A process for synthesizing quinolone compound intermediates using a microreactor

Abstract

The invention discloses a method for synthesizing a quinolone intermediate by continuous flow reaction. Specifically, the method adopts a microchannel reactor, improves the selectivity and conversion rate of the reaction, improves the conversion rate of compound ii to more than 95%, and improves the yield to more than 85%, avoids the use of solvents such as methanol and methyl tert-butyl ether in the intermittent reaction process, simplifies the post-processing method, shortens the overall operation time from about 24 hours to a few minutes, greatly improves the production efficiency, and can realize the continuity and automation of the whole process, the product has high purity and high yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic compound synthesis, and in particular relates to a process for synthesizing a quinolone compound intermediate by using a microreactor. Background Art

[0002] Nemonoxacin malate, with a structural formula as shown in Formula V and a chemical name of 7-[(3S,5S)-3-amino-5-methyl-piperidin-1-yl]-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid malate hemihydrate, is the world's first fluoroquinolone-free antibacterial drug developed by Procter & Gamble in the United States. It has completed Phase II clinical research on diabetic foot infection in the United States with significant results.

[0003]

[0004] Nemofloxacin malate formula v is prepared by salifying the intermediate nemofloxacin shown in formula iv. The intermediate nemofloxacin vi is generally prepared by condensing and hydrolyzing 1-cyclopropyl-7-fluoro-8-methoxy-4-oxy-1,4-dihydro-quinoline-3-carboxylic acid diacetic acid boric anhydride iii and a piperidine derivative iv in the presence of an acid-binding agent. The synthetic route is shown in reaction formula I:

[0005]

[0006] The methylation reaction of (S)-2-tert-butoxycarbonylamino-pentanedioic acid dimethyl ester i is the step of (2S,4S)-2-tert-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester ii. The main operating condition is to add (S)-2-tert-butoxycarbonylamino-pentanedioic acid dimethyl ester i to a LiHMDS solution at a low temperature of less than -78°C, and then add iodomethane to carry out a methylation reaction. After the reaction is completed, methanol and acid water (such as hydrochloric acid) are successively added for quenching, and an extraction solvent (such as ethyl acetate, methyl tert-butyl ether) is added for extraction and stratification. The organic phase is concentrated to dryness under reduced pressure, and then a crystallization solvent (such as methyl tert-butyl ether, ethyl acetate, n-heptane) is added for slurry crystallization, and filtered and dried to obtain (2S,4S)-2-tert-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester ii.

[0007] The synthetic methods of (S)-2-tert-butoxycarbonylamino-dimethyl glutarate methylation reaction reported in the prior art are as follows:

[0008] Route 1 is a method described in the piperidine derivative compound patent [patent number: CN102093260B] and [application number: US20100152452A1], and the specific route is as follows:

[0009]

[0010] This route uses compound i as the starting raw material. First, the carbonyl α carbon of compound i is deprotonated under the action of LiHMDS, that is, the LiHMDS reagent removes the H atom on the carbonyl α carbon of compound i; the obtained intermediate is methylated with iodomethane; after quenching, a solution of compound ii is obtained. This route uses LiHMDS reagent, which requires low temperature (≤-78°C), harsh reaction conditions, and is not easy to operate. This phenomenon is particularly obvious in scale-up production; and the processing operation is complicated, and it needs to be quenched with alcohol and acid aqueous solution in sequence at low temperature. The introduction of alcohol solvent in the quenching process is not conducive to the separation and purification of the reaction solvent, and the reaction time is long. The conventional 30~60g scale laboratory test reaction usually takes 2 days, and the 80~100kg scale workshop production takes 3-4 days.

[0011] Route 2 is a method described in the preparation patent [application number: US005731348A], and the specific synthesis method is as follows:

[0012]

[0013] The reaction mechanism of synthetic route 2 is consistent with that of synthetic route 1. In this route, compound iii is firstly dehydrogenated at -78°C using an organic lithium reagent (LiHMDS), and then connected to the alkylation skeleton through a halogenated alkane. The reaction temperature is still -78°C and the reaction time is 24h. Compound iv is then obtained by quenching and purification under alcohol and acid water conditions. This route still cannot solve the problem described in route 1. Summary of the invention

[0014] In view of some of the shortcomings of the above preparation methods, the present invention provides a method for continuously synthesizing (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester ii intermediate using a microreactor. The method has mild reaction conditions, short reaction time, good safety, simple operation, economic and environmental protection, high yield, good product quality, and is easy to industrialize.

[0015] The first aspect of the present invention provides a method for continuously synthesizing a compound of formula II using a microreactor, comprising the following steps:

[0016] S1) reacting compound i with a hydrogenation agent and a methylation agent in an inert solvent at -78°C to -20°C to obtain a reaction solution containing a compound of formula ii;

[0017] S2) quenching the reaction solution obtained in step S1) with an acidic solution at -20°C to 40°C to obtain a compound of formula ii;

[0018] .

[0019] In another preferred embodiment, in step S1), the hydrogenation reagent is a lithium reagent, preferably, the hydrogenation reagent is selected from: lithium hexamethyldisilazide (LiHDMS), lithium diisopropylamide (LDA), butyl lithium, sodium hexamethyldisilazide (NaHMDS), preferably lithium hexamethyldisilazide (LiHDMS).

[0020] In another preferred embodiment, in step S1), the methylating agent is selected from: methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl bromide, preferably methyl iodide.

[0021] In another preferred embodiment, the microreactor comprises a reaction module and a post-processing module, wherein step S1) is performed in the reaction module, and step S2) is performed in the post-processing module.

[0022] In another preferred embodiment, the reaction module includes a reaction unit A and / or a reaction unit B, and step S1) includes the following steps:

[0023] i-1) at -78°C to -20°C, a solution of compound i and a hydrogenation reagent solution are pre-cooled and introduced into unit A for reaction;

[0024] i-2) at -78°C to -20°C, the reaction solution of step i-1) flows into unit B, and the methylation reagent solution is sent into unit B for reaction to obtain a reaction solution containing compound ii;

[0025] or i'-1) at -78°C to -20°C, a solution of compound i, a methylating agent solution and a hydrogen extraction agent solution are pre-mixed and introduced into unit A or B for reaction to obtain a reaction solution of compound ii;

[0026] Or i''-1) At -78°C to -20°C, a solution of compound i and a methylating agent solution are fed into unit A for pre-mixing and then a hydrogen extraction agent solution is fed into unit B for reaction to obtain a reaction solution of compound ii.

[0027] In another preferred embodiment, the solvent of the solution of compound i is selected from: tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, or a combination thereof.

[0028] In another preferred embodiment, the solvent of the hydrogen removal reagent solution is selected from tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, or a combination thereof.

[0029] In another preferred embodiment, the solvent of the methylating agent solution is selected from tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, or a combination thereof.

[0030] In another preferred embodiment, the solution concentration of compound i is 200-400 g / L, preferably 280-350 g / L, and more preferably 300-320 g / L.

[0031] In another preferred embodiment, the hydrogenation reagent solution is a lithium reagent solution, preferably a lithium hexamethyldisilazide solution (LiHMDS in tetrahydrofuran solution). Preferably, the concentration of the hydrogenation reagent solution is 0.8-1.3 mol / L, preferably 0.8-1.0 mol / L.

[0032] In another preferred embodiment, the molar ratio of compound i to the lithium reagent (such as lithium hexamethyldisilazide (LiHMDS)) is 1:1.7-3.0, preferably 1:2.0.

[0033] In another preferred embodiment, the concentration of the methylating agent solution is 500-700 g / L, preferably 550-650 g / L.

[0034] In another preferred embodiment, in step i-1), the residence time of the mixed material in unit A does not exceed 200 seconds, preferably 5-190 seconds, more preferably 10-150 seconds, and more preferably 10-80 seconds.

[0035] In another preferred embodiment, in step i'-1), the residence time of the mixed material in unit A / unit B does not exceed 400 seconds, preferably 50-350 seconds, more preferably 100-300 seconds.

[0036] In another preferred embodiment, the molar ratio of compound i to the methylating agent is 1:1.0-3.0, preferably 1:1.2.

[0037] In another preferred embodiment, in step i-2), the residence time of the mixed material in unit B does not exceed 300 seconds, preferably 30-200 seconds, more preferably 65-150 seconds, more preferably 75-120 seconds.

[0038] In another preferred embodiment, in step i-1), the reaction temperature of the unit A is -50 to -20°C, preferably -40 to -20°C.

[0039] In another preferred embodiment, in step i'-1), the reaction temperature of the unit A is preferably -60 to -20°C, more preferably -60 to -40°C.

[0040] In another preferred embodiment, in step i-2), the reaction temperature of the unit B is -50 to -20°C, preferably -30 to -20°C.

[0041] In another preferred embodiment, the post-processing module includes a reaction unit C, and step S2) includes the following steps:

[0042] i-3) The obtained reaction solution of compound ii flows into unit C at -78°C to -20°C, and an acidic solution is simultaneously sent into unit C to quench the reaction, thereby obtaining a stable quenched reaction solution containing compound ii.

[0043] In another preferred embodiment, the solvent of the acidic solution is selected from: water, alcohol, or a combination thereof; the acid is selected from: hydrochloric acid, sulfuric acid, or a combination thereof.

[0044] In another preferred embodiment, the alcohol is selected from: methanol, ethanol, or a combination thereof.

[0045] In another preferred embodiment, the acidic solution is selected from aqueous hydrochloric acid solution or aqueous sulfuric acid solution.

[0046] In another preferred embodiment, the acidic solution may contain salt or not, preferably, the salt is NaCl, KCl, NH4Cl, or a combination thereof.

[0047] In another preferred embodiment, the acidic solution is a NaCl aqueous solution of hydrochloric acid.

[0048] In another preferred embodiment, step S2) further includes the steps of standing for stratification, crystallization and filtration.

[0049] In another preferred embodiment, the purity of the compound of formula ii obtained in step S2) after post-treatment is greater than 90%, preferably greater than 94%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%.

[0050] In another preferred embodiment, the molar ratio of compound i to acid is 1:5.0~10.0.

[0051] In another preferred embodiment, the residence time of the reaction solution in unit C does not exceed 100 seconds, preferably 1-50 seconds, more preferably 1-15 seconds.

[0052] In another preferred embodiment, the microreactor may be composed of one or more of the following reactors: Corning reactor, microwell (silicon carbide, Hastelloy, 316L) reactor, Shen's (Hastelloy, 316L) reactor.

[0053] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 A flow chart of the method of the present invention is shown. DETAILED DESCRIPTION

[0055] Through extensive and in-depth research, the inventors of the present application unexpectedly developed a method for continuously synthesizing (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester using a microchannel reactor. The method improves the selectivity and conversion rate of the reaction, the conversion rate of (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester is increased to more than 95%, and the yield is increased to more than 85%. The use of solvents such as methanol and methyl tert-butyl ether in the intermittent reaction process is avoided, and the post-processing method is simplified, so that the overall operation time is shortened from about 24 hours to a few minutes, which greatly improves the production efficiency, and can realize the continuity and automation of the entire process. The product has high purity and high yield, and is suitable for industrial production.

[0056] In the present invention, "compound of formula ii", "(2S,4S)-2-tert-butoxycarbonylamino-4-methyl-glutaric acid dimethyl ester" and "quinolone compound intermediate" have the same meaning and can be used interchangeably.

[0057] In the present invention, "main raw material" and "compound i" have the same meaning.

[0058] Microreactor

[0059] Microreactors include microchannels, microheat exchangers, micromixing reactors, etc., which are microreactors with characteristic dimensions between 10 and 1000 μm manufactured using precision machining technology. The "micro" in microreactor does not specifically refer to the size of the microreactor equipment, nor does it mean that the output of microreactor equipment products is small, but rather means that the channels of the process fluid are at the micron level, and the microreactor can contain hundreds or thousands of microchannels. The annual throughput of compound ii synthesized using a laboratory microreactor (10 ml) in this application can reach 5 tons / year, and the annual throughput of compound ii synthesized using an industrial microreactor (300 ml) can reach 150 to 250 tons / year. The microreactor used in this application can be one or more of a Corning reactor, a microwell (silicon carbide, Hastelloy, 316L) reactor, or a Shen's (Hastelloy, 316L) reactor.

[0060] Method for continuously synthesizing compound of formula II using microreactor

[0061] The present invention utilizes a microreactor to continuously synthesize the compound of formula ii, preferably through the following steps: (S)-2-tert-butoxycarbonylamino-pentanedioic acid dimethyl ester i is used as a starting material, and after hydrogen extraction reaction, methylation reaction, and quenching reaction, (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester ii is obtained.

[0062] Preferably, the present invention adopts a microchannel one-pot continuous flow method to prepare compound ii, and the microreactor is divided into three units, namely A, B, and C. The specific reaction route is as follows:

[0063]

[0064] 1) The solution of compound i and the organic lithium reagent are mixed and reacted in unit A at a reaction temperature of -50 to -20°C; 2) The intermediate i-1 and the methylating agent are simultaneously introduced into unit B for reaction to obtain a reaction solution of intermediate ii-1; 3) The reaction solution containing intermediate ii-1 and an acidic solution (such as hydrochloric acid aqueous solution) are introduced into unit C for reaction to obtain compound ii intermediate. The reaction temperature of unit C is -20 to 20°C. The flow chart is as follows: Figure 1 As shown in method 1.

[0065] Preferably, the present application can also be implemented through a flow chart such as Figure 1 The method shown in method two or three is as follows:

[0066] i'-1) at -78°C to -20°C, a solution of compound i, a methylating agent solution and a hydrogen extraction agent solution are pre-mixed and introduced into unit A or B for reaction to obtain a reaction solution of compound ii;

[0067] Or i''-1) At -78°C to -20°C, a solution of compound i and a methylating agent solution are fed into unit A for pre-mixing and then a hydrogen extraction agent solution is fed into unit B for reaction to obtain a reaction solution of compound ii.

[0068] Preferably, the organic solvent for dissolving compound i is tetrahydrofuran or ethyl acetate.

[0069] Preferably, the reagent for quenching compound ii is aqueous hydrochloric acid solution or aqueous sulfuric acid solution.

[0070] Preferably, the molar ratio of compound i to the lithium reagent (such as lithium hexamethyldisilazide (LiHMDS)) is 1:1.7~3.0, preferably 1:2.0; the molar ratio of the methylating agent to compound i is 1:1.0~3.0, preferably 1:1.2, and the molar ratio of hydrochloric acid / sulfuric acid solution to compound i is 1:5.0~10.0, 1:2.5~5.0, preferably 1:5.5, 1:3.0.

[0071] The above three units A, B and C can add a delayed tubular reactor after the microreactor according to the reaction residence time requirements.

[0072] Preferably, the specific steps of the present invention are as follows:

[0073] 1') dissolving compound i in tetrahydrofuran or ethyl acetate until the liquid is clear and ready for use; the tetrahydrofuran or ethyl acetate solution of compound i and the hexamethyldisilazane solution are respectively pumped into unit A of the microreactor after precooling, and reacted at -50 to -20°C;

[0074] Wherein, the concentration of the tetrahydrofuran / ethyl acetate solution of compound i is 200-400 g / L, preferably 280-350 g / L; the concentration of the lithium hexamethyldisilazide solution (LiHMDS tetrahydrofuran solution) is 0.8-1.3 mol / L, preferably 0.8-1.0 mol / L;

[0075] The molar ratio of compound i to lithium hexamethyldisilazide (LiHMDS) is 1:1.7-3.0, preferably 1:2.0;

[0076] The residence time of the mixed material in unit A does not exceed 200 seconds, preferably 10 to 80 seconds;

[0077] 2') The reaction solution obtained in step 1') flows into unit B of the microreactor, and a tetrahydrofuran / ethyl acetate solution of a methylating agent is fed into unit B, and the mixture is fully reacted at a reaction temperature of -50 to -20°C (preferably -30 to -20°C) to obtain a reaction solution containing compound ii;

[0078] The methylating agent is one of methyl iodide, dimethyl sulfate and dimethyl carbonate; preferably methyl iodide.

[0079] The concentration of the tetrahydrofuran solution of the methylating agent is 500-700 g / L, preferably 550-650 g / L;

[0080] The molar ratio of compound i to the methylating agent is 1:1.0 to 3.0, preferably 1:1.2, and the residence time in the B unit is no more than 300 seconds, preferably 65 to 150 seconds;

[0081] 3') The reaction solution obtained in step 2') is directly flowed into the C unit of the microreactor without treatment, and an acidic solution (such as hydrochloric acid aqueous solution) is pumped into the C unit to react at a reaction temperature of -20~20°C (preferably 10~20°C) until the reaction is complete. After the reaction is completed, it flows out of the microreactor and enters the reaction tank to obtain a reaction solution of compound ii.

[0082] Wherein, the concentration of the acidic aqueous solution is 100-400 g / L, preferably 160-260 g / L, and the molar ratio of compound i to the acid is 1:5.0-10.0, preferably 1:5.5;

[0083] The residence time of the reaction solution in the C unit is no more than 100 seconds, preferably 1-50 seconds, more preferably 1-15 seconds.

[0084] The microreactors used in the present invention include Corning reactors, microwell (silicon carbide, Hastelloy, 316L) reactors, and Shen's (Hastelloy, 316L) reactors. According to common sense of use, industrial scale-up production can be carried out by appropriately increasing the size of the reactor.

[0085] Uses of Compound II

[0086] In the present invention, the obtained (2S, 4S)-2-tert-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester ii is further subjected to aminolysis, cyanation, ring closure and other reaction steps to obtain a piperidine derivative iv, and further, it is subjected to condensation, hydrolysis and salt formation reaction with 1-cyclopropyl-7-fluoro-8-methoxy-4-oxy-1,4-dihydro-quinoline-3-carboxylic acid diacetic acid boric anhydride iii to prepare the nemofloxacin malate finished product.

[0087] Compared with the prior art, the present invention has the following main advantages:

[0088] (1) The present invention combines the advantages of efficient mass transfer and heat transfer of microchannel reactors to improve the conversion rate and selectivity of the reaction. The conversion rate of compound ii is increased to more than 95%, and the product yield can be increased to more than 85%, which greatly reduces the difficulty of subsequent purification and separation.

[0089] (2) The present invention avoids the use of solvents such as methanol and methyl tert-butyl ether in the reaction and post-treatment process, so that the organic phase can be directly layered in the post-treatment process, which effectively solves a large number of problems such as cumbersome operations and difficult waste liquid recovery in the intermittent process post-treatment process.

[0090] (3) The reaction time of the present invention is shortened from 24 hours to minutes, and the residual raw materials are reduced from the original 7-15% to 3-5%, which greatly reduces the energy consumption of the reaction and the economic cost of the process.

[0091] (4) The present invention significantly increases the reaction temperature, avoids ultra-low temperature conditions, and reduces energy consumption and safety risks.

[0092] 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.

[0093] Example 1

[0094] In a 1L three-necked flask, 190g of the main raw material, 162g of methyl bromide and 635g of tetrahydrofuran were added to prepare a compound i / methyl bromide tetrahydrofuran solution, which was flowed into the A unit module at a flow rate of 32ml / min. Lithium hexamethyldisilazide with a concentration of 1.2mol / L was simultaneously flowed into the A unit at a flow rate of 50ml / min. The reaction residence time was 267 seconds, and the reaction temperature of the reaction unit was controlled at -55°C. After the reaction liquid flows out of unit A, the prepared 200 g / L hydrochloric acid and sodium chloride aqueous solution is simultaneously pumped into unit C at a flow rate of 52 ml / min. The residence time of the reaction unit is 5.8 seconds, and the reaction temperature controlled by the reaction unit is 0°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 97.42%, the diastereomer is 1.22%, and the total yield is 83.74%.

[0095] Example 2

[0096] A 380 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 21 ml / min. In addition, a 620 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit A at a flow rate of 13.0 ml / min. The residence time of the reaction unit was 8 seconds, and the reaction temperature of the reaction unit was controlled at -78°C. After the reaction solution flowed out of unit A, lithium hexamethyldisilazide with a concentration of 1.2 mol / L was simultaneously flowed into unit B at a flow rate of 50 ml / min. The reaction residence time was 274 seconds, and the reaction temperature was controlled at -50°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid and sodium chloride aqueous solution is pumped into unit C at a flow rate of 35 ml / min. The residence time of the reaction unit is 5.1 seconds, and the reaction temperature controlled by the reaction unit is 40°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The intermediate compound ii is obtained by suction filtration. The purity of this batch of samples is 95.17%, the diastereomer is 1.99%, and the total yield is 81.11%.

[0097] Example 3

[0098] A 320 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 21 ml / min. In addition, 1.2 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 50 ml / min. The reaction residence time was 194 seconds and the reaction temperature was controlled at -50°C. After the reaction liquid flowed out of unit A, the prepared 320 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 13.0 ml / min. The reaction unit residence time was 297 seconds and the reaction temperature was controlled at -20°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid and sodium chloride aqueous solution is simultaneously pumped into unit C at a flow rate of 35 ml / min. The residence time of the reaction unit is 3.9 seconds, and the reaction temperature controlled by the reaction unit is 0°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The intermediate compound ii is obtained by suction filtration. The purity of this batch of samples is 96.41%, the diastereomer is 1.17%, and the total yield is 80.6%.

[0099] Example 4

[0100] A 320 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 21 ml / min. In addition, 1.2 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 50 ml / min. The reaction residence time was 152 seconds and the reaction temperature was controlled at -40°C. After the reaction liquid flowed out of unit A, the prepared 725 g / L bromomethyl tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 16 ml / min. The reaction unit residence time was 164.5 seconds and the reaction temperature was controlled at -50°C. After the reaction liquid flows out of unit B, the prepared 400g / L aqueous solution of ammonium hydrochloride and chloride is simultaneously pumped into unit C at a flow rate of 18ml / min. The residence time of the reaction unit is 98 seconds, and the reaction temperature controlled by the reaction unit is -20°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The intermediate compound ii is obtained by suction filtration. The purity of this batch of samples is 95.94%, the diastereomer is 1.44%, and the total yield is 84.85%.

[0101] Example 5

[0102] A 380 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 21 ml / min. In addition, 1.2 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 50 ml / min. The reaction residence time was 102 seconds and the reaction temperature was controlled at -35°C. After the reaction liquid flowed out of unit A, the prepared 810 g / L bromomethyl tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 11 ml / min. The residence time of the reaction unit was 80.5 seconds and the reaction temperature of the reaction unit was controlled at -35°C. After the reaction liquid flows out of unit B, the prepared 100 g / L hydrochloric acid aqueous solution is pumped into unit C at a flow rate of 65 ml / min. The residence time of the reaction unit is 2.7 seconds, and the reaction temperature controlled by the reaction unit is 20°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 93.45%, the diastereomer is 1.79%, and the total yield is 83.2%.

[0103] Example 6

[0104] A 200 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 30 ml / min. In addition, 0.9 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 75 ml / min. The reaction residence time was 64 seconds and the reaction temperature was controlled at -30°C. After the reaction liquid flowed out of unit A, the prepared 210 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 15 ml / min. The reaction unit residence time was 79 seconds and the reaction temperature was controlled at -35°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid aqueous solution is pumped into unit C at a flow rate of 35 ml / min. The residence time of the reaction unit is 4.9 seconds, and the reaction temperature controlled by the reaction unit is 0°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 98.45%, the diastereomer is 0.44%, and the total yield is 81.7%.

[0105] Example 7

[0106] A 400 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 20 ml / min. In addition, 0.8 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 80 ml / min. The reaction residence time was 10.1 seconds and the reaction temperature was controlled at -45°C. After the reaction liquid flowed out of unit A, the prepared 350 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 13 ml / min. The residence time of the reaction unit was 76 seconds and the reaction temperature of the reaction unit was controlled at -45°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid aqueous solution is pumped into unit C at a flow rate of 35 ml / min. The residence time of the reaction unit is 34.7 seconds, and the reaction temperature controlled by the reaction unit is 10°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 96.17%, the diastereomer is 1.24%, and the total yield is 87.14%.

[0107] Example 8

[0108] A 380 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 11 ml / min. In addition, 0.9 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 35 ml / min. The reaction residence time was 16.0 seconds and the reaction temperature was controlled at -25°C. After the reaction liquid flowed out of unit A, the prepared 650 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 7 ml / min. The reaction unit residence time was 160.1 seconds and the reaction temperature was controlled at -25°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid aqueous solution is pumped into unit C at a flow rate of 17 ml / min. The residence time of the reaction unit is 14.9 seconds, and the reaction temperature controlled by the reaction unit is 0°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 95.21%, the diastereomer is 1.33%, and the total yield is 88.4%.

[0109] Example 9

[0110] A 380 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 30 ml / min. In addition, 1.0 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 60 ml / min. The reaction residence time was 4.5 seconds and the reaction temperature was controlled at -25°C. After the reaction liquid flowed out of unit A, the prepared 650 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 12 ml / min. The reaction unit residence time was 50.7 seconds and the reaction temperature was controlled at -25°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid aqueous solution is pumped into unit C at a flow rate of 51 ml / min. The residence time of the reaction unit is 3.1 seconds, and the reaction temperature controlled by the reaction unit is -20°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 94.33%, the diastereomer is 1.71%, and the total yield is 87.4%.

[0111] Example 10

[0112] A 300 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 21 ml / min. In addition, 1.3 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 35 ml / min. The reaction residence time was 75 seconds and the reaction temperature was controlled at -25°C. After the reaction liquid flowed out of unit A, the prepared 650 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 10 ml / min. The reaction unit residence time was 76 seconds and the reaction temperature was controlled at -25°C. After the reaction liquid flows out of unit B, the prepared 100 g / L sulfuric acid aqueous solution is pumped into unit C at a flow rate of 35 ml / min. The residence time of the reaction unit is 3.2 seconds, and the reaction temperature controlled by the reaction unit is 0°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added for cooling and crystallization. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 90.41%, the diastereomer is 4.33%, and the total yield is 78.2%.

[0113] Embodiment 11

[0114] A 380 g / L ethyl acetate solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 21 ml / min. In addition, 1.0 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 49 ml / min. The reaction residence time was 34 seconds and the reaction temperature was controlled at -20°C. After the reaction liquid flowed out of unit A, the prepared 650 g / L iodomethane tetrahydrofuran solution was simultaneously flowed into unit B at a flow rate of 13 ml / min. The residence time of the reaction unit was 116.9 seconds and the reaction temperature of the reaction unit was controlled at -25°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid aqueous solution is pumped into unit C at a flow rate of 35 ml / min. The residence time of the reaction unit is 68 seconds, and the reaction temperature controlled by the reaction unit is -10°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 90.33%, the diastereomer is 3.12%, and the total yield is 78.1%.

[0115] Example 12

[0116] A 380 g / L tetrahydrofuran solution of the main raw material was prepared in a 1L three-necked flask and flowed into unit A at a flow rate of 21 ml / min. In addition, 0.8 mol / L lithium hexamethyldisilazide was simultaneously flowed into unit A at a flow rate of 65 ml / min. The reaction residence time was 10.0 seconds and the reaction temperature was controlled at -35°C. After the reaction liquid flowed out of unit A, the prepared 578 g / L tetrahydrofuran solution of dimethyl sulfate was simultaneously flowed into unit B at a flow rate of 13 ml / min. The residence time of the reaction unit was 121.4 seconds and the reaction temperature of the reaction unit was controlled at -45°C. After the reaction liquid flows out of unit B, the prepared 200 g / L hydrochloric acid aqueous solution is pumped into unit C at a flow rate of 48 ml / min. The residence time of the reaction unit is 3.8 seconds, and the reaction temperature controlled by the reaction unit is -10°C. The liquid flowing out of the unit is allowed to stand for stratification, and the organic layer is evaporated to near dryness, and n-heptane is added to cool and crystallize. The compound ii intermediate is obtained by suction filtration. The purity of this batch of samples is 95.33%, the diastereomer is 1.49%, and the total yield is 87.1%.

[0117] Comparative Example 1

[0118] Under nitrogen protection, at -78°C, a solution of 1M LiHMDS in tetrahydrofuran (1500 ml) was added to a 5L four-necked flask. At not less than -60°C, a solution of compound i (210 g in 1000 ml of dry tetrahydrofuran) was added dropwise to the solution, and then stirred at -78°C for 6.5 h. At -60°C, iodomethane (176 g in 100 ml of anhydrous tetrahydrofuran) was added to the resulting solution. The reaction was stirred at -78°C for 7.0 h, and then the reaction was quenched with methanol (35 g) at -60°C and 2N hydrochloric acid (1500 ml) at -25°C. Toluene (1500 ml) was added to the resulting solution and stirred for 0.5-1.0 hour, the organic layer was separated, and the solution was treated with a sodium thiosulfate solution (175 g in 1000 ml of water) for 30 minutes under stirring, during which the color changed from dark brown to light yellow. The organic layer was evaporated in vacuo, and n-heptane was added to cool and crystallize. The intermediate compound ii was obtained by suction filtration. The purity of this batch of samples was 94.74%, the diastereomer was 1.94%, and the total yield was 84.2%.

[0119] Comparative Example 2

[0120] Under nitrogen protection, at -78°C, a solution of 1M LiHMDS in tetrahydrofuran (500ml) was added to a 2L four-necked flask. At not less than -60°C, a solution of compound i (70g in 350ml of dry tetrahydrofuran) was added dropwise to the solution, and then stirred at -78°C for 8.5h. At -65°C, iodomethane (60g in 35ml of anhydrous tetrahydrofuran) was added to the resulting solution. The reaction was stirred at -78°C for 12.0h, and then the reaction was quenched with methanol (35g) at -78°C and 2N hydrochloric acid (1500ml) at -25°C. Methyl tert-butyl ether (350ml) was added to the resulting solution and stirred for 0.5-1.0h. The organic layer was separated and treated with sodium thiosulfate solution (60g in 350ml of water) for 30 minutes under stirring, during which the color changed from dark brown to light yellow. The organic layer was evaporated in vacuo, and n-heptane was added to cool and crystallize. The intermediate compound ii was obtained by suction filtration. The purity of this batch of samples was 95.19%, the diastereomer was 1.94%, and the total yield was 84.7%.

[0121] Comparative Example 3

[0122] Under nitrogen protection, at -78°C, add a 1M LiHMDS solution in tetrahydrofuran (500 ml) to a 2L four-necked flask, and at not less than -60°C, dropwise add a solution of compound i (70 g in 350 ml of dry tetrahydrofuran solution) to the solution, and then stir at -78°C for 8.5 h. At -65°C, add iodomethane (60 g in 35 ml of anhydrous tetrahydrofuran solution) to the resulting solution. Stir at -78°C for 12.0 h, and then directly quench the reaction with 2N hydrochloric acid (1500 ml) at -78°C (the system exothermic significantly, severe freezing during the quenching process, and poor properties of the reaction liquid). Methyl tert-butyl ether (350 ml) was added to the formed solution and stirred for 0.5-1.0 hours. The organic layer was separated and treated with sodium thiosulfate solution (60 g in 350 ml of water) for 30 minutes under stirring. During this period, the color of the solution changed from dark brown to light yellow. The organic layer was evaporated in vacuo, and n-heptane was added to cool and crystallize. The intermediate compound ii was obtained by suction filtration. The purity of the batch sample was 80.71%, the diastereomer was 6.71%, and the total yield was 70.5%.

[0123] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for continuously synthesizing a compound of formula II using a microreactor, characterized in that: The steps include: S1) at -60°C to -20°C, a solution of compound i, a methylating agent solution and a hydrogen extraction agent solution are pre-mixed and sent to unit A or B for reaction to obtain a reaction solution of compound ii; Alternatively, at -60°C to -20°C, a solution of compound i and a methylating agent solution are fed into unit A for pre-mixing, and then a hydrogen extraction agent solution is fed into unit B for reaction to obtain a reaction solution of compound ii; S2) quenching the reaction solution obtained in step S1) with an acidic solution at -20°C to 40°C to obtain a compound of formula ii; ； Wherein, the solvent of the solution of compound i is selected from the following group: tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, or a combination thereof; The hydrogen extraction reagent is selected from the group consisting of lithium hexamethyldisilazide (LiHDMS), lithium diisopropylamide (LDA), butyl lithium, sodium hexamethyldisilazide (NaHMDS); The methylating agent is selected from the group consisting of methyl iodide, dimethyl sulfate, and methyl bromide; The solvent of the acidic solution is water; and the acidic solution contains salt or does not contain salt, and the salt is selected from the following group: NaCl, KCl, NH4Cl, or a combination thereof; Wherein, the step S2) is performed in a post-processing module, the post-processing module includes a reaction unit C, and the step S2) includes the following steps: The reaction liquid containing compound ii is directly flowed into unit C of the microreactor without treatment, and the acidic solution is pumped into unit C to react at a reaction temperature of -20 to 40°C until the reaction is complete. After the reaction is completed, it flows out of the microreactor and enters a reaction tank to obtain a reaction liquid of compound ii; The reaction solution stays in unit C for no more than 100 seconds; The step S2) further comprises standing for stratification.

2. The method according to claim 1, characterized in that The microreactor comprises a reaction module and a post-processing module, wherein step S1) is performed in the reaction module, and step S2) is performed in the post-processing module.

3. The method according to claim 2, characterized in that The reaction module includes a reaction unit A and / or a reaction unit B, and step S1) includes the following steps: i-1) at -50°C to -20°C, a solution of compound i and a hydrogenation reagent solution are pre-cooled and introduced into unit A for reaction; i-2) at -50°C to -20°C, the reaction solution of step i-1) flows into unit B, and the methylation reagent solution is sent into unit B for reaction to obtain a reaction solution containing compound ii; or i'-1) at -60°C to -20°C, a solution of compound i, a methylating agent solution and a hydrogen extraction agent solution are pre-mixed and introduced into unit A or B for reaction to obtain a reaction solution of compound ii; Or i''-1) At -78°C to -20°C, a solution of compound i and a methylating agent solution are fed into unit A for pre-mixing and then a hydrogen extraction agent solution is fed into unit B for reaction to obtain a reaction solution of compound ii.

4. The method according to claim 2, characterized in that The post-processing module includes a reaction unit C, and step S2) includes the following steps: i-3) The obtained reaction solution of compound ii flows into unit C at -78°C to -20°C, and an acidic solution is simultaneously sent into unit C to quench the reaction, thereby obtaining a stable quenched reaction solution containing compound ii.

5. The method according to any one of claims 1 to 4, characterized in that The acid of the acidic solution is selected from the group consisting of hydrochloric acid, sulfuric acid, or a combination thereof.

6. The method according to claim 1, characterized in that The salt is NaCl or NH4Cl.

7. The method according to claim 1, characterized in that In the step S1), the hydrogen extraction reagent is sodium hexamethyldisilazane (NaHMDS); and the methylation reagent is methyl iodide.

8. The method according to claim 1, characterized in that The purity of the compound of formula ii obtained in step S2) after post-treatment is greater than 90%.

9. The method according to claim 1, characterized in that The purity of the compound of formula ii obtained in step S2) after post-treatment is greater than 94%.

10. The method according to claim 1, characterized in that The purity of the compound of formula ii obtained in step S2) after post-treatment is greater than 95%.

11. The method according to claim 1, characterized in that The purity of the compound of formula ii obtained in step S2) after post-treatment is greater than 96%.

12. The method according to claim 1, characterized in that The purity of the compound of formula ii obtained in step S2) after post-treatment is greater than 97%.

13. The method according to claim 1, characterized in that The purity of the compound of formula ii obtained in step S2) after post-treatment is greater than 98%.

14. The method according to claim 1, wherein: The molar ratio of compound i to acid is 1:5.0~10.

0.

15. The method according to claim 4, characterized in that The residence time of the reaction solution in unit C is 1-50 seconds.

16. The method according to claim 1, wherein: The microreactor can be composed of one or more of the following reactors: Corning reactor, micro-well reactor, Shen's reactor.

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