Synthesis of bicyclo[1.1.1]pentane derivatives via triple carbene-mediated c2-substitution

Abstract

The application relates to the technical field of chemical synthesis, and particularly discloses a synthesis method of a triplet carbene-mediated C2-substituted bicyclo[1.1.1]pentane derivative, which successfully opens up a synthesis path of C2-substituted bicyclo[1.1.1]pentane (BCP) by inserting bicyclo[1.1.0]butane (BCB) under photosensitive conditions; the 1,4-dibasic radical species generated by the triplet carbene has a faster recombination rate; the method not only lays a solid foundation for the application of bicyclo[1.1.1]pentane in medicinal chemistry, but also overcomes the limitation of traditional benzene rings in metabolic stability and water solubility by replacing a bioisostere and using a three-dimensional bridged ring structure. In addition, the synthesized derivatives exhibit excellent biological activity, and experimental data prove that the derivatives have significant fungal inhibition activity in tests such as botrytis cinerea, thereby providing important technical support for the design and development of new drugs.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and specifically discloses a method for synthesizing triplet carbene-mediated C2-substituted bicyclic [1.1.1]pentane derivatives. Background Technology

[0002] Bioisosteres are groups or substituents that, in a biological sense, possess similar physical and chemical properties. These groups or substituents can exhibit similar, related, or opposite biological activities during metabolism. Specifically, bioisosteres not only share similar molecular size and shape (including bond angles and hybridization), but also exhibit similarities in electron distribution (including polarizability, inductive effect, conjugation effect, charge, dipole, etc.), conformation, lipid-water partition coefficient, pKa, chemical reactivity (including metabolic similarity), and hydrogen bond forming ability.

[0003] In the field of drug design, the concept of bioisosteres is widely used to design new drugs by replacing functional groups in drug molecules. These new drugs can further improve drug properties while maintaining their original biological activity, such as increasing efficacy, solving pharmacokinetic problems, reducing off-target effects, and regulating physicochemical properties. In recent years, guided by the concept of "escape plane" drug design, the use of three-dimensional bicyclic [1.1.1] bridged ring derivatives to replace two-dimensional planar aromatic hydrocarbons has attracted widespread attention from medicinal chemists.

[0004] Taking the benzene ring as an example, as a common aromatic ring structure, the benzene ring is widely present in 45% of commercially available small molecule drugs. However, the introduction of the benzene ring structure often reduces the metabolic stability and water solubility of drug molecules. For example, the common analgesic acetaminophen, due to the presence of the phenol structure within the molecule, is easily oxidized by cytochrome P450 enzymes to N-acetylbenzoquinone imine, which has hepatotoxic effects. Replacing the benzene ring with a carbon sp... 3 Isosteric skeletons can effectively overcome the limitations of benzene ring structures on drug activity, leading to further improvements in the physicochemical properties of small molecule drugs. Bicyclic [1.1.1]pentanes (BCPs) are favored by researchers due to their unique three-dimensional stereochemical complexity. 1,3-disubstituted BCPs have been widely used as bioelectronic isosteres for para-disubstituted benzene rings, and functional group derivatization at the 2-position of the bridge between BCPs and BCHs molecules can provide a solution for replacing ortho- or meta-substituted aromatics in drug molecules. Summary of the Invention

[0005] To address the problems existing in the prior art, the first aspect of this invention proposes a method for synthesizing a bicyclic [1.1.1]pentane derivative as shown in formula (I), comprising: Compound II, an organic solvent, a catalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, and compound III were mixed and reacted under controlled temperature and light irradiation to obtain compound I.

[0006] Wherein, the R 1 Selected from hydrogen, substituted or unsubstituted monocyclic aryl, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted alkoxy, carboxyl, amino, halogen, -C(O)R 1a -OC(O)R 1b -C(O)OR 1c -SR 1d -C(O)NHR 1e -S(O)2NHR 1f -(CH2) p OR 1g ; The R 1a R 1b R 1c R 1d R 1e R 1f R 1g Each is independently selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted fused-ring heterocyclic group, substituted or unsubstituted monocyclic aryl, substituted or unsubstituted fused-ring aryl; The R 2 Each group is independently selected from hydrogen, substituted or unsubstituted phosphate ester groups, substituted or unsubstituted monocyclic heterocyclic groups, substituted or unsubstituted straight-chain alkyl groups, substituted or unsubstituted branched alkyl groups, halogens, carboxyl groups, amino groups, cyano groups, borate pinacol ester groups, and -C(O)R groups. 2a -OC(O)R 2b -C(O)OR 2c -SR 2d -C(O)NHR 2e -S(O)2NHR 2f -(CH2) q R 2g -OR 2h -SR 2i -Se-R 2j -NHC(O)R 2k The R 2a R 2b R 2c R 2d R 2e R2f R 2g R 2h R 2i R 2j R 2k Each is independently selected from hydrogen, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted straight-chain alkyl group, substituted or unsubstituted straight-chain alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted monocyclic aryl group, and substituted or unsubstituted fused-ring aryl group; The R 3 It is selected from hydrogen, substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heterocyclic, substituted or unsubstituted fused heterocyclic, and substituted or unsubstituted alkyl.

[0007] In a specific embodiment of the method for synthesizing the bicyclic [1.1.1]pentane derivative as shown in formula (I) as described in the first aspect, the R 1 The hydrogen on R is optional 1x Replace, R 1x Selected from methyl, ethyl, tert-butyl, amino protecting group, monocyclic aryl, F, Cl, Br, I, -OR 1aa -C(O)OR 1ab -(CH) m R 1ac ; The R 1aa R 1ab R 1ac Each is independently selected from monocyclic aryl, methyl, ethyl, tert-butyl, F, Cl, Br, I; The R 2 The hydrogen on R is optional 2y Replace, R 2y Selected from F, Cl, Br, I, methyl, ethyl, tert-butyl, amino protecting group, monocyclic aryl, F, Cl, Br, I, -OR 2aa -C(O)OR 2ab -(CH) n R 2ac ; The R 2aa R 2ab R 2ac Each is independently selected from monocyclic aryl, methyl, ethyl, and tert-butyl groups; The R 3 The hydrogen on R is optional 3z Instead, the R 3z Selected from F, Cl, Br, I, methyl, ethyl, tert-butyl; The R 1x R 2y R 3zThe hydrogen atoms can be optionally replaced by F, Cl, Br, or I; The m and n are each independently selected from any integer from 0 to 10.

[0008] A second aspect of this invention provides a bicyclic [1.1.1]pentane derivative with the following structure: , , , , , .

[0009] A third aspect of this invention provides a method for synthesizing compound BCP-boscalid 71, comprising: S1: Mix compound 7 and organic solvent, add trifluoroacetic acid, react to obtain crude product; S2: The crude product from step S1, compound 49, and 4-methylthiophenol were mixed, and an organic solvent and water were added. The mixture was reacted under light irradiation at a wavelength of 370-450 nm to obtain compound S23.

[0010] S2: Dissolve compound S23 in an organic solvent, add alkali, react, dry, filter, and concentrate under reduced pressure to obtain the crude product; S3: Dissolve the crude product obtained in step S2 in an organic solvent, add DPPA and DIPEA to obtain a reaction mixture, add tetrahydrofuran to the reaction mixture, and then add a base to obtain compound S24.

[0011] S4: Compound S25 is reacted with an organic solvent, oxaloyl chloride is added, compound S24 is added, and a base is added to obtain compound BCP-boscalid 71. .

[0012] A fourth aspect of this invention provides a method for synthesizing the compound BCP-fluxapyroxad 72, comprising: S1: Compound 7 is mixed with an organic solvent, trifluoroacetic acid is added, the reaction is carried out, and the extract phase is obtained by extraction. The solvent is removed from the extract phase to obtain the crude product. S2: The crude product obtained in step S1, compound 49, 4-methylthiophenol, organic solvent, and water are mixed and reacted under light irradiation of 370~450nm to obtain compound S26. ; S3: Compound S26 is mixed with an organic solvent, a base is added, and the mixture reacts to obtain a mixture; S4: Mix the mixture from step S3, DPPA, DIPEA, and base, and react to obtain compound S27;

[0013] S5: Mix compound S28 with an organic solvent, add oxaloyl chloride organic solvent, then add compound S27 and a base to obtain compound BCP-fluxapyroxad 72; .

[0014] The fifth aspect of this invention provides a method for synthesizing the compound BCP-tasosartan 77, comprising: S1: Add sodium hydride to the organic solution of compound S43, and then add compound S34 to obtain compound S44;

[0015] S2: Compound S44 and n Bu2SnO was mixed, and then TMSN3 was added. The reaction yielded the compound BCP-tasosartan77. .

[0016] The sixth aspect of this invention discloses a synthesis of compound BCP-candesartan 78, comprising: S1: Add compound S34 and tetrabutylammonium iodide to a suspension of compound S45, base, and sec-butanol, and react to obtain compound S46.

[0017] S2: Compound S46 and n Bu2SnO was mixed, followed by the addition of an organic solvent and TMSN3, and the reaction was carried out to obtain compound S47;

[0018] S3: Dissolve compound S47 in a mixed solvent of organic solvent and water, add alkali, and react to obtain compound BCP-candesartan 78; .

[0019] The seventh aspect of this invention discloses a synthesis of compound BCP-fimasartan 79, comprising: S1: Compound S48, an organic solvent mixture, and lithium hydride are mixed together, and then compound S34 is added. The reaction yields compound S49.

[0020] S2: Compound S49 n A mixture of Bu₂SnO was then added, followed by the addition of an organic solvent and TMSN₃, and the reaction yielded compound S50.

[0021] S3: Compound S50, organic solvent, and Lawesson's reagent are mixed and reacted to give compound BCP-fimasartan79; .

[0022] The eighth aspect of this invention discloses the synthesis of the compound BCP-tolvaptan 80, comprising: S1: Dissolve compound 55 in an organic solvent mixture, then add an aqueous solution of sodium periodate and an aqueous solution of ruthenium trichloride, add acid, extract the organic phase, concentrate the organic phase, and obtain a mixture; S2: Mix the mixture obtained in step S1, 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzodiazepine-5-one, HATU, and an organic solvent, and add DIPEA to obtain compound S51.

[0023] Sodium borohydride was added to an alcoholic solution of compound S51, and the reaction yielded compound BCP-tolvaptan 80. .

[0024] The ninth aspect of this invention discloses the synthesis of compound BCP-phthalylsulfathiazole 81, comprising: S1: Compound 53 and SOCl2 are mixed and reacted to obtain an acid chloride solution; S2: Compound S52, organic solvent and base are mixed to obtain a mixture. An acid chloride solution is added dropwise to the mixture, and the reaction is carried out to obtain compound S53.

[0025] S3: Add alkali to an alcoholic solution of compound S53 and react to obtain compound BCP-phthalylsulfathiazole 81; .

[0026] "Room temperature" refers to the indoor ambient temperature, which can be 12-37℃, 20-30℃, 25-30℃, or approximately 25℃.

[0027] The CAS number of the catalyst TXT is 492-22-8; All reagents used in this invention are purchased from the open and legal market and have not undergone further purification.

[0028] Advantages of this invention: This invention opens up a novel and convenient synthetic route for obtaining C2-substituted bicyclo[1.1.1]pentane (BCP) by inserting a triplet carbene into bicyclo[1.1.0]butane (BCB) under photosensitized conditions. Compared with the singlet carbene route, the 1,4-diradical species generated by the triplet carbene in this invention have a faster recombination rate and can effectively suppress the occurrence of fragmentation side reactions. This method not only lays a solid foundation for the application of bicyclo[1.1.1]pentane in medicinal chemistry, but also overcomes the limitations of traditional benzene rings in terms of metabolic stability and water solubility by using a three-dimensional bridged ring structure through bioisosteric substitution. In addition, the various derivatives synthesized in this invention exhibit excellent biological activity, and experimental data confirm that they have significant in vitro fungicidal effects in tests such as *Botrytis cinerea*, providing important technical support for the design and development of new drugs. Detailed Implementation

[0029] Example 1

[0030] BCB (0.2 mmol, 1.0 equivalent) and [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (Ir-F, 4 μmol, 4.5 mg, 2 mol%) were sequentially added to a flame-dried reaction flask equipped with a magnetic stirrer. The flask was evacuated and purged with argon three times to remove oxygen. Then, anhydrous acetonitrile (MeCN, 2 mL) was added via syringe, followed by diazo 2 (0.6 mmol, 3.0 equivalent). The reaction flask was sealed with parafilm and placed at -40°C with temperature control. The reaction was carried out in an ethanol bath at °C. The reaction system was irradiated with a blue LED at a wavelength of 450 nm and a power of 32 W from 5 cm above the liquid surface for 12–24 hours. After the reaction was complete, acetonitrile was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the dicyclopentane product BCP.

[0031] Example 2 Compound 1a (0.05 mmol, 1.0 equivalent) and the photocatalyst were added to a dry reaction tube equipped with a magnetic stir bar. The system was evacuated and purged with argon gas, repeated three times to ensure complete displacement. Subsequently, 0.5 mL of CH2Cl2 was added via syringe, followed by compound 2a (0.15 mmol).

[0032] The reaction tube was placed approximately 5 cm from the light source and irradiated with a 32 W blue LED at a wavelength of 450 nm, while the reaction was stirred for approximately 12 hours. After the reaction was complete, 1,3,5-trimethoxybenzene was added as an internal standard, and the solvent was removed by evaporation. The crude product was then subjected to… 1 1H NMR analysis was used to determine the yield.

[0033] The screening of photocatalysts is shown in Table 1.

[0034] Example 3 Compound 1a (0.05 mmol, 1.0 equivalent) and the photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (Ir-F, 0.001 mmol) were added to a dry reaction tube equipped with a magnetic stir bar. The system was evacuated and purged with argon gas, repeated three times to ensure complete displacement. Then, 0.5 mL of organic solvent and compound 2a (0.15 mmol) were added via syringe. The reaction tube was placed approximately 5 cm from the light source and irradiated with a 450 nm wavelength, 32 W blue LED, while stirring for approximately 12 hours. After the reaction was complete, 1,3,5-trimethoxybenzene was added as an internal standard, and the solvent was evaporated to remove it. The crude product was then subjected to… 1 1H NMR analysis was used to determine the yield, and the solvents were shown in Table 2.

[0035] Example 4 Compound 1a (0.05 mmol, 1.0 equivalent) and the photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6(Ir-F) were added to a dry reaction tube equipped with a magnetic stir bar. The system was evacuated and purged with argon gas, repeated three times to ensure adequate displacement. Subsequently, MeCN organic solvent was added via syringe, followed by compound 2a.

[0036] The reaction tube was placed approximately 5 cm from the light source and irradiated with a 32 W blue LED at a wavelength of 450 nm, while the reaction was stirred for approximately 12 hours. After the reaction was complete, 1,3,5-trimethoxybenzene was added as an internal standard, and the solvent was removed by evaporation. The crude product was then subjected to… 11H NMR analysis was used to determine the yield, as shown in Table 3 for the reaction conditions: Table 3

[0037] Example 5

[0038] Compound 1af (4.61 g, 20 mmol, 1.0 equivalence) and photocatalyst Ir-F (337 mg, 0.3 mmol, 1.5 mol%) were sequentially added to a flame-dried 250 mL round-bottom flask equipped with a magnetic stirrer. After evacuation and purging with argon three times, anhydrous acetonitrile (133 mL) was added via syringe, followed by 2a (5.71 g, 50 mmol, 2.5 equivalence). The reaction mixture was cooled to -30°C. The reaction was carried out at °C and stirred for approximately 36 hours under irradiation with a 450 nm blue LED (32 W, approximately 5 cm distance). After concentration and desolvation of the reaction solution, the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30:1) to give product 47 (4.09 g, yield 65%), which was a colorless oil.

[0039] 1 H NMR (400 MHz, CDCl3): δ 7.34 – 7.22 (m, 5H), 4.14 (qq, J = 7.3, 3.7Hz, 2H), 3.29 (d, J = 7.0 Hz, 1H), 2.99 (dd, J = 9.8, 2.9 Hz, 1H), 2.27 (dd, J = 7.0, 2.8 Hz, 1H), 2.23 (dd, J = 9.7, 1.8 Hz, 1H), 2.17 (s, 1H), 1.48 (s,9H), 1.22 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 169.68, 168.14, 137.53, 128.28, 127.37,126.74, 81.10, 64.21, 60.43, 52.50, 48.58, 45.65, 41.35, 28.11, 14.32. HRMS (ESI) m / z[M+Na] + calcd. for C 19 H 24 O4Na, 339.1567; found, 339.1564. Example 6: Synthesis of compound BCP-boscalid 71

[0040] Compound 7 (1.33 g, 3.8 mmol, 1.0 equivalent) was dissolved in anhydrous CH₂Cl₂ (15 mL) in a dry 50 mL reaction flask. After cooling the solution to 0 °C, trifluoroacetic acid (TFA, 1.45 mL, 19 mmol, 5.0 equivalent) was slowly added dropwise. The reaction mixture was heated to room temperature and stirred for 12 hours. After the reaction was complete, the reaction was quenched with water and extracted with CH₂Cl₂. The combined organic layers were washed with saturated brine, dried (Na₂SO₄), filtered to remove the drying agent, and concentrated to remove the solvent. The resulting crude product did not require purification and was used directly in the next reaction step.

[0041] The crude product, compound 49 (CAS: 2835535-92-5, 164 mg, 0.4 mmol, 10 mol%), and 4-methylthiophenol (25 mg, 0.2 mmol, 5 mol%) were added to a dry Schlenk tube equipped with a magnetic stir bar. CH2Cl2 (11 mL) and H2O (2 mL) were then added under argon protection. The reaction tube was sealed tightly and the reaction was stirred for 12 hours under 400 nm LED (6W) illumination. After illumination, the organic phase was transferred to a round-bottom flask, and the aqueous phase was further extracted with CH2Cl2. The combined organic phases were concentrated under reduced pressure to remove solvents, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to give product S23 (786 mg, 83% overall yield in both steps).

[0042] Compound S23 (590 mg, 2.35 mmol) was dissolved in methanol (10 mL), and sodium hydroxide (NaOH, 560 mg, 14 mmol, 6.0 equivalents) was added. The reaction mixture was stirred at 50 °C for 6 hours, and then quenched with 1 M hydrochloric acid. The reaction solution was diluted with diethyl ether (Et2O, 200 mL), the organic layer was washed with water and saturated brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting mixture was used directly in the next reaction step.

[0043] The mixture was dissolved in anhydrous toluene (12 mL), and DPPA (510 μL, 2.35 mmol, 1.0 equivalent) was added dropwise, followed by DIPEA (430 μL, 2.35 mmol, 1.0 equivalent). The reaction mixture was stirred at 85 °C for 4 hours, then cooled to room temperature, and tetrahydrofuran (THF, 16 mL) was added, followed by 2 M NaOH (aqueous solution, 6.7 mL). After stirring at room temperature for 20 hours, the mixture was diluted with water and extracted with ethyl acetate (EtOAc, 5 × 30 mL). The combined organic phases were washed with saturated brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting crude amine S₂₄ was used directly in the next reaction.

[0044] Compound S25 (370 mg, 2.35 mmol, 1.0 equivalent) was dissolved in anhydrous dichloromethane (CH2Cl2, 55 mL), and oxalyl chloride (313 μL, 3.53 mmol, 1.5 equivalent) and one drop of anhydrous DMF were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was redissolved in anhydrous dichloromethane (55 mL) and cooled to 0 °C. Subsequently, an anhydrous dichloromethane solution (27 mL) of crude amine S24 was added, followed by dropwise addition of triethylamine (650 μL, 4.7 mmol, 2.0 equivalent). The reaction mixture was restored to room temperature and stirred for 4 hours, then quenched with water and extracted with dichloromethane (3 × 100 mL). After merging the organic layers, the product was washed with saturated brine, dried (Na2SO4), and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give the product BCP-boscalid 71, a white solid (433 mg, 55% overall yield of the three steps).

[0045] Example 7: Synthesis of compound BCP-fluxapyroxad 72

[0046] Compound 7 (815 mg, 2.2 mmol, 1.0 equivalent) was dissolved in anhydrous dichloromethane (8 mL) in a flame-dried 25 mL vial. After cooling to 0 °C, trifluoroacetic acid (TFA, 0.8 mL, 11 mmol, 5.0 equivalent) was added dropwise. The reaction mixture was brought to room temperature and stirred for 12 hours. The reaction was quenched with water and then extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried (Na₂SO₄), and concentrated. The resulting crude product was used directly in the next reaction without purification.

[0047] In a dried Schlenk tube, the crude product from the previous step, compound 49 (90 mg, 0.22 mmol, 10 mol%), and 4-methylthiophenol (14 mg, 0.11 mmol, 5 mol%) were added, followed by the addition of 6 mL of dichloromethane and 1.2 mL of water under argon protection. The tube was sealed and irradiated with a 400 nm LED light source (6 W) for 12 hours with stirring. After irradiation, the organic phase was transferred to a 50 mL round-bottom flask, and the aqueous phase was further extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give product S26 (387 mg, 65% overall yield from both steps).

[0048] Compound S26 (270 mg, 1.0 mmol) was dissolved in methanol (4 mL), and sodium hydroxide (NaOH, 240 mg, 6.0 mmol, 6.0 equivalents) was added. The reaction mixture was stirred at 50 °C for 6 hours, and then quenched with 1 M hydrochloric acid. The reaction solution was diluted with diethyl ether (Et₂O, 100 mL). The organic layer was washed successively with water and saturated brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting crude acid was used directly in the next reaction step.

[0049] Dissolve the crude acid in dry toluene (5 mL), and add DPPA (220 g / mL) dropwise. L, 1.0 mmol, 1.0 equivalent), followed by the addition of DIPEA (180 L, 1.0 mmol, 1.0 equivalent). L (1.0 mmol, 1.0 equivalent). The reaction mixture was stirred at 85 °C for 4 hours and then cooled to room temperature. Tetrahydrofuran (THF, 7 mL) was added, followed by 2 M sodium hydroxide solution (3 mL). After stirring at room temperature for another 20 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (EtOAc, 5 × 20 mL). The organic phases were combined, washed with saturated brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting crude amine S₂₇ was used directly in the next reaction.

[0050] S28 (176 mg, 1.0 mmol, 1.0 equivalent) was dissolved in dry dichloromethane (CH2Cl2, 24 mL), and oxalyl chloride (127 mg / mL) was added at room temperature. L (1.5 mmol, 1.5 equivalents) and one drop of dry DMF. The reaction mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and the residue was redissolved in dry dichloromethane (24 mL) and cooled to 0 °C. Then a solution of the above crude amine S27 (dissolved in 12 mL of dichloromethane solvent) was added, followed by the dropwise addition of triethylamine (277 L, 1.5 mmol, 1.5 equivalents). L (2.0 mmol, 2.0 equivalent). The reaction mixture was brought to room temperature and stirred for 4 hours, then quenched with water and extracted three times with dichloromethane (3 × 50 mL). The combined organic layers were washed with saturated brine, dried (Na2SO4), and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give product BCP-fluxapyroxad 72, white solid, 192 mg, overall yield of 52% for the three steps.

[0051] 1 H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.16 (s, 1H), 6.88 – 6.81 (m,2H), 6.80 (t, J = 54.2 Hz, 1H), 4.53 (t, J = 6.7 Hz, 1H), 3.88 (s, 3H), 2.79(s, 1H), 2.73 (dd, J = 9.9, 3.7 Hz, 1H), 2.22 (dd, J = 6.6, 3.7 Hz, 1H), 2.10(d, J = 2.7 Hz, 1H), 2.01 (dd, J = 9.9, 2.7 Hz, 1H); 19 F NMR (376 MHz, CDCl3): δ -108.66 (dd, J = 54.2, 15.4 Hz), -134.49 –-136.54 (m), -138.37 (d, J = 18.0 Hz), -161.04 (td, J = 20.5, 6.6 Hz); 13 C NMR (100 MHz, CDCl3): δ 161.78, 151.65 – 149.60 (m), 151.54 –149.52 (m), 142.62 (t, J = 28.9 Hz), 139.94 (dt, J = 251.4, 15.4 Hz), 135.57,122.68 (dd, J = 12.8, 3.6 Hz), 122.53 (dt, J= 8.9, 4.7 Hz), 116.75, 112.07(t, J = 232.6 Hz), 111.80 (dd, J = 17.3, 3.7 Hz), 67.08, 47.73, 46.78, 46.50, 39.55, 34.11. HRMS (ESI) m / z [M+Na] + calcd. for C 17 H 14 F5N3ONa, 394.0949; found, 394.0946. Example 8: Synthesis of compound BCP-tasosartan 77

[0052] Under an argon atmosphere, sodium hydride (0.4 mmol, 2.2 equivalents) was added to an anhydrous DMF (0.8 mL) solution of compound S43 (35 mg, 0.20 mmol, 1.1 equivalents) at 0°C. After stirring the resulting mixture for 30 minutes, a DMF (0.4 mL) solution of compound S34 (47 mg, 0.18 mmol, 1.0 equivalents) was added. After 5 hours, thin-layer chromatography (TLC) confirmed complete consumption of the starting material. The reaction mixture was cooled to 0°C, quenched with an aqueous ammonium chloride solution, and then extracted with ethyl acetate (EtOAc). The combined organic phases were washed successively with water (10 mL) and saturated brine (6 mL). The organic phase was dried over anhydrous sodium sulfate (Na₂SO₄) and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (TLC) (eluent: dichloromethane / methanol = 13 / 1) to obtain the target product S44, which was a white foamy solid (34 mg, yield 53%).

[0053] Compound S44 (33 mg, 0.09 mmol, 1.0 equivalent) was added to a Schlenk tube equipped with a magnetic stirrer under an argon atmosphere. n Bu₂SnO (12 mg, 0.05 mmol, 0.55 equivalents). Anhydrous toluene (1 mL) and TMSN₃ (60 mg / mL) were then added. The resulting mixture (0.45 mmol, 5.0 equivalents) was stirred at 50°C for 5 days. Thin-layer chromatography (TLC) analysis showed that the starting material could not be further converted, so the reaction was terminated and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (eluent: dichloromethane / methanol = 20 / 1) to give the target product BCP-tasosartan 77 as a white solid (17 mg).

[0054] Example 9: Synthesis of compound BCP-candesartan 78

[0055] Compound S34 (39 mg, 0.15 mmol, 1.0 equivalent) and tetrabutylammonium iodide (6 mg, 0.015 mmol, 10 mol%) were added to a suspension of S45 (44 mg, 0.2 mmol, 1.3 equivalent) and potassium carbonate (K2CO3, 41 mg, 0.3 mmol, 2 equivalent) in sec-butanol (0.5 mL). The reaction mixture was stirred at 45°C for 15 hours. After the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (TLC) (eluent: petroleum ether / tetrahydrofuran = 2.5 / 1) to give product S46 as a white frothy solid (57 mg, 95% yield).

[0056] Compound S46 (56 mg, 0.14 mmol, 1.0 equivalent) was added to a Schlenk tube equipped with a magnetic stirrer under an argon atmosphere. n Bu₂SnO (0.07 mmol, 0.5 equivalents). Anhydrous toluene (2 mL) and TMSN₃ (92 μL) were then added. The resulting mixture (L, 0.7 mmol, 5.0 equivalents) was stirred at 50°C for 5 days. Thin-layer chromatography (TLC) analysis showed that the starting material could not be further converted, so the reaction was terminated and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (eluent: dichloromethane / methanol = 20 / 1) to give the target product S47 as a pale yellow syrup (12 mg, yield 28%), and 19 mg of the starting material was recovered.

[0057] Compound S47 (12 mg, 0.027 mmol) was dissolved in a tetrahydrofuran / water mixture (1:1, 1 mL, v / v), and lithium hydroxide monohydrate (LiOH·H2O, 4 mg, 0.1 mmol) was added. The reaction mixture was stirred vigorously at room temperature for 3 hours, and the reaction proceeds were completely reacted as monitored by thin-layer chromatography (TLC). The reaction system was adjusted to pH 4–5 with acetic acid, extracted with ethyl acetate (EtOAc, 3 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 8:1) to give the target compound BCP-candesartan 78 as a white solid in 52% (6 mg) yield.

[0058] Example 10: Synthesis of compound BCP-fimasartan 79

[0059] Under an argon atmosphere, lithium hydride (LiH, 6 mg, 0.75 mmol, 2.5 equivalents) was added at 0°C to a suspension of compound S48 (100 mg, 0.4 mmol, 1.3 equivalents) in anhydrous ethyl acetate (EtOAc, 1.6 mL) and DMF (0.2 mL). The resulting mixture was stirred at 0°C for 30 minutes, followed by the addition of compound S34 (78 mg, 0.3 mmol, 1.0 equivalents). After 2 hours, thin-layer chromatography (TLC) confirmed complete consumption of the starting material. The reaction mixture was cooled to 0°C, quenched with an aqueous ammonium chloride solution, and then extracted with ethyl acetate (EtOAc, 12 mL × 2). The combined organic phases were washed successively with water (10 mL) and saturated brine (6 mL). The organic phases were dried over anhydrous sodium sulfate (Na₂SO₄) and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (TLC) (eluent: dichloromethane / methanol = 20 / 1) to give the target product S49 as a white, foamy solid (111 mg, yield 85%). Under an argon atmosphere, compound S49 (110 mg, 0.26 mmol) was added to a 10 mL Schlenk tube equipped with a magnetic stirrer. nBu₂SnO (32 mg, 0.13 mmol) was then added. Anhydrous toluene (2 mL) and TMSN₃ (0.17 mL, 1.3 mmol) were subsequently added, and the resulting mixture was stirred at 50°C for 5 days. Thin-layer chromatography (TLC) analysis showed that the starting material could not be further converted, so the reaction was terminated and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (eluent: dichloromethane / methanol = 20 / 1) to give the target product S50 as a pale yellow syrup (62 mg, 69% yield based on recovery of the starting material), and 28 mg of the starting material was recovered.

[0060] Under an argon atmosphere, compound S50 (32 mg, 0.067 mmol), dried toluene (2 mL), and Lawesson's reagent (CAS: 19172-47-5, 30 mg, 0.074 mmol, 1.1 equivalence) were added to a dried 10 mL Schlenk tube equipped with a magnetic stir bar. The reaction mixture was then stirred at 85°C for 2 hours. Thin-layer chromatography (TLC) analysis showed that the reaction system gradually became complex, therefore the reaction was terminated, and the solvent was removed under reduced pressure. Purification by preparative TLC (eluent: dichloromethane / methanol = 14 / 1) yielded compound BCP-fimasartan 79 as a colorless, foamy solid (12 mg, 36% yield), while 10 mg of the starting material was recovered.

[0061] Example 11: Synthesis of compound BCP-tolvaptan 80

[0062] Compound 55 (67 mg, 0.3 mmol, 1.0 equivalent) was dissolved in a mixed solvent of dichloromethane (CH₂Cl₂, 2 mL) and acetonitrile (2 mL) under an argon atmosphere at room temperature. Subsequently, a solution of sodium periodate (NaIO₄, 1.3 g, 6 mmol, 20.0 equivalent) dissolved in water (2.5 mL) and a solution of ruthenium trichloride (RuCl₃, 3 mg, 0.015 mmol, 0.05 equivalent) dissolved in water (0.5 mL) were added sequentially. The resulting mixture was vigorously stirred at room temperature for 17 hours. 1 M hydrochloric acid (HCl) was added, followed by extraction with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate (Na₂SO₄), filtered, and concentrated by rotary evaporation. The crude product was used directly in the next reaction without further purification.

[0063] At room temperature, DIPEA (210) was added to a 2.5 mL solution of the crude product, 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzodiazepine-5-one (CAS: 137977-97-0, 138 mg, 0.32 mmol, 1.05 equivalents), and HATU (168 mg, 0.33 mmol, 1.1 equivalents) in DMF. L (0.96 mmol, 3.0 equivalent). After stirring the mixture for 12 hours, it was quenched with water (5 mL). Extracted with ethyl acetate (EtOAc, 20 mL × 3), the combined organic layers were washed successively with water and saturated brine, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PTLC, eluent: petroleum ether / ethyl acetate = 2:1) to give compound S51 (85.5 mg, 65% overall yield in both steps).

[0064] Sodium borohydride (NaBH4, 8 mg, 0.2 mmol, 2 equivalents) was added to a solution of compound S51 (44 mg, 0.1 mmol, 1.05 equivalents) in methanol (1 mL) under stirring. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water (5 mL). The resulting mixture was extracted with ethyl acetate (EtOAc, 20 mL × 3), and the combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PTLC, eluent: petroleum ether / ethyl acetate = 1:1) to give the target compound BCP-tolvaptan 80 in 88% yield (38.6 mg).

[0065] Example 12: Synthesis of compound BCP-Phthalylsulfathiazole 81

[0066] Compound 53 (27.6 mg, 0.15 mmol, 1.0 equivalent) and SOCl2 (1.5 mL) were added sequentially to a dried microwave-safe reaction tube (equipped with a magnetic stir bar). The reaction tube was sealed with a rubber stopper and heated to 80°C. The reaction was stirred at °C for 5 hours. After the reaction was complete, the solvent was removed under reduced pressure. The resulting crude solid was dissolved in tetrahydrofuran (THF, 1 mL) and used directly in the next reaction step.

[0067] In a separate dried reaction tube, a magnetic stir bar was added, followed by the sequential addition of compound S52 (46 mg, 0.18 mmol, 1.2 equivalents), THF (1 mL), and triethylamine (42 μL, 0.3 mmol, 2.0 equivalents). The reaction tube was then cooled in an ice-water bath. A tetrahydrofuran solution of the crude solid obtained in the previous step was added dropwise to the reaction tube, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was treated with 2 M hydrochloric acid. The resulting aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH = 20:1) to give a white solid product S53 in 54% (34.4 mg) yield.

[0068] Sodium hydroxide (NaOH, 20 mg, 0.5 mmol, 10.0 equivalent) was added to a methanol solution (4 mL) of compound S53 (21 mg, 0.05 mmol) at 50 °C. The reaction mixture was stirred at °C for 2 hours. After the reaction was completed, 1 M hydrochloric acid was added to quench the reaction. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: CH2Cl2 / MeOH = 5 / 1) to give a white solid product BCP-Phthalylsulfathiazole 81 in 62% (12.2 mg).

[0069] Example 13 The antifungal activity of four compounds (BCP-boscalid71, boscalid, BCP-fluxapyroxad 72, and fluxapyroxad) at a concentration of 50 μg / mL was evaluated using a mycelial growth inhibition method. The test solutions were prepared as follows: each compound (15.0 mg) was dissolved in 0.6 mL of dimethyl sulfoxide (DMSO), and then mixed with 299.4 mL of potato dextrose agar (PDA) medium. For the blank control group, an equal volume of DMSO was added to the medium. Fluxapyroxad and boscalid were used as positive control fungicides at the same concentration. All experiments were performed aseptically in petri dishes, with three replicates for each treatment. Inhibition rates were calculated using the following formula: Table 4. In vitro fungicidal activity of the tested compounds against Botrytis cinerea. ; Inhibition rate (%) = [(d C - d T ) / ( d C - 0.9)] × 100% d C Control group mycelial growth diameter (cm) d T Mycelial diameter in the treatment group (cm)

Claims

1. A two-ring as shown in formula (Ⅰ) [ 1.1.1] Methods for synthesizing pentane derivatives, including: Compound II, an organic solvent, a catalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, and compound III were mixed and reacted under controlled temperature and light irradiation to obtain compound I. ； Wherein, the R 1 Selected from hydrogen, substituted or unsubstituted monocyclic aryl, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted alkoxy, carboxyl, amino, halogen, -C(O)R 1a -OC(O)R 1b -C(O)OR 1c -SR 1d -C(O)NHR 1e -S(O)2NHR 1f -(CH2) p OR 1g ; The R 1a R 1b R 1c R 1d R 1e R 1f R 1g Each is independently selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted fused-ring heterocyclic group, substituted or unsubstituted monocyclic aryl, substituted or unsubstituted fused-ring aryl; The R 2 Each group is independently selected from hydrogen, substituted or unsubstituted phosphate ester groups, substituted or unsubstituted monocyclic heterocyclic groups, substituted or unsubstituted straight-chain alkyl groups, substituted or unsubstituted branched alkyl groups, halogens, carboxyl groups, amino groups, cyano groups, borate pinacol ester groups, and -C(O)R groups. 2a -OC(O)R 2b -C(O)OR 2c -SR 2d -C(O)NHR 2e -S(O)2NHR 2f -(CH2) q R 2g -OR 2h -SR 2i -Se-R 2j -NHC(O)R 2k The R 2a R 2b R 2c R 2d R 2e R 2f R 2g R 2h R 2i R 2j R 2k Each is independently selected from hydrogen, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted straight-chain alkyl group, substituted or unsubstituted straight-chain alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted monocyclic aryl group, and substituted or unsubstituted fused-ring aryl group; The R 3 It is selected from hydrogen, substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heterocyclic, substituted or unsubstituted fused heterocyclic, and substituted or unsubstituted alkyl.

2. The method for synthesizing the bicyclic [1.1.1]pentane derivative as shown in formula (I) according to claim 1, characterized in that, The R 1 The hydrogen on R is optional 1x Replace, R 1x Selected from methyl, ethyl, tert-butyl, amino protecting group, monocyclic aryl, F, Cl, Br, I, -OR 1aa -C(O)OR 1ab -(CH) m R 1ac ; The R 1aa R 1ab R 1ac Each is independently selected from monocyclic aryl, methyl, ethyl, tert-butyl, F, Cl, Br, I; The R 2 The hydrogen on R is optional 2y Replace, R 2y Selected from F, Cl, Br, I, methyl, ethyl, tert-butyl, amino protecting group, monocyclic aryl, F, Cl, Br, I, -OR 2aa -C(O)OR 2ab -(CH) n R 2ac ; The R 2aa R 2ab R 2ac Each is independently selected from monocyclic aryl, methyl, ethyl, and tert-butyl groups; The R 3 The hydrogen on R is optional 3z Instead, the R 3z Selected from F, Cl, Br, I, methyl, ethyl, tert-butyl; The R 1x R 2y R 3z The hydrogen atoms can be optionally replaced by F, Cl, Br, or I; The m and n are each independently selected from any integer from 0 to 10.

3. A bicyclic [1.1.1]pentane derivative, with the structure as follows: 、 、 、 、 、 。 4. Synthesis of compound BCP-boscalid 71, including: S1: Mix compound 7 and organic solvent, add trifluoroacetic acid, react to obtain crude product; S2: The crude product from step S1, compound 49, and 4-methylthiophenol were mixed, and an organic solvent and water were added. The mixture was reacted under light irradiation at a wavelength of 370-450 nm to obtain compound S23. ； S2: Dissolve compound S23 in an organic solvent, add alkali, react, dry, filter, concentrate under reduced pressure to obtain crude product; S3: Dissolve the crude product obtained in step S2 in an organic solvent, add DPPA and DIPEA to obtain a reaction mixture, add tetrahydrofuran to the reaction mixture, and then add a base to obtain compound S24. ； S4: Compound S25 is reacted with an organic solvent, oxaloyl chloride is added, compound S24 is added, and a base is added to obtain compound BCP-boscalid 71. 。 5. The synthesis of compound BCP-fluxapyroxad 72, including: S1: Compound 7 is mixed with an organic solvent, trifluoroacetic acid is added, the reaction is carried out, and the extract phase is obtained by extraction. The solvent is removed from the extract phase to obtain the crude product. S2: The crude product obtained in step S1, compound 49, 4-methylthiophenol, organic solvent, and water are mixed and reacted under light irradiation of 370~450 nm to obtain compound S26. ； S3: Compound S26 is mixed with an organic solvent, a base is added, and the mixture reacts to obtain a mixture; S4: Mix the mixture from step S3, DPPA, DIPEA, and base, and react to obtain compound S27; ； S5: Mix compound S28 with an organic solvent, add oxaloyl chloride organic solvent, then add compound S27 and a base to obtain compound BCP-fluxapyroxad 72; 。 6. The synthesis of compound BCP-tasosartan 77, including: S1: Add sodium hydride to the organic solution of compound S43, and then add compound S34 to obtain compound S44; ； S2: Compound S44 and n A mixture of Bu2SnO and TMSN3 was added and reacted to obtain compound BCP-tasosartan 77. 。 7. The synthesis of compound BCP-candesartan 78, including: S1: Add compound S34 and tetrabutylammonium iodide to a suspension of compound S45, base, and sec-butanol, and react to obtain compound S46. ； S2: Compound S46 and n Bu2SnO was mixed, followed by the addition of an organic solvent and TMSN3, and the reaction was carried out to obtain compound S47; ； S3: Dissolve compound S47 in a mixed solvent of organic solvent and water, add alkali, and react to obtain compound BCP-candesartan 78; 。 8. The synthesis of compound BCP-fimasartan 79, including: S1: Compound S48, an organic solvent mixture, and lithium hydride are mixed together, and then compound S34 is added. The reaction yields compound S49. ； S2: Compound S49 n A mixture of Bu₂SnO was then added, followed by the addition of an organic solvent and TMSN₃, and the reaction yielded compound S50. ； S3: Compound S50, organic solvent, and Lawesson's reagent are mixed and reacted to give compound BCP-fimasartan 79; 。 9. The synthesis of compound BCP-tolvaptan 80, including: S1: Dissolve compound 55 in an organic solvent mixture, then add an aqueous solution of sodium periodate and an aqueous solution of ruthenium trichloride, add acid, extract the organic phase, concentrate the organic phase, and obtain a mixture; S2: Mix the mixture obtained in step S1, 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzodiazepine-5-one, HATU, and an organic solvent, and add DIPEA to obtain compound S51. ； Sodium borohydride was added to an alcoholic solution of compound S51, and the reaction yielded compound BCP-tolvaptan 80. 。 10. The synthesis of compound BCP-phthalylsulfathiazole 81, including: S1: Compound 53 and SOCl2 are mixed and reacted to obtain an acid chloride solution; S2: Compound S52, organic solvent and base are mixed to obtain a mixture. An acid chloride solution is added dropwise to the mixture, and the reaction is carried out to obtain compound S53. ； S3: Add alkali to the alcoholic solution of compound S53 and react to obtain compound BCP-phthalylsulfathiazole81; 。

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