A method for the continuous flow synthesis of dihydromorphine
By using a continuous flow microchannel reactor and a wet palladium-carbon catalyst in the hydrogenation process of morphine base, the reaction conditions were optimized, solving the problems of low efficiency and high impurities in traditional processes, and achieving the production of high-purity and high-safety dihydromorphine products.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- YICHANG HUMANWELL PHARMA CO LTD
- Filing Date
- 2023-12-06
- Publication Date
- 2026-07-07
AI Technical Summary
Traditional olefin hydrogenation processes are inefficient, produce many impurities in the morphine base hydrogenation process, and have unstable reaction conditions, making it difficult to guarantee safety and product quality.
A continuous flow microchannel reactor was used to control temperature and pressure, and a wet palladium-on-carbon catalyst was employed. This simplified the raw material drying process, optimized the ratio of reaction solvent and materials, ensured precise control of reaction conditions, and reduced the generation of byproducts.
It improves the purity and production safety of dihydromorphine products, simplifies the process, reduces the catalyst activity requirement, and enhances reaction efficiency and product quality stability.
Smart Images
Figure CN117756813B_ABST
Abstract
Description
Technical Field
[0001] This article relates to the field of chemical drug synthesis, specifically to a method for synthesizing dihydromorphine, an intermediate of hydromorphone hydrochloride, using a continuous flow microchannel reactor. Background Technology
[0002] Hydromorphone hydrochloride, a morphine-like psychotropic drug, is chemically known as (-)-4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. It is a safe, highly effective, and selective opioid analgesic with rapid onset of action, widely used in general anesthesia, perioperative neuroprotection, and preemptive analgesia.
[0003] (5α,6α)-4,5-epoxy-17-methylmorphinan-3,6-diol is a key intermediate in the synthesis of hydromorphone hydrochloride, obtained by hydrogenation of morphine base.
[0004]
[0005] Olefin hydrogenation is a common organic synthesis reaction. The process described above involves adding hydrogen atoms to the carbon-carbon double bonds of morphine base, reducing it to dihydromorphine. After a series of reactions and post-processing, the final product, hydromorphone hydrochloride, is obtained, which has high economic value. However, the efficiency and selectivity of olefin hydrogenation are affected by many reaction conditions, such as solvent type, catalyst type, reaction temperature, pressure, and hydrogen flow rate. Traditional hydrogenation processes require the use of dry palladium on carbon and cannot guarantee constant reaction pressure and hydrogen flow rate, resulting in longer reaction times and lower efficiency. Furthermore, the product contains two large mono-impurities. Additionally, the traditional process requires the raw material morphine base to be dried before feeding, making the pretreatment process complex.
[0006] Currently, microchannel technology, due to its better heat transfer efficiency and hydrogen flow control capabilities, can greatly improve reaction efficiency and product quality. Furthermore, because microchannel reactors are smaller in size, the total amount of reactants is also reduced. Therefore, compared with traditional hydrogenation processes, microchannel reactors greatly improve the intrinsic safety level of morphine base hydrogenation processes. Summary of the Invention
[0007] This application provides a method for synthesizing dihydromorphine using a continuous flow microreactor. The method controls the temperature and pressure of the continuous flow microchannel reactor, as well as the selection of the reaction solvent and the concentration and ratio of the raw materials and catalyst for dihydromorphine synthesis. This eliminates the drying process of raw materials in traditional processes, reduces the activity requirement of the palladium-carbon catalyst, reduces the generation of key impurities in the hydrogenation reaction process of traditional processes, reduces the content of by-products, and improves the purity of dihydromorphine products and the safety of production.
[0008] This application provides a method for synthesizing dihydromorphine using a continuous flow microreactor, comprising: using morphine base as a starting material, and obtaining dihydromorphine through a hydrogenation reduction reaction in a continuous flow microreactor.
[0009]
[0010] In one exemplary embodiment, the method includes the following steps:
[0011] 1) Set the temperature and pressure of the continuous flow microreactor;
[0012] 2) Material A, which contains morphine and catalyst, is injected into the preheating module of the continuous flow microreactor through a liquid connection pipe for preheating;
[0013] 3) The preheated material A is injected into the reaction module of the continuous flow microreactor, and hydrogen gas is injected into the reaction module as material B through the gas connection pipe. After mixing and reacting with material A, a reaction solution is obtained.
[0014] 4) Take samples of the reaction solution flowing out in step 3) and monitor the reaction conversion rate;
[0015] 5) The reaction liquid is subjected to gas-liquid separation, filtration, concentration, crystallization and drying to obtain the product dihydromorphine.
[0016] In one exemplary embodiment, in step 1), the temperature of the continuous flow microreactor is 80-110°C and the pressure is 0.8-1.0 MPa; preferably, the temperature of the continuous flow microreactor is 100°C and the pressure is 1.0 MPa.
[0017] In one exemplary embodiment, in step 2), the catalyst is palladium on carbon.
[0018] In an exemplary embodiment, in step 2), material A is an organic solution containing the morphine and the palladium on carbon;
[0019] Optionally, the organic solvent in the organic solution is at least one of anhydrous ethanol, anhydrous methanol, and ethyl acetate; preferably, the organic solvent is anhydrous methanol.
[0020] Optionally, the morphine has a mass fraction of 4.18%-8.01% and the palladium on carbon has a mass fraction of 4.0%-8.0%; preferably, the morphine has a mass fraction of 8.01% and the palladium on carbon has a mass fraction of 8.0%.
[0021] In one exemplary embodiment, in step 2), the palladium on carbon is at least one of wet palladium on carbon with a palladium mass fraction of 5% or 10%; preferably, the palladium on carbon is wet palladium on carbon with a palladium mass fraction of 10%.
[0022] In one exemplary embodiment, in step 2), the injection rate of material A is 10-90 g / min; preferably, the injection rate of material A is 50 g / min.
[0023] In one exemplary embodiment, in step 3), the reaction module is one or more sets of micro-reaction channels connected in series.
[0024] In an exemplary embodiment, in step 3), the reaction module consists of six interconnected micro-reaction channels, namely a first reaction module, a second reaction module, a third reaction module, a fourth reaction module, a fifth reaction module, and a sixth reaction module connected in series. The first reaction module is connected to the preheating module. Hydrogen gas, as material B, is injected into the first reaction module through a gas connection pipe. The preheated material A and material B are mixed in the first reaction module and react completely in the first, second, third, fourth, fifth, and sixth reaction modules.
[0025] In an exemplary embodiment, step 3) includes the following steps: injecting the preheated material A into the first reaction module, and simultaneously injecting hydrogen as material B into the first reaction module through a gas connection pipe to mix with the preheated material A. The mixture is then passed through the first reaction module, the second reaction module, the third reaction module, the fourth reaction module, the fifth reaction module, and the sixth reaction module in sequence to react and obtain the reaction liquid.
[0026] In one exemplary embodiment, in step 3), the injection rate of material B is 100-1080 ml / min; preferably, the injection rate of material B is 630 g / min.
[0027] In an exemplary embodiment, in step 3), the equivalent ratio of material B to material A is (1:1.9)-(1:3.8); preferably, the equivalent ratio of material B to material A is 1:1.99.
[0028] In one exemplary embodiment, in step 4), the crystallization solvent is a 95% (v / v) ethanol solution.
[0029] Compared with related technologies, this application has the following technical advantages:
[0030] (1) Using this technology can simplify the traditional process and eliminate the morphine drying step;
[0031] (2) Using this technology, dry palladium carbon in the traditional process can be replaced with wet palladium carbon, reducing the activity requirement of palladium carbon;
[0032] (3) This technology can effectively suppress side reactions, precisely control reaction conditions, control the growth of key impurities dihydrocodeine and dihydronitrogen oxidized morphine during the synthesis of dihydromorphine, and improve product purity.
[0033] (3) The product quality obtained by this technology is stable, the continuous operation efficiency is high, the residence time is fixed, and the backmixing is minimal, which helps to solve the problem of different batches.
[0034] (4) The amount of hydrogen and instantaneous organic solvent is greatly reduced during the reaction process, and the reaction process is inherently safe.
[0035] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the solutions described in the description and the accompanying drawings. Attached Figure Description
[0036] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.
[0037] Figure 1 This is an HPLC chromatogram of the reaction conversion rate in Example 1;
[0038] Figure 2 This is the HPLC chromatogram of the reaction conversion rate in Example 2;
[0039] Figure 3 This is the HPLC chromatogram of the reaction conversion rate in Example 3;
[0040] Figure 4 This is the HPLC chromatogram of the reaction conversion rate in Example 4;
[0041] Figure 5 This is the HPLC chromatogram of the reaction conversion rate in Example 5;
[0042] Figure 6 This is the HPLC chromatogram of the reaction conversion rate in Example 6;
[0043] Figure 7 This is the HPLC chromatogram of the reaction conversion rate in Example 7;
[0044] Figure 8 This is the HPLC chromatogram of the reaction conversion rate in Example 8;
[0045] Figure 9 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 1.
[0046] Figure 10 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 2.
[0047] Figure 11 The HPLC chromatogram shows the conversion rates of the three reactions in the comparative example.
[0048] Figure 12 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 4.
[0049] Figure 13 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 5.
[0050] Figure 14 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 6.
[0051] Figure 15 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 7.
[0052] Figure 16 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 8.
[0053] Figure 17 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 9.
[0054] Figure 18 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 10.
[0055] Figure 19 The HPLC chromatogram shows the reaction conversion rate of Comparative Example XI.
[0056] Figure 20 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 12.
[0057] Figure 21 The HPLC chromatogram shows the conversion rate of Comparative Example 13.
[0058] Figure 22 The HPLC chromatogram shows the reaction conversion rate of Comparative Example XIV.
[0059] Figure 23 The HPLC chromatogram shows the reaction conversion rate of Comparative Example 15.
[0060] Figure 24 The HPLC chromatogram shows the reaction conversion rate of Comparative Example XVI.
[0061] Figure 25 This is a schematic diagram illustrating the structure and working principle of the continuous flow microreactor of this application.
[0062] In the attached figures, the following labels are used:
[0063] 1: Preheating module; 2: First reaction module; 3: Second reaction module; 4: Third reaction module; 5: Fourth reaction module; 6: Fifth reaction module; 7: Sixth reaction module; 8: Material B; 9: Material A; 10: Gas flow meter; 11: Diaphragm pump; 12: Sampling valve; 13: Gas-liquid separator; 14: Back pressure valve; 15: N2. Detailed Implementation
[0064] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of the present invention will be described in detail below. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be arbitrarily combined with each other.
[0065] The present invention will be further described in detail below with reference to the accompanying drawings and specific examples, but these examples should not be construed as limiting the present invention.
[0066] according to Figure 25 It is known that material A is pumped into the preheating module 1 and then into the first reaction module 2 via the diaphragm pump 11 and the liquid connection pipe, while material B is directly introduced into the first reaction module 2 via the gas flow meter 10 and the gas connection pipe to merge with material A. After the mixture is reacted by the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7, the reaction liquid can be sent to the gas-liquid separator 13 and other post-processing equipment for post-processing by sampling and monitoring through the sampling valve 12.
[0067] In the embodiments of this application:
[0068] Morphine was purchased from Gansu State Farms Pharmaceutical Alkali Plant;
[0069] The wet palladium on carbon was purchased from Shaanxi Ruike New Materials Co., Ltd.
[0070] Dry palladium on carbon was purchased from Alfa America;
[0071] Anhydrous ethanol was purchased from Shanghai Zhenxing Chemical Plant No. 1;
[0072] Hydrogen was purchased from Yichang Jinxiaoheyuan Gas Co., Ltd.
[0073] The HPLC instrument used for detection was a Dionex liquid chromatograph.
[0074] In this application, the equivalent ratio of material B (H2) to material A is calculated as follows:
[0075]
[0076] In the following specific embodiments, operations without specified conditions are performed under standard conditions or conditions recommended by the manufacturer. Raw materials without specified manufacturers and specifications are all commercially available products.
[0077] Example 1
[0078] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0079] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 50 g / min for preheating.
[0080] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0081] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0082] 5) HPLC monitoring showed a reaction conversion rate of 97.71%;
[0083] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.55% and dihydrocodeine impurity content of 1.22%.
[0084] Example 2
[0085] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0086] 2) Prepare a solution (material A) with 5.05% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at a rate of 10 g / min through the liquid connection tube for preheating.
[0087] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0088] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0089] 5) HPLC monitoring showed a reaction conversion rate of 96.91%;
[0090] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.12% and dihydrocodeine impurity content of 1.84%.
[0091] Example 3
[0092] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0093] 2) Prepare a solution (material A) with morphine and 10% wet palladium on carbon using anhydrous ethanol, which has a morphine mass fraction of 6.56% and a palladium on carbon mass fraction of 4.0%. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 90 g / min for preheating.
[0094] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0095] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0096] 5) HPLC monitoring showed a reaction conversion rate of 98.15%;
[0097] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.16% and dihydrocodeine impurity content of 1.29%.
[0098] Example 4
[0099] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0100] 2) Prepare a solution (material A) with morphine and 10% wet palladium on carbon using anhydrous ethanol, which has a morphine mass fraction of 8.01% and a palladium on carbon mass fraction of 4.0%. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 50 g / min for preheating.
[0101] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 100 ml / min;
[0102] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0103] 5) HPLC monitoring showed a reaction conversion rate of 98.19%;
[0104] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.18% and dihydrocodeine impurity content of 1.21%.
[0105] Example 5
[0106] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0107] 2) Prepare a solution (material A) with morphine and 10% wet palladium on carbon using anhydrous ethanol, which has a morphine mass fraction of 8.01% and a palladium on carbon mass fraction of 4.0%. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 50 g / min for preheating.
[0108] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0109] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0110] 5) HPLC monitoring showed a reaction conversion rate of 98.40%;
[0111] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.14% and dihydrocodeine impurity content of 1.17%.
[0112] Example 6
[0113] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0114] 2) Prepare a solution (material A) with morphine and 10% wet palladium on carbon using anhydrous ethanol, which has a morphine mass fraction of 8.01% and a palladium on carbon mass fraction of 8.0%. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 50 g / min for preheating.
[0115] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0116] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0117] 5) HPLC monitoring showed a reaction conversion rate of 98.50%;
[0118] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.17% and dihydrocodeine impurity content of 1.13%.
[0119] Example 7
[0120] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0121] 2) Prepare a solution (material A) with 8.01% morphine and 8.0% palladium on carbon by mixing ethyl acetate with 10% wet palladium on carbon. Inject the solution into the preheating module 1 of the reaction at a rate of 50 g / min through a liquid connecting pipe for preheating.
[0122] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 1080 ml / min;
[0123] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0124] 5) HPLC monitoring showed a reaction conversion rate of 97.33%;
[0125] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.17% and dihydrocodeine impurity content of 1.49%.
[0126] Example 8
[0127] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0128] 2) Prepare a solution (material A) with morphine and 10% wet palladium on carbon by mixing with anhydrous methanol to form a solution with morphine mass fraction of 8.01% and palladium on carbon mass fraction of 8.0%, and inject it into the preheating module 1 of the reaction through the liquid connection tube at a rate of 50 g / min for preheating;
[0129] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0130] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0131] 5) HPLC monitoring showed a reaction conversion rate of 99.86%.
[0132] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product with 0% oxidizing impurity content and 0% dihydrocodeine impurity content.
[0133] Comparative Example 1
[0134] 1) Control the temperature of the preheating module and the reaction module at 80℃ and the pressure at 0.1MPa;
[0135] 2) Prepare a solution (material A) with 4.18% morphine mass fraction and 4.0% palladium carbon mass fraction by mixing morphine base and 5% wet palladium carbon (palladium content is 5%) with anhydrous ethanol, and inject it into the preheating module 1 of the reaction through the liquid connecting pipe at 10g / min for preheating;
[0136] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 100 ml / min;
[0137] 4) Material A in step 2) and material B in step 3) pass through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 in sequence to obtain a reaction solution;
[0138] 5) HPLC monitoring showed a reaction conversion rate of 44.59%.
[0139] 6) The reaction solution was filtered, the filtrate was evaporated and concentrated, 95% (v / v) ethanol was added to induce crystallization, and the solution was filtered and dried to obtain the crude product; the content of nitrogen oxide impurities was 1.59%, and the content of dihydrocodeine impurities was 0.53%.
[0140] Comparative Example 2
[0141] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 0.5MPa;
[0142] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at a rate of 10 g / min for preheating.
[0143] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 100 ml / min;
[0144] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0145] 5) HPLC monitoring showed the reaction conversion rate to be 82.43%;
[0146] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 8.31% and dihydrocodeine impurity content of 3.03%.
[0147] Comparative Example 3
[0148] 1) Control the temperature of the preheating module and the reaction module at 110℃ and the pressure at 0.5MPa;
[0149] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at a rate of 10 g / min for preheating.
[0150] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 100 ml / min;
[0151] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0152] 5) HPLC monitoring showed a reaction conversion rate of 82.88%;
[0153] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 1.63% and dihydrocodeine impurity content of 0.95%.
[0154] Comparative Example 4
[0155] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 0.9MPa;
[0156] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at a rate of 10 g / min for preheating.
[0157] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 100 ml / min;
[0158] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0159] 5) HPLC monitoring showed the reaction conversion rate to be 88.68%;
[0160] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 1.81% and dihydrocodeine impurity content of 1.16%.
[0161] Comparative Example 5
[0162] 1) Control the temperature of the preheating module and the reaction module at 110℃ and the pressure at 1.0MPa;
[0163] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at a rate of 10 g / min for preheating.
[0164] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 100 ml / min;
[0165] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0166] 5) HPLC monitoring showed a reaction conversion rate of 94.21%;
[0167] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 3.40% and dihydrocodeine impurity content of 1.13%.
[0168] Comparative Example 6
[0169] 1) Control the temperature of the preheating module and the reaction module at 130℃ and the pressure at 1.0MPa;
[0170] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at a rate of 10 g / min for preheating.
[0171] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 100 ml / min;
[0172] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0173] 5) HPLC monitoring showed a reaction conversion rate of 89.07%;
[0174] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 5.47% and dihydrocodeine impurity content of 2.74%.
[0175] Comparative Example 7
[0176] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 0.1MPa;
[0177] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at a rate of 30 g / min through the liquid connection tube for preheating.
[0178] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 360 ml / min;
[0179] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0180] 5) HPLC monitoring showed a reaction conversion rate of 96.24%;
[0181] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 2.21% and dihydrocodeine impurity content of 1.23%.
[0182] Comparative Example 8
[0183] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0184] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction through the liquid connection tube at a rate of 70 g / min for preheating.
[0185] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 840 ml / min;
[0186] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0187] 5) HPLC monitoring showed a reaction conversion rate of 96.14%;
[0188] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.44% and dihydrocodeine impurity content of 2.41%.
[0189] Comparative Example 9
[0190] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0191] 2) Prepare a solution (material A) with 4.18% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction through the liquid connection tube at a rate of 90 g / min for preheating.
[0192] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 1080 ml / min;
[0193] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0194] 5) HPLC monitoring showed a reaction conversion rate of 93.67%;
[0195] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 3.48% and dihydrocodeine impurity content of 1.96%.
[0196] Comparative Example 10
[0197] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0198] 2) Prepare a solution (material A) with 4.65% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction through the liquid connection tube at a rate of 50 g / min for preheating.
[0199] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0200] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0201] 5) HPLC monitoring showed a reaction conversion rate of 94.57%;
[0202] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 0.31% and dihydrocodeine impurity content of 3.07%.
[0203] Comparative Example 11
[0204] 1) Control the temperature of the preheating module and the reaction module at 80℃ and the pressure at 0.1MPa;
[0205] 2) Prepare a solution (material A) with morphine and 5% wet palladium on carbon using anhydrous ethanol, which has a morphine mass fraction of 5.73% and a palladium on carbon mass fraction of 4.0%. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 50 g / min for preheating.
[0206] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0207] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0208] 5) HPLC monitoring showed a reaction conversion rate of 94.81%;
[0209] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 2.55% and dihydrocodeine impurity content of 1.25%.
[0210] Comparative Example Twelve
[0211] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0212] 2) Prepare a solution (material A) with 6.01% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at 50 g / min through the liquid connection tube for preheating.
[0213] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0214] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0215] 5) HPLC monitoring showed a reaction conversion rate of 95.87%;
[0216] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 1.73% and dihydrocodeine impurity content of 1.74%.
[0217] Comparative Example Thirteen
[0218] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0219] 2) Prepare a solution (material A) with 6.01% morphine and 4.0% palladium on carbon by mixing morphine and 5% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction at 50 g / min through the liquid connection tube for preheating.
[0220] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0221] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, and the fourth reaction module 5 to obtain a reaction solution;
[0222] 5) HPLC monitoring showed the reaction conversion rate to be 80.64%;
[0223] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 3.65% and dihydrocodeine impurity content of 1.04%.
[0224] Comparative Example 14
[0225] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0226] 2) Prepare a solution (material A) with 6.01% morphine and 4.0% palladium on carbon by mixing morphine and 10% wet palladium on carbon with anhydrous ethanol. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 50 g / min for preheating.
[0227] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0228] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5 and the fifth reaction module 6 to obtain a reaction solution;
[0229] 5) HPLC monitoring showed the reaction conversion rate to be 92.59%;
[0230] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 2.2% and dihydrocodeine impurity content of 4.12%.
[0231] Comparative Example 15
[0232] 1) Control the temperature of the preheating module and the reaction module at 100℃ and the pressure at 1.0MPa;
[0233] 2) Prepare a solution (material A) with morphine and 10% wet palladium on carbon using anhydrous ethanol, which has a morphine mass fraction of 8.01% and a palladium on carbon mass fraction of 2.0%. Inject the solution into the preheating module 1 of the reaction through a liquid connecting pipe at a rate of 50 g / min for preheating.
[0234] 3) Hydrogen gas (material B) is introduced into the first reaction module 2 through the gas connection pipe at a flow rate of 630 ml / min;
[0235] 4) Material A from step 2) and material B from step 3) are passed sequentially through the first reaction module 2, the second reaction module 3, the third reaction module 4, the fourth reaction module 5, the fifth reaction module 6 and the sixth reaction module 7 to obtain a reaction solution;
[0236] 5) HPLC monitoring showed a reaction conversion rate of 96.53%;
[0237] 6) Filter the reaction solution, concentrate the filtrate, add 95% (v / v) ethanol to crystallize, filter and dry to obtain crude product, with nitrogen oxide impurity content of 1.32% and dihydrocodeine impurity content of 1.59%.
[0238] Comparative Example 16
[0239] Preparation via traditional batch reaction:
[0240] 1) Dry the morphine alkaloids to remove moisture;
[0241] 2) Prepare a solution of anhydrous morphine and 10% dry palladium on carbon with anhydrous ethanol to obtain a solution with a morphine mass fraction of 6.25% and a palladium on carbon mass fraction of 4.0%, and add it to the reaction flask;
[0242] 3) Control the temperature at 65-75℃, purge with nitrogen, then introduce hydrogen gas and perform a hydrogenation reaction at atmospheric pressure;
[0243] 4) HPLC monitoring showed a reaction conversion rate of 96.6%;
[0244] 5) Filter the reaction solution, concentrate the filtrate, add ethanol to crystallize, filter and dry to obtain crude product, with an oxidizing impurity content of 1.18% and a dihydrocodeine impurity content of 1.37%.
[0245] test:
[0246] Table 1 shows a comparison of the purity and quality of the dihydromorphine raw material produced by Example 8 and the dihydromorphine raw material produced by a conventional reactor (Comparative Example 16). Among them, key impurity 1 is nitrogen oxide impurity and key impurity 2 is dihydrocodeine.
[0247] Table 1 Quality of Continuous Flow Dihydromorphine Products
[0248] Serial Number type purity Key impurity 1 Key impurity 2 Example 8 Continuous flow reaction 99.8％ Not detected Not detected Comparative Example 16 Traditional process reaction 96.6％ 1.2％ 1.4％
[0249] Based on the above embodiments, comparative examples, and Table 1, it can be seen that:
[0250] 1) Based on Comparative Examples 1 to 6, the optimal temperature conditions for the preheating module and the reaction module were determined to be 100℃ and 1.0 MPa.
[0251] 2) Based on Examples 1, 5, 7, 8 and 9, the optimal injection rate of morphine base and palladium on carbon (material A) was 50 g / min; the optimal injection rate of hydrogen (material B) was 630 ml / min.
[0252] 3) Based on Examples 2, 3, 4, Comparative Examples 9, 10, 11 and 12, the optimal mass fraction of morphine alkaloid was determined to be 8.01%;
[0253] 4) Based on Examples 3, 4, 12, 13 and 14, the optimal total number of modules for the preheating module and the reaction module is 7.
[0254] 5) Based on Examples 3, 4, 5, 6, Comparative Example 13, Comparative Example 14, and Comparative Example 15, the optimal wet palladium on carbon content was 10%, and the optimal palladium on carbon content was 8.0%.
[0255] 6) Based on Examples 6, 7, and 8, anhydrous methanol was selected as the optimal solvent;
[0256] 7) Comparative Example 16 is a control group for hydrogenation reaction carried out under conventional processes. The comparison between Comparative Example 16 and Example 8 demonstrates that although continuous flow microchannel reactions are inherently highly efficient, direct use without any trial and error cannot eliminate the two impurities. Therefore, through extensive experimentation with reaction conditions, this application has obtained a set of process parameters and conditions that can effectively eliminate the two reaction impurities.
[0257] This application describes several embodiments, but these descriptions are exemplary and not restrictive, and it will be apparent to those skilled in the art that there are many more embodiments and implementations within the scope of the embodiments described herein.
Claims
1. A method for synthesizing dihydromorphine using a continuous flow microreactor, comprising: Dihydromorphine was obtained by hydrogenation reduction reaction of morphine base in a continuous flow microreactor: ； The method includes the following steps: 1) Set the temperature of the continuous flow microreactor to 80-110℃ and the pressure to 0.8-1.0MPa; 2) Material A, mixed with morphine and catalyst, is injected into the preheating module of the continuous flow microreactor through a liquid connection pipe at an injection rate of 10-90 g / min for preheating; the catalyst is at least one of wet palladium on carbon with a mass fraction of 5% or 10% palladium; material A is an organic solution containing the morphine and the palladium on carbon, wherein the mass fraction of the morphine is 4.18%-8.01% and the mass fraction of the palladium on carbon is 4.0%-8.0%; 3) The preheated material A is fed into the reaction module of the continuous flow microreactor. The reaction module consists of 6 interconnected micro-reaction channels, namely the first reaction module, the second reaction module, the third reaction module, the fourth reaction module, the fifth reaction module, and the sixth reaction module connected in series. At the same time, hydrogen gas, as material B, is injected into the reaction module through the gas connection pipe at a rate of 100-1080 ml / min. After mixing and reacting with material A, a reaction solution is obtained. 4) Take samples of the reaction solution flowing out in step 3) and monitor the reaction conversion rate; 5) The reaction liquid is subjected to gas-liquid separation, filtration, concentration, crystallization and drying to obtain the product dihydromorphine.
2. The method according to claim 1, wherein, In step 1), the temperature of the continuous flow microreactor is 100°C and the pressure is 1.0 MPa.
3. The method according to claim 1, wherein, In step 2), the palladium on carbon is wet palladium on carbon with a mass fraction of 10% palladium.
4. The method according to claim 1, wherein, In step 2), the organic solvent in the organic solution is at least one of anhydrous ethanol, anhydrous methanol, and ethyl acetate.
5. The method according to claim 4, wherein, The organic solvent is anhydrous methanol.
6. The method according to claim 1, wherein, In step 2), the mass fraction of morphine is 8.01%, and the mass fraction of palladium on carbon is 8.0%.
7. The method according to claim 1, wherein, In step 2), the injection rate of material A is 50 g / min.
8. The method according to claim 1, wherein, Step 3) includes the following steps: injecting the preheated material A into the first reaction module, and simultaneously injecting hydrogen as material B into the first reaction module through a gas connection pipe to mix with the preheated material A. The mixture is then passed through the first reaction module, the second reaction module, the third reaction module, the fourth reaction module, the fifth reaction module, and the sixth reaction module in sequence to react and obtain the reaction solution.
9. The method according to claim 1, wherein, In step 3), the injection rate of material B is 630 g / min; and / or The equivalence ratio of material B to material A is (1:1.9)-(1:3.8).
10. The method according to claim 9, wherein, The equivalent ratio of material B to material A is 1:1.
99.
11. The method according to any one of claims 1 to 10, wherein, In step 4), the crystallization solvent is a 95% ethanol solution.