, insitu preparation of sodium hypochlorite involves purging or injecting of chlorine gas into sodium hydroxide solution or absorption of chlorine gas into a flowing stream of sodium hydroxide by using Venturi device. The application of Venturi device in above embodiment offers efficient gas -liquid mixing to have the advantage of higher reactant conversion due to freshly prepared / insitu prepared sodium hypochlorite solution.
In an embodiment, the present invention reaction scheme is disclosed as below:
In an embodiment, the present invention process involves using sodium hypohalite solution such as sodium hypochlorite, sodium hypobromite and like which can be prepared externally or else prepare insitu.
In an embodiment of the invention, the compound (R)-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid ((R)-CMH) can be prepared by any method known in prior art.
In another embodiment, the purification process involves treating technical grade (S)-pregabalin with solvent(s) selected from alcohols and water or mixture thereof; more preferably using isopropyl alcohol or water or mixture thereof.
In further embodiment, the present invention process provides (S)-pregabalin having purity of greater than 99%, preferably greater than 99.5% by HPLC and more preferably greater than 99.8% by HPLC.
Advantages of present invention process using OBR (Oscillating Baffled Reactor) is that the chemical reaction completes within lesser residence time i.e. about forty five to fifty minutes, when compared to normal batch reactor process, which requires about three to five hours. The method of the present invention allows one to directly obtain pregabalin with high purity and reduced reaction time. Moreover, the method offers several additional advantages over the known methods such as better reaction control, better temperature control , lower energy overheads of the reaction and easy to up-scale by numbering up for larger throughputs.
In some embodiments of the invention, OBR and associated vessels may be constructed of any material which is not reactive with any of the reactants, solvents, or products.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or
Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
EXAMPLES:
Example 1: Preparation of Pregabalin
In a stirred tank reactor, first solution is prepared by adding (R)-(-)-3- (carbamoyl methyl)-5-methyl hexanoic acid (1000 g) to solution of sodium hydroxide (250 g) in water (1500 ml) and further cooled to 5 ± 5°C. In another separate feed tank, second solution of sodium hypochlorite (3100 ml) is cooled to 5 ± 5°C. Both solutions are fed to Oscillating Baffled Reactor at controlled flow rate between 15 to 25 ml/min with 45-90 min of residence time by keeping 60-120 OBR oscillation strokes. Reaction mixture transferred to second OBR and degassed for 45- 60 min residence time by heating to about 40±5°C.
After completion of reaction, reaction mixture is transferred to continuous stirred tank reactor and cone. HC1 is added to reaction mixture to maintain pH around 7.5. The precipitated product is filtered and batch is dried to obtain technical grade pregabalin. Yield: 61%; HPLC Purity: 91%
Example 2: Preparation of Pregabalin
In a stirred tank reactor, first solution is prepared by adding (R)-(-)-3- (carbamoyl methyl)-5-methyl hexanoic acid (1000 g) to solution of sodium hydroxide (250 g) in water (1500 ml) and further cooled to 10±5°C. In another separate feed tank, second solution of sodium hypochlorite (3200 ml) is cooled to 7 ± 5°C. Both solutions are fed to Oscillating Baffled Reactor at controlled flow rate between 20 to 30 ml/min with 50-90 min of residence time by keeping 60-120 OBR strokes. Reaction mixture transferred to second OBR and degassed for 30-60 min residence time and heated to about 40±5°C.
After completion of reaction, reaction mixture is further transferred to continuous stirred tank reactor and cone. HC1 is added to reaction mixture to maintain pH around 7.5. The precipitated product is filtered and batch is dried to obtain technical grade pregabalin. Yield: 67%; HPLC Purity: 95.9%
Example 3: Preparation of Pregabalin
In a stirred tank reactor, first solution is prepared by adding (R)-(-)-3- (carbamoyl methyl)-5-methyl hexanoic acid (1000 g) to solution of sodium hydroxide (250 g) in water (1500 ml) and further cooled to 5 ± 5°C. In another separate feed tank, second solution of sodium hypochlorite (3300 ml) is cooled to 10±5°C. Both solutions are fed to Oscillating Baffled Reactor at controlled flow rate between 25 to 30 ml/min. with 45-90 min of residence time by keeping 60-120 OBR strokes. Reaction mixture transferred to second OBR and degassed for 30-60 min residence time and heated to about 40±5°C.
After completion of reaction, reaction mixture is further transferred in CSTR and cone. HC1 is added to reaction mixture to maintain pH around 7.5. The precipitated product is filtered and batch is dried to obtain technical grade pregabalin. Yield: 68%; HPLC Purity: 98.1%
Example 4: Preparation of Pregabalin
To the reaction vessel, (R)-(-)-3-(carbamoyl methyl)-5-methyl hexanoic acid (100 g) added to the solution of sodium hydroxide (104.5 g) in water (430 ml) and the reaction mixture is cooled to 3 ± 3°C. Chlorine gas (38 g) is injected into reaction vessel using Venturi device at same temperature along with stirring. The reaction mixture was further stirred for about one hour at 37±3°C.
After completion of reaction, cone. HC1 is added to reaction mixture followed by addition of sodium hydroxide solution to maintain pH around 7.5. The precipitated product is filtered, washed with water and batch is dried to obtain technical grade pregabalin. Yield: 73.2 g; HPLC Purity: 92.77 %
Example 5: Purification of Pregabalin
To the above obtained pregabalin (150 g) isopropanol (750 ml) and water (750 ml) is added and the reaction mixture is heated and charcoal is added to the reaction mixture. The reaction mixture is filtered. The filtrate is cooled and the precipitated product is filtered and batch is dried to obtain pure pregabalin (125 g). Yield: 83% Purity: 99.92%
Claims
We Claim:
1. A process for the preparation of Pregabalin comprises reacting (R)-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid ((R)-CMH) with sodium hypohalite wherein the reaction is carried out in an Oscillating Baffled Reactor.
2. The process as claimed in claim 1, wherein the process is carried out using single column or multiple columns of Oscillating Baffled Reactor (OBR) operated in continuous mode of operation.
3. The process as claimed in claim 1, wherein the Oscillatory Baffled Reactor comprising a vertical reactor column with one or more inlet and outlet; one or more perforated baffles within the reactor column; and an oscillatory means which during use provides oscillatory flow of a fluid relative to the baffle.
4. The process as claimed in claim 3, wherein the oscillatory means comprises a reciprocating piston creating up and down or back and forth motions.
5. The process as claimed in claim 4, wherein the piston is operated between 30 -150 strokes per minutes.
6. The process as claimed in claim 1, wherein the process comprising of administering (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid ((R)- CMH) solution as a first flowing stream and administering sodium hypohalite as a second flowing stream into an Oscillating Baffled Reactor at a temperature in the range of 0 - 80 °C.
. The process as claimed in claim 6, wherein the first and second flowing stream are separately and simultaneously passed into Oscillating Baffled Reactor with a flow rate between 5 to 50 ml per minute and the residence time of first and second flowing stream in OBR is between 30-150 minutes.
8. The process as claimed in claim 6, wherein temperature is in the range of 0 - 45 °C. . The process as claimed in claim 6, wherein first flowing stream comprising solution of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid ((R)-CMH), and second flowing stream comprising aqueous solution of sodium hypohalite.
10. The process as claimed in claim 9, wherein the aqueous solution of sodium hypohalite is selected from sodium hypochlorite and sodium hypobromite.
11. The process as claimed in claim 9, wherein the solution of (R)-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid ((R)-CMH) is prepared by dissolving (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid in water optionally in the presence of base.
12. The process as claimed in claim 6, further comprising steps of ageing, degassing and neutralizing reaction mixture to obtain pregabalin.
13. The process as claimed in claim 12, further comprising of purification of pregabalin using alcohol, water or mixture thereof.
14. The process as claimed in claim 13, wherein pregabalin obtained is having purity greater than 99% by HPLC.
15. The process as claimed in claim 11, wherein the base is selected from sodium hydroxide.
16. A process for the preparation of Pregabalin comprises reacting (R)-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid ((R)-CMH) with sodium hypohalite wherein sodium hypohalite is prepared insitu using venturi device.
17. The process as claimed in claim 17, wherein sodium hypohalite is selected from sodium hypochlorite
18. The process as claimed in claim 17, wherein insitu preparation of sodium hypochlorite using venture device comprises direct purging or injecting of chlorine gas in to the sodium hydroxide solution or to the solution of (R)(-)-3- (carbamoylmethyl)-5-methylhexanoic acid, sodium hydroxide and water.
19. The process as claimed in claim 17, wherein the reaction is carried out in an OBR reactor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202121034925 | 2021-08-03 | ||
| IN202121034925 | 2021-08-03 |
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| WO2023012822A1 true WO2023012822A1 (en) | 2023-02-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IN2022/050691 WO2023012822A1 (en) | 2021-08-03 | 2022-08-01 | Continuous process for preparation of pregabalin |
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| WO (1) | WO2023012822A1 (en) |
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2022
- 2022-08-01 WO PCT/IN2022/050691 patent/WO2023012822A1/en unknown
Non-Patent Citations (2)
| Title |
|---|
| BIZOTIC LIFESCIENCE PVT. LTD, REPORT: 2 TON PER MONTH PREGABALIN MANUFACTURE, 23 November 2015 (2015-11-23), pages 5 * |
| KOIZUMI HIROAKI, TAKAHASHI TETSUO: "The Continuous Flow Reaction of the Hofmann Rearrangement", THE JOURNAL OF THE SOCIETY OF CHEMICAL INDUSTRY , JAPAN, NIPPON KAGAKUKAI, TOKYO, JP, vol. 68, no. 1, 5 January 1965 (1965-01-05), JP , pages 102 - 105, XP009543300, ISSN: 0023-2734, DOI: 10.1246/nikkashi1898.68.102 * |
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