A process for the preparation of exatecan and intermediates thereof

Abstract

The application provides a preparation method of exatecan and intermediates thereof, in particular, the application provides a preparation method of a compound represented by formula a07, and a preparation method of exatecan comprising the method. The method provided by the application adopts a brand-new design route, starting materials are easier to obtain, and a reaction route is shorter, compared with the prior art, and the total yield is significantly improved. In addition, by adopting the method provided by the application, the compound represented by formula a07 is prepared, and reaction post-treatment can be simplified, after multiple reactions are completed, the crude product can be simply treated and then put into the next reaction.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical synthesis technology, and in particular relates to a method for preparing eczema and its intermediates. 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 function.

[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. Summary of the Invention

[0014] To address the aforementioned shortcomings in the existing technology, this invention provides a novel method for preparing compounds represented by formula a07 that balances reaction yield and is suitable for industrial-scale production.

[0015] Specifically, the present invention provides a method for preparing a compound represented by formula a07.

[0016]

[0017] The method includes the following steps:

[0018] The 2-bromo-6-fluorotoluene is reacted with 3-butenoic acid via the Heck reaction to convert it into compounds shown in formulas a01 and a02:

[0019]

[0020] The products a01 and a02 obtained by reacting 2-bromo-6-fluorotoluene with 3-butenoic acid are converted into the compound represented by formula a03 by hydrogenation reduction:

[0021]

[0022] The compound represented by formula a03 is converted into the compound represented by formula a04 via an intramolecular Friedel-Crafts reaction:

[0023]

[0024] Preferably,

[0025] The compound represented by formula a04 is converted into the compound represented by formula a05 through a nitration reaction:

[0026]

[0027] To convert the compound represented by formula a05 into the compound represented by formula a07:

[0028]

[0029] In the above method, preferably, the 2-bromo-6-fluorotoluene reacts with 3-butenoic acid via a Heck reaction to obtain a mixture of products a01 and a02. The two do not need to be separated and can be directly used in the next reduction reaction to convert them into a compound represented by formula a03.

[0030] Preferably, the mixture of compounds represented by formulas a01 and a02 is converted into a compound represented by formula a03 by Pd / C hydrogenation reduction. Preferably, the crude product obtained by the reaction, represented by formula a03, can be directly used for intramolecular Friedel-Crafts reaction to convert into a compound represented by formula a04 after simple filtration and concentration.

[0031] More preferably, the Heck reaction between 2-bromo-6-fluorotoluene and 3-butenoic acid is carried out in a solvent system containing tetra(triphenylphosphine)palladium and an organic base (e.g., diisopropylethylamine), preferably, the solvent being DMF, tetrahydrofuran, dichloromethane, etc.

[0032] More preferably, the molar ratio of 2-bromo-6-fluorotoluene to 3-butenoic acid in the Heck reaction is 0.8 to 1.2:1, the amount of tetrakis(triphenylphosphine)palladium is a catalyst, for example, the molar ratio of tetrakis(triphenylphosphine)palladium to 2-bromo-6-fluorotoluene is 1:50 to 55; and the molar ratio of the organic base (e.g., diisopropylethylamine) to 2-bromo-6-fluorotoluene is 1 to 2:1.

[0033] Furthermore, a mixture of a01 and a02 can be converted into a compound represented by formula a03 by palladium on carbon catalytic hydrogenation.

[0034] Furthermore, the compound represented by formula a03 is converted into the compound represented by formula a04 via an intramolecular Friedel-Crafts reaction. Preferably, the reaction is carried out in a system containing trifluoroacetic acid and trifluoroacetic anhydride. More preferably, the molar ratio of the compound represented by formula a03 to trifluoroacetic anhydride is 1:2 to 2.5, and the reaction temperature is controlled at no more than 10°C.

[0035] In the above method, the compound represented by formula a04 is converted into the compound represented by formula a05 through a nitration reaction. Preferably, in the nitration reaction, the molar ratio of the compound represented by formula a04 to fuming nitric acid is 0.8 to 1:1. Further, it is preferable to first dissolve the compound represented by formula a04 in concentrated sulfuric acid, prepare a mixed acid by mixing fuming nitric acid and concentrated sulfuric acid, and slowly add the mixed acid dropwise to the concentrated sulfuric acid solution of the compound represented by formula a04 at room temperature, and react at a temperature not exceeding 35°C.

[0036] Furthermore, in the reaction that converts the compound represented by formula a05 into the compound represented by formula a07, preferably, the compound represented by formula a05 is first mixed with isoamyl nitrite and a base and reacted, and then acetic acid, acetic anhydride, and Pt / C are added to carry out a hydrogenation reaction; preferably, the molar ratio of the compound represented by formula a05 to isoamyl nitrite is 1:1 to 1.5; wherein, the base is potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide, preferably potassium tert-butoxide, more preferably, the molar ratio of potassium tert-butoxide to the compound represented by formula a05 is 1:1 to 1.5, preferably 1:1.2.

[0037] In another aspect, the present invention provides a method for preparing a compound represented by formula a07, comprising:

[0038] The compound represented by formula a05,

[0039]

[0040] Transformed into the compound represented by formula a07

[0041]

[0042] Preferably, the method includes the following steps: reacting the compound represented by formula a05 with nitrosoamyl ester under alkaline conditions, then adding acetic acid and acetic anhydride, and then initiating a hydrogenation reduction reaction to obtain the compound represented by formula a07.

[0043] The alkali is potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide.

[0044] The hydrogenation reduction reaction is a reduction reaction carried out under H2 conditions with Pt / C as the catalyst.

[0045] Preferably, the molar ratio of the compound represented by formula a05 to isoamyl nitrite is 1:1 to 1.5; the molar ratio of the base to the compound represented by formula a05 is 1:1 to 1.5, preferably 1:1.2.

[0046] In another aspect, the present invention provides a method for preparing a compound represented by formula a05, wherein the compound represented by formula a05 is obtained by nitration of a compound represented by formula a04.

[0047]

[0048] Preferably, in the nitration reaction, the molar ratio of the compound represented by formula a04 to fuming nitric acid is 0.8 to 1:1.

[0049] Furthermore, the present invention also provides a method for preparing a compound represented by formula a04, wherein the compound represented by formula a04 is obtained by converting a compound represented by formula a03 through an intramolecular Friedel-Crafts reaction.

[0050]

[0051] Preferably, the Friedel-Crafts reaction is carried out in a system containing trifluoroacetic acid and trifluoroacetic anhydride; more preferably, the molar ratio of the compound represented by formula a03 to trifluoroacetic anhydride is 1:2 to 2.5, and the reaction temperature is controlled at no more than 10°C.

[0052] Furthermore, another aspect of the present invention provides a method for preparing a compound represented by formula a03, wherein the compound represented by formula a03 is obtained by a reduction reaction of a compound represented by formula a01 and / or a02.

[0053]

[0054] Furthermore, another aspect of the present invention provides a method for preparing compounds represented by formulas a01 and / or a02, wherein the compounds represented by formulas a01 and / or a02 are obtained by reacting 2-bromo-6-fluorotoluene with 3-butenoic acid. Preferably, the Heck reaction between 2-bromo-6-fluorotoluene and 3-butenoic acid is carried out in a solvent system containing tetrakis(triphenylphosphine)palladium and an organic base (e.g., diisopropylethylamine); more preferably, the solvent is DMF, tetrahydrofuran, dichloromethane, etc.

[0055] Furthermore, the molar ratio of 2-bromo-6-fluorotoluene to 3-butenoic acid in the Heck reaction is 0.8 to 1.2:1, the amount of tetra(triphenylphosphine)palladium is the catalyst amount, for example, the molar ratio of tetra(triphenylphosphine)palladium to 2-bromo-6-fluorotoluene is 1:50 to 55; the molar ratio of the organic base (e.g., diisopropylethylamine) to 2-bromo-6-fluorotoluene is 1 to 2:1.

[0056] In another aspect of the present invention, a method for preparing eczema is also provided, the method comprising the steps of preparing a compound represented by formula a07, and / or a05, and / or a04, and / or a03, and / or a02, and / or a01 using the method described above.

[0057] Methods for preparing eczema using compounds represented by formula a07 are disclosed in documents such as WO2019044946A1, WO1996026181A1, CN111065621A, and EP0495432B1, and the contents of these documents are incorporated herein by reference.

[0058] The method for preparing the compound represented by formula a07 provided by this invention has easier access to starting materials, a shorter reaction route, and a significantly improved overall yield compared with the prior art.

[0059] Furthermore, the method provided by this invention simplifies the post-reaction processing of compounds represented by formula a07. After multiple reactions, the crude product can be fed into the next reaction after only simple processing. For example, the mixture of formulas a01 and a02 obtained after the Heck reaction of 2-bromo-6-fluorotoluene and 3-butenoic acid does not need to be separated and can be directly used for hydrogenation reduction to prepare the compound represented by formula a03. After the hydrogenation reduction reaction, the compound represented by formula a03 can be directly used in the next reaction through a simple extraction operation.

[0060] 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. Attached Figure Description

[0061] Figure 1 The HPLC chromatogram of the compound represented by formula a07, prepared by the method provided in this invention, is shown below. The purity of the compound represented by formula a07 is 98.76%, and its peak data are shown in the table below:

[0062] Detector A 220nm

[0063] 1 16.497 27218 2441 -- 86593 0.442 2 17.358 1915 187 3.357 57991 0.031 3 18.399 3618 505 4.394 156764 0.059 4 18.890 1045 155 2.493 132703 0.017 3 21.305 6080602 883772 12.086 196299 98.758 6 21.982 1108 193 3.731 266889 0.018 7 22.940 3873 572 5.278 226050 0.063 8 24.662 16825 2435 8.919 260898 0.273 9 25.993 5140 731 6.786 272836 0.083 10 27.345 6525 820 6.263 221190 0.106 11 27.483 2120 351 0.332 33270 0.034 12 47.528 7101 262 29.918 66495 0.115 total 6157090 892424 100.000 . Detailed Implementation

[0064] 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.

[0065] Example 1: Preparation of compounds shown in formulas a01 and a02

[0066] 10.0 g of 2-bromo-6-fluorotoluene (52.9 mmol) and 5.5 g of 3-butenoic acid (63.5 mmol) were dissolved in 80 mL of LDM. The solution was degassed under reduced pressure and purged with nitrogen. Then, 1.2 g of tetrakis(triphenylphosphine)palladium (1.06 mmol) and 11.2 g of diisopropylethylamine (87.0 mmol) were added to the solution, and the mixture was purged with nitrogen again. The reaction mixture was stirred at 90 °C for 4 hours, and then the solvent was removed under vacuum. 150 mL of isopropyl acetate and 150 mL of 5% NaOH solution were added to the residue. The mixture was stirred at room temperature for 10 minutes, and then the aqueous phase was separated. The aqueous phase was adjusted to pH 3 with 10% hydrochloric acid solution and extracted twice with 100 mL of dichloromethane. The organic phases were combined and concentrated to dryness under reduced pressure to obtain a mixture of a01 and a02, 9.6 g (yield: 93%). The crude product was used directly in the next reaction.

[0067] Example 2: Preparation of the compound shown in formula a03

[0068] 9.6 g (49.4 mmol) of the crude product obtained in Example 1 was dissolved in 120 mL of THF, and 0.5 g of 10% Pd / C was added. The mixture was stirred vigorously at 40 °C and 1 atm H2 for 6 hours. The reaction solution was filtered to remove the catalyst, and the catalyst was washed with 30 mL of THF. The filtrates were combined and concentrated to dryness under reduced pressure to give 9.6 g of the target compound (yield: 99%). The crude product was used directly in the next reaction step.

[0069] Example 3: Preparation of the compound shown in formula a04

[0070] 9.6 g (48.9 mmol) of the crude compound represented by formula a03 was dissolved in 19 mL of trifluoroacetic acid and cooled to 5 °C. 20.5 g (97.8 mmol) of trifluoroacetic anhydride was slowly added dropwise while maintaining the reaction temperature ≤10 °C. After reacting at 5-10 °C for 1 hour, the temperature was gradually increased to room temperature and the reaction continued for another 4 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in 120 mL of ethyl acetate and washed three times with 30 mL of 5% NaHCO3 solution. The organic phase was then concentrated to dryness. The residue was purified by silica gel column chromatography to give 8.1 g of the target compound (yield: 93%).

[0071] Example 4: Preparation of the compound shown in formula a05

[0072] 8.1 g (45.5 mmol) of the compound represented by formula a04 was dissolved in 100 mL of concentrated sulfuric acid, and a mixed acid was prepared by dissolving 2.9 mL of fuming nitric acid (47.8 mmol) and 16 mL of concentrated sulfuric acid. The mixed acid was slowly added dropwise to the sulfuric acid solution of the compound represented by formula a04 at room temperature, with the reaction temperature controlled to ≤35 °C during the addition. After the addition was complete, the mixture was stirred at 35 °C for 1 hour. After the reaction was complete, the reaction mixture was poured into 1 kg of crushed ice and stirred for 30 minutes. The precipitated solid was collected by filtration. The solid was dried and purified by silica gel column chromatography to give 4.4 g of the compound represented by formula a05 (yield 43%).

[0073] Example 5: Preparation of the compound shown in formula a07

[0074] 5.0 g of the compound represented by formula a05 (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%, HPLC chromatogram as shown below. Figure 1 As shown.

[0075] 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 the compound represented by formula a07, The method includes the following steps: The 2-bromo-6-fluorotoluene is reacted with 3-butenoic acid via the Heck reaction to convert it into a mixture of compounds shown in formulas a01 and a02: ， ； A mixture of compounds represented by formulas a01 and a02 obtained by reacting 2-bromo-6-fluorotoluene with 3-butenoic acid is converted into a compound represented by formula a03 by hydrogenation reduction: ； The compound represented by formula a03 is converted into the compound represented by formula a04 via an intramolecular Friedel-Crafts reaction: ； The compound represented by formula a04 is converted into the compound represented by formula a05 through a nitration reaction: ； To convert the compound represented by formula a05 into the compound represented by formula a07: ； The process of converting the compound represented by formula a05 into the compound represented by formula a07 includes the following steps: The compound represented by formula a05 is reacted with nitrosoamyl ester under alkaline conditions, followed by the addition of acetic acid and acetic anhydride, and then a hydrogenation reduction reaction is initiated to obtain the compound represented by formula a07.

2. A method for preparing the compound represented by formula a07, comprising: The compound represented by formula a05, ， Transformed into the compound represented by formula a07 ， The process of converting the compound represented by formula a05 into the compound represented by formula a07 includes the following steps: The compound represented by formula a05 is reacted with nitrosoamyl ester under alkaline conditions, followed by the addition of acetic acid and acetic anhydride, and then a hydrogenation reduction reaction is initiated to obtain the compound represented by formula a07.

3. The method according to claim 1 or 2, wherein, The alkali is potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide.

4. The method according to claim 1 or 2, wherein, The hydrogenation reduction reaction is a reduction reaction carried out under H2 conditions with Pd / C as the catalyst.

5. The method according to claim 2, wherein, The compound represented by formula a05 is obtained by nitration of the compound represented by formula a04. 。 6. The method according to claim 5, wherein, The compound represented by formula a04 is obtained by converting the compound represented by formula a03 through an intramolecular Friedel-Crafts reaction: 。 7. The method according to claim 6, wherein, The compound represented by formula a03 is obtained by converting the compounds represented by formulas a01 and / or a02 through a hydrogenation reduction reaction: ， 。 8. The method according to claim 7, wherein, The compounds represented by formulas a01 and / or a02 are obtained by reacting 2-bromo-6-fluorotoluene with 3-butenoic acid.

9. A method for preparing eczema, the method comprising the step of preparing a compound represented by formula a07 using the method according to any one of claims 1 to 8.

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