Process for the preparation of an intermediate of exatecan and uses thereof
By preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene in a microchannel reactor and reacting it with nitrosoamyl ester under alkaline conditions, the compound a07 was obtained by hydrogenation reduction. This solved the problems of complex synthetic routes and safety issues of eczetidine intermediates, and achieved high-yield and safe industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD
- Filing Date
- 2021-07-06
- Publication Date
- 2026-06-09
AI Technical Summary
In the existing technology, the synthetic route of the intermediate compound a07 of eczema is complicated, the yield is low and it is not suitable for industrial production, especially the nitration reaction poses safety risks.
1-Nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was prepared using a microchannel reactor. By controlling the reaction conditions and solvent ratio, the safety and efficiency of the nitration reaction were achieved. The nitration reaction was carried out with nitrosoamyl ester under alkaline conditions, followed by hydrogenation reduction to obtain compound a07.
It simplifies the reaction route, increases the overall yield, reduces production costs, enhances reaction safety, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This application belongs to the field of pharmaceutical synthesis technology, and in particular relates to a method for preparing an eczema intermediate and its application. Background Technology
[0002] Exatecan is a DNA topoisomerase I inhibitor, a water-soluble camptothecin derivative, and its structural formula is shown below:
[0003]
[0004] Ecinotecan has excellent anti-tumor properties.
[0005] Trastuzumabderuxtecan (DS-8201) is a next-generation antibody-drug conjugate that links the HER2-targeting agent trastuzumab to an exatecan derivative via a protein molecule, delivering the cytotoxic agent directly to cancer cells. Compared to conventional chemotherapy, it significantly reduces the toxicity of cytotoxic agents to normal cells. On January 15, 2021, the U.S. Food and Drug Administration (FDA) officially approved DS-8201 for patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have previously received trastuzumab treatment.
[0006] The compound Exatecan and its preparation method are disclosed in EP0495432B1, and the synthetic route involved is as follows:
[0007]
[0008] The synthesis of the intermediate compound a07 involved repeated reactions of decarbonylation, oxidation, and carbonylation, resulting in low atom utilization and a yield of only 3.69%.
[0009] WO1996026181A1 and CN111065621A disclose compound a07 as a key intermediate in the synthesis of ixotecan. The above-mentioned method for synthesizing intermediate compound a07 requires repeated ring-closing, ring-opening, oxidation, and reduction reactions, which is a long route and complex reaction operation, and is not suitable for industrial scale-up production.
[0010]
[0011] The synthesis of compound a07 was optimized using WO2019044946A1, and the reaction route is as follows:
[0012]
[0013] The method has high starting material prices and limited market supply. Moreover, the yield of the first step of bromination reaction is low, only 30%. In the step of reducing nitro to amino, the post-processing is complicated and the entire reaction route is long, which is not conducive to industrial-scale production.
[0014] The inventors have discovered that using 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene as an intermediate to prepare compound a07 and icitecan offers advantages such as shortening the reaction route, simplifying multiple post-processing steps, and increasing the overall yield of icitecan. However, there are currently no literature reports on the preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, nor are there any reports on using 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene as an intermediate in the preparation of icitecan.
[0015] Conventional nitration is a hazardous chemical process, and accidents frequently occur in production. Microchannel reactors, with their advantages of high heat exchange and safety, are suitable for hazardous processes like nitration. Summary of the Invention
[0016] The purpose of this invention is to provide a new method for preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, which balances reaction yield and safety of nitration reaction and is suitable for industrial-scale production, and to use it in the preparation of the compound shown in Formula 07 and isotheca, in order to overcome the above-mentioned deficiencies in the prior art.
[0017] To this end, the inventors investigated the use of a microchannel reactor for the nitration reaction of compound a04 to prepare compound 0a5;
[0018]
[0019] Specifically, the first aspect of the present invention provides a method for preparing 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, the method comprising the following steps:
[0020] Preparation of reaction solution: Dissolve the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene in an acidic solvent; preferably, the volume (mL) ratio of the acidic solvent to the weight (g) of the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 5-20:1, more preferably 8-15:1; the acidic solvent is sulfuric acid, acetic acid, or trifluoroacetic acid.
[0021] Preparation of mixed acid solution: Nitric acid is slowly added to sulfuric acid under stirring conditions; preferably, the nitric acid is nitric acid with a mass fraction of not less than 90%, the sulfuric acid is concentrated sulfuric acid with a mass fraction of not less than 70%, and the weight ratio of nitric acid to sulfuric acid is 1:1.5 to 10, preferably 1:1.8 to 3; more preferably, the nitric acid is nitric acid with a mass fraction of not less than 97%, the sulfuric acid is concentrated sulfuric acid with a mass fraction of not less than 98%, and the weight ratio of nitric acid to sulfuric acid is 1:1.5 to 10, preferably 1:1.8 to 3.
[0022] The prepared reaction solution and the prepared mixed acid solution were added to a microchannel reactor to carry out the nitration reaction. The reaction residence time and the molar ratio of mixed acid to reaction substrate were controlled by controlling the flow rate of the feed pump.
[0023] In the above method, preferably, the molar ratio of nitric acid to the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 1 to 1.2:1. The nitration reaction temperature is 25 to 100°C, preferably 30 to 60°C.
[0024] Furthermore, the reaction residence time of the reaction liquid and the mixed acid solution in the microchannel reactor is controlled to be 30 to 120 seconds, preferably 50 to 100 seconds, by controlling the flow rate of the feed pump.
[0025] Preferably, the above method further includes, after the reaction is completed at a set temperature, introducing the reaction solution into cold water, filtering and collecting the solid precipitated in the water after the reaction is completed, washing with water until neutral, drying under vacuum, and optionally further purifying by silica gel column chromatography to obtain the solid, which is 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene.
[0026] In the above method, preferably, the microchannel reactor is a Corning G1 glass reactor system.
[0027] A second aspect of the present invention also provides a method for preparing eczema, comprising the following steps:
[0028] (1) 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was prepared using the method described in this invention;
[0029] (2) React 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene with nitrosoisoamyl ester under alkaline conditions, then add acetic acid and acetic anhydride, and then begin the hydrogenation reduction reaction to obtain the compound represented by formula a07:
[0030]
[0031] (3) The compound represented by formula a07 is converted into eczetidine.
[0032] Furthermore, the alkali mentioned in step (2) is potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide;
[0033] The hydrogenation reduction reaction is a reduction reaction carried out under H2 conditions with Pt / C as a catalyst.
[0034] Preferably, the molar ratio of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene to nitrosoisoamyl ester is 1:1 to 1.5; the molar ratio of the base to 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene to nitrosoisoamyl ester is 1:1 to 1.5, preferably 1:1.2.
[0035] The compounds represented by formula a07 can be synthesized into eczema via methods known in the art, such as, but not including, those described in the background section of this invention.
[0036] The present invention provides a method for converting 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene into 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene via nitration in a microchannel reactor. This 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is then reacted with nitrosoamyl ester under alkaline conditions, followed by hydrogenation reduction to obtain a compound represented by formula a07. Compound a07 is then used to prepare iscetecan. This route offers advantages such as readily available starting materials, a shorter reaction path, and a significantly higher overall yield compared to existing technologies.
[0037] The conversion of 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene into 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene via nitration in a microchannel reactor is highly efficient, significantly shortens the reaction time, and requires less nitric acid, thus reducing waste liquid discharge.
[0038] Secondly, the method provided by this invention greatly improves the safety of the reaction and can achieve the goal of pursuing inherent safety in chemical production.
[0039] Third, the method provided by this invention for preparing the compound represented by formula a07 has the advantages of high yield and suitability for industrial production. As the compound represented by formula a07 is a key intermediate for the preparation of ixotecan, it also directly improves the overall yield of ixotecan and reduces production costs. Detailed Implementation
[0040] The technical solutions and advantages of the present invention will be further explained below with reference to specific embodiments. It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of this application can be combined with each other.
[0041] Unless otherwise specified, the microchannel reactor used in the following examples is a G1 Corning glass reactor, the nitric acid used is commercially available 97% fuming nitric acid, the concentrated sulfuric acid is commercially available 98% concentrated sulfuric acid, and other reagents / raw materials used are commercially available.
[0042] Example 1: Preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene
[0043] 30.0 g of 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was dissolved in 240 mL of concentrated sulfuric acid to prepare a reaction solution. 11.0 g of fuming nitric acid was slowly added to 19.9 g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 45 °C, and the flow rate of the reaction solution was adjusted to ensure a reaction residence time of 50 seconds. Simultaneously, the flow rate of the mixed acid was adjusted to ensure a flow rate proportional to that of the reaction solution. After the reaction was complete, the precipitated solid was collected by filtration through cold water and washed with water until the eluent was neutral. After drying, the solid was purified by silica gel column chromatography to obtain 17.6 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, with a yield of 46.8%.
[0044] Example 2: Preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene
[0045] 30.0 g of the raw material 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was dissolved in 450 mL of acetic acid to prepare a reaction solution. 13.1 g of fuming nitric acid was slowly added to 39.3 g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 60 °C, and the flow rate of the reaction solution was adjusted to ensure a reaction residence time of 100 seconds. Simultaneously, the flow rate of the mixed acid was adjusted to ensure a feed rate proportional to the reaction solution. After the reaction was complete, the precipitated solid was collected by filtration through cold water and washed with water until the eluent was neutral. The solid was dried and purified by silica gel column chromatography to obtain 20.7 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, with a yield of 55.1%.
[0046] Example 3: Preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene
[0047] 30.0 g of 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was dissolved in 360 mL of trifluoroacetic acid to prepare a reaction solution. 12.0 g of fuming nitric acid was slowly added to 36.0 g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 55 °C, and the flow rate of the reaction solution was adjusted to ensure a reaction residence time of 90 seconds. Simultaneously, the flow rate of the mixed acid was adjusted to ensure a feed rate proportional to the reaction solution. After the reaction was complete, the precipitated solid was collected by filtration through cold water and washed with water until the eluent was neutral. The solid was dried and purified by silica gel column chromatography to obtain 19.2 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, with a yield of 51.2%.
[0048] Example 4: Preparation of the compound shown in formula a07
[0049] 5.0 g of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene (22.4 mmol) was dissolved in 75 mL of THF and cooled to 10 °C. Then, 3.4 g of isoamyl nitrite (29.0 mmol) and 3.0 g of potassium tert-butoxide (26.8 mmol) were added. The mixture was stirred at 10 °C for 12 hours, followed by the addition of 25 mL of acetic acid and 25 mL of acetic anhydride, and then 0.5 g of 5% Pt / C. The mixture was stirred at room temperature under a 1 atm H₂ atmosphere for 6 hours. After the reaction was complete, the reaction mixture was filtered to remove the catalyst. The solid was washed with 25 mL of THF, and the filtrates were combined and concentrated to dryness under reduced pressure. The residue was dissolved in a mixture of 50 mL of THF and 50 mL of ethyl acetate, washed twice with 40 mL of saturated sodium bicarbonate solution, and then once with 40 mL of saturated brine. The organic phase was concentrated to dryness under reduced pressure. The residue was recrystallized from acetonitrile. 4.4 g of white solid a07 was obtained (overall yield: 67%), HPLC: 98.7%.
[0050] Based on the above-described preferred embodiments according to this application, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the technical concept of this application. The technical scope of this application is not limited to the contents of the specification, but must be determined according to the scope of the claims.
Claims
1. A method for preparing eczema, comprising the following steps: (1) 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was converted into 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene by nitration in a microchannel reactor; (2) React 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene with nitrosoamyl ester under alkaline conditions, then add acetic acid and acetic anhydride, and obtain the compound represented by formula a07 by hydrogenation reduction reaction: ， (3) Convert the compound represented by formula a07 into eczema; The preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene includes the following steps: Preparation of reaction solution: Dissolve the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene in an acidic solvent; Preparation of mixed acid solution: Slowly add nitric acid to sulfuric acid under stirring conditions; The prepared reaction solution and the prepared mixed acid solution were added separately to a microchannel reactor for nitration. The reaction residence time and the molar ratio of mixed acid to reaction substrate were controlled by controlling the flow rate of the feed pump.
2. The method according to claim 1, wherein, The volume ratio of the acidic solvent to the weight ratio of the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 5 to 20:1, where the volume unit is milliliters and the weight unit is grams.
3. The method according to claim 1, wherein, The volume ratio of the acidic solvent to the weight ratio of the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 8 to 15:1, where the volume unit is milliliters and the weight unit is grams.
4. The method according to claim 1, wherein, The acidic solvent is sulfuric acid, acetic acid, or trifluoroacetic acid.
5. The method according to claim 1, wherein, The nitric acid used to prepare the mixed acid is nitric acid with a mass fraction of not less than 90%, and the sulfuric acid is concentrated sulfuric acid with a mass fraction of not less than 70%. The weight ratio of nitric acid to sulfuric acid is 1:1.5 to 10.
6. The method according to claim 1, wherein, The nitric acid used to prepare the mixed acid is nitric acid with a mass fraction of not less than 97%, and the sulfuric acid is concentrated sulfuric acid with a mass fraction of not less than 98%.
7. The method according to claim 1, wherein, The mixed acid solution is prepared in a weight ratio of nitric acid to sulfuric acid of 1:1.8 to 3.
8. The method according to claim 1, wherein, The molar ratio of nitric acid to the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 1 to 1.2:
1.
9. The method according to claim 1, wherein, The nitration reaction temperature is 25–100℃.
10. The method according to claim 1, wherein, The nitration reaction temperature is 30–60℃.
11. The method according to claim 1, wherein, The reaction residence time of the reaction solution and the mixed acid solution in the microchannel reactor is 30 to 120 seconds.
12. The method according to claim 1, wherein the reaction residence time of the reaction solution and the mixed acid solution in the microchannel reactor is 50 to 100 seconds.
13. The method according to any one of claims 1 to 12 further includes, after the reaction is completed at a set temperature, introducing the reaction solution into cold water, filtering and collecting the solid precipitated in the water after the reaction is completed, washing with water until neutral, drying under vacuum, and optionally further purifying by silica gel column chromatography to obtain the solid, which is 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene.
14. The method according to claim 1, wherein, The alkali mentioned in step (2) is potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide; The hydrogenation reduction reaction is a reduction reaction carried out under H2 conditions with Pt / C as the catalyst.
15. The method according to claim 1, wherein the molar ratio of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene to nitrosoamyl ester in step (2) is 1:1 to 1.5; and the molar ratio of the base to 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 1:1 to 1.
5.
16. The method according to claim 1, wherein the molar ratio of the base to 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene in step (2) is 1:1.2.