A method for synthesizing deuterated fuquinline

Abstract

The application discloses a synthesis method of deuterated fuqiutini, and relates to the technical field of organic synthesis. The synthesis method of deuterated fuqiutini provided by the application creatively uses heterogeneous recoverable methyl reagent or deuterated methyl reagent in a synthesis process. The raw material conversion rate of the process is high, and a (deuterium)methylated catechol compound is obtained in almost quantitative yield. The reagent can be recovered, the production cost is greatly reduced, and the use of expensive and highly toxic deuterated iodomethane is avoided. Further reaction with a deuterated benzofuran compound can obtain multi-deuterated fuqiutini. The whole synthesis method is simple in process, few in steps, high in deuterium substitution rate, and high in atom utilization rate. The methyl reagent or deuterated methyl reagent can be recycled, and the method is a green synthesis method of deuterated fuqiutini and is suitable for large-scale industrial production of pharmaceutical enterprises.

Description

Technical Field

[0001] This invention relates to the field of technology, and more particularly to a method for synthesizing deuterated fruquintinib. Background Technology

[0002] Deuterium, an isotope of hydrogen, is commonly known as "heavy hydrogen." Studies have found that replacing one or more carbon-hydrogen bonds (CH) at specific metabolic sites on drug molecules with carbon-deuterium bonds (CD) can prolong drug metabolism, reduce the production of toxic metabolites and drug-drug interactions, thereby reducing dosage, improving safety, and achieving better efficacy. Since the FDA approved the first deuterium-labeled drug, bubenazine (structural formula 1), in 2017, the application of deuterium in medicinal chemistry has exploded. In 2021, the National Medical Products Administration approved donafenib (structural formula 2) for the treatment of hepatocellular carcinoma. Donafenib replaces the hydrogen atom of the methyl group on the pyridylmethylamine group of the sorafenib molecule with deuterium, thus optimizing metabolic performance.

[0003]

[0004] Fruquintinib (structural formula 3) was approved for marketing in China on September 5, 2018, for the treatment of metastatic colorectal cancer. Developed by Hutchison MediPharma, fruquintinib is a highly selective vascular endothelial growth factor receptor and is the first anticancer drug independently invented, researched by Chinese doctors, and developed by a Chinese company. Looking at the structures of the two marketed deuterated drugs, both achieve efficacy optimization by introducing deuterated methyl groups. Therefore, it is foreseeable that combining the "magic methyl" in medicinal chemistry with deuteration strategies can significantly improve efficacy. Pharmacokinetic studies have found that replacing the methyl groups on the oxygen and nitrogen atoms of fruquintinib with deuterated methyl groups (see structural formula 4) results in greater stability in hepatic microsomal enzymes and significantly better pharmacodynamic / pharmacokinetic properties. As an active pharmaceutical ingredient, it can improve drug efficacy and reduce drug toxicity.

[0005]

[0006] Currently, the commonly used heteroatom deuterium methylating agent is deuterated iodomethane; however, it is expensive, heavily reliant on imports, highly volatile, and relatively toxic, and has been classified as a Group 3 carcinogen by the International Agency for Research on Cancer (IARC) of the World Health Organization. These drawbacks pose challenges to the industrial-scale production of deuterated fruquintinib. Therefore, a simple, inexpensive, and universal synthetic route is urgently needed to achieve the large-scale production of deuterated fruquintinib. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a simple, inexpensive and universal method for synthesizing deuterated fruquintinib.

[0008] To address the above problems, the present invention proposes the following technical solution:

[0009] This invention provides a method for synthesizing deuterated fruquintinib, comprising the following steps:

[0010] S1. Catechol compound 1 was reacted with an excess of heterogeneous polythiamyl methyl reagent under the action of an inorganic base. After the reaction was completed, the mixture was filtered, the filtrate was collected, and the solvent was evaporated by rotary evaporation to obtain compound 3.

[0011] S2. Compound 3 is subjected to amination, cyclization, and chlorination to obtain compound 6;

[0012] S3. The compound 6 and the deuterated benzofuran compound 7' are reacted in a molar ratio of 1:1 under the action of alkali. After the reaction is completed, the solid phase is collected by solid-liquid separation to obtain deuterated fruquintinib.

[0013] Wherein, the structural formula of the heterogeneous polythiamethylene methyl reagent is (1) or (2), where n is 200-300;

[0014] The structural formula of the deuterated benzofuran compound 7' is (3);

[0015]

[0016] A further technical solution is that the synthesis method further includes:

[0017] When catechol compound 1 reacts with heterogeneous polythiamyl methyl reagent of structural formula (2) in step S1, compound 6 in step S3 reacts with benzofuran compound 7 under the action of alkali to obtain hexadeuterated fruquintinib, structural formula (4); the structural formula of benzofuran compound 7 is (5).

[0018]

[0019] The further technical solution is that the deuterated fruquintinib is a trideuterated fruquintinib, structural formula (6); or a nonadeuterated fruquintinib, structural formula (7);

[0020]

[0021] A further technical solution is that the molar ratio of the catechol compound 1 to the inorganic base is 1:1-4.

[0022] A further technical solution is that the inorganic base is selected from one or more combinations of alkali metal carbonates, alkali metal hydrides, alkali metal hydroxides, or alkali metal acetates.

[0023] A further technical solution is that the inorganic base is selected from one or more combinations of potassium hydroxide, sodium hydroxide, sodium hydrogen hydride, potassium carbonate, sodium carbonate, sodium acetate, and potassium acetate.

[0024] A further technical solution is that, in step S1, the filter cake obtained by filtration after the reaction is completed is mainly polythiane (TT Polymer), which can be recovered after washing and used to prepare heterogeneous polythiane methyl reagent.

[0025] A further technical solution is that the filter cake is washed with water and then washed with organic solvent to obtain polythiane. Polythiane is then reacted with methanol or deuterated methanol to prepare heterogeneous polythiane methyl reagents with structural formulas (1) or (2).

[0026] A further technical solution is that, in step S3, the molar ratio of compound 6 to the base is 1:1-4; the base is an alkali metal alkoxide, alkali metal carbonate, alkali metal hydride, alkali metal hydroxide, or alkali metal acetate.

[0027] A further technical solution is that the alkali is one or more combinations of potassium tert-butoxide, sodium tert-butoxide, potassium ethoxide, sodium ethoxide, potassium methoxide, sodium methoxide, potassium hydroxide, sodium hydroxide, sodium hydrogen hydride, potassium carbonate, sodium carbonate, sodium acetate, and potassium acetate.

[0028] A further technical solution is that the reactions in steps S1 and S3 further include a solvent, which is selected from one or more of the following: ethanol, methanol, cyclohexane, n-hexane, n-pentane, n-heptane, petroleum ether, diethyl ether, tetrahydrofuran, dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

[0029] A further technical solution is that the amount of solvent used is the amount of solvent required for the reaction.

[0030] A further technical solution is that the reaction in step S1 is carried out at room temperature.

[0031] In some embodiments, room temperature is defined as 0-50°C.

[0032] In some embodiments, room temperature is defined as 20-40°C.

[0033] In some embodiments, room temperature means 25-35°C.

[0034] A further technical solution is that the reaction time of step S1 is more than 8 hours, such as 12 hours, 24 hours, 36 hours, 40 hours, 72 hours, etc.; the reaction is judged to be completed by TLC detection to determine whether the raw materials have reacted completely.

[0035] Compared with the prior art, the technical effects achieved by the present invention include:

[0036] The present invention provides a method for synthesizing deuterated fruquintinib that innovatively utilizes heterogeneous recyclable methyl or deuterated methyl reagents during the synthesis process. This process boasts high raw material conversion rates and recyclable reagents, significantly reducing production costs and avoiding the use of expensive and highly toxic deuterated iodomethane. Further reaction with deuterated benzofuran compounds yields multi-deuterated fruquintinib. The entire synthesis method is simple, involves few steps, has a high deuteration rate, and allows for the recycling of methyl or deuterated methyl reagents, resulting in high atom utilization. It is a green synthesis method for deuterated fruquintinib, suitable for large-scale industrial production in pharmaceutical companies. Attached Figure Description

[0037] Figure 1 The 1H NMR spectrum of the hexadeuterated fruquintinib synthesized in Example 5 of this invention;

[0038] Figure 2 The carbon NMR spectrum of the hexadeuterated fruquintinib synthesized in Example 5 of this invention;

[0039] Figure 3 The 1H NMR spectrum of the nonadeuterated fruquintinib synthesized in Example 4 of this invention;

[0040] Figure 4 The image shows the carbon NMR spectrum of the nine-deuterated fruquintinib synthesized in Example 4 of this invention. Detailed Implementation

[0041] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the embodiments described below are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0042] It should be understood that, when used in this specification and the appended claims, the terms "comprising" and "including" indicate the presence of the described features, integrals, steps, or operations, but do not exclude the presence or addition of one or more other features, integrals, steps, operations, and / or a collection thereof.

[0043] It should also be understood that the terminology used in this specification of embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to limit the embodiments of the invention. As used in this specification of embodiments of the invention and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms unless the context clearly indicates otherwise.

[0044] The term “room temperature” means 0-50°C; in some embodiments, room temperature means 20-40°C, and in some embodiments, room temperature means 25-35°C.

[0045] The amount of solvent required for the reaction as described in this invention is preferably sufficient to completely dissolve the reactants, and can be adapted to different reactants. In some embodiments, the amount of solvent required for the reaction may also be adapted to be more than the amount required to just dissolve the reactants.

[0046] General Synthesis Process

[0047] Generally, the compounds of the present invention can be prepared by the methods described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0048] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0049] In the examples described below, all temperatures are in degrees Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0050] The solvents used in this invention, such as ethanol, methanol, cyclohexane, n-hexane, n-pentane, n-heptane, petroleum ether, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile, are all dried beforehand using drying methods suitable for use in the art.

[0051] In this invention, thin-layer chromatography (TLC) involves coating a suitable stationary phase onto a glass plate, plastic, or aluminum substrate to form a uniform thin layer. After spotting and development, the ratio shift value (Rf) is compared with the ratio shift value (Rf) of the chromatogram obtained by the same method for a suitable reference substance. This method is used for drug identification, impurity detection, or content determination. Thin-layer chromatography is an important experimental technique for the rapid separation and qualitative analysis of small amounts of substances, and it is also used to track reaction progress.

[0052] Example 1: Methylation of catechol compounds

[0053] The reaction process is as follows:

[0054]

[0055] The specific procedure is as follows: dissolve catechol compound 1 (168 mg, 1.0 mmol) in 10 ml of acetonitrile solution, add heterogeneous polythiamethylene reagent 2 (3000 mg) and potassium carbonate (280 mg, 2.0 mmol), stir at room temperature for 24 hours, and TLC detect that the starting material has reacted completely. After the reaction is completed, filter, collect the filtrate and concentrate to obtain compound 3 (194 mg, yield 99%).

[0056] The solid filter cake was successively washed with water, then with an organic solvent, and finally dried to obtain polythiamethylene (TT Polymer) (2800 mg), with a recovery rate greater than 93%. The polythiamethylene can be recycled with methanol to prepare heterogeneous polythiamethylene methyl reagent 2.

[0057] Example 2: Deuterylation of catechol compounds

[0058] The reaction process is as follows:

[0059]

[0060] The specific procedure is as follows: dissolve catechol compound 1 (168 mg, 1.0 mmol) in 10 ml of acetonitrile solution, add heterogeneous polythiamane deuterium methyl reagent 2' (3000 mg) and potassium carbonate (280 mg, 2.0 mmol), stir at room temperature for 24 hours, and TLC detect that the starting material has reacted completely. After the reaction is completed, filter, collect the filtrate and concentrate to obtain compound 3' (200 mg, yield 99%).

[0061] The solid filter cake was successively washed with water, then with an organic solvent, and finally dried to obtain polythiamethylene (TT Polymer) (2800 mg), with a recovery rate of 93%. The polythiamethylene can be recycled by reacting it with deuterated methanol to prepare heterogeneous polythiamethylene deuterated methyl reagent 2'.

[0062] Example 3: Synthesis of Trideuterated Fruquintinib

[0063] The reaction process is as follows:

[0064]

[0065] The specific procedure was as follows: Compound 3 was subjected to amination, cyclization, and chlorination to obtain quinazoline 6. Compound 6 (230 mg, 1.0 mmol) and acetonitrile (3 mL) were added to a reaction flask, followed by deuterated benzofuran compound 7' (208 mg, 1.0 mmol) and potassium carbonate (210 mg, 1.5 mmol). The reaction system was mixed and stirred, heated to 85 °C and refluxed for 10 hours. The mixture was concentrated and evaporated to dryness. The product was washed successively with water, ethanol, and petroleum ether to obtain the target product, hexadeuterated fruquintinib 8 (345 mg, yield 87%).

[0066] The NMR data are as follows: 1 HNMR(600MHz,(CD3)2SO)δ2.68(s,3H),4.02(s,3H,CH3),4.03(s,3H,CH3),7.29(dd,J=2.0,8.5Hz,1H),7.4 3(s,1H),7.62(s,1H),7.66(d,J=2.0Hz,1H),7.84(d,J=8.5Hz,1H),8.01(q,J=4.5Hz,1H),8.56(s,1H)ppm; 13 C NMR (150MHz, (CD3)2SO): δ13.7,56.0,56.2,100.7,105.6,106.7,109.7,112.6,118.0,120.7,1 23.6,148.9,149.4,150.1,152.2,152.9,155.8,158.3,163.2,165.1ppm.MS(m / e): 397.1(M+1).

[0067] Example 4: Synthesis of nine-deuterated fruquintinib

[0068] The reaction process is as follows:

[0069]

[0070] The specific procedure was as follows: Compound 3' was subjected to amination, cyclization, and chlorination to obtain quinazoline 6'. Compound 6' (230 mg, 1.0 mmol) and acetonitrile (3 mL) were added to a reaction flask, followed by deuterated benzofuran compound 7' (208 mg, 1.0 mmol) and potassium carbonate (210 mg, 1.5 mmol). The reaction system was mixed and stirred, heated to 85°C, and refluxed for 10 hours. The mixture was concentrated and evaporated to dryness. The product was washed successively with water, ethanol, and petroleum ether to obtain the target product, nonadeuterated fruquintinib 9 (342 mg, yield 85%). Structural characterization is shown in [link to structural characterization]. Figure 3and Figure 4 .

[0071] The NMR data are as follows: 1 H NMR(600MHz,(CD3)2SO)δ2.64(s,3H),7.25(dd,J=2.1,8.5Hz,1H),7.38(s,1H),7.5 8(s,1H),7.62(d,J=2.1Hz,1H),7.80(d,J=8.5Hz,1H),7.94(s,1H),8.52(s,1H)ppm; 13 C NMR (150MHz, (CD3)2SO): δ13.7,25.4,55.3,100.7,105.6,106.7,109.7,112.7,118.0,120.7,1 23.6,148.9,149.4,150.1,152.2,152.9,155.8,158.3,163.2,165.1ppm.MS(m / e): 403.1(M+1).

[0072] Example 5: Synthesis of Hexadeuterated Fruquintinib

[0073] The reaction process is as follows:

[0074]

[0075] The specific procedure was as follows: Compound 3' was subjected to amination, cyclization, and chlorination to obtain quinazoline 6'. Compound 6' (230 mg, 1.0 mmol) and acetonitrile (3 mL) were added to a reaction flask, followed by benzofuran compound 7 (208 mg, 1.0 mmol) and potassium carbonate (210 mg, 1.5 mmol). The reaction system was mixed and stirred, heated to 85 °C, and refluxed for 10 hours. The mixture was concentrated and evaporated to dryness. The product was washed successively with water, ethanol, and petroleum ether to obtain the target product, hexadeuterated fruquintinib 10 (355 mg, yield 89%). Structural characterization is shown in [link to structural characterization]. Figure 1 and Figure 2 .

[0076] The NMR data are as follows: 1 HNMR(600MHz, (CD3)2SO) δ2.68(s,3H),2.87(d,J=4.6Hz,3H),7.29(dd,J=2.1,8.5Hz,1H),7.42(s,1 H),7.62(s,1H),7.66(d,J=2.1Hz,1H),7.84(d,J=8.5Hz,1H),8.01(q,J=4.5Hz,1H),8.56(s,1H)ppm; 13C NMR (150MHz, (CD3)2SO): δ13.7,26.1,100.7,105.6,106.7,109.7,112.6,118.0,120.7,123. 6,148.9,149.4,150.1,152.2,152.9,155.8,158.3,163.2,165.1ppm.MS(m / e): 400.1(M+1).

[0077] In summary, the synthetic method for deuterated fruquintinib provided by this invention innovatively utilizes heterogeneous recyclable methyl or deuterated methyl reagents during the methylation synthesis process. This process boasts a high raw material conversion rate, yielding (deuterated)methylated catechol compounds in near-quantitative yield. The reagents are recyclable, significantly reducing production costs and avoiding the use of expensive and highly toxic deuterated iodomethane. Further reaction with (deuterated)benzofuran compounds yields multi-deuterated fruquintinib. The entire synthetic method is simple, involves few steps, achieves a high deuteration rate, allows for the recycling of methyl or deuterated methyl reagents, and has high atom utilization. It represents a green synthetic method for deuterated fruquintinib, suitable for large-scale industrial production in pharmaceutical companies.

[0078] In the above embodiments, the descriptions of each embodiment have different focuses. For parts that are not described in detail in a certain embodiment, please refer to the relevant descriptions in other embodiments.

[0079] The above description describes specific embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in the present invention, and these modifications or substitutions should all be covered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for synthesizing deuterated fruquintinib, characterized in that, Includes the following steps: S1. Catechol compound 1 is reacted with an excess of heterogeneous polythiamyl methyl reagent under the action of an inorganic base. After the reaction is completed, the mixture is filtered, the filtrate is collected, and the solvent is evaporated by rotary evaporation to obtain compound 3 or compound 3'. S2. Compound 3 or compound 3' is subjected to amination, cyclization, and chlorination to obtain compound 6 or compound 6', respectively. S3. The compound 6 or compound 6' is reacted with deuterated benzofuran compound 7' or benzofuran compound 7 in a molar ratio of 1:1 under the action of alkali. After the reaction is completed, the solid phase is collected by solid-liquid separation to obtain deuterated fruquintinib. The structural formula of the catechol compound 1 is (I). （I）； The structural formula of the heterogeneous polythiane methyl reagent is (1) or (2), where n is 200-300; （1）； （2）； When the polythiamyl reagent of the structure (1) is used in step S1, the reaction yields compound 3, and in step S2, compound 6 is obtained. In step S3, compound 6 reacts with deuterated benzofuran compound 7' of the structure (3) to obtain trideuterated fruquintinib of the structure (6). （3）； （6）； When the polythiane deuterated methyl reagent of the structure (2) is used in step S1, the reaction yields compound 3', and in step S2, compound 6' is obtained. In step S3, compound 6' reacts with deuterated benzofuran compound 7' of the structure (3) to obtain nonadeuterated fruquintinib of the structure (7). （7）； When the polythiane deuterated methyl reagent of the structure (2) is used in step S1, the reaction yields compound 3', and in step S2, compound 6' is obtained. In step S3, compound 6' reacts with benzofuran compound 7 of the structure (5) to obtain hexadeuterated fruquintinib of the structure (4). （4）； （5）； In step S1, the inorganic base is potassium carbonate; in step S3, the base is potassium carbonate; the reactions in steps S1 and S3 also include a solvent, which is acetonitrile.

2. The method for synthesizing deuterated fruquintinib as described in claim 1, characterized in that, The molar ratio of the catechol compound 1 to the inorganic base is 1:1-4.

3. The method for synthesizing deuterated fruquintinib as described in claim 1 or 2, characterized in that, In step S3, the molar ratio of compound 6 to the base is 1:1-4.

4. The method for synthesizing deuterated fruquintinib as described in claim 1, characterized in that, In step S1, the filter cake obtained by filtration after the reaction is completed is polythiane, which can be recovered after washing and used to prepare heterogeneous polythiane methyl reagent.

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