[0001] The invention relates to a process for asymmetric hydrogenation of α- acetoxy acrylates to enantiopure O-acetyl lactates with Rh-catalysts based on chiral bisphospholane ligands in propylene carbonate (PC) as green solvent and to the apparatus suitable for operating that process. In particular the invention integrates a Spaltrohrkolonne into that enantiopure O-acetyl lactate production process.

[0002] Enantiopure lactic acid plays an increasing role as building block for the synthesis of biodegradable chiral poly-(lactic acids) (PLA) which have a similar application range like polyethylene terephthalate (PET). Lactic acid is a sophisticated intermediate of the production of cleaning agents, liquid soaps and softening agents. Recently, the interest in enantiopure lactic acid was growing constantly. This is because of the biodegradability of the polymeric form PLA. PLA is generally used in biomedical applications, in tissue engineering and for the preparation of bio plastics.

[0003] in general the lactic acid monomer is produced from sugar feedstocks by fermentation. This includes the difficulty of extracting the generated lactic acid from the fermentation solution. In addition most of the known solvents are toxic to micro organisms, are uneconomic or possess inappropriate solvent features.

[0004] An alternative methodology to produce chiral enantiopure compounds is the chemical synthesis by asymmetric hydrogenation using homogeneous catalysis. This environmentally friendly technology has reached a high level of application in industry. Attainable high rates and selectivities has given rise to the use in chemical manufacturing of pharmaceuticals, animal health products, agrochemicals, flavours, pheromones, fungicides, and fragrances.

[0005] For this reaction a metal catalyst is required to decrease reaction temperature as well as pressure. Homogenous catalysts are dissolvable in the substrate containing solvent. In this regard homogenous rhodium(l), ruthenium(ll) or iridium(l) catalysts based on chiral phosphorus ligands plays important roles. Lots of chiral ligands have been synthesized in the past to overcome limitations in the hydrogenation of standard. In general, chiral ligand can be classified by their coordination abilities (mono- or be-dentate, P-P, P-N etc.), by their backbone nature and by their source of chirality (atropisomers, metallocene, chiral C-skeleton, stereogenic phosphorus etc.). Improvement of catalyst ligands is mainly achieved by modifications of steric features (like the bite angle α) as well as by alteration of the electronic surrounding at the metal centre. This leads to families of ligands comprising strongly related members. Examples represent commercially available bisphospholanes of the caWSium M series and those of the DUPHOS family in both enantiomeric forms that allows the production of L- and D-lactic acid. Appropriate ligands out of these both classes show superior behaviour in the Rh-catalyzed hydrogenation of a broad range of substrates, but only small structural changes causes striking differences in the catalytic features. Also, Rh-precatalysts are generated in propylene carbonate (PC).

[0006] Additionally, to the choice of the appropriate ligand of the catalyst the selection of the solvent is obligatory. Commonly used solvents like methanol, tetrahydrofuran, dichloromethane and toluene differ strongly in use and limitations. Fluorinated alcohols and ionic liquids are characterized by high prices, toxicity or problems with purification. Another class of solvents of interest are organic carbonates, especially cyclic carbonates. These carbonates are characterized by a high boiling point and a low vapour pressure. They are inflammable and show only low viscosity.

[0007] Propylene carbonate (PC) is of particular interest, because of its low toxicity and easy combustibility. According to these features propylene carbonate can be considered to be an ecologically and economically benign solvent ("green solvent"). Moreover it can be synthesised environmentally friendly out of propylene oxide (the latter can be derived from propylene and H ₂ O ₂ via HPPO technology) by reaction with supercritical CO ₂ using transition metal catalysts. Propylene carbonate belongs to a class of aprotic highly dipolar solvents (AHD). Its physical properties are highly unique and are only met by those of acetonitrile that do not belong to the AHD group.

Propylene carbonate has been established in industry for pharmaceutical and medical applications and as solvent for extractions and coating processes. In academic research propylene carbonate has been used for the stabilization of Pd clusters in Heck-reaction and as solvent in Rh-catalyzed hydroformylation reactions in temperature depending multi-component solvent systems (TMS). Propylene carbonate was also employed for the asymmetric heterogeneous Ir-catalyzed hydrogenation of ketones. Recently, propylene carbonate was identified as a beneficial solvent in Pd- catalyzed asymmetric allylic alkylations, aminations and in Sonogashira reactions.

[0008] The high boiling point (242 ⁰ C) characterizes propylene carbonate as a green solvent, but may increase the intricacy of product separation. For unpolar substrates satisfactory solutions are established. For example, the extraction with n- hexane and the use of a TMS system are conventionally used. More polar products like alkylation and amination products can be separated from propylene carbonate via column chromatography with an eluent mixture n-hexane : ethyl acetate higher than 6 : 1. The distillation of products out of propylene carbonate under vacuum is also problematic, because oxygen-oxygen interactions between the product and propylene carbonate cause propylene carbonate to be codistilled.

[0009] An opportunity to improve distillation is to use a Spaltrohrkolonne. This method is also described in the literature as Spaltrohrcolumn, slit tube column, or with its detained description Fischer HMS 500. The advantage of this entity is a series connection of multiple distillation devices for thermal separation of substances. The effect of separation in comparison to conventional distillation is improved because of the steam counter flow that allows multiple contact of the steam with the liquid sample.

[0010] The task of the invention therefore is 1) to identify propylene carbonate (PC) as a suitable solvent for the asymmetric hydrogenation of α-acetoxy acrylates to O-acetyl lactates, 2) to identify appropriate ligands for Rh-catalysts in propylene carbonate for the hydrogenation of α-acetoxy acrylates, and 3) to separate O-acetyl lactates from propylene carbonate by Spaltrohrkolonne. A further task of the invention is to make the process more environmentally friendly. And also a task of the present invention is to optimize the conversion into the end product resulting in high yields and in enantiopure stereoisomers without remaining propylene carbonate-impurities. Further tasks are to make the process cost-effective and to keep reaction times as short as possible but thereby implementing the latter terms and conditions. It is also object of this invention to provide the apparatus suitable to operate such a process.

[0011] This is achieved by a process for asymmetric hydrogenation of prochiral α-acetoxy acrylic acid esters for the synthesis of enantiopure lactic acid esters by the use of Rh-catalyzed bisphospholane ligands in a unit using an autoclave, and a distillation process. In a first process step α-acetoxy acrylic acid esters (1) and Rh- catalyzed bisphospholane ligands are dissolved in a solvent as substrate solution, in a second process step the substrate solution is added to an evacuated autoclave, in a third process step H ₂ is fed into the autoclave, in a fourth process step the asymmetric hydrogenation reaction is carried out under H ₂ -pressure, and in a fifth process step the reaction product composed of solvent, lactic acid esters (2), remaining α-acetoxy acrylic acid esters (1) and Rh-catalyzed bisphospholane ligands is transferred into a distillation unit, is being distilled and enantiopure lactic acid esters (2) are separated from solvent, α-acetoxy acrylic acid esters (1) and Rh-catalyzed bisphospholane ligands. In this process propylene carbonate is used as solvent in the first process step, and the distillation is performed in a Spaltrohrkolonne in the fifth process step.

[0012] Further embodiments of the invention relate to the types of heterocyclic phosphine ligands used in this process. These ligands can be chosen out of the DuPHOS family (5a, 5b) and the catAsium M series (10a, 10c, 1Od), BASPHOS (8), or Ferrotane (12). Depending on the used enantiomeric form of the ligand of the catalyst pure D- or L-enantioselective O-acetyl lactates (2) can be generated.

[0013] Optionally, Rh-catalysts are synthesized as Rh(L)(1, 5-cyclooctadiene)]BF ₄ or [Rh(L)(norbomadiene)]BF ₄ prior to use as described in WO 2005/049629 A1 or are used from chemical suppliers without further purification. (L) stands for heterocyclic phosphine ligands in which (L) stands for heterocyclic phosphine ligands that will be bound to the catalyst and then pronounced as Rh-catalyzed bisphospholane ligands.

[0014] A further option of the current invention in the first process step is that the Rh-catalyzed bisphospholane ligands are put into the autoclave in their solid state, before evacuation. This approach ensures that all traces of oxygen can be removed in the autoclave.

[0015] Further embodiments of the invention relate to the reaction conditions in the fourth process step. The asymmetric hydrogenation in the autoclave is being carried out at an initial H ₂ -pressure of 1 - 20 bar and a temperature of 20 - 40 ⁰ C. The substrate solution contains a concentration of 0.4 to 0.5 mmol/mL α-acetoxy acrylic acid esters (1) and 1 mol% Rh-catalyzed bisphospholane ligands. To obtain improved enantioselective yields the ratio of catalyst and -acetoxy acrylic acid esters (1) is important.

[0016] Optionally, the ethyl ester group of the prochiral substrate can be replaced by a methyl ester group. This substitution optimizes the atom economy and therefore the environmental friendliness of the reaction. Both, ethyl O-acetoxy acrylate and methyl O-acetoxy acrylate are synthesized as described in Fryzuk, M. D. et a/., J. Am. Chem. Soc. 1978, 100, 5491 - 5494. [0017] Further embodiments of to the invention are the distillation temperature and pressure settings of the fifth process step. These are defined as an oil bath temperature in the range of 107 - 112 ⁰ C, a sump temperature in the range of 90 - 98 0C, a shell temperature of the Spaltrohrkolonne in the range of 70 - 90 ⁰ C, a distillation 5 temperature at the top of the Spaltrohrkolonne of 52 - 95 ⁰ C, and the distillation pressure being selected from a pressure range of 6.5 to 9 mbar. A pressure less than 6 mbar is not recommended because under this condition the product will not be passed into liquid phase. The ideal distillation conditions for methyl-2-acetoxyacrylat are the following parameters: an oil bath temperature of 107 ⁰ C, a sump temperature of 94 °C, i o a temperature of the shell side of the Spaltrohrkolonne of 80 °C, a distillation temperature at the top of the Spaltrohrkolonne of 52.5 ⁰ C. The same ideal distillation conditions are true for ethyl-2-acetoxyacrylat but the distillation temperature at the top of the Spaltrohrkolonne is 58 ⁰ C. Therefore the optimal distillation range is tightened for ethyl-2-acetoxyacrylat resulting in fewer yields.

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[0018] The described process of asymmetric hydrogenation with separation of the enantiopure lactic acid esters is to be operated in an apparatus comprising an autoclave, a Spaltrohrkolonne, a means for conveying the substrate solution into the autoclave, a means for evacuation of the autoclave, a means for transferring the 0 reaction product to the Spaltrohrkolonne, a means for the collection of the separated end product, and a means for the collection of solvent, catalyst and remaining starting material.

[0019] Optionally, the apparatus is of isobaric and/or isothermic nature and has an5 automatic hydrogen detection unit. Both features allow easy controlling of the reaction process.

[0020] In the following, the invention is illustrated by 3 figures summarizing the underlying issues. 0

[0021] Fig. 1 shows the constitution of bisphospholane Rh-catalysts. In this structure R is selected from a group comprising an alkyl-group (C ₁ - C ₃ ), a phenyl group, or a CH ₂ OR"-group. In said CH ₂ OR"-group R" is an H-group, an alkyl-group (Ci to C ₃ ), or a benzyl-group. R' _n is referred to be an H-group, or an OR"'-group with n5 being 1 or 2.. In said OR'"-group R" ¹ is an alkyl-group (C1-C3), or a benzyl-group. P stands for phosphorus. There are two different opportunities for electronic or steric fine tuning of the skeletal structure of such catalyst. First, the bite angle α can be modified and thus influence the steric features of the catalyst. Second, the electronic surrounding at the metal centre can be altered. Both modifications lead to striking differences in the catalytic features of these compounds. Alternatively to the shown cyclic structure (13) of the Rh-catalyst an acyclic structure can be introduced. Examples for cyclic groups are four- or five-membered ring structures as shown in ligands (10a), (10c) in Fig. 3, or aromatic structures as shown by way of example in ligand (5a) in Fig. 3. Examples for acyclic groups are ethylene or propylene bridges as shown in ligands (3), (6) or (7) in Fig. 3.

[0022] Fig. 2 shows the general hydrogenation of lactic acid precursors (1) by the use of Rh-catalyst in propylene carbonate (PC). Lactic acid precursors (1) are dissolved in propylene carbonate plus ligand bound catalyst. The reaction is carried out under an initial H ₂ pressure of 1 - 10 bar. Hereby R is an ethyl ester group or a methyl ester group. (L) in [Rh(L)(COD)]BF ₄ stands for different ligands that can be bound to the catalyst. These ligands will be selected out of the range presented in Fig. 3 ( 3 - 12). (COD) in [Rh(L)(COD)]BF ₄ stands for 1 ,5 cyciooctadiene but can be substituted by norbomadiene.

[0023] Fig. 3 shows the different heterocyclic phosphine ligands (3 - 12) considered in this invention. These ligands comprise many structural and electronic variations.

[0024] The invention is further exemplified by 5 tables summarizing results of the underlying reactions.

[0025] Table 1 shows the reaction of chiral phosphine ligands in the Rh-catalyzed hydrogenation of ethyl O-acetoxy acrylate (1).

10 bar initial H ₂ pressure, 1 mol% [Rh(L)(1 , 5 Cyclooctadiene)]BF ₄ catalyst, 0.4 mmol ethyl O-acetoxy acrylate in 2 mL propylene carbonate are used. Amount of conversion and amount of enantioselectivity are given in %. Ligand numbering corresponds to the numbering introduced in Fig. 3. (R) is referred to (RJ-O-acetyl ethyl lactate, and (S) is referred to fS>O-acetyl ethyl lactate.

[0026] It is shown that small changes in the structure of the bisphospholanes result in dramatic effects on the catalytic reaction. Rh-catalysts based on the ligands Me-DuPHOS (5a), Et-DuPHOS (5b), BOSPHOS (8), and Me-caMSium M (O) (10a) are very active. Binaphane (11) also shows good performance.

[0027] Table 2 shows the Rh-catalyzed hydrogenation of ethyl O-acetoxy acrylate (1) with Me-DuPHOS (5a) and Me-caMSium M(O) (10a) as ligands carried out at different initial pressure and varying solvents. 1 mol% [Rh(L)(1 , 5 Cyclooctadiene)]BF ₄ catalyst, 0.4 mmol ethyl O-acetoxy acrylate (1) in 2 mL solvent are used. ² [Rh(caMSium M)(norbomadiene)]BF ₄ is used; ³ catalyst is prehydrogenated for 1 h in propylene carbonate ; ⁴ The precatalyst was stirred for 24 h in MeOH before use; 5 GC = glycerine carbonate. Ligand numbering corresponds to the numbering introduced in Fig. 3. (R) is referred to (RJ-O-acetyl ethyl lactate, and (S) is referred to (SJ-O-acetyl ethyl lactate.

[0028] Both ligands, Me-DuPHOS (5a) and Me-cal4Sium (O) (10a), show good to excellent enantioselectivites independent of which of the following solvent is used: propylene carbonate, methanol, methylene chloride, tetrahydrofuran or glycerine carbonate.

[0029] But reaction time depends clearly on the used Rh-ligand and initial H ₂ pressure. At 10 bar initial hydrogen pressure in combination with Rh(Me-DuPHOS)- catalyst (5a) leads to fast reactions in all solvents, whereas hydrogenation is slowed down by a factor of 5 to 30 at 1 bar initial H ₂ -pressure. Enantioselectivity is highest by the use of methanol as solvent.

[0030] If Me-catASium M (O) (10a) is used the pressure effect is much less pronounced. Also results with propylene carbonate as solvent are better then those done in methanol as solvent. Only a slight deceleration of the reaction in propylene carbonate at 1 bar in comparison to 10 bars can be observed. This behaviour is unique in comparison to other solvents. For example, in tetrahydrofuran or methylene chloride the reaction does not come to completion. The enantioselectivity is constantly high in all conditions in propylene carbonate. [0031] The use of [Rh(catASium M)(norbornadiene)]BF ₄ as precatalyst further decreased reaction time. It is a well known effect, that reaction times with precatalysts bearing 1 ,5-cyclooctadiene as stabilizing counterligand are characterized by longer reaction times in comparison to catalysts characterized by a norbornadiene constitution.

[0032] Processes in presence of propylene carbonate are more efficient in comparison to the use of MeOH and H ₂ O as solvent, because the ring opening of the anhydride unit of the ligand can be avoided. By way of example, such a reaction can be investigated by ³¹ P-NMR measurements. ¹ H and ¹³ C NMR data are taken in deuterated chloroform and MeOH-d ⁴ at 300 MHz. Proton chemical shifts are referenced to TMS standard. Carbon chemical shifts are referred to the carbon signal of the solvent at 77.0 ppm.

[0033] Table 3 shows the Rh-catalyzed hydrogenation of ethyl O-acetoxy acrylate (1) in propylene carbonate with Et-catASium M (O) (10b) and Et-caMSium M (N) (10g) as ligands. 1 mol% [Rh(L)(1 ,5 Cyclooctadiene)]BF ₄ catalyst, 0.4 mmol ethyl O-acetoxy acrylate (1) in 2 mL solvent are used. Ligand numbering corresponds to the numbering introduced in Fig. 3. (R) is referred to (7?J-0-acetyl ethyl lactate, and (S) is referred to fSj-O-acetyl ethyl lactate.

[0034] The use of Et-caMSium M (O) (10b) or Et-catASium M (N) (10g) results in optimal enantioselectivites. Ligand 10b catalysis reaction approx. 3 fold faster than the ligand 10g. Therefore, the steric effect exerted by bulky alkyl groups in 2 and 5 positions of the phospholanes is pivotal for the achievement of high enantioselectivity.

[0035] Table 4 shows the Rh-catalyzed hydrogenation of methyl O-acetoxy acrylate (1) in propylene carbonate with Me-cat4Sium M ligands (10a, 10b), with ligand of the DuPHOS family (5a, 5b) as well as with BASPHOS (8). 1 mol% [Rh(L)(1 ,5 Cyclooctadiene)]BF ₄ catalyst, 0.4 mmol methyl O-acetoxy acrylate in 2 ml_ solvent are used. The ligand BASPHOS (8) was used in combination with the precatalyst [Rh(L)(norbornadiene)]BF ₄ . Ligand numbering corresponds to the numbering introduced in Fig. 3. (R) is referred to fRJ-O-acetyl methyl lactate, and (S) is referred to (S)-O-acetyl methyl lactate.

[0036] Optimal asymmetric hydrogenation is still possible after replacement of the ethyl by a methyl ester group in the prochiral substrate (1) if the following ligands are used: Et-DuPHOS (5b), BASPHOS (8), Me-caWSium M (O) (10a), Et-caWSium M (O) (10b). But this is not true for Me-DuPHOS (5a) if used as catalyst ligand in combination with the prochiral substrate containing a methyl ester group.

[0037] In the processes defined above, in which hydrogenations at an initial pressure of 10 bar are described, an isothermic hydrogenation device with automatic hydrogen pressure detection is used. 1 mol% catalyst is filled in the autoclave and it is evacuated three times followed by hydrogen flushing. 0.4 mmol substrate is dissolved in 2 mL solvent and filled into the autoclave via a syringe.

[0038] In the processes defined above, in which hydrogenations at an initial pressure of 1 bar are described, an isothermic and isobaric hydrogenation device with automatic hydrogen consumption detection is used. 1 mol% catalyst is filled in the autoclave and it is evacuated three times followed by hydrogen flushing. 0.4 mmol substrate is dissolved in 2 mL solvent and filled into the autoclave via a syringe.

[0039] For determination of conversion yield and amount of enantioselectivity a chiral GC (50m Chiraldex β-pm; Astec) is used. Conversion rates of 100 % can be achieved using Me- or Et-catASium M-ligands. Enantioselectivites of 99 % can be achieved, if ethyl O-acetoxy acrylate (1) in propylene carbonate is used and the hydrogenation is performed in 1 to 10 bar initial H ₂ pressure.

[0040] Table 5 shows the separation of ethyl O-acetoxy acrylate and methyl O- acetoxy acrylate from propylene carbonate by Spaltrohrkolonne. The product mixture is distilled using a HMS 500 C Spaltrohrkolonne from Fischer technology. All experiments are accomplished with a mixture of 100 mL propylene carbonate with 6.7 g of ethyl O-acetoxy acrylate or methyl O-acetoxy acrylate (and mixtures) (1). [a] Yield in comparison to maximum compound which can be distilled; [b] Determined by 1 H-NMR (300 MHz, CDCI3); [c] The experiment is done with mixtures of 32 mL propylene carbonate and 812 mg product; The product fraction is collected in a cooled flask (-78 ⁰ C); [d] A 100 mL solution, containing 6.7 g of a mixture. The previously done hydrogenation is stopped after 70 % conversion to analyze the separation of product and starting material in mixtures. The fraction is free of propylene carbonate but contains a mixture of starting material : product = 14 : 86 et %. Ligand numbering corresponds to the numbering introduced in Figure 2.

[0041] An improved separation can be achieved at 7.5 mbar vacuum. The end product is free of propylene carbonate impurities and 86 % can be distilled out of the reaction phase (entry 2). The pure end product is enriched in the first fraction while non-converted starting material is found in the second fraction (entry 3).

[0042] Determination of purity of end product is achieved by ¹ H-NMR at 300 MHz in deuterated chloroform. The process described above leads to 77 % yield of ethyl O-acetoxy acrylate and 79 - 96 % yield of methyl O-acetoxy acrylate and thus leads to a successful separation of the end product from propylene carbonate.

[0043] A further example for the invention is given in the following work protocol: A 2 L autoclave is evacuated and rinsed with argon several times. A solution comprising 20.06 g (139 mmol) methyl-2-acetoxyacrylat (1), 0.55 mmol Rh-catalyst and 360 mL propylene carbonate are injected into the autoclave. The reaction is carried out using an initial H ₂ -pressure of 20 bar. Following hydrogenation 120 mL of the reaction product is transferred into a glass flask that is fixed to the Spaltrohrkolonne using a rubber joint. The following starting parameters are chosen: oil bath temperature: 85 ⁰ C, shell temperature of the Spaltrohrkolonne: 70 ⁰ C, and vacuum 8 mbar. The parameters were brought to an optimum by which the oil bath temperature is 107 ⁰ C, the sump temperature is 94 ⁰ C, the temperature of the shell of the Spaltrohrkolonne is 80 ⁰ C, the temperature at the top of the Spaltrohrkolonne is 52.5 ⁰ C, and the vacuum is adjusted to 7 mbar. The ratio of reflux and sampling is adjusted to 4:1. Hereby, distillation starts when a sump temperature of 90 ⁰ C is reached. For yield optimization the temperature of the shell of the Spaltrohrkolonne should be stepwise increased up to 90 °C. A change of distillation fraction is necessary when the temperature at the top of the Spaltrohrkolonne is increased to 94.5 ⁰ C as this is the start of the distillation of propylene carbonate.

[0044] The advantages of the proposed process are: • process is operable at low pressure

• propylene carbonate can be synthesized environmentally friendly, it is characterized by low toxicity and easy biodegradability

• commercially available catalysts can be chosen

• under these conditions the disturbing opening of the maleic anhydride moiety in the catalyst ligand can be prevented

• high yield of enantioselectivity

• environmentally friendly key technology

• use of propylene carbonate allows shortening of reaction times

• economically friendly key technology