Patent Description:
Nemonoxacin malate has a structural formula as shown in formula v, and a chemical na me of <NUM>-[(<NUM>, <NUM>)-<NUM>-amino-<NUM>-methyl-piperidin-<NUM>-yl]-<NUM>-cyclopropyl-<NUM>-methoxy-<NUM>-oxo-<NUM>,<NUM>-dihydroqui noline-<NUM>-carboxylate malate hemihydrate. It is the world's first fluoroquinolone-free antibacteria I drug developed by Procter & Gamble, US. , and Phase II clinical studies on community pn eumonia and diabetic foot infection have been completed in the United States, with significa nt effects. Phase III clinical trials of community pneumonia with oral dosage form jointly con ducted by Chinese Mainland and Taiwan have also been completed, and marketed in <NUM>.

Nemonoxacin malate of formula v is prepared by salifying the intermediate Nemonoxacin as shown in formula iv. The intermediate Nemonoxacin vi is generally prepared by condensation and hydrolysis of <NUM>-cyclopropyl-<NUM>-fluoro-<NUM>-methoxy-<NUM>-oxo-<NUM>,<NUM>-dihydro-quinolin-<NUM>-carboxylic acid diacetate boric anhydride iii and piperidine derivative iv in the presence of an acid binding agent, and the synthesis route is as shown in reaction formula I:
<CHM>
wherein, the step of methylating dimethyl (S)-<NUM>-tert-butyloxycarbonylamino-glutarate i into dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate ii includes under main operating conditions of a low temperature less than -<NUM>, adding dimethyl (S)-<NUM>-tert-butyloxycarbonylamino-glutarate i to the LiHMDS solution, and then adding iodomethane thereto for the methylation reaction, after the completion of the reaction, adding methanol and an acid water (such as hydrochloric acid) successively for quenching, adding an extraction solvent (such as ethyl acetate, and methyl tert-butyl ether) for extraction and layering, concentrating the organic phase under reduced pressure to dryness, then adding a crystallization solvent (such as methyl tert-butyl ether, ethyl acetate, and n-heptane) for slurrying and crystallizing, filtering and drying same to obtain dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate ii.

The synthesis methods for methylating dimethyl (S)-<NUM>-tert-butyloxycarbonylamino-glutarate publicly reported in the prior art are as follows:
Route <NUM> is a method described in the patent of a piperidine derivative compound [Patent No.: <CIT>], [Application No.: <CIT>]. The specific route is as follows:
<CHM>.

In this route, compound i is used as the starting raw material, the deprotonation of the carbonyl alpha carbon of compound i is first carried out under the action of LiHMDS, i.e. using the LiHMDS reagent to pull out the H atom on the carbonyl alpha carbon of compound i, the obtained intermediate is subjected to methylation with iodomethane, then a solution of compound ii is obtained after quenching. The route uses a LiHMDS reagent, which requires low temperature (less than or equal to -<NUM>), the reaction conditions are harsh and difficult to operate, this phenomenon is particularly obvious in the scale-up production. Moreover, the processing operation is complex, and needs to be quenched with an alcohol and an acid water solution successively at low temperature, an alcohol solvent is introduced in the quenching process, which is not conducive to the separation and purification of the reaction solvent, and the reaction time is long, a laboratory small test reaction of a conventional <NUM>-<NUM> scale usually takes <NUM> days, and a workshop production of <NUM>-<NUM> scale takes <NUM>-<NUM> days.

Route <NUM> is a method described in the preparation patent [Application No.: <CIT>]. The specific synthesis method is as follows:
<CHM>.

The reaction mechanism of synthetic route <NUM> is consistent with that of synthetic route <NUM>. In this route, the hydrogen atom in compound iii is first pulled out with an organic lithium reagent (LiHMDS) at an ultra-low temperature of -<NUM>, and then the resulting product is connected to an alkylation skeleton through a haloalkane still at a reaction temperature of -<NUM> for a reaction time of <NUM>, then the compound iv is obtained by quenching and purifying with alcohol and acid water successively. This route still cannot solve the problem as described in route <NUM>.

In view of the shortcomings existing in the above preparation methods, the present disclosure provides a method for continuously synthesizing an intermediate dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate ii by a microreactor. The method has advantages of mild reaction conditions, shorter reaction time, good safety, simple operation, economy and environmental protection, high yield, good product quality and ease of industrial production.

According to a first aspect of the present disclosure <NUM>, a method for continuously synthesizing compound of formula ii using a microreactor is provided, wherein it comprises the following steps:.

In another preferred embodiment, in step S1), the hydrogen pulling reagent is a lithium reagent, preferably the hydrogen pulling reagent is selected from lithium hexamethyldisilazide (LiHDMS), lithium diisopropylamide (LDA), butyl lithium, sodium hexamethyldisilazide (NaHMDS), preferably lithium hexamethyldisilazide (LiHDMS).

In another preferred embodiment, in step S1), the methylation reagent is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, bromomethane, and preferably iodomethane.

In another preferred embodiment, the microreactor comprises a reaction module and a post-processing module, wherein the step S1) is carried out in the reaction module and the step S2) is carried out in the post-processing module.

In another preferred embodiment, the reaction module comprises a reaction unit A and/or a reaction unit B, and the step S1) comprises the following steps:.

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

In another preferred embodiment, the solvent of the solution of hydrogen-pulling reagent is selected from tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, or a combination thereof.

In another preferred embodiment, the solvent of the solution of methylation reagent is selected from tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, or a combination thereof.

In another preferred embodiment, the concentration of the solution of compound i is <NUM>-<NUM>/L, preferably <NUM>-<NUM>/L, and more preferably <NUM>-<NUM>/L.

In another preferred embodiment, the solution of hydrogen-pulling reagent is a solution of lithium reagent, preferably a solution of lithium hexamethyldisilazide (a solution of LiHMDS in tetrahydrofuran), preferably the concentration of the solution of hydrogen-pulling reagent is <NUM>-<NUM> mol/L, preferably <NUM>-<NUM> mol/L.

In another preferred embodiment, the molar ratio of compound i to lithium reagent (such as lithium hexamethyldisilazide (LiHMDS)) is <NUM>:<NUM>-<NUM>, preferably <NUM>:<NUM>.

In another preferred embodiment, the concentration of the solution of methylation reagent is <NUM>-<NUM>/L, preferably <NUM>-<NUM>/L.

In another preferred embodiment, in step i-<NUM>), the residence time of the mixed materials in the unit A is not more than <NUM> seconds, preferably <NUM> to <NUM> seconds, more preferably <NUM> to <NUM> seconds, and more preferably <NUM> to <NUM> seconds.

In another preferred embodiment, in step i'-<NUM>), the residence time of the mixed materials in the unit A/unit B is not more than <NUM> seconds, preferably <NUM> to <NUM> seconds, and more preferably <NUM> to <NUM> seconds.

In another preferred embodiment, the molar ratio of compound i to methylation reagent is <NUM>:<NUM>-<NUM>, preferably <NUM>:<NUM>.

In another preferred embodiment, in step i-<NUM>), the residence time of the mixed materials in the unit B is not more than <NUM> seconds, preferably <NUM> to <NUM> seconds, more preferably <NUM> to <NUM> seconds, and more preferably <NUM> to <NUM> seconds.

In another preferred embodiment, in step i-<NUM>), the reaction temperature of the unit A is -<NUM> to - <NUM>, preferably -<NUM> to -<NUM>.

In another preferred embodiment, in step i'-<NUM>), the reaction temperature of the unit A is preferably -<NUM> to -<NUM>, and more preferably -<NUM> to -<NUM>.

In another preferred embodiment, in step i-<NUM>), the reaction temperature of the unit B is -<NUM> to - <NUM>, preferably -<NUM> to -<NUM>.

In another preferred embodiment, the post-processing module includes a reaction unit C, and the step S2) includes the following steps:
i-<NUM>) flowing the obtained reaction solution of compound ii into the unit C, and at the same time feeding an acid solution into the unit C for quenching reaction at -<NUM> to -<NUM> to obtain a stable quenching reaction solution containing compound ii.

In another preferred embodiment, the solvent of the acid solution is selected from water, alcohol, or a combination thereof, and the acid is selected from hydrochloric acid, sulfuric acid, or a combination thereof.

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

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

In another preferred embodiment, the acid solution comprises a salt or no salt, preferably the salt is NaCl, KCI, NH<NUM>Cl, or a combination thereof.

In another preferred embodiment, the acid solution is hydrochloric acid in aqueous sodium chloride solution.

In another preferred embodiment, the step S2) also includes steps of static stratification, crystallization and filtration.

In another preferred embodiment, the purity of the compound of formula ii obtained in step S2) after post-processing is greater than <NUM>%, preferably greater than <NUM>%, more preferably greater than <NUM>%, more preferably greater than <NUM>%, more preferably greater than <NUM>%, and more preferably greater than <NUM>%.

In another preferred embodiment, the molar ratio of compound i to acid is <NUM>:<NUM>-<NUM>.

In another preferred embodiment, the residence time of the reaction solution in the unit C is not more than <NUM> seconds, preferably <NUM> to <NUM> seconds, and more preferably <NUM> to <NUM> seconds.

In another preferred embodiment, the microreactor is composed of one or more of the following reactors: Corning reactor, micro-well (silicon carbide, Hastelloy, <NUM>) reactor, and Shen's (Hastelloy, <NUM>) reactor.

It should be understood that within the scope of the present disclosure, the above technical features of the present disclosure and the technical features described in detail below (such as in the embodiments) can be combined with each other to form a new or preferred technical solution. It will not be repeated herein in order to avoid redundancy.

<FIG> shows the flow diagram of the method according to the present disclosure.

Through extensive and intensive researches, the inventor of the present application unexpectedly developed a method for continuously synthesizing dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate using a microchannel reactor. The method improves the selectivity and conversion rate of the reaction, and the conversion rate of dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate is increased to more than <NUM>% and the yield is increased to more than <NUM>%; avoids the use of a solvent such as methanol, and methyl tert-butyl ether, etc., in the intermittent reaction process, which simplifies the post-processing method, shortens the overall operation time from about <NUM> hours to a few minutes, greatly improving the production efficiency, and realizing the continuity and automation of the whole process; and thus makes the product have high purity and high yield, which is suitable for industrial production.

In the present disclosure, the "compound of formula ii", "dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate" and "quinolones compound intermediate" have the same meaning and can be used interchangeably.

In the present disclosure, the "main raw material" and "compound i" have the same meaning.

The microreactor includes a microchannel reactor, a micro heat transfer reactor, and a micro mixing reactor, etc., and it is a minitype reactor with a feature size of <NUM> to <NUM>,<NUM> manufactured by precision machining technology. The "micro" of the microreactor neither specially refer to the overall dimension size of the microreactor equipment, nor the small output of product by the microreactor equipment, but means that the channel of the process fluid is at the micron level, and the microreactor can comprise hundreds of thousands of microchannels. In this application, the annual flux of compound ii can reach <NUM> tons/year by using laboratory microreactor (<NUM>), and <NUM> to <NUM> tons/year by using industrial microreactor (<NUM>). The microreactor used in this application can be one or more of Corning reactor, micro-well (silicon carbide, Hastelloy, <NUM>) reactor, and Shen's (Hastelloy, <NUM>) reactor.

The present disclosure uses a microreactor to continuously synthesize the compound of formula ii, preferably dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate ii can be obtained by using dimethyl (S)-<NUM>-tert-butyloxycarbonylamino-glutarate i as the starting material, followed by the steps of hydrogen pulling reaction, methylation reaction and quenching reaction,
<CHM>.

Preferably, in the present disclosure, the compound ii is prepared by the microchannel one-pot method in a continuous flow. The microreactor is divided into three units A, B and C, and the specific reaction route is as follows:
<CHM>
<CHM>
<NUM>) mixing the solution of compound i with an organic lithium reagent in the unit A at a reaction temperature of -<NUM> to -<NUM>; <NUM>) feeding the intermediate i-<NUM> and a methylation reagent into the unit B at the same time for reacting to obtain a reaction solution of intermediate ii-<NUM>; <NUM>) feeding the reaction solution containing intermediate ii-<NUM> and an acid solution (such as an aqueous hydrochloric acid solution) into the unit C for reacting to obtain the intermediate compound ii with a reaction temperature of unit C being -<NUM> to <NUM>, wherein the flow diagram of which is as shown in mode <NUM> of <FIG>.

Preferably, the present application can also be carried out by the method as shown in the mode <NUM> or <NUM> of the flow diagram of <FIG>:.

Preferably, the organic solvent for dissolving compound i is tetrahydrofuran and ethyl acetate.

Preferably, the reagent for quenching compound ii adopts an aqueous hydrochloric acid solution and an aqueous sulfuric acid solution.

Preferably, the molar ratio of compound i to lithium reagent (such as lithium hexamethyldisilazide (LiHMDS)) is <NUM>: <NUM>-<NUM>, preferably <NUM>: <NUM>, the molar ratio of methylation reagent to compound i is <NUM>: <NUM>-<NUM>, preferably <NUM>: <NUM>, and the molar ratio of hydrochloric acid/sulfuric acid solution to compound i is <NUM>: <NUM>-<NUM>, <NUM>: <NUM>-<NUM>, and preferably <NUM>: <NUM> and <NUM>: <NUM>.

For the above three units A, B and C, a delayed tubular reactor can be added behind the microreactor according to the need of reaction residence time.

Preferably, the specific steps of the present disclosure are as follows:.

The concentration of the solution of methylation reagent in tetrahydrofuran is <NUM>-<NUM>/L, preferably <NUM>-<NUM>/L;.

Wherein, the concentration of the aqueous acid solution is <NUM>-<NUM>/L, preferably <NUM>-<NUM>/L, and the molar ratio of compound i to acid is <NUM>:<NUM>-<NUM>, preferably <NUM>:<NUM>;
the residence time of the reaction solution in the unit C is not more than <NUM> seconds, preferably <NUM> to <NUM> seconds, and more preferably <NUM> to <NUM> seconds.

The microreactor used in the present disclosure includes Corning reactor, micro-well (silicon carbide, Hastelloy, <NUM>) reactor, and Shen's (Hastelloy, <NUM>) reactor. According to the common sense of use, the size of the reactor can be appropriately increased for industrial scale-up production.

In the present disclosure, the obtained dimethyl (<NUM>,<NUM>)-<NUM>-tert-butyloxycarbonylamino-<NUM>-methyl-glutarate ii further undergoes reaction steps such as ammonolysis, cyanidation, cyclization, etc., to obtain a piperidine derivative iv, and further, which can undergo condensation, hydrolysis and salifying reactions with <NUM>-cyclopropyl-<NUM>-fluoro-<NUM>-methoxy-<NUM>-oxo-<NUM>,<NUM>-dihydro-quinolin-<NUM>-carboxylic acid diacetate boric anhydride iii to produce the finished product of Nemonoxacin malate.

The present disclosure will be further described below in combination with specific examples. It should be understood that these examples are only used to explain the present disclosure rather than limiting the scope of the present disclosure. The experimental methods without indicating specific conditions in the following examples are generally in accordance with the conventional conditions or the conditions recommended by the manufacturers. Unless otherwise stated, percentages and parts are calculated by weight.

<NUM> of main raw materials, <NUM> of bromomethane and <NUM> of tetrahydrofuran were added into a <NUM> three-necked flask to prepare a solution of compound i/bromomethane in tetrahydrofuran, which was flowed into the unit A module at a flow rate of <NUM>/min, and lithium hexamethyldisilazide with a concentration of <NUM> mol/L was let to flow into the unit A at a flow rate of <NUM>/min at the same time, the reaction residence time was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit A, the prepared <NUM>/L of hydrochloric acid in aqueous sodium chloride solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit A at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit A, lithium hexamethyldisilazide with a concentration of <NUM> mol/L was flowed into the unit B at a flow rate of <NUM>/min. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of hydrochloric acid in aqueous sodium chloride solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM> mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of hydrochloric acid in aqueous sodium chloride solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM> mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of bromomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of hydrochloric acid in aqueous ammonium chloride solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM> mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of bromomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous hydrochloric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM> mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at - <NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous hydrochloric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM>. 8mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous hydrochloric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM> mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous hydrochloric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM>. 0mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous hydrochloric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM>. 3mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at - <NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous sulfuric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at <NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in ethyl acetate was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM> mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at - <NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of iodomethane in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous hydrochloric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM>/L of main raw material in tetrahydrofuran was prepared in a <NUM> three-necked flask, and flowed into the unit A at a flow rate of <NUM>/min, additionally lithium hexamethyldisilazide with a concentration of <NUM>. 8mol/L was flowed into the unit A at a flow rate of <NUM>/min at the same time. The reaction residence time was <NUM> seconds, and the reaction temperature was controlled at -<NUM>. After the reaction solution flowed out of the unit A, a prepared solution of <NUM>/L of dimethyl sulfate in tetrahydrofuran was flowed into the unit B at a flow rate of <NUM>/min at the same time. The residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. After the reaction solution flowed out of the unit B, the prepared <NUM>/L of aqueous hydrochloric acid solution was simultaneously pumped into the unit C at a flow rate of <NUM>/min, the residence time of the reaction unit was <NUM> seconds, and the reaction temperature of the reaction unit was controlled at -<NUM>. The liquid material flowing out of the unit was stood still for layering, the organic layer was rotary evaporated to nearly dryness, n-heptane was added therein, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM> LiHMDS in tetrahydrofuran (<NUM>) was added to a <NUM> four-necked flask at -<NUM> under the protection of nitrogen, then a solution of compound i (a solution of <NUM> compound i in <NUM> of dry tetrahydrofuran) was added dropwise thereto at no less than -<NUM>, and then stirred at -<NUM> for <NUM>. lodomethane (a solution of <NUM> iodomethane in <NUM> anhydrous tetrahydrofuran) was added to the formed solution at -<NUM>. The reaction was stirred at -<NUM> for <NUM>, then the reaction was quenched with methanol (<NUM>) at a condition of -<NUM> and 2N hydrochloric acid (<NUM>) at a condition of -<NUM>. Toluene (<NUM>) was added into the formed solution, the mixture was stirred for <NUM> to <NUM>, the organic layer was separated, and treated with a solution of sodium thiosulfate (a solution of <NUM> sodium thiosulfate in <NUM> water) for <NUM> minutes with stirring, during this time, the color of which changed from dark brown to light yellow. The organic layer was evaporated under vacuum, n-heptane was added, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

A solution of <NUM> LiHMDS in tetrahydrofuran (<NUM>) was added to a <NUM> four-necked flask at - <NUM> under the protection of nitrogen, then a solution of compound i (a solution of <NUM> compound i in <NUM> of dry tetrahydrofuran) was added dropwise thereto at no less than -<NUM>, and then stirred at -<NUM> for <NUM>. lodomethane (a solution of <NUM> iodomethane in <NUM> anhydrous tetrahydrofuran) was added to the formed solution at -<NUM>. The reaction was stirred at -<NUM> for <NUM>, then the reaction was quenched with methanol (<NUM>) at a condition of -<NUM> and 2N hydrochloric acid (<NUM>) at a condition of -<NUM>. Methyl tert-butyl ether (<NUM>) was added into the formed solution, the mixture was stirred for <NUM> to <NUM>, the organic layer was separated, and treated with a solution of sodium thiosulfate (a solution of <NUM> sodium thiosulfate in <NUM> water) for <NUM> minutes with stirring, during this time, the color of which changed from dark brown to light yellow. The organic layer was evaporated under vacuum, n-heptane was added, then cooled and crystallized, suction filtered to obtain the intermediate compound ii. The purity of this batch of samples was <NUM>%, with the epimer of <NUM>%, and a total yield of <NUM>%.

Claim 1:
A method for continuously synthesizing compound of formula ii using a microreactor, wherein it comprises the following steps:
S1) reacting compound i with a hydrogen-pulling reagent and a methylation reagent at -<NUM> to - <NUM>, in an inert solvent to obtain a reaction solution containing compound of formula ii;
S2) quenching the reaction solution obtained in step S1) with an acid solution at -<NUM> to <NUM> to obtain the compound of formula ii;
<CHM>