Process for preparing alkyl-3-hydroxy-2-methylene alkanoates

Abstract

The invention relates to a new process for preparing alkyl-3-hydroxy-2-methylene alkanoates of the general formula (I).

Description

[0001] BCS241013 Foreign text NR / ed 30.06.2025

[0002] - 1 -

[0003] Method for the preparation of alkyl-3-hydroxy-2-methylenealkanoates

[0004] The present invention relates to a new process for the preparation of alkyl-3-hydroxy-2-methylenealkanoates of general formula (I).

[0005] Alkyl-3-hydroxy-2-methylenealkanoates of general formula (I) are important precursors of agrochemical active ingredients (see WO 2018 / 228985).

[0006] Numerous methods for its preparation are described in the prior art, for example Chem. Rev 2010, 110, 5447-5674; J. Org. Chem 2003, 68, 692-700; J. Org. Chem 2010, 75, 8615-8626;

[0007] J. Org. Chem 2001, 66, 5413 - 5418; Tetrahedron 2014, 70, 97 - 102; US 2004 / 0176243 Al.

[0008] US 5 703 270 A describes a process for producing a vinyl compound with a hydroxy group by reacting a vinyl compound with an aldehyde.

[0009] When the compounds of the present invention are prepared using methods known from the literature, the resulting yields are insufficient for large-scale synthesis, or stoichiometric amounts of auxiliary substances are used in combination with high dilution by solvent or water. This results in reaction times of up to four days or more. This, too, is not advantageous for large-scale synthesis and, due to the low space-time yields, leads to high costs, among other things.

[0010] The invention was therefore based on the objective of providing a process for the production of alkyl-3-hydroxy-2-methylenealkanoates of general formula (I) which is suitable for large-scale synthesis and has a high yield in the shortest possible time.

[0011] The problem was solved by a process for the preparation of alkyl-3-hydroxy-2-methylenealkanoates of general formula (I)

[0012] (I) wherein

[0013] R 1 H, Ci-Ce-Alkyl ist, BCS241013 Foreign text NR / ed 30.06.2025

[0014] R 2 Ci-C4-alkyl is characterized in that the compounds of the general formula (II)

[0015] (H), with compounds of the general formula (III)

[0016] (HI), with the addition of:

[0017] - a tertiary amine catalyst and an alcohol of general formula (IV) R 3 OH or

[0018] - a tertiary amine catalyst and H2O or

[0019] - a tertiary amine catalyst and an alcohol of general formula (IV) R 3 OH and H2O react, whereby

[0020] R 1 and R 2 the above-mentioned meanings and

[0021] R 3 Ci-Co-alkyl is.

[0022] Preferred residue definitions for the compounds of general formulas (I), (II), (III) and (IV) are the following:

[0023] R 1 is methyl, ethyl, z-propyl, z-butyl,

[0024] R 2 is Methyl, Ethyl,

[0025] R 3 is Ci-C4 alkyl.

[0026] Particularly preferred residual definitions for the compounds of general formulas (I), (II),

[0027] (III) and (IV) are the following:

[0028] R 1 is Methyl, z-Propyl, z-Butyl, BCS241013 Foreign text NR / ed 30.06.2025

[0029] R 2 is methyl

[0030] R 3 is Ci-C4 alkyl.

[0031] Particularly preferred residue definitions for the compounds of the general formulas (I),

[0032] (II), (III) and (IV) are the following:

[0033] R 1 is methyl, z-butyl,

[0034] R 2 is methyl

[0035] R 3 is Ci-C4 alkyl.

[0036] Most preferred residue definitions for the compounds of general formulas (I), (II),

[0037] (III) and (IV) are the following:

[0038] R 1 is methyl

[0039] R 2 is methyl

[0040] R 3 is methyl.

[0041] According to the invention, a process for the preparation of alkyl-3-hydroxy-2-methylenealkanoates of general formula (I) worm

[0042] R 1H, Ci-Co-alkyl is,

[0043] R 2 Ci-C4-alkyl is characterized in that the compounds of the general formula (II) BCS241013 Foreign text NR / ed 30.06.2025

[0044] (II), with compounds of the general formula (III) with the addition of a tertiary amine catalyst, an alcohol of the general formula (IV) R 3 OH and H2O react, with the molar ratio of alcohol to water being 3:1 to 1:3, R 1 and R 2 the above-mentioned meanings and

[0045] R 3 Ci-Co-alkyl is.

[0046] Explanation of the processes and intermediate product

[0047] Scheme 1

[0048] The problem was solved by a process for the preparation of alkyl-3-hydroxy-2-methylenealkanoates of general formula (I) characterized in that the compounds of general formula (II) are reacted with compounds of general formula (III) with the addition of a tertiary amine catalyst, an alcohol of general formula (IV) R 3 OH and H2O react, with the molar ratio of alcohol to water being 3:1 to 1:3.

[0049] R 1 and R 2 the above-mentioned meanings and

[0050] R 3 Ci-Cö-Alkyl is. BCS241013 Foreign text NR / ed 30.06.2025

[0051] - 5 -

[0052] The combinations of formula (II) and (III) are known from the literature, e.g. from the references cited in the introduction.

[0053] Examples of tertiary amine catalysts that can be used include: triethylenediamine (DABCO), 3-quinuclidinol (3-hydroxyquinuclidine), quinuclidine, PPhs, DBU and combinations of these amine catalysts.

[0054] The use of triethylenediamine, quinuclidine, and 3-quinuclidinol, or mixtures thereof, is preferred. The use of triethylenediamine is particularly preferred.

[0055] The use of 0.1 to 0.4 equivalents (eq) of the tertiary amine catalyst is preferred, based on 1 equivalent of the compounds of general formula (II).

[0056] Particularly preferred is the use of 0.15 to 0.25 equivalents of the tertiary amine catalyst based on 1 equivalent of the compounds of general formula (II).

[0057] The ratio of the compounds of general formula (III) and (II) to each other can vary. Preferably, 1 to 2 equivalents of the compounds of general formula (III) are used in relation to 1 equivalent of the compounds of general formula (II), particularly preferably 1 to 1.5 equivalents of the compounds of formula (III) in relation to 1 equivalent of the compounds of general formula (II), and most particularly preferably 1 to 1.3 equivalents of the compounds of general formula (III) in relation to 1 equivalent of the compounds of general formula (II).

[0058] The cycling is usually carried out in a temperature range of 0°C to 70°C, preferably 10°C to 50°C.

[0059] Furthermore, the cyclization is carried out in the presence of a solvent or diluent or a combination thereof, namely an alcohol of the general formula (IV) R 3OH and / or water. Preferably, methanol and / or water are used. The combination of methanol and water is particularly preferred.

[0060] In a combination of alcohol of the general formula (IV) R 3 A wide range of ratios between water and alcohol is possible. Mixtures of water and an alcohol of the general formula (IV) R are preferred. 3 OH selected in ratios between 100:1 and 1:100, particularly preferably between 10:1 and 1:10, and most preferably between 3:1 and 1:3 based on the ratio of water to alcohol. BCS241013 Foreign text NR / ed 30.06.2025

[0061] - 6 -

[0062] The combination of methanol and water in a molar ratio of 3:1 to 1:3 is particularly preferred.

[0063] Examples

[0064] The present invention will be explained in more detail with reference to the following examples, without limiting the invention to these.

[0065] Measurement methods

[0066] The products were characterized using 'H-NMR spectroscopy and / or LC / MS (Liquid Chromatography Mass Spectrometry).

[0067] The NMR spectra were determined using a Bruker Avance 400 equipped with a flow-through sampler (60 pl volume). In some cases, the NMR spectra were measured using a Bruker Avance II 600.

[0068] Example 1: Synthesis of rac-methyl-3-hydroxy-2-methylene-butanoate (1-1)

[0069] 59.8 g (0.51 mol, 0.18 eq) of 1,4-diazabicyclo[2.2.2]octane were dissolved in 46.5 g of methanol and treated with 250 g (2.87 mol, 1.0 eq) of methyl acrylate. At 15–20 °C, a solution of 152.7 g (3.45 mol, 1.2 eq) of acetaldehyde in 24.6 g of water, cooled to 5 °C, was added over 15 min. After complete addition, the reaction was stirred at 30 °C for 24 h. After removal of the methanol by distillation, the pH was adjusted to 3 with 160 g of 20% hydrochloric acid, and the solution was extracted three times with 100 mL of tert-butyl methyl ether each time. The collected organic extracts were combined, washed once with 100 g of aqueous sodium bicarbonate solution, and the solvent was removed by distillation. After azeotropic drying of the residue with toluene, 325.1 g (94.9 wt%, 82% yield) were obtained as a colorless liquid.

[0070] 'H-NMR (400 MHz, CDCh): 6.22 (m, 1H), 5.84 (m, 1H), 4.62 (quint. 1H), 3.79 (s, 3H), 2.74 (br s, 1H) 1.39 (s, 3H) ppm.

[0071] Example 2: Preparation of rac-methyl 3-hydroxy-2-methylene butanoate (1-1)

[0072] In a 1 L reactor under nitrogen, 24.6 g of water (0.48 eq.) and 46.5 g of methanol (0.5 eq.) were placed at 20 °C, and 59.8 g of triethylenediamine (DABCO, 0.18 eq.) were dissolved therein. Subsequently, 115.0 g of methyl acrylate (1.33 mol. 0.46 eq.) were added, followed by BCS241013 Foreign Text NR / ed 30.06.2025

[0073] - 7 - A mixture of 135.0 g methyl acrylate (1.55 mol, 0.54 eq.) and 152.7 g acetaldehyde (1.2 eq.) was added at 10-20 °C for 1 h. The mixture was then heated to 30 °C and stirred at this temperature for 24 h. Subsequently, the solution was cooled to 0-5 °C and 200.0 g of 30 wt% aqueous sulfuric acid were added, and the pH was adjusted to 1. The phases were separated, the lower aqueous phase was extracted three times with 100 mL of tert-butyl methyl ether (MTBE) each time, and the combined organic phases were then washed with a 20 wt% aqueous potassium bicarbonate solution at pH 7. After phase separation and distillation removal of the solvent and water, the product was isolated as a colorless oil: 323.3 g (95.4 wt.%, yield 82%).

[0074] Example 3: Preparation of rac-methyl 3-hydroxy-2-methylene butanoate (1-1)

[0075] In a 1 L reactor under nitrogen, 93.1 g of methanol (1.0 eq) were placed at 20 °C and 59.8 g of triethylenediamine (DABCO, 0.18 eq) were dissolved therein. Subsequently, 250.0 g of methyl acrylate (2.87 mol, 1.0 eq) were added, followed by a mixture of 152.7 g of acetaldehyde (1.2 eq) in 49.2 g of water (0.95 eq) over 1 h at 0 °C. The mixture was then heated to 30 °C and stirred at this temperature for 24 h. Subsequently, at 20 °C, pH was adjusted to 3 with 167.0 ml of 20 wt% aqueous hydrochloric acid, and the aqueous phase was extracted three times with 100 mL of tert-butyl methyl ether (MTBE) each time. The combined organic phases were then washed with an 8 wt% aqueous sodium bicarbonate solution at pH 7. After phase separation and removal of the solvent and water by distillation, the product was isolated as a colorless oil: 338.6 g (88.6 wt%, yield 80%).

[0076] Example 4: Preparation of rac-Isobutyl 3-hydroxy-2-methylene-butanoate (1-2)

[0077] In a 500 mL reactor under nitrogen, 15.5 g of triethylenediamine (DABCO, 0.20 eq) was placed. Subsequently, 90 g of isobutyl acrylate (686.7 mmol, 1.0 eq), 31 g of butanol (0.60 eq), and 3.7 g of water (0.30 eq) were added successively and the mixture was cooled in a water bath to 10–20 °C. Then, 40 g of acetaldehyde (1.3 eq) was added over 20 minutes. The mixture was then heated to 40 °C and stirred at this temperature for 3 days.

[0078] The solution was then cooled to room temperature and treated with 200 mL of tert-butyl methyl ether (MTBE) and 150 mL of 2M HCl, and pH adjusted to 1. The phases were separated, and the lower aqueous phase was extracted twice with 200 mL of MTBE each time. After phase separation and removal of the solvent and water by distillation, the product was isolated as a colorless oil: 107 g (96 wt.%, yield 87%). BCS241013 Foreign text NR / ed 30.06.2025

[0079] - 8 -

[0080] ' H NMR (600 MHz, CDC13) ö (ppm): 6.20 (s, 1H), 5.80 (s, 1H), 4.60 q, J = 6.5 Hz, 1H), 3.95 (d, J = 6.6 Hz, 2H), 2.85 (s, 1H), 2.03 - 1.92 (m, 1H), 1.37 (d, J= 6.5 Hz, 3H), 0.94 (d, J= 6.8 Hz, 6H).

[0081] 13 C (151 MHz, CDCh) ö (ppm): 166.77, 143.87, 123.94, 70.99, 67.34, 27.85, 22.21, 19.22.

[0082] Table 1

[0083] Turnover after HPLC after 24 h at 20 °C

[0084] Table 2

[0085] Reactions with 1.1 eq acetaldehyde. Conversion by HPLC after 18 h at 20 °C

[0086] Table 3

[0087] Reactions with 20 mol% DABCO, 40 °C, 1.3 eq acetaldehyde. Conversion by HPLC BCS241013 Foreign text NR / ed 30.06.2025

[0088] -9-

Claims

BCS241013 Foreign text NR / ed 30.06.2025 Patent claims:

1. Process for the preparation of alkyl-3-hydroxy-2-methylenealkanoates of general Formula (I) (I) wherein R 1 H, Ci-Ce-alkyl is, R 2 Ci-C4-alkyl is characterized in that the compounds of the general formula (II) (H), with compounds of the general formula (III) (HI), upon addition of a tertiary amine catalyst, an alcohol of general formula (IV) R 3 OH and H2O react, with the molar ratio of alcohol to water being 3:1 to 1:3, R 1 and R 2 the above-mentioned meanings and R 3 Ci-Co-alkyl is. BCS241013 Foreign text NR / ed 30.06.2025 - 11 - 2. The method of claim 1, wherein the residue definitions for the compounds of general formulas (I), (II), (III) and (IV) are as follows: R 1 is methyl, ethyl, z-propyl, z-butyl, R 2 is Methyl, Ethyl, R 3 is Ci-C4 alkyl.

3. Method according to any one of claims 1 to 2, wherein the residue definitions for the compounds of general formulas (I), (II), (III) and (IV) are as follows: R 1 is methyl, z-propyl, z-butyl, R 2 is methyl R 3 is Ci-C4 alkyl.

4. Method according to any one of claims 1 to 3, wherein the residue definitions for the compounds of general formulas (I), (II), (III) and (IV) are as follows: R 1 is methyl, z-butyl, R 2 is methyl R 3 is Ci-C4 alkyl.

5. Method according to any one of claims 1 to 4, wherein the residue definitions for the compounds of general formulas (I), (II), (III) and (IV) are as follows: R 1 is methyl R 2 is methyl R 3 is methyl.

6. Method according to any one of claims 1 to 5, characterized in that 0.1 to 0.4 equivalents of tertiary amine catalyst are used based on 1 equivalent of the compound of general formula (II).

7. Method according to any one of claims 1 to 5, characterized in that 0.15 to 0.25 equivalents of tertiary amine catalyst based on 1 equivalent of the compound of general formula (II) are used. BCS241013 Foreign text NR / ed 30.06.2025 - 12 - 8. A method according to any one of claims 1 to 7, characterized in that the solvent is a combination of methanol and water in a molar ratio of 3:1 to 1:3, wherein the tertiary amine catalyst is DABCO.

9. Method according to any one of claims 1 to 8, characterized in that the reaction is carried out at 10°C to 50°C.

10. Method according to any one of claims 1 to 7, characterized in that the tertiary amine catalyst is DABCO.

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