WO2001002090A1 - Method and multipurpose reactor for synthesis and crystallisation - Google Patents

Abstract

The invention concerns a method and a multipurpose reactor for synthesis and crystallisation in a liquid medium, based on synthesis in a hot process reaction zone (1), of a compound dissolved in the reaction medium at a reaction temperature, driving the reaction medium towards a cold process crystallisation zone (19), and crystallising said dissolved compound. The invention is characterised in that, prior to its being introduced into the crystallisation zone, the reaction medium is gradually cooled by heat exchange with the crystallisation juice coming from the corresponding zone, in a intermediate heat-exchanging zone (5). Said heat exchange is preferably carried out by recirculation of the crystallisation juice, thereby ensuring a back mixing in the intermediate zone consisting in particular of a plate column (6).

Description

 Multifunctional synthesis and crystallization process and reactor.

The present invention relates to a new process for synthesis and crystallization in a liquid medium. It also relates to a multifunctional synthesis and crystallization reactor in a liquid medium, of the type comprising a hot reaction zone and a cold crystallization zone, in particular suitable for the implementation of such a process. It also relates to the crystallized product capable of being obtained by the use of this reactor and this process. It also relates to the use of this reactor and of this process to lead to particular characteristics of the crystallized product.

The invention applies very particularly to the synthesis and crystallization of products having a high solubility in the reaction medium at the temperature of the reaction, in particular in the field of organic chemistry.

The invention finds an advantageous application in the production of amides, in particular pharmaceutical amides, obtained by reaction between an amine and a carboxylic acid, including derivatives of carboxylic acid. More particularly, the invention applies to the production of N-acetyl-p-aminopheinπol (APAP) or paracetamol.

Crystallization can be done according to various cumulative principles, in particular: by evaporation, by change of solvent, in the presence of a crystallization promoter, by cold.

In practice, synthesis and crystallization of this type of product are carried out in separate units, reaction unit and crystallization unit, and then require means of transfer from one unit to another (in particular pipes and thermostated pumps) with , in the case of crystallization by cold, all the difficulties linked to the transfer of the sensitive liquid from a hot environment to a cold environment, in particular the phenomena of shielding by crystallization and agglomeration on the cold zones, which can lead to the encrustation of the transfer means and of the crystallization unit. Different types of crystallizers are described in Handbook of Industrial Crystallization 1993, Edited by Allan S. Myerson, Published by Butterworth- Heinemann, eg p 118-124.

From US Pat. No. 3,600,701, a multifunctional synthesis and crystallization reactor is known comprising a reaction zone of small dimensions and maintained at high temperature, representing approximately 10% of the size of the reactor, and a crystallization section of large dimension. and disposed immediately in contact with the reaction zone so as to allow the reaction product to flow directly and rapidly from the reaction zone to the crystallization zone, which is provided with a stirring device. The reaction zone is provided with a feed while the crystallization zone is provided at its lower part with a withdrawal device. This reactor is used for carrying out a reaction in a liquid medium at elevated temperature, followed by crystallization of the product in the crystallization zone which is maintained at a temperature below the reaction zone. This arrangement does not allow an equilibrium displacement. It is solely based on the difference in solubility at different temperatures, the oversized volume of the crystallization zone making it possible to rapidly cool the reaction product by quenching. This has the consequence that the reaction is difficult to control, the assembly lacks operational flexibility and the conversion is limited by the thermodynamics of the reaction.

The present invention aims to provide a multifunctional integrated reactor and a method, in particular a method suitable for the implementation of such a reactor, allowing the synthesis and the crystallization of products, in particular of products having a high solubility in the reaction medium at the reaction temperature.

Another objective of the invention is to provide such a reactor and method making it possible to produce with a high yield, by increasing conversion thanks to a shift in equilibrium and / or by an increase in selectivity in the case of consecutive reactions.

Yet another objective is to provide such a reactor and process that can operate discontinuously (batch) or, preferably, continuously.

Yet another objective of the invention is to provide such a reactor and method making it possible to minimize the shielding phenomena which can lead to the encrustation of the crystallization zone.

Yet another objective of the invention is to provide such an advantageous reactor and process on the economic plane, since it employs little equipment (pumps, pipes, etc.), requiring less thermal insulation or tracing and less energy to keep it running.

Yet another objective of the invention is to provide such a reactor and process which is advantageous from the safety point of view, in particular because of the integrated configuration and the resulting reduction in the risks of leaks and contamination.

Yet another objective of the invention is to provide such a reactor and process which is advantageous in terms of safety, by avoiding the waiting times between operations and transfers of material from a reaction unit to a crystallization unit. . Yet another objective of the invention is to propose such a reactor and process making it possible to comply under favorable conditions with the Good Manufacturing Practices in force in Europe.

Yet another objective of the invention is to propose such a reactor which is of compact constitution, not requiring the use of pumps and pipes between the different functional areas, and ensuring an advantage in terms of space and cost of production and d 'installation.

Yet another objective of the invention is to propose such a process and reactor making it possible to control the characteristics of the final product.

The first object of the invention is a process for synthesis and crystallization in a liquid medium, of the type comprising hot synthesis, in a zone of O 01/02090

hot reaction R, of a compound which is in the dissolved state in the reaction medium at the reaction temperature, sending the reaction medium from zone R to a zone of cold crystallization C, and cold crystallization of said compound dissolved. This process is characterized in that a progressive cooling of the reaction medium is ensured before admitting it into the crystallization zone, this cooling preferably being provided by heat exchange between the reaction medium and the crystallization juice, in an intermediate zone . A progressive cooling of the reaction medium is ensured, which will only be admitted into the cooled crystallization zone when its temperature has been sufficiently lowered to reduce the risks of shielding or nucleation which could otherwise lead to encrustation of the crystallizer. In other words, this process makes it possible to control the temperature difference between R and C, a difference which is determined by the reaction system.

According to the preferred embodiment of the invention, the progressive cooling is only ensured by the exchange of heat between the fluids present in the reactor. By definition, functioning is adiabatic.

According to the most preferred method, a direct heat exchange is ensured by mixing the crystallization juice and the reaction medium, by recirculating or recycling the crystallization juice from the crystallization zone to the reaction zone (we speak of retro -mixture), while substantially maintaining the crystals in the crystallization zone. The crystallization of the product in the crystallization zone makes it possible to shift the reaction equilibrium in the reaction zone and to ensure high conversion and selectivity.

Recirculation is preferably carried out so as to recycle the finest crystals, also called fines, and to allow their resolubilization when they return to their solubilization temperature. This arrangement makes it possible to limit or avoid obtaining fines and therefore a heterogeneous crystal population. As we will see later, it can help promote the growth and production of large crystals. The controlled mixture between crystallization juice and reaction medium creates the desired temperature gradient.

Recirculation and progressive cooling are preferably provided by and in a multistage column.

The progressiveness of the cooling is designed to avoid shielding phenomena and can therefore depend on the reaction system, that is to say on the sensitivity of the reactive species to drops in temperature. It should be noted that this sensitivity may vary depending on the initial temperature and the concentration. For example, a rapid drop of 8 ° C in a saturated APAP solution to 80 ° C can cause a shielding phenomenon. The drop should be around 25 to 30 ° C when the APAP solution is at 30 ° C.

Consequently, if the column stages are preferably identical or equivalent in the sense that they make it possible to ensure, notably in connection with the back-mixing, substantially equal temperature drops, it is however possible to use stages leading to different temperature drops, taking into account the differences in shielding sensitivity as a function of the initial temperature.

As an indication, the cooling progressiveness can be between 3 and 50 ° C for one stage or per stage. In the case of APAP and equivalent reaction systems in terms of shielding sensitivity, it is preferred that this progressiveness is between 3 and 20 ° C., in particular between 4 and 8 ° C.

Preferably, the method according to the invention implements an integrated multifunctional reactor. This notion of multifunctional integrated reactor will be explained below during the description of the reactor according to the invention. The reaction systems to which this process applies are those in which the desired product can be crystallized in the reaction medium by simple lowering of temperature. Any other dissolved compound present in the reaction system must have a solubility greater than the solubility of the desired product, at the crystallization temperature. The reactions used can be reactions for dissociation of a starting product or reactions involving at least two reagents.

By way of example, these systems can follow the minimum scheme A + B ^ C + D, C being the product to be recovered by crystallization. B and D can be liquid and are therefore by definition called mixture-solvent, A and C being solids dissolved at the reaction temperature. The crystallization of C, coupled with recirculation, displaces the equilibrium, which favors the conversion of A. As we saw above, the solubility of the product C to be crystallized must be lower than the solubility of A at temperature crystallization. This process can also be applied to reaction systems of the minimal type A '-> B' - C (consecutive reactions) where B 'is the product to be recovered by crystallization. The crystallization of B 'prevents its conversion into by-product C.

The invention can therefore be applied to a large number of industrial syntheses, in particular those involving organic species, which often have a high solubility in the reaction medium. It can in particular be applied in the production of amides obtained by acetylation reaction between an amino and a carboxylic acid (this concept including useful carboxylic acid derivatives), in particular corresponding to the following formula: RCOOH, with R chosen from: - preferably alkyls, especially C1-C12, preferably C1-C4,

- alkenyls, in particular C2-C12,

- aryls, preferably mono or bicyclic, in particular phenyl,

- cycloalkyls, in particular C5-C7, and

- aralkyls, especially C7-C12, preferably benzyl. These RCOOH are preferably those miscible with the solvent or mixture-solvent of the reaction. The reaction temperature is preferably between 80 and 150 ° C.

These reactions are usually carried out with an excess of RCOOH. The invention on the other hand makes it possible to approach, and even to work under, steochiometric conditions. 01/02090

The amines can in particular be aromatic amines.

It may, for example, be the reaction for producing APAP (see example 2): p-aminophenol + AcOH ^ N-acetyl-p-aminophenol + H 0.

By way of example, there may also be mentioned the syntheses of acetylsalicylic acid and aspartic acid and their crystallization by cold:

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acide salicylique anhydride acide acide acétique acétylsalicylique acétique

salicylic acid anhydride acetic acid acetylsalicylic acetic

acide fuma rique acide as partique

fumaric acid asic acid

The process according to the invention can also use a catalyst for the reaction concerned. For an acetylation reaction (eg for the production of APAP), a homogeneous acetylation catalyst can be used, for example sulfuric acid, boric acid or hydrochloric acid. These reactions can therefore use a solvent for the starting product and a solvent for the final product to be crystallized. The reaction medium then comprises a mixture of these solvents, insofar as the crystallization medium must be qualitatively identical to the reaction medium. According to particular methods of the process according to the invention, one can then provide, cumulatively or not:

- distillation of the solvent for the final product to be crystallized, e.g. the water solvent for APAP, in zone R;

- reinjection of the distillate or new solvent into zone C; the withdrawal of liquid from zone C and preferably the reinjection of this liquid after filtration, or of replacement liquid, into zone R.

A second object of the present invention is a multifunctional integrated synthesis and crystallization reactor in liquid medium, of the type comprising a heated reaction zone R intended to contain reaction medium, and a cooled crystallization zone C intended to contain crystallized product and juice of crystallization, characterized in that these two zones are connected together by an intermediate zone arranged so on the one hand, to be able to ensure a main circulation of reaction medium from zone R towards zone C, and on the other hand , include a means of heat exchange between reaction medium and crystallization juice designed to provide a temperature gradient between zone R and zone C. This reactor is in particular capable of implementing the method according to the invention. The term “multifunctional integrated reactor according to the invention” means a reactor formed in one piece, comprising the different zones, each zone preferably being functionally connected to another zone directly. Such an integrated arrangement creates a synergy between the different zones and the reactions of which they are the seat. The use of an integrated reactor, preferably capable of working continuously, ensures the various objectives, eg economic and safety, set out above. According to the preferred embodiment of the invention, the reactor comprises means for recirculating crystallization juice from zone C, towards the intermediate zone and zone R. This intermediate zone is arranged in the zone of direct heat exchange between hot liquid from zone R and cold liquid from zone C. In other words, the intermediate zone is designed to admit and mix together both the main circulation of liquid from zone R to zone C and a recirculation of liquid from zone C. The reactor can then lead to an equilibrium shift.

If necessary, the intermediate zone can also be provided with a cooling device, in particular with a progressive cooling device. It is however particularly preferred not to use it and to design this intermediate zone to operate solely on a heat exchange between the liquids coming from zones R and C. By definition we will then speak of an adiabatic heat exchange zone. Preference remains for direct heat exchange by mixing liquids.

To ensure this progressive cooling by contact between the liquids coming from zones R and C, this intermediate zone can advantageously comprise several stages of mixing of the liquids, these stages preferably being identical to each other. For their design, indications have been discussed above during the description of the process. Preferably, the intermediate zone comprises a column with trays, this column preferably being provided with stirring means, the assembly being notably arranged so as to be able to ensure the main flow from R to C, as well as a recirculation flow. from C to R, possibly in combination with stirring means which can be and are preferably provided in zones R and C as will be seen below.

The agitation and the opening of the plates separating the stages of the column are decisive for the main and recirculation flows, and for the back-mixing. Experience has shown that the recirculation rate and therefore the back-mixing increase with agitation and the opening of the trays. The man of profession has great latitude to set these parameters according to the desired goal.

It will also be noted that the opening of the plates can consist of from 1 to several orifices, preferably with a central orifice. The stirring device of the crystallization zone preferably contributes to the recirculation flow. It is preferably designed to properly suspend the crystallized solid while keeping it in the crystallization zone.

Recirculation can tend to entrain the finest crystals which go up in the intermediate zone where they can be resolubilized. We can then speak of a recycling of the fines that we can favor or limit at will by acting on the back-mixing, e.g. on the parameters of agitation and the opening of the trays. By playing with these parameters, the particle size of the crystals is modified. Generally, an increase in recirculation results in an increase in the average size of the crystals. The back-mixing rate will be optimized as a function of the reaction system, e.g. as a function of the optimum reaction and crystallization temperatures and the quality of the production required.

Zone R preferably comprises a means for supplying reagent and zone C means for withdrawing crystallized product. These supply and withdrawal means can be designed to allow continuous operation of the reactor. Thus, the withdrawal means can be controlled by the supply means, itself regulated in order to control the production.

The R and C zones are preferably also provided with stirring means.

The different types of stirring means that can be used preferably include:

- for zone R: means of agitation making it possible to ensure good homogenization of the feed in R; preferably of the radial movable type; ex: Rushton turbine;

- for zone C: stirring means making it possible to suspend the crystals; in particular of the axial movable type (e.g. propeller with profiled blades), possibly associated with the radial type in the vicinity of the connection with the intermediate zone to ensure continuity, and / or at the foot of zone C to avoid the formation of a crust of crystals; - for the intermediate zone: means of agitation to ensure recirculation; preferably of the radial mobile type; ex: straight blade turbines; - possibly associated with baffles, counter-blades or similar means, located on the periphery with respect to the stirring means. Preferably, the zones R, intermediate and C are aligned in this order along the same vertical axis, the zone R being placed above. It is therefore preferred that the means for agitating the upper, lower and intermediate zones are carried by the same drive shaft located on the vertical axis.

Zone C is provided with a cooling device, preferably by fluid, e.g. water or oil, and in particular a device of the serpentine type, making it possible to install the crystallization temperature in the corresponding zone.

Note that the coil can play a role in agitation by being placed coaxially with the agitation tree. It can make it possible to promote and channel the current lines generated by the axial mobile. According to a particularly advantageous embodiment of the invention, this cooling device is arranged so as to be able to be connected to a source of hot fluid for a periodic passage of hot fluid intended to dissolve any seeds of crystals which could form on contact with the cooling device (shielding phenomenon). The cooling device can therefore consist of two thermostated baths, one of which is instructed to maintain zone C at the crystallization temperature, the other being fixed at a higher temperature, these two baths being connected to the part of the device located in zone C, for example the coil, by solenoid valves or similar means making it possible to successively admit the cold fluid and the hot fluid. According to an additional arrangement of the invention, it is possible to use a zone C provided with a double envelope also allowing the circulation of cooling fluid. Similarly, in this case, it may be advantageous to provide means allowing the periodic passage of hot fluid to avoid the formation of crystal seeds on the walls of the zone of C.

Advantageously, the cooling device combines an internal serpentine type device and a double jacket, which are preferably connected so as to be cooled and optionally heated in common. According to a particular form of the invention, a distillation column is connected to the reactor. It is used to distill a solvent in the following two cases: - a solvent, in particular a solvent produced by the reaction, increases the solubility of the product to be crystallized; it is removed by distillation to promote crystallization; - The solvent interferes with the reaction in zone R; if, moreover, this solvent reduces the solubility of the product to be crystallized, it can be reintroduced into zone C as will be seen below. In the case of APAP, distillation makes it possible to increase the temperature in zone R and the titer in acetic acid. The reaction equilibrium is shifted towards the production of APAP because the acetylation reaction of APAP will see its speed increase faster, according to Arrhenius' law, than that of hydrolysis of APAP. Furthermore, the water being removed from the reaction medium by distillation, the equilibrium will be all the more shifted towards the formation of APAP. Overall, the conversion in the reactor increases. On the other hand, the elimination of solvent in zone R must be able to be compensated at another point of the reactor. In this case, a compensation admission is provided for this purpose, opening into zone C.

Compensation can be done either by condensation of the distillate and its reintroduction into zone C, or more freely with a stream of new, independent solvent, which is particularly advantageous when the distilled or new solvent promotes crystallization, by lowering the solubility of the product to be crystallized. Note that distillation without compensation will be avoided in a reactor operating discontinuously.

The crystallization zone may include a regulated supply, even in the absence of a distillation column, to provide an appropriate liquid promoting crystallization, e.g. water.

The introduction of liquid (compensating or not) into zone C offers a particularly advantageous additional possibility. Indeed, by correctly adjusting the temperature of this liquid, it is possible to suppress all or part of the cooling of the zone C by the cooling device (for example double jacket and / or coil). In this case, a device for regulating the temperature of this liquid is provided, connected to the inlet.

Furthermore, if we take the example of APAP, an acetic concentration gradient will be established between zone R (very rich) and zone C (very poor). The crystallization will therefore be carried out with a much lower APAP solubility, which makes it possible to further increase the crystallization yield and therefore the overall conversion yield of the reactor.

Downstream of the means for withdrawing the crystallized product, it is possible to have a filtration means for separating the liquid from the crystallized product. Means can also be provided for reinjecting this liquid or a replacement liquid, at an appropriate point of the reactor, in particular in zone R, which therefore then includes an admission of this liquid.

The interior of the reactor, in particular the crystallization zone and the intermediate zone, including the plates and the stirring means, can be provided with a non-stick coating, e.g. Teflon®.

To return to the process according to the invention, provision may also be made for adjusting the various parameters, such as agitation, feed rate, recirculation rate, geometric parameters, depending on the desired end product; and all other characteristics eg distillation, re-injection, compensations, etc. ; as described above with regard to the reactor. When the process and the reactor are started continuously, it is preferable to fill the reactor with the starting composition, to cut supplies and withdrawals, and therefore to operate the reactor in batch until a state is obtained. thermal equilibrium (temperatures required for reaction and crystallization). When this is reached, it switches to continuous operation.

The present invention also relates to the crystallized products capable of being obtained by the implementation of the process and / or of the reactor according to the invention. These products, in particular amides of pharmaceutical interest, e.g. APAP, are characterized by a population of agglomerated crystals substantially free of fines. They are also characterized by a larger average crystal size (e.g. from 10 to 60%) under identical conditions, to what is usually obtained.

A further subject of the invention is the compositions, e.g. pharmaceuticals, comprising one or more products as obtained according to the invention.

The present invention will now be described with the aid of embodiments taken by way of nonlimiting examples and referring to the appended drawing in which:

- Figure 1 is a schematic representation in median cross section of a multi-functional reactor;

- Figure 2 is a graph showing the evolution over time of the solid rate in the crystallizer, in batch;

- Figure 3 is a graph showing the evolution over time of the mass average diameter of the crystals, in batch; - Figure 4 is a graph showing the conversion rate as a function of the feed rate. Example 1 - Description of a multifunctional reactor according to the invention (see Figure 1):

The reactor firstly comprises a reaction zone 1 comprising a double jacket 2 connected to pipes for admission and discharge of heating fluid, symbolized by the arrows 3, respectively 3 '. The reaction zone is also provided with a reagent supply, symbolized by the arrow 4.

At its lower part, the reaction zone is structurally and functionally connected to a column 5, which comprises plates 6, each having a central opening 7, and two end plates 8, each provided with three peripheral orifices 9, defining a passage area equal to that provided by each central opening 7.

At its lower part, this column is itself structurally and functionally connected to a crystallization zone 10, provided with a double envelope 11 and a coil which, for reasons of clarity, has not been shown. It will be noted that the double envelope and the coil are connected together and are connected to an inlet and an outlet for cooling fluid, symbolized by the arrows 12, respectively 13. Finally, the crystallization zone is provided at its lower part with a valve

14 for withdrawing the crystallized product.

The reactor further comprises a shaft 15, connected to a rotation device whose rotation speed can be varied, this shaft penetrating into the reactor through the upper part of the reaction zone and extending coaxially through the zone of reaction 1, column 5 and in a substantial part of the crystallization zone 10. The plates 8 have a central bore serving as a bearing for this shaft.

The shaft 15 carries, so as to be able to drive them in rotation, stirring means. The reactor thus comprises a radial agitation mobile 16 placed at mid-height, and, regularly spaced around its internal periphery, four vertical counter blades 17; each stage of the column comprises a radial agitation mobile 18; the plates are separated from each other by three spacers, not shown, which interact with the mobiles in the manner of counter-blades; and the crystallization zone comprises two radial mobiles 19 and 20, at the head and at the foot of the zone, these mobiles being of the same type as the mobiles 18, and an axial mobile 21, placed at mid-height; four counter-blades 22 are arranged vertically on the internal periphery of the zone, being regularly spaced.

If the reactor is intended to be used continuously, there is preferably provided in the reaction zone a float placed on the surface of the liquid and which allows, when it goes to a predetermined level, the periodic triggering of the valve 14.

The double jacket 11 and the coil of the crystallization zone are connected to thermostatically controlled water baths, one of these baths being regulated at a crystallization temperature, for example 30 ° C. and the second bath being maintained at a temperature about 80 ° C. The assembly is provided with solenoid valves so as to allow the admission either of cold fluid, or of hot fluid, it being understood that the admission of hot fluid is carried out intermittently and on a short duration in order to dissolve the seeds of crystals which could form on the heat exchange walls (coil and double jacket), without significantly disturbing the temperature in zone 10.

The multistage columns have been modeled, eg by HF HAUG, AlChE Journal, May 1971, Vol. 17, No. 3, p 585-589; F corresponds to the main flow passing through the column, f the back-mixing flow, N the stirring speed (Hz), T the diameter of the column, H the height of a stage, D the diameter of the agitator, at the opening surface of the plates, At the surface of the plates, E is a correction factor linked to the stirring mobile. It was arbitrarily given a value of 0.1 for a six-blade Rushton-Oldshue type turbine. For other configurations, E is the ratio of the number of power of the agitating mobiles chosen to that of this six-blade turbine. For turbines with more or less than six blades, the number of power is, by approximation, proportional to the square root of the number of blades.

u =

The back-mixing flow rate f depends on the stirring speed N and on the geometrical dimensions of the apparatus and can be represented by the following equations, (1) for continuous operation and (2) for discontinuous operation:

Furthermore, if we consider that there is no heat exchange through the walls of the column and that the heat transfers by conduction between the stages are negligible compared to the heat exchanges by direct mixing of fluids, the temperature of a stage n can be expressed, compared to stages n + 1 (next stage below) and n - 1 (preceding stage above), by the formula (3):

(F + f) T _n -ι + fT _{n + 1} ^τ n = (3)

F + 2f

These theoretical data allow a person skilled in the art to develop the column he needs according to the reaction system.

Example 2: Implementation of the multifunctional reactor of Example 1

2 - 1. Reaction implemented: Synthesis of N-acetyl-p-aminophenol (APAP) by acetylation of p-aminophenol (PAP):

O

It is a balanced reaction between acetylation of PAP and hydrolysis of APAP. The acetylation reaction takes place at around 100 ° C. The solvent is the water + acetic acid mixture.

2 - 2. Characteristics of the reactor:

The reactor was produced according to the principle of FIG. 1, with the. following features:

- reaction zone 1: • volume 2.5 I

• diameter 150 mm

• agitator mobile: Rushton turbine 75 mm in diameter

• 4 15 mm counter blades (= 10% of the diameter of the area)

- column 5: • 10 stages of 0.1 I (9 trays + 2 end trays)

• diameter 60 mm

• 10% opening trays

• height of each stage: 30 mm • stirring mobiles: turbines with straight blades 40 mm in diameter.

- crystallization zone 10:

• volume 1, 25 I • diameter 100 mm

• stirring mobiles:

+ propeller with profiled blades of 60 mm in diameter (ref 21) + 2 turbines with straight blades of 40 mm in diameter (ref 19 and 20).

• 4 10 mm counter blades (= 10% of the diameter of the area). 2 - 3. Operating protocol:

Step 1: making the feed mixture:

Into a 40 I tank, stirred and heated to 65 ° C by a metal coil, an AcOH + water mixture at 40% by weight of AcOH is introduced. When this mixture of liquids has reached the temperature of 65 ° C., solid PAP and APAP are introduced which dissolve therein after a certain time.

The composition (% by weight) of this mixture is as follows:

- PAP 12% - APAP 11%

- AcOH 32%

- Water 45%.

The presence of APAP in the feed mixture is not essential, but allows a stable operating speed to be reached more quickly. Therefore, in general, the feed mixture may also not include APAP, or only understand it at start-up if it is a continuous operation.

A batch experiment was carried out in parallel, and continuously with a sufficient quantity of feed mixture to fill the reactor and ensure a given flow rate for 12 hours.

Step 2: Course of the experiment:

Using a pump, the reactor is filled (reaction zone 1, column 5 and crystallization zone 10) with the feed mixture, the stirring being started in the reactor. At the same time, the reactor is brought to temperature operating temperature, namely a set temperature of 100 ° C for the reaction zone 1 and a set temperature of 30 ° C for the crystallization zone 10. Once the reactor is full, the pump is stopped, then waits for the system to stabilize in temperature. Temperature regulation and stirring are maintained.

Continuously, in order to avoid shielding on the walls when triggering the crystallization by nucleation, the crystallization is initiated by the injection into the crystallization zone of a suspension of solid APAP in an AcOH + water mixture identical to that of the feed mixture. This injection is carried out before the crystallization temperature is reached.

In the case of batch operation, the system is allowed to evolve without power.

In the case of continuous operation, as soon as the temperature has stabilized, the pump is restarted to supply the pilot with a mixture, this supply taking place at the level of the reaction zone, and it is drawn off from the crystallization zone the liquid + crystallized solid suspension. A steady state is obtained when the analyzes reveal that the concentrations and the level of crystallized solid no longer change.

2 - 4: Results: The thermal equilibrium could be maintained throughout the process, ie approximately 100 ° C. in the reaction zone and approximately 30 ° C. in the crystallization zone.

No shielding was noted, except for a slight layer on the coil, but which has stabilized.

2 - 4 - 1 In batch: (stirring speed 200 rpm)

Two experiments referenced 1 and 1 bis were carried out, which demonstrated the reproducibility.

The tables below and FIG. 2 show the change in the level of solid in the crystallizer, measured by taking a small amount of the suspension from the crystallization zone. mass crystals

Xs = solid content = crystal mass + liquid

Experiment 1

Experience 1 bis

Les tableaux ci-dessous et la figure 3 montrent l'évolution de la taille des cristaux.

The tables below and Figure 3 show the evolution of the size of the crystals.

D = mean diameter of the crystals with respect to the volume distribution of the crystal sample; laser diffraction particle size measurement, model Mastersizer® S long bench-MAM 5005, from Malvern Instruments Ltd.

Experience 1 bis

The evolution over time of the parameters was consistent: - increase in the average size of the crystals in zone 10 increase in the level of solid in zone 1. decrease in the concentration of para-aminophenol in zone 1. increase in the synthesis of APAP in zone 1 at the start of the cycle, then decrease following its consumption by crystallization.

2 - 4 - 2 Continuously: a) Temperature gradient in the reactor:

The experiment was carried out under the following conditions:

- stirring speed 200 rpm

- feed rate 11 g / min.

Measurement of the temperatures on the outer wall of the column (5) using a thermocouple:

On constate une variation de température de 6 °C environ par étage.

There is a temperature variation of approximately 6 ° C per stage.

b) Influence of the variation of the stirring speed on the particle size

- constant feed rate: 15 g / min

- steady state reached in around 10 h.

(measurement method: laser diffraction particle size - see above)

c) Influence of the feed rate on the particle size (constant stirring speed: 200 rpm)

d) shift of equilibrium:

Feed composition:

PAP 15% P / P

AcOH / PAP = 1, 2 (molar ratio)

The rest: water.

The X _rc conversion rate of the PAP was monitored as a function of the feed rate. By comparing the theoretical maximum conversion rate calculated from the thermodynamic equilibrium constant of the reaction under the same conditions (horizontal line in FIG. 4), it was possible to determine the threshold of overshoot at F = 67 ml / h. 2 - 4 - 3 Comparison

The average size of the APAP crystals obtained according to the invention was compared with what it is possible to obtain by using a conventional crystallizer. This conventional crystallizer consists of a 1 l tank cooled (diameter and height 100 mm), propeller with profiled blades identical to that of the crystallization zone 10 in the reactor according to the invention, placed at one third of the height and in the lower part of the tank, and 4 10 mm counter-blades.

For identical feeding conditions, with a flow rate of 15 g / min, we obtained:

It should be understood that the invention defined by the appended claims is not limited to the particular embodiments indicated in the description above, but encompasses variants thereof which do not depart from the scope or the spirit of the present invention.

Claims

1. A method of synthesis and crystallization in a liquid medium, comprising the synthesis, in a hot reaction zone, of a compound in the dissolved state in the reaction medium at the reaction temperature, the sending of reaction medium from the zone of reaction towards a cold crystallization zone, and the crystallization of said dissolved compound, characterized in that, before admitting it into the crystallization zone, progressive cooling of the reaction medium is ensured by heat exchange with juice crystallization from the corresponding zone, in an intermediate heat exchange zone. 2. Method according to claim 1, characterized in that one ensures a recirculation of crystallization juice from the crystallization zone towards the reaction zone, in the intermediate zone and in that the progressive cooling of the reaction medium is ensured by mixing of reaction medium from the reaction zone and of crystallization juice, in this intermediate heat exchange zone. 3. Method according to claim 2, characterized in that a mixture of reaction medium and crystallization juice is provided in an intermediate zone formed by a column with several stages. 4. Method according to claim 3, characterized in that one provides a substantially identical cooling to each stage. 5. Method according to claim 2 or 3, characterized in that the recirculation ensures at the same time the entrainment of fines in the intermediate zone and a dissolution of at least part of these fines. 6. Method according to one of claims 1 to 5, characterized in that the solvent is distilled from the reaction zone. 7. Method according to one of claims 1 to 6, characterized in that there is provided, in a controlled manner in the crystallization zone, a liquid promoting crystallization. 8. Method according to claim 7, characterized in that one adjusts the temperature of this liquid so as to ensure all or part of the cooling of the crystallization zone. 9. Method according to one of claims 1 to 8, characterized in that the synthesis and the crystallization are carried out continuously, by means of a supply of reagents and a withdrawal of the crystallized product. 10. Method according to any one of claims 1 to 9, characterized in that it implements an integrated multifunctional reactor. 11. Method according to any one of claims 1 to 10, applied to the production of amides obtained by reaction between an amine, preferably an aromatic amine, and a carboxylic acid. 12. Method according to claim 11, characterized in that it implements one of the following reactions: (I)

O (2i) O \\

(3i)

13. Integrated multifunctional synthesis and crystallization reactor in liquid medium, comprising a heated reaction zone (1) intended to contain reaction medium, and a cooled crystallization zone (10) intended to contain crystallization juice, characterized in that that these two zones (1, 10) are connected together by an intermediate zone (5) arranged so as to be able to ensure a main circulation of reaction medium from zone (1) to zone (10), and on the other hand, a temperature gradient between zone (1) and zone (10). 14. Reactor according to claim 13, characterized in that the reactor comprises means for recirculating crystallization juice from the zone (10) towards the intermediate zone (5), so as to ensure therein a mixture between crystallization juice and medium reaction. 15. Reactor according to claim 14, characterized in that the intermediate zone (5) comprises several stages of mixing. 16. Reactor according to claim 15, characterized in that the stages are designed to ensure substantially equivalent temperature reductions. 17. Reactor according to claim 15 or 16, characterized in that the intermediate zone (5) comprises a column with plates, the plates (6) comprising one or more orifices (7). 18. Reactor according to any one of claims 15 to 17, characterized in that stirring means (18) are placed in each stage or between the plates (6). 19. Reactor according to any one of claims 13 to 18, characterized in that the reaction zone (1), the crystallization zone (10) and the intermediate zone (5) are provided with stirring means (16, 17, 18, 19, 20). 20. Reactor according to any one of claims 13 to 19, characterized in that the crystallization zone (10) comprises a regulated supply designed for the admission of liquid. 21. Reactor according to any one of claims 13 to 20, characterized in that the reaction zone (1) is connected to a distillation device. 22. Reactor according to any one of claims 13 to 21, characterized in that the reaction zone (1) comprises means for supplying (4) reagents and in that the crystallization zone (10) comprises means withdrawal (14) of crystallized product. 23. Reactor according to any one of claims 13 to 22, characterized in that the reaction (1), intermediate (5) and crystallization (10) zones are aligned in this order along the same vertical axis, the reaction (1) being placed in the upper position. 24. Reactor according to claims 19 and 23, characterized in that the means for agitating these zones (1, 5, 10) are carried by the same motor shaft (15) located on the vertical axis.