A continuous flow reaction method for asymmetric allylic alkylation

Abstract

The present invention relates to the field of chemical synthesis technology, and in particular to a continuous flow reaction method for asymmetric allylic alkylation reaction, comprising: S1: sending the substances participating in the template reaction into the continuous flow reaction system in a split flow path; the substances participating in the template reaction include reaction substrates, nucleophiles and catalysts; the nucleophiles are Grignard reagents; the catalysts include copper salts, chiral ligands and solvents; the continuous flow reaction system includes a material transport unit, a mixing unit, a reaction unit and a collection unit; the reaction unit includes a reactor and a temperature control module; S2: adjusting the reaction parameters to obtain the asymmetric allylic alkylation reaction product. The present invention uses Grignard reagents as nucleophiles, selects inexpensive and low-toxic monovalent copper salts and chiral ligands as catalysts, and makes the reaction safer, the reaction conditions milder, easier to operate, and greatly shortens the reaction time by means of continuous flow, making it easier to achieve scale-up production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a continuous flow reaction method for asymmetric allylic alkylation reaction. Background Art

[0002] Asymmetric allyl is an important intermediate in organic synthesis and is widely used in the design of many drugs and other products. At present, the copper-catalyzed asymmetric allylic carbon-carbon bond construction using Grignard reagents often has high regioselectivity and is an important method for synthesizing target chiral small molecules. The copper-catalyzed asymmetric allylic alkylation reaction using Grignard reagents still has some bottlenecks in industrialization, which are mainly manifested in the following three aspects:

[0003] (1) Long reaction time: The intermittent reaction time of this type of reaction may take 1-2 hours or longer.

[0004] (2) Harsh reaction temperature conditions: The laboratory usually uses Grignard reagents to carry out this reaction, which requires harsh low temperature conditions of -78°C.

[0005] (3) The use of active metal reagents is dangerous and has high economic costs.

[0006] Reactor-based continuous flow chemistry is becoming a powerful technology for synthesizing small molecule compounds. Some researchers have applied it to chemical synthesis and achieved the expected results. However, due to the diversity of chemical reaction types and the complexity of the process, each type of chemical reaction process, and even the synthesis process of each substance, is a set of independent reaction systems and independent reaction procedures. Currently, there is no continuous flow preparation process that can be used as a reference in asymmetric allylic alkylation reactions. Summary of the invention

[0007] In view of this, the object of the present invention is to provide a continuous flow reaction method for asymmetric allylic alkylation reaction, which can shorten the reaction time, reduce the temperature requirements and cost of the reaction, and is safer and more environmentally friendly.

[0008] The present invention is achieved through the following technical solutions:

[0009] A continuous flow reaction method for asymmetric allylic alkylation reaction, comprising:

[0010] S1: The substances involved in the template reaction are sent into the continuous flow reaction system in different ways;

[0011] The substances involved in the template reaction include reaction substrates, nucleophilic reagents and catalysts; the nucleophilic reagents are Grignard reagents; the catalysts include copper salts and chiral ligands; the continuous flow reaction system includes a material transport unit, a mixing unit, a reaction unit and a collection unit; the reaction unit includes a reactor, a temperature control module and an ultrasonic module;

[0012] S2: Adjusting the reaction parameters to obtain an asymmetric allylic alkylation reaction product.

[0013] Further, the reaction substrate is a cyclic substrate R-Br;

[0014] The nucleophile includes methylmagnesium bromide, ethylmagnesium bromide, butylmagnesium bromide, isobutylmagnesium bromide, phenethylmagnesium bromide, 4-methyl-3-pentenylmagnesium bromide, dodecylmagnesium bromide, cyclopentylmagnesium bromide, cyclohexylmagnesium bromide or benzylmagnesium bromide.

[0015] Further, the copper salt is any one of copper (I) thiophene-2-carboxylate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cuprous bromide dimethyl sulfide or copper (II) trifluoromethanesulfonate;

[0016] The ligand is an L2 ligand;

[0017] The solvent is dichloromethane, anhydrous methyl tert-butyl ether or anhydrous n-hexane.

[0018] Preferably, the copper salt is cuprous chloride or cuprous bromide dimethyl sulfide; and the solvent is dichloromethane.

[0019] Furthermore, in the step S1, the reaction substrate, Grignard reagent and catalyst are divided into three flow paths or two flow paths and fed into a continuous flow reaction system;

[0020] The reactor of the continuous flow reaction system is a tubular reactor or a zigzag metal reactor made of PFA material; the internal volume of the reactor is 0.018-0.64 ml.

[0021] Further, in step S2, the reaction parameters include:

[0022] Flow rate of reactants:

[0023] When transported in three streams, the flow rate of the catalyst is 0.3-1.2 ml / min, the flow rate of the reaction substrate is 0.15-0.6 ml / min; the flow rate of the nucleophile is 0.15-0.6 ml / min;

[0024] When transported in two flow paths, the catalyst and the reaction substrate are in one flow path, and the flow rate is 1.2 ml / min; the flow rate of the nucleophile is 0.6 ml / min;

[0025] The reaction temperature is -20 to 25°C; the residence time is 0.6 to 64s.

[0026] Preferably, the present invention provides a continuous flow reaction method for asymmetric allylic alkylation reaction, wherein the reactor of the continuous flow reaction system is a zigzag metal reactor; the internal liquid holding capacity of the zigzag metal reactor is preferably 18 microliters; the reaction temperature is -10°C, and the residence time is 0.6s.

[0027] Furthermore, the molar ratio of the reaction substrate, nucleophile and catalyst is reaction substrate:nucleophile:catalyst=1:1.2:0.075; the molar ratio of copper salt and chiral ligand in the catalyst is copper salt:chiral ligand=1:1.1.

[0028] Furthermore, before the substance participating in the template reaction in S1 enters the continuous flow reaction system, the pipeline of the continuous flow reaction system is ensured to be in an anhydrous and oxygen-free environment; preferably, an inert gas is pre-filled to make the pipeline in an anhydrous and oxygen-free environment. Nucleophilic reagents are extremely sensitive to water and oxygen, and will be quenched and inactivated when exposed to air. Inert gases such as nitrogen and argon can achieve the same effect.

[0029] Furthermore, the template reaction described in S1 is preferably an asymmetric allylic alkylation (AAA) reaction (ie, AAA reaction) with a yield greater than 80% and an enantioselectivity (ee value) greater than 90%.

[0030] Furthermore, the temperature control module is a low temperature circulation module, preferably a low temperature circulation module using a solvent with a freezing point below -20 degrees, such as ethanol, isopropanol or glycerol, as a medium. The reactor is completely or partially placed in the low temperature circulation module.

[0031] Furthermore, the reaction unit also includes an auxiliary module; the auxiliary module mainly acts on the reactor to promote better and faster mixing of the reaction substances in the reactor.

[0032] Preferably, the auxiliary module is an ultrasound module.

[0033] Furthermore, the collection unit uses methanol to quench the reaction product.

[0034] Beneficial effects of the present invention:

[0035] The present invention uses Grignard reagent as a nucleophilic reagent in an asymmetric allylic alkylation (AAA) reaction, selects cheap and low-toxic monovalent copper salts and chiral ligands as catalysts, and combines AAA reaction with continuous flow technology to achieve:

[0036] 1. The reaction time is shortened. The method of the present invention can shorten the reaction time to as fast as 0.6 seconds, which is at least 1 to 2 hours compared to the prior art, and increases the reaction rate by more than 6,000 times.

[0037] 2. The use of active Grignard reagents is safer, the reaction conditions are milder, and the operation is easier. Compared with the harsh low temperature conditions of -78°C required for the reaction in the prior art, the process of the present invention is accurate, efficient, and rapid. The allylic alkylation reaction is carried out at -10°C using such active metal organic reagents, and still maintains good yield and selectivity. The use of active metal organic reagents in the present invention no longer requires intermittent manual dripping, but instead uses a pump to continuously inject, while reacting to generate products, while continuously transferring the products away, which simplifies the operation and reduces the risk of manual operation and the risk of violent heat release due to the large-scale aggregation reaction of nucleophilic reagents.

[0038] 3. The prior art requires harsh low temperature conditions of -78°C to carry out the reaction, which requires high energy consumption and needs to be maintained for 1 to 2 hours, and has high economic costs. The continuous flow reaction of the present invention completes the reaction in seconds at -10°C or -20°C, and has better economic cost control.

[0039] 4. The process of the present invention has a small amplification effect, and is easier to achieve a hundred-gram or even larger-scale amplification production. Through precise reaction flow rate and reaction time control, the reaction system of the process of the present invention can achieve continuous synthesis of multi-step reactions, has a huge process potential with low economic cost, and is more convenient to achieve industrialization.

[0040] The present invention combines the advantages of continuous flow technology, overcomes the difficulties of copper-catalyzed allylic alkylation reaction involving Grignard reagent in industrial production, and utilizes the advantages of continuous flow technology to make up for the shortcomings of copper-catalyzed asymmetric allylic alkylation reaction using Grignard reagent in traditional batch reactors, thereby realizing the automated continuous synthesis of target molecules while still obtaining high yield and high corresponding selectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope of the present invention.

[0042] Figure 1 The invention discloses a three-stream continuous flow system of a tubular reactor.

[0043] Figure 2 Schematic diagram of the template reaction principle used in the continuous flow reaction system experiment of the present invention.

[0044] Figure 3 The invention discloses a three-stream continuous flow system of a zigzag channel metal reactor.

[0045] Figure 4 The continuous flow system of the present invention has two flow paths.

[0046] Figure 5 This is an expanded structure diagram of the nucleophile.

[0047] Figure 6 Generate monitoring charts of product yield and ee value for scale-up and stability experiments. DETAILED DESCRIPTION

[0048] As used herein:

[0049] "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0050] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0051] When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described in this article, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0052] In these examples, parts and percentages are by mass unless otherwise indicated.

[0053] "Parts by mass" refers to the basic unit of measurement for expressing the mass ratio of multiple components. 1 part can represent any unit mass, such as 1g or 2.689g. If we say that the mass of component A is a parts and the mass of component B is b parts, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it means that the mass of component A is aK and the mass of component B is bK (K is an arbitrary number, indicating a multiple factor). It should not be misunderstood that, unlike the mass parts, the sum of the mass of all components is not limited to 100 parts.

[0054] "And / or" is used to indicate that one or both of the stated situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0055] The present invention provides a continuous flow reaction method for asymmetric allylic alkylation reaction, comprising:

[0056] S1: The substances involved in the template reaction are sent into the continuous flow reaction system in different ways;

[0057] The substances involved in the template reaction include reaction substrates, nucleophilic reagents and catalysts; the nucleophilic reagents are Grignard reagents; the catalysts include copper salts and chiral ligands; the continuous flow reaction system includes a material transport unit, a mixing unit, a reaction unit and a collection unit; the reaction unit includes a reactor, a temperature control module and an ultrasonic module;

[0058] S2: Adjusting the reaction parameters to obtain an asymmetric allylic alkylation reaction product.

[0059] In some embodiments, the catalyst further includes a solvent.

[0060] In some embodiments, the reaction substrate is a cyclic substrate R-Br.

[0061] In some embodiments, the nucleophilic agent includes methylmagnesium bromide, ethylmagnesium bromide, butylmagnesium bromide, isobutylmagnesium bromide, phenethylmagnesium bromide, 4-methyl-3-pentenylmagnesium bromide, dodecylmagnesium bromide, cyclopentylmagnesium bromide, cyclohexylmagnesium bromide or benzylmagnesium bromide. The structure diagram of the above nucleophilic agent can be found in Figure 5 .

[0062] In some embodiments, in step S1, the reaction substrate, Grignard reagent and catalyst are divided into three flow paths or two flow paths and fed into a continuous flow reaction system;

[0063] In some embodiments, the reactor of the continuous flow reaction system is a tubular reactor or a zigzag metal reactor made of PFA material; the internal volume of the reactor is 0.018-0.64 ml.

[0064] In these examples, the zigzag reactor has a better reaction effect than the straight reactor, which may be due to its smaller inner diameter, which can be as small as 0.3*0.5mm. The special shape design of the zigzag reactor enables better reaction mixing.

[0065] In some embodiments, the copper salt is any one of thiophene-2-carboxylate copper (I), cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cuprous bromide dimethyl sulfide or trifluoromethanesulfonate copper (II); the ligand is L2 ligand; the solvent is dichloromethane, anhydrous methyl tert-butyl ether or anhydrous n-hexane.

[0066] Preferably, the copper salt is cuprous chloride or cuprous bromide dimethyl sulfide; and the solvent is dichloromethane.

[0067] In some embodiments, in step S2, the reaction parameters include:

[0068] The flow rate of the reaction material; the reaction temperature is -20 to 25°C, and the residence time is 0.6 to 64s.

[0069] When transported in three streams, the flow rate of the catalyst is 0.3-1.2 ml / min, the flow rate of the reaction substrate is 0.15-0.6 ml / min; the flow rate of the nucleophile is 0.15-0.6 ml / min;

[0070] When transported in two flow paths, the catalyst and the reaction substrate are in one flow path with a flow rate of 1.2 ml / min; the flow rate of the nucleophilic reagent is 0.6 ml / min.

[0071] In some embodiments, the present invention provides a continuous flow reaction method for asymmetric allylic alkylation reaction. Preferably, the reactor of the continuous flow reaction system is a zigzag metal reactor; the internal liquid holding capacity of the zigzag metal reactor is preferably 18 microliters; the reaction temperature is -10°C, and the residence time is 0.6s.

[0072] In some embodiments, the molar ratio of the reaction substrate, nucleophile and catalyst is reaction substrate:nucleophile:catalyst=1:1.2:0.075; the molar ratio of copper salt and chiral ligand in the catalyst is copper salt:chiral ligand=1:1.1.

[0073] In some embodiments, before the substance participating in the template reaction in S1 enters the continuous flow reaction system, the pipeline of the continuous flow reaction system is ensured to be in an environment without water and oxygen; preferably, an inert gas is pre-filled to make the pipeline in an environment without water and oxygen. Nucleophilic reagents are extremely sensitive to water and oxygen, and will be quenched and inactivated when exposed to air. Inert gases such as nitrogen and argon can achieve the same effect.

[0074] In some embodiments, the template reaction described in S1 is preferably an asymmetric allylic alkylation (AAA) reaction (ie, AAA reaction) with a yield greater than 80% and an enantioselectivity (ee value) greater than 90%.

[0075] In some embodiments, the temperature control module is a low temperature circulation module, preferably a low temperature circulation module using a solvent with a freezing point below -20 degrees, such as ethanol, isopropanol or glycerol, as a medium. The reactor is completely or partially placed in the low temperature circulation module.

[0076] In some embodiments, the reaction unit further comprises an auxiliary module; the auxiliary module is mainly used to promote better and faster mixing of the reaction substances.

[0077] Preferably, the auxiliary module is an ultrasound module.

[0078] In some embodiments, the collection unit uses methanol to quench the reaction product.

[0079] The embodiments of the present invention will be described in detail below in conjunction with specific examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0080] The present invention selects an AAA reaction with a yield greater than 80% and an enantioselectivity (ee value) greater than 90% as a template reaction for a continuous flow reaction. On this basis, according to the characteristics of this type of reaction, specific equipment units in the continuous flow system, including a material transport unit, a mixing unit, a reactor, a collecting unit, etc., are optimized to construct a preliminary continuous flow system. On the basis of this system, parameters of the continuous flow process, including temperature, concentration, flow rate, reactor volume (length and inner diameter) and reactor type, etc., are optimized to obtain a continuous flow reaction system and reaction procedure with a yield and ee value not lower than that of the prior art, and the system is industrially applied to actual production.

[0081] After optimizing the continuous flow experimental conditions, a systematic investigation was conducted on the effects of different allylic substrates and Grignard reagents with different functional groups on the reaction, such as the effects of steric effects and electronic effects on the reaction results. On this basis, the stability and applicability of the allylic alkylation continuous flow process were systematically evaluated.

[0082] Experiment 1 Continuous Flow Reaction Method for Asymmetric Allyl Alkylation

[0083] 1.1 Design of continuous flow system

[0084] According to the characteristics of intermittent reaction, a preliminary continuous flow system was designed ( Figure 1 ). A PFA pipe with an inner diameter of 0.8 mm (Nanjing Runze Fluid, model 0.8*1.6 mm) was selected as a tubular reactor, three material delivery paths were designed, a syringe pump was used as a material delivery module, a T-type mixer was used as a connection and mixing unit, the reactor was placed in a low-temperature cycle with ethanol as a medium for temperature control, and an ultrasonic module was added to promote better and faster mixing, and the product was directly quenched with methanol to carry out the next step of NMR yield and enantioselectivity testing (GC Agilent 7890B chiral column test).

[0085] 1.2 Continuous flow experiment in a tubular reactor with three flow paths

[0086] Select the template reaction of the cyclic substrate (reaction principle as Figure 2 The reaction mixture was transformed into the continuous flow system designed in 1.1, with the copper salt and the ligand as one flow path, the cyclic substrate and the Grignard reagent as the other two flow paths, and the three flow paths were injected into the pipeline filled with nitrogen by a syringe pump.

[0087] The copper salt selected was copper (I) thiophene-2-carboxylate, which was consistent with the intermittent reaction. The flow rate of the ligand copper salt was set to 0.3 ml / min, the flow rates of the substrate and the Grignard reagent were both 0.15 ml / min, the length of the tubular reactor was 127 cm, the internal volume was 0.64 ml, the residence time was 64 s, and the entire continuous flow reaction was carried out at room temperature (25°C). An ultrasonic module was added from the outside to assist mixing, and finally a yield of more than 99% and an ee value of 67% were obtained (Table 1, entry 1).

[0088] Keeping other conditions unchanged, doubling the flow rate, shortening the residence time by half to 32 s, and the ee value is 69% (see Table 1, entry 2). Doubling the flow rate again, further shortening the residence time by half, and the ee value is 64% (see Table 1, entry 3).

[0089] By changing different types of copper salts, an experimental group of seven different types of copper salts, including thiophene-2-carboxylate copper (I), cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cuprous bromide dimethyl sulfide and trifluoromethanesulfonate copper (II), was set up, and the experimental results are shown in entries 4 to 10 in Table 1. Among them, cuprous chloride and cuprous bromide dimethyl sulfide performed best, reaching an ee value of 70% at room temperature (Table 1, entries 4 and 8).

[0090] It is worth noting that cuprous chloride and chiral ligands are slightly soluble in dichloromethane, and can be seen suspended by naked eyes. A peristaltic pump is required for feeding. Cuprous bromide dimethyl sulfide can be completely dissolved in dichloromethane after combining with ligands, and a syringe pump is selected for feeding. Cuprous chloride with a smaller molecular weight and lower price is selected for optimization of reaction solvents. It is found that compared with anhydrous methyl tert-butyl ether and anhydrous n-hexane (Table 1, entries 10 and 11), dichloromethane still has a better reaction effect.

[0091] Table 1

[0092] Entry Rt / s [CuX] solvent <![CDATA[yield a [%]]]> <![CDATA[ee b [%]]]> 1 64 TqCy DCM >99 67 2 32 TqCy DCM >99 69 3 16 TqCy DCM >99 64 4 32 CuCl DCM >99 70 5 32 CuBr DCM >99 69 6 32 CuI DCM >99 64 7 32 CuCN DCM >99 51 8 32 <![CDATA[CuBr·SMe2]]> DCM >99 70 9 32 <![CDATA[Cu(OTf)2]]> DCM >99 61 10 32 CuCl MTBE >99 53 11 32 CuCl Hexane >99 52

[0093] illustrate: a NMR yield, dibromomethane was used as internal standard; b Directly measured by gas phase chiral column.

[0094] Therefore, the above experiments verified that in a three-stream tubular reactor system, with a residence time of 32 s, using cuprous chloride or cuprous bromide dimethyl sulfide and dichloromethane as the solvent, the continuous flow experiment had the best effect.

[0095] 1.3 Continuous flow experiment of metal reactor with three flow paths

[0096] Based on the tubular reactor experiment in 1.2 (Table 2, item 1), the effects of different types of reactors, reaction temperature and reaction concentration on the reaction results were compared. The first reactor was a metal reactor with a two-inlet and one-outlet zigzag channel with a smaller inner diameter (Shenzhen Yizheng Technology Co., Ltd., item number B.01.00.00), with an inner diameter of 300*500 μm (e.g. Figure 3 As shown in Figure 2, the liquid holding volume is about 18 microliters. Under the same reaction conditions at room temperature, the metal reactor with a zigzag channel only needs a shorter residence time than the tubular reactor, and 0.6s can obtain an ee value of 73% (Table 2, entry 2). When the reaction temperature is reduced to 0 degrees, the ee value can reach 81% (Table 2, entry 3). However, due to the small inner diameter of this type of reactor, the slightly soluble cuprous chloride has the risk of agglomeration and blocking the passage (the ultrasonic module can reduce the risk of clogging). Using soluble cuprous bromide dimethyl sulfide for reaction, almost the same results as cuprous chloride are obtained (Table 2, entry 4).

[0097] It is worth noting that the study found that when the concentration of the reactant was reduced by half, the ee value decreased by 11% (Table 2, entry 5), proving that reducing the concentration is not beneficial to the reaction method of the present invention.

[0098] 1.4 Continuous flow experiment with two flow paths

[0099] The copper salt and ligand flow path is combined with the reaction substrate flow path into one, simplifying the overall continuous flow system into two flow paths ( Figure 4 ), indirectly increasing the concentration of the reaction solution (when there are three streams, the bromine substrate is diluted as one stream, and after two streams, the bromine substrate is directly incorporated into the catalyst stream without dilution), and the results show that the ee value is indeed improved to 85% (Table 2, entry 6). On this basis, the reaction temperature is lowered, and the ee value reaches 96% at -10 degrees and 97% at -20 degrees (see Table 2, entries 7 and 8).

[0100] Table 2

[0101] <![CDATA[entry a ]]> [Cu] t / ℃ Rt / s <![CDATA[yield b [%]]]> <![CDATA[ee c [%]]]> <![CDATA[1 d ]]> CuCl rt 32 >99 70 2 CuCl rt 0.6 >99 73 3 CuCl 0 0.6 >99 81 4 <![CDATA[CuBr·SMe2]]> 0 0.6 >99 82 <![CDATA[5 e ]]> <![CDATA[CuBr·SMe2]]> 0 0.6 >99 71 <![CDATA[6 f ]]> <![CDATA[CuBr·SMe2]]> 0 0.6 >99 85 <![CDATA[7 f ]]> <![CDATA[CuBr·SMe2]]> -10 0.6 >99 96 <![CDATA[8 f ]]> <![CDATA[CuBr·SMe2]]> -20 0.6 >99 97

[0102] illustrate: a Zigzag metal reactor with three flow paths; b NMR yield, dibromomethane was used as internal standard; c Directly measured by gas phase chiral column; d PFA tubular reactor; e The reaction concentration was diluted by one half; f Two flow paths

[0103] In summary, the final result of the optimization of the continuous flow experimental conditions is that using a zigzag reactor, copper bromide dimethyl sulfide and L2 ligand within a reaction time of 0.6 s, at -10 degrees Celsius, a reaction effect of 96% ee value and 99% conversion rate can be obtained.

[0104] Scale-up and stability of a continuous flow reaction method for experimental diasymmetric allylic alkylation

[0105] After completing the optimization of the above-mentioned continuous flow experimental conditions and substrate expansion work, methyl magnesium bromide was selected as the nucleophilic reagent to carry out a scale-up experiment on the reaction of the continuous flow system to verify its amplification effect and the stability of the experimental results.

[0106] The experimental scale was increased from the basic 0.5mml to 12mmol, amplified 24 times to gram-scale reaction, and the experiment was carried out at -10℃. After the flow path was stable, the yield and ee value of the generated product were monitored every four minutes. A total of eight sets of data were obtained. Figure 6 It can be seen that the yield of the target product in the whole process is maintained at 98% to 99%, and the enantioselectivity is maintained at 96% to 97%. It has strong stability and basically no obvious fluctuation. Therefore, the continuous flow system can complete a gram-level asymmetric allylic alkylation reaction with high yield and enantioselectivity within 41 minutes with a residence time of 0.6 s and no amplification effect, which verifies the stability and practicality of the system.

[0107] Compared with the harsh low temperature conditions of -78°C and a reaction time of 1 hour under intermittent conditions, the reaction time was shortened 6,000 times and the reaction conditions were milder while maintaining the same good reaction effect.

[0108] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

[0109] In addition, those skilled in the art will appreciate that, although some embodiments herein include certain features included in other embodiments but not other features, the combination of features of different embodiments is meant to be within the scope of the present invention and to form different embodiments. For example, in the above claims, any one of the claimed embodiments may be used in any combination. The information disclosed in this background technology section is intended only to deepen the understanding of the overall background technology of the present invention and should not be regarded as an admission or in any form of implication that the information constitutes prior art known to those skilled in the art.

Claims

1. A continuous flow reaction method for asymmetric allylic alkylation reaction, characterized in that: include: S1: The substances involved in the template reaction are sent into the continuous flow reaction system in different ways; The substances involved in the template reaction include reaction substrates, nucleophilic reagents and catalysts; the nucleophilic reagents are Grignard reagents; the catalysts include copper salts and chiral ligands; the continuous flow reaction system is a two-stream flow path, including a material transport unit, a mixing unit, a reaction unit and a collection unit; the reaction unit includes a reactor, a temperature control module and an ultrasonic module; S2: adjusting the reaction parameters to obtain an asymmetric allylic alkylation product; Wherein, the reactor is a zigzag reactor, the copper salt is copper bromide dimethyl sulfide, and the chiral ligand is L2 ligand. The reaction time was 0.6 s and the reaction temperature was -10 degrees Celsius; The reaction substrate is The nucleophilic reagent includes methylmagnesium bromide, ethylmagnesium bromide, butylmagnesium bromide, isobutylmagnesium bromide, phenethylmagnesium bromide, 4-methyl-3-pentenylmagnesium bromide, dodecylmagnesium bromide, cyclopentylmagnesium bromide, and cyclohexylmagnesium bromide.

2. The continuous flow reaction method for asymmetric allylic alkylation according to claim 1, characterized in that: The internal volume of the reactor of the continuous flow reaction system is 0.018-0.64 ml.

3. The continuous flow reaction method for asymmetric allylic alkylation according to claim 1, characterized in that: The catalyst also includes a solvent, which is dichloromethane, anhydrous methyl tert-butyl ether or anhydrous n-hexane; The molar ratio of copper salt to chiral ligand in the catalyst is copper salt: chiral ligand = 1:1.

1.

4. The continuous flow reaction method for asymmetric allylic alkylation according to claim 1, characterized in that: In step S2, the reaction parameters include: Flow rate of reactants: When transported in two flow paths, the catalyst and the reaction substrate are in one flow path with a flow rate of 1.2 ml / min; the flow rate of the nucleophilic reagent is 0.6 ml / min.

5. The continuous flow reaction method for asymmetric allylic alkylation according to claim 1, characterized in that: The molar ratio of the reaction substrate, the nucleophilic agent and the catalyst is reaction substrate:nucleophilic agent:catalyst=1:1.2:0.

075.

6. The continuous flow reaction method for asymmetric allylic alkylation according to claim 1, characterized in that: Before the substances participating in the template reaction in S1 enter the continuous flow reaction system, the pipeline of the continuous flow reaction system is in a water-free and oxygen-free environment.

7. The continuous flow reaction method for asymmetric allylic alkylation according to claim 1, characterized in that: The temperature control module is a low temperature circulation module; the reactor is completely or partially placed in the low temperature circulation module.

8. The continuous flow reaction method for asymmetric allylic alkylation according to claim 1, characterized in that: The collection unit uses methanol to quench the reaction product.

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