Method for producing cis-4-aminotetrahydrofuran-2-carboxylic acid esters

Abstract

The invention relates to a novel method for producing salts of cis-4-aminotetrahydrofuran-2-carboxylic acid esters of the general formula (I).

Description

[0001] Process for the preparation of cis-4-aminotetrahydrofuran-2-carboxylic acid esters

[0002] The present invention relates to a novel process for the preparation of the salts of cis-4-aminotetrahydrofuran-2-carboxylic acid esters of the general formula (I).

[0003] Cis-4-Aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride (CAS 1304126-28-0) of the 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).

[0004] The first published synthetic route was by Walker et al. (Synthesis 2011, 7, 1113-1119). Methyl 4-(tert-butoxycarbonylamino)fiirane-2-carboxylate (CAS 1170719-58-0, Wolter et al., Org. Lett. 2009, 11, 2804) was used as the precursor. However, methyl 4-(tert-butoxycarbonylamino)fiirane-2-carboxylate is not economically viable on a large scale due to the high cost of the reagents for preparation, low yields, safety risks, and phosphate waste. For example, lithiation with scc-butyllithium (34% yield) and a Curtius rearrangement with DPPA (diphenylphosphonazide) are necessary. Therefore, this route for the production of cis-4-aminotetrahydrofuran-2-carboxylic acid esters is not feasible on an industrial scale.

[0005] The synthesis via 4-bromofiirane-2-carboxylic acid methyl ester (CAS 58235-80-6, WO 2021 / 170464) is also cost-intensive due to the bromination and the subsequent inefficient coupling with tert-butyl carbamate (25% yield, WO 2021 / 170464) and leads to large amounts of waste.

[0006] In light of the previously described prior art, the present invention seeks to find a process for the production of cis-4-aminotetrahydrofuran-2-carboxylic acid esters that is cost-effective and can be used on an industrial scale. It is also desirable to obtain these compounds in an environmentally friendly manner, in high yield, and with high purity, so that they do not require further complex purification, which would then also allow the corresponding crop protection agents to be produced on an industrial scale.

[0007] The above-described problem - simple, cost-effective and large-scale production - is solved by a process for the preparation of compounds of general formula (I) in the form of a salt where R 1 represents (Ci-Cg)alkyl or (C3-Cg)cycloalkyl, characterized in that compounds of the general formula (II) in the form of a salt

[0008] (II), in the presence of hydrogen, a rhodium catalyst in a solvent to give compounds of the general formula (I) in the form of a salt.

[0009] In another embodiment, an acid is added to the reaction mixture.

[0010] Preferred radical definitions for the compounds of general formulas (I) and (II) are the following:

[0011] R 1 stands for (C i -C g) alkyl .

[0012] Particularly preferred radical definitions for the compounds of general formulas (I) and (II) are the following:

[0013] R 1 stands for CH3.

[0014] The reaction for preparing compounds of formula (I) is shown in Scheme 1.

[0015] Scheme 1

[0016] The compounds of 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.

[0017] The pressure during the reaction is 1 to 100 bar, preferably 5 to 50 bar, particularly preferably 20 to 50 bar. The temperature during the reaction is 0°C to 100°C, preferably 10°C to 80°C, particularly preferably 20 to 40°C.

[0018] The following rhodium catalysts or mixed catalysts consisting of rhodium and one or more other metals can be used as catalysts, for example: Rh / C, Rh / Alox, Rh+Pd / C, Rh+Pt / C, Rh+Cu / C, Rh+Ru / C; preferably: Rh / C, Rh+Pd / C, Rh / Alox; particularly preferably: Rh / C, Rh / Alox.

[0019] The catalysts are used with a precious metal loading of 0.5-10% precious metal on the support material; preferably, 1-5% precious metal is applied to the support material.

[0020] The catalysts are used in an amount of 0.1-10 wt.% with respect to the compounds of formula (II); preferably 0.5-5 wt.% are used.

[0021] The amount of catalyst used is calculated based on the dry mass of the catalysts. The catalysts can be used dry or water-moist. Water-moist catalysts can be washed with a dry solvent under an inert gas atmosphere before the reaction to remove adhering water. Alternatively, the water can be removed by azeotropic distillation with a suitable solvent. Toluene, for example, can be used for azeotropic distillation.

[0022] The catalyst can be reused or used once or, preferably, multiple times. Reactivation of the catalyst can be advantageous for its reuse, for example, by suitable washing, for example, by washing with methanol or acidic methanol.

[0023] The compounds of formula (II) are used as salts, optionally with an acid. A further acid or acid mixture can also 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.

[0024] The molar ratio of the acid to the compound of formula (II) is 0-100%, preferably 0-10%. Suitable solvents and solvent mixtures are, for example, R'OH. R^H / toluene, preferably R'OH.

[0025] If the compounds of general formula (I) are obtained 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.

[0026] Compounds of general formula (II) are prepared according to WO 2022 / 018057.

[0027] Explanation of the procedure

[0028] Examples

[0029] The present invention is explained in more detail with reference to the following examples, without limiting the invention to them.

[0030] The products were characterized by 'H-NMR spectroscopy and / or GC / MS (Gas Chromatography Mass Spectrometry).

[0031] The NMR spectra were measured using a Bruker AV III 600.

[0032] 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, then 1-10 mg of dry sample was added to 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.

[0033] The 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 analysis (internal standard: diethyl phthalate). The samples, reference standard, and internal standard are dissolved in methanol.

[0034] Preparation of rac-cis-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride

[0035] Example 1

[0036] A solution of 50 g of methyl 4-aminofuran-2-carboxylate hydrochloride (282 mmol) in 250 g of methanol was treated with 2.5 g of a 5% Rh / C catalyst (dry, 1.22 mmol Rh) in a 600 ml autoclave, and the autoclave was purged three times with 5 bar argon. The mixture was stirred under 50 bar hydrogen for 16 h at 50°C and 600 rpm. The autoclave was cooled, depressurized, and the mixture filtered through a suction filter. The filtrate was concentrated to 123 g under reduced pressure, and 250 ml of toluene was added dropwise at 0°C. The mixture was stirred at 0°C for 30 min, and the precipitate was filtered off with suction, washed twice with 15 ml of toluene, and dried under reduced pressure at 50°C.

[0037] Yield: 36.2 g (66% of theory) of the target compound

[0038] Purity (quant. NMR): 93.5% of the target compound

[0039] 'H-NMR (DMSO-d6, 600 MHz): 1.95-2.04 (1H, m), 2.59-2.67 (1H, m), 3.70 (3H, s), 3.75-3.85 (2H, m), 3.9-3.97 (1H, m), 4.45-4.52 (1H, t), 8, 2-8.5 (3H, br) ppm.

[0040] GC / MS (m / z): 217 [M+TMS], 202, 187, 172, 158, 142, 128, 116, 100, 89, 73, 59, 54

[0041] Example 2

[0042] A solution of 5 g of methyl 4-aminofuran-2-carboxylate hydrochloride (28.2 mmol) in 25 g of methanol was treated in a 100 ml autoclave with 0.15 g of a 1% Rh+1% Pd / C catalyst (50% water-moist, 0.0073 mmol Rh, and 0.007 mmol Pd). The autoclave was purged three times with 5 bar argon. The mixture was then stirred under 50 bar hydrogen pressure for 16 h at 65°C and 600 rpm. The autoclave was cooled and depressurized. The reaction mixture was weighed, and the supernatant solution was analyzed.

[0043] Yield: 38.0 g solution

[0044] GC / FID: 76.1 fl.% of the target compound, 3.1 fl.% trans-isomer Purity (quant. NMR): 8.71% of the target compound, 0.47% trans-isomer

[0045] Yield (quant. NMR): 64.7% of theory

[0046] Examples 3 to 9

[0047] The following experiments (Table 1) were carried out analogously to the experimental procedure for the preparation of Example 1: Table 1

[0048] 1 ' Based on dry weight. 2) Determined by quantitative GC directly from the reaction solution, 3) Determined by GC FID directly from the reaction solution

Claims

Patent claims:

1. Method for the preparation of compounds of general formula (I) in the form of a salt (I) wherein R 1 for (Ci-Cg)alkyl or (C3-Cg)cycloalkyl, characterized in that compounds of the general formula (II) are in the form of a salt (II) are reacted in the presence of hydrogen, a rhodium catalyst in a solvent to give compounds of the general formula (I) in the form of a salt.

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 -Cg) 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 CFL.

4. Method according to one of claims 1 to 3, characterized in that an acid is added to the reaction mixture.

5. The method according to claim 4, characterized in that a further acid or acid mixture is added to the reaction mixture.

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

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

8. A method according to any one of claims 1 to 7, characterized in that 0.1 to 10 wt.% Catalyst (dry weight) is used in relation to the compound of formula (II).

9. Method according to claim 8, characterized in that Rh / C or Rh / Alox is used as the catalyst.

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