A method for the photocatalytic CH activation synthesis of GW 610 or its deuterated product.

Abstract

The application discloses a kind of GW 610 or its deuterated products and its photocatalytic C-H activation synthesis method, comprising the following steps: 5-fluorobenzo [d] thiazole, thianthrenium salt, catalyst, additive and organic solvent are mixed, in inert atmosphere, under the irradiation of light source, reaction is prepared GW 610 or its deuterated compound;The catalyst includes metal copper catalyst and semiconductor photocatalyst, and the mass ratio of metal copper catalyst and semiconductor photocatalyst is 1:1~5;The additive is tBuOLi, Cs2CO3, tBuOK, tBuONa or K2CO3.The purpose is to solve the problems existing in the synthesis of deuterated phenolic drug synthesis, such as high energy consumption, low yield, multi-step reaction and resource waste.

Description

Technical Field

[0001] This invention relates to the field of preparation of anticancer drug molecule GW 610 and deuterated chemicals, specifically to a method for the photocatalytic CH activation synthesis of GW 610 or its deuterated product. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] Aromatic heterocycles are common structural motifs in many bioactive natural products and drugs. Among them, 2-(3,4-dimethoxyphenyl)-5-fluorobenzo[d]thiazole (GW 610, NSC 721648) is an antitumor agent that has shown effective and selective anticancer activity against lung cancer, colon cancer, and breast cancer cell lines. Most drugs undergo cytochrome P450 (CYP)-mediated oxidative metabolism. Replacing the CH bond of a drug molecule with a more stable CD bond can improve its pharmacokinetics or toxicity characteristics. The most significant deuteration effect is seen in the oxygen-linked CD3 group, followed by the nitrogen-linked group. The world's first deuterated drug approved by the US FDA, deutetrabenazine, is a vesicular monoamine transporter 2 inhibitor used to treat chorea associated with Huntington's disease and tardive dyskinesia. Structurally, deutetrabenazine is a deuterium isotope of tetrabenazine. The introduction of deuterium prolongs the half-life of deutetrabenazine, thereby reducing the frequency of administration.

[0004] GW 610 shares some structural similarities with bubenazine. Deuterylation of GW 610 with a methoxy group to synthesize d6-GW 610 holds promise for improving its pharmacokinetics. This could potentially avoid or reduce certain unfavorable or harmful metabolic pathways in vivo, thereby increasing or retaining certain beneficial or effective metabolites. This would enhance or prolong the drug's mechanism of action and target effect, while simultaneously reducing adverse reactions and interactions caused by metabolites.

[0005] Currently, the most direct synthetic method for aryl heterocycles is the CH activation of the heterocyclic molecule. Some methods involve the reaction of copper-catalyzed CH activation of the heterocyclic molecule with iodobenzene molecules to synthesize aryl heterocyclic compounds. However, the stringent conditions and high temperatures of this reaction limit its application (J Am Chem Soc, 129(2007), pp. 12404-12405). In addition, the homogeneous photocatalyst Ir(ppy)3 reacts with CuI under visible light to yield coupling products, but the yield is relatively low, typically around 50%.

[0006] Another approach involves induced cyclization via a nucleophilic reaction at the amino group adjacent to the bromine atom on the benzothiazole ring. The starting material, 2-bromo-5-fluoroaniline, reacts with 3,4-dimethoxybenzoyl chloride to generate benzisoxazole, which is then converted to the corresponding thiabenzisoxazole. Regioselective cyclization using sodium hydride in hot NMP yields the desired 5-bromobenzothiazole. However, this synthetic method is complex and involves multiple steps. Developing an efficient, convenient, and economical method for synthesizing d6-GW 610 is urgently needed. Summary of the Invention

[0007] To address the technical problems existing in the prior art, this invention proposes a method for the photocatalytic CH activation synthesis of GW 610 or its deuterated products, aiming to solve the problems of high energy consumption, low yield, multiple reaction steps, and resource waste in the synthesis of deuterated phenolic drugs.

[0008] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0009] In a first aspect, the present invention provides a photocatalytic CH activation synthesis method for GW 610 or its deuterated product, comprising the following steps:

[0010] 5-fluorobenzo[d]thiazole, thiaanthraium salt, catalyst, additive (the additive is used to promote the activation of the CH bond of the thiazole ring), and organic solvent are mixed and reacted under an inert atmosphere and a light source to prepare GW 610 or its deuterated compound.

[0011] The catalyst includes a copper catalyst and a semiconductor photocatalyst, wherein the mass ratio of the copper catalyst to the semiconductor photocatalyst is 1:1 to 5.

[0012] The additive is tBuOLi, Cs2CO3, tBuOK, tBuONa or K2CO3.

[0013] This invention realizes deuterated GW 610 anticancer drug molecules based on organic semiconductors and metal catalysts, such as... Figure 5 As shown, the reaction mechanism is as follows: Under light irradiation, the semiconductor photocatalyst undergoes charge separation to generate redox centers, which reduce thiaanthraium salt with a single electron and then cleave it to generate aryl radicals; the additive inorganic base removes hydrogen from 5-fluorobenzo[d]thiazole to form a carbanion and reacts with Cu. Ⅰ The formation of complex intermediate A allows the holes generated by the semiconductor photocatalyst to oxidize Cu. Ⅰ Cu Ⅱ The process generates an important intermediate B, which captures the aryl radical formed by the thiaanthraium salt to yield a stable intermediate C. Finally, C undergoes reductive elimination to give the final product 2, completing the copper ion cycle.

[0014] In some embodiments, the mass ratio of 5-fluorobenzo[d]thiazole, thiaanthraium salt, catalyst, additive and organic solvent is 35-45:150-250:20-40:60-80:3500-4500.

[0015] In some embodiments, the organic solvent is dimethylacetamide, acetonitrile, or dimethylformamide.

[0016] In some embodiments, the copper catalyst is one or more of CuI, CuBr2, Cu(dap)2Cl, CuOAc, or CuBr.

[0017] In some embodiments, the semiconductor photocatalyst is one or more of TiO2, ZnO, ZnS, CdS, CdSe, ZnCdS, or carbon nitride (PCN) and a mixture thereof.

[0018] In some embodiments, the structural formula of the thiaanthraium salt is:

[0019] X is -CH3 or -CD3; Y is -CH3 or -CD3.

[0020] The corresponding reaction equations are shown below:

[0021]

[0022] In some embodiments, the wavelength of the light source is 200-2000 nm.

[0023] Preferably, the wavelength of the light source is 400-450nm, and more preferably 420nm.

[0024] In some embodiments, the reaction temperature is 20-80°C and the reaction time is 5-12 hours.

[0025] Secondly, the present invention provides GW 610 or its deuterated product, prepared by the aforementioned preparation method.

[0026] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:

[0027] This invention uses the drug precursor 5-fluorobenzo[d]thiazole as a raw material and a more reactive thiaanthraium salt as a deuterium source. Under the synergistic action of a photocatalyst and a metal catalyst, 5-fluorobenzo[d]thiazole undergoes hydrocarbon activation at room temperature and pressure, followed by a coupling reaction with the thiaanthraium salt, thereby preparing GW 610 and deuterated GW 610 drug molecules. This invention features mild reaction conditions, high reaction efficiency, high deuteration rate, and high yield. Furthermore, it avoids the use of highly toxic and hazardous reagents, reducing pollution and waste, lowering costs, and making it suitable for industrial production. Attached Figure Description

[0028] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0029] Figure 1 The hydrogen nuclear magnetic resonance spectrum of GW 610 in Example 1 of this invention;

[0030] Figure 2 The image shows the carbon NMR spectrum of GW 610 in Example 1 of this invention;

[0031] Figure 3 The hydrogen nuclear magnetic resonance spectrum of d6-GW 610 in Example 2 of this invention;

[0032] Figure 4 The carbon NMR spectrum of d6-GW 610 in Example 2 of this invention;

[0033] Figure 5 This is a schematic diagram illustrating the synthesis mechanism of GW 610 and its deuterated products according to the present invention. Detailed Implementation

[0034] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0035] To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of the invention.

[0036] The present invention will be described in detail below through embodiments.

[0037] Example 1

[0038] The synthesis method of GW 610 is as follows:

[0039]

[0040] Thianthracene 5-oxide (1.16 g, 5 mmol), o-phenylene ether (0.69 g, 5 mmol), and 20 mL MeCN were placed in a 100 mL round-bottom flask. The system temperature was lowered to 0 °C, and trifluoromethanesulfonic anhydride (1.0 mL, 7.5 mmol) and HBF4 OEt2 (1.8 g, 5.5 mmol) were added under stirring. After stirring at 0 °C for 2 h, the system temperature was restored to room temperature and stirring was continued for 2 h. The reaction was terminated by adding 30 mL of water, and 100 mL of dichloromethane was added for extraction. The organic phase was dried over NaSO4 and concentrated to 5 mL. Diethyl ether was added to precipitate the product, which was then filtered and dried to obtain thiaracene 5-oxide product 4 (1.6 g, 73%).

[0041] 0.3 mmol (46 mg) of 5-fluorobenzo[d]thiazole 3, 200 mg of thiaanthraquinone salt 4, 11.0 mg of CuI, 20 mg of PCN photocatalyst, and 67 mg of tBuOLi were weighed and added to a 10 mL reaction flask. 4 mL of anhydrous acetonitrile was added, and the reaction system was purged under argon protection. The flask was then placed under a 420 nm light source for 12 hours. After the reaction, the light source was removed, and the reaction mixture was filtered through a diatomaceous earth filter. The mixture was then extracted with 5.0 mL of CH2Cl2, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless liquid. The solvent was removed by rotary evaporation, and the purified target product was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). 1 HNMR, 13 The structure was determined by tests such as C-NMR, such as Figure 1 and Figure 2 As shown.

[0042] 1 H NMR(500MHz,Chloroform-d)δ7.77(dd,J=8.7,5.1Hz,1H),7.73–7.66(m,2H),7.57(dd,J=8.3 ,2.1Hz,1H),7.12(td,J=8.8,2.5Hz,1H),6.93(d,J=8.4Hz,1H),4.02(s,3H),3.95(s,3H).13C NMR (126MHz, CDCl3) δ 170.39, 162.91, 160.98, 155.13, 155.03, 151.82, 149.38, 130.26, 126.41, 122.14, 122.06, 121.19, 113.53, 113.34, 111.03, 109.73, 109.11, 108.92, 56.14, 56.06. Yield 89%.

[0043] Example 2

[0044] The synthesis method of d6-GW 610 is as follows:

[0045]

[0046] Thianthracene 5-oxide (1.16 g, 5 mmol), d6-phthalic acid dimethyl ether (0.69 g, 5 mmol), and 20 mL of MeCN were placed in a 100 mL round-bottom flask. The system temperature was lowered to 0 °C, and trifluoromethanesulfonic anhydride (1.0 mL, 7.5 mmol) and HBF4OEt2 (1.8 g, 5.5 mmol) were added under stirring. After stirring at 0 °C for 2 h, the system temperature was restored to room temperature and stirring was continued for 2 h. The reaction was terminated by adding 30 mL of water, and 100 mL of dichloromethane was added for extraction. The organic phase was dried over NaSO4 and concentrated to 5 mL. Diethyl ether was added to precipitate the product, which was then filtered and dried to obtain thiaracene 5-oxide product (1.8 g, 80%).

[0047] 0.3 mmol (46 mg) of 5-fluorobenzo[d]thiazole 2, 200 mg of thiaanthraquinone salt 5, 11.0 mg of CuI, 20 mg of PCN photocatalyst, and 67 mg of tBuONa were weighed and added to a 10 mL reaction flask. 4 mL of anhydrous acetonitrile was added, and the reaction system was purged under argon protection. The flask was then placed under a 420 nm light source for 12 hours. After the reaction, the light source was removed, and the reaction mixture was filtered through a diatomaceous earth filter. The mixture was then extracted with 5.0 mL of CH2Cl2, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless liquid. The solvent was removed by rotary evaporation, and the purified target product was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). 1 HNMR, 13 The structure was determined by tests such as C-NMR, such as Figure 3 and Figure 4 As shown.

[0048] 1 H NMR (600MHz, Chloroform-d) δ7.80 (dd, J=8.3, 2.0Hz, 1H), 7.69 (d, J=2.0Hz, 1H), 7. 42(ddd,J=28.5,8.6,3.4Hz,2H), 7.03(td,J=9.0,2.6Hz,1H), 6.95(d,J=8.4Hz,1H). 13C NMR (151MHz, CDCl3) δ 164.84, 160.89, 159.30, 152.20, 149.22, 146.98, 143.09, 143.01, 121.28, 119.35, 112.20, 112.03, 110.97, 110.51, 109.97, 106.74, 106.11, 105.94. Yield 92%, deuteration rate 99%.

[0049] Example 3

[0050] The synthesis method of d6-GW 610 is as follows:

[0051]

[0052] Thianthracene 5-oxide (1.16 g, 5 mmol), d6-phthalic acid dimethyl ether (0.69 g, 5 mmol), and 20 mL of MeCN were placed in a 100 mL round-bottom flask. The system temperature was lowered to 0 °C, and trifluoromethanesulfonic anhydride (1.0 mL, 7.5 mmol) and HBF4OEt2 (1.8 g, 5.5 mmol) were added under stirring. After stirring at 0 °C for 2 h, the system temperature was restored to room temperature and stirring was continued for 2 h. The reaction was terminated by adding 30 mL of water, and 100 mL of dichloromethane was added for extraction. The organic phase was dried over NaSO4 and concentrated to 5 mL. Diethyl ether was added to precipitate the product, which was then filtered and dried to obtain thiaracene 5-oxide product (1.8 g, 80%).

[0053] 0.3 mmol of 5-fluorobenzo[d]thiazole 2, 200 mg of thiaanthranzium salt 5, 11.0 mg of CuI, 20 mg of TiO2 photocatalyst, and 67 mg of tBuOK were weighed and added to a 10 mL reaction flask. 4 mL of anhydrous acetonitrile was added, and the reaction system was purged under argon protection. The flask was then placed under a 420 nm light source for 12 hours. After the reaction, the light source was removed, and the reaction mixture was filtered through a diatomaceous earth filter. The mixture was then extracted with 5.0 mL of CH2Cl2, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless liquid. The solvent was removed by rotary evaporation, and the purified target product was obtained by column chromatography (eluent: petroleum ether / ethyl acetate). 1 HNMR, 13 The structure was confirmed by C-NMR and other tests, with a yield of 92% and a deuteration rate of 99%.

[0054] Example 4

[0055] The difference from Example 3 is that the light source wavelength is 450 nm; otherwise, they are the same as in Example 3. The yield of the prepared d6-GW610 was 78%, and the deuteration rate was 99%.

[0056] Example 5

[0057] The difference from Example 3 is that the light source wavelength is 400 nm; all other aspects are the same as in Example 3. The yield of the prepared d6-GW610 was 72%, and the deuteration rate was 99%.

[0058] Example 6

[0059] The difference from Example 3 is that the light source wavelength is 350 nm; otherwise, they are the same as in Example 3. The yield of the prepared d6-GW610 was 68%, and the deuteration rate was 99%.

[0060] Example 7

[0061] The difference from Example 3 is that the light source wavelength is 500 nm; all other aspects are the same as in Example 3. The yield of the prepared d6-GW610 was 52%, and the deuteration rate was 99%.

[0062] Comparative Example 1

[0063] The difference from Example 3 is that the addition of 67 mg tBuOK was omitted; otherwise, it was the same as Example 3. The yield of the prepared d6-GW 610 was 12%, and the deuteration rate was 99%.

[0064] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for photocatalytic CH activation to synthesize GW 610 or its deuterated product, characterized in that: Includes the following steps: GW 610 or its deuterated compound was prepared by mixing 5-fluorobenzo[d]thiazole, thiaanthraium salt, catalyst, additive and organic solvent and reacting them under an inert atmosphere and light source irradiation. The catalyst includes a copper catalyst and a semiconductor photocatalyst, wherein the mass ratio of the copper catalyst to the semiconductor photocatalyst is 1:1 to 5. The additive is tBuOLi, tBuOK, or tBuONa; The organic solvent is dimethylacetamide, acetonitrile, or dimethylformamide; The copper catalyst is one or more of CuI, Cu(dap)2Cl, and CuBr; The semiconductor photocatalyst is one or a mixture of TiO2 or carbon nitride; The structural formula of the thiaanthracin salt is: X is -CH3 or -CD3; Y is -CH3 or -CD3; The wavelength of the light source is 400-450nm; The reaction temperature is 20-80℃.

2. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 1, characterized in that: The mass ratio of 5-fluorobenzo[d]thiazole, thiaanthraium salt, catalyst, additive and organic solvent is 35-45:150-250:20-40:60-80:3500-4500.

3. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 1, characterized in that: The wavelength of the light source is 420nm.

4. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 1, characterized in that: The reaction time is 5-12 hours.

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