OF /-2-nitro-l-butanol

CROSS-REFERENCES TO RELATED APPLICATION [0001] This application takes priority to Indian provisional patent application No. 201941031316 entitled DEVELOPMENT OF CONTINUOUS FLOW PROCESS FOR THE MANUFACTURE OF £//-2-amino- 1 -butanol fded on 2 August, 2019.

FIELD OF THE INVENTION

[0002] The disclosure generally relates to process for manufacturing a chemical substance and, in particular, apparatus and method for manufacturing a drug intermediate.

DESCRIPTION OF THE RELATED ART

[0003] Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis primarily affecting lungs is one of the top 10 causes of death worldwide. FDA approved first line anti TB drugs include rifampicin, ethambutol, isoniazid and pyrazinamide. Though TB is treatable and mendable, investments by low- and middle- income countries are on the rise when it comes to TB care and treatment. India has been identified as one of the high burden countries and Indian government has announced an aim to eradicate the disease by 2025. Though India is one of the largest producers of ethambutol, ri/-2 -amino- 1 -butanol which is the key intermediate for synthesis of ethambutol is mostly imported as there is no significant local production. Hence there is a pressing need to develop process technology for indigenous manufacturing of dl-2- amino-1 -butanol.

[0004] Pelkey el al., Can J Chem, 2006, 84(1 0), 1338-1342 discloses a procedure for preparation of z//-2-nitro- 1 -butanol from 1-nitropropane and methanol in the presence of aqueous solution of sodium hydroxide. US 4,067,905 indicates a procedure for preparation of z//-2-nitro- 1 -butanol from 1-nitropropane and formaldehyde in aqueous medium in the presence of phase transfer agent which is followed by subsequent reduction to <i/-2-amino-l -butanol using a hydrogenation mixture at 8-12 bar pressure. Aguiar et al. (2019) discusses continuous flow process for producing .S'-2-amino-butan- 1 - ol with L-methionine as starting material.

[0005] The current processes for the synthesis of c//-2-amino- 1 -butanol are all batch processes and suffer from bottlenecks/challenges which include safe handling of raw materials, need for excessive use of reagents and its recovery, lack of reaction control, low yield and atom economy. No continuous process that is economical to use is currently available.

SUMMARY OF THE INVENTION

[0006] Systems, devices and methods for continuous flow manufacture of dl- 2-nitro- 1 -butanol are disclosed. The process comprises the steps of providing (201) an aqueous solution of sodium hydroxide (A) and a solution of 1 -nitropropane (B) dissolved in an alcohol, and pumping a predetermined first molar ratio of solution A and solution B to mix in a first tubular reactor for a first residence time to form a solution mixture as intermediate product stream. In the next step, an aqueous solution of formaldehyde is pumped to react with the intermediate product stream at a second predetermined molar ratio in a second tubular reactor for a second residence time to form a product stream. In a third step, the product stream is quenched in glacial acetic acid to obtain a quench liquor having ri/-2-nitro- 1 -butanol. The first and the second tubular reactors are maintained at a temperature of 35° C or less.

[0007] In various embodiments, the alcohol is methanol or ethanol. In some embodiments the process may further comprise extracting the ri/-2-nitro-l -butanol from the quench liquor using a solvent. In some embodiments the solvent is dichloromethane. In some embodiments the process cycle is completed in 30 minutes or less.

[0008] In some embodiments the second residence time is 3-8 times the first residence time. In some embodiments the predetermined first and second molar ratios are 1. In some embodiments the conversion to ri/-2-nitro-l -butanol is 89% or more.

[0009] A process for production of ri/-2-amino-l -butanol is disclosed, comprising hydrogenating the ri/-2-nitro- 1 -butanol to form ri/-2-amino- 1 -butanol using one of: reduction by hydrazine hydrate using Raney nickel catalyst, reduction by zinc and sulphuric acid, or reduction by hydrogen in the presence of 10%Pd on charcoal.

[0010] A continuous flow reactor (100) for production of z//-2-nitro- 1 -butanol using 1 -nitropropane as starting material is disclosed. The reactor comprises a first reservoir (101) configured to store a solution of 1 -nitropropane and connected to a first pump (111), a second reservoir (102) configured to store a solution of NaOH and connected to a second pump (112), wherein the first pump and the second pump are connected via tubing to join a first stream entering a first tubular reactor (130), the first tubular reactor having a first length and configured to output a mixture of solutions from reservoir (101) and (102) as intermediate product stream. A third reservoir (103) is configured to store a solution of formaldehyde and connected to a third pump (113), and the third pump is configured to pump the formaldehyde solution to join the intermediate product stream entering a second tubular reactor (150). The second tubular reactor has a second length that is 3-8 times the first length and configured to output an end product having dl-2- nitro-1 -butanol. The equipment is further provided with a quench reservoir (160) having glacial acetic acid configured to retain the <2/-2-nitro-l -butanol from being converted to other products. The first and the second tubular reactors are configured to be maintained at a temperature or 35° C or less.

[0011] This and other aspects are described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The invention has other advantages and features, which will be more readily apparent from the following detailed description of the invention and the appended claims, when taken in conjunction with the accompanying drawings, in which:

[0014] FIG. 1 illustrates a continuous process for preparation of <2/-2-nitro-l -butanol from 1-nitropropane.

[0015] FIG. 2 illustrates a continuous flow reactor for producing <2/-2-nitro-l -butanol from 1-nitropropane.

DETAILED DESCRIPTION

[0016] While the invention has been disclosed with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention. In addition, many modifications may be made to adapt to a particular situation or material to the teachings of the invention without departing from its scope.

[0017] Throughout the specification and claims, the following terms take the meanings explicitly associated herein unless the context clearly dictates otherwise. The meaning of “a”, “an”, and “the” include plural references. The meaning of “in” includes “in” and “on.” Referring to the drawings, like numbers indicate like parts throughout the views. Additionally, a reference to the singular includes a reference to the plural unless otherwise stated or inconsistent with the disclosure herein.

[0018] The present subject matter describes methods, systems, and apparatuses to produce ri/-2-nitro-l -butanol from 1-nitropropane using a continuous flow reactor. In various embodiments, the invention discloses a continuous process (200) for manufacture of ri/-2-nitro-l -butanol using Henry reaction. The method includes the steps of providing (201) an aqueous solution of sodium hydroxide (A) and a solution of 1- nitropropane (B) dissolved in an alcohol. The solutions A and B may then be pumped, and fed to a first tubular reactor in step 203. In some embodiments, the pumping (203) may be done at a predetermined first molar ratio of solution A and solution B for a first residence time. The solutions from reservoir (101) and (102) are configured to form a premix solution as intermediate product .

[0019] An aqueous solution of formaldehyde (C) is then pumped (205) to react with the intermediate product stream in a second tubular reactor for a second residence time to form a product stream. The aqueous solution of formaldehyde may be pumped at a predetermined ratio with reference to the ri/-2-nitro- 1 -butanol intermediate product. In the next step, the product stream emerging out of the second tubular reactor may be quenched (207) in glacial acetic acid to neutralize the reaction products. At the end of step 207 the quench liquor is configured to have <2/-2-nitro- 1 -butanol as primary reaction product. In various embodiments, the first and the second tubular reactors are maintained at a temperature of 35° C or less.

[0020] In some embodiments, the method may further include the step of extracting (209) the z//-2-n itro- 1 -butanol from the quench liquor using a solvent such as dichloromethane. In various embodiments, the alcohol may be methanol or ethanol. In various embodiments, the process 200 may have a residence time of 30 minutes or less to output the product.

[0021] In various embodiments, in step 205 the second residence time in the second tubular reactor may be 3-8 times the first residence time spent in the first tubular reactor (203). In various embodiments the predetermined first or the second molar ratio is 1. In some embodiments the first or the second predetermined molar ratio varies in the range 0.75-1.5.

[0022] In various embodiments the conversion of <2/-2-nitro-l -butanol is 89% or more for a reaction cycle of 30 minutes or less. In some embodiments the conversion of <2/-2-nitro-l -butanol is 78% or more for a residence time of 20 minutes or less.

[0023] In various embodiments the invention discloses a continuous flow reactor (100) for production of z//-2-nitro- 1 -butanol using 1-nitropropane as starting material. The reactor comprises a first reservoir (101) configured to store a solution of 1- nitropropane (A) and connected to a first pump (111) and a second reservoir (102) configured to store an aqueous solution of NaOH (B) and connected to a second pump (112). The first pump and the second pump are connected via tubing at a T joint 120 to join and mix with a first stream entering a first tubular reactor (130). The first tubular reactor 130 is configured to have a first length and configured to output a mixture of solutions from reservoir (101) and (102) as an intermediate product stream. A third reservoir (103) configured to store a solution of formaldehyde (C) is connected to a third pump (113), to pump the formaldehyde solution C and join and mix with the intermediate product stream at a second T joint 121. The T joint is connected to tubing to lead to a second tubular reactor (150). In various embodiments the second tubular reactor is configured to have a second length that is 3-8 times the first length. The second tubular reactor is configured to form an end product having <2/-2-nitro- 1 -butanol. In various embodiments, the reactor 150 is configured to enable complete reaction of the dl-2-nitro- 1 -butanol. In various embodiments the apparatus 100 includes a quench reservoir (160) having glacial acetic acid that receives the product stream from the reactor 150. The quench reservoir is configured to retain the <2/-2-nitro- 1 -butanol from being converted to other products. In various embodiments the first and the second tubular reactors are configured to be maintained at a temperature or 35° C or less. In some embodiments the first and second tubular reactors may be provided with sensors and heat extraction devices to ensure control of temperature.

[0024] In various embodiments, the invention discloses a process for production of r//-2-amino-l -butanol by hydrogenation of the dl-2-nitro-l -butanol from the continuous flow process. The reaction scheme to produce <2/-2-amino-l -butanol from 1-nitropropane is illustrated in (I) below. In one embodiment, the hydrogenation step is performed using sulphuric acid and zinc dust to form the <2/-2-amino-l -butanol. In one embodiment, the hydrogenation is performed using hydrazine hydrate in the presence of Raney nickel catalyst. In one embodiment, the conversion to <2/-2 -amino- 1 -butanol is performed by hydrogen under pressure in the presence of 10%Pd catalyst over charcoal.

1-nitropropane methanal rf/-2-nitro- 1-butanol Pd/C <Z/-2-amino-l -butanol

8-10 bar

. (I)

[0025] In some embodiments the dimensions of the tubing may be so as to provide a large surface or contact area for the reactants in the first tubular reactor or the second tubular reactor to react more thoroughly. The tubular reactors 130 and 150 may also be configured in a shape suitable to enable compactness and to have suitable heat transfer characteristics for maintaining the temperature and to prevent extraneous reaction products from forming.

[0026] In various embodiments, the method and apparatus disclosed are configured to control the causes increase in temperature (max. 45 °C) caused by addition of NaOH to 1-nitropropane. With increase in temperature and higher molar equivalents of reagents, side product 2-ethyl-2-nitro- 1,3 -propanediol is formed (max. 10 -15 %). However, the method and apparatus disclosed are configured to control the temperature of the reaction mixture to be 35 °C or less so that the formation of extraneous reaction products is minimized. Further, quenching of the reaction mixture in situ at the exit of the reactor is configured to minimize the formation of side product 2-ethyl-2-nitro-l,3- propanediol.

[0027] The methods and apparatus disclosed herein offer a highly economical way to produce <2/-2 -amino- 1 -butanol, an important intermediate in the production of ethambutol to treat tuberculosis. The current invention facilitates reduction of reaction time using continuous flow process technology, grants better temperature control through high mass and heat transfers. The invention has the advantages of optimal use of reactants and reagents in flow reactor, thereby ensuring cost effective process. Over exposure of starting materials to reagents is circumvented, thereby reducing the formation of undesired reaction products. The continuous flow process is amenable to online monitoring and control of reaction progress using spectroscopic techniques. Process design and reaction engineering are also modifiable to any scale of production. The continuous flow process technology capacitates optimization of operation conditions and study of intrinsic reaction kinetics.

[0028] Although the detailed description contains many specifics, these should not be construed as limiting the scope of the invention but merely as illustrating different examples and aspects of the invention. It should be appreciated that the scope of the invention includes other embodiments not discussed herein. Various other modifications, changes and variations which will be apparent to those skilled in the art may be made in the arrangement, operation and details of the system and method of the present invention disclosed herein without departing from the spirit and scope of the invention as described here.

EXAMPLES

[0029] EXAMPLE 1: Preparation of i//-2-nitro-l-butanol from 1-nitropropane and formaldehyde in the presence of methanol solvent

[0030] To a solution of 1-nitropropane (19 .96 g, 0.224 moles) in methanol (100 ml), was added 8.979 g (224.48 mmol) of sodium hydroxide in 20 ml of water and stirred at room temperature (30 °C) for about 15-30 minutes. After the salt formation was complete, 20 ml (0 .724 moles) of 37% formalin solution was added dropwise and the reaction mixture was stirred at RT for about 3 hours. The reaction mixture was cooled to 15-20 °C and neutralized with glacial acetic acid and extracted with dichloromethane. The solvent was dried over anhydrous sodium sulphate and evaporated under vacuum. <2/-2-nitro-l -butanol was obtained as a colourless liquid. The GC purity of the crude sample was found to be 95%. % yield= 72.92%.

[0031] EXAMPLE 2 Preparation of i//-2-nitro-l-butanol from 1-nitropropane and formaldehyde in the presence of aqueous sodium hydroxide

[0032] To 1-nitropropane (49.9 g, 0.56 moles), was added 22.5 g (0.56 mol) of sodium hydroxide in 250 ml of water and stirred at room temperature (30 °C) for about 15-30 minutes. 50 ml (0.62 moles) of 37% formalin solution was added dropwise and the reaction mixture was stirred at RT for about 2 hours. The reaction mixture was cooled to 15-20 °C and neutralized with glacial acetic acid and extracted with dichloromethane. The solvent was dried over anhydrous sodium sulphate and evaporated under vacuum. dl- 2-nitro-l- butanol was obtained as a colourless liquid. The GC purity of the crude sample was found to be 99%. Yield= 91.5%.

[0033] EXAMPLE 3 Preparation of i//-2-nitro-l-butanol from 1-nitropropane and formaldehyde in the presence of triethylamine

[0034] To 1-nitropropane (4.46 g, 0.05 moles) in methanol (10 ml), was added 5.3 g (0.05 mol) of triethylamine and stirred at room temperature (30 °C) for about 15-30 minutes. 3.78 ml (0.05 mol) of 37% formalin solution was added dropwise and the reaction mixture was stirred at RT for about 2 hours. The reaction mixture was cooled to 15-20 °C and neutralized with glacial acetic acid and extracted with dichloromethane. The solvent was dried over anhydrous sodium sulphate and evaporated under vacuum. dl-2-nitro-l -butanol was obtained as a colourless liquid. The GC purity of the crude sample was found to be 84.6%. Yield= 75%.

[0035] EXAMPLE 4 Reduction of i//-2-nitro-l-butanol using zinc and sulphuric acid

[0036] Sulphuric acid (52.13g of 30% acid) was added with constant stirring to a mixture of dl-2-nitro-l -butanol (5g, 0.04 mol), zinc dust (12.5 g, 0.19 mol) and 30 ml of absolute alcohol. The acid was added dropwise with constant stirring in such a manner that temperature remained below 40 °C. The progress of the reaction was monitored by GC. Zinc sulphate was removed by fdtration and washed with absolute alcohol. The filtrate and combined washings were basified with 50% NaOH solution. The weight of the crude product was 2.5 g and was found to be 80% pure according to GC. The crude product was distilled under reduced pressure to obtain ri/-2-amino- 1 -butanol.

[0037] EXAMPLE 5 Reduction of r//-2-nitro-l -butanol using Raney nickel and hydrazine hydrate

[0038] To a solution of ri/-2-nitro- 1 -butanol (5g, 0.04 mol) in 2-propanol (25 ml) stirred at room temperature was added Raney nickel (0 .5 g, 0.008 mol) and stirred at RT for 15 minutes followed by dropwise addition of 100% hydrazine hydrate (10.2 g, 0.2 mol). The reaction mixture was heated at 50 °C for about an hour. The reaction progress was monitored by GC. Raney nickel was removed by fdtration and the filtrate was concentrated under vacuum. Yield= 80%.

[0039] EXAMPLE 6 Reduction of i//-2-nitro- 1-butanol using 10% Pd/C and hydrogen

[0040] ri/-2-nitro-l -butanol (10 g, 0.08 mol) dissolved in methanol (100 ml) was reduced with hydrogen in the presence of 0.447 g of 10% palladium supported upon charcoal. The reduction is carried out at a temperature between 50-55 °C and the pressure was in between 8-10 bars for about 3 hours. The reaction mixture was filtered and washed thoroughly with methanol. The filtrate was concentrated under vacuum to yield the crude product whose purity was assessed by GC (97 .86%). Yield= 91%.

[0041] EXAMPLE 7 Continuous flow process for preparation of dl- 2-nitro-l- butanol

[0042] For the continuous flow experiment, solutions of aqueous sodium hydroxide (1.1 M), 37% formaldehyde (1.3 M) and pure 1-nitropropane were used. These solutions were delivered to the reactor using HPLC pumps with PEEK (PCI analytics LS class pump) and SS pump heads (PCI analytics LS class pump, Jasco PU 2089 plus). The aqueous sodium hydroxide and 1-nitropropane was pumped at equal volumetric flow rates where these solutions contact initially in a T-junction followed by the reactor coil of dimensions (i.d. = 1.5 mm, length of coil = 1 m). The formaldehyde solution was pumped at equal volumetric flow rate as aq. sodium hydroxide/formaldehyde solution. The nitropropane + sodium hydroxide mixture comes into contact with formaldehyde solution in a T-junction followed by the reactor coil of dimensions (i.d. = 1.5 mm, length of coil= 5 m). The reaction mixture at the exit of the coil was quenched using glacial acetic acid. The neutralized solution was extracted using dichloromethane. The organic layer was separated and dried with anhydrous sodium sulphate. Conversion of 90% (by GC) was obtained for the synthesis of <2/-2-nitro-l -butanol.

[0043] Table 1 below lists the results of conversion of 1-nitropropane to <2/-2-nitro-l- butanol by Henry reaction for different total residence times (t) (equimolar ratio of all reagents). Experiments were also conducted by manipulating mole ratios of sodium hydroxide (NaOH) and formaldehyde (by keeping other reagents molar ratio constant) to find out the optimal conversion. Optimal conversion of 89 % of <2/-2-nitro-l -butanol was obtained at residence time of 30 minutes for equimolar ratios of all reagents, as shown in Table 1.

Table 1: Yield of <2/-2-nitro-l -butanol for Various Mole Ratios of Reactants and Total

Residence Time (x)

[0044] While the invention has been disclosed with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention. In addition, many modifications may be made to adapt to a particular situation or material the teachings of the invention without departing from its scope as delineated in the appended claims.