WO2023161204A1 - Method for producing cis-4-aminotetrahydrofuran-2-carboxylic acid esters - Google Patents

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

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

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

Methyl cis-4-aminotetrahydrofuran-2-carboxylate hydrochloride (CAS 1304126-28-0) of the general formula (I) (with R ^{1 =} methyl) is an important building block for the synthesis of crop protection agents (WO 2012/130798, WO 2021/170464) .

The first published synthetic route is 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) is used as a precursor. However, methyl 4-(tert-butoxycarbonylamino)fiirane-2-carboxylate cannot be produced economically on an industrial scale because of the high costs of the reagents for production, the low yields, safety risks and phosphate waste. For example, a lithiation with scc-butyllithium (34% yield) and a Curtius rearrangement with DPPA (diphenylphosphonazide) are necessary for this. Therefore, this route for preparing cis-4-aminotetrahydrofuran-2-carboxylic acid esters on an industrial scale is not feasible.

The synthesis via methyl 4-bromofirane-2-carboxylate (CAS 58235-80-6, WO 2021/170464) is also expensive and leads to bromination and the subsequent inefficient coupling with tert-butyl carbamate (25% yield, WO 2021/170464). too much waste.

In the light of the prior art described above, the object of the present invention is to find a process for preparing cis-4-aminotetrahydrofuran-2-carboxylic acid esters which is inexpensive 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 in high purity, so that they do not have to be subjected to any further complex purification, as a result of which the corresponding crop protection agents can then also be produced on an industrial scale.

worin R¹ fur (Ci-Cg)Alkyl oder (C3-Cg)Cycloalkyl steht, dadurch gekennzeichnet, dass Verbindungen der allgemeinen Formel (II) in Form eines Salzes

The problem described above--simple, inexpensive and industrial-scale production--is achieved by a process for the production of compounds of the general formula (I) in the form of a salt

wherein R ¹ is (Ci-Cg)alkyl or (C3-Cg)cycloalkyl, characterized in that compounds of general formula (II) are in the form of a salt

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

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

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

R ¹ is (C i -Cg)alkyl.

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

^R1 represents CH3.

The reaction to prepare compounds of formula (I) is shown in Scheme-1.

Scheme 1

The compounds of formula (II) in the form of a salt react 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.

The pressure during the reaction is from 1 to 100 bar, preferably from 5 to 50 bar, particularly preferably from 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.

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; preferred: Rh/C, Rh+Pd/C, Rh/Alox; particularly preferred: Rh/C, Rh/Alox.

The catalysts are used with a precious metal loading of 0.5-10% precious metal on the carrier material; 1-5% noble metal is preferably applied to the carrier material.

The catalysts are used in an amount of 0.1-10% by weight, based on the compounds of the formula (II); 0.5-5% by weight are preferably used.

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

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

The compounds of the formula (II) are used as salts, optionally with an acid. Another acid or an acid mixture can also be added to the reaction mixture. The following acids are preferably used for salt formation with compounds of the formula (II) and/or as an additive: HCl, H2SO4, MsOH, TfOH, TFA. HCl is particularly preferred.

The molar ratio of the acid to the compound of formula (II) is 0-100%, preferably 0-10%. Suitable solvents and solvent mixtures are e.g.: R'OH. R^H/toluene, preferred is R'OH.

When the compounds of general formula (I) are obtained in the form of their salts, for example the hydrochloride, the salt-free form can be obtained by treating the salt with a base, for example triethylamine.

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

Explanation of the procedure

examples

The present invention is explained in more detail using the following examples, without restricting the invention to these. measurement method

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

The NMR spectra were measured with a Bruker AV III 600.

The GC/MS samples were measured with 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 were mixed with 250 μl of N-methyl-N-trimethylsilyltrifluoroacetamide for silylation. After a reaction time of 1-5 minutes, the samples were diluted with 1 ml acetonitrile and measured.

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

Preparation of methyl rac-cis-4-aminotetrahydrofuran-2-carboxylate hydrochloride

example 1

A solution of 50 g of methyl 4-aminofuran-2-carboxylate hydrochloride (282 mmol) in 250 g of methanol was added in a 600 ml autoclave with 2.5 g of a 5% Rh/C catalyst (dry, 1.22 mmol Rh) and the autoclave was flushed three times with 5 bar argon. The mixture was stirred under 50 bar of hydrogen at 50° C. and 600 rpm for 16 h. The autoclave was cooled and vented, and the mixture was filtered through a suction filter. The filtrate was concentrated under reduced pressure to 123 g, 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 at 50°C under reduced pressure.

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

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

'H-NMR (DMSO-d6, 600MHz): 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 .

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

example 2

A solution of 5 g of methyl 4-aminofuran-2-carboxylate hydrochloride (28.2 mmol) in 25 g of methanol was added to 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) added. The autoclave was flushed three times with 5 bar argon. The mixture was then heated under a hydrogen pressure of 50 bar for 16 h at 65° C. and 600 rpm touched. The autoclave was cooled and vented. The reaction mixture was weighed and the supernatant analyzed.

Yield: 38.0 g solution

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

Yield (quant. NMR): 64.7% of theory

Examples 3 to 9

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

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. Process for the preparation of compounds of general formula (I) in the form of a salt

(I), wherein R ¹ is (Ci-Cg)alkyl or (C3-Cg)cycloalkyl, characterized in that compounds of general formula (II) in the form of a salt

(II), in the presence of hydrogen, a rhodium catalyst in a solvent to give compounds of general formula (I) in the form of a salt. 2. Process according to Claim 1, characterized in that the radical definitions for the compounds of general formulas (I) and (II) are the following: R ¹ is (C i -Cg)alkyl. 3. Process according to Claim 1, characterized in that the radical definitions for the compounds of general formulas (I) and (II) are the following: ^R1 stands for CFL. 4. The method according to any one of claims 1 to 3, characterized in that the reaction mixture is added to an acid. 5. The method according to claim 4, characterized in that a further acid or acid mixture is added to the reaction mixture. 6. The method according to claim 4 or 5, characterized in that HCl is added as the acid to the reaction mixture. 7. The method according to any one of claims 1 to 6, characterized in that R ¹ corresponds to methyl and the solvent is methanol. 8. The method according to any one of claims 1 to 7, characterized in that 0.1 to 10% by weight Catalyst (dry weight) are used, based on the compound of the formula (II). 9. Process according to claim 8, characterized in that Rh/C or Rh/Alox is used as the catalyst.