WO2015001330A1

WO2015001330A1 - Lactate production process

Info

Publication number: WO2015001330A1
Application number: PCT/GB2014/051992
Authority: WO
Inventors: Edward Leslie Marshall; Alan Keasey; Stephen Donegan; Michael Dunning
Original assignee: Plaxica Limited
Priority date: 2013-07-01
Filing date: 2014-07-01
Publication date: 2015-01-08
Also published as: GB201311780D0

Abstract

A process for producing alkyl R-lactate and alkyl S,S-lactyllactate is provided. The process comprises:(a) admixing (i) a first mixture comprising R,R-and S,S-lactide with (ii) a second mixture comprising a C₁-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate; and(b) reacting the lactide with the alkyl alcohol to produce alkyl R-lactate and alkyl S,S-lactyllactate, wherein alkyl R-lactate is produced in the presence of a lipase enzyme. Also provided are processes for the production of R-lactic acid, oligomeric R-lactic acid, R,R-lactide,poly-R-lactic acid, S-lactic acid,alkyl S-lactate, oligomeric S-lactic acid,S,S-lactide, poly-S-lactic acidand stereocomplex polylactic acid.

Description

LACTATE PRODUCTION PROCESS

Field of the invention

The present invention relates to processes for producing alkyl R-lactate and alkyl S,S- lactyllactate from a mixture comprising R,R- and S,S-lactide. The invention also relates to the production of downstream products, such as R-lactic acid, S-lactic acid, alkyl R-lactate, oligomeric R-lactic acid, oligomeric S-lactic acid, R,R-lactide, S,S-lactide, poly-R-lactic acid, poly-S-lactic acid and stereocomplex polylactic acid.

Background of the invention

Lactic acid (2-hydroxypropanoic acid) and its cyclic dimer lactide (3,6-dimethyl-l,4- dioxan-2,5-dione) are important building blocks for the chemical and pharmaceutical industries. One example of their use is in the manufacture of polylactic acid, a polymer whose ability to be produced from a variety of renewable feedstocks and biodegradability makes it an attractive candidate to replace more conventional petrochemical polymers.

Polylactic acid can be prepared via a multi-step process involving (a) dehydration of lactic acid to produce lactide (via an oligomerisation-depolymerisation process), and (b)

polymerisation of the lactide under carefully controlled conditions to ensure that long polymer chains are produced in preference to shorter oligomers. Alternatively polylactic acid can be prepared directly from the condensation polymerisation of lactic acid, though obtaining high molecular weight material is generally more difficult than via the ring-opening polymerisation of lactide.

Lactide, the cyclic dimer of lactic acid, exists in three different stereoisomeric forms: R,R-lactide, S,S-lactide, and R,S-lactide. R,R-lactide and S,S-lactide are enantiomers of each other, and a mixture containing substantially equal quantities of R,R- and S,S- lactide is referred to as racemic lactide or rac-lactide. R,S-lactide is also known as meso-\actide, and is a diastereoisomer of R,R- and S,S-lactide.

Today virtually all large scale production of the lactic acid available commercially is carried out by fermentation processes, see for example Strategic Analysis of the Worldwide Market for Biorenewable Chemicals M2F2-39, Frost and Sullivan, 2009. Lactic acid is chiral and can be made in two enantiomeric forms, respectively L-lactic acid (hereinafter referred to as S-lactic acid) on the one hand and D-lactic acid (hereinafter R-lactic acid) on the other.

Since the most readily available source of lactic acid is S-lactic acid, the principal lactide employed commercially to date has been S,S-lactide and the polymer produced poly- L-lactic acid (PLLA) (hereinafter poly S-lactic acid). However the physical and chemical properties of poly S-lactic acid are limited relative to conventional polymers, as are those of the corresponding poly D-lactic acid (PDLA) (hereinafter poly R-lactic acid) which to date has limited their utility, particularly with respect to more durable and/or engineering applications. It has been found that deficiencies can be overcome by using mixtures of poly S-lactic acid and poly R-lactic acid which are prepared by, for example, melt blending. It is believed that in these so-called 'stereocomplex' polymer mixtures close packing of the poly S-lactic acid and poly R-lactic acid chains occasioned by their differing chirality improves polymer crystallinity which leads to improvements in the properties referred to above. This permits the use of stereocomplex polylactic acid for a much wider range of consumer durable applications, making it a viable alternative to traditional commodity polymers such as polyethylene terephthalate, polypropylene and polystyrene. This approach however requires access to large quantities of poly R-lactic acid and therefore ultimately to large quantities of R-lactic acid, or to suitable derivatives thereof.

In addition to the use of fermentation methods, it is known to produce lactic acid by conventional chemical transformation. Jeon et al (Tetrahedron Letters, 47, (2006), 6517- 6520) disclose the laboratory observation that rac-lactide can be alcoholised with various alcohols in the presence of a solvent and the supported lipase enzyme Novozym 435, to produce a mixture containing the corresponding alkyl R-lactate and alkyl S,S-lactyllactate. However, this reference does not deal with the problem of providing an efficient and economic process for producing R-lactic acid-based materials on an industrial scale.

WO2013/011295 discloses processes for producing an aliphatic ester of lactic acid using different solvents. In particular, WO2013/011295 discloses that processes involving contacting a mixture of R,R- and S,S-lactide with an aliphatic alcohol and an enzyme in the presence of a ketone solvent have significant advantages, including that the use of ketone solvents results in high conversion of starting material to product with high enantiomeric excess, whilst displaying solubility properties amenable to industrial scale synthesis.

However, the process described in WO2013/011295 also has some disadvantages. If recycling of the ketone solvent is desired, on industrial scale significant energy input is required as are appropriate facilities for recovery of the ketone solvent. Whilst this is feasible, there remains a need for further methods suitable for industrial scale production of single enantiomers of lactic acid and its derivatives.

The present inventors have now identified a process for producing alkyl R-lactate and alkyl S,S-lactyllactate from racemic lactide which is suitable for use on an industrial scale and which does not require the presence of a ketone solvent.

Accordingly, the present invention provides a process for producing alkyl R-lactate and alkyl S,S-lactyllactate comprising:

(a) admixing (i) a first mixture comprising R,R- and S,S-lactide with (ii) a second mixture comprising a Ci-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate; and

(b) reacting the lactide with the alkyl alcohol to produce alkyl R-lactate and alkyl S,S- lactyllactate, wherein alkyl R-lactate is produced in the presence of a lipase enzyme.

Brief description of the Drawings

Figures 1 to 7 show embodiments of the process of the invention.

Detailed description of the Invention

The present invention facilitates production of alkyl R-lactate and alkyl S,S- lactyllactate on an industrial scale. The inventors have surprisingly found that product mixtures from lipase-catalysed alcoholysis of racemic lactide in alkyl alcohol themselves act as good solvents for dissolving significant quantities of R,R- and S,S-lactide mixtures. In addition, such feedstocks have been found to be well-tolerated in the lipase enzyme-catalysed alcoholysis reaction and, as a result, conversion of large quantities of R,R- and S,S-lactide mixtures to alkyl R-lactate and alkyl S,S-lactyllactate can be achieved in high enantiomeric excess using low solvent volumes. The inventors have also found that solvent usage can be reduced even further whilst still achieving good conversion to alkyl R-lactate and alkyl S,S- lactyllactate in high enantiomeric excess, by means of an iterative process involving carrying out steps (a) and (b), adding further R,R- and S,S-lactide to the resulting mixture, and again carrying out lipase enzyme-catalysed alcoholysis. Typically the enantiomeric excess of the alkyl R-lactate produced by the process is at least 80%, preferably at least 90%, more preferably at least 95%, still more preferably at least 98%), most preferably at least 99%. Typically the enantiomeric excess of the alkyl S,S- lactyllactate produced by the process is at least 80%>, preferably at least 90%, more preferably at least 95%, still more preferably at least 98%, most preferably at least 99%. Typically the enantiomeric excess of each of the alkyl R-lactate and the alkyl S,S-lactyllactate produced by the process is at least 80%, preferably at least 90%, more preferably at least 95%, still more preferably at least 98%, most preferably at least 99%.

Step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide with (ii) a second mixture comprising a Ci-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate. The mixture of R,R- and S,S-lactide may be racemic or scalemic (i.e. non racemic). Typically the molar ratio of R,R- to S,S-lactide is in the range of from 3 :7 to 7:3, preferably from 4:6 to 6:4, more preferably from 45:55 to 55:45, still more preferably from 48:52 to 52:48; yet more preferably from 49:51 to 51 :49; most preferably about 50:50.

The mixture of R,R- and S,S-lactide used in the process can in principle be derived from any source. One example of a suitable source is racemic lactic acid produced by treating a monosaccharide (including glucose, fructose, xylose, and mixtures thereof) or a number of other carbohydrates (including formaldehyde, glyceraldehyde, dihydroxyacetone and glycerol) with a base in aqueous solution at elevated temperature. For example, a Group IA metal, Group IIA metal or quaternary ammonium hydroxide may be used, as described for example in WO2012/052703 or WO2012/131299. Typically the racemic lactic acid produced in these processes can be converted into racemic lactide by dehydration processes well-known in the art, for example via an oligomerisation-depolymerisation process.

Preferably the mixture comprising R,R- and S,S-lactide is free or substantially free of the corresponding R,S-diastereoisomer (meso lactide). Preferably the mixture comprising R,R- and S,S-lactide contains less than 5 wt% R,S-lactide, more preferably less than 3 wt%, still more preferably less than 2 wt%, most preferably less than 1 wt%. If desired, R,S-lactide may be separated from R,R- and S,S-lactide by routine methods well known in the art.

The Ci-C₈ alkyl group present in the alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate is preferably a C₂ to C₈ alkyl group, for example ethyl, n-propyl, i-propyl or n-butyl. More preferably the alkyl group is a C₃ to C₈ alkyl group, yet more preferably a C₃ to C₄ alkyl group. In some preferred embodiments, the alkyl alcohol is i-propanol, the alkyl R-lactate is i-propyl R-lactate, and the alkyl S,S-lactyllactate is i-propyl S,S-lactyllactate. In some preferred embodiments, the alkyl alcohol is n-propanol, the alkyl R-lactate is n-propyl R-lactate, and the alkyl S,S-lactyllactate is n-propyl S,S- lactyllactate. In particularly preferred embodiments, the alkyl alcohol is n-butanol, the alkyl R-lactate is n-butyl R-lactate, and the alkyl S,S-lactyllactate is n-butyl S,S-lactyllactate. In some embodiments, the alkyl group is a linear alkyl group.

Mixtures comprising Ci-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate have been found to be effective solvents for dissolution of mixtures of R,R- and S,S-lactide and for enzyme-catalysed production of alkyl R-lactate. Whilst in some embodiments additional organic solvents may be present (e.g. traces of solvents, for example remaining from previous synthesis steps), preferably steps (a) and (b) are carried out in the absence or in the substantial absence of additional organic solvent (i.e. no organic solvent other than Ci-C₈ alkyl alcohol, alkyl R-lactate or alkyl S,S-lactyllactate is present). Preferably the mixture of components (i) and (ii) contains less than 5 wt% additional organic solvent, more preferably less than 2 wt% additional organic solvent, yet more preferably less than 1 wt% additional organic solvent. Steps a) and b) are particularly preferably carried out in the absence or in the substantial absence of a ketone solvent.

The solvent mixture may contain some water, but typically less than 5 wt% of the mixture of components (i) and (ii) is water.

In some preferred embodiments the second mixture (component (ii)) comprises at least

3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S-lactyllactate, more preferably at least

4 wt% n-butyl R-lactate and at least 3.5 wt% n-butyl S,S-lactyllactate. In some preferred embodiments the second mixture comprises at at least 9 wt% n-butyl R-lactate and at least 6.5 wt% n-butyl S,S-lactyllactate, more preferably at least 9.5 wt% n-butyl R-lactate and at least 7 wt% n-butyl S,S-lactyllactate. Preferably, the second mixture comprises at least 65 wt% n-butanol, more preferably at least 75 wt% n-butanol. In some preferred embodiments the second mixture comprises at least 3 wt% n-butyl R-lactate, at least 3 wt% n-butyl S,S- lactyllactate, and at least 65 wt% n-butanol, more preferably at least 4 wt% n-butyl R-lactate, at least 3.5 wt% n-butyl S,S-lactyllactate, and at least 75 wt% n-butanol. In some preferred embodiments the second mixture comprises at least 9 wt% n-butyl R-lactate, at least 6.5 wt% n-butyl S,S-lactyllactate, and at least 65 wt% n-butanol, more preferably at least 9.5 wt% n- butyl R-lactate, at least 7 wt% n-butyl S,S-lactyllactate, and at least 75 wt% n-butanol. Preferably, the second mixture comprises n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate and the weight ratio of the first mixture to the second mixture is in the range of from 1 :20 to 1 :5, more preferably from 1 : 15 to 1 :5, still more preferably from 1 : 12 to 1 :5.

Appropriate stirring means may be used to ensure good mixing of R,R- and S,S- lactide with the mixture comprising alkyl alcohol, alkyl R-lactate and alkyl S,S-lactyllactate. Step (a) is preferably carried out at a temperature of at least 20 °C, at least 30 °C, at least 40°C, at least 50°C or at least 60 °C. In some preferred embodiments, step (a) is carried out a temperature in the range of from 30 °C to 100 °C. In some preferred embodiments, step (a) is carried out at a temperature in the range of from 50°C to 75°C. In some preferred

embodiments, step (a) is carried out at a temperature in the range of from 50°C to 70°C. In some preferred embodiments, step (a) is carried out at a temperature of about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C or about 75 °C.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide with (ii) a second mixture comprising n-butyl alcohol, n- butyl R-lactate and n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a second mixture comprising n-butyl alcohol, n-butyl R-lactate and n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a second mixture comprising at least 65 wt% n-butyl alcohol, at least 3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a second mixture comprising at least 65 wt% n-butyl alcohol, at least 3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of the first mixture to the second mixture is in the range of from 1 :20 to 1 :5.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide with (ii) a second mixture comprising n-butyl alcohol, n- butyl R-lactate and n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C, and the mixture of components (i) and (ii) contains less than 5 wt% additional organic solvent.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a second mixture comprising n-butyl alcohol, n-butyl R-lactate and n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C, and the mixture of components (i) and (ii) contains less than 5 wt% additional organic solvent.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a second mixture comprising at least 65 wt% n-butyl alcohol, at least 3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C, and the mixture of components (i) and (ii) contains less than 5 wt% additional organic solvent.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a second mixture comprising at least 65 wt% n-butyl alcohol, at least 3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of the first mixture to the second mixture is in the range of from 1 :20 to 1 :5, and the mixture of components (i) and (ii) contains less than 5 wt% additional organic solvent.

Step (b) comprises reacting the R,R- and S,S-lactide with the Ci-C₈ alkyl alcohol to produce alkyl R-lactate and alkyl S,S-lactyllactate, wherein alkyl R-lactate is produced in the presence of a lipase enzyme. R,R- and S,S-lactide react with the Ci-C₈ alkyl alcohol to produce alkyl R,R-lactyllactate and alkyl S,S-lactyllactate. The lipase enzyme is able to stereoselectively catalyse the reaction of alkyl R,R-lactyllactate with alkyl alcohol to produce alkyl R-lactate, with the reaction of alkyl S,S-lactyllactate to produce alkyl S-lactate proceeding at a considerably slower rate. Hence, whilst step (a) may be carried out in the absence of lipase enzyme, use of an enzyme is required in step (b).

The product mixture of step (b) comprises alkyl R-lactate and alkyl S,S-lactyllactate. In some embodiments the product mixture may also contain some lactide (e.g. R,R-lactide and/or S,S-lactide), and/or alkyl R,R-lactyllactate, for example where the reaction has not proceeded fully to completion. Preferably the product mixture resulting from step (b) comprises less than 1 wt% lactide, more preferably less than 0.5 wt%, still more preferably less than 0.2 wt%, most preferably less than 0.1 wt% (e.g. the combined amount of R,R- lactide and/or S,S-lactide is less than 1 wt% of the product mixture, more preferably less than 0.5 wt%, still more preferably less than 0.2 wt%, most preferably less than 0.1 wt%).

Preferably the product mixture resulting from step (b) comprises less than 1 wt% alkyl R,R- lactylactate (e.g. n-butyl R,R-lactyllactate), more preferably less than 0.5 wt%, still more preferably less than 0.2 wt%, most preferably less than 0.1 wt%.

Preferably the lipase enzyme is one which is either chemically or physically immobilised on a support (e.g. a porous support) for example a polymer resin bead or a silica, alumina or aluminosilicate bead, or is physically aggregated by inter-enzyme cross-linking. One particularly preferred example is Candida antarctica lipase B, a serine hydrolase with known enantiomeric selectivity towards the hydrolysis of esters. In this aspect of the invention, the Candida antarctica lipase B is most preferably chemically or physically bound to micro or nano beads made of a polymer resin for example a polyacrylate resin, as is the case for example in the commercially available material Novozym 435. Other preferred enzymes include CalB immo, an immobilised Candida antarctica lipase B adsorbed to a methacrylate carrier, manufactured by c-LEcta, IMMCALB-T2-150, an immobilised

Candida antarctica lipase B covalently attached to dry acrylic beads, manufactured by Chiralvision; IMMCALBY-T2-150, a generic Candida antarctica lipase B covalently attached to dry acrylic beads manufactured by Chiralvision; IMMCALB-Tl-350, a Candida antarctica lipase B absorbed on dry polypropylene beads, manufactured by Chiralvision; and cross-linked aggregate of Candida antarctica lipase B, manufactured by CLEA. The enzyme may also be a recombinant Candida antarctica lipase B from Aspergillus oryzae, supplied by Sigma Aldrich (non-immobilised). Preferably the lipase enzyme (e.g. Candida antarctica lipase B, Novozym 435) is recovered and recycled to the process.

Step (b) is carried out under conditions suitable to effect high conversion of R,R- and S,S-lactide to alkyl R-lactate and alkyl S,S-lactyllactate. Step (b) is suitably carried out at a temperature such that reaction rates are significant on the one hand and that the enzyme does not deteriorate with long term use on the other. Preferably step (b) is carried out at a temperature in the range of from 25°C to 80°C, more preferably at a temperature in the range of from 40°C to 75°C, still more preferably at a temperature in the range of from 50°C to 75°C, yet more preferably in the range from 50°C to 70°C. In one preferred embodiment, step (b) is carried out at a temperature of about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C or about 75 °C.

Step (b) may be carried out on an industrial scale on a number of ways. For example, if a supported lipase enzyme is used the reaction may be carried out batchwise in a single stirred or highly back-mixed tank. The residence times of the reactants and the enzyme in the stirred tank will be selected so as to ensure good conversion of R,R- and S,S-lactide to alkyl R-lactate and alkyl S,S-lactyllactate, typically in the range of up to 24 hours, preferably up to 10 hours, more preferably in the range of from 1 to 8 hours. The amount of supported enzyme used will typically be in the range up to 10%, preferably up to 5%, by weight of the mixture comprising R,R- and S,S-lactide. Where step (b) is operated in a batch-type reactor, the product mixture may be separated from the enzyme by, for example, filtration of the enzyme, or by decanting or siphoning off the mixture. Preferably, in the case of a batch-type process, the enzyme is re-used at least once, more preferably at least twice, still more preferably at least 5 times, yet more preferably at least 10 times, most preferably at least 20 times.

More preferably, step (b) comprises passing the mixture from step (a) (i.e. the mixture comprising R,R- and S,S-lactide, Ci-C₈ alkyl alcohol, alkyl R-lactate and alkyl S,S- lactyllactate) through a packed bed of lipase enzyme which is chemically or physically immobilised on a support (e.g. Novozym 435), e.g. at a temperature in the range of from 50°C to 75°C. Good solubility of the substrate in the solvent mixture enables such processes to work effectively. Typically the immobilised enzyme is stored in a packed bed column, and the mixture from step a) is passed along the column, bringing it into contact with the enzyme, with a residence time selected so as to ensure high conversion. This arrangement permits continuous generation of product by flow operations and separation of product and enzyme without the need for filtration of the enzyme. In a particularly preferred embodiment, the packed bed is vertical, and the mixture from step (a) is fed into the top of the column. In one preferred embodiment, the step of reacting R,R- and S,S-lactide with alkyl alcohol is carried out continuously in a tower reactor by for example trickling the liquid reactants down through a fixed or fluidised bed of supported enzyme contained therein. A product mixture comprising alkyl R-lactate, alkyl S,S-lactyllactate and alkyl alcohol can then be recovered from the bottom of the tower. In this arrangement, the contact time of the reactants with the bed is typically in the range of up to 24 hours. Preferably residence times (contact time of the reactants with the bed) are in the range of from 10 minutes to 4 hours, more preferably from 10 minutes to 2 hours. Arrangements of this type permit continuous or semi-continuous generation of alkyl R-lactate and alkyl S,S-lactyllactate by flow operations. In the case of processes where the mixture from step (a) is passed through a packed bed of enzyme (i.e. a continuous or semi-continuous flow process), product and enzyme are continually being separated from one another and the enzyme is continually being recycled.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide with (ii) a second mixture comprising n-butyl alcohol, n- butyl R-lactate and n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C; and step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C.

In some preferred embodiments, step (a) comprises admixing (i) a mixture of R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a mixture comprising at least 65 wt% n-butyl alcohol, at least 3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S- lactyllactate, at a temperature in the range of from 50°C to 75°C; and step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C.

In some preferred embodiments, step (a) comprises admixing (i) a mixture of R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a mixture comprising at least 65 wt% n-butyl alcohol, at least 3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S- lactyllactate, at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of components (i) and (ii) is in the range of from 1 :20 to 1 :5; and step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C.

In some preferred embodiments, step (a) comprises admixing (i) a mixture of R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a mixture comprising at least 65 wt% n-butyl alcohol, at least 9 wt% n-butyl R-lactate and at least 6.5 wt% n-butyl S,S- lactyllactate, at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of components (i) and (ii) is in the range of from 1 :20 to 1 :5; and step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C.

Preferably, the mixture comprising Ci-C₈ alkyl alcohol, alkyl R-lactate and alkyl S,S- lactyllactate used in step (a) has been produced by step (a^') reacting a mixture comprising R,R- and S,S-lactide with Ci-C₈ alkyl alcohol in the presence of a lipase enzyme. In some preferred embodiments, for example in the case of a continuous or semi-continuous process, the product mixture of step (a^') is divided into first and second portions, the first portion being used as a solvent mixture for dissolution of and reaction of further R,R- and S,S-lactide (in steps (a) and (b)), the second portion being subjected to separate processing, e.g.

separation of alkyl R-lactate and alkyl S,S-lactyllactate, for example by distillation.

Accordingly, in some preferred embodiments the process of the invention comprises:

(a^') reacting a mixture comprising R,R- and S,S-lactide with a Ci-C₈ alkyl alcohol in the presence of a lipase enzyme to produce a mixture comprising the Ci-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate, wherein alkyl R- lactate is produced in the presence of a lipase enzyme;

(a) admixing (i) a mixture comprising further R,R- and S,S-lactide with (ii) at least a portion of the product mixture of step (a ); and

(b) reacting the further R,R- and S,S-lactide with alkyl alcohol to produce further alkyl R-lactate and further alkyl S,S-lactyllactate, wherein the further alkyl R-lactate is produced in the presence of a lipase enzyme.

Preferences for step (a^') are the same as for step (b) above. In particular, step (a^') is preferably carried out by passing the mixture comprising R,R- and S,S-lactide and Ci-C₈ alkyl alcohol through a packed bed of lipase enzyme (e.g. Novozym 435), preferably at a temperature in the range of from 50°C to 75°C. Preferably the Ci-C₈ alkyl is n-butyl (i.e. the alkyl alcohol is n-butanol) and the weight ratio of the mixture of R,R- and S,S-lactide to the n-butanol is in the range of from 1 :20 to 1 :5, more preferably from 1 : 15 to 1 :5, still more preferably from 1 : 12 to 1 :5.

Where the product mixture of step (a^') is divided into first and second portions, typically at least 10 wt% of the product mixture from step (a^') is admixed with further mixture comprising R,R- and S,S-lactide, more preferably at least 20%, still more preferably at least 30 wt%, yet more preferably at least 40 wt%. Preferably the weight ratio of the first portion to the second portion is in the range of from 1 :9 to 9: 1, more preferably from 2:8 to 8:2, still more preferably from 3 :7 to 7:3, yet more preferably from 4:6 to 6:4; still more preferably from 45:55 to 55:45, most preferably about 50:50.

In some preferred embodiments step (a ) comprises passing a mixture of R,R- and S,S-lactide and n-butanol through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce a mixture comprising n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate; step (a) comprises admixing (i) a mixture comprising further R,R- and S,S- lactide with (ii) at least a portion of the product mixture of step (a^') at a temperature in the range of from 50°C to 75°C; and step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce n- butyl R-lactate and n-butyl S,S-lactyllactate.

In some preferred embodiments step (a ) comprises passing a mixture of R,R- and S,S-lactide in a molar ratio of from 6:4 to 4:6 and n-butanol through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce a mixture comprising n-butanol, n- butyl R-lactate and n-butyl S,S-lactyllactate, wherein the weight ratio of the mixture of R,R- and S,S-lactide to the n-butanol is in the range of from 1 :20 to 1 :5; step (a) comprises admixing (i) a mixture comprising further R,R- and S,S-lactide in a molar ratio of from 6:4 to 4:6 with (ii) at least 40 wt% of the product mixture of step (a^') at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of components (i) and (ii) is in the range of from 1 : 20 to 1 :5; and step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce n-butyl R-lactate and n-butyl S,S-lactyllactate.

In some preferred embodiments, the process of the invention comprises:

(a^') reacting a mixture comprising R,R- and S,S-lactide with Ci-C₈ alkyl alcohol in the presence of a lipase enzyme to produce a mixture comprising Ci-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate, wherein alkyl R- lactate is produced in the presence of a lipase enzyme;

(a) admixing (v) at least a portion of the product mixture from step (a^') with (vi) further Ci-C₈ alkyl alcohol and with (i) a mixture comprising further R,R- and S,S-lactide;

(b) reacting the further R,R- and S,S-lactide with alkyl alcohol to produce further alkyl R-lactate and further alkyl S,S-lactyllactate, wherein the further alkyl R-lactate is produced in the presence of a lipase enzyme. The Ci-C₈ alkyl alcohol used in step (a) is the same as that used in step (a^'). The product mixture of step (a^') may be divided into first and second portions prior to step (a), the first portion being used as a solvent mixture for dissolution of and reaction of further R,R- and S,S-lactide, the second portion being subjected to separate processing, e.g. separation of alkyl R-lactate and alkyl S,S-lactyllactate, for example by distillation. Typically at least 10 wt% of the product mixture from step (a^') is taken on to step (a), more preferably at least 20%, still more preferably at least 30 wt%, yet more preferably at least 40 wt%. Preferably the weight ratio of the first portion to the second portion is in the range of from 1 :9 to 9: 1, more preferably from 2:8 to 8:2, still more preferably from 3 :7 to 7:3, yet more preferably from 4:6 to 6:4; still more preferably from 45:55 to 55:45, most preferably about 50:50.

Where step (a) comprises admixing (v) at least a portion of the product mixture from step (a') with (vi) further Ci-C₈ alkyl alcohol and with (i) a mixture comprising further R,R- and S,S-lactide, the weight ratio of (vi) further Ci-C₈ alkyl alcohol to (v) product mixture from step (a^') is typically in the range of from 2:8 to 8:2, preferably from 3 :7 to 7:3, still more preferably from 4:6 to 6:4; yet more preferably from 45:55 to 55:45, most preferably about 50:50.

In some preferred embodiments step (a ) comprises passing a mixture of R,R- and S,S-lactide and n-butanol through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce a mixture comprising n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate; step (a) comprises admixing (v) at least a portion of the product mixture from step (a') with (vi) further n-butanol and with (i) a mixture comprising further R,R- and S,S-lactide at a temperature in the range of from 50°C to 75°C; and step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce n-butyl R-lactate and n-butyl S,S-lactyllactate.

As discussed above, it has been found that solvent usage can be further reduced whilst still achieving good conversion to alkyl R-lactate and alkyl S,S-lactyllactate in high enantiomeric excess by means of an iterative process. Accordingly, in some preferred embodiments the process of the invention comprises:

(a) admixing (i) a mixture comprising R,R- and S,S-lactide with (ii) a mixture comprising a Ci-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate;

(b) reacting the R,R- and S,S-lactide with the alkyl alcohol to produce alkyl R-lactate and alkyl S,S-lactyllactate, wherein alkyl R-lactate is produced in the presence of a lipase enzyme; (c) admixing (iii) a mixture comprising further R,R- and S,S-lactide with (iv) at least a portion of the product mixture of step (b); and

(d) reacting the further R,R- and S,S-lactide with alkyl alcohol to produce further alkyl R-lactate and further alkyl S,S-lactyllactate, wherein the further alkyl R-lactate is produced in the presence of a lipase enzyme.

In some preferred embodiments, for example in the case of a continuous or semi- continuous process, the product mixture of step (b) is divided into first and second portions, the first portion being used as a solvent mixture for dissolution of and reaction of further R,R- and S,S-lactide, the second portion being subjected to separate processing, e.g. separation of alkyl R-lactate and alkyl S,S-lactyllactate, for example by distillation.

In some preferred embodiments the product mixture of step (b) comprises at least 7 wt% n-butyl R-lactate and at least 7 wt% n-butyl S,S-lactyllactate, more preferably at least 9 wt% n-butyl R-lactate and at least 7.5 wt% n-butyl S,S-lactyllactate. In some preferred embodiments, the product mixture of step (b) comprises at least 15 wt% n-butyl R-lactate and at least 11 wt% n-butyl S,S-lactyllactate, more preferably at least 16 wt% n-butyl R-lactate and at least 12 wt% n-butyl S,S-lactyllactate. In some preferred embodiments, the product mixture of step (b) comprises at least 60 wt% n-butanol, more preferably at least 65 wt% n- butanol. In some preferred embodiments the product mixture of step (b) comprises at least 7 wt% n-butyl R-lactate, at least 7 wt% n-butyl S,S-lactyllactate, and at least 60 wt% n-butanol, more preferably at least 7 wt% n-butyl R-lactate, at least 7 wt% n-butyl S,S-lactyllactate, and at least 65 wt% n-butanol. In some preferred embodiments the product mixture of step (b) comprises at least 15 wt% n-butyl R-lactate, at least 11 wt% n-butyl S,S-lactyllactate, and at least 60 wt% n-butanol, more preferably at least 16 wt% n-butyl R-lactate, at least 12 wt% n- butyl S,S-lactyllactate, and at least 65 wt% n-butanol.

Preferably the product mixture of step (b) (i.e. component (iv)) comprises n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate, and the weight ratio of component (iii) to component (iv) is in the range of from 1 :20 to 1 :5, more preferably from 1 : 15 to 1 :5, still more preferably from 1 : 12 to 1 :5.

Step (c) is carried out under conditions suitable to effect dissolution of R,R- and S,S- lactide in the product mixture from step (b). Appropriate stirring means may be used to ensure good mixing. Step (c) is preferably carried out at a temperature of at least 20°C, at least 30°C, at least 40°C, at least 50°C or at least 60°C. In some preferred embodiments, step (c) is carried out a temperature in the range of from 30°C to 100°C. In some preferred embodiments, step (c) is carried out at a temperature in the range of from 50°C to 75°C. In some preferred embodiments, step (c) is carried out at a temperature in the range of from 50°C to 70°C. In some preferred embodiments, step (c) is carried out at a temperature of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C or about 75°C.

Step (d) is carried out under conditions suitable to effect high conversion of R,R- and S,S-lactide to alkyl R-lactate and alkyl S,S-lactyllactate. Step (d) is suitably carried out at a temperature such that reaction rates are significant on the one hand and that the enzyme does not deteriorate with long term use on the other. Preferably step (d) is carried out at a temperature in the range of from 25°C to 80°C, more preferably at a temperature in the range of from 40°C to 75°C, still more preferably at a temperature in the range of from 50°C to 75°C, yet more preferably at a temperature in the range of from 50°C to 70°C. In one preferred embodiment, step (d) is carried out at a temperature of about 50 °C, about 55°C, about 60°C, about 65°C, about 70°C or about 75°C. Preferences for other features of step (d) (for example the lipase enzyme, how step (d) is performed, e.g. passing the mixture from step (c) through a packed bed of lipase enzyme which is chemically or physically immobilised on a support) are the same as those described above for step (b).

In some preferred embodiments, for example in the case of a continuous or semi- continuous process, the product mixture of step (b) is divided into first and second portions, the first portion being used as a solvent mixture for dissolution of and reaction of further R,R- and S,S-lactide (in steps (c) and (d)), the second portion being subjected to separate processing, e.g. separation of alkyl R-lactate and alkyl S,S-lactyllactate, for example by distillation. Typically at least 10 wt% of the product mixture from step (b) is admixed with (iii) further mixture comprising R,R- and S,S-lactide, more preferably at least 20%, still more preferably at least 30 wt%, yet more preferably at least 40 wt%. Preferably the weight ratio of the first portion to the second portion is in the range of from 1 :9 to 9: 1, more preferably from 2:8 to 8:2, still more preferably from 3 :7 to 7:3, yet more preferably from 4:6 to 6:4; still more preferably from 45:55 to 55:45, most preferably about 50:50.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide with (ii) a second mixture comprising n-butyl alcohol, n- butyl R-lactate and n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to

75°C; step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce n-butyl R-lactate and n-butyl S,S- lactyllactate; step (c) comprises admixing (iii) a mixture comprising further R,R- and S,S- lactide with (iv) at least a portion of the product mixture of step (b), at a temperature in the range of from 50°C to 75°C; and step (d) comprises passing the mixture from step (c) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n-butyl S,S-lactyllactate.

In some preferred embodiments, step (a) comprises admixing (i) a first mixture comprising R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a second mixture comprising n-butyl alcohol, n-butyl R-lactate and n-butyl S,S-lactyllactate at a temperature in the range of from 50°C to 75°C; step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce n- butyl R-lactate and n-butyl S,S-lactyllactate; step (c) comprises admixing (iii) a mixture comprising further R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (iv) at least a portion of the product mixture of step (b), at a temperature in the range of from 50°C to 75°C; and step (d) comprises passing the mixture from step (c) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n- butyl S,S-lactyllactate.

In some preferred embodiments, step (a) comprises admixing (i) a mixture of R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) a mixture comprising at least 65 wt% n-butyl alcohol, at least 3 wt% n-butyl R-lactate and at least 3 wt% n-butyl S,S- lactyllactate, at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of component (i) to component (ii) is in the range of from 1 : 12 to 1 :5; step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C to produce n-butyl R-lactate and n-butyl S,S-lactyllactate; step (c) comprises admixing (iii) a mixture of further R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (iv) at least a portion of the product mixture of step (b), at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of component (iii) to component (iv) is in the range of from 1 : 12 to 1 :5; and step (d) comprises passing the mixture from step (c) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n-butyl S,S-lactyllactate.

In some preferred embodiments, the process of the invention comprises:

(b) reacting the R,R- and S,S-lactide with the alkyl alcohol to produce alkyl R-lactate and alkyl S,S-lactyllactate, wherein alkyl R-lactate is produced in the presence of a lipase enzyme;

(c) admixing (vii) at least a portion of the product mixture from step (b) with (viii) further Ci-C₈ alkyl alcohol and with (iii) a mixture comprising further R,R- and S,S-lactide; and

The product mixture of step (b) may be divided into first and second portions prior to step (c), the first portion being used as a solvent mixture for dissolution of and reaction of further R,R- and S,S-lactide, the second portion being subjected to separate processing, e.g. separation of alkyl R-lactate and alkyl S,S-lactyllactate, for example by distillation. The Ci- C₈ alkyl alcohol used in step (c) is the same as that used in step (a).

Typically at least 10 wt% of the product mixture from step (b) is taken on to step (c), more preferably at least 20%, still more preferably at least 30 wt%, yet more preferably at least 40 wt%. Preferably the weight ratio of the first portion to the second portion is in the range of from 1 :9 to 9: 1, more preferably from 2:8 to 8:2, still more preferably from 3 :7 to 7:3, yet more preferably from 4:6 to 6:4; still more preferably from 45:55 to 55:45, most preferably about 50:50.

Where step (c) comprises admixing (vii) at least a portion of the product mixture from step (b) with (viii) further Ci-C₈ alkyl alcohol and with (iii) a mixture comprising further R,R- and S,S-lactide, the weight ratio of (viii) Ci-C₈ alkyl alcohol to (vii) product mixture from step (b) is typically in the range of from 2:8 to 8:2, preferably from 3 :7 to 7:3, still more preferably from 4:6 to 6:4; yet more preferably from 45:55 to 55:45, most preferably about 50:50.

In some preferred embodiments the process of the invention comprises: (a^') reacting a mixture comprising R,R- and S,S-lactide with Ci-C₈ alkyl alcohol in the presence of a lipase enzyme to produce a mixture comprising Ci-C₈ alkyl alcohol, the corresponding alkyl R-lactate and the corresponding alkyl S,S-lactyllactate, wherein alkyl R- lactate is produced in the presence of a lipase enzyme;

(a) admixing (i) a mixture comprising further R,R- and S,S-lactide with (ii) at least a portion of the product mixture of step (a^');

(b) reacting the further R,R- and S,S-lactide with alkyl alcohol present in the product mixture of step (a^') to produce further alkyl R-lactate and alkyl S,S-lactyllactate, wherein alkyl R-lactate is produced in the presence of a lipase enzyme;

(c) admixing (iii) a mixture comprising further R,R- and S,S-lactide with (iv) at least a portion of the product mixture of step (b) ; and

In some preferred embodiments step (a^') comprises passing a mixture comprising R,R- and S,S-lactide and n-butanol through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a temperature in the range of from 50°C to 75°C, to produce a mixture comprising n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate; step (a) comprises admixing (i) a mixture comprising further R,R- and S,S-lactide with (ii) at least a portion of the product mixture of step (a^') at a temperature in the range of from 50°C to 75°C; step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n-butyl S,S-lactyllactate; step (c) comprises admixing (iii) a mixture comprising further R,R- and S,S-lactide with (iv) at least a portion of the product mixture of step (b), at a temperature in the range of from 50°C to 75°C; and step (d) comprises passing the mixture from step (c) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a

temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n- butyl S,S-lactyllactate.

In some embodiments step (a ) comprises passing a mixture of R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 and n-butanol through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a temperature in the range of from 50°C to 75°C, to produce a mixture comprising n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate, wherein the weight ratio of the mixture of R,R- and S,S-lactide to the n-butanol is in the range of from 1 :20 to 1 :5; step (a) comprises admixing (i) a mixture of further R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (ii) at least a portion of the product mixture of step (a^'), at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of the mixture of further R,R- and S,S-lactide to the product of step (a^') is in the range of from 1 :20 to 1 :5; step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n-butyl S,S-lactyllactate; step (c) comprises admixing (iii) a mixture of further R,R- and S,S-lactide in a molar ratio of from 4:6 to 6:4 with (iv) at least a portion of the product mixture of step (b), at a temperature in the range of from 50°C to 75°C, wherein the weight ratio of the mixture of further R,R- and S,S- lactide to n-butanol is in the range of from 1 :20 to 1 :5; and step (d) comprises passing the mixture from step (c) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n-butyl S,S-lactyllactate.

In some preferred embodiments the process of the invention comprises:

(b) reacting the further R,R- and S,S-lactide with alkyl alcohol to produce further alkyl R-lactate and further alkyl S,S-lactyllactate, wherein the further alkyl R-lactate is produced in the presence of a lipase enzyme;

(d) reacting the further R,R- and S,S-lactide with alkyl alcohol to produce further alkyl R-lactate and further alkyl S,S-lactyllactate, wherein the further alkyl R-lactate is produced in the presence of a lipase enzyme. In some preferred embodiments step (a^') comprises passing a mixture comprising R,R- and S,S-lactide and n-butanol through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a temperature in the range of from 50°C to 75°C, to produce a mixture comprising n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate; step (a) comprises admixing (v) at least a portion of the product mixture from step (a^') with (vi) further n-butanol and with (i) a mixture comprising further R,R- and S,S-lactide at a temperature in the range of from 50°C to 75°C; step (b) comprises passing the mixture from step (a) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n-butyl S,S- lactyllactate; step (c) comprises admixing (vii) at least a portion of the product mixture from step (b) with (viii) further n-butanol and with (iii) a mixture comprising further R,R- and S,S- lactide at a temperature in the range of from 50°C to 75°C; and step (d) comprises passing the mixture from step (c) through a packed bed of Candida antarctica lipase B enzyme which is chemically or physically immobilised on a support, at a temperature in the range of from 50°C to 75°C, to produce further n-butyl R-lactate and n-butyl S,S-lactyllactate.

A preferred embodiment of the process of the invention is shown in Figure 1. A mixture 4 containing alkyl alcohol, alkyl R-lactate and alkyl S,S-lactyllactate (e.g. n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate) is introduced into vessel 11 and heated to a temperature in the range of from 65 to 70°C. A mixture 1A of R,R- and S,S-lactide (e.g. racemic lactide) is then introduced into vessel 11 and mixed with the alkyl alcohol, alkyl R- lactate and alkyl S,S-lactyllactate, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3A exits vessel 11 and is introduced to column 21 containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g. Novozym 435). Mixture 3A is passed through the packed bed of enzyme at a temperature in the range of from 55 to 60°C, and the lactide reacts with alkyl alcohol (e.g. n- butanol). Product mixture 4A containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R- lactyllactate also, exits column 21.

A further preferred embodiment of the process of the invention is shown in Figure 2.

Alkyl alcohol (e.g. n-butanol) 2 is introduced into vessel 10 via valve 30 and is heated to a temperature in the range of from 65 to 70°C. A mixture 1 of R,R- and S,S- lactide (e.g. racemic lactide) is then introduced into vessel 10 and mixed with the alkyl alcohol, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3 exits vessel 10 and is introduced to column 20 containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g. Novozym 435). Mixture 3 is passed through the packed bed of enzyme at a temperature in the range of from 55 to 60°C, and the lactide reacts with alkyl alcohol (e.g. n-butanol). Product mixture 4 containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S- lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, exits column 20 and is returned to vessel 10 via valves 30 and 31. Further mixture 1A of R,R- and S,S-lactide (e.g. racemic lactide) is introduced into vessel 10 and mixed with mixture 4, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3A exists vessel 10 and is introduced to column 20. Mixture 3A is passed through the packed bed of enzyme at a temperature in the range of from 55-60°C to produce a product mixture 4A containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n- butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also.

Figure 3 shows a variant of the process shown in Figure 2 which includes a further iteration of the process of the invention. In that embodiment, product stream 4A is returned to vessel 10 via valves 30 and 31. Further mixture IB of R,R- and S,S-lactide (e.g. racemic lactide) is introduced into vessel 10 and mixed with mixture 4A, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3B exists vessel 10 and is introduced to column 20. Mixture 3B is passed through the packed bed of enzyme at a temperature in the range of from 65-70°C to produce a product mixture 4B containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n- butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, which exits column 20.

Figures 4 and 5 show further variants of the process in which a series of vessels and columns containing lipase enzyme are utilised. In the embodiment shown in Figure 4, alkyl alcohol (e.g. n-butanol) 2 is introduced into vessel 10 and is heated to a temperature in the range of from 65 to 70°C. A mixture 1 of R,R- and S,S- lactide (e.g. racemic lactide) is then introduced into vessel 10 and mixed with the alkyl alcohol, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3 exits vessel 10 and is introduced to column 20 containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g. Novozym 435). Mixture 3 is passed through the packed bed of enzyme at a temperature in the range of from 55 to 60°C, and the lactide reacts with alkyl alcohol (e.g. n-butanol). Product mixture 4 containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, exits column 20 and is passed to vessel 11. Further mixture 1A of R,R- and S,S-lactide (e.g. racemic lactide) is introduced into vessel 11 and mixed with mixture 4, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3A exists vessel 11 and is introduced to column 21 containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g. Novozym 435). Mixture 3A is passed through the packed bed of enzyme at a temperature in the range of from 55-60°C, to produce a product mixture 4A containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol) , and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, exits column 21.

Figure 5 shows a variant of the process shown in Figure 4 which includes a further iteration of the process of the invention. In that embodiment, product stream 4A passes to vessel 12. Further mixture IB of R,R- and S,S-lactide (e.g. racemic lactide) is introduced into vessel 12 and mixed with mixture 4A, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3B exists vessel 12 and is introduced to column 22. Mixture 3B is passed through the packed bed of enzyme at a temperature in the range of from 55-60°C to produce a product mixture 4B containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, which exits column 22.

Figures 6 and 7 show further embodiments of the invention in which product mixture containing alkyl R-lactate and alkyl S,S-lactate is divided into two portions, the first of which is used as a solvent mixture for dissolution of and reaction of further R,R- and S,S-lactide, and the second portion being subjected to separate processing. Figure 6 shows an

embodiment in which alkyl alcohol (e.g. n-butanol) 2 is introduced into vessel 10 via valve 30 and is heated to a temperature in the range of from 65 to 70°C. A mixture 1 of R,R- and S,S- lactide (e.g. racemic lactide) is then introduced into vessel 10 and mixed with the alkyl alcohol, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3 exits vessel 10 and is introduced to column 20 containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g.

Novozym 435). Mixture 3 is passed through the packed bed of enzyme at a temperature in the range of from 55 to 60°C, and the lactide reacts with alkyl alcohol (e.g. n-butanol). The product mixture containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R- lactate, n-butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, exits column 20 and is divided via valve 31 into two streams 4 and 104 of approximately equal mass. Stream 104 is taken on for subsequent processing, e.g. separation of the products by distillation. Stream 4 is returned to vessel 10 via valve 30. Further alkyl alcohol (e.g. n- butanol) 2A and further mixture 1A of R,R- and S,S-lactide (e.g. racemic lactide) are then introduced into vessel 10 and mixed with mixture 4, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3A exists vessel 10 and is introduced to column 20. Mixture 3A is passed through the packed bed of enzyme at a temperature in the range of from 55-60°C to produce a further product mixture containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S- lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, which exits column 20 and is divided via valve 31 into two streams 4A and 104A of approximately equal mass. Stream 104A is taken on for subsequent processing, e.g. separation of the products by distillation. Stream 4A is returned to vessel 10 via valve 30. Further alkyl alcohol (e.g. n-butanol) 2B and further mixture IB of R,R- and S,S-lactide (e.g. racemic lactide) are introduced into vessel 10 and mixed with mixture 4A, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3B exits vessel 10 and is introduced to column 20. Mixture 3B is passed through the packed bed of enzyme at a temperature in the range of from 55-60°C to produce a further product mixture containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, which exits column 20 and is divided via valve 31 into two streams 4B and 104B of approximately equal mass. Stream 104B is taken on for subsequent processing, e.g. separation of the products via distillation. Stream 4B may be returned to vessel 10 and the iterative process repeated as desired.

Figure 7 shows an embodiment in which alkyl alcohol (e.g. n-butanol) 2 is introduced into vessel 10 and is heated to a temperature in the range of from 65 to 70°C. A mixture 1 of R,R- and S,S- lactide (e.g. racemic lactide) is then introduced into vessel 10 and mixed with the alkyl alcohol, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3 exits vessel 10 and is introduced to column 20 containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g. Novozym 435). Mixture 3 is passed through the packed bed of enzyme at a temperature in the range of from 55 to 60°C, and the lactide reacts with alkyl alcohol (e.g. n-butanol). Product mixture containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol), and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, exits column 20 and is divided via valve 30 into two streams 4 and 104 of approximately equal mass. Stream 104 is taken on for subsequent processing, e.g. separation of the products via distillation. Stream 4 is passed to vessel 11. Further mixture 1A of R,R- and S,S-lactide (e.g. racemic lactide) and alkyl alcohol 2A are introduced into vessel 11 and mixed with mixture 4, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3A exists vessel 11 and is introduced to column 21

containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g. Novozym 435). Mixture 3A is passed through the packed bed of enzyme at a temperature in the range of from 55-60°C, to produce a product mixture containing alkyl R- lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol) , and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, exits column 21, and is divided via valve 31 into two streams 4A and 104A of approximately equal mass. Stream 104A is taken on for subsequent processing, e.g. separation of the products via distillation. Stream 4A is passed to vessel 12. Further mixture IB of R,R- and S,S-lactide (e.g. racemic lactide) and alkyl alcohol 2B are introduced into vessel 12 and mixed with mixture 4A, whilst maintaining the temperature in the range 65-70°C, until the lactide has dissolved. The resulting mixture 3B exists vessel 12 and is introduced to column 22 containing a packed bed of Candida antarctica lipase B enzyme immobilised on a support (e.g. Novozym 435). Mixture 3B is passed through the packed bed of enzyme at a temperature in the range of from 55-60°C, to produce a product mixture containing alkyl R-lactate, alkyl S,S-lactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S-lactyllactate and n-butanol) , and optionally small quantities of unreacted byproducts such as R,R-lactide, S,S-lactide and/or alkyl R,R-lactyllactate also, exits column 22, and is divided via valve 32 into two streams 4B and 104B of approximately equal mass.

The products of the process may be separated by routine methods. For example, alkyl R-lactate, alkyl S,S-lactyllactate and alkyl alcohol (e.g. n-butyl R-lactate, n-butyl S,S- lactyllactate and n-butanol) may be separated by distillation under reduced pressure.

The alkyl R-lactate obtained by the process of the invention can be converted into further useful downstream products by routine methods. Accordingly, the invention also provides a process for producing R-lactic acid, oligomeric R-lactic acid, R,R-lactide or poly R-lactic acid comprising producing alkyl R-lactate according to the invention; and converting at least a portion of the alkyl R-lactate into R-lactic acid, oligomeric R-lactic acid, R,R- lactide or poly-R-lactic acid. For example, R-lactic acid be produced by reacting alkyl R- lactate with water in the presence of an acid, such as hydrochloric acid or sulphuric acid. Alkyl R-lactate may also be converted into oligomeric R-lactic acid, for example by heating the alkyl R-lactate and removing alcohol. Alternatively, alkyl R-lactate may be converted into R-lactic acid, and the R-lactic acid converted into oligomeric R-lactic acid, for example by heating the R-lactic acid and removing water. Alkyl R-lactate may also be converted into R,R-lactide. For example, alkyl R-lactide may be converted into oligomeric R-lactic acid, and the oligomeric R-lactic acid may be converted into R,R-lactide by heating in the presence of a transesterification catalyst. Alkyl R-lactate may also be converted into poly-R-lactic acid, for example by conversion into R,R-lactide, and polymerising the R,R-lactide to produce poly R-lactic acid (e.g. by contacting with a catalyst at elevated temperature).

The alkyl S,S-lactyllactate obtained by the process of the invention can also be converted into further useful downstream products by routine methods. Accordingly, the invention also provides a process for producing S-lactic acid, alkyl S-lactate, oligomeric S- lactic acid, S,S-lactide or poly S-lactic acid comprising producing alkyl S,S-lactyllactate according to the invention; and converting at least a portion of the alkyl S,S-lactyllactate into S-lactic acid, alkyl S-lactate, oligomeric S-lactic acid, S,S-lactide or poly-S-lactic acid. For example, S-lactic acid be produced by reacting alkyl S,S-lactyllactate with water in the presence of an acid, such as hydrochloric acid or sulphuric acid. Alkyl S,S-lactyllactate may also be converted into alkyl S-lactate, for example by reacting alkyl S,S-lactyllactate with an alkyl alcohol, e.g. in the presence of an acid. Alkyl S,S-lactyllactate may also be converted into oligomeric S-lactic acid, for example by heating the alkyl S,S-lactyllactate and removing alcohol. Alternatively, alkyl S,S-lactyllactate may be converted into S-lactic acid, and the S- lactic acid converted into oligomeric S-lactic acid, for example by heating the S-lactic acid and removing water. Alkyl S,S-lactyllactate may also be converted into S,S-lactide. For example, alkyl S,S-lactyllactide may be converted into oligomeric S-lactic acid, and the oligomeric S-lactic acid may be converted into S,S-lactide by heating in the presence of a transesterification catalyst. Alkyl S,S-lactyllactate may also be converted into poly S-lactic acid, for example by conversion into S,S-lactide, and polymerising the S,S-lactide to produce poly S-lactic acid (e.g. by contacting with a catalyst at elevated temperature).

The invention also provides a process for producing stereocomplex polylactic acid, comprising producing poly R-lactic acid according to the invention, and combining the poly R-lactic acid with poly S-lactic acid, for example using melt blending, to produce stereocomplex polylactic acid.

The invention also provides a process for producing stereocomplex polylactic acid, comprising producing poly S-lactic acid according to the invention, and combining the poly S-lactic acid with poly R-lactic acid, for example using melt blending, to produce stereocomplex polylactic acid.

The invention also provides a process for producing stereocomplex polylactic acid, comprising producing poly R-lactic acid and poly S-lactic acid according to the invention, and combining the poly S-lactic acid with poly R-lactic acid, for example using melt blending, to produce stereocomplex polylactic acid.

Examples

The following examples illustrate the invention.

Example 1: Production of n-butyl R-lactate and n-butyl S,S-lactyllactate from racemic lactide

Stage 1) Preparation of a mixture containing n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate

Racemic lactide (a 50:50 mixture of R,R- and S,S-lactide) was dissolved in n-butanol at 10% by weight at a temperature of 70°C. The mixture was held in a jacketed 1 litre feed vessel equipped with reflux condenser. The mixture was then gravity fed through a 400 mm reflux column over a 5 g enzyme bed (containing Novozym 435 CaLB enzyme) at the base of the column. The feed vessel and reflux column was kept at 70°C using a recirculating water heater, and the enzyme bed and any other 'exposed' areas of the system were held at 70°C using thermo-regulated flexible heat cable. Flow rate was controlled by a Watson Marlow 120S peristaltic pump connected downstream of the enzyme bed, and product mixture was collected in an appropriate vessel. The flow of reactants over the enzyme bed (and hence the residence time) was adjusted in order to achieve conversion to n-butyl R-lactate in excess of 99%. The average flow rate was 0.5 ml/minute. Samples were collected on a regular basis from the column, and analysed by chiral gas chromatography to monitor the following:

a. TON (turn-over number) - moles of R,R-lactide converted to n-butyl R-lactate per moles of enzyme used

b. Conversion of R,R-lactide to n-butyl R-lactate (%)

c. Enantiomeric excess of n-butyl R-lactate (%>).

Analysis of the product mixture (termed "stage 1 product") showed that it contained a mixture of n-butyl R-lactate (9.9 wt%) and n-butyl S,S-lactyllactate (7.6 wt%) in n-butanol (82.3 wt%). Conversion of the R,R-lactide present in the racemic lactide starting material to n-butyl R-lactate was in excess of 97% (the mixture also contained 0.2 wt% n-butyl R,R- lactyllactate). The enantiomeric excess of the n-butyl R-lactate was 100%, with no formation of n-butyl S-lactate being observed. In total, 640g of n-butyl R-lactate was produced from 642g of racemic lactide over a 240 hour period.

Stage 2) Production of alkyl R-lactate and alkyl S,S-lactyllactate

10%) by weight racemic lactide was dissolved in the stage 1 product at 65°C. The resulting mixture was passed over an enzyme bed containing Novozyme N435 CaLB enzyme as described for Stage 1 above, except that the temperature was 65°C.

Analysis of the product mixture (termed "stage 2 product") showed that it contained n-butyl R-lactate (16.9wt%) and n-butyl S,S-lactyllactate (12.8 wt%) in n-butanol (70.1 wt%>). Conversion of the R,R-lactide present in the racemic lactide that was added to the stage 1 product to n-butyl R-lactate was in excess of 97%> (the mixture also contains 0.2wt%> n-butyl R,R-lactyllactate). The enantiomeric excess of the n-butyl R-lactate was 100%>. In total, 435g of n-butyl R-lactate was produced from 435g of racemic lactide over a 160 hour period. Stage 3) Production of further alkyl R-lactate and alkyl S,S-lactyllactate

10% by weight racemic lactide was dissolved in the stage 2 product at 65°C. The resulting mixture was passed over an enzyme bed containing Novozyme N435 CaLB enzyme as described for Stage 1 above, except that the temperature was 65°C.

Analysis of the product mixture (termed "stage 3 product") showed that it contained n-butyl R-lactate (24.6 wt%) and n-butyl S,S-lactyllactate (18.5 wt%) in n-butanol (56.7 wt%). Conversion of the R,R-lactide present in the racemic lactide (the racemic lactide which was dissolved in the stage 1 product) to n-butyl R-lactate was in excess of 97% (the mixture also contained 0.2 wt% n-butyl R,R-lactyllactate). The enantiomeric excess of the n- butyl R-lactate was 100%. In total, 239g of n-butyl R-lactate was produced from 241g of racemic lactide over a 92 hour period.

Summary

Conversion of R,R-lactide to n-butyl R-lactate was >97% for all stages. The same enzyme bed was used for all stages. There was no decrease in optical purity of the product from stage 1 to 3. During the course of the experiment the enantiomeric excess of the n-butyl R-lactate remained at 100%.

Over the full course of the experiment (798 hours) a TON of 3 x 10⁵ was achieved with a corresponding productivity of 1.05 g n-butyl R-lactate / 1 g enzyme / hr.

In summary, mixtures containing n-butanol, n-butyl R-lactate and n-butyl S,S- lactyllactate (the product mixture from a lipase-catalysed alcoholysis reaction) are suitable solvents for dissolution of racemic lactide and enzyme-catalysed production of n-butyl R- lactate. Conversion of large quantities of racemic lactide to alkyl R-lactate and alkyl S,S- lactyllactate can be achieved using low solvent volumes, especially where multiple cycles of (i) dissolving racemic lactide in product mixture and (ii) carrying out enzyme-catalysed alcoholysis are performed.

Example 2: Solubility of racemic lactide in different solvents

Solubility studies were conducted with racemic lactide (a racemic mixture of R,R- and S,S-lactide) in n-butanol, the "stage 1 product" from Example 1 (containing n-butanol, n- butyl R-lactate and n-butyl S,S-lactyllactate), and the "stage 2 product" from Example 1 (containing n-butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate). Racemic lactide was found to have a solubility in n-butanol of 10% by weight at

70°C.

Racemic lactide was found to have a solubility in the product mixture of Example 1, stage 1 of 12.5 wt% at 70°C.

Racemic lactide was found to have a solubility in the product mixture of Example stage 2 of 16 wt% at 70 °C.

Summary

Lactide has improved solubility in solvent mixtures containing n-butanol, n-butyl R- lactate and n-butyl S,S-lactyllactate, compared with n-butanol as solvent.

Claims

1. A process for producing alkyl R-lactate and alkyl S,S-lactyllactate comprising:

2. A process as claimed in claim 1, wherein the mixture comprising R,R- and S,S-lactide is racemic lactide.

3. A process as claimed in claim 1 or claim 2, wherein alkyl is n-butyl.

4. A process as claimed in any one of claims 1 to 3, wherein step a) is carried out at a temperature in the range of from 50°C to 75°C.

5. A process as claimed in any one of claims 1 to 4, wherein the lipase enzyme is a Candida antarctica lipase B.

6. A process as claimed in any one of claims 1 to 5, wherein the lipase enzyme is chemically or physically immobilised on a support.

7. A process as claimed in claim 6, wherein the product of step (a) is passed through a packed bed of lipase enzyme.

8. A process as claimed in any one of claims 1 to 7, wherein step (b) is carried out at a temperature in the range of from 50°C to 75°C.

9. A process as claimed in any one of claims 1 to 8, wherein the weight ratio of (i) the first mixture comprising R,R- and S,S-lactide to (ii) the second mixture comprising n- butanol, n-butyl R-lactate and n-butyl S,S-lactyllactate is in the range of from 1 : 12 to 1 :5.

10. A process as claimed in any one of claims 1 to 9, wherein the mixture comprising Ci- C₈ alkyl alcohol, alkyl R-lactate and alkyl S,S-lactyllactate has been produced by (a^') reacting a mixture comprising R,R- and S,S-lactide with Ci-C₈ alkyl alcohol in the presence of a lipase enzyme.

11. A process as claimed in any one of claims 1 to 10 comprising:

carrying out steps (a) and (b);

(c) admixing (iii) a mixture comprising further R,R- and S,S-lactide with (iv) at least a portion of the product mixture of step (b); and

(d) reacting the further R,R- and S,S-lactide with alkyl alcohol to produce further alkyl R- lactate and further alkyl S,S-lactyllactate, wherein the further alkyl R-lactate is produced in the presence of a lipase enzyme.

12. A process as claimed in claim 11, wherein the weight ratio of the mixture comprising further R,R- and S,S-lactide to the product mixture of step (b) is in the range of from 1 : 12 to 1 :5.

13. A process for producing R-lactic acid, oligomeric R-lactic acid, R,R-lactide or poly- R-lactic acid comprising producing alkyl R-lactate according to any one of claims 1 to 12; and converting at least a portion of the alkyl R-lactate into R-lactic acid, oligomeric R-lactic acid, R,R-lactide or poly-R-lactic acid.

14. A process for producing S-lactic acid, alkyl S-lactate, oligomeric S-lactic acid, S,S- lactide or poly-S-lactic acid comprising producing alkyl S,S-lactyllactate according to any one of claims 1 to 12; and converting at least a portion of the alkyl S,S-lactyllactate into S- lactic acid, alkyl S-lactate, oligomeric S-lactic acid, S,S-lactide or poly-S-lactic acid.

15. A process for producing stereocomplex polylactic acid comprising producing poly-R- lactic acid according to claim 13, and combining the poly-R-lactic acid with poly-S-lactic acid to produce stereocomplex lactic acid.

16. A process for producing stereocomplex polylactic acid comprising producing poly-S- lactic acid according to claim 14, and combining the poly-S-lactic acid with poly-R-lactic acid to produce stereocomplex lactic acid.

17. A process for producing stereocomplex polylactic acid comprising producing poly-R- lactic acid according to claim 13 and producing poly-S-lactic acid according to claim 14, and combining the poly-S-lactic acid with the poly-R-lactic acid to produce stereocomplex lactic acid.