Continuous flow synthesis process and system of ketolactone intermediate

Abstract

The invention discloses a continuous flow synthesis process and system for a ketolactone intermediate, and the process comprises the following steps: taking a solution obtained by dissolving sodium carbonate and isovitamin C sodium salt in a solvent water as a feed stream, taking 30% hydrogen peroxide as another feed stream, the two strands of feed are pre-cooled and mixed and then directly flow into a reaction zone, oxidation reaction is carried out at a certain temperature, and reaction liquid directly flows into a quenching zone after the reaction is finished; the reaction equation is as follows: the total reaction time of each equivalent amount of # imgabs0 # is controlled to be 1-3 minutes. The problem of potential safety hazards of a traditional kettle type synthesis method is solved, safety and controllability are achieved, the equivalent number of 30% hydrogen peroxide is greatly reduced compared with that of a kettle type process, and the reaction time can be accurately controlled to be 1-3 min; and the product is high in yield and high in purity.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a continuous flow synthesis process and system for an erythrolactone intermediate. Background Art

[0002] Erythrolactone intermediate (I) is an important intermediate for the synthesis of erythrolactone (II), and erythrolactone can be directly dehydrated to obtain tetronic acid (III). Tetronic acid, also known as tetronic acid, is widely present in natural products, has special pharmaceutical activity, and is also a key intermediate for a variety of medicines or pesticides.

[0003]

[0004] The original synthesis methods of tetronic acid reported in the prior art are:

[0005] The first is to brominate ethyl acetoacetate under high temperature and high pressure conditions to obtain 3-bromo-2,4(3H,5H)-furandione, followed by metal-catalyzed reduction to obtain tetronic acid.

[0006] The second method is to react diethylmalonic acid with chloroacetyl chloride to obtain 3-ethoxy-tetrakis acid, and finally remove the ester group to obtain tetrakis acid.

[0007]

[0008] The third method, Chinese patent document CN104130225A discloses a new route, which uses the low-cost natural product sodium salt of isovitamin C as the starting material, and finally obtains tetronic acid through oxidation, cyclization and dehydration.

[0009]

[0010] At present, the above three processes all adopt the traditional kettle process to produce quaternary keto acid. Method 1 and method 2 have complex routes, harsh conditions and low yields. The oxidation process of method 3 has potential safety hazards, and hydrogen peroxide is prone to explosion during mass production. Therefore, those skilled in the art are in urgent need of developing a continuous synthesis process of erythrolactone intermediate (I) that is intrinsically safe, simple to operate, efficient, high-purity, and easy to mass-produce. Summary of the invention

[0011] In view of the problems existing in the above-mentioned prior art, the present invention aims to provide a continuous flow synthesis process and system for erythroleucone lactone intermediates, which solves the potential safety hazard problems of traditional kettle synthesis methods. It is not only safe and controllable, but also has a 30% significantly reduced hydrogen peroxide equivalent number compared to the kettle process, and the reaction time can be accurately controlled within 1 to 3 minutes; and the product yield is high and the quality is excellent.

[0012] Based on the continuous flow process of the present invention, raw materials are continuously added, and products are obtained by continuous and uninterrupted production. During the process, materials flow continuously without interruption or waiting, that is, products are produced continuously, which is a highly efficient production process. When the process operation reaches a steady state in a short period of time, the composition of the material at any position in the reactor, the temperature and other state parameters do not change with time, and the production process and product quality are stable. Therefore, the continuous flow process of the present invention also has the characteristics of short reaction time, high efficiency, and easy operation.

[0013] To achieve one of the above purposes, a continuous flow synthesis process of an erythrolactone intermediate is provided, comprising the following steps:

[0014] A solution obtained by dissolving sodium carbonate and sodium isovitamin C in solvent water is used as one feed, and 30% hydrogen peroxide is used as another feed. The two feeds are mixed after being pre-cooled and directly flow into the reaction zone to carry out oxidation reaction at a certain temperature. After the reaction is completed, the reaction liquid directly flows into the quenching zone;

[0015] The reaction equation is as follows:

[0016]

[0017] The total reaction time for each equivalent is controlled within 1 to 3 minutes.

[0018] Preferably, the temperature of the feed is controlled to be -5°C to 5°C after precooling; the reaction zone includes a first reaction zone and a second reaction zone arranged in series downstream of the precooling zone, the temperature of the first reaction zone is -5°C to 5°C, and the temperature of the second reaction zone is 20°C to 30°C; the temperature of the quenching zone is 40°C to 60°C.

[0019] Preferably, the aqueous solution of sodium carbonate and sodium isovitamin C is temperature controlled at 10-20° C.; and the 30% hydrogen peroxide is placed in an ice water bath.

[0020] Preferably, the molar ratio of the sodium salt of isovitamin C, sodium carbonate and 30% hydrogen peroxide is 1:(1-2):(2-4).

[0021] Preferably, the volume of the solvent water is 10 to 20 times the mass of isovitamin C sodium salt.

[0022] The second object of the present invention is to provide a continuous flow synthesis system of erythrolactone intermediates, which is used to perform the continuous flow synthesis process of erythrolactone intermediates. The system includes at least two feed pipelines, one of which is used to transport aqueous solution raw materials of sodium carbonate and sodium isovitamin C salt, and the other is used to transport H2O2; it also includes a reaction zone and a quenching zone connected in sequence with the feed pipeline; the feed pipeline is connected to the reaction zone through a pre-cooling zone, and the reaction zone includes a first reaction zone and a second reaction zone connected in series; the temperature of the pre-cooling zone is controlled to be -5℃~5℃, the temperature of the first reaction zone is -5℃~5℃, the temperature of the second reaction zone is 20℃~30℃, and the temperature of the quenching zone is 40℃~60℃.

[0023] Preferably, the precooling zone and the reaction zone, and the reaction zone and the quenching zone are connected to each other through pipelines with three-way ball valves.

[0024] Preferably, the reaction zone adopts any one or more of a glass reactor, a tubular reactor and a continuously stirred microreactor connected in series, wherein the material of the tubular reactor is selected from one or more of PFA, PTFE, FEP and silicon carbide.

[0025] Preferably, the first reaction zone and the second reaction zone both adopt tubular reactors, and the tubular reactors connected in series form the reaction zone; a terminal back pressure valve is arranged between the second reaction zone and the quenching zone.

[0026] Preferably, the first reaction zone and the second reaction zone both use glass coils with the inlet at the bottom and the outlet at the top, and the glass coils connected in series form a reaction zone with dual temperature ranges.

[0027] The beneficial effects of the present invention are:

[0028] 1) The present invention breaks through the traditional kettle process and realizes the continuous synthesis of erythrolactone intermediates. Raw materials flow in continuously, products flow out continuously, the reaction system is stable, the reaction residence time is shortened, the production efficiency of the process is greatly improved, and the high purity of the product is guaranteed.

[0029] 2) The present invention reduces the potential safety hazard of hydrogen peroxide in the traditional kettle reaction and the risk caused by the accumulated pressure of carbon dioxide gas generated in the reaction system.

[0030] 3) The present invention realizes precise control of reactions at different stages through the design of different temperature zones, greatly improving reaction efficiency and saving energy consumption, and further improving safety.

[0031] 4) The continuous flow synthesis process and system of the present invention greatly improve the degree of automation of the reaction, achieve precise control of parameters, reduce the generation of by-products, and improve product yield and quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The present invention is further described below in conjunction with the accompanying drawings and embodiments.

[0033] Figure 1 The figure is a synthesis schematic diagram of an embodiment of the present invention.

[0034] Figure 2 This is a synthetic schematic diagram of another embodiment of the present invention.

[0035] Figure 3 This is a synthetic schematic diagram of another embodiment of the present invention.

[0036] The meanings of the reference numerals are as follows:

[0037] 1-feeding pipeline, 11-first feeding pipeline, 12-second feeding pipeline; 2-precooling zone, 21-first precooling zone, 22-second precooling zone; 3-reaction zone, 31-first reaction zone, 32-second reaction zone; 40-three-way valve, 4-quenching zone. DETAILED DESCRIPTION

[0038] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0039] The solvents used in the present invention are all analytically pure. The materials used as raw materials in the examples are all purchased.

[0040] According to a preferred embodiment of the present invention, a continuous flow synthesis process of an erythrolactone intermediate comprises the following steps:

[0041] A solution obtained by dissolving sodium carbonate and sodium isovitamin C in solvent water is used as one feed, and 30% hydrogen peroxide is used as another feed. The two feeds are mixed after being pre-cooled and directly flow into the reaction zone to carry out oxidation reaction at a certain temperature. After the reaction is completed, the reaction liquid directly flows into the quenching zone;

[0042] The reaction equation is as follows:

[0043]

[0044] The total reaction time is controlled within 1 to 3 minutes.

[0045] So far, this embodiment uses sodium isovitamin C, sodium carbonate, and 30% hydrogen peroxide as raw materials, and obtains the erythrolactone intermediate through precooling, peroxidation reaction, and quenching. After quenching, no post-treatment is required, and the subsequent reaction is directly carried out. The total reaction residence time is controlled within a short range of 1 to 3 minutes, which not only innovatively breaks through the limitations of traditional processes and realizes the continuous synthesis of erythrolactone intermediates, but also shortens the reaction time, which is conducive to continuous, efficient, safe and stable production.

[0046] Preferably, after precooling, the temperature of the feed (first temperature zone) is controlled to be -5°C to 5°C; the reaction zone includes a first reaction zone and a second reaction zone arranged in series downstream of the precooling zone, the temperature of the first reaction zone (second temperature zone) is -5°C to 5°C, the temperature of the second reaction zone (third temperature zone) is 20°C to 30°C; the temperature of the quenching zone (fourth temperature zone) is 40°C to 60°C. Based on this, the reaction temperature conditions are milder and the safety is greatly improved. The product yield is high and the product quality is excellent.

[0047] The temperature of the aqueous solution of sodium carbonate and isovitamin C sodium salt is controlled at 10-20° C. to prevent the raw materials from deteriorating due to temperature increase; 30% hydrogen peroxide needs to be placed in an ice water bath to slow down the decomposition speed.

[0048] The molar ratio of the sodium salt of isovitamin C, sodium carbonate and 30% hydrogen peroxide is 1:(1-2):(2-4). Based on this, the equivalent number of the dangerous reagent 30% hydrogen peroxide of the present invention is reduced from 4.5 equivalents required by the traditional kettle synthesis method to 2.04 equivalents, the reaction temperature condition is mild, and the safety is greatly improved.

[0049] The volume of the solvent water is 10 to 20 times the mass of the sodium salt of isovitamin C, which is conducive to the stable feeding of the aqueous solution of sodium salt of isovitamin C. In addition, activated carbon is used in the quenching zone to catalyze and decompose excess H2O2.

[0050] As another preferred embodiment of the present invention, a continuous flow synthesis system of erythrolactone intermediates is used to perform the continuous flow synthesis process of erythrolactone intermediates, the system comprises at least two feed pipelines 1, the first feed pipeline 11 is used to transport the aqueous solution raw material of sodium carbonate and sodium isovitamin C salt, and the second feed pipeline 12 is used to transport H2O2; it also includes a reaction zone 3 and a quenching zone 4 connected in sequence with the feed pipeline 1; the feed pipeline 1 is connected to the reaction zone 3 through the precooling zone 2, and the reaction zone 3 includes a first reaction zone connected in series 31 and the second reaction zone 32; specifically, the first feed pipeline 11 is connected to the first reaction zone 31 through the first precooling zone 21, and the second feed pipeline 12 is connected to the first reaction zone 31 through the second precooling zone 22; the temperature range of the first temperature zone T1 of the precooling zone 2 is controlled to be -5°C to 5°C, the temperature range of the second temperature zone T2 of the first reaction zone 31 is controlled to be -5°C to 5°C, the temperature range of the third temperature zone T3 of the second reaction zone 32 is controlled to be 20°C to 30°C, and the temperature range of the fourth temperature zone T4 of the quenching zone 4 is controlled to be 40°C to 60°C. In practical applications, the first precooling zone 21 and the second precooling zone 22 are connected to the first reaction zone 3 through a pipeline with a three-way ball valve, and the reaction zone and the quenching zone 4 are also connected through a pipeline with a three-way ball valve.

[0051] The reaction zone 3 is a series connection of any one or more of a glass reactor, a tubular reactor and a continuously stirred microreactor, wherein the material of the tubular reactor is selected from one or more of PFA, PTFE, FEP, silicon carbide and the like.

[0052] As a preferred embodiment, Figure 1 As shown, the first reaction zone 31 and the second reaction zone 32 both adopt tubular reactors, and the tubular reactors connected in series form the reaction zone 3; a terminal back pressure valve is arranged between the second reaction zone 32 and the quenching zone 4 to adjust the pressure to 0.1-1.8 MPa.

[0053] As another preferred embodiment, Figure 2 As shown, both the first reaction zone 31 and the second reaction zone 32 use glass coils with the inlet at the bottom and the outlet at the top, and the glass coils connected in series form a dual-temperature reaction zone 3.

[0054] In addition, combined Figure 3 As shown, the first reaction zone 31 adopts a tubular reactor, and the second reaction zone 32 adopts a glass flask. At the same time, the glass flask can be directly used as a quenching zone 4 to remove excess H2O2.

[0055] Regardless of which reaction zone setting form is adopted, the residence time of the two materials entering through the two feed pipes after mixing in the reaction zone is controlled to be 1 to 3 minutes to carry out the efficient reaction of the present invention.

[0056] Based on the continuous flow synthesis process and system of the present invention, the following specific implementations are carried out (in the following embodiments, for raw materials: the prepared aqueous solution of sodium carbonate and sodium isovitamin C salt is temperature-controlled at 10-20°C to prevent the raw materials from deteriorating due to temperature increase, and 30% hydrogen peroxide is placed in an ice water bath to slow down the decomposition rate; for temperature control: the raw material bottle and the pipeline can be placed in a water bath for temperature control):

[0057] Example 1

[0058] Use Figure 1 The continuous flow synthesis system shown in the figure comprises two feed pipes 1, one of the first feed pipes 11 is used to transport the aqueous solution raw materials of sodium carbonate and sodium isovitamin C salt, and the other is used to transport H2O2; it also comprises a reaction zone 3 and a quenching zone 4 which are sequentially connected with the feed pipe 1; the feed pipe 1 is connected to the reaction zone 3 through a precooling zone 2, and the reaction zone 3 comprises a first reaction zone 31 and a second reaction zone 32 which are connected in series; the precooling zone 2, the reaction zone 3 and the quenching zone 4 are connected through a pipeline with a three-way ball valve 40. A terminal back pressure valve is arranged between the second reaction zone 32 and the quenching zone 4. Among them, both reaction zones use PFA pipes as tubular reactors, the length of which is 5m, and the liquid holding capacity is 25.5ml in total. After checking the airtightness of the device, the back pressure is adjusted to 1MPa.

[0059] Sodium isovitamin C (10.0 g, 1 eq) and sodium carbonate (5.35 g, 1 eq) dissolved in water (200 mL, 20 v) are taken as the first feed into the first feed pipeline 11, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30% H2O2 is taken into the second feed pipeline 12 as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of the first feed (aqueous solution of sodium carbonate and sodium isovitamin C) is set to 10 mL / min, and the flow rate of the second feed (30% H2O2) is set to 0.5 mL / min.

[0060] The two streams of materials are mixed in the three-way pipe in the pre-cooling zone 2 (temperature zone T1, 0°C) and then flow into the first reaction zone 31 (T2, 0°C), and then flow into the second reaction zone 32 (T3, 30°C). The reaction is completed by sampling at the three-way ball valve 40 on the connecting pipe between the reaction zone 3 and the quenching zone 4, and then flow into the quenching zone (T4, 50°C) to confirm that the starch potassium iodide test paper does not turn blue (indicating that the H2O2 reaction is complete).

[0061] After the system reached stability, a 5-min sample was collected, quenched with activated carbon and filtered, the filtrate was adjusted to pH = 1 with 36 wt% HCl, then concentrated under pressure, and the residue was extracted by reflux with ethyl acetate. Then, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.28 g of a white solid, with a yield of 90.1% and a purity of 96.2%.

[0062] Example 2

[0063] The two reaction zone pipes were PFA pipes, both of which were 5 m long and had a total liquid holdup of 25.5 mL, similar to the continuous flow synthesis system of Example 1. The back pressure after testing the airtightness of the device was 1 MPa.

[0064] Sodium isovitamin C (10.0 g, 1 eq) and sodium carbonate (5.35 g, 1 eq) are dissolved in water (200 mL, 20 v) and fed into the first feed pipe 11 as the first feed, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30% H2O2 is fed into the second feed pipe 12 as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of the aqueous solution of sodium carbonate and sodium isovitamin C is set to 20 mL / min; the flow rate of 30% H2O2 is set to 1 mL / min.

[0065] The two streams of materials flow through the pre-cooling zone 2 (temperature zone 1, 0°C) and then flow into the first reaction zone 31 (temperature zone 2, 0°C) after being mixed in the three-way valve, and then flow into the second reaction zone 32 (temperature zone 3, 30°C). The three-way ball valve 40 is used for sampling and control reaction completion, and then flows into the quenching zone 4 (temperature zone 4, 50°C) to confirm that the starch potassium iodide test paper does not turn blue.

[0066] After the system reached stability, a 5-min sample was collected, quenched with activated carbon and filtered, the filtrate was adjusted to pH = 1 with 36 wt% HCl, then concentrated under pressure, and the residue was extracted by reflux with ethyl acetate. Then, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.54 g of a white solid, with a yield of 89.5% and a purity of 95.8%.

[0067] Example 3

[0068] The two reaction zone pipes were PFA pipes, both of which were 5 m long and had a total liquid holdup of 25.5 mL, similar to the continuous flow synthesis system of Example 1. The back pressure after testing the airtightness of the device was 1 MPa.

[0069] Sodium isovitamin C (10.0 g, 1 eq) and sodium carbonate (5.35 g, 1 eq) are dissolved in water (200 mL, 20 v) and fed into the first feed pipe 11 as the first feed, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30% H2O2 is fed into the second feed pipe 12 as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of the aqueous solution of sodium carbonate and sodium isovitamin C is set to 20 mL / min; the flow rate of 30% H2O2 is set to 1.2 mL / min.

[0070] The two streams of materials flow through the pre-cooling zone 2 (temperature zone 1, 0°C) and then flow into the first reaction zone 31 (temperature zone 2, 0°C) after being mixed in the three-way valve, and then flow into the second reaction zone 32 (temperature zone 3, 20°C). The three-way ball valve 40 is used for sampling and control reaction completion, and then flows into the quenching zone 4 (temperature zone 4, 50°C) to confirm that the starch potassium iodide test paper does not turn blue.

[0071] After the system reached stability, a 5-min sample was collected, quenched with activated carbon and filtered, the filtrate was adjusted to pH = 1 with 36 wt% HCl, then concentrated under pressure, and the residue was extracted with ethyl acetate under reflux. Then, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.61 g of a white solid, with a yield of 92.0% and a purity of 97.0%.

[0072] Example 4

[0073] The continuous flow synthesis system is basically the same as that of Example 1, and the two reaction zone pipelines are PFA pipelines, except that the length of the two PFA pipelines is 10 m, and the total liquid holding capacity is 51 mL. The back pressure after the airtightness of the device is tested is 1 MPa.

[0074] Sodium isovitamin C (50.0 g, 1 eq) and sodium carbonate (26.75 g, 1 eq) are dissolved in water (1000 mL, 20 v) and fed into the first feed pipe 11 as the first feed, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30% H2O2 is fed into the second feed pipe 12 as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of the aqueous solution of sodium carbonate and sodium isovitamin C is set to 40 mL / min; the flow rate of 30% H2O2 is set to 2 mL / min.

[0075] The two streams of materials flow through the pre-cooling zone 2 (temperature zone 1, 0°C) and then flow into the first reaction zone 31 (temperature zone 2, 0°C) after being mixed in the three-way valve, and then flow into the second reaction zone 32 (temperature zone 3, 25°C). The three-way ball valve 40 is used for sampling and control reaction completion, and then flows into the quenching zone 4 (temperature zone 4, 50°C) to confirm that the starch potassium iodide test paper does not turn blue.

[0076] After the system reached stability, a 20-min sample was collected, quenched with activated carbon and filtered, the filtrate was adjusted to pH = 1 with 36 wt% HCl, then concentrated under pressure, and the residue was extracted by reflux with ethyl acetate. Then, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 17.6 g of white solid, with a yield of 88.0% and a purity of 94.9%.

[0077] Example 5

[0078] Use Figure 1 The continuous flow synthesis system shown in the figure comprises two feed pipes 1, one of the first feed pipes 11 is used to transport the aqueous solution raw materials of sodium carbonate and sodium isovitamin C salt, and the other is used to transport H2O2; it also comprises a reaction zone 3 and a quenching zone 4 which are sequentially connected with the feed pipe 1; the feed pipe 1 is connected to the reaction zone 3 through a precooling zone 2, and the reaction zone 3 comprises a first reaction zone 31 and a second reaction zone 32 which are connected in series; the precooling zone 2, the reaction zone 3 and the quenching zone 4 are connected through a pipeline with a three-way ball valve 40. A terminal back pressure valve is arranged between the second reaction zone 32 and the quenching zone 4. Among them, both reaction zones use PFA pipes as tubular reactors, the length of which is 5m, and the liquid holding capacity is 25.5ml in total. After checking the airtightness of the device, the back pressure is adjusted to 1MPa.

[0079] Sodium isovitamin C (10.0 g, 1 eq) and sodium carbonate (5.35 g, 1 eq) dissolved in water (200 mL, 20 vol) are taken as the first feed into the first feed pipeline 11, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30 vol% H2O2 is taken into the second feed pipeline 12 as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of the first feed (the aqueous solution of sodium carbonate and sodium isovitamin C) is set to 10 mL / min, and the flow rate of the second feed (30% H2O2) is set to 1 mL / min.

[0080] The two streams of materials are mixed in the three-way pipe in the pre-cooling zone 2 (temperature zone T1, 0°C) and then flow into the first reaction zone 31 (T2, 0°C), and then flow into the second reaction zone 32 (T3, 30°C). The reaction is completed by sampling at the three-way ball valve 40 on the connecting pipe between the reaction zone 3 and the quenching zone 4, and then flow into the quenching zone (T4, 50°C) to confirm that the starch potassium iodide test paper does not turn blue (indicating that the H2O2 reaction is complete).

[0081] After the system reached stability, a 5-min sample was collected, quenched with activated carbon and filtered, the filtrate was adjusted to pH = 1 with 36 wt% HCl, then concentrated under pressure, and the residue was extracted with ethyl acetate under reflux. Then, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.26 g of white solid, with a yield of 89.0% and a purity of 95.3%.

[0082] In combination with the above, the reaction results of Examples 1-5 are shown in Table 1:

[0083] Table 1. Reaction results of Examples 1-5

[0084]

[0085] Note: There is a ±2% deviation between the measured flow rate of the two channels a / b and the set flow rate of the plunger pump

[0086] Example 6

[0087] Use Figure 2 The continuous flow synthesis system shown in the figure includes two feed pipes 1, one of the first feed pipes 11 is used to transport the aqueous solution raw materials of sodium carbonate and sodium isovitamin C salt, and the other is used to transport 30% H2O2; it also includes a reaction zone 3 and a quenching zone 4 connected in sequence with the feed pipe 1; the feed pipe 1 is connected to the reaction zone 3 through a precooling zone 2, and the reaction zone 3 includes a first reaction zone 31 and a second reaction zone 32 connected in series; the precooling zone 2, the reaction zone 3 and the quenching zone 4 are connected through a pipeline with a three-way ball valve (not shown in the figure). Among them, the reaction zone adopts a customized double-temperature zone glass coil, the reaction liquid enters from the bottom and exits from the top, and the inner diameter is larger than the PFA pipe used in Examples 1-5 (such as the inner diameter is three times the relationship, which is 5.4mm), and no back pressure is required. The total liquid holding capacity is 50ml.

[0088] Sodium isovitamin C (30.0 g, 1 eq) and sodium carbonate (16.05 g, 1 eq) dissolved in water (600 mL, 20 vol) are taken as the first feed into the first feed pipeline 11, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30 vol% H2O2 is taken into the second feed pipeline 12 as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of the first feed (the aqueous solution of sodium carbonate and sodium isovitamin C) is set to 20 mL / min, and the flow rate of the second feed (30% H2O2) is set to 1 mL / min.

[0089] The two streams of materials flow through the pre-cooling zone 2 (temperature zone T1, 0°C) and then flow into the first reaction zone 31 (T2, 0°C) after mixing in the three-way, and then flow into the second reaction zone 32 (T3, 30°C). The reaction is completed by sampling at the three-way ball valve 40 on the connecting pipe between the reaction zone 3 and the quenching zone 4, and then flow into the quenching zone (T4, 50°C) to confirm that the starch potassium iodide test paper does not turn blue.

[0090] After the system reached stability, a 5-min sample was collected, quenched with activated carbon and filtered, the filtrate was adjusted to pH = 1 with 36 wt% HCl, then concentrated under pressure, and the residue was extracted with ethyl acetate under reflux. Then, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.59 g of a white solid, with a yield of 91.4% and a purity of 96.6%.

[0091] Example 7

[0092] The continuous flow synthesis system is basically the same as that of Example 6. The reaction pipeline is a customized double-temperature zone glass coil, the reaction liquid enters from the bottom and exits from the top, and the inner diameter is large, so no back pressure is required. The total liquid holding capacity is 50 mL.

[0093] Sodium isovitamin C (30.0 g, 1 eq) and sodium carbonate (16.05 g, 1 eq) are dissolved in water (600 mL, 20 v) and fed into the first feed pipe 11 as the first feed, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30% H2O2 is taken as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of the aqueous solution of sodium carbonate and sodium isovitamin C is set to 40 mL / min; the flow rate of 30% H2O2 is set to 2 mL / min.

[0094] The two streams of materials flow into reaction zone 1 (temperature zone 2, 0°C) after being mixed in a three-way precooling zone (temperature zone 1, 0°C), and then flow into reaction zone 2 (temperature zone 3, 30°C). The reaction is completed by sampling at the three-way ball valve 40 on the pipeline connecting reaction zone 3 and quenching zone 4, and then flow into the quenching zone (temperature zone 4, 50°C) to confirm that the starch potassium iodide test paper does not turn blue. After the system reaches stability, collect 5min samples, filter after activated carbon quenching, adjust the pH of the reaction solution to 1 with 36wt% HCl, then concentrate under pressure, and extract the residue with ethyl acetate reflux. Then filter, and the filtrate is concentrated under reduced pressure to obtain 5.14g of white solid, with a yield of 90.5% and a purity of 95.4%.

[0095] In combination with the above, the reaction results of Examples 6-7 are shown in Table 2:

[0096] Table 2. Reaction results of Examples 6-7

[0097]

[0098] Example 8

[0099] Use Figure 3The continuous flow synthesis system shown in the figure comprises two feed pipes 1, one of the first feed pipes 11 is used to transport the aqueous solution raw materials of sodium carbonate and sodium isovitamin C salt, and the other is used to transport 30% H2O2; it also comprises a reaction zone 3 and a quenching zone 4 which are sequentially connected with the feed pipe 1; the feed pipe 1 is connected to the reaction zone 3 through a precooling zone 2, and the reaction zone 3 comprises a first reaction zone 31 and a second reaction zone 32 which are connected in series. The first reaction zone 31 uses a PFA pipe as a tubular reactor, and the second reaction zone 32 uses a flask as a glass reactor, and the flask can be directly heated and quenched after the reaction is completed, so that the flask can also serve as the quenching zone 4.

[0100] Sodium isovitamin C (10.0 g, 1 eq) and sodium carbonate (5.35 g, 1 eq) are dissolved in water (200 mL, 20 v) and fed into the first feed pipe 11 as the first feed, and the molar concentration of sodium isovitamin C is 0.24 mol / L; 30% H2O2 is taken as the second feed, and its molar concentration is 9.8 mol / L. The flow rate of sodium isovitamin C aqueous solution is set to 20 mL / min; the flow rate of 30% H2O2 is set to 1 mL / min.

[0101] The two streams of material are mixed in the pre-cooling zone (temperature zone 1, 0°C) and then flow into the reaction zone 1 (temperature zone 2, 0°C), and then flow into the flask zone (temperature zone 3, 30°C). After the mid-control reaction is completed, the temperature is raised to 50°C for quenching, and it is confirmed that the starch potassium iodide test paper does not turn blue. After the system reaches stability, collect 5min samples, filter after activated carbon quenching, and adjust the pH of the reaction solution to 1 with 36wt% HCl. Then, pressurize and concentrate, and extract the residue with ethyl acetate reflux. Then filter, and the filtrate is concentrated under reduced pressure to obtain 2.54g of white solid, with a yield of 89.6% and a purity of 97.2%.

[0102] Example 9

[0103] The continuous flow synthesis system of this example is basically the same as that of Example 8. Figure 3 As shown, the reaction zone includes a PFA pipe as the first reaction zone, i.e., the low-temperature zone, with a length of 5 m and a liquid holding capacity of 12.75 mL, and also includes a flask as the second reaction zone, wherein the flask zone is directly heated and quenched after the reaction is completed.

[0104] Take isovitamin C sodium salt (10.0g, 1eq) and sodium carbonate (5.35g, 1eq) and dissolve them in water (200mL, 20v), and enter the first feed pipe 11 as the first feed, and the molar concentration of isovitamin C sodium salt is 0.24mol / L; take 30% H2O2 as the second feed, and its molar concentration is 9.8mol / L. The flow rate of isovitamin C sodium salt aqueous solution is set to 30mL / min; the flow rate of 30% H2O2 is set to 1.5mL / min. The two streams of materials flow into reaction zone 1 (temperature zone 2, 0℃) after three-way mixing in the pre-cooling zone (temperature zone 1, 0℃), and then flow into the flask zone (temperature zone 3, 30℃). After the mid-control reaction is completed, the temperature is raised to 50℃ for quenching, and it is confirmed that the starch potassium iodide test paper does not turn blue. After the system reached stability, a 5-min sample was collected, quenched with activated carbon and filtered, the filtrate was adjusted to pH = 1 with 36 wt% HCl, then concentrated under pressure, and the residue was extracted with ethyl acetate under reflux. Then, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 3.82 g of white solid, with a yield of 90.0% and a purity of 95.3%.

[0105] In combination with the above, the reaction results of Examples 8-9 are shown in Table 3:

[0106] Table 3. Reaction results of Examples 8-9

[0107]

[0108] Combined with the reaction results in Tables 1-3, the continuous flow reaction of the present invention is reduced from 4.5 equivalents of the kettle method (the patent document CN104130225A also uses 30% H2O2, the molar concentration is 9.8 mol / L, "%" represents the mass percentage, and its equivalent is 4.5) to 2.04 equivalents, the reaction temperature conditions are mild, and the safety is greatly improved. The product yield is high and the product quality is excellent.

[0109] The above-mentioned ideal embodiments of the present invention are inspirations. Through the above-mentioned description content, relevant personnel can make various changes and modifications without departing from the technical idea of ​​the present invention. These equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A continuous flow synthesis process for an erythrolactone intermediate, characterized in that: The steps include: A solution obtained by dissolving sodium carbonate and sodium isovitamin C in solvent water is used as one feed, and 30% hydrogen peroxide is used as another feed. The two feeds are mixed after being pre-cooled and directly flow into the reaction zone to carry out oxidation reaction at a certain temperature. After the reaction is completed, the reaction liquid directly flows into the quenching zone; The reaction equation is as follows: The reaction residence time is controlled at 1 to 3 minutes.

2. The continuous flow synthesis process according to claim 1, characterized in that: After precooling, the temperature of the feed is controlled to be -5°C to 5°C; the reaction zone includes a first reaction zone and a second reaction zone which are sequentially arranged in series downstream of the precooling zone, the temperature of the first reaction zone is -5°C to 5°C, and the temperature of the second reaction zone is 20°C to 30°C; the temperature of the quenching zone is 40°C to 60°C.

3. The continuous flow synthesis process according to claim 1, characterized in that: The temperature of the aqueous solution of sodium carbonate and sodium isovitamin C salt is controlled at 10-20° C.; the 30% hydrogen peroxide is placed in an ice water bath.

4. The continuous flow synthesis process according to claim 1, characterized in that: The molar ratio of the isovitamin C sodium salt, sodium carbonate and 30% H2O2 is 1:(1-2):(2-4).

5. The continuous flow synthesis process according to claim 1, characterized in that: The volume of the solvent water is 10 to 20 times the mass of isovitamin C sodium salt.

6. A continuous flow synthesis system for an erythrolactone intermediate, used for performing the continuous flow synthesis process for an erythrolactone intermediate as claimed in any one of claims 1 to 5, characterized in that: The invention comprises at least two feed pipelines, one of which is used to transport aqueous solution raw materials of sodium carbonate and sodium isovitamin C salt, and the other is used to transport H2O2; it also comprises a reaction zone and a quenching zone which are sequentially connected with the feed pipelines; the feed pipeline is connected to the reaction zone through a precooling zone, and the reaction zone comprises a first reaction zone and a second reaction zone which are connected in series; the temperature of the precooling zone is controlled to be -5°C to 5°C, the temperature of the first reaction zone is -5°C to 5°C, the temperature of the second reaction zone is 20°C to 30°C, and the temperature of the quenching zone is 40°C to 60°C.

7. The continuous flow synthesis system according to claim 6, characterized in that: The precooling zone and the reaction zone, and the reaction zone and the quenching zone are connected to each other through pipelines with three-way ball valves.

8. The continuous flow synthesis system according to claim 6, characterized in that: The reaction zone adopts any one or more of a glass reactor, a tubular reactor and a continuously stirred microreactor connected in series, wherein the material of the tubular reactor is selected from one or more of PFA, PTFE, FEP and silicon carbide.

9. The continuous flow synthesis system according to claim 6, characterized in that: The first reaction zone and the second reaction zone both adopt tubular reactors, and the tubular reactors connected in series form the reaction zone; a terminal back pressure valve is arranged between the second reaction zone and the quenching zone.

10. The continuous flow synthesis system according to claim 6, characterized in that: The first reaction zone and the second reaction zone both use glass coils with the inlet at the bottom and the outlet at the top, and the glass coils connected in series form a reaction zone with dual temperature ranges.

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