Process for preparing alkyl-4-oxotetrahydrofuran-2-carboxylate

Abstract

The present invention relates to a novel process for preparing alkyl-4-oxotetrahydrofuran-2-carboxylate (I).

Description

[0001] Process for the preparation of alkyl 4-oxotetrahydrofuran-2-carboxylate

[0002] The present invention relates to a novel process for the preparation of alkyl 4-oxotetrahydrofuran-2-carboxylate (I).

[0003] Methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I) is an important precursor of agrochemical (cf. WO2018 / 228985) active ingredients.

[0004] The synthesis of methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I) is known, e.g., from Helv. Chim. Acta 1959, 1177 and WO 2016 / 205633. However, starting from dimethyl(Z)-butenedioate, three reaction steps are necessary to produce methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I), which results in a loss of yield. Furthermore, the reagents used in the prior art (e.g., sodium powder, NaH, TMSCHN2, CH2N2) are not suitable for large-scale synthesis, as safe handling of these chemicals on a large scale is difficult or they are highly toxic.

[0005] In the light of the previously described prior art, the present invention is based on the object of developing a process for the preparation of the compounds of general formula (I) starting from compounds of general formula (II) and (III) in only two reaction steps, which process is also suitable for large-scale production.

[0006] The above-described object is achieved by a process for the preparation of compounds of the general formula (I)

[0007] (I), wherein

[0008] R 1 (Ci-C4)-alkyl, characterized in that compounds of the general formula (II) wherein

[0009] R 2 (Ci-C4)-alkyl, with compounds of the general formula (III) where R 1 as defined above, by adding MO'Bu, wherein

[0010] M is an alkali metal ion, cyclization products with the general formula (IV) (IV), where R 1 as defined above, which undergo dealkoxycarbonylation under non-hydrolytic conditions to form compounds of general formula (I). Preferred radical definitions for the compounds of general formulas (I), (II), (III), (IV) and MOBu are as follows: R 1stands for ethyl or methyl,

[0011] R 2 stands for ethyl or methyl,

[0012] M stands for sodium or potassium.

[0013] Particularly preferred radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and MCfBu are the following:

[0014] R 1 stands for methyl,

[0015] R 2 stands for methyl,

[0016] M stands for sodium. Explanation of the process

[0017] The reaction conditions for the preparation of compounds of general formula (I) are explained in detail below.

[0018] Scheme 1 The compounds of general formula (II) react with compounds of general formula (III) in the presence of IVlO'Bu to form cyclization products of general formula (IV), which undergo dealkoxycarbonylation under non-hydrolytic conditions and react to form compounds of general formula (I).

[0019] After cyclization, in addition to the actual product, the compounds of general formula (IV), the reactant of general formula (III) and the intermediate of general formula (V) may also be contained in the reaction mixture.

[0020] The compounds of general formula (II) and (III) are commercially available. Surprisingly, the compounds of general formula (III) can be used as the / or Z isomer. This is not known from the literature. Under the reaction conditions, isomerization between the Z and / isomers occurs.

[0021] The compounds of general formula (I) possess a stereocenter. Consequently, the product exists in the form of a racemate.

[0022] Cyclization:

[0023] The cyclization is known from the state of the art and is carried out using NaH or sodium powder (Helv. Chim. Acta 1959, 1177; WO 2016 / 205633). These reagents are not suitable for large-scale synthesis because their safe handling on a large scale is difficult.

[0024] The yield of the process according to the invention is higher (> 30%) than that of the prior art process using NaH or sodium powder (< 30%). Furthermore, the reaction is also suitable for industrial scale use due to the presence of the / c / V-butoxide base.

[0025] The slow addition of IMO'Bu is advantageous for achieving a high yield.

[0026] Preferably, MOtBu is added over 0.5 to 8 hours, particularly preferably over 3 to 5 hours.

[0027] The molar ratio of MOtBu relative to compounds of general formula (II) is 0.8 to 3 equivalents, preferably 0.9 to 1.2 equivalents.

[0028] The molar ratio of compounds of general formula (II) to compounds of general formula (III) is 0.8 to 3 equivalents, preferably 0.9 to 1.2 equivalents. The temperature can be varied within a wide range and depends, for example, on the solvent. It is preferably 0°C to 70°C for the reaction, most preferably 40°C to 60°C.

[0029] The reaction is usually carried out in a solvent, preferably THF, toluene, or MeTHF. The solvent is preferably an anhydrous ("dry" or absolute) solvent.

[0030] Dealkoxycarbonylation (Organic Reactions, Vol 81):

[0031] While ester cleavage / decarboxylation to 4-oxotetrahydrofurancarboxylic acid occurs with sulfuric acid in water (see Helv. Chim. Acta 1959, 1177; WO 2016 / 205633), under non-hydrolytic, e.g., anhydrous, reaction conditions, the ester can remain in compounds of general formula (I), so that the additional step of re-esterification, which is carried out in the prior art with CH2N2, can be omitted. This also eliminates the numerous extractions of 4-oxotetrahydrofurancarboxylic acid required in the prior art, which is difficult to isolate from water.

[0032] The yield can be significantly increased (>95% compared to 75% with sulfuric acid in the state of the art). Toxic reagents such as diazomethane can be dispensed with.

[0033] The reagent (see Table 1) is used in excess, optionally in combination with a solvent. Preferably, the reagent is also used as a solvent.

[0034] The reaction temperature depends on the reagent or solvent. Table 1 lists some of these reaction conditions as examples, but is not limited to these.

[0035] Table 1: Dealkoxycarbonylation

[0036] Examples

[0037] The present invention is explained in more detail with reference to the following examples, without limiting the invention to them.

[0038] Measurement method

[0039] The products were characterized by 'H-NMR.

[0040] Example 1 Methyl 4-oxotetrahydrofuran 2,3-dicarboxylate

[0041] 108 g of methyl glycolate (1.2 mol) and 172 g of dimethyl maleate (1.2 mol) are placed in a 2 l kettle with a heating / cooling jacket along with 800 mL of THF. The mixture is heated to 50°C, and then a solution of 120 g of NaO'Bu (1.25 mol) in 800 mL of THF is added over 3 hours. During the first few minutes, the internal temperature rises to 53°C and then remains at 50°C. After adding approximately 15% of the base, the reaction mixture becomes cloudy and a solid precipitates. After the end of the base addition, the reaction mixture is stirred for another 1 hour at 50°C and then cooled to -1°C. 215 g of acetic acid (3.6 mol) is added over 20 minutes. The temperature of the reaction mixture rises to 6°C. The reaction mixture is then cooled to 1°C, and 47.1 g of HCl gas is introduced below the surface over 45 minutes. The temperature of the reaction mixture rises to 8.5°C.The solvent THF is removed by distillation at a pressure of 50 mbar and a temperature of 50°C. An oil remains.

[0042] Methyl 4-oxotetrahydrofuran-2-carboxylate. The oil from the previous reaction step is added to 200 ml of acetic acid, and the resulting solid is filtered off. The filtrate is heated to 118°C for 6 hours. The acetic acid is then distilled off at 50°C and a pressure of 4 mbar. The product is purified by distillation. The product is an oil (87.4 g, 46% yield). ^-NMR (600MHZ, DMSO-d6): d (ppm) = 4.97 (dd, J= 8.8, 5.1 Hz, 1H), 4.02 (d, J= 16.7 Hz, 1H), 3.99 (d, J= 16.7 Hz, 1H), 3.69 (s, 3H), 2.88 (dd, J= 18.2, 8.8 Hz, 1H), 2.60 (dd, J= 18.2, 5.1 Hz, 1H).

[0043] Table 2: Comparison of yield

Claims

Patent claims:

1. Method for the preparation of compounds of general formula (I) (I) wherein R 1 (Ci-C4)-alkyl is characterized in that compounds of the general formula (II) in which R 2 (Ci-C4)-Alkyl is, with compounds of the general formula (III) (III), wherein R 1 as defined above, by adding MO'Bu, wherein M is an alkali metal ion Cyclization products using the general formula (IV) yield (IV) wherein R 1 as defined above, which under non-hydrolytic conditions undergo dealkoxycarbonylation and react to form compounds of general formula (I).

2. Method according to claim 1, characterized in that the residue definitions for the compounds of the general formulas (I), (II), (III), (IV) and IYlO'Bu are the following: R 1 stands for ethyl or methyl, R 2 stands for ethyl or methyl, M stands for sodium or potassium.

3. Method according to claim 1, characterized in that the residue definitions for the compounds of the general formulas (I), (II), (III), (IV) and IVlO'Bu are the following: R 1 stands for Methyl, R 2 stands for methyl, M stands for sodium.

4. Method according to one of claims 1 to 3, characterized in that the cycling is carried out at 0°C to 70°C.

5. Method according to one of claims 1 to 3, characterized in that the cycling is carried out at 40°C to 60°C.

6. Method according to any one of claims 1 to 5, characterized in that the solvent is cyclized THF, toluene or Me-THF.

7. The method of claim 6, characterized in that anhydrous solvent is used for the cyclization.

8. The method of any one of claims 1 to 7, characterized in that MO'Bu is used in the Cyclization is added over 0.5 to 8 hours.

9. Method according to one of claims 1 to 8, characterized in that MO'Bu is added during cyclization.

10. Method according to any one of claims 1 to 9, characterized in that the reagent or solvent for the dealkoxycarbonylation is AcOH.