CHEMICAL REACTIONS IN MICRO MIXING REACTOR

INTRODUCTION

Aspects of the present patent application relate to a process for preparing active pharmaceutical
ingredients, its intermediates, salts and esters thereof by employing the continuous flow micro mixing reactor technology.

Some of the continuous flow micro mixing reactor technologies, such as micro mixing reactor, micro reactor, plug flow reactor, spinning disk reactor, loop reactor, static mixer, continuous stir tank reactor (CSTR) etc, as an individual, as well in combination could be used. These technologies, compared to those commonly used today, are expected to bring dramatic improvements in manufacturing and processing, substantially decreasing the equipment size, production capacity ratio, energy consumption and ultimately resulting in less expensive, sustainable technologies.

US patent No. 5,314,506 discloses direct crystallization of high surface area particles of active pharmaceutical ingredients of high purity and stability by using impinging fluid jet streams in a continuous crystallization process to achieve high intensity micro mixing of fluids so as to form a homogeneous composition prior to the start of nucleation.

There is a continuing need in pharmaceutical industry to provide processes for the preparation of active pharmaceutical ingredients and its intermediates with simple, reduced capital investment, reliable scale-up, reduced time cycle, minimal impurities, increased rate of reaction and increased inherent safety techniques. The technology involved in the present invention involves the use of micro mixing reactor, which gives all the advantages discussed here above.

SUMMARY

In an aspect, the present application provides processes for the preparation of a compound, embodiments comprising:
a) providing respective solutions of one or more reactants and/or reagents in respective suitable solvents;
b) carrying out the reaction in micro mixing reactor using the solutions obtained in step (a);
c) optionally quenching the reaction mass; and
d) isolating the product.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is schematic diagram of a micro mixing reactor containing two inlets and one micro mixing.
Figure 2 is schematic diagram of a micro mixing reactor containing three inlets and two micro mixings.
Figure 3 is schematic diagram of a micro mixing reactor containing two inlets and 4 micro mixings.
Figure 4 is schematic diagram of a micro mixing reactor containing two inlets with loop, CSTR and continuous extractor.

DETAILED DESCRIPTION

In an aspect, the present application provides processes for the preparation of a compound, embodiments comprising:
a) providing respective solutions of one or more reactants or reagents in respective suitable solvents;
b) carrying out the reaction in micro mixing reactor using the solutions obtained in step (a);
c) optionally quenching the reaction mass; and
d) isolating the product.

The terms reactant and reagent as used herein may be used interchangeably for a chemical compound. Reactant or reagent as used herein refers to a reagent or reagent that is defined by International Union of Pure and Applied Chemistry (IUPAC) (1996). As per the definition it is a "substance or compound that is added to a system in order to bring about a chemical reaction or is added to see if a reaction occurs".

Different types of reactions that may be carried out in the process of the present invention using micro mixing reactor include, but not limited to acylation, alkylation, condensation, oxidation, nitration, reduction, coupling reaction, Grignard reaction, various types of substitution, various types of addition reactions, various types of elimination reactions, hydrolysis, isomerization, racemization, resolution, and so on.

Depending on the nature of the reactants and reagents, suitable solvents may be used in the process of the present invention, which include, but are not limited to: water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionoate, ethyl propionoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1 2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, nitromethane or the like; or any mixtures thereof.

A schematic drawing of the micro mixing reactor setup is as shown in Figures 1, 2, 3 and 4. The micro mixing reactor made up of SS-316 / Hastelloy® consists of two inlets and one outlet. Hastelloy® is a registered trademark name of Haynes International, Inc. This type of micro mixer reactor is based on the principle of high shear axial collision. For that purpose each micro mixing reactor contains two inlets at 180° angle with diameter varying from 0.05-5 mm and an outlet at 90° to both the inlets with diameter varying from 0.05-5 mm and having mixing volume of 0.02-100 mL. The micro mixing reactor was connected through stainless-steel tubing to pumps P1, P2 for feeding the reactants or reagents with the flow rate varying from about 1 mL/minute to about 200 L/minute and with the pressure varying from about 0.5 bar to about 200 bar. Product can be collected from the outlet of reactor. To vary the residence time and pressure, flow rates were changed. The micro mixing reactor was placed in a double jacketed stainless-steel water bath equipped with Julabo heating and cooling circulator with external temperature sensor. To increase the residence time or to offer multiple collisions series of micro mixers were connected with one another resulting in maximum conversion. Further workup steps were also carried out in micro mixing reactors connected in series (as shown in the figure 3). An external coil was also connected to the outlet of micro mixer for the reactions which are moderately slow.

Productivity of the micro mixture reactor may be increased by changing the dimensions of micro mixing reactor so as to get higher production rates or connecting a number of low volume micro mixing reactors in parallel.

Suitable pumps may be used for the pumping of the reagents or reactants or quenching agents in to micro mixing reactor, which include but not limited to high pressure piston pump, slurry pump, rotary vane pump, peristaltic pump, centrifugal pump or the like.

Suitable temperatures for the reaction of step (b) depend on the type reaction and the type of reactants and reagents being used for the said reaction. For example the said temperatures may be less than about 200°C, less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about -10°C, less than about -20°C, or any other suitable temperatures.

Suitable quenching reagents that may be used in step (c) include, but not limited to, salts, organic acids, inorganic acids, resins, or the like. Suitably aqueous solutions containing from about 5% to about 50%, or from about 10% to about 20% (weight/volume) of the quenching reagents may be used.

Step (d) involves isolating product.

The isolation may be effected by conventional methods known in the art including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, adding seed crystals, or the like. Suitable temperatures for isolation may be less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 5°C, less than about 0°C, less than about -10X, less than about -20°C, or any other suitable temperatures. Suitable times for isolation may be less than about 6 hours, less than about 4 hours, less than about 2 hours, less than about 1 hour, or longer times may be used. The exact temperatures and times required for complete isolation may be readily determined by a person skilled in the art and will also depend on parameters, such as for example, concentrations or temperatures of the solution or slurry. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Suitable techniques that may be used for removal of solvent include, but are not limited to rotational distillation using a device, such as, for example, a Buchi® Rotavapor®, spray drying, agitated thin-film drying, freeze drying (lyophilization), or the like, optionally under reduced pressure.

Certain specific aspects and embodiments of this application are described in the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the disclosure in any manner.

Examples

Example-1: Preparation of 6-methoxy 2-acetyl naphthalene
Solution A: 100 g of 2-methoxy naphthalene and nitro benzene (236 mL) charged into round bottom flask and stirred for 10 minutes. The obtained clear solution is heated to 50°C. Solution B: Aluminum chloride (102.8 g) is added to nitrobenzene (300 mL) in portions at 0°C. Acetyl chloride (60.Og) is added to the reaction mixture at 0°C. Temperature of the resultant reaction mixture is gradually raised to room temperature. Connected the pump-1 inlet to solution A and pump-2 inlet to solution B and both the pumps outlets are connected to micro mixing reactor. The outlet of micro mixing reactor was connected to round bottom flask. Solution A and solution B are simultaneously fed into micro mixing reactor with the flow rate of 85 mL/minute and 100 mL/minute respectively. The reaction mixture obtained from out let of micro mixing reactor is transferred in to round bottom flask and heated to 55°C. Reaction mass is stirred at 55°C for 10 minutes and then cooled to 0.5°C. Hydrochloric acid (29 mL) is added and stirred for 30 minutes. The layers are separated and organic layer is distilled at 80°C under 1.5 mbar vacuum for 30 minutes. Methanol (600 mL) is added to the residue and the methanol is evaporated completely. Methanol (260 mL) is added to the residue and heated to 60°C. The reaction mass is cooled to 28°C and stirred for 30 minutes, further cooled to 0°C and stirred for 2 hours. Separated solid is collected by filtration and washed with methanol (10 mL). The solid is dried at 45°C for 12 hours to afford 85.0 g of title compound.

Example-2: Preparation of Pantoprazole

Solution A: 100 g of pantoprazole sulfide is dissolved in acetonitrile (5 L). Solution B: Charged sodium hydroxide (10.8 g) and water (43.2 mL) in to round bottom flask and cooled to 25°C. The resultant solution is charged in to sodium hypochlorite solution (150 mL) and stirred for 10 minutes. Connected the pump-1 inlet to solution A and pump-2 inlet to solution B and both the pumps outlets are connected to Micro mixing reactor. The outlet of micro mixing reactor was connected to round bottom flask. Flow rate of pump-1 was set as 150 mL/minute and rate of pump-2 was set as 52 mL/minute. Solution A and solution B is simultaneously fed into micro mixing reactor at room temperature and the reaction mass is collected from the outlet of the micro mixing reactor in water (2 L). The resultant reaction mass is stirred at 28°C for 35 minutes and collected by filtration. Filtrate is charged in to round bottom flask, cooled to 3°C and stirred at 3°C for 15 minutes. Reaction mass pH is adjusted to 6.2 with 1N hydrochloric acid (200 mL) and stirred at 4°C for 1 hour 30 minutes. The separated solid is collected by filtration and washed with water (200 mL). The solid is dried at 40°C under reduced pressure for 22 hours. The obtained solid and ethyl acetate (100 mL) is charged in to round bottom flask. The reaction mixture is stirred at 28°C for 1 hour 30 minutes, further cooled to 4°C and stirred for 1 hour 30 minutes. The separated solid is collected by filtration and washed with ethyl acetate (100 mL). The solid is dried at 40° under reduced pressure for 6 hours to afford 75 g of title compound. Chemical purity by HPLC: 99.47%, Sulfone impurity: 0.07%

Example-3: Preparation of Rabeprazole

Solution A: Sodium hydroxide (30 g) and water (120 mL) solution is added to the 100 g of rabeprazole sulfide and acetonitrile (300 mL) at 10-15°C. Solution B: Sodium hypochlorite solution (180 mL). Connected the pump-1 inlet to solution A and pump-2 inlet to solution B and both the pumps outlets are connected to micro mixing reactor. The outlet of micro mixing reactor was connected to round bottom flask. Flow rate of pump-1 was set as 109 mL/minute and rate of pump-2 was set as 41 mL/minute. Solution A and solution B is simultaneously fed into micro mixing reactor at room temperature. Reaction mixture obtained from the outlet of the micro mixing reactor is collected in to sodium thiosulphate solution obtained by dissolving 40 g of sodium thiosulphate in water (200 mL) and stirred at 28°C for 30 minutes. To the resultant reaction mass carbon (20 g) and water (450 mL) is charged and stirred for 40 minutes. Filtered the reaction mass through Hyflow bed and washed with water (300 ml_). Filtrate is charged in to round bottom flask, cooled to 4°C and stirred at 3°C for 15 minutes. Reaction mass pH is adjusted to 8.4 with acetic acid (30 mL) and stirred at 3°C for 15 minutes. Rabeprazole (500 mg) seed is added to the reaction mass and further continued the stirring at 4°C for 2 hours. The separated solid is collected by filtration and washed with water (300 mL). Wet compound and water (510 mL) is charged in to round bottom flask and stirred for 1 hour. Separated solid is collected by filtration and washed with water (200 mL). The solid is dried at 41°C under reduced pressure for 12 hours to afford 89 g of title compound. Chemical purity by HPLC: 99.48%, Sulfone impurity: Not detected

Example-4: Preparation of Omeprazole

Solution A: Omeprazole sulfide (1.0 kg) is dissolved in chloroform (4 L) and cooled to-10°C.

Solution B: Per acetic acid (1.4 kg), chloroform (1.0 L) and methanol (1.2 L) charged into flask and cooled to -10°C.

Solution C: Sodium hydroxide (830 g) is dissolved in water (830 mL) and cooled to-10°C.
Connected pump-1 inlet to solution A, pump-2 inlet to solution B, pump-3 inlet to solution C and pump-4 inlet to acetic acid (200 mL). Flow rate of pump-1 was set as 525 mL/minute, pump-2 was set as 357.7 mL/minute, pump-3 was set as 905.0 mL/minute and pump-4 was set as 2.0 mL/minute. Solution A and solution B is simultaneously fed into micro mixing reactor connected to loop followed by 3 CSTR at room temperature. After overflow of the reaction mixture from the CSTR 1 into CSTR 2, started fed of the solution C, into reactor 2. After overflow of the reaction mixture from reactor 2 into CSTR 3, started fed of the acetic acid into reactor 3. After overflow from the reactor 3, reaction mixture pH was measured and transferred into decanter. Layers were separated, organic layer is extracted using two lots of sodium hydroxide solution (first lot: obtained by dissolving 77 g of sodium hydroxide in 2150 mL; second lot: obtained by dissolving 58 g of sodium hydroxide in 1660 mL of water) and combined aqueous layers were washed with chloroform (850 mL). The resultant aqueous layer was distilled, pre cooled acetone (1660 mL) is added to the reaction mixture at 8°C and stirred for 45 minutes. Reaction mass pH is adjusted to 8.42 using acetic acid (180 mL) at 6°C and stirred for 2 hours. Separated solid is filtered, washed with mixture of water (500 ml_) & acetone (500 mL) and finally with acetone (2.6 L). Sodium hydroxide (110 g) and water (1660 mL) charged into round bottom and stirred for 5 minutes. The above wet compound is charged into sodium hydroxide solution and cooled to 12°C. Chilled methanol (1660 mL) is added into reaction mixture and stirred for 40 minutes. Reaction mass pH is adjusted to 8.25 using acetic acid (180 mL) at 10°C and stirred for 1 hour. Separated solid is filtered, washed with mixture of water (500 mL) & methanol (500 mL) and finally with methanol (500 mL). The solid is dried at 43° under reduced pressure for 21 hours to afford 775 g of title compound.

Chemical purity by HPLC: 99.86%, Sulfone impurity: 0.07%

CLAIMS:

1. A processes for the preparation of active pharmaceutical ingredients, its intermediates, salts and esters, which includes one or more of the following steps, individually or in the sequence recited:

a) providing respective solutions of one or more reactants or reagents in respective suitable solvents;

b) carrying out the reaction in micro mixing reactor using the solutions obtained in step (a);

c) optionally quenching the reaction mass; and

d) isolating the product.

2. The process of claim 1, wherein the active pharmaceutical ingredients are proton pump inhibitors such as Omeprazole, Rabeprazole, Esomeprazole, Pantoprazole, Lansoprazole.

3. The process of claim 1, wherein the suitable reactions are acylation, alkylation, condensation, oxidation, nitration, reduction, coupling reaction, Grignard reaction, various types of substitution, various types of addition reactions, various types of elimination reactions, hydrolysis, isomerization, racemization and resolution.

4. The process of claims 1-4, wherein the suitable reactions are oxidation reactions or acylation reactions.