GW 610 or deuterated product thereof and photocatalytic C-H activation synthesis method of GW 610 or deuterated product thereof

Abstract

The invention discloses GW 610 or a deuterated product thereof and a photocatalytic C-H activation synthesis method of the GW 610 or the deuterated product thereof, and the method comprises the following steps: mixing 5-fluorobenzo [d] thiazole, thianthrene onium salt, a catalyst, an additive and an organic solvent, and reacting in an inert atmosphere under the irradiation of a light source to prepare the GW 610 or the deuterated product thereof; the catalyst comprises a metal copper catalyst and a semiconductor photocatalyst, and the mass ratio of the metal copper catalyst to the semiconductor photocatalyst is 1: (1-5); and the additive is tBuOLi, Cs2CO3, tBuOK, tBuONa or K2CO3, and the additive is tBuOLi, Cs2CO3, tBuOK, tBuONa or K2CO3. The invention aims to solve the problems of high energy consumption, low yield, multi-step reaction, resource waste and the like in the synthesis of deuterated phenol drugs.

Description

Technical Field

[0001] The invention relates to the field of preparation of anticancer drug molecule GW 610 and deuterated chemicals, and in particular to a GW610 or a deuterated product thereof and a photocatalytic CH activation synthesis method thereof. Background Art

[0002] The statements herein merely provide background information related to the present 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 shows potent 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 bonds of drug molecules with more stable CD bonds can improve their pharmacokinetics or toxicity characteristics of drugs. The most obvious deuterated effect is CD3 linked to oxygen, followed by nitrogen-linked groups. Deutetrabenazine, the world's first deuterated drug approved by the US FDA, is a vesicular monoamine transporter 2 inhibitor used to treat chorea associated with Huntington's disease and tardive dyskinesia. Structurally, deutetrabenazine is a deuterated isotope isomer of tetrabenazine. The introduction of deuterium prolongs the half-life of deutetrabenazine, thereby reducing the frequency of dosing.

[0004] GW 610 has some structural similarities with tetrabenazine. Adding methoxy to it and deuterated methylating it to synthesize d6-GW 610 is expected to improve its pharmacokinetics, avoid or reduce certain unfavorable or harmful metabolic pathways in the body, thereby increasing or retaining certain favorable or effective metabolites, enhancing or prolonging the drug's mechanism of action and target effect, while reducing adverse reactions and interactions caused by metabolites.

[0005] At present, the most direct way to synthesize aromatic heterocycles is to perform CH activation on heterocyclic molecules. Some methods synthesize aromatic heterocyclic compounds by reacting heterocyclic molecules with iodobenzene molecules catalyzed by copper. The harsh conditions and high temperature 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 obtain coupling products, but the yield is relatively low, usually around 50%.

[0006] Another method is to induce cyclization by nucleophilic reaction on the amine group ortho 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 into the corresponding thiobenzoisoxazole. Sodium hydride is used in hot NMP for regioselective cyclization to finally generate the desired 5-bromobenzothiazole. This synthesis method has many steps and the synthesis process is relatively complicated. It is urgent to develop an efficient, convenient and economical method to synthesize d6-GW 610. Summary of the invention

[0007] In view of the technical problems existing in the prior art, the present invention proposes a GW 610 or its deuterated product and a photocatalytic CH activation synthesis method thereof, aiming to solve the problems of high energy consumption, low yield, multi-step reaction and waste of resources in the synthesis of deuterated phenol drugs.

[0008] In order to achieve the above object, the present invention is implemented through the following technical solutions:

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

[0010] Mixing 5-fluorobenzo[d]thiazole, thianthrenium salt, catalyst, additive (the additive is used to promote activation of the CH bond of the thiazole ring) and organic solvent, and reacting them in an inert atmosphere under irradiation with a light source to prepare GW 610 or a deuterated compound thereof;

[0011] The catalyst comprises a metallic copper catalyst and a semiconductor photocatalyst, and the mass ratio of the metallic copper catalyst to the semiconductor photocatalyst is 1:1-5;

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

[0013] The present invention realizes deuterated GW 610 anticancer drug molecules based on organic semiconductors and metal catalysts, such as Figure 5 As shown in the figure, the reaction mechanism is as follows: under light conditions, the semiconductor photocatalyst undergoes charge separation to generate a redox center, which undergoes single-electron reduction of the thianthrenium salt and undergoes cleavage to generate an aromatic radical; the additive inorganic base extracts hydrogen from 5-fluorobenzo[d]thiazole to form a carbon negative and reacts with Cu Ⅰ The complex intermediate A is formed, and the holes generated by the semiconductor photocatalyst can further oxidize Cu Ⅰ Cu Ⅱ , generating an important intermediate B, which captures the aromatic radical formed by the thianthrenium salt to obtain a stable intermediate C. Finally, C undergoes reductive elimination to obtain the final product 2, completing the cycle of copper ions.

[0014] In some embodiments, the mass ratio of 5-fluorobenzo[d]thiazole, thianthrinium 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 metallic copper catalyst is one or more of CuI, CuBr2, Cu(dap)2Cl, CuOAc or CuBr.

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

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

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

[0020] The corresponding reaction equation is as follows:

[0021]

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

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

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

[0025] In a second aspect, the present invention provides GW 610 or a deuterated product thereof, which is prepared by the preparation method.

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

[0027] The present invention uses drug precursor 5-fluorobenzo[d]thiazole as a raw material, uses a thianthrenium salt with higher reaction activity as a deuterium source, and realizes carbon-hydrogen activation of 5-fluorobenzo[d]thiazole at room temperature and pressure under the synergistic effect of a photocatalyst and a metal catalyst, and a coupling reaction with the thianthrenium salt, thereby preparing GW 610 and deuterated GW 610 drug molecules. The present invention has mild reaction conditions, high reaction efficiency, high deuteration rate, and high yield. It also avoids the use of highly toxic reagents and highly dangerous reagents, reduces pollution and waste, reduces costs, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0029] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of GW 610 in Example 1 of the present invention;

[0030] Figure 2 is the carbon NMR spectrum of GW 610 in Example 1 of the present invention;

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

[0032] Figure 4 is the carbon nuclear magnetic resonance spectrum of d6-GW 610 in Example 2 of the present invention;

[0033] Figure 5 The diagram is a synthesis mechanism diagram of GW 610 and its deuterated product of the present invention. DETAILED DESCRIPTION

[0034] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0035] In order to make the purpose, technical solution and effect of the present invention clearer and more specific, the present invention is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0036] The present invention is described in detail below by way of examples.

[0037] Example 1

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

[0039]

[0040] Thianthracene 5-oxide (1.16 g, 5 mmol), o-phenylenedimethyl ether (0.69 g, 5 mmol) and 20 ml MeCN were placed in a 100 ml round-bottom flask, and the system temperature was lowered to 0°C. Trifluoromethanesulfonic anhydride (1.0 ml, 7.5 mmol) and HBF4 OEt2 (1.8 g, 5.5 mmol) were added under sufficient stirring. After stirring at 0°C for 2 h, the system temperature was restored to room temperature and continued to stir for 2 h. 30 ml of water was added to the reaction system to terminate the reaction, and 100 ml of dichloromethane was added for extraction. The organic phase was dried over NaSO4 and concentrated to 5 ml. Ether was added to precipitate, and the thianthracene salt product 4 (1.6 g, 73%) was obtained by suction filtration and drying.

[0041] 0.3 mmol (46 mg) of 5-fluorobenzo[d]thiazole 3, 200 mg of thianthrinium 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 bottle, 4 mL of anhydrous acetonitrile was added, the reaction system was replaced with an argon protection state, and then the reaction bottle was placed under a 420 nm light source for 12 hours of light reaction. After the reaction was completed, the light source was removed, the reaction mixture was filtered with diatomaceous earth, and then extracted with 5.0 mL of CH2Cl2. The extract was dried with anhydrous sodium sulfate and concentrated to obtain a colorless liquid. The solvent was removed by rotary evaporation, and then the pure target product was obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate). 1 HNMR, 13 C-NMR and other tests to determine the structure, such as Figure 1 and Figure 2 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 (126 MHz, 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-o-phenylenedimethyl ether (0.69 g, 5 mmol) and 20 ml MeCN were placed in a 100 ml round-bottom flask, and the system temperature was lowered to 0°C. Trifluoromethanesulfonic anhydride (1.0 ml, 7.5 mmol) and HBF4OEt2 (1.8 g, 5.5 mmol) were added under sufficient stirring. After stirring at 0°C for 2 h, the system temperature was restored to room temperature and continued to stir for 2 h. 30 ml of water was added to the reaction system to terminate the reaction and 100 ml of dichloromethane was added for extraction. The organic phase was dried over NaSO4 and concentrated to 5 ml. Ether was added to precipitate, and the thianthracene salt product 5 (1.8 g 80%) was obtained by suction filtration and drying.

[0047] 0.3mmol (46mg) 5-fluorobenzo[d]thiazole 2, 200mg thianthrene salt 5, 11.0mg CuI, 20mg PCN photocatalyst and 67mg tBuONa were weighed and added to a 10mL reaction bottle, 4mL anhydrous acetonitrile was added, the reaction system was replaced with argon protection, and then the reaction bottle was placed under a 420nm light source for 12 hours of light reaction. After the reaction was completed, the light source was removed, the reaction mixture was filtered with diatomaceous earth, and then extracted with 5.0mL CH2Cl2, the extract was dried with anhydrous sodium sulfate, and concentrated to obtain a colorless liquid. The solvent was removed by rotary evaporation, and then the pure target product was obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate). 1 HNMR, 13 C-NMR and other tests to determine the structure, such as Figure 3 and Figure 4 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 (151 MHz, 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-o-phenylenedimethyl ether (0.69 g, 5 mmol) and 20 ml MeCN were placed in a 100 ml round-bottom flask, and the system temperature was lowered to 0°C. Trifluoromethanesulfonic anhydride (1.0 ml, 7.5 mmol) and HBF4OEt2 (1.8 g, 5.5 mmol) were added under sufficient stirring. After stirring at 0°C for 2 h, the system temperature was restored to room temperature and continued to stir for 2 h. 30 ml of water was added to the reaction system to terminate the reaction and 100 ml of dichloromethane was added for extraction. The organic phase was dried over NaSO4 and concentrated to 5 ml. Ether was added to precipitate, and the thianthracene salt product 5 (1.8 g 80%) was obtained by suction filtration and drying.

[0053] 0.3mmol 5-fluorobenzo[d]thiazole 2, 200mg thianthrene salt 5, 11.0mg CuI, 20mg TiO2 photocatalyst and 67mg tBuOK were weighed and added to a 10mL reaction bottle, 4mL anhydrous acetonitrile was added, the reaction system was replaced with argon protection, and then the reaction bottle was placed under a 420nm light source for 12 hours of light reaction. After the reaction, the light source was removed, the reaction mixture was filtered with diatomaceous earth, and then extracted with 5.0mL CH2Cl2, the extract was dried with anhydrous sodium sulfate, and concentrated to obtain a colorless liquid. The solvent was removed by rotary evaporation, and then the pure target product was obtained by column chromatography (developing solvent: 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 wavelength of the light source is 450 nm, and the rest is the same as Example 3. The yield of the prepared d6-GW610 is 78%, and the deuteration rate is 99%.

[0056] Example 5

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

[0058] Example 6

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

[0060] Example 7

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

[0062] Comparative Example 1

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

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing GW 610 or its deuterated product by photocatalytic CH activation, characterized in that: The steps include: 5-fluorobenzo[d]thiazole, thianthrenium salt, catalyst, additive and organic solvent are mixed, and reacted under light source in an inert atmosphere to prepare GW 610 or a deuterated compound thereof; The catalyst comprises a metallic copper catalyst and a semiconductor photocatalyst, and the mass ratio of the metallic copper catalyst to the semiconductor photocatalyst is 1:1-5; The additive is tBuOLi, Cs2CO3, tBuOK, tBuONa or K2CO3.

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, thianthrinium 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 organic solvent is dimethylacetamide, acetonitrile or dimethylformamide.

4. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 1, characterized in that: The metal copper catalyst is one or more of CuI, CuBr2, Cu(dap)2Cl, CuOAc or CuBr.

5. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 1, characterized in that: The semiconductor photocatalyst is a mixture of one or more of TiO2, ZnO, ZnS, CdS, CdSe, ZnCdS or carbon nitride.

6. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 1, characterized in that: The structural formula of the thianthrenium salt is: X is -CH3 or -CD3; Y is -CH3 or -CD3.

7. 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 200-2000nm.

8. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 7, characterized in that: The wavelength of the light source is 400-450nm, preferably 420nm.

9. The method for photocatalytic CH activation synthesis of GW 610 or its deuterated product according to claim 1, characterized in that: The reaction temperature is 20-80°C, and the reaction time is 5-12h.

10. A method for photocatalytic CH activation synthesis of GW 610 or its deuterated product, characterized in that: Prepared by the method described in any one of claims 1 to 9.

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