WO2009023515A2

WO2009023515A2 - Reactors and methods for processing reactants therein

Info

Publication number: WO2009023515A2
Application number: PCT/US2008/072461
Authority: WO
Inventors: Timothy Michael Braden; Miguel Angel Gonzalez; Amy Rebecca Jines; Martin David Johnson; Wei-Ming Sun
Original assignee: Eli Lilly And Company
Priority date: 2007-08-09
Filing date: 2008-08-07
Publication date: 2009-02-19
Also published as: WO2009023515A3

Abstract

A reactor is provided and methods for its use provided to process reactants containing solids and/or reactants having an explosive potential. In order to prevent clogging, reactant feeds containing solids can be moved through the reactor without a mechanical pump and/or without forcing the slurry through a restricting orifice. An expansion chamber downstream from the reaction zone is provided to maintain a rapid gas expansion within the pressure limits of the reactor system. A variety of processes can be carried out in the preferred reactor. The processes include, but are not limited to reacting, polymerizing, crystallizing, re-crystallizing, mixing, emulsifying, isomerizing, purifying, digesting, and the like.

Description

REACTORS AND METHODS FOR PROCESSING REACTANTS THEREIN

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 60/954,920, filed August 9, 2007, and U.S. Provisional Application No. 61,016,125 filed December 21, 2007, which are herby incorporated by reference in their entirety.

FIELD OF INVENTION

The present disclosure relates to a novel reactor system and a method for processing a reactant or reactants in the reactor system capable of regulating back pressure without a back-pressure regulator having a restricting orifice in the reactant' s flow path and optionally without contacting the one or more reactants with a pump. Processing can include a variety of transformations including, but not limited to reacting, polymerizing, crystallizing, distilling, filtering, recrystallizing, mixing, emulsifying, isomerizing, purifying, digesting, distilling and the like. The term "reactor" includes reactor, continuous flow reactor, semi-continuous flow reactor, semi-batch reactor, or fed batch reactor.

BACKGROUND

One well-known type of laboratory equipment for small scale continuous reactions is a reactor in which reactants can be combined and moved through a reaction zone and product collected. Such a reactor is a generally tubular or channeled device in which a chemical process or physical transformation takes place in a system having confined lateral dimensions, typically in the range of from about 0.0001 to about 0.400 of an inch. Reactors can be configured to operate in a continuous manner, in a batch manner or in a semi-continuous, or continuous manner and can in general process gases, liquids, solids, and combinations thereof. A potential benefit of a continuous reactor is its high ratio of surface area to volume that enables efficient transfer of heat into and out of the system. As a result, improved temperature control is generally possible with continuous reactors compared to batch reactors. This ability is particularly advantageous when carrying out exothermic reactions. Reactors can also include tubular or channeled regions with in-line conventional reactors. Further advantages provided by such reactors typically include improved energy efficiency, kinetics, safety, reliability, and scalability. In spite of these advantages, reactors frequently encounter a variety of problems including:

(a) clogging of mechanical pumps and/or restricting orifices in contact with slurries due to the presence of solids; (b) difficulty in pressurizing, controlling, and metering multiphase systems into a reactor at high pressures to provide a range of controlled flow rates through the reactor's flow path, particularly slow overall flow rates;

(c) depressurizing, controlling, and metering a multiphase mixture from the reactor's flow path, and where applicable, separating a vapor from a slurry at slow overall flow rates;

(d) damage to a mechanical pump caused by the presence of solids in the material being pumped;

(e) pressure swings caused by alternating plugs of liquid and gas passing through restricting orifices in the system; and (f) poor mixing of multiple phases in flow tubes or channels, for systems where flow velocity is low and the system's dimensions are too large for diffusion or dispersion to provide fast mixing times or systems with highly viscous fluids flowing at low overall velocity.

In addition, conventional reactors are unable to safely operate with explosive mixture which otherwise provide improved product yields, reaction rates and the like.

What is needed is a method for processing a reactant with a small scale batch, continuous or semi-continuous reactor to provide the advantages of such a system while avoiding the common problems associated with conventional reactors, and an improved reactor system that can be easily scaled up and which is capable of providing these advantages The present disclosure addresses these needs.

SUMMARY

A first aspect of the present disclosure involves a back pressure separating device (BPSD) for separating a gas from a flowable reaction product produced in a reactor and/or for providing a back pressure to the reactor without a restricting orifice in the reactant' s flow-path.

The device includes at least one reservoir, a controlled pressure source, and a vent. The first reservoir is positioned downstream from a reactor and adapted: (i) for fluid communication with the reactor; (ii) to receive the flow-able reaction product from the reactor; and (iii) to provide a headspace over the reaction product received therein, the reservoir having an exit port for removal of the degassed product. The controlled pressure source is in communication with the headspace and adapted to maintain a back pressure on the reservoir and reactor. The vent is in fluid communication with the headspace and adapted for the removal of a gas/vapor at a controlled rate. Preferred embodiments of the BPSD have an exit port for removal of the liquid portion of a reactor effluent. The BPSD can provide a back pressure against a product flow under a pressure provided by a pump, a pressurized feed tank, or a gas source maintained at an appropriate pressure. The device can exert a back pressure on the reactor without a flow-restricting orifice that contacts a liquid or slurry stream. One or more additional reservoirs in fluid communication with the first reservoir and other components of the BPSD can similarly be included. The additional reservoirs downstream from the first can be periodically isolated from the reactor system and depressurized to allow for removal of product without interrupting flow and/or pressure within the reactor. A novel aspect of this design provides a method for isolating downstream reservoirs, depressurizing them, and forwarding liquid and/or slurries semi-continuously to a product tank without a flow- restricting orifice that contacts a liquid stream, and without interrupting flow from the reactor into a first reservoir. Preferred BPSD's include a transfer valve between the first and second reservoirs and preferred second reservoirs include exit ports equipped with first and second exit valves to assist in removing processed reactant and for re- pressurizing the second reservoir after its removal. Operation of this system allows for removal of processed reactant without creating a pressure fluctuation within the reactor itself. A further aspect of the present disclosure includes a reactor system or device for processing a reactant. The reactor system includes a reactor having a flow path, a first pressure source upstream from the reactor, a second pressure source downstream from the reactor. The flow path typically includes upstream and downstream regions and a processing zone between the two regions. For reactors containing gaseous reactants, products and the like, the incorporation of a BPSD (described above) downstream from the reactor and upstream from the second pressure source provides additional advantages. The pressure source upstream from the reactor can include a pump, a pressurized feed tank, a transfer reservoir which sequentially alternates between lower pressures during a fill step to a higher pressure during a discharge step or a restricting orifice in a vent creating a back-pressure. An adjustable valve can function as a restrictive orifice. The upstream pressure source should be capable of creating a pressure differential across the reactor's flow path to cause flow to move through the reactor for further processing or collection in a BPSD. The reactor system can be configured to provide a continuous flow, a pulsating flow or provide for the flow of separate slugs of reactant through the reactor. The reactor can include a region within the flow-path where heat can be added, removed, or its transfer minimized. This enables rapid heating or cooling in the reaction zone or adjacent to the reactor inlet or outlet. The reactor can have a variety of forms including, but not limited to a region of tubing or a separate vessel. Reactor systems having an upstream loading region and a feed tank to supply reactant to the system at a predetermined pressure are particularly suited for processing segregated slugs of reactants and for handling slurries. Preferred feed tanks are capable of handling pressures above and below atmospheric pressure to allow movement of reactants to and from the feed tank utilizing vacuum and/or pressures above atmospheric pressure. A novel aspect of the reactors disclosed is that they do not require a mechanical pump to move a mass that can contain slurries of suspended solids through the reactor at an accurate and controlled flow rate. Instead, the system can push finite volumes of slurry precise distances through the reactor system during precise time intervals, with no restricting orifices in the slurry's flow path. The linear velocity of the reactant, whether a continuous stream or a slug of reactant, can be controlled or metered indirectly by restricting downstream gas venting. Examples of suitable processing zones include, but are not limited to generally tubular structures and non-tubular vessels, whether agitated or not. Flow paths for the various reactors can include a pre-reactor heat exchanger, a reacting region, a post reactor heat exchanger, and a collecting region.

Reactors systems can also have a vessel or vessels in series in place of a BPSD to receive product and to step down the product's pressure. The vessels-in-series include a plurality of adjacent vessels aligned in series and adapted to provide periodic fluid communication between the flow path and a first vessel, periodic fluid communication between adjacent vessels and a periodic back pressure to the flow path. Each vessel has a volume and is adapted to receive at least a partial volume of processed reactant from the flow path or a prior vessel to provide a volume expansion and a pressure drop for the partial volume of processed reactant received.

The reactor systems described above can be advantageously utilized to provide a pulsating flow through the reactor system to improve mixing and maintain a suspension of any solids present to avoid plugging. The direction of flow in the reactor system can be periodically reversed by reversing the pressure differential across the reactor or for reactions containing a gas by expanding a finite volume of the gas contained therein to reduce a first or second pressure and cause a surge in flow in the direction of the lowered pressure that is reversed by restoring the original first or second pressure. Reactors for providing a pulsating flow can advantageously include an expanded cross section upstream and/or downstream from the reactor to dampen the effect of a pressure change, modify the volumetric distance of fluid movement in the forward or reverse direction for a given pressure differential across the reactor, or the release of gas from the system. An in-line reservoir provides a particularly suitable region having an expanded cross section. An advantage of this form of pulsating flow is that it promotes the mixing and the suspension of any solids present when the overall average fluid flow through the reactor is very low or zero without the use of a mechanical pump. These advantages can be achieved utilizing only sequenced block valves and regulated pressure differentials. The number of forward pulses per each reverse pulse can be varied, for example 20 forward pulses for every one reverse pulse, therefore the back and fourth movement is better described as pulsed or pulsating rather than oscillatory.

Finally, the reaction systems described above further having an expanded volume region in fluid communication with the BPSD or with vessels-in-series can be utilized to process reactants under conditions which provide processing advantages, but have an unsafe explosive potential. The expanded volume region (also referred to as a pressurizable volume) is adapted to provide sufficient expansion volume to contain an explosive increase in volume upon the explosion of the contents of the reactor system and maintain a safe and acceptable pressure inside the reactor system. In preferred embodiments, the expanded volume contains an inert gas and is designed to maintain and sustain elevated pressures. Because the explosive regime of the reactor is upstream of the BPSD while the inerted expansion zone is downstream from the BPSD, minimal dilution of the reaction zone with the inerting gas occurs, even though the zones are in fluid communication with each other. Unlike conventional safety regimes, the current system is not limited by an activation time nor is it subject to possible failure of a rupture disc, a relief valve and the like.

A further aspect of the present disclosure provides for a method for processing a reactant with a reactor comprising the acts of providing a reactor having a flow path, where the flow path includes upstream and downstream regions and a processing zone therebetween; positioning the reactant in the upstream region of the flow path; moving the reactant through the processing zone to effect processing by providing a pressure differential across the flow path, wherein the pressure differential provides a base pressure and an elevated pressure, and the pressure differential causes the reactant to move through the processing region in the direction of the base pressure and away from the elevated pressure; and collecting the processed reactant from the flow path. For preferred embodiments, moving the reactant is accomplished without causing the reactant or processed reactant to come in contact with a flow-restricting device and/or a pump. Examples of processes which can be carried out utilizing this method include, but are not limited to, batch, continuous, and semi-continuous processes. Preferred methods include providing a reactor having a BPSD in communication with the reactor's flow path or vessels-in-series.

By periodically alternating the direction of the pressure differential across the reactor's flow path the direction of flow can be periodically reversed, enhancing mixing and improving the suspension of any solids present. A method for processing a reactant utilizing a pulsating flow through the reactor system includes the steps of providing a reactor having a flow path, the flow path including a processing region therein; positioning the reactant in the flow path; moving the reactant through the flow path by providing a pressure differential across the flow path, wherein the pressure differential provides a base pressure and an elevated pressure, and the pressure differential causes the reactant to move through the processing region in the direction of the base pressure and away from the elevated pressure; periodically altering the pressure differential to produce a pulsating flow of reactant through the processing region; and forming a processed reactant in the processing region. Reversal of the pressure differential can be accomplished by causing the base pressure to become the elevated pressure thus causing the elevated pressure to become the base pressure. Additionally, an elevated pressure can be reduced and re-established to cause a forward or backward surge of reactants that is reversed upon reestablishing the original elevated pressure. Pulsation of reactant flow is enhanced for reactants containing at least some gas, whether a reactant or an inert gas. The overall direction of flow in a pulsating flow system can be controlled by maintaining the pressure differential in one direction for longer periods of time, by maintaining a greater pressure differential in one direction compared to the other direction, and/or by allowing gas to exit downstream from the reactor at a controlled rate. Typically, this controlled rate is equal to the desired average volumetric flow rate through the reactor's flow path. By providing a reactor having a flow path and, additionally having a loading region, in addition to the flow path, individual slugs of reactants can be processed through the reactor. Additional steps for the method include positioning the reactant in the loading region to form a segregated slug of reactant therein; and moving the segregated slug from the loading region through the processing zone to effect processing by providing a pressure differential across the flow path, wherein the pressure differential provides a base pressure and an elevated pressure, and the pressure differential causes the reactant to move through the processing region in the direction of the base pressure and away from the elevated pressure. For preferred embodiments of the method moving the segregated slug is accomplished without subjecting the slug to a positive pressure created by fluid contact with a pump.

Preferred methods additionally include providing a reactor having a BPSD or vessels-in-series rather than a restricting orifice in communication with the reactor's flow path. The loading region can either be mechanically agitated or un-agitated. The loading region can be filled from a feed tank by vacuum or by applying pressure to the feed tank. The flow from the loading region, whether a homogeneous liquid, or a slurry, can be forced to undergo pulsating flow in the forward and reverse direction, if desired, to facilitate the suspension of any solids present and to minimize the plugging of solids. For preferred embodiments, reactor system components, including, but not limited to the loading zone, are arranged to take advantage of gravity in the different physical mass transfer processes. A similar physical orientation of valves, pushouts and the like can also eliminate dead volume or carry-over from one slug to the next. When the reactor's components are arranged in this manner, the loading region can be completely emptied between slugs.

By providing a reactor having a flow path, and additionally having an expanded volume region in fluid communication with the reactor's flow path, reactants can be safely processed under conditions which provide processing advantages, but which would otherwise have an unsafe explosive potential, wherein the expanded volume region is adapted to provide sufficient expansion volume to contain an explosive volume and maintain a safe and acceptable pressure inside the reactor system upon explosion of the reactants contained in the reactor system. The so called "expansion" volume is preferentially a chamber or vessel with fixed volume, not normally part of the equipment that actually changes volume; however, it is call "expansion" volume because localized high volumetric concentrations of exploding gas molecules expand from reactive volume of the system into the inerted volume of the system, as the two fixed volume zones of the reactor system are in fluid communication. In addition to providing this reactor, the method further includes positioning the reactant in the flow path; creating a pressure differential across the flow path containing the reactant, wherein the pressure differential provides a base pressure and an elevated pressure, and the pressure differential causes the reactant to move in the direction of the base pressure and away from the elevated pressure, and moving the reactant through the flow path to effect processing. The pressure differential can be created in part with either a pump or a pressurized loading tank upstream from the flow path. Methods utilizing the explosion safe reactor can be carried out as described above to provide pulsating flow and to process individual segregated slugs of reactants. Preferred methods include providing a reactor having a BPSD in communication with the reactor's flow path. The preferred methods additionally include providing a reactor without a restricting orifice in the reactant' s flow path.

A reactant can be any material that undergoes a transformation in the reactor, including, but not limited to, reacting, polymerizing, crystallizing, re-crystallizing, mixing, emulsifying, isomerizing, purifying, digesting, and the like. Additional reactants, catalysts, solvents and the like can be included in the mixture contained in the reactant reservoir or can be added to the reactant stream or slug as it moves through the flow path. The addition of further reactants can be typically accomplished through connections to the flow path having a valve system capable of introducing an appropriate amount of additional reactant(s) to the moving reactants under an elevated pressure. As used herein, the term reactant also contemplates non-reactive components such as solvents, diluents, inert gases, adsorbents, absorbents, scavengers, membrane capsules, surfactants, seeds, inhibitors, enzymes, ligands, and the like, as well as components such as catalysts which are not converted into product. A reactant can be introduced as a continuous stream or a segregated slug.

An elevated fluid pressure is any pressure that is higher than a base pressure measured either downstream or upstream from the reactant and which is sufficient to move a continuous stream of reactants or a segregated slug within the flow path at an overall average rate suitable to effect the desired processing. Typically, an elevated pressure is greater than atmospheric pressure; however, if the flow path is maintained at a pressure lower than atmospheric pressure, the elevated pressure can similarly be at or below atmospheric pressure. Although a variety of elevated fluid pressures can be used, elevated gas pressures are preferred. The preferred gas can be an inert gas, such as for example nitrogen gas, or can be a reactant.

The flow path can be configured as a continuous reactor, a batch reactor, or a semi-continuous reactor, depending on the particular transformation being carried out. A flow path having at least a gradual decline is generally preferred to allow gravity to assist in minimizing any retained reactant materials. The flow path can contain, but is not limited to, a heating zone, a cooling zone, a reaction zone, a depressurization zone, a collecting zone and a combination thereof, and can be configured to accomplish the desired transformation.

Some examples of transformations that can be carried out in the reactor systems disclosed herein include, but are not limited to oxidations, reductions, carbonylations, polymerizations, cyclizations, addition reactions, reactions in the explosive regime, eliminations, substitution reactions, insertion reactions, rearrangements, and the like. A variety of methods can be utilized to control the mass flow rate of reactants entering and exiting from a reactor's flow path. The following methods illustrate some examples. The mass flow rate of a liquid or a slurry into and through a reactor system can be controlled and accurately metered by the following techniques: (a) adjusting the finite volume of the slug flow feeder and its transfer frequency; and/or (b) maintaining a regulated pressure differential across the reactor and controlling the metering of gases and/or vapors vented downstream from the reactor to indirectly affect the mass of reactant entering the system, with only gases and/or vapors being allowed to contact the restricting orifices or metering valves. In this manner, most of the pressure drop across the reactor system occurs at the gas restricting orifice at the exit of the BPSD downstream from the reactor, and only a small pressure drop occurs through the reactor itself. One embodiment of the finite volume slug flow feeder includes a pressure swing feed chamber system having two parallel fill-empty chambers. While material in one pressure chamber is pushed into the reactor, the off-line pressure chamber fills with material from a feed tank, and the parallel chambers continue in alternating fashion. Additionally, the mass flow rate of liquid into a reactor system can be accomplished with a mechanical pump working at a controlled pumping rate. Devices particularly suitable for use with a slug flow method typically include a loading region and a reactant source in fluid communication with the flow path. Reactant sources can include, but are not limited to a mechanical pump and one or more loading vessels adapted to contain a reactant at a pressure sufficient to cause the reactant to flow into the loading region or zone.

The mass flow rate of a gas into and through a reactor system can be controlled and accurately metered by the following techniques: (a) adjusting the finite volume of the slug flow feeder and its transfer frequency; (b) maintaining a regulated pressure differential across the reactor and controlling the metering of gases and/or vapors vented downstream from the reactor to indirectly affect the mass of reactant entering the system, with only gases and/or vapors being allowed to contact the restricting orifices or metering valves; (c) utilizing a mechanical pump working at a controlled pumping rate; and (d) restricting gas flow on the inlet side of reactor with a flow restricting valve or controller. The mass flow rate of a liquid or a slurry out of a reactor system can be controlled and accurately metered by the following techniques: (a) utilizing automated block valves to sequence a liquid or slurry through a series of pressure chambers; (b) first removing at least a portion of a gas phase present through the BPSD and then utilizing automated block valves to sequence a liquid or slurry through a series of pressure chambers; and (c) isolating and depressurizing the contents of a slug flow tank and utilizing a pressure differential across the slug flow tank to empty its contents. Although not preferred, liquids or fluids not prone to plugging when traversing regions of restricted flow can be removed from a reactor system at a controlled rate through a restricting orifice metering valve or back pressure regulator for fluids.

The mass flow rate of a gas out of a reactor system can be controlled and accurately metered by the following techniques: (a) passing the gas or vapor phase through a restricting orifice; (b) ) utilizing automated block valves to sequence all phases through a series of pressure chambers; and (c) gas or vapor exits a restricting orifice or metering valve after passing through the reaction zone and an inerted explosion safe blowdown chamber where there are no flow restrictions between the reaction zone and the blowdown chamber. Generally pulsating flow refers to flow that periodically changes linear velocity, periodically reverses its direction, periodically surges in one direction or another and/or periodically stops and starts. Two general methods are described herein for implementing a pulsating flow through a reactor system. The first involves establishing a sufficient pressure differential across reactant in a flow path to cause reactant to move, periodically reversing the pressure differential sufficiently to cause the reactant to stop or reverse its direction of flow, and sufficiently re-establishing the original pressure differential to renew the reactants original direction of flow. The number of forward pulses per each reverse pulse can be varied, therefore the back and fourth movement is better described as pulsed than oscillatory. The second method involves establishing a pressure differential across reactant contained in a flow path to cause the reactant to move, periodically and then sufficiently increasing the pressure differential to cause the reactant to move or surge forward, and then sufficiently re-establishing the original pressure differential to renew the reactants original direction of flow. The release of gas bubbles from any degassing that occurs with a drop in pressure in this process aids in mixing and keeping solids suspended.

The following examples illustrate these methods with embodiments of reactors described herein. As noted above, the methods involve establishing an initial pressure differential across a reactant in a reactor's flow path involving an elevated pressure and a base pressure where the first or elevated pressure is greater than the second or base pressure. Once this initial pressure differential is established, flow can be interrupted and/or reversed by any of the following steps: (a) increasing the second pressure; (b) decreasing the first pressure; (c) decreasing the second pressure; and/or (d) increasing the first pressure.

(a) For a reactor of the type illustrated in FIG. 5, an additional gas (inert or reactant gas) can be supplied downstream from the reactor and prior to the device that meters gas flow out of the reactor system to cause the second pressure to become the elevated pressure. The volume of fluid movement in either direction is controlled by the volume of a vapor chamber on the inlet side of the reactor. The frequency of forward and reverse movement of the reactant is controlled by altering the cycle time of the pressure swings. (b) For a reactor of the type illustrated in FIG.6, intermediate agitated chamber

541 executes an automated pressure swing cycle in which the intermediate vessel fill at pressure lower than reactor base pressure and discharges to the reactor at pressure higher than base pressure. Because it is a finite volume chamber that isolates from the downstream parts of the reactor system, volumetric flow rate of the fluids that this pressure swing chamber are forwarding is precisely controlled by the cycle time of the pressure swings and the relative pressure differential during the chamber fill step.

In summary, methods and devices for mass flow into a reactor system, mass flow within the reactor system, and mass flow out of a reactor system are described. Described below are aspects of a variety of embodiments of the claimed invention. This discussion is provided to help clarify certain features of specific embodiments of both devices and methods and the discussion is not intended to limit the scope of applicant's claimed invention.

The slug flow reactor method can be used for production by automated batch reactor assembly line. Its preferred embodiments use automated valves and slurry transfer systems to sequentially fill and empty a reactor.

Embodiments of the explosion safe reactor device and method can be used for conducting reactions in the explosive regime, for example oxidations with pure oxygen. In preferred embodiments, it provides inerted reactor volume for expansion of exploding gases in fluid communication with reactor. It does not necessarily rely on mechanical pressure relief device to respond to explosion. A vapor liquid separator can remove liquid and slurry between reactive region and inerted region. The explosive regime of reaction zone is up stream of vapor liquid separator, and expansion volume for exploding gasses is downstream from vapor liquid separator.

The pressure swing fluid transfer chamber method can be used for pumping and flow metering of slurries. A mechanical pump is not required for slurries. Instead, automated sequenced block valves and pressure transfers can be used for generating and controlling overall volumetric throughput. Typically, each block valve is either fully open or fully closed, according to an automated sequence, rather than relying on restricting orifice for volumetric flow metering of slurries. For certain embodiments, the method involves filling and emptying finite volume intermediate chambers at finite times for controlling overall mass flow rate. Furthermore, the intermediate pressure swing chambers can include the reactor itself. To completely fill the pressure swing loading zone, one option is to utilize an up-flow loading zone with overflow zone and automated blow back from overflow zone to feed tank. Furthermore, one embodiment utilizes gravity, physical valve orientation, overflow chamber, blow backs, downhill flow and inert gas push-outs to completely fill finite volumes and eliminate dead volumes or carryover from slug to slug, The parallel alternating pressure swing fluid transfer chamber device and related method can be also used for slurry transfer and flow metering. While one chamber empties by pressure difference, the other fills, and they continue in an alternating fashion. No mechanical pump is needed for slurries. Instead, automated sequenced block valves and pressure transfers are used. Each block valve can be either fully open or fully closed, according to the automated sequence. It is not necessary for slurries to flow through restricting orifices to control overall volumetric throughput. Instead, the approach is to fill and empty finite volume intermediate chambers at finite times for controlling overall mass flow rate. The expansion chambers-in-series (also referred to as vessels-in-series) device and method can be used for depressurization of flowing slurry and flow metering. No active flow through restricting orifices is necessary to de-pressurize liquid or slurry stream, only sequenced block valves and finite volume pressure chambers. Each block valve can be either fully open or fully closed, according to the automated sequence. This minimizes fouling and plugging.

The cylinders in series back pressure regulator device and method can be used for orifice free and pulse free fluid flow out of a reactor system. Part of the preferred approach is to isolate second cylinder in series, depressurize, empty, and re-pressurize before valving back on line. No active flow through restricting orifices is necessary to de-pressurize liquid or slurry stream, only sequenced block valves that can be either fully open or fully closed to minimize fouling and plugging. A preferred pulsed flow generator on the inlet side of the reactor can be used for forward and reverse direction flow pulses. This does not require the use of a mechanical agitator or pumping device to generate pulsed flow, only sequenced block valves and regulated pressure differences. Each block valve can be either fully open or fully closed, according to the automated sequence. It can generate flow surges in forward and reverse direction at user defined amplitude and frequency by varying pressure swing volumes and valve cycle times. It can function with one regulated pressure source upstream from the reactor, and controlled venting downstream.

A pulsed flow generator on the outlet side of the reactor can be used for forward and reverse direction flow pulses. It can function with either a vapor liquid separator or expansion vessels-in-series on the downstream side of the reactor. It does not need a mechanical agitator or pumping device to generate pulsed flow, only sequenced block valves and regulated pressure differences. Each block valve can be either fully open or fully closed, according to the automated sequence. It does not require active flow through restricting orifice for controlling overall volumetric throughput of slurries. Contents in the reactor system move in forward and reverse direction at user defined amplitude and frequency by varying pressure swing volumes and valve cycle times. It can function with two regulated pressure sources, one up stream and one down stream. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a schematic of a reactor system of the present disclosure, particularly suitable for conducting a slug flow process.

FIG. 2 is an alternative design of a reactor system of the present disclosure, particularly suitable for conducting a slug flow process with the added ability to apply micro pressure swings to fluids or slurries moving through process lines in addition to macro pressure swings on the intermediate chambers. FIG. 3 is a further alternative design of a reactor system of the present disclosure, particularly suitable for conducting a slug flow process with alternative finite volume slug measure out zone which can completely fill in the upwards direction. FIG. 4 is a further alternative design of a larger scale semi-continuous reactor system of the present disclosure, particularly suitable for conducting a slug flow process.

FIG. 5 is a schematic of an alternative design of a reactor system of the present disclosure suitable for providing a pulsating flow of reactants. FIG. 6 is a schematic of an alternative design of a reactor of the present disclosure suitable for carrying out a continuous crystallization process and continuously transferring slurry from the crystallizer by a combination of macro and micro pressure swing techniques utilizing pulsating flow movement of the slurry to maintain suspension of solids. FIG. 7 is a schematic of an alternative design of a reactor system of the present disclosure having an explosion safe expansion chamber in communication with the reactor's flow path, wherein the chamber can be made to hold inert contents and pressurized.

FIG. 8 is a schematic of an alternative design of a reactor system of the present disclosure having cylinders-in-series in the BPSD to facilitate the depressurization of reactants exiting the reacting zone and having the capability for forward and reverse direction pulses.

FIG. 9 is a schematic of a reactor system having two pressure swing loading chambers operated in parallel to deliver reactant(s) into the reactor's flow path. DESCRIPTION

For the purposes of promoting an understanding of what is claimed, references will now be made to the embodiments illustrated and specific language will be used to describe the same. It will nevertheless be understood that no limitation of scope of what is claimed is thereby intended, such alterations and further modifications and such further applications of the principles thereof as illustrated therein being contemplated as would normally occur to one skilled in the art to which the disclosure relates.

Embodiments of reactor systems are described herein which are suitable for processing a continuous stream of reactant(s), for processing a continuous steam of reactant(s) moved through the reactor in a pulsating stream, for processing segregated slugs of reactant(s), for processing reactants under explosive conditions in an explosive safe manner, and for combinations thereof. Preferred embodiments of each of these reactors move process streams and/or slugs through the reactor portion of the system without contacting the process streams with a restricting orifice. Similarly, preferred reactor systems do not contact a process stream containing a solid with a pump. The preferred embodiments of the reactor systems move reactant(s) and processed reactant(s) through the reactor system utilizing a pressure differential across the process stream being moved. Furthermore, the preferred embodiments of the reactor systems can move reactants(s) and processed reactant(s) through the reactor system utilizing a pressure differential into and out of finite volume chambers at finite times in order to accurately and precisely meter overall volumetric flow rates. Movement of a process stream through a reactor system in this manner provides an efficient movement of slurries through the reactor system without clogs and plugs and minimizes wear on pumps typically caused by pumping slurries.

Slug Flow Reactor

An overview of one embodiment of the reactor system particularly suitable for a slug flow operation is apparent from FIG. 1. At least one component of the reactant feed is provided in a tank 1, which is operated in a fashion to maintain the material under proper conditions. For example, the tank 1 may include a mixer 2 and temperature control. A pressure system is preferably coupled with the tank through valve 26 and is used to move feed from the tank as desired. For example, referring to FIG. 1, an initial slug of feed is obtained by opening valve 4 and then opening valve 26 connecting the tank headspace with 30 psig nitrogen gas. Alternatively, valve 26 may remain open for extended periods of time and multiple fill-empty cycles of the pressure swing loading zone 29. This allows the nitrogen gas to force the feed material from the tank and into the line between valves 4 and 5. Valve 4 is then closed and valve 7 is opened, then valve 5 is opened, allowing high pressure nitrogen gas through valve 3 to push the feed slug along the reactor pathway beyond valve 5. Alternatively, a vacuum can be pulled on the line between valves 4 and 5, by opening and closing valve 33 to a vacuum source, prior to opening valve 4. In this manner, the line between valves 4 and 5 fills with process fluids from the tank 1 even if tank 1 is operated at lower pressures. Furthermore, the line between valves 4 and 5 can include a tank or other sealed container 29 rather than a process line only. Intermediate pressure swing vessel 29 may or may not be equipped with a mechanical agitator. Furthermore the elevated pressure gas supply used to push reactants from measure out zone 29 into the reactor 20 can also be used after each cycle to blow back through the dip tube or bottom valve of feed tank 1. This is accomplished by maintaining higher pressure gas through 32 than vapor headspace of feed tank 1 and temporarily opening valve 4 long enough to blow back through the transfer line into the feed tank 1. The benefit is that this helps to ensure representative aliquots of slurries or reagents are pulled from feed tank 1 for each measured out slug.

It will be appreciated that other feeds may be combined with the slug as it moves along the pathway to the reactor. As shown in FIG. 1, such additional feeds may enter through valves 8 or 9, downstream of a heater 10. Alternatively, additional feeds may enter upstream of the heater or at other suitable locations, depending on the nature of these other materials.

The slug moves to the reactor 20, and after a suitable process time for the process being performed the reaction product exits the reactor 20 through valve 11, optional cooling system 15 and into depressurization vessel 27. After adjusting the reaction product slug to desired product tank temperature, the intermediate vessel 27 may be depressurized independent of the reactor by closing valve 11 and opening valve 48. Finally, the reaction product slug is pushed from intermediate pressure swing vessel 27 into the product tank 31. Gases/vapors included in the product can pass through valves 12 and/or 13 and to a BPSD 55 which maintain a constant pressure on the reactor 20 or the intermediate chamber 27. Gases/vapors included in the product after its pressure is adjusted in intermediate chamber 27 may also exit the product tank through valve 52.

The flow rate of the slug through the transfer lines of the reactor system is controlled by venting downstream of the slug, for example through a metering valve 21 or 49. This controls volumetric flow rate of fluids either entering the reactor or exiting the reactor. The overall reaction time in the reactor can be controlled by setting the wait time between sequenced valve cycles that initiate flow to fill the reactor and empty the reactor. Alternatively, the flow rate can be selected to provide the desired residence time for the slug while in the reactor if the material slugs are continuously flowing through the reactor. When the reactor system is operated in repeating or sequenced batch mode, residence time in the reactor can be precisely controlled by a timer. Sequenced batch mode means that the reactor fills and then completely empties each cycle. In sequenced batch mode, the flow rate of the slug through heat exchanger upstream and downstream of the reactor system is controlled by venting downstream of the slug, for example through a metering valve 21 or 49. No slug flow occurs through upstream and downstream transfer lines during the specified reaction time period in sequenced batch mode. After the set time period in the reactor, the block valve 11 at the reactor exit port opens.

As described more fully hereafter, heaters and/or coolers can be positioned along the flow path as desired. One advantage of the preferred reactor system illustrated in FIG. 1 is that small volumes of reactant feed and reaction product can be moved through the system at highly controlled rates. Coupled with the preferred, small dimensions of the flow path, this allows for precise control of the temperature of the feed/product stream as it moves through the system.

When a slug has fully moved through the system, the flow path will typically be filled with the high pressure gas that pushed the slug along. The system is then ready for another slug to be moved through the system in the same fashion as for the prior slug. Alternatively, the system may be automatically flushed with a solvent prior to processing another slug of reactant(s). Solvent can be introduced from the tank and pump system 16, with solvent entering through valve 17 (FIG. 1), or by pressure transfer of the solvent form tank 16 into pressure swing loading zone 29 without the use of a mechanical pump. Alternatively, the reactor can remain liquid filled and operate as a Continuous

Stirred Tank Reactor (CSTR), with slugs of feed entering the reactor at a set frequency, and slugs of product similarly exiting the reactor. When operated in this manner, fluids exit the reactor through valve 11 through a dip tube in reactor 20 that can be elevated to desired minimum liquid level in 20 and contents may exit reactor 20 through a bottom valve rather than a dip tube... Alternatively, automated level control can be used in reactor 20 so that the timing of valve 11 opening and closing can be adjusted to maintain constant liquid level set point in reactor 20.

The embodiment of the reactor system illustrated in FIG. 1 is particularly suitable for the laboratory scale transformation of a reactant in discrete, segregated slugs without the use of pumps to move the reactant through the reactor system. Suitable materials of construction include, but are not limited to, stainless steel, hastelloy, tetrafluoroethylene, glass, and polymer lined glass or metal materials. The choice of materials of construction depends on the materials processed as well as pressures and temperatures utilized for the transformation, and the selection of same is well within the skill in the art.

Preferred embodiments of the reactor include a loading zone or region 29 and a flow path 30. The flow path can include a heating zone 10, a reacting zone 20, a cooling zone 15, collecting zones 27, 28, and 31, and combinations of these zones. The loading zone is designed for positioning a segregated slug of reactant(s) therein leading to the reactor 20. Heating and cooling zones may be provided at any location along the flow path, and operate in the customary fashion to affect the slug being processed. For example, a heating zone may be provided upstream of the reactor to preheat the segregated slug of reactant(s), or cooling the segregated slug if the reaction target temperature is lower than feed tank temperature. The reacting zone is designed to cause the desired processing step to occur under the conditions provided. The reacting zone 20 can be operated at elevated pressure, atmospheric pressure, or vacuum. Furthermore, a plurality of reaction vessels 20 in series can be utilized with similar pressure swing mass transfers from one to the next to conduct a series of sequential reaction steps. A cooling zone may be provided downstream of the reactor to cool the processed, segregated slug to prevent product loss and impurity formation through unwanted side reactions, or a heating zone for continuous or semi-continuous reactions that occur at desired temperatures lower than subsequent downstream processing steps. An initial collecting zone 27 is provided to collect the product contained in the segregated slug and allow for the separation of inert or unreacted gases, depressurization, cooling, or re-pressurization prior to reaction product moving into the product tank. Initial collecting zone 27 can be equipped with a mechanical agitator which is advantageous if solids form in collecting zone 27 prior to reaching product tank 31. Solid formation is more likely when collecting zone 27 is cooled.

For preferred reactor systems, the inside diameter of the flow path, e.g., the reactor's process lines typically range from about 0.08" to about 0.305" for the research scale system particularly when the process will be used for slurries with solids in flow. In these preferred systems, channel width is similar if the reactor's heat exchangers are plate style or shell-and-tube type. The smallest internal dimension in the reactor's transfer lines is typically at least 10 times larger than the largest solid particle diameter that will be present during a transformation, in order to prevent fouling.

At a laboratory scale level, a preferred feed tank for holding one or more reactants from which to form a segregated slug is typically in the order of about 100 mL to about 100 L. The reaction vessel is typically on the order of from about 10 mL to about 1 L if operating in a sequenced batch style, and from about 10 mL to about 10 L if operating in a continuous stirred tank reactor (CSTR) mode. Pilot or production scale process vessels can be orders of magnitude larger. In a sequenced batch mode, the reactor fills and completely empties for every reaction cycle. For a CSTR mode, the reactor remains filled near a desired reaction volume level, with slugs of feed reactants/reagents periodically entering the reactor and slugs of product fluids periodically exiting the reactor at similar frequencies.

Like other reactors, preferred reactors utilize components having confined lateral dimensions or static mix elements with potentially smaller characteristic dimension than the reactor itself for transfer into and out of the reaction zone. This structural feature allows a reactant slug to be quickly preheated or pre-cooled, because the ratio of the surface area to the total unit volume in the heating and cooling zones is high. As a result, a pre-heater, such as a heat exchanger, can preheat a segregated slug of reactant much faster than reactant could be heated in a traditional jacketed batch reactor. Similarly, preferred embodiments of the reactor system can allow for rapid cool down of a reaction product. The ability to more efficiently heat and/or cool the segregated slug as it passes through the flow path can contribute to a better conversion, better selectivity, better reproducibility of reaction outcome, and avoids maintaining the reactants at reacting temperatures for undesirably long periods. Certain reaction modes allow the reactor to remain at the reaction temperature even though the overall system can exhibit a sequenced batch operation.

Embodiments of the reactor system can be designed to operate over a wide range of temperatures and pressures. The laboratory scale reactor can be operated at temperatures as low as about -70 ⁰C to temperatures greater than about 400 ⁰C, which allows for the optimization of reaction conditions with regard to conversion, selectivity and the like. Because of rapid heating and cooling in the transfer systems into and out of the reactor, the feed and product tanks can be maintained at ambient conditions or lower temperatures. Therefore, reagents are only exposed to extreme conditions for finite, controlled, and scalable processing times. The use of high pressures can ensure that a reaction occurs in a single phase because solvents are maintained below their boiling point at the selected temperature. Similarly, lower boiling solvents can be utilized at high pressure to take advantage of a solvent's process efficacy, lower cost, reduced toxicity, and the like.

The physical orientation of the slug metering valves in the reactor system can also enhance the reactor's efficiency by eliminating so-called "dead legs" and "carry-over" during an inert gas push-out after a slug transfer. By mounting the metering or block valves vertically above the flow channel, any residual fluid will flow downward into the vacated tube as the gas flows through.

The reactor's flow rates can be controlled indirectly by controlling the pressure applied to a slug and by metering the downstream gas venting through a restrictive orifice beyond the reactant's flow path. As a result, flow control can be achieved without the need to pump the reactants. Typical flow rates range from 0.1 mL/min to 1.OL/min at laboratory scale. Typical flow rates may be several orders of magnitude higher for pilot or production scale.

This also allows monitoring of the system's status by examining pressure trends within the system. Pressure trends can indicate whether the valves are operating properly and whether a clog has formed in the system. As a result, the slug mass flow rates can be controlled as the fluid flows through heat exchangers upstream and downstream from the reactor. Because only a vapor phase flows through the restricting orifice, viscous liquids and slurries can be pushed through the reactor with minimal risk of clogging or plugging by the volumetric flow metering device. In addition, pressure trends and given volume differences in a reactor can provide information about the rate a slug is moving through the reactor. A gradual increase in the pressure within a closed downstream chamber is evidence that a slug of reactant was pushed into the reactor. An example of this can be illustrated with the reactor illustrated in FIG. 2. Before mass transfer of a slug from the measure out zone 102 into the reactor 110, chamber 170 downstream from the reactor is initially vented down to a pressure lower than reactor pressure by opening valve 172. Then, once the transfer of reactants from measure out zone 102 begins, valve 172 is closed and valves 145 and 114 are opened. Valve 128 is closed. Increasing pressure indicated by the pressure transmitter on chamber 170 is an indication of volumetric flow rate from measure out zone 102 into reactor 110. This pressure trend must be corrected for potential gas generation by the reaction or side reactions being carried out in the reactor 110. Vessel 170 is sufficiently larger than the measure out zone 102 that affect its pressure increase on volumetric flow of gas through valve 146 is insignificant. A similar observance within a pressure transmitter on a closed downstream chamber located after the cool down system is evidence that a slug of reactant has been pushed through the cool down system and has passed into the collector. This is similar to the method described above; except that downstream gas venting flows into chamber 143 through valve 156 downstream from product collection chamber 113 rather than through valve 114.

Reactants suitable for processing in the preferred reactor can contain solids, liquids, multiple solid and multiple liquid phases, and a gas phase. Examples of multiple liquid phases include, but are not limited to, dispersions of one liquid in another liquid, emulsions, and the like. Similarly, if a gas is a reactant in the transformation being carried out, this gas can be utilized to create the elevated pressure and to replenish the gas consumed from the headspace.

As noted above, the preferred reactor is particularly suited for handling slurries that contain one or more solid reactants and slurries in which a solid reactant is formed in the transformation carried out in the reactor. By moving precise volumes of slurry at precise and pre-programmed time periods utilizing an elevated fluid pressure instead of a pump, a slug of reactant(s) can be placed in the loading region and moved through the flow path at a controlled flow rate without a pump. The ability to move solids through the flow path at particularly high temperatures and/or pressures to effect processing provides additional options for process optimization.

The ability to control and maintain a controlled flow rate through a reactor can influence the reproducibility of a process carried out in a reactor. By utilizing an elevated fluid pressure to move reactant into a loading region and through the flow path, instead of a pump, the preferred reactor can provide superior reproducibility and maximum process efficiency. The preferred reactor can move even heavy slurries at very slow overall flow rates. Although instantaneous flow rates between finite volumes can be quite high (e.g. rapid instantaneous flow into the measure out zone, flow out of the measure out zone and into the reaction, or flow out of the reactor and into a collection vessel) overall average flow rates through the system from the feed tanks to the product tanks can remain quite low, in the range less than about 0.1 mL/min to about 1.0 L/min, with minimal risk of clogging. Such slow flow rates with heavy slurries would be difficult or impossible using a pump to move the reactant(s) through the flow path for extended times without clogging.

Reactants that remain unreactive at ambient temperature can be combined in the reactant reservoir for subsequent positioning in the loading region. For situations in which one or more reactants react upon contact at ambient temperatures, selected reactant(s) can be added to the segregated slug after positioning in the loading zone and during passage through the flow path or after passage through the flow path and into the stopped flow reaction vessel (See valves 8 and 9 in FIG. 1). Addition can occur either before or after the heating or cooling zone. Similarly, a catalyst that effects processing of the reactants at ambient temperatures can be added to the segregated slug in this same manner.

The reacting zone or region can be operated as a continuous reactor, a batch reactor, a semi-continuous reactor, or a continuous stirred tank reactor. In addition, the reacting zone can be configured to contain a wide variety of reacting chambers. Particularly suitable reacting chambers include, but are not limited to, agitated vessels, tubes or channels, high shear mixers, static mixers, microwave reactors, electrochemical reactors, ultrasonic reactors, photo-energy reactors and the like. In addition, a plurality of reaction zones in series can be utilized for a series of transformations. Reactors such as microwave reactors and photo-energy reactors perform particularly well in a small scale reactor. Finally, the preferred reactor is particularly suited for optimizing reaction conditions by processing segregated slugs of reactants at a variety of temperatures, pressures and with other varied processing conditions, collecting each processed slug of material, analyzing the product produced with each set of conditions, determining which processing conditions provide the optimum product, and scaling up the optimum process for production. Processes carried out in the preferred reactor can be readily scaled up.

Because each segregated slug of reactant processed in a preferred reaction scale reactor can be viewed as an individual process or reaction, the research scale reactor of the present disclosure is particularly suitable for optimizing and scaling up a variety of processes with regard to yield, purity, reaction kinetics and the like. Optimization and scale up can be carried out by initially operating the reactor in research mode with preprogrammed process parameter changes, such as for example, temperature, residence time, reaction stoichiometry, concentration and the like, between each slug. For some processes, a factorial study may be appropriate. The optimization processes can be carried out in a variety of ways, but an automated batch process with automated product collection is particularly useful. Once samples have been analyzed and optimum processing conditions have been determined, the reactor can be switched from research mode to production mode, and the reactor can cycle a substantial number of times utilizing a constant set of parameters to generate needed quantities of processed reactant in a "batch reactor assembly line" mode. Finally, once larger production volumes are required, a process can be scaled up to the microreactor illustrated in FIG. 4 and can be readily carried out with minimal further optimization.

FIG. 2 illustrates a further embodiment of a reactor suitable for carrying out processing of a reactant in a manner similar to the laboratory version described above. Referring to FIG. 2, a feed tank 100 maintains a pressurized head space controlled by a regulated nitrogen system 115 through valve 117. In a first step, reactant feed from feed tank 100 is transferred through valve 105 into a loading zone 102 which extends generally from open valve 105 to closed valve 106. Valve 105 is then closed to isolate the reactant slug from the feed reservoir. Valves 119 and 106 are opened and the high pressure nitrogen source 115 exerts pressure on the reactant slug, moving it through from loading zone 102 and into reactor 110. If utilized, other streams including, but not limited to, other reactants, catalysts, solvents, and the like can be added to the reactant slug prior to or after entry into reactor 110. The new capability illustrated by the device shown in FIG. 2 that is lacking in the device shown in FIG. 1 is the ability to generate back and fourth pulsating flow of the reagent slugs as they are pushed through transfer lines into or out of the reactor. This is described more below.

For a research scale cyclization reaction of keto-amide to form substituted imidazole described in detail below, a slug flow reactor system was constructed with a 25 ml Hastelloy pressure reactor (See FIG. T). The materials of construction for this reactor system included hastelloy, stainless steel, and Teflon. All automated block valves were air actuated ¹Zt" stainless steel ball valves. All process lines that transfer materials, including slurries, between the feed tank, the pressure swing measure out zone, the reactor, and the product receiver were minimum size of ¹Zt" o.d. and 0.18" i.d. stainless steel tubing. This reactor system was rated for 2000 psig and is capable of temperatures in the range -70 to 300 ⁰C.

FIG. 3 illustrates a more advanced version of the slug flow reactor shown in FIG.

2. In addition to the concepts shown in FIG. 2, the reactor illustrated in FIG. 3 provides a more precise measure out zone for fluid slugs. The measure out zone from valve 204 to valve 209 is more precise because it uses gravity, uphill flow, and overflow from the measure out zone to ensure that the zone is completely filled with liquid or slurry regardless of pressure fluctuations in the feed tank and the emptied measure out zone. For example the device illustrated in FIG. 3, has a measure out zone 207 between valves 204, 206, 208, and 209 having a finite volume. Measure out zone 207 completely fills with liquid because it fills from the bottom and is allowed to overflow sending excess fluids into overflow chamber 223. After the precisely measured out volume slug is transferred into the reactor, excess measured out material in the overflow vessel 223 is pushed back into feed tank 200. This helps to ensure that representative slugs are measured out from feed tank 200 until it is emptied.

Although other materials of construction can be used, the measure out zone illustrated in FIG. 3 and utilized in this work was constructed with hastelloy, glass, and Teflon materials of construction. All automated block valves in the pressure swing measure out zone are air actuated ¹Zt" or ¹A" hastelloy ball valves and associated piping between the valves are hastelloy tubing with minimum internal diameter of 0.18".

This concept further illustrated in FIG 2 and in FIG. 3 provides an option of pulsating the slugs back and forth as they are forced through the flow path, particularly a heating or cooling zone. Such a back and forth pulsating can be effective to inhibit or relieve a clog or partial clog which could form and interfere with the movement through the flow path. The back and forth movement in the forward and reverse direction is generated by alternating between 'blow', 'suck', 'blow', 'suck' and so on upstream from the slug, to mimic the effect of a plunger. The pulsating movement of the slug can be accomplished by intermittingly reversing the pressure differential across the slug by controlling the upstream pressure. By causing the elevated pressure upstream from the slug to drop below the base pressure on the downstream side of the slug, restoring the original pressure differential, and repeating these steps, a pulsation of the pressure differential and the direction of the slugs movement will result. This procedure can be affected manually or through a series of automated steps.

Referring to the device illustrated in FIG 2, a back and fourth pulsating flow of reagent slugs as they are pushed through transfer lines into or out of the reactor can be accomplished by sequencing valves 129, 132, and 134, and regulating pressure in 115 at a value different than the pressure in the vent downstream from valve 134. For example, while valve 119 is opened and macro pressure differential is forwarding material from measure out zone 102 into reactor 110, the sequenced valve cycle is initiated for valves 129, 132, and 134. The repeating valve cycle is to open 129, close 129, open 132, close 132, open 134, close 134 sequentially, and continue repeating this series of opening/closing valves. This causes pulsating flow in the forward and reverse direction for material traveling from measure out zone 102 to reactor 110. Vapor is venting downstream from the reactor through open valves 114, 145, and 146. Finally, the vapors vent out of the system through valves 172 and 173. Pressure in vessel 170 or downstream from valve 173 is maintained lower than pressure in vessel 136 at all times, so that overall average mass flow is in the forward direction. However, vessels 136 and 143 push back and fourth against each other with each cycle of valves 129, 132, and 134, because they alternate between being the higher pressure vessel relative to one another. The back and fourth pulsating action serves to minimize solids plugging and fouling in the transfer lines.

This same back and fourth flow can be applied during transfer out of reactor 110 and into collection vessel 113. In this case, valve 128 can be opened rather than valve 119, but the sequenced cycle for valves 129, 132, and 134 and the micro pulsating effects are the same as described in the previous paragraph.

Referring to FIG. 3, the pulsating flow is generated by cycling valves 229, 232, and 234 in a sequence that increases and decreases the pressure in the lower cylinder below valve 232. The reactant slug moves intermittently into the reactor and then into the collection subsystem 213. The reactor system is configured, in combination with the gas pressure and other reaction parameters, to cause the reactant slug to have a desired residence time in the reactor. In one embodiment, the reactor has a relatively long section of tubing which is received within a bath that helps maintain the reactant slug at the desired temperature. The design of the reactor is not critical; however the preferred design could operate at a low throughput and could function at high or low temperatures and pressures. Like the reactors discussed above, a variety of reactor types can be utilized.

Upon exiting the reactor 110 (see FIG. 2), the reactant slug moves to a heat exchanger subsystem 112 and the product is recovered. The collection process typically involves a collector subsystem 113 downstream from the cool down system, and a vapor/liquid separator 168. In preferred operations, the process vapor liquid separation occurs in the product collection and depressurization zone 113 and the separators in section 168 serve as vent knockout for reaction conditions that provide foaming. Alternatively, as illustrated in FIG. 3, upon exiting the reactor, the reactant slug can move directly into a vapor liquid separating reservoir. The product slug is cooled and depressurized in this collection vessel before it is pushed out of the system into product containers. Finally, the flow restricting metering valve associated with the vent is downstream from a second vapor liquid separator to minimize fouling of the metering valve with liquids, solids, slurries, polymer, and the like. In FIG. 4, the reactor's measure out zone from valve 304 through valve 325 is a stirred tank in communication with a vacuum source through valve 309 that can cause the tank to fill from the top rather than from the bottom through a pressurized feed tank rather than an open tube. Also, the depressurization vessel downstream from the reactor is a stirred tank 359 rather than an un-agitated pressure vessel or cylinder. Reactor for Pulsating Flow

The pulsating flow tube continuous reactor illustrated in FIGS. 5 and 6 generates mixing, even if the average linear velocity of fluids in the tube is low or zero. FIG. 5 illustrates an entire tube reactor system designed for generating pulsating flow with pulsed movement in the forward direction with automated valves 412, 414, and 416 on the downstream end of the reactor. The system can also generate forward pulses with pulsed flow in the forward direction with the operation of automated valve 434 on the front end of the reactor. In addition, the device illustrated in FIG. 5 has also demonstrated the ability to generate pulsating flow with pulsed movement in the reverse direction with the operation of automated valve 429, on the downstream end of the reactor. In general, forward and reverse direction pulses, and pulses generated by actions of automated block valve on the front end versus back end of the flow tube reactor, can all vary independently in frequency and magnitude. In other words, there may be multiple pulses with pulsed flow in the forward direction for each one pulse in the reverse direction, and vice versa. FIG. 6, on the other hand, illustrates a pulsating flow feed system which generates the back and forth motion from automated valves 527, 529, and 531 on the front end of the reactor, without showing the downstream reactor. Pulsating flow overcomes the low Reynolds numbers of laminar flow in open tubes with small overall average linear velocities through the reactor. One preferred reactor system utilizes an automated block valve and gas pressure regulators to pulsate pressure in a vapor liquid separator at the reactor exit, which causes the fluid in the reactor tubes to move in forward and reverse direction at user defined amplitude and frequency. A feature relevant to commercial systems is that such a reactor enables tunable mixing in continuous and semicontinuous flow tube reactors at research and manufacturing scale, largely independent of overall average flow rates and volumes through the system. Such reactor systems allow chemical transformations to be carried out that would not be possible or practical in most large scale batch processing equipment. Examples include vapor-liquid reactions at elevated pressures above 50 bar, reactions with superheating up to 400⁰C, or reactions with hazardous compounds.

For a pilot scale crystallization, a system having a crystallization tank of 30 liters volume and a pressure swing slurry transfer chamber of 1 liter was constructed (See FIG. 6). The reactor feed system operated for continuous crystallization is described below.

For a 30 liter scale hydroformylation of methyl methacrylate described in detail below, a reactor system having a reactor volume of about 8 liters was constructed (See FIGS. 5 and 8). This reactor system was able to contain about 5 liters of liquid and about 3 liters of vapor and provided a favorable ratio of the branched to liner aldehyde product ratio (32: 1) and low to zero levels of unreacted methyl methacrylate.

The preferred reactor system illustrated in FIG. 5 included the following components:

• A 500 ml syringe pumps 405 with automated valve package

• A reactor 410 having a volume of 8.2 liters and constructed from 316SS tubing. The reactor 410 consisted of three ¹A" outer diameter tubes in series. Each tube was coiled in cylindrical shape. As assembled, gas and liquid flow entered the bottom of each tube and exited the top. The tubes were connected in series by a 1Zt" o.d. tube that connected the top of the first tube in series with to the bottom of the next and so on. The first coil had the greatest diameter, and the third coil in series had the smallest diameter, allowing the inner coils to fit inside the outer coil.

The reactor was assembled to allow >98% of the internal diameter of the tube reactor assembly to be in the uphill flow direction, so that most of the reactor remains liquid-filled. The large diameter of the tubing and the uphill flow direction facilitated passage of the gas bubbles through the liquid phase so that excess gas reagent could be used without pushing out the majority of the liquid or slurry from the reactor.

• A twenty-four inch diameter constant temperature bath (not shown) was used to contain the coiled reactor tube. After placement inside the constant temperature bath, the bath was filled with water. A diaphragm pump (not shown) was used for pump-around agitation to maintain good mixing in the constant temperature bath and a circulator with heat transfer fluid was pumped in and out of the jacket to maintain a set temperature inside the reactor bath (55⁰C). • A BPSD received the outflow from the reactor. Throughout the duration of the 30 liter hydroformylation campaign in the 8.2 liter reactor, the BPSD's operation was varied. This is described in detail below. In one embodiment, the BPSD including cylinders 409 and 426 and valves 407, 411, 421, 419, 422, 428, 431, 432, 427 and 425 allowed separation of the product slurry from excess reagent gas and product slurry depressurized and collected in a product tank. In addition, valve 429 was oscillated to apply the pulsating pressure that caused the slurry to flow back and fourth along the length of the tube reactor. In another embodiment, the BPSD included depressurization chambers 413, 415, and 417, and automated sequenced block valves 412, 414, and 416. Each of the operating modes utilized are described in more detail below.

• Instrumentation (pressure & temperature transmitters, block & metering valves)

• Distributed Control System (DCS).

The pulsating effect in the system is achieved by creating sudden changes in pressure. Basic programming in the DCS will open and close a block valve 429 to create this effect. In one embodiment of the method, the block valve closes for about 10 seconds and opens for about 60 seconds, while the volumetric gas flow rate from the front end of the reactor through valve 434 is restricted to less than the volumetric flow rate of gas exiting the system at the back end of the reactor; creating a differential pressure of about 20 psi between cycles. The frequency of cycles can be controlled by modifying how long the valve remains open. The longer the valve remains open the fewer cycles that will be achieved. The amplitude or magnitude of differential pressure is controlled by how long the valve remains closed (less time, less pressure swing between valve cycles). Volumetric gas flow rate exiting the reactor system is restricted by one of two methods, or a combination of both. The gas vent 460 associated with catchpot 430 is opened to allow excess gas to exit the system, allowing 1 to 2 SCFH through the vent 460. Alternatively, the volumetric gas flow rate exiting the system is metered and restricted by allowing the vapor to exit the reactor system through sequenced valves and expansion chambers 413, 415, and 417. The back-and-fourth distance that the liquid travels along the length of the tube during this process will depend on the applied pressure and the capacity of the pressure swing vapor chamber 406 installed upstream the reactor. Samples of flowing reaction product slurry are periodically taken in the sampling cylinder through valve 424, which is isolated and depressurized before emptying into sample container. For about half of the hydroformylation of 30 liters of methyl methacrylate described in detail below, slurry phase exiting the reactor follows the flow path through vessels 409 and 427. The method involves forwarding fluids or slurries from chamber 409, to chamber 426, and then to the product tank from pressure chamber 426. A useful aspect of this device is that there are no restricting orifices for liquids or slurries flowing between the reactor and the product tank, only sequenced block valves that alternate between open and closed. This minimizes solids fouling and plugging. Referring to FIG. 5, normal flow path for operating the device in this mode of operation is from reactor through valves 408, 411, 419, 422, 427, and into the product tank. Normal flow of process fluids from the reactor into the product tank is not through valves 412, 414, and 416 in this mode of operation. A product tank is shown in the FIG. 5 downstream from valve 427. This mode of operation can use gravity for fluid flow from chamber 409 to chamber 426 before isolating and emptying chamber 426 to the product tank, or it can use pressure drop through the direct process lines between chambers. Between valve cycles, when reaction product fluids are flowing continuously out of the reactor, valves 411, 419, 422, and 428 are open. Valve 431 can also be opened to supply a constant regulated back pressure onto the reactor through chamber 409. At the periodic cycle set by the automation system, cylinder 426 is isolated and emptied into the product tank. This is done by the following sequence: Close valve 411 and close valve 428 to isolate chamber 426. Open valve 425 to partially vent down pressure from chamber 426, if desired. Close valve 425. Open valve 427 to create fluid communication between chamber 426 and product tank. Open valve 421 to blow through chamber 426 to product tank with inert gas. Close valve 421. Close valve 427 to isolate chamber 426 from the product tank. Open valve 432 to re-pressurize chamber 426. Close valve 432. Open valve 411 to re-establish fluid communication between chambers 409 and 426. Open valve 428 to establish fluid communication equalizing pressure in the vapor spaces of chambers 409 and 426 so that fluids may flow into chamber 426 by gravity or slight pressure difference. The venting cycle that includes the opening of valve 425 before opening valve 427 is optional, because another advantageous way to operate this system is to use the vapor pressure on chamber 426 equal to reactor pressure to forward the fluids into the product tank without first venting chamber 426. Either way, the re-pressurization of chamber 426 by opening valve 431 before opening valves 411 and 428 makes it possible to operating this device without any fluctuations on back pressure to the reactor.

For the second half of the hydro formylation of 30 liters of methyl methacrylate and for the entire 192 liter hydro formylation campaign described in detail below, a slurry phase exited the reactor through expansion chambers 413, 415, and 417. In this operating mode, a pulsating effect inside the reactor was created by expanding finite volume of gas to lower the gases pressure. As illustrated in FIG. 8, pressure cylinders can be installed in series to facilitate this process. FIG. 8 provides a simplified version of FIG. 5, showing less of the auxiliary details in order to clearly emphasize the concept of the expansion chambers in series. For the 8 liter reactor, three cylinders 721 (300 ml), 723 (70 ml), and 725 (300 ml) were installed at the backend of the system. Block valves 720, 722, and 724 controlled by DCS programming opened and closed to forward the unit of material from one closed chamber to the next at predetermined times. This sudden forward movement from chamber 723 to 725, when the automated block valve 722 between them open, results in a temporary drop in pressure at the back end of the reactor. This drop in pressure forces the liquid inside the reactor to move abruptly and promotes mixing with the gas. Timing on opening and closing of the block valves 720, 722, and 724 together with the time between cycles, allows the system to equalize and stabilize. The frequency of the cycles was controlled by the sequence's timing while the amplitude was controlled by selection of the sample cylinders used. Cylinder size and flow rate need to be considered together to ensure that system flooding doesn't occur. Either of the techniques described above can be utilized with the reactor system illustrated and either method promotes mixing of multiple phases in a flow tube reactor. A further embodiment of the pulsating flow reactor is a combination of the two operating modes described in the previous paragraphs. Here, flow exits the reactor through the in-series cylinders 721, 723, and 725, through the automated sequenced block valves as shown in FIG. 8. Each cycle causes fluid in the reactor to surge in the forward direction at the moment when valve 720 opens. In addition, a second gas cylinder regulated to higher than base pressure periodically applies elevated pressure to cylinder 721 on the back end of the reactor by briefly opening the automated block valve 726. Each time the valve is briefly opened, a flow surge in the reverse direction is experienced by the contents in the reactor. Amplitude and frequency of the pressure driven flow surges in each direction are adjustable over wide ranges by changing valve sequence times, difference between pressure regulators, and volumes of vapor chambers up stream and down stream from the reactor. This operating mode was used for 2 weeks out of the 5 week production campaign for hydro formylation of 190 liters of METHYL METHACRYLATE, described in detail below.

For scale up of the hydro formylation of methyl methacrylate to a 190 liter campaign described in detail below, a reactor system having reactor volume of about 30 liters was constructed. FIG. 5 and FIG. 8 relate to the 30 liter scaled up version of the pulsating flow tube reactor as well. The systems differed in that the reactor and the expansion chambers at the reactor exit have larger volumes. This reactor was constructed from about 550 feet length of %" outer diameter stainless steel tubing. Tubing coils for forward direction flow in the uphill direction were connected in series, with ¹Zt" outer diameter and 0.18" inner diameter stainless steel tubing connecting the top of the first coil in series to the bottom of the second coil in series, and so on. This is similar to the design of the 8.2 liter tube reactor, but larger. Furthermore, the scaled up version of expansion chambers 413, 415, and 417 illustrated in FIG. 5 were 300 ml, 3700 ml, and 14,000 ml, respectively. A noteworthy aspect of this campaign was that the continuous tube reactor ran for a total of 317 hours without shutdown due to solids fouling and plugging. The number of times that automated valves 412, 414, and 416 cycled through their automated sequence during this campaign was about 7900 times without blockage, even though solids from polymerized methyl methacrylate and precipitated catalyst flowed through the valves for the duration of the campaign.

Finally, an embodiment of the reactor that is used for feeding liquid or slurry into the inlet side of the reactor without a mechanical pump is illustrated in FIG. 9. Two pressurizable loading chambers 805 and 806 are operated in parallel at the reactor inlet where the reagent gas from 875 and the reagent liquid or slurry first mix. While one loading chamber fills, the other is emptied in the forward direction into the reactor. The supply pressure to empty the loading chamber into the reactor is the reagent gas. The rate at which the liquid or slurry exits the loading chamber through block valves 814 or 815 is controlled indirectly by the cycling rate of the automated block valves 819, 821, and 823 of the in-series de-pressurization cylinders at the reactor exit. The pressure swing parallel feed chamber device can work by the automation of sequenced block valves and pressure differences. While one feed chamber fills, the other empties, and they continually alternate. A total valve cycle is described as follows. The first half of the cycle is to forward fluids from pot 805 into the reactor, and at the same time to refill pot 806 from the feed tank. The valve sequence is executed in the order: Close valve 812. Close valve 809. Close valve 815. Open valve 808. Open valve 814. Open valve 811. Wait until chamber 806 is vented to vent pressure. Close valve 811. Open valve 813. Wait for a programmed cycle delay time. The cycle delay time provides adequate time for the off-line chamber to refill and for the on-line chamber to empty into the reactor. In addition, a useful aspect of this programmed cycle delay time is that it sets and controls an accurate rate of volumetric flow versus time for fluids from feed tank 801. Then, after the delay time, the second half of the valve cycle is to forward fluids from pot 806 and refill pot 805. The valve sequence is executed in the order: Close valve 813. Close valve 808. Close valve 814. Open valve 809. Open valve 815. Open valve 807. Close valve 807. Open valve 812. Wait the programmed cycle delay time. Finally, go back to the beginning of the first half of the valve cycle by closing valve 812, etc. The vent downstream from valves 807 or 811 could be atmospheric pressure, less than atmospheric pressure, or greater than atmospheric pressure, as long as the venting pressure is less than the pressure on the feed tank which re-loads the alternating pressure swing feed chambers.

For the same reactor system utilized for the hydroformylation of methyl methacrylate described in detail below, a pressure swing alternating parallel feed chamber slurry feeder was constructed and is illustrated in FIG. 9. This modification of the 30 liter reactor system was necessary for processing some of the feed tanks of methyl methacrylate and catalyst feed solutions. Because the solutions contained polymerized monomer, they had become too viscous to pump with the existing mechanical pump. The pressure swing chambers 805 and 806 illustrated in FIG. 9 were each 300 ml volume, constructed from 316 stainless steel, and pressure rated to 1800 psig. Sequenced valves 807, 808, 809, 811, 812, 813, 814, and 815 were all ¹A" stainless steel ball valves, and all associated process lines and fittings in contact with feed liquid or slurry were ¹Zt" outer diameter compression fitting style components. Explosion Safe Reactor

An explosion safe reactor illustrated in FIG. 7 is generally operated in a continuous flow mode. In order to maintain an explosion safe reaction environment a large fraction of the internal volume of the reactors (a pressurizable volume) 660 is inserted in communication with the reactor 610 and cylinder through generally wide lines. Flow restrictions between the reactor and the pressurizable or expansion volume 660 having smaller cross sectional areas than the characteristic dimension of the reactor itself (e.g. inner diameter) should be avoided. This arrangement provides a pressurizable volume 660 within the reactor system and allows sufficient room for gas to occupy during an explosion without exceeding the safe pressure limits of the reactor system. The explosive regime of reactor is up stream from the BPSD and the pressurizable volume 660 for exploding gasses is downstream from the BPSD. The required pressurizable volume for a given system can be calculated utilizing well known techniques and thermodynamic constants. The first step is to calculate the maximum number of gas molecules that could form during an explosion. The second step is to ensure that the pressurize-able volume has sufficient size and pressure rating to contain all of the exploding gas and not exceed pressure limits of the entire system. Flow of liquids or slurries, along with a fraction of the diluted vapor phase, through the reactor system and depressurization are controlled by sequenced block valves 623 and 625 and finite volume pressure chambers 622 and 624 rather than restricting orifices.

The reactor system described above is illustrated in FIG. 7 and was constructed for the palladium catalyzed aerobic oxidation of sec-phenylethyl alcohol reaction described in detail below. Alternatively, a standard restricting orifice control valve and level controller on vessel 622 can be used with this system if solids plugging and fouling is not an issue. In either case, the elimination of restricting orifices and pressure relief devices between the BPSD and the pressurize-able volume 660 which can be made inert with an inert gas facilitates passage of expanding gases into the volume 660 upon an unintended explosion of reactants.

Sequenced block valves allowed the reactor product solution to be depressurized and collected continuously into a product tank. The cylinders in series back pressure regulation system shown in FIGS. 5 and 8 can also be used with this reactor. However, the custom BPSD used for this reactor as shown in FIG. 7 does not cause any pressure pulsation on the reactor itself when the block valves cycle. This type of sequenced valve and dual chamber back pressure regulator can be used on any reactor for depressurizing and collecting product where pulsating reactor pressures are not desired. As with the other BPSD's described herein, a novel aspect of this device is that there are no restricting orifices for liquids or slurries flowing between the reactor and the product tank, only sequenced block valves that alternate between open and closed. This minimizes solids fouling and plugging.

Referring to FIG. 7, normal flow path for operating the device in this mode of operation is from reactor through valves 623 and 625, and into the product tank. This mode of operation can use gravity for fluid flow from chamber 622 to chamber 624 before isolating and emptying chamber 624 to the product tank, or it can use pressure drop through the direct process lines between chambers. Between valve cycles, when reaction product fluids are flowing continuously out of the reactor, valves 623 and 628 are open. At the periodic cycle executed by the automation system, cylinder 624 is isolated and emptied into the product tank. One way this can be done is by the following sequence: Close valves 628 and 623. Open valve 630, wait for vent down of pressure in chamber 624, then close valve 630. This venting step is optional. Open valve 625 to establish fluid communication between chamber 624 and product tank. Open valve 629 to blow fluids from chamber 624 into product tank with inert gas. Close valve 629. Close valve 625. Open valve 634 and wait until cylinder 624 pressure rises to reactor pressure. Then, close valve 634, open valve 623, and open valve 628 to re-establish fluid communication between chambers 622 and 624 so that product solution or slurry enters chamber 624.

For preferred embodiments of this reactor system, the process lines from the reactor, through the BPSD, and into the pressurizable volume containing an inert gas, have the same or a greater cross-sectional area than the flow path. These wide lines provide a path free of constrictions from the reaction zone to the explosion safe region to allow exploding gases in the reaction zone to easily expand into the explosion safe region 660.

For a research scale palladium catalyzed aerobic oxidation of sec-phenylethyl alcohol described in detail below, an explosion safe reactor with 5 ml stainless steel tube reactor volume and 2 liter stainless steel pressurize-able explosion safe volume that could contain an inert gas was constructed and is illustrated in FIG. 7. This prototype of the explosion safe reactor system includes a reactor constructed from a ¹Zt" stainless steel tube positioned inside a ¹A" tube heating jacket. The reactor system allows for liquid reactants and a gas to flow through the reactor co-currently in the uphill direction. The reactor system can be operated in the same manner as a co-current absorption column without packing. The reactor contents continuously flow out the top of the reaction zone within reactor 652 and into the BPSD. When appropriate, the BPSD is flushed with large volumes of an inert gas to minimize an explosive risk. This reactor system allows product, whether a liquid or slurry, to exit the bottom of the BPSD through valves 623 and 625, and allows a gas phase to exit the top of the BPSD into and through the expansion volume 660. The block valves 623 and 625 adapted to cycle to isolate the lower pressure cylinder in series so that it can be depressurized and emptied without disrupting the flow reactor or the reactor system pressure. Other means of back pressure regulation for the liquid or slurry exiting pressure chamber 622 are suitable, including standard back pressure regulators, if the liquid is not prone to fouling or plugging. Wide process lines with minimal flow restriction lead from the top of cylinder 622 into the expansion volume. When appropriate, the expansion volume 660 can be fed large volumes of an inert gas. This is generally advisable when large amounts of oxygen are present. Should a deflagration occur in an oxygen rich reaction zone, the pressurizable volume 660 containing an inert gas will receive the expanding gases produced and prevent a build up of pressure that exceeds the reactor system's pressure limits. At the outlet of the pressurizable volume 660, flow of gas out the system can be restricted with small orifice metering valves or control valves. A desired constant reactor pressure can be set by supplying regulated inert gas to the top cylinder of the BPSD.

A scaled up version of the explosion safe reactor was constructed having a reaction volume of 20 ml and a pressurize-able volume of 7 liters that could contain an inert gas. The reactor was made from ¹A" outer diameter, 0.37" inner diameter stainless steel tubing, and the explosion safe inerted pressurize-able volume was constructed of %" outer diameter 0.065" walled stainless steel tubing. Slug Flow Method

(a) The Reaction of A + B → C

If reactants A and B are unreactive when combined at ambient temperatures, but react when heated to an elevated temperature, the reactor illustrated in FIG. 2, can be utilized as described above to create a segregated slug of reactants A and B, and to process the reactant slug at an elevated temperature to form and isolate product C. If a catalyst is required to effect the desired processing, the catalyst can be added to the reactant slug through valve 126 and the combined reactants are processed in the same manner. If reactants A and B are reactive at ambient temperatures, then they are fed to the reactor separately. If only one feed contains solids, the other feeds can be added to the reactor easily with pumps or other traditional metering devices. If more than one feed contains solids, then additional subsystems like feed tank 100 and measure out zone 102 are used. The methods for reacting A and B can also be carried out if either A and/or B are solids and provided the catalyst is similarly a solid. In addition, the process of reacting A and B at an elevated temperature, with or without a catalyst, can also be carried out in the reactor if product C is a solid and crystallizes from the reactant slug before or after cooling.

(b) Cyclization of keto-amide I to form substituted imidazole II

This reaction was carried out in the reaction system illustrated in FIG. 2. In a 500 mL flask the following reactants and solvent were combined with stirring: 50 g of the keto-amide I, 89.13 g ammonium acetate, and 200 mL of methanol. Dissolution of the ammonium acetate was endothermic causing the solution to cool. The solution was stirred under a nitrogen blanket to allow the solution to adjust to ambient temperature. The solution was added to the charging tank of the reactor system, tank 100 (See FIG. 2). The reactor 110 was pressurized to about 1000 psi with nitrogen. A 500 psi regulated pressure source was applied to move a 12 mL slug of reactant into the loading zone which started at atmospheric pressure. Then, the 1000 psi nitrogen pressure source was applied to move the 12 mL slug of reactant from feed tank 100 (See FIG. 2) into the loading zone 102 and into the 25mL stirred reactor preheated to 140-150 ⁰C. Mass flow rate of the forward movement of the slurry from the loading zone 102 into the reactor 110 was controlled and metered by controlling the venting rate of vapor from the reactor through valves 114, 145, and 146, with valve 128 closed. When vapor exited the reactor, slurry and vapor from the loading zone were allowed to push into the reactor. In this manner, slurry flow into the reactor was indirectly metered by downstream venting through a restricting orifice 146. Only gases exiting the reactor system were allowed to contact the restricting orifice. The downstream orifice accounted for the majority of the pressure drop and controlled the pressure driving force for mass flow into the reactor system.

The reactants were maintained in the reactor with stirring for 60 minutes at 140- 150 ⁰C and at 1000 psi of nitrogen pressure. At the end of 60 minutes, the reaction product was forced to move further down the flow path, into a collection vessel where the reaction product was depressurized. Again, vapor exiting the downstream orifice provided the driving force for movement of reactants through the reactor's flow path. The same 1000 psi pressure source was maintained on the inlet side of the reactor during the mass transfer. The process was repeated seven times (once each hour) utilizing an automated series of block valves. The reactor system experienced no fouling and/or plugging from solids during the seven hour period of semi-continuous slug flow, even though the reactants fed to the reactor from feed tank 100 contained un-dissolved solids, and the reaction product flowing from pressure swing vessel 113 and product tank 159 also contained precipitated solids. The reaction profile was very similar to product prepared in a batch process. HPLC analysis showed that in situ yield of imidazole was about 70%. The main by-products of the reaction were de-protected product (not shown in the scheme, but included in the R-group) and a polymer. A noteworthy aspect of this 7 hour laboratory scale reactor demonstration is that slurry was semi-continuously fed to the reactor inlet and removed from the reactor outlet at an overall volumetric flow rate of only 0.2 ml/min. This is significant because it is more difficult to operate continuously with solids in flow at small scales than at large scales.

(c) Recrystallization of D

Solid D can be suspended in a solvent in which D is soluble at elevated temperatures and processed in segregated slugs through the various embodiments of the reactors disclosed. The slurry is maintained in the reactant reservoir, a segregated slug of the slurry is formed, and the slug is exposed to an elevated pressure to move the slug through the pre-heater where the slurry's temperature is increased sufficiently to dissolve D in the solvent. The hot solution of D is transported on to the cool down region to reduce the solution's temperature sufficiently for at least a portion of D in the reactant slug to crystallize. Variations in the cooling rate and the system's pressure can be investigated to provide an optimum crystal size and structure. This method is particularly useful for polish filtering of poorly soluble active ingredient molecules just prior to final crystallization. This so-called "polish filtration" is an important step in the manufacture of Active Pharmaceutical Ingredients (APIs) under cGMP processing guidelines, however it is often difficult to accomplish for poorly soluble compounds without using relatively large volumes of solvent. The fast heat up and fast cool down in flow mode minimizes molecule residence time at elevated temperature, and the elevated pressure facilitates superheating to enhance solubility. Similarly, antisolvent, reactive, or other types of crystallization, in addition to cooling crystallization, are possible with this system described.

Cd) Digestion of E

Solid E can be suspended in a solvent in which E is only slightly soluble at elevated temperatures and the resulting slurry processed in segregated slugs through the various embodiments of the reactors disclosed. The slurry is maintained in the reactant reservoir, a segregated slug of the slurry is formed and the slug exposed to an elevated fluid pressure to move the slug through the pre-heater to increase the slurry's temperature sufficiently to create and maintain an equilibrium between dissolved E and undissolved E. The hot slurry containing E is transported through the reactor and on to the cool down region to cool the slurry contained in the segregated reactant slug prior to the isolation of the fully digested E present in the fully processed segregated slug of reactant. Variations in the residence time in the reactor, the cooling rate and the system's pressure can be investigated to provide an optimum form of solid E from the digestion process.

Pulsating Flow Method

(a) Hydro formylation of methyl methacrylate

MeO₂C ^Me°>^C

methyl branched linear methacrylate aldehyde aldehyde

(i) Several runs of the hydroformylation reaction outlined above were carried out in an 8 to 9 liter flow reactor of the type illustrated in FIG. 5. A solution of reactants was prepared by combining 39.48 g of carbonylhydridotris(triphenylphosphine)rhodium and 8.44 kg of 2-propenoic acid, 2-methyl-, methyl ester (methyl methacrylate, or MMA) with agitation and a nitrogen sparge. A first run was carried out by loading the reactor with the reactant solution and maintaining the reactor and its contents at about 55°C and at about 1000 psi. The reactor pressure was established by creating a base pressure with nitrogen at the exit of the reactor in the BPSD downstream from the reactor, and introducing hydrogen and carbon monoxide at a 50:50 molar ratio into the reactor at an elevated pressure. The pressure differential caused reactant gases to flow through the reactor and into the BPSD. The majority of the pressure differential between the regulated source of hydrogen and carbon monoxide and the reactor exit was realized across the gas metering valve at the reactor inlet to control the flow rate of hydrogen and carbon monoxide. Pulsation of reactant flow was achieved by periodically causing the nitrogen pressure to become the elevated pressure and returning the nitrogen pressure to the base pressure. After 66 hours of reaction time, contents of the reactor were emptied and analyzed by GC. The ratio of branched aldehyde to linear aldehyde was 24: 1. Subsequently, improved results were obtained by using reactant gas (CO and H2) to establish the base pressure on the downstream end of the reactor rather than nitrogen or other inert gas. This avoided back diffusion of nitrogen into the back end of the reactor causing dilution of the reagent gas. The ratio of branched aldehyde to linear aldehyde was similar, but the reaction time was about 24 hours instead of 66 hours to achieve full conversion of the methyl methacrylate starting material.

The reaction was repeated in a flow-mode where liquid and gaseous reactants were continuously moved through the reactor and product continuously collected. Liquid was continuously pumped with high pressure pumps. During this reaction an internal liquid volume of about 5 liters and an internal vapor volume of about 3 liters were maintained. The pulsating effect during the reaction was achieved by periodically reversing the pressure differential across the reactor. Valve positions causing forward movement through the reactor were maintained for about 60 seconds and valve positions causing backward movement through the reactor system were maintained for about 10 seconds to reverse the pressure differential across the reactor. The pressure differential created between cycles by this process was about 20 psi. The process carried out in this manner gave a 32:1 ratio of branched aldehyde to linear aldehyde, substantially less polymer formation, and essentially no unreacted methyl methacrylate. Placement of a reservoir for containing a combination of liquid and vapor or gas upstream from the reactor facilitates the pulsatory motion of the reactants by providing a volume of gas that can compress and facilitate the backward motion of the reactants when the pressure differential is reversed. In this operating mode, product flowed from the reactor to a product tank through intermediate chambers 409 and 426. Chamber 426 was periodically isolated from chamber 409 and the reactor, depressurized, emptied to the product tank, and then re-pressurized to reactor pressure before putting chamber 426 back on line in fluid communication with chamber 409. As such, the valve cycling to periodically push product slurry to the product tank did not result in pressure pulsations on the reactor. The method is documented above. Referring to FIG. 5, normal flow path for operating the device in this mode of operation is from reactor through valves 408, 411, 419, 422, 427, and into the product tank. See the previous section of this patent for more details regarding the operation of this device.

Finally, this reaction was repeated in the same 8.2 liter reactor system (FIG. 5) in a third operating mode. First, vapor and liquid reactants were passed continuously through the reactor, without any direct off-gassing at the reactor exit from the vapor liquid separator. Secondly, reactor pressure was controlled by the gas supply pressure at the reactor inlet rather than by a second gas source supplied through the BPSD at the tube reactor outlet. Finally, the total vapor and liquid flow out of the reactor, and the total vapor and liquid flow out of the reactor exit was metered by the cylinders in series system shown in FIG. 5. Flow rates and reactor pressure in this system were controlled without the use of a restricting orifice. Flow into and through the cylinders in series was controlled by three automated block valves, sequenced as follows. The first valve in series opened briefly and then closed. This filled a 70 ml chamber with vapor, liquid, and solid precipitate from the tube reactor exit. Then, the second valve in series opened briefly and then closed. This cause the pressurized 70 ml slug to expand into a 300 ml chamber, which served to depressurize the slug by a factor approximately equal to the volume ratio, 300/70. Finally, the third automated block valve opened briefly and then closed. This caused the slug of vapor, liquid, and solid in the 300 ml chamber to expand into the 5-gallon product collection tank. Vapor exited the vent in the top of the product collection tank and was diluted with nitrogen and sent to vent treatment system. The automated sequence of these three valves was repeated about once every 2 minutes. This operation continued for about 2 days, continuously collecting product in the product tank. The process carried out in this manner gave a 32: 1 ratio of branched aldehyde to linear aldehyde, substantially less polymer formation, and essentially no unreacted methyl methacrylate.

(ii) The hydroformylation process was carried out in a 30 L continuous reactor over a 5 week period with breaks in the run for about 8 hours each weekday night and for about 2 days over weekends. Approximately 192 L of reactant solution was processed. The same tube reactor was used for the entire campaign, but changes in operating mode were made each week. A novel aspect of the reactor system used included the back pressure regulating devices (BPSD). As described more fully above, the custom designed BPSD incorporated into this reactor system did not have any restricting orifices, only automated sequenced block valves with ¹Zt" openings that were either fully opened or fully closed.

During this period 317 hours of run-time was achieved without a shutdown due to solids fouling and/or plugging. Although the reaction mixture was initially homogeneous, solids precipitated during the process. Catalyst precipitation and polymerization of methyl methacrylate were responsible for solid formation. The catalyst precipitated out of solution because it was less soluble in the product branched aldehyde than the starting material. Some methyl methacrylate polymerized in the reactor because of the long residence time (15-30 hours) and the elevated reactor temperature (55°C).

Although the reactor was manually emptied 4 times during the 317 hour campaign, it was not cleaned during this period. The solids formed throughout the process were transported through the reactor by the pulsating flow of the reactants without leaving a significant deposit on the reactor's inside walls. Different modes of pulsating flow were successfully utilized in this process.

In addition to minimizing solids fouling and plugging inside the reactor tube, the more difficult challenge of avoiding solids fouling and plugging at the reactor exit was also met. The greater fouling potential at the reactor exit resulted because the reaction mixture, upon leaving the reactor, cooled from 55°C to room temperature, and the pressure decreased from 1000 psig in the reactor to atmospheric pressure in the product tank.

During the process, the reactor contents; including a combination of vapor, liquid, and solids; passed semi-continuously through a series of expansion chambers. Increasing volumes of each expansion chamber in series caused the pressure of each product slug transferred to sequentially decrease until the product was collected in tank vented to atmospheric pressure. Because block valves between the expansion chambers were opened and closed in sequence, back pressure on the reactor was maintained between 950 psig and 1000 psig at all times during the process. The momentary decrease in pressure in the reactor when the first automated block valve in series (valve 412 in FIG. 5) opened into the first expansion chamber 413 in series provided a desired effect. By causing the reactor contents to suddenly surge forward a finite distance, solids were maintained in a suspended state and the gas and slurry phases were more intimately mixed. As a result, the risk of solids plugging and fouling and/or plugging was minimized.

Synthesis gas Of H₂ and CO in a 50:50 molar ratio (Syngas) was the vapor phase reagent feed, and methyl methacrylate containing dissolved catalyst made up the liquid phase feed. The syngas was fed to the reactor from a pressure cylinder through gas flow metering devices. Liquid feed was fed to the continuous reactor with high pressure mechanical pumps for the duration of the 192 liter, 5 week campaign. However, a sixth week of the campaign was started without using a mechanical pump for the liquid feed. During the sixth week added to the end of the 192 campaign, the pumps were replaced with pressurized dual feed tanks described in more detail below. Otherwise the tube reactor and the chemistry remained substantially the same. Only the equipment and methods for mass flow of reactant feed into the reactor and mass flow out of the reactor were changed from one week to the next. As a result of these changes, the type of pulsating movement of fluids through the reactor varied from one week to the next in order to demonstrate the various approaches to minimizing solids fouling and plugging in this process.

For the first 4 weeks of operation, the continuous reactor was operated in pulsating flow mode with forward direction pulses only. During week 5, the continuous reactor was operated in pulsating flow mode with pulses in the forward and reverse direction, with about 20 to 25 forward pulses for every one reverse direction pulse. Finally, in a sixth week of operation the continuous reactor was operated in pulsating flow mode with pulses in the forward and reverse direction, but without utilizing a mechanical pump to provide the liquid feed. Between the fifth and sixth week of operation the high pressure mechanical pumps were replaced with the alternating pressure cylinder slug flow liquid feed system described above. The results for week 3 and week 5 are provided in detail below to illustrate the different performances obtained with these different forms of pulsating flow.

By the fourth week of reactor operation utilizing pulsations in the forward direction only, temporary blockages became apparent from the reactor pressure trends. Each time this was observed the reactant's pulsating flow freed itself of plugs requiring no manual intervention to restore flow. At the beginning of the fifth week of operation, in an effort to eliminate these temporary blockages and the related pressure swings in the reactor, the reactor's operating mode was modified beginning with the week 5 of operation. The modification involved operating the continuous reactor with pulses in the forward and reverse direction, about 20 forward pulses for every one reverse direction pulse. The pressure trend data logged by the process control system for the entire week demonstrated that the periodic pulses in the reverse direction substantially reduced the temporary partial blockages observed when compared to those observed when operating with only a forward pulsation of reactants with only forward pulsations of reactants.

During the first day of week 6, after the 192 liter campaign was complete, the continuous reactor was operated in pulsating flow mode with pulses directed in the forward and reverse directions. For the week 6 operation, the alternating pressure cylinder slug flow liquid feed system illustrated in FIG. 9 replaced the mechanical pumps used in earlier operations. This was in part necessitated by the partial polymerization of the methyl methacrylate contained in the stored reaction mixture. Because of the increased polymer content of the reaction mixture, the mechanical pumps could not deliver the more viscous solution. The alternating pressure cylinder slug flow liquid feed system utilized to deliver slugs of reaction mixture to a reactor described above proved able to push the more viscous reaction mixture into the reactor. During this first day of week 6 operations, 190 - 210 mL slugs of reactant solution were semi-continuously fed into the 30 liter reactor at an elevated pressure of 1000 psig and a reaction temperature of about 55°C.

The dual pressure cylinder system with sequenced block valves was able to cycle between filling and delivery modes to provide a semi-continuous stream of reactant solution into the reactor. While the high viscosity reagent solution in one cylinder was pushed into the reactor, the parallel off-line cylinder filled with the reagent solution available from the feed tank containing reactant solution and pressurized to 30 psi. The data obtained for week 3 and week 5 of operation is provided below. As noted above, the equipment and/or methods utilized in the campaign were different and novel for each week of operation.

As operated, the liquid phase occupied about 16 liters of the reactor's volume and the gas phase occupied about 14 liters of the reactor's volume. The reactor utilized included a total length of from about 500 to about 550 feet of % inch outer diameter 316 stainless steel tubing constructed into 5 overlapping co-axial coils having outer diameters of about 22 inches, 20 inches, 18 inches, 16 inches and 14 inches, respectively. The height of each coil was about 21 inches. The individual coils were connected with VA inch outer diameter tubes connecting the top of one coil with the bottom the next coil to allow the flow path to have a generally upper direction. Mechanical pumps were utilized to introduce the liquid reactants into the reactor's flow path until the last week of operation. Product exiting the reactor was directed into a BPSD equipped with a total of three in- series cylinders to assist in depressurizing the product stream containing a vapor, a liquid and/or a solid. This reactor system controls flow rates and reactor pressure without the use of a restricting orifice having contact with liquids and/or solids.

The in-series cylinders were utilized to depressurize the multiphase mixture coming out of the reacting region of the reactor to provide a controlled mass flow rate of product feed to a collecting tank, where vapor separated from the liquid phase of the product feed. The depressurization sequence involved sequentially opening and closing valves related to the cylinders in series to reduce the process feed's pressure by a volume expansion and at the same time maintaining the appropriate reaction pressure in the reacting portion of the reactor. The volumes of the pressure cylinders in series in the direction of flow were 300 mL, 3700 mL, and 14,000 mL, respectively. Thus, the pressure of each product slug was sequentially stepped down from lOOOpsig to about 50- 100 psig, then to about 10-20 psig, depending on the ratio of vapor to slurry coming out of the reactor. In the reactor itself, the up and down pressure swing was from about 1020 psig to about 1000 psig each time the valves cycled to forward a product slug into the product tank. This occurred about 20 to 25 times per hour.

Week 3 of the 192 liter campaign will be described here. The reactor was empty at the beginning of the week and was emptied at the end of the week; therefore yield calculation is straightforward for this time period. The reactor ran for a total of 60.5 hours during week 3. The pumps stopped pumping liquid feed into the reactor but the Syngas reagent feed continued to flow for the last 20 hours of operation time for the week. This was done to finish converting all of the methyl methacrylate starting material so that the reactor could be emptied for the weekend. Total mass of methyl methacrylate plus catalyst feed solution pumped into the reactor from the feed tanks was 22.18 kg. Methyl methacrylate and catalyst feed solution was prepared in batch feed tanks throughout the duration of the campaign. Each batch feed tank contained 16 liters of methyl methacrylate and about 138 g of carbonylhydridotris(triphenylphosphine)rhodium. Therefore the week 3 used one full feed tank and one partial feed tank. Liquid reactants were introduced into the reactor's flow path at a rate of 11 mL/min. to provide a residence time of about 24 hours. Syngas flow was about 2-3 equivalents on a molar basis compared to methyl methacrylate. Total mass of crude product slurry collected in product tanks was 27.46 kg. GC results showed that crude product solution had 0.15 area % unreacted MMA, 93.37 area % branched aldehyde, and 3.07 area % linear aldehyde. The mass of solids filtered from the crude reaction product was 0.637 kg. Crude yield for the week was 88% on a molar basis in the unpurified reaction product slurry. After purification by fractional distillation, overall yield of purified branched aldehyde product was greater than 75% based on MMA limiting reagent.

By week 4 of the campaign with pulsations in the forward direction only, temporary blockages became apparent from the reactor pressure trends. As described in the previous paragraphs, the reactor freed itself of plugs with no manual intervention and without stopping the continuous reaction because of the pulsating flow. However, to prevent the temporary blockages from forming and the consequential larger pressure swings in the reactor, the operating mode was modified during week 5. During week 5, the continuous reactor was operated in pulsating flow mode with pulses in the forward and reverse direction, with about 20 forward pulses for every one reverse direction pulse. The pressure trend data logged by the process control system for week 5 compared to week 4 demonstrated that the periodic pulses in the reverse direction did in fact reduce temporary blockages in the reactor. The reactor started out emptied at the beginning of the week and was emptied at the end of the week, making yield calculation straightforward for this time period.

The reactor ran for a total of 65.5 hours during week 5 of the 192 liter campaign. The pumps stopped pumping liquid feed into the reactor but the Syngas reagent feed continued to flow for the last 20 hours of operation time for the week. This was done to finish converting all of the methyl methacrylate starting material so that the reactor could be emptied for the weekend. Each batch feed tank contained 16 liters of methyl methacrylate and about 138 g of carbonylhydridotris(triphenylphosphine)rhodium. Therefore week 5 used about 2 full batch feed tanks. Liquid reactants were introduced into the reactor's flow path at a rate of 11 mL/min. to provide a residence time of about 24 hours. Syngas flow was about 2-3 equivalents on a molar basis compared to methyl methacrylate. Total mass of methyl methacrylate plus catalyst feed solution pumped into the reactor from the feed tanks was 30.12 kg. Total mass of crude product slurry collected in product tanks was 37.63 kg. GC results showed that crude product solution had 0.03 area % unreacted MMA, 95.59 area % branched aldehyde, and 3.16 area % linear aldehyde. The mass of solids filtered from the crude reaction product was 0.153 kg. Crude yield for the week was 92% on a molar basis in the unpurified reaction product slurry. After purification by fractional distillation, overall yield of purified branched aldehyde product was greater than 80% based on MMA limiting reagent. The lower amount of polymer solids filtered from the crude product on week 5 compared to week 3, and the higher % desired branched aldehyde in the crude product solution, were evidence that the pulsed flow in the reverse direction in addition to pulsed flow in the forward direction gave better mixing and better reaction results. In the reactor itself, the up and down pressure swing caused by pulsed flow in the forward direction was about 1020 psig to about 1000 psig each time valves 412, 414, and 416 completed one open-close sequence (See FIG. 5). This occurred about 20 to 25 times per hour. In addition, the up and down pressure swing caused by pulsed flow in the reverse direction was about 1040 psig to 1020 psig each time valve 429 completed one open-close cycle. On the first day of week 6, after the 192 liter 5 week campaign, the continuous reactor was operated in pulsating flow mode with pulses in the forward and reverse direction, but the reactor did not use a mechanical pump for the liquid feed. Rather, the reactor used the alternating pressure cylinder slug flow liquid feed system.

The pressure swing alternating parallel feed pots were constructed of stainless steel and were rated for pressures up to 1900 psig. The stainless steel 300 ml parallel pots were the pressure limiting part of the equipment. Stainless steel ¹Zt" o.d. tubing, ¹Zt" compression fittings, and VA" block valves were used to construct the system. The pressure swing pots filled with 190-210 mL of viscous feed solution/slurry and alternated between fill and feed cycles. The cycling of the parallel pots worked very well. Overall average liquid volumetric throughput from the parallel pressure swing feed chambers into the reactor was about 11 mL/min. was achieved. Each pot filled with 190-210 mL of viscous feed solution/slurry in about 2.5 minutes. Each parallel pot completely emptied into the reactor about once every 35-40 minutes during the pushout cycle evidenced by a consistent volume of feed filling each parallel pot over an extended time of cycling. Therefore, about 190-210 mL of solution/slurry was pushed into the reactor about every 17-20 minutes. This proved to be a very good way to feed solution./slurry to a continuous reactor that was not pumpable against as much as 1000 psig of back pressure with existing mechanical pumps.

(b) Crystallization Method

A slurry transfer process can be carried out with reactors described for moving slurries such as, for example the reactor illustrated in FIG. 6. To effect one embodiment of this method, the reactor can be operated semi-continuously to transfer a slurry from a feed tank into continuous reactor, from a continuous crystallizer to a pressure filter, etc. Temperatures, pressures, and average mass flow rate are all adjustable over wide ranges. The operation can be carried out without the need for a mechanical pump. The method provides for movement of a slurry at a precisely metered overall mass flow rates without solids plugging which is especially challenging at very low flow rates. Additionally, the method can continuously "pump" slurries from a vessel at low pressure (e.g. atmospheric pressure) into a reactor or continuous unit operation at very high pressure (e.g. 1000 psig pressure reactor). Rather than a mechanical pump, the method relies upon the slug flow concept of pressure transfers through automated sequenced block valves into and out of a finite volume intermediate pressure vessel.

A pressure swing slurry transfer system was constructed as illustrated in FIG. 6 for use as a continuous crystallizer. Although other materials of construction can be utilized, the system was constructed from glass, Teflon, hastelloy, and stainless steel materials of construction. The main crystallization tank was a 30 liter glass vessel with agitation and jacketed temperature control. The pressure swing transfer vessel was a 1 liter hastelloy vessel with agitation and jacketed temperature control. Automated block valves 533, 534, 535, 536, 537, 538, 539, and 540 were ¹Z₄" air actuated hastelloy ball valves. Valves 544 and 542 were ¹A" air actuated hastelloy ball valves. Valves 527, 529, and 531 were ¹Zt" air actuated stainless steel ball valves. Valves 545 and 548 were ¹A" air actuated stainless steel ball valves. Valves 546 and 547 were ¹Zt" air actuated stainless steel ball valves. All process lines and automated valves through which slurry flowed either had openings of at least ¹A " or were ¹A" diameter tubing. The slurry transfer system was used to semi-continuously meter slurry out of a 30 liter continuous crystallizer and into a pressure filter. The continuous crystallization tank was operated at 0⁰C and atmospheric pressure. The filter was operated at 0⁰C and 15 psig pressure. Overall mass flow rate of the slurry from the crystallizer to the filter is adjustable and can range from about 1 liter per 5 minutes to 1 liter per day (and even down to lower overall average volumetric flow, e.g. 1 liter in several days). Overall mass flow rate can be adjusted by changing the frequency that the automated block valves cycle through their repeating sequence. For example, if the continuous crystallizer is operated at an overall mass flow rate of 4 liters per hour, then the automated sequence can repeat once every 15 minutes, causing 1 liter of slurry to be transferred at a time.

The 30 liter stirred tank 552 was initially filled with slurry at 0 psig and vented. The 1 liter transfer vessel 541 was initially at 15 psig and empty. Valves 535 and 546 were in communication with a house vacuum system. A vacuum was pulled on the 1 liter transfer vessel 541 by opening valve 535, valve 540 and all valves therebetween. When the pressure in the 1 -liter slurry transfer vessel was sufficiently reduced, the valve 540 to the vacuum was closed. Then valve 544 was opened to pull 1 liter of slurry out from the 30 liter continuous crystallizer 552 into the 1 -liter transfer vessel 541. When the transfer was complete, the contents of the transfer line between the crystallizer 552 and the transfer vessel 541 were blown back into the crystallizer 552 to empty the transfer line by opening valve 534 and all valves between valve 534 and vessels 552 and 541.

Once the transfer line was empty valve 544 between the vessels was closed, the 1 liter transfer vessel 541 was pressurized to 15 psig, and valve 542 below the transfer vessel was opened to begin the pressure transfer of the slurry to a filter (or other unit operation). After the transfer had begun, flow from the transfer vessel was transformed into a pulsating flow mode, causing the slurry to move forward from the 1 -liter vessel in a generally forward/backward manner. This is accomplished by opening and closing valve 527, then valve 529, then valve 531 in repeating sequence. Overall average mass flow proceeded in the forward direction because average pressure in vessel 525 was higher than downstream continuous process vent from the pressure filter. For example, the slurry can move forward 12 inches, back 11 inches, forward 12 inches, back 11 inches, and so on. The forward/backward motion keeps solids suspended and transfer lines from plugging with solids during the transfer. Completion of the transfer is indicated when pressure in the filter headspace reaches the same pressure as the 1 -liter transfer vessel (e.g. 15 psig). The cycle was repeated after a set time delay. When the unit is operated in this manner the slurry can be transferred at a rate of 1 liter per cycle.

This method provides for an effective way to semi-continuously "pump" slurries with accurate overall mass metering, even at pressures as high as 1000 psig and at overall average volumetric flow rates as low of less than 0.1 ml/min without plugging of transfer lines. The volume of the slurry transferred per cycle can be changed by the selection of a transfer vessel having a different volume or by partially filling the existing transfer vessel during each cycle. The discharge pressure of the slurry transfer vessel can be changed by adjusting the pressure regulator controlling the inert gas to a different pressure. The frequency of the pulsating forward and reverse direction flow can be changed by altering the wait time between valve cycles for valves 527, 529, and 531. The magnitude of the pulsating forward and reverse direction flow can be changed by volume of the pressure cylinders 525 and 526.

Methods in Explosion Safe Reactor

Palladium catalyzed Aerobic Oxidation of sec-phenylethyl alcohol

A reactor of the type illustrated in FIG. 7 having an expansion volume of an inert gas downstream from the reacting zone was utilized in this process. The pathway between the BPSD and the expansion volume region included generally wide process lines with minimal flow restrictions. The expansion volume region was sized to maintain the volume of gas that could be generated upon the explosion of the reactor contents without exceeding the reactors pressure limitations. For the present reaction, the expansion volume region had an internal volume of two liters. Stock solutions of reactants and catalyst were introduced into the reactor with mechanical pumps and oxygen provided from an oxygen cylinder having a regulator to control output pressure and a flow metering device to control the volumetric flow rate of oxygen. The downstream BPSD was operated at 15 psig pressure and continuously flushed with copious amounts of nitrogen gas to maintain oxygen containing gases contained therein below the flammable limit. As a result, the continuous flow reaction zone operated at a back pressure of 15 psig.

Stock solutions of catalyst (A) and alcohol (B) were prepared. Stock solution A was obtained by diluting 0.673 g (3.0 mM) of Pd(OAc)₂ to 100 mL with anhydrous toluene to provide a solution containing a small amount of insoluble material which was filtered off when solution A was transferred into a mechanical pump. Stock solution B was obtained by combining sec-phenylethyl alcohol (3.66 g, 30 mM), triethylamine (0.303 g, 3 mM), and tetradecane (0.198 g, 1 mM) and tetrahydrofuran (15 mL, anhydrous) and diluting the combined components to 50 mL with anhydrous toluene. The two stock solutions were introduced into the reactor with mechanical pumps into the bottom of a heated reactor that included ¹A inch stainless steel tube inside of a Vi inch tube heating jacket. The reactor and heating jacket were mounted in a vertical position to cause liquid flow to be uphill. The stock solutions were pumped at individual flow rates of 0.047 mL/minute into the reactor maintained at approximately 60⁰C while oxygen at 15 psi was introduced co-currently into the reactant stream within the reactor's flow-path upstream from the reactor. The volumetric flow rate of oxygen was controlled with a restricting orifice metering valve. Supply pressure of pure oxygen up stream from the metering valve was about 50 psig, while pressure downstream from the metering valve was approximately equal to the reactor pressure (15 psig) because there was little pressure drop across the flow tube reactor at these operating rates. The desired reactor pressure was maintained by controlling the supply of regulated inert gas to the vapor liquid separator vessel 622 (See FIG. 7). Samples were taken at thirty minute intervals and analyzed by GC. After about 120 minutes the GC yield of acetophenone stabilized at between about 85 to about 88 %.

In this operating mode, product solution flowed from the reactor to a product tank through intermediate chambers 622 and 624. Chamber 624 was periodically isolated from chamber 622 and the reactor, depressurized, emptied to the product tank, and then re-pressurized to reactor pressure before putting it back on line in fluid communication with chamber 622. The valve cycling to periodically push product solution to the product tank did not result in pressure pulsations on the reactor. The method is further documented above. Referring to FIG. 7, the typical flow path for operating the device in this mode of operation is from reactor through valves 623 and 625 and into the product tank. A more detailed discussion of how valves 623, 625, 628, 634, 629, and 630 can be sequenced to accomplish back pressure regulation, vapor-liquid separation and liquid product collection is provided above. While applicant's invention has been described in detail above with reference to specific embodiments, it will be understood that modifications and alterations in embodiments disclosed may be made by those practiced in the art without departing from the spirit and scope of the disclosure. All such modifications and alterations are intended to be covered.

Claims

What is claimed is:

1. A BPSD device for separating a gas from a flow-able reaction product and for providing a back pressure to a reactor, the device comprising:

(a) a first reservoir, downstream from the reactor, and adapted: (i) for fluid communication with the reactor; (ii) to receive the flow-able reaction product from the reactor; and (iii) to provide a headspace over the reaction product received therein, the reservoir having an exit port for removal of the degassed product;

(b) a controlled pressure source in communication with the headspace, adapted to maintain a back pressure on the reservoir and reactor; and (c) a vent in fluid communication with the headspace adapted for removal of gas at a controlled rate.

2. The device of claim 1, further comprising a second reservoir in fluid communication with the first reservoir through a transfer valve, the second reservoir having exit ports equipped with first and second exit valves, the first exit valve adapted for the removal of the flow-able reaction product, the second exit valve adapted for the transfer of a gas or vapor, wherein by manipulating the transfer valve and the first and second exit valves, the flow-able reaction product received in the first reservoir can be transferred and isolated in the second reservoir, the second reservoir can be depressurized and emptied and re-pressurized without creating a pressure fluctuation within the reactor and without contacting the flow-able product with a restricting orifice.

3. The device of claim 2, further comprising an expansion volume, the expansion volume adapted to communicate with the reactor through the headspace within the first reservoir and to contain an explosive volume derived from the reactor without exceeding the device or reactors pressure limit.

4. The device of claim 3, wherein the expansion volume contains a venting port having a restricting orifice.

5. The device of claim 4, wherein the expansion volume is adapted to be filled with an inert gas through the headspace of the first reservoir.

6. The device of claim 5, wherein the expansion volume is downstream from the first reservoir.

7. A device for processing a reactant comprising: (a) a flow path having upstream and downstream regions and a processing zone therebetween, the processing zone adapted to receive and process a reactant;

(b) a first pressure source in fluid communication with the upstream region and a second pressure source in fluid communication with the downstream region, wherein the pressures sources are adapted to provide a pressure differential across the flow path; and

(c) a back pressure separating device including a reservoir in fluid communication with the flow path, and the second pressure source, the back pressure separating device adapted to receive a processed reactant from the processing zone through the flow path and provide a headspace over the processed reactant received therein, the headspace in fluid communication with a vent having a restricting orifice, the headspace adapted for the accumulation of any gas contained in the processed reactant.

8. The device of claim 7, wherein the back pressure separating device further comprises a second reservoir in communication with the first reservoir through a transfer valve, the second reservoir having exit ports equipped with first and second exit valves, the first exit valve adapted for the removal of the flow-able reaction product, the second exit valve adapted for the transfer of a gas or vapor, wherein by manipulating the transfer valve and the first and second exit valves, the flow-able reaction product received in the first reservoir can be transferred and isolated in the second reservoir, the second reservoir can be depressurized and emptied and re-pressurized without creating a pressure fluctuation within the flow-path and without contacting the processed reactant with a restricting orifice.

9. The device of claim 7, wherein the first pressure source is a mechanical pump.

10. The device of claim 7, wherein the first pressure source is a regulated compressed gas.

11. The device of claim 7, wherein the second pressure source is a regulated compressed gas.

12. The device of claim 7, wherein the second pressure source is the orifice positioned in the vent adapted to release pressure derived from the first pressure source at a rate sufficient to provide a desired back pressure within the flow-path.

13. The device of claim 12, wherein the orifice is an adjustable valve.

14. The device of claim 7, wherein at least one pressure source is a compressed gaseous reactant.

15. The device of claim 7, wherein processing zone has a generally tubular structure.

16. The device of claim 7, wherein processing zone includes a non-tubular agitated vessel.

17. The device of claim 7, wherein the flow path includes a pre-reactor heat exchanger, a reacting region, a post reactor heat exchanger, and a collecting region.

18. The device of claim 7 further comprising an expansion volume in fluid communication with the flow-path and with the back pressure regulating device.

19. The device of claim 7, further comprising a plurality of vessels- in- series, wherein the plurality of vessels- in- series is in fluid communication with the back pressure separating device and adapted to provide a pressure reduction for a volume of processed reactant received from the back pressure separating device.

20. The device of claim 7, further comprising a loading region and a reactant source, wherein the loading region is in fluid communication with the upstream region of the flow path and the reactant source is in fluid communication with the loading region.

21. The device of claim 20, wherein the reactant source is a mechanical pump.

22. The device of claim 20, wherein the reactant source is a loading vessel adapted to contain reactant at a pressure sufficient to cause the reactant to flow into the loading region.

23. The device of claim 20, wherein the reactant source includes at least two parallel vessels, wherein each parallel vessel is in communication with the loading zone through at least two valves adapted to control fluid communication between each parallel vessel and the loading region and wherein each parallel vessel is adapted to contain reactant at a pressure sufficient to cause the reactant to flow into the loading region through an open valve.

24. A device for processing a reactant comprising: (a) a flow path having upstream and downstream regions and a processing zone therebetween, the processing zone adapted to receive and process a reactant; (b) a first pressure source in fluid communication with the upstream region and a back pressure source in fluid communication with the downstream region, wherein the pressures sources are adapted to provide a pressure differential across the flow path; and (c) a plurality of adjacent vessels aligned in series and adapted to provide (i) periodic fluid communication between the flow path and a first vessel, (ii) periodic fluid communication between adjacent vessels and (iii) a periodic back pressure to the flow path, wherein each vessel has a volume and is adapted to receive at least a partial volume of processed reactant from the flow path or a prior vessel to provide a volume expansion and a pressure drop for the partial volume of processed reactant received.

25. The device of claim 24, wherein the first pressure source is a mechanical pump.

26. The device of claim 24, wherein the first pressure source is a regulated compressed gas.

27. The device of claim 24, wherein the second pressure source is a regulated compressed gas.

28. The device of claim 24, wherein the second pressure source is the orifice positioned in the vent adapted to release pressure derived from the first pressure source at a rate sufficient to provide a desired back pressure within the flow-path.

29. The device of claim 28, wherein the orifice is an adjustable valve.

30. The device of claim 24, wherein at least one pressure source is a compressed gaseous reactant.

31. The device of claim 24, wherein processing zone has a generally tubular structure.

32. The device of claim 24, wherein processing zone includes a non-tubular agitated vessel.

33. The device of claim 24, wherein the flow path includes a pre-reactor heat exchanger, a reacting region, a post reactor heat exchanger, and a collecting region.

34. The device of claim 24 further comprising an expansion volume in fluid communication with the flow-path and with the back pressure regulating device.

35. The device of claim 24, further comprising a back pressure separating device including a reservoir in fluid communication with the flow path, and the second pressure source, the back pressure separating device adapted to receive a processed reactant from the processing zone through the flow path, deliver the processed reactant to the vessels-in-series, and provide a headspace over the processed reactant received therein, the headspace in fluid communication with a vent having a restricting orifice and adapted for the accumulation of any gas contained in the processed reactant.

36. The device of claim 24, further comprising a loading region and a reactant source, wherein the loading region is in fluid communication with the upstream region of the flow path and the reactant source is in fluid communication with the loading region.

37. The device of claim 36, wherein the reactant source is a mechanical pump.

38. The device of claim 36, wherein the reactant source is a loading vessel adapted to contain reactant at a pressure sufficient to cause the reactant to flow into the loading region.

39. The device of claim 36, wherein the reactant source includes at least two parallel vessels, wherein each parallel vessel is in communication with the loading zone through at least two valves adapted to control fluid communication between each parallel vessel and the loading region and wherein each parallel vessel is adapted to contain reactant at a pressure sufficient to cause the reactant to flow into the loading region through an open valve.

40. A method for processing a reactant with a reactor comprising the acts of:

(a) providing a reactor having a flow path, wherein the flow path includes upstream and downstream regions and a processing zone therebetween, the processing zone adapted to receive and process a reactant and the flow path is free of a restrictive orifice contacting the reactant or a processed reactant;

(b) positioning the reactant in the upstream region of the flow path; and

(c) moving the reactant through the processing zone to effect processing by providing a pressure differential across the flow path, wherein the pressure differential provides a base pressure and an elevated pressure, and the pressure differential causes the reactant to move through the processing region in the direction of the base pressure and away from the elevated pressure; and

(d) collecting the processed reactant from the flow path.

41. The method of claim 40, wherein providing a reactor includes providing a reactor having a valves to establish a pressure differential and to control moving the reactant through the flow path, wherein all valves in contact with moving reactant or processed reagent are block valves only capable of being fully open or fully closed.

42. The method of claim 40, wherein the moving is accomplished by periodically altering the pressure differential to produce a pulsating flow of reactant through the reactor.

43. The method of claim 42, wherein altering the pressure differential involves periodically altering the magnitude of the differential while maintaining its direction.

44. The method of claim 42, wherein altering the magnitude of the pressure differential involves increasing the elevated pressure.

45. The method of claim 42, wherein altering the magnitude of the pressure differential involves decreasing the base pressure.

46. The method of claim 42, wherein providing a reactor involves providing a reactor having a loading zone in fluid communication with the upstream region of the flow path and positioning involves positioning a segregated slug of reactant in the loading zone.

47. The method of claim 46, wherein creating a pressure differential involves periodically reversing the pressure differential and the moving involves moving the reactant through the flow path with an pulsating motion.

48. The method of claim 46, wherein creating a pressure differential involves periodically altering the magnitude of the differential while maintaining its direction.

49. The method of claim 48, wherein altering the magnitude of the pressure differential involves increasing the elevated pressure.

50. The method of claim 48, wherein altering the magnitude of the pressure differential involves decreasing the base pressure.

51. The method of claim 42 , wherein providing a reactor includes providing a reactor having a flow path including a loading zone, a pre-processing heat exchange region, a processing region, a post-processing heat exchange region, and a collecting region, and the method further includes the acts of positioning a reactant slug within the loading zone, passing the reactant slug through the preprocessing heat exchanger region, processing the reactant slug within the processing region, cooling the processed slug within the post-processing heat exchange region, and collecting the processed slug in the collecting region.

52. The method of claim 51 , wherein said positioning the reactant in the loading zone involves positioning a reactant containing a solid therein.

53. The method of claim 51 , wherein said providing a processed slug involves providing a processed slug containing a solid.

54. The method of claim 51, wherein said providing a reactor involves providing a reactor having a BPSD in fluid communication with said flow path.

55. The method of claim 54, wherein collecting the processed reactant involves isolating a reservoir within the BPSD, depressurizing the isolated reservoir, emptying the isolated reservoir, and re-pressurizing the isolated reservoir.

56. The method of claim 42, wherein said providing a reactor involves providing a reactor having a plurality of vessels-in-series in fluid communication with said flow path.

57. The method of claim 56, wherein collecting the processed reactant involves moving the processed reactant sequentially through the vessels-in-series to at least partially depressurize the processed reactant, and removing the partially depressurized processed reactant from the vessels-in-series.

58. The method of claim 42, wherein providing a reactor involves providing a reactor having an expansion volume in fluid communication with the processing zone and downstream region and positioning the reactant in the upstream region of the flow path involves positioning the reactant having an explosive potential.

59. The method of claim 58, wherein providing a reactor further involves providing a reactor having a BPSD in fluid communication with the expansion volume and the downstream region of the flow path and wherein moving the reactant through the processing zone additionally involves moving an inert gas through the zone with the reactant and allowing at least a portion of the inert gas to collect in the expansion volume and in the BPSD.

60. The method of claim 58, wherein providing a reactor further involves providing a reactor having a plurality of vessels-in series in fluid communication with the expansion volume and the downstream region of the flow path and wherein moving the reactant through the processing zone additionally involves moving an inert gas through the zone with the reactant and allowing at least a portion of the inert gas to collect in the expansion volume.

61. The method of claim 42, wherein the moving said reactant through the processing zone is carried out in a continuous manner, a semi-continuous manner or in a batch manner.

62. A method for processing a reactant with a reactor comprising the acts of:

(a) providing a reactor having a flow path, the flow path including a processing region therein;

(b) positioning the reactant in the flow path; (c) moving the reactant through the flow path by providing a pressure differential across the flow path, wherein the pressure differential provides a base pressure and an elevated pressure, and the pressure differential causes the reactant to move through the processing region in the direction of the base pressure and away from the elevated pressure; (d) periodically altering the pressure differential to produce a pulsating flow of reactant through the processing region; and

(e) forming a processed reactant in the processing region.

63. The method of claim 62, wherein altering the pressure differential involves periodically altering the magnitude of the differential while maintaining its direction.

64. The method of claim 62, wherein altering the magnitude of the pressure differential involves increasing the elevated pressure.

65. The method of claim 62, wherein altering the magnitude of the pressure differential involves decreasing the base pressure.

66. The method of claim 62, wherein the moving is accomplished without subjecting the reactant to a positive pressure created by fluid contact with a pump.

67. The method of claim 62, wherein the moving is accomplished without subjecting the reactant or processed reactant to a restrictive orifice.

68. The method of claim 62, wherein providing a reactor includes providing a reactor having a flow path including a pre-reactor heat exchange region, a reacting region, a post-reactor heat exchange region, and a collecting region.

69. The method of claim 62, wherein the providing a reactor includes providing a reactor having a BPSD in fluid communication with the flow path and the method further comprises collecting the processed reactant in the BPSD.

70. The method of claim 62, wherein the providing a reactor includes providing a reactor having a plurality of vessels-in- series in periodic fluid communication with the flow path and adapted to receive a volume of processed reactant and provide a reduction in pressure upon passage of the volume of processed reactant through the plurality of vessels-in-series and the method further comprises removing the processed reactant through the plurality of vessels-in-series.

71. The method of claim 62, wherein the providing a reactor includes providing a reactor having a expansion volume in fluid communication with the processing region, wherein the expansion volume is sized and constructed to receive and maintain an explosive volume from the processing region and moving the reactant involves moving a reactant having an explosive potential across the flowpath.

72. The method of claim 71 , wherein moving the reactant through the flow path additionally involves moving an inert gas through the flow path with the reactant and allowing at least a portion of the inert gas to collect in the expansion volume.

73. The method of claim 62, wherein the forming of the processed reactant is carried out in a continuous manner, a semi-continuous manner or in a batch manner.

74. The method of claim 62 , wherein providing a reactor includes providing a reactor having a flow path including a loading zone, a pre-processing heat exchange region, a processing region, a post-processing heat exchange region, and a collecting region, and the method further includes the acts of positioning a reactant slug within the loading zone, passing the reactant slug through the preprocessing heat exchanger region, processing the reactant slug within the processing region, cooling the processed slug within the post-processing heat exchange region, and collecting the processed slug in the collecting region.

75. The method of claim 74, wherein said positioning the reactant in the loading zone involves positioning a reactant containing a solid therein.

76. The method of claim 74, wherein said providing a processed slug involves providing a processed slug containing a solid.

77. The device of claim 75, wherein the reactant source is a mechanical pump.

78. The device of claim 75, wherein the reactant source is a loading vessel adapted to contain reactant at a pressure sufficient to cause the reactant to flow into the loading region.

79. The device of claim 75, wherein the reactant source includes at least two parallel vessels, wherein each parallel vessel is in communication with the loading zone through at least two valves adapted to control fluid communication between each parallel vessel and the loading region and wherein each parallel vessel is adapted to contain reactant at a pressure sufficient to cause the reactant to flow into the loading region through an open valve.

80. A method for processing a segregated slug of reactant with a reactor to provide a processed reactant slug, the method comprising the acts of:

(a) providing a reactor having a loading region and a flow path;

(b) positioning the reactant in the loading region to form a segregated slug of reactant therein; and

(c) moving the reactant slug from the loading region through the processing zone to effect processing by providing a pressure differential across the flow path, wherein the pressure differential provides a base pressure and an elevated pressure, and the pressure differential causes the reactant to move through the processing region in the direction of the base pressure and away from the elevated pressure, wherein moving the segregated slug is accomplished without subjecting the slug to a positive pressure created by fluid contact with a pump.

81. The method of claim 80, wherein the method further includes periodically altering the pressure differential to cause a pulsating flow through the reactor's flow path.

82. The method of claim 81, wherein periodically altering the pressure differential involves periodically increasing the magnitude of the pressure differential to cause a pulsating flow of the segregated slug through the flow path.

83. The method of claim 80, wherein periodically altering the pressure differential involves periodically decreasing the magnitude of the pressure differential to cause a pulsating flow of the segregated slug through the flow path.

84. The method of claim 80, wherein periodically altering the pressure differential involves periodically reversing the direction of the pressure differential to cause a pulsating flow of the segregated slug through the flow path.

85. The method of claim 80, further comprising the acts of providing, positioning and moving to effect the processing of an additional segregated slug.

86. The method of claim 80, wherein the act of providing a reactor includes providing a reactor having a flow path including a pre-processing heat exchange region, a processing region, a post-processing heat exchange region, and a collecting region, wherein the method of processing a segregated slug further involves preheating the reactant slug in the pre-processing heat exchange region and cooling the processed reactant slug in the post-processing heat exchange region, and collecting the processed segregated slug in the collecting region.

87. The method of claim 80, wherein moving the reactant slug from the loading region through the processing zone to effect processing involves a form of processing selected from the group consisting of an oxidation, a reduction, a carbonylation, a polymerization, a cyclization, an addition reaction, an explosive regime reaction, an elimination reaction, a substitution reaction, an insertion reaction, and a rearrangement.

88. The method of claim 80, wherein the moving said reactant slug through the processing zone is carried out in a continuous manner, a semi-continuous manner or in a batch manner.

89. The method of claim 80, wherein providing a reactor involves providing a reactor wherein the flow path is free of a restrictive orifice and the moving is carried out without contacting the reactant or a processed reactant with the restrictive orifice.