Process for the preparation of an intermediate of exatecan and uses thereof

Abstract

This invention provides a method for preparing ixenocarb intermediates and their applications. Specifically, an organic solvent solution of 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthic acid is reacted with a mixed acid in a microchannel reactor via a nitration reaction to convert it into 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthic acid. This method has high reaction efficiency, low acid consumption, reduced waste discharge, and short reaction time, greatly improving reaction safety. This invention also provides a method for preparing ixenocarb using this method. The method employs a novel design route, making the starting materials easier to obtain and the reaction route shorter. Compared with existing technologies, the overall yield of ixenocarb is significantly improved.

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] Ixotecon.

[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 reactions are prone to explosion. In addition, the byproducts of nitration reactions (nitro compounds or polynitro compounds may be explosives / flammable materials) themselves have stability issues and can undergo secondary decomposition (deflagration) at certain temperatures. Therefore, there are often significant safety hazards in production. 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 organic solvent; preferably, the organic solvent is one or a mixture of more than one of dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride.

[0021] In a preferred embodiment of the present invention, the volume (ml) ratio of the organic solvent to the weight (g) of the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 5 to 20:1, more preferably 8 to 15:1.

[0022] To prepare a mixed acid solution: Slowly add nitric acid to sulfuric acid while stirring.

[0023] In one specific embodiment of the present invention, the nitric acid is nitric acid with a mass fraction of not less than 90%, preferably 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 70%, preferably concentrated sulfuric acid with a mass fraction of not less than 98%; more preferably, the weight ratio of the nitric acid to the sulfuric acid is 1:1.5 to 10, preferably 1:2 to 6.

[0024] In a more specific embodiment of the present invention, 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 1:2 to 6.

[0025] Furthermore, the prepared reaction solution and the prepared mixed acid solution are added to a microchannel reactor to carry out the nitration reaction, and the reaction residence time and the molar ratio of mixed acid and reaction substrate are controlled by controlling the flow rate of the feed pump.

[0026] 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 120°C, preferably 30 to 100°C.

[0027] Furthermore, the reaction residence time of the reaction liquid and the mixed acid solution in the microchannel reactor is controlled to be 30 seconds to 180 seconds, preferably 50 to 150 seconds, by controlling the flow rate of the feed pump.

[0028] Preferably, the above method further includes, after the reaction is completed at a set temperature, introducing the reaction solution into cold water, separating the organic layer, concentrating it, and further purifying it by silica gel column chromatography or recrystallization to obtain a solid, namely 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene.

[0029] In one specific embodiment of the present invention, the method further includes, after the reaction is completed at a set temperature, introducing the reaction solution into cold water, allowing it to stand and separate into layers, separating the organic layer, extracting the aqueous phase with an organic solvent such as dichloromethane, chloroform or carbon tetrachloride, combining the organic phases, washing with sodium bicarbonate solution and water, and then concentrating. Optionally, the obtained solid is further purified by silica gel column chromatography to obtain 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene.

[0030] In the above method, preferably, the microchannel reactor is a Corning G1 glass reactor system.

[0031] A second aspect of the present invention also provides a method for preparing eczema, comprising the following steps:

[0032] (1) 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was prepared using the method described in this invention;

[0033] (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:

[0034]

[0035] (3) The compound represented by formula a07 is converted into eczetidine.

[0036] Furthermore, the alkali mentioned in step (2) is potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide;

[0037] The hydrogenation reduction reaction is a reduction reaction carried out under H2 conditions with Pt / C as a catalyst.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] The method involves dissolving 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene in an organic solvent and then reacting it with mixed acid in a microchannel reactor to convert it into 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene. This reduces the amount of acid used, thereby reducing pollution. Furthermore, the method of this invention significantly shortens the reaction time and saves energy.

[0042] 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.

[0043] 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

[0044] 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.

[0045] Unless otherwise specified, the microchannel reactor used in the following examples is a Corning G1 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.

[0046] Example 1: 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 300 mL of dichloromethane to prepare a reaction solution. 13.1 g of fuming nitric acid was slowly added to 65.5 g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 65 °C, and the flow rate of the reaction solution was adjusted to ensure a residence time of 140 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 organic layer was separated, and the aqueous layer was extracted with 150 mL of dichloromethane and combined with the organic layer. The organic phase was washed with 300 mL of saturated sodium bicarbonate solution and 300 mL of water, respectively, and then concentrated to dryness under reduced pressure. The obtained solid was purified by silica gel column chromatography to give 20.6 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, with a yield of 54.8%.

[0048] Example 2: Preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene

[0049] 30.0 g of the raw material 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was dissolved in 270 mL of 1,2-dichloroethane to prepare a reaction solution. 12.0 g of fuming nitric acid was slowly added to 48.0 g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 100°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 flow rate proportional to that of the reaction solution. After the reaction was completed, the same post-processing method as in Example 1 was used to obtain 23.3 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, with a yield of 62.0%.

[0050] Example 3: Preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene

[0051] 30.0 g of the raw material 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was dissolved in 300 mL of chloroform 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 75°C, and the flow rate of the reaction solution was adjusted to ensure a material residence time of 120 seconds. Simultaneously, the flow rate of the mixed acid was adjusted to ensure it was fed at a rate proportional to the reaction solution. Using the same post-processing method as in Example 1, 21.8 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was obtained, with a yield of 58.2%.

[0052] Example 4: Preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene

[0053] 30.0 g of the raw material 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was dissolved in 450 mL of chloroform to prepare a reaction solution. 12.5 g of fuming nitric acid was slowly added to 37.8 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 material residence time of 110 seconds. Simultaneously, the flow rate of the mixed acid was adjusted to ensure it was fed at a rate proportional to the reaction solution. Using the same post-processing method as in Example 1, 22.7 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was obtained, with a yield of 60.6%.

[0054] Example 5: Preparation method of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene

[0055] 30.0 g of the raw material 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was dissolved in 150 mL of chloroform to prepare a reaction solution. 12.0 g of fuming nitric acid was slowly added to 72.0 g of concentrated sulfuric acid to prepare a mixed acid solution. The reaction temperature was controlled at 75°C, and the flow rate of the reaction solution was adjusted to ensure a material residence time of 150 seconds. Simultaneously, the flow rate of the mixed acid was adjusted to ensure it was fed at a rate proportional to the reaction solution. Using the same post-processing method as in Example 1, 21.0 g of the product 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene was obtained, with a yield of 56%.

[0056] Example 6: Preparation of the compound shown in formula a07

[0057] 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 for 6 hours under a 1 atm H₂ atmosphere. 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%.

[0058] The compounds represented by formula a07 can be synthesized into eczema via methods known in the art, including but not limited to the methods disclosed in EP0495432B1.

[0059] 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. 1-Nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene, the method comprising the following steps: Preparation of reaction solution: Dissolve the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene in an organic 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. The organic solvent is one or more of dichloromethane, 1,2-dichloroethane, or chloroform, or a mixture thereof.

2. The method according to claim 1, wherein, The ratio of the volume of the organic solvent (in milliliters) to the weight (in grams) of the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 5 to 20:

1.

3. The method according to claim 1, wherein, The ratio of the volume of the organic solvent (in milliliters) to the weight (in grams) of the reaction substrate 3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is 8 to 15:

1.

4. The method according to claim 1, wherein, 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%.

5. The method according to claim 1, wherein, The nitric acid is nitric acid with a mass fraction of not less than 97%.

6. The method according to claim 1, wherein, 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 weight ratio of nitric acid to sulfuric acid is 1:1.5~10.

8. The method according to claim 1, wherein, The weight ratio of nitric acid to sulfuric acid is 1:2~6.

9. 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.

10. The method according to claim 1, wherein, The nitration reaction temperature is 25~120℃.

11. The method according to claim 1, wherein, The nitration reaction temperature is 30~100℃.

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 30 seconds to 180 seconds.

13. 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 50-150 seconds.

14. The method according to any one of claims 1 to 13 further includes, after the reaction is completed, introducing the reaction solution into water, separating the organic layer, concentrating it, and further purifying it by silica gel column chromatography or recrystallization to obtain a solid, namely 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene.

15. A method for preparing eczema, comprising the following steps: (1) 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene is prepared by the method according to any one of claims 1 to 14; (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, followed by hydrogenation reduction reaction to obtain the compound represented by formula a07: ； (3) The compound represented by formula a07 is converted into eczema.

16. The method according to claim 15, 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.

17. The method according to claim 15, wherein, In step (2), the molar ratio of 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene to nitrosoamyl ester to nitrosoamyl 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 nitrosoamyl ester is 1:1 to 1.

5.

18. The method according to claim 15, wherein the molar ratio of the base in step (2) to 1-nitro-3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthalene and nitrosoamyl ester is 1:1.2.

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