To a solution of carbonic acid diethyl ester (0.2 mol) in 50 mL of toluene was added 60% of NaH (10 g, 0.25 mol) and the mixture was heated to reflux. To this mixture was added dropwise a solution of the ketone (0.1 mol) with reflux and the reaction mixture was refluxed for another 2 hrs. After cooling down, the mixture was poured into 0.2M HCl aqueous solution and the layers were separated. The aqueous layer was extracted with AcOEt for three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the product (yield: ~90%), which was purified by silica gel column chromatography.
Reference: Molecules 2004, 9(3), 135 – 157.
J. Med. Chem. 1991, 34(1), 357-366.
通过乙酸酯和相应的取代酯缩合（Claisen Condensation）是一种制备芳香β- 酮酸酯的常用方法，α-H 的酯在强碱作用下与没有α-H 的酯缩合成β-酮酸酯的反应。
To a suspension of ethyl benzoate (0.1 mol) and NaH(60%, 3.0 g, 0.075mol) in 100 mL ethylene glycol dimethyl ether was added dropwise ethyl acetate over 15 min and the mixture was refluxed for 2 hr. The resultant mixture was cooled down and put into 100 mL of cold 5% Na2CO3 aqueous solution and extracted with ether. The aqueous layer was acidified with 1N HCl and extracted with ether for three times. The combined organic layers were washed with brined, dried and concentrated in vacuo to give the product (yield: 51%), which was purified by silica gel column chromatography.
Reference: Bioorg. Med. Chem. 2004, 11(13), 135 – 157.
Publ.: US2004/214870 A1 (2004/10/28)三、通过腈合成β-酮酸酯
Zinc dust (894 mg, 13.7 mmol)was suspended in dry tetradrofuran (3 mL) under nitrogen and sonicated for 10 min at room temperature. Ethyl bromoacetate (2 drops) was added, and the mixture was heated under refluc for 5 min. A solution of benzonitrile (640 mg, 2.74 mmol) in dry tetrahydrofuran (6 mL) was added and the mixture refulxed for 5 min. A solution of ethyl bromoacetate (1.822 g, 10.94 mmol) in dry tetrahydrofuran (2 mL) was added dropwise over 1 h at reflux and, after a further 10 min, the mixture was allowed to cool to room temperature. Aqueous potassium carbonate (1 mL, 50% solution) was added and the mixture was stirred for 45 min, then filtered through Arbocel filter aid which was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to give a yellow gum. This material was treated with a mixture of 20% aqueous trifluoroacetic acid and dichloromethane and stirred at room temperature for 15 min. The mixture was neutralized by the addition of saturated aqueous sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried and concentrated under reduced pressure and the crude product was purified by flash chormatography (gradient elution with ethyl acetate/methanol) to give the title product(480 mg, 54%). Futher purification by chromatography gave a white solid.
Refence: J. Med. Chem.; EN; 1992; 35(7); 3115 – 3129.
To a stirred suspension of commercial zinc dust (8.3 g, 126 mmol) in THF (60 mL) wasadded MeSO3H (60 mg, 0.6 mmol) at room temperature The mixture was refluxed for 10 min and (S)-4-chloro-3-trimethylsilyloxybutyronitrile( 12.0 g, 63 mmol) was added. To the mixture was added tert-butyl bromoacetate (19.7 g, 101 mmol) over 1 h using a syringe pump. After 30 min, the mixture was cooled to 0 –5 °C and aq 3 N HCl (40 mL) was added dropwise. After 2 h, all the organicvolatiles were removed in vacuo and the remaining mixture was extracted with EtOAc (60 mL). The separated organic layer was washed with H2O, dried(MgSO4) and concentrated. Columnchromatography (EtOAc–hexane, 1:3) of the residue afforded 12.1g (85%) of the product as a viscous oil.
Reference: Synthesis 2004, 16, 2629–2632.
To a suspension of potassium ethyl malonate (19 mmol) in acetonitrile (50 mL) was sequentially added triethyl amine (4.1 mL, 29mmol) and magnesium chloride (11.8 g, 0.12mol) and the reaction mixture was stirred for 2 hours at room temperature. The acyl chloride(0.05 mol) was then added and the mixture was heated at 60 oC for 18 hours, concentrated under reduced pressure and partitioned between ethyl acetate (100 mL) with 0.2M HCl (25mL). The ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (Yield: ~80%).
Reference: Publ.: US2002/40022 A1 (2002/04/04)
To a suspension of barium oxide (purity: 90percent, 29.9 g, 0.176 mol) and 0.5 mL of water in 150 ml of toluene was added dropwise t-butyl acetoacetate (94.7 g, 0.6 mol) at 20~30℃ over 1 hour and the mixture was stirred for 1 hour. Into the obtained solution was dropped 23.2 g (0.15 mol) of phenylacetyl chloride at 20 ~ 30℃ over 1 hour and stirring was continued for additional 1 hour. 26.1 g (0.35 mol) of tert-butanol was added to the reaction mixture, which was then stirred for 16 hours. The mixture was acidified to pH= 1 with dil.HCl and the insoluble barium salt was filtered off. After separating out, the toluene layer was washed with satd. NHCO3 and brine, concentrated under reduced pressure to yield the title compound (Yield: 65%), which was purified by silica gel column chromatography.
Reference: Publ.: US2004/2507
A mixture of 3, 4,5-trimethoxybenzoic acid (24.7 g, 116 mmol) and CDI (20.8 g, 128 mmol) in dry THF (300 mL) (Caution: gas evolution) was stirred for 4 h at r. t, then potassium ethylmalonate (20 g, 128 mmol) and MgCl2 (12.2 g, 128 mmol) were added portionwise. The reaction mixture was stirred at 40℃ for 2 days. The precipitate was removed by filtration, and the filtrate was diluted with water and acidified with 1N HC1 until PH-4. The mixture was extracted with ether (200 ml) and washed with water (2 x 100 mL), aq. NaHCO3 and water, then dried over MgSO4. Evaporation provided a crude product, which was purifiedwith flash chromatography on silica to give the beta-keto ester (18 g, 58percent) as a white solid.
Reference: Publ.: WO2004/106296 A1
To a solution of Cbz-LtBuGly-OH (20.53 g, 77.4 mmol, 1 equiv) in THF (150 mL) was added CDI (13.81 g, 85.14 mmol, 1.1 equiv) at 23 °C. The resulting mixture was stirred at 23 °C for 1 h. In a separate flask, n-butyllithium (101.6 mL of a 1.6 M solution in hexanes, 162.5 mmol,2.1 equiv) was added to a solution of diisopropylamine (22.78 mL, 162.5 mmol, 2.1 equiv) in THF (100 mL) at -78 °C. The reaction mixture was stirred for 15 min at -78°C, warmed to 0°C for 5 min, and then cooled back to -78 °C. A solution of tert-butyl acetate (21.9 mL, 162.5mmol, 2.1 equiv) in THF (10 mL) was added via cannula, and the resulting mixture was stirred at -78 °C for 10 min. The Cbz-L-tBuGly-OH/CDI solution prepared above was then added dropwise to the lithium enolate at -78 °C. The resulting mixture was stirred at -78 °C for 1 h, quenched with 1 M HCl (100 mL), and extracted with EtOAc (2 * 100 mL). Thecombined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10% EtOAc inhexanes) to afford the product (12.1 g, 44%, contaminated with 10% minor impurities) as a pale yellow oil.
Refence: J. Med. Chem.; 1999; 42; 1203-1212
To a stirred solution of (E)-4-oxodec-8-enoic acid (2.25 g, 12.2 mmol) in THF (60 mL) at 0°C was added carbonyldiimidazole (2.38 g, 14.7 mmol). After 15 min at 0 °C, the ice bath was removed and the reaction mixture was allowed to warm to 20 °C for 1 h. In a separate flask, mono-tert-butyl malonate (4.30 g, 26.9 mmol) was dissolved in THF (60 mL), cooled to-78 °C, and to this was added Bu2Mg (13.4 mL of a 1.0 M solution in heptane, 13.4 mmol) via syringe. The mixture was stirred for 15 min at -78 °C and then for 1 h at 20 °C. The solvent was removed and the acyl imidazolide was added via cannula to the magnesium salt, rinsing the flask with an additional portion of THF (10 mL). After 18 h the reaction was quenched by the addition of 10% aq citric acid solution (30 mL), the layers were separated, and the aqueous component was extracted with Et2O (2 × 60 mL). The combined organic components were washed with saturated aq NaHCO3solution (30 mL) and brine (30 mL), dried (MgSO4), and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography (SiO2, petrol/Et2O 8:2) to afford tertbutyl (E)-3,6-dioxododec-10-enoate as a clear yellow oil (2.06 g, 60%).
Reference: J. Org. Chem. 2003, 68, 6153-6159.六、通过Medrum’s Acid合成β-酮酸酯
该类方法也是一个比较通用的方法，可以用来制备芳基和烷基β-酮酸酯。羧酸或酰氯首先和Medrum’s Acid 反应得到相应酰化的Medrum’s Acid，其再醇解得到相应的产物。而在醇解时候，使用不同的醇则得到相应的不同酯，如用叔丁醇则可得叔丁酯(Ref.Org. Biomol. Chem. 2004, 2(10), 1504 – 1510)。
6.1 通过Medrum’s Acid 和2-噻吩甲酸反应合成β-酮酸酯示例
A solution of thiophene-2-carboxylic acid (8.9 g, 68.5 mmol),
2,2-dimethyl-1,3-dioxane-4,6-dione (12.0 g, 81.6 mmol), and DMAP (17.0 g, 138 mmol) in dry DCM (100 mL) was cooled to 0 ℃ and treated with a solution of DCC (75 ml, 1.0 M in DCM, 75 mmol). The mixture was allowed to stir at room temperature for 2 h and the dicyclohexylurea was then filtered and washed with DCM. The filtrate was concentrated under reduced pressure and the residue was dissolved in absolute ethanol (400 mL). The solution was then treated with a solution of p-toluenesulfonic acid monohydate (32 g, 168mmol) in absolute ethanol (100 mL) and refluxed under argon for 1 h. At this time, the ethanol was removed under reduced pressure and the residue was dissolved in EtOAc and washed sequentially with H2O (300 mL), saturated NaHCO3 (200 mL, 1 N HCl (200 ml), saturated NaCl, and dried (MgSO4). The solvent was removed at reduced pressure and the residue was filtered through a pad of silica with 10percent EtOAc/90percent hexanes to afford the desired product as an oil (13 g, 96%).
Reference: Publ.: US2004/2507.
6.2 通过Medrum’s Acid和2-苯乙酸反应合成β-酮酸酯示例
A previously described procedure was used to prepare Meldrum's acid; recrystallization from H2O-acetone separated the 1,3-dioxane 2,2-dimethyl-1,3-dioxane-4,6-dione as colorless needles. This product was acylated by a recently described procedure employing 65.0 mL(0.805 mmol) of anhydrous pyridine, 44.2 g (0.306 mmol) of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione), 46.9 g (0.303 mol) of PhCOCl, and 230 mL of CH2Cl2. The crude product was recrystallized from Et2O-hexane to separate the acylated product 5-(1-hydroxy-2-phenylethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione as orange prisms. In a similar manner, a mixture of 2.77 g (10.6 mmol) of the β-ketoe ster 22 (mp 90-92℃), 2.73 g of t-BuOH, and 50 mL of PhH was refluxed for 4 h and then concentrated under reduced pressure. Distillation of the residual red-orangeliquid (3.09 g) in a short-path still(100-105 ℃ and 0.8 mm) separated 2.42 g (98%) of the keto ester tert-butyl 3-oxo-4-phenylbutanoate as a pale yellow liquid.
Reference: J. Org. Chem. 1982, 47, 2413-2419.
6.3 通过Medrum’s Acid和3-氨基-3-噻吩丁酸反应合成β-酮酸酯示例
A mixture of Meldrum’s acid (0.021mol) and pyridine (0.05 mol) in dry methylene chloride (50 ml) was stirred for 0.5 h at room temperature. The reaction mixture was then cooled at 0°C and 3-amino-3-(thiophen-3-yl)propanoic acid (0.02 mol) was added dropwise. The reaction mixture was quenched after 2 h at 0°C by adding an aqueous HCl (1N) solution and extracted twice with methylene chloride (50 ml). The combined organic layers were dried over calcium chloride and evaporated in vacuo. The Meldrum’s adduct was refluxed for 4 h inmethanol (50 ml) and evaporated to dryness. The oily residue was dissolved in methylene chloride (50 ml), washed with a saturated aqueous NaHCO3 solution, dried over calcium chloride and evaporated to dryness to give the product (79%).
Reference: Tetrahedron Letters 2001, 42, 8997–8999.
6.4 通过Medrum’s Acid 和酰氯反应合成芳基的β-酮酸乙酯示例：
To a DCM solution of 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (10 g) and DMAP (17 g) was added dropwise a solution of 3-methyl-4-nitro-benzoyl chloride (14 g) in DCM with ice cooling. After stirring at room temperature for 3 hours and then adding 100 mL of ethanol, the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off under the reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain ethyl 3- (3-me- thyl-4-nitro-phenyl)-3-oxo-propionate (12.4 g).
Reference: Publ.: WO2005/95351.
To a suspension of anhydrous tin (II) chloride (2.5 g, 13.2 mmol) in 150 mL of DCM was added ethyl diazoacetate (8.3 g, 72.8 mmol). Then 3-nitrobenzaldehyde (10.0 g, 66.2 mmol) was added as a solid in small portions over 30 min and the resulting suspension was stirred at room temperature for 24 h. Additional tin (II) chloride (2.5 g) was added and the reaction was stirred an additional 24 h. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with 4:1 hexanes/ethyl acetate) to afford 5 g (32 percent) of the title compound.
Reference: J. Org. Chem. 1994, 488-490.