Process for preparing cis-4-aminotetrahydrofuran-2-carboxylic acid esters

Abstract

The invention relates to a new process for preparing salts of cis-4-aminotetrahydrofuran-2-carboxylic acid esters of the general formula (I).

Description

[0001] BCS241009 Foreign NR / ed 30.06.2025

[0002] Method for the preparation of cis-4-aminotetrahydrofuran-2-carboxylic acid esters

[0003] The present invention relates to a new process for the preparation of the salts of cis-4-aminotetrahydrofiiran-2-carboxylic acid of general formula (I).

[0004] Cis-4-Aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride (CAS 1304126-28-0) of general formula (I) (with R 1= Methyl) is an important building block for the synthesis of plant protection products (WO 2012 / 130798, WO 2021 / 170464).

[0005] The first published synthetic route is by Walker et al. (Synthesis 2011, 7, 1113-1119). It uses 4-(tert-Butoxycarbonylamino)fiiran-2-carboxylic acid methyl ester (CAS 1170719-58-0, Wolter et al., Org. Lett. 2009, 11, 2804) as a precursor. However, 4-(tert-Butoxycarbonylamino)fiiran-2-carboxylic acid methyl ester is not a suitable starting material or intermediate for large-scale synthesis: The costs are high because the reagents for its preparation are very expensive, the yields are low, the safety risks are high, and undesirable phosphate waste is generated, making large-scale production uneconomical. Examples of this disadvantageous preparation include lithiation with scc-butyllithium with a yield of only 34% and a Curtius rearrangement requiring DPPA (diphenylphosphonazide).Therefore, the industrial-scale production of cis-4-aminotetrahydrofiiran-2-carboxylic acid ester via this precursor 4-(tert-butoxycarbonylamino)fiiran-2-carboxylic acid methyl ester is not feasible.

[0006] The synthesis via 4-bromofiiran-2-carboxylic acid methyl ester (CAS 58235-80-6, WO 2021 / 170464) is also costly due to the bromination and the subsequent inefficient coupling with tert-butylcarbamate (25% yield, WO 2021 / 170464) and leads to large quantities of environmentally harmful waste.

[0007] WO 2023 / 161204 describes the preparation of the compounds of general formula (I) by hydrogenation. A disadvantage of this process is the formation of by-products, which results in an isolated yield of the desired product in high purity of only 60-70%.

[0008] The present invention was therefore based on the objective of improving the process in such a way as to reduce the formation of by-products and increase the isolated yield of the desired product, while obtaining the product in the same or higher purity and at lower cost.

[0009] It has now been found that the formation of the minor components occurs mainly through intermolecular reactions of the compounds of general formula (II) with themselves and is favored by long reaction times. However, long reaction times are necessary for economic reasons to achieve high conversion with a small amount of catalyst in batch processes.

[0010] The previously described problem – simple, cost-effective and large-scale production – is solved by a process for the production of compounds of general formula (I) in the form of a salt BCS241009 Foreign NR / ed 30,06,2025 wherein

[0011] R 1 for (Ci-Ce)alkyl or (C3-Ce)cycloalkyl, characterized in that compounds of the general formula (II) are in the form of a salt

[0012] (II) wherein

[0013] R 1 (Ci-Ce)alkyl or (C3-Ce)cycloalkyl stands for, are dissolved in a solvent and continuously pumped together with hydrogen through a reactor that is charged with a rhodium catalyst.

[0014] In another embodiment, an acid is added to the reaction mixture.

[0015] Preferred residual definitions for the compounds of general formulas (I) and (II) are the following:

[0016] R 1 stands for (C i -Ce) alkyl .

[0017] Particularly preferred residual definitions for the compounds of general formulas (I) and (II) are the following:

[0018] R 1 stands for CH3.

[0019] The reaction for the preparation of compounds of formula (I) is shown in Scheme 1. BCS241009 Foreign NR / ed 30,06,2025

[0020] Scheme 1

[0021] The compounds of general formula (II) in the form of a salt react in the presence of hydrogen, a rhodium catalyst in a solvent to form compounds of general formula (I) in the form of a salt.

[0022] The process according to the invention can be carried out in a tubular reactor as a fixed-bed reaction with a fixed catalyst, or as a fluidized-bed reaction with a catalyst in a swirling motion, or in one or more continuously stirred tank reactors (CSTRs), or in a continuously operated loop reactor. The fixed-bed reactor is preferred. The CSTR or loop reactor is also preferred. The CSTR or loop reactor is particularly preferred. The hydrogenation is carried out in the liquid phase, for example, using trickling or sump operation.

[0023] alternative

[0024] Batch hydrogenation achieves similarly high yields to continuous hydrogenation by increasing the amount of catalyst, thus shortening the reaction time. For this method to be economically viable, the catalyst must be reused multiple times. This requires pumping out the reaction solution and adding fresh starting material. This method was already mentioned in WO 2023 / 161204, but it needs to be modified by using a higher amount of catalyst to reduce the reaction time and consequently the formation of byproducts.

[0025] The pressure during the reaction is 1 to 100 bar, preferably 5 to 50 bar, and particularly preferably 20 to 50 bar. The molar ratio of hydrogen to compounds of formula (II) must be greater than or equal to two equivalents of hydrogen per equivalent of the compounds of formula (II); preferably 2 to 10 equivalents of hydrogen; particularly preferably 3 to 5 equivalents of hydrogen.

[0026] The reaction temperature is 0°C to 100°C, preferably 10°C to 80°C, particularly preferably 20°C to 40°C. BCS241009 Foreign NR / ed 30.06.2025

[0027] Rhodium catalysts or mixed catalysts consisting of rhodium and one or more other metals can be used as catalysts, with rhodium and possibly other metals being applied to a support material.

[0028] Suitable substrate materials include, for example, activated carbon, aluminum oxide, silicon dioxide, silicon carbide, calcium oxide, titanium dioxide and / or zirconium dioxide; aluminum oxide is preferred; activated carbon is also preferred.

[0029] The catalysts are used with a precious metal loading of 0.1-10% on the support material; preferably 0.5-5% precious metal is applied to the support material.

[0030] The compounds of formula (II) are reacted to form compounds of formula (I) in a catalyst loading of 0.01-1 g (II) / g catalyst / min; preferably 0.05-0.2 g (II) / g catalyst / min are reacted to form compounds of formula (I), preferably also 0.01-0.1 g (II) / g catalyst / min are reacted to form compounds of formula (I).

[0031] Reactivation of the catalyst, for example by suitable washing with a solvent or solvent mixture, can be advantageous for its reuse, for example by washing with methanol, methanol / dichloromethane or acid methanol.

[0032] The compounds of formula (II) are used as salts, optionally with an acid. An additional acid or acid mixture can be added to the reaction mixture. The following acids are preferably used for salt formation with compounds of formula (II) and / or as additives: HCl, H₂SO₄, MsOH, TfOH, TFA. HCl is particularly preferred. The molar ratio of the acid to the compound of formula (II) is 100–110%, preferably 100–105%.

[0033] Suitable solvents and solvent mixtures are, for example: R'OH, R'OH / toluene, R'OH / dichloromethane, preferably R'OH and R'OH / dichloromethane, particularly preferred are methanol and methanol / dichloromethane.

[0034] If the compounds of general formula (I) occur in the form of their salts, e.g. as hydrochloride, the salt-free form can be obtained by treating the salt with a base, e.g. triethylamine.

[0035] Compounds of general formula (II) are manufactured according to WO 2022 / 018057 Al. BCS241009 Foreign NR / ed 30.06.2025

[0036] Explanation of the procedure

[0037] Examples

[0038] The present invention is explained in more detail with reference to the following examples, without limiting the invention to these. Experimental setup for fixed-bed hydrogenation (Examples 1-4)

[0039] Experimental setup for CSTR hydrogenation (Examples 5-10) BCS241009 Foreign NR / ed 30.06.2025

[0040] Measurement methods

[0041] The products were characterized using 'H-NMR spectroscopy and / or GC / MS (Gas Chromatography Mass Spectrometry).

[0042] The NMR spectra were measured using a Bruker AV III 600.

[0043] The GC / MS samples were analyzed using a Shimadzu GCMS-QP-2010-Ultra coupled with an additional FID (flame ionization detector). For this purpose, the samples were first evaporated, and then 1-10 mg of dry sample was reacted with 250 pL of N-methyl-N-trimethylsilyltrifluoroacetamide for silylation. After a reaction time of 1-5 minutes, the samples were diluted with 1 mL of acetonitrile and analyzed.

[0044] Quantitative GC determinations were performed on an Agilent HB7890 B-series GC. The technique is based on GC with FID detection, an RTX-5 amine column, and internal standard evaluation (internal standard: diethyl phthalate). The samples, reference standard, and internal standard are dissolved in methanol.

[0045] Production of rac-cis-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride

[0046] Example 1

[0047] A solution of 25 g of 4-aminofuran-2-carboxylic acid methyl ester hydrochloride (141 mmol) in 480 g of methanol and 120 g of dichloromethane was pumped at a flow rate of 7 to 15 ml / min and mixed with hydrogen in a static mixer. The mixture was then pumped downwards through a vertically mounted tubular reactor (9 mm diameter, 70 mm length) heated to 30°C and charged with 4 g of rhodium catalyst (5% rhodium on aluminum oxide powder). The total pressure was adjusted to 30 bar via a pressure relief valve downstream of the tubular reactor. The resulting reaction mixture was depressurized to ambient pressure downstream of the pressure relief valve, the gas phase was separated, and the reaction solution was collected in fractions. The conversion of the reactant to the desired target product was determined by quantitative gas chromatography.

[0048] Table 1 BCS241009 Foreign NR / ed 30.06.2025

[0049] Example 2

[0050] A solution of 41.7 g of 4-aminofiiran-2-carboxylic acid methyl ester hydrochloride (219 mmol, 93% purity) in 667 g of methanol and 333 g of dichloromethane was pumped at a flow rate of 7.5 ml / min and mixed with hydrogen (5 nL / h) in a static mixer. The mixture was then pumped downwards through a vertically mounted tubular reactor (9 mm diameter, 700 mm length) heated to 30°C. The reactor contained 22.5 g of rhodium catalyst (3% rhodium on aluminum oxide spheres, approximately 1 mm in diameter), and the remaining reactor volume was charged with 1.5 mm glass beads. The total pressure was set to 30 bar via a pressure relief valve downstream of the tubular reactor. The reaction mixture was then depressurized to ambient pressure after the pressure relief valve, and the resulting fraction (902 g) was concentrated to 80 g under reduced pressure. The obtained solution was transferred to a three-necked flask with a KPG stirrer and rinsed with 20 ml of methanol.250 ml of toluene were added dropwise to the solution over 30 minutes at room temperature, and the resulting suspension was then stirred overnight at 0°C. The suspension was filtered through a Büchner filter, and the resulting solid was dried under reduced pressure.

[0051] Fraction yield: 33.5 g (81% of theory) of the target compound.

[0052] Content (quant. GC): 96.1% of the target compound

[0053] 1 H-NMR (DMSO-d6, 600 MHz): 1.98-2.05 (1H, m), 2.57-2.66 (1H, m), 3.69 (3H, s), 3.75-3.84 (2H, m), 3.91-3.98 (1H, m), 4.46-4.5 Ifff (1H, t), 8, 3-8, 6 (3H, br) ppm.

[0054] GC / MS (m / z): 217 [M+TMS], 202, 187, 172, 158, 142, 128, 116, 100, 89, 73, 59, 54.

[0055] Example 3

[0056] A solution of 70 g of 4-aminofiiran-2-carboxylic acid methyl ester hydrochloride (367 mmol, 93% purity) in 1120 g of methanol and 560 g of dichloromethane was pumped at a flow rate of 15 ml / min and mixed with hydrogen (10 nL / h) in a static mixer. The mixture was then pumped downwards through a vertically mounted tubular reactor (9 mm diameter, 700 mm length) heated to 30°C. The reactor contained 30.2 g of rhodium catalyst (3% rhodium on aluminum oxide beads, approximately 1 mm in diameter), and the remaining reactor volume was charged with 1.5 mm glass beads. The total pressure was set to 30 bar via a pressure relief valve downstream of the tubular reactor. The reaction mixture was then depressurized to ambient pressure after the pressure relief valve, and the resulting fraction (1620 g) was concentrated to 210 g under reduced pressure. The obtained solution was transferred to a three-necked flask equipped with a KPG stirrer. 630 ml of toluene were added dropwise to the solution over 1 hour at 0°C, and the resulting suspension was then stirred for 2 hours at 0°C.The suspension was filtered through a Nutsche filter, washed twice with 50 ml of toluene, and the resulting solid was dried under reduced pressure.

[0057] Fraction yield: 48.4 g (71% of theory) of the target compound.

[0058] Content (quant. GC): 97.7% of the target compound.

[0059] Example 4

[0060] A solution of 29.99 g of 4-aminofuran-2-carboxylic acid methyl ester hydrochloride (157 mmol, 93% purity) in 480 g of methanol and 240 g of dichloromethane was pumped at a flow rate of 12 ml / min and mixed with hydrogen (8 nL / h) in a static mixer. The mixture was then pumped upwards through a vertically mounted tubular reactor (9 mm diameter, 700 mm length) heated to 30°C. The reactor contained 30.2 g of rhodium catalyst (3% rhodium on aluminum oxide beads, approximately 1 mm in diameter), and the remaining reactor volume was charged with 1.5 mm glass beads. The total pressure was adjusted to 30 bar via a pressure relief valve downstream of the tubular reactor. The reaction mixture was depressurized to ambient pressure after passing through the pressure relief valve, and the resulting fraction (745 g) was concentrated to 90 g under reduced pressure. The solution was then transferred to a three-necked flask equipped with a KPG stirrer.260 ml of toluene were added dropwise to the solution over 1 hour at 0°C, and the resulting suspension was then stirred for 2 hours at 0°C. The suspension was filtered through a Büchner filter, washed twice with 30 ml of toluene, and the resulting solid was dried under reduced pressure.

[0061] Fraction yield: 22.2 g (75.5% of theory) of the target compound.

[0062] Content (quant. GC): 97.0% of the target compound.

[0063] Example 5 (HPLM2853-301, comparison test to BCS221007, Example 1)

[0064] 50 g of a 5% Rh / C catalyst (50% wet water) were washed with methanol and filtered. The methanol-wet catalyst was then placed in a 600 ml autoclave containing 210 ml MeOH under 50 bar hydrogen pressure and stirred at 50°C. A solution of 50 g of 4-aminofiiran-2-carboxylic acid methyl ester hydrochloride (275 mmol, 97.7% purity) in 1616 g methanol, cooled to 0°C, was continuously pumped into the autoclave using an HPLC pump at a flow rate of 10 ml / min. The hydrogen pressure was also increased (flow rate 10 NL / h) until reaction solution was continuously forced from the autoclave through a diaphragm-loaded pressure relief valve set to 50 bar, via a riser tube with a pre-installed sintered metal filter (10 pm). The reaction solution was collected in a receiving vessel and then concentrated to 100 g under reduced pressure. The resulting solution was transferred to a three-necked flask equipped with a KPG stirrer and rinsed with 20 ml of MeOH.200 ml of toluene were added dropwise to the solution over 20 minutes at 0°C, and the resulting suspension was then stirred for 1 hour at 0°C. The suspension was filtered through a Büchner filter, washed twice with 50 ml of toluene / MeOH 4:1, and the resulting solid was dried under reduced pressure.

[0065] Yield: 39.57 g (76.7% of theory) of the target compound.

[0066] Content (quant. NMR): 96.9% of the target compound.

[0067] Example 6 (HPLM2853-290, like Example 5 but 30 bar H2 and 25°C)

[0068] In a 600 ml autoclave, 15 g of a 5% Rh / C catalyst (dry) was dissolved in 210 ml of MeOH under 30 bar hydrogen pressure and stirred at 25 °C. A solution of 50 g of 4-aminofiiran-2-carboxylic acid methyl ester hydrochloride (276 mmol, 98.1% purity) in 1616 g of methanol, cooled to 0 °C, was continuously pumped into the autoclave using an HPLC pump at a flow rate of 10 ml / min. The hydrogen pressure was simultaneously increased (flow rate 10 NL / h) until reaction solution was continuously forced from the autoclave through a diaphragm-loaded pressure relief valve set to 30 bar, via a riser tube with a pre-installed sintered metal filter (10 pm). The reaction solution was collected in a receiving vessel and then concentrated to 100 g under reduced pressure. The received BCS241009 foreign NR / ed 30.06.2025

[0069] The solution was transferred to a three-necked flask equipped with a KPG stirrer and rinsed with 20 ml of MeOH. 200 ml of toluene were added dropwise to the solution over 1 h at 0°C, and the resulting suspension was stirred for another 1 h at 0°C. The suspension was filtered through a Büchner filter, washed twice with 30 ml of toluene, and the resulting solid was dried under reduced pressure.

[0070] Yield: 37.3 g (72.2% of theory) of the target compound.

[0071] Content (quant. GC): 97.1% of the target compound.

[0072] Example 7 (HPLM2853-292, like Example 6 but with added HCl)

[0073] In a 600 ml autoclave, 15 g of a 5% Rh / C catalyst (dry) was placed in a mixture of 210 ml MeOH and 0.3 ml of a 3M solution of hydrogen chloride in methanol at 30 bar hydrogen pressure and stirred at 25 °C. A solution of 50 g of 4-aminofiiran-2-carboxylic acid methyl ester hydrochloride (276 mmol, 98.1% purity) in a mixture of 1614 g methanol and 3.35 ml of a 3M solution of hydrogen chloride in methanol, cooled to 0 °C, was continuously pumped into the autoclave using an HPLC pump at a flow rate of n 10 ml / min. Furthermore, the hydrogen pressure was increased (flow rate 10 NL / h) until reaction solution from the autoclave was continuously forced through a riser pipe with a pre-installed sintered metal filter (10 pm) and a diaphragm-loaded pressure-holding valve set to 30 bar. The reaction solution was collected in a receiving vessel and then concentrated to 100 g under reduced pressure.The obtained solution was transferred to a three-necked flask equipped with a KPG stirrer and rinsed with 20 ml of MeOH. 200 ml of toluene were added dropwise to the solution over 1 h at 0°C, and the resulting suspension was then stirred for another 1 h at 0°C. The suspension was filtered through a Büchner filter, washed twice with 30 ml of toluene, and the resulting solid was dried under reduced pressure.

[0074] Yield: 37.6 g (71.8% of theory) of the target compound.

[0075] Content (quant. GC): 95.7% of the target compound.

[0076] Example 8 (HPLM2853-293, like Example 7 but crystallized with MTBE)

[0077] In a 600 ml autoclave, 15 g of a 5% Rh / C catalyst (dry) was placed in a mixture of 210 ml MeOH and 0.3 ml of a 3M solution of hydrogen chloride in methanol at 30 bar hydrogen pressure and stirred at 25 °C. A solution of 50 g of 4-aminofiiran-2-carboxylic acid methyl ester hydrochloride (276 mmol, 98.1% purity) in a mixture of 1614 g methanol and 3.35 ml of a 3M solution of hydrogen chloride in methanol, cooled to 0 °C, was continuously pumped into the autoclave using an HPLC pump at a flow rate of n 10 ml / min. Furthermore, the hydrogen pressure was increased (flow rate 10 NL / h) until reaction solution from the autoclave was continuously forced through a riser pipe with a pre-installed sintered metal filter (10 pm) and a diaphragm-loaded pressure-holding valve set to 30 bar. The reaction solution was collected in a receiving vessel and then concentrated to 100 g under reduced pressure.The obtained solution was transferred to a three-necked flask equipped with a KPG stirrer and rinsed with 20 ml of MeOH. 200 ml of a mixture of MTBE and methanol 85 / 15 (v / v) was added dropwise to the solution over 1 h at 0°C, and the resulting suspension was then stirred for another 1 h at 0°C. BCS241009 Foreign NR / ed 30.06.2025.

[0078] The suspension was aspirated via a Nutsche filter, washed twice with 30 ml of MTBE / MeOH mixture 85 / 15 (v / v) and the resulting solid was dried under reduced pressure.

[0079] Yield: 43.1 g (82.5% of theory) of the target compound.

[0080] Content (quant. GC): 96.1% of the target compound.

[0081] Example 9 (HPLM2853-294, like Example 6 but crystallized with MTBE instead of toluene)

[0082] In a 600 ml autoclave, 15 g of a 5% Rh / C catalyst (dry) was dissolved in 210 ml of MeOH under 30 bar hydrogen pressure and stirred at 25 °C. A solution of 50 g of 4-aminofuran-2-carboxylic acid methyl ester hydrochloride (276 mmol, 98.1% purity) in 1616 g of methanol, cooled to 0 °C, was continuously pumped into the autoclave using an HPLC pump at a flow rate of 10 ml / min. The hydrogen pressure was simultaneously increased (flow rate 10 NL / h) until reaction solution was continuously forced from the autoclave through a diaphragm-loaded pressure relief valve set to 30 bar, via a riser tube with a pre-installed sintered metal filter (10 pm). The reaction solution was collected in a receiving vessel and then concentrated to 100 g under reduced pressure. The obtained solution was transferred to a three-necked flask with a KPG stirrer and rinsed with 20 ml of MeOH.200 ml of a mixture of MTBE and methanol 85 / 15 (v / v) were added dropwise to the solution over 1 h at 0°C, and the resulting suspension was then stirred for another 1 h at 0°C. The suspension was filtered through a Büchner filter, washed twice with 30 ml of MTBE / MeOH mixture 85 / 15 (v / v), and the resulting solid was dried under reduced pressure.

[0083] Yield: 43.56 g (84.1% of theory) of the target compound.

[0084] Content (quant. GC): 96.8% of the target compound.

[0085] Example 10 (HPLM2853-276, like Example 9 but with Rh / Alox at 30°C)

[0086] In a 600 ml autoclave, 15 g of a 5% Rh / Alox catalyst (dry) was dissolved in 210 ml of MeOH under 30 bar hydrogen pressure and stirred at 30°C. A solution of 50 g of 4-aminofuran-2-carboxylic acid methyl ester hydrochloride (276 mmol, 94.7% purity) in 1616 g of methanol, cooled to 0°C, was continuously pumped into the autoclave using an HPLC pump at a flow rate of 10 ml / min. The hydrogen pressure was simultaneously increased (flow rate 10 NL / h) until reaction solution was continuously forced from the autoclave through a diaphragm-loaded pressure relief valve set to 30 bar, via a riser tube with a pre-installed sintered metal filter (10 pm). The reaction solution was collected in a receiving vessel and then concentrated to 87 g under reduced pressure. The obtained solution was transferred to a three-necked flask with a KPG stirrer and rinsed with 20 ml of MeOH.200 ml of a mixture of MTBE and methanol 85 / 15 (v / v) were added dropwise to the solution over 1 h at 0°C, and the resulting suspension was then stirred for another 1 h at 0°C. The suspension was filtered through a Büchner filter, washed twice with 30 ml of a mixture of MTBE / MeOH 60 / 40 (v / v), and the resulting solid was dried under reduced pressure.

[0087] Yield: 42.77 g (87.5% of theory) of the target compound.

[0088] Salary (quant. GC): 99.1% of the target connection. BCS241009 Overseas NR / ed 30.06.2025

[0089] Example 11, Batch hydrogenation for comparison, repetition of Example 8 from BCS221007 and isolation of the product (HPLM2853-291)

[0090] A solution of 50 g of 4-aminofiiran-2-carboxylic acid methyl ester hydrochloride (276 mmol, 98.1%) in 1200 g of methanol and 2.5 mL of a 3 M solution of hydrogen chloride in methanol was mixed with 1 g of a 5% Rh / C catalyst (dry) in a 2000 mL autoclave, and the autoclave was purged three times with 5 bar argon. The mixture was stirred under 40 bar hydrogen at 25°C for 22 h. The autoclave was cooled and depressurized. The reaction mixture was filtered through a Büchner funnel, and the catalyst was washed with methanol. 1262 g of solution containing 3.0% (quantitative GC) of the target compound were obtained, corresponding to a crude yield of 75.5%. The filtrate was concentrated to 100 g under reduced pressure, and 250 mL of toluene were added dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes, the precipitate was filtered off, washed with toluene / MeOH 4 / 1, and dried under reduced pressure.

[0091] Yield: 34.5 g (63.3% of theory) of the target compound. Purity (quant. GC): 91.9% of the target compound.

Claims

BCS241009 Foreign NR / ed 30.06.2025 Patent claims:

1. Method for the preparation of compounds of general formula (I) in the form of a salt wherein R 1 for (Ci-Ce)alkyl or (C3-Ce)cycloalkyl, characterized in that compounds of the general formula (II) are in the form of a salt wherein R 1 (Ci-Ce)alkyl or (C3-Ce)cycloalkyl stands for, are dissolved in a solvent and continuously pumped together with hydrogen through a reactor that is charged with a rhodium catalyst.

2. Method according to claim 1, characterized in that the residual definitions for the compounds of general formulas (I) and (II) are the following: R 1 stands for (C i -Ce) alkyl .

3. Method according to claim 1, characterized in that the residual definitions for the compounds of general formulas (I) and (II) are the following: R 1 stands for CH3.

4. Method according to one of claims 1 to 3, characterized in that an acid is added to the reaction mixture. BCS241009 Foreign NR / ed 30.06.2025 5. Method according to claim 4, characterized in that a further acid or acid mixture is added to the reaction mixture.

6. A method according to claim 4 or 5, characterized in that HCl is added to the reaction mixture as an acid.

7. A method according to any one of claims 1 to 6, characterized in that R 1 Methyl corresponds to methanol as the solvent.

8. Method according to any one of claims 1 to 6, characterized in that R 1Methyl corresponds to and the solvent is a solvent mixture of dichloromethane and methanol.

9. Method according to any one of claims 1 to 8, characterized in that 0.1 to 10 wt.% catalyst (dry weight) is used based on compound of formula (II) .

10. Method according to claim 9, characterized in that Rh / C or Rh / Alox is used as the catalyst.

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