A method for synthesizing β-ester-γ-butyrolactone

Abstract

This invention belongs to the field of chemical technology and discloses a method for synthesizing β-ester-γ-butyrolactone. Under the action of a copper catalyst, β-ester-γ-butyrolactone (I, II) is synthesized by reacting a Grignard reagent, an α,β-unsaturated dicarboxylic acid ester, and a ketone (reaction formulas 1 and 2). The use of a copper-Lewis acid composite catalyst system enables the acquisition of the target compound with higher diastereoselectivity. The Grignard reagent R of this invention... 1 MgX is easy to prepare, widely available, and cheaper than organozinc reagents; using composite catalysts significantly improves the diastereoselectivity of the product.

Description

Technical Field

[0001] This invention belongs to the field of chemical technology, specifically relating to a method for synthesizing β-ester-γ-butyrolactone. Background Technology

[0002] β-Ester-γ-butyrolactone can serve as an intermediate in the synthesis of compounds with important applications. The β-carboxy-γ-butyrolactone produced by hydrolysis exhibits antitumor, antibacterial, and antimicrobial activities. [1-3] .

[0003] In the literature, β-ester-γ-butyrolactone was synthesized by reacting the deprotonated intermediate of the substituted succinate with a carbonyl compound. [4-6] However, this requires strong alkali and low temperature conditions. Gall uses CoBr2 to catalyze the reaction between aryl halides, itaconic acid esters, and zinc to generate β-ester-γ-butyrolactone. [7] Its hydrolysis product, β-carboxy-γ-butyrolactone, has an inhibitory effect on the growth of nasopharyngeal carcinoma, colon cancer, breast cancer, and leukemia cells. [8] However, Gall's synthetic method is only applicable to reactions involving aryl halides (producing aryl anions), and the cyclization reaction requires a temperature of 60°C; while alkyl halides cannot form the corresponding β-ester-γ-butyrolactone. A 2014 Chinese patent discloses a method for generating β-carboxy-γ-butyrolactone by reacting a copper compound-catalyzed alkylating agent, maleate ester, and aldehyde / ketone. [9] In this method, the alkylating agent is either a pre-prepared alkyl zinc or alkyl zinc halide, or an alkyl zinc reagent formed in situ by reacting alkyl lithium with a stoichiometric zinc halide or a Grignard reagent with a stoichiometric zinc halide. However, this method suffers from high costs associated with alkyl zinc or requires stoichiometric zinc halides, and the reaction exhibits low diastereoselectivity. Therefore, further research into low-cost, high diastereoselective methods for synthesizing β-ester-γ-butyrolactone is of significant value.

[0004] References

[0005] [1] Blanc, D.; Madec, J.; Popowyck, F.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Adv. Synth. Catal. 2007, 349, 943.

[0006] [2] Barros, MT; Maycock, CD; Ventura, MROrg. Lett. 2003, 5, 4097.

[0007] [3] Jacobi, PA; Herradura, P. Tetrahedron Lett. 1996, 37, 8297.

[0008] [4] Blanc, D.; Madec, J.; Popowyck, F.; Ayad, T.; Phanavath, P.; Ratovelomanana-Vidal, V.; Genêt, JPAdv.Synth.Catal., 2007, 349, 943.

[0009] [5]Soorukram, D.; Yodwaree, S.; Tuchinda, P.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Arkivoc, 2012(ix)21.

[0010] [6] Pohmakotr, M.; Soorukram, D.; Tuchinda, P.; Prabbai, S.; Kongsaeree, P.; Reutrakul, V. Tetrahedron Lett., 2004, 45, 4315.

[0011] [7] Le Floch, C.; Le Gall, E.; Leonel, E.; Koubaa, J.; Martens, T.; Retailleau, P. Eur. J. Org. Chem. 2010, 27, 5279.

[0012] [8] Le Floch, C.; Le Gall, E.; Leonel, E.; Martens, T.; Cresteil, T. Bioorg. Med. Chem Lett. 2011, 21, 7054.

[0013] [9] Li Zhengning, Li Zhiqiang, Li Ruirui. A method for synthesizing β-hydroxyacyl-γ-hydroxy-γ-butyrolactone, ZL201410385205.6 (authorization announcement date: 2016.08.24), (application date: 2014.08.06). Summary of the Invention

[0014] This invention provides a method using Grignard reagents (R 1A method for synthesizing β-ester-γ-butyrolactone using MgX as an alkylating agent. β-ester-γ-butyrolactone (I, II) is synthesized by reacting Grignard reagents, α,β-unsaturated dicarboxylic esters, and ketones (reactions 1 and 2) under copper catalysis. The use of a copper-Lewis acid composite catalyst system allows for higher diastereoselectivity in obtaining the target compound.

[0015]

[0016] The method specifically involves adding a Grignard reagent to a mixture of ketone, α,β-unsaturated dicarboxylic acid ester, and copper catalyst, and stirring the mixture in an organic solvent for 0.5-2 hours.

[0017] Copper catalysts can be formed from copper salts and organophosphorus ligands in the reaction system or be pre-prepared copper-phosphorus complexes; or they can be composed of copper salts and Lewis acids.

[0018] Furthermore, the Grignard reagent has the structure R 1 MgX, where R 1 C 1-8 Alkyl groups; or phenyl, p-tolyl, m-tolyl, o-tolyl, p-methoxyphenyl; X = Cl, Br, I.

[0019] Furthermore, the α,β-unsaturated dicarboxylic acid esters include fumarate diester, maleate diester, and itaconic acid diester, wherein R 2 C 1-8 Hydrocarbon group.

[0020] Furthermore, the R mentioned above 3 COR 4 It is a chain ketone, in which R 3 R 4 C 1-8 alkyl or aryl; or cyclic ketone, wherein R 3 +R 4 (CH2) 4-8 .

[0021] Furthermore, the copper salt is CuX', CuX'2, CuSO4, Cu(NO3)2, Cu(OAc)2 or its crystalline hydrate, wherein X' is one of F, Cl, Br, I, O3SCF3; or CuF(PPh3)3·2MeOH;

[0022] Furthermore, the organophosphorus ligands have structural formulas L1 to L5, specifically as follows:

[0023]

[0024] Furthermore, the Lewis acid is one of LiX”, MgX”2, AlX”3, TiCl4, and BF3, wherein X” is one of F, Cl, Br, I, O3SCF3. Furthermore, the organic solvent is diethyl ether, tetrahydrofuran, benzene, or toluene, etc.

[0025] Furthermore, the initial concentration of the ketone in the reaction system is 0.1-2 mol / L in terms of molar concentration; the ratio of α,β-unsaturated dicarboxylic acid ester to ketone is 1-3 in terms of molar amount; the amount of copper salt or copper-phosphine complex is 0.1-2% of the α,β-unsaturated dicarboxylic acid ester in terms of the number of moles of copper; the amount of organophosphine ligand is 0.1-2% of the α,β-unsaturated dicarboxylic acid ester; the ratio of Grignard reagent to α,β-unsaturated dicarboxylic acid ester is 1-2.5 in terms of the molar amount of alkyl group; and the amount of Lewis acid is 0-100 times that of the copper catalyst.

[0026] The beneficial effects of this invention are: (1). Grignard reagent R 1 MgX is easy to prepare and widely available, and is cheaper than organozinc reagents; (2) The diastereoselectivity of the product is significantly improved by using composite catalysts. Attached Figure Description

[0027] Figure 1 The superior product in Example 1 1 H NMR spectrum;

[0028] Figure 2 The superior product in Example 1 13 C NMR spectrum;

[0029] Figure 3 The superior product in Example 3 1 H NMR spectrum;

[0030] Figure 4 The superior product in Example 3 13 C NMR spectrum;

[0031] Figure 5 The superior product in Example 4 1 H NMR spectrum;

[0032] Figure 6 The superior product in Example 4 13 C NMR spectrum;

[0033] Figure 7 The superior product in Example 5 1 H NMR spectrum;

[0034] Figure 8 The superior product in Example 5 13C NMR spectrum;

[0035] Figure 9 The superior product in Example 6 1 H NMR spectrum;

[0036] Figure 10 The superior product in Example 6 13 C NMR spectrum;

[0037] Figure 11 The superior product in Example 7 1 H NMR spectrum;

[0038] Figure 12 The superior product in Example 7 13 C10 NMR spectrum. Detailed Implementation

[0039] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can all be obtained commercially.

[0040] Example 1

[0041]

[0042] In an argon atmosphere, magnesium iodide (57 mg), cuprous iodide (1.9 mg), tetrahydrofuran (2 mL), dimethyl itaconic acid (1.581 g), and acetophenone (116 μL) were added to a reaction flask. The temperature was maintained at 0 °C. A tetrahydrofuran solution of ethyl magnesium bromide (1 mol / L, 2.5 mL) was added dropwise, and the reaction was stirred for 45 min. A saturated ammonium chloride aqueous solution (5 mL) was added, and the phases were separated. The aqueous phase filtrate was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Octadecyl alcohol was used as an internal standard, and the yield was determined to be 86% by GC internal standard method. The product dr value was 6.01:1.

[0043] The NMR spectrum of the superior product of this embodiment is shown in the attached figure. Figure 1 and Figure 2 . 1H NMR (500MHz, CDCl3) δ7.44(d,J=7.7Hz,2H),7.36(t,J=7.3Hz,2H),7.32(d,J=6.7Hz,1H),3.82(s,3H),3.39(d,J=17.8Hz ,1H),2.61(d,J=17.8Hz,1H),1.67(s,3H)1.42-1.33(m,1H),1.17-1.07(m,1H),1.01-0.93(m,2H),0.71(t,J=6.2Hz,3H). 13 C NMR (126MHz, CDCl3) δ173.78,172.28,139.46,127.92,127.80,125.62,89.01,57.86,52.24,36.51,36.40,25.04,18.39,13.90.

[0044] Example 2

[0045] As in Example 1, magnesium iodide was replaced with TiCl4 (155 mg), the reaction yield was 83%, and the product dr value was 6.9:1.

[0046] Example 3

[0047]

[0048] In an argon atmosphere, CuF(PPh3)3·2MeOH (4.7 mg), dimethyl itaconic acid (158 mg), and acetophenone (116 μL) were added to the reaction flask. The temperature was maintained at 0 °C. A tetrahydrofuran solution of magnesium phenyl bromide (1 mol / L, 2.5 mL) was added. After stirring for 45 min, a saturated ammonium chloride aqueous solution (5 mL) and dilute hydrochloric acid (2 mol / L, 1.0 mL) were added. The phases were separated, and the aqueous phase filtrate was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography was used to obtain a mixture of γ-butyrolactone isomers (239 mg, yield 77%, dr value 3.26:1).

[0049] The NMR spectrum of the superior product of this embodiment is shown in the attached figure. Figure 3 and Figure 4 . 1H NMR (500MHz, CDCl3) δ7.52(d,J=7.5Hz,2H),7.34(t,J=7.4Hz,2H),7.28(t,J=7.1Hz,1H),7.12(d,J=8.1Hz,3H),6.84(d,J=6.6H z,2H),3.72(s,3H),3.19(d,J=18.1Hz,1H),2.69(d,J=13.8Hz,1H),2.63(d,J=18.1Hz,1H),2.11(d,J=13.8Hz,1H),1.65(s,3H). 13 C NMR (126MHz, CDCl3) δ173.69,171.97,139.31,135.89,129.82,128.67,12 8.33,128.28,127.28,126.13,89.33,58.99,52.57,40.56,35.72,25.41.

[0050] Example 4

[0051]

[0052] In an argon atmosphere, CuF(PPh3)3·2MeOH (9.3 mg), dimethyl itaconic acid (158 mg), acetophenone (116 μL), and tetrahydrofuran (2.0 mL) were added to a reaction flask. A tetrahydrofuran solution of isopropyl magnesium bromide (1 mol / L, 2.5 mL) was added dropwise while maintaining the temperature at 0 °C. The mixture was stirred for 45 min. A saturated ammonium chloride aqueous solution (5 mL) and dilute hydrochloric acid (2 mol / L, 2.0 mL) were added. The phases were separated, and the aqueous phase filtrate was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the product (252 mg, yield 75%, dr value 2.28:1).

[0053] The NMR spectrum of the superior product of this embodiment is shown in the attached figure. Figure 5 and Figure 6 . 1 H NMR(500MHz,Chloroform-d)δ7.42-7.33(m,5H),3.83(s,3H),3.44(d,J=17.8Hz,1H),2.69(d,J=17.8Hz,1H) ,1.66(s,3H),1.36-1.24(m,2H),0.99(dd,J=14.2,4.9Hz,1H),0.76(d,J=6.6Hz,3H),0.68(d,J=6.6Hz,3H). 13C NMR (126MHz, CDCl3) δ174.36,173.16,139.51,128.18,128.11,126.03,89.73,57.36,52.51,42.43,36.29,25.47,25.17,24.45,22.13.

[0054] Example 5

[0055]

[0056] Under an argon atmosphere, CuF(PPh3)3·2MeOH (9.3 mg), tetrahydrofuran (2.0 mL), dimethyl itaconic acid (158 mg), and acetone (74 μL) were added to a reaction flask. The temperature was maintained at 0 °C. A tetrahydrofuran solution of magnesium ethyl bromide (1 mol / L, 2.5 mL) was added dropwise, and the mixture was stirred for 45 min. A saturated ammonium chloride aqueous solution (5 mL) and dilute hydrochloric acid (2 mol / L, 1.0 mL) were added. The phases were separated, and the aqueous phase filtrate was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography was used to obtain the product (203 mg, 95% yield).

[0057] The NMR spectrum of the superior product of this embodiment is shown in the attached figure. Figure 7 and Figure 8 . 1 H NMR (500MHz, CDCl3) δ3.75(s,3H),3.21(d,J=17.8Hz,1H),2.54(d,J=17.8Hz,1H),1.95(td,J=12.7,4.3Hz,1H),1. 48(s,3H),1.44(td,J=12.7,4.3Hz,1H),1.31(s,3H),1.29-1.23(m,1H),1.16-1.05(m,1H),0.95(t,J=7.3Hz,3H). 13 C NMR (126MHz, CDCl3) δ174.12,172.50,86.37,56.81,52.32,36.30,34.60,24.87,22.85,18.64,14.29.

[0058] Example 6

[0059]

[0060] Under an argon atmosphere, CuF(PPh3)3·2MeOH (9.3 mg), dimethyl itaconic acid (158 mg), and (4-pyridyl)acetone (110 μL) were added to a reaction flask. The temperature was maintained at 0 °C. A tetrahydrofuran solution of magnesium ethyl bromide (1 mol / L, 2.5 mL) was added, and the mixture was stirred for 45 min. A saturated ammonium chloride aqueous solution (5 mL) and dilute hydrochloric acid (2 mol / L, 1.0 mL) were added. The phases were separated, and the aqueous phase filtrate was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain the product (227 mg, yield 82%, dr value 3.63:1).

[0061] The NMR spectrum of the superior product of this embodiment is shown in the attached figure. Figure 9 and Figure 10 . 1 H NMR (500MHz, CDCl3) δ8.65(d,J=6.6Hz,2H),7.43(d,J=6.6Hz,2H),3.86(s,3H),3.46(d,J=16.5Hz,1H) ,2.68(d,J=19.8Hz,1H),1.66(s,3H),1.26(t,J=10.3Hz,2H),1.04-0.95(m,2H),0.75(t,J=6.9Hz,3H). 13 C NMR (126MHz, CDCl3) δ173.31,172.07,150.02,148.51,120.94,88.14,57.69,52.89,36.80,36.28,25.14,18.47,14.11.

[0062] Example 7

[0063]

[0064] Under an argon atmosphere, CuF(PPh3)3·2MeOH (9.3 mg), THF (2.0 mL), diisopropyl fumarate (202 μL), and cyclohexanone (104 μL) were added to a reaction flask. The temperature was maintained at 0 °C. A THF solution of ethyl magnesium bromide (1 mol / L, 2.5 mL) was added, and the reaction was stirred for 45 min. A saturated ammonium chloride aqueous solution (5 mL) was added, and the mixture was quenched with dilute hydrochloric acid (2 mol / L, 1.0 mL). The phases were separated, and the aqueous phase filtrate was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain the product (182 mg, yield 68%, dr value 1.76:1).

[0065] The NMR spectrum of the superior product of this embodiment is shown in the attached figure. Figure 11 and Figure 12 . 1 H NMR (500MHz, CDCl3) δ5.14-5.04(m,1H),3.22-3.13(m,1H),2.75(d,J=11.7Hz,1H),1.90-1. 55(m,10H),1.32-1.29(m,3H),1.29-1.27(m,3H),1.24-1.13(m,2H),0.95(t,J=7.5Hz,3H). 13 C NMR (126MHz, CDCl3) δ176.41,169.19,83.25,69.05,56.67,43.20,37.59,32.58,25.04,22.85,22.48,21.76,21.43,10.98.

[0066] Comparative Example (Example 1 in ZL 201410385205.6)

[0067] Under nitrogen protection, CuF(PPh3)3·2MeOH (8.0 mg), DPEPos (5.0 mg), toluene (2.0 mL), dimethyl itaconic acid (0.164 g, 1.03 mmol), and acetophenone (0.100 mL) were added to a dry reaction flask. The mixture was stirred and the temperature was maintained at 0 °C. A hexane solution of diethylzinc (15%, w / w, 1.70 mL) was added, and the mixture was stirred for another 2.5 h. Add saturated ammonium chloride aqueous solution (5.0 mL) and dilute hydrochloric acid (2 mol / L, 1.0 mL), separate the phases, extract the aqueous phase with toluene (3 × 10.0 mL), combine the extracted organic phases and wash with sodium bicarbonate solution (5.0 mL), saturated brine (2.0 mL), dry with anhydrous sodium sulfate, concentrate, and obtain a mixture of β-propyl-β-methoxyacyl-γ-methyl-γ-phenyl-γ-cyclobutyl ester isomers (isomer ratio 73:27) (0.246 g, yield 91%) by column chromatography, which is a colorless liquid.

[0068] The embodiments described above are merely preferred embodiments of the present invention, and not all feasible embodiments of the present invention. Any obvious modifications made by those skilled in the art without departing from the principles and spirit of the present invention should be considered to be included within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing β-ester-γ-butyrolactone, characterized in that, β-ester-γ-butyrolactone is synthesized from Grignard reagents, α,β-unsaturated dicarboxylic esters, and ketones under the action of a copper catalyst, as shown in the following reaction formula: The method specifically involves adding a Grignard reagent to a mixture of ketone, α,β-unsaturated dicarboxylic acid ester, and copper catalyst, and stirring the mixture in an organic solvent for 0.5-2 hours. The structure of Grignard reagent is R 1 MgX, where R 1 C 1-8 Alkyl; or phenyl, p-tolyl, m-tolyl, o-tolyl, p-methoxyphenyl; X = Cl, Br, I; R 2 C 1-8 hydrocarbon group; R 3 COR 4 It is a chain ketone, in which R 3 R 4 C 1-8 alkyl or aryl; or cyclic ketone, wherein R 3 +R 4 (CH2) 4-8 .

2. The method for synthesizing β-ester-γ-butyrolactone according to claim 1, characterized in that, The copper catalyst is a copper-phosphine complex formed by copper salt and organophosphine ligand in the reaction system or a pre-prepared copper-phosphine complex.

3. The method for synthesizing β-ester-γ-butyrolactone according to claim 1, characterized in that, Copper catalysts are catalysts composed of copper salts and Lewis acids.

4. The method for synthesizing β-ester-γ-butyrolactone according to claim 1, characterized in that, α,β-unsaturated dicarboxylic acid esters include fumarate diester, maleate diester, and itaconic acid diester.

5. The method for synthesizing β-ester-γ-butyrolactone according to claim 2 or 3, characterized in that, The copper salt is CuX', CuX'2, CuSO4, Cu(NO3)2, Cu(OAc)2 or its crystalline hydrate, wherein X' is one of F, Cl, Br, I, O3SCF3; or CuF(PPh3)3·2MeOH.

6. The method for synthesizing β-ester-γ-butyrolactone according to claim 2, characterized in that, The organophosphine ligands described herein have structural formulas L1 to L5, and the specific structural formulas are as follows:

7. The method for synthesizing β-ester-γ-butyrolactone according to claim 3, characterized in that, Lewis acids are one of LiX”, MgX”2, AlX”3, TiCl4, and BF3, where X” is one of F, Cl, Br, I, O3SCF3.

8. The method for synthesizing β-ester-γ-butyrolactone according to claim 2, characterized in that, The initial concentration of the ketone in the reaction system is 0.1-2 mol / L in terms of molar concentration; the ratio of α,β-unsaturated dicarboxylic acid ester to ketone is 1-3 in terms of molar amount; the amount of copper salt or copper-phosphine complex used is 0.1-2% of the α,β-unsaturated dicarboxylic acid ester in terms of the number of moles of copper; the amount of organophosphine ligand used is 0.1-2% of the α,β-unsaturated dicarboxylic acid ester; and the ratio of Grignard reagent to α,β-unsaturated dicarboxylic acid ester is 1-2.5 in terms of the molar amount of alkyl group.

Images