Method for co-producing beta-hydroxy ester, beta-hydroxy carboxylic acid and alpha, beta-unsaturated carboxylic acid
By adopting the α-coupling strategy mediated by microreactors and organometallic lithium in the synthesis of β-hydroxyesters, β-hydroxycarboxylic acids and α,β-unsaturated carboxylic acids, the problems of harsh reaction conditions and unstable yields in the prior art are solved, and an efficient and continuous synthesis process is achieved, which reduces costs and provides a technical approach for green cleaning.
Patent Information
- Application Number
- CN202411833980.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-12
- Publication Date
- 2025-04-25
AI Technical Summary
The prior art has problems such as harsh reaction conditions, unstable yields, and limited industrial-scale applications in the synthesis of β-hydroxy esters, β-hydroxy carboxylic acids and α,β-unsaturated carboxylic acids.
By leveraging the mass transfer and mixing advantages of microreactors, the ester α-coupling strategy mediated by organometallic lithium is adopted to achieve efficient synthesis of β-hydroxy ester at room temperature, and the continuous and efficient synthesis of β-hydroxy carboxylic acid and α,β-unsaturated carboxylic acid is achieved through continuous flow strategy and online separation process.
The efficient and continuous synthesis of β-hydroxyesters, β-hydroxycarboxylic acids and α,β-unsaturated carboxylic acids is achieved, reducing industrial refrigeration costs, reducing post-treatment process flow and cost, and providing a green cleaning technical approach.
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Figure CN119874608A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to a method for the co-production of β-hydroxy ester, β-hydroxy carboxylic acid and α,β-unsaturated carboxylic acid, belonging to the field of chemistry and chemical engineering. Background Art
[0002] β-Hydroxyesters, β-hydroxycarboxylic acids, and α,β-unsaturated carboxylic acids are three types of structures that are widely found in natural products, drug intermediates, and other functional molecules. Among them, the Reformatsky reaction and the organometallic lithium-mediated ester α-coupling strategy are widely used in the synthesis of β-hydroxyesters. Although the metal zinc-mediated Reformatsky coupling reaction has the advantages of mild reaction conditions and high yield, it requires the pre-preparation of α-haloesters, which greatly limits its substrate flexibility. In addition, the solid-liquid suspension reaction system also has the problems of slow reaction rate and unstable yield, which limits its industrial-scale application. Although the organometallic lithium-mediated ester α-coupling strategy can overcome the above problems and solve the Reformatsky reaction, the required ultra-low temperature -78oC environment makes the reaction conditions very harsh and the industrial refrigeration cost is high. Kappe et al. (Tetrahedron, 2018, vol 74, Page: 3113-3117; Reaction Chemistry Engineering, 2019, vol 4, Page: 1571-1578) took advantage of the heat and mass transfer of microreactors and realized the preparation of β-hydroxy esters from sterically hindered tert-butyl esters mediated by lithium diisopropylamide at 0-20°C, but the preparation of sterically hindered methyl and ethyl esters was not possible.
[0003] The preparation of β-hydroxycarboxylic acids can be obtained by pre-preparing the enol silyl ether of carboxylic acids and then coupling them with aldehydes / ketones. However, carboxylic acids with large steric hindrance are difficult to couple by pre-preparing the enol silyl ether. In addition, the Knoevenagel condensation and the Horner–Wadsworth–Emmons reaction can both achieve a one-pot preparation of α,β-unsaturated carboxylic acids. The environmental pollution caused by the pyridine solvent used in the Knoevenagel condensation limits its industrial application, and the problems of phosphorus-containing wastewater and complex phosphorus-containing byproducts in the Horner–Wadsworth–Emmons reaction further increase the cost and difficulty of industrial post-treatment. Summary of the invention
[0004] In view of the above problems, the present invention gives full play to the advantages of microreactors in mixing, mass transfer and heat transfer, firstly adopts an ester α-coupling strategy mediated by organic metal lithium to achieve mild and efficient synthesis of β-hydroxy ester at room temperature, and then realizes the online separation of intermediates by designing a continuous flow strategy, so as to realize the continuous and efficient synthesis of downstream products β-hydroxy carboxylic acid and α, β-unsaturated carboxylic acid. In the synthesis of β-hydroxy ester, the equimolar condensation of ester with atom economy and aldehyde / ketone substrate is realized, which greatly inhibits the formation of self-condensation by-products, and the synthesis yield is higher than 95%; the synthesis yields of downstream β-hydroxy carboxylic acid and α, β-unsaturated carboxylic acid are higher than 90%; by designing a good post-processing strategy, the continuous and efficient separation of β-hydroxy ester, β-hydroxy carboxylic acid and α, β-unsaturated carboxylic acid can be achieved without column chromatography treatment and by simple treatment, and the product purity is greater than 90%. The present invention provides a continuous, efficient, green and clean technical approach for the industrial synthesis of β-hydroxy ester, β-hydroxy carboxylic acid and α, β-unsaturated carboxylic acid.
[0005] The purpose of the present invention is to realize the continuous and efficient synthesis of β-hydroxy esters, β-hydroxy carboxylic acids and α, β-unsaturated carboxylic acids based on the mass transfer and mixing advantages of a microreactor.
[0006] According to one aspect of the present application, a method for co-producing β-hydroxy ester, β-hydroxy carboxylic acid and α,β-unsaturated carboxylic acid is provided, which includes three parts: preparing β-hydroxy ester based on Aldol condensation, preparing β-hydroxy carboxylic acid by hydrolysis of β-hydroxy ester, and preparing α,β-unsaturated carboxylic acid by dehydration of β-hydroxy carboxylic acid having α-hydrogen, and comprising the following steps:
[0007] (1) mixing an organometallic reagent solution and an ester solution in a first microchannel reactor to perform reaction I to obtain a lithium enolate intermediate, mixing the lithium enolate intermediate and an aldehyde solution or a ketone solution in a second microchannel reactor to perform reaction II, and acid quenching I to obtain a β-hydroxy ester;
[0008] (2) mixing the β-hydroxy ester with an aqueous solution of an inorganic base, reacting III in a third microchannel reactor, and acid quenching II to obtain a β-hydroxy carboxylic acid;
[0009] (3) R 1 The β-hydroxycarboxylic acid having H is mixed with an aqueous sulfuric acid solution, and reacted in a fourth microchannel reactor to obtain an α,β-unsaturated carboxylic acid having an E-configuration;
[0010] The first microchannel reactor, the second microchannel reactor, the third microchannel reactor, and the fourth microchannel reactor are connected in sequence;
[0011] The organometallic reagent is selected from at least one of methyl lithium, n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide;
[0012] The solvent in the organic metal reagent solution is selected from at least one of tetrahydrofuran, n-hexane, cyclohexane and n-heptane;
[0013] The ester has a structure shown in Formula I:
[0014]
[0015] The lithium enolate intermediate has a structure shown in Formula II:
[0016]
[0017] The aldehyde or ketone has a structure shown in Formula III:
[0018]
[0019] The β-hydroxy ester has a structure shown in Formula IV:
[0020]
[0021] The β-hydroxycarboxylic acid has a structure shown in Formula V:
[0022]
[0023] The α,β-unsaturated carboxylic acid has a structure shown in Formula VI:
[0024]
[0025] in,
[0026] R 1 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted aryl or substituted aryl, R 2 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted aryl or substituted aryl, R 3 is selected from one of methyl and ethyl, R 4 is selected from one of hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted aryl or substituted aryl, R 5 One selected from hydrogen, halogen, aliphatic chain, methoxy, and unsubstituted aryl or substituted aryl.
[0027] M is selected from one of Li, Na and K.
[0028] The hydraulic diameters of the first microchannel reactor, the second microchannel reactor, the third microchannel reactor and the fourth microchannel reactor are 100 μm to 500 mm.
[0029] The aldehyde is selected from at least one of aliphatic aldehydes, aromatic aldehydes, oxygen-containing aromatic aldehydes, sulfur-containing aromatic aldehydes, and nitrogen-containing aromatic aldehydes;
[0030] Optionally, the aldehyde is selected from at least one of acetaldehyde, n-valeraldehyde, 3-pyridinealdehyde, benzaldehyde, and phenylacetaldehyde;
[0031] The ketone is selected from at least one of aliphatic ketones, aromatic ketones, oxygen-containing aromatic ketones, sulfur-containing aromatic ketones, and nitrogen-containing aromatic ketones;
[0032] Optionally, the ketone is selected from at least one of acetone, butanone, acetophenone and benzophenone;
[0033] The solvent in the lipid solution, aldehyde solution or ketone solution is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane and n-heptane.
[0034] The molar ratio of the lipid to the organometallic lithium reagent is 1:1 to 1.8;
[0035] The temperature of the reaction I is 0 to 30°C;
[0036] The reaction time I is 0.1 to 1 s;
[0037] The temperature of the reaction II is -10 to 30°C;
[0038] The reaction time of II is 1s to 10min;
[0039] The molar ratio of the aldehyde or ketone to the lipid is 1:1-2.
[0040] The inorganic base is selected from at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate;
[0041] The molar ratio of the beta-hydroxy ester to the inorganic base is 1:10-20.
[0042] The temperature of the reaction III is 0 to 60°C;
[0043] The time of the reaction III is 1 to 10 minutes.
[0044] The concentration of the sulfuric acid aqueous solution is 75-98wt%;
[0045] The temperature of the reaction III is 80-180°C;
[0046] The time of the reaction III is 60 to 240 minutes.
[0047] In the acid quenching I and the acid quenching II,
[0048] The quenching temperature is 0 to 20°C;
[0049] The quenching is carried out in a quenching kettle;
[0050] 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;
[0051] The concentration of the acid is 0.5 to 3 mol / L;
[0052] The acid contains at least one of sodium sulfate, sodium carbonate, sodium chloride, sodium hydrogen phosphate and sodium hydrogen carbonate, and the concentration thereof is saturated.
[0053] 1. Optionally, the following steps are included:
[0054] (1) Preparation of β-hydroxy esters based on Aldol condensation reaction
[0055] The organic metal lithium reagent solution and the methyl ester or ethyl ester solution with at least one α-hydrogen are pumped into the first microchannel reactor in a certain ratio, and reacted at 0℃-30℃ for 0.1s-1s to generate a lithium enolate intermediate; then the lithium enolate intermediate and the aldehyde or ketone solution are pumped into the second microchannel reactor, and the molar ratio of the aldehyde or ketone to the methyl ester or ethyl ester is controlled to be 1:1-1:2, and reacted at -10℃-30℃ for 1s-10min to generate β-hydroxy ester. Under alkaline conditions, β-hydroxy ester exists in the reaction system in the form of lithium alcohol, so the reaction solution is directly flowed into the quenching kettle filled with an acid-containing aqueous solution, and the β-hydroxy ester lithium salt is converted into β-hydroxy ester and enters the organic phase to obtain the product β-hydroxy ester with a yield greater than 80%. The reaction equation is as follows:
[0056]
[0057] Among them, R1 includes but is not limited to hydrogen, halogen, fatty chain, methoxy and unsubstituted or substituted aryl, R2 includes but is not limited to hydrogen, halogen, fatty chain, methoxy and unsubstituted or substituted aryl, R3 is methyl or ethyl, R4 includes but is not limited to hydrogen, halogen, fatty chain, methoxy and unsubstituted or substituted aryl, and R5 includes but is not limited to hydrogen, halogen, fatty chain, methoxy and unsubstituted or substituted aryl.
[0058] (2) Hydrolysis of β-hydroxy esters to β-hydroxy carboxylic acids
[0059] The β-hydroxy ester and inorganic alkali aqueous solution generated in step (1) are introduced into the third microchannel reactor at a certain flow rate, reacted at a certain temperature for 1 min-10 min, and rapidly hydrolyzed under the catalysis of the base to generate β-hydroxycarboxylic acid sodium salt. The generated β-hydroxycarboxylic acid is directly flowed into a quenching kettle filled with saturated sodium sulfate acid aqueous solution, and β-hydroxycarboxylic acid is generated through acid-base neutralization, and the β-hydroxycarboxylic acid enters the aqueous phase to obtain the product β-hydroxycarboxylic acid, with a yield of more than 80%. The reaction equation is as follows:
[0060]
[0061] (3) Dehydration of β-hydroxycarboxylic acid containing α-hydrogen to prepare α,β-unsaturated carboxylic acid
[0062] The α-hydrogen-containing β-hydroxycarboxylic acid generated in step (2) and a certain concentration of sulfuric acid aqueous solution are introduced into the fourth microchannel reactor in a certain proportion, reacted at a certain temperature for a certain time, and an E1 elimination process occurs under acid catalysis to generate an E-configuration α,β-unsaturated carboxylic acid with a yield greater than 80%. The reaction equation is as follows:
[0063]
[0064] The beneficial effects of this application include:
[0065] The present invention proposes a method for rapidly preparing β-hydroxy esters, β-hydroxy carboxylic acids, and α,β-unsaturated carboxylic acids based on microreactor continuous flow technology. Compared with the traditional autoclave process, the mass transfer and mixing advantages of the microreactor realize the transformation of the organic metal lithium reagent-mediated preparation of β-hydroxy esters from the traditional ultra-low temperature environment to room temperature mild operation; through the reasonable design of the continuous online separation process, the rapid downstream conversion of the β-hydroxy ester product to manufacture β-hydroxy carboxylic acids and α,β-unsaturated carboxylic acids is realized. The process of the present invention has mild synthesis conditions and high product yield, realizes the continuous manufacture of β-hydroxy esters, β-hydroxy carboxylic acids, and α,β-unsaturated carboxylic acids, reduces the process flow of post-processing, reduces the post-processing cost, and realizes efficient production. BRIEF DESCRIPTION OF THE DRAWINGS
[0066] Figure 1 This is a schematic diagram of the device used in the embodiment of the present application.
[0067] Among them, N2 Gas-nitrogen gas storage tank; 1: organic metal lithium reagent storage tank; 2: ester solution storage tank; 3: aldehyde / ketone solution storage tank; 4: quenching liquid storage tank; 5: Aldol condensation reaction quenching kettle; 6: inorganic alkali aqueous solution storage tank; 7: hydrolysis reaction quenching kettle; 8: concentrated sulfuric acid; R1: the first microchannel reactor; R2: the second microchannel reactor; R3: the third microchannel reactor; R4: the fourth microchannel reactor. DETAILED DESCRIPTION
[0068] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.
[0069] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.
[0070] Examples 1 to 9 prepare β-hydroxy esters, Examples 10 to 11 prepare β-hydroxy carboxylic acids, and Examples 12 to 13 prepare α,β-unsaturated carboxylic acids
[0071] Example 1
[0072] The experimental process adopted Figure 1 The device shown;
[0073] Before the reaction begins, an organometallic reagent solution and an ester, aldehyde / ketone solution of a specific concentration are pre-prepared. During the entire operation, the organometallic reagent solution storage tank is stored at 0°C. 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 the ester 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 the aldehyde / ketone solution, set the flow rate of the horizontal flow pump to 10 ml / min; set the residence time in the first microchannel reactor to 1 s, and the residence time in the second microchannel reactor to 1 min, 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-hydroxy ester condensation product;
[0074] Example 2
[0075] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 1.2 mol / L lithium diisopropylamide tetrahydrofuran solution, and the aldehyde solution is a 1 mol / L 3-pyridinealdehyde 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 95% and a purity of 98% as monitored by high performance liquid chromatography.
[0076] 1H NMR (400MHz, CDCl3): δ (ppm) 8.52 (d, J = 2.3Hz, 1H), 8.43 (dd, J = 4.9, 1.7Hz, 1H), 7.76 (dt, J = 7.9, 2.0Hz, 1H), 7.28 (ddd, J = 7. 9,4.8,0.9Hz,1H),5.18(dd,J=8.9,4.2Hz,1H),4.90(s,1H),4.16(q,J=7.1Hz,2H),2.94-2.45(m,2H),1.25(t,J=7.1Hz,3H).
[0077] The structure of the product deduced from the above data is as follows:
[0078]
[0079] Example 3
[0080] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 1.2 mol / L lithium diisopropylamide tetrahydrofuran solution, and the aldehyde solution is a 1 mol / L phenylpropionaldehyde 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 colorless oily product with a weighed yield of 88% and a purity of 96% as monitored by high performance liquid chromatography.
[0081] 1H NMR (400MHz, CDCl3): δ (ppm) 1.28 (t, J = 7.2 Hz, 3H), 1.76 (dddd, J = 20.5, 9.6, 6.8, 4. 1Hz,1H),1.87(dddd,J=13.7,9.2,8.9,5.5Hz,1H),2.46(dd,J=16.4,8.5Hz,1H),2. 53(dd,J=16.4,3.4Hz,1H)2.73(ddd,J=13.7,9.2,6.8Hz,1H),2.83(ddd,J=15.0,9. 9,6.8Hz,1H),3.02(bs,1H),4.00(m,1H),4.15(q,J=7.2Hz,2H),7.13-7.31(m,5H).
[0082] The structure of the product deduced from the above data is as follows:
[0083]
[0084] Example 4
[0085] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L tetrahydrofuran solution of methyl phenylacetate, the organic metal reagent solution is a 1.2 mol / L tetrahydrofuran solution of lithium diisopropylamide, and the aldehyde solution is a 1 mol / L tetrahydrofuran solution of valeraldehyde. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a colorless oily product with a weighed yield of 86% and a purity of 93% as monitored by high performance liquid chromatography.
[0086] 1H NMR (400MHz, CDCl3): δ (ppm) 7.42-7.28 (m, 43H), 4.24-4.17 (m, 1H), 3.69 (s, 3H), 3.60 (d, J = 6.3Hz, 1H), 2.42 (s, 1H), 1.42-1.26 (m, 6H), and 0.90(t,J=7.1Hz,4H).
[0087] The structure of the product deduced from the above data is as follows:
[0088]
[0089] Example 5
[0090] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L phenoxyethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 1.2 mol / L lithium diisopropylamide tetrahydrofuran solution, and the aldehyde solution is a 1 mol / L 2-methoxybenzaldehyde tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain a colorless oily product with a weighed yield of 92% and a purity of 95% as monitored by high performance liquid chromatography.
[0091] 1H NMR (400MHz, CDCl3): δ (ppm) 7.47-7.42 (m, 1H), 7.30-7.23 (m, 3H), 7.01-6.92 (m, 2H), 6.91-6.79 (m, 3H), 5.38 (t, J=5.8Hz,1H),5.01(d,J=5.3Hz,1H),4.11-4.04(m,2H),3.87(s,3H),3.41(d,J=6.3Hz,1H),1.08(t,J=7.1Hz,3H)
[0092] The structure of the product deduced from the above data is as follows:
[0093]
[0094] Example 6
[0095] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L phenoxyethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 1.2 mol / L lithium diisopropylamide tetrahydrofuran solution, and the aldehyde solution is a 1 mol / L 3-methoxybenzaldehyde 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 colorless oily product with a weighed yield of 89% and a purity of 93% as monitored by high performance liquid chromatography.
[0096] 1H NMR (400MHz, CDCl3): δ (ppm) 7.30-7.21 (m, 3H), 7.07-6.94 (m, 3H), 6.89-6.82 (m, 3H), 5.23-5.18 (m, 1H ),4.77(d,J=5.8Hz,1H),4.20-4.12(m,2H),3.80(s,3H),2.88(d,J=4.4Hz,1H),1.14(t,J=7.1Hz,3H).
[0097] The structure of the product deduced from the above data is as follows:
[0098]
[0099] Example 7
[0100] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 1.2 mol / L lithium diisopropylamide tetrahydrofuran solution, and the ketone solution is a 1 mol / L acetone tetrahydrofuran solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain a colorless oily product with a weighed yield of 98% and a purity of 96% as monitored by high performance liquid chromatography.
[0101] 1H NMR (400MHz, CDCl3): δ (ppm) 4.18 (q, J = 7.2Hz, 2H), 2.48 (s, 2H), 1.33-1.24 (m, 9H).
[0102] The structure of the product deduced from the above data is as follows:
[0103]
[0104] Example 8
[0105] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L tetrahydrofuran solution of methyl propionate, the organic metal reagent solution is a 1.2 mol / L tetrahydrofuran solution of lithium diisopropylamide, and the ketone solution is a 1 mol / L tetrahydrofuran solution of benzophenone. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a colorless oily product with a weighed yield of 78% and a purity of 88% as monitored by high performance liquid chromatography.
[0106] 1H NMR (300MHz, CDCl3): δ (ppm) 7.63 (d, J = 8.3Hz, 2H), 7.52 (d, J = 8.3Hz, 2H), 7.37-7.26 (m, 4H ),7.17-7.22(m,2H),4.82(s,1H),3.7(s,3H),3.59(q,J=7.0Hz,1H),1.20(d,J=7.1Hz,3H).
[0107] The structure of the product deduced from the above data is as follows:
[0108]
[0109] Example 9
[0110] The specific reaction process is similar to that of Example 1, wherein the ester solution is a 1 mol / L tetrahydrofuran solution of methyl propionate, the organic metal reagent solution is a 1.2 mol / L tetrahydrofuran solution of lithium diisopropylamide, and the aldehyde solution is a 1 mol / L tetrahydrofuran solution of 4-fluorobenzaldehyde. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a colorless oily product with a weighed yield of 89% and a purity of 94% as monitored by high performance liquid chromatography.
[0111] 1H NMR (300MHz, CDCl3): δ (ppm) 7.37-7.26 (m, 2H), 7.10-6.95 (m, 2H), 4.68 (d, J= 7.9Hz,1H),3.7(s,3H)3.20(s,1H),2.72-2.57(m,1H),1.01(d,J=7.2Hz,3H).
[0112] 1H NMR (300MHz, CDCl3): δ (ppm), 7.37-7.26 (m, 2H), 7.10-6.95 (m, 2H), 5.00 (d, J= 4.0Hz,1H),3.9(s,3H),3.20(s,1H),2.72-2.57(m,1H),1.08(d,J=7.2Hz,3H).
[0113] The structure of the product deduced from the above data is as follows:
[0114]
[0115] Example 10
[0116] The experimental process adopted Figure 1 The device shown;
[0117] Before the reaction begins, pre-prepare organometallic reagent solutions and ester and aldehyde / ketone solutions of specific concentrations. During the entire operation, the storage tank for the organometallic reagent solution is kept at 0°C. 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 stabilizes, open the storage tank containing the ester 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 the aldehyde / ketone solution, set the flow rate of the horizontal flow pump to 10 ml / min; set the residence time in the first microchannel reactor to 1s, 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 30m l / min, the reaction liquid and the quenching liquid are mixed and then enter the quenching tank, and the aqueous phase is discharged after phase separation; the flow rate of the horizontal flow pump is set to 30ml / min, and the upper organic phase of the quenching tank and the inorganic alkali aqueous solution are continuously pumped into the third microchannel reactor; the reaction is operated at 20°C throughout the process, and the residence time is set to 5min; after the reaction liquid enters the hydrolysis reaction quenching kettle, a saturated sodium sulfate aqueous solution is added to accelerate the separation of the organic phase and the aqueous phase, and the pH is adjusted to 7; the upper organic phase is discharged, the lower aqueous phase is retained, and the water is removed by reduced pressure distillation. The residual solid is soaked in ethyl acetate, and the filtrate is retained by filtration; after the solvent ethyl acetate is removed by reduced pressure distillation, a β-hydroxycarboxylic acid product is obtained.
[0118] Embodiment 11
[0119] The specific reaction process is similar to that of Example 10, wherein the ester solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 1.2 mol / L lithium diisopropylamide tetrahydrofuran solution, the aldehyde solution is a 1 mol / L 3-pyridinealdehyde tetrahydrofuran solution, and the alkali aqueous solution is a 3.5 mol / L lithium hydroxide solution. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain an off-white solid with a weighed yield of 92% and a purity of 100% as monitored by high performance liquid chromatography.
[0120] 1H NMR (400MHz, D2O): δ (ppm) 8.65-8.60 (m, 1H), 8.55-8.49 (m, 1H), 8.34 (dt, J = 8.2, 1.8 Hz,1H),7.80(dd,J=8.1,5.5Hz,1H),5.15(dd,J=7.6,6.2Hz,1H),2.70-2.54(m,2H).
[0121] The structure of the product deduced from the above data is as follows:
[0122]
[0123] Example 12
[0124] The experimental process adopted Figure 1 The device shown;
[0125] Before the reaction begins, pre-prepare organometallic reagent solutions and ester and aldehyde / ketone solutions of specific concentrations. During the entire operation, the storage tank for the organometallic reagent solution is kept at 0°C. Open the nitrogen storage tank, and introduce nitrogen into the reaction system for 10 minutes to displace the air in the system. After the pressure in the system stabilizes, open the storage tank containing the ester 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 streams of raw material liquid into the first microchannel reactor; after the operation is stable, open the storage tank containing the aldehyde / ketone solution, set the flow rate of the horizontal flow pump to 10 ml / min; set the residence time in the first microchannel reactor to 1s, 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 liquid and the quenching liquid are mixed and then enter the quenching tank. After phase separation The aqueous phase was discharged; the flow rate of the horizontal flow pump was set to 30 ml / min, and the upper organic phase of the quenching tank and the inorganic alkali aqueous solution were continuously pumped into the third microchannel reactor; the reaction was run at 20°C throughout the process, and the residence time was set to 5 min; after the reaction liquid entered the hydrolysis reaction quenching kettle, a saturated sodium sulfate aqueous solution was added to accelerate the separation of the organic phase and the aqueous phase; the flow rate of the horizontal flow pump was set to 30 ml / min, and the lower aqueous phase and the 75 wt% sulfuric acid solution were continuously pumped into the fourth microchannel reactor; the reaction was run at 140°C throughout the process, and the residence time was set to 180 min; the reaction liquid was passed into a liquid storage tank, the pH was adjusted to 7, a large amount of white solid was precipitated, the solid was collected by filtration, and an α, β-unsaturated carboxylic acid product of E configuration was obtained after washing.
[0126] Embodiment 13
[0127] The specific reaction process is similar to that of Example 12, wherein the ester solution is a 1 mol / L ethyl acetate tetrahydrofuran solution, the organic metal reagent solution is a 1.2 mol / L lithium diisopropylamide tetrahydrofuran solution, the aldehyde solution is a 1 mol / L 3-pyridinealdehyde tetrahydrofuran solution, and the alkali aqueous solution is a 3.5 mol / L lithium hydroxide solution. After the reaction is completed, the pH is adjusted to 7, and the solid product is collected. The yield is 95%, and the purity monitored by high performance liquid chromatography is 100%;
[0128] 1H NMR (400MHz, DMSO-d6): δ (ppm) 12.58 (s, 1H), 8.86 (d, J = 2.2Hz, 1H), 8.59 (dd, J = 4.8, 1.6Hz, 1H), 8.1 7(dt,J=8.0,2.0Hz,1H),7.63(d,J=16.1Hz,1H),7.45(dd,J=8.0,4.8Hz,1H),6.70(d,J=16.1Hz,1H).
[0129] The structure of the product deduced from the above data is as follows:
[0130]
[0131] Comparative Example 1
[0132] The experimental process adopted Figure 1 The device shown;
[0133] Before the reaction begins, an organometallic reagent solution and an ester, aldehyde / ketone solution of a specific concentration are pre-prepared. During the entire operation, the organometallic reagent solution storage tank is stored at 0°C. 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 the ester solution and the storage tank containing the organometallic reagent, set the flow rate of the horizontal pump for pumping the ester solution to 2.5 ml / min, and the flow rate of the organic metal reagent solution to 1 ml / min. The two raw material liquids enter the first microchannel reactor, and the reaction temperature is set to 0°C and the residence time is 5s; after the operation is stable, open the storage tank containing the aldehyde / ketone solution, set the flow rate of the horizontal pump to 1.13 ml / min, set the reaction temperature of the second microchannel reactor to 20°C, and the residence time is 2.2 min; after the operation is stable, open the quenching liquid storage tank, set the flow rate of the horizontal pump to 1.5 ml / min, and the reaction liquid and the quenching liquid are mixed and then enter the quenching tank, stirred at 20°C for 5 minutes, and after the operation is completed, the stirring is terminated, the aqueous phase is discharged after waiting for phase separation, and the upper organic phase is retained. The solvent is removed by reduced pressure distillation to obtain a β-hydroxy ester condensation product.
[0134] Comparative Example 2
[0135] The specific reaction process is similar to that of Comparative Example 1, wherein the ester solution is a 0.2 mol / L tetrahydrofuran solution of tert-butyl propionate, the organic metal reagent is a 2.5 mol / L tetrahydrofuran solution of lithium diisopropylamide, and the aldehyde solution is a 1.15 mol / L tetrahydrofuran solution of benzophenone. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a colorless oily product with a weighed yield of 78% and a purity of 85% monitored by high performance liquid chromatography;
[0136] 1H NMR (300MHz, CDCl3): δ (ppm) 7.63 (d, J = 8.3Hz, 2H), 7.52 (d, J = 8.3Hz, 2H), 7.37-7.26 (m, 4H) ,7.17-7.22(m,2H),4.82(s,1H),3.59(q,J=7.0Hz,1H),1.32(s,9H),1.20(d,J=7.1Hz,3H).
[0137] The structure of the product deduced from the above data is as follows:
[0138]
[0139] Comparative Example 3
[0140] The specific reaction process is similar to that of Comparative Example 1, wherein the ester solution is a 0.2 mol / L tetrahydrofuran solution of methyl propionate, the organic metal reagent is a 2.5 mol / L tetrahydrofuran solution of lithium diisopropylamide, and the aldehyde solution is a 1.15 mol / L tetrahydrofuran solution of benzophenone. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a colorless oily product with a weighed yield of 18% and a purity of 25% monitored by high performance liquid chromatography;
[0141] 1H NMR (300MHz, CDCl3): δ (ppm) 7.63 (d, J = 8.3Hz, 2H), 7.52 (d, J = 8.3Hz, 2H), 7.37-7.26 (m, 4H ),7.17-7.22(m,2H),4.82(s,1H),3.7(s,3H),3.59(q,J=7.0Hz,1H),1.20(d,J=7.1Hz,3H).
[0142] The structure of the product deduced from the above data is as follows:
[0143]
[0144] Comparative Example 4
[0145] The experimental process adopted Figure 1 The device shown;
[0146] Before the reaction begins, an organometallic reagent solution and an ester, aldehyde / ketone solution of a specific concentration are pre-prepared. During the entire operation, the organometallic reagent solution storage tank is stored at 0°C. 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 the ester solution and the storage tank containing the organometallic reagent, set the flow rate of the ester solution pumping advection pump to 3 ml / min, and the flow rate of the organometallic reagent solution pumping to 3 ml / min, and the two raw material liquids enter the first microchannel reactor, and the reaction temperature is set to 20°C and the residence time is 5s; after the operation is stable, open the storage tank containing the aldehyde / ketone solution, set the flow rate of the advection pump to 3 ml / min, set the reaction temperature of the second microchannel reactor to 20°C, and the residence time is 80s; after the operation is stable, open the quenching liquid storage tank, set the flow rate of the advection pump to 1.5 ml / min, and the reaction solution and the quenching liquid are mixed and then enter the quenching tank, stirred at 20°C for 5 minutes, and after the operation is completed, the stirring is terminated, the aqueous phase is discharged after waiting for phase separation, and the upper organic phase is retained. The solvent is removed by reduced pressure distillation to obtain a β-hydroxy ester condensation product;
[0147] Comparative Example 5
[0148] The specific reaction process is similar to that of Comparative Example 4, wherein the ester solution is a 0.4 mol / L tetrahydrofuran solution of tert-butyl propionate, the organic metal reagent is a 0.44 mol / L tetrahydrofuran solution of lithium diisopropylamide, and the aldehyde solution is a 0.48 mol / L tetrahydrofuran solution of 4-fluorobenzaldehyde. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a colorless oily product with a weighed yield of 92% and a purity of 95% monitored by high performance liquid chromatography;
[0149] 1H NMR (300MHz, CDCl3): δ (ppm) 7.37-7.26 (m, 2H), 7.10-6.95 (m, 2H), 4.68 (d, J = 7 .9Hz,1H),3.20(s,1H),2.72-2.57(m,1H),1.43(s,9H),1.01(d,J=7.2Hz,3H).
[0150] 1H NMR (300MHz, CDCl3): δ (ppm), 7.37-7.26 (m, 2H), 7.10-6.95 (m, 2H), 5.00 (d, J= 4.0Hz,1H),3.20(s,1H),2.72-2.57(m,1H),1.40(s,9H),1.08(d,J=7.2Hz,3H).
[0151] The structure of the product deduced from the above data is as follows:
[0152]
[0153] Comparative Example 6
[0154] The specific reaction process is similar to that of Comparative Example 4, wherein the ester solution is a 0.4 mol / L tetrahydrofuran solution of methyl propionate, the organic metal reagent is a 0.44 mol / L tetrahydrofuran solution of lithium diisopropylamide, and the aldehyde solution is a 0.48 mol / L tetrahydrofuran solution of 4-fluorobenzaldehyde. After the reaction is completed, the organic phase is retained, and the solvent is removed by distillation under reduced pressure to obtain a colorless oily product with a weighed yield of 35% and a purity of 67% monitored by high performance liquid chromatography;
[0155] 1H NMR (300MHz, CDCl3): δ (ppm) 7.37-7.26 (m, 2H), 7.10-6.95 (m, 2H), 4.68 (d, J= 7.9Hz,1H),3.7(s,3H)3.20(s,1H),2.72-2.57(m,1H),1.01(d,J=7.2Hz,3H).
[0156] 1H NMR (300MHz, CDCl3): δ (ppm), 7.37-7.26 (m, 2H), 7.10-6.95 (m, 2H), 5.00 (d, J= 4.0Hz,1H),3.9(s,3H),3.20(s,1H),2.72-2.57(m,1H),1.08(d,J=7.2Hz,3H).
[0157] The structure of the product deduced from the above data is as follows:
[0158]
[0159] Comparative Example 7
[0160] The specific reaction process is similar to that of Example 10, wherein the ester solution is a 1 mol / L tetrahydrofuran solution of tert-butyl acetate, the aldehyde solution is a 1 mol / L tetrahydrofuran solution of 3-pyridinealdehyde, the alkali aqueous solution is a 3.5 mol / L lithium hydroxide solution, and the residence time of the third microchannel reactor is set to 5 min; after the reaction is completed, the organic phase is retained, and the solvent is removed by vacuum distillation to obtain an off-white solid, with a weighed yield of 29% and a purity of 67% monitored by high performance liquid chromatography;
[0161] 1H NMR (400MHz, D2O): δ (ppm) 8.65-8.60 (m, 1H), 8.55-8.49 (m, 1H), 8.34 (dt, J = 8.2, 1.8 Hz,1H),7.80(dd,J=8.1,5.5Hz,1H),5.15(dd,J=7.6,6.2Hz,1H),2.70-2.54(m,2H).
[0162] The structure of the product deduced from the above data is as follows:
[0163]
[0164] 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 co-producing β-hydroxy ester, β-hydroxy carboxylic acid and α,β-unsaturated carboxylic acid, characterized in that: The following steps are involved: (1) mixing an organometallic reagent solution and a lipid solution in a first microchannel reactor to perform reaction I to obtain a lithium enolate intermediate, mixing the lithium enolate intermediate and an aldehyde solution or a ketone solution in a second microchannel reactor to perform reaction II, and acid quenching I to obtain a β-hydroxy ester; (2) mixing the β-hydroxy ester with an aqueous solution of an inorganic base, reacting III in a third microchannel reactor, and acid quenching II to obtain a β-hydroxy carboxylic acid; (3) mixing a β-hydroxycarboxylic acid in which R1 is H with an aqueous sulfuric acid solution, and performing reaction IV in a fourth microchannel reactor to obtain an α,β-unsaturated carboxylic acid of E-configuration; The first microchannel reactor, the second microchannel reactor, the third microchannel reactor, and the fourth microchannel reactor are connected in sequence; The organometallic reagent is selected from at least one of methyl lithium, n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, 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 ester has a structure shown in Formula I: The lithium enolate intermediate has a structure shown in Formula II: The aldehyde or ketone has a structure shown in Formula III: The β-hydroxy ester has a structure shown in Formula IV: The β-hydroxycarboxylic acid has a structure shown in Formula V: The α,β-unsaturated carboxylic acid has a structure shown in Formula VI: in, R1 is selected from one of hydrogen, halogen, fatty chain, methoxy and unsubstituted or substituted aryl, R2 is selected from one of hydrogen, halogen, fatty chain, methoxy and unsubstituted or substituted aryl, R3 is selected from one of methyl and ethyl, R4 is selected from one of hydrogen, halogen, fatty chain, methoxy and unsubstituted or substituted aryl, and R5 is selected from one of hydrogen, halogen, fatty 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 hydraulic diameters of the first microchannel reactor, the second microchannel reactor, the third microchannel reactor and the fourth microchannel reactor are 100 μm to 500 mm.
3. The method according to claim 1, characterized in that The aldehyde is selected from at least one of aliphatic aldehydes, aromatic aldehydes, oxygen-containing aromatic aldehydes, sulfur-containing aromatic aldehydes, and nitrogen-containing aromatic aldehydes; Preferably, the aldehyde is selected from at least one of acetaldehyde, n-valeraldehyde, 3-pyridinealdehyde, benzaldehyde, and phenylacetaldehyde; The ketone is selected from at least one of aliphatic ketones, aromatic ketones, oxygen-containing aromatic ketones, sulfur-containing aromatic ketones, and nitrogen-containing aromatic ketones; Preferably, the ketone is selected from at least one of acetone, butanone, acetophenone and benzophenone; The solvent in the ester solution, aldehyde solution or ketone solution is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane and n-heptane.
4. The method according to claim 1, characterized in that: The molar ratio of the ester to the organometallic lithium reagent is 1:1 to 1.8; The temperature of the reaction I is 0 to 30°C; The reaction time I is 0.1 to 1 s; The temperature of the reaction II is -10 to 30°C; The reaction time of II is 1s to 10min; The molar ratio of the aldehyde or ketone to the ester is 1:1-2.
5. The method according to claim 1, characterized in that The inorganic base is selected from at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; The molar ratio of the beta-hydroxy ester to the inorganic base is 1:10-20. The temperature of the reaction III is 0 to 60°C; The time of the reaction III is 1 to 10 minutes.
6. The method according to claim 1, characterized in that The concentration of the sulfuric acid aqueous solution is 75-98wt%; The temperature of the reaction III is 80-180°C; The time of the reaction III is 60 to 240 minutes.
7. The method according to claim 1, characterized in that In the acid quenching I and the acid quenching II, The quenching temperature is 0 to 20°C; The quenching is carried out in a quenching kettle; 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 0.5 to 3 mol / L; The acid contains at least one of sodium sulfate, sodium carbonate, sodium chloride, sodium hydrogen phosphate and sodium bicarbonate.