Method for preparing rerugolix intermediate by utilizing micro-packed bed hydrogenation
Reduction of rilugoli nitro raw materials through micro-filled bed hydrogenation technology solves the problems of equipment corrosion and high cost under high pressure and acidic conditions in the prior art, realizes the preparation of high-purity products and continuous use of catalysts, and provides A green, safe and low-cost nitro reduction method is used.
Patent Information
- Application Number
- CN202310717480.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-06-16
- Publication Date
- 2024-12-17
AI Technical Summary
In the existing reduction method of rilugoli nitro compounds, the use of high pressure and corrosive acids leads to corrosion of equipment, high cost, the catalyst does not have continuous use, and the dedimethylamine impurities are difficult to remove, affecting the purity and safety of the product. sex.
Using micro-filled bed hydrogenation technology, the hydroreduction of the rilugoli nitro raw material is carried out through the micro reactor, and high heat and mass transfer efficiency and catalyst life tests are used to shorten the reaction time, improve the purity, and continuously use the catalyst to avoid Acid conditions and high pressure reduce equipment corrosion and costs.
The preparation of high-purity Rylugoli intermediates is realized, which reduces process costs, improves safety and automation, reduces dedimethylamine impurities, and provides a green, safe and low-cost nitro reduction technology.
Smart Images
Figure CN119143722A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to a method for preparing a relugolix intermediate by hydrogenation using a micro-packed bed. Background Art
[0002] Relugoli is a small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist jointly developed by Takeda Pharmaceutical Company Limited and Myovant of Japan, and has the potential to be used for indications such as uterine fibroids, endometriosis, and prostate cancer.
[0003] The original research company Takeda Pharmaceutical Company disclosed its synthesis method for the first time (WO2004067535), and the specific synthesis route is as follows:
[0004]
[0005] In the prior art, the methods for reducing relugoli nitro compounds include metal reduction, catalytic hydrogenation reduction, hydrazine hydrate reduction, etc. Patent CN114685468 reports a method for reducing relugoli nitro compounds with zinc powder and ammonium chloride, which produces a large amount of waste solids and wastewater, and has high environmental pressure and cost; Patent CN114230576 reports a reduction method with palladium carbon and hydrazine hydrate, but hydrazine hydrate is expensive, needs to be stored at low temperatures, is highly toxic, has strong irritation and corrosion effects on human mucous membranes, and has high safety risks.
[0006] The methods for reducing the nitro group of relugoli reported so far mostly use catalytic hydrogenation reduction methods, using solvents such as alcohols and esters as media, using suitable catalysts, and reducing the nitro compound of relugoli under heating and pressurization conditions. This method meets the principle of atom economy and environmental protection requirements, and is more in line with the development needs of clean processes. At present, the catalytic hydrogenation process is mostly carried out in a hydrogenation kettle. Since the reaction is a three-phase reaction of gas, liquid and solid, acidic conditions, high pressure and a long reaction time are usually required to ensure sufficient contact between the three phases and the full progress of the hydrogenation reaction. The above conditions are prone to produce dedimethylamine impurities, which are difficult to remove in subsequent steps and have a greater quality risk.
[0007]
[0008] Secondly, the above method requires the use of a high-pressure reactor, which is generally made of stainless steel. The use of acid will cause corrosion to the equipment, and equipment that is resistant to high pressure and acid corrosion is relatively expensive. Summary of the invention
[0009] In view of the problems existing in the prior art, the present invention provides a method for preparing a relugoli intermediate by using a micro-packed bed hydrogenation. Compared with conventional reactors, the microreactor has the advantages of high heat and mass transfer coefficient, good mixing performance, easy temperature control and process controllability. The present invention uses micro-packed bed hydrogenation technology to reduce the nitro raw material of relugoli, and avoids the use of corrosive strong acid through process intensification; by strengthening the gas-liquid-solid three-phase mass transfer, the reaction time is greatly reduced, the purity of the obtained product is high, and the impurities of dedimethylamine are small; through the catalyst life test, the micro-packed bed hydrogenation system can achieve the preparation of a relugoli intermediate with a purity of more than 98% within a long working cycle of 100 hours, realizing the continuous use of the catalyst and greatly reducing the material cost; realizing the continuity and automation of the process, and having higher safety.
[0010] The present invention provides a method for preparing a relugolix intermediate by hydrogenation using a micro-packed bed, characterized in that it comprises the steps of:
[0011] (1) mixing the nitro raw material of relugolix with a reaction solvent to prepare a raw material solution;
[0012] (2) introducing the raw material solution obtained in step (1) and hydrogen into a micro-packed bed reactor filled with a solid particle catalyst for reaction;
[0013] (3) separating the gas-liquid mixture obtained after the reaction is completed, and collecting and treating the product solution to obtain the relugolix intermediate;
[0014] In step (1), the reaction solvent is one or more of ethanol, tetrahydrofuran, ethyl acetate, and acetonitrile; the mass concentration of the raw material solution is 2wt% to 20wt%, preferably 5wt% to 20wt%.
[0015] In step (2), the reaction temperature is 25-85°C, preferably 45-80°C; the reaction pressure is 1-5Mpa, preferably 1.5-2.5Mpa; the hydrogen flow rate is 10-80ml / min, preferably 20-60ml / min; the raw material solution flow rate is 0.2-2ml / min, preferably 0.3-1.0ml / min.
[0016] In step (2), the solid particle catalyst is at least one of a platinum carbon catalyst, a palladium carbon catalyst, a palladium / silicon dioxide catalyst, a nickel carbon catalyst, and a nickel / silicon dioxide catalyst.
[0017] In step (2), the residence time of the raw material solution and hydrogen in the micro-packed bed reactor is 5-20 minutes.
[0018] In step (3), the purity of the relugolix intermediate obtained after gas-liquid separation is greater than 98%.
[0019] The reaction formula of the reaction of the present invention is as follows:
[0020]
[0021] The present invention utilizes micro-filling hydrogenation technology to reduce the nitro raw material of relugoli. Compared with the prior art, the present invention has the following advantages:
[0022] (1) The reaction of the present invention has a small liquid holding volume, a high degree of automation, and an easy-to-control reaction process, thereby achieving the inherent safety of the nitro reduction reaction;
[0023] (2) Avoid the use of corrosive strong acids and reduce corrosion to equipment;
[0024] (3) In the traditional kettle hydrogenation process, the catalyst cannot be reused between batches and needs to be replaced, which results in high process costs. However, the present invention can achieve continuous utilization of the catalyst, thus reducing process costs.
[0025] (4) The present invention can accurately control the reaction parameters, the reduction reaction is thorough, the reaction time is shortened, and the reaction product has few impurities and high purity;
[0026] (5) Compared with traditional technologies, the present invention provides a green, safe, low-cost and high-efficiency nitro reduction technology. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 Flow chart of the preparation of relugolix intermediates using micro-packed bed hydrogenation. DETAILED DESCRIPTION
[0028] The present invention will be further described below in conjunction with specific examples. Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methodology, scheme and reagent described herein, and simple improvements to the present invention under the premise of the technical solution of the present invention all belong to the protection scope of the present invention. It should also be understood that the terms used herein are only for describing specific embodiments, and are not intended to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present invention belongs.
[0029] Comparative Example 1
[0030] Add 60 ml of ethanol, 6 g of relugolix nitro raw material, and 40 g of hydrochloric acid to the autoclave and stir the solvent. Add 12 g of 10% palladium carbon under nitrogen atmosphere, replace with nitrogen and hydrogen, and stir at room temperature for 6 hours. Filter the palladium carbon, and the reaction solution is tested by HPLC. The purity is 95.83%, and the dedimethylamine impurity is 2.49%. ESI (+): m / z 532.21 [M+1] + , 1H-NMR: (400MHz, DMSO)δ=9.272(br,2H),7.490~7.414(m,3H),7.237(s,2H),7.105(t,2H),4.915(s,2H),4 .386(s,2H),4.258(q,2H),3.994(s,2H),2.541~2.498(m,6H),1.548(d,2H),1.281(s,3H),0.817(d,3H).
[0031] Example 1
[0032] The nitro raw material of relugoli was mixed with ethanol to prepare a solution with a mass concentration of 15%. The solution was mixed with hydrogen in a mixer and flowed through a micro-packed bed reactor equipped with a nickel-carbon catalyst (3.9 g). The reaction temperature was set to 65°C, the reaction pressure was 3.0 MPa, the hydrogen flow rate was 50 ml / min, the material flow rate was 0.5 ml / min, and the residence time was about 11 minutes; the product was separated by a gas-liquid separator and collected. The product solution was tested by HPLC, and the purity was 99.70%, and the dedimethylamine impurity was 0.05%. The product solution was concentrated to obtain the product. ESI (+): m / z 532.21 [M+1] + , 1 H-NMR: (400MHz, DMSO)δ=9.272(br,2H),7.490~7.414(m,3H),7.237(s,2H),7.105(t,2H),4.915(s,2H),4 .386(s,2H),4.258(q,2H),3.994(s,2H),2.541~2.498(m,6H),1.548(d,2H),1.281(s,3H),0.817(d,3H).
[0033] Example 2
[0034] The nitro raw material of relugoli was mixed with tetrahydrofuran to prepare a solution with a mass concentration of 10%. The solution was mixed with hydrogen in a mixer and flowed through a micro-packed bed reactor equipped with a platinum carbon catalyst (3.1 g). The reaction temperature was set to 80°C, the reaction pressure was 1.5 MPa, the hydrogen flow rate was 30 ml / min, the material flow rate was 0.3 ml / min, and the residence time was about 18 minutes; the product was separated by a gas-liquid separator and collected. The product solution was tested by HPLC, and the purity was 99.21%, and the dedimethylamine impurity was 0.08%. The product solution was concentrated to obtain the product. ESI (+): m / z 532.21 [M+1] + , 1H-NMR: (400MHz, DMSO)δ=9.272(br,2H),7.490~7.414(m,3H),7.237(s,2H),7.105(t,2H),4.915(s,2H),4 .386(s,2H),4.258(q,2H),3.994(s,2H),2.541~2.498(m,6H),1.548(d,2H),1.281(s,3H),0.817(d,3H).
[0035] Example 3
[0036] The nitro raw material of relugoli was mixed with ethyl acetate to prepare a solution with a mass concentration of 15%. The solution was mixed with hydrogen in a mixer and flowed through a micro-packed bed reactor equipped with a palladium / silicon dioxide catalyst (2.6 g). The reaction temperature was set to 35°C, the reaction pressure was 2.5 MPa, the hydrogen flow rate was 50 ml / min, the material flow rate was 0.4 ml / min, and the residence time was about 14 minutes; the product was separated by a gas-liquid separator and collected. The product solution was tested by HPLC, and the purity was 99.30%, and the dedimethylamine impurity was 0.09%. The product solution was concentrated to obtain the product. ESI (+): m / z 532.21 [M+1] + , 1 H-NMR: (400MHz, DMSO)δ=9.272(br,2H),7.490~7.414(m,3H),7.237(s,2H),7.105(t,2H),4.915(s,2H),4 .386(s,2H),4.258(q,2H),3.994(s,2H),2.541~2.498(m,6H),1.548(d,2H),1.281(s,3H),0.817(d,3H).
[0037] Example 4
[0038] The nitro raw material of relugoli was mixed with acetonitrile to prepare a solution with a mass concentration of 15%. The solution was mixed with hydrogen in a mixer and flowed through a micro-packed bed reactor equipped with a nickel / silicon dioxide catalyst (3.8 g). The reaction temperature was set to 75°C, the reaction pressure was 2.5 MPa, the hydrogen flow rate was 50 ml / min, the material flow rate was 0.8 ml / min, and the residence time was about 7 minutes; the product was separated by a gas-liquid separator and collected. The product solution was tested by HPLC, and the purity was 99.11%, and the dedimethylamine impurity was 0.10%. The product solution was concentrated to obtain the product. ESI (+): m / z 532.21 [M+1] + , 1H-NMR: (400MHz, DMSO)δ=9.272(br,2H),7.490~7.414(m,3H),7.237(s,2H),7.105(t,2H),4.915(s,2H),4 .386(s,2H),4.258(q,2H),3.994(s,2H),2.541~2.498(m,6H),1.548(d,2H),1.281(s,3H),0.817(d,3H).
[0039] Example 5
[0040] The flow chart of preparing relugolix intermediate by micro-packed bed hydrogenation is shown in Figure 1 .
[0041] The nitro raw material of relugoli is mixed with a solvent to prepare a raw material solution, which is mixed with hydrogen in a mixer and flows through a micro-packed bed reactor equipped with a catalyst. The reaction conversion is controlled by parameters such as temperature, pressure, hydrogen flow rate, and material flow rate. After the reaction is completed, the product is separated by a gas-liquid separator and collected. According to tests, the micro-packed bed hydrogenation system can achieve the preparation of a relugoli intermediate with a purity of more than 98% within a long working cycle of 100 hours. In the traditional kettle hydrogenation process, the catalyst cannot be reused between batches and needs to be replaced, and the process cost is relatively high. This method can achieve the continuous use of the catalyst, improve the utilization rate of the catalyst, and greatly reduce the process cost.
Claims
1. A method for preparing a relugolix intermediate by hydrogenation in a micro-packed bed, characterized in that: Includes steps: (1) mixing the nitro raw material of relugolix with a reaction solvent to prepare a raw material solution; (2) introducing the raw material solution obtained in step (1) and hydrogen into a micro-packed bed reactor filled with a solid particle catalyst for reaction; (3) separating the gas-liquid mixture obtained after the reaction is completed, and collecting and treating the product solution to obtain the relugolix intermediate; The reaction formula of the reaction is as follows:
2. The method according to claim 1, characterized in that In step (1), the reaction solvent is one or more of ethanol, tetrahydrofuran, ethyl acetate, and acetonitrile.
3. The method according to any one of claims 1 to 2, characterized in that: In step (1), the mass concentration of the raw material solution is 2wt% to 20wt%, preferably 5wt% to 20wt%.
4. The method according to any one of claims 1 to 3, characterized in that: In step (2), the reaction temperature is 25-85°C, preferably 45-80°C.
5. The method according to any one of claims 1 to 4, characterized in that: In step (2), the reaction pressure is 1-5 MPa, preferably 1.5-2.5 MPa.
6. The method according to any one of claims 1 to 5, characterized in that: In step (2), the hydrogen flow rate of the reaction is 10-80 ml / min, preferably 20-60 ml / min.
7. The method according to any one of claims 1 to 6, characterized in that: In step (2), the flow rate of the raw material solution of the reaction is 0.2-2 ml / min, preferably 0.3-1.0 ml / min.
8. The method according to any one of claims 1 to 7, characterized in that: In step (2), the fixed particle catalyst is at least one of a platinum carbon catalyst, a palladium carbon catalyst, a palladium / silicon dioxide catalyst, a nickel carbon catalyst, and a nickel / silicon dioxide catalyst.
9. The method according to any one of claims 1 to 8, characterized in that: In step (2), the residence time of the raw material solution and hydrogen in the micro-packed bed reactor is 5-20 minutes.
10. The method according to any one of claims 1 to 9, characterized in that: In step (3), the purity of the relugolix intermediate obtained after gas-liquid separation is greater than 98%.