Process for the manufacture of lactide

Related application: this application claims priority to European application No. 10167636.9 filed on June 29, 2010, the whole content of this application being incorporated herein by reference for all purposes.

The present invention relates to a process for the manufacture of lactide, the cyclic diester of lactic acid.

Lactide is a key intermediate for the manufacture of polylactic acid (or polylactide) (PLA), which is a biodegradable, thermoplastic polymer derived from renewable resources. The synthesis of the lactide is the most important step in the conventional PLA manufacturing process. It is this step that will govern the price of the final polymer. The lactide must also be as pure as possible in order to be able to carry out the ring-opening polymerization leading to corresponding PLA with high molecular weights.

The preparation of cyclic diesters of alpha-hydroxyacids such as lactide is usually conducted in two distinct steps involving first preparing an oligomer of the alpha-hydroxyacid, i.e. a relatively short chain condensation polymer thereof having typically a molecular weight of a few thousands g/mol, then heating the oligomer under reduced pressure to generate the desired cyclic diester. Lactide synthesis is for instance disclosed in US patent No. 1095205 or in US patent No. 5374743. This process has the disadvantage to require a lot of energy and to lead to impure products requiring further purification steps and the treatment of the by-products.

Direct syntheses of lactide have also been disclosed. For example, US patent No. 3322791 discloses the preparation of lactide by heating lactic acid at a temperature of 100 to 250°C in the presence of a titanium alkoxide. This process seems to be advantageous in view of the classical polymerization /

depolymerization process but the yield is still quite limited, being of only 60%. Furthermore, titanium alkoxide is consumed and thus cannot be recycled in such a process. Attempts have also been made to synthesize cyclic diesters of alpha- hydroxyacids in vapor phase, as disclosed in international patent application WO92/00292 or WO93/19058. Such vapor phase processes require specific equipment and a lot of energy. The degradation as well as the polymerization of the alpha-hydroxyacid must also be avoided during its vaporization. Another example is given by international patent application WO93/19058 which discloses the direct synthesis of cyclic diesters of hydroxyacids, in particular lactide, by removing water from a feedstream comprising the hydroxyacid until a polymerization degree of less than or equal to 4 is attained. This process leads to the production of many by-products, requires important additional separation and purification steps and leads to a very low yield, well below 50%. International patent application WO93/19058 also discloses the possibility to produce cyclic diesters of hydroxyacids by azeotropic distillation of a diluted solution of the alpha-hydroxyacid in an organic solvent. Such a method has the main drawback to require the use of a huge amount of organic solvents, especially aromatic solvents such as benzene or toluene, or of solvents such as acetonitrile, which is not compatible with an environmental friendly process. This is especially not compatible with the synthesis of "green" polymers such as PLA and PGA (polyglycolide), manufactured from bio-sourced lactide or glycolide. Recently, US 2009/0318713 has disclosed a process for the synthesis of lactide by reacting the calcium or magnesium salt of the lactic acid with a strong acid, the salt of which with the metal being hygroscopic, to obtain the cyclic diester dispersed in the hygroscopic salt. This process requires first the preparation of the lactic acid metal salt. Then, by reacting said lactic acid metal salt with a strong acid, it leads to a huge amount of salts, such as calcium sulfate, that needs to be treated or destroyed, which is not environmentally friendly. Another disadvantage of this process is its low yield, below 50%.

The purpose of the present invention is to provide a process for the synthesis of lactide which does not present the above-mentioned disadvantages. In particular, the purpose of the present invention is to provide an

environmentally friendly, simple and economic process which enables the manufacture of lactide with a high yield, without numerous subsequent separation and purification steps.

The present invention therefore relates to a process for the manufacture of lactide comprising heating lactic acid in the presence of at least one hygroscopic salt, wherein the hygroscopic salt is present in an amount of at least 1 mol per mol of lactic acid.

Indeed, it has been surprisingly found that, when heated in the presence of at least 1 mol of hygroscopic salt per mol of lactic acid, lactic acid readily forms the corresponding lactide, which can be easily separated from the reaction medium. One of the essential features of the present invention resides in the use of a hygroscopic salt in an amount of at least 1 mol per mol of lactic acid. It has indeed been found that, in the presence of a lower amount of hygroscopic salt, a lower yield in lactide is obtained, an increased amount of oligomers being synthesized. Without being bound by any theory, it is believed that the lactic acid will be dispersed into the hygroscopic salt which will isolate the lactic acid molecules from one another, like in shells, and thus favor dimerisation and cyclisation of the lactic acid molecules to form lactide, rather than

oligomerisation of the lactic acid.

In the process of the invention, the hygroscopic salt can by any kind of hygroscopic salt know in the art, for instance selected from the group consisting of magnesium oxide, calcium chloride, magnesium sulfate, calcium sulfate, zinc sulfate, in particular zinc sulfate. The hygroscopic salt may be under its anhydrous form, a partially hydrated form, or a fully hydrated form. For example, if zinc sulfate is used as hygroscopic salt, it can be added as anhydrous zinc sulfate (ZnS0 ₄ ), as zinc sulfate monohydrate (ZnS0 ₄ .H ₂ 0), as zinc sulfate heptahydrate (ZnS0 ₄ .7H ₂ 0) or as a mixture thereof, for instance as zinc sulfate monohydrate.

In the present process, the hygroscopic salt is typically added in an amount of at least 1 mol per mol of lactic acid, in particular of at least 2 mol per mol of lactic acid, in many cases of at least 3 mol per mol of lactic acid, for instance of at least 3 or 4 mol per mol of lactic acid. The drying agent is usually added in an amount of at most 10 mol per mol of lactic acid, particularly of at most 8 mol per mol of lactic acid, for example at most 6 or 7 mol per mol of lactic acid. The hygroscopic salt may thus be added in an amount of from 1 to 10 mol per mol of lactic acid, especially of from 2 to 8 mol per mol, conveniently of from 3 to 5 mol per mol.

In the present process, lactic acid is typically heated in the presence of the hygroscopic salt at a temperature from 80 to 250°C, preferably from 100 to 220°C, more preferably from 120 to 200°C, for instance about 140, 160 or

180°C. Said heating may be conducted at atmospheric pressure or under reduced pressure, preferably under reduced pressure, especially under a pressure equal to or less than 500 mbar, commonly equal to or less than 200 mbar, particularly equal to or less than 100 mbar, in particular equal to or less than 50 mbar, conveniently equal to or less than 10 mbar, for example equal to or less than 5 mbar. The pressure is generally equal to or higher than 0.1 mbar, most often equal to or higher than 0.5 mbar, for instance equal to or higher than 1 mbar. In a specific embodiment, the heating may be initiated at atmospheric pressure and then continued under a progressive vacuum until the required pressure is attained, for instance a pressure from 0.1 to 10 mbar, in particular from 1 to 5 mbar.

The heating time depends upon the reaction temperature and pressure and this parameter may be within wide ranges. Most often, the heating is conducted during 1 to 24 hours, often from 2 to 12 hours, for instance around 3 or 4 hours, but it can also be continued for a longer time such as 12 to 20 hours, for example around 17 or 18 hours.

In a particular embodiment of the present process, water can be added to the reaction medium prior to the heating step. Said water may be added first to at least part of the lactic acid and/or first to at least part of the hygroscopic salt. Depending on its concentration into the added water, the hygroscopic salt may be substantially insoluble, partially soluble or substantially fully soluble into the water, in particular soluble or at least partially soluble, especially soluble. If useful, the water can be heated to favor the solubilization of the hygroscopic salt. Conveniently, the water is used to solubilize at least part of the hygroscopic salt and/or at least part of the lactic acid. Especially, part of the water is used to solubilize at least part of the hygroscopic salt, in particular part of the

hygroscopic salt, and the remaining part of the water is used to solubilize at least part of the lactic acid, particularly substantially all the lactic acid. For instance, part of the water may be first mixed with part of the hygroscopic salt and the remaining part of the water may be first mixed with the lactic acid, then both solutions can then be mixed to form a mixture of the lactic acid and of at least part of the hygroscopic salt. The amount of water added is not particularly limited but water is most often added in a total amount of from 1 to 10 mol per mol of lactic acid, in particular from 2 to 8 mol per mol, more particularly from about 5 to 7 mol per mol. Advantageously, the amounts of added water and of hygroscopic salt are such that at least 80 wt% of the added water is trapped by the hygroscopic salt as hydration water, especially such that at least 90 wt% of the added water is trapped, in particular such that substantially all the added water is trapped. For example, the hygroscopic salt may be added in excess regarding the amount of added water.

In a specific variant of this particular embodiment, part of the hygroscopic salt may be dissolved in part of the water to be added, optionally heated prior to the addition of the hygroscopic salt and subsequently cooled down and the lactic acid may be dissolved in the remaining part of the water to be added, both solutions being then mixed to forming a homogeneous aqueous solution of part of the hygroscopic salt and of the lactic acid. The remaining part of the hygroscopic salt may then be added to this aqueous solution. If the hygroscopic salt is added in a total amount such that at least 80 wt% of the added water is trapped by the hygroscopic salt as hydration water, especially such that at least 90 wt% of the added water is trapped, in particular such that substantially all the added water is trapped, said addition typically leads to the formation of a paste or of a solid, comprising the lactic acid and the hygroscopic salt, at least partially in its hydrated form. The advantage of this first variant is that the lactic acid is therefore substantially homogeneously dispersed in the at least partially hydrated hygroscopic salt in an easy way.

In a further embodiment of the present process, the lactic acid, the hygroscopic salt, and the optionally added water can be mixed in a mixer, in a mixing reactor, or directly into an extruder, to produce a paste which can then be extruded in the form of rods that can be subsequently introduced into a granulator to form granules containing the lactic acid, the hygroscopic salt and the optionally added water. Such a granulation is advantageous since it increases the surface area of the solid resulting from the mixing of the lactic acid and the hygroscopic salt, which will allow an easier evaporation of the water optionally initially present in the medium and of the water formed during the heating step, as well as an easier recovery of the produced lactide. Furthermore, the granulated mixture will be easier to handle.

In the process of the present invention, at least part of the water optionally initially present in the medium (in the form of free water and/or of water trapped by the hygroscopic salt i.e. hydration water), and/or at least part of the water formed during the heating step, due to the dimerisation and cyclisation of lactic acid, may be removed from the reaction medium, typically by distillation or evaporation during the heating step. In the process of the present invention, it is also possible to remove at least part of the water optionally initially present in the medium, in the form of free water and/or in the form of hydration water, by distillation or evaporation prior to the heating of the lactic acid in the presence of the hygroscopic salt to produce lactide.

Thus, in another particular embodiment, which can be combined with the particular embodiment described above, prior to the heating of the lactic acid in the presence of the hygroscopic salt as defined above, a first heating step may be conducted to first remove at least part of the water initially present in the reaction medium. In this other particular embodiment, said first heating step is typically conducted in conditions of temperature, pressure and duration such that at least part of the water present as free water and/or as water linked to the hygroscopic salt (i.e. hydration water), is removed from the reaction medium. Especially, the conditions of the first heating step are such that substantially all the free water optionally present is removed from the reaction medium. If the hygroscopic salt is present in the reaction medium in its fully hydrated or at least partially hydrated form, the conditions of the first heating step are conveniently such that, after said first heating step, the hygroscopic salt is present in a hydration state such that at least 1 mol of water per mol of lactic acid could be trapped by the hygroscopic salt, in the form of hydration water. Said conditions of temperature, pressure and duration are usually selected such that degradation of the lactic acid does not occur or is at least limited. Said conditions of temperature, pressure and duration are generally selected such that oligomerisation of the lactic acid does not occur or is at least limited. Said conditions are in particular selected such that at least 60% by weight of the lactic acid remains unchanged in the reaction medium at the end of said first heating step, more often such that at least 70% of the lactic acid remains unchanged, most often at least 80%o. The first heating step may for instance be conducted at atmospheric pressure and at a temperature about 100°C. The first heating step may also be conducted under reduced pressure and at a temperature below 100°C, preferably at a temperature equal to or below 70°C, more preferably equal to or below 50°C, the reduced pressure being adapted to allow the removal of at least part of the water, for instance under a reduced pressure of less than 50 mbar, especially of less than 20 mbar, more especially of less than 10 mbar, for example around 5, 4 or 3 mbar.

The process of the present invention is typically conducted in the absence of any organic solvent. Indeed, organic solvents would contaminate the lactide and would require recycling of said solvent. Furthermore, a process which does not include any organic solvent is more environmentally friendly.

The reaction may be conducted in any kind of reactor, and advantageously in a still or in a distillation apparatus which allows the removal of the water from the reaction mixture and which allows subsequent separation of at least part of the lactide from the reaction medium. Distillation systems suitable for this purpose are common knowledge and are frequently used for separation. In the process of the present invention, the lactide can be removed from the reaction medium and recovered progressively, as it is formed. This can typically be performed if the reaction is conducted in a still or in a distillation apparatus. It can also be left in the reaction medium during the heating step and be collected after the heating step, for instance by distillation, especially by vacuum distillation, for instance by heating the reaction medium at a temperature from 160 to 260°C, for example from 215 to 240°C, under reduced pressure, for example at a pressure below 10 mbar, in particular equal to or lower than 5 mbar, for example around 1 to 3 mbar. The lactide may also be removed from the reaction mixture by extraction, for instance using toluene, acetone,

tetrahydrofurane or methylene dichloride as an extraction solvent. This would be followed by evaporation of the extraction solvent or by crystallization from solution and separation. Advantageously, the lactide is recovered by vacuum distillation.

In the present process, the recovered lactide can be used immediately for some applications, without further purification steps. The lactide may also be purified, for instance by distillation or chromatographic processes. As the main contaminants of the recovered lactide are typically lactic acid and the dimer of lactic acid, said products can be recycled in the present process.

This process also leads to a quite huge amount of at least partially dehydrated hygroscopic salt, which can be recycled in the present process, even directly or after purification, for instance by calcination.

In a preferred embodiment of the process of the present invention, at least part of the hygroscopic salt, recovered after collection of the lactide from the reaction medium, particularly substantially all the hygroscopic salt, is directly recycled in the first step of the process. Without being bound by any theory, it is believed that said directly recycled hygroscopic salt will be mainly contaminated with lactic acid oligomers, especially trimers which are usually not removed from the reaction medium by distillation. Said directly recycled hygroscopic salt could also be contaminated by lactic acid, not removed from the reaction medium by distillation due to its affinity for the hygroscopic salt. Without being bound by any theory, it is indeed believed that part of the lactic acid could be somehow adsorbed onto the hygroscopic salt, due to specific interactions. In this preferred embodiment, fresh lactic acid and optional water are added to the recycled hygroscopic salt to form a new reaction medium. During the heating step of this new reaction medium, lactic acid oligomers will be hydrolyzed, especially if water was added to the reaction medium. Thus, at least part, and especially substantially all, of the lactic acid trapped in the form of oligomers will be released and will thus be able to react to form lactide. If lactic acid was also somehow adsorbed onto the hygroscopic salt, less newly added lactic acid will adsorb, and thus globally more lactic acid will be available to react to form lactide, compared to the same reaction conducted with fresh hygroscopic salt. The global yield in lactide, calculated on more than one production step, when at least part of the hygroscopic salt is directly recycled (i.e. without prior purification), will thus increase significantly, in particular above 50%, especially above 60%, in particular above 70%.

In a first embodiment, the present invention thus also relates to a process for the manufacture of lactide comprising the steps of:

(a) heating lactic acid in the presence of a hygroscopic salt, said hygroscopic salt being present in a molar ratio of hygroscopic salt to lactic acid of at least 1 , to form lactide, and

(b) recovering at least part of the lactide, said lactide being possibly recovered from the reaction medium (b) progressively, as it is formed.

In a second embodiment, the present invention relates to a process for the

manufacture of lactide comprising the steps of:

(a) heating lactic acid in the presence of a hygroscopic salt, said hygroscopic salt being present in a molar ratio of hygroscopic salt to lactic acid of at least 1 , under conditions such that

(i) if free water is present in the reaction medium, after said heating,

substantially all the free water is removed and,

(ii) if the hygroscopic salt is present in the reaction medium in its fully or partially hydrated form, after said heating step (a), the hygroscopic salt is present in a hydration state such that at least 1 mol of water per mol of lactic acid could be trapped by the hygroscopic salt, in the form of hydration water,

(b) heating the reaction medium of step (a) at a temperature from 80 to 250°C, the heating being preferably conducted under reduced pressure, to form lactide, and

(c) recovering at least part of the lactide, said lactide being possibly recovered from the reaction medium (b) progressively, as it is formed. In a third embodiment, optionally combined with the second one, the present invention relates to a process for the manufacture of lactide comprising the steps of:

(a) heating lactic acid in the presence of a hygroscopic salt, said hygroscopic salt being present in a molar ratio of hygroscopic salt to lactic acid of at least 1 , to form lactide, and

(b) recovering at least part of the lactide by distillation, said lactide being

possibly recovered from the reaction medium (b) progressively, as it is formed,

(c) recycling at least part of the hygroscopic salt, recovered as the distillation feet, directly into step (a), i.e. without any prior purification step.

The present invention is further illustrated below without limiting the scope thereto.

Should the disclosure of any patents, patent applications, and publications which are incorporated herein by reference conflict with the description of the present application to the extent that it might render a term unclear, the present description shall take precedence.

Examples

In the following examples, a B1JCHI Glass Oven B-585 was used, equipped with a boiler (80 ml round-bottomed flask, called Bl) and with one or two separate vessels in line with the boiler (called B2 and, when present, B3, B2 being between Bl and B3). Vessel Bl was fully located in the oven and vessels B2 and B3 were located out of the oven.

Example 1

9.0 g of water (0.5 mol) were added to 28.8 g of ZnS0 ₄ .7H ₂ 0 (0.1 mol) and the mixture was heated to 100°C to solubilize the ZnS0 ₄ .7H ₂ 0. A clear solution was obtained and it was allowed to cool to room temperature. The solution remained clear.

1 1.2 g of lactic acid as an 80 wt% solution in water (i.e. 9.0 g / 0.1 mol lactic acid and 2.24 g / 0.12 mol H ₂ 0) were added to the ZnS0 ₄ .7H ₂ 0 solution, then 53,7 g of ZnS0 ₄ .H ₂ 0 (0.3 mol) were added while mixing, to produce a paste which rapidly solidifies when mixing is stopped.

The solid was introduced into flask Bl which was connected with B2 and placed in a ventilated oven at 45 °C during about 6 hours under 4 mbar. After 6 hours, 20.9 g of water were collected in B2. 9.56 g of the mixture present in Bl were kept into Bl which was connected with vessels B2 and B3 and heated at 90°C during 4 hours at 4 mbar. 0.25 g of matter (mainly water) were collected into B3, which was replaced.

Bl was then heated at 140°C during 3 hours at 4 mbar. 0.42 g of a jellified product were collected in B2 and 0.14 g of a solid product were collected in B3. Ή-NMR analysis of the content of B2 and B3 showed the following composition:

- B2: 58% lactic acid, 12% dimer and 22% lactide,

- B3: 75% lactic acid, 8% dimer and 17% lactide.

The global yield in lactide was 14%.

Example 2

9.1 g of water (0.5 mol) were added to 28.8 g of ZnS0 ₄ .7H ₂ 0 (0.1 mol) and the mixture was heated to 100°C to solubilize the ZnS0 ₄ .7H ₂ 0. A clear solution was obtained and it was allowed to cool to room temperature. The solution remained clear.

10.9 g of lactic acid as a 90 wt% solution in water (i.e. 9.78 g / 0.1 mol lactic acid and 1.09 g / 0.06 mol H ₂ 0) were added to the ZnS0 ₄ .7H ₂ 0 solution, then 53.7 g of ZnS0 ₄ .H ₂ 0 (0.3 mol) were added while mixing, to produce a paste which rapidly solidifies when mixing is stopped. The mixture was kept in a dessicator. At the time of using the mixture, it was weighted again and it was noted that 1.9 g of water had evaporated. The composition at the time of the experiment was 71,7% ZnS0 ₄ .H ₂ 0, 9,78% lactic acid and 18,53 H ₂ 0.

22.5 g of the solid were introduced into Bl which was connected with B2 and placed in a ventilated oven at 55°C during about 24 hours under 3 mbar. After 24 hours, 3.93 g of water were collected in B2.

B2 was replaced and Bl was heated at 180°C during 20 min at atmospheric pressure and then at 180°C during 3 hours at 3 mbar. 0.57 g of matter were collected into B2. ¹ H-NMR analysis of the content of B2 showed the following composition: 30% lactic acid, 3% dimer and 67% lactide, which corresponds to a global yield in lactide of 22%.

Example 3

Example 2 was reproduced but 22.6 g of the solid were introduced into Bl which was connected with B2 and placed in a ventilated oven at 75°C during a bout 6 hours under 3 mbar. After 6 hours, water was collected in B2.

B2 was replaced and Bl was heated at 180°C during 17 hours at 3 mbar.

1.0 g of matter was collected into B2. ¹ H-NMR analysis of the content of B2 showed the following composition: 4% lactic acid, 5% dimer and 91% lactide, which corresponds to a global yield in lactide of 51%.