Process for producing cis-4-aminotetrahydrofuran-2-carboxylic acid ester

Abstract

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

Description

[Technical field]

[0001] The present invention relates to a novel process for preparing salts of cis-4-aminotetrahydrofuran-2-carboxylic acid esters of general formula (I). [Background technology]

[0002] General formula (I) (wherein, R 1 Methyl cis-4-aminotetrahydrofuran-2-carboxylate hydrochloride (CAS 1304126-28-0) (=methyl) is an important building block for the synthesis of crop protection products (WO 2012 / 130798, WO 2021 / 170464).

[0003] The first published synthetic route is by Walker et al. (Synthesis 2011, 7, 1113-1119). The precursor used is methyl 4-(tert-butoxycarbonylamino)furan-2-carboxylate (CAS1170719-58-0, Wolter et al., Org. Lett. 2009, 11, 2804). However, methyl 4-(tert-butoxycarbonylamino)furan-2-carboxylate cannot be prepared in an economically viable manner on an industrial scale due to the high cost of reagents for the preparation, low yields, safety risks and phosphate waste. As an example, this requires lithiation with sec-butyllithium (yield 34%) and Curtius rearrangement with DPPA (diphenylphosphonic acid azide). Therefore, this route is not feasible for the preparation of cis-4-aminotetrahydrofuran-2-carboxylate on an industrial scale.

[0004] Furthermore, synthesis via methyl 4-bromofuran-2-carboxylate (CAS 58235-80-6, WO 2021 / 170464) is expensive and results in large amounts of waste due to inefficient bromination and subsequent coupling with tert-butyl carbamate (25% yield, WO 2021 / 170464). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2012 / 130798 Brochure [Patent Document 2] International Publication No. 2021 / 170464 Brochure [Non-patent literature]

[0006] [Non-Patent Document 1] Walker et al., Synthesis 2011, 7, 1113-1119 [Non-Patent Document 2] Wolter et al., Org.Lett.2009, 11, 2804 Summary of the Invention [Problem to be solved by the invention]

[0007] In light of the above prior art, the object of the present invention is to find a method for preparing 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 yields and with high purity so that no further complex purification is required, so that the corresponding crop protection products can also be produced on an industrial scale. [Means for solving the problem]

[0008] The above objective of simple, cost-effective, industrial-scale preparation of a compound of general formula (I) in the form of a salt [ka] (In the formula, R 1 is (C1-C6) alkyl or (C3-C6) cycloalkyl) A method for preparing Compounds of formula (II) in the form of salts [ka] to a compound of general formula (I) in the form of a salt in the presence of hydrogen and a rhodium catalyst in a solvent.

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

[0010] Preferred definitions of the radicals of the compounds of general formulae (I) and (II) are as follows: R 1 is (C1-C6) alkyl.

[0011] Particularly preferred definitions of the radicals of the compounds of general formulae (I) and (II) are as follows: R 1 is CH3.

[0012] Reactions for preparing compounds of formula (I) are shown in Scheme 1.

[0013] Scheme 1 [ka] The compound of formula (II) in the form of a salt is reacted in the presence of hydrogen and a rhodium catalyst in a solvent to form a compound of general formula (I) in the form of a salt.

[0014] The pressure during the reaction is from 1 to 100 bar, preferably from 5 to 50 bar, particularly preferably from 20 to 50 bar.

[0015] The temperature during the reaction is 0°C to 100°C, preferably 10°C to 80°C, and particularly preferably 20°C to 40°C.

[0016] The catalyst used may be the following rhodium catalysts or mixed catalysts consisting of rhodium and one or more further metals, such as 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.

[0017] The catalyst is used at a precious metal loading of 0.5% to 10% precious metal on the support material; preferably, 1 to 5% precious metal is applied to the support material.

[0018] The catalyst is used in an amount of 0.1 to 10% by weight based on the compound of formula (II); preferably, 0.5 to 5% by weight is used.

[0019] The amount of catalyst used is calculated based on the dry weight of the catalyst. The catalyst may be used in a dry or water-wet state. To remove the adhering water, the water-wet catalyst may be washed and then reacted with a dry solvent under an inert gas atmosphere. Alternatively, the water may be removed by azeotropic distillation with a suitable solvent. For example, toluene may be used for the azeotropic distillation.

[0020] The catalyst may be reused or used once or, preferably, multiple times. Reactivation of the catalyst, for example by suitable washing, for example washing with methanol or acidic methanol, may be advantageous for its reuse.

[0021] The compound of formula (II) is optionally used as a salt with an acid.Another acid or acid mixture may be further added to the reaction mixture.Preferably, the following acids are used for salt formation with the compound of formula (II) and / or as additives: HCl, H2SO4, MsOH, TfOH, TFA. HCl is particularly preferred.

[0022] The molar ratio of the acid to the compound of formula (II) is 0 to 100%, preferably 0 to 10%.

[0023] Examples of suitable solvents and solvent mixtures are 1 O.H., R.1 OH / toluene; R 1 OH is preferred.

[0024] When the compounds of general formula (I) are obtained in the form of their salts, for example as hydrochlorides, the salt-free forms can be obtained by treating the salt with a base, for example triethylamine.

[0025] The compound of general formula (II) is prepared according to WO 2022 / 018057.

[0026] Finding the method Working Example The present invention will be elucidated in more detail by the following examples, but the present invention is not limited to these examples.

[0027] Measurement method The product 1 Characterized by 1 H NMR spectroscopy and / or GC-MS (gas chromatography-mass spectrometry).

[0028] NMR spectra were measured using a Bruker AV III 600.

[0029] GC-MS samples were measured using a Shimadzu GCMS-QP-2010-Ultra coupled to an additional FID (Flame Ionization Detector). For this purpose, samples were first evaporated and then 1-10 mg of the dried sample was mixed with 250 μl of N-methyl-N-trimethylsilyltrifluoroacetamide for silylation. After a reaction time of 1-5 min, the sample was diluted with 1 ml of acetonitrile and measured.

[0030] Quantitative GC measurements were performed on a GC Agilent HB7890 B series. The technique is based on GC with FID detection, an RTX-5 amine column and internal standard evaluation (internal standard: diethyl phthalate). Samples, reference standards and internal standards are dissolved in methanol.

[0031] Preparation of methyl rac-cis-4-aminotetrahydrofuran-2-carboxylate hydrochloride Example 1 A solution of 50 g (282 mmol) of methyl 4-aminofuran-2-carboxylate hydrochloride in 250 g of methanol was mixed with 2.5 g (dry, 1.22 mmol of Rh) of 5% Rh / C catalyst in a 600 ml autoclave and the autoclave was purged three times with 5 bar of argon. The mixture was stirred at 50° C. and 600 rpm under 50 bar of hydrogen for 16 hours. The autoclave was cooled and depressurized and the mixture was filtered through a suction filter. The filtrate was concentrated under reduced pressure to 123 g and 250 ml of toluene were added dropwise at 0° C. The mixture was stirred for 30 minutes at 0° C. and the precipitate was isolated by suction filtration, washed twice with 15 ml of toluene and dried at 50° C. under reduced pressure. Yield: 36.2 g of the target compound (66% of theory) Purity (quantitative NMR): 93.5% of target compound 1 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. GC-MS (m / z): 217 [M+TMS], 202, 187, 172, 158, 142, 128, 116, 100, 89, 73, 59, 54

[0032] Example 2 A solution of 5 g (28.2 mmol) of methyl 4-aminofuran-2-carboxylate hydrochloride in 25 g of methanol was mixed with 0.15 g of 1% Rh+1% Pd / C catalyst (50% water wet, 0.0073 mmol of Rh and 0.007 mmol of Pd) in a 100 ml autoclave. The autoclave was purged three times with 5 bar of argon. The mixture was then stirred at 65° C. and 600 rpm under 50 bar of hydrogen pressure for 16 hours. The autoclave was cooled and depressurized. The reaction mixture was weighed and the supernatant solution was analyzed. Yield: 38.0 g solution GC-FID: Target compound 76.1 area %, trans isomer 3.1 area % Purity (quantitative NMR): 8.71% target compound, 0.47% trans isomer Yield (quantitative NMR): 64.7% of theoretical

[0033] Examples 3 to 9 The following experiments (Table 1) were carried out similarly to the experimental procedures for the preparation of Example 1:

[0034] [Table 1]

Claims

1. Compounds of formula (I) in the form of salts 【Chemistry 1】 (In the formula, R 1 (C 1 ~C 6 ) alkyl or (C 3 ~C 6 ) cycloalkyl A method for preparing Compounds of formula (II) in the form of salts 【Chemistry 2】 into a compound of general formula (I) in the form of a salt in the presence of hydrogen and a rhodium catalyst in a solvent. method.

2. The definitions of the groups of the compounds of the general formulae (I) and (II) are as follows: R 1 (C 1 ~C 6 ) alkyl; The method of claim 1.

3. The definitions of the groups of the compounds of the general formulae (I) and (II) are as follows: R 1 CH 3 That is, The method of claim 1.

4. 4. The process according to claim 1, wherein an acid is added to the reaction mixture.

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

6. 6. The process according to claim 4 or 5, characterized in that the acid added to the reaction mixture is HCl.

7. R 1 7. The process according to claim 1, characterized in that: corresponds to methyl and the solvent is methanol.

8. 8. The process according to claim 1, characterized in that 0.1% to 10% by weight of catalyst (dry weight), based on the compound of formula (II), is used.

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

Images