Preparation method and application of 2-acyl benzothiazole compounds

Abstract

The application relates to a preparation method and application of a 2-acyl benzothiazole compound, which comprises the following steps: placing sulfur ylide in a sealed tube, adding a solvent to dissolve, and obtaining a first reaction system; adding nitrosobenzene into the first reaction system, stirring at a certain temperature for a certain time, and obtaining a second reaction system; adding sodium hydrosulfide, dimethyl sulfoxide, a metal salt, potassium persulfate and an alkali into the second reaction system, heating and stirring in the sealed tube to react, and obtaining a third reaction system; and carrying out post-treatment on the third reaction system to obtain the 2-acyl benzothiazole compound.The application has the advantages that the reaction condition is mild, the price of the sodium hydrosulfide sulfur source is low, and the reaction yield is high; the substrate applicability range is wide, various substrate structures can tolerate the reaction condition, and the 2-acyl benzothiazole derivative with diversified structures can be rapidly prepared.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and particularly relates to a method for preparing and applying 2-acylbenzothiazole compounds. Background Technology

[0002] 2-Acylbenzothiazole is considered a key dominant structural unit and pharmacophore in medicinal chemistry. It is widely found in various drugs and bioactive molecules, exhibiting diverse biological activities. This core structural unit can be found in various antiviral and antituberculosis drugs (Structure–Activity Relationship Studies of SARS-CoV-2 MainProtease Inhibitors Containing 4-Fluorobenzothiazole-2-carbonyl Moieties. J.Med. Chem. 2023, 66 (19), 13516–13529; S8-Catalyzed Triple Cleavage of Bromodifluoro Compounds for the Assembly of N-containing Heterocycles. Chem.Sci., 2019, 10, 6828–6833), as well as enzyme inhibitors such as 17β-HSD1, FAAH, and cPLA2α (Optimization of Hydroxybenzothiazoles as Novel Potent and Selective Inhibitors of 17β-HSD1. J. Med. Chem., 2012, 55, 2469–2473; Discovery and Development of Fatty Acid Amide Hydrolase (FAAH) Inhibitors. J. Med. Chem., 2008, 51(23), 7327–7343; Design of novel and potent cPLA2α inhibitors containing an α-methyl-2-ketothiazole as a metabolically stable serine trap. Bioorg. Med. Chem. Lett., 2011, 21, 3128–3133). Therefore, developing efficient and novel synthetic methods for 2-acylbenzothiazoles is of significant research value.

[0003] Traditional synthetic methods for this skeleton typically involve cyclization and condensation reactions between 2-aminothiophenol and various aryl functionalized compounds. Commonly used aryl compounds include aromatic methyl ketones (Oxidant / Solvent-Controlled I2-Catalyzed Domino Annulation for Selective Synthesis of 2-Aroylbenzothiazoles and 2-Arylbenzothiazoles under Metal-Free Conditions. J. Org. Chem. 2021, 86, 310–321), 2-oxo-2-arylacetaldehyde derivatives (Mechanochemical Thiolation of α-IminoKetones: A Catalyst-Free, One-Pot, Three-Component Reaction. ACS Omega.2025, 10, 4636–4650), and aryl sulfonium salts (Annulative Coupling of Sulfoxonium Ylides with 2-Amino(thio)phenols: Easy Access to 2-Acyl Benzox(thio)azoles, Org. Biomol. Chem.). 2024, 22, 8773–8780), Synthesis of 2-Keto(hetero)aryl Benzox(thio)azoles through Base Promoted Cyclization of 2-Amino(thio)phenols with α, α-Dihaloketones. J. Org. Chem. 2016, 81, 1, 51-56), Metal-free Oxidative Carbonylation on Enaminone C=C Bond for the CascadeSynthesis of Benzothiazole-containing Vici-nal Diketones. Green Chem.2016, 18, 402-405), aryl acetylene (Elemental Sulfur Mediated 2-substituted Benzothiazole Formation from 2-Aminobenzenethiols and Arylacetylenes or Styrenes Under Metal-free Conditions. Org. Biomol. Chem. 2017, 15, 10024-10028), and styrene compounds (Iodine-Promoted Oxidative Amidation of Terminal Alkenes–Synthesis of α-Ketoamides, Benzothiazoles, and Quinazolines. Eur. J. Org. Chem. 2015, 1428–1432). Other strategies employ pre-synthesized benzothiazoles with aromatic methyl ketones (Visible-light-induced 4-CzIPN / LiBr System: A Tireless Electron Shuttle to Enable Reductive Deoxygenation of N-heteroaryl Carbonyls. Org. Chem. Front. 2021, 8, 4419-4425), arylic acids (Tunable C–H Arylation and Acylation of Azoles with Car-boxylic Acids by Pd / Cu Cooperative Catalysis. Org. Chem. Front. 2021, 8, 2543-2550), keto acids (K2S2O8 Activation by Glucose at Room Temperature for The Synthesis and Functionalization of Heterocycles in Water. Chem. Commun. 2021, 57, 8437-8440), or terminal alkynes (Acyl Radicals from Terminal Alkynes: Photoredox-CatalyzedAcylation of Heteroarenes. Chem. Eur. J.Coupling can be performed (2018, 24, 10617–10620), or structural modification can be achieved through metal-catalyzed carbonylative insertion reactions (Palladium-catalyzed Carbonylative CH Activation of Heteroarenes. Angew. Chem. Inter. Ed. 2010, 49, 7316-731). However, these methods all have certain limitations: on the one hand, structurally diverse aminobenzylthiophenol and benzothiazole precursors are still difficult to obtain; on the other hand, the required reaction conditions are often quite harsh, frequently involving high temperatures or special catalysts. In addition, in-situ sulfidation strategies for the synthesis of 2-acylbenzothiazoles are receiving increasing attention. Recent advances in this field include: the three-component reaction system developed by Nguyen et al. involving o-halonitrobenzenes, acetophenones, and elemental sulfur (Al-Mourabit, Concise Access to 2-Aroylbenzothiazoles by Redox Condensation Reaction between o-Halonitrobenzenes, Acetophenones, and Elemental Sulfur. Org. Lett. 2015, 17, 2562-2565); and the innovative method reported by Jiang et al. for the controlled synthesis of styrene, aniline, and sulfur (Anilineortho C−H Sulfuration / Cyclization with Elemental Sulfur for Efficient Synthesis of 2-Substituted Benzothiazoles under Metal-Free Conditions. Adv. Synth. Catal. 2018, 360, 1622 – 1627); and the reaction pathway used by Xue's group with α-iodoacetophenone, o-iodoaniline and sodium hydrosulfide as sulfur sources (A Novel Self-Sequence Reaction Network Involving a Set of Six Reactions in One Pot: The Synthesis of Substituted Benzothiazoles from Aromatic Ketones and Anilines. Org. Lett. 2013, 15, 890-893).While these advances have broadened the substrate applicability to some extent, the stringent reaction conditions still cannot meet the diverse synthetic needs of active drug molecules. Therefore, exploring novel synthetic methods for preparing 2-acylbenzothiazoles using readily available starting materials under mild conditions remains a topic worthy of in-depth research. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing and applying 2-acylbenzothiazole compounds.

[0005] In a first aspect, a method for preparing 2-acylbenzothiazole compounds is provided, comprising:

[0006] S1: Place the sulfur ylide in a sealed tube and add solvent to dissolve it to obtain the first reaction system;

[0007] S2: After adding nitrosobenzene to the first reaction system, stir at a certain temperature for a certain time to obtain the second reaction system;

[0008] S3: Add sodium hydrosulfide, dimethyl sulfoxide, metal salt, potassium persulfate and alkali to the second reaction system in sequence, and heat and stir the reaction in a sealed tube for 4-24 hours to obtain the third reaction system;

[0009] S4: The third reaction system is post-processed to obtain 2-acylbenzothiazole compounds.

[0010] As a preferred embodiment, the structural formula of the thioylide in S1 is:

[0011]

[0012] Wherein, R1 is phenyl, substituted phenyl, alkane group or heterocyclic aryl, and R4 is phenyl or alkane group.

[0013] As a preferred embodiment, the structural formula of nitrosobenzene in S2 is:

[0014]

[0015] Wherein, R2 is a phenyl or a substituted phenyl.

[0016] Preferably, in S2, the specific temperature is 0–40°C; the specific time is 2–10 minutes; and in S3, the heating temperature range of the heating reaction is 40–60°C.

[0017] Preferably, in S1, the solvent is selected from at least one of acetonitrile, dimethyl sulfoxide, 1,4-dioxane, and 1,2-dichloroethane; in S3, the metal salt is selected from at least one of ferric chloride, ferric bromide, copper acetate, copper bromide, and potassium ferricyanide.

[0018] Preferably, in S3, the base is selected from at least one of pyridine, potassium carbonate, triethylamine, 4-DMAP, and 2-chloropyridine.

[0019] Preferably, in S1 to S3, the concentration of the sulfur ylide in the solvent is 0.1 to 1 mmol / mL; the amount of nitrosobenzene is 1 equivalent of the sulfur ylide; the amount of alkali is 1 to 2 equivalents of the sulfur ylide; the amount of potassium persulfate is 1 to 2.5 equivalents of the sulfur ylide; the amount of sodium hydrosulfide is 1 to 2.5 equivalents of the sulfur ylide; the amount of metal salt is 0.1 to 0.5 equivalents of the sulfur ylide; and the amount of dimethyl sulfoxide is 1 to 5 times the mass-volume ratio of the sulfur ylide.

[0020] Preferably, in step S4, the post-processing includes: removing the solvent under reduced pressure, separating the residue by extraction with a water / ethyl acetate system, drying the combined organic phase with anhydrous sodium sulfate and concentrating under reduced pressure, and purifying the 2-acylbenzothiazole compound by rapid column chromatography.

[0021] In a second aspect, 2-acylbenzothiazole compounds prepared by any of the methods described in the first aspect are provided.

[0022] Thirdly, the application of the method described in any of the first aspects in the synthesis of 17β-HSD1 inhibitors is provided.

[0023] The beneficial effects of this invention are:

[0024] 1. This invention proposes a method for preparing 2-acylbenzothiazole compounds. This method has mild reaction conditions, uses inexpensive sodium hydrosulfide as a sulfur source, and has a high reaction yield. It has a wide range of substrate applicability, and various substrate structures can tolerate the reaction conditions, which is beneficial for the rapid preparation of 2-acylbenzothiazole derivatives with diverse structures.

[0025] 2. This invention proposes a method for preparing the 17β-HSD1 inhibitor (2-fluoro-3-hydroxyphenyl)(6-hydroxybenzo[d]thiazol-2-yl) methyl ketone using this synthetic strategy. This strategy greatly shortens the synthetic steps and improves the overall yield of the inhibitor. Attached Figure Description

[0026] Figure 1 This is a hydrogen spectrum of a product provided in an embodiment of this application;

[0027] Figure 2 This is the proton spectrum of another product provided in the embodiments of this application;

[0028] Figure 3 This is the proton spectrum of another product provided in the embodiments of this application;

[0029] Figure 4This is the hydrogen spectrum of another product provided in the embodiments of this application. Detailed Implementation

[0030] The present invention will be further described below with reference to embodiments. The description of the embodiments below is only for the purpose of helping to understand the present invention. It should be noted that those skilled in the art can make several modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

[0031] Example 1

[0032] As an example, this embodiment one provides a method for preparing 2-acylbenzothiazole compounds. The structural formula of the 2-acylbenzothiazole compounds is as follows:

[0033]

[0034] Wherein, R1 is phenyl, substituted phenyl, alkane group or heterocyclic aryl group, and R3 is halogen, alkoxy group, alkane, aromatic group and hydroxyl group and other various substitutions.

[0035] The preparation method of this 2-acylbenzothiazole compound includes the following steps:

[0036] S1: Place the sulfur ylide in a sealed tube and add solvent to dissolve it;

[0037] S2: Add nitrosobenzene to the reaction system obtained in step S1 and stir at a certain temperature for a certain time;

[0038] S3: Add sodium hydrosulfide, dimethyl sulfoxide, metal salt, potassium persulfate, and alkali sequentially to the reaction system of S2, and heat and stir in a sealed tube for 4-24 hours.

[0039] S4: Remove the solvent from the reaction system obtained in step S3 under reduced pressure. Extract the residues separately using a water / ethyl acetate system. Dry the combined organic phases with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by rapid column chromatography to obtain the target product.

[0040] In step S1, the structural formula of the thioylide is:

[0041]

[0042] R1 is phenyl, substituted phenyl, alkane group or heterocyclic aryl, and R4 is phenyl or alkane group.

[0043] In step S2, the structural formula of nitrosobenzene is:

[0044]

[0045] R2 is a phenyl or a phenyl with various substituted forms.

[0046] The reaction temperature range in step S2 is 0–40°C; the stirring time is 2–10 minutes.

[0047] In step S3, the heating temperature range is 40–60°C.

[0048] Solvents include one or more of acetonitrile, dimethyl sulfoxide, 1,4-dioxane, and 1,2-dichloroethane.

[0049] The metal salt in step S3 includes one or more of ferric chloride, ferric bromide, copper acetate, copper bromide, and potassium ferricyanide.

[0050] The base in step S3 includes one or more of pyridine, potassium carbonate, triethylamine, and 2-chloropyridine.

[0051] The overall reaction formula for this preparation method is:

[0052]

[0053] Example 2

[0054] As another embodiment, this embodiment two proposes a new method for synthesizing the 17β-HSD1 inhibitor (2-fluoro-3-hydroxyphenyl)(6-hydroxybenzo[d]thiazol-2-yl) methyl ketone based on embodiment one. This strategy greatly shortens the synthesis steps of the inhibitor and improves the overall yield.

[0055] The specific reaction formula is as follows:

[0056]

[0057] In this embodiment, 2-(dimethyl-λ) 4(-Thionyl)-1-(2-fluoro-3-hydroxyphenyl)ethyl-1-one (1.0 mmol, 1.0 equivalent) was placed in a 25 mL sealed tube and dissolved in acetonitrile (2.5 mL). 4-Nitrophenol (1.0 mmol, 1.0 equivalent) was added, and the mixture was stirred at 20 °C for 5 min. Subsequently, NaSH (2.0 mmol, 2.0 equivalent), DMSO (2.5 mL), FeCl3 (0.1 mmol, 0.1 equivalent), K2S2O8 (2.0 mmol, 2.0 equivalent), and pyridine (2.0 mmol, 2.0 equivalent) were added sequentially. The reaction tube was sealed, and the reaction was heated at 60 °C for 12 h (the reaction progress was monitored by TLC). After cooling, the solvent was removed under reduced pressure. The residue was extracted with water (3 × 15 mL) and ethyl acetate (3 × 15 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. Purification by rapid column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) yielded the target product (2-fluoro-3-hydroxyphenyl)(6-hydroxybenzo[d]thiazol-2-yl) methyl ketone, with the following 1H NMR spectrum: Figure 1 As shown.

[0058] Pale yellow solid, yield 52%.

[0059] 1 H NMR (400 MHz, CDCl3) 9.26 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.55-7.49 (m, 2H), 7.27 (td, J = 8.2 Hz, 1.6 Hz, 1H),7.25-7.17 (m, 2H); 13 C NMR (100 MHz, CD3Cl3): 186.9, 163.7, 159.3, 152.1,149.5, 148.6, 146.3, 146.4, 140.5, 127.6, 127.7, 127.4, 125.1, 124.9, 122.4,122.2, 122.1, 118.8, 107.4 HRMS (ESI): m / z calcd for [M+H] + : 289.0210, found:289.0210.

[0060] Example 3

[0061] As another embodiment, this embodiment three proposes, based on embodiment one, to use the preparation method of this 2-acylbenzothiazole compound to obtain a (benzo[d]thiazole-2-yl)(phenyl) methyl ketone, the structural formula of which is:

[0062]

[0063] 1.0 mmol (1.0 equivalent) of 2-(dimethyl-λ4-sulfinyl)-1-phenyl-1-one was placed in a 25 mL sealed tube and dissolved in acetonitrile (2.5 mL). Nitrosene (1.0 mmol, 1.0 equivalent) was added, and the mixture was stirred at 20°C for 5 minutes. Subsequently, NaSH (2.0 mmol, 2.0 equivalent), DMSO (2.5 mL), FeCl3 (0.1 mmol, 0.1 equivalent), K2S2O8 (2.0 mmol, 2.0 equivalent), and pyridine (2.0 mmol, 2.0 equivalent) were added sequentially. The reaction tube was sealed and heated at 60°C for 12 hours (reaction progress monitored by TLC). After cooling, the volatile components (acetonitrile and some DMSO) were removed under reduced pressure. The residue was extracted with water (3 × 15 mL) and ethyl acetate (3 × 15 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The target product was purified by rapid column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1), and its 1H NMR spectrum is shown below. Figure 2 As shown.

[0064] Pale yellow solid, yield 86%.

[0065] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.1 Hz, 2H), 8.25 (d, J = 7.8Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.67 (dd, J = 8.1, 6.5 Hz, 1H), 7.59 (dd,J = 10.9, 4.9 Hz, 3H), 7.54 (d, J = 5.8 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ185.5, 167.2, 153.9, 137.1, 135.0, 134.0, 131.3, 128.6, 127.7, 127.0, 125.8,122.3. HRMS (ESI): m / z calcd for C14 H9NOS +H + : 240.0478, found: 240.0484.

[0066] Example 4

[0067] As another embodiment, this embodiment four proposes to replace ferric chloride with potassium ferricyanide, while keeping other conditions unchanged, and also obtains (benzo[d]thiazol-2-yl)phenyl)methyl ketone.

[0068] Pale yellow solid, yield 55%.

[0069] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.1 Hz, 2H), 8.25 (d, J = 7.8Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.67 (dd, J = 8.1, 6.5 Hz, 1H), 7.59 (dd,J = 10.9, 4.9 Hz, 3H), 7.54 (d, J = 5.8 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ185.5, 167.2, 153.9, 137.1, 135.0, 134.0, 131.3, 128.6, 127.7, 127.0, 125.8,122.3. HRMS (ESI): m / z calcd for C 14 H9NOS +H + : 240.0478, found: 240.0484.

[0070] Example 5

[0071] As another embodiment, this embodiment five proposes to replace ferric chloride with copper acetate, while keeping other conditions unchanged, to obtain (benzo[d]thiazol-2-yl)(phenyl) methyl ketone with a yield of 75%.

[0072] 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.1 Hz, 2H), 8.25 (d, J = 7.8Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.67 (dd, J = 8.1, 6.5 Hz, 1H), 7.59 (dd,J = 10.9, 4.9 Hz, 3H), 7.54 (d, J = 5.8 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ185.5, 167.2, 153.9, 137.1, 135.0, 134.0, 131.3, 128.6, 127.7, 127.0, 125.8,122.3. HRMS (ESI): m / z calcd for C 14 H9NOS +H + : 240.0478, found: 240.0484.

[0073] Example 6

[0074] As another embodiment, this embodiment six is ​​based on embodiment three, but replaces pyridine with 4-DMAP, while keeping other conditions unchanged, and also obtains (benzo[d]thiazolyl-2-yl)phenyl)methyl ketone, with a yield of 61%.

[0075] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.1 Hz, 2H), 8.25 (d, J = 7.8Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.67 (dd, J = 8.1, 6.5 Hz, 1H), 7.59 (dd,J = 10.9, 4.9 Hz, 3H), 7.54 (d, J = 5.8 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ185.5, 167.2, 153.9, 137.1, 135.0, 134.0, 131.3, 128.6, 127.7, 127.0, 125.8,122.3. HRMS (ESI): m / z calcd for C 14 H9NOS +H +: 240.0478, found: 240.0484.

[0076] Example 7

[0077] As another embodiment, this embodiment seven is based on embodiment three, but replaces pyridine with potassium carbonate, while keeping other conditions unchanged, and also obtains (benzo[d]thiazolyl-2-yl)phenyl)methyl ketone, with a yield of 36%.

[0078] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.1 Hz, 2H), 8.25 (d, J = 7.8Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.67 (dd, J = 8.1, 6.5 Hz, 1H), 7.59 (dd,J = 10.9, 4.9 Hz, 3H), 7.54 (d, J = 5.8 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ185.5, 167.2, 153.9, 137.1, 135.0, 134.0, 131.3, 128.6, 127.7, 127.0, 125.8,122.3. HRMS (ESI): m / z calcd for C 14 H9NOS +H + : 240.0478, found: 240.0484.

[0079] Example 8

[0080] As another embodiment, this embodiment eight, based on embodiment three, adds 2-(dimethyl-λ) 4 -sulfinyl)-1-phenyl-1-one is replaced with 1-(4-fluorophenyl)-2-(dimethyl-λ) 4 -sulfinyl) ethyl-1-one yields a benzo[d]thiazolyl-2-yl(4-fluorophenyl) methyl ketone, with the following structural formula:

[0081]

[0082] Pale yellow solid, yield 97%.

[0083] 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J = 8.5, 5.7 Hz, 2H), 8.28 (d, J =7.9 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.66 -7.55 (m, 2H), 7.28 (t, J = 8.7Hz, 2H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 183.6, 167.4 (d, J = 64.4 Hz), 165.2,153.9, 137.0, 134.2 (d, J = 9.3 Hz), 131.3, 127.8, 127.0, 125.7, 122.2, 115.8(d, J = 21.7 Hz). HRMS (ESI): m / z calcd for C 14 H8FNOS+H + : 258.0383, found:258.0383.

[0084] Example 9

[0085] As another embodiment, Embodiment Nine, based on Embodiment Three, adds 2-(dimethyl-λ) 4 -sulfinyl)-1-phenyl-1-one is replaced with 2-(dimethyl-λ) 4 -sulfinyl)-1-(4-chlorophenyl)ethyl-1-one, yielding a benzo[d]thiazol-2-yl(4-chlorophenyl)methyl ketone, the 1H NMR spectrum of which is shown below. Figure 3 As shown, its structural formula is:

[0086]

[0087] Pale yellow solid, yield 92%.

[0088] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 8.6 Hz, 2H), 8.28-8.20 (m, 1H), 8.06-7.98 (m, 1H), 7.59 (m, 2H), 7.54 (d, J = 8.6 Hz, 2H). 13 C{ 1H} NMR (100MHz, CDCl3): δ 184.1, 166.9, 153.9, 140.7, 137.1, 133.3, 132.8, 128.9, 127.9,127.1, 125.8, 122.3. HRMS (ESI): m / z calcd for C 14 H8ClNOS+H + : 274.0088 and276.0059, found: 274.0087 and 276.0054.

[0089] Example 10

[0090] As another embodiment, this embodiment ten, based on embodiment three, adds 2-(dimethyl-λ) 4 Replace -sulfinyl)-1-phenyl-1-one with 2-(dimethyl-λ) 4 -sulfinyl)-1-(4-bromophenyl)ethyl-1-one yields a benzo[d]thiazolyl-2-yl(4-bromophenyl)methyl ketone, the structural formula of which is:

[0091]

[0092] Pale yellow solid, yield 85%.

[0093] 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.6 Hz, 2H), 8.27 – 8.21 (m,1H), 8.06 – 7.98 (m, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.63-7.53 (m, 2H). 13 C{ 1 H}NMR (100 MHz, CDCl3) δ 184.3,166.8, 153.9, 137.1, 133.7, 132.8, 131.9, 129.6,127.9, 127.1, 125.8, 122.3. HRMS (ESI): m / z calcd for C 14 H8BrNOS +H + : 317.9583and 319.9563, found: 317.9583 and 319.9563.

[0094] Example 11

[0095] As another embodiment, this embodiment eleven, based on embodiment three, adds 2-(dimethyl-λ) 4 Replace -sulfinyl)-1-phenyl-1-one with 2-(dimethyl-λ) 4 -Thionyl)-1-(4-nitrophenyl)ethane-1-one yields a benzo[d]thiazolyl-2-yl(4-nitrophenyl)methyl ketone with the following structural formula:

[0096]

[0097] Pale yellow solid, yield 71%.

[0098] 1 H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 8.3 Hz, 2H), 8.39 (d, J = 8.3Hz, 2H), 8.26 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.60 (dd, J =14.0, 6.9 Hz, 2H). 13 C{ 1 H} NMR (100 MHz, CDCl3): δ 183.9, 165.9, 153.8, 150.6,139.8, 137.3, 132.3, 128.3, 127.4, 126.0, 123.5, 122.4. HRMS (ESI): m / z calcdfor C 14 H8N2O3S+H + : 285.0328, found: 285.0327.

[0099] Example 12

[0100] As another embodiment, this embodiment twelve, based on embodiment three, adds 2-(dimethyl-λ) 4 Replace -sulfinyl)-1-phenyl-1-one with 2-(dimethyl-λ) 4 -Thionyl)-1-(4-trifluoromethylphenyl)ethane-1-one yields a benzo[d]thiazolyl-2-yl(4-trifluoromethylphenyl) methyl ketone, with the following structural formula:

[0101]

[0102] Pale yellow solid, yield 69%.

[0103] 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.2 Hz, 2H), 8.25 (d, J = 7.6Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.60 (m, 2H). 13 C{ 1 H} NMR (100 MHz, CDCl3): δ 184.6, 166.3, 153.9, 137.8, 137.2, 135.1, 134.7,131.6, 128.1, 127.2, 125.9, 125.5 (d, J = 3.6 Hz), 122.3. HRMS (ESI): m / zcalcd for C 15 H8F2NOS+H + : 308.0351, found: 308.0359.

[0104] Example 13

[0105] As another embodiment, this embodiment thirteen, based on embodiment three, adds 2-(dimethyl-λ) 4 Replace -sulfinyl)-1-phenyl-1-one with 2-(dimethyl-λ) 4 -Thionyl)-1-(4-methylphenyl)ethane-1-one yields a benzo[d]thiazolyl-2-yl(4-methylphenyl)methyl ketone with the following structural formula:

[0106]

[0107] Pale yellow solid, yield 79%.

[0108] 1 H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.1 Hz, 2H), 8.24 (d, J = 7.9Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.56 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H),2.47 (s, 3H). 13 C{ 1H} NMR (100 MHz, CDCl3): δ 185.0, 167.5, 153.9, 145.1,137.0, 132.4, 131.5, 129.3, 127.6, 126.9, 125.7, 122.2, 21.9. HRMS (ESI): m / zcalcd for C 15 H 11 NOS+H + : 254.0634, found: 254.0634.

[0109] Example 14

[0110] As another embodiment, this embodiment fourteen, based on embodiment three, adds 2-(dimethyl-λ) 4 Replace -sulfinyl)-1-phenyl-1-one with 2-(dimethyl-λ) 4 -Thionyl)-1-(4-methoxyphenyl)ethane-1-one, yielding a benzo[d]thiazol-2-yl(4-methoxyphenyl)methyl ketone with the following structural formula:

[0111]

[0112] Pale yellow solid, yield 84%.

[0113] 1 H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 8.9 Hz, 2H), 8.23 ​​(d, J = 8.2Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.61-7.50 (m, 2H), 7.04 (d, J = 8.9 Hz,2H), 3.92 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3): δ 183.5, 168.0, 164.5, 154.0,136.9, 133.9, 127.8, 127.4, 126.8, 125.6, 122.2, 113.9, 55.6. HRMS (ESI): m / zcalcd for C 15 H 11 NO2S+H + : 270.0583, found: 270.0583.

[0114] Example 15

[0115] As another embodiment, this embodiment fifteen, based on embodiment three, adds 2-(dimethyl-λ) 4 Replace -sulfinyl)-1-phenyl-1-one with 2-(dimethyl-λ) 4 (-thionyl)-1-(furan-2-yl)ethane-1-one yields a benzo[d]thiazolyl-2-yl(furan-2-yl)methyl ketone with the following structural formula:

[0116]

[0117] Pale yellow solid, yield 70%.

[0118] 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 3.5 Hz, 1H), 8.22 (d, J = 8.1Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.83 (s, 1H), 7.57 (m, 2H), 6.69 (d, J =2.8 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl3): δ 172.2, 166.1, 153.9, 149.9, 149.0,136.9, 127.6, 127.0, 125.6, 125.1, 122.3, 113.0. HRMS (ESI): m / z calcd forC 12 H7NO2S+H + : 230.0270, found: 230.0272.

[0119] Example 16

[0120] As another embodiment, Embodiment Sixteen replaces nitrosobenzene with p-chloronitrosobenzene based on Embodiment Three, yielding a (6-chlorobenzo[d]thiazolyl)(phenyl) methyl ketone with the following structural formula:

[0121]

[0122] Pale yellow solid, yield 63%.

[0123] 1 H NMR (400 MHz, CDCl3) δ 8.55 (m, 2H), 8.15 (d, J = 6.3 Hz, 1H), 8.00 (s, 1H), 7.68 (m, 1H), 7.56 (m, 3H). 13 C{1 H} NMR (100 MHz, CDCl3) δ 185.0,167.7, 152.4, 138.2, 134.7, 134.1, 134.1, 131.3, 128.6, 128.0, 126.5, 121.8.HRMS (ESI): m / z calcd for C 14 H8ClNOS+H + : 274.0088 and 276.0059, found: 274.0088 and 276.0062.

[0124] Example 17

[0125] As another embodiment, Embodiment Seventeen replaces the nitrosobenzene in Embodiment Three with p-bromonitrosobenzene, yielding a (6-bromobenzo[d]thiazolyl)(phenyl) methyl ketone with the following structural formula:

[0126]

[0127] Pale yellow solid, yield 58%.

[0128] 1 H NMR (400 MHz, CDCl3) δ 8.55 (m, 2H), 8.16 (s, 1H), 8.08 (m, 1H), 7.68 (m, 2H), 7.57 (m, 2H). 13 C{ 1 H} NMR (100 MHz, CDCl3): δ 185.0, 167.7,152.7, 138.6, 134.8, 134.2, 131.3, 130.7, 128.6, 126.8, 124.8, 122.0. HRMS(ESI): m / z calcd for C 14 H8BrNOS+H + : 317.9583 and 319.9563, found: 317.9586 and319.9563.

[0129] Example 18

[0130] As another embodiment, Embodiment Eighteen replaces nitrosobenzene with p-cyanonitrobenzene based on Embodiment Three, obtaining a (6-cyanobenzo[d]thiazolyl)(phenyl) methyl ketone with the following structural formula:

[0131]

[0132] Pale yellow solid, yield 30%.

[0133] 1 H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.71 (t, J = 7.3 Hz, 1H),7.58 (t, J = 7.5 Hz, 2H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 184.5, 171.1, 155.9,137.2, 134.5, 134.3, 131.4, 129.7, 128.7, 127.3, 126.5, 118.2, 111.2. HRMS(ESI): m / z calcd for C 15 H8N2OS+H + : 265.0430, found: 265.0437.

[0134] Example 19

[0135] As another embodiment, Embodiment Nineteen replaces nitrosobenzene with p-methylnitrosobenzene based on Embodiment Three, yielding a (6-methylbenzo[d]thiazolyl)(phenyl) methyl ketone, the 1H NMR spectrum of which is shown below. Figure 4 As shown, its structural formula is:

[0136]

[0137] Pale yellow solid, yield 63%.

[0138] 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 7.6 Hz, 2H), 8.12 (d, J = 8.4Hz, 1H), 7.80 (s, 1H), 7.66 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 2.55 (s, 3H). 13 C{ 1H} NMR (100 MHz, CDCl3): δ 185.7,166.3, 152.3, 138.5, 137.5, 135.3, 134.0, 131.4, 129.0, 128.7, 125.4, 121.9,22.0. HRMS (ESI): m / z calcd for C 15 H 11 NOS +H + : 254.0634, found: 254.0637.

[0139] Example 20

[0140] As another embodiment, this embodiment twenty replaces nitrosobenzene with 4-methoxynitrosobenzene based on embodiment three, obtaining a (6-methoxybenzo[d]thiazolyl)(phenyl) methyl ketone with the following structural formula:

[0141]

[0142] Pale yellow solid, yield 53%.

[0143] 1 H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 9.0Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.41 (s, 1H), 7.18 (dd, J = 9.0, 2.0 Hz, 1H), 3.92 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3): δ185.3, 164.6, 159.8, 148.6, 139.2, 135.2, 133.8, 131.2, 128.5, 126.5, 117.7,103.4, 55.9. HRMS (ESI): m / z calcd for C 15 H 11 NO2S+H + : 270.0583, found:270.0586.

Claims

1. A method for producing a 2-acylbenzothiazole compound, characterized by, include: S1: Place the sulfur ylide in a sealed tube and add solvent to dissolve it to obtain the first reaction system; S2: After adding nitrosobenzene to the first reaction system, stir at a certain temperature for a certain time to obtain the second reaction system; S3: Add sodium hydrosulfide, dimethyl sulfoxide, metal salt, potassium persulfate and alkali to the second reaction system, and heat and stir the reaction in a sealed tube for 4-24 hours to obtain the third reaction system; S4: The third reaction system is post-processed to obtain 2-acylbenzothiazole compounds.

2. The method for preparing 2-acylbenzothiazole compounds according to claim 1, characterized in that, In S1, the structural formula of the thioylide is: Wherein, R1 is phenyl, substituted phenyl, alkane group or heterocyclic aryl, and R4 is phenyl or alkane group.

3. The method for preparing 2-acylbenzothiazole compounds according to claim 2, characterized in that, In S2, the structural formula of nitrosobenzene is: Wherein, R2 is a phenyl or a substituted phenyl.

4. The method for preparing 2-acylbenzothiazole compounds according to claim 3, characterized in that, In S2, the specified temperature is 0–40°C; the specified time is 2–10 minutes; in S3, the heating temperature range of the heating reaction is 40–60°C.

5. The method for preparing 2-acylbenzothiazole compounds according to claim 4, characterized in that, In S1, the solvent is selected from at least one of acetonitrile, dimethyl sulfoxide, 1,4-dioxane, and 1,2-dichloroethane; in S3, the metal salt is selected from at least one of ferric chloride, ferric bromide, copper acetate, copper bromide, and potassium ferricyanide.

6. The method for preparing 2-acylbenzothiazole compounds according to claim 5, characterized in that, In S3, the base is selected from at least one of pyridine, potassium carbonate, triethylamine, 4-DMAP, and 2-chloropyridine.

7. The method for preparing 2-acylbenzothiazole compounds according to claim 6, characterized in that, In S1 to S3, the concentration of the sulfur ylide in the solvent is 0.1–1 mmol / mL; the amount of nitrosobenzene used is 1–1.5 times the equivalent of sulfur ylide; the amount of alkali used is 1–2 times the equivalent of sulfur ylide; the amount of potassium persulfate used is 1–2.5 times the equivalent of sulfur ylide; the amount of sodium hydrosulfide used is 1–2.5 times the equivalent of sulfur ylide; the amount of metal salt used is 0.1–0.5 times the equivalent of sulfur ylide; and the amount of dimethyl sulfoxide used is 1–5 times the mass-volume ratio of sulfur ylide.

8. The method for preparing 2-acylbenzothiazole compounds according to claim 7, characterized in that, In S4, the post-processing includes: removing the solvent under reduced pressure, separating the residue by extraction with a water / ethyl acetate system, drying the combined organic phase with anhydrous sodium sulfate and concentrating under reduced pressure, and purifying the 2-acylbenzothiazole compound by rapid column chromatography.

9. A 2-acylbenzothiazole compound prepared by the method according to any one of claims 1 to 8.

10. The use of the method as described in any one of claims 1 to 9 in the synthesis of 17β-HSD1 inhibitors.

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