阅读说明：本技术 一种阿加曲班中间体的连续流合成方法 (Continuous flow synthesis method of argatroban intermediate ) 是由 崇永江 卓子健 庞玉宁 闫刚云 王亚新 袁永绪 于 2021-07-16 设计创作，主要内容包括：本发明提供一种阿加曲班中间体的连续流合成方法,所述的合成工艺是以阿加曲班中间体Ⅰ为原料,经钯炭加氢步骤得到阿加曲班中间体Ⅱ,所述的合成工艺在微通道反应器中进行。该方法包括将化合物Ⅰ与催化剂和溶剂的混合溶液作为物料一,将氢气作为物料二,通过微通道反应器,连续流氢化合成中间体Ⅱ,反应温度为80至200℃,反应时间为84至140秒,压力为5至15bar。其中,X代表氢原子、甲基、乙基。与现有的常规釜式反应器相比,该工艺反应时间短,反应持液体积小,无放大效应,不需要加压氢化釜,提高了反应的安全性,目标产物转化率在90％以上,纯度在99％以上,有利于工业化生产。(The invention provides a continuous flow synthesis method of an argatroban intermediate, which is characterized in that the argatroban intermediate I is used as a raw material, and an argatroban intermediate II is obtained through a palladium-carbon hydrogenation step, wherein the synthesis process is carried out in a microchannel reactor. The method comprises the steps of taking a mixed solution of a compound I, a catalyst and a solvent as a material I, taking hydrogen as a material II, and carrying out continuous flow hydrogenation to synthesize an intermediate II through a microchannel reactor, wherein the reaction temperature is 80-200 ℃, the reaction time is 84-140 seconds, and the pressure is 5-15 bar. Wherein, X represents a hydrogen atom, a methyl group or an ethyl group. Compared with the existing conventional kettle type reactor, the process has the advantages of short reaction time, small reaction liquid holding volume, no amplification effect, no need of a pressurized hydrogenation kettle, improvement of the reaction safety, conversion rate of the target product of more than 90 percent, purity of more than 99 percent and contribution to industrial production.)

1. A continuous flow synthesis method of argatroban intermediate is characterized in that: taking the argatroban intermediate I, a mixed solution of a catalyst and a solvent as a material I, taking hydrogen as a material II, reacting through a microchannel reactor, and carrying out continuous flow hydrogenation under a proper condition to synthesize an argatroban intermediate II; the synthetic route is as follows:

wherein, X represents a hydrogen atom, a methyl group or an ethyl group.

2. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the argatroban intermediate I is (2R,4R) -1- [ (2S) -5- [ [ imino (nitroamino) methyl ] amino ] -2- [ [ (3-methyl-8-quinolyl) sulfonyl ] amino ] -1-oxopentyl ] -4-methyl-2-piperidinecarboxylic acid or piperidinecarboxylate;

the argatroban intermediate II is (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid or piperidinecarboxylate.

3. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the argatroban intermediate II comprises diastereoisomer mixtures of the argatroban intermediate II in any ratio.

4. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the catalyst is a palladium-carbon catalyst, preferably a palladium-carbon catalyst with a palladium loading of 10 wt%, and the mass ratio of the argatroban intermediate I to the metal palladium in the palladium-carbon catalyst is 1:0.006 to 0.024.

5. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the solvent is a mixed solvent of an alcohol solvent and an acid solvent, the alcohol solvent comprises but is not limited to methanol, ethanol, isopropanol and ethylene glycol, the acid solvent comprises but is not limited to formic acid and acetic acid, and the volume ratio of the alcohol solvent to the acid solvent is 1: 2-6.

6. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the mass volume ratio of the argatroban intermediate I to the mixed solvent is 1g:10-30 ml.

7. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the flow rate of the first material is 15-30g/min, and the flow rate of the second material is 180-360ml/min under standard conditions.

8. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the reaction temperature is 80 to 200 ℃, and the reaction pressure is 5 to 15 bar.

9. A continuous flow synthesis process of argatroban intermediates according to claim 1, characterized in that: the reaction time is 60 to 140 s.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a continuous flow synthesis method of an argatroban intermediate.

Background

Argatroban, chinese name: (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid of the formula:

was first synthesized by Mitsubishi chemical institute, japan in 1990, 2 months, and was approved for the treatment of peripheral thrombotic diseases and acute stroke, and later approved by the FDA in the united states for the treatment and prevention of thrombosis and heparin-induced immune disease-thrombocytopenia (HIT) in 2000. In 2005, argatroban injection "dabei" from tianjin drug research institute was approved by the national food and drug administration for marketing.

The synthesis route of argatroban in the prior art is as follows:

starting material N, as described in patents EP0008746, US4258192, US4201863, JP8115267^GReaction of-nitro-L-arginine (1) with di-tert-butyl dicarbonate to give N^G-nitro-N²-tert-butoxycarbonyl-L-arginine (2), amide-condensing with (2R,4R) -4-methylpiperidine-2-carboxylic acid ethyl ester (3) to produce a compound (4), removing tert-butoxycarbonyl under acidic conditions to produce a compound (5), condensing with 3-methyl-8-quinolinesulfonyl chloride (6) to produce a compound (7), and hydrolyzing, hydrogenating, and hydrating to obtain argatroban monohydrate; the reaction route is as follows:

synthetic routes such asEP0823430, CN101348463A, CN101348481A, N^G-nitro-L-arginine (1) and 3-methylquinoline-8-sulfonyl chloride (6) are condensed to generate a compound (9), then the compound (9) and (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate (3) are condensed to generate a compound (7), a compound (I) is obtained through hydrolysis, and then hydrogenation and hydration are carried out to obtain argatroban monohydrate; the reaction route is as follows:

the inventor finds that in the existing synthesis route, the compound I is used as a key intermediate of two synthesis routes, argatroban is required to be synthesized by a catalytic hydrogenation process, a traditional batch hydrogenation reaction kettle is used, the process is high in temperature and pressure, the consumed time is long, the conversion rate is low, impurities are more, and safety risks exist.

Disclosure of Invention

Aiming at the problems, the invention aims to optimize the traditional hydrogenation process and provides a continuous flow synthesis method of an argatroban intermediate, which adopts a continuous flow technology and uses a microchannel reactor to catalyze and hydrogenate the argatroban intermediate I to prepare an argatroban intermediate II. Compared with the conventional kettle type catalytic hydrogenation process, the method avoids the problems of high temperature and high pressure, long reaction time and the like in the hydrogenation process, thereby ensuring the safety in the production process; the process has short reaction time, small liquid holding volume and no amplification effect, essentially changes the reaction safety, has the target product conversion rate of more than 90 percent and the purity of more than 99 percent, and is beneficial to industrial production.

The invention is realized by adopting the following technical scheme:

a continuous flow synthesis method of argatroban intermediate is characterized in that a mixed solution of argatroban intermediate I, a catalyst and a solvent is used as a material I, hydrogen is used as a material II, the materials are reacted through a microchannel reactor, and continuous flow hydrogenation is carried out under proper conditions to synthesize an argatroban intermediate II; the synthetic route is as follows:

wherein, X represents a hydrogen atom, a methyl group or an ethyl group.

Wherein, the argatroban intermediate I is (2R,4R) -1- [ (2S) -5- [ [ imino (nitro amino) methyl ] amino ] -2- [ [ (3-methyl-8-quinolyl) sulfonyl ] amino ] -1-oxopentyl ] -4-methyl-2-piperidinecarboxylic acid compound, wherein X represents hydrogen atom, methyl and ethyl.

Wherein, the argatroban intermediate II is a (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidine carboxylic acid compound, wherein X represents a hydrogen atom, methyl and ethyl.

As a further illustration of the invention, wherein the catalyst used for the hydrogenation comprises a palladium on carbon catalyst, the weight ratio of argatroban intermediate I to metallic palladium in the palladium on carbon catalyst is from 1:0.006 to 0.024. Preferably, the catalyst used for the hydrogenation is a 10 wt% palladium on carbon catalyst, the weight ratio of argatroban intermediate I to palladium on carbon catalyst is 1:0.006 to 0.02.

The invention further describes the method, wherein the solvent is a mixed solvent of an acid solvent and an alcohol solvent, the acid solvent includes but is not limited to formic acid, acetic acid and other liquid organic acids, the alcohol solvent includes but is not limited to methanol, ethanol, isopropanol, ethylene glycol and the like, and the volume ratio of the alcohol solvent to the acid solvent is preferably 1ml:2-6 ml. Preferably, the volume ratio of the alcohol solvent to the acid solvent is 1ml to 4 ml.

As further illustration of the invention, the mass-to-volume ratio of the argatroban intermediate I to the mixed solvent is preferably 1g:10-30ml, more preferably 1g:20 ml.

As a further illustration of the present invention, it is preferred that the flow rate of the first material is 15 to 30g/min, more preferably 20g/min, and the flow rate of the second material is 180 to 360ml/min, more preferably 240nl/min under the standard condition.

As a further illustration of the invention, the preferred reaction temperature is from 80 to 200 ℃ and the preferred reaction pressure is from 5 to 15 bar. More preferably the reaction temperature is 140 ℃ and more preferably the reaction pressure is 6-9 bar.

As a further illustration of the invention, among others, a preferred reaction time is from 60 to 140 s.

Compared with the prior art, the invention has the following beneficial effects:

1) compared with the conventional pressurized hydrogenation reactor, the continuous flow synthesis of the microchannel reactor is adopted, so that the volume of reaction liquid is small, the potential safety hazard of hydrogenation reaction is reduced, and the safety of reaction and production is greatly improved. The process has the advantages of short reaction time, small reaction liquid holding volume, no amplification effect, substantial change of reaction safety, conversion rate of a target product of more than 90 percent, purity of a product in a reaction liquid of more than 80 percent, molar yield of related products obtained by the reaction liquid through post-treatment steps of catalyst separation, reduced pressure concentration, pH value adjustment, dissolution and decoloration, recrystallization, drying and the like of the reaction liquid of more than 65 percent, purity of the product of more than 99.0 percent and contribution to industrial production.

2) An alcohol-acid system is adopted as a reaction solvent, and the method is suitable for the microchannel reactor made of glass materials.

3) The reaction time is greatly shortened from 5 to 24 hours of the kettle reaction to 60 to 140 seconds.

4) The reaction process has no amplification effect, and provides a new continuous flow reaction method for preparing the argatroban intermediate II from the argatroban intermediate I.

5) The invention utilizes the high-efficiency mixing and excellent mass transfer and heat transfer performance of the microreactor, strengthens the interphase mass transfer and heat transfer capacity in the reaction process, can obviously reduce the volume of the reactor, improves the reaction yield and improves the production efficiency and safety. The method can solve the problems of low production efficiency, poor product purity, high device danger and the like in the hydrogenation kettle process, can realize continuous automatic operation of the process, and has the advantages of high yield, good safety and the like.

Drawings

The invention will be further described with reference to the accompanying drawings;

FIG. 1 shows a flow chart of a continuous flow synthesis process of argatroban intermediate I.

Detailed Description

For a more clear understanding of the objects, features and advantages of the present invention, reference is made to the following description taken in conjunction with the accompanying drawings and specific examples. Unless otherwise specified, the starting materials are all commercially available; a high-flux microchannel reactor G1 type is adopted; corning incorporated, usa.

Example 1: preparation of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. as shown in fig. 1, flow path one: preparing feed liquid, namely stirring 15.0g of the compound (I), 3.0g of 10 wt% palladium-carbon catalyst, 300ml of acetic acid and 150ml of absolute ethyl alcohol, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 30g/min through a metering module;

3. a second flow path: material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 260 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 10 bar;

5. the system was set at a circulating temperature of 140 ℃ and the reaction solution was collected after 89 seconds of reaction through 8 reaction modules (68ml volume) of the continuous flow reactor. The purity of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction solution was 86.19%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid, the purity of liquid chromatography is 99.24 percent, the maximum single impurity content is 0.28 percent, and the molar yield is 68.1 percent.

Example 2: preparation of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. as shown in fig. 1, flow path one: preparing feed liquid, namely stirring 15.0g of the compound (I), 7.5g of 10 wt% palladium-carbon catalyst, 200ml of acetic acid and 100ml of absolute ethyl alcohol, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 20g/min through a metering module;

3. a second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 240 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 6.0 bar;

5. the system was set at a circulation temperature of 100 ℃ and after reaction for 102 seconds through 8 reaction modules (68ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction solution was 91.60%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid, the purity of liquid chromatography is 99.47 percent, the maximum single impurity content is 0.217 percent, and the molar yield is 72.3 percent.

Comparative test example 1: preparation of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid

Adding 15.0g of the compound (I), 3.0g of 10 wt% palladium-carbon catalyst, 300ml of acetic acid and 150ml of absolute ethyl alcohol into a high-pressure hydrogenation kettle, replacing air in the kettle with nitrogen for three times after adding, replacing nitrogen in the kettle with hydrogen for three times, pressurizing the hydrogen to 10bar, heating to 140 ℃ for reaction, and carrying out heat preservation hydrogenation reaction for 24 hours.

After the reaction was completed, the purity of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction mixture was 80.47%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid, the purity of liquid chromatography is 98.60 percent, the maximum single impurity content is 0.67 percent, and the molar yield is 52.6 percent.

Comparative test example 2: preparation of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. as shown in fig. 1, flow path one: preparing feed liquid, namely stirring 15.0g of the compound I, 3.0g of 10 wt% palladium-carbon catalyst and 450ml of water, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 30g/min through a metering module;

3. a second flow path: material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 260 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 10 bar;

5. the system was set to a circulating temperature of 140 ℃ and the reaction solution was collected after 90 seconds of reaction through 8 reaction modules (68ml volume) of the continuous flow reactor. The purity of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction solution was 71.45%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid, the purity of liquid chromatography is 96.55 percent, the maximum single impurity content is 1.23 percent, and the molar yield is 40.3 percent.

The results show that the reaction stability and the reproducibility are good by adopting an alkyd system compared with a water system; reaction parameters are adjusted, and repeated experiments prove that the alkyd system has obvious advantages.

In patent CN111471085A, a microreactor technology is selected to perform a catalytic hydrogenation reaction of compound I, a reaction solvent is an alkaline aqueous solution, a substrate (argatroban piperidine carboxylate intermediate) is insoluble in water, and the solubility in alkaline water is improved, but the stability is not good, an alkali degradation impurity is easily generated in the reaction process, and the argatroban intermediate I piperidine carboxylate compound is easily generated a degradation impurity in the alkaline aqueous solution, and the related piperidine formate compound is also unstable under the process conditions. Meanwhile, the reaction conditions are high temperature and high pressure, but most of the reaction modules of the microreactor are made of glass materials, the conditions can cause irreversible loss after long-time application, the application in the microreactor has limitation, and the microreactor made of glass materials is easily damaged after multiple times of use. The reaction system of the present invention is different from the above reaction system, and the amount of hydrogen used is much smaller.

The hydrogenation reduction conditions of CN111471085A are as follows: adding 10% palladium-carbon into the water phase in the previous process, mixing uniformly, introducing the mixture and hydrogen into a microreactor for reduction reaction, filtering feed liquid, and transferring to the next process; the using amount of 10% palladium carbon is 5-10% of the weight of the N-nitro-L-arginine; the flow rate of the mixed liquid is 10 ml/min-30 ml/min, hydrogen is introduced, the nitrogen in the microreactor is subjected to back pressure, the pressure is controlled to be 10-20 bar, the flow rate is 800-1000 ml/min, the residence time is 1-5 min, and the reaction temperature is 90-120 ℃.

Example 3: preparation of methyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. a first flow path: preparing feed liquid, namely stirring 15.0g of the compound (I), 3.0g of 10 wt% palladium-carbon catalyst, 200ml of formic acid and 100ml of methanol, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 20g/min through a metering module;

3. a second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 180 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 5.0 bar;

5. the system was set at a circulation temperature of 80 ℃ and after reaction for 103 seconds through 8 reaction modules (68ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 82.34%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidine methyl formate, the purity of liquid chromatogram is 99.08%, the maximum single impurity content is 0.53%, and the molar yield is 67.9%.

Example 4: preparation of methyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. a first flow path: preparing feed liquid, namely stirring 15.0g of the compound (I), 7.5g of 10 wt% palladium-carbon catalyst, 375ml of acetic acid and 75ml of methanol, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 30g/min through a metering module;

3. a second flow path: material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 360 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 9.0 bar;

5. the system was set at a circulation temperature of 200 ℃ and the reaction solution was collected after reaction through 8 reaction modules (68ml volume) of the continuous flow reactor for 70 seconds. The purity of (2R,4R) -methyl 1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate in the reaction solution was 86.12%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidine methyl formate, the purity of liquid chromatogram is 99.12 percent, the maximum single impurity content is 0.48 percent, and the molar yield is 69.2 percent.

Example 5: preparation of ethyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. a first flow path: preparing feed liquid, namely stirring 15.0g of the compound (I), 3.0g of 10 wt% palladium-carbon catalyst, 200ml of acetic acid and 100ml of absolute ethyl alcohol, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 15g/min through a metering module;

3. a second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 180 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 10 bar;

5. the system was set to a circulating temperature of 125 ℃ and the reaction solution was collected after 140 seconds of reaction through 8 reaction modules (68ml volume) of the continuous flow reactor. The purity of (2R,4R) -methyl 1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate in the reaction solution was 87.64%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain the ethyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate, the purity of liquid chromatography is 99.31 percent, the maximum single impurity is 0.44 percent, and the molar yield is 70.1 percent.

Example 6: preparation of ethyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. a first flow path: preparing feed liquid, namely stirring 15.0g of the compound (I), 7.5g of 10 wt% palladium-carbon catalyst, 360ml of acetic acid and 60ml of absolute ethyl alcohol, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 20g/min through a metering module;

3. a second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 180 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 6.5 bar;

5. the system was set to a circulating temperature of 150 ℃ and the reaction solution was collected after 90 seconds of reaction through 8 reaction modules (68ml volume) of the continuous flow reactor. The purity of (2R,4R) -methyl 1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate in the reaction solution was 83.78%. The reaction solution was filtered to recover the catalyst. Concentrating the filtrate under reduced pressure, diluting, adjusting pH to 8-9, dissolving in methanol, decolorizing with activated carbon, recrystallizing with methanol-water, and vacuum drying to obtain ethyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate with liquid chromatography purity of 99.17%, maximum single impurity content of 0.58% and molar yield of 68.1%.

Example 7: preparation of ethyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. a first flow path: preparing feed liquid, namely stirring 15.0g of the compound (I), 5g of 10 wt% palladium-carbon catalyst, 120ml of acetic acid and 30ml of absolute ethyl alcohol, pumping into a microchannel reactor through a material pump, and setting the flow rate to be 15g/min through a metering module;

3. a second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 180 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 5 bar;

5. the system was set to a circulating temperature of 180 ℃ and the reaction solution was collected after 120 seconds of reaction through 8 reaction modules (68ml volume) of the continuous flow reactor. The purity of (2R,4R) -methyl 1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate in the reaction solution was 87.25%. The reaction solution was filtered to recover the catalyst. The filtrate is decompressed, concentrated, diluted and then the pH value is adjusted to 8 to 9, the activated carbon is decolored after the methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out to obtain the ethyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate, the purity of liquid chromatogram is 99.24 percent, the maximum single impurity content is 0.41 percent, and the molar yield is 69.6 percent.

Example 8: preparation of methyl (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate

1. The device comprises the following steps: the continuous flow microchannel reactor determines a microchannel connection mode according to the reference of FIG. 1, a mixed reaction module determines according to the flow velocity and the reaction residence time, and a heat exchange medium is heat conduction oil;

2. a first flow path: preparing feed liquid, namely stirring 15.0g of the compound (I), 4g of 10 wt% palladium-carbon catalyst, 300ml of acetic acid and 50ml of methanol, pumping the mixture into a microchannel reactor through a material pump, and setting the flow rate to be 25g/min through a metering module;

3. a second flow path: material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 270 ml/min;

4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 9.0 bar;

5. the system was set at a circulation temperature of 130 ℃ and the reaction solution was collected after 140 seconds of reaction through 8 reaction modules (68ml volume) of the continuous flow reactor. The purity of (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 89.12%. The reaction solution was filtered to recover the catalyst. Concentrating the filtrate under reduced pressure, diluting, adjusting pH value to 8-9, dissolving in methanol, decolorizing with activated carbon, recrystallizing with methanol-water, and vacuum drying to obtain (2R,4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1,2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester with liquid chromatography purity of 99.13%, maximum single impurity of 0.48% and molar yield of 70.22%.

The foregoing is merely exemplary of embodiments of the present invention and is not intended to limit the invention in any manner. The scope of the present invention is defined by the claims and is not limited by the embodiments described above, and any simple modifications or equivalent changes and modifications made to the above embodiments according to the technical spirit of the present invention are included in the scope of the present invention.