Site-directed chlorination of steroids

Abstract

The present application relates to the site-specific chlorination method of steroid compound, belong to the technical field of organic synthesis, the site-specific chlorination method of the present application, its characterized in to include the following steps: under the condition of power supply and illumination, steroid compound and chlorine source occur reaction in electrolyte solution 1h-24h, obtain chlorinated steroid compound.This method has the characteristics of economical and mild chlorine source, simple post-processing, can adapt multiple site chlorination, easy to industrialization amplification and strong substrate universality.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a site-directed chlorination method for steroidal compounds. Background Technology

[0002] Steroids are a class of organic compounds with important physiological functions and pharmacological activities. Their core structure consists of four fused rings, and their unique spatial configuration and diverse substituents make them extremely valuable in pharmaceuticals, agriculture, and materials. In pharmacology, glucocorticoids, sex hormones, and some bile acid derivatives all belong to steroids. They participate in physiological regulation and, after chemical modification, form a large number of clinically used drugs such as cortisone, hydrocortisone, dexamethasone, and prednisolone, which have anti-inflammatory, immunosuppressive, anti-allergic, and metabolic regulatory effects. Therefore, the synthesis and modification of steroids occupy an irreplaceable position in drug development.

[0003] Chlorinated steroid derivatives play a crucial role in steroid drug development. Chlorinated products at different positions can serve as key intermediates with unique functions: 9α-chlorosteroid intermediates achieve stereoselective construction through steps such as "elimination to generate 9,11-olefin – hydroxyhalogenation – dehalogenation," providing a pure chemical method for the synthesis of glucocorticoids such as hydrocortisone that is independent of microbial fermentation, has a short reaction route, mild conditions, and is cost-effective; 5α-chloro compounds often serve as key intermediates for double bond adjustment and conformational control, contributing to the synthesis of specific steroids such as testosterone. The synthesis of 14β-chlorosteroids; 14β-chlorosteroid derivatives can be used to modify the C / D ring spatial configuration of the steroid skeleton, and related compounds have shown potential value in the synthesis of novel anti-inflammatory drugs and steroid receptor modulators; 17α-chlorosteroids are closely related to the modification of steroid side chains and are often used as transition intermediates for introducing or modifying functional groups such as hydroxyl and ketone groups to prepare a variety of 17-substituted steroid drugs. It can be seen that using 5α, 9α, 14β, and 17α-chlorosteroids as starting materials or key intermediates, a number of representative steroid compounds with pharmaceutical significance have been derived.

[0004] However, the synthesis of 5α, 9α, 14β, and 17α chlorosteroids still has significant drawbacks: First, there are obvious shortcomings in the selection of chlorine sources. Traditional techniques often use dichloroiodobenzene, an organic iodine compound that is scarce and expensive. During its chlorination process, toxic byproducts such as iodobenzene, elemental iodine, and hydrogen chloride gas are generated. These wastes are subject to strict environmental regulations and have extremely high treatment costs. At the same time, dichloroiodobenzene is a strong oxidizing / chlorinating agent, and the reaction conditions are violent. Under improper conditions, there is a risk of runaway. It also requires an anhydrous or special organic solvent environment, making it difficult to scale up the reaction. Second, when chlorinating different sites, traditional techniques often require adjustment of some reaction conditions or even replacement of the entire reaction system, which is not conducive to large-scale industrial production. Finally, the substrate universality of the various chlorination methods that have been developed is poor. They cannot tolerate raw materials containing unsaturated bonds, ether bonds, or hydroxyl groups (such as testosterone and hydroxyprogesterone), making it difficult for the chlorination reaction to occur precisely at the target site. It is easy to generate polychlorinated or oxidized byproducts.

[0005] Therefore, developing new synthetic strategies has become an urgent need in steroid chemistry research and applications. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a site-directed chlorination method for steroidal compounds. This method features an economical and mild chlorine source, simple post-processing, adaptability to multiple chlorination sites, ease of industrial scale-up, and broad substrate versatility.

[0007] The purpose of this invention is to provide a method for site-directed chlorination of steroidal compounds, comprising the following steps: under conditions of electricity and light, reacting a steroidal compound with a chlorine source in an electrolyte solution for 1-24 hours to obtain a chlorinated steroidal compound;

[0008] The steroidal compound is selected from the following compounds:

[0009] ;

[0010] in, This indicates whether it is a single or double bond.

[0011] X in IS-1, IS-2, II-S-1, II-S-2, III-S and IV-S 1 Independently selected from -C(=O)- or -S(=O)2-;

[0012] X 2 Independently selected from -O- or -NH-;

[0013] R 1 It can be independently connected to the quinary ring via a single or double bond, or form a helical ring with the quinary ring; when R 1When connected to the pentagonal ring via a single bond, it is independently selected from -H, -OH, -CN, Cl-C. 20 Alkyl, C1-C6 acyl, C1-C 20 Alkoxycarbonyl, C1-C 20 Acyloxy or C1-C 10 sulfonyloxy; when R 1 When connected to the pentagonal ring via a double bond, it is independently selected or * represents a connection site; when R 1 When it forms a spiral with the quinary ring it is in, it is * represents a spiro atom site;

[0014] R 2 Independently selected from -H, C1-C6 alkyl, C1-C 10 Alkoxy or C1-C 10 Acyloxy group;

[0015] R 1 and R 2 Cyclic or non-cyclic;

[0016] R 3 Independently selected from -H, -CH3, or -CF3;

[0017] R 4 Independently connected to the hexa-membered ring via a single or double bond; when R 4 When connected to the six-membered ring via a single bond, it is independently selected from -H, C6-C. 10 aryloxy or C1-C 20 Acyloxy group; when R 4 When connected to the hexa-membered ring via a double bond, it is independently selected * represents a connection point;

[0018] R 5 Independently selected from -H or C1-C6 alkyl groups;

[0019] R 6 Independently connected to the hexa-membered ring via a single or double bond; when R 6 When connected to the six-membered ring via a single bond, it is independently selected from -H; when R 6 When connected to the hexa-membered ring via a double bond, it is independently selected * represents a connection point;

[0020] The chlorine source is selected from one or more of pyridine hydrochloride (Py·HCl), hydrochloric acid (HCl), magnesium chloride (MgCl2), cerium chloride (CeCl3), and sodium chloride (NaCl); a suitable chlorine source can largely balance factors such as safety, cost, post-processing difficulty, industrial scale-up possibility, and yield.

[0021] The solute in the electrolyte solution is selected from one or more of tetrabutylammonium tetrafluoroborate (TBABF4), tetrabutylammonium perchlorate (TBAClO4), lithium perchlorate (LiClO4), and tetrabutylammonium hexafluorophosphate (TBAPF6). The ions of these solutes are chemically inert in the reaction system and will not participate in the core reaction between the steroid compound and the chlorine source. Furthermore, they are not prone to redox reactions (such as anodic oxidation) on the electrode surface under energized conditions, thus stably playing the role of conducting current and ensuring the stability of the reaction system. The solvent is selected from one or more of acetonitrile (MeCN), ethyl acetate (EtOAc), dichloromethane (DCM), and acetone (ACE).

[0022] In one embodiment of the present invention, the solvent of the electrolyte solution includes acetonitrile and ethyl acetate; the composite solvent can simultaneously meet the reaction's requirements for solubility, conductivity and chemical inertness: they can all dissolve steroidal compounds, chlorine sources and selected electrolyte solutes well, avoid uneven reaction caused by the precipitation of raw materials, and ensure sufficient contact of each reaction component; and have suitable dielectric constants, which can ensure that the electrolyte solution dissociates enough ions to maintain good conductivity of the system to meet the requirements of the electrostatic reaction; at the same time, they are not prone to redox reactions under the electrostatic and light conditions of the reaction, and will not have side reactions with steroidal compounds, chlorine sources or generated chlorinated products.

[0023] In one embodiment of the present invention, the volume ratio of acetonitrile and ethyl acetate is (2.8-3.2):2; when used in combination, the balance between conductivity and solubility can be optimized by adjusting the ratio, so that the two components in the system are better matched, thereby achieving a higher reaction yield.

[0024] In one embodiment of the present invention, the energizing conditions are: constant voltage of 2V-4V or constant current of 2mA-10mA. When using constant current electrolysis mode, the voltage will continue to rise as the reaction proceeds, resulting in a decrease in system stability and a low final yield. Even if the current intensity is adjusted, the yield can only be maintained at 24%-45%. However, using constant voltage electrolysis mode can effectively solve this problem. Especially under constant voltage conditions of 2V-4V, it can significantly improve the reaction rate, shorten the reaction time, and minimize the formation of by-products.

[0025] In one embodiment of the present invention, the illumination conditions are: wavelength of 365nm-495nm and power of 10W-50W.

[0026] In one embodiment of the present invention, simultaneous energization and illumination can create a photo-electro-catalytic synergistic effect, efficiently promoting the generation and stabilization of chlorine free radicals: the energizing condition can activate the chlorine source through electrode reactions (such as promoting the oxidation of chlorine source ions to generate chlorine source molecules), providing a basic source of free radicals for the reaction, while the illumination of a specific wavelength can further excite the chlorine source molecules to decompose into chlorine free radicals, reducing the energy barrier for free radical generation, while inhibiting the recombination quenching of chlorine free radicals, significantly improving the generation rate and utilization rate of free radicals; this synergistic effect can not only accelerate the reaction process and shorten the reaction time, but also reduce the side reactions that may occur under single energizing conditions, improve the selectivity of the reaction and the yield of the target product, while the illumination power can balance the free radical generation efficiency and system stability, avoiding the problem of over-reaction caused by excessive power or the problem of insufficient catalytic effect due to insufficient power.

[0027] In one embodiment of the present invention, the reaction temperature is 20°C-30°C.

[0028] In one embodiment of the present invention, the amount of chlorine source used is 5-15 equivalents of the steroid compound.

[0029] In one embodiment of the present invention, the concentration of the steroidal compound in the electrolyte solution is 0.005 mmol / mL to 0.02 mmol / mL. When the concentration is below 0.005 mmol / mL, the steroidal compound molecules are sparsely distributed in the system, and the probability of collisions between chlorine radicals induced by energization and light and substrate molecules is greatly reduced, resulting in a slower reaction rate and a higher likelihood of side reactions, leading to a decrease in yield. When the concentration is above 0.02 mmol / mL, the substrate and chlorine source are difficult to dissolve effectively in the solvent, and the turbidity of the system affects the passage of light, which is not conducive to the generation of chlorine radicals. Excessive concentration of chlorine source may induce side reactions such as polychlorination or chlorine addition, reducing the selectivity and yield of the target product. Within this concentration range, the collision frequency of substrate molecules and the mass transfer efficiency of the system can be balanced, which can ensure the efficient reaction of chlorine radicals with steroidal compounds and avoid the disadvantages caused by excessively high or low concentrations, thus helping the free radical reaction to proceed in a targeted manner and maximizing the yield.

[0030] In one embodiment of the present invention, the concentration of the electrolyte solution is 0.045 mol / L to 0.055 mol / L.

[0031] In one embodiment of the present invention, the reaction is carried out under a protective atmosphere and includes the following steps: adding a steroidal compound and a chlorine source into a reaction vessel, sealing it, purging it with a protective atmosphere, then adding an electrolyte solution, purging it again with a protective atmosphere and maintaining the protective atmosphere, and carrying out the reaction under the conditions of electricity and light to obtain a chlorinated steroidal compound.

[0032] In one embodiment of the invention, the protective atmosphere is selected from nitrogen and / or argon.

[0033] In one embodiment of the present invention, the products corresponding to IS-1 and IS-2 are 9α-chlorosteroid compounds;

[0034] The products corresponding to II-S-1 and II-S-2 are 14β-chlorosteroid compounds;

[0035] The product corresponding to III-S is a 17α-chlorosteroid compound;

[0036] The product corresponding to IV-S is a 5α-chlorosteroid compound.

[0037] In one embodiment of the present invention, the chlorosteroid compound corresponding to the steroid compound is as follows:

[0038] .

[0039] The technical solution of the present invention has the following advantages compared with the prior art:

[0040] (1) The site-directed chlorination method of the present invention adopts a photo-electro-catalytic synergistic strategy. By controlling the types of solute and solvent in the electrolyte solution, and combining chlorine sources such as pyridine hydrochloride, hydrochloric acid, and magnesium chloride that are stable and easy to post-process, highly active chlorine radicals can be generated. This method can not only achieve chlorination of multiple sites of steroidal compounds, but also does not require changes in reaction conditions due to changes in chlorination sites. It only requires simple adjustment of the chain length of the iodine-containing directing group or the position of the iodine atom in the substrate. At the same time, it has strong substrate universality and can tolerate active groups such as hydroxyl groups and unsaturated bonds that are difficult to control in traditional techniques. The mechanism is as follows: after the chlorine radical is generated in situ, it will interact with the iodine atom of the directing group in a non-covalent weak interaction. Under the guidance of the iodine atom in the steroidal compound skeleton, it selectively activates C(sp³)-H bonds with steric hindrance sites such as 5α-, 9α-, 14α- and 17α-, and generates specific alkyl radical intermediates through highly selective hydrogen atom transfer (HAT), thereby achieving precise chlorination. This method can efficiently synthesize specific site monochlorinated steroidal compounds that are difficult to prepare by other methods, and provides a reliable approach to solving the problem of poor regioselectivity in traditional HAT reactions.

[0041] (2) The site-directed chlorination method described in this invention exhibits excellent functional group compatibility with most steroidal compounds, and can tolerate active groups that are difficult to control in traditional techniques, such as unsaturated bonds, ether bonds, and hydroxyl groups. It has stronger substrate universality and can efficiently obtain site-directed monochlorinated products in high yield. The preparation method is simple to operate, has mild reaction conditions, and does not produce toxic byproducts. At the same time, the obtained chlorinated products can be used to construct more different structures through a rapid and efficient dechlorination conversion strategy. This characteristic breaks through the limitation of traditional synthetic methods in introducing complex functional groups into steroidal compounds, and provides an efficient way for the diverse modification of steroidal compounds, showing significant application value in the fields of drug molecule design and synthetic chemistry. Detailed Implementation

[0042] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0043] In this invention, unless otherwise stated, the percentage content mentioned in the specification refers to mass percentage for solid-liquid mixtures and solid-solid mixtures, and to volume percentage for liquid-liquid mixtures.

[0044] In this invention, unless otherwise stated, the percentage concentrations mentioned in the specification refer to the final concentration, that is, the proportion of the added ingredient in the system after its addition.

[0045] In this invention, unless otherwise stated, the hydrochloric acid referred to in the specification refers to a 37% hydrochloric acid aqueous solution;

[0046] Example 1

[0047] The site-directed chlorination method for steroidal compounds in this embodiment specifically includes the following steps:

[0048] The steroid compound IS-1a (1.0 equivalent) and the chlorine source HCl (5.0 equivalent) were added to a pre-dried 10 mL double-necked glass electrochemical reaction tube equipped with a magnetic stir bar, rubber stopper, threaded PTFE cap, and a diameter of 0.3 × 1.0 × 1.0 cm. 3 Graphite anode and 0.02×1.0×1.0cm 3A platinum foil cathode (0.5 cm between two electrodes, without a separate electrolytic cell) was sealed and purged with nitrogen for 5 min. Then, an electrolyte solution with a concentration of 0.05 mol / L (solute: TBAClO4, solvent volume: 5 mL) was added through a syringe. After purging with nitrogen for another 5 min, a nitrogen balloon was connected to maintain the nitrogen atmosphere. The reaction was started at room temperature (25 °C). While the electrode was powered on (6 mA), a blue light source (wavelength: 456 nm, power: 10 W) was placed 5 cm away from the reaction tube for irradiation, and a fan was turned on for effective heat dissipation. After the reaction was completed for 6 h, the residue on the electrode surface was washed with ethyl acetate and the organic phases were combined. After dilution with water, the mixture was extracted three times with ethyl acetate. The organic phase was dried and concentrated with anhydrous sodium sulfate. The residue was purified by silica gel rapid column chromatography to obtain the chlorosteroid compound IP-1a.

[0049]

[0050] The amount of steroid compound IS-1a, the choice of solvent, and the yield are shown in Table 1.

[0051] Table 1

[0052]

[0053] Example 2

[0054] The experiment was basically the same as in Example 1, except that the amount of steroid compound IS-1a was 0.05 mmol and the solvent was MeCN / EtOAc (3 / 2). The effects of different energizing and light irradiation conditions on the yield were investigated.

[0055] The power supply conditions, lighting conditions, and yield are shown in Table 2.

[0056] Table 2

[0057]

[0058] Example 3

[0059] The reaction was basically the same as in Example 1, except that the amount of steroidal compound IS-1a was 0.05 mmol, the solvent was MeCN / EtOAc (3 / 2), the wavelength of the light source was 390 nm and the power was 10 W, and the reaction time was 2 h. The effects of different electrolyte salts and chlorine sources on the yield were investigated.

[0060] The selection of electrolyte salts, the selection and dosage of chlorine source, and the yield are shown in Table 3.

[0061] Table 3

[0062]

[0063] Example 4

[0064] The reaction was basically the same as in Example 1, except that the amount of steroid compound used was 0.05 mmol, the chlorine source was pyridine hydrochloride (10.0 equivalents), the solute of the electrolyte solution was TBABF4, the solvent was MeCN / EtOAc (3 / 2), the voltage was 3.0 V, the wavelength of the light source was 390 nm and the power was 10 W, and the reaction time was 2 h. The effects of different steroid compounds on the yield were investigated.

[0065] The yield and other information of chlorosteroid compounds prepared from different steroid compounds are as follows:

[0066] (1) IP-1a: Yield 90%; white solid; melting point 50℃-52℃. f =0.3(nHex / EtOAc, 20:1). 1 H NMR(400 MHz, CDCl3) δ 8.48-8.45(m, 1H), 8.07-8.03(m, 1H), 7.89-7.85(m, 1H), 7.21-7.16(m, 1H), 5.28-5.22(m, 1H), 2.67-2.58(m,1H), 2.38-2.29(m, 1H), 1.93-1.63(m, 12H), 1.56-1.48(m, 4H), 1.43-1.22(m,12H), 1.10(s, 3H), 0.92(d, J=6.4 Hz, 3H), 0.86(dd, J=6.4, 1.6 Hz, 6H), 0.68 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 164.5, 141.7, 138.9, 133.1, 130.2, 128.9, 94.0, 90.7, 70.7, 55.8, 49.3, 42.8, 42.5, 39.7, 39.4, 36.2, 36.0, 35.9, 33.3,32.3, 29.8, 28.2, 28.2, 28.2, 28.0, 26.4, 26.3, 23.9, 23.8, 23.0, 22.7, 18.8,14.8, 12.1. FT-IR: ν(cm -1 ) 2931, 2865, 1717, 1256, 1239, 1119, 745. HRMS[ASAP] calculated value C 34 H 50 IO2 [M-HCl+H] + 617.2850, measured value 617.2839.

[0067] (2) IP-1b: Yield 85%; white solid; melting point 49℃-51℃. f =0.3(nHex / EtOAc, 20:1). 1 H NMR(400 MHz, CDCl3) δ 8.48-8.46(m, 1H), 8.07-8.03(m, 1H), 7.89-7.85(m, 1H), 7.21-7.16(m, 1H), 5.29-5.25(m, 1H), 2.68-2.58(m,1H), 2.39-2.29(m, 1H), 1.96-1.75(m, 8H), 1.74-1.58(m, 4H), 1.55-1.28(m, 10H),1.24-1.13(m, 4H), 1.11(s, 3H), 1.08-0.95(m, 3H), 0.93(d, J=6.4 Hz, 3H), 0.87-0.80(m, 9H), 0.68(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 164.5, 141.7, 138.9,133.1, 130.2, 128.9, 94.0, 90.7, 70.7, 55.7, 49.3, 46.0, 42.8, 42.5, 39.5,36.3, 36.0, 34.0, 33.3, 32.3, 29.8, 29.3, 28.2, 28.2, 28.0, 26.4, 26.3, 26.1,23.8, 23.2, 20.0, 19.2, 18.8, 14.8, 12.1, 12.1. FT-IR: ν(cm -1 ) 2955, 2932, 2868, 1716, 1264, 1116, 739. HRMS [ASAP] calculated value C 36 H 52 IO2 [M-HCl+H] + 645.3163, measured value 645.3156.

[0068] (3) IP-1c: Yield 76%; white solid; melting point 55℃-57℃. f =0.3(nHex / EtOAc, 20:1). 1H NMR(400 MHz, CDCl3) δ 8.46-8.43(m, 1H), 8.05-8.01(m, 1H), 7.89-7.86(m, 1H), 7.21-7.16(m, 1H), 5.35-5.31(m, 1H), 2.99-2.92(m, 1H), 2.52-2.42(m, 1H), 2.34-2.22(m, 1H), 2.16-1.83(m, 10H), 1.78-1.67(m,4H), 1.58-1.48(m, 2H), 1.46-1.24(m, 6H), 1.21(s, 3H), 1.16-1.06(m, 4H), 0.92(d, J=6.4 Hz, 3H), 0.87(dd, J=6.4, 2.0 Hz, 6H), 0.70(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 164.2, 141.8, 138.8, 132.9, 130.2, 128.8, 94.0, 90.4, 70.3, 55.8, 49.1, 42.7, 41.9, 41.4(q, J=24.7 Hz), 39.6, 36.2, 36.0, 35.9, 35.7, 33.2,31.7, 30.7, 29.4, 28.1, 28.1, 26.1, 25.3, 23.8, 23.7, 23.0, 22.7, 18.7, 17.3(q, J=3.7 Hz), 12.1; 19 F NMR(376 MHz, CDCl3) δ -61.2. FT-IR: ν(cm -1 ) 2951,2868, 1718, 1255, 1115, 1096, 745. HRMS [ASAP] calculated value C 35 H 47 F3IO2 [M-HCl+H] + 685.2724, measured value 685.2722.

[0069] (4) IP-1d: Yield 83%; white solid; melting point 135℃-137℃. f =0.3(nHex / EtOAc, 20:1). 1H NMR(400 MHz, CDCl3) δ 8.48-8.45(m, 1H), 8.07-8.03(m,1H), 7.89-7.85(m, 1H), 7.21-7.16(m, 1H), 5.28-5.25(m, 1H), 2.68-2.59(m, 1H),2.39-2.30(m, 1H), 1.96-1.85(m, 4H), 1.78-1.63(m, 6H), 1.59-1.38(m, 6H), 1.31-1.12(m, 5H), 1.10(s, 3H), 0.72(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 164.4, 141.7,138.9, 133.1, 130.2, 128.9, 94.0, 90.8, 70.6, 47.5, 42.6, 41.0, 40.0, 40.0,34.9, 33.3, 32.3, 29.9, 28.2, 28.0, 26.6, 26.4, 25.0, 20.5, 17.6, 14.7. FT-IR: ν(cm -1 ) 2933, 2860, 1703, 1565, 1255, 1239, 746, 731. HRMS [ASAP] calculated value C 26 H 34 IO2 [M-HCl+H] + 505.1598, measured value 505.1606.

[0070] (5) IP-1e: Yield 82%; white solid; melting point 46℃-48℃. f =0.3(nHex / EtOAc, 10:1). 1H NMR(400 MHz, CDCl3) δ 8.45-8.42(m, 1H), 8.04-8.01(m,1H), 7.86-7.83(m, 1H), 7.19-7.14(m, 1H), 5.26-5.22(m, 1H), 4.20-4.03(m, 2H),2.65-2.56(m, 1H), 2.43(t, J=9.6 Hz, 1H), 2.36-2.26(m, 1H), 2.15-2.04(m, 1H),1.95-1.81(m, 8H), 1.80-1.46(m, 7H), 1.45-1.29(m, 3H), 1.24(t, J=7.2 Hz, 3H),1.07(s, 3H), 0.66(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 173.9, 164.3, 141.6,138.7, 133.0, 130.1, 128.8, 94.0, 90.0, 70.5, 60.0, 54.8, 48.8, 44.0, 42.4,39.6, 34.4, 33.2, 32.2, 29.7, 27.9, 27.9, 26.2, 26.2, 23.9, 23.4, 14.6, 14.6,13.5. FT-IR: ν(cm -1 ) 2933, 2865, 1716, 1281, 1256, 1239, 746. HRMS [ASAP] calculated value C 29 H 39 ClIO4 [M+H] + 613.1576, measured value 613.1584.

[0071] (6) IP-1f: Yield 75%; white solid; melting point 136℃-138℃. f =0.3(nHex / EtOAc, 10:1). 1H NMR(400 MHz, CDCl3) δ 8.45-8.43(m, 1H), 8.05-8.01(m, 1H), 7.87-7.84(m, 1H), 7.20-7.15(m, 1H), 5.55-5.53(m, 1H), 5.28-5.24(m, 1H), 4.14(q, J=7.2 Hz, 2H), 2.87-2.81(m, 2H), 2.67-2.58(m, 1H), 2.38-2.28(m, 1H), 2.05-1.98(m, 3H), 1.92-1.82(m, 3H), 1.76-1.67(m, 4H), 1.65-1.47(m,4H), 1.43-1.37(m, 1H), 1.35-1.30(m, 2H), 1.27(t, J=7.2 Hz, 3H), 1.11(s, 3H),0.83(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 175.1, 167.4, 164.3, 141.7, 138.8,133.0, 130.2, 128.8, 108.9, 94.0, 89.7, 70.5, 59.6, 46.5, 46.3, 42.6, 39.4,33.2, 32.3, 31.6, 30.3, 29.8, 27.9, 27.9, 26.3, 26.1, 23.9, 18.4, 14.7, 14.5.FT-IR: ν(cm -1 ) 2967, 2933, 1715, 1705, 1257, 1177, 745. HRMS [ASAP] calculated value C 30 H 39 ClIO4 [M+H] + 625.1576, measured value 625.1584.

[0072] (7) IP-1g: Yield 88%; white solid; melting point 145℃-147℃. f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.46-8.44(m, 1H), 8.05-8.02(m,1H), 7.89-7.85(m, 1H), 7.21-7.16(m, 1H), 5.29-5.26(m, 1H), 2.68-2.59(m, 1H),2.49(dd, J=19.6, 8.4 Hz, 1H), 2.38-2.29(m, 1H), 2.13-2.00(m, 4H), 1.97-1.84(m, 4H), 1.78-1.67(m, 3H), 1.56-1.48(m, 3H), 1.44-1.26(m, 4H), 1.13(s, 3H), 0.88(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 220.0, 164.4, 141.7, 138.8, 133.0,130.2, 128.8, 94.0, 89.4, 70.4, 47.8, 44.5, 42.6, 39.3, 35.8, 33.2, 32.3,29.3, 27.9, 27.8, 26.3, 25.1, 21.4, 14.7, 13.7. FT-IR: ν(cm -1 ) 2969, 2884,1717, 1681, 1257, 1240, 1037, 747. HRMS [ASAP] calculated value C 26 H 33 ClIO3 [M+H] + 555.1157, measured value 555.1165.

[0073] (8) IP-1h: Yield 84%; white solid; melting point 109℃-111℃. f =0.4(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.45-8.43(m, 1H), 8.05-8.01(m,1H), 7.87-7.84(m, 1H), 7.20-7.15(m, 1H), 5.26-5.23(m, 1H), 2.66-2.56(m, 2H),2.36-2.27(m, 1H), 2.18-2.12(m, 1H), 2.11(s, 3H), 2.03-1.80(m, 8H), 1.75-1.63(m, 3H), 1.53-1.35(m, 4H), 1.29-1.15(m, 3H), 1.08(s, 3H), 0.61 (s, 3H); 13 C NMR(100 MHz, CDCl3) δ 209.4, 164.3, 141.6, 138.8, 133.0, 130.1, 128.8, 94.0,89.9, 70.5, 63.2, 49.4, 44.1, 42.4, 39.4, 35.0, 33.2, 32.2, 31.6, 29.8, 27.9,27.9, 26.3, 26.2, 23.9, 22.7, 14.6, 13.4. FT-IR: ν(cm -1 ) 2933, 2859, 1703, 1255, 1239, 746, 731. HRMS [ASAP] calculated value C 28 H 37 ClIO3 [M+H] + 583.1470, measured value 583.1473.

[0074] (9) IP-1i: Yield 77%; white solid; melting point 60℃-62℃. f =0.4(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.46-8.44(m, 1H), 8.06-8.02(m,1H), 7.88-7.85(m, 1H), 7.21-7.16(m, 1H), 5.28-5.24(m, 1H), 2.67-2.57(m, 2H),2.37-2.29(m, 1H), 2.27(d, J=8.8 Hz, 1H), 2.12(s, 3H), 2.09-2.02(m, 2H), 1.96-1.87(m, 4H), 1.79-1.62(m, 4H), 1.55-1.51(m, 1H), 1.50-1.45(m, 1H), 1.42-1.36(m, 2H), 1.33-1.25(m, 2H), 1.20-1.14(m, 1H), 1.08(s, 3H), 0.95(d, J=6.8 Hz,3H), 0.64(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 209.3, 164.3, 141.6, 138.8, 133.0,130.2, 128.8, 94.0, 90.0, 72.6, 70.5, 48.0, 45.8, 42.5, 39.3, 35.2, 33.2,32.7, 32.3, 32.2, 31.0, 29.7, 27.9, 27.9, 26.3, 26.1, 22.2, 14.7, 14.1. FT-IR: ν(cm -1 ) 2933, 2864, 1715, 1702, 1257, 1239, 747. HRMS [ESI] calculated value C 29 H 38 ClIO3Na [M+Na] + 619.1446, measured value 619.1448.

[0075] (10) IP-1j: Yield 66%; white solid; melting point 180℃-182℃. R f =0.3(nHex / EtOAc, 10:1). 1H NMR(400 MHz, CDCl3) δ 8.47-8.44(m, 1H), 8.07-8.03(m, 1H), 7.89-7.85(m, 1H), 7.20-7.15(m, 1H), 5.28-5.25(m, 1H), 3.96-3.84(m,4H), 2.68-2.59(m, 1H), 2.39-2.30(m, 1H), 2.22-2.11(m, 2H), 2.01-1.82(m, 6H),1.80-1.62(m, 3H), 1.55-1.37(m, 4H), 1.33-1.27(m, 2H), 1.24-1.15(m, 2H), 1.11(s, 3H), 0.87(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 164.5, 141.7, 138.8, 133.1,130.2, 128.9, 119.1, 94.0, 89.6, 70.6, 65.3, 64.8, 46.1, 43.7, 42.5, 39.9,34.3, 33.3, 32.3, 29.3, 28.0, 27.9, 27.3, 26.4, 25.5, 22.3, 14.7, 14.4. FT-IR: ν(cm -1 ) 2943, 2869, 1709, 1282, 1261, 1113, 747. HRMS [ASAP] calculated value C 28 H 37 ClIO4 [M+H] + 599.1420, measured value 599.1430.

[0076] (11) IP-1k: Yield 63%; white solid; melting point 66℃-68℃. f =0.4(nHex / EtOAc, 10:1). 1H NMR(400 MHz, CDCl3) δ 8.47-8.45(m, 1H), 8.06-8.03(m, 1H), 7.89-7.86(m, 1H), 7.21-7.16(m, 1H), 5.28-5.25(m, 1H), 4.46-4.40(m, 1H), 3.50-3.45(m, 1H), 3.36(t, J=11.2 Hz, 1H), 2.67-2.58(m, 1H), 2.36-2.28(m, 1H), 2.15-2.07(m, 1H), 1.95-1.85(m, 7H), 1.81-1.62(m, 6H), 1.57-1.36(m, 7H), 1.33-1.25(m, 3H), 1.12(s, 3H), 0.97(d, J=6.4 Hz, 3H), 0.80-0.77(m,6H); 13 C NMR(100 MHz, CDCl3) δ 164.4, 141.7, 138.9, 133.1, 130.2, 128.9,109.4, 94.0, 90.1, 80.7, 70.6, 67.0, 62.1, 49.1, 42.6, 41.7, 40.8, 39.2,35.9, 33.3, 32.2, 31.6, 31.3, 30.4, 29.7, 29.0, 28.0, 27.9, 26.4, 26.4, 17.3,16.5, 14.7, 14.7. FT-IR: ν(cm -1 ) 2950, ​​2927, 2858, 1717, 1259, 1241, 747. HRMS[ASAP] calculated value C 34 H 47 ClIO4 [M+H] + 681.2202, measured value 681.2209.

[0077] (12) IP-1l: Yield 81%; white solid; melting point 81℃-83℃. f =0.4(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.45-8.43(m, 1H), 8.05-8.01(m, 1H), 7.88-7.84(m, 1H), 7.20-7.16(m, 1H), 5.27-5.24(m, 1H), 4.99-4.93(m,1H), 2.64-2.55(m, 2H), 2.35-2.26(m, 1H), 2.24-2.17(m, 1H), 2.10-2.03(m, 1H),2.00(d, J=7.6 Hz, 1H), 1.97-1.90(m, 3H), 1.89-1.85(m, 1H), 1.77-1.66(m, 3H),1.62-1.44(m, 5H), 1.43-1.35(m, 2H), 1.31(d, J=7.6 Hz, 3H), 1.10(s, 3H), 0.87-0.81(m, 1H), 0.76(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 181.2, 164.3, 141.6,138.8, 133.0, 130.2, 128.8, 94.0, 89.8, 82.5, 70.4, 58.7, 47.6, 42.5, 41.9,38.9, 36.1, 34.3, 33.2, 32.5, 32.2, 29.3, 27.9, 27.8, 26.3, 26.2, 18.0, 14.7,13.8. FT-IR: ν(cm -1 ) 2931, 2859, 1768, 1714, 1258, 1239, 747. HRMS [ESI] calculated value C 29 H 36 ClIO4Na [M+Na] + 633.1239, measured value 633.1237.

[0078] (13) IP-1m: Yield 60%; white solid; melting point 82℃-84℃. f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.46-8.44(m, 1H), 8.05-8.01(m,1H), 7.88-7.84(m, 1H), 7.20-7.15(m, 1H), 5.27-5.24(m, 1H), 3.76(t, J=8.4 Hz,1H), 2.66-2.57(m, 1H), 2.37-2.27(m, 1H), 2.11-2.02(m, 1H), 2.00-1.86(m, 4H),1.77-1.70(m, 3H), 1.67-1.62(m, 2H), 1.54-1.37(m, 6H), 1.29-1.19(m, 3H), 1.10(s, 3H), 0.76(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 164.4, 141.6, 138.8, 133.0,130.2, 128.8, 94.0, 90.4, 81.3, 70.6, 44.1, 43.3, 42.5, 39.6, 33.2, 32.8,32.3, 30.5, 29.6, 27.9, 27.9, 26.3, 25.7, 23.0, 14.7, 11.2. FT-IR: ν(cm -1 )3389, 2933, 2861, 1716, 1258, 1240, 747. HRMS [ASAP] calculated value C 26 H 33 ClIO3 [MH] - 555.1168, measured value 555.1161.

[0079] (14) IP-1n: Yield 71%; white solid; melting point 81℃-83℃. f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.13-8.11(m, 1H), 7.83-7.79(m,1H), 7.71-7.67(m, 1H), 7.19-7.14(m, 1H), 6.38(d, J=7.2 Hz, 1H), 4.32-4.27(m,1H), 2.44(dd, J=19.6, 8.4 Hz, 1H), 2.37-2.28(m, 1H), 2.16-1.94(m, 6H), 1.92-1.84(m, 1H), 1.83-1.76(m, 3H), 1.72-1.66(m, 1H), 1.59-1.53(m, 3H), 1.52-1.43(m, 2H), 1.38-1.26(m, 3H), 1.13(s, 3H), 0.88(s, 3H); 13 C NMR (100 MHz, CDCl3) δ219.9, 165.3, 140.4, 137.2, 136.4, 130.4, 126.0, 94.5, 90.2, 47.8, 45.1,44.5, 42.7, 39.2, 35.8, 32.9, 32.7, 29.8, 29.3, 27.9, 27.9, 27.9, 25.9, 25.1,21.4, 14.8, 13.7. FT-IR: ν(cm -1 ) 3316, 2926, 2860, 1733, 1637, 1520, 1260,747, 729. HRMS [ESI] calculated value C 26 H 33 ClINO2Na [M+Na] + 576.1137, measured value 576.1141.

[0080] (15) IP-1o: Yield 70%; white solid; melting point 61℃-63℃. f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.27-8.22(m, 1H), 7.97-7.92(m,1H), 7.90-7.86(m, 1H), 7.30-7.25(m, 1H), 4.88-4.82(m, 1H), 2.47-2.32(m, 2H),2.17-2.00(m, 4H), 1.95-1.75(m, 5H), 1.68-1.55(m, 3H), 1.53-1.35(m, 4H), 1.32-1.23(m, 1H), 1.20-1.09(m, 2H), 1.00(s, 3H), 0.84(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 219.8, 142.4, 139.8, 136.1, 130.8, 126.6, 94.1, 88.1, 80.5, 47.7,44.3, 42.2, 39.1, 35.8, 33.6, 31.6, 29.2, 27.8, 27.6, 27.2, 26.9, 24.9, 21.3,14.5, 13.7. FT-IR: ν(cm -1 ) 2958, 2930, 2902, 1735, 1356, 1181, 897, 751. HRMS[ASAP] calculated value C 25 H 33 ClISO4 [M+H] + 591.0827, measured value 591.0835.

[0081] (16) IP-2a: Yield 73%; white solid; melting point 170℃-172℃. f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.41-8.39(m, 1H), 8.02-7.99(m,1H), 7.89-7.85(m, 1H), 7.21-7.16(m, 1H), 5.05-5.03(m, 1H), 2.58-2.50(m, 1H),2.37-2.25(m, 6H), 2.19-2.15(m, 2H), 2.11-2.03(m, 2H), 2.02-1.94(m, 2H), 1.85-1.70(m, 4H), 1.65-1.52(m, 2H), 1.46-1.41(m, 2H), 1.27(s, 3H), 0.84(s, 3H); 13 CNMR(100 MHz, CDCl3) δ 211.0, 164.7, 141.8, 138.7, 132.7, 130.2, 128.8, 94.0,88.3, ​​82.4, 45.3, 44.8, 43.4, 42.0, 39.7, 38.7, 37.9, 33.1, 30.0, 29.7, 28.7,28.3, 26.3, 24.1, 16.5, 14.7. FT-IR: ν(cm -1 ) 2957, 2937, 2866, 1703, 1280, 1260, 743. HRMS [ASAP] calculated value C 26 H 33 ClIO3 [M+H] + 555.1157, measured value 555.1167.

[0082] (17) IP-2b: Yield 33%; white solid; melting point 162℃-164℃. f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.40-8.38(m, 1H), 8.03-7.99(m,1H), 7.89-7.85(m, 1H), 7.21-7.16(m, 1H), 5.06-5.03(m, 1H), 2.86-2.79(m, 2H),2.38-2.22(m, 4H), 2.21-2.17(m, 1H), 2.16-2.06(m, 5H), 2.04-1.98(m, 2H), 1.79-1.74(m, 1H), 1.71-1.64(m, 2H), 1.56-1.44(m, 3H), 1.42(s, 3H), 1.23(d, J=7.2Hz, 3H), 0.84(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 210.8, 164.7, 141.8, 138.7,132.7, 130.2, 128.8, 94.0, 87.2, 82.5, 48.8, 45.4, 45.2, 44.9, 42.7, 41.2,40.5, 34.3, 30.0, 29.2, 28.9, 28.0, 26.1, 24.1, 20.5, 19.4, 16.5. FT-IR: ν(cm -1 ) 2954, 2927, 1713, 1277, 1258, 1118, 742. HRMS [ASAP] calculated value C 27 H 35 ClIO3 [M+H] + 569.1314, measured value 569.1320.

[0083] (18) IP-2c: Yield 83%; white solid; melting point 69℃-71℃. f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.40-8.38(m, 1H), 8.01-7.98(m,1H), 7.87-7.84(m, 1H), 7.80-7.76(m, 2H), 7.34-7.30(m, 2H), 7.20-7.15(m, 1H),5.01(d, J=6.0 Hz, 1H), 4.42-4.33(m, 1H), 2.43(s, 3H), 2.30-2.21(m, 2H), 2.13-2.00(m, 2H), 1.96-1.74(m, 6H), 1.70-1.60(m, 3H), 1.58-1.34(m, 6H), 1.30-1.26(m, 1H), 1.23-1.17(m, 1H), 1.04(s, 3H), 0.78(s, 3H); 13 C NMR(100 MHz, CDCl3) δ164.6, 144.5, 141.7, 138.6, 134.6, 132.7, 130.2, 129.9, 128.8, 127.7, 94.0,89.0, 82.3, 81.5, 45.2, 43.4, 41.7, 39.6, 36.7, 35.0, 31.5, 30.0, 29.4, 28.2,28.2, 28.1, 26.4, 24.0, 21.7, 16.4, 15.3. FT-IR: ν(cm -1 ) 2934, 2868, 1716,1257, 1175, 932, 745, 670. HRMS [ESI] calculated value C 33 H 40 ClISO5Na [M+Na] + 733.1222, measured value 733.1221.

[0084] (19) IP-2d: Yield 87%; white solid; melting point 162℃-164℃. f =0.3(nHex / EtOAc, 10:1). 1H NMR(400 MHz, CDCl3) δ 8.41-8.39(m, 1H), 8.02-7.99(m,1H), 7.88-7.85(m, 1H), 7.21-7.16(m, 1H), 5.02(d, J=6.0 Hz, 1H), 4.74-4.65(m,1H), 2.34-2.17(m, 3H), 2.12-2.04(m, 1H), 2.01(s, 3H), 2.00-1.71(m, 7H), 1.67-1.63(m, 1H), 1.60-1.44(m, 4H), 1.41-1.31(m, 3H), 1.29-1.21(m, 2H), 1.09(s,3H), 0.80(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 170.6, 164.7, 141.7, 138.7, 132.7,130.2, 128.8, 94.0, 89.1, 82.4, 73.0, 45.3, 43.5, 42.1, 39.7, 36.5, 34.3,31.5, 30.0, 29.5, 28.3, 28.3, 27.4, 26.5, 24.1, 21.5, 16.5, 15.4. FT-IR: ν(cm -1 ) 2944, 2879, 1733, 1712, 1277, 1261, 1241, 743. HRMS [ESI] calculated value C 28 H 36 ClIO4Na [M+Na] + 621.1239, measured value 621.1241.

[0085] (20) IP-2e: Yield 71%; white solid; melting point 74℃-76℃. f =0.4(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.40-8.38(m, 1H),8.02-7.98(m, 1H), 7.88-7.84(m, 1H), 7.74-7.67(m, 4H), 7.45-7.41(m, 2H), 7.20-7.15(m, 1H), 6.87-6.83(m, 1H), 5.01(d, J=6.0 Hz, 1H), 4.85-4.76(m, 1H), 2.31-2.16(m, 3H), 2.11-2.00(m, 1H), 1.99-1.86(m, 4H), 1.81-1.75(m, 1H), 1.73-1.66(m, 2H), 1.65(s, 6H), 1.60-1.53(m, 2H), 1.52-1.42(m, 3H), 1.40-1.39(m, 3H),1.28-1.21(m, 2H), 1.04(s, 3H), 0.79(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 194.3,173.1, 164.6, 159.8, 141.7, 138.7, 138.4, 136.5, 132.7, 132.0, 131.3, 130.3,130.2, 128.8, 128.6, 117.4, 94.0, 89.0, 82.4, 79.5, 77.5, 74.4, 45.2, 43.4,42.1, 39.7, 36.5, 33.9, 31.3, 30.0, 29.4, 28.3, 28.2, 27.1, 26.5, 25.6, 25.4,24.0, 16.5, 15.4. FT-IR: ν(cm -1 ) 2970, 2936, 2871, 1717, 1653, 1597, 1276,1257, 1141, 927, 763, 747. HRMS [ASAP] calculated value C 43 H 48 Cl2IO6 [M+H] + 857.1867, measured value 857.1871.

[0086] (twenty one) IP-2f: Yield 75%; white solid; melting point 65℃-67℃. f =0.4(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.40-8.37(m, 1H), 8.01-7.97(m, 1H), 7.87-7.83(m, 1H), 7.19-7.14(m, 1H), 5.14-5.03(m, 1H), 5.01(d, J=5.6Hz, 1H), 4.78-4.68(m, 1H), 4.28-4.16(m, 1H), 2.32-2.16(m, 3H), 2.10-2.02(m,1H), 2.01-1.83(m, 6H), 1.78-1.71(m, 1H), 1.69-1.61(m, 2H), 1.60-1.51(m, 3H),1.50-1.44(m, 2H), 1.42(s, 9H), 1.34(d, J=7.2 Hz, 3H), 1.30-1.19(m, 3H), 1.08(s, 3H), 0.79(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 172.9, 164.6, 155.2, 141.7,138.7, 132.7, 130.2, 128.7, 94.0, 89.0, 82.4, 79.7, 73.9, 49.4, 45.2, 43.4,42.0, 39.7, 36.5, 34.0, 31.4, 30.0, 29.4, 28.4, 28.3, 28.2, 27.2, 26.5, 24.0,18.9, 16.5, 15.4. FT-IR: ν(cm -1 ) 3370, 2934, 2869, 1713, 1257, 1163, 745, 730.HRMS [ESI] calculated value C 34 H 47 ClINO6Na [M+Na] + 750.2029, measured value 750.2035.

[0087] (twenty two) IP-2h: Yield 83%; white solid; melting point 147℃-149℃. f =0.4(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.40-8.37(m, 1H), 8.01-7.98(m,1H), 7.89-7.86(m, 1H), 7.21-7.16(m, 1H), 5.86-5.84(m, 1H), 5.07(d, J=6.0 Hz,1H), 2.81-2.71(m, 1H), 2.56-2.47(m, 1H), 2.46-2.38(m, 3H), 2.38-2.20(m, 3H),2.17-2.10(m, 1H), 2.06-2.02(m, 2H), 1.94-1.89(m, 1H), 1.88-1.79(m, 3H), 1.78-1.69(m, 2H), 1.45(s, 3H), 1.35-1.29(m, 1H), 0.87(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.4, 166.3, 164.7, 141.8, 138.7, 132.6, 130.3, 128.8, 126.4, 94.0,86.5, 82.1, 45.6, 45.0, 43.8, 39.1, 34.1, 31.2, 30.7, 30.0, 28.9, 27.9, 26.4,24.1, 20.5, 16.4. FT-IR: ν(cm -1 ) 2947, 2927, 2880, 1715, 1664, 1261, 1111,744. HRMS [ESI] calculated value C 26 H 30 ClIO3Na [M+Na] + 575.0820, measured value 575.0819.

[0088] (twenty three) IP-2i: Yield 35%; white solid; melting point 85℃-87℃. f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.39-8.37(m, 1H), 8.01-7.98(m,1H), 7.89-7.86(m, 1H), 7.21-7.16(m, 1H), 5.97-5.95(m, 1H), 5.07(d, J=6.0 Hz,1H), 2.60-2.50(m, 3H), 2.36-2.23(m, 5H), 2.22-2.15(m, 2H), 2.07-1.98(m, 1H),1.87-1.75(m, 4H), 1.74-1.69(m, 2H), 1.51-1.45(m, 1H), 1.36-1.28(m, 1H), 0.89(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 198.9, 164.7, 161.1, 141.8, 138.7, 132.6,130.3, 128.8, 127.3, 94.0, 82.2, 80.4, 48.9, 45.3, 45.1, 43.0, 36.3, 34.5,34.3, 30.0, 28.0, 26.1, 23.9, 22.1, 16.5. FT-IR: ν(cm -1 ) 2969, 2943, 1713, 1655, 1277, 1260, 748. HRMS [ESI] calculated value C 25 H 28 ClIO3Na [M+Na] + 561.0664, measured value 561.0670.

[0089] (twenty four) IP-2j: Yield 40%; pale yellow solid; melting point 231℃-233℃. R f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.37-8.35(m, 1H), 7.99-7.95(m, 1H), 7.88-7.84(m, 1H), 7.18-7.14(m, 1H), 7.03(d, J=10.4 Hz, 1H), 6.30(dd,J=10.4, 2.0 Hz, 1H), 6.18-6.16(m, 1H), 5.06(d, J=6.0 Hz, 1H), 2.61-2.51(m,1H), 2.49-2.43(m, 1H), 2.37-2.21(m, 3H), 2.16-2.03(m, 3H), 1.84-1.69(m, 5H),1.54-1.49(m, 1H), 1.45(s, 3H), 0.90(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 186.2,164.6, 163.9, 151.9, 141.9, 138.7, 132.5, 130.2, 129.3, 128.8, 126.8, 94.0,82.4, 82.0, 49.7, 45.1, 43.1, 39.6, 31.9, 30.2, 30.0, 28.0, 27.6, 24.1, 22.2,16.5. FT-IR: ν(cm -1 ) 2959, 2922, 2863, 1708, 1660, 1621, 1276, 1261, 745. HRMS[ESI] calculated value C 26 H 28 ClIO3Na [M+Na] + 573.0664, measured value 573.0660.

[0090] (25) IP-2k: Yield 83%; pale yellow solid; melting point 214-216℃. R f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.48-8.46(m, 1H), 8.05-8.02(m, 1H), 7.92-7.89(m, 1H), 7.23-7.18(m, 1H), 5.85-5.83(m, 1H), 3.05-2.96(m, 1H), 2.85-2.76(m, 1H), 2.70-2.57(m, 2H), 2.55-2.47(m, 1H), 2.46-2.42(m,2H), 2.39-2.33(m, 1H), 2.24-2.16(m, 1H), 2.08(s, 3H), 2.06-2.02(m, 2H), 1.92-1.84(m, 2H), 1.82-1.74(m, 1H), 1.72-1.62(m, 2H), 1.57-1.51(m, 1H), 1.46(s,3H), 1.41-1.32(m, 1H), 0.74(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 203.6, 198.2,165.9, 164.2, 142.4, 139.0, 131.7, 130.4, 129.0, 126.4, 97.0, 94.2, 86.4,47.2, 45.5, 45.4, 38.8, 34.1, 31.0, 30.7, 30.1, 29.0, 27.6, 26.5, 26.1, 23.2,20.5, 14.4. FT-IR: ν(cm -1 ) 2973, 2884, 1717, 1672, 1303, 1266, 749, 726. HRMS[ESI] calculated value C 28 H 33 ClIO4 [M+H] + 595.1107, measured value 595.1102.

[0091] (26) IP-2l: Yield 78%; pale yellow solid; melting point 197℃-199℃. f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.47-8.45(m, 1H), 8.05-8.01(m, 1H), 7.92-7.89(m, 1H), 7.22-7.18(m, 1H), 5.92-5.90(m, 1H), 3.05-2.96(m, 1H), 2.84-2.75(m, 1H), 2.71-2.56(m, 2H), 2.53-2.47(m, 1H), 2.46-2.41(m,2H), 2.30-2.22(m, 1H), 2.07(s, 3H), 2.06-2.01(m, 2H), 1.93-1.85(m, 2H), 1.73-1.65(m, 2H), 1.57-1.51(m, 2H), 1.47(s, 3H), 1.41-1.34(m, 1H), 1.11(d, J=6.4Hz, 3H), 0.74(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 203.6, 198.6, 167.0, 164.2,142.4, 139.0, 131.7, 130.4, 129.0, 124.4, 96.9, 94.2, 87.0, 47.2, 45.8, 45.2,38.6, 35.1, 33.9, 32.8, 31.2, 30.1, 29.1, 27.7, 26.5, 23.1, 21.3, 18.1, 14.4.FT-IR: ν(cm -1 ) 2969, 2880, 1718, 1699, 1662, 1292, 1268, 750. HRMS [ESI] calculated value C 29 H 35 ClIO4 [M+H] + 609.1263, measured value 609.1266.

[0092] (27) IP-2m: Yield 65%; white solid; melting point 255℃-257℃. f =0.3(nHex / EtOAc, 1:1). 1H NMR(400 MHz, CDCl3) δ 8.49-8.46(m, 1H), 8.06-8.02(m, 1H), 7.95-7.91(m, 1H), 7.24-7.19(m, 1H), 5.86-5.84(m, 1H), 4.98-4.93(m,1H), 4.63-4.57(m, 1H), 2.98-2.89(m, 1H), 2.86-2.76(m, 1H), 2.66-2.56(m, 2H),2.52-2.43(m, 3H), 2.40-2.33(m, 1H), 2.36-2.19(m, 1H), 2.15(s, 3H), 2.10-2.05(m, 2H), 2.04-1.98(m, 1H), 1.91-1.85(m, 1H), 1.83-1.77(m, 2H), 1.72-1.62(m,2H), 1.46(s, 3H), 1.45-1.38(m, 1H), 0.82(s, 3H); 13 C NMR (100 MHz, CDCl3) δ198.7, 198.2, 170.7, 165.8, 164.6, 142.7, 139.2, 131.4, 130.5, 129.1, 126.5,95.8, 94.2, 86.4, 67.3, 48.3, 45.6, 45.4, 38.8, 34.1, 31.0, 30.7, 30.7, 29.1,26.8, 26.2, 23.1, 20.6, 20.5, 13.7. FT-IR: ν(cm -1 ) 2954, 2934, 2876, 1730, 1714, 1667, 1237, 1079, 747. HRMS [ESI] calculated value C 30 H 34 ClIO6Na [M+Na] + 675.0981, measured value 675.0987.

[0093] (28) IP-2n: Yield 74%; white solid; melting point 219℃-221℃. f =0.2(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.39-8.36(m, 1H), 8.00-7.97(m, 1H), 7.92-7.89(m, 1H), 7.23-7.18(m, 1H), 5.85-5.82(m, 1H), 2.83-2.74(m,1H), 2.61-2.33(m, 9H), 2.26-2.18(m, 1H), 2.11-2.06(m, 2H), 1.92-1.85(m, 1H),1.83-1.74(m, 2H), 1.71-1.62(m, 2H), 1.48(s, 3H), 1.12(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.1, 165.4, 162.7, 142.6, 138.9, 131.1, 130.5, 128.9, 126.5, 116.9, 94.1, 85.9, 80.8, 49.7, 45.5, 43.1, 39.2, 35.1, 34.1, 30.9, 30.7,28.8, 26.3, 26.1, 23.3, 20.4, 15.8. FT-IR: ν(cm -1 ) 2943, 2870, 2360, 1735, 1673, 1259, 1232, 745, 729. HRMS [ESI] calculated value C 27 H 30 ClINO3 [M+H] + 578.0953, measured value 578.0951.

[0094] (29) IP-2o: Yield 72%; white solid; melting point 79-81℃. f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.37-8.34(m, 1H), 8.00-7.96(m,1H), 7.87-7.83(m, 1H), 7.19-7.14(m, 1H), 5.82-5.79(m, 1H), 5.05(d, J=6.0 Hz,1H), 4.81-4.72(m, 1H), 2.82(d, J=10.8 Hz, 1H), 2.73-2.63(m, 2H), 2.52-2.42(m,2H), 2.41-2.26(m, 2H), 2.22-2.13(m, 1H), 2.11-2.05(m, 1H), 2.04(s, 3H), 2.01-1.89(m, 2H), 1.83-1.77(m, 1H), 1.75-1.64(m, 2H), 1.51-1.47(m, 1H), 1.47(s,3H), 1.42-1.37(m, 1H), 0.81(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 197.0, 170.3,164.7, 159.7, 141.8, 138.6, 132.5, 130.2, 128.8, 126.4, 94.0, 85.0, 81.1,71.1, 51.6, 45.5, 39.8, 37.7, 30.8, 30.3, 29.2, 27.7, 27.3, 25.8, 21.3, 20.9,16.4. FT-IR: ν(cm -1 ) 2968, 2946, 2884, 1725, 1717, 1681, 1256, 1238, 747, 730.HRMS [ESI] calculated value C 28 H 32 ClIO5Na [M+Na] + 633.0875, measured value 633.0879.

[0095] (30) II-P-1a: Yield 65%; white solid; melting point 147℃-149℃. R f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 7.66-7.63(m, 2H), 7.06-7.02(m, 2H), 5.01-4.97(m, 1H), 3.55(s, 2H), 2.56-2.51(m, 2H), 2.50-2.42(m, 1H),2.36-2.30(m, 1H), 2.29-2.24(m, 1H), 1.97-1.90(m, 1H), 1.72-1.65(m, 1H), 1.63-1.53(m, 2H), 1.46-1.42(m, 3H), 1.41-1.38(m, 2H), 1.29-1.25(m, 1H), 1.24(s,3H), 1.22-1.15(m, 4H), 0.99-0.90(m, 2H), 0.75(s, 3H); 13 C NMR(100 MHz, CDCl3)δ 218.7, 170.2, 137.6, 134.4, 131.5, 92.4, 88.8, 70.5, 55.8, 50.5, 42.5,41.7, 39.7, 36.3, 33.4, 32.8, 32.5, 32.2, 30.1, 27.9, 27.2, 25.9, 19.3, 16.6,11.2. FT-IR: ν(cm -1 ) 2970, 2923, 2861, 1730, 1256, 1133, 764, 751. HRMS [ESI] calculated value C 27 H 34 ClIO3Na [M+Na] + 591.1133, measured value 591.1139.

[0096] (31) II-P-1b: Yield 44%; white solid; melting point 150℃-152℃. R f =0.3(nHex / EtOAc, 10:1). 1H NMR(400 MHz, CDCl3) δ 8.13-8.10(m, 2H),7.67-7.64(m, 2H), 7.58-7.53(m, 1H), 7.47-7.42(m, 2H), 7.07-7.03(m, 2H), 5.09(dd, J=8.0, 3.2 Hz, 1H), 5.02-4.98(m, 1H), 3.56(s, 2H), 2.60-2.51(m, 1H), 2.42-2.35(m, 1H), 2.34-2.22(m, 2H), 2.13-2.03(m, 1H), 1.97-1.89(m, 1H), 1.72-1.66(m, 1H), 1.64-1.58(m, 2H), 1.56-1.49(m, 1H), 1.47-1.40(m, 3H), 1.36-1.29(m, 2H), 1.28-1.25(m, 1H), 1.24(s, 3H), 1.22-1.07(m, 3H), 1.00-0.87(m, 2H),0.76(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.3, 166.4, 137.6, 134.4, 132.9,131.5, 130.8, 129.9, 128.5, 92.5, 91.1, 82.7, 70.7, 51.4, 50.4, 43.3, 41.7,39.8, 36.3, 35.9, 35.2, 32.9, 32.6, 29.6, 28.8, 28.2, 26.0, 19.9, 16.9, 11.3.FT-IR: ν(cm -1 ) 2941, 2919, 2859, 1723, 1709, 1276, 1255, 1113, 714. HRMS[ASAP] calculated value C 34 H 39 ClIO4 [MH] - 673.1587, measured value 673.1584.

[0097] (32) II-P-1c: Yield 40%; white solid; melting point 80℃-82℃. R f =0.3(nHex / EtOAc, 10:1). 1H NMR(400 MHz, CDCl3) δ 7.65-7.62(m, 2H),7.27-7.24(m, 2H), 7.09-7.02(m, 4H), 5.00-4.96(m, 1H), 4.77(dd, J=8.0, 3.2 Hz,1H), 3.71(q, J=7.2 Hz, 1H), 3.54(s, 2H), 2.43(d, J=7.2 Hz, 2H), 2.42-2.29(m,2H), 2.25-2.11(m, 2H), 1.92-1.78(m, 3H), 1.70-1.63(m, 1H), 1.59-1.54(m, 1H),1.52(d, J=7.2 Hz, 3H), 1.48-1.36(m, 5H), 1.23-1.13(m, 5H), 0.90(s, 3H), 0.88(d, J=6.8 Hz, 6H), 0.85-0.80(m, 1H), 0.72(s, 3H); 13 C NMR (100 MHz, CDCl3) δ174.5, 170.3, 140.5, 137.9, 137.7, 134.4, 131.5, 129.3, 127.6, 92.5, 90.9,82.3, 70.7, 51.2, 50.3, 45.8, 45.2, 43.2, 41.7, 39.8, 36.3, 35.9, 35.0, 32.9,32.6, 30.3, 29.6, 28.8, 28.2, 26.0, 22.5, 22.5, 19.8, 18.1, 16.4, 11.3. FT-IR: ν(cm -1 ) 2938, 2925, 2855, 1726, 1711, 1232, 1150, 764, 750. HRMS [ASAP] calculated value C 40 H 51 ClIO4 [MH] - 757.2526, measured value 757.2519.

[0098] (33) II-P-1d: Yield 40%; white solid; melting point 60℃-62℃. R f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.23-8.19(m, 2H),7.89-7.85(m, 2H), 7.68-7.62(m, 2H), 7.07-7.01(m, 2H), 5.09(dd, J=8.0, 2.8 Hz,1H), 5.02-4.97(m, 1H), 3.55(s, 2H), 3.09(t, J=7.6 Hz, 4H), 2.61-2.51(m, 1H), 2.41-2.22(m, 3H), 2.13-2.02(m, 1H), 1.96-1.88(m, 1H), 1.72-1.66(m, 1H), 1.63-1.50(m, 7H), 1.46-1.38(m, 3H), 1.36-1.29(m, 2H), 1.28-1.25(m, 1H), 1.23(s,3H), 1.20-1.07(m, 3H), 0.99-0.89(m, 2H), 0.87(t, J=7.6 Hz, 6H), 0.76(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 170.3, 165.1, 144.2, 137.6, 134.4, 134.1, 131.5,130.5, 127.2, 92.4, 91.2, 83.5, 70.7, 51.5, 50.4, 50.2, 43.3, 41.7, 39.8,36.3, 35.7, 35.2, 32.9, 32.6, 29.6, 28.8, 28.2, 25.9, 22.2, 19.8, 16.9, 11.3,11.3. FT-IR: ν(cm -1 ) 2933, 2873, 1717, 1275, 1156, 1087, 764, 736. HRMS [ESI] calculated value C 40 H 53 ClINSO6Na [M+Na] + 860.2219, measured value 860.2224.

[0099] (34) II-P-1e: Yield 37%; white solid; melting point 72℃-74℃. R f =0.3(nHex / EtOAc, 5:1). 1H NMR(400 MHz, CDCl3) δ 8.20-8.18(m,1H), 8.11-8.08(m, 1H), 7.67-7.63(m, 2H), 7.07-7.03(m, 2H), 7.01-6.98(m, 1H),5.05-4.98(m, 2H), 3.89(d, J=6.8 Hz, 2H), 3.56(s, 2H), 2.79(s, 3H), 2.60-2.50(m, 1H), 2.40-2.34(m, 1H), 2.33-2.23(m, 2H), 2.22-2.16(m, 1H), 2.14-2.06(m,1H), 2.05-1.88(m, 2H), 1.73-1.65(m, 2H), 1.56-1.49(m, 2H), 1.47-1.39(m, 4H),1.35-1.26(m, 4H), 1.24(s, 3H), 1.20-1.18(m, 1H), 1.09(d, J=6.8 Hz, 6H), 0.98-0.93(m, 1H), 0.77(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 170.3, 167.6, 162.6,162.0, 161.1, 137.6, 134.4, 132.7, 132.2, 131.5, 126.2, 122.5, 115.5, 112.7,103.0, 92.4, 90.8, 83.4, 75.8, 70.7, 51.3, 50.3, 43.2, 41.7, 39.8, 36.3,35.9, 35.1, 32.9, 32.6, 29.7, 28.8, 28.3, 28.2, 25.9, 24.0, 19.9, 19.2, 17.6,17.0, 11.3. FT-IR: ν(cm -1 ) 2969, 2928, 1951, 1730, 1706, 1274, 1260, 1095,751. HRMS [ASAP] calculated value C 43 H 51 ClISN2O5 [M+H] + 869.2246, measured value 869.2248.

[0100] (35) II-P-1f: Yield 34%; white solid; melting point 61℃-63℃. R f=0.3(nHex / EtOAc, 5:1). 1 H NMR(400 MHz, CDCl3) δ 7.65-7.61(m, 2H),7.05-7.01(m, 2H), 5.77(d, J=9.6 Hz, 1H), 5.42(s, 1H), 4.99-4.96(m, 1H), 4.83(dd, J=8.0, 3.2 Hz, 1H), 3.54(s, 2H), 2.77-2.62(m, 5H), 2.58-2.52(m, 1H), 2.43-2.29(m, 3H), 2.22-2.12(m, 2H), 2.05-1.93(m, 2H), 1.92-1.82(m, 3H), 1.80-1.71(m, 4H), 1.66-1.55(m, 4H), 1.54-1.45(m, 3H), 1.42(s, 3H), 1.39-1.27(m,5H), 1.21-1.15(m, 3H), 1.13(s, 3H), 1.07-1.00(m, 2H), 0.95(d, J=6.0 Hz, 3H), 0.84(d, J=7.2 Hz, 3H), 0.73(s, 3H); 13 C NMR(100 MHz, CDCl3) δ 171.9, 171.3,170.3, 137.6, 134.4, 131.5, 104.6, 92.2, 91.6, 90.8, 82.6, 80.2, 70.7, 51.7,50.9, 50.3, 45.3, 43.2, 41.7, 39.8, 37.4, 36.3, 36.3, 36.0, 35.0, 34.2, 32.9,32.6, 31.9, 29.5, 29.4, 28.7, 28.2, 26.1, 25.9, 24.7, 22.1, 20.3, 19.9, 16.8,12.2, 11.3. FT-IR: ν(cm -1 ) 2927, 2868, 1728, 1254, 1152, 1009, 730. HRMS [ESI] calculated value C 46 H 62 ClIO 10 Na [M+Na] + 959.2968, measured value 959.2969.

[0101] (36) II-P-1g: Yield 45%; white solid; melting point 59℃-61℃. f =0.3(nHex / EtOAc, 5:1). 1 H NMR(400 MHz, CDCl3) δ 7.66-7.61(m, 2H), 7.05-7.01(m, 2H), 5.00-4.96(m, 1H), 4.73-4.68(m, 1H), 3.61(d, J=15.2 Hz, 1H), 3.54(s, 2H), 3.02(d, J=15.2 Hz, 1H), 2.61-2.49(m, 2H), 2.43-2.35(m, 1H), 2.34-2.19(m, 4H), 2.13-2.03(m, 2H), 1.95(d, J=18.4 Hz, 1H), 1.91-1.83(m, 1H),1.73-1.65(m, 2H), 1.59-1.48(m, 3H), 1.47-1.36(m, 5H), 1.28(s, 3H), 1.23-1.16(m, 3H), 1.14(s, 3H), 1.11-1.00(m, 2H), 0.96-0.90(m, 1H), 0.89(s, 3H), 0.85-0.81(m, 1H), 0.74(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 214.7, 170.3, 137.6,134.4, 131.5, 92.4, 90.0, 89.4, 70.7, 58.2, 51.6, 50.2, 48.1, 48.0, 43.1,42.9, 42.6, 41.7, 39.8, 36.3, 35.6, 35.1, 32.9, 32.6, 30.0, 28.7, 28.2, 27.0,25.9, 25.0, 20.1, 19.9, 19.9, 17.3, 11.3. FT-IR: ν(cm -1 ) 2943, 2861, 1730, 1341, 1256, 1157, 903, 882, 750, 731. HRMS [ESI] calculated value C 37 H 50 ClISO6Na [M+Na] + 807.1954, measured value 807.1947.

[0102] (37) II-P-1h: Yield 42%; white solid; melting point 47℃-49℃. R f =0.3(nHex / EtOAc, 10:1). 1 H NMR(400 MHz, CDCl3) δ 7.68-7.58(m, 2H),7.08-6.98(m, 2H), 5.02-4.95(m, 1H), 4.86-4.80(m, 1H), 4.73-4.64(m, 1H), 3.54(s, 2H), 2.67-2.59(m, 4H), 2.48-2.38(m, 1H), 2.37-2.27(m, 1H), 2.24-2.11(m,2H), 2.01-1.82(m, 4H), 1.70-1.63(m, 3H), 1.62-1.56(m, 1H), 1.55-1.32(m, 8H),1.28-1.16(m, 5H), 1.14(s, 3H), 1.08-1.00(m, 2H), 0.98-0.91(m, 2H), 0.88(d, J=7.2 Hz, 6H), 0.85-0.82(m, 1H), 0.75(s, 3H), 0.74(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 172.1, 171.9, 170.3, 137.6, 134.4, 131.5, 92.4, 90.9, 82.5, 74.6,70.7, 50.9, 50.3, 47.1, 43.2, 41.7, 41.0, 39.8, 36.3, 36.0, 35.0, 34.3, 32.9,32.6, 31.5, 29.8, 29.6, 29.5, 28.7, 28.2, 26.3, 25.9, 23.5, 22.1, 20.9, 19.9,16.8, 16.4, 11.3. FT-IR: ν(cm -1 ) 2928, 2861, 1727, 1254, 1150, 799, 733. HRMS[ASAP] calculated value C 41 H 58 IO6 [M-HCl+H] + 773.3273, measured value 773.3274.

[0103] (38) II-P-1i: Yield 38%; white solid; melting point 81℃-83℃. R f=0.3(nHex / EtOAc, 5:1). 1 H NMR(400 MHz, CDCl3) δ 7.59-7.57(m, 1H), 7.54-7.51(m, 1H), 7.19-7.15(m, 1H), 7.03-6.98(m, 1H), 5.02-4.99(m, 1H), 2.90(t, J=7.2 Hz, 2H), 2.62(t, J=7.2 Hz, 2H), 2.51-2.47(m, 2H), 2.32-2.25(m, 2H), 2.00-1.93(m, 1H), 1.64-1.58(m, 2H), 1.48-1.38(m, 6H), 1.34-1.26(m, 4H), 1.25(s,3H), 1.24-1.22(m, 1H), 1.10-1.03(m, 2H), 0.87-0.81(m, 1H), 0.77(s, 3H); 13 CNMR(100 MHz, CDCl3) δ 218.8, 172.1, 143.1, 137.4, 135.4, 130.3, 127.8, 94.6,88.9, 70.0, 55.9, 50.4, 42.5, 39.9, 36.4, 35.9, 33.4, 32.9, 32.7, 32.2, 30.7,30.1, 27.9, 27.2, 26.0, 19.4, 16.6, 11.3. FT-IR: ν(cm -1 ) 2932, 2861, 1739, 1724, 1260, 1151, 750. HRMS [ASAP] calculated value C 28 H 37 ClIO3 [M+H] + 583.1470, measured value 583.1476.

[0104] (39) III-Pa: Yield 73%; white solid; melting point 52℃-54℃. R f =0.3(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.34-8.32(m, 1H), 7.94-7.87(m,2H), 7.22-7.17(m, 1H), 5.15-5.11(m, 1H), 3.65(s, 3H), 2.90(t, J=14.4 Hz, 1H),2.55-2.48(m, 1H), 2.47-2.37(m, 2H), 2.32-2.18(m, 3H), 2.14-2.02(m, 5H), 2.01-1.99(m, 1H), 1.93-1.78(m, 7H), 1.72-1.67(m, 1H), 1.60-1.54(m, 1H), 1.53-1.42(m, 3H), 1.08(s, 3H), 1.02(d, J=6.8 Hz, 3H), 0.87(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 212.1, 174.2, 164.8, 142.1, 138.6, 132.5, 130.5, 128.5, 94.3, 93.2,72.5, 51.7, 49.9, 45.5, 44.7, 42.5, 41.2, 40.4, 38.9, 37.0, 36.7, 35.3, 35.0,34.5, 31.8, 31.0, 28.8, 22.7, 22.0, 21.2, 14.7, 14.6. FT-IR: ν(cm -1 ) 2944,2870, 1750, 1711, 1276, 1257, 746. HRMS [ESI] calculated value C 32 H 43 ClIO5 [M+H] + 669.1838, measured value 669.1830.

[0105] (40) III-Pb: Yield 48%; white solid; melting point 51℃-53℃. f =0.4(nHex / EtOAc, 2:1). 1H NMR(400 MHz, CDCl3) δ 8.35-8.31(m, 1H), 7.94-7.86(m,2H), 7.21-7.16(m, 1H), 5.16-5.09(m, 1H), 3.67(s, 3H), 3.15(s, 3H), 2.90(t, J=14.4 Hz, 1H), 2.54-2.44(m, 2H), 2.43-2.31(m, 2H), 2.30-2.16(m, 3H), 2.12-1.98(m, 5H), 1.96-1.87(m, 3H), 1.86-1.75(m, 3H), 1.70-1.64(m, 1H), 1.58-1.42(m,4H), 1.23-1.17(m, 1H), 1.07(s, 3H), 1.03(d, J=6.4 Hz, 3H), 0.87(s, 3H); 13 CNMR(100 MHz, CDCl3) δ 212.2, 164.8, 142.1, 138.6, 132.5, 130.5, 128.5, 94.3,93.7, 72.6, 61.3, 49.9, 45.4, 44.7, 42.5, 41.1, 40.4, 38.9, 37.0, 36.7, 35.3,35.0, 34.5, 31.0, 28.4, 22.7, 22.0, 21.2, 14.8, 14.6. FT-IR: ν(cm -1 ) 2940,2870, 1710, 1654, 1276, 1258, 748. HRMS [ASAP] calculated value C 33 H 46 ClINO5 [M+H] + 698.2104, measured value 698.2092.

[0106] (41) III-Pc: Yield 67%; white solid; melting point 87℃-89℃. f =0.4(nHex / EtOAc, 1:1). 1H NMR(400 MHz, CDCl3) δ 8.33-8.30(m, 1H), 7.93-7.86(m, 2H), 7.21-7.16(m, 1H), 5.68(d, J=8.0 Hz, 1H), 5.26-5.20(m, 1H), 5.14-5.07(m, 3H), 4.28(dd, J=12.4, 4.4 Hz, 1H), 4.07(dd, J=12.4, 2.0 Hz, 1H), 3.84-3.79(m, 1H), 2.89(t, J=14.4 Hz, 1H), 2.52-2.39(m, 3H), 2.34-2.12(m, 5H),2.09-2.05(m, 5H), 2.03-1.98(m, 12H), 1.90-1.78(m, 6H), 1.70-1.64(m, 1H),1.60-1.42(m, 4H), 1.07(s, 3H), 1.01(d, J=6.4 Hz, 3H), 0.87(s, 3H); 13 C NMR(100MHz, CDCl3) δ 212.1, 173.4, 170.2, 169.4, 169.0, 164.7, 142.1, 138.5, 132.5,130.4, 128.4, 94.3, 93.3, 91.8, 72.8, 72.5, 70.3, 67.7, 61.3, 49.9, 45.4,44.7, 42.5, 41.0, 40.3, 38.9, 37.0, 36.6, 35.3, 35.0, 34.4, 31.6, 31.0, 28.4,22.7, 22.0, 21.2, 20.9, 20.7, 14.7, 14.6. FT-IR: ν(cm -1 ) 2943, 2872, 1757,1713, 1256, 1211, 1074, 1036, 748. HRMS [ESI] calculated value C 45 H 58 ClIO 14 Na [M+Na] + 1007.2452, measured value 1007.2410.

[0107] (42) IV-Pa: Yield 54%; dr = 2.3 : 1; white solid; melting point 71℃-73℃. R f=0.4(nHex / EtOAc, 10:1). 1 H NMR(400 MHz, CDCl3) δ 7.68-7.60(m,2H), 7.08-6.99(m, 2H), 5.44-5.34(m, 0.7H), 4.80-4.76(m, 1H), 4.75-4.66(m,0.3H), 3.56-3.52(m, 2H), 2.21-2.10(m, 2H), 2.08-1.78(m, 8H), 1.76-1.67(m,3H), 1.60-1.49(m, 4H), 1.48-1.36(m, 4H), 1.23-1.11(m, 3H), 1.09-1.04(m, 3H), 0.72-0.68(m, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.7, 170.7, 170.5, 137.7, 137.7,134.1, 131.5, 131.5, 92.6, 88.9, 84.3, 82.4, 82.1, 73.1, 70.5, 49.7, 46.1,45.1, 45.0, 43.2, 42.1, 41.4, 41.3, 40.7, 39.7, 36.5, 36.3, 34.9, 34.3, 31.7,31.6, 31.4, 30.0, 29.5, 28.3, 28.1, 27.4, 26.7, 26.5, 24.5, 24.1, 21.5, 21.5,20.9, 16.8, 16.5, 16.2, 15.4. FT-IR: ν(cm -1 ) 2938, 2868, 1729, 1241, 1025, 1008, 730. HRMS [ASAP] calculated value C 29 H 38 IO4 [M-HCl+H] + 577.1809, measured value 577.1812.

[0108] Comparative Example 1

[0109] The process is essentially the same as in Example 4, except that the steroid compound IS-2h is not irradiated, thus failing to yield the target chlorinated steroid compound. This is because when the steroid compound contains an olefinic functional group, selective chlorination cannot be achieved under conventional electrolysis conditions; instead, an addition reaction occurs.

[0110] Comparative Example 2

[0111] Steroid compound IS-1j (0.05 mmol) and dichloroiodobenzene (0.075 mmol) were added to a pre-dried 10 mL chemical reaction tube. After sealing the tube, it was purged with nitrogen for 5 min. Then, dichloromethane (1 mL) was added via syringe, and a nitrogen balloon was connected to maintain an inert atmosphere. A light source (wavelength 390 nm, power 10 W) was placed 5 cm away from the reaction tube for irradiation, and a fan was turned on for effective heat dissipation. After 1 h, the reaction was completed. The organic phases were washed with dichloromethane, combined, diluted with water, and extracted three times with dichloromethane (5 mL). The organic phases were washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography, but the target chlorosteroid compound could not be obtained. This is because when the steroid compound contains ether functional groups, the use of dichloroiodobenzene produces hydrogen chloride gas as a byproduct, making the ether bonds intolerant.

[0112] Comparative Example 3

[0113] Similar to Comparative Example 2, and with steroid compound IS-1m, the target chlorosteroid compound could not be obtained. This is because when the steroid compound contains a hydroxyl functional group, the dichloroiodobenzene used has strong oxidizing properties, making the hydroxyl group difficult to tolerate.

[0114] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for site-directed chlorination of steroidal compounds, characterized in that, The process includes the following steps: under conditions of electricity and light, a steroid compound reacts with chlorine source in an electrolyte solution for 1-24 hours to obtain a chlorinated steroid compound; the conditions of electricity are: constant voltage of 2V-4V or constant current of 2mA-10mA; the conditions of light are: wavelength of 365nm-495nm and power of 10W-50W. The steroidal compound is selected from the following compounds: ； in, This indicates whether it is a single or double bond. X in IS-1, IS-2, II-S-1, II-S-2, III-S and IV-S 1 Independently selected from -C(=O)- or -S(=O)2-; X 2 Independently selected from -O- or -NH-; R 1 It can be independently connected to the quinary ring via a single or double bond, or form a helical ring with the quinary ring; when R 1 When connected to the pentagonal ring via a single bond, it is independently selected from -H, -OH, -CN, Cl-C. 20 Alkyl, C1-C6 acyl, C1-C 20 Alkoxycarbonyl, C1-C 20 Acyloxy or C1-C 10 sulfonyloxy; when R 1 When connected to the pentagonal ring via a double bond, it is independently selected or * represents a connection site; when R 1 When it forms a spiral with the quinary ring it is in, it is * represents a spiro atom site; R 2 Independently selected from -H, C1-C6 alkyl, C1-C 10 Alkoxy or C1-C 10 Acyloxy group; R 1 and R 2 Cyclic or non-cyclic; R 3 Independently selected from -H, -CH3, or -CF3; R 4 Independently connected to the hexa-membered ring via a single or double bond; when R 4 When connected to the six-membered ring via a single bond, it is independently selected from -H, C6-C. 10 aryloxy or C1-C 20 Acyloxy group; when R 4 When connected to the hexa-membered ring via a double bond, it is independently selected * represents a connection point; R 5 Independently selected from -H or C1-C6 alkyl groups; R 6 Independently connected to the hexa-membered ring via a single or double bond; when R 6 When connected to the six-membered ring via a single bond, it is independently selected from -H; when R 6 When connected to the hexa-membered ring via a double bond, it is independently selected * represents a connection point; The chlorine source is selected from one or more of pyridine hydrochloride, hydrochloric acid, magnesium chloride, cerium chloride, and sodium chloride; The solute in the electrolyte solution is selected from one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium perchlorate, lithium perchlorate, and tetrabutylammonium hexafluorophosphate; the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, and acetone. The products corresponding to IS-1 and IS-2 are 9α-chlorosteroid compounds; The products corresponding to II-S-1 and II-S-2 are 14β-chlorosteroid compounds; The product corresponding to III-S is a 17α-chlorosteroid compound; The product corresponding to IV-S is a 5α-chlorosteroid compound.

2. The method for site-directed chlorination of steroidal compounds according to claim 1, characterized in that, The solvents for the electrolyte solution include acetonitrile and ethyl acetate.

3. The method for site-directed chlorination of steroidal compounds according to claim 2, characterized in that, The volume ratio of acetonitrile to ethyl acetate is (2.8-3.2):

2.

4. The method for site-directed chlorination of steroidal compounds according to claim 1, characterized in that, The amount of chlorine source used is 5-15 equivalents of the steroid compound.

5. The method for site-directed chlorination of steroidal compounds according to claim 1, characterized in that, The concentration of the steroid compound in the electrolyte solution is 0.005 mmol / mL to 0.02 mmol / mL.

6. The method for site-directed chlorination of steroidal compounds according to claim 1, characterized in that, The concentration of the electrolyte solution is 0.045 mol / L to 0.055 mol / L.

7. The method for site-directed chlorination of steroidal compounds according to claim 1, characterized in that, The reaction was carried out under a protective atmosphere.

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