Synthetic method of heteroaryl halide or aryl halide

Abstract

The invention discloses a synthetic method of a heteroaryl halide or an aryl halide, which comprises the step of directly halogenating a heteroaromatic ring compound or a carbon-hydrogen bond of an aromatic ring compound in the presence of a catalyst, a halogenating reagent and a solvent to prepare the corresponding halide. The 2-thiophenylbenzoic acid is used as the catalyst, so that the reaction has the advantages of high substrate compatibility, simplicity and convenience in operation, cheap and safe halogenation reagent and the like. By adopting the method disclosed by the invention, the heteroaryl / aryl halide can be efficiently prepared, and the method has a wide application prospect in actual production.

Description

Technical Field

[0001] The present invention belongs to but is not limited to the technical field of chemical synthesis, and in particular relates to a method for synthesizing heteroaryl halides or aryl halides. Background Art

[0002] In organic synthesis, aryl halides are indispensable synthetic intermediates, widely used in a variety of metal-catalyzed coupling reactions. Furthermore, in medicinal chemistry, chlorine is a crucial element in drug molecules, significantly improving multiple pharmacological parameters, including efficacy, a phenomenon summarized as the "Magic Chloro" effect (J. Med. Chem. 2023, 66, 5305). Therefore, the efficient synthesis of aryl halides has long been a goal pursued by synthetic chemists. Direct halogenation of carbon-hydrogen bonds in heteroaromatic or aromatic compounds is the most efficient synthetic strategy. Initially, elemental halogens were used as halogenation reagents, but these reagents suffered from drawbacks such as corrosiveness and toxicity. Consequently, safer and simpler halogenation reagents such as N-halosuccinimide, trichloroisocyanuric acid, and dibromohydantoin were developed and widely used. However, these reagents suffer from insufficient halogenation activity, limiting their substrate range. Despite the development of various catalyst activation strategies, direct halogenation of heteroaromatic and drug substrates remains a challenge. For example, Baran et al., in their study of the halogenation of voriconazole, tried more than 20 existing chlorination and bromination conditions, but none of them achieved the desired yield. They reported a new type of isomeric amide chlorination and bromination reagent, which only achieved 52% and 79% yields for the chlorination and bromination of voriconazole, respectively, while iodination of voriconazole has not yet been achieved (Nat. Chem. 2024, 16, 1539). In addition, the chlorination and bromination reagents have defects such as long synthetic routes and high prices, which highlights the limitations of the existing technology and urgently needs to develop a halogenation method that is cheaper and suitable for heterocyclic iodination. Summary of the Invention

[0003] The purpose of the present invention is to provide a method for synthesizing heteroaryl halides or aryl halides, which has the advantages of mild reaction conditions, inexpensive halogenation reagents and excellent functional group compatibility, and can be used for the late-stage modification synthesis of various drug molecules.

[0004] Specifically, the present invention provides a method for synthesizing a heteroaryl halide or an aryl halide, the method comprising the following steps: halogenating the carbon-hydrogen bond of a heteroaromatic ring compound or an aromatic ring compound in the presence of a catalyst, a halogenating agent XY, and a solvent to obtain the heteroaryl halide or the aryl halide;

[0005] The chemical formula of the method is as follows:

[0006]

[0007] Here, the heteroaromatic ring compound or aromatic ring compound has a structure shown in formula (I), and the heteroaryl halide or aryl halide has a structure shown in formula (II); wherein represents heteroaryl or aryl; R 1 ,R 2 ,R 3 ,R 4 ,R 5 R is independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, alkoxy, benzyloxy, acyloxy, acyl, ester, amide, monoalkylamino, dialkylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl; 1 ,R 2 ,R 3 ,R 4 ,R 5 Can be the same or different; or R 1 and R 2 、R 2 With R 3 、R 3 With R 4 、R 4 and R 5 Combined to form a cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, benzocycloalkyl or substituted benzocycloalkyl, benzoheterocycloalkyl or substituted benzoheterocycloalkyl, aromatic ring or substituted aromatic ring, aromatic heterocycle or substituted aromatic heterocycle;

[0008] The halogenating agent is XY, wherein the structure of the halogenating agent is

[0009]

[0010] The catalyst is

[0011] The solvent is one or a mixture of nitromethane, dichloromethane, chloroform, N,N-dimethylformamide, acetonitrile, hexafluoroisopropanol, dimethyl sulfoxide, and ethyl acetate.

[0012] Preferably, It is a heteroaromatic ring or aromatic ring structure such as benzene, naphthalene, anthracene, indole, azaindole, pyrrole, thiophene, triazole, pyrimidine, pyrazole, imidazole, etc. In some preferred embodiments, the heteroaromatic ring compound or aromatic ring compound is one of voriconazole, sulfadiazine, clotrimazole, celecoxib, piribedil, letrozole, amodiaquine, sulfamethoxazole, fluconazole, sulfamethoxazole, zanthoxylum bungeanum, sulfadiazine, epoxiconazole, ketoconazole, difenoconazole, dasatinib, naproxen, apremilast, myclobutanil, aniracetam, imatinib, ipriflavone, bifonazole, and propamide.

[0013] Furthermore, the temperature of the halogenation reaction is room temperature to 60° C., and some embodiments of the present invention successfully produce products in high yields based on the above mild temperature conditions.

[0014] Furthermore, the molar ratio of the heteroaromatic ring or aromatic ring compound to the halogenating agent is 1:1.2~4C. Some embodiments of the present invention successfully produce products with high yields based on the reaction conditions of the above raw material molar ratios.

[0015] Furthermore, the molar ratio of the heteroaromatic ring or aromatic ring compound to the catalyst is 1:0.01 to 0.5. In some embodiments of the present invention, the product is successfully obtained in high yield under the reaction conditions based on the addition amount of the catalyst in the above range.

[0016] The benefits of the present invention lie in its ability to directly halogenate carbon-hydrogen bonds in heteroaromatic and aromatic rings using an easily synthesized catalyst (one-step synthesis) and inexpensive, readily available halogenation reagents (such as halogenated succinimide NXS) under mild conditions (neutral conditions, room temperature to 60°C). The process is suitable for the halogenation of complex molecules such as natural products, drug molecules, and peptides, and has broad application prospects in actual production. In particular, the present invention addresses the problem of achieving ideal yields in existing literature for the halogenation of complex heterocyclic drugs, achieving significantly improved yields compared to existing synthetic methods. This provides an effective and feasible synthetic pathway for the production of modified products of more complex heterocyclic drugs.

[0017] Taking the halogenation reaction of some complex heterocyclic drugs as substrates as an example, the inventors compared the synthesis method of the present invention with the existing aromatic ring or aromatic heterocyclic halogenation methods in the literature (see Chem. Sci. 2024, 15, 13058; Org. Lett. 2017, 19, 4243; Org. Lett. 2015, 17, 1042). The results are as follows to reflect the benefits of the present invention.

[0018]

[0019] When voriconazole is used as a substrate for halogenation reaction, the chlorination, bromination and iodination reactions of the present invention can respectively obtain the target product with a yield of 75%, 92% and 85%, while the catalysts reported in other literatures do not obtain halogenated products.

[0020] When epoxiconazole is used as a substrate for halogenation reaction, the chlorination, bromination and iodination reactions of the present invention can respectively obtain the target product with a yield of 58%, 59% and 66%, while the catalysts reported in other literatures do not obtain halogenated products.

[0021] When letrozole is used as a substrate for halogenation reaction, the chlorination, bromination and iodination reactions of the present invention can respectively obtain the target product with yields of 84%, 84% and 73%, while the catalysts reported in other literatures do not obtain halogenated products.

[0022] When celecoxib is used as a substrate for halogenation reaction, the chlorination, bromination and iodination reactions of the present invention can respectively obtain the target product with yields of 92%, 72% and 87%, which are higher than those of catalyst-mediated halogenation reactions reported in other literatures.

[0023] When piribedil is used as a substrate for halogenation reaction, the chlorination and bromination reactions of the present invention can respectively obtain the target product in yields of 90% and 72%, which are higher than those of catalyst-mediated halogenation reactions reported in other literatures. DETAILED DESCRIPTION

[0024] To make the objectives, technical solutions, and advantages of this application more clearly understood, embodiments of the present invention are described in detail below. It should be noted that, unless there is a conflict, the embodiments and features in the embodiments of this application may be combined in any manner. It must be noted that the following embodiments are intended to illustrate the present invention and are not intended to limit it. Simple modifications to the present invention based on its essence fall within the scope of protection claimed by the present invention.

[0025] Example 1: Preparation of chlorovoriconazole (Compound 1)

[0026]

[0027] To a 5ml brown bottle, add voriconazole (69.8mg), N-chlorosuccinimide (53.41mg), 2-(phenylthio)benzoic acid (4.6mg), and chloroform (2mL). Stir at 60°C for 30 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 57.56mg of chlorovoriconazole (75% yield).

[0028] 1 H NMR(400MHz, CDCl3)δ8.98(s,1H),8.64(s,1H),7.60(td,J=17.2,9.6Hz,1H),7.52(s,1H),6.90–6.80(m,2H ), 6.49 (s, 1H), 4.66 (d, J = 14.4Hz, 1H), 4.26 (d, J = 14.4Hz, 1H), 4.19 (q, J = 7.2Hz, 1H), 1.11 (d, J = 6.8Hz, 3H). 13C NMR(101MHz,CDCl3)δ162.74(dd,J C-F =249.2,12.2Hz),159.67(d,J C-F =12.6Hz),158.84(dd,J C-F =245.1,11.7Hz),157.22,154.59,153.37(d,J=7.7Hz),150.70,145.40(d,J C-F =21.6Hz),142.87,130.60(dd,J C-F =9.1,5.6Hz),123.71(dd,J=11.4,3.1Hz),111.60(dd,J C-F =20.2,2.9Hz)104.10(dd,J C-F =27.3,25.8Hz),77.80(d,J C-F =5.0Hz),55.55(d,J C-F =4.6Hz),36.72(d,J C-F =6.2Hz),15.80. 19 F NMR(376MHz, CDCl3)δ-109.06(d,J F-F =10.5Hz),-110.30(d,J F-F =7.5Hz),-135.21.HRMS(ESI):Calcd.for C 16 H 13 ClF3N5O[M+H] + m / z 384.0834, Found m / z 384.0833.

[0029] Example 2: Preparation of chloroepiconazole (Compound 2)

[0030]

[0031] To a 5ml brown bottle, add 98.93mg of epoxiconazole, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 34 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then rotary evaporated to remove the solvent and separated by column chromatography to obtain 63.37mg of chloroepoxiconazole (58% yield).

[0032] 1H NMR (400MHz, CDCl3) δ7.73(s,1H),7.61(dd,J=6.8,2.0Hz,1H),7.47(dd,J=6.8,2.0Hz,1H),7.42 –7.34(m,4H),7.03(t,J=8.8Hz,2H),4.65(d,J=14.8Hz,1H),4.21(s,1H),3.95(d,J=14.8Hz,1H). 13 C NMR(101MHz,CDCl3)δ162.69(d,J C-F =246.5Hz),151.46,132.97,132.16,131.96(d,J C-F =3.2Hz),129.85,129.30,128.16(d,J C-F =8.6Hz),128.12,127.24,115.61(d,J C-F =21.7Hz),64.52,63.26,50.70. 19 F NMR(376MHz,CDCl3)δ-112.36.HRMS(ESI):Calcd.for C 17 H 12 Cl2FN3O[M+H] + m / z 364.0415, Found m / z 364.0416.

[0033] Example 3: Preparation of difenoconazole (Compound 3)

[0034]

[0035] To a 5ml brown bottle, add 81.25mg of diconazole, 53.41mg of N-chlorosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of ethyl acetate. Stir at 60°C for 35 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then rotary evaporated to remove the solvent and separated by column chromatography to obtain 75.80mg of diconazole (86% yield).

[0036] 1H NMR (400MHz, CDCl3) δ7.84(s,1H),7.81(s,0.8×1H),7.59(dd,J=8.8,2.8Hz,1×1+0.8×1H),7.32(d,J=8.8Hz,0.8×2H),7.01(d,J =2.0Hz,1H),7.00(d,J=2.0Hz,0.8×1H),6.96(dd,J=8.8,2.8Hz,1×2+0.8×2H),6.82(dd,J=8.8,2.8Hz,1H),6.80(dd,J=8.8,2.8 Hz,1H),4.76(d,J=14.0Hz,0.8×1H),4.72(d,J=14.0Hz,1H),4.67(d,J=14.0Hz,1H),4.63(d,J=14.0Hz,0.8×1H),4.12–4.02(m, 0.8 × 2H), 4.02–3.91 (m, 2H), 3.32 (t, J = 8.0 Hz, 0.8 × 1H), 3.16 (t, J = 8.0 Hz, 1H), 1.18 (d, J = 6.0 Hz, 0.8 × 3H), 1.10 (d, J = 6.0 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ158.41,158.33,154.22,151.01,150.90,143.53,143 .37,133.30,133.17,131.55,130.77,129.98,129.66,129.62,129.51,120 .99,120.95,120.69,120.45,116.04,115.90,107.43,107.32,74.15,72.8 2,71.24,71.20,53.23,52.92,29.51,17.88,17.74.HRMS(ESI):Calcd.for C 19 H 16 Cl3N3O3[M+H] + m / z 440.0330, Found m / z 440.0325.

[0037] Example 4: Preparation of chlorinated letrozole (Compound 4)

[0038]

[0039] To a 5ml brown bottle, add 85.59mg of letrozole, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of N,N-dimethylformamide and stir at 60°C for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to obtain 80.58mg of chloroletrozole in an 84% yield.

[0040] 1 H NMR (400MHz, CDCl3) δ7.92 (s, 1H), 7.68 (d, J = 8.0Hz, 4H), 7.33 (d, J = 8.0Hz, 4H), 6.84 (s, 1H). 13 C NMR(101MHz, CDCl3)δ152.00,142.28,141.10,132.68,128.99,117.82,113.01,64.23.HRMS(ESI):Calcd.for C 17 H 10 ClN5[M+H] + m / z 320.0698, Found m / z320.0696.

[0041] Example 5: Preparation of chloromyclobutanil (Compound 5)

[0042]

[0043] To a 5ml brown bottle, add 86.63mg of myclobutanil, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 20 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 33.94mg of myclobutanil (35% yield).

[0044] 1 H NMR (400MHz, CDCl3) δ7.86 (s, 1H), 7.37 (d, J = 8.8Hz, 2H), 7.25 (d, J = 8.8Hz, 2H), 4.53 (d, J = 14. 0Hz, 1H), 4.47 (d, J = 14.0Hz, 1H), 2.19–2.12 (m, 2H), 1.51–1.12 (m, 6H), 0.89 (t, J = 7.2Hz, 3H). 13C NMR (101MHz, CDCl3) δ171.10,151.71,135.12,132.97,129.49,127.65,119.65,55.54,48.53,36.34,26.98,22.40,13.67.HRMS(ESI):Calcd.forC 15 H 16 Cl2N4[M+H] + m / z323.0825, Found m / z 323.0824.

[0045] Example 6: Preparation of dichlorofluconazole (Compound 6)

[0046]

[0047] To a 5ml brown bottle, add 91.99mg of fluconazole, 160.24mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of hexafluoroisopropanol, and stir at 60°C for 15 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 72.03mg of chlorofluconazole (64% yield).

[0048] 1 H NMR (400MHz, CDCl3) δ7.79 (s, 2H), 7.49–7.39 (m, 1H), 6.88–6.73 (m, 2H), 5.43 (s, 1H), 4.82 (d, J = 14.4Hz, 2H), 4.55 (d, J = 14.4Hz, 2H). 13 C NMR(101MHz,CDCl3)δ163.29(dd,J C-F =250.0,12.6Hz),158.72(dd,J C-F =245.5,12.2Hz),151.30,143.49,129.80(dd,J C-F =9.4,5.4Hz),121.95(dd,J C-F =13.0,3.8Hz),112.09(dd,J C-F =20.4,3.5Hz),104.39(t,J C-F =26.1Hz),75.35(d,J C-F =4.7Hz),53.37(d,J C-F =5.1Hz). 19 F NMR(376MHz,CDCl3)δ-108.38(d,JF-F =7.1Hz),-108.50(d,J F-F =10.9Hz).HRMS(ESI):Calcd.forC 13 H 10 Cl2F2N6O[M+H] + m / z375.0334, Found m / z 375.0336.

[0049] Example 7: Preparation of chlorocelecoxib (Compound 7)

[0050]

[0051] To a 5ml brown bottle, add 114.41mg of celecoxib, 139.45mg of trichloroisocyanuric acid, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 36 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 162.55mg of chlorocelecoxib (92% yield).

[0052] 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.23(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),5.26(s,2H),2.41(s,3H). 13 C NMR (101MHz, CDCl3) δ142.22,141.85,141.54,140.64(q,J C-F =37.8Hz),140.45,129.90,129.63,127.56,125.04,123.28,120.37(q,J C-F =268.5Hz),109.78,21.43. 19 F NMR(376MHz,CDCl3)δ-62.69.HRMS(ESI):Calcd.for C 17 H 13 ClF3N3O2S[M+H] + m / z 416.0442, Found m / z 416.0439.

[0053] Example 8: Preparation of chloropiribedil (Compound 8)

[0054]

[0055] To a 5ml brown bottle, add 89.50mg of piribedil, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform, and stir at room temperature for 12 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to obtain 89.85mg of chloropiribedil (90% yield).

[0056] 1 H NMR (400MHz, CDCl3) δ8.20(s,2H),6.88(s,1H),6.76(d,J=0.8Hz,2H),5.95(s,2H),3.77(t,J=5.2Hz,1H),3.44(s,2H),2.46(t,J=5.2Hz,1H). 13 C NMR (101MHz, CDCl3) δ159.81,155.80,147.67,146.69,131.68,122.25,118.00,109.47,107.89,100.91,62.79,52.65,43.97.HRMS(ESI):Calcd.for C 16 H 17 ClN4O2[M+H] + m / z 333.1113, Found m / z333.1113.

[0057] Example 9: Preparation of chlorinated dasatinib (Compound 9)

[0058]

[0059] To a 5ml brown bottle, add 97.60mg of dasatinib, 53.41mg of N-chlorosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of N,N-dimethylformamide and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to yield 85.68mg of chlorodasatinib (82% yield).

[0060] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),8.32(s,1H),7.42(dd,J=7.2,1.6Hz,1H),7.30(d,J=7.2Hz,1H),7.27(t, J=7.6Hz,1H),4.53(s,1H),3.58–3.53(m,6H),2.64–2.55(m,4H),2.53–2.50(m,2H),2.48(s,3H),2.26(s,3H). 13 C NMR(101MHz,DMSO-d6)δ162.25,161.93,160.77,159.73,154.07,138.78,133.38,132.39,129.64,129 .05,128.23,127.02,126.03,97.11,60.03,58.20,52.89,47.30,24.79,18.29.HRMS(ESI):Calcd.forC 22 H 25 Cl2N7O2S[M+H] + m / z 522.1241, Found m / z 522.1240.

[0061] Example 10: Preparation of chloroimatinib (Compound 10)

[0062]

[0063] To a 5ml brown bottle, add imatinib (98.72mg), N-chlorosuccinimide (53.41mg), 2-(phenylthio)benzoic acid (4.6mg), and N,N-dimethylformamide (2mL). Stir at 60°C for 16 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 52.80mg of chloroimatinib (50% yield).

[0064] 1H NMR (400MHz, CDCl3) δ9.17(s,1H),9.23(d,J=2.0Hz,1H),8.66(dd,J=4.8,1.2Hz,1H),8.45(s,1H),8.38(s,1H),8.34(d,J=8.0Hz,1H),7.85(d,J= 8.0Hz,2H),7.46(d,J=8.0Hz,2H),7.39(dd,J=8.0,4.8Hz,1H),7.23(d,J =10.8Hz,2H),3.56(s,2H),2.65–2.42(br,8H),2.30(s,3H),2.60(s,3H). 13 C NMR (101MHz, CDCl3) δ164.78,160.38,158.78,158.51,150.68,150.05,142.82,137.22,136.22,133.33,132.84,131.86,1 30.10,129.38,126.97,126.10,123.09,118.67,117.73,114.79,62.31,54.84,52.73,45.70,17.52.HRMS(ESI):Calcd.for C 29 H 30 ClN7O[M+H] + m / z 528.2274, Found m / z 528.2268.

[0065] Example 11: Preparation of Chloro-ipriflavone (Compound 11)

[0066]

[0067] To a 5ml brown bottle, add 84.10mg of ipriflavone, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 15 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 76.49mg of chloroipriflavone (81% yield).

[0068] 1H NMR (400MHz, CDCl3) δ8.16(d,J=9.2Hz,1H),8.03(s,1H),7.56(d,J=9.2Hz,2H),7.44(t,J=9.2Hz,2H ),7.39(d,J=9.2Hz,1H),7.06(d,J=9.2Hz,1H),4.77(dt,J=12.0,6.0Hz,1H),1.45(d,J=6.4Hz,6H). 13 C NMR (101MHz, CDCl3) δ175.26,158.12,153.37,152.69,131.43,128.88,128.42,128 .21,125.20,125.09,118.93,111.88,110.85,72.64,21.96.HRMS(ESI):Calcd.for C 18 H 15 ClO3[M+H] + m / z 315.0783, Found m / z 315.0781.

[0069] Example 12: Preparation of chlorosulfanilamide (Compound 12)

[0070]

[0071] To a 5ml brown bottle, add 84.09mg of sulfaquinone, 48.07mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 18 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 82.15mg of chlorosulfaquinone (87% yield).

[0072] 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),7.76(s,1H),7.73(s,2H),7.61(d,J=8.8Hz,1H),6.81(d,J=8.8Hz,1H),6.28(s,2H),3.89(s,3H). 13 C NMR(101MHz,DMSO-d6)δ148.88,138.15,133.88,133.16,129.19,128.05,126.63,115.34,113.74,53.70.HRMS(ESI):Calcd.for C 11 H 11 ClN4O3S[M+H] +m / z 315.0314, Found m / z 315.0318.

[0073] Example 13: Preparation of chlorosulfamethoxazole (Compound 13)

[0074]

[0075] To a 5ml brown bottle, add 75.98mg of sulfamethoxazole, 48.07mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of hexafluoroisopropanol. Stir at 60°C for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 47.47mg of chlorosulfamethoxazole (55% yield).

[0076] 1 H NMR (400MHz, CDCl3) δ7.90(br,1H),7.74(d,J=2.0Hz,1H),7.51(dd,J=8.4,2.0Hz,1H),6.73(d,J=8.4Hz,1H),6.21(s,1H),2.37(s,3H). 13 C NMR(101MHz, CDCl3)δ170.98,157.51,147.50,128.95,127.47,127.25,118.35,114.68,95.51,12.75.HRMS(ESI):Calcd.for C 10 H 10 ClN3O3S[M+H] + m / z 288.0205, Found m / z 288.0205.

[0077] Example 14: Preparation of dichlorosulfadiazine (Compound 14)

[0078]

[0079] To a 5ml brown bottle, add 75.08mg of sulfadiazine, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of ethyl acetate. Stir at room temperature for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 90.00mg of chlorosulfadiazine (94% yield).

[0080] 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H),8.53(d,J=4.8Hz,2H),7.74(s,2H),7.06(t,J=4.8Hz,1H),6.48(s,2H). 13 C NMR (101MHz, DMSO-d6) δ158.45,156.74,145.27,127.72,126.61,116.63,115.86.

[0081] Example 15: Preparation of chlorinated naproxen (Compound 15)

[0082]

[0083] To a 5ml brown bottle, add 69.08mg of naproxen, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, 36.65mg of 4-dimethylaminopyridine, and 3mL of chloroform. Stir at 60°C for 24 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 46.06mg of chloronaproxen (58% yield).

[0084] 1 H NMR (400MHz, CDCl3) δ8.18(d,J=9.2Hz,1H),7.72(d,J=9.2Hz,2H),7.54(dd,J=8.8,1.6H z,1H),7.28(d,J=9.2Hz,1H),4.02(s,3H),3.90(q,J=8.8Hz,1H),1.58(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ180.39,152.59,135.66,131.15,129.43,127.82,127.34 ,126.37,124.07,116.82,114.02,56.94,45.09,18.00.HRMS(ESI):Calcd.forC 10 H8Cl2N4O2S[M+H] + m / z318.9818, Found m / z 318.9816.

[0085] Example 16: Preparation of chloro-zanthoxanthin (Compound 16)

[0086]

[0087] To a 5ml brown bottle, add 64.86mg of xanthox ...

[0088] 1 H NMR (400MHz, CDCl3) δ8.16 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 9.6 Hz, 1H), 4.28 (s, 3H). 13 C NMR(101MHz, CDCl3)δ159.62,146.95,143.52,140.15,131.86,125.59,116.12,115.45,114.16,105.70,61.41.HRMS(ESI):Calcd.for C 12 H7ClO4[M+H] + m / z 251.0106, Found m / z 251.0108.

[0089] Example 17: Preparation of chloronapropamide (Compound 17)

[0090]

[0091] To a 5ml brown bottle, add 81.41mg of napropamide, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of ethyl acetate. Stir at 60°C for 15 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 52.29mg of chloronapropamide (51% yield).

[0092] 1H NMR (400MHz, CDCl3) δ8.33(d,J=8.4Hz,1H),8.29(d,J=8.4Hz,0.45H),8.19(d,J=8.4Hz,1H),7.78(d,J=8.4Hz,0.45H),7.61(t, J=8.4Hz,1H),7.53(t,J=8.4Hz,1H),7.47(t,J=8.4Hz,0.45H),7.45(d,J=8.4Hz,0.45H),7.40(d,J=8.4Hz,1H),7.32(t,J=8.4H z,0.45H),6.82(d,J=8.4Hz,0.45H),6.73(d,J=8.4Hz,1H),5.11(q,J=6.8Hz,0.45H),5.08(q,J=6.8Hz,1H),3.60–3.33(m,1×4+ 0.45×4H), 1.72 (d, J=6.8Hz, 1×3+0.45×3H), 1.11 (t, J=6.8Hz, 1×3+0.45×3H), 1.05 (t, J=6.8Hz, 3H), 0.98 (t, J=6.8Hz, 0.45×3H). 13 C NMR (101MHz, CDCl3) δ170.17,169.82,153.19,152.34,134.59,131.43,127.52,127.42,126.71,126.39,126.08,125.72,125.60, 125.27,124.22,123.92,122.45,122.01,120.91,105.80,105.77,74.56,74.42,41.04,40.35,40.31,17.91,14.10,14.06,12.56.

[0093] Example 18: Preparation of Chloroaniracetam (Compound 18)

[0094]

[0095] To a 5ml brown bottle, add 65.79mg of aniracetam, 80.12mg of N-chlorosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of acetonitrile, and stir at 60°C for 12 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 59.36mg of chloroaniracetam (78% yield).

[0096] 1H NMR (400MHz, CDCl3) δ7.69 (d, J=2.0Hz, 1H), 7.56 (dd, J=8.8, 2.0Hz, 1H), 6.92 (d, J=8. 8Hz,1H),3.94(s,3H),3.91(t,J=7.2Hz,2H),2.61(t,J=7.6Hz,2H),2.17–2.09(m,2H). 13 C NMR (101MHz, CDCl3) δ174.65,168.83,157.99,131.60,129.80,126.85,121.82,110.61,56.22,46.69,33.26,17.61.HRMS(ESI):Calcd.for C 12 H 12 ClNO3[M+H] + m / z254.0579, Found m / z 254.0585.

[0097] Example 19: Preparation of Chloraprostenone (Compound 19)

[0098]

[0099] To a 5ml brown bottle, add 92.1mg of apremilast, 53.41mg of N-chlorosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform, and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to obtain 88.10mg of chloroapremilast, with a yield of 89%.

[0100] 1 H NMR (400MHz, CDCl3) δ9.46(s,1H),8.78(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,1H),7.52(d,J=8.4Hz,1H),7.30(s,1H),6.87(s,1H),6.36(dd,J=11.6,2 .8Hz,1H),4.52(t,J=14.8Hz,1H),4.09(q,J=6.8Hz,2H),3.85(s,3H),3.4 9(dd,J=14.8,2.8Hz,1H),3.02(s,3H),2.26(s,3H),1.46(t,J=6.8Hz,3H). 13C NMR (101MHz, CDCl3) δ169.66,169.21,167.96,150.24,147.65,137.71,136.20,131.10,126.00,125.06,124. 06,118.31,115.10,113.37,112.71,64.94,56.21,53.68,45.85,40.96,24.96,14.60.HRMS(ESI):Calcd.forC 22 H 23 ClN2O7S[M+H] + m / z 495.0988, Found m / z 495.0979.

[0101] Example 20: Preparation of chloro-N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester (Compound 20)

[0102]

[0103] To a 5ml brown bottle, add 90.32mg of N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester, 53.41mg of N-chlorosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 72.50mg of chloro-N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester (76% yield).

[0104] 1 H NMR (400MHz, CDCl3) δ7.23(d,J=8.4Hz,2H),7.20(d,J=6.8Hz,1H),7.15(d,J=7.2H z,2H),6.92(d,J=1.6Hz,1H),6.81(d,J=8.0Hz,1H),6.74(dd,J=8.4,1.6Hz,1H),6. 34(d,J=7.6Hz,1H),5.88(s,1H),4.94(s,1H),4.69(q,J=12.8,6.0Hz,1H),4.30(d ,J=6.8Hz,1H),3.63(s,3H),3.00(d,J=6.4Hz,2H),2.95–2.86(m,2H),1.36(s,9H). 13C NMR (100MHz, CDCl3) δ171.14,170.91,150.58,146.87,136.38,129.67,129.28,129.16,128.69, 127.01,119.82,116.32,80.36,55.83,53.24,52.33,38.18,36.88,28.20.HRMS(ESI):Calcd.for C 24 H 29 ClN2O6[M+H] + m / z 477.1787, Found m / z 477.1783.

[0105] Example 21: Preparation of Bromovoriconazole (Compound 21)

[0106]

[0107] To a 5ml brown bottle, add voriconazole (69.8mg), N-bromosuccinimide (71.2mg), 2-(phenylthio)benzoic acid (4.6mg), and chloroform (2mL). Stir at 60°C for 24 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 78.79mg of bromovoriconazole (92% yield).

[0108] 1 H NMR (400MHz, CDCl3) δ8.97(d,J=2.0Hz,1H),8.62(s,1H),7.58(td,J=9.6,6.8Hz,1H),7.54(s,1H),6.89–6.76(m ,2H),6.49(s,1H),4.65(d,J=14.0Hz,1H),4.26(d,J=14.0Hz,1H),4.18(q,J=14.0Hz,1H),1.09(d,J=6.8Hz,3H). 13 C NMR(101MHz,CDCl3)δ162.75(dd,J C-F =248.4,12.3Hz),159.54(d,J C-F =12.6Hz),158.71(dd,J C-F =245.5,11.6Hz),157.07,154.42,153.20(d,J C-F =7.8Hz),151.82,145.26(d,J C-F =21.5Hz),130.46(dd,J C-F=9.0,5.1Hz),123.64(dd,J C-F =11.7,3.8Hz),103.97(t,J C-F =27.1Hz),77.67(d,J C-F =5.0Hz),55.99(d,J C-F =4.0Hz),36.49(d,J C-F =6.1Hz),15.64. 19 F NMR(376MHz, CDCl3)δ-108.95(d,J F-F =11.28Hz),-110.41(d,J F-F =7.52Hz),-135.14.

[0109] Example 22: Preparation of Bromoepoxiconazole (Compound 22)

[0110]

[0111] To a 5ml brown bottle, add 98.93mg of epoxiconazole, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 30 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then rotary evaporated to remove the solvent, and column chromatography is performed to obtain 72.33mg of bromoepoxiconazole (59% yield).

[0112] 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),7.61(dd,J=6.8,2.4Hz,1H),7.47(dd,J=6.8,2.4Hz,1H),7.40 –7.35(m,4H),7.02(t,J=8.8Hz,2H),4.66(d,J=14.8Hz,1H),4.21(s,1H),3.98(d,J=14.8Hz,1H). 13 C NMR(101MHz,CDCl3)δ162.67(d,J C-F =248.6Hz),152.76,132.99,132.15,131.97(d,J C-F =2.9Hz),130.07,129.80,129.27,128.22(d,J=8.3Hz),128.14,127.18,115.54(d,J C-F =21.7Hz),64.59,63.14,51.38. 19F NMR (376MHz,CDCl3)δ-112.41.

[0113] Example 23: Preparation of difenoconazole (Compound 23)

[0114]

[0115] To a 5ml brown bottle, add 81.25mg of diconazole, 71.19mg of N-bromosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of ethyl acetate. Stir at 60°C for 30 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 67.92mg of bromodiconazole (70% yield).

[0116] 1 H NMR (400MHz, CDCl3) δ7.89(s,1H),7.86(s,0.8×1H),7.59(dd,J=8.8,2.8Hz,1×1+0.8×1H),7.33(d,J=8.8Hz,1×2+0.8×2H),7.02( d,J=2.0Hz,1H),7.01(d,J=2.0Hz,0.8×1H),6.97(dd,J=8.8,2.8Hz,1×2+0.8×2H),6.83(dd,J=8.8,2.8Hz,1H),6.81(dd,J=8.8,2 .8Hz,1H),4.78(d,J=14.0Hz,0.8×1H),4.75(d,J=14.0Hz,1H),4.70(d,J=14.0Hz,1H),4.66(d,J=14.0Hz,0.8×1H),4.13–4.03(m ,0.8×2H),4.03–3.91(m,2H),3.32(t,J=8.0Hz,0.8×1H),3.16(t,J=8.0Hz,1H),1.19(d,J=6.0Hz,0.8×3H),1.11(d,J=6.0Hz,3H). 13C NMR (101MHz, CDCl3) δ158.45,158.37,154.30,152.37,152.27,133.39,133.26,131.69,131.27,131.09,130.91,130.03,129.73,129. 70,129.56,121.02,120.98,120.75,120.53,116.10,115.96,107.50,107.39,74.16,72.87,71.28,71.23,53.99,53.66,17.91,17.76.

[0117] Example 24: Preparation of Bromoletrozole (Compound 24)

[0118]

[0119] To a 5ml brown bottle, add 85.59mg of letrozole, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of N,N-dimethylformamide and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to yield 81.95mg of chloroletrozole (84% yield).

[0120] 1 H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.68 (d, J = 8.4Hz, 4H), 7.32 (d, J = 8.4Hz, 4H), 6.87 (s, 1H). 13 C NMR (101MHz, CDCl3) δ153.35,141.21,132.71,130.20,129.03,117.87,113.06,65.07.

[0121] Example 25: Preparation of bromomyclobutanil (Compound 25)

[0122]

[0123] To a 5ml brown bottle, add 86.63mg of myclobutanil, 191.89mg of pyridinium tribromide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 15 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 89.34mg of bromomyclobutanil (81% yield).

[0124] 1H NMR (400MHz, CDCl3) δ7.91(s,1H),7.36(d,J=8.8Hz,2H),7.24(d,J=8.8Hz,2H),4.56(d,J=14.0 Hz,1H),4.48(d,J=14.0Hz,1H),2.16(t,J=7.2Hz,2H),1.56–1.08(m,6H),0.89(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ153.05,135.09,132.91,131.06,129.48,127.72,119.74,56.11,48.53,36.31,26.99,22.42,13.71.

[0125] Example 26: Preparation of Bromofluconazole (Compound 26)

[0126]

[0127] To a 5ml brown bottle, add 91.99mg of fluconazole, 213.58mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of hexafluoroisopropanol, and stir at 60°C for 24 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 123.90mg of bromofluconazole (89% yield).

[0128] 1 H NMR (400MHz, CDCl3) δ7.79 (s, 2H), 7.49–7.39 (m, 1H), 6.88–6.73 (m, 2H), 5.43 (s, 1H), 4.82 (d, J = 14.4Hz, 2H), 4.55 (d, J = 14.4Hz, 2H). 13 C NMR(101MHz,CDCl3)δ163.29(dd,J C-F =250.0,12.6Hz),158.72(dd,J C-F =245.5,12.2Hz),151.30,143.49,129.80(dd,J C-F =9.4,5.4Hz),121.95(dd,J C-F =13.0,3.8Hz),112.09(dd,J C-F =20.4,3.5Hz),104.39(t,J C-F =26.1Hz),75.35(d,J C-F=4.7Hz),53.37(d,J C-F =5.1Hz). 19 F NMR(376MHz,CDCl3)δ-108.38(d,J F-F =7.1Hz),-108.50(d,J F-F =10.9Hz).

[0129] Example 27: Preparation of brominated celecoxib (Compound 27)

[0130]

[0131] To a 5ml brown bottle, add 114.41mg of celecoxib, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 24 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 99.42mg of brominated celecoxib (72% yield).

[0132] 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.15(d,J=8.4Hz,2H),5.15(s,2H),2.40(s,3H). 13 C NMR(101MHz,CDCl3)δ143.64,142.10,141.99(q,J C-F =37.6Hz),141.51,140.48,129.84,129.76,127.44,125.02,123.82120.42(q,J C-F =268.6Hz),94.44,21.42. 19 F NMR (376MHz,CDCl3)δ-62.62.

[0133] Example 28: Preparation of Piribedil Bromide (Compound 28)

[0134]

[0135] To a 5ml brown bottle, add 89.50mg of piribedil, 191.89mg of pyridinium tribromide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform, and stir at room temperature for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to obtain 81.48mg of piribedil bromide (72% yield).

[0136] 1 H NMR (400MHz, CDCl3) δ8.26(s,2H),6.88(s,1H),6.75(s,2H),5.95(s,2H),3.77(t,J=4.8Hz,1H),3.44(s,2H),2.46(t,J=4.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ159.80,157.79,147.65,146.66,131.70,122.19,109.42,107.86,105.53,100.88,62.77,52.63,43.89.

[0137] Example 29: Preparation of Bromodasatinib (Compound 29)

[0138]

[0139] To a 5ml brown bottle, add 97.60mg of dasatinib, 127.93mg of pyridinium tribromide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of N,N-dimethylformamide and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to yield 102.04mg of bromodasatinib (90% yield).

[0140] 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),8.31(s,1H),7.42(dd,J=7.6,1.6Hz,1H),7.31(d,J=7.6Hz,1H),7.28(t, J=7.6Hz,1H),4.52(s,1H),3.58–3.52(m,6H),2.64–2.55(m,4H),2.54–2.51(m,2H),2.49(s,3H),2.26(s,3H). 13C NMR(101MHz,DMSO-d6)δ162.94,162.70,162.31,159.67,155.68,138.77,133.34,132.37, 129.63,129.05,128.24,127.02,125.55,88.32,60.00,58.16,52.80,47.86,24.62,18.28.

[0141] Example 30: Preparation of Imatinib Bromide (Compound 30)

[0142]

[0143] To a 5ml brown bottle, add imatinib (98.72mg), N-bromosuccinimide (71.19mg), 2-(phenylthio)benzoic acid (4.6mg), and N,N-dimethylformamide (2mL). Stir at 60°C for 20 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to yield 74.73mg of imatinib bromide (65% yield).

[0144] 1 H NMR(400MHz, CDCl3)δ9.40(s,1H),9.23(d,J=1.6Hz,1H),8.71–8.63(m,2H),8.52(d,J=5.2Hz,1H),8.41(s,1H),7.90(d,J=8.4Hz,2H),7 .48(d,J=8.0Hz,2H),7.44–7.39(m,2H),7.21(d,J=4.8Hz,1H),7.09(s,1H),3.59(s,2H),2.65–2.43(br,8H),2.34(s,3H),2.32(s,3H). 13 C NMR (101MHz, CDCl3) δ164.86,162.90,160.42,159.22,151.51,148.52,142.83,137.55,135.49,134.10,133.61 ,133.20,132.70,129.55,127.15,125.78,123.90,114.38,108.68,107.25,62.45,55.01,52.81,45.83,17.65.

[0145] Example 31: Preparation of Bromoclotrimazole (Compound 31)

[0146]

[0147] To a 5ml brown bottle, add 103.45mg of clotrimazole, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 12 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 63.56mg of bromoclotrimazole (50% yield).

[0148] 1 H NMR(400MHz, CDCl3)δ7.43(dd,J=8.0,1.2Hz,1H),7.39–7.35(m,7H),7.33(s,1H),7.29(dd ,J=8.0,1.2Hz,1H),7.17(dd,J=5.6,2.0Hz,4H),6.93(dd,J=8.0,1.2Hz,1H),6.74(s,1H). 13 C NMR (101MHz, CDCl3) δ140.06,139.63,139.63,138.63,135.45,132.30,130.29,130.06,128.39,128.14,127.11,120.59,114.84,75.77.

[0149] Example 32: Preparation of Bromo-ipriflavone (Compound 32)

[0150]

[0151] To a 5ml brown bottle, add 84.10mg of ipriflavone, 107.39mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 18 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 87.29mg of bromoipriflavone (81% yield).

[0152] 1 H NMR (400MHz, CDCl3) δ8.23(d,J=9.2Hz,1H),8.05(s,1H),7.56(d,J=9.2Hz,2H),7.44(t,J=9.2Hz,2H ),7.40(d,J=9.2Hz,1H),7.03(d,J=9.2Hz,1H),4.78(dt,J=12.0,6.0Hz,1H),1.46(d,J=6.0Hz,6H). 13C NMR (101MHz, CDCl3) δ175.27,159.22,154.35,152.80,131.45,128.86,128.41,128.20,126.31,125.00,119.12,111.89,100.69,72.72,21.97.

[0153] Example 33: Preparation of Bromoketoconazole (Compound 33)

[0154]

[0155] To a 5ml brown bottle, add 106.29mg of ketoconazole, 71.19mg of N-bromosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform, and stir at 60°C for 25 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, and then column chromatography is performed to obtain 69.58mg of bromoketoconazole with a yield of 57%.

[0156] 1 H NMR (400MHz, CDCl3) δ7.51(d,J=8.4Hz,1H),7.45(s,1H),7.38(d,J=2.4Hz,1H),7.19(dd,J=8.4,2.0Hz,1H),7.02(d, J=3.2Hz,1H),6.92–6.90(m,2H),6.87(d,J=8.4Hz,1H),6.67(dd,J=8.8,3.2Hz,1H),4.42(d,J=14.8Hz,1H),4.30(d,J =14.8Hz,1H),4.26(tt,J=6.0,4.8Hz,1H),3.79(dd,J=8.5,6.4Hz,1H),3.67(br,2H),3.65(dd,J=8.8,4.8Hz,1H),3.5 9(dd,J=9.2,4.8Hz,1H),3.54(t,J=4.4Hz,2H),3.17(dd,J=9.2,6.4Hz,1H),2.84(dt,J=15.2,4.4Hz,4H)2.06(s,3H). 13C NMR (101MHz, CDCl3) δ168.88,154.63,143.58,138.60,135.63,134.22,132.73,131.11,129.24,128.12,127.02, 121.29,121.06,120.53,119.80,113.77,107.79,74.30,67.33,67.09,52.07,51.51,50.91,46.43,41.50,21.22.

[0157] Example 34: Preparation of Bromosulfanilamide (Compound 34)

[0158]

[0159] To a 5ml brown bottle, add 84.09mg of sulfaquinoxaline, 64.07mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 90.52mg of bromosulfaquinoxaline (84% yield).

[0160] 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),7.92(d,J=1.6Hz,1H),7.74(s,2H),7.65(dd,J=8.8,1.6Hz,1H),6.80(d,J=8.8Hz,1H),6.23(s,2H),3.90(s,3H). 13 C NMR (101MHz, DMSO-d6) δ149.92,138.15,133.83,133.15,132.33,128.53,127.11,113.61,105.09,53.68.

[0161] Example 35: Preparation of Bromosulfamethoxazole (Compound 35)

[0162]

[0163] To a 5ml brown bottle, add 75.98mg of sulfamethoxazole, 64.07mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 65.77mg of bromosulfamethoxazole (66% yield).

[0164] 1 H NMR (400MHz, CDCl3) δ7.89(d,J=2.0Hz,1H),7.54(dd,J=8.4,2.0Hz,1H),6.71(d,J=8.4Hz,1H),6.20(s,1H),4.63(s,2H),2.37(s,3H). 13 C NMR (101MHz, DMSO-d6) δ170.20,157.69,150.24,131.41,127.67,125.86,114.08,105.55,95.37,12.05.

[0165] Example 36: Preparation of Bromosulfadiazine (Compound 36)

[0166]

[0167] To a 5ml brown bottle, add 75.08mg of sulfadiazine, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of ethyl acetate. Stir at room temperature for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 84.47mg of bromosulfadiazine (69% yield).

[0168] 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.53(d,J=4.8Hz,2H),7.93(s,2H),7.07(t,J=4.8Hz,1H),6.25(s,2H),6.25(s,2H). 13 C NMR (101MHz, DMSO-d6) δ158.47,156.75,146.91,131.51,128.05,115.91,105.70.

[0169] Example 37: Preparation of Bromonaproxen (Compound 37)

[0170]

[0171] To a 5ml brown bottle, add 69.08mg of naproxen, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, 36.65mg of 4-dimethylaminopyridine, and 3mL of chloroform. Stir at 60°C for 20 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 77.91mg of bromonaproxen (84% yield).

[0172] 1 H NMR (400MHz, CDCl3) δ8.18(d,J=8.8Hz,1H),7.72(d,J=8.8Hz,2H),7.70(s,1H),7.53(dd,J=8. 8,1.2Hz,1H),7.26(d,J=8.8Hz,1H),4.02(s,3H),3.91(q,J=6.8Hz,1H),1.61(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ179.53,153.84,135.72,132.45,129.75,128.83,127.62,126.77,126.39,113.98,108.56,57.06,44.95,18.07.

[0173] Example 38: Preparation of Bromoamodiaquine (Compound 38)

[0174]

[0175] To a 5ml brown bottle, add 106.76mg of amodiaquine, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform, and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to obtain 119.99mg of bromoamodiaquine (92% yield).

[0176] 1H NMR (400MHz, CDCl3) δ8.49(d,J=5.6Hz,1H),8.00(d,J=2.0Hz,1H),7.82(d,J=8.8Hz,1H),7.43(dd,J=8.8,2.0Hz,1H),7.2 2(d,J=2.0Hz,1H),6.85(d,J=2.0Hz,1H),6.64(d,J=5.6Hz,1H),3.81(s,2H),2.67(q,J=6.8Hz,4H),1.15(t,J=6.8Hz,6H). 13 C NMR (101MHz, CDCl3) δ152.81,151.79,149.35,148.83,135.30,129.91,128.84, 125.97,125.57,123.42,121.36,120.96,117.36,101.58,56.75,46.41,11.08.

[0177] Example 39: Preparation of Bromo-Xanthoxytoxin (Compound 39)

[0178]

[0179] To a 5ml brown bottle, add 64.86mg of xanthoxytoxin, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 12 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 76.13mg of chloroxanthoxytoxin (86% yield).

[0180] 1 H NMR (400MHz, CDCl3) δ8.11(d,J=9.6Hz,1H),7.72(s,1H),6.87(s,1H),6.44(d,J=9.6Hz,1H),4.28(s,3H). 13 C NMR (101MHz, CDCl3) δ159.75,146.88,146.58,143.65,142.60,132.37,127.94,115.7,107.41,105.49,61.40.

[0181] Example 40: Preparation of Bromopropamide (Compound 40)

[0182]

[0183] To a 5ml brown bottle, add 81.41mg of naproxamide, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of ethyl acetate. Stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 85.11mg of bromonaproxamide (81% yield).

[0184] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=8.4Hz,1H),8.15(d,J=8.4Hz,1H),7.61(D,J=8.4Hz,1H),7.60(t,J=8.4Hz,1H),7.52(t,J=8.4Hz,1H) ,6.68(d,J=8.4Hz,1H),5.08(q,J=6.8Hz,1H),3.57–3.31(m,4H),1.72(d,J=6.8Hz,3H),1.10(t,J=6.8Hz,3H),1.00(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.73,153.00,132.57,129.28,127.79,126.89,126.8 4,126.09,122.45,114.00,106.40,74.49,41.04,40.33,17.88,14.09,12.56.

[0185] Example 41: Preparation of Bromo-Aniracetam (Compound 41)

[0186]

[0187] To a 5ml brown bottle, add 65.79mg of aniracetam, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of acetonitrile, and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 83.18mg of bromoaniracetam (93% yield).

[0188] 1H NMR (400MHz, CDCl3) δ7.84 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.8, 2.0 Hz, 1H), 6.87 (d, J = 8. 8Hz,1H),3.92(s,3H),3.88(t,J=8.0Hz,2H),2.58(t,J=8.0Hz,2H),2.15–2.06(m,2H). 13 C NMR (101MHz, CDCl3) δ174.60,168.58,158.71,134.55,130.47,127.21,110.65,110.37,56.26,46.61,33.17,17.51.

[0189] Example 42: Preparation of Apremilast Bromide (Compound 42)

[0190]

[0191] To a 5ml brown bottle, add 92.1mg of apremilast, 71.19mg of N-bromosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform, and stir at 60°C for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to obtain 100.33mg of bromoapremilast, with a yield of 93%.

[0192] 1 H NMR (400MHz, CDCl3) δ9.44(s,1H),8.74(d,J=8.0Hz,1H),7.64(t,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.33(s,1H),7.00(s,1H),6.30(dd,J=11.6,2 .8Hz,1H),4.49(t,J=14.0Hz,1H),4.05(q,J=6.8Hz,2H),3.82(s,3H),3.4 6(dd,J=14.0,2.8Hz,1H),3.00(s,3H),2.24(s,3H),1.43(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.59,169.12,167.93,150.10,148.14,137.57,136.08,131.00,127.88,1 24.92,118.19,115.61,114.98,113.45,112.98,64.71,56.12,53.56,48.61,40.89,24.84,14.47.

[0193] Example 43: Preparation of dibromo-N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester (Compound 43)

[0194]

[0195] To a 5ml brown bottle, add 90.32mg of N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester, 53.41mg of N-chlorosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 82.84mg of bromo-N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester (69% yield).

[0196] 1 H NMR (400MHz, CDCl3) δ7.27(t,J=7.6Hz,2H),7.23(d,J=7.6Hz,1H),7.19(d,J=7.6Hz,2H),7.11(s,2H),6.48(d,J=7.6Hz,1H),6.18(s ,1H),4.99(s,1H),4.72(q,J=5.6Hz,1H),4.35(d,J=6.4Hz,1H),3.68(s,3H),3.05(d,J=6.4Hz,2H),3.00–2.88(m,2H),1.39(s,9H). 13 C NMR (101MHz, CDCl3) δ171.07,170.92,155.32,148.63,136.32,132.66,130.30,1 29.20,128.67,127.01,109.87,80.36,55.85,53.11,52.40,38.15,36.46,28.17.

[0197] Example 44: Preparation of iodinated voriconazole (Compound 44)

[0198]

[0199] To a 5ml brown bottle, add 69.8mg of voriconazole, 89.99mg of N-iodosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 20 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 80.78mg of iodovoriconazole (85% yield).

[0200] 1 H NMR(400MHz, CDCl3)δ9.03(d,J=2.4Hz,1H),8.68(d,J=1.2Hz,1H),7.69–7.59(m,2H),6.93–6.83(m,2H), 6.57(s,1H),4.71(d,J=14.2Hz,1H),4.32(d,J=12.8Hz,1H),4.25(q,J=6.8Hz,1H),1.15(d,J=7.2Hz,3H). 13 C NMR(101MHz,CDCl3)δ162.87(dd,J C-F =248.6,12.6Hz),159.61(d,J C-F =12.6Hz),158.71(dd,J C-F =245.8,11.9Hz),157.19,154.54,153.80,153.33(d,J C-F =7.7Hz),145.44,145.23,130.56(dd,J C-F =9.3,5.7Hz),123.81(dd,J C-F =11.7,3.7Hz),111.53(dd,J C-F =20.6,3.0Hz),104.32(t,J C-F =56.0Hz),101.48,77.90(d,J C-F =5.0Hz),57.16(d,J C-F =4.2Hz),36.55(d,J C-F =5.8Hz),15.75. 19 FNMR(376MHz,CDCl3)δ-108.77(d,J F-F =10.5Hz),-110.46(d,J F-F =7.1Hz),-134.99.

[0201] Example 45: Preparation of iodoepiconazole (Compound 45)

[0202]

[0203] To a 5ml brown bottle, add 98.93mg of epoxiconazole, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 36 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to obtain 90.22mg of iodoepoxiconazole (66% yield).

[0204] 1 H NMR(400MHz, CDCl3) δ7.83(s,1H),7.63(dd,J=7.2,2.4Hz,1H),7.47(dd,J=7.2,2.4Hz,1H),7.40 –7.29(m,4H),7.01(t,J=8.8Hz,2H),4.65(d,J=14.8Hz,1H),4.23(s,1H),3.99(d,J=14.8Hz,1H). 13 C NMR(101MHz,CDCl3)δ162.71(d,J C-F =246.6Hz),154.72,133.00,132.16,131.98(d,J C-F =3.1Hz),129.79,129.28,128.45(d,J C-F =8.3Hz),128.26,127.18,115.53(d,J C-F =21.6Hz),100.96,64.80,63.02,52.55. 19 F NMR (376MHz,CDCl3)δ-112.32.

[0205] Example 46: Preparation of iodinated difenoconazole (Compound 46)

[0206]

[0207] To a 5ml brown bottle, add 81.25mg of diconazole, 71.19mg of N-iodosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of ethyl acetate. Stir at 60°C for 30 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to obtain 67.05mg of iodoconazole (63% yield).

[0208] 1H NMR (400MHz, CDCl3) δ7.93(s,1H),7.91(s,0.8×1H),7.59(d,J=8.8Hz,1×1+0.8×1H),7.33(d,J=8.8Hz,1×2+0.8×2H),7.02(d,J =2.0Hz,1H),7.01(d,J=2.0Hz,0.8×1H),6.97(dd,J=8.8,2.8Hz,1×2+0.8×2H),6.83(dd,J=8.8,2.8Hz,1H),6.81(dd,J=8.8,2.8 Hz,1H),4.80(d,J=14.0Hz,0.8×1H),4.76(d,J=14.0Hz,1H),4.72(d,J=14.0Hz,1H),4.68(d,J=14.0Hz,0.8×1H),4.12–4.01(m ,1.6H),4.01–3.89(m,2H),3.30(t,J=8.0Hz,0.8×1H),3.11(t,J=8.0Hz,1H),1.18(d,J=6.0Hz,0.8×3H),1.10(d,J=6.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ158.41,158.33,154.27,154.21,154.13,133.37,133.24,131.74,130.96,130.01,129.74,129.70,129.52,121. 01,120.97,120.72,120.50,116.11,115.96,107.55,107.44,101.97,101.72,74.10,72.86,71.22,71.13,55.03,54.63,17.85,17.73.

[0209] Example 47: Preparation of iodine letrozole (Compound 47)

[0210]

[0211] To a 5ml brown bottle, add 85.59mg of letrozole, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of N,N-dimethylformamide and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to yield 90.05mg of iodinated letrozole (73% yield).

[0212] 1H NMR (400MHz, CDCl3) δ8.03 (s, 1H), 7.69 (d, J = 8.4Hz, 4H), 7.31 (d, J = 8.4Hz, 4H), 6.87 (s, 1H). 13 C NMR (101MHz, CDCl3) δ155.30,141.42,132.73,129.07,117.93,113.05,101.47,66.44.

[0213] Example 48: Preparation of iodine myclobutanil (Compound 48)

[0214]

[0215] To a 5ml brown bottle, add 86.63mg of myclobutanil, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 24 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 65.93mg of iodinated myclobutanil (53% yield).

[0216] 1 H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.36 (d, J = 8.4Hz, 2H), 7.22 (d, J = 8.4Hz, 2H), 4.57 (d, J = 14.0 Hz,1H),4.50(d,J=14.0Hz,1H),2.17(t,J=7.6Hz,2H),1.62–1.09(m,6H),0.89(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ155.00,135.10,132.94,129.50,127.89,119.86,102.27,57.12,48.64,36.30,27.03,22.44,13.73.

[0217] Example 49: Preparation of iodofluconazole (Compound 49)

[0218]

[0219] To a 5ml brown bottle, add 91.99mg of fluconazole, 269.98mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of hexafluoroisopropanol, and stir at 60°C for 18 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 45.20mg of iodofluconazole (27% yield).

[0220] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 2H), 7.52–7.41 (m, 1H), 6.90–6.71 (m, 2H), 5.73 (s, 1H), 4.84 (d, J = 14.4Hz, 2H), 4.61 (d, J = 14.4Hz, 2H). 13 C NMR(101MHz,CDCl3)δ163.30(dd,J C-F =250.1,12.4Hz),158.79(dd,J C-F =245.4,11.7Hz),154.36,129.98(dd,J C-F =9.7,5.6Hz),122.29(dd,J C-F =13.1,3.7Hz),112.08(dd,J C-F =20.7,3.1Hz),104.52(t,J C-F =26.3Hz),102.21,75.42(d,J C-F =4.6Hz),55.35(d,J C-F =4.9Hz). 19 F NMR(376MHz, CDCl3)δ-107.04(d,J F-F =10.5Hz),-108.72(d,J F-F =7.5Hz).

[0221] Example 50: Preparation of iodinated celecoxib (Compound 50)

[0222]

[0223] To a 5ml brown bottle, add 114.41mg of celecoxib, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 30 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 132.39mg of iodinated celecoxib (87% yield).

[0224] 1 H NMR (400MHz, CDCl3) δ7.81(d,J=8.4Hz,2H),7.34(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),5.33(s,2H),2.39(s,3H). 13 C NMR(101MHz,CDCl3)δ147.05,145.19(q,J C-F =36.9Hz),142.12,141.36,140.45,130.02,129.82,127.36,124.98,120.52(q,J C-F =268.5Hz),60.87,21.43. 19 F NMR (376 MHz, CDCl3) δ-62.30.

[0225] Example 51: Preparation of iodinated clotrimazole (Compound 51)

[0226]

[0227] To a 5ml brown bottle, add 103.45mg of clotrimazole, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 2mL of acetonitrile and stir at 60°C for 12 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate and extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent and column chromatography to yield 69.20mg of iodoclotrimazole (49% yield).

[0228] 1 H NMR (400MHz, CDCl3) δ7.55(s,1H),7.42(dd,J=8.0,1.6Hz,1H),7.36–7.32(m,6H),7.26(dd,J=15. 2,1.2Hz,2H),7.19(dd,J=6.0,2.4Hz,4H),7.09(s,1H),6.94(dd,J=8.0,1.6Hz,1H),6.76(s,1H). 13 C NMR (101MHz, CDCl3) δ140.66,140.20,138.93,135.49,132.18,130.39,130.10,129.85,128.15,128.00,127.72,127.01,121.58,75.18.

[0229] Example 52: Preparation of Iodinated Ipriflavone (Compound 52)

[0230]

[0231] To a 5ml brown bottle, add 84.10mg of ipriflavone, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 15 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 65.81mg of iodoipriflavone (54% yield).

[0232] 1 H NMR (400MHz, CDCl3) δ8.26(d,J=8.8Hz,1H),8.06(s,1H),7.56(d,J=8.8Hz,2H),7.44(t,J=7838Hz,2 H),7.40(d,J=8.8Hz,1H),6.95(d,J=8.8Hz,1H),4.79(dt,J=12.0,6.0Hz,1H),1.47(d,J=6.0Hz,6H). 13 C NMR (101MHz, CDCl3) δ175.46,161.85,156.85,152.98,131.57,128.90,128.47,128.23,127.99,124.96,119.21,111.28,72.89,22.07.

[0233] Example 53: Preparation of iodinated sulfamethoxazole (Compound 53)

[0234]

[0235] To a 5ml brown bottle, add 84.09mg of sulfaquinone, 80.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 15 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 95.05mg of iodosulfaquinone (78% yield).

[0236] 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.12(d,J=2.0Hz,1H),7.74(s,2H),7.66(dd,J=8.4,2.0Hz,1H),6.74(d,J=8.4Hz,1H),6.10(s,2H),3.89(s,3H). 13 C NMR (101MHz, DMSO-d6) δ152.58,149.64,138.72,138.08,133.88,133.13,129.20,127.49,112.31,53.66.

[0237] Example 54: Preparation of iodinated sulfamethoxazole (Compound 54)

[0238]

[0239] To a 5ml brown bottle, add 75.98mg of sulfamethoxazole, 80.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of hexafluoroisopropanol. Stir at 60°C for 12 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 92.14mg of iodosulfamethoxazole (81% yield).

[0240] 1 H NMR (400MHz, CDCl3) δ8.09(d,J=2.0Hz,1H),7.56(dd,J=8.4,2.0Hz,1H),6.67(d,J=8.4Hz,1H),6.21(s,1H),2.38(s,3H). 13 C NMR (101MHz, CDCl3) δ170.98,157.54,151.10,138.36,128.69,128.08,113.26,95.53,81.84,12.78.

[0241] Example 55: Preparation of iodinated sulfadiazine (Compound 55)

[0242]

[0243] To a 5ml brown bottle, add 75.08mg of sulfadiazine, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at room temperature for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 88.86mg of iodinated sulfadiazine (59% yield).

[0244] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.53(d,J=4.8Hz,2H),8.13(s,2H),7.07(t,J=4.8Hz,1H),5.88(s,2H). 13 C NMR (101MHz, DMSO-d6) δ158.49,156.80,150.95,138.58,129.50,115.98,79.27.

[0245] Example 56: Preparation of iodinated zanthoxylum bungeanum toxin (Compound 56)

[0246]

[0247] To a 5ml brown bottle, add 64.86mg of xanthoxytoxin, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of chloroform. Stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 77.99mg of chloroxanthoxytoxin (76% yield).

[0248] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J = 9.6 Hz, 1H), 7.73 (s, 1H), 6.76 (s, 1H), 6.39 (d, J = 9.6 Hz, 1H), 4.28 (s, 3H). 13 C NMR (101MHz, CDCl3) δ159.96,147.06,146.60,145.37,143.26,133.12,132.40,118.34,116.11,110.64,61.33.

[0249] Example 57: Preparation of iodinated propamide (Compound 57)

[0250]

[0251] To a 5ml brown bottle, add 81.41mg of naproxamide, 134.99mg of N-iodosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of ethyl acetate. Stir at 60°C for 8 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 109.64mg of iodonaproxamide (92% yield).

[0252] 1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.4Hz,1H),8.28(d,J=8.4Hz,1H),8.01(d,J=8.4Hz,1H),7.90(d,J=8.4Hz,1H),7.78( dd,J=8.4,2.8Hz,1H),7.57(t,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.49–7.46(m,2H),7.43(d,J=8.4Hz,1H),7.32(t, J=8.4Hz,1H),6.82(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),5.11(q,J=6.8Hz,1H),5.07(q,J=6.8Hz,1H),3.60–3.33(m ,1×4+1×4H),1.72(d,J=6.8Hz,1×3+1×3H),1.11(t,J=6.8Hz,1×3+1×3H),1.00(t,J=6.8Hz,3H),0.99(t,J=6.8Hz,1×3H) 13 C NMR (101MHz, CDCl3) δ170.08,169.63,154.01,153.12,136.64,134.82,134.52,131.70,128.13,127.35,126.64,126.33,126.09,125 .65,125.21,122.49,121.95,120.85,107.31,105.71,89.00,74.28,41.00,40.98,40.29,40.24,17.86,17.82,14.05,14.01,12.51.

[0253] Example 58: Preparation of Iodinated Aniracetam (Compound 58)

[0254]

[0255] To a 5ml brown bottle, add 65.79mg of aniracetam, 106.79mg of N-bromosuccinimide, 6.9mg of 2-(phenylthio)benzoic acid, and 3mL of acetonitrile, and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 92.15mg of iodinated aniracetam (89% yield).

[0256] 1 H NMR (400MHz, CDCl3) δ8.06 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.4, 2.0Hz, 1H), 6.79 (d, J=8. 4Hz, 1H), 3.91 (s, 3H), 3.89 (d, J = 7.2Hz, 2H), 2.59 (t, J = 8.0Hz, 2H), 2.15–2.07 (m, 2H). 13 C NMR (101MHz, CDCl3) δ174.65,168.83,157.99,131.60,129.80,126.85,121.82,110.61,56.22,46.69,33.26,17.61.

[0257] Example 59: Preparation of Iodo-Apremilast (Compound 59)

[0258]

[0259] To a 5ml brown bottle, add 92.1mg of apremilast, 89.99mg of N-iodosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform, and stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 106.07mg of iodoapremilast, with a yield of 93%.

[0260] 1H NMR (400MHz, CDCl3) δ9.45(s,1H),8.75(d,J=8.4Hz,1H),7.65(t,J=8.4Hz,1H),7.50(d,J=8.4Hz,1H),7.39(s,1H),7.23(s,1H),6.16(dd,J=12.0,2 .8Hz,1H),4.52(t,J=14.8Hz,1H),4.04(q,J=6.8Hz,2H),3.83(s,3H),3.4 1(dd,J=14.8,2.8Hz,1H),3.03(s,3H),2.25(s,3H),1.43(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.75,169.15,168.12,149.98,149.23,137.61,136.13,131.80,131.07,1 24.97,121.91,118.25,115.01,113.03,86.45,64.56,56.14,54.01,53.71,41.11,24.88,14.45.

[0261] Example 60: Preparation of iodo-N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester (Compound 60)

[0262]

[0263] To a 5ml brown bottle, add 90.32mg of N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester, 53.41mg of N-chlorosuccinimide, 4.6mg of 2-(phenylthio)benzoic acid, and 2mL of chloroform. Stir at 60°C for 10 hours. After the reaction, adjust the pH to neutral with saturated sodium bicarbonate, then extract with ethyl acetate. The organic layer is then subjected to rotary evaporation to remove the solvent, followed by column chromatography to yield 54.57mg of iodo-N-tert-butyloxycarbonyl-L-phenylalanine-L-tyrosine methyl ester (48% yield).

[0264] 1H NMR(400MHz,CDCl3)δ7.27(s,2H),7.22(dd,J=14.4,6.8Hz,2H),7.17(d,J=7.2Hz,1H),7.14(d,J=7.2Hz,2H),6.38(d,J=7.2Hz,1H),5.79(s,1H),4.88(s,1H),4.63(q,J=12.8,6.0Hz,1H),4.27(d,J=6.4Hz,1H),3.62(s,3H),3.00(d,J=6.8Hz,2H),2.91–2.79(m,2H),1.33(s,9H). 13 C NMR(100MHz,CDCl3)δ171.03,170.93,155.32,152.83,139.82,136.33,131.76,129.20,128.69,127.01,80.36,55.91,53.15,52.38,38.18,35.93,28.19。

Claims

1. A method for synthesizing a heteroaryl halide or an aryl halide, characterized in that: The method comprises the following steps: halogenating the carbon-hydrogen bond of a heteroaromatic compound or an aromatic compound in the presence of a catalyst, a halogenating agent XY, and a solvent to obtain a heteroaryl halide or an aryl halide; the chemical formula of the method is as follows: The heteroaromatic ring compound or aromatic ring compound has a structure represented by formula (I), and the heteroaryl halide or aryl halide has a structure represented by formula (II); in, represents heteroaryl or aryl; R 1 ,R 2 ,R 3 ,R 4 ,R 5 R is independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, alkoxy, benzyloxy, acyloxy, acyl, ester, amide, monoalkylamino, dialkylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl; 1 ,R 2 ,R 3 ,R 4 ,R 5 Can be the same or different; or R 1 and R 2 、R 2 With R 3 、R 3 With R 4 、R 4 and R 5 Combined to form a cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, benzocycloalkyl or substituted benzocycloalkyl, benzoheterocycloalkyl or substituted benzoheterocycloalkyl, aromatic ring or substituted aromatic ring, aromatic heterocycle or substituted aromatic heterocycle; The halogenating agent is XY, and the structure of the halogenating agent is The catalyst is The solvent is selected from one or more of nitromethane, dichloromethane, chloroform, N,N-dimethylformamide, acetonitrile, hexafluoroisopropanol, dimethyl sulfoxide, and ethyl acetate.

2. The method for synthesizing heteroaryl halides or aryl halides according to claim 1, wherein: The temperature of the halogenation reaction is from room temperature to 60°C.

3. The method for synthesizing heteroaryl halides or aryl halides according to claim 1, wherein: The molar ratio of the heteroaromatic ring or aromatic ring compound to the halogenating agent is 1:1.2-4.

4. The method for synthesizing heteroaryl halides or aryl halides according to claim 1, wherein: The molar ratio of the heteroaromatic ring or aromatic ring compound to the catalyst is 1:0.01 to 0.5.

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