The invention relates to a process for producing a complex of lactic acid and an amine, and in particular to a process for producing a complex of lactic acid and a water- immiscible amine.

Lactic acid is an important industrial chemical which finds use, for example, in the production of polylactic acid. Lactic acid is commonly prepared from microbial fermentation of carbohydrates, although chemical processes for preparing lactic acid are also known. In a typical fermentation process, biomass is fermented with microorganisms to produce either D- or L- lactic acid. Current industrial scale manufacturers operate large-scale fermentation processes for the production of optically active lactic acid, and the patent literature is replete with improvements in such processes. Since lactic acid-producing organisms are inhibited in an acidic environment, basic substances such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates (e.g. calcium carbonate) are normally added during the

fermentation process to neutralise the acid produced and maintain activity. Thus, the product of a fermentation process is usually a lactate salt.

A number of chemical processes for the production of racemic lactic acid from carbohydrate sources are also known. For example, GB 400,413, dating from 1933, describes an improved process for preparing lactic acid or lactates comprising reacting a carbohydrate- containing material with a strong alkali such as sodium, potassium, calcium, barium or strontium hydroxide at a temperature of at least 200 °C and at a pressure above atmospheric. Again, the product of the reaction is a lactate salt.

For subsequent processing of the lactate species, lactic acid must be recovered from the reaction or fermentation mixture in a suitable form. One known method for obtaining lactic acid in a useful form can be to add sulfuric acid to the mixture, to produce lactic acid and metal sulfate. However, in the case where calcium lactate is used as the feedstock (which is common for fermentation processes), large quantities of calcium sulfate are produced which require disposal. An alternative approach is provided by US 5,892,109 (Baniel et al), which describes a process in which a fermentation broth metal lactate feed is combined with a water-immiscible amine in the presence of carbon dioxide to form a biphasic mixture having an aqueous phase and a lactic acid-rich organic phase. However, in order to obtain good recovery of lactic acid-containing species, use of carbon dioxide at high pressure is required. A further process for recovery of lactic acid from a fermentation broth containing calcium lactate is described in US 4,444,881 (Urbas). The process involves addition of a molar equivalent of a water-soluble tertiary amine carbonate to a solution containing the calcium lactate. However, the process of US 4,444,881 is for use with amines that form water-soluble carbonates, and water-immiscible amines such as trihexylamine and

trioctylamine are taught as being unsuitable. In the case where the lactate product (described in US 4,444,881 as a trialkylammonium salt of lactic acid) is obtained by extraction, an organic solvent which is insoluble or sparingly soluble in water is used to extract the product.

The present inventors have now found an improved process which permits the economic production of complexes of lactic acid and amines, without the need to use high pressures of carbon dioxide.

Accordingly the invention provides a process for the production of a complex of lactic acid and a water-immiscible amine ("Complex"), comprising contacting an aqueous solution of metal lactate with a mixture comprising a water-immiscible amine and an alcohol, in the presence of carbon dioxide, to produce said complex, characterised in that said contacting in the presence of carbon dioxide is carried out at a pressure of not more than 250 kPa gauge, and in the substantial absence of hydrocarbon solvent. Surprisingly, it has been found that the use of an alcohol in the substantial absence of a hydrocarbon solvent facilitates production of Complex in mixtures using water-immiscible amines using low pressures of carbon dioxide.

The product formed by the process of the invention is referred to herein as a Complex. In such a Complex, both ion pair and hydrogen bond interactions may occur between the lactic acid and the water-immiscible amine. The precise form of the Complex will depend on the environment in which it is found. The Complex may be regarded as a partly ionised liquid or, alternatively, as a simple salt between the acid and the amine, existing in

equilibrium with free acid and amine. For example, in the case of trioctylamine,

trioctylammonium lactate may be produced.

The step of contacting in the presence of carbon dioxide is carried out at a pressure of not more than 250 kPa gauge, i.e. the vessel or container in which the process is carried out is at a pressure of not more than 250 kPa above atmospheric pressure. In some embodiments, the step of contacting is carried out at a pressure of not more than 200 kPa gauge. In some -embodiments, the step of contacting is carried out at a pressure of not more than 150 kPa gauge. In some embodiments, the step of contacting is carried out at a pressure of not more than 100 kPa gauge. In some embodiments, the step of contacting is carried out at a pressure of not more than 50 kPa gauge. Carbon dioxide may be added in any suitable form, for example as a solid (e.g. dry ice) or, more preferably, as a gas.

The vessel or container in which the process is carried out may be under pressure (up to 250 kPa gauge), but is preferably at substantially atmospheric pressure (e.g. a small overpressure of carbon dioxide gas from a pressurised cylinder or other source is bubbled through the solution and/or mixture, and the vessel/container permits passage of gas from the system).

The process is carried out in the substantial absence of hydrocarbon solvent, preferably in the complete absence of hydrocarbon solvent. In some embodiments, the process of the invention is carried out in the substantial absence of any other solvent (i.e. any solvent other than water, alcohol and water-immiscible amine).

The process of the invention may be carried out with agitation, and use of equipment which promotes good mixing between the carbon dioxide, the water immiscible amine, the alcohol and water facilitates rapid formation of Complex. The process of the invention may for example be carried out in a jet flow reactor, e.g. a vessel equipped with a pump and a jet flow Venturi mixer. The process of the invention is normally carried out at a temperature in the range of from 5 to 90 °C. Preferably, the process of the invention is carried out at room temperature (e.g. from 15 to 30 °C, for example at about 25 °C). In another, less preferred embodiment, the reaction may be carried out at elevated temperature (for example at a temperature in the range of from 35 to 65 °C). The process of the present invention may be carried out in a batch, semi-continuous or continuous process. The process of the invention involves contacting an aqueous solution of metal lactate with a mixture comprising a water-immiscible amine and an alcohol, in the presence of carbon dioxide. Preferably, the metal cation of the metal lactate is a cation of an alkali metal (e.g. lithium, sodium, potassium) or an alkaline earth metal (e.g. magnesium, calcium, barium). In one

embodiment, the metal is lithium. In another embodiment, the metal is sodium. In a still further embodiment, the metal is barium.

The process of the invention is carried out in the presence of an alcohol. Preferably, the alcohol is an aliphatic alcohol. Preferably, the alcohol has from 1 to 12 carbon atoms. More preferably, the alcohol is an aliphatic alcohol having from 2 to 10 carbon atoms. Still more preferably, the alcohol is an aliphatic alcohol having from 3 to 8 carbon atoms. Most preferably, the alcohol is an aliphatic alcohol having from 4 to 6 carbon atoms. In one embodiment, the alcohol is selected from the group consisting of wo-propanol, n-propanol, n- butanol, n-pentanol, n-hexanol, n-heptanol and n-octanol. In one embodiment, the alcohol is n-butanol. In another embodiment, the alcohol is n-octanol (octan-l-ol), In another embodiment, the alcohol is n-hexanol (hexan-l-ol).

The process of the invention requires the use of a water-immiscible amine. A water- immiscible amine is an amine which forms a biphasic mixture when mixed with water. Such amines generally have a total of at least 12 carbon atoms. In one embodiment, the amine has at least 18 carbon atoms. In another embodiment the amine has at least 24 carbon atoms. In one embodiment the amine has a total of up to 60 carbon atoms (e.g. the amine has a total of from 12 to 60, from 18 to 60 or from 24 to 60 carbon atoms). In another embodiment, the amine has a total of up to 42 carbon atoms (e.g. the amine has a total of from 12 to 42, from 18 to 42, or from 24 to 42 carbon atoms). In a still further embodiment, the amine has a total of up to 30 carbon atoms (e.g. the amine has a total of from 12 to 30, from 18 to 30 or from 24 to 30 carbon atoms). Preferably, the water-immiscible amine is a trialkylamine. More preferably, the amine is a trialkylamine having at least 18 carbon atoms. Still more preferably, the amine is a trialkylamine in which each alkyl group has at least 3, preferably at least 4, carbon atoms. In one embodiment, the amine is a symmetrical trialkylamine.

Preferably, the amine is selected from the group consisting of trihexylamine, triheptylamine, trioctylamine, trinonylamine and tridecylamine. In one preferred embodiment, the amine is trioctylamine. In another preferred embodiment, the amine is trihexylamine. Mixtures of amines may also be used. For example, in one preferred embodiment a mixture of tertiary amines known as Alamine 336® is used. Alamine 336® is a water insoluble, tri-octyl/decyl amine. In one preferred embodiment, the amine is a mixture of trialkylamines having alkyl groups which are octyl and/or decyl groups.

In the process of the invention, metal bicarbonate and/or carbonate is produced as a by-product. In one preferred embodiment, the process of the invention is carried out in the presence of added metal bicarbonate and/or carbonate (for example, where the metal lactate is sodium lactate, in the presence of added sodium bicarbonate and/or carbonate, or where the metal lactate is barium lactate, in the presence of added barium bicarbonate and/or carbonate). It is believed that the presence of added metal bicarbonate and/or carbonate assists formation of the Complex.

The process of the invention requires water, water-immiscible amine and alcohol. Preferably, those components are present in a combined volume ratio compared to the amount of metal lactate of from 0.5 ml combined volume per mmol metal lactate to 25 ml combined volume per mmol metal lactate, more preferably, those components are present in a combined volume ratio compared to the amount of metal lactate of from 0.5 ml combined volume per mmol metal lactate to 20 ml combined volume per mmol metal lactate, still more preferably from 1 ml combined volume per mmol metal lactate to 10 ml combined volume per mmol metal lactate, yet more preferably from 1 ml combined volume per mmol metal lactate to 5 ml combined volume per mmol metal lactate. The volume ratio of water to water- immiscible amine is preferably in the range of from 1 :5 to 5: 1, more preferably from 1 :3 to 3: 1. The volume ratio of water to alcohol is preferably in the range of from 1 :5 to 5: 1, more preferably from 1 :3 to 3: 1. The volume ratio of water-immiscible amine to alcohol is preferably in the range of from 1 :3 to 3:1, more preferably from 1 :2 to 2 : 1 , most preferably about 1 :1. In one embodiment, water, water-immiscible amine and alcohol are present in a combined volume ratio, compared to the amount of metal lactate, of from 1ml combined volume per mmol metal lactate to 25 ml combined volume per mmol metal lactate, the volume ratio of water to water-immiscible amine is from 1 :5 to 5:1, and the volume ratio of water to alcohol is from 1 :5 to 5:1. In one embodiment, water, water-immiscible amine and alcohol are present in a combined volume ratio, compared to the amount of metal lactate, of from 1 ml combined volume per mmol metal lactate to 5 ml combined volume per mmol metal lactate, the volume ratio of water to water-immiscible amine is from 1 :3 to 3 : 1 , and the volume ratio of water to alcohol is from 1 :3 to 3: 1. In one embodiment, the metal is an alkali metal or an alkaline earth metal (especially lithium, sodium or barium), the water-immiscible amine is a trialkylamine having at least 18 carbon atoms, and the alcohol is an aliphatic alcohol having from 4 to 8 carbon atoms. Within this embodiment, the following specific embodiments may be mentioned:

i) the water-immiscible amine is a trialkylamine having at least 18 carbon atoms in which each alkyl group has at least 3 carbon atoms,

ii) the water-immiscible amine is a symmetrical trialkylamine having at least 18 carbon atoms,

iii) the water-immiscible amine is a trialkylamine having from 18 to 48 carbon atoms in which each alkyl group has at least 3 carbon atoms,

iv) the water-immiscible amine is a symmetrical trialkylamine having from 18 to 48 carbon atoms,

v) the water- immiscible amine is a trialkylamine having from 18 to 30 carbon atoms in which each alkyl group has at least 4 carbon atoms,

vi) the water-immiscible amine is a symmetrical trialkylamine having from 18 to 30 carbon atoms, vii) the water-immiscible amine is trihexylamine, triheptylamine, trioctylamine, trinonylamine and/or tridecylamine,

viii) the water-immiscible amine is a mixture of trialkylamines having alkyl groups which are octyl and/or decyl groups,

ix) the metal is lithium, sodium or barium, the water-immiscible amine is

trihexylamine, triheptylamine, trioctylamine, trinonylamine and/or tridecylamine, and the alcohol is wo-propanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol and/or n- octanol,

x) the metal is lithium, sodium or barium, the water-immiscible amine is a mixture of trialkylamines having alkyl groups which are octyl and/or decyl groups, and the alcohol is wo-propanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol and/or n-octanol, xi) the metal is lithium, sodium or barium, the water- immiscible amine is

trihexylamine, triheptylamine, trioctylamine, trinonylamine and/or tridecylamine, and the alcohol is n-propanol, n-butanol, n-pentanol and/or n-hexanol,

xii) the metal is lithium, sodium or barium, the water-immiscible amine is a mixture of trialkylamines having alkyl groups which are octyl and/or decyl groups, and the alcohol is n-propanol, n-butanol, n-pentanol and/or n-hexanol,

xiii) the metal is lithium, sodium or barium, the water-immiscible amine is trihexylamine, triheptylamine, trioctylamine, trinonylamine and/or tridecylamine, and the alcohol is n-butanol,

xiv) the metal is lithium, sodium or barium, the water-immiscible amine is a mixture of trialkylamines having alkyl groups which are octyl and/or decyl groups, and the alcohol is n-butanol.

The metal lactate may be obtained from any suitable source by known methods, for example by a carbohydrate fermentation process which involves addition of a basic substance such as an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate to neutralise the lactic acid produced. In an alternative, preferred embodiment, the metal lactate is produced by a chemical process, for example by reaction of a carbohydrate with a strong alkali. More preferably the metal lactate is produced by reaction of a monosaccharide (e.g. glucose and/or fructose) with a metal hydroxide (e.g. an alkali or alkaline metal earth hydroxide, such as lithium hydroxide, sodium hydroxide or barium hydroxide).

In the case where the metal carbonate and/or bicarbonate precipitates from the reaction mixture, the Complex may be separated by filtration of solid metal carbonate and/or bicarbonate. The Complex may also be separated from metal carbonate and/or bicarbonate by phase separation. Advantageously, where the Complex is separated from metal carbonate and/or bicarbonate by phase separation, the process of the invention allows for simple recovery of the Complex in good yield, without the need to use further organic solvent to assist the extraction/phase separation. The presence of a water-immiscible amine and water in the process of the invention results in a biphasic mixture, into the amine phase of which the Complex generally partitions, thus allowing separation from metal carbonate and/or bicarbonate and from other by-products present in the aqueous layer. Thus, in a preferred embodiment, the Complex is separated from metal carbonate and/or bicarbonate by phase separation, without addition of further organic solvent. It is of course possible to add a further solvent during a subsequent extraction/phase separation step, and in an alternative but less preferred embodiment, additional organic solvent is added during a subsequent extraction/phase separation step to assist extraction and/or separation of the Complex.

The Complex may be subject to purification and/or additional processing steps. For example, alcohol and/or water- immiscible amine present in an extract containing the

Complex may be removed by distillation, and optionally recycled.

The Complex may be converted into lactic acid, and the present invention further provides a process for the production of lactic acid, comprising producing a complex of lactic acid and a water-immiscible amine by a process according to the invention, and converting the Complex into lactic acid. For example, lactic acid may be obtained by reaction of the Complex with an acid such as hydrochloric acid or sulphuric acid.

The Complex may also be converted into an ester of lactic acid, for example by converting the Complex into lactic acid, and reacting the lactic acid with an alcohol. Thus, the present invention further provides a process for the production of an ester of lactic acid, comprising producing a complex of lactic acid and a water-immiscible amine by a process according to the invention, and converting the Complex into the ester of lactic acid.

The present invention also provides a process for the production of lactic acid oligomer, comprising producing a complex of lactic acid and a water-immiscible amine by a process according to the invention, and converting the Complex into lactic acid oligomer. The Complex may be converted into lactic acid oligomer directly, or optionally the Complex may be converted into lactic acid or into an ester of lactic acid, before the lactic acid or the ester of lactic acid is converted into lactic acid oligomer.

The Complex may also be reacted to form lactide, a cyclic dimer of lactic acid that is itself useful in the production of polylactic acid. The invention therefore further provides a process for the production of lactide, comprising producing a complex of lactic acid and a water-immiscible amine by a process according to the invention, optionally converting the Complex into lactic acid, an ester of lactic acid, or lactic acid oligomer, and converting the Complex, lactic acid, ester of lactic acid or lactic acid oligomer into lactide. For example, the Complex may be heated to produce lactic acid oligomer (also known as a pre-polymer or oligomer of lactic acid) which is contacted with a transesterification catalyst to produce lactide. Alternatively, lactic acid or an ester of lactic acid may be heated to produce lactic acid oligomer which is contacted with a transesterification catalyst to produce lactide.

Lactide may be polymerised to form polylactic acid. The invention therefore further provides a process for the production of polylactic acid, comprising producing lactide by a process according to the invention, and polymerising the lactide to form polylactic acid. This polymerisation may be carried out by contacting lactide with a catalyst at elevated

temperature.

The following examples illustrate the invention.

Example 1:

A 20 ml aqueous solution containing sodium lactate (4.7 g, 42 mmols) and sodium hydroxide (1.6 g, 40 mmols) was stirred at room temperature for 60 minutes with a mixture of n-butanol : trioctylamine pre-saturated with water (2:1 ratio by volume, 80 ml combined volume of alcohol and amine, 100 ml total reaction mixture volume) whilst bubbling C0 ₂ through the mixture at a rate of 65 ml/min. A precipitate of sodium carbonate gradually formed and, once the C0 ₂ flow was terminated, the precipitate was filtered off under vacuum. The filtrate then separated on standing into a more dense aqueous layer (less than 10 ml) and a less dense organic phase. The concentration of lactic acid remaining in the aqueous layer was determined by acidification and analysis by liquid chromatography. Extraction efficiency into the organic layer was 77.1%.

Example 2:

100 g of a reaction product mixture arising from the reaction of glucose with 4 eq. NaOH (addition of the glucose to the base in water over 2 h, 100 °C, sodium lactate content 23.5 g), 100 g trioctylamine and 100 g n-butanol were charged to a round bottomed flask fitted with overhead stirring, C0 ₂ line, gas outlet port and charge port. The C0 ₂ purge (approx. 500 ml/min) was started while ensuring that the outlet sat beneath the phase boundary and the mixture was stirred vigorously (approx 250 rpm) for 120 mins at room temperature. Samples were taken by switching off the stirring and allowing the phases to separate before sampling from the appropriate layer using a pipette or similar. At the end of the C0 ₂ addition period, the reaction mixture was filtered and allowed to stand. Analysis of the aqueous layer revealed that ca. 85% of the original sodium lactate had transferred out of the aqueous phase.

Example 3

100 g solution of barium lactate product (77 ml water containing 0.13 moles barium lactate, produced from reaction of barium hydroxide with glucose), 220 g n-butanol and 110 g tri(n-octyl)amine (0.312 moles) were charged to a 1L glass vessel equipped with a valve at the bottom of the reactor connected to a pump and a jet flow Venturi mixer. Overhead stirring was started at 250 rpm and the re-circulating pump was switched on at 3L/min. C0 ₂ was then introduced at 500 ml/min (measured using a flowmeter) into the Venturi to ensure good mixing at a rate. The formation of a pale coloured precipitate quickly becomes apparent. After 120 minutes the C0 ₂ addition was stopped and extraction efficiency, measured by the amount of residual lactate in the aqueous layer, was >95% as measured by HPLC.

The same apparatus can be readily modified to allow the reaction to be conducted in a continuous manner. The re-circulation loop features a valve immediately after the pump to allow sampling, but which may also be used to continuously remove the product mixture. Additional feeds of barium lactate, n-butanol and tri(n-octylamine) and may be added by pumps to maintain a constant volume within the apparatus.

Example 4

20 ml of an aqueous mixture containing barium lactate (3.94 mmols, arising from the reaction of glucose with barium hydroxide (90 °C, 2 h)) and other barium carboxylate salts was stirred with trihexylamine (15 ml, 44.2 mmols) and n-butanol (45 ml, 3: 1 v/v

trihexylamine) while C0 ₂ was bubbled through the mixture (room temperature, 2 h). After this time the pale coloured precipitate was filtered off and the filtrate separated into aqueous (11 ml) and organic (62 ml) phases. The aqueous phase was analysed by HPLC and found to have a concentration of 0.0185 M in lactate, corresponding to 0.2035 mmols un-extracted lactate. The extraction efficiency was therefore 94.8%.

Example 5 20 ml of an aqueous solution containing barium lactate (7.2 mmols, 14.4 mmols lactate, previously synthesised from the reaction of barium hydroxide with racemic lactic acid) was stirred with trioctylamine (15 mis, 34.3 mmols, 2.4 eq) and n-butanol (5 ml, 1 :3 v/v trioctylamine) while C0 ₂ was bubbled through the mixture (room temperature, 2 h). The precipitate was filtered off and the filtrate separated into aqueous (19 ml) and organic (20.5 ml) phases. A sample of the aqueous phase was analysed by HPLC and found to be 0.2796 M in lactate, corresponding to 5.31 mmols residual lactate. The extraction efficiency was therefore 63%.

Example 6

25 ml aqueous solution containing a lithium lactate (61.05 mmols, Sigma Aldrich) and lithium hydroxide (68 mmols, Sigma Aldrich) was stirred with tri(n-octyl)amine (49 ml, 112 mmols,) and n-butanol (98 ml, 2: 1 v/v trioctylamine) while C0 ₂ was bubbled through the solution at ~100ml/min for 150 minutes hours at room temperature. The precipitate thus formed was filtered under suction and washed with water. The filtrate had an upper organic phase and lower aqueous phase. The washings were combined with the lower aqueous phase of the filtrate to give a total aqueous volume of 69mls. HPLC analysis of the aqueous phase confirmed that 50.6% of the initial concentration of lactate had been transferred to the organic layer.

Example 7

Extraction of reaction mixtures containing Barium Lactate

1. Preparation of reaction mixtures containing barium lactate:

A. To a 500 mL flask was charged barium hydroxide octahydrate (47.68 g). The flask was heated in oil to 100 °C. A solution of 0.4 M Fructose (18.0071 g fructose made up to 250 mL in a volumetric flask using deionised water) was then added over a period of 60 minutes to the heated barium hydroxide whilst keeping the temperature between 90-100 °C. The reaction mixture was cooled to room temperature. A sample was taken and analysed for lactic acid content by HPLC.

B. To a 500 mL flask was charged barium hydroxide octahydrate (23.68 g). The flask was heated in oil to 100 °C. A solution of 0.2 M Mannose (9.0080 g fructose made up to 250 mL in a volumetric flask using deionised water) was then added over a period of 60 min to the heated barium hydroxide whilst keeping the temperature between 90-100 °C. The reaction mixture was cooled to room temperature. A sample was taken and analysed for lactic acid content by HPLC.

Appropriate volumes from the reaction mixtures produced in step A and step B were used in the extraction processes described below.

2. Extraction process:

A known volume of the reaction mixture from A or B (50 mL) was taken in a suitable reaction vessel equipped with overhead stirrer and a C0 ₂ sparge. Appropriate trialkylamine (50 mL) and appropriate alcohol solvent (30 mL) were added. These were stirred with continuous sparging of C0 ₂ (g) (i.e. a small overpressure of carbon dioxide gas was bubbled through the mixture) for 90 mins at room temperature. The resulting BaC0 ₃ precipitate was filtered and the layers of filtrate were separated. The lower aqueous layer was analysed by HPLC for lactic acid content. From this analysis the % extraction of lactic acid into organic phase was calculated. The partition coefficient (K) was also calculated, by dividing the concentration of the lactic acid in the organic phase by the concentration of the lactic acid in the aqueous phase.

Details of the reaction mixture, alcohol and trialkylamine used, and the results, are shown in Table 1. The results show that good extraction of lactic acid into the organic phase is achieved using the method of the invention, without needing to use high pressures of carbon dioxide.

Table 1

* Volume of separated organic layer separated is calculated based on total volume (130 mL) - aqueous layer separated volume A = Fructose reaction mixture (50 ml) B = Mannose reaction mixture (50 ml)