Method for preparing opioid reduzate intermediate and application of opioid reduzate intermediate

Abstract

The invention provides a method for preparing an opioid reduzate intermediate and application of the opioid reduzate intermediate. The method comprises the following steps: carrying out first reduction reaction on hydrazine hydrate and hydrogen peroxide; the product in the step (1) and a compound shown in a formula I are subjected to a second reduction reaction, a compound shown in a formula II is obtained, and the first reduction reaction and the second reduction reaction are carried out in a continuous flow reactor; r1 is selected from carbonyl and-C-OR5, R5 is selected from hydrogen, C1-20 alkyl, hetero-alkyl and carbonyl, R2 is selected from hydrogen, C1-20 alkyl, hetero-alkyl and carbonyl, R3 is selected from hydrogen, C1-20 alkyl, aryl, hetero-aryl, cycloalkyl, hetero-alkyl, aryl alkyl or hetero-aryl alkyl, and R4 is selected from hydrogen and hydroxyl. According to the method, hydrogen peroxide and hydrazine hydrate in a specific proportion are mixed in a continuous flow reactor, diazene is obtained in situ, diazene reduction replaces hydrogenation reduction reaction, operation is safe and stable, the product yield is high, impurities are few, cost is low, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical technology, and more specifically, to a method for preparing opioid reducing intermediates and their applications. Background Technology

[0002] The production and consumption of non-natural opioids have steadily increased over the past 20 years. Common non-natural opioids, such as hydromorphone, nalbuphine, oxycodone, naltrexone, naloxone, and buprenorphine, can be synthesized semi-synthetically from natural opioids like morphine, thebaine, or codeine through reduction, de-N-methylation, and de-O-methylation processes. Hydrogenation reduction reactions are widely used in the synthesis of non-natural opioids. Currently reported methods for obtaining reduction intermediates include batch and continuous transition metal-catalyzed hydrogenation reduction and diazepine reduction. However, these methods have limitations: hydrogen is a highly flammable gas that forms explosive mixtures with air over a wide concentration range, posing significant safety risks during reduction hydrogenation. The immobilized catalysts used in continuous flow hydrogenation reduction require customization to ensure conversion efficiency and selectivity during production; furthermore, direct use of microchannels for reaction enhancement carries the risk of solid blockage and gas accumulation. Additionally, diazepines are unstable, and the accumulation of diazepines in batch reactions poses an explosion risk.

[0003] Therefore, there is still a need to develop simple, efficient, and safe methods for reducing opioid intermediates. Summary of the Invention

[0004] The purpose of this application is to solve at least one of the above-mentioned problems.

[0005] Therefore, in one aspect of this application, the present invention provides a method for preparing the compound shown in Formula II. According to an embodiment of this application, the method includes: (1) performing a first reduction reaction of hydrazine hydrate with hydrogen peroxide; (2) performing a second reduction reaction of the product obtained in step (1) with the compound shown in Formula I to obtain the compound shown in Formula II, wherein the first reduction reaction and the second reduction reaction are carried out in a continuous flow reactor;

[0006]

[0007] Wherein, R1 is selected from carbonyl, -C-OR5,

[0008] R5 is selected from hydrogen, C 1～20 Alkyl, heteroalkyl, carbonyl

[0009] R2 is selected from hydrogen, C 1～20 Alkyl, heteroalkyl, carbonyl

[0010] R3 is selected from hydrogen, C 1～20Alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroalkyl, arylalkyl, or heteroarylalkyl

[0011] R4 is selected from hydrogen or hydroxyl groups.

[0012] R1, R2, R3, and R4 in the compound shown in Formula I are the same as R1, R2, R3, and R4 in the compound shown in Formula II.

[0013] The molar ratio of hydrazine hydrate, hydrogen peroxide, and the compound shown in Formula I is 2.00:(0.1–1.50):(0.05–2.00), for example 2.00:0.1:(0.05–2.00), 2.00:0.2:(0.05–2.00), 2.00:0.3:(0.05–2.00), 2.00:0.4:(0.05–2.00), 2.00:0.5:(0.05–2.00), 2.00:0.6:(0.05–2.00), 2.00:0.7:(0.05–2.00), 2.00:0.8:(0.05–2.00), 2.00:0.9:(0.05–2.00), or 2.00:1. 0∶(0.05~2.00), 2.00∶1.1∶(0.05~2.00), 2.00∶1.2∶(0.05~2.00), 2.00∶1.3∶(0.05~2.00), 2.00∶1.4∶(0.05~2.00), 2.00∶1.5∶(0.05~2.00), 2.00∶(0.1~1.50)∶0.05, 2.00∶(0.1~1.50)∶0.10, 2.00∶(0.1~1.50)∶0.15, 2.00∶(0.1~1.50)∶0.20, 2.00∶(0.1~1.50)∶0.25, 2.00∶(0.1~1.0)∶0.30, 2.00∶( 0.1~1.50)∶0.35, 2.00∶(0.1~1.50)∶0.40, 2.00∶(0.1~1.50)∶0.45, 2.00∶(0.1~1.50)∶0.50, 2.00∶(0.1~1.50)∶0.55, 2.00∶(0.1~1.50)∶0.60, 2.00∶ (0.1~1.50)∶0.65, 2.00∶(0.1~1.50)∶0.70, 2.00∶(0.1~1.50)∶0.75, 2.00∶(0.1~1.50)∶0.80, 2.00∶(0.1~1.50)∶0.85, 2.00∶(0.1~1.50)∶0.90, 2.00 ∶(0.1~1.50)∶0.95, 2.00∶(0.1~1.50)∶1.00, 2.00∶(0.1~1.50)∶1.05, 2.00∶(0.1~1.50)∶1.10, 2.00∶(0.1~1.50)∶1.15, 2.00∶(0.1~1.50)∶1.20, 2.0 0∶(0.1~1.50)∶1.25、2.00∶(0.1~1.50)∶1.30、2.00∶(0.1~1.50)∶1.35、2.00∶(0.1~1.50)∶1.40、2.00∶(0.1~1.50)∶1.45、2.00∶(0.1~1.50)∶1.50、2.2.00:(0.1~1.50):1.55, 2.00:(0.1~1.50):1.60, 2.00:(0.1~1.50):1.65, 2.00:(0.1~1.50):1.70, 2.00:(0.1~1.50):1.75, 2.00:(0.1~1.50):1.80, 2.00:(0.1~1.50):1.85, 2.00:(0.1~1.50):1.90, 2.00:(0.1~1.50):1.95, 2.00:(0.1~1.50):2.00 or any range of any two of these ratios, for example, 2.00:(0.8~1.2):(0.05~0.9). Therefore, the conversion rate of the compound shown in Formula I is higher than 50%.

[0014] The method described in this application obtains diazoxide in situ by mixing hydrogen peroxide and hydrazine hydrate in a continuous flow reactor. The diazoxide reduction replaces the hydrogenation reduction reaction. Compared with batch reactor conditions, the operation is safer and more controllable, the product yield is high (91.3% to 97.6%), there are fewer reaction impurities, the purity is high, the production cost is low, the process is stable, and it is suitable for industrial-scale production.

[0015] Unless otherwise specified herein, "R1, R2, R3, R4 in the compound shown in Formula I are the same as R1, R2, R3, R4 in the compound shown in Formula II" means that R1 in the compound shown in Formula I is the same as R1 in the compound shown in Formula II, R2 in the compound shown in Formula I is the same as R2 in the compound shown in Formula II, R3 in the compound shown in Formula I is the same as R3 in the compound shown in Formula II, and R4 in the compound shown in Formula I is the same as R4 in the compound shown in Formula II. However, R1, R2, R3, R4 in the compound shown in Formula I may be the same or different (i.e., R1, R2, R3, R4 in the compound shown in Formula II may be the same or different), and are not specifically limited, all of which are within the scope of protection of this application.

[0016] According to embodiments of the present invention, the above method may further include at least one of the following technical features:

[0017] According to an embodiment of the present invention, R1 is selected from carbonyl, -C-OH, and / or

[0018] R2 is selected from hydrogen, -CH3, -COOCH2CH3, -OCH3, and / or

[0019] R3 is selected from -CH3, -COOCH2CH3, and / or

[0020] R4 is selected from hydrogen or hydroxyl.

[0021] According to an embodiment of the present invention, the compound represented by Formula I has the following structure:

[0022]

[0023] And / or, the compound represented by Formula II has the following structure:

[0024]

[0025]

[0026] According to an embodiment of the present invention, the molar ratio of hydrazine hydrate, hydrogen peroxide, and the compound shown in Formula I is 2.00:(0.8–1.20):(0.05–0.9). Therefore, the conversion rate of the compound shown in Formula I is higher than 70%.

[0027] According to an embodiment of the present invention, the molar ratio of hydrazine hydrate, hydrogen peroxide and the compound shown in Formula I is 2:1:0.2.

[0028] According to an embodiment of the present invention, the pressure of the first reduction reaction and the second reduction reaction is 0 to 10 MPa and / or the temperature is 0°C to 60°C, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 MPa or any two of these ratios, or 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C or any two of these ratios.

[0029] According to an embodiment of the present invention, the pressure of the first reduction reaction and the second reduction reaction is 1 MPa and / or the temperature is 0 °C.

[0030] According to an embodiment of the present invention, the hydrazine hydrate is pumped to reactor 1 via pump 1, the hydrogen peroxide is pumped to reactor 1 via pump 2, the compound represented by formula I is pumped to reactor 2 via pump 3, and / or the first reduction reaction product is pumped to reactor 2.

[0031] According to an embodiment of the present invention, the delivery rate of the hydrazine hydrate, hydrogen peroxide and / or the compound represented by Formula I is 1.0 to 10.0 mL / min.

[0032] According to some specific embodiments of the present invention, the delivery rate of the hydrazine hydrate, hydrogen peroxide and / or the compound represented by Formula I is 1.0 mL / min or 10.0 mL / min.

[0033] According to an embodiment of the present invention, the hydrazine hydrate is pre-dissolved in solvent A, the concentration of the hydrazine hydrate being 0.5–2.5 mol / L, and / or

[0034] The hydrogen peroxide is pre-dissolved in solvent B, and the concentration of the hydrogen peroxide is 0.1–2.5 mol / L, and / or

[0035] The compound represented by Formula I is pre-dissolved in solvent C, and the concentration of the compound represented by Formula I is 0.01–2.5 mol / L.

[0036] According to an embodiment of the present invention, solvent A, solvent B, and solvent C are each independently selected from one or more of water, methanol, ethanol, isopropanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and tetrahydrofuran.

[0037] According to an embodiment of the present invention, solvent A, solvent B, and solvent C are methanol.

[0038] In a second aspect of the invention, the invention provides for the use of the compound of formula II prepared by the method of the first aspect in the preparation of a medicament for the prevention and / or treatment of pain.

[0039] According to an embodiment of the present invention, the pain includes neuropathic pain.

[0040] Compared with the prior art, the beneficial effects of the present invention include at least one of the following:

[0041] (1) This application uses a continuous flow / microchannel device and inexpensive and readily available liquid reactants to avoid the problem of uneven mass transfer in the solid-liquid-gas three-phase mixture of traditional hydrogenation reduction reaction.

[0042] (2) No concentration of diazoxide accumulates during the reaction, and the reaction process is relatively safe.

[0043] (3) The reduction of double bonds by in-situ diazoxide can achieve a good yield (91.3% to 97.6%) and high purity. It avoids the use of high-pressure hydrogen and transition metal catalysts, and the post-processing is simple with small amounts of waste, making it more suitable for large-scale industrial production.

[0044] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0045] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0046] Figure 1 The HPLC chromatogram of the compound prepared by the method described in Example 1 of the present invention is shown.

[0047] Figure 2 The HPLC chromatogram of the compound prepared by the method described in Example 2 of this invention;

[0048] Figure 3 The HPLC chromatogram of the compound prepared by the method described in Example 3 of this invention;

[0049] Figure 4 The HPLC chromatogram of the compound prepared by the method described in Example 4 of this invention;

[0050] Figure 5 The HPLC chromatogram of the compound prepared by the method described in Example 5 of this invention;

[0051] Figure 6 The HPLC chromatogram of the compound prepared by the method described in Example 6 of the present invention;

[0052] Figure 7 The HPLC chromatogram of the compound prepared by the method described in Example 6 of the present invention;

[0053] Figure 8 The conversion rate diagram is for the reaction optimization according to Example 8 of the present invention;

[0054] Figure 9 This is a flowchart of a reaction apparatus according to an embodiment of the present invention. Detailed Implementation

[0055] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0056] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this invention, "multiple" or "a plurality of" means at least two, two types, such as two, two, three, three, etc., unless otherwise explicitly specified.

[0057] In this document, the terms “comprising,” “having,” or “including” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0058] In this document, the term “optionally” generally means that an event or condition described below may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0059] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0060] This document also includes isotopically labeled compounds of the present invention that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Exemplary isotopes that may also be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0061] Compounds of the present invention comprising other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotope-labeled compounds of the present invention, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted (i.e., 3 H), and carbon-14 (i.e. 14 C), with particular preference for isotopes. Additionally, heavier isotopes, such as deuterium (i.e.,...), are used. 2 H-substitution can provide some therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0062] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0063] In this paper, the minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes, for example, prefix C. a～b This refers to a carbon atom, which is "a" to "b". For example, "C 1～n "C" refers to a saturated / unsaturated carbon chain, either straight or branched, containing 1, 2, 3, 4, 5, ..., or n carbon atoms; further understanding, "C" 1～n "Should be interpreted as any subranges included, such as C" 1～20 In, containing C 1～19 C 1～18 C 1～17 C 1～16 C 1～15 C 1～14 C 1～13 C 1～12 C 1～11 C 1～10 C 1～9 C 1～8 C 1～7 C 1～6 C 1～5 C 1～4 C 1～3 C 1～2 C 2～19 C 2～18 C 2～17 C 2～16 C 2～15 C 2～14 C 2～13 C 2～12 C 2～11 C 2～10、 C 2～9 C 2～8 C 2～7 C 2～6 C 2～5 C 2～4 C 2～3 C 3～19 C 3～18 C 3～17 C 3～16 C 3～15 C 3～14 C 3～13 C 3～12 C3～11 、C 3～10 、C 3～9 、C 3～8 、C 3～7 、C 3～6 、C 3～5 、C 3～4 、C 4～19 、C 4～18 、C 4～17 、C 4～16 、C 4～15 、C 4～14 、C 4～13 、C 4～12 、C 4～11 、C 4～10 、C 4～9 、C 4～8 、C 4～7 、C 4～6 、C 4～5 、C 5～19 、C 5～18 、C 5～17 、C 5～16 、C 5～15 、C 5～14 、C 5～13 、C 5～12 、C 5～11 、C 5～10 、C 5～9 、C 5～8 、C 5～7 、C 5～6 、C 6～19 、C 6～18 、C 6～17 、C 6～16 、C 6～15 、C 6～14 、C 6～13 、C 6～12 、C 6～11 、C 6～10 、C 6～9 、C 6～8 、C 6～7 、C 7～19 、C 7～18 、C 7～17 、C 7～16 、C 7～15 、C 7～14 、C 7～13 、C 7～12 、C 7～11 、C 7～10 、C 7～9 、C 7～8 、C 8～19 、C 8～18 、C 8～17 、C 8～16 、C 8～15C 8～14 C 8～13 C 8～12 C 8～11 C 8～10 C 8～9 C 9～19 C 9～18 C 9～17 C 9～16 C 9～15 C 9～14 C 9～13 C 9～12 C 9～11 C 9～10 C 10～19 C 10～18 C 10～17 C 10～16 C 10～15 C 10～14 C 10～13 C 10～12 C 10～11 C 11～19 C 11～18 C 11～17 C 11～16 C 11～15 C 11～14 C 11～13 C 11～12 C 13～19 C 13～18 C 13～17 C 13～16 C 13～15 C 13～14 C 13～13 C 13～19 C 13～18 C 13～17 C 13～16 C 13～15 C 13～14 C 14～19 C 14～18 C 14～17 C 14～16 C 14～15 C 15～19 C 15～18 C 15～17 C 15～16 C 16～19 C 16～18 C 16～17 C 17～19 C 17～18 C 18～19 .

[0064] It should be noted that the term "C" is used in this article. 1～20 For example, in "C" 1～20In the context of the definition of "alkyl", it refers to an alkyl group having a finite number of carbon atoms from 1 to 20, namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbon atoms. Further understanding, the term "C"... 1～20 "Should be interpreted as any subranges included therein."

[0065] In this invention, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 1～20 The alkyl group is a straight-chain or branched, saturated monovalent hydrocarbon group. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or its isomers. In particular, the group has 1, 2, or 3 carbon atoms (“C…”). 1～3 Alkyl), such as methyl, methylene, ethyl, n-propyl or isopropyl.

[0066] The present invention will now be described with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way.

[0067] Example 1

[0068] Continuous flow preparation of opioid reducing intermediates: In this example, continuous flow reduction of the opioid double bond intermediate morphine is used, and its structural formula is as follows:

[0069]

[0070] Step 1: Prepare each solution at room temperature. Using methanol as solvent, prepare 2.0 mol / L hydrazine hydrate solution A, 1.0 mol / L hydrogen peroxide solution B, and 0.1 mol / L morphine alkaloid solution C separately, and degas them by sonication for 3 minutes.

[0071] Step 2, as follows Figure 9 As shown, pumps 1 and 2 deliver solutions A and B to reactor 1 at flow rates of 1.0 mL / min and 1.0 mL / min, respectively, to begin the mixing reaction. The resulting reaction solution continues to be transported through pipelines, and pump 3 delivers solution C to reactor 2 at a flow rate of 1.0 mL / min to mix with the reaction solution. Reactors 1 and 2 are placed in a temperature-controlled zone, with the temperature controlled at 0°C and the pressure at 1 MPa. The reaction products are collected at the inlet.

[0072] Step 3: 30 mL of the collected reaction solution was quenched with 10 mL of 2.0 mol / L hydrochloric acid and kept under control. The solution was concentrated under reduced pressure below 45 °C until no methanol was detected. Then, 20 mL of dichloromethane and 10 mL of 10% sodium chloride were added for extraction, retaining the organic phase. The organic phase was concentrated to dryness to obtain compound II-1, which was then analyzed by HPLC using conventional methods in the field. The results are as follows: Figure 1 As shown, the yield of compound II-1 obtained in this embodiment was 95.3%, and the purity was 98.50%.

[0073] Example 2

[0074] Continuous flow preparation of opioid reducing intermediates: In this embodiment, continuous flow reduction of the opioid double bond intermediate codeine is used, and its structural formula is as follows:

[0075]

[0076] Step 1: Prepare each solution at room temperature. Using methanol as the solvent, prepare 2.0 mol / L hydrazine hydrate solution A, 1.0 mol / L hydrogen peroxide solution B, and 0.2 mol / L codeine solution C separately, and degas them by sonication for 3 minutes.

[0077] Step 2, as follows Figure 9 As shown, pumps 1 and 2 deliver solutions A and B to reactor 1 at flow rates of 1.0 mL / min and 1.0 mL / min, respectively, to begin the mixing reaction. The resulting reaction solution continues to be transported through pipelines, and pump 3 delivers solution C to reactor 2 at a flow rate of 1.0 mL / min to mix with the reaction solution. Reactors 1 and 2 are placed in a temperature-controlled zone, with the temperature controlled at 0°C and the pressure at 1 MPa. The reaction products are collected at the inlet.

[0078] Step 3: 30 mL of the collected reaction solution was quenched with 10 mL of 2.0 mol / L hydrochloric acid and kept under control. The solution was concentrated under reduced pressure below 45°C until no methanol was detected. Then, 20 mL of dichloromethane and 10 mL of 10% sodium chloride were added for extraction, retaining the organic phase. The organic phase was concentrated to dryness to obtain compound II-2, which was then analyzed by HPLC. The experimental method was the same as in Example 1, and the results are as follows. Figure 2 As shown, the yield of compound II-2 obtained in this embodiment was 97.6%, and the purity was 99.54%.

[0079] Example 3

[0080] In this example, a continuous flow method was used to prepare opioid reducing intermediates. The compound 14-hydroxy-3,17-diethoxycarbonylnormorphone, with the following structural formula, was reduced using a continuous flow method:

[0081]

[0082] Step 1: Prepare the solutions at room temperature. Using methanol as the solvent, prepare 2.0 mol / L hydrazine hydrate solution A, 1.0 mol / L hydrogen peroxide solution B, and 0.1 mol / L 14-hydroxy-3,17-diethoxycarbonylnormorphone solution C, and degas them by sonication for 3 minutes.

[0083] Step 2, as follows Figure 9 As shown, pumps 1 and 2 deliver solutions A and B to reactor 1 at flow rates of 1.0 mL / min and 1.0 mL / min, respectively, to begin the mixing reaction. The resulting reaction solution continues to be transported through pipelines, and pump 3 delivers solution C to reactor 2 at a flow rate of 1.0 mL / min to mix with the reaction solution. Reactors 1 and 2 are placed in a temperature-controlled zone, with the temperature controlled at 0°C and the pressure at 1 MPa. The reaction products are collected at the outlet.

[0084] Step 3: 30 mL of the collected reaction product was quenched with 10 mL of 2.0 mol / L hydrochloric acid and kept under control. The mixture was concentrated under reduced pressure below 45°C until no methanol was detected. Then, 20 mL of dichloromethane and 10 mL of 10% sodium chloride were added for extraction, retaining the organic phase. The organic phase was concentrated to dryness to obtain compound II-3, which was analyzed by HPLC. The experimental method was the same as in Example 1, and the results are as follows. Figure 3 As shown, the yield of compound II-3 obtained in this embodiment was 91.3%, and the purity was 99.47%.

[0085] Example 4

[0086] Continuous flow preparation of opioid reducing intermediates: In this example, continuous flow reduction of compound 1,4-hydroxycodeinone was used, the structural formula of which is as follows:

[0087] Step 1: Prepare each solution at room temperature. Using methanol as the solvent, prepare 2.0 mol / L hydrazine hydrate solution A, 1.0 mol / L hydrogen peroxide solution B, and 0.1 mol / L 1,4-hydroxycodeinone solution C separately, and degas them by sonication for 3 minutes.

[0088] Step 2, as follows Figure 9 As shown, pumps 1 and 2 deliver solutions A and B to reactor 1 at flow rates of 1.0 mL / min and 1.0 mL / min, respectively, to begin the mixing reaction. The resulting reaction solution continues to be transported through pipelines, and pump 3 delivers solution C to reactor 2 at a flow rate of 1.0 mL / min to mix with the reaction solution. Reactors 1 and 2 are placed in a temperature-controlled zone, with the temperature controlled at 0°C and the pressure at 1 MPa. The reaction products are collected at the inlet.

[0089] Step 3: 30 mL of the collected reaction product was quenched with 10 mL of 2.0 mol / L hydrochloric acid and kept under control. The mixture was concentrated under reduced pressure below 45°C until no methanol was detected. Then, 20 mL of dichloromethane and 10 mL of 10% sodium chloride were added for extraction, retaining the organic phase. The organic phase was concentrated to dryness to obtain compound II-4, which was analyzed by HPLC. The experimental method was the same as in Example 1, and the results are as follows. Figure 4 As shown, the yield of compound II-2 obtained in this embodiment was 95.1%, and the purity was 99.12%.

[0090] Example 5

[0091] In this embodiment, the opioid reducing intermediate was prepared by continuous flow reduction of the opioid double bond intermediate morphine, which has the structural formula I-1.

[0092] Step 1: Prepare each solution at room temperature. Using methanol as the solvent, prepare 2.0 mol / L hydrazine hydrate solution A, 1.0 mol / L hydrogen peroxide solution B, and 0.2 mol / L morphine alkaloid solution C separately, and degas them by sonication for 3 minutes.

[0093] Step 2, as follows Figure 9 As shown, pumps 1 and 2 deliver solutions A and B to reactor 1 at flow rates of 10.0 mL / min and 10.0 mL / min, respectively, to begin the mixing reaction. The resulting reaction solution continues to be transported through pipelines, and pump 3 delivers solution C to reactor 2 at a flow rate of 10.0 mL / min to mix with the reaction solution. Reactors 1 and 2 are placed in a temperature-controlled zone, with the temperature controlled at 5°C and the pressure at 1 MPa. The reaction products are collected at the inlet.

[0094] Step 3: 30 mL of the collected reaction solution was quenched with 10 mL of 2.0 mol / L hydrochloric acid and kept under control. The solution was concentrated under reduced pressure below 45 °C until no methanol was detected. Then, 20 mL of dichloromethane and 10 mL of 10% sodium chloride were added for extraction, retaining the organic phase. The organic phase was concentrated to dryness to obtain compound II-1, which was then analyzed by HPLC. The results are as follows: Figure 5 As shown, the yield of compound II-1 obtained in this embodiment was 94.7%, and the purity was 99.57%.

[0095] Example 6

[0096] In this embodiment, the opioid reducing intermediate was prepared by continuous flow reduction of the opioid double bond intermediate morphine, which has the structural formula I-1.

[0097] Step 1: Prepare each solution at room temperature. Using methanol as solvent, prepare 2.0 mol / L hydrazine hydrate solution A, 2.0 mol / L hydrogen peroxide solution B, and 0.2 mol / L morphine alkaloid solution C separately, and degas them by sonication for 3 minutes.

[0098] Step 2, as follows Figure 9 Pumps 1 and 2 deliver solutions A and B to reactor 1 at flow rates of 1.0 mL / min and 1.0 mL / min, respectively, to initiate the mixing reaction. The resulting reaction solution continues to be transported through pipelines, and pump 3 delivers solution C to reactor 2 at a flow rate of 10.0 mL / min to mix with the reaction solution. Reactors 1 and 2 are placed in a temperature-controlled zone, with the temperature controlled at 0°C and the pressure at 1 MPa. The reaction products are collected at the inlet.

[0099] Step 3: Add 10 mL of 2.0 mol / L hydrochloric acid to 30 mL of the collected reaction solution for quenching and control. Concentrate under reduced pressure below 45 °C until no methanol is detected. Then, extract with 20 mL of dichloromethane and 10 mL of 10% sodium chloride, retaining the organic phase. Concentrate the organic phase to dryness to obtain compound II-1, which is then analyzed by HPLC. The experimental method is the same as in Example 1. The results are as follows. Figure 6 As shown, the yield of compound II-1 obtained in this embodiment was 37.5%, and the purity was 97.52%.

[0100] Example 7

[0101] Opioid reducing intermediates were prepared under batch conditions. In this embodiment, the opioid double bond intermediate morphine was reduced under batch conditions, and its structural formula is I-1.

[0102] Step 1: Prepare each solution at room temperature. Using methanol as the solvent, prepare 1.0 mol / L hydrazine hydrate solution A, 1.0 mol / L hydrogen peroxide solution B, and 0.1 mol / L morphine solution C separately, and degas them by sonication for 3 minutes.

[0103] Step 2: Add 20 mL of the above hydrazine hydrate solution A and 20 mL of morphine base solution C to a 100 mL three-necked flask, stir and cool to 0 °C, then slowly add 10 mL of the above hydrogen peroxide solution B dropwise at a temperature controlled at 5 °C for 1 hour; after the addition is complete, continue stirring and reacting for another hour.

[0104] Step 3: Add 10 mL of 2.0 mol / L hydrochloric acid to 30 mL of the reaction solution obtained in Step 2 for quenching and control. Concentrate under reduced pressure below 45°C until no methanol is detected. Then, extract with 20 mL of dichloromethane and 10 mL of 10% sodium chloride, retaining the organic phase. After concentrating the organic phase to dryness, compound II-1 is obtained. HPLC analysis is performed using conventional methods in the field. The results are as follows: Figure 7 As shown, the yield of compound II-1 was 0.06%, with almost no target product obtained.

[0105] Example 8

[0106] In this embodiment, continuous flow reaction conditions were used to optimize the reduction of the opioid double bond intermediate morphine, whose structural formula is I-1.

[0107] Step 1: Prepare each solution at room temperature. Using methanol as solvent, prepare a 2.0 mol / L hydrazine hydrate solution A, a hydrogen peroxide solution B with a concentration range of 0.1–2.5 mol / L, and a morphine alkaloid solution C with a concentration range of 0.01–2.5 mol / L, and degas them by sonication for 3 minutes.

[0108] Step 2, as follows Figure 9 As shown, pumps 1 and 2 deliver solutions A and B to reactor 1 at flow rates of 1.0 mL / min and 1.0 mL / min, respectively, to begin the mixing reaction. The resulting reaction solution continues to be transported through pipelines, and pump 3 delivers solution C to reactor 2 at a flow rate of 10.0 mL / min to mix with the reaction solution. Reactors 1 and 2 are placed in a temperature-controlled zone, with the temperature controlled at 0°C and the pressure at 1 MPa. The reaction products are collected at the inlet.

[0109] Step 3: Quench the reaction solution containing the reaction products obtained in Step 2 and control the reaction. Collect experimental data to obtain the optimized conversion rate. Figure 8 The result is as follows Figure 8 As shown, when the concentration of hydrogen peroxide is 0.10–1.50 mol / L and the concentration of morphine is 0.05–2.00 mol / L, that is, when the molar ratio of hydrazine hydrate, hydrogen peroxide, and morphine is 2.00:(0.10–1.50):(0.05–2.00), the conversion rate is greater than 50%. When the concentration of hydrogen peroxide is 0.8–1.20 mol / L and the concentration of morphine is 0.05–0.9 mol / L, that is, when the molar ratio of hydrazine hydrate, hydrogen peroxide, and morphine is 2.00:(0.8–1.20):(0.05–0.9), the conversion rate is greater than 70%.

[0110] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," "some implementations," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0111] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing the compound of formula II, characterized in that, include: (1) Hydrazine hydrate is subjected to a first reduction reaction with hydrogen peroxide; (2) The product obtained in step (1) is subjected to a second reduction reaction with the compound shown in Formula I to obtain the compound shown in Formula II. The first reduction reaction and the second reduction reaction are carried out in a continuous flow reactor; R1 is selected from carbonyl, -C-OR5, R5 is selected from hydrogen, C 1～20 Alkyl, heteroalkyl, carbonyl R2 is selected from hydrogen, C 1～20 Alkyl, heteroalkyl, carbonyl R3 is selected from hydrogen, C 1～20 Alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroalkyl, arylalkyl, or heteroarylalkyl R4 is selected from hydrogen or hydroxyl groups. R1, R2, R3, and R4 in the compound shown in Formula I are the same as R1, R2, R3, and R4 in the compound shown in Formula II. The molar ratio of hydrazine hydrate, hydrogen peroxide, and the compound shown in Formula I is 2.00:(0.1-1.50):(0.05-2.00).

2. The method according to claim 1, characterized in that, R1 is selected from carbonyl, -C-OH, and / or R2 is selected from hydrogen, -CH3, -COOCH2CH3, -OCH3, and / or R3 is selected from -CH3, -COOCH2CH3, and / or R4 is selected from hydrogen or hydroxyl.

3. The method according to claim 1, characterized in that, The compound represented by Formula I has the following structure: And / or, the compound represented by Formula II has the following structure:

4. The method according to claim 1, characterized in that, The molar ratio of hydrazine hydrate, hydrogen peroxide, and the compound shown in Formula I is 2.00:(0.80-1.20):(0.05-0.90); Optionally, the molar ratio of the hydrazine hydrate, hydrogen peroxide, and the compound represented by Formula I is 2:1:0.

2.

5. The method according to claim 1, characterized in that, The pressure of the first reduction reaction and the second reduction reaction is 0-10 MPa and / or the temperature is 0℃-60℃; Optionally, the pressure of the first reduction reaction and the second reduction reaction is 1 MPa and / or the temperature is 0 °C.

6. The method according to claim 1, characterized in that, The hydrazine hydrate is pumped into reactor 1 via pump 1, the hydrogen peroxide is pumped into reactor 1 via pump 2, the compound represented by formula I is pumped into reactor 2 via pump 3, and / or the first reduction reaction product is pumped into reactor 2.

7. The method according to claim 1, characterized in that, The hydrazine hydrate is pre-dissolved in solvent A, the concentration of which is 0.5–2.5 mol / L, and / or The hydrogen peroxide is pre-dissolved in solvent B, and the concentration of the hydrogen peroxide is 0.1–2.5 mol / L, and / or The compound represented by Formula I is pre-dissolved in solvent C, and the concentration of the compound represented by Formula I is 0.01–2.5 mol / L.

8. The method according to claim 8, characterized in that solvent A, solvent B, and solvent C are each independently selected from one or more of water, methanol, ethanol, isopropanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and tetrahydrofuran; Optionally, solvent A, solvent B, and solvent C are methanol.

9. Use of the compound of formula II prepared by the method according to any one of claims 1 to 9 in the preparation of a medicament for the prevention and / or treatment of pain.

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