DESC:FIELD OF THE INVENTION
The present invention relates to an improved process of preparation of Venlafaxine and salt thereof.
BACKGROUND OF THE INVENTION
Venlafaxine hydrochloride is known by the chemical name 1-[(2-dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride. Venlafaxine has the following formula (I):

Venlafaxine is an anti-depressant and acts by inhibiting synaptosomal uptake of norepinephrine (3H-NE) and serotonin (14C-5HT). US 4,535,186 disclose Venlafaxine and its preparation. The process in US’ 186 is shown as below:

The final stage of the above mentioned process involves N-Methylation using formaldehyde and formic acid and this process usually take around 6-10 Hrs and 95-97o C for completion of reaction.
Considering the importance of Venlafaxine in the pharmaceutical field, there is still the need of an efficient improved process, particularly of an efficient continuous process for the preparation venlafaxine with reduced time, and improved quality and thus making the process more commercially feasible.
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, as well as the ability to use higher temperatures and pressures than traditional pharmaceutical batch equipment may allow. 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, consistency, waste production, and cost.
In order to achieve these improved processes, it is critical that careful and thorough studies of reaction conditions are carried out. Fortunately, continuous flow chemistry lends itself to efficient experimentation as a result of its capability for changing multiple variables in sequence. For instance, the flow rate of a single reagent and the temperature of a reactor can be varied to collect data over a range of operating parameters without having to modify the experimental setup. Additionally, the ease of scalability of continuous flow chemistry allows for process development to be performed at lower scales before transitioning to a production scale, further reducing time and waste.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide an improved process for preparation of venlafaxine and salt thereof comprising methylation of 1-[2-Amino-1(4-methoxyphenyl) ethyl] cyclohexanol represented by formula (II) using a micro reactor.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for preparation of venlafaxine and salt thereof using a continuous flow reactor or micro reactor.
The present invention relates to flow chemistry, a chemical reaction is performed in a continuously flowing stream in a network of interconnecting channels.
With a batch reactor, all of the reagents are added initially to the reactor and remain in the reactor for the same length of time. With a continuous flow reactor or micro reactor, the feed is continuously metered into the reactor and the product is continuously removed.
The present invention relates to an improved process of preparation of venlafaxine comprises reacting the compound of formula (II) with formaldehyde and formic acid in a micro reactor.
In an embodiment, the process is conducted in continuous mode.
The preparation of mixtures of input materials to form streams of materials may be carried out in advance in micro mixers or in upstream mixing zones. The input materials are then introduced into a micro reactor individually or as mixtures. For example, two streams A and B can be continuously introduced into the reactor and continuously mixed therein so that the reaction takes place.
In an embodiment, the process comprises preparing reaction solution of compound of formula (II), formaldehyde, formic acid in water and then passing into the micro reactor.
In an embodiment, the process comprises preparing first reaction solution of compound of formula (II) in formic acid and water and second reaction solution comprises formaldehyde and formic acid in water and then feeding the same into micro reactor simultaneously.
In an embodiment, the micro reactor is a continuous flow reactor.
In embodiment, the process involves continuous feeding of reaction solution into micro reactor followed by removal of venlafaxine.
In an embodiment, the reaction mixture stream flowing in said micro reactor is maintained at a reaction temperature in the range of 90 to 175 °C, preferably 130-150 °C.
The flow rate and reactor dimensions have to be properly adjusted in order to obtain an optimal residence time of the reaction mixture in the micro reactor with the aim of completing the reaction. The residence time in the reactor is long enough to achieve at least substantial conversion of the compound of formula (II) to compound of formula (I) but short enough to substantially suppress undesirable side reactions.
In an embodiment, the reaction time in the flow reactor or “Residence time” of the reaction mixture stream or reactants in the micro reactor is the range between about 3 minutes and about 30 minutes, or between about 3 and about 10 minutes.
Reactor used may be a Continuous Pinch Tube Flow-Reactor (Amar-4P Model) from Amar Equipment Pvt. Ltd. or Micro-reactor (Amar-2 Model) from Amar Equipment Pvt. Ltd or any other suitable reactor. Flow rate and pressure ranges used are characteristics of the reactor model. Flow rate varies according to entire reactor volume and residence time.
In an embodiment of the invention, the mole ratio of compound of formula (II) and formaldehyde is in the range of 2.42 to 3.15 moles while formic acid is in the range of 6.77-8.59 moles.
In some embodiments, the solution of the compound of formula (II), formic acid, and formaldehyde as neat or as a solution can be introduced into the micro reactor separately or, as an alternative, the solution of the compound of formula (II), formic acid, and formaldehyde as neat or as a solution can be pre-mixed before the introduction into the micro reactor.
Venlafaxine obtained from the micro reactor is isolated or can be converted in-situ in to Venlafaxine HCl.
In an embodiment after collecting the solution comprising venlafaxine compound of formula (I) from the micro reactor, the venlafaxine base is then isolated by adjusting the pH of the reaction solution and extracting in toluene followed by distilling out toluene. Venlafaxine base is converted to HCl salt using IPA.HCl or any other known method.
In an embodiment of the invention, the compound of formula (II) can be prepared by any known methods, for e.g. by following the scheme below:

The method of the present invention allows one to directly obtain the compound of formula (I) 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 of the reaction and easy scale up for larger output. In addition the process of the present invention allows less moles of formaldehyde.
In some embodiments of the invention, continuous flow reactor or micro reactor and associated vessels may be constructed of any material which is not reactive with any of the reactants, solvents, or products and sustain at high temperature and pressure.
In some embodiments of the invention, the processes and/or steps not performed in the micro reactor such as separation process/device may be either flow-type devices/processes or batch-type, as desired or any such appropriate device.
The below scheme illustrates non-limiting embodiment showing synthetic representation of N-methylation according to present invention using flow reactor.

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
Reference Example 1: Preparation of compound of formula (II):
900 ml Methanolic Ammonia solution and 1-[cyano (4-methoxyphenyl) methyl] Cyclohexanol (150 gm) were charged in the hydrogenator reactor under nitrogen atmosphere. Raney Nickel was added in the reactor and hydrogen pressure was applied. After completion of the reaction, reaction mass is filtered through hyflo bed and filtrate is evaporated to obtain 1-[2-Amino-1(4-methoxyphenyl) ethyl] cyclohexanol. Process water (600 ml) & Formic Acid (29.3gm) were added in the above residue of 1-[2-Amino-1(4-methoxyphenyl) ethyl] cyclohexanol (formula (II)) and stirred to obtain clear solution. Clear aqueous solution was washed with dichloride methane.
Reference Example 2: Preparation of compound of formula (II):
900 ml Methanolic Ammonia solution and 1-[cyano (4-methoxyphenyl) methyl] Cyclohexanol (150 gm) were charged in the hydrogenator reactor under nitrogen atmosphere. Raney Nickel was added in the reactor and hydrogen pressure was applied. After completion of the reaction, reaction mass is filtered through hyflo bed and filtrate is evaporated to obtain 1-[2-Amino-1(4-methoxyphenyl) ethyl] cyclohexanol. Process water (450 ml) & Formic Acid (29.3gm) were added in the above residue of 1-[2-Amino-1(4-methoxyphenyl) ethyl] cyclohexanol (formula (II)) and stirred to obtain clear solution. Clear aqueous solution was washed with dichloride methane.
Example 1: Preparation of Venlafaxine HCl:
To the above aqueous solution (Reference example 1); formic acid (208.6 gm) and formaldehyde (115.05 gm) were added and the resultant combined solution was injected into a micro reactor at 140°C for 10 minute residence time. The reacted solution coming out from the micro reactor was collected. To the combined reaction mass toluene (600 ml) was added and was stirred followed by addition of sodium hydroxide solution to adjust pH 11.0 to 12.0 at 10 - 20?C. The organic layer was separated and distilled to get residue. Isopropyl alcohol was added to residue to obtain clear solution and adjusted pH approximately 2.0 using IPA.HCl at 10 - 15?C and stirred for 30 minutes. The solid was filtered and washed with IPA and dried to obtain pure Venlafaxine HCl. Yield: 1.15 w/w, and purity by HPLC (99.96%)
Example 2: Preparation of venlafaxine hydrochloride
To the above aqueous solution (Reference example 1); (208.6g) Formic Acid & (115.05g) Formaldehyde were added and injected in the Micro-reactor at 100°C for Residence Time 27 Minutes. Maximum converted RM solution coming out of the Micro-reactor was basified by Aq.NaOH and extracted by (600ml) Toluene. Toluene was distilled and IPA (750ml) was added in the RM. Acidified with IPA.HCl and isolation by successive leaching, Venlafaxine HCl was isolated as a pure compound.
EXAMPLE-3: Preparation of venlafaxine hydrochloride
To the above aqueous solution (Reference example 1); (208.6g) Formic Acid & (115.05g) Formaldehyde were added and kept aside (Solution-A). Initially Micro-reactor was accustomed in two different temperature zones-exactly half portion at 90°C and rest at 140°C. From this design, already prepared Solution-A was run for 10 Minutes Residence Time. Maximum converted RM coming out of the Micro-reactor was basified by Aq.NaOH and extracted by (600ml) Toluene. Toluene was distilled and IPA (750ml) was added in the RM. Acidified with IPA.HCl and isolation by successive leaching, Venlafaxine HCl was isolated as a pure compound. Yield: 1.14 w/w and purity by HPLC (99.96%).
EXAMPLE-4: Preparation of venlafaxine hydrochloride
The above aqueous solution (Reference example 2) designated as Solution-1. (150ml) Water was added to (208.6g) Formic Acid & (115.05g) Formaldehyde; this combined solution is designated as Solution-2. Both Solution-1 & Solution-2 were injected separately in the Micro-reactor at 140°C for 10 Minutes residence Time. Maximum converted RM coming out of the Micro-reactor was basified by Aq.NaOH and extracted by (600ml) Toluene. Toluene was distilled and IPA (750ml) was added in the RM. Acidified with IPA.HCl and isolation by successive leaching, Venlafaxine HCl was isolated as a pure compound. Yield: 1.10w/w and purity by HPLC (99.91%).
EXAMPLE-5: Preparation of venlafaxine hydrochloride
The above aqueous solution (Reference example 2) designated as Solution-1. (150ml) Water was added to (208.6g) Formic Acid & (115.05g) Formaldehyde; this combined solution is designated as Solution-2. Micro-reactor was accustomed in two different temperature zones-exactly half portion at 90°C and rest at 140°C. From this design, already prepared Both Solution-1 & Solution-2 were injected separately in the Micro-reactor at 140°C for 10 Minutes residence Time. Maximum converted RM coming out of the Micro-reactor was basified by Aq.NaOH and extracted by (600ml) Toluene. Toluene was distilled and IPA (750ml) was added in the RM. Acidified with IPA.HCl and isolation by successive leaching, Venlafaxine HCl was isolated as a pure compound with yield: 1.01 w/w and purity by HPLC (99.92%).
,CLAIMS:We claim:
1. A process of preparation of venlafaxine comprising reacting the compound of formula (II) with formaldehyde and formic acid in a micro reactor

2. The process as claimed in claim 1, wherein the process is conducted in continuous mode at elevated temperature and pressure.
3. The process as claimed in claim 1, wherein the micro reactor is heated to a temperature in the range of 90 to 175 °C.
4. The process as claimed in claim 1, which comprises preparing reaction solution of compound of formula (II), formaldehyde, formic acid in water, and then passing into the micro reactor.
5. The process as claimed in claim 1, which comprises preparing first reaction solution of compound of formula (II) in formic acid and water and second reaction solution comprises formaldehyde and formic acid in water and then feeding the same into micro reactor simultaneously.
6. The process as claimed in claim 1 wherein the micro reactor is a continuous flow reactor
7. The process as claimed in claim 1, wherein the reaction time or residence time of the reactants in the micro reactor is the range of 2-30 minutes.
8. The process as claimed in claim 1, further comprises collecting venlafaxine solution from the micro reactor and converting into its salt.
9. The process as claimed in claim 1, wherein the said reaction involves continuous feeding of reaction solution into micro reactor followed by removal of venlafaxine.