WO2010107690A1

WO2010107690A1 - Separation apparatus

Info

Publication number: WO2010107690A1
Application number: PCT/US2010/027298
Authority: WO
Inventors: Denis Har; Mauricio Loo
Original assignee: Novartis Ag
Priority date: 2009-03-16
Filing date: 2010-03-15
Publication date: 2010-09-23

Abstract

A separation apparatus (2) for removing heavy metal impurities from a liquid reaction product. The separation apparatus (2) containing a mixture (8) of at least two removal components therein. Each removal component is capable of retaining one or more catalyst impurities and each removal component being substantially retained within the separation apparatus.

Description

Separation Apparatus

The present invention relates to a separation apparatus for removing heavy metal impurities from a liquid reaction product, in particular to a separation apparatus for removing catalyst metal impurities from the product of an organic synthesis.

In organic chemistry of science in general, heavy metals such as Pd, Fe, Rh, Ti, Ag etc are routinely used during a synthesis. Their removal (clean-up) from the process stream produced following the reaction can be a challenging task. There are a variety of methods available to a chemist for such clean-up and these include distillation, extraction and adsorption, however a chemist typically has to use a process of trial and error to develop appropriate conditions and achieve the appropriate product purity in which the heavy metals are present, but at a level below a predetermined limit, for example 5parts per million (ppm) .

A typical example of a clean-up process following a reaction catalysed by Pd might be that initially a chemist will try, in a batch-wise manner, using activated carbon, a common Pd scavenger. The activated carbon is added into the reaction mixture which is then heated for a few hours, cooled and filtered. A sample of the filtrate is submitted for Pd content analysis. The result may be better than before, but still unacceptably high so the chemist will have no choice but to perform further clean-up operations until the purity specifications are met. The chemist may have to decide whether to try again with activated carbon, or try a different process or removal component. For example, the chemist could combine an organic process stream with an aqueous solution of L-cysteine. The mixture could then be heated for a few hours, cooled and the resulting layers separated. The Pd impurity should have migrated into the aqueous layer, assisted by the L-cysteine.

This process can be time consuming and, particularly on a laboratory scale, inconvenient if several different products need to be created for testing, each of which may require a different purification process.

The present invention seeks to provide a more convenient separation apparatus and method.

The present invention provides a separation apparatus for removing heavy metal impurities from a liquid reaction product the separation apparatus containing a mixture of at least two removal components therein, each removal component being capable of retaining one or more catalyst impurities and each removal component being substantially retained within the separation apparatus.

By providing a single apparatus which contains a mixture of removal components the number of potential interactions with the heavy metal impurities is increased and the probability of successful purifying is increased. For instance, Pd can take on many forms as it can have an oxidation state of 0, +2 and +4. Also, different organic groups can be attached onto the Pd atoms in the reaction mixture. Different forms of Pd may have a different affinity toward a removal component. For example, some Pd may get removed quickly by bonding rapidly onto the removal component, but others may bond weakly or never at all. By adding at least one further removal component to create a "cocktail" of removal components more potential modes of interaction are introduced and thus there is a greater chance of successful removal of the Pd, or other heavy metal impurities.

Such a mixture of removal components has particular advantages for a lab scale clean up process as costly optimisation of the process, such as selection of an appropriate removal component, is unlikely to be required and there is an increased chance of successful cleanup.

The separation apparatus may contain a mixture of at least three removal components therein and may contain at least four removal components. They may be substantially homogeneously mixed within the apparatus, roughly mixed, or substantially separate within the apparatus, for example in substantially separate layers.

The separation apparatus may comprise a packed bed in which the removal components are substantially immobilised within a container, such as a separation column. The container being adapted to permit fluid to flow into the container, through the packed bed of immobilised removal components and then out of the container. In such a system the removal components are retained within the separation apparatus. Alternative embodiments may include a fluidised bed arrangement.

The removal components are each capable of retaining at least one of the heavy metal, possibly catalyst, impurities. At least one of the removal components may be capable of chemically bonding to one or more heavy metal impurities. The removal component may be capable of bonding, substantially permanently or reversibly, to one or more heavy metal impurities. The impurities may be absorbed and / or adsorbed by one or more of the removal components . One or more heavy metal impurities may be filtered from a flow passing through the separation apparatus so that the impurity is physically retained in the removal component and therefore the apparatus .

The removal components may include activated carbon, for example that available from PICA, Quadrapure™ (from Reaxa™) , Thiosilica™ (from SiliCycle™) , trimercaptotriazine (from Degussa™) , and Smopex™ (from Johnson Matthey™) . It should be understood that the mixture may include two or more of these, and / or other components. The mixture can be in any proportion, although substantially equal proportions of each removal component may be used in some embodiments .

The heavy metal impurities may include one or more of Pd, Fe, Rh, Ti and Ag. Other heavy metal impurities may also be present. The heavy metal impurities may be present due to their use as a catalyst in an initial reaction process, or for other reasons.

At least one of the removal components may be capable of retaining one or more Palladium impurities and in one embodiment all of the removal components are capable of retaining one or more Palladium impurities. One or more of the removal components may be capable of retaining non-heavy metal impurities in addition to heavy metal impurities . The invention also provides a process for removing heavy metal impurities from a liquid reaction product, the method comprising the steps of: a) passing the reaction product through a separation apparatus to produce a processed product, the separation apparatus being substantially as described above.

The processed product, which may be a mixture, may be passed through the separation apparatus at least one further time. This increases the contact time between the impurity containing liquid and the removal components without the need for the separation apparatus to increase in size. The increased contact time and recycle through the apparatus increases the chances of the impurities being retained within the apparatus. In one embodiment the processed product is passed through the separation apparatus between 9 and 19 additional times.

A separation kit which includes the separation apparatus may further comprise a first reservoir which is initially charged with a reaction product and a pump for moving the reaction product to the separation apparatus . The reaction product may flow down through the separation apparatus under gravity, or may be pumped through the separation apparatus regardless of orientation using the same or an additional pump. In one embodiment the liquid is forced upwards through the separation apparatus against gravity. The liquid leaving the separation apparatus may be taken to a second reservoir, or may be returned to the first reservoir from where it is recycled through the separation apparatus .

It should be noted that the number of times that the liquid is recycled through the separation apparatus is not an absolute number due to mixing within the reservoir, but is based on the initial volume of liquid which is charged to the system and the volume of liquid which is passed through the separation apparatus during the separation process and assuming a perfectly stirred reservoir. A stirrer may be included in the first reservoir.

The liquid from the first reservoir may be cycled through the apparatus as described above for a predetermined time period rather than a predetermined number of times . Suitable time periods are at least 12 hrs, 24 hrs, 36 hrs and at least 48 hrs.

The separation apparatus may comprise a jacketed column in which the mixture of removal components is housed. A temperature controller may be provided to maintain the temperature of the jacket at predetermined elevated level. The predetermined elevated level may be above 30⁰C, may be above 40⁰C and may be above 45⁰C. The predetermined elevated level may be below 80⁰C, may be below 70⁰C and may be below 60⁰C. The temperature range may be between 40⁰C and 60⁰C. In an alternative embodiment the liquid stream is heated as above before passing through the separation apparatus.

It should be understood that throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", implies the inclusion of the stated integer or step, or group of integers or steps . The invention will now be further described, by way of example only, with reference to the following drawings in which:

Figure 1 shows a schematic view of a separation kit including a separation apparatus.

Figure 1 shows a schematic view of a separation kit 1 including a separation apparatus 2. In this case the separation apparatus 2 is a packed bed column containing a mixture comprising a plurality of removal components.

In use, the liquid product of a reaction to be "cleaned- up" is put into a first reservoir 4. As an example, the reaction may be an organic synthesis reaction in which one or more heavy metal catalysts are used and which subsequently need to be separated from a desired product. From the first reservoir 4 a pump 6 moves the liquid to an inlet 12 of the separation apparatus 2.

From the inlet 12, the liquid passes through a distributor 14 and into the packed bed comprising a mixture of removal components 8. The liquid passes upwards through the packed bed and a collector 16 collects the liquid that exits the packed bed and channels it to an outlet 10.

From the outlet 16 the processed product is returned to the first reservoir 4 where a stirrer 18 mixes the reservoir contents. The pump 6 continues to pass the liquid through the separation apparatus until a total volume substantially equivalent to between 10 and 20 times the initial volume of content of the reservoir has passed through the separation apparatus 2. The separation apparatus 2 in this case is a jacketed column and the temperature within the jacket is maintained at about 50 degrees Celsius by a temperature controller 20.

The mixture of removal components 8 in this case comprise a mixture of at least two removal components selected from the following list: activated carbon available from PICA, Quadrapure™ (from Reaxa) , Thiosilica™ (from SiliCycle) , trimercaptotriazine (from Degussa) , and Smopex (from Johnson Matthey) .

Specific Examples Experimental Procedure:

The separation apparatus set-up was substantially as shown in Figure 1. Generally, the inlet/outlet of an jacketed glass housing was connected in series to a pump and a reservoir via l/8inch (3.2mm) PTFE tubing. The temperature of the jacketed housing was maintained using a circulating bath.

Substantially equal quantities of three different removal components were added into a jacketed glass housing. The jacketed glass housing was substantially 25cm in height and had an internal diameter of lcm.

The removal components added to the housing created a bed volume of about 18mL. The removal components were • 3g of activated carbon (PICA-HPIOO™ from

PICAPure™)

• 3g of Thiosilica™ (Thiosilica™ (40-63 μm) from

Silicycle™) and • 3g of QuadraPure-TU™ (QuadraPure-TU™ (400-600 μm) from SAFC™) Example 1

A solution of 1Og of reaction mixture containing 4,138 ppm of palladium and 10OmL of tetrahydrofuran was prepared and magnetically stirred in the reservoir. The temperature of the jacketed housing was maintained at 50⁰C to 55°C using a circulating bath. The pump was turned on and began circulating the solution through the loop, into the housing and out back to the reservoir at a flow rate of about lmL/min. A sample of the solution (~2mL) was aliquoted from the reservoir at 24h and at 42h and the Pd count was tested.

Results

The procedure was complete . The apparatus was drained of its THF solution into the reservoir. The Pd free solution was then concentrated to give the desired product .

Example 2

The same apparatus set up was used as for Example 1 and a solution was prepared in the same way, but in this case the 10-g reaction mixture initially contained 487 ppm of Pd. A sample of the solution (~2mL) was aliquoted from the reservoir at 18h and at 43h and the Pd count was tested. Results

Pd count

Sample at 0 h 487 ppm

Sample at 18h (27 ⁰C to 55 ⁰C) 74 ppm

Sample at 43h (55 ⁰C) 1 ppm

It should be understood that the invention has been described above by way of example only and that modifications in detail can be made without departing from the scope of the claims.

Claims

1. A separation apparatus for removing heavy metal impurities from a liquid reaction product the separation apparatus containing a mixture of at least two removal components therein, each removal component being capable of retaining one or more heavy metal impurities and each removal component being substantially retained within the separation apparatus .

2. A separation apparatus as claimed in claim 1, in which the separation apparatus contains a mixture of at least three removal components therein.

3. A separation apparatus as claimed in claim 2, in which the separation apparatus contains a mixture of at least four removal components therein.

4. A separation apparatus as claimed in claim 1, in which the separation apparatus comprises packed bed.

5. A separation apparatus as claimed in claim 1, in which at least one of the removal components is capable of bonding to one or more heavy metal impurities.

6. A separation apparatus as claimed in claim 5, in which the removal component is one of activated carbon, Quadrapure"*, Thiosilica™, trimercaptotriazine or Smopex™.

7. A separation apparatus as claimed in claim 1, in which the removal components are each capable of retaining one or more Palladium impurities .

8. A separation apparatus as claimed in claim 7, in which the separation apparatus contains at least activated carbon, Thiosilica™ and QuadraPure-TU™.

9. A process for removing heavy metal impurities from a liquid reaction product, the method comprising the steps of: a) passing the reaction product through a separation apparatus to produce a processed product, the separation apparatus being as claimed in claim 1.

10. A process as claimed in claim 9, in which the processed product is passed through the separation apparatus at least one further time.