DESC:FIELD OF THE INVENTION
The present invention relates to a continuous process for the preparation of Ethambutol dihydrochloride.

BACKGROUND OF THE INVENTION
Ethambutol dihydrochloride, chemically known as (2S,2’S)-2,2’-(Ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride (Formula-1) is an important bacteriostatic antimycobacterial drug for treatment of tuberculosis:

US Patent number 3,769,347 describes a batch process for synthesis of Ethambutol dihydrochloride, wherein 16 moles of d-2-amino-butan-1-ol (Formula-2) is required for reaction with 1 mole of ethylene dichloride (EDC).

The batch process has the following drawbacks such as:
a) use of excess d2AB leads to impurity formation
b) inconsistent product quality
c) high exothermicity of the reaction requires temperature control to prevent impurity formation

There is an unmet need to provide a process for the preparation of Ethambutol dihydrochloride that obviates the use of excess d2AB, long reaction times and critical temperature control which results a product of consistent purity and yield.

SUMMARY OF THE INVENTION
A main object of present invention is to provide a continuous process for the preparation of Ethambutol dihydrochloride resulting high & consistent purity and yields.
Another object of the present invention is to provide a continuous process for the preparation of Ethambutol dihydrochloride, devoid of using excess d-2-amino-butan-1-ol.
Yet another object of the present invention is to provide a continuous process for the preparation of Ethambutol dihydrochloride, requiring short reaction time when compare to process known in literature.
Yet another objective of the present invention is to provide a continuous process for the preparation of Ethambutol dihydrochloride capable of running at the individual scale.

DESCRIPTION OF DRAWING:
Figure 1: Block diagram of continuous process for preparation of Ethambutol

DETAILED DESCRIPTION OF THE INVENTION
In accordance with the objects of present invention to provide a continuous process for preparing Ethambutol dihydrochloride by reacting d-2-amino-butan-1-ol and ethylene dichloride depicted as per Scheme-1.

Scheme-1: Preparation of Ethambutol dihydrochloride (Formula-1) from reaction between d-2-amino-butan-1-ol and ethylene dichloride

d-2-amino-butan-1-ol is primary amine, during reaction with ethylene dichloride excess of d-2-amino-butan-1-ol is resulting to undesired side reactions and lead to formation of piperazines, aziridines or linear condensation by product (polymer) of d2AB. It is also to be noted that excess use of d-2-amino-butan-1-ol makes process complex and increases cost of recovery for d2AB. While, lower ratio of d-2-amino-butan-1-ol with ethylene dichloride in batch mode gives product with low quality. According to present invention, the reaction of d2AB with EDC in continuous process involving use of micro/meso type reactor is, resulting pharmaceutically acceptable purity of Ethambutol dihydrochloride even at low mole ratio of d2AB and EDC.

The present invention further provides continuous process, wherein reagent streams are continuously pumped into a flow reactor. The reagent for preparing Ethambutol 2HCl are mixed and allowed to react. In batch process the reaction is carried out in conventional reaction condition, such as choosing to dilute and/or cool reactions in order to retain thermal control and/or reaction selectivity. In a continuous reactor, mixing is rapid and heat can be readily added or removed from reaction mixtures enabling reactions to be performed at higher rate and temperatures thought previously unsafe in conventional reaction-ware. Hence, preferably continuous process is suitable of kinetically controlled reaction and further increased the acceptability at commercial scale.

The micro/meso type reactor technology is used for reaction of d2AB with EDC to produce Ethambutol dihydrochloride with high yield and purity. The said reaction is carried out at higher temp and pressure. The results of reaction between ethylene dichloride with d-2-amino-butan-1-ol at various molar ratio, temperature and pressure are depicted in Table-1 below:

Table-1: Design of experiment for preparing Ethambutol dihydrochloride in continuous process:
Sr.
No. Mole ratio
(d2AB:EDC) Temperature Pressure Reaction time (Min) Remarks
1 Above 5:1 Reaction proceeds for completion but yield and quality are compared to 4:1 ratio at same temperature and pressure. Reaction time also increases when the molar ration of d2AB : EDC increase because of concentration decrease.
2 4:1 80 2 30 Reaction doesn’t proceed for completion. Poor yield
3 95 3.5 20 Reaction doesn’t proceed for completion. Poor yield
4 120 3.5 19 Reaction proceeds for completion but yield and purity is less.
5 140 3.5 10 Reaction completed with good yield and less impurity.
6 150 4.5 8 Reaction completed with high yield and less impurity.
7 170 5 16 Reaction completed with less yield and high impurity.
8 3.5:1 Reaction is not completed by using the given molar ratio
9 3:1 Reaction is not completed by using this molar ratio
10 2:1 Reaction is not completed by using this molar ratio

Table-1 described design of experiment for optimization of d2AB to EDC molar ratio in different operating condition. The temperature of reaction is ranging from 80 to 165°C at pressure ranging between 2 to 5 kg/cm2. Preferably, the temperature is between 120 to 150°C and pressure is 3.5 to 5 kg/cm2. The preferably molar ratio of d-2-amino-butan-1-ol (d2AB) to Ethylene dichloride (EDC) is 4:1. The molar ration of d-2-amino-butan-1-ol to Ethylene dichloride used in the range of 2 to 3.5: 1 then reaction doesn’t proceed to completion.
The desired reaction is performed using micro/meso type reactor technology so that the desired reaction condition is achieved and facilitate towards the commercialization of a process (as disclosed in Figure-1). The scale-up is avoided and a reasonable number of reactors are connected in parallel for production at large scale.

Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. It means designing and developing formulations and manufacturing processes to ensure a predefined quality. Thus, QbD requires an understanding how process variables influence product quality.

The present invention is illustrated with following examples without limiting the scope of the invention.

Example 1 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 12:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using Advance Flow Reactor for continuous reaction.
Premix solution of 182.9 gm d2AB and 17.07 gm EDC is passed through advance flow reactor (detail shown in Fig-1) at particular flow rate using high pressure pump. Reactor utility side is maintained at temperature ranging from 80 to 165°C preferably at 140°C. 200 gm of Reaction mass is collected from continuous system and processed in batch for workup to obtain pure ETB.HCl. Reaction mass cool to 55°C and 12.8 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 62.5 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 18ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML. Reaction mass cooled and desired moisture level is maintained. Mass is filtered to obtained crude (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified using 2-Propanol+Water. The wet cake is dried to result 27 gm pharmaceutical grade ETB.HCl.
• Advance Flow Reactor (AFR) module used for instant process is 8,
• Volume of one Reactor module 8 ml,
• Total volume of AFR: 64 ml; Size of one reactor module : 200 mm x 200 mm,
• Flow rate of premix solution : 10 gm/min by pump,
• Residence time for reaction : 6.4 min,
• Reaction mass processing time : 25 min (after steady state condition).

Example 2 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 4:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using Advance Flow Reactor for continuous reaction.
Premix solution of 156.6 gm d2AB and 43.36 gm EDC is passed through advance flow reactor using a pump. Reactor utility side is maintained at 140°C. 200 gm of continuously collected Reaction mass is processed in batch to obtained pure ETB.HCl. Reaction mass cool to 55°C and 32.5 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 158.5 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 48ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML to a pH of 2.5 by maintaining temp at 55°C. Reaction mass cooled to 45°C and 5-7% moisture is maintained. Mass is filtered to obtained crude (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified by 2-Propanol+Water, cake is dried at 65°C. 55 gm pharmaceutical grade ETB.HCl is obtained.

Example 3 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 4:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using Advance Flow Reactor for continuous reaction.
Premix solution of 270.59 gm d2AB and 74.41 gm EDC is passed through coil reactor immersed in oil bath at flow rate of 3.6 gm/min using HPLC pump. Oil temp is maintained at 140°C and pressure at 3-4kg/cm2. 345 gm of continuously collected Reaction mass is processed in batch to obtained pure ETB.HCl. Reaction mass cool to 55°C and 55.7 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 272 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 81.6ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML to a pH of 2.5 by maintaining temp at 55oC. Reaction mass cooled to 45°C and 5-7% moisture is maintained. Mass is filtered to obtained crude (2S, 2’S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified by 2-Propanol+Water, cake is dried at 65°C. 108 gm pharmaceutical grade ETB.HCl is obtained. Coil pipe diameter : 2 mm; Coil diameter : 90 mm; No of turns : 45; Heat transfer area : 0.1317 m2; Internal volume : 36 ml.

Example 4 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 4:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using PHE+Coil Reactor for continuous reaction.
Premix solution of 227.06 gm d2AB and 62.94 gm EDC is passed through series of PHE reactor with hot oil circulation followed by coil reactor immersed in oil bath at flow rate of 4.1 gm/min using HPLC pump. Oil temp is maintained at 140°C and pressure at 3-4kg/cm2. 290 gm of continuously collected Reaction mass is processed in batch to obtained pure ETB.HCl. Reaction mass cool to 55°C and 47.18 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 231 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 69 ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML to a pH of 2.5 by maintaining temp at 55°C. Reaction mass cooled to 45°C and 5-7% moisture is maintained. Mass is filtered to obtained crude (2S, 2’S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified by 2-Propanol+Water, cake is dried at 65°C. 74.83 gm pharmaceutical grade ETB.HCl is obtained.

Example 5 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 4:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using Coil Reactor for continuous reaction
Premix solution of 235.29 gm d2AB and 64.71 gm EDC is passed through coil reactor immersed in oil bath at flow rate of 4.16 gm/min using HPLC pump. Oil temp is maintained at 150°C and pressure at 4-5kg/cm2. 300 gm of continuously collected Reaction mass is processed in batch to obtained pure ETB.HCl. Reaction mass cool to 55°C and 48.8 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 236.6 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 70 ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML to a pH of 2.5 by maintaining temp at 55°C. Reaction mass cooled to 45°C and 5-7% moisture is maintained. Mass is filtered to obtained crude (2S, 2’S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified by 2-Propanol+Water, cake is dried at 65°C. 94.6 gm pharmaceutical grade ETB.HCl is obtained.

Example 6 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 4:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using Coil Reactor for continuous reaction
Premix solution of 235.29 gm d2AB and 64.71 gm EDC is passed through coil reactor immersed in oil bath at flow rate of 5.59 gm/min using HPLC pump. Oil temp is maintained at 150C and pressure at 4-5kg/cm2. 300 gm of continuously collected Reaction mass is processed in batch to obtained pure ETB.HCl. Reaction mass cool to 55°C and 48.8 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 236.6 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 70 ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML to a pH of 2.5 by maintaining temp at 55°C. Reaction mass cooled to 45°C and 5-7% moisture is maintained. Mass is filtered to obtained crude (2S, 2’S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified by 2-Propanol+Water, cake is dried at 65°C. 96.14 gm pharmaceutical grade ETB.HCl is obtained.

Example 7 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 4:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using Coil Reactor for continuous reaction
Premix solution of 180.39 gm d2AB and 49.61 gm EDC is passed through coil reactor immersed in oil bath at flow rate of 1.9 gm/min using HPLC pump. Oil temp is maintained at 120°C and pressure at 3-4kg/cm2. 230 gm of continuously collected Reaction mass is processed in batch to obtained pure ETB.HCl. Reaction mass cool to 55°C and 37.4 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 182 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 53.6ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML to a pH of 2.5 by maintaining temp at 55°C. Reaction mass cooled to 45°C and 5-7% moisture is maintained. Mass is filtered to obtained crude (2S, 2’S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified by 2-Propanol+Water, cake is dried at 65°C. 108 gm pharmaceutical grade ETB.HCl is obtained.

Example 8 Synthesis of (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydro- chloride) i.e. ETB.HCl in 4:1 molar ratio of d-2-amino-butan-1-ol and ethylene dichloride using Coil Reactor for continuous reaction
Premix solution of 180.39 gm d2AB and 49.61 gm EDC is passed through coil reactor immersed in oil bath at flow rate of 2 gm/min using HPLC pump. Oil temp is maintained at 80°C and pressure at 2 kg/cm2. 230 gm of continuously collected Reaction mass is processed in batch to obtained pure ETB.HCl. Reaction mass cool to 55°C and 37.4 gm NaOH flakes added. Excess d-2-amino-butan-1-ol is recovered by vacuum distillation. 182 ml 2-Propanol is added to the distillation residue at 60°C and stirred for 1hr. Sodium chloride is filtered and cake is washed with 53.6ml 2-Propanol. Meso Ethambutol is isolated by crystallization. Dry HCl gas is purged in ML to a pH of 2.5 by maintaining temp at 55°C. Reaction mass cooled to 45°C and 5-7% moisture is maintained. Mass is filtered to obtained crude (2S, 2’S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol dihydrochloride). This crude cake is purified by 2-Propanol + Water, cake is dried at 65°C. 20 gm pharmaceutical grade ETB.HCl is obtained.
,CLAIMS:1. A continuous process for the preparation of Ethambutol dihydrochloride wherein d-2-amino-1-butanol is reacted with ethylene dichloride in about 2:1 to 5:1 molar ratio in hydrogen atmosphere at 80oC to 165°C.
2. The process according to claim 1 wherein the molar ratio of d-2-amino-1-butanol to ethylene dichloride is 4:1.
3. The process according to claim 1 wherein reaction is carried at 145-155°C.
4. The process according to claim 1 wherein the pressure ranges from 2 to 5 kg/m2.
5. The process according to claim 4 wherein the pressure is between 4.3 to 4.7 kg/m2.