• An infectious death causing disease Tuberculosis (TB) that primarily affects lungs is treatable and mendable but expensive treatment.
• FDA approved first line   anti TB drugs   include rifampicin, ethambutol, isoniazid, pyrazinamide.
• Though India is one of the largest producers of ethambutol, dl-2-amino-1-butanol; the key intermediate for synthesis of ethambutol is mostly  imported as there is no significant local production.
• Further, available batch processes for dl-2-amino-1-butanol  synthesis  suffer  from bottlenecks/challenges including safe handling of  raw materials, excessive use of reagents and its  recovery, lack of reaction control, low , etc.

Hence there is a need to develop an improved method to overcome above-mentioned issues.

Process Flow

A continuous process for preparation of dl-2-nitro-1-  butanol comprises of the following steps:

• Providing an aqueous solution of sodium hydroxide (A) and 1- nitro-propane (B)  dissolved in an alcohol (methanol or ethanol);
• Pumping a predetermined first molar ratio  of solution A and B to mix in a first tubular  reactor for a first residence time to form  intermediate product stream solution  mixture;
• Pumping formaldehyde aqueous solution 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;
• Quenching the product stream in glacial acetic  acid to obtain a quench liquor having dl-2-nitro-1-  butanol, wherein the first and the second tubular  reactors are maintained at temperature ≥ 35° C.

Reactor Design

The Continuous Flow Reactor comprises:

• A first reservoir configured to store a solution of 1-nitropropane (starting material) and connected to a first pump,
• A second reservoir for storing a solution of NaOH and connected to a second pump,
• Wherein the first pump and the second pump are connected with a tubing to join the first stream entering a first tubular  reactor, and the first tubular reactor having  a first length and is configured to output a  mixture of solutions from first and second  reservoir as intermediate product  stream.
• A third reservoir is to store a solution of formaldehyde and connected to a third pump, wherein, the third pump is configured  to pump the formaldehyde solution to join  the intermediate product stream entering a  second tubular reactor.
• Further, 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 having glacial acetic acid wherein the dl-2-nitro-1-butanol is extracted  from the quench liquor using a solvent  (dichloromethane) from being converted to  other products.

The first & second tubular reactors are  configured to be maintained at a temperature ≥ 35° C.

The process have a following properties:

• The process cycle is completed in ≥30 minutes;
• The predetermined first & second molar ratio= 1.
• The conversion to dl-2-nitro-1-butanol is ≤89%.
• The second residence time is 3-8 times the first residence time.

A continuous process for preparation of dl-2-  nitro-1-butanol from 1-nitropropane is shown  in FIG. 1 & a continuous flow reactor for  producing dl-2-nitro-1-butanol from 1-  nitropropane is shown in FIG. 2.