Method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a method for synthesizing 3-hydroxy-3-alkyl propionate based on a continuous flow reaction technology. According to the method, a continuous flow reaction device is adopted for synthesis, acetate, lithium diisopropylamide and an aldehyde compound are taken as raw materials, and 3-hydroxy-3-alkyl propionate is synthesized through lithium-hydrogen exchange and alkyl aldehyde addition reaction. According to the method provided by the invention, the reaction process is easy to control, the danger coefficient of the reaction operation and process is greatly reduced, and the safety and reliability of the reaction are improved. Meanwhile, by the method, the reaction efficiency is remarkably improved, and the synthesis time is shortened from dozens of hours to dozens of minutes, even dozens of minutes; in addition, different 3-hydroxy-3-alkyl propionate products can be prepared by introducing different substrates and switching, the applicability is high, and the industrial application value is high.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology. Background Art

[0002] 3-Hydroxy-3-alkyl propionate (also known as β-hydroxy fatty acid ester) is an important intermediate and molecular building block in the fields of medicine, fine chemicals and polymer materials. By further reacting it, other functional groups can be introduced to synthesize compounds with special structures and properties, which are used in the synthesis of fine chemicals in the fields of drugs, fragrances, cosmetics, etc. For example, poly(β-hydroxyalkanoates) [PHA] prepared therefrom has a variety of excellent properties, including thermoplasticity, tissue affinity, optical activity, biodegradability and biocompatibility. These properties enable PHA to have a wide range of applications. The biodegradability of PHA enables it to be decomposed by microorganisms in the environment, reducing environmental pollution. As an ideal biodegradable plastic, it can be used to manufacture packaging materials, surgical sutures, etc.; at the same time, the high added value of PHA in the fields of medicine and others has been continuously developed.

[0003] Currently, the methods for synthesizing 3-hydroxy-3-alkyl propionate mainly include chemical synthesis method and biological synthesis method. Among them, the classical method for preparing 3-hydroxy-3-alkyl propionate by chemical synthesis method is as follows: First, ethyl bromoacetate reacts with active zinc to generate zinc ethyl bromoacetate, and then it reacts with fatty aldehyde by addition reaction to generate 3-hydroxy-3-alkyl propionate. In the first step of this method, the reaction between zinc and ethyl bromoacetate is slow to initiate. After the reaction forms, the temperature rises due to heat release, and the reaction is not easy to control. The risk factor is high during scale-up production, and there is a scale-up effect; in the second step of the reaction, in the addition reaction of zinc ethyl bromoacetate and fatty aldehyde, the fatty aldehyde needs to be slowly added dropwise at room temperature to reflux temperature. After the dropwise addition is completed, the reaction is continued to stir for several hours to dozens of hours (the reaction time depends on the structure and reaction activity of the fatty aldehyde, such as 3 - 24 hours). Its reaction process is long, the reaction efficiency is low, and it is not conducive to scale-up production.

[0004] There is also research disclosure that hydrogen esterification reaction of CO, tridentate Schiff base Cr(Ⅲ) metal catalyst, cocatalyst, and alkylene oxide in organic alcohol generates β-hydroxy propionate. The reaction temperature of this method is 40 - 80 °C, the reaction pressure is 2 - 4 MPa, and the reaction time is several hours to dozens of hours. During the reaction process, not only a transition metal catalyst is required, but also CO gas is used, and the pressure needs to be controlled, requiring a pressure vessel. Its reaction time is long, the reaction conditions are not easy to control, the requirements for equipment are high, and there is a scale-up effect.

[0005] Therefore, there is an urgent need to provide a method for preparing 3-hydroxy-3-alkyl propionate that is fast, efficient, and has easy reaction control, which is conducive to improving the production efficiency of 3-hydroxy-3-alkyl propionate and expanding production. Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology. The method provided by the present invention uses a continuous flow process of lithium-hydrogen exchange and alkyl aldehyde addition reaction to prepare 3-hydroxy-3-alkyl propionate. This method has easy reaction control, high reaction efficiency, is safe and reliable, can avoid unstable factors and scale-up effects in the reaction, and is conducive to the expansion of production and large-scale production applications of 3-hydroxy-3-alkyl propionate.

[0007] The present invention provides a method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology. The method provided by the present invention uses acetate, lithium diisopropylamide, and aldehyde compound as raw materials and synthesizes 3-hydroxy-3-alkyl propionate by using continuous flow reaction technology.

[0008] Specifically, a method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology is carried out by using a continuous flow reaction device, and includes the following steps: acetate 1 undergoes a lithium-hydrogen exchange reaction with lithium diisopropylamide to generate alkoxycarbonylethyllithium 2; then the alkoxycarbonylethyllithium 2 and aldehyde compound 3 undergo a nucleophilic addition reaction to generate an alcohol lithium intermediate 4; finally, the alcohol lithium intermediate 4 is quenched with an acidic solution to obtain 3-hydroxy-3-alkyl propionate 5.

[0009] The reaction route of the method provided by the present invention is as follows:

[0010]

[0011] Among them, R1 is a C1-C4 straight-chain alkyl or branched-chain alkyl; R2 is a C2-C9 straight-chain alkyl, branched-chain alkyl, or cycloalkyl.

[0012] In some embodiments of the present invention, the R1 is one of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

[0013] In some embodiments of the present invention, the acidic solution is selected from one of dilute hydrochloric acid solution, dilute sulfuric acid solution, and saturated ammonium chloride solution.

[0014] In some embodiments of the present invention, the acetate 1, the lithium diisopropylamide, and the aldehyde compound 3 need to be diluted in a solvent before the reaction to form an acetate solution, a lithium diisopropylamide solution, and an aldehyde compound solution, respectively.

[0015] In some embodiments of the present invention, the solvent includes at least one of diethyl ether, tetrahydrofuran, and n-hexane.

[0016] In some embodiments of the present invention, the concentration of the lithium diisopropylamide solution is 0.5 - 2.0 mol / L; preferably 0.8 - 1.5 mol / L, such as 1.0 mol / L.

[0017] In some embodiments of the present invention, the concentration of the acetate solution is 0.5 - 3.0 mol / L; preferably 0.8 - 2.0 mol / L, such as 1.0 mol / L.

[0018] In some embodiments of the present invention, the concentration of the aldehyde compound solution is 0.5 - 3.0 mol / L; preferably 0.8 - 2.0 mol / L, such as 1.0 mol / L.

[0019] In some embodiments of the present invention, the molar ratio of the lithium diisopropylamide to the acetate 1 is 1:(1.0 - 1.5); preferably 1:(1.1 - 1.2). The molar ratio of the acetate 1 to the aldehyde compound 3 is 1:(0.7 - 1.2), preferably 1:(0.9 - 1.1). The molar ratio of the acetate 1 to the acidic solution is 1:(2.0 - 4.0).

[0020] In some embodiments of the present invention, the continuous flow reaction device includes:

[0021] Continuous flow experiment pumps, including a first continuous flow experiment pump, a second continuous flow experiment pump, and a third continuous flow experiment pump;

[0022] Mixers, the mixer includes a first mixer and a second mixer, the first continuous flow experiment pump and the second continuous flow experiment pump are respectively connected to the first mixer; the third continuous flow experiment pump is connected to the second mixer;

[0023] Reaction tubes, the reaction tubes include a first reaction tube and a second reaction tube, the first reaction tube is located between the first mixer and the second mixer;

[0024] Quenching device, the quenching device is connected to the second mixer, the second reaction tube is located between the second mixer and the quenching device;

[0025] Temperature control system, the continuous flow experiment pumps, the mixers, the reaction tubes, and the quenching device are controlled by the temperature control system.

[0026] In some embodiments of the present invention, the continuous flow reaction device further includes raw material tanks, which include an acetate 1 raw material tank, a lithium diisopropylamide raw material tank, and an aldehyde compound 3 raw material tank. The acetate 1 raw material tank, the lithium diisopropylamide raw material tank, and the aldehyde compound 3 raw material tank are respectively connected to the first continuous flow experiment pump, the second continuous flow experiment pump, and the third continuous flow experiment pump.

[0027] In some embodiments of the present invention, the continuous flow reaction device further includes a product receiving device, which is connected to the quenching device and is used to receive the crude product of 3-hydroxy-3-alkyl propionate synthesized.

[0028] More specifically, a method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology includes the following steps:

[0029] Under a protective atmosphere, lithium diisopropylamide and acetate 1 are respectively pumped into the first mixer of the continuous flow reaction device at a flow rate of 10-50 mL / min, and mixed at -50°C to -10°C to obtain a first mixed material. The first mixed material undergoes a lithium-hydrogen exchange reaction through a first reaction tube to generate alkoxycarbonylethyllithium 2; the alkoxycarbonylethyllithium 2 further reacts with aldehyde compound 3 pumped into the second mixer at a flow rate of 10-50 mL / min, and is mixed at -50°C to -10°C to obtain a second mixed material; the second mixed material undergoes a nucleophilic addition reaction through a second reaction tube to generate an alcohol lithium intermediate 4; the alcohol lithium intermediate 4 enters the quenching device and is quenched by an acidic solution to obtain the crude product of 3-hydroxy-3-alkyl propionate.

[0030] In some embodiments of the present invention, the flow rate of the pumped lithium diisopropylamide is 20-40 mL / min; the flow rate of the pumped acetate 1 is 20-40 mL / min; the flow rate of the pumped aldehyde compound 3 is 20-40 mL / min.

[0031] In some embodiments of the present invention, the residence time (i.e., the passing time) of the first mixed material in the first reaction tube is 0.5-5 min, preferably 1-3 min, such as 1 min, 2 min.

[0032] In some embodiments of the present invention, the residence time (i.e., the passing time) of the second mixed material in the second reaction tube is 0.5-5 min, preferably 1-3 min, such as 1 min, 2 min.

[0033] In some embodiments of the present invention, the temperature of the quenching is -20°C to 10°C.

[0034] In some embodiments of the present invention, the crude 3-hydroxy-3-alkyl propionate is purified by extraction and rectification to obtain 3-hydroxy-3-alkyl propionate.

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0036] (1) The method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology provided by the present invention uses the continuous flow reaction technology under low temperature conditions, with acetate, lithium diisopropylamide and aldehyde compound as raw materials, and synthesizes 3-hydroxy-3-alkyl propionate through lithium-hydrogen exchange and alkyl aldehyde addition reaction. This method solves the problems in traditional methods such as difficult reaction control, unstable mass transfer and heat transfer of lithium reagents, high risk coefficient during scale-up production, existence of scale-up effect, long reaction process and low reaction efficiency.

[0037] (2) The method provided by the present invention has an easily controllable reaction process, greatly reduces the risk coefficient of reaction operation and process, improves the safety and reliability of the reaction, avoids unstable factors and scale-up effect in the reaction, is conducive to the expansion production and large-scale production application of 3-hydroxy-3-alkyl propionate, and has a wide application prospect.

[0038] (2) The method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology provided by the present invention not only significantly improves the reaction efficiency, shortens the synthesis time from dozens of hours to dozens of minutes, or even more than ten minutes; but also can prepare different 3-hydroxy-3-alkyl propionate products by switching different substrates, has strong applicability and high industrial application value. Description of the Drawings

[0039] Figure 1 It is a schematic diagram of the continuous flow reaction device for synthesizing 3-hydroxy-3-alkyl propionate in the embodiment of the present invention;

[0040] Explanation of the reference numerals in the drawings: 1 is the raw material tank for acetate 1, 3 is the raw material tank for lithium diisopropylamide, 5 is the raw material tank for aldehyde compound 3, 2 is the first continuous flow experiment pump, 4 is the second continuous flow experiment pump, 6 is the third continuous flow experiment pump, 7 is the first mixer, 8 is the first reaction tube, 9 is the second mixer, 10 is the second reaction tube, 11 is the quenching device, and 12 is the product receiving device. Detailed Embodiments

[0041] In order to make those skilled in the art more clearly understand the technical solutions described in the present invention, the following examples are listed for illustration. It should be noted that the following examples do not limit the protection scope required by the present invention. The raw materials, reagents or devices involved in the embodiments of the present invention can be obtained from conventional commercial channels without special instructions, or can be obtained by existing known methods.

[0042] A method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology provided by an embodiment of the present invention is synthesized by using a continuous flow reaction device. As Figure 1 shown, the continuous flow reaction device includes: a raw material tank, a continuous flow experiment pump, a mixer, a reaction tube, a quenching device 11, a product receiving device 12 and a temperature control system. Among them, the raw material tank specifically includes an acetate 1 raw material tank 1, a lithium diisopropylamide raw material tank 3 and an aldehyde compound 3 raw material tank 5; the continuous flow experiment pump specifically includes a first continuous flow experiment pump 2, a second continuous flow experiment pump 4 and a third continuous flow experiment pump 6; the acetate 1 raw material tank 1, the lithium diisopropylamide raw material tank 3 and the aldehyde compound 3 raw material tank 5 are respectively connected to the first continuous flow experiment pump 2, the second continuous flow experiment pump 4 and the third continuous flow experiment pump 6. The mixer specifically includes a first mixer 7 and a second mixer 9, and the first continuous flow experiment pump 2 and the second continuous flow experiment pump 4 are respectively connected to the first mixer 7; the third continuous flow experiment pump 6 is connected to the second mixer 9. The reaction tube includes a first reaction tube 8 and a second reaction tube 10, and the first reaction tube 8 is located between the first mixer 7 and the second mixer 9. The reaction tube is selected from a PTFE Teflon tube or a 316 stainless steel tube. The quenching device 11 is connected to the second mixer 9, and the second reaction tube 10 is located between the second mixer 9 and the quenching device 11. The product receiving device 12 is connected to the quenching device 11 and is used to receive the crude product of 3-hydroxy-3-alkyl propionate synthesized. The continuous flow experiment pump, the mixer, the reaction tube and the quenching device 11 are controlled by a temperature control system.

[0043] The method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology provided by an embodiment of the present invention uses the above continuous flow reaction device to prepare 3-hydroxy-3-alkyl propionate, balances the system pressure with a protective atmosphere (such as nitrogen), and uses a continuous flow experiment pump for continuous feeding and discharging to achieve continuous production. The specific synthesis process is as in Examples 1 to 16.

[0044] Example 1

[0045] A method for synthesizing methyl 3-hydroxyoctanoate based on continuous flow reaction technology. The structural formula of methyl 3-hydroxyoctanoate is as follows:

[0046] The method includes the following steps:

[0047] Before the reaction, the pipeline was filled with tetrahydrofuran solvent. Under nitrogen protection, 1.0 mol / L lithium diisopropylamide solution (LDA) and 1.1 mol / L methyl acetate solution were pumped into the first mixer 7 at a flow rate of 20 mL / min through the second continuous flow experimental pump 4 and the first continuous flow experimental pump 2, respectively. The temperature of the first mixer 7 was controlled at -40 ° C. The first mixed material was mixed and the first mixed material was passed through the first reaction tube 8 for lithium hydrogen exchange reaction. The residence time was controlled to be 2 min to generate alkane. Oxycarbonylethyllithium 2; alkoxycarbonylethyllithium 2 is further mixed with 1.0 mol / L n-hexanal pumped into a second mixer 9 at a flow rate of 20 mL / min at -40°C to produce a second mixed material. The second mixed material then undergoes a nucleophilic addition reaction in a second reaction tube 10 with a controlled residence time of 1 minute to produce a lithium alkoxide intermediate 4. The lithium alkoxide intermediate 4 enters a quenching device 11 and is quenched with a saturated ammonium chloride solution to produce a crude 3-hydroxy-3-alkyl propionate, which is received in a product receiving device 12. The crude 3-hydroxy-3-alkyl propionate is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined and dried over anhydrous magnesium sulfate. The solvent is rotary evaporated, and the remaining liquid is vacuum distilled to obtain a colorless liquid product, namely, 3-hydroxy-3-alkyl propionate. The product is tested to have a GC purity of 98.2% and a yield of 66.7%. GCMS 125 (M-49) (all results mentioned below were obtained using an Agilent 5975 inert MSD).

[0048] 1 H NMR (400MHz, CDCl3) δ = 4.00 (s, 1H), 3.72 (s, 3H), 2.86 (d, J = 4.0, 1H), 2.52 (dd, J = 16.4,3.1,1H),2.41(dd,J=16.4,9.0,1H),1.53-1.26(m,8H),0.89(t,J=6.7,3H).

[0049] Example 2

[0050] Example 2 provides a method for synthesizing methyl 3-hydroxyoctanoate based on continuous flow reaction technology. The difference from Example 1 is that the flow rate of lithium diisopropylamide solution (LDA), methyl acetate solution and n-hexanal solution is increased from 20 mL / min to 50 mL / min. The rest of the synthesis process is the same as that of Example 1, and a colorless liquid product is obtained. After testing, the GC purity is 95.5% and the yield is 49.9%.

[0051] Comparing Example 1 and Example 2, it can be seen that when the flow rates of lithium diisopropylamide solution (LDA), methyl acetate solution and n-hexanal solution are controlled to be 20-40 mL / min, it is more conducive to improving the product yield.

[0052] Example 3

[0053] Example 3 provides a method for synthesizing methyl 3-hydroxynonanoate based on continuous flow reaction technology. The structural formula of methyl 3-hydroxynonanoate is as follows:

[0054] The difference between Example 3 and Example 1 is that the aldehyde compound 3-n-hexanal is replaced with n-heptanal, and the rest of the synthesis process is the same as that in Example 1, obtaining a colorless liquid product. After testing, the GC purity is 98.3%, and the yield is 68.2%. GCMS 139 (M-49).

[0055] 1 1H NMR (600 MHz, DMSO) δ = 4.65 (d, J = 5.8, 1H), 3.81 (dd, J = 4.8, 2.6, 1H), 3.58 (s, 3H), 2.39 (dd, J = 14.7, 4.8, 1H), 2.29 (dd, J = 14.7, 8.3, 1H), 1.39 - 1.20 (m, 10H), 0.86 (t, J = 7.0, 3H).

[0056] Example 4

[0057] Example 4 provides a method for synthesizing methyl 3-hydroxynonanoate based on continuous flow reaction technology. The difference between Example 4 and Example 3 is that the temperature of the lithium-hydrogen exchange reaction and the nucleophilic addition reaction is controlled at 10°C, and the rest of the synthesis process is the same as that in Example 3, obtaining a yellow liquid product. After testing, the GC purity is 95.4%, and the yield is 13.1%.

[0058] Comparing Example 3 and Example 4, it can be seen that in the method provided by the present invention, controlling the temperature of the lithium-hydrogen exchange reaction and the nucleophilic addition reaction is crucial and is a decisive factor for the yield of the product.

[0059] Example 5

[0060] A method for synthesizing methyl 3-hydroxydecanoate based on continuous flow reaction technology. The structural formula of methyl 3-hydroxydecanoate is as follows:

[0061] The difference between Example 5 and Example 1 is that the aldehyde compound 3-n-hexanal is replaced with n-octanal, and the rest of the synthesis process is the same as that in Example 1, obtaining a yellow liquid product. After testing, the GC purity is 98.2%, and the yield is 79.2%. GCMS 153 (M-49).

[0062] 11H NMR (400 MHz, CDCl3) δ 4.05 - 3.96 (m, 1H), 3.71 (s, 3H), 2.52 (dd, J = 16.3, 3.3 Hz, 1H), 2.41 (dd, J = 16.3, 8.9 Hz, 1H), 1.47 (ddd, J = 12.8, 12.0, 6.3 Hz, 3H), 1.28 (s, 9H), 0.88 (t, J = 6.8 Hz, 3H).

[0063] Example 6

[0064] Example 6 provides a method for synthesizing methyl 3 - hydroxydecanoate based on continuous - flow reaction technology. The difference between Example 6 and Example 5 is that the concentration of n - octanal is increased to 3.0 mol / L, and the flow rate of the pumped n - octanal solution is decreased to 7.0 mL / min. The rest of the synthesis process is the same as that in Example 5, obtaining a yellow liquid product. After testing, the GC purity is 93.2% and the yield is 45.3%.

[0065] Example 7

[0066] Example 7 provides a method for synthesizing methyl 3 - hydroxydecanoate based on continuous - flow reaction technology. The difference between Example 7 and Example 5 is that the residence time of the first mixed material passing through the first reaction tube 8 is shortened from 2 min to 0.5 min, and the residence time of the second mixed material passing through the second reaction tube 10 is shortened from 1 min to 0.5 min. The rest of the synthesis process is the same as that in Example 5, obtaining a yellow liquid product. After testing, the GC purity is 97.0% and the yield is 20.5%.

[0067] Comparing Example 5 and Example 7, it can be seen that controlling the residence time of the first and second mixed materials in the reaction tube to be 1 - 3 min is more conducive to improving the product yield and synthesis efficiency. It is found that when the residence time is too short, it will not only affect the synthesis efficiency but also the product yield.

[0068] Example 8

[0069] Example 8 provides a method for synthesizing methyl 3 - hydroxydodecanoate based on continuous - flow reaction technology. The structural formula of methyl 3 - hydroxydodecanoate is as follows:

[0070] The difference between Example 8 and Example 1 is that the aldehyde compound 3 n - hexanal is replaced by n - decanal, and the rest of the synthesis process is the same as that in Example 1, obtaining a colorless liquid product. After testing, the GC purity is 98.3% and the yield is 77.3%. GCMS 181 (M - 49).

[0071] Example 9

[0072] Example 9 provides a method for synthesizing methyl 3-hydroxyheptanoate based on continuous flow reaction technology. The structural formula of methyl 3-hydroxyheptanoate is as follows:

[0073] The difference between Example 9 and Example 1 is that the aldehyde compound 3-n-hexanal is replaced with n-pentanal, and the rest of the synthesis process is the same as that of Example 1. A colorless liquid product is obtained. After testing, the GC purity is 98.4% and the yield is 73.1%. GCMS 143 (M-17).

[0074] Example 10

[0075] Example 10 provides a method for synthesizing ethyl 3-hydroxydodecanoate based on continuous flow reaction technology. The structural formula of ethyl 3-hydroxydodecanoate is as follows:

[0076]

[0077] The difference between Example 10 and Example 8 is that methyl acetate is replaced with ethyl acetate, and the rest of the synthesis process is the same as that of Example 8. A colorless liquid product is obtained. After testing, the GC purity is 97.6% and the yield is 71.1%.

[0078] 1 H NMR (600 MHz, CDCl3) δ = 4.17 (q, J = 7.1, 2H), 4.00 (s, 1H), 2.93 (s, 1H), 2.50 (dd, J = 16.4, 3.0, 1H), 2.40 (dd, J = 16.4, 9.2, 1H), 1.47 - 1.38 (m, 2H), 1.33 -

[0079] 1.21 (m, 17H), 0.88 (t, J = 7.0, 3H).

[0080] Example 11

[0081] Example 11 provides a method for synthesizing ethyl 3-hydroxyundecanoate based on continuous flow reaction technology. The structural formula of ethyl 3-hydroxyundecanoate is as follows:

[0082] The difference between Example 11 and Example 10 is that the aldehyde compound 3-n-decanal is replaced with n-nonanal, and the rest of the synthesis process is the same as that of Example 10. A colorless liquid product is obtained. After testing, the GC purity is 97.4% and the yield is 70.9%.

[0083] 11H NMR (600 MHz, CDCl3) δ = 4.17 (q, J = 7.1, 2H), 4.04 - 3.97 (m, 1H), 2.50 (dd, J = 16.4, 3.0, 1H), 2.40 (dd, J = 16.4, 9.1, 1H), 1.53 (dd, J = 17.7, 8.2, 1H), 1.47 -

[0084] 1.40 (m, 2H), 1.28 (dd, J = 15.7, 8.7, 14H), 0.88 (t, J = 7.0, 3H).

[0085] Example 12

[0086] Example 12 provides a method for synthesizing ethyl 3-hydroxyhexanoate based on continuous flow reaction technology. The structural formula of ethyl 3-hydroxyhexanoate is as follows:

[0087] The difference between Example 12 and Example 11 is that the aldehyde compound 3-nonanal is replaced with n-butanal, and the rest of the synthesis process is the same as that of Example 11. The obtained product is a yellow liquid. After testing, the GC purity is 97.5% and the yield is 74.9%.

[0088] 1 1H NMR (600 MHz, CDCl3) δ = 4.17 (q, J = 7.1, 2H), 4.01 (s, 1H), 2.98 (s, 1H), 2.50 (dd, J = 16.4, 3.0, 1H), 2.40 (dd, J = 16.4, 9.1, 1H), 1.55 - 1.36 (m, 4H), 1.28 (t, J = 7.1, 3H), 0.97 - 0.90 (m, 3H).

[0089] Example 13

[0090] Example 13 provides a method for synthesizing ethyl 3-hydroxyoctanoate based on continuous flow reaction technology. The structural formula of ethyl 3-hydroxyoctanoate is as follows:

[0091] The difference between Example 13 and Example 1 is that methyl acetate is replaced with ethyl acetate, and the rest of the synthesis process is the same as that of Example 1. The obtained product is a yellow liquid. After testing, the GC purity is 97.6% and the yield is 65.9%.

[0092] 11H NMR (600 MHz, CDCl3) δ = 4.17 (q, J = 7.1, 2H), 4.00 (s, 1H), 2.50 (dd, J = 16.4, 2.9, 1H), 2.40 (dd, J = 16.4, 9.1, 1H), 1.53 (dd, J = 17.8, 8.2, 1H), 1.46 - 1.40 (m, 2H), 1.28 (t, J = 7.1, 12H), 0.88 (t, J = 6.9, 3H).

[0093] Example 14

[0094] Example 14 provides a method for synthesizing ethyl 3 - hydroxyvalerate based on continuous - flow reaction technology. The structural formula of ethyl 3 - hydroxyvalerate is as follows:

[0095] The difference between Example 14 and Example 10 is that the aldehyde compound 3 - decanal is replaced with propionaldehyde, and the rest of the synthesis process is the same as that in Example 10. A colorless liquid product is obtained. After testing, the GC purity is 97.1%, the yield is 65.5%, and the GCMS is 146.

[0096] Example 15

[0097] Example 15 provides a method for synthesizing tert - butyl 3 - hydroxyvalerate based on continuous - flow reaction technology. The structural formula of tert - butyl 3 - hydroxyvalerate is as follows:

[0098] The difference between Example 15 and Example 14 is that ethyl acetate is replaced with tert - butyl acetate, and the rest of the synthesis process is the same as that in Example 14. A colorless liquid product is obtained, with a GC purity of 97.3% and a yield of 62.7%.

[0099] 1 1H NMR (600 MHz, CDCl3) δ = 3.89 (d, J = 3.6, 1H), 3.12 (d, J = 3.5, 1H), 2.43 (dd, J = 16.3, 3.0, 1H), 2.32 (dd, J = 16.3, 9.1, 1H), 1.51 (dd, J = 30.1, 4.5, 2H), 1.47 (s, 9H), 0.96 (t, J = 7.5, 3H).

[0100] Example 16

[0101] Example 16 provides a method for synthesizing tert - butyl 3 - hydroxy - 3 - cyclopropylpropionate based on continuous - flow reaction technology. The structural formula of tert - butyl 3 - hydroxy - 3 - cyclopropylpropionate is:

[0102] Example 16 is different from Example 15 in that the aldehyde compound 3-n-propionaldehyde is replaced by cyclopropanecarbaldehyde, and the rest of the synthesis process is the same as that of Example 15. A colorless liquid product is obtained. After testing, the GC purity is 97.8% and the yield is 50.2%.

[0103] 1 H NMR(600MHz,CDCl3)δ=3.05(d,J=3.4,1H),2.79(s,1H),2.31(dd,J=21.5,6.1,2H),1.24(s,9H),0.70(d,J=8.1,1H),0.30(d,J=35.4,2H),0.17(d,J=4.8,1H),0.04--0.04(m,1H).

[0104] The above-described embodiments merely represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent for the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention shall be subject to the appended claims.

Claims

1. A method for synthesizing 3-hydroxy-3-alkyl propionate based on continuous flow reaction technology, characterized in that, Synthesis is carried out using a continuous flow reaction device, including the following steps: Lithium hydrogen exchange reaction of acetate 1 with lithium diisopropylamide to generate alkoxycarbonylethyllithium 2; then nucleophilic addition reaction of the alkoxycarbonylethyllithium 2 and aldehyde compound 3 to generate an alcohol lithium intermediate 4; finally, the alcohol lithium intermediate 4 is quenched with an acidic solution to obtain 3-hydroxy-3-alkylpropionate 5; The reaction route of the method is as follows: Wherein, R1 is a C1-C4 straight-chain alkyl or branched-chain alkyl; R2 is a C2-C9 straight-chain alkyl, branched-chain alkyl or cycloalkyl.

2. The method according to claim 1, characterized in that The R1 is selected from one of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

3. The method according to claim 1 or 2, characterized in that, The acetate 1, the lithium diisopropylamide and the aldehyde compound 3 need to be diluted in a solvent before the reaction to form an acetate solution, a lithium diisopropylamide solution and an aldehyde compound solution respectively; the solvent includes at least one of diethyl ether, tetrahydrofuran, n-hexane.

4. The method according to claim 3, wherein The concentration of the lithium diisopropylamide solution is 0.5-2.0 mol / L; the concentration of the acetate solution is 0.5-3.0 mol / L; the concentration of the aldehyde compound solution is 0.5-3.0 mol / L.

5. The method according to claim 1 or 2, characterized in that, The molar ratio of the lithium diisopropylamide to the acetate 1 is 1:(1.0-1.5); the molar ratio of the acetate 1 to the aldehyde compound 3 is 1:(0.7-1.2); the molar ratio of the acetate 1 to the acidic solution is 1:(2.0-4.0).

6. The method according to claim 1 or 2, characterized in that, The continuous flow reaction device includes: Continuous flow experimental pumps, including a first continuous flow experimental pump, a second continuous flow experimental pump and a third continuous flow experimental pump; Mixers, the mixers include a first mixer and a second mixer, the first continuous flow experimental pump and the second continuous flow experimental pump are respectively connected to the first mixer; the third continuous flow experimental pump is connected to the second mixer; Reaction tubes, the reaction tubes include a first reaction tube and a second reaction tube, the first reaction tube is located between the first mixer and the second mixer; Quenching device, the quenching device is connected to the second mixer, and the second reaction tube is located between the second mixer and the quenching device; Temperature control system, the continuous flow experimental pumps, the mixers, the reaction tubes and the quenching device are controlled by the temperature control system.

7. The method according to claim 6, characterized in that Including the following steps: Under a protective atmosphere, the lithium diisopropylamide and the acetate 1 are respectively pumped into the first mixer of the continuous flow reaction device at a flow rate of 10-50 mL / min, and mixed at -50°C to -10°C to obtain a first mixed material. The first mixed material undergoes a lithium hydrogen exchange reaction through the first reaction tube to generate alkoxycarbonylethyllithium 2; the alkoxycarbonylethyllithium 2 further reacts with the aldehyde compound 3 pumped into the second mixer at a flow rate of 10-50 mL / min, and is mixed at -50°C to -10°C to obtain a second mixed material; the second mixed material undergoes a nucleophilic addition reaction through the second reaction tube to generate an alcohol lithium intermediate 4; the alcohol lithium intermediate 4 enters the quenching device and is quenched with an acidic solution to obtain a crude product of 3-hydroxy-3-alkylpropionate.

8. The method according to claim 7, wherein The flow rate of the pumped lithium diisopropylamide is 20 to 40 mL / min; the flow rate of the pumped acetate 1 is 20 to 40 mL / min; the flow rate of the pumped aldehyde compound 3 is 20 to 40 mL / min.

9. The method according to claim 7, characterized in that, The residence time of the first mixed material in the first reaction tube is 0.5 to 5 min; the residence time of the second mixed material in the second reaction tube is 0.5 to 5 min.

10. The method according to claim 7, characterized in that, The temperature of the quenching is -20°C to 10°C.

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