Continuous preparation method of 3-chloro-3-methylbutyric acid

Abstract

The invention belongs to the field of flow chemistry, and particularly relates to a continuous preparation method of 3-chloro-3-methylbutyric acid, which comprises the following steps: (1) respectively pumping a feed liquid A containing 3, 3-dimethylacrylic acid and hydrochloric acid into a first microreactor for addition reaction to obtain a reaction liquid C; (2) mixing the reaction liquid C with hydrogen chloride gas to obtain a feed liquid C, pumping the feed liquid C into a second microreactor, and carrying out an addition reaction to obtain 3-chloro-3-methylbutyric acid; or (1 ') respectively pumping the feed liquid A containing 3, 3-dimethylacrylic acid and hydrochloric acid into the first microreactor for addition reaction to obtain the 3-chloro-3-methylbutyric acid, and the continuous preparation method is green, environment-friendly, economical and efficient.

Description

Technical Field

[0001] The invention belongs to the field of flow chemistry, and specifically relates to a continuous preparation method of 3-chloro-3-methylbutyric acid. Background Art

[0002] Gliquidone is an insulin secretagogue and a second-generation oral sulfonylurea hypoglycemic drug used to treat type 2 diabetes. Among them, 3-chloro-3-methylbutyric acid is an important intermediate for the preparation of gliquidone. With the increasing incidence of diabetes year by year, the market demand for gliquidone tablets has shown a steady growth trend. In order to further reduce the cost of medication for diabetic patients, it is of great significance to continuously optimize the synthesis process of gliquidone intermediate 3-chloro-3-methylbutyric acid and reduce its production cost.

[0003] At present, the synthesis of 3-chloro-3-methylbutyric acid involves the addition reaction of 3,3-dimethylacrylic acid and HCl. When it is mass-produced in an industrial batch reactor, the following problems will arise: (1) The reaction safety is low. If the heat dissipation is not timely, the local temperature will be too high, which may have the risk of explosion and pose a great safety hazard; (2) The HCl addition reaction will produce a large amount of waste acid, which will pollute the environment; (3) The selectivity is poor, and anti-Markovnikov addition by-products will be generated, and the selectivity and yield of the reaction are low. For the HCl addition reaction, the traditional intermittent addition method has certain disadvantages: (1) The addition process involves a two-phase reaction, and the mass transfer process is slow, resulting in a long reaction time; (2) The acid water generated by the HCl gas when it encounters water vapor has a corrosive effect on metals, and using it in an intermittent reactor will reduce the service life of the reactor; (3) There are large differences between different batches due to different mixing and mass transfer capabilities.

[0004] In view of the above-mentioned difficult-to-overcome defects of the traditional intermittent process mode, such as high safety risk, long reaction time, low yield, poor process repeatability, complicated operation, etc., there is an urgent need in the art to provide a continuous preparation method of 3-chloro-3-methylbutyric acid. Summary of the invention

[0005] The object of the present invention is to provide a continuous preparation method of 3-chloro-3-methylbutyric acid.

[0006] The first aspect of the present invention provides a continuous preparation method of 3-chloro-3-methylbutyric acid, comprising the steps of:

[0007] (1) pumping a feed liquid A containing 3,3-dimethylacrylic acid and hydrochloric acid into a first microreactor respectively for addition reaction to obtain a reaction liquid C; (2) mixing the reaction liquid C with hydrogen chloride gas to obtain a feed liquid C, and pumping the feed liquid C into a second microreactor for addition reaction to obtain 3-chloro-3-methylbutyric acid; or

[0008] (1') Pumping feed liquid A containing 3,3-dimethylacrylic acid and hydrochloric acid into the first microreactor respectively for addition reaction to obtain 3-chloro-3-methylbutyric acid.

[0009] In one or more embodiments, the concentration of the hydrochloric acid is 36-38 wt %.

[0010] In one or more embodiments, step (1) has one or more of the following features:

[0011] The solvent of the feed liquid A is selected from one or both of dichloromethane and dichloroethane, preferably dichloroethane;

[0012] In the feed liquid A, the concentration of 3,3-dimethylacrylic acid is 0.1-2 mol / L, preferably 1-2 mol / L;

[0013] In the first microreactor, the molar ratio of 3,3-dimethylacrylic acid to hydrogen chloride molecules is 1:(2-8), preferably 1:(6-8).

[0014] In one or more embodiments, step (1) has one or more of the following features:

[0015] The temperature of the addition reaction is 40-100°C, preferably 75-80°C;

[0016] The residence time of the addition reaction is 10-60 min, preferably 40-60 min;

[0017] The feed liquid A and hydrochloric acid are pumped into the first microreactor by the first feed pump and the second feed pump respectively and simultaneously, mixed and subjected to addition reaction.

[0018] In one or more embodiments, step (2) has one or more of the following features:

[0019] The flow rate of hydrogen chloride gas is 1.543-4.630 mL / min, preferably 3-4.630 mL / min;

[0020] In the feed liquid C, the concentration of 3-chloro-3-methylbutyric acid is 0.1-2 mol / L, preferably 1-2 mol / L;

[0021] The amount of hydrogen chloride gas used is 1 to 3 times the molar number of 3,3-dimethylacrylic acid in the feed liquid A, preferably 2 to 3 times.

[0022] In one or more embodiments, step (2) has one or more of the following features:

[0023] The temperature of the addition reaction is 20-30°C, preferably 20-25°C;

[0024] The system pressure of the addition reaction is 60-80 psi, preferably 70-80 psi;

[0025] The residence time of the addition reaction is 5-20 min, preferably 10-15 min;

[0026] The hydrogen chloride gas is transported from a hydrogen chloride cylinder into the second microreactor.

[0027] In one or more embodiments, the step (1') has one or more of the following features:

[0028] The solvent of the feed liquid A is selected from one or both of dichloromethane and dichloroethane, preferably dichloroethane;

[0029] In the feed liquid A, the concentration of 3,3-dimethylacrylic acid is 0.1-4 mol / L, preferably 2-4 mol / L;

[0030] In the first microreactor, the molar ratio of 3,3-dimethylacrylic acid to hydrogen chloride molecules is 1:(2-8), preferably 1:(6-8).

[0031] In one or more embodiments, the step (1') has one or more of the following features:

[0032] The temperature of the addition reaction is 40-100°C, preferably 75-80°C;

[0033] The residence time of the addition reaction is 1-25 min, preferably 2-5 min;

[0034] The system pressure of the addition reaction is 20-60 psi, preferably 40-50 psi;

[0035] The feed liquid A and hydrochloric acid are pumped into the first microreactor by the first feed pump and the second feed pump respectively and simultaneously, mixed and subjected to addition reaction.

[0036] The second aspect of the present invention provides a continuous synthesis device for implementing the continuous preparation method described in the first aspect of the present invention:

[0037] The continuous synthesis device comprises a first microreactor and a second microreactor connected in sequence through a pipeline;

[0038] The continuous synthesis device also includes a first feed pump and a second feed pump for feeding the first microreactor;

[0039] The continuous synthesis device also includes a hydrogen chloride gas source for delivering hydrogen chloride gas into the second microreactor;

[0040] The continuous synthesis device also includes a first micro-mixer disposed in front of the first micro-reactor and a second micro-mixer disposed in front of the second micro-reactor;

[0041] or

[0042] The continuous synthesis device comprises a third microreactor;

[0043] The continuous synthesis device also includes a third feed pump and a fourth feed pump for feeding the third microreactor;

[0044] The continuous synthesis device further comprises a third micro mixer arranged before the third microreactor.

[0045] In one or more embodiments, the first microreactor, the second microreactor and the third microreactor are each independently a PTFE capillary reactor, a PFA capillary reactor, a glass chip reactor or a silicon carbide microreactor.

[0046] In one or more embodiments, the diameters of the first microreactor, the second microreactor and the third microreactor are each independently selected from 0.5-1.6 mm, preferably 0.5-0.8 mm.

[0047] In one or more embodiments, the first feed pump, the second feed pump, the third feed pump, and the fourth feed pump are each independently a syringe pump or a cross-flow pump.

[0048] In one or more embodiments, the first micromixer, the second micromixer, and the third micromixer are each independently a T-type three-way mixer or a cross mixer.

[0049] In one or more embodiments, a check valve is further disposed between the hydrogen chloride gas source and the second microreactor.

[0050] The present invention has the following beneficial effects:

[0051] (1) The continuous process realized by the present invention using a microreactor is simple to operate, has a rapid reaction, effectively simplifies the experimental operation process, reduces the generation of three wastes, effectively improves the addition reaction, reduces the amount of concentrated hydrochloric acid used, shortens the reaction time, and effectively prevents the irritating odor caused by the overflow of concentrated hydrochloric acid and the damage to the human body and the environment.

[0052] (2) The present invention conducts continuous operation of the addition reaction, strengthens the mixing process, and improves selectivity. In some preferred embodiments, the method of the present invention can obtain the target product 3-chloro-3-methylbutyric acid with a total yield of more than 60% (e.g., more than 60%, more than 70%, more than 80%, more than 82%, more than 83%, more than 85%, more than 86%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%). In some preferred embodiments, the method of the present invention can obtain the target product 3-chloro-3-methylbutyric acid with a total residence time of less than 5 min (e.g., less than 70 min, less than 60 min, less than 50 min, less than 20 min, less than 10 min, less than 5 min, less than 3 min, less than 1 min). Therefore, the synthesis speed and reaction yield of the continuous synthesis method of the present invention have been greatly improved.

[0053] (3) The method of the present invention has high operational safety. The present invention uses a microreactor to prepare 3-chloro-3-methylbutyric acid, which simplifies the experimental operation process. The microreactor has efficient heat and mass transfer performance and no amplification effect. It is a green, environmentally friendly, economical and efficient method for generating 3-chloro-3-methylbutyric acid.

[0054] (4) The continuous synthesis method of the present invention includes two specific preparation methods. The first method is: 3,3-dimethylacrylic acid and hydrochloric acid are subjected to addition reaction in the first microreactor, and the unreacted 3,3-dimethylacrylic acid is further subjected to addition reaction with hydrogen chloride gas in the second microreactor; the second method is: 3,3-dimethylacrylic acid is subjected to addition reaction with hydrochloric acid only in the first microreactor. Both methods can avoid generating anti-Markovnikov addition by-products within the defined reaction temperature range, and the yield can reach more than 90%. The difference is that in the first method, both gaseous and liquid reactants are used. Although the required residence time is longer, reaching more than one hour, less wastewater is generated because less equivalents of concentrated hydrochloric acid are used. The second method requires more equivalents of concentrated hydrochloric acid, but the reaction residence time is shorter. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 It is a schematic diagram of the structure of a continuous flow synthesis device in one or more embodiments of the present invention.

[0056] Figure 2 It is a schematic diagram of the structure of a continuous flow synthesis device in one or more embodiments of the present invention.

[0057] The following are the descriptions of the reference numerals:

[0058] The first injection pump-A; the second injection pump-B; the hydrogen chloride gas source-D; the first microreactor-C; the second microreactor-E; the reaction liquid containing 3-chloro-3-methylbutyric acid-F; MFC-gas flow controller; CV-check valve; BPR-back pressure valve. DETAILED DESCRIPTION

[0059] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0060] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0061] Herein, “comprising”, “including”, “containing” and similar terms encompass the meanings of “consisting essentially of” and “consisting of”. For example, when “A comprises B and C” is disclosed herein, “A consists essentially of B and C” and “A consists of B and C” should be deemed to be disclosed herein.

[0062] In this article, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible secondary ranges and individual values ​​within the range (including integers and fractions).

[0063] In this document, unless otherwise specified, percentage refers to mass percentage and ratio refers to mass ratio.

[0064] Herein, when describing embodiments or examples, it should be understood that they are not used to limit the present invention to these embodiments or examples. On the contrary, all substitutes, improvements and equivalents of the methods and materials described in the present invention can be included in the scope limited by the claims.

[0065] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.

[0066] In order to overcome the defects of the prior art, such as complex processing operation, large environmental pollution, low safety factor, high production cost and low efficiency, the present invention provides a continuous preparation method of 3-chloro-3-methylbutyric acid. The continuous preparation method of the present invention continuously operates the processing process, which can save a large amount of organic solvents and labor costs. The continuous preparation method of the present invention is carried out in a microreactor, which has a large specific surface area and a small liquid holding capacity, and can greatly improve its mass transfer and heat transfer efficiency, so that the danger in the production process is reduced, and it has an intrinsic safety characteristic; secondly, the addition reaction of the present invention is carried out in a microreactor, and its mixing performance is far better than that of an intermittent reactor, which can reduce the use of acidic reagents and reduce the discharge of "three wastes"; finally, based on the advantages of efficient mixing and precise control of the microreactor, the method of the present invention can effectively reduce the generation of by-products in the reaction, improve product quality, and realize the green, safe and efficient continuous preparation of high-purity 3-chloro-3-methylbutyric acid.

[0067] Herein, the continuous preparation method of 3-chloro-3-methylbutyric acid includes the addition reaction shown in the following formula:

[0068]

[0069] The present invention provides a continuous preparation method of 3-chloro-3-methylbutyric acid, comprising the steps of:

[0070] (1) pumping a feed liquid A containing 3,3-dimethylacrylic acid and hydrochloric acid into a first microreactor respectively for addition reaction to obtain a reaction liquid C; (2) mixing the reaction liquid C with hydrogen chloride gas to obtain a feed liquid C, and pumping the feed liquid C into a second microreactor for addition reaction to obtain 3-chloro-3-methylbutyric acid; or

[0071] (1') Pumping feed liquid A containing 3,3-dimethylacrylic acid and hydrochloric acid into the first microreactor respectively for addition reaction to obtain 3-chloro-3-methylbutyric acid.

[0072] In some embodiments, the concentration of the hydrochloric acid is 36-38 wt%, such as 36 wt%, 37 wt%, 38 wt%. The hydrochloric acid can be purchased directly, or the hydrochloric acid can be prepared to a specified concentration in a laboratory.

[0073] In step (1), the solvent of the feed liquid A is a conventional organic solvent in the art, as long as it can dissolve 3,3-dimethylacrylic acid and 3-chloro-3-methylbutyric acid and is not miscible with water. Exemplary solvents of the feed liquid A can be selected from one or both of dichloromethane and dichloroethane, preferably dichloroethane.

[0074] In step (1), the concentration of 3,3-dimethylacrylic acid in the feed solution A is 0.1-2 mol / L, for example, 0.1 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1 mol / L, 1.2 mol / L, 1.5 mol / L, 1.8 mol / L, preferably 1-2 mol / L.

[0075] In step (1), the 3,3-dimethylacrylic acid and hydrogen chloride molecules in the first microreactor for addition reaction can be selected in a conventional molar ratio. In some embodiments, the molar ratio of 3,3-dimethylacrylic acid and hydrogen chloride molecules in the first microreactor is 1:(2-8), such as 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, preferably 1:(6-8).

[0076] In step (1), the addition reaction can be carried out under conventional temperature conditions in the art. In some embodiments, the temperature of the addition reaction is 40-100°C, such as 40°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, preferably 75-80°C.

[0077] In step (1), the addition reaction can be carried out under conventional time conditions in the art. In some embodiments, the residence time of the addition reaction is 10-60 min, such as 10 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, preferably 40-60 min.

[0078] In some embodiments, in step (1), the feed liquid A and hydrochloric acid are pumped into the first microreactor separately and simultaneously by the first feed pump and the second feed pump, mixed and subjected to addition reaction.

[0079] In step (2), the flow rate of hydrogen chloride gas can be adjusted according to other reaction conditions. In some embodiments, the flow rate of hydrogen chloride gas is 1.543-4.630 mL / min, such as 1.6 mL / min, 1.8 mL / min, 2 mL / min, 2.2 mL / min, 2.5 mL / min, 2.8 mL / min, 3 mL / min, 3.3 mL / min, 3.5 mL / min, 3.8 mL / min, 4.2 mL / min, 4.5 mL / min, 4.6 mL / min, preferably 3-4.630 mL / min.

[0080] In some embodiments, the concentration of 3-chloro-3-methylbutyric acid in the feed liquid C is 0.1-2 mol / L, for example, 0.1 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1 mol / L, 1.2 mol / L, 1.5 mol / L, 1.8 mol / L, preferably 1-2 mol / L.

[0081] In step (2), a conventional amount of hydrogen chloride gas can be used for the addition reaction. In some embodiments, the amount of hydrogen chloride gas used is 1-3 times the molar number of 3,3-dimethylacrylic acid in the feed liquid A, preferably 2-3 times.

[0082] In step (2), the addition reaction can be carried out under conventional temperature conditions in the art. In some embodiments, the temperature of the addition reaction is 20-30°C, such as 22°C, 24°C, 25°C, 26°C, 28°C, 30°C, preferably 20-25°C.

[0083] In step (2), the addition reaction can be carried out under conventional pressure conditions in the art. In some embodiments, the system pressure of the addition reaction is 60-80 psi, such as 60 psi, 65 psi, 70 psi, 75 psi, 80 psi, preferably 70-80 psi.

[0084] In step (2), the addition reaction can be carried out under conventional time conditions in the art. The residence time of the addition reaction is 5-20 min, such as 5 min, 10 min, 5 min, 20 min, preferably 10-15 min.

[0085] Herein, the hydrogen chloride gas is delivered into the second microreactor from a hydrogen chloride cylinder.

[0086] In step (1'), the solvent of the feed liquid A is a conventional organic solvent in the art, as long as it can dissolve 3,3-dimethylacrylic acid and 3-chloro-3-methylbutyric acid and is immiscible with water. Exemplary solvents of the feed liquid A can be selected from one or both of dichloromethane and dichloroethane, preferably dichloroethane.

[0087] In step (1'), the concentration of 3,3-dimethylacrylic acid in the feed solution A is 0.1-4 mol / L, for example, 0.1 mol / L, 0.2 mol / L, 0.5 mol / L, 0.8 mol / L, 1 mol / L, 1.5 mol / L, 2 mol / L, 2.5 mol / L, 3 mol / L, 3.5 mol / L, 4 mol / L, preferably 2-4 mol / L.

[0088] In step (1'), the 3,3-dimethylacrylic acid and hydrogen chloride molecules in the first microreactor for addition reaction can be selected in a conventional molar ratio. In some embodiments, the molar ratio of 3,3-dimethylacrylic acid and hydrogen chloride molecules in the first microreactor is 1:(2-8), such as 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, preferably 1:(6-8).

[0089] In step (1'), the addition reaction can be carried out under conventional temperature conditions in the art. In some embodiments, the temperature of the addition reaction is 40-100°C, such as 40°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, preferably 75-80°C.

[0090] In step (1'), the addition reaction can be carried out under conventional time conditions in the art. In some embodiments, the residence time of the addition reaction is 1-25 min, such as 1 min, 2 min, 5 min, 8 min, 10 min, 12 min, 15 min, 20 min, preferably 2-5 min.

[0091] In step (1'), the system pressure of the addition reaction may be 20-60 psi, such as 20 psi, 25 psi, 30 psi, 35 psi, 40 psi, 45 psi, 50 psi, 55 psi, preferably 40-50 psi.

[0092] In some embodiments, in step (1'), the feed liquid A and hydrochloric acid are pumped into the first microreactor by the first feed pump and the second feed pump respectively and simultaneously, mixed and subjected to addition reaction.

[0093] The present invention also provides a continuous synthesis device for implementing the continuous preparation method of the present invention.

[0094] In some embodiments, the continuous synthesis device includes a first microreactor and a second microreactor connected in sequence by a pipeline. The continuous synthesis device also includes a first feed pump and a second feed pump for feeding the first microreactor. The continuous synthesis device also includes a hydrogen chloride gas source for conveying hydrogen chloride gas into the second microreactor. The continuous synthesis device also includes a first micromixer arranged in front of the first microreactor and a second micromixer arranged in front of the second microreactor.

[0095] In other embodiments, the continuous synthesis device includes a third microreactor. The continuous synthesis device also includes a third feed pump and a fourth feed pump for feeding the third microreactor. The continuous synthesis device also includes a third micro mixer arranged before the third microreactor.

[0096] The first microreactor, the second microreactor and the third microreactor can be selected from conventional materials and conventional models of the art. In some embodiments, the first microreactor, the second microreactor and the third microreactor are each independently a PTFE material capillary reactor, a PFA material capillary reactor, a glass chip reactor or a silicon carbide microreactor. In some embodiments, the diameter of the first microreactor, the second microreactor and the third microreactor is each independently selected from 0.5-1.6mm, such as 0.5mm, 0.6mm, 0.7mm, 0.8mm, 1mm, 1.2mm, 1.5mm, 1.6mm, preferably 0.5-0.8mm.

[0097] The first feed pump, the second feed pump, the third feed pump and the fourth feed pump can be selected from conventional materials and conventional models in the art. In some embodiments, the first feed pump, the second feed pump, the third feed pump and the fourth feed pump are each independently a syringe pump or a horizontal flow pump.

[0098] The first micromixer, the second micromixer and the third micromixer can be made of conventional materials and models in the art. In some embodiments, the first micromixer, the second micromixer and the third micromixer are each independently a T-type three-way mixer or a cross mixer.

[0099] In some embodiments, in the continuous synthesis device of the present invention, a check valve is further provided between the hydrogen chloride gas source and the second microreactor.

[0100] 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 without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0101] The reagents and raw materials used in the present invention are commercially available.

[0102] The continuous flow synthesis device of 3-chloro-3-methylbutyric acid under the first scheme is composed of two injection pumps, an HCl cylinder, a gas mass flow controller, a check valve, a polytetrafluoroethylene back pressure valve, two microreactors and two T-type tees. The detailed connections are as follows: Figure 1As shown. The first feed pump A and the second feed pump B are used to transport feed liquid A and feed liquid B into the first microreactor C, and the reaction liquid C is mixed with HCl gas and enters the second microreactor E; the hydrogen chloride gas source D (HCl gas cylinder) is used to transport HCl gas into the second microreactor E, and the reaction liquid F containing 3-chloro-3-methylbutyric acid is collected at the outlet. The materials of the two microreactors can be PTFE or PFA, and glass chip reactors or silicon carbide microreactors can also be used. The reagents used in the experiment are all AR grade, and the feed ratios in the embodiments are all molar ratios.

[0103] Example 1

[0104] In the continuous synthesis device, the connecting pipe is a PTFE pipe, the first microreactor is 9.6m long and 0.8mm in diameter; the second microreactor is 4m long and 0.5mm in diameter, and the feed pumps are both syringe pumps. The first microreactor is made of PFA, and the second microreactor is made of PTFE.

[0105] Take 4.0048g (100.12g / mol, 0.04mol) of 3,3-dimethylacrylic acid, add dichloromethane, dilute to 20mL, and use as feed A. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 37wt%). Feed liquid A and feed liquid B are pumped into the first microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0344mL / min, feed liquid B flow rate is 0.0459mL / min, HCl gas flow rate is regulated by gas mass flow controller to 1.543mL / min, the first microreactor residence time is 60min, the temperature is 80℃; the second microreactor residence time is 10min, the temperature is 25℃, the system pressure is controlled at 80psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 89% as detected by GC.

[0106] Example 2

[0107] In the continuous synthesis device, the connecting pipe is a PTFE pipe, the first microreactor is 9.6m long and 0.8mm in diameter; the second microreactor is 4m long and 0.5mm in diameter, and the feed pumps are both syringe pumps. The first microreactor is made of PTFE, and the second microreactor is made of PFA.

[0108] Take 4.0048g of 3,3-dimethylacrylic acid, add dichloromethane to it, and adjust the volume to 20mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 36wt%). Feed liquid A and feed liquid B are pumped into the first microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0344mL / min, feed liquid B flow rate is 0.0459mL / min, and the HCl gas flow rate is regulated by the gas mass flow controller to be 3.087mL / min. The residence time of the first microreactor is 60min and the temperature is 80℃; the residence time of the second microreactor is 10min, the temperature is 25℃, and the system pressure is controlled at 80psi, and HCl addition reaction is carried out to obtain reaction liquid F. The yield is 92% as detected by GC.

[0109] Example 3

[0110] In the continuous synthesis device, the connecting pipe is a PTFE pipe, the first microreactor is 9.6m long and 0.8mm in diameter; the second microreactor is 4m long and 0.5mm in diameter, and the feed pumps are both syringe pumps. The first microreactor is made of PFA, and the second microreactor is made of PTFE.

[0111] Take 4.0048g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 20mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 38wt%). Feed liquid A and feed liquid B are pumped into the first microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0344mL / min, feed liquid B flow rate is 0.0459mL / min, and the HCl gas flow rate is regulated by the gas mass flow controller to be 4.630mL / min. The first microreactor has a residence time of 60min and a temperature of 80°C; the second microreactor has a residence time of 10min and a temperature of 25°C, and the system pressure is controlled at 80psi, and HCl addition reaction is carried out to obtain reaction liquid F. The yield is 93% as detected by GC.

[0112] Example 4

[0113] In the continuous synthesis device, the connecting pipe is a PTFE pipe, the first microreactor is 9.6m long and 0.5mm in diameter; the second microreactor is a glass chip reactor with a diameter of 1mm and an internal channel volume of 1.17mL, and the feed pumps are all syringe pumps. The material of the first microreactor is PFA.

[0114] Take 4.0048g of 3,3-dimethylacrylic acid, add dichloromethane to it, and adjust the volume to 20mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 37wt%). Feed liquid A and feed liquid B are pumped into the first microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0344mL / min, feed liquid B flow rate is 0.0459mL / min, and the HCl gas flow rate is regulated by the gas mass flow controller to be 1.5434mL / min. The residence time of the first microreactor is 60min and the temperature is 80℃; the residence time of the second microreactor is 10min, the temperature is 25℃, and the system pressure is controlled at 80psi, and HCl addition reaction is carried out to obtain reaction liquid F. The yield is 93% as detected by GC.

[0115] The reaction solution F is purified to obtain an addition product, the structure of which is:

[0116]

[0117] The continuous flow synthesis device of 3-chloro-3-methylbutyric acid under the second scheme consists of two injection pumps, a polytetrafluoroethylene back pressure valve, a PTFE capillary microreactor and a T-type three-way connection. The detailed connections are as follows: Figure 2 As shown. The first feed pump A and the second feed pump B are used to transport feed liquid A and feed liquid B into the microreactor, and the reaction liquid F containing 3-chloro-3-methylbutyric acid is collected at the outlet. The material of the microreactor is PTFE. The reagents used in the experiment are all AR grade, and the feed ratios in the embodiments are all molar ratios.

[0118] Example 5

[0119] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0120] Take 2.0024 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 10 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 36wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0673 mL / min, feed liquid B flow rate is 0.0897 mL / min, total residence time is 5 min, microreactor temperature is 80 ° C, system pressure is controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 60% as detected by GC.

[0121] Example 6

[0122] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0123] Take 2.0024 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 20 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 37wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0589 mL / min, feed liquid B flow rate is 0.0981 mL / min, total residence time is 5 min, microreactor temperature is 80 ° C, system pressure is controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 82% as detected by GC.

[0124] Example 7

[0125] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0126] Take 2.0024 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 10 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 38wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, with feed liquid A flow rate of 0.0523 mL / min, feed liquid B flow rate of 0.105 mL / min, total residence time of 5 min, microreactor temperature of 80 ° C, system pressure controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 83% as detected by GC.

[0127] Example 8

[0128] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0129] Take 2.0024 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 10 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 36wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0471 mL / min, feed liquid B flow rate is 0.110 mL / min, total residence time is 5 min, microreactor temperature is 80°C, system pressure is controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 86% as detected by GC.

[0130] Example 9

[0131] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0132] Take 2.0024 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 10 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 37wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, with feed liquid A flow rate of 0.0428 mL / min, feed liquid B flow rate of 0.114 mL / min, total residence time of 5 min, microreactor temperature of 80 ° C, system pressure controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 89% as detected by GC.

[0133] Example 10

[0134] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0135] Take 0.7509 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 5 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 38wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, with feed liquid A flow rate of 0.0523 mL / min, feed liquid B flow rate of 0.105 mL / min, total residence time of 5 min, microreactor temperature of 80 ° C, system pressure controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 89% as detected by GC.

[0136] Embodiment 11

[0137] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0138] Take 1.2515g of 3,3-dimethylacrylic acid, add dichloromethane to it, and adjust the volume to 5mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 36wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, with feed liquid A flow rate of 0.0362mL / min, feed liquid B flow rate of 0.121mL / min, total residence time of 5min, microreactor temperature of 80℃, system pressure controlled at 40psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 92% as detected by GC.

[0139] Example 12

[0140] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0141] Take 1.5018g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 5mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 37wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0314mL / min, feed liquid B flow rate is 0.126mL / min, total residence time is 5min, microreactor temperature is 80℃, system pressure is controlled at 40psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 92% as detected by GC.

[0142] Example 13

[0143] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0144] Take 1.7521 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 5 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 38wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0277 mL / min, feed liquid B flow rate is 0.129 mL / min, total residence time is 5 min, microreactor temperature is 80 ° C, system pressure is controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 92% as detected by GC.

[0145] Embodiment 14

[0146] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0147] Take 2.0024 g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 5 mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 36wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, with feed liquid A flow rate of 0.0248 mL / min, feed liquid B flow rate of 0.132 mL / min, total residence time of 5 min, microreactor temperature of 80 ° C, system pressure controlled at 40 psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 93% as detected by GC.

[0148] Embodiment 15

[0149] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 9.6 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0150] Take 4.0048g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 10mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 37wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0149mL / min, feed liquid B flow rate is 0.0793mL / min, total residence time is 20min, microreactor temperature is 80℃, system pressure is controlled at 40psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 92% as detected by GC.

[0151] Example 16

[0152] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0153] Take 4.0048g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 10mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 38wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, with feed liquid A flow rate of 0.124mL / min, feed liquid B flow rate of 0.661mL / min, total residence time of 1min, microreactor temperature of 80℃, system pressure controlled at 40psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 86% as detected by GC.

[0154] Embodiment 17

[0155] In the continuous synthesis device, the connecting pipe is a PTFE pipe with a length of 4 m and a diameter of 0.5 mm, and the feed pumps are all syringe pumps.

[0156] Take 4.0048g of 3,3-dimethylacrylic acid, add dichloromethane to it, and dilute to 10mL, as feed A for standby. Feed liquid B is commercially purchased concentrated hydrochloric acid (concentration is 37wt%). Feed liquid A and feed liquid B are pumped into the microreactor by feed pump A and feed pump B respectively, feed liquid A flow rate is 0.0413mL / min, feed liquid B flow rate is 0.220mL / min, total residence time is 3min, microreactor temperature is 80℃, system pressure is controlled at 40psi, HCl addition reaction is carried out to obtain reaction liquid F. The yield is 91% as detected by GC.

[0157] The reaction solution F is purified to obtain an addition product, the structure of which is:

[0158]

Claims

1. A continuous preparation method of 3-chloro-3-methylbutyric acid, characterized in that: Includes steps: (1) pumping a feed liquid A containing 3,3-dimethylacrylic acid and hydrochloric acid into a first microreactor respectively for addition reaction to obtain a reaction liquid C; (2) mixing the reaction liquid C with hydrogen chloride gas to obtain a feed liquid C, and pumping the feed liquid C into a second microreactor for addition reaction to obtain 3-chloro-3-methylbutyric acid; or (1') Pumping feed liquid A containing 3,3-dimethylacrylic acid and hydrochloric acid into the first microreactor respectively for addition reaction to obtain 3-chloro-3-methylbutyric acid.

2. The continuous preparation method according to claim 1, characterized in that: The concentration of the hydrochloric acid is 36-38 wt %.

3. The continuous preparation method according to claim 1, characterized in that: The step (1) has one or more of the following features: The solvent of the feed liquid A is selected from one or both of dichloromethane and dichloroethane, preferably dichloroethane; In the feed liquid A, the concentration of 3,3-dimethylacrylic acid is 0.1-2 mol / L, preferably 1-2 mol / L; In the first microreactor, the molar ratio of 3,3-dimethylacrylic acid to hydrogen chloride molecules is 1:(2-8), preferably 1:(6-8).

4. The continuous preparation method according to claim 1, characterized in that: The step (1) has one or more of the following features: The temperature of the addition reaction is 40-100°C, preferably 75-80°C; The residence time of the addition reaction is 10-60 min, preferably 40-60 min; The feed liquid A and hydrochloric acid are pumped into the first microreactor by the first feed pump and the second feed pump respectively and simultaneously, mixed and subjected to addition reaction.

5. The continuous preparation method according to claim 1, characterized in that: The step (2) has one or more of the following features: The flow rate of hydrogen chloride gas is 1.543-4.630 mL / min, preferably 3-4.630 mL / min; In the feed liquid C, the concentration of 3-chloro-3-methylbutyric acid is 0.1-2 mol / L, preferably 1-2 mol / L; The amount of hydrogen chloride gas used is 1 to 3 times the molar number of 3,3-dimethylacrylic acid in the feed liquid A, preferably 2 to 3 times.

6. The continuous preparation method according to claim 1, characterized in that: The step (2) has one or more of the following features: The temperature of the addition reaction is 20-30°C, preferably 20-25°C; The system pressure of the addition reaction is 60-80 psi, preferably 70-80 psi; The residence time of the addition reaction is 5-20 min, preferably 10-15 min; The hydrogen chloride gas is transported from a hydrogen chloride cylinder into the second microreactor.

7. The continuous preparation method according to claim 1, characterized in that: The step (1') has one or more of the following characteristics: The solvent of the feed liquid A is selected from one or both of dichloromethane and dichloroethane, preferably dichloroethane; In the feed liquid A, the concentration of 3,3-dimethylacrylic acid is 0.1-4 mol / L, preferably 2-4 mol / L; In the first microreactor, the molar ratio of 3,3-dimethylacrylic acid to hydrogen chloride molecules is 1:(2-8), preferably 1:(6-8).

8. The continuous preparation method according to claim 1, characterized in that: The step (1') has one or more of the following characteristics: The temperature of the addition reaction is 40-100°C, preferably 75-80°C; The residence time of the addition reaction is 1-25 min, preferably 2-5 min; The system pressure of the addition reaction is 20-60 psi, preferably 40-50 psi; The feed liquid A and hydrochloric acid are pumped into the first microreactor by the first feed pump and the second feed pump respectively and simultaneously, mixed and subjected to addition reaction.

9. A continuous synthesis device for implementing the continuous preparation method according to any one of claims 1 to 8, characterized in that: The continuous synthesis device comprises a first microreactor and a second microreactor connected in sequence through a pipeline; The continuous synthesis device also includes a first feed pump and a second feed pump for feeding the first microreactor; The continuous synthesis device also includes a hydrogen chloride gas source for delivering hydrogen chloride gas into the second microreactor; The continuous synthesis device also includes a first micro-mixer disposed in front of the first micro-reactor and a second micro-mixer disposed in front of the second micro-reactor; or The continuous synthesis device comprises a third microreactor; The continuous synthesis device also includes a third feed pump and a fourth feed pump for feeding the third microreactor; The continuous synthesis device further comprises a third micro mixer arranged before the third microreactor.

10. The continuous synthesis device according to claim 9, characterized in that: The first microreactor, the second microreactor and the third microreactor are each independently a PTFE capillary reactor, a PFA capillary reactor, a glass chip reactor or a silicon carbide microreactor; The diameters of the first microreactor, the second microreactor and the third microreactor are each independently selected from 0.5-1.6 mm, preferably 0.5-0.8 mm; The first feed pump, the second feed pump, the third feed pump and the fourth feed pump are each independently a syringe pump or a horizontal flow pump; The first micromixer, the second micromixer and the third micromixer are each independently a T-type three-way mixer or a cross-type mixer; A check valve is also provided between the hydrogen chloride gas source and the second microreactor.

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