Method for preparing alkyl 4-oxotetrahydrofuran-2-carboxylates

Abstract

The present invention relates to a novel process for the preparation of alkyl 4-oxotetrahydrofuran-2-carboxylates (I). JPEG2024509536000014.jpg36170

Description

[Technical Field]

[0001] The present invention relates to a novel process for the preparation of alkyl 4-oxotetrahydrofuran-2-carboxylates (I). [Background technology]

[0002] Methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I) is an important precursor of pesticide (see WO 2018 / 228985) active substances.

[0003] The synthesis of methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I) is known, for example, from Helv. Chim. Acta 1959, 1177 and WO 2016 / 205633. However, when starting from dimethyl (Z)-butenedioate, three reaction steps are required to prepare methyl 4-oxotetrahydrofuran-2-carboxylate of formula (I), which results in a reduced yield. Furthermore, the reagents used in the prior art (e.g., sodium powder, NaH, TMSCHN2, CH2N2) are not suitable for industrial-scale synthesis. This is because these chemicals are difficult to handle safely on a large scale or are highly toxic. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2018 / 228985 [Patent Document 2] International Publication No. 2016 / 205633 [Non-patent literature]

[0005] [Non-Patent Document 1] Helv.Chim.Acta 1959, 1177 Summary of the Invention [Problem to be solved by the invention]

[0006] In light of the above prior art, it is an object of the present invention to develop a process for the preparation of compounds of general formula (I) starting from compounds of general formula (II) and (III) in only two reaction steps, which is also suitable for large-scale production. [Means for solving the problem]

[0007] The above object is to provide a compound represented by the general formula (I) [ka] (In the formula, R 1 is (C1-C4) alkyl) A method for preparing a compound of general formula (II) [ka] (In the formula, R 2 is (C1-C4) alkyl) is a compound of the general formula (III) [ka] (In the formula, R 1 is as defined above), and MO-Z in Z-OH. (wherein M is an alkali metal ion, Z is (C1-C4) alkyl, excluding t-butyl), to form a compound of general formula (IV) [ka] (In the formula, R 1 is as defined above), This is achieved by a process which is characterized by reacting via dealkoxycarbonylation under non-hydrolytic conditions to form a compound of general formula (I).

[0008] Preferred definitions of the radicals of the compounds of general formulae (I), (II), (III), (IV), MO-Z, and Z-OH are as follows: R 1 is ethyl or methyl, R 2 is ethyl or methyl, M is sodium or potassium; Z is ethyl or methyl.

[0009] Particularly preferred definitions of the radicals of the compounds of general formulae (I), (II), (III), (IV), MO-Z and Z-OH are as follows: R 1 is methyl, R 2 is methyl, M is sodium, Z is methyl.

[0010] Instructions: The reaction conditions for preparing the compounds of general formula (I) are described in detail below. Scheme 1 [ka]

[0011] Compounds of general formula (II) react with compounds of general formula (III) in the presence of MO-Z in Z-OH to form cyclized products of general formula (IV), which react via dealkoxycarbonylation under non-hydrolytic conditions to form compounds of general formula (I).

[0012] During cyclization, in addition to the actual product, residual intermediates of general formulas (V) and (VI) may also be present in the reaction mixture along with the compound of general formula (IV), which will react further under the given reaction conditions to form the product of general formula (IV).

[0013] The compounds of general formula (II) and (III) are commercially available. Surprisingly, the compounds of general formula (III) can be used in the form of E or Z isomers, with equivalent results. This is not known from the literature. Under the reaction conditions, isomerization between E and Z isomers occurs.

[0014] The compounds of general formula (I) have a stereocenter, so that the products exist in racemic form.

[0015] Cyclization: The cyclization is known from the prior art and is carried out using NaH or sodium powder (Helv. Chim. Acta 1959, 1177; WO 2016 / 205633). These reagents are difficult to handle safely on a large scale and are therefore not suitable for industrial-scale synthesis.

[0016] The yield of the reaction according to the invention is higher (more than 30%) than the yields of the reactions described in the prior art using NaH or sodium powder (less than 30%). Furthermore, the use of an alkoxide base means that the reaction can be used on an industrial scale.

[0017] To achieve high yields, the advantage is the slow addition of the alkoxide base, for example by metered addition.

[0018] Furthermore, when used as a solvent, and the alcohol further formed during cyclization is removed by distillation, the equilibrium of the reaction to form the product can be shifted, increasing the yield.

[0019] The molar ratio of MO-Z to the compound of general formula (II) is 0.8 to 3 equivalents, preferably 0.9 to 1.2 equivalents.

[0020] The molar ratio of Z-OH to the compound of general formula (II) is 1 to 10 equivalents, preferably 4 to 7 equivalents.

[0021] The molar ratio of the compound of general formula (II) to the compound of general formula (III) is 0.8 to 3 equivalents, preferably 0.9 to 1.2 equivalents.

[0022] The reaction temperature may vary within a wide range and is determined, for example, depending on the solvent. The reaction is preferably carried out at 15 to 70°C, particularly preferably 40 to 60°C.

[0023] The reaction is usually carried out in a solvent, preferably anisole, THF, toluene, xylene, or Me-THF. The solvent may contain Z-OH. Preferably, this is an anhydrous ("dry" or pure) solvent.

[0024] Dealkoxycarbonylation (Organic Reactions, Vol. 81): When an aqueous solution of sulfuric acid is used (see Helv. Chim. Acta 1959, 1177; WO 2016 / 205633), ester cleavage / decarboxylation to 4-oxotetrahydrofuran-2-carboxylic acid occurs under non-hydrolytic reaction conditions, such as anhydrous reaction conditions, while the ester in the compound of general formula (I) remains. This means that an additional step of new esterification using CH2N2, as in the prior art, is not necessary. As a result, there is no need for repeated extraction of 4-oxotetrahydrofuran-2-carboxylic acid, which is difficult to isolate from water, as is required in the prior art.

[0025] As a result, yields can be substantially increased (over 95% compared to 75% using sulfuric acid in the prior art) and the use of toxic reagents such as diazomethane can be avoided.

[0026] The reagents (see Table 1) are used in excess, optionally in combination with a solvent. Preferably, the reagents are also used as solvents.

[0027] The temperature of the reaction depends on the reagents / solvents.

[0028] Table 1 lists some of these reaction conditions by way of example, but not limitation.

[0029] [Table 1] [Example]

[0030] The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[0031] Measurement method The product 1 It was characterized by H-NMR.

[0032] Example 1 [ka] 4-Oxotetrahydrofuran-2,3-dicarboxylic acid methyl ester 356 g of methyl glycolate (3.95 mol) and 541 g of dimethyl maleate (3.75 mol) are added to a vessel (6 L) equipped with a heating / cooling jacket along with 2.175 L of anisole. The mixture is heated to 49°C, and then 783 g of 30% sodium methoxide (NaOMe = NaOmethyl) in methanol is added over 6 hours. The internal temperature rises to 55°C during the first few minutes and then remains at 50°C. After approximately 30% of the base has been added, the reaction mixture becomes cloudy and a solid precipitates. At the end of the base addition, a brownish suspension still remains that is easily stirrable. The reaction mixture is cooled to 20°C and stirred overnight. The next day, the reaction mixture is heated to 50°C (heating jacket at 55°C) and 849 g of methanol is removed by distillation over 6 hours at a pressure of 360 mbar (initial) to 60 mbar (final). The reaction mixture is then cooled to 20°C and stirred overnight. This reaction mixture is then added at 10°C to a mixture of dilute sulfuric acid prepared from 2.373 L of water and 225 g of concentrated sulfuric acid (2.17 mol) contained in a vessel (6 L) equipped with a heating / cooling jacket. The reaction mixture is stirred at 10-12°C for 2 hours and then warmed to 20°C. The biphasic mixture is then separated, and the aqueous phase is extracted with anisole. The combined organic phases are concentrated to 990 g.

[0033] 4-Oxotetrahydrofuran-2-carboxylic acid methyl ester The oil from the previous reaction step is added to 1200 mL of acetic acid. To this, 67.6 g of trifluoroacetic acid is added, and the reaction mixture is stirred at 115-118 °C for 24 hours. The acetic acid is then distilled off, and the product is purified by distillation. The product is an oil (350 g, 66% yield). NMR data 11H-NMR (600 MHz, DMSO-d6): δ (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).

[0034]

Table 2

Claims

1. General formula (I) 【Chemistry 1】 (In the formula, R 1 (C 1 ~C 4 ) alkyl) A method for preparing a compound of general formula (II) 【Chemistry 2】 (In the formula, R 2 (C 1 ~C 4 ) alkyl) is a compound of the general formula (III) 【Transformation 3】 (In the formula, R 1 is as defined above) and MO-Z in Z-OH (wherein M is an alkali metal ion, Z is (C 1 ~C 4 ) alkyl) to form a compound of general formula (IV) 【Chemistry 4】 (In the formula, R 1 is as defined above), which reacts under non-hydrolytic conditions via dealkoxycarbonylation to form a compound of general formula (I).

2. 2. The method according to claim 1, characterized in that the definitions of the groups of the compounds of general formulae (I), (II), (III), (IV), MO-Z and Z-OH are as follows: R 1 is ethyl or methyl, R 2 is ethyl or methyl, M is sodium or potassium; Z is ethyl or methyl.

3. 2. The method according to claim 1, characterized in that the definitions of the groups of the compounds of general formulae (I), (II), (III), (IV), MO-Z and Z-OH are as follows: R 1 is methyl, R 2 is methyl, M is sodium, Z is methyl.

4. In addition to the cyclization product having general formula (IV), intermediates (V) and (VI): 【Transformation 5】 (wherein R 1 , R 2 , and Z are as defined above).

4. The method according to claim 1, wherein R is a methyl group, R is a methyl group, and R is a methyl group.

5. 5. The process according to claim 1, wherein the alcohol Z-OH is removed by distillation during the cyclization reaction.

6. 6. The process according to any one of claims 1 to 5, characterized in that the cyclization is carried out at 15 to 70°C.

7. 6. The process according to any one of claims 1 to 5, characterized in that the cyclization is carried out at 40 to 60°C.

8. 8. The process according to claim 1, wherein the solvent for the cyclization is anisole, THF, toluene, xylene, or Me-THF.

9. 9. The method according to claim 8, characterized in that the solvent also comprises Z-OH, wherein Z is as defined in any one of claims 1 to 3.

10. 10. The process according to claim 8 or 9, characterized in that an anhydrous solvent is used for the cyclization.

11. 11. The method according to claim 1, wherein MO-Z in Z-OH is metered in.

12. 12. The process according to any one of claims 1 to 11, characterized in that NaO methyl is used for the cyclization.

13. 13. The process according to any one of claims 1 to 12, characterized in that the reagent / solvent in the dealkoxycarbonylation is acetic acid or consists of a mixture of acetic acid and trifluoroacetic acid.

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