Method for synthesizing beta-ketone ester

Abstract

The invention discloses a method for synthesizing beta-ketone ester, which comprises the following steps: mixing an organic metal reagent solution and an ester A solution in a first microchannel reactor, reacting I to obtain an enol intermediate, mixing the enol intermediate and an ester B solution in a second microchannel reactor, reacting II, and carrying out acid quenching to obtain the beta-ketone ester, the first micro-channel reactor and the second micro-channel reactor are communicated in sequence; the organic metal reagent is selected from at least two of methyl lithium, n-butyllithium, sec-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and potassium tert-butoxide; a solvent in the organic metal reagent solution is selected from at least one of tetrahydrofuran, normal hexane, cyclohexane and normal heptane.

Description

Technical Field

[0001] The present application relates to a method for synthesizing β-ketoester, belonging to the field of organic synthesis. Background Art

[0002] β-Ketoester compounds are widely present in natural products, drug intermediates and other functionalized molecules. As a very important class of organic intermediates, they are widely used in the synthesis of various natural products and drugs. Claisen ester condensation, as an ancient organic synthesis method, is widely used in the synthesis of β-ketoester compounds. In a strong alkaline environment, the ester with α-hydrogen is deprotonated to form an enol ester intermediate, and then condenses with the same ester or different esters to form β-ketoester. Depending on whether condensation occurs with the same ester, it can be divided into self-ester condensation reaction and cross-ester condensation reaction. Among them, cross-ester condensation reaction is more likely to generate a rich structure of β-ketoester structure and is widely used in various syntheses.

[0003] Conventional cross-ester condensation reaction process is, first under strong alkaline environment, ester with α-hydrogen is deprotonated to generate lithium enolate intermediate, then cross-condensation is carried out by introducing ester (such as formates, carbonates, aromatic acid esters etc.) without α-hydrogen. However, ester with α-hydrogen itself is also easy to undergo condensation reaction under strong alkaline conditions, producing self-condensation by-products, especially for ethyl acetate or methyl acetate with small steric hindrance etc. In order to ensure yield, it is often necessary to feed ester with α-hydrogen by excessive feeding, which not only causes the problem of poor atom economy, but also easily causes the problem that self-condensation by-products are difficult to separate from the cross-condensation main product, greatly increasing separation cost and post-processing difficulty. When cross-ester condensation is carried out for aromatic acid ester with carbonyl inertness, it is necessary to use large steric hindrance strong base such as lithium diisopropylamide to deprotonate the ester containing α-hydrogen under ultra-low temperature conditions to quickly provide sufficient lithium enolate intermediate. If the carbonyl inertness of the aromatic ester is too strong, the inertness of the carbonyl in the substrate will also increase the probability of the deprotonated lithium enolate intermediate undergoing condensation itself, thus requiring a large excess of feed to ensure the smooth progress of the reaction. If necessary, the aromatic ester substrate must be activated in advance (acyl chloride, imidazole activation) to increase the activity of the carbonyl attacked by nucleophilic attack. In summary, the existing cross-ester condensation strategy, especially for inert substrates of aromatic esters, has the problems of harsh reaction conditions, pre-activation treatment, poor atom economy, low yield, and high impurity content, which restricts the industrial application of this reaction in the preparation of β-ketoesters. Summary of the invention

[0004] In view of the above-mentioned problems, the present invention has developed a type of continuous flow technology based on a microreactor that is widely applicable to the rapid preparation of β-ketoesters by cross-ester condensation. The present invention utilizes the significant advantages of microreactors in mixing, mass transfer, and heat transfer, and the reaction can be carried out smoothly at close to room temperature. Based on the "double base" system, the two types of esters can obtain a satisfactory yield at a molar ratio close to 1.0, and no self-condensation products are produced, which greatly improves the atomic economy of this type of reaction and greatly reduces the post-processing cost, realizes continuous, safe, and efficient synthesis, greatly improves the accessibility of industrial applications, and provides an efficient and concise technical approach for the industrial synthesis of β-ketoesters.

[0005] The purpose of the present invention is to realize mild, efficient and safe synthesis of β-ketoester based on the remarkable advantages of microreactor in mixing, mass transfer and heat transfer. To achieve the above purpose, the present invention discloses a method for rapidly preparing β-ketoester by cross-ester condensation based on microreactor continuous flow technology. The process steps involved in the present invention are three parts: organic metal-mediated hydrogen extraction reaction to generate lithium enolate intermediate, nucleophilic addition-substitution reaction and quenching reaction.

[0006] According to one aspect of the present application, there is provided a method for synthesizing β-ketoester, comprising the following steps:

[0007] The organic metal reagent solution and the lipid A solution are mixed in the first microchannel reactor to perform reaction I to obtain an enol intermediate, and the enol intermediate and the lipid B solution are mixed in the second microchannel reactor to perform reaction II, acid quenching to obtain a β-ketoester;

[0008] The first microchannel reactor and the second microchannel reactor are connected in sequence;

[0009] The organometallic reagent is selected from at least two of methyl lithium, n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, and potassium tert-butoxide;

[0010] The solvent in the organic metal reagent solution is selected from at least one of tetrahydrofuran, n-hexane, cyclohexane and n-heptane;

[0011] The lipid A has a structure shown in Formula I:

[0012]

[0013] The enol intermediate has a structure shown in Formula II:

[0014]

[0015] The lipid B has a structure shown in formula III:

[0016]

[0017] The β-ketoester has a structure shown in Formula IV:

[0018]

[0019] in,

[0020] R1 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted or substituted aryl, R2 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted or substituted aryl, R3 is selected from one of C1-C6 alkyl, and R4 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted or substituted aryl;

[0021] M is selected from one of Li, Na and K.

[0022] Optionally, the organometallic reagent comprises component one and component two;

[0023] The first component is lithium diisopropylamide;

[0024] The second component is selected from at least one of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium tert-butoxide, and potassium tert-butoxide;

[0025] The molar ratio of component one to component two is 1:1-2;

[0026] Optionally, the molar ratio of component one to component two is 1:1.2 to 1.8.

[0027] The solvent in the lipid A solution and the lipid B solution is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, and n-heptane;

[0028] The concentrations of the lipid A solution and the lipid B solution are 0.2-1.5 mol / L;

[0029] Optionally, the concentrations of the lipid A solution and the lipid B solution are 0.5-1 mol / L.

[0030] The molar ratio of lipid A to the organometallic reagent is 1:1.4-3;

[0031] Optionally, the molar ratio of lipid A to organometallic reagent is 1:1.8-2.6.

[0032] The molar ratio of lipid A to lipid B is 1-1.2:1.

[0033] The temperature of the reaction I is 0 to 30°C;

[0034] The reaction time I is 0.1 to 1 s.

[0035] The temperature of the reaction II is 0 to 30°C;

[0036] The time of the reaction II is 1 s to 1 min.

[0037] Optionally, the lipid B is selected from at least one of methyl formate, aromatic methyl ester, oxygen-containing aromatic ester, sulfur-containing aromatic ester and nitrogen-containing aromatic ester.

[0038] The acid is selected from at least one of dilute sulfuric acid, dilute hydrochloric acid, dilute phosphoric acid, citric acid, sodium citrate-citric acid buffer solution, acetic acid, trifluoroacetic acid, and ammonium chloride-dilute hydrochloric acid solution;

[0039] The concentration of the acid is 0.1 to 2 mol / L;

[0040] The acid contains at least one of sodium sulfate, sodium carbonate, sodium chloride, sodium hydrogen phosphate and sodium bicarbonate.

[0041] The quenching temperature is 0 to 20°C;

[0042] The quenching time is 1 to 5 minutes;

[0043] The quenching is carried out in a quenching kettle.

[0044] Specifically, the steps include:

[0045] (1) Hydrogen extraction reaction mediated by the organometallic reagent:

[0046] The mixed organic metal reagent solution and the ester A solution with α-hydrogen are pumped into the first channel microreactor, and reacted at 0-30°C for 0.1-1s to generate a lithium enolate intermediate. The organic metal reagent in the mixed organic metal reagent solution is at least two of methyl lithium, n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, and potassium tert-butoxide; the solvent in the mixed organic metal reagent solution is at least one of tetrahydrofuran, n-hexane, cyclohexane, and n-heptane; the solvent of the ester A solution includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, and n-heptane, preferably tetrahydrofuran;

[0047] (2) Nucleophilic addition-substitution reaction:

[0048] The active intermediate solution and the ester B solution generated in step (1) are pumped into a second microchannel reactor, wherein the molar ratio of ester A to ester B is 1:1-1.2:1, and a nucleophilic addition-substitution reaction is carried out at 0-30° C. for a reaction time of 1 s-1 min to generate a β-ketoester enolate. The solvent of the ester B solution comprises at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, and n-heptane, preferably tetrahydrofuran;

[0049] (3) Quenching reaction:

[0050] The β-ketoester enolate generated in step (2) is introduced into a quenching kettle filled with an acid aqueous solution, and reacts with the acid at a certain temperature for a certain time to generate a stable β-ketoester product with a yield greater than 80%.

[0051] The beneficial effects of this application include:

[0052] The present invention innovatively proposes a method for rapidly preparing β-ketoesters by cross-ester condensation based on microreactor continuous flow technology; compared with the traditional kettle process, the present invention achieves a breakthrough from ultra-low temperature conditions to near room temperature conditions; when condensing aromatic esters with substrate inertness, mild and efficient synthesis of aromatic esters without pre-activation and under the condition of a molar ratio of two types of esters close to 1.0 is achieved; the reaction yield is high, no self-condensation by-products are generated, and a high-purity β-ketoester product can be obtained through a simple post-treatment process, and direct feeding of downstream reactions can be achieved without a complicated column chromatography process, which reduces the process time of post-treatment and reduces the process cost of post-treatment, and provides a fast and efficient synthesis route for downstream conversion based on β-ketoester; the method has a wide substrate applicability, a simple and efficient process, a synthesis yield of more than 80%, and a synthesis purity of more than 90%, which greatly improves the accessibility of industrial synthesis of β-ketoesters. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 Schematic diagram of the device used in Example 1.

[0054] N2 Gas-N2 gas storage tank; 1: organic metal reagent storage tank; 2: ester A solution storage tank; 3: ester B solution storage tank; 4: quenching liquid storage tank; 5: quenching kettle; R1: first microchannel reactor; R2: second microchannel reactor; DETAILED DESCRIPTION

[0055] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0056] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0057] Example 1

[0058] use Figure 1The device shown; before the reaction starts, a mixed organic metal reagent solution and ester A and ester B solutions of specific concentrations are pre-prepared, and the organic metal reagent solution storage tank is stored at 0°C throughout the operation. Open the nitrogen storage tank, and introduce nitrogen into the reaction system for 10 minutes to replace the air in the system. After the pressure in the system is stable, open the storage tank containing ester A solution and the storage tank containing the organometallic reagent, set the flow rate of the horizontal flow pump to 10 ml / min, and pump the two raw material liquids into the first microchannel reactor; after the operation is stable, open the storage tank containing ester B solution, set the flow rate of the horizontal flow pump to 10 ml / min; set the residence time in the first microchannel reactor to 0.5s, and the residence time in the second microchannel reactor to 1min, and operate the reaction at 20°C throughout the process; after the operation is stable, open the quenching liquid storage tank, set the flow rate of the horizontal flow pump to 30 ml / min, and the reaction solution and the quenching liquid are mixed and then enter the quenching tank, stir at 20°C for 5 minutes, and after the operation is completed, end the stirring, wait for phase separation and then discharge the aqueous phase, retain the upper organic phase, and remove the solvent by reduced pressure distillation to obtain a β-ketoester condensation product.

[0059] Example 2

[0060] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the mixed organic metal reagent solution is a 1 mol / L lithium diisopropylamide and a 1.2 mol / L lithium bistrimethylsilylamide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 92% and a purity of 96% as monitored by high performance liquid chromatography;

[0061] 1 H NMR (400MHz, CDCl3): δ (ppm) 9.09 (d, J = 1.9 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.20 (dt, J = 8.0 ,1.6Hz,1H),7.47-7.36(m,1H),4.16(q,J=7.1Hz,2H),3.97(s,2H),1.28(t,J=7.1Hz,3H)minor tautomer:12.52(s,1H),8.93(d,J=1.9Hz,1H),8.63(dd,J=4.8,1.5Hz,1H),8.06-7.95(m ,1H),7.33(dd,J=7.9,4.9Hz,1H),5.66(s,1H),4.22(q,7.1Hz,2H),1.28(t,J=7.1Hz,3H).

[0062] 13C NMR (100MHz, CDCl3): δ (ppm) 191.6,172.8,168.7,167.0,154.2,151.9,150.0,147 .4,135.9,133.5,131.2,129.2,123.9,123.5,88.6,61.9,60.7,46.0,14.3,14.1.

[0063] The structure of the product deduced from the above data is as follows:

[0064]

[0065] Example 3

[0066] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the mixed organic metal reagent solution is composed of a 1 mol / L lithium diisopropylamide and a 1.2 mol / L lithium bistrimethylsilylamide tetrahydrofuran solution, the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution, the residence time in the first microchannel reactor is 2 min, the residence time in the second microchannel reactor is 2 min, after the reaction is completed, the organic phase is retained, and the solvent is removed by reduced pressure distillation to obtain a light yellow oily product with a weighed yield of 62% and a purity of 72% monitored by high performance liquid chromatography;

[0067] Example 4

[0068] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the mixed organic metal reagent solution is a 1 mol / L lithium diisopropylamide and a 1.2 mol / L lithium bistrimethylsilylamide tetrahydrofuran solution, the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution, and the reaction temperature is set to 0°C; after the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain a light yellow oily product with a weighed yield of 76% and a purity of 89% as monitored by high performance liquid chromatography;

[0069] Example 5

[0070] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the mixed organic metal reagent solution is a 1 mol / L lithium diisopropylamide and a 1.2 mol / L lithium bistrimethylsilylamide tetrahydrofuran solution, the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution, and the reaction temperature is set to -20°C; after the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain a light yellow oily product with a weighed yield of 89% and a purity of 93% as monitored by high performance liquid chromatography;

[0071] Example 6

[0072] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L tetrahydrofuran solution of methyl propionate, the mixed organic metal reagent solution is composed of a 1 mol / L tetrahydrofuran solution of lithium diisopropylamide and a 1.2 mol / L tetrahydrofuran solution of lithium bistrimethylsilylamide, and the ester B solution is a 1 mol / L tetrahydrofuran solution of methyl formate. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 89% and a purity of 92% as monitored by high performance liquid chromatography;

[0073] 1 H NMR (400MHz, CDCl3): δ (ppm) 9.72 (d, J = 2.4Hz, 1H), 3.79 (s, 3H), 3.23 (dt, J = 7.1, 2.4Hz 1H), 1.94 (dq, J = 7.4, 7.2Hz, 2H), 0.99 (t, J = 6.2Hz, 3H).

[0074] 13 C NMR (400MHz, CDCl3): δ (ppm) 197.4, 170.0, 60.0, 52.3, 20.1, 11.5.

[0075] The structure of the product deduced from the above data is as follows:

[0076]

[0077] Example 7

[0078] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L tetrahydrofuran solution of tert-butyl propionate, the mixed organic metal reagent solution is a 1 mol / L tetrahydrofuran solution of lithium diisopropylamide and 1.2 mol / L tetrahydrofuran solution of lithium bistrimethylsilylamide, and the ester B solution is a 1 mol / L tetrahydrofuran solution of methyl formate. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 96% and a purity of 98% as monitored by high performance liquid chromatography;

[0079] 1 H NMR (400MHz, CDCl3): δ (ppm) 9.72 (d, J = 1.6Hz, 1H), 3.28 (qd, J = 7.2, 1.5Hz, 1H), 1.46 (s, 9H), 1.27 (d, J = 7.2Hz, 3H).

[0080] 13 C NMR (400MHz, CDCl3): δ (ppm) 197.8, 169.0, 82.2, 53.5, 28.0, 10.1.

[0081] The structure of the product deduced from the above data is as follows:

[0082]

[0083] Example 8

[0084] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L tetrahydrofuran solution of tert-butyl acetate, the mixed organic metal reagent solution is a 1 mol / L tetrahydrofuran solution of lithium diisopropylamide and 1.2 mol / L tetrahydrofuran solution of lithium bistrimethylsilylamide, and the ester B solution is a 1 mol / L tetrahydrofuran solution of methyl 2-cyano-4-pyridine. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 85% and a purity of 98% as monitored by high performance liquid chromatography.

[0085] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.96 (d, J = 5.0Hz, 1H), 8.18 (s, 1H), 7.82 (m, 1H), 3.9 (s, 2H), 1.41 (s, 9H).

[0086] 13 C NMR (400MHz, CDCl3): δ (ppm) 190.5, 165.2, 152.5, 143.2, 135.4, 126.2, 122.6, 116.6, 83.4, 47.2, 27.9

[0087] The structure of the product deduced from the above data is as follows:

[0088]

[0089] Example 9

[0090] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L tetrahydrofuran solution of methyl phenylacetate, the mixed organic metal reagent solution is a 1 mol / L tetrahydrofuran solution of lithium diisopropylamide and 1.2 mol / L tetrahydrofuran solution of lithium bistrimethylsilylamide, and the ester B solution is a 1 mol / L tetrahydrofuran solution of methyl methoxyacetate. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 96% and a purity of 98% as monitored by high performance liquid chromatography;

[0091] 1H NMR (400MHz, CDCl3): δ (ppm) 3.35 (s, 3H), 3.74 (s, 3H), 3.86 (s, 1H), 4.08 (s, 2H), 7.31-7.36 (m, 5H).

[0092] The structure of the product deduced from the above data is as follows:

[0093]

[0094] Example 10

[0095] The specific reaction process is similar to that of Example 1, wherein the ester A solution is a 1 mol / L tetrahydrofuran solution of methyl 2-methoxyphenylacetate, the mixed organic metal reagent solution is a 1 mol / L tetrahydrofuran solution of lithium diisopropylamide and 1.2 mol / L bistrimethylsilyl lithium amide, and the ester B solution is a 1 mol / L tetrahydrofuran solution of methyl methoxyacetate. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 87% and a purity of 92% as monitored by high performance liquid chromatography.

[0096] 1 H NMR (400MHz, CDCl3): δ (ppm) 3.36 (s, 3H), 3.74 (s, 3H), 3.81 (s, 3H), 4.11 (d, J = 7.2Hz, 2H), 5.32 (s, 1H), 6.88-6.94 (m, 2H), 7.23-7.33 (m, 2H).

[0097] The structure of the product deduced from the above data is as follows:

[0098]

[0099] Comparative Example 1

[0100] A mixed organic metal reagent solution and ester A and ester B solutions of specific concentrations are pre-prepared, and the organic metal reagent solution storage tank is kept at 0°C throughout the operation. Open the nitrogen storage tank, and introduce nitrogen into the reactor system for 10 minutes to replace the air in the system. After the pressure in the system is stable, open the storage tank containing the organic metal reagent, pump 100 ml of the organic metal reagent into the reactor, and cool to -78°C; open the ester A solution storage tank, and drop 100 ml of the tetrahydrofuran solution of ester A into the reactor, control the dropping temperature to be lower than -60°C, stir for 15 minutes, and restore the reaction temperature to -78°C; drop 100 ml of the tetrahydrofuran solution of ester B into the reaction mixture, control the dropping temperature to be lower than -60°C, maintain the reaction temperature at -78°C and stir for 15 minutes, and then slowly restore to room temperature and stir for 2 hours; open the quenching liquid storage tank, drop 300 ml of the quenching liquid into the reactor, maintain stirring at room temperature for 15 minutes; stop stirring, wait for phase separation and then discharge the aqueous phase, recover the organic phase, and remove the solvent by reduced pressure distillation to obtain a β-ketoester condensation product.

[0101] Comparative Example 2

[0102] The specific reaction process is similar to that of Comparative Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate solution in tetrahydrofuran, the mixed organic metal reagent solution is composed of a 1 mol / L lithium diisopropylamide and a 1.2 mol / L lithium bistrimethylsilylamide solution in tetrahydrofuran, and the ester B solution is a 1 mol / L nicotinate methyl ester solution in tetrahydrofuran. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 59% and a purity of 86% monitored by high performance liquid chromatography.

[0103] Comparative Example 3

[0104] The specific reaction process is similar to that of Comparative Example 1, and the whole operation is carried out at room temperature. The ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the mixed organic metal reagent solution is composed of a 1 mol / L lithium diisopropylamide and a 1.2 mol / L lithium bistrimethylsilylamide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by reduced pressure distillation to obtain a light yellow oily product with a weighed yield of 70% and a purity of 88% monitored by high performance liquid chromatography.

[0105] Comparative Example 4

[0106] The specific reaction process is similar to that of Comparative Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 2 mol / L lithium diisopropylamide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 22% and a purity of 30% monitored by high performance liquid chromatography.

[0107] Comparative Example 5

[0108] The specific reaction process is similar to that of Comparative Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate solution in tetrahydrofuran, the organic metal reagent solution is a 2 mol / L lithium bis(trimethylsilyl)amide solution in tetrahydrofuran, and the ester B solution is a 1 mol / L nicotinate methyl ester solution in tetrahydrofuran. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 25% and a purity of 32% monitored by high performance liquid chromatography.

[0109] Comparative Example 6

[0110] The specific reaction process is similar to that of Comparative Example 1, wherein the ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 2 mol / L potassium tert-butoxide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain a light yellow oily product with a weighed yield of 9% and a purity of 25% monitored by high performance liquid chromatography.

[0111] Comparative Example 7

[0112] The specific reaction process is similar to that of Comparative Example 1, and the whole operation is carried out at room temperature. The ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 2 mol / L potassium tert-butoxide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain a light yellow oily product with a weighed yield of 40% and a purity of 42% monitored by high performance liquid chromatography.

[0113] Comparative Example 8

[0114] The specific reaction process is similar to that of Example 1, and a continuous flow operation is adopted. The ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 2 mol / L lithium diisopropylamide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain a light yellow oily product with a weighed yield of 2% and a purity of 1% monitored by high performance liquid chromatography.

[0115] Comparative Example 9

[0116] The specific reaction process is similar to that of Example 1, and a continuous flow operation is adopted. The ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 2 mol / L lithium bis(trimethylsilyl)amide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 68% and a purity of 88% monitored by high performance liquid chromatography.

[0117] Comparative Example 10

[0118] The specific reaction process is similar to that of Example 1, and a continuous flow operation is adopted. The ester A solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 2 mol / L potassium tert-butoxide tetrahydrofuran solution, and the ester B solution is a 1 mol / L nicotinate methyl ester tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a light yellow oily product with a weighed yield of 32% and a purity of 39% monitored by high performance liquid chromatography.

[0119] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for synthesizing β-ketoesters, characterized in that: The following steps are involved: The organic metal reagent solution and the lipid A solution are mixed in the first microchannel reactor to perform reaction I to obtain an enol intermediate, and the enol intermediate and the lipid B solution are mixed in the second microchannel reactor to perform reaction II, acid quenching to obtain a β-ketoester; The first microchannel reactor and the second microchannel reactor are connected in sequence; The organometallic reagent is selected from at least two of methyl lithium, n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, and potassium tert-butoxide; The solvent in the organic metal reagent solution is selected from at least one of tetrahydrofuran, n-hexane, cyclohexane and n-heptane; The lipid A has a structure shown in Formula I: The enol intermediate has a structure shown in Formula II: The lipid B has a structure shown in formula III: The β-ketoester has a structure shown in Formula IV: in, R1 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted or substituted aryl, R2 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted or substituted aryl, R3 is selected from one of C1-C6 alkyl, and R4 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted or substituted aryl; M is selected from one of Li, Na and K.

2. The method according to claim 1, characterized in that The organometallic reagent comprises component one and component two; The first component is lithium diisopropylamide; The second component is selected from at least one of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium tert-butoxide, and potassium tert-butoxide; The molar ratio of component one to component two is 1:1-2; Preferably, the molar ratio of component one to component two is 1:1.2-1.

8.

3. The method according to claim 1, characterized in that The solvent in the lipid A solution and the lipid B solution is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, and n-heptane; The concentrations of the lipid A solution and the lipid B solution are 0.2-1.5 mol / L; Preferably, the concentrations of the lipid A solution and the lipid B solution are 0.5-1 mol / L.

4. The method according to claim 1, characterized in that: The molar ratio of lipid A to the organometallic reagent is 1:1.4-3; Preferably, the molar ratio of lipid A to organometallic reagent is 1:1.8-2.

6.

5. The method according to claim 1, characterized in that The molar ratio of lipid A to lipid B is 1-1.2:

1.

6. The method according to claim 1, characterized in that The temperature of the reaction I is 0 to 30°C; The reaction time I is 0.1 to 1 s.

7. The method according to claim 1, characterized in that The temperature of the reaction II is 0 to 30°C; The time of the reaction II is 1 s to 1 min.

8. The method according to claim 1, characterized in that: The lipid B is selected from at least one of methyl formate, aromatic methyl ester, oxygen-containing aromatic ester, sulfur-containing aromatic ester and nitrogen-containing aromatic ester.

9. The method according to claim 1, characterized in that: The acid is selected from at least one of dilute sulfuric acid, dilute hydrochloric acid, dilute phosphoric acid, citric acid, sodium citrate-citric acid buffer solution, acetic acid, trifluoroacetic acid, and ammonium chloride-dilute hydrochloric acid solution; The concentration of the acid is 0.1 to 2 mol / L; The acid contains at least one of sodium sulfate, sodium carbonate, sodium chloride, sodium hydrogen phosphate and sodium bicarbonate.

10. The method according to claim 1, characterized in that The quenching temperature is 0 to 20°C; The quenching time is 1 to 5 minutes; The quenching is carried out in a quenching kettle.

Images