Synthesis method of (Z) type conjugated enol phosphate

Abstract

The invention discloses a synthesis method of (Z) type conjugated enol phosphate, which comprises the following steps: (1) synthesis of enol phosphate: reacting 4-chloroacetoacetate with phosphite ester, ending LC-MS (liquid chromatography-mass spectrometry) detection, and separating and purifying the product to obtain enol phosphate; and (2) synthesis of (Z) type conjugated enol phosphate: mixing enol phosphate, triethylamine and acetonitrile, stirring at room temperature for reaction, ending LC-MS detection, and separating and purifying the product to obtain the (Z) type conjugated enol phosphate. The method has the advantages of milder reaction conditions, higher efficiency, higher yield and better selectivity.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for synthesizing (Z)-type conjugated enol phosphate esters. Background Technology

[0002] Conjugated enol phosphate compounds have a wide range of biological activities and are the core framework of a series of important pesticides, such as dichlorvos, phorate, and phosphamidon, which are all widely used pesticides.

[0003] Retrosynthetic analysis reveals that, ( Z The key to the synthesis of 2-conjugated enol phosphates lies in the stereospecific construction of an enol double bond linked to the phosphate ester and conjugated with the carbonyl group. Two synthetic routes have been reported in the literature, using ethyl 2-chloroacetoacetate and ethyl acetoacetate as reactants, respectively, to construct phosphate esters containing conjugated alkenes. Each route has its advantages and disadvantages, but the resulting conjugated enol phosphates are not monomorphic products, especially the highly reactive isomers. Z The content of the configuration was not high enough, and the yield was only moderate.

[0004] Existing technology synthesis route 1 Using ethyl 2-chloroacetoacetate as a raw material, trimethyl phosphite was added, and the reaction was carried out at 80 °C for 24 hours to obtain two configurations of compound A and compound B (compound A:B = 1:2.6). .

[0005] Existing technology synthesis route two The reaction started with ethyl acetoacetate, which reacted with dimethyl phosphate, and then potassium tert-butoxide was used to provide alkaline conditions. Carbon tetrachloride was used as the polyhalogenating agent and acetonitrile was used as the solvent. The reaction was carried out at room temperature for 30 minutes to give compounds A and B with two configurations (compound A: compound B = 3:7). .

[0006] In replicating the methods reported in existing technologies, we found that the construction of conjugated enol phosphates was achieved in both methods. Z / E A mixture of two configurations of conjugated enol phosphate esters, while the highly active configuration of conjugated enol phosphate ester pesticides is... Z Configuration. Current methods, whether using ethyl 2-chloroacetoacetate or ethyl acetoacetate as a starting material, cannot prepare a single highly active configuration, and the product yield is only moderate. These shortcomings have prompted those skilled in the art to seek methods with milder conditions, higher efficiency, higher yields, and better selectivity. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing (Z)-type conjugated enol phosphates, which has the advantages of milder reaction conditions, higher efficiency, higher yield, and better selectivity.

[0008] The technical solution adopted by this invention to solve its technical problem is: A method for synthesizing (Z)-type conjugated enol phosphate esters includes the following steps: (1) Synthesis of enol phosphate: 4-chloroacetoacetate reacts with phosphite. The reaction should end when LC-MS detection is completed. The product is then separated and purified to obtain enol phosphate. (2) Synthesis of (Z) type conjugated enol phosphate: Enol phosphate, triethylamine and acetonitrile are mixed and stirred at room temperature. The reaction should end when LC-MS detection is completed. The product is separated and purified to obtain (Z) type conjugated enol phosphate.

[0009] The reaction route of this invention is as follows: R is ethoxy, methoxy, benzyloxy, or isopropoxy; 1 It is methoxy, ethoxy, or phenyl; R 2 It can be methoxy, ethoxy, or phenyl.

[0010] Preferably, the 4-chloroacetoacetate is methyl 4-chloroacetoacetate, ethyl 4-chloroacetoacetate, benzyl 4-chloroacetoacetate, or isopropyl 4-chloroacetoacetate.

[0011] Preferably, the phosphite is trimethoxyphosphite, triethoxyphosphite, phenyl dimethoxyphosphite, or methoxydiphenylphosphite.

[0012] Preferably, in step (1), the molar ratio of 4-chloroacetoacetate to phosphite is 1:1.2 to 2.

[0013] Preferably, in step (1), the reaction temperature is 25-40℃.

[0014] Preferably, in step (2), the ratio of enol phosphate: triethylamine: acetonitrile is 1 mmol: 0.1-0.2 mmol: 15-20 mL.

[0015] The beneficial effects of this invention are: (1) This synthetic method uses 4-chloroacetoacetate as the starting material and obtains the target product, conjugated enol phosphate, through a two-step reaction involving the Perkow reaction and the 1,3-hydrogen migration reaction; it has stereospecificity and can achieve highly active single-component synthesis. Z Synthesis of conjugated enol phosphate esters; (2) The raw materials used in the reaction route are 4-chloroacetoacetate, phosphite, and triethylamine, all of which are common chemicals that are inexpensive and readily available on the market; (3) The reaction route has mild reaction conditions, simple purification methods, and high yield of the target product (greater than 92% in the second step). Detailed Implementation

[0016] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0017] In this invention, unless otherwise specified, all raw materials and equipment used are commercially available or commonly used in the field. The methods described in the following embodiments are conventional methods in the field, unless otherwise specified.

[0018] Example 1 (1) Synthesis of 1-methoxyethoxycarbonyl-1-vinyldimethoxyphosphate In a 50 mL reaction flask, methyl 4-chloroacetoacetate (15.0 g, 0.1 mol) and trimethyl phosphite (14.9 g, 0.12 mol) were added. The mixture was stirred at 40 °C for 18 hours. After the reaction was completed, the trimethyl phosphite was removed under vacuum (15 kPa) at 50 °C to obtain 25 g of viscous oil. The obtained viscous oil (25 g) was dissolved in 2 times its weight of potassium hydroxide aqueous solution (50 g, potassium hydroxide:water weight ratio 1:60) and extracted three times with 2 times its weight of dichloromethane (50 g × 3 times). The layers were separated by a separatory funnel. The organic phase was washed twice with 2 times its weight of saturated brine (50 g × 2 times), and the aqueous phase was extracted once with 1 times its weight of dichloromethane (25 g × 1 time). The organic phases were combined and dried for 0.5 hours with 0.5 times its weight of anhydrous magnesium sulfate (12.5 g). After filtration, the organic phase was evaporated by rotary evaporation (15 kPa) at 15 °C. After removing the solvent dichloromethane at 35°C (kPa), a colorless oily liquid was obtained, with a yield of 90.3%.

[0019] Spectral data of 1-methoxyethoxycarbonyl-1-vinyldimethoxyphosphate: 1 H NMR (600 MHz, CDCl3)δ 5.00 (s, 1H), 4.69 (s, 1H), 3.78 (d, J = 11.3 Hz, 6H), 3.68 (s, 3H), 3.21 (s, 2H). 13 C NMR (151 MHz, CDCl3) δ 169.19, 148.03 (d, J= 9.0 Hz), 109.98, 101.07 (d, J = 4.5 Hz), 54.79 (d, J = 6.0 Hz), 52.15, 40.25 (d, J = 6.0 Hz). 31 P NMR (243 MHz, CDCl3) δ -4.74.

[0020] (2) Z Synthesis of 2-methoxycarbonyl-1-methylvinyldimethoxyphosphate 1-Methoxyethoxycarbonyl-1-vinyldimethoxyphosphate (4.48 g, 2.0 mmol) was dissolved in 20 mL of acetonitrile, and triethylamine (0.02 g, 0.2 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by vacuum distillation under vacuum (15 kPa) at 50 °C. The residue (5.3 g) was dissolved in twice its weight of water (10.6 g), and extracted three times with twice its weight of ethyl acetate (10.6 g × 3 times). The ethyl acetate was removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z The crude product of type 3 conjugated enol phosphate (3) was separated by column chromatography (eluent ratio of n-hexane:ethyl acetate = 1:0.5). The eluent containing the product was then removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z 2-Methoxycarbonyl-1-methylvinyldimethoxyphosphate, pure product, yield: 93%.

[0021] ( Z Spectral data of 2-methoxycarbonyl-1-methylvinyldimethoxyphosphate: 1 H NMR (600 MHz, CDCl3) δ 5.73 (s, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.78(d, J = 12.2 Hz, 6H), 2.34 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.07, 162.90 (d, J= 7.5 Hz), 109.99, 106.25 (d, J = 6.0 Hz), 60.09, 54.91 (d, J = 7.5 Hz), 18.33 (d, J = 4.5 Hz), 14.13. 31 P NMR (243 MHz, CDCl3) δ -5.93.

[0022] Example 2 (1) Synthesis of 1-ethoxyethcarbonyl-1-vinyldimethoxyphosphate In a 50 mL reaction flask, ethyl 4-chloroacetoacetate (16.4 g, 0.1 mol) and methyl phosphite (14.9 g, 0.12 mol) were added. The mixture was stirred at 40 °C for 18 hours. After the reaction was completed, trimethyl phosphite was removed under vacuum (15 kPa) at 50 °C to obtain 26 g of viscous oil. The obtained viscous oil (26 g) was dissolved in 2 times its weight of potassium hydroxide aqueous solution (52 g, potassium hydroxide:water weight ratio 1:1:75) and extracted three times with 2 times its weight of dichloromethane (52 g × 3 times). The layers were separated by a separatory funnel. The organic phase was washed twice with 2 times its weight of saturated brine (50 g × 2 times), and the aqueous phase was extracted once with 1 times its weight of dichloromethane (26 g × 1 time). The organic phases were combined and dried for 0.5 hours with 0.5 times its weight of anhydrous magnesium sulfate (13 g). After filtration, the organic phase was rotary evaporated (15 kPa) at 15 °C. After removing the solvent dichloromethane at 35°C (kPa), a colorless oily liquid was obtained, with a yield of 82%.

[0023] Spectral data of 1-ethoxyethcarbonyl-1-vinyldimethoxyphosphate: 1 H NMR (600 MHz, CDCl3) δ 4.92 (s, 1H), 4.62 (s, 1H), 4.07 (q, J = 7.1Hz, 2H), 3.73 (s, 3H), 3.71 (s, 3H), 3.13 (s, 2H), 1.17 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 168.65, 148.15 (d, J = 9.0 Hz), 100.78 (d, J=4.5 Hz), 61.01, 54.70 (d, J = 4.5 Hz), 40.41 (d, J = 6.0 Hz), 13.97. 31 P NMR (243 MHz, CDCl3) δ -5.03.

[0024] (2) Z Synthesis of 2-ethoxycarbonyl-1-methylvinyldimethoxyphosphate 1-Ethoxyethoxycarbonyl-1-vinyldimethoxyphosphate (4.76 g, 0.2 mmol) was dissolved in 20 mL of acetonitrile, and triethylamine (0.02 g, 0.02 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by vacuum distillation under vacuum (15 kPa) at 50 °C. The residue (6.0 g) was dissolved in twice its weight of water (12.0 g), and extracted three times with twice its weight of ethyl acetate (12.0 g × 3 times). The ethyl acetate was removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z The crude product of type 3 conjugated enol phosphate (3) was separated by column chromatography (eluent ratio of n-hexane:ethyl acetate = 1:1). The eluent containing the product was then removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z 2-ethoxycarbonyl-1-methylvinyldimethoxyphosphate, pure product, yield: 92%.

[0025] ( Z Spectral data of 2-ethoxycarbonyl-1-methylvinyldimethoxyphosphate: 1 H NMR (600 MHz, CDCl3) δ 5.73 (s, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.78(d, J = 12.2 Hz, 6H), 2.34 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.07, 162.90 (d, J = 7.5 Hz), 109.99, 106.25 (d, J= 6.0 Hz), 60.09, 54.91 (d, J = 7.5 Hz), 18.33 (d, J = 4.5 Hz), 14.13. 31 P NMR (243 MHz, CDCl3) δ -5.93.

[0026] Example 3 (1) Synthesis of 1-methoxyethoxycarbonyl-1-vinylphenylmethoxyphosphonate In a 50 mL reaction flask, ethyl 4-chloroacetoacetate (16.4 g, 0.10 mol) and dimethyl phenylphosphite (20.4 g, 0.12 mol) were added. The mixture was stirred at 40 °C for 18 hours. After the reaction was completed, trimethyl phosphite was removed under vacuum (15 kPa) at 50 °C to obtain 32 g of viscous oil. The obtained viscous oil (32 g) was dissolved in twice its weight of potassium hydroxide aqueous solution (64 g, potassium hydroxide:water weight ratio 1:70) and extracted three times with twice its weight of dichloromethane (64 g × 3 times). The layers were separated by a separatory funnel. The organic phase was washed twice with twice its weight of saturated brine (64 g × 2 times), and the aqueous phase was extracted once with one weight of dichloromethane (32 g × 1 time). The organic phases were combined and dried for 0.5 times its weight of anhydrous magnesium sulfate (16 g) for 0.5 hours. After filtration, the organic phase was rotary evaporated (15 kPa) at 15 °C. After removing the solvent dichloromethane at 35°C (kPa), a colorless oily liquid was obtained, with a yield of 88%.

[0027] Spectral data of 1-methoxyethoxycarbonyl-1-vinylphenylmethoxyphosphonate: 1 H NMR (600 MHz, CDCl3) δ 7.90 – 7.79 (m, 2H), 7.60 –7.58(m, 1H), 7.51–7.47(m, 2H), 4.97 (t, J = 2.2 Hz, 1H), 4.67 (t, J = 2.1 Hz, 1H), 3.83 (d, J = 11.4Hz, 3H), 3.68 (s, 3H), 3.31 – 3.17 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 169.33, 147.98 (d, J= 8.3 Hz), 132.93 (d, J =3.1 Hz), 131.99 (d, J = 10.2 Hz), 128.58, 101.62 (d, J = 4.6 Hz), 60.38, 53.04 (d, J = 6.0 Hz), 52.14, 40.85 (d, J = 4.7 Hz), 31.57, 22.64, 14.14 (d, J = 12.0Hz). 31 P NMR (243 MHz, CDCl3) δ 16.37.

[0028] (2) Z Synthesis of 2-methoxycarbonyl-1-methylvinylphenylmethoxyphosphonate 1-Methoxyethoxycarbonyl-1-vinylphenylmethoxyphosphonate (5.40 g, 2.0 mmol) was dissolved in 20 mL of acetonitrile, and triethylamine (0.02 g, 0.2 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by vacuum distillation under vacuum (15 kPa) at 50 °C. The residue (6.5 g) was dissolved in twice its weight of water (13.0 g), and extracted three times with twice its weight of ethyl acetate (13.0 g × 3 times). The ethyl acetate was removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z The crude product of type 3 conjugated enol phosphate (3) was separated by column chromatography (eluent ratio of n-hexane:ethyl acetate = 1:0.8). The eluent containing the product was then removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z 2-ethoxycarbonyl-1-methylvinylmethylethoxyphosphonate, pure product, yield: 97%.

[0029] ( Z Spectral data of 2-methoxycarbonyl-1-methylvinylphenylmethoxyphosphonate: 1H NMR (600 MHz, CDCl3) δ 7.94 – 7.65 (m, 2H), 7.61 – 7.50 (m, 1H), 7.46 –7.44 (m, 2H), 5.75 (s, 1H), 3.81–3.77 (m, 3H), 3.66 – 3.45 (m, 3H),2.47 – 2.18 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.64, 163.49 (d, J = 8.7 Hz), 133.24 (d, J = 3.1 Hz), 131.84 (d, J = 10.4Hz), 128.71 (d, J = 15.7 Hz), 126.39 (d, J =193.2 Hz), 106.11, 53.11 (d, J = 5.9 Hz), 51.19, 18.95. 31 P NMR (243 MHz, CDCl3) δ 15.97.

[0030] Example 4 (1) Synthesis of 1-isopropoxyethoxy-1-vinyldiphenylphosphonate In a 50 mL reaction flask, isopropyl 4-chloroacetoacetate (16.4 g, 0.10 mol) and diphenyl methoxyphosphonate (25.9 g, 0.12 mol) were added. The mixture was stirred at 40 °C for 18 hours. After the reaction was completed, trimethyl phosphite was removed under vacuum (15 kPa) at 50 °C to obtain 50 g of viscous oil. The obtained viscous oil (50 g) was dissolved in 100 g of potassium hydroxide aqueous solution (potassium hydroxide:water weight ratio 1:70) and extracted three times with 100 g of dichloromethane. The layers were separated by a separatory funnel. The organic phase was washed twice with 100 g of saturated brine (100 g × 2 times), and the aqueous phase was extracted once with 1 g of dichloromethane (50 g × 1 time). The organic phases were combined and dried for 0.5 hours with 25 g of anhydrous magnesium sulfate. After filtration, the organic phase was rotary evaporated (15 kPa). After removing the solvent dichloromethane at 35°C (kPa), a colorless oily liquid was obtained, with a yield of 93%.

[0031] Spectral data of 1-isopropoxyethoxy-1-vinyldiphenylphosphonate: 1H NMR (600 MHz, CDCl3) δ 7.89 – 7.79 (m, 4H), 7.52 – 7.45 (m, 2H), 7.45 –7.35 (m, 4H), 4.85 (s, 1H), 4.53 (s, 1H), 3.09 (s, 2H), 1.99 (s, 1H),1.42 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 168.30, 148.63 (d, J = 9.4 Hz), 132.37 (d, J =2.8 Hz), 131.68 (d, J = 10.5 Hz), 131.05 (d, J = 138.4 Hz), 128.52 (d, J = 13.5Hz), 101.00 (d, J = 5.2 Hz), 81.31, 60.34, 42.81, 27.95, 21.01, 14.18. 31 P NMR (243 MHz, CDCl3) δ 29.13.

[0032] (2) Z Synthesis of 2-isopropyloxycarbonyl-1-methylvinyl diphenyl phosphate 1-Isopropoxyethoxycarbonyl-1-vinyldiphenylphosphonate (7.17 g, 2.0 mmol) was dissolved in 20 mL of acetonitrile, and triethylamine (0.02 g, 0.2 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by vacuum distillation under vacuum (15 kPa) at 50 °C. The residue (10 g) was dissolved in twice its weight of water (20.0 g), and extracted three times with twice its weight of ethyl acetate (20.0 g × 3 times). The ethyl acetate was removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z The crude product of type 3 conjugated enol phosphate (3) was separated by column chromatography (eluent ratio of n-hexane:ethyl acetate = 1:0.8). The eluent containing the product was then removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z 2-Isopropyloxycarbonyl-1-methylvinyl diphenyl phosphate, pure product. Yield: 94%.

[0033] ( Z Spectral data of 2-isopropyloxycarbonyl-1-methylvinyl diphenyl phosphate: 1 H NMR (600 MHz, CDCl3) δ 7.92 – 7.71 (m, 4H), 7.54 – 7.52 (m, 2H), 7.47 –7.44 (m, 4H), 5.80 (s, 1H), 2.34 (s, 3H), 1.39 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 165.71, 162.64 (d, J = 9.7 Hz), 132.65 (d, J =2.7 Hz), 131.53 (d, J = 10.5 Hz), 130.80 (d, J = 138.4 Hz), 128.71 (d, J = 13.6Hz), 108.39 (d, J = 5.7 Hz), 80.23, 28.17, 19.23 (d, J = 4.2 Hz). 31 P NMR (243 MHz, CDCl3) δ 30.06.

[0034] Example 5 (1) Synthesis of 1-benzyloxyethoxycarbonyl-1-vinyldimethoxyphosphate In a 50 mL reaction flask, benzyl 4-chloroacetoacetate (22.6 g, 0.10 mol) and trimethyl phosphonite (17.8 g, 0.12 mol) were added. The mixture was stirred at 40 °C for 18 hours. After the reaction was completed, the trimethyl phosphonite was removed under vacuum (15 kPa) at 50 °C to obtain 52 g of viscous oil. The obtained viscous oil (52 g) was dissolved in 2 times its weight of potassium hydroxide aqueous solution (104 g, potassium hydroxide:water weight ratio 1:70) and extracted three times with 2 times its weight of dichloromethane (104 g × 3 times). The layers were separated by a separatory funnel. The organic phase was washed twice with 2 times its weight of saturated brine (104 g × 2 times), and the aqueous phase was extracted once with 1 times its weight of dichloromethane (52 g × 1 time). The organic phases were combined and dried for 0.5 hours with 0.5 times its weight of anhydrous magnesium sulfate (26 g). After filtration, the organic phase was rotary evaporated (15 kPa) at 15°C. After removing the solvent dichloromethane at 35°C (kPa), a colorless oily liquid was obtained. Yield: 89%.

[0035] Spectral data of 1-benzyloxyethoxycarbonyl-1-vinyldimethoxyphosphate: 1 H NMR (600 MHz, CDCl3) δ 7.33 – 7.29 (m, 5H), 5.13 (s, 2H), 5.01 (s, 1H), 4.70 (s, 1H), 3.79 (d, J = 11.3 Hz, 3H), 3.73 (d, J = 11.4 Hz (6H), 3.27 (s, 2H). 13 C NMR (151 MHz, CDCl3) δ 168.60, 147.97 (d, J = 7.5 Hz), 135.45,128.52, 128.28, 101.19 (d, J = 3.5 Hz), 98.38, 98.20, 66.87, 54.79, 40.53. 31 P NMR (243 MHz, CDCl3) δ -4.95.

[0036] (2) Z Synthesis of 2-benzyloxycarbonyl-1-methylvinyldimethoxyphosphate 1-Isopropyloxyethoxycarbonyl-1-vinylmethylmethoxyphosphate (6.00 g, 2.0 mmol) was dissolved in 20 mL of acetonitrile, and triethylamine (0.02 g, 0.2 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by vacuum distillation under vacuum (15 kPa) at 50 °C. The residue (7.2 g) was dissolved in twice its weight of water (14.4 g), and extracted three times with twice its weight of ethyl acetate (14.4 g × 3 times). The ethyl acetate was removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z The crude product of type 3 conjugated enol phosphate (3) was separated by column chromatography (eluent ratio of n-hexane:ethyl acetate = 1:0.8). The eluent containing the product was then removed by rotary evaporation under vacuum (15 kPa) at 50 °C to obtain ( Z 2-Benzyloxycarbonyl-1-methylvinyldimethoxyphosphate, pure product, yield: 94%.

[0037] ( Z Spectral data of 2-benzyloxycarbonyl-1-methylvinyldimethoxyphosphate: 1 H NMR (600 MHz, CDCl3) δ 7.43 – 7.28 (m, 5H), 5.86 (s, 1H), 5.14 (s,2H), 3.84 (s, 3H), 3.82 (s, 3H), 2.42 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.98, 163.57, 135.86, 128.53, 128.21,105.93 (d, J = 4.5 Hz), 66.06, 55.00 (d, J = 6.0 Hz), 18.54 (d, J = 4.5 Hz). 31 P NMR (243 MHz, CDCl3) δ -5.94.

[0038] Example 6 The difference between this embodiment and Example 1 is that in step (1), trimethyl phosphite (0.2 mol) is stirred at 25°C for 24 hours; the rest is the same as in Example 1.

[0039] Example 7 The difference between this embodiment and Example 1 is that in step (1), trimethyl phosphite (0.15 mol) is stirred at 30°C for 24 hours; the rest is the same as in Example 1.

[0040] Example 8 The difference between this embodiment and Example 1 is that in step (2), 1-methoxyethoxycarbonyl-1-vinyldimethoxyphosphate (2.0 mmol) is dissolved in 15 mL of acetonitrile, and triethylamine (0.4 mmol) is added to it. The mixture is stirred at room temperature for 4 hours. Otherwise, it is the same as in Example 1.

[0041] In summary, the overall effect of the above examples is that this invention enables the achievement of a single configuration with a yield greater than 92%. Z Synthesis of conjugated enol phosphate esters.

[0042] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for synthesizing (Z)-type conjugated enol phosphate, characterized in that, Includes the following steps: (1) Synthesis of enol phosphate: 4-chloroacetoacetate reacts with phosphite. The reaction should end when LC-MS detection is completed. The product is then separated and purified to obtain enol phosphate. (2) Synthesis of (Z) type conjugated enol phosphate: Enol phosphate, triethylamine and acetonitrile are mixed and stirred at room temperature. The reaction should end when LC-MS detection is completed. The product is separated and purified to obtain (Z) type conjugated enol phosphate.

2. The synthesis method according to claim 1, characterized in that, The 4-chloroacetoacetate is methyl 4-chloroacetoacetate, ethyl 4-chloroacetoacetate, benzyl 4-chloroacetoacetate, or isopropyl 4-chloroacetoacetate.

3. The synthesis method according to claim 1, characterized in that, The phosphite is trimethoxyphosphite, triethoxyphosphite, phenyl dimethoxyphosphonite, or methoxydiphenylphosphonite.

4. The synthesis method according to claim 1, characterized in that, In step (1), the molar ratio of 4-chloroacetoacetate to phosphite is 1:1.2 to 2.

5. The synthesis method according to claim 1, characterized in that, In step (1), the reaction temperature is 25-40℃.

6. The synthesis method according to claim 1, characterized in that, In step (2), the ratio of enol phosphate: triethylamine: acetonitrile is 1 mmol: 0.1-0.2 mmol: 15-20 mL.

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