Preparation method of 4-oxotetrahydrofuran-2-carboxylic alkyl ester

Abstract

This invention relates to a novel method for preparing alkyl 4-oxotetrahydrofuran-2-carboxylic acid esters (I).

Description

[0001] This invention relates to a novel method for preparing alkyl 4-oxotetrahydrofuran-2-carboxylic acid esters (I).

[0002] Methyl 4-oxotetrahydrofuran-2-carboxylic acid of formula (I) is an important precursor for active substances in agrochemicals (see WO2018 / 228985).

[0003] The synthesis of methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I) is known from, for example, Helv. Chim. Acta 1959, 1177 and WO 2016 / 205633. However, if dimethyl (Z)-butenedioic acid is used as the starting material, the preparation of methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I) requires three steps, accompanied by yield loss. Furthermore, the reagents used in the prior art (e.g., sodium powder, NaH, TMSCHN2, CH2N2) are unsuitable for industrial-scale synthesis because these chemicals are difficult to handle safely on a large scale or are highly toxic.

[0004] In view of the above-mentioned prior art, the object of the present invention is to develop a method for preparing compounds of general formula (I) that is also suitable for large-scale production, starting from compounds of general formulas (II) and (III) and involving only two reaction steps.

[0005] The above objective is achieved by a method for preparing compounds of general formula (I).

[0006]

[0007] in

[0008] R 1 It is an (C1-C4) alkyl group.

[0009] The compound characterized by general formula (II)

[0010]

[0011] in

[0012] R 2 It is an (C1-C4) alkyl group.

[0013] and compounds of general formula (III)

[0014]

[0015] Where R 1 As defined above,

[0016] By adding MO t Bu,

[0017] in

[0018] M is an alkali metal ion.

[0019] Cyclic products of general formula (IV) are generated

[0020]

[0021] Where R 1 As defined above,

[0022] It undergoes dealkyloxycarbonylation under non-hydrolytic conditions and reacts to form a compound of general formula (I).

[0023] Preferred General formula (I), (II), (III), (IV) and MO t The functional groups of Bu compounds are defined as follows:

[0024] R 1 It is ethyl or methyl.

[0025] R 2 It is ethyl or methyl.

[0026] M represents sodium or potassium.

[0027] Specially Selected General formula (I), (II), (III), (IV) and MO t The functional groups of Bu compounds are defined as follows:

[0028] R 1 It is methyl.

[0029] R 2 It is methyl.

[0030] M stands for sodium.

[0031] Method Description

[0032] The reaction conditions for preparing compounds of general formula (I) will be described in detail below.

[0033] Option 1

[0034]

[0035] in MO t In the presence of Bu, compounds of general formula (II) and general formula (III) react to form a cyclized product of general formula (IV), which undergoes dealkyloxycarbonylation under non-hydrolytic conditions and reacts to form a compound of general formula (I).

[0036] After the cyclization reaction, in addition to the actual product, namely the compound of general formula (IV), the reaction mixture may also contain residual reactants of general formula (III) and intermediates of general formula (V).

[0037] Compounds of general formulas (II) and (III) are commercially available. Surprisingly, compounds of general formula (III) can be used as either the E or Z isomer. This is unknown in the literature. Under the reaction conditions, isomerization occurs between the E and Z isomers.

[0038] Compounds of general formula (I) have a stereocenter. Therefore, the product exists in racemic form.

[0039] Cycloning:

[0040] Cyclization is known in the prior art, where it is carried out using NaH or sodium powder (Helv. Chim. Acta 1959, 1177; WO 2016 / 205633). These reagents are not suitable for industrial-scale synthesis because they are difficult to handle safely on a large scale.

[0041] The yield of the method of the present invention (>30%) is higher than that of the prior art methods using NaH or sodium powder (<30%). Furthermore, the use of tert-butoxide base means that the reaction can also be applied on an industrial scale.

[0042] Slowly add MO t Bu is not conducive to obtaining a high yield.

[0043] Join MO t Bu Preferred Perform for 0.5 to 8 hours. More 3 to 5 hours.

[0044] MO t The molar ratio of Bu to compounds of general formula (II) is 0.8 to 3 equivalents. Preferred 0.9 to 1.2 equivalents.

[0045] The molar ratio of compounds of general formula (II) to compounds of general formula (III) is 0.8 to 3 equivalents. Preferred 0.9 to 1.2 equivalents.

[0046] Temperature can vary over a wide range and depends on factors such as the solvent. Reaction Preferred 0℃ to 70℃ Very special Other preferred 40℃ to 60℃.

[0047] The reaction usually takes place in a solvent. Preferred In THF, toluene, or Me-THF. Preferred Anhydrous ("dry" or pure) solvent.

[0048] Dealkylation carbonylation (Organic Reactions, vol. 81):

[0049] When using an aqueous sulfuric acid solution (see Helv. Chim. Acta 1959, 1177; WO 2016 / 205633), ester bond cleavage / decarboxylation occurs to form 4-oxotetrahydrofurancarboxylic acid, while the ester bond of compounds of general formula (I) is preserved under non-hydrolytic (e.g., anhydrous) reaction conditions, meaning that no additional re-esterification step is required (achieved in the prior art by CH2N2). Therefore, the numerous extraction steps for 4-oxotetrahydrofurancarboxylic acid (which is difficult to separate from water) required in the prior art are also unnecessary.

[0050] The yield can thus be significantly increased (>95% compared to 75% using sulfuric acid in existing technologies). Toxic reagents such as diazomethane can be discarded.

[0051] The reagent (see Table 1) may be used in excess, and optionally in combination with the solvent. Preferably The reagent is also used as a solvent.

[0052] The reaction temperature depends on the reagent / solvent.

[0053] Table 1 lists some examples of reaction conditions, but there are no restrictions on them.

[0054] Table 1: Dealkyloxycarbonylation

[0055] Example

[0056] The present invention is described in more detail through the following embodiments, but is not intended to limit the invention thereto.

[0057] Measurement methods

[0058] The product passes through 1 H NMR characterization.

[0059] Example 1

[0060]

[0061] Dimethyl 4-oxotetrahydrofuran-2,3-dicarboxylic acid ester

[0062] 108 g of methyl glycolate (1.2 mol), 172 g of dimethyl maleate (1.2 mol), and 800 mL of THF were added to a 2 L container equipped with a heating / cooling jacket. The mixture was heated to 50 °C, and then 120 g of NaO was added over 3 hours. tBu (1.25 mol) was dissolved in 800 mL of a solution prepared with THF. The internal temperature rose to 53 °C in the first few minutes and was maintained at 50 °C. After adding approximately 15% alkali, the reaction mixture became turbid and a solid precipitated. After the alkali addition was complete, the reaction mixture was stirred at 50 °C for 1 hour and then cooled to -1 °C. Then, 215 g of acetic acid (3.6 mol) was added over 20 minutes. The reaction mixture was heated to 6 °C. The reaction mixture was then cooled to 1 °C, and 47.1 g of HCl gas was passed under the liquid surface over 45 minutes. The reaction mixture was heated to 8.5 °C. The solvent THF was removed by distillation at 50 mbar and 50 °C, yielding an oily substance.

[0063] 4-Oxotetrahydrofuran-2-carboxylic acid methyl ester

[0064] The oily residue from the previous reaction was added to 200 mL of acetic acid, and the resulting solid was filtered off. The filtrate was heated to 118 °C and maintained for 6 hours. Then, the acetic acid was removed by distillation at 50 °C and 4 mbar. The product was purified by distillation. The product was an oily residue (87.4 g, 46%).

[0065] 1 H NMR (600MHz, DMSO-d6): δ (ppm) = 4.97 (dd, J = 8.8, 5.1Hz, 1H), 4.02 (d, J = 16.7Hz, 1H), 3.99 ( d,J=16.7Hz,1H),3.69(s,3H),2.88(dd,J=18.2,8.8Hz,1H),2.60(dd,J=18.2,5.1Hz,1H).

[0066] Table 2: Yield Comparison

[0067]

[0068]

Claims

1. Method for preparing compounds of general formula (I) in R 1 It is an (C1-C4) alkyl group. Its features Compounds of general formula (II) in R 2 It is an (C1-C4) alkyl group. and compounds of general formula (III) Where R 1 As defined above, By adding MO t Bu, in M is an alkali metal ion. Cyclic products of general formula (IV) are generated Where R 1 As defined above, It undergoes dealkyloxycarbonylation under non-hydrolytic conditions and reacts to form a compound of general formula (I). The reagent / solvent for dealkyloxycarbonylation is AcOH.

2. The method according to claim 1, characterized in that... General formula (I), (II), (III), (IV) and MO t The functional groups of Bu compounds are defined as follows: R 1 It is ethyl or methyl. R 2 It is ethyl or methyl. M represents sodium or potassium.

3. The method according to claim 1, characterized in that... General formula (I), (II), (III), (IV) and MO t The functional groups of Bu compounds are defined as follows: R 1 It is methyl. R 2 It is methyl. M stands for sodium.

4. The method according to any one of claims 1 to 3, characterized in that... Cycloning is carried out at temperatures ranging from 0°C to 70°C.

5. The method according to any one of claims 1 to 3, characterized in that... Cyclization is carried out at 40°C to 60°C.

6. The method according to any one of claims 1 to 3, characterized in that... The solvent for the cyclization reaction is THF, toluene, or Me-THF.

7. The method according to claim 6, characterized in that... The cyclization reaction uses anhydrous solvents.

8. The method according to any one of claims 1 to 3, characterized in that... MO was added during the cyclization process over 0.5 to 8 hours. t Bu.

9. The method according to any one of claims 1 to 3, characterized in that... Metered addition of MO during cyclization t Bu.

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