CN117800913A - Geldanamycin derivatives and application thereof - Google Patents

Geldanamycin derivatives and application thereof Download PDF

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CN117800913A
CN117800913A CN202211185487.6A CN202211185487A CN117800913A CN 117800913 A CN117800913 A CN 117800913A CN 202211185487 A CN202211185487 A CN 202211185487A CN 117800913 A CN117800913 A CN 117800913A
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俞晓明
杨皓然
卞传才
张智
李云锋
李永强
刘迪
杨林茂
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Institute of Materia Medica of CAMS
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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a group of geldanamycin derivatives, which are C18 deoxidized and monosubstituted hydroquinone geldanamycin derivatives, and the structural general formula of the geldanamycin derivatives is shown as I. The compound disclosed by the invention has an obvious inhibition effect on lung cancer and glioma cells, and the group of derivatives lays a foundation for the research and development of anti-tumor medicaments taking geldanamycin as a lead.

Description

Geldanamycin derivatives and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, relates to a new geldanamycin structure remodelling, in particular to a C18 deoxidized and monosubstituted hydroquinone geldanamycin and application thereof in anti-tumor drugs.
Background
Heat shock protein 90 (Heat shock protein, hsp 90) is a molecular chaperone that is widely present in eukaryotic and prokaryotic cells and assists in the correct folding of nascent peptide chains or denatured proteins, and is also an important tumor marker, in close association with the occurrence and development of cancer.
Geldanamycin (Geldanamycin) is the earliest discovered natural product that inhibits Hsp90, which can prevent Hsp90 from gaining energy by competitively binding to the ATP domain at the N-terminus of Hsp90, thereby inhibiting its chaperone activity, ultimately causing ubiquitination of numerous client proteins that rely on Hsp90, leading to apoptosis of tumor cells.
Although geldanamycin has good anti-tumor activity, the problems of poor water solubility, strong hepatotoxicity and the like limit the clinical application of the natural product, and the derivatives 17-AAG and 17-DMAG of the geldanamycin exit from clinical tests due to the problem of hepatotoxicity. Researches show that the cause of hepatotoxicity of geldanamycin is the terephthalquinone structure in the skeleton, and the invention directly solves the hepatotoxicity problem by modifying the terephthalquinone structure in the geldanamycin. In the geldanamycin derivatives described so far, no compound having the same structure as the compound of the present invention has been found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a group of C18 deoxidized and monosubstituted hydroquinone geldanamycin derivatives and application thereof in preparing antitumor drugs.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a group of geldanamycin derivatives is a group of C18 deoxidized and monosubstituted hydroquinone geldanamycin derivatives, and the structural general formula of the geldanamycin derivatives is shown as I.
Wherein:
r is hydrogen or halogen, C1-C6 alkyl.
Among the geldanamycin derivatives, the preferred modes are:
R is hydrogen or halogen, C1-C4 saturated alkyl, halogen selected from fluorine, chlorine, bromine and iodine.
Among the geldanamycin derivatives mentioned above, the most preferred mode is:
r is hydrogen, chlorine and methyl.
The preparation of the geldanamycin derivative according to the invention can be achieved by the following steps.
As shown in the above route, commercial crotyl alcohol is used as a raw material to sequentially synthesize the compound A through Sharpless asymmetric epoxidation, ring opening and alkynyl methylation reaction. The compound B is synthesized by taking commercial S-glycidol as a raw material and sequentially carrying out hydroxyl protection, epoxy ring opening, hydroxyl methylation, dihydroxylation and fracture oxidation reaction. The compounds A and B complete fragment connection through zirconium hydrogenation coupling reaction to synthesize the compound C. And then removing TIPS protecting groups from the compound C, performing TBS protection on the primary and secondary hydroxyl groups, removing PMB protecting groups, and performing oxidation reaction to synthesize the compound D.
As shown in the above route, E is synthesized from commercially available 5-halosalicylaldehyde as a raw material through a metal-catalyzed coupling reaction with an alkylating agent. The 5-halogenated salicylaldehyde and the compound E are sequentially introduced through nitro, and the compound F is synthesized through a phenolic hydroxyl protection reaction. F, synthesizing bromobenzyl G through reduction, protection and bromination reaction of aldehyde group and nitro. Bromobenzyl G is subjected to Evans prosthetic H-induced asymmetric alkylation, reduction reaction to synthesize a compound I, evans prosthetic H can be prepared into Kurata H, kusumi K, otsuki K, et al Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold [ J ]. Bioorganic & medicinal chemistry letters,2012,22 (1): 144-148.I by a literature method, and phenyl sulfone groups are introduced into the compound M for reaction. The compound J is synthesized by taking commercial 2-hydroxy-3-nitrobenzoic acid methyl ester as a raw material and sequentially carrying out phenolic hydroxyl protection, nitro reduction and protection reaction. Methyl ester of J is reduced and bromobenzyl K is synthesized. Bromobenzyl K is subjected to Evans prosthetic group H induced asymmetric alkylation and reduction reaction to synthesize the compound L. L is introduced into the reaction to synthesize the compound M through iodination and phenylsulfonyl.
As shown in the above route, the compounds D and M undergo an affinity addition reaction under the action of lithium diisopropylamine to complete the connection and synthesis of the compound N. N is subjected to hydroxyl oxidation, benzene sulfone removal, asymmetric reduction and methylation of carbonyl, primary hydroxyl TBS protecting groups are selectively removed, and aldehyde O is synthesized through oxidation reaction. O reacts with commercial HWE reagent P to introduce cis double bond at C4-C5 to synthesize compound Q. And reducing and oxidizing the Q by methyl ester to obtain aldehyde R. Q reacts with commercial phosphorus ylide reagent S to introduce trans double bond at C2-C3 position to synthesize compound T. And (3) removing the amino protecting group from T, hydrolyzing ethyl ester, closing the ring of lactam, introducing carbamoyl and removing MOM protecting group to complete the synthesis of the general formula I.
The geldanamycin derivative is applied to the preparation of antitumor drugs.
Wherein: the geldanamycin derivative is preferably: 18-deoxyhydroquinone geldanamycin GA-H, 18-chlorohydroquinone geldanamycin GA-Cl and 18-methylhydroquinone geldanamycin GA-Me. The application in the antitumor drug preferably refers to the application in the drugs of resisting human colon cancer cells HCT116, human pancreatic cancer cells Capan2, human gastric cancer cells HGC27, human lung cancer cells A549, human glioma cells U251 and human prostate cancer cells DU 145.
Detailed Description
The following detailed description of the embodiments of the present invention is provided merely to illustrate the invention and is not intended to limit the scope of the invention.
Preparation example:
diethyl L-tartrate (1.7 mL,8.3 mmol) was dissolved in anhydrous dichloromethane (150 mL) and addedMolecular sieves (4.7 g) and argon shield,after cooling to-20℃and adding titanium tetraisopropoxide (2 mL,6.9 mmol), tert-butanol peroxide (58.2 mL,277.4 mmol) was added dropwise and stirred for 30 min. Crotyl alcohol (10 g,138.7 mmol) was dissolved in anhydrous dichloromethane (50 mL) and added over 1 hour, after which the reaction was continued for 3.5 hours. TLC monitored the reaction was complete, the reaction was warmed to 0deg.C, saturated aqueous sodium thiosulfate was added and stirred for 30-60 min, warmed to room temperature, the reaction solution was filtered with celite, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, most of the solvent was evaporated under reduced pressure, then dichloromethane (300 mL), imidazole (18.05 g,277.4 mmol) and argon were added to the reaction flask, the temperature was lowered to 0deg.C, tert-butyldiphenylchlorosilane (43.3 mL,166.4 mmol) was added dropwise and after the addition was completed, it was allowed to react at room temperature for 30 min. TLC was used to monitor completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude product as a colourless oil compound (35.3 g, 78%) by flash column chromatography (petroleum ether/ethyl acetate: 95/5). 1 H NMR(400MHz,CDCl 3 )δ7.72–7.69(m,4H),7.47–7.38(m,6H),3.82–3.74(m,2H),2.90–2.85(m,2H),1.30(d,J＝4.9Hz,3H),1.08(s,9H). 13 C NMR(101MHz,CDCl 3 )δ135.75,135.70,133.48,129.86,127.85,127.83,64.17,59.56,52.39,26.90,19.37,17.45.
Preparation example 2:
dissolving trimethylsilylacetylene (9 g,92.1 mmol) in anhydrous toluene (115 mL), argon shielding, cooling to-78deg.C, dropwise adding n-butyllithium (38 mL,92.1 mmol), stirring at-78deg.C for 30 min, adding directly into ice water, stirring for 30 min, sequentially adding diethylaluminum chloride (45 mL,92.1 mmol) and anhydrous toluene (15 mL) of the product of preparation 1 (9 g,30.7 mmol), cooling to room temperature, reacting for 14 hr, TLC monitoring reaction completely, dropwise adding saturated potassium sodium tartrate solution into the reaction solution, stirring with ethyl acetate (100 mL) for 1 hr to separate layers, extracting with ethyl acetate, and mixingAnd the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate: 5/1) to give the compound as a colorless oil (12.9 g, 99%). 1 H NMR(400MHz,CDCl 3 )δ7.70–7.67(m,4H),7.47–7.38(m,6H),3.91(dd,J＝10.2,3.7Hz,1H),3.80(dd,J＝10.2,6.3Hz,1H),3.61–3.56(m,1H),2.67-2.61(m,1H),2.59(d,J＝5.0Hz,1H),1.26(d,J＝6.9Hz,3H),1.09(s,9H),0.08(s,9H). 13 C NMR(101MHz,CDCl 3 )δ135.67,135.64,133.27,133.22,129.98,129.95,127.94,127.93,108.09,86.60,74.83,66.14,30.42,27.03,19.47,17.26,0.18.
Preparation example 3:
the product of preparation 2 (1.29 g,3.04 mmol) was dissolved in methanol (11 mL), potassium carbonate (460 mg,3.34 mmol) was added at room temperature and stirred for 5 hours, TLC monitored complete reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered and spun-dried to give crude oil. The crude product was dissolved in dichloromethane (11 mL), argon protected, cooled to 0deg.C, diisopropylethylamine (1.59 mL,9.12 mmol) and bromomethyl methyl ether (0.74 mL,9.12 mmol) were added sequentially, after the dropwise addition was completed, the reaction was allowed to warm to room temperature overnight, TLC monitored for completion, the reaction solution was quenched with saturated aqueous ammonium chloride solution, dichloromethane extracted, the organic phase dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product flash column chromatographed (petroleum ether/ethyl acetate: 95/5) to give the compound as a colourless oil (1.05 g, 88%). 1 H NMR(400MHz,CDCl 3 )δ7.71–7.68(m,4H),7.43–7.36(m,6H),4.79(d,J＝6.8Hz,1H),4.72(d,J＝6.8Hz,1H),3.89-3.80(m,2H),3.68-3.64(m,1H),3.36(s,3H),2.91–2.83(m,1H),2.02(d,J＝2.5Hz,1H),1.21(d,J＝7.1Hz,3H),1.07(s,9H). 13 C NMR(101MHz,CDCl 3 )δ135.76,133.53,133.50,129.83,129.81,127.81,96.70,86.37,80.31,69.67,64.27,55.89,27.88,26.95,19.35,16.56.
Preparation example 4:
the product of preparation 3 (1.05 g,2.76 mmol) was dissolved in anhydrous tetrahydrofuran (11 mL), the temperature was lowered to-78℃under argon protection, n-butyllithium (1.7 mL,4.14 mmol) was added dropwise, after the completion of the dropwise addition, methyl iodide (0.34 mL,5.52 mmol) was added dropwise after the completion of the dropwise addition, and the reaction was allowed to stand at room temperature overnight. TLC was used to monitor completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude product as a colorless oily compound (1.01 g, 90%) by flash column chromatography (petroleum ether/ethyl acetate: 95/5). 1 H NMR(400MHz,CDCl 3 )δ7.72–7.69(m,4H),7.43–7.36(m,6H),4.83(d,J＝6.8Hz,1H),4.73(d,J＝6.8Hz,1H),3.85(d,J＝4.9Hz,2H),3.63–3.59(m,1H),3.37(s,3H),2.82–2.74(m,1H),1.73(d,J＝2.4Hz,3H),1.17(d,J＝7.0Hz,3H),1.07(s,9H). 13 C NMR(101MHz,CDCl 3 )δ135.77,133.63,129.77,129.74,127.78,96.69,81.05,81.00,77.08,64.73,55.83,28.15,26.93,19.35,17.23,3.65.
Preparation example 5:
the product of preparation 4 (1.1 g,2.68 mmol) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (4.02 mL,4.02 mmol) was added dropwise, the reaction was stirred at room temperature for 3 hours, TLC monitored complete reaction, quenched by dropwise addition of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the compound (458 mg, 99%) as a colourless oil. 1 H NMR(400MHz,CDCl 3 )δ4.76(d,J＝6.9Hz,1H),4.68(d,J＝6.9Hz,1H),3.83(ddd,J＝11.3,8.5,2.5Hz,1H),3.67(ddd,J＝11.8,6.7,3.6Hz,1H),3.42(s,3H),3.39(td,J＝7.1,2.6Hz,1H),2.94(dd,J＝8.5,4.0Hz,1H),2.65–2.57(m,1H),1.76(d,J＝2.4Hz,3H),1.17(d,J＝7.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ97.48,85.01,80.08,77.92,63.90,55.94,28.62,17.89,3.61.
Preparation example 6:
potassium tert-butoxide (37.3 g,332.14 mmol) was added to anhydrous tetrahydrofuran (300 mL), argon was purged, the temperature was lowered to 0℃and a solution of the product of preparation 5 (28.6 g,166.07 mmol) in anhydrous tetrahydrofuran (82 mL) was added dropwise, after the completion of the dropwise addition, the reaction was allowed to proceed to room temperature for 30 minutes. The reaction was again cooled to 0deg.C, 4-methoxychlorobenzyl (29.2 mL,215.89 mmol) was added dropwise, and the mixture was allowed to stand at room temperature overnight to react. TLC was used to monitor completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude product as a colorless oily compound (41.7 g, 86%) by flash column chromatography (petroleum ether/ethyl acetate: 9/1). 1 H NMR(500MHz,CDCl 3 )δ7.27(d,J＝5.8Hz,2H),6.87(d,J＝8.5Hz,2H),4.80(d,J＝6.8Hz,1H),4.71(d,J＝6.8Hz,1H),4.49(s,2H),3.80(s,3H),3.68–3.60(m,3H),3.39(s,3H),2.76–2.73(m,1H),1.76(d,J＝2.0Hz,3H),1.18(d,J＝5.6Hz,3H). 13 C NMR(126MHz,CDC l3 )δ159.21,130.54,129.35,113.80,96.58,80.71,79.41,77.25,73.08,70.71,55.80,55.38,28.56,17.53,3.69.
Preparation example 7:
s-glycidol (25 g,337.66 mmol) was dissolved in dichloromethane (1249 mL), triethylamine (79.8 mL,574.02 mmol) and 4-dimethylaminopyridine (12.38 g,101.3 mmol) were added sequentially, under the protection of argon, triisopropylchlorosilane (79.5 mL,371.43 mmol) was added dropwise, the reaction was completed at room temperature for 5 hours, TLC was monitored to complete the reaction, the reaction solution was washed sequentially with 1N aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, aqueous dichloromethane was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, dried by spin-drying, crude flash column chromatography (petroleum etherEthyl acetate: 95/5) to give a colorless liquid compound (73.1 g, 94%). 1 H NMR(400MHz,CDCl 3 )δ3.91(dd,J＝11.7,3.2Hz,1H),3.74(dd,J＝11.7,4.7Hz,1H),3.12–3.09(m,1H),2.76(dd,J＝5.2,4.1Hz,1H),2.66(dd,J＝5.2,2.7Hz,1H),1.09–1.04(m,21H). 13 C NMR(101MHz,CDCl 3 )δ64.06,52.72,44.58,18.04,12.08.
Preparation example 8:
trimethylsulfur iodide (26.6 g,130.3 mmol) was added to anhydrous tetrahydrofuran (230 mL), the temperature was lowered to-10℃under the protection of argon, and n-butyllithium (52 mL,125.9 mmol) was added dropwise, and the reaction was completed for 30 minutes. The product of preparation 7 (10 g,43.4 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 4.5 hours, TLC was monitored to completion, water was added to the reaction solution to quench the reaction solution to clarify, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, and crude product was purified by flash column chromatography (petroleum ether/ethyl acetate: 98/2) to give a colorless liquid compound (8.37 g, 79%). 1 H NMR(400MHz,CDCl 3 )δ5.87–5.79(m,1H),5.35(dt,J＝17.3,1.6Hz,1H),5.19(dt,J＝10.6,1.5Hz,1H),4.22–4.17(m,1H),3.75(ddd,J＝9.8,3.7,0.4Hz,1H),3.56–3.52(m,1H),2.68(brs,1H),1.10–1.04(m,21H). 13 C NMR(126MHz,CDCl 3 )δ136.75,116.64,73.30,67.39,18.07,12.03.
Preparation example 9:
sodium hydride (2.74 g,68.6 mmol) was added to anhydrous tetrahydrofuran (100 mL), argon was purged, the temperature was lowered to 0 ℃, the product of preparation 8 (8.37 g,34.3 mmol) was dissolved in anhydrous tetrahydrofuran (13 mL), added dropwise, and the reaction was allowed to proceed to room temperature for 30 minutes after the completion of the dropwise addition. The reaction system was again cooled to 0℃and methyl iodide (8.8 mL,137.2 mmol) was added dropwise, and the mixture was transferred toAfter 3 hours at room temperature, TLC was monitored to complete, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude product as a colorless liquid compound (8.27 g, 93%). 1 H NMR(400MHz,CDCl 3 )δ5.74(ddd,J＝17.1,10.4,6.7Hz,1H),5.31–5.23(m,2H),3.77(m,1H),3.66(ddd,J＝14.3,10.6,5.3Hz,2H),3.35(s,3H),1.09–1.04(m,21H). 13 C NMR(101MHz,CDCl 3 )δ136.38,117.93,83.98,66.58,57.10,18.11,12.13.
Preparation example 10:
the product of preparation 9 (8.27 g,32.03 mmol) was dissolved in acetone/water (9/1, 74 mL), N-methylmorpholine N-oxide (5.63 g,48.05 mmol) and potassium osmium carbonate dihydrate (118 mg,0.32 mmol) were added sequentially, reacted overnight at room temperature, the reaction was monitored to completion by TLC, the reaction solution was extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and dried by spin-on to give crude oil. The crude product was directly dissolved in tetrahydrofuran/water (7/5, 176 mL), sodium periodate (9.6 g,44.84 mmol) was added and reacted at room temperature for 3 hours, TLC was monitored to complete the reaction, the reaction solution was filtered through celite, washed with 10% sodium thiosulfate, extracted with methylene chloride, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin, and the crude product was flash column chromatographed (petroleum ether/ethyl acetate: 4/1) to give a colorless oily compound (7.14 g, 86%) which was rapidly taken into the next reaction. 1 H NMR(400MHz,CDCl 3 )δ9.73(s,1H),4.00(d,J＝5.0Hz,2H),3.68(td,J＝5.0,1.4Hz,1H),3.50(s,3H),1.10–1.03(m,21H). 13 C NMR(101MHz,CDCl 3 )δ203.08,86.64,63.16,58.71,17.99,11.96.
Preparation example 11:
the product of preparation 6 (2.5 g,8.56 mmol) was dissolved in anhydrousTo toluene (90 mL), zirconium chlorohydrate (4.6 g,17.98 mmol) was added, and after the reaction was performed at 50℃for 6 hours under argon gas, the reaction solution was allowed to warm to room temperature, cooled to-78℃and diethyl zinc (8.56 mL,12.84 mmol) was added dropwise, and after the dropwise addition was completed, the reaction was directly performed in an ice bath, and continued for 1 hour. The product of preparation 10 (3.34 g,12.84 mmol) was dissolved in anhydrous toluene (16 mL), added dropwise, after the dropwise addition, the reaction was continued for 1 hour, TLC was monitored to complete the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, filtered through celite, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, and the crude product was flash column chromatographed (petroleum ether/ethyl acetate: 5/1) to give the compound (2.5 g, 52%) as a colorless oil. 1 H NMR(400MHz,CDCl 3 )δ7.23(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),5.33(d,J＝9.9Hz,1H),4.77(d,J＝6.7Hz,1H),4.65(d,J＝6.7Hz,1H),4.42(dd,J＝13.2,11.6Hz,2H),3.97(t,J＝4.9Hz,1H),3.79(s,3H),3.77(d,J＝4.7Hz,1H),3.66(dd,J＝10.5,5.9Hz,1H),3.56–3.50(m,2H),3.50(s,3H),3.44–3.40(m,1H),3.37(s,3H),3.28–3.24(m,1H),2.80–2.73(m,1H),2.74(d,J＝4.8Hz,1H),1.67(d,J＝1.2Hz,3H),1.09–1.04(m,21H),1.02(d,J＝6.8Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ159.23,134.80,130.56,129.96,129.29,113.80,96.74,83.08,80.36,75.71,73.09,71.18,63.60,59.75,55.80,55.36,34.32,18.11,18.10,16.74,13.06,12.00.
Preparation example 12:
the product of preparation 11 (4.65 g,8.39 mmol) was dissolved in dry tetrahydrofuran (151 mL), tetrabutylammonium fluoride (12.6 mL,12.59 mmol) was added dropwise and the reaction was stirred at room temperature for 1 hour, TLC monitored complete, the reaction solution was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 1/1) to give compound (3.15 g, 94%) as a colourless oil. 1 H NMR(400MHz,CDCl 3 )δ7.25–7.22(m,2H),6.88–6.84(m,2H),5.38(d,J＝10.2Hz,1H),4.74(d,J＝6.8Hz,1H),4.63(d,J＝6.8Hz,1H),4.44(s,2H),3.94(dd,J＝7.8,1.8Hz,1H),3.79(s,3H),3.60–3.50(m,4H),3.48(s,3H),3.44–3.40(m,1H),3.36(s,3H),3.20(ddd,J＝8.7,5.3,3.5Hz,1H),2.85–2.74(m,1H),2.65(d,J＝2.2Hz,1H),2.57(dd,J＝7.5,5.7Hz,1H),1.67(s,3H),1.00(d,J＝6.9Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ159.31,134.22,131.58,130.30,129.44,113.86,96.35,83.35,80.17,78.99,73.12,70.38,60.49,58.48,55.84,55.38,34.58,16.52,12.13.
Preparation example 13:
the product of preparation 12 (3.15 g,7.91 mmol) was dissolved in anhydrous dichloromethane (79 mL), argon was used to protect, the temperature was reduced to 0 ℃,2, 6-lutidine (3.7 mL,31.64 mmol) was added, tert-butyldimethylsilyl triflate (5.45 mL,23.73 mmol) was added dropwise, after the addition was completed, the reaction was continued for 1 hour at 0 ℃, TLC was monitored for completion of the reaction, the reaction solution was washed with 10% aqueous citric acid, dichloromethane was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) was used to give the colorless oily compound (4.44 g, 90%). 1 H NMR(500MHz,CDCl 3 )δ7.23(d,J＝8.4Hz,2H),6.86(d,J＝8.5Hz,2H),5.15(d,J＝9.9Hz,1H),4.78(d,J＝6.8Hz,1H),4.65(d,J＝6.8Hz,1H),4.42(dd,J＝19.5,11.5Hz,2H),3.94(d,J＝6.4Hz,1H),3.80(s,3H),3.60(dd,J＝11.0,2.9Hz,1H),3.54(dd,J＝9.9,2.8Hz,1H),3.47(s,4H),3.41–3.36(m,2H),3.36(s,3H),3.15(td,J＝6.9,3.0Hz,1H),2.73(dt,J＝9.3,7.1Hz,1H),1.62(s,3H),1.00(d,J＝6.7Hz,3H),0.88(d,J＝5.8Hz,18H),0.05(s,9H),-0.01(s,3H). 13 C NMR(126MHz,CDCl 3 )δ159.23,135.72,130.55,129.71,129.31,113.82,96.76,85.65,80.49,78.79,73.15,71.30,63.66,60.19,55.83,55.38,34.19,26.06,25.99,18.41,18.36,16.74,12.58,-4.60,-4.78,-5.10.
Preparation example 14:
the product of preparation 13 (39 g,62.26 mmol) was dissolved in dichloromethane/phosphate buffer (ph=7) (10/1,1.4L), cooled to 0 ℃,2, 3-dichloro-5, 6-dicyanobenzoquinone (28.27 g,124.52 mmol) was added, the reaction was allowed to proceed to room temperature, TLC monitored to completion, saturated aqueous sodium bicarbonate solution was added to the reaction solution, stirring vigorously to clear layers, dichloromethane extraction, drying of the organic phase over anhydrous sodium sulfate, filtration, spin-drying, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to afford the compound as a colourless oil (29.1 g, 92%). 1 H NMR(400MHz,CDCl 3 )δ5.14(d,J＝10.0Hz,1H),4.76(d,J＝6.7Hz,1H),4.64(d,J＝6.7Hz,1H),3.96(d,J＝6.3Hz,1H),3.64–3.55(m,2H),3.46(s,3H),3.45–3.43(m,1H),3.43(s,3H),3.41–3.40(m,1H),3.28–3.24(m,1H),3.16(td,J＝6.8,3.2Hz,1H),3.07(dd,J＝8.6,4.3Hz,1H),2.63–2.53(m,1H),1.61(s,3H),1.00(d,J＝6.7Hz,3H),0.88(d,J＝4.6Hz,18H),0.04(s,9H),-0.01(s,3H). 13 C NMR(101MHz,CDCl 3 )δ135.93,129.28,97.75,86.86,85.67,78.70,64.33,63.62,60.08,55.92,34.80,26.04,25.96,18.42,18.34,16.93,12.59,-4.66,-4.81,-5.17,-5.20.
Preparation example 15:
the product of preparation 14 (8 g,15.8 mmol) was dissolved in dichloromethane (158 mL), dimethylsulfoxide (15.1 mL,212.6 mmol) and diisopropylethylamine (19.3 mL,110.6 mmol) were added, argon was purged, the temperature was reduced to 0℃and the pyridine-trioxide complex (5 g,31.6 mmol) was added in portions and the reaction at 0℃was continued for 1 hour. TLC was used to monitor completion of the reaction, water quenching was added to the reaction solution, extraction was performed with methylene chloride, the organic phase was washed with 10% aqueous citric acid, dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give a colorless oily compound (7.8 g, 98%) which was rapidly taken into the next reaction. 1 H NMR(400MHz,CDCl 3 )δ9.57(d,J＝2.4Hz,1H),5.23(d,J＝9.9Hz,1H),4.69(d,J＝6.8Hz,1H),4.64(d,J＝6.8Hz,1H),3.94(d,J＝6.2Hz,1H),3.65(dd,J＝6.7,2.4Hz,1H),3.56(dd,J＝11.0,3.4Hz,1H),3.46(s,3H),3.42–3.37(s,4H),3.13(td,J＝6.9,3.5Hz,1H),2.89–2.80(m,1H),1.62(s,3H),1.05(d,J＝6.8Hz,3H),0.88(d,J＝5.2Hz,18H),0.01(d,J＝23.2Hz,12H). 13 C NMR(101MHz,CDCl 3 )δ202.42,137.34,127.11,97.19,85.88,85.56,78.54,63.55,60.18,56.17,34.20,26.04,25.96,18.39,18.34,16.27,12.71,-4.68,-4.82,-5.19,-5.22.
Preparation example 16:
5-Chlorosalicylaldehyde (20 g,127.7 mmol) was dissolved in glacial acetic acid (327 mL), concentrated nitric acid (43 mL) was diluted with glacial acetic acid (60 mL), concentrated sulfuric acid (30 mL) was diluted with glacial acetic acid (60 mL), added dropwise, the reaction was completed at room temperature for 3.5 hours after the dropwise addition, TLC was monitored to complete the reaction, the reaction solution was directly poured into an ice-water mixture (1L), after standing for 15 minutes, filtration was performed, the cake was washed with a large amount of ice water, dichloromethane was dissolved, the cake was dried over anhydrous sodium sulfate, filtered, and dried by air to give a yellow solid product (24.4 g, 95%). 1 H NMR(400MHz,CDCl 3 )δ11.23(s,1H),10.39(s,1H),8.33(d,J＝2.7Hz,1H),8.08(d,J＝2.7Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ187.74,155.02,136.65,130.59,126.62,125.65.
Preparation example 17:
sodium hydride (3 g,75 mmol) was added to anhydrous tetrahydrofuran (350 mL), and the product of preparation 16 (10 g,50 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) under argon, and added dropwise, after which the reaction was carried out at 50℃for 30 minutes. Bromomethyl ether (8.16 mL,100 mmol) is added dropwise, after the dropwise addition, reflux reaction is carried out for 7 hours, TLC monitors the reaction completion, the reaction system is cooled by ice bath, ice water is added dropwise for quenching until the solution is clear, and ethyl acetate extraction is carried out rapidlyThe reaction mixture was separated, the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, dried, the crude product was dissolved in tetrahydrofuran (375 mL), sodium borohydride (1.89 g,50 mmol) was slowly added at room temperature, the reaction was completed, the reaction was quenched with acetone for 30 minutes, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and the crude product was flash column chromatographed (petroleum ether/ethyl acetate: 4/1) to give the compound as a white solid (9.8 g, 80%). 1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝2.7Hz,1H),7.67(d,J＝2.7Hz,1H),5.12(s,2H),4.69(s,2H),3.63(s,3H),3.02(brs,1H). 13 C NMR(101MHz,CDCl 3 )δ148.21,139.71,134.42,130.33,124.71,101.91,60.01,58.11.
Preparation example 18:
the product of preparation 17 (11.6 g,47 mmol) was dissolved in dichloromethane (282 mL), argon protected, cooled to 0deg.C, 2, 6-lutidine (20 mL,169.2 mmol) was added dropwise, tert-butyldisilyl triflate (32 mL,141 mmol) was added dropwise, after the addition was complete, the reaction was allowed to proceed to room temperature for 1 h, TLC monitored complete, the reaction was washed with 10% aqueous citric acid, dichloromethane extracted, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the compound as a colourless oil (15.13 g, 89%). 1 H NMR(500MHz,CDCl 3 )δ7.73(s,2H),5.05(s,2H),4.85(s,2H),3.54(s,3H),0.96(s,9H),0.14(s,6H). 13 C NMR(101MHz,CDCl 3 )δ146.48,140.34,132.17,130.09,123.53,101.86,59.93,57.90,26.01,18.51,5.25.
Preparation example 19:
the product of preparation 18 (31.5 g,87.2 mmol) was dissolved in methanol (436 mL) and platinum dioxide (1.58 g,5% wt) was added and hydrogen was introduced and the reaction was stirred at room temperature for 4After an hour, TLC was monitored to complete the reaction, and the reaction mixture was filtered through celite and dried to give crude oil. The crude product was directly dissolved in anhydrous N, N-dimethylformamide (326 mL), argon was used to protect it, the temperature was reduced to 0deg.C, sodium hydride (19.5 g, 4819 mmol) was slowly added dropwise, allyl bromide (28 mL,326 mmol) was added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 4 hours, TLC was monitored to completion, the reaction solution was placed in an ice bath, quenched with saturated aqueous ammonium chloride solution, extracted with petroleum ether, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-on, flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the colorless oily compound (28.41 g, 85%). 1 H NMR(400MHz,CDCl 3 )δ7.13(d,J＝2.8Hz,1H),6.79(d,J＝2.6Hz,1H),5.72(ddt,J＝16.6,10.2,6.3Hz,2H),5.18(q,J＝1.5Hz,1H),5.16(q,J＝1.2Hz,1H),5.14(dq,J＝2.8,1.5Hz,2H),5.09(s,2H),4.83(s,2H),3.69(d,J＝6.9Hz,4H),3.53(s,3H),0.96(s,9H),0.12(s,6H). 13 C NMR(101MHz,CDCl 3 )δ145.61,143.78,137.66,134.33,129.41,120.84,120.45,118.10,98.41,60.31,57.75,53.94,26.12,18.58,-5.19.
Preparation example 20:
the product of preparation 19 (28 g,68.1 mmol) was dissolved in tetrahydrofuran (544 mL), tetrabutylammonium fluoride (81.7 mL,81.7 mmol) was added dropwise at room temperature and the reaction was stirred for 2 hours, monitored by TLC for completion, the reaction solution was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the compound (19.8 g, 98%) as a colourless oil. 1 H NMR(400MHz,CDCl 3 )δ6.99(d,J＝2.5Hz,1H),6.86(d,J＝2.5Hz,1H),5.72(ddt,J＝16.6,10.3,6.3Hz,2H),5.20–5.15(m,4H),5.10(s,2H),4.58(d,J＝6.4Hz,2H),3.70(d,J＝6.3Hz,4H),3.56(s,3H),3.03(t,J＝6.8Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ147.77,144.42,137.04,134.18,129.60,123.18,121.74,118.23,98.65,61.03,57.79,53.90.
Preparation example 21:
the product of preparation 20 (7.1 g,23.9 mmol) was dissolved in anhydrous dichloromethane (239 mL), displaced with argon, cooled to 0deg.C, triphenylphosphine (6.38 g,35.85 mmol) and N-bromosuccinimide (9.4 g,35.85 mmol) were added sequentially, the reaction was turned to room temperature after the addition was completed for 1 hour, TLC monitored the reaction was complete, the reaction was quenched with copious amounts of water, dichloromethane extracted, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 95/5) to give the compound as a colourless oil (7.89 g, 92%). 1 H NMR(400MHz,CDCl 3 )δ7.02(d,J＝2.5Hz,1H),6.83(d,J＝2.5Hz,1H),5.72(ddt,J＝16.8,10.4,6.3Hz,2H),5.19(q,J＝1.5Hz,1H),5.17(s,3H),5.15(t,J＝1.3Hz,2H),4.54(s,2H),3.72(d,J＝6.3Hz,4H),3.61(s,3H). 13 C NMR(101MHz,CDCl 3 )δ147.11,144.76,134.03,133.77,129.28,124.06,122.42,118.40,98.27,58.04,53.82,28.11.
Preparation example 22:
evans prosthetic group H (6.5 g,27.86 mmol) is dissolved in anhydrous tetrahydrofuran (60 mL), argon is used for protection, the temperature is reduced to minus 78 ℃, bis (trimethylsilyl) sodium amide (13.9 mL,27.86 mmol) is added dropwise, the reaction is carried out for 30 minutes after the dropwise addition, the product of preparation 21 (5 g,13.93 mmol) is dissolved in anhydrous tetrahydrofuran (10 mL), the dropwise addition is carried out, the reaction is continued for 5 hours after the dropwise addition, TLC monitors that the reaction is complete, saturated ammonium chloride aqueous solution is added into the reaction solution for quenching until the reaction is clear, ethyl acetate extraction, the organic phase anhydrous sodium sulfate is dried, filtering and spin-drying are carried out, the crude product is directly dissolved in anhydrous tetrahydrofuran (173 mL), the argon is used for protection, the temperature is reduced to 0 ℃, lithium borohydride (10.5 mL,42.05 mmol) is added dropwise after the dropwise addition, the reaction is carried out overnight, TLC monitors that the reaction is complete, saturated ammonium chloride aqueous solution is added dropwise into the reaction solution for quenching until the reaction is clear, diethyl ether is extracted, and the organic phase anhydrous sodium sulfate is dried Drying, filtration, spin-drying and flash column chromatography of the crude product (petroleum ether/ethyl acetate: 4/1) afforded the product as a colourless oil (2.79 g, 59%). 1 H NMR(400MHz,CDCl 3 )δ6.80(d,J＝2.5Hz,1H),6.76(d,J＝2.5Hz,1H),5.72(ddt,J＝16.6,10.2,6.4Hz,2H),5.18(q,J＝1.4Hz,1H),5.15(q,J＝1.3Hz,1H),5.13(dt,J＝2.4,1.3Hz,2H),5.09(dd,J＝6.4,5.6Hz,2H),3.69(d,J＝6.3Hz,4H),3.56(s,3H),343–3.32(m,2H),2.78(dd,J＝13.4,7.6Hz,1H),2.53(dd,J＝13.4,6.5Hz,1H),2.27(t,J＝6.1Hz,1H),1.92(dq,J＝12.3,6.6Hz,1H),0.96(d,J＝6.8Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ147.44,144.32,136.22,134.21,129.04,124.44,120.11,118.23,98.69,66.46,58.10,54.02,37.14,33.51,17.01.
Preparation example 23:
triphenylphosphine (3.21 g,12.25 mmol) was dissolved in anhydrous dichloromethane (35 mL), argon was used to protect, the temperature was reduced to 0deg.C, imidazole (1.04 g,15.32 mmol) and iodine (3.5 g,13.79 mmol) were added sequentially, the product of preparation 22 (3.46 g,10.21 mmol) was dissolved in anhydrous dichloromethane (6 mL), added dropwise, the reaction was allowed to proceed to room temperature for 1 hour after the dropwise addition, TLC monitored for reaction completion, and the reaction solution was directly spun-dried, crude flash column chromatography (petroleum ether/ethyl acetate: 95/5) to give the product as a colourless oil (4.23 g, 92%). 1 H NMR(400MHz,CDCl 3 )δ6.81(d,J＝2.5Hz,1H),6.77(d,J＝2.5Hz,1H),5.72(ddt,J＝16.7,10.3,6.4Hz,2H),5.18(q,J＝1.4Hz,1H),5.15(q,J＝1.2Hz,1H),5.13(d,J＝1.2Hz,2H),5.08(dd,J＝8.4,5.6Hz,2H),3.70(d,J＝6.4Hz,4H),3.56(s,3H),3.25(dd,J＝9.7,4.4Hz,1H),3.11(dd,J＝9.7,6.0Hz,1H),2.68–2.58(m,2H),1.89–1.81(m,1H),0.99(d,J＝6.6Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ147.71,144.45,135.81,134.31,128.80,124.07,120.30,118.18,98.42,57.94,53.93,37.55,35.59,20.85,17.46.
Preparation example 24:
the product of preparation 23 (4.23 g,9.42 mmol) was dissolved in N, N-dimethylformamide (47 mL), sodium salt of benzenesulfonic acid (3.1 g,18.84 mmol) was added and reacted at room temperature for 72 hours, TLC monitored a small amount of starting material remaining, quenched with water in the reaction solution, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (3.66 g, 84%). 1 H NMR(400MHz,CDCl 3 )δ7.83(q,J＝1.4,0.8Hz,1H),7.81(t,J＝1.7Hz,1H),7.64–7.60(m,1H),7.54–7.50(m,2H),6.73(d,J＝2.5Hz,1H),6.60(d,J＝2.5Hz,1H),5.69(ddt,J＝16.0,10.9,6.3Hz,2H),5.17–5.12(m,4H),5.00(dd,J＝6.8,5.6Hz,2H),3.66(d,J＝6.5Hz,4H),3.48(s,3H),3.10(dd,J＝14.3,3.8Hz,1H),2.93(dd,J＝14.3,8.6Hz,1H),2.73(dd,J＝13.5,7.9Hz,1H),2.59(dd,J＝13.5,7.0Hz,1H),2.38–2.30(m,1H),1.11(d,J＝6.7Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ147.64,144.46,139.90,134.83,134.19,133.64,129.33,128.94,127.88,123.80,120.44,118.24,98.39,61.43,57.85,53.89,37.35,30.05,20.11.
Preparation example 25:
diisopropylamine (634. Mu.L, 4.52 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL), argon was used to protect the reaction, n-butyllithium (1.9 mL,4.52 mmol) was added dropwise to the reaction mixture, the reaction was carried out for 30 min, the product of preparation 24 (2.1 g,4.52 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), the product of preparation 15 (1.52 g,3.01 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), the reaction was carried out for 30 min, the dropwise addition was completed, the reaction was continued for 1 h, TLC was monitored to completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with diethyl ether, the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying, and the crude product was purified by flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give a colorless oily product (2.53 g, 87%).
Preparation example 26:
the product of preparation 25 (4.3 g,4.44 mmol) was dissolved in dichloromethane (44 mL), argon protected, cooled to 0deg.C, sodium bicarbonate (1.5 g,17.76 mmol) and Dess-Martin oxidant (2.83 g,6.67 mmol) were added sequentially, the reaction was allowed to proceed to room temperature for 2 hours, TLC monitored the reaction was complete, the reaction was quenched with saturated aqueous sodium thiosulfate, extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (3.82 g, 89%).
Preparation example 27:
the product of preparation 26 (3.82 g,3.97 mmol) was dissolved in anhydrous methanol/anhydrous tetrahydrofuran (3/2) (32 mL), argon protected, cooled to-78deg.C, samarium iodide (80 mL) was added dropwise until the reaction became green, TLC monitoring was complete, the reaction was quenched with large amounts of saturated aqueous potassium sodium tartrate solution, stirred vigorously at room temperature for 1 h, extracted with diethyl ether, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (3.02 g, 92%). 1 H NMR(400MHz,CDCl 3 )δ6.79(d,J＝2.5Hz,1H),6.73(d,J＝2.5Hz,1H),5.71(ddt,J＝16.6,10.2,6.3Hz,2H),5.23(d,J＝9.7Hz,1H),5.17–5.12(m,4H),5.06(s,2H),4.57(s,2H),3.92(d,J＝5.8Hz,1H),3.72(d,J＝5.3Hz,1H),3.69(d,J＝6.3Hz,4H),3.57(dd,J＝11.0,3.6Hz,1H),3.54(s,3H),3.47(s,3H),3.42(dd,J＝11.0,7.5Hz,1H),3.32(s,3H),3.16(ddd,J＝7.5,6.3,3.6Hz,1H),2.84–2.76(m,1H),2.59–2.49(m,3H),2.42–2.29(m,2H),1.64(d,J＝1.3Hz,3H),0.94(d,J＝6.8Hz,3H),0.89–0.87(m,21H),0.05–0.04(m,9H),-0.01(s,3H). 13 C NMR(101MHz,CDCl 3 )δ210.27,147.72,144.42,136.43,136.42,134.33,128.75,128.50,124.12,120.02,118.13,98.37,97.23,86.60,85.87,78.69,77.16,63.78,60.26,57.81,56.32,53.92,45.67,37.50,34.78,29.58,26.05,25.98,20.08,18.39,18.34,15.48,12.52,-4.64,-4.80,-5.12,-5.18.
Preparation example 28:
the product of preparation 27 (3.02 g,3.66 mmol) was dissolved in anhydrous diethyl ether (48 mL), argon was purged to 0deg.C, cyclohexene (2.97 mL,29.28 mmol), 2-methoxypropene (2.67 mL,29.28 mmol) was added sequentially, then zinc borohydride (9.15 mL,9.15 mmol) was added dropwise, the reaction was allowed to proceed to room temperature for 3 hours, TLC monitored to completion, saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, diethyl ether was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) was performed as a colorless oil (2 g, 66%). 1 H NMR(400MHz,CDCl 3 )δ6.82(d,J＝2.5Hz,1H),6.70(d,J＝2.5Hz,1H),5.71(ddt,J＝16.6,10.2,6.3Hz,2H),5.17–5.11(m,5H),5.07–5.04(m,2H),4.70(d,J＝6.8Hz,1H),4.58(d,J＝6.9Hz,1H),4.01(d,J＝5.1Hz,1H),3.69(d,J＝6.3Hz,4H),3.64(dd,J＝11.0,3.4Hz,1H),3.55(s,3H),3.47–3.42(m,4H),3.24(s,3H),3.22–3.17(m,2H),3.15(ddd,J＝6.9,5.6,3.4Hz,1H),2.59(d,J＝7.4Hz,2H),2.53–2.45(m,1H),2.14(d,J＝8.2Hz,1H),1.64(d,J＝1.2Hz,3H),1.55–1.51(m,1H),1.11–1.04(m,1H),0.97(d,J＝6.6Hz,3H),0.88(s,21H),0.05(s,3H),0.04(d,J＝1.0Hz,6H),0.00(s,3H). 13 C NMR(101MHz,CDCl 3 )δ147.79,144.37,137.25,135.50,134.37,129.26,128.61,124.12,119.64,118.07,99.46,98.31,92.29,85.72,77.74,69.41,63.27,59.79,57.70,55.91,53.92,38.89,37.42,34.88,29.84,26.03,25.99,19.16,18.37,18.34,17.74,13.00,-4.59,-4.78,-5.11,-5.16.
Preparation example 29:
the product of preparation 28 (2.4 g,2.9 mmol) was dissolved in anhydrous dichloromethane (49 mL) and protected by argon1, 8-Didimethylaminonaphthalene (3.73 g,17.4 mmol) and trimethyloxonium tetrafluoroboric acid (1.3 g,8.7 mmol) were added sequentially at room temperature and stirred for 5 hours, TLC monitored complete reaction, celite was filtered off, the organic phase was dried sequentially with 0.5N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated brine, anhydrous sodium sulfate, filtered, spun-dried, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (1.88 g, 77%). 1 H NMR(400MHz,CDCl 3 )δ6.82(d,J＝2.5Hz,1H),6.71(d,J＝2.5Hz,1H),5.72(ddt,J＝16.6,10.2,6.4Hz,2H),5.18–5.11(m,5H),5.05(s,2H),4.82(d,J＝2.4Hz,1H),4.59(d,J＝5.7Hz,1H),4.01(d,J＝5.5Hz,1H),3.69(d,J＝7.4Hz,4H),3.65(dd,J＝10.9,3.3Hz,1H),3.60(d,J＝9.6Hz,1H),3.55(s,3H),3.45(s,3H),3.43–3.41(m,1H),3.39(s,3H),3.29(s,3H),3.20(d,J＝10.5Hz,1H),3.16(ddd,J＝7.3,5.8,3.3Hz,1H),2.62(dd,J＝13.5,5.8Hz,1H),2.50(ddd,J＝15.9,11.6,7.8Hz,2H),2.00(dtt,J＝13.0,6.5,3.5Hz,1H),1.74(ddd,J＝14.0,10.7,3.1Hz,1H),1.62(d,J＝1.2Hz,3H),1.20–1.13(m,1H),1.04(d,J＝6.6Hz,3H),0.89(s,9H),0.87(s,9H),0.77(d,J＝6.6Hz,3H),0.06(s,3H),0.03(d,J＝1.0Hz,6H),0.01(s,3H). 13 C NMR(101MHz,CDCl 3 )δ147.70,144.32,137.20,135.44,134.44,129.92,128.62,124.13,119.65,118.04,98.27,97.52,85.96,81.23,79.59,77.76,63.52,59.95,57.73,56.92,56.20,53.92,38.63,36.71,34.52,30.32,26.02,26.01,19.12,18.37,18.33,17.79,13.04,-4.55,-4.76,-5.08,-5.13.
Preparation example 30:
the product of preparation 29 (2.92 g,3.47 mmol) was dissolved in methanol/dichloromethane (1/1) (62 mL), camphorsulfonic acid (846 mg,3.64 mmol) was added and the reaction was stirred at room temperature for 3.5 hours, monitored by TLC to complete the reaction, triethylamine (2.9 mL,20.82 mmol) was added to the reaction solution and the reaction was continued for 15 min, the reaction solution was directly spin-dried, and crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the product as a colourless oil (2.02 g, 81%). 1 H NMR(400MHz,CDCl 3 )δ6.81(d,J＝2.5Hz,1H),6.72(d,J＝2.5Hz,1H),5.72(ddt,J＝16.7,10.3,6.4Hz,2H),5.20–5.12(m,5H),5.05(s,2H),4.81(d,J＝6.6Hz,1H),4.60(d,J＝6.6Hz,1H),4.04(d,J＝7.1Hz,1H),3.69(d,J＝6.4Hz,4H),3.57(dd,J＝8.8,1.6Hz,2H),3.54(s,3H),3.50(s,3H),3.39(s,3H),3.36–3.32(m,1H),3.30(s,3H),3.25–3.21(m,2H),2.63(dd,J＝13.5,5.8Hz,1H),2.56–2.47(m,2H),2.16(brs,1H),2.05–1.96(m,1H),1.73(ddd,J＝14.2,10.7,3.4Hz,1H),1.61(d,J＝1.2Hz,3H),1.16(ddd,J＝14.0,10.3,1.9Hz,1H),1.04(d,J＝6.6Hz,3H),0.89(s,9H),0.78(d,J＝6.6Hz,3H),0.08(s,3H),0.02(s,3H). 13 C NMR(101MHz,CDCl 3 )δ147.68,144.34,137.17,134.64,134.44,131.14,128.63,124.17,119.69,118.06,98.28,97.47,84.38,81.10,80.08,79.61,61.77,59.77,57.77,57.07,56.20,53.93,38.58,37.02,34.46,30.42,25.95,19.04,18.28,17.51,12.36,-4.53,-4.76.
Preparation example 31:
the product of preparation 30 (2.02 g,2.78 mmol) was dissolved in anhydrous dichloromethane (28 mL), dimethylsulfoxide (2.64 mL,37.17 mmol) and diisopropylethylamine (3.4 mL,19.46 mmol) were added, argon was purged, the temperature was lowered to 0℃and the pyridine-trioxide complex (885 mg,5.56 mmol) was added in portions and the reaction was continued at 0℃for 1 hour. TLC was used to monitor completion of the reaction, water quenching was added to the reaction solution, extraction was performed with methylene chloride, the organic phase was washed with 10% aqueous citric acid, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give a colorless oily aldehyde compound (1.93 g, 96%).
18-crown-6 (3.52 g,13.3 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), argon shielded, cooled to-78deg.C, and potassium bis (trimethylsilyl) amide (3.99 mL,3.99 mmol) was added dropwise and reacted for 15 min. Methyl bis (2, 2-trifluoroethyl) phosphonoacetate P (1.13 mL,5.32 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and the mixture was added dropwise, and the reaction was continued for 30 minutes after the completion of the dropwise addition. The aldehyde compound (1.93 g,2.66 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and added dropwiseAfter the addition was completed, the reaction was continued for 1 hour, TLC was monitored to complete the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the crude product was purified by flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give a colorless oily product (1.98 g, 95%). 1 H NMR(400MHz,CDCl 3 )δ6.81(d,J＝2.5Hz,1H),6.71(d,J＝2.5Hz,1H),5.99–5.89(m,2H),5.71(ddt,J＝16.6,10.2,6.4Hz,2H),5.20–5.11(m,5H),5.04(s,2H),4.88(dd,J＝8.9,5.6Hz,1H),4.82(d,J＝6.6Hz,1H),4.59(d,J＝6.5Hz,1H),4.02(d,J＝5.3Hz,1H),3.69–3.66(m,7H),3.59(dd,J＝9.5,1.2Hz,1H),3.54(s,3H),3.38(s,3H),3.30(s,3H),3.26(s,3H),3.21(d,J＝10.5Hz,1H),2.62(dd,J＝13.5,5.8Hz,1H),2.54–2.43(m,2H),1.98(ddq,J＝12.7,6.1,3.3Hz,1H),1.73(ddd,J＝14.1,10.7,3.2Hz,1H),1.62(d,J＝1.2Hz,3H),1.15(ddd,J＝14.2,10.3,1.8Hz,1H),1.03(d,J＝6.6Hz,3H),0.86(s,9H),0.73(d,J＝6.6Hz,3H),0.03(s,3H),-0.01(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.30,147.67,147.03,144.32,137.25,135.61,134.43,130.81,128.60,124.11,122.15,119.62,118.03,98.26,97.47,81.23,81.20,79.56,79.51,57.74,57.56,56.86,56.17,53.90,51.36,38.58,36.73,34.49,30.40,25.95,18.98,18.38,17.72,12.87,-4.61,-4.69.
Preparation example 32:
the product of preparation 31 (860 mg,1.1 mmol) was dissolved in anhydrous dichloromethane (11 mL), argon was purged, the temperature was reduced to-78 ℃, diisobutylaluminum hydride (2.75 mL,2.75 mmol) was added dropwise, and the reaction was continued for 1 hour after the addition was completed. The reaction mixture was stirred vigorously at room temperature until a clear layer was formed, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and flash column chromatographed (petroleum ether/ethyl acetate: 3/1) to give the product as a colourless oil (737 mg, 89%). 1 H NMR(400MHz,CDCl 3 )δ6.82(d,J＝2.5Hz,1H),6.72(d,J＝2.5Hz,1H),5.87–5.80(m,1H),5.72(ddt,J＝16.6,10.2,6.4Hz,2H),5.25(ddt,J＝11.5,9.0,1.3Hz,1H),5.18–5.10(m,5H),5.05(s,2H),4.81(d,J＝6.6Hz,1H),4.60(d,J＝6.6Hz,1H),4.16(t,J＝5.5Hz,1H),4.04(d,J＝6.0Hz,1H),3.91(ddd,J＝8.9,6.3,0.9Hz,1H),3.69(d,J＝6.3Hz,4H),3.58(dd,J＝9.3,1.5Hz,1H),3.54(s,3H),3.39(s,3H),3.29(s,3H),3.28(s,3H),3.24(d,J＝10.4Hz,1H),2.63(dd,J＝13.5,5.7Hz,1H),2.55–2.43(m,2H),2.22(brs,1H),2.00(dtq,J＝12.5,6.4,3.4Hz,1H),1.73(ddd,J＝14.1,10.6,3.3Hz,2H),1.56(d,J＝1.2Hz,3H),1.16(ddd,J＝14.2,10.3,2.0Hz,1H),1.03(d,J＝6.6Hz,3H),0.88(s,9H),0.77(d,J＝6.6Hz,3H),0.07(s,3H),0.03(s,3H). 13 C NMR(101MHz,CDCl 3 )δ147.68,144.34,137.20,134.46,134.42,133.17,131.56,129.57,128.64,124.10,119.68,118.06,98.29,97.43,81.06,81.04,80.67,79.76,58.85,57.77,56.98,56.89,56.19,53.92,38.52,36.80,34.52,30.40,26.01,19.03,18.48,17.69,12.83,-4.63.
Preparation example 33:
the product of preparation 32 (630 mg,0.84 mmol) was dissolved in anhydrous dichloromethane (8.36 mL), dimethylsulfoxide (794. Mu.L, 11.25 mmol) and diisopropylethylamine (1.02 mL,5.85 mmol) were added, argon was purged, the temperature was lowered to 0℃and the pyridine-trioxide complex (266 mg,1.67 mmol) was added in portions and the reaction at 0℃was continued for 1 hour. TLC was used to monitor completion of the reaction, water quenching was added to the reaction solution, dichloromethane extraction, washing of the organic phase with 10% aqueous citric acid, drying over anhydrous sodium sulfate, filtration, spin-drying, direct dissolution of the crude product in anhydrous toluene (17 mL), argon protection, addition of ylide reagent S (606 mg,1.67 mmol), reaction at 80℃for 1 hour, TLC monitoring completion of the reaction, direct spin-drying of the reaction solution, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (635 mg, 91%). 1 H NMR(400MHz,CDCl 3 )δ7.51(dt,J＝12.1,1.2Hz,1H),6.80(d,J＝2.5Hz,1H),6.71(d,J＝2.5Hz,1H),6.46(t,J＝11.9Hz,1H),5.71(ddt,J＝16.6,10.2,6.3Hz,2H),5.46(t,J＝10.5Hz,1H),5.17–5.10(m,5H),5.04(s,2H),4.81(d,J＝6.6Hz,1H),4.58(d,J＝6.5Hz,1H),4.21(q,J＝7.1Hz,2H),4.11(dd,J＝9.7,6.6Hz,1H),4.01(d,J＝6.5Hz,1H),3.68(d,J＝6.3Hz,4H),3.58–3.54(m,1H),3.53(s,3H),3.38(s,3H),3.29(s,3H),3.25(s,3H),3.19(d,J＝10.5Hz,1H),2.61(dd,J＝13.5,5.8Hz,1H),2.53–2.39(m,2H),2.01–1.92(m,1H),1.88(d,J＝1.1Hz,3H),1.70(td,J＝6.9,3.4Hz,1H),1.54(d,J＝1.2Hz,3H),1.30(t,J＝7.1Hz,3H),1.12(ddd,J＝14.2,10.2,1.6Hz,1H),1.01(d,J＝6.6Hz,3H),0.87(s,9H),0.71(d,J＝6.6Hz,3H),0.07(s,3H),0.02(s,3H). 13 C NMR(101MHz,CDCl 3 )δ168.34,147.67,144.32,137.20,134.81,134.71,134.42,132.14,131.64,129.65,128.60,127.61,124.10,119.64,118.03,98.25,97.43,81.29,81.15,80.17,79.55,77.16,60.81,57.72,56.97,56.84,56.16,53.91,38.63,36.71,34.46,30.36,25.94,19.13,18.36,17.64,14.43,12.82,12.53,-4.55,-4.71.
Preparation example 34:
the product of preparation 33 (635 mg,0.76 mmol) was dissolved in acetonitrile (23.8 mL), pyridine/hydrogen fluoride pyridine solution/acetonitrile (1/1/2.5) (26.6 mL) was added dropwise at room temperature, the reaction was completed for 72 hours, TLC was monitored to complete the reaction, the reaction solution was placed in an ice bath, saturated aqueous sodium bicarbonate solution was added dropwise, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-on, and crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) gave the product as a colourless oil (521 mg, 95%). 1 H NMR(400MHz,CDCl 3 )δ7.47(dt,J＝12.1,1.3Hz,1H),6.79(d,J＝2.5Hz,1H),6.71(d,J＝2.5Hz,1H),6.54(t,J＝11.7Hz,1H),5.71(ddt,J＝16.6,10.2,6.3Hz,2H),5.49(t,J＝10.5Hz,1H),5.33(d,J＝10.7Hz,1H),5.17–5.10(m,4H),5.04(s,2H),4.77(d,J＝6.6Hz,1H),4.57(d,J＝6.6Hz,1H),4.20(qd,J＝7.2,1.6Hz,2H),4.17–4.12(m,1H),3.90(d,J＝7.7Hz,1H),3.68(d,J＝6.3Hz,4H),3.54–3.51(m,4H),3.37(s,3H),3.30(s,3H),3.28(s,3H),3.16(dt,J＝10.4,1.8Hz,1H),2.86(d,J＝1.5Hz,1H),2.60(dd,J＝13.5,5.9Hz,1H),2.53–2.42(m,2H),1.99–1.92(m,1H),1.90(d,J＝1.2Hz,3H),1.67(s,1H),1.60(d,J＝1.2Hz,3H),1.29(t,J＝7.1Hz,3H),1.12(ddd,J＝14.2,10.2,2.0Hz,1H),1.02(d,J＝6.7Hz,3H),0.70(d,J＝6.6Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ168.11,147.66,144.33,137.14,134.42,133.46,133.32,132.74,131.36,130.60,128.99,128.59,124.13,119.67,118.05,98.25,97.41,81.07,79.99,79.97,78.89,60.94,57.73,56.95,56.64,56.13,53.90,38.65,36.92,34.46,30.41,19.11,17.47,14.40,12.98,12.58.
Example 35:
the product of preparation 34 (430 mg,0.596 mmol) was dissolved in anhydrous dichloromethane (26 mL), N-dimethylbarbituric acid (372 mg, 2.284 mmol) and tetrakis triphenylphosphine palladium (138 mg,0.119 mmol) were sequentially added at room temperature, the reaction was performed under reflux for 4 hours under argon protection, the reaction solution was completely monitored by TLC, washed with 0.5N aqueous sodium hydroxide solution, extracted with dichloromethane, dried over organic phase anhydrous sodium sulfate, filtered, dried by spin-drying, the crude product was dissolved in methanol/tetrahydrofuran/water (2/2/1) (22.3 mL), lithium hydroxide (304 mg,12.67 mmol) was added at room temperature, the reaction was completely monitored by TLC, sodium dihydrogen phosphate (10% wt,23 mL) was added to the reaction solution, the aqueous phase was adjusted to saturation with solid sodium chloride, extracted with dichloromethane, the organic phase anhydrous sodium sulfate was dried, filtered, dried by spin-drying, directly dissolved in anhydrous toluene (222.6 mL), diisopropylethylamine (1.33.8 ℃ C.) and bis (58 mmol) were sequentially added at room temperature, water-58 mmol) was added to the solution, the crude product was directly quenched by dry phase, the aqueous solution was saturated with water (516 mg, water-saturated aqueous solution was added at room temperature, water-saturated with water, water-saturated solution was added to be saturated with water, saturated aqueous solution was completely, saturated solution was obtained by flash-phase was added dropwise, and saturated solution was saturated with water (58 mg, saturated solution was added dropwise, saturated solution was saturated.
The ring-closed product was dissolved in anhydrous dichloromethane (10.8 mL), argon protected, cooled to 0deg.C, trichloroacetyl isocyanate (103 μL,0.864 mmol) was added dropwise, after the dropwise addition was completed, the reaction was continued for 1 hour, TLC monitored to complete the reaction, anhydrous methanol (10.8 mL), potassium carbonate (275 mg,1.987 mmol) was added to the reaction solution, the reaction was allowed to react for 1 hour at room temperature, TLC monitored to complete the reaction, water was added to the reaction solution until clear, dichloromethane extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 3/2) to give pale yellow solid product (257 mg, 85%).
Aluminum trichloride (450 mg,3.375 mmol) was suspended in anhydrous dichloromethane (30 mL), argon was used to protect it, anisole (37.8 mL,0.864 mmol) was added dropwise, after the addition was completed, the reaction was continued for 5 min, the pale yellow solid product 34 (80 mg,0.125 mmol) was dissolved in anhydrous dichloromethane (4.8 mL), added dropwise, the reaction solution was warmed to room temperature over 2 hours after the addition was completed, the reaction was continued for 1 hour, TLC was monitored for completion of the reaction, the reaction solution was quenched with 0.5N hydrochloric acid solution and saturated ammonium chloride solution, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and flash column chromatography (petroleum ether/ethyl acetate: 1/1) was performed on crude product to obtain pale yellow solid product GA-Cl (50 mg, 71%). 1 H NMR(400MHz,DMSO-d6,100℃)δ8.80(s,1H),8.73(s,1H),7.57(s,1H),6.82(d,J＝2.6Hz,1H),6.73(d,J＝11.4Hz,1H),6.46(t,J＝11.3Hz,1H),6.09(s,2H),5.52(t,J＝10.2Hz,1H),5.44(d,J＝9.6Hz,1H),4.90(d,J＝4.1Hz,1H),4.19(dd,J＝9.4,4.1Hz,1H),3.46–3.43(m,1H),3.28(s,3H),3.15(s,3H),3.09(q,J＝5.1Hz,1H),3.02(s,1H),2.76(dd,J＝13.3,5.8Hz,1H),2.54–2.49(m,1H),2.42(dd,J＝13.3,6.3Hz,1H),2.01(dd,J＝12.5,6.1Hz,1H),1.96(s,3H),1.54(s,3H),1.52–1.49(m,1H),1.38–1.33(m,1H),0.89(dd,J＝9.9,6.7Hz,6H). 13 C NMR(101MHz,DMSO-d6,100℃)δ169.29,155.60,144.93,134.36,132.61,132.38,131.47,129.98,129.16,126.22,125.61,125.11,122.48,118.80,80.46,79.96,78.63,72.57,55.88,55.46,38.21,32.73,32.49,28.00,20.27,14.15,12.20,11.72.
Preparation example 36:
the product of preparation 35 (20 g,101.45 mmol) was dissolved in anhydrous tetrahydrofuranTo the furan (812 mL) was slowly added sodium hydride (6 g,152.17 mmol) and reacted at 50℃for 30 minutes under argon. Bromomethyl ether (16.4 mL,202.9 mmol) was added dropwise, after the addition was completed, the reaction was refluxed for 7 hours, TLC was monitored to complete the reaction, the reaction system was cooled in an ice bath, saturated aqueous sodium bicarbonate solution was added dropwise to the reaction solution, quenched, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, and the crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate: 2/1) to give a white solid product (17.89 g, 73%). 1 H NMR(400MHz,CDCl 3 )δ8.02(dd,J＝7.9,1.8Hz,1H),7.88(dd,J＝8.1,1.8Hz,1H),7.30(t,J＝8.0Hz,1H),5.14(s,2H),3.93(s,3H),3.50(s,3H). 13 C NMR(101MHz,CDCl 3 )δ164.92,150.16,135.24,128.14,127.89,124.31,102.56,58.10,52.91.
Preparation example 37:
the product of preparation 36 (5 g,20.74 mmol) was dissolved in methanol (104 mL), palladium on carbon (500 mg,10% wt) was added, hydrogen was introduced, the reaction was monitored at room temperature overnight by TLC, the reaction solution was filtered through celite, and dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the compound as a colourless oil (4.16 g, 95%). Aniline (4.16 g,19.71 mmol) was dissolved in anhydrous N, N-dimethylformamide (79 mL), protected by argon, cooled to 0deg.C, sodium hydride (4.73 g,118.26 mmol) was slowly added, allyl bromide (6.8 mL,78.84 mmol) was added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 4 hours, TLC monitored the reaction was complete, the reaction solution was placed in an ice bath, quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the compound as a colourless oil (4.71 g, 82%). 1 H NMR(400MHz,CDCl 3 )δ7.32(dd,J＝6.5,2.9Hz,1H),7.07–7.02(m,2H),5.74(ddt,J＝16.6,10.2,6.3Hz,2H),5.18(q,J＝1.4Hz,1H),5.13(s,4H),5.11(q,J＝1.1Hz,1H),3.89(s,3H),3.76(d,J＝6.3Hz,4H),3.53(s,3H). 13 C NMR(101MHz,CDCl 3 )δ167.34,149.44,144.50,134.56,127.62,125.16,123.87,117.89,98.88,57.71,54.23,52.28.
Preparation example 38:
lithium aluminum hydride (3.9 g,102.4 mmol) was suspended in anhydrous tetrahydrofuran (200 mL), argon was used to protect, the temperature was lowered to 0 ℃, the product of preparation 37 (15 g,51.2 mmol) was dissolved in anhydrous tetrahydrofuran (56 mL), added dropwise at room temperature, the reaction was carried out for 1 hour at room temperature after the addition was completed, TLC was monitored to complete the reaction, the reaction solution was placed in an ice bath, water was added dropwise, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-drying, and crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) was obtained as a colorless oily compound (13.34 g, 99%). 1 HNMR(400MHz,CDCl 3 )δ7.05–6.98(m,2H),6.92(dd,J＝7.5,2.2Hz,1H),5.74(ddt,J＝16.5,10.2,6.3Hz,2H),5.19(q,J＝1.4Hz,1H),5.16(s,2H),5.15–5.14(m,2H),5.12(q,J＝1.2Hz,1H),4.63(d,J＝6.7Hz,2H),3.71(d,J＝6.3Hz,4H),3.56(s,3H),3.16(t,J＝6.7Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ149.59,143.30,135.77,134.80,124.58,123.81,121.92,117.73,98.71,61.58,57.67,54.14.
Preparation example 39:
the product of preparation 38 (13.4 g,50.92 mmol) was dissolved in anhydrous dichloromethane (509 mL), displaced with argon, cooled to 0℃and triphenylphosphine (20 g,76.38 mmol) and N-bromosuccinimide (13.6 g,76.38 mmol) were added sequentially, the reaction was turned to room temperature after the addition was completed and was allowed to react for 1 hour, TLC monitored the reaction was complete, the reaction solution was quenched with a large amount of water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 95/5) to give the compound as a colourless oil (14.94 g, 90%). 1 H NMR(400MHz,CDCl 3 )δ7.05(dd,J＝7.6,1.8Hz,1H),7.00(t,J＝7.7Hz,1H),6.90(dd,J＝7.8,1.8Hz,1H),5.74(ddt,J＝16.6,10.2,6.3Hz,2H),5.23(s,2H),5.18(q,J＝1.4Hz,1H),5.15–5.13(m,2H),5.12–5.11(m,1H),4.63(s,2H),3.72(d,J＝6.3Hz,4H),3.63(s,3H). 13 C NMR(101MHz,CDCl 3 )δ148.78,143.67,134.66,132.53,124.71,124.31,122.54,117.89,98.24,57.93,54.05,29.26.
Preparation example 40:
evans prosthetic group H (46.2 g,198.11 mmol) was dissolved in anhydrous tetrahydrofuran (400 mL), argon was used to protect, the temperature was reduced to-78 ℃, sodium bis (trimethylsilyl) amide (99 mL,198.11 mmol) was added dropwise after the addition was completed, the product of preparation 39 (32.2 g,99.06 mmol) was dissolved in anhydrous tetrahydrofuran (95 mL), added dropwise, the reaction was continued for 3 hours after the addition was completed, TLC was monitored for completion of the reaction, saturated aqueous ammonium chloride was added to the reaction solution to quench it, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-drying, the crude product was directly dissolved in anhydrous tetrahydrofuran (1.38L), argon was used to protect, the temperature was reduced to 0 ℃, lithium borohydride (84.2 mL,336.8 mmol) was added dropwise, the reaction was completed, saturated aqueous ammonium chloride solution was quenched in the reaction solution dropwise, diethyl ether was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product was obtained as a colorless oily column (16 g, 53%) was obtained as a flash-colorless oily column after rapid chromatography (16 g). 1 H NMR(400MHz,CDCl 3 )δ6.97–6.94(m,1H),6.83(s,1H),6.81(d,J＝1.8Hz,1H),5.75(ddt,J＝16.6,10.2,6.4Hz,2H),5.17(q,J＝1.4Hz,1H),5.14(s,2H),5.13–5.12(m,2H),5.10(q,J＝1.1Hz,1H),3.70(d,J＝6.4Hz,4H),3.58(s,3H),3.41–3.32(m,2H),2.80(dd,J＝13.3,7.8Hz,1H),2.60(dd,J＝13.3,6.2Hz,1H),2.45(s,1H),1.98–1.90(m,1H),0.97(d,J＝6.9Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ149.02,143.25,134.83,134.62,125.12,123.98,120.07,117.73,98.76,66.46,58.00,54.28,37.27,33.51,17.16.
Preparation example 41:
triphenylphosphine (11.09 g,42.26 mmol) was dissolved in anhydrous dichloromethane (121 mL), argon was used to protect it, imidazole (3.6 g,52.83 mmol) and iodine (12.07 g,47.55 mmol) were added sequentially, the product of preparation 40 (10.75 g,35.22 mmol) was dissolved in anhydrous dichloromethane (20 mL), added dropwise, the reaction was allowed to proceed to room temperature for 1 hour after the dropwise addition, TLC was monitored to complete the reaction, and the reaction solution was dried directly by spin-drying, crude flash column chromatography (petroleum ether/ethyl acetate: 95/5) to give the product as a colourless oil (13 g, 89%). 1 H NMR(400MHz,CDCl 3 )δ6.94(t,J＝7.7Hz,1H),6.83(td,J＝7.8,1.6Hz,2H),5.75(ddt,J＝16.6,10.2,6.4Hz,2H),5.17–5.10(m,6H),3.71(d,J＝6.3Hz,4H),3.58(s,3H),3.28(dd,J＝9.6,4.3Hz,1H),3.12(dd,J＝9.6,6.2Hz,1H),2.72–2.62(m,2H),1.93–1.82(m,1H),1.01(d,J＝6.6Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ149.33,143.40,134.96,134.32,124.74,123.72,120.27,117.66,98.45,57.78,54.18,37.63,35.68,21.02,18.12.
Preparation example 42:
the product of preparation 41 (15.9 g,38.3 mmol) was dissolved in N, N-dimethylformamide (192 mL), sodium salt of benzenesulfonic acid (12.6 g,76.6 mmol) was added, the reaction was continued overnight at room temperature, TLC monitored to leave a small amount of starting material remaining, water quenching was performed in the reaction solution, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (15 g, 92%). 1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝8.3,1.2Hz,2H),7.62–7.58(m,1H),7.52–7.48(m,2H),6.89–6.86(m,1H),6.79(dd,J＝8.0,1.6Hz,1H),6.64(dd,J＝7.5,1.6Hz,1H),5.71(ddt,J＝16.6,10.2,6.3Hz,2H),5.15(q,J＝1.4Hz,1H),5.12–5.09(m,3H),5.04(q,J＝5.7Hz,2H),3.65(d,J＝6.6Hz,4H),3.49(s,3H),3.14(dd,J＝14.3,3.5Hz,1H),2.92(dd,J＝14.3,9.0Hz,1H),2.75–2.64(m,2H),2.45–2.33(m,1H),1.13(d,J＝6.7Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ149.27,143.39,140.12,134.83,133.46,133.30,129.26,127.89,124.46,123.87,120.41,117.71,98.41,61.52,57.69,54.13,37.60,30.07,20.15.
Preparation example 43:
diisopropylamine (2.9 mL,20.82 mmol) was dissolved in anhydrous tetrahydrofuran (168 mL), protected by argon, cooled to-78 ℃, n-butyllithium (8.7 mL,20.82 mmol) was added dropwise, reacted for 30 min, the product of preparation 42 (8.94 g,20.82 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), added dropwise, reacted for 30 min, the product of preparation 15 (7 g,13.88 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), added dropwise, the reaction was continued for 1 h after the addition, TLC was monitored for completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with diethyl ether, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (11.4 g, 88%).
Preparation example 44:
the product of preparation 43 (13 g,13.9 mmol) was dissolved in dichloromethane (139 mL), argon protected, cooled to 0deg.C, sodium bicarbonate (4.7 g,55.6 mmol) and Dess-Martin oxidant (8.8 g,20.85 mmol) were added sequentially, the reaction was allowed to proceed to room temperature for 1 h, TLC monitored to completion, the reaction was quenched with saturated aqueous sodium thiosulfate, extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate, filtered, dried, and flash column chromatographed crude (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (10.7 g, 83%).
Preparation example 45:
the product of preparation 44 (10 g,10.74 mmol) was dissolved in anhydrous methanol/anhydrous tetrahydrofuran (3/2) (86 mL), argon protected, cooled to-78deg.C, samarium iodide (214 mL) was added dropwise until the reaction became green, TLC monitored the reaction was complete, the reaction was quenched with a large amount of saturated aqueous potassium sodium tartrate solution, stirred vigorously at room temperature for 1 hour, extracted with diethyl ether, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, and crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (7.48 g, 88%). 1 H NMR(400MHz,CDCl 3 )δ6.95–6.89(m,1H),6.82–6.77(m,2H),5.79–5.69(m,2H),5.24–5.05(m,7H),4.56(dd,J＝8.7,2.2Hz,2H),3.91(d,J＝6.2Hz,1H),3.73(d,J＝5.2Hz,1H),3.69(d,J＝6.3Hz,4H),3.59–3.55(m,4H),3.47(s,3H),3.42–3.38(m,1H),3.30(s,3H),3.18–3.09(m,1H),2.80(ddd,J＝9.7,6.8,5.3Hz,1H),2.62(dd,J＝7.1,2.9Hz,2H),2.51(dd,J＝16.9,4.0Hz,1H),2.42–2.29(m,2H),1.63(s,3H),0.93(d,J＝6.8Hz,3H),0.90–0.87(m,21H),0.05–0.03(m,9H),-0.02(s,3H). 13 C NMR(101MHz,CDCl 3 )δ210.47,149.32,143.35,136.33,134.98,134.92,128.62,124.70,123.66,119.94,117.61,98.41,97.12,86.49,85.89,78.77,63.81,60.29,57.69,56.29,54.17,45.78,37.58,34.70,29.77,26.06,25.99,20.19,18.39,18.34,15.42,12.50,-4.64,-4.80,-5.12,-5.18.
Preparation example 46:
the product of preparation 45 (7.3 g,9.22 mmol) was dissolved in anhydrous diethyl ether (120 mL), argon was purged to 0deg.C, cyclohexene (7.5 mL,73.76 mmol) was added sequentially, 2-methoxypropene (6.7 mL,73.76 mmol) was then added dropwise to zinc borohydride (23 mL,23.06 mmol), the reaction was allowed to proceed to room temperature for 3 hours, TLC was monitored to complete the reaction, saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, diethyl ether was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin-on to obtain a crude flash column chromatography (petroleum ether/ethyl acetate: 5/1) as colorless The product was oily (4.58 g, 63%). 1 H NMR(400MHz,CDCl 3 )δ6.90(t,J＝7.6Hz,1H),6.83(dd,J＝7.5,1.4Hz,1H),6.76(dd,J＝7.8,1.5Hz,1H),5.74(ddt,J＝16.7,10.2,6.4Hz,2H),5.19–5.06(m,7H),4.68(d,J＝6.9Hz,1H),4.57(d,J＝6.9Hz,1H),4.01(d,J＝5.6Hz,1H),3.69(d,J＝6.3Hz,4H),3.64(dd,J＝10.9,3.5Hz,1H),3.57(s,3H),3.47–3.42(m,4H),3.23(dd,J＝9.6,1.7Hz,1H),3.18(s,3H),3.14(dd,J＝9.7,4.4Hz,2H),2.63(d,J＝7.4Hz,2H),2.51(dtd,J＝9.8,6.6,3.2Hz,1H),2.19–2.11(m,1H),1.64(s,3H),1.61–1.51(m,1H),1.12–1.05(m,1H),0.97(d,J＝6.5Hz,3H),0.88(s,21H),0.05(s,3H),0.04(s,6H),0.00(s,3H). 13 C NMR(101MHz,CDCl 3 )δ149.39,143.32,135.73,135.47,135.06,129.37,124.86,123.46,119.58,117.54,99.40,98.34,92.19,85.74,77.80,69.52,63.30,59.83,57.60,55.93,54.20,39.09,37.52,34.84,29.94,26.04,26.01,19.69,18.38,18.36,17.74,13.00,-4.57,-4.77,-5.11,-5.15.
Preparation example 47:
the product of preparation 46 (4 g,5.04 mmol) was dissolved in anhydrous dichloromethane (86 mL), 1, 8-bis-dimethylaminonaphthalene (6.48 g,30.24 mmol) and trimethyloxonium tetrafluoroboric acid (2.24 g,15.12 mmol) were added sequentially at room temperature under argon shield, the reaction was stirred for 3 hours, TLC was monitored to complete the reaction, celite was filtered off, the organic phase was washed sequentially with 0.5N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated brine, anhydrous sodium sulfate, filtered, dried, flash column chromatographed crude (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (3.26 g, 80%). 1 H NMR(400MHz,CDCl 3 )δ6.92(t,J＝7.7Hz,1H),6.83(dd,J＝7.6,1.6Hz,1H),6.77(dd,J＝7.9,1.7Hz,1H),5.75(ddt,J＝16.6,10.2,6.4Hz,2H),5.18–5.08(m,7H),4.83(d,J＝6.6Hz,1H),4.59(d,J＝6.6Hz,1H),4.01(d,J＝5.4Hz,1H),3.69(d,J＝6.4Hz,4H),3.66–3.58(m,2H),3.57(s,3H),3.45(s,3H),3.44–3.40(m,1H),3.39(s,3H),3.28(s,3H),3.23–3.20(m,1H),3.16(ddd,J＝7.3,5.7,3.3Hz,1H),2.67(dd,J＝13.4,5.8Hz,1H),2.59–2.45(m,2H),2.11–1.99(m,1H),1.76(ddd,J＝14.0,10.7,3.1Hz,1H),1.62(d,J＝1.3Hz,3H),1.17(ddd,J＝14.2,10.6,1.8Hz,1H),1.04(d,J＝6.6Hz,3H),0.89(S,9H),0.87(S,9H),0.78(d,J＝6.6Hz,3H),0.06(s,3H),0.02(d,J＝1.0Hz,6H),0.01(s,3H). 13 CNMR(101MHz,CDCl 3 )δ149.27,143.28,135.69,135.41,135.11,130.02,124.76,123.48,119.56,117.52,98.30,97.50,85.97,81.27,79.76,77.82,63.52,59.97,57.62,56.95,56.19,54.17,38.78,36.87,34.47,30.41,26.02,26.02,19.15,18.37,18.34,17.76,13.03,-4.55,-4.75,-5.08,-5.13.
Preparation example 48:
the product of preparation 47 (2.76 g,3.42 mmol) was dissolved in methanol/dichloromethane (1/1) (62 mL), camphorsulfonic acid (284 mg,3.59 mmol) was added and the reaction was stirred at room temperature for 30 min, monitored by TLC for completion, triethylamine (2.85 mL,20.52 mmol) was added to the reaction solution and the reaction was continued for 15 min, and the reaction solution was directly dried by spin-drying, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the product as a colourless oil (1.7 g, 72%). 1H NMR (400 MHz, CDCl) 3 )δ6.92(t,J＝7.7Hz,1H),6.83(d,J＝7.1Hz,1H),6.77(d,J＝7.6Hz,1H),5.74(ddt,J＝16.7,10.3,6.4Hz,2H),5.21–5.08(m,7H),4.80(d,J＝6.6Hz,1H),4.59(d,J＝6.5Hz,1H),4.03(d,J＝7.3Hz,1H),3.69(d,J＝6.3Hz,4H),3.55(d,J＝6.6Hz,5H),3.50(s,3H),3.38(s,3H),3.37–3.32(m,1H),3.30(s,3H),3.26–3.19(m,2H),2.68(dd,J＝13.3,5.8Hz,1H),2.59–2.50(m,2H),2.18(t,J＝6.1Hz,1H),2.03(brs,1H),1.74(ddd,J＝17.5,10.4,5.0Hz,1H),1.61(s,3H),1.21–1.14(m,1H),1.04(d,J＝6.6Hz,3H),0.89(s,9H),0.79(d,J＝6.5Hz,3H),0.08(s,3H),0.01(s,3H). 13 C NMR(101MHz,CDCl 3 )δ149.25,143.27,135.64,135.08,134.61,131.21,124.79,123.50,119.61,117.53,98.31,97.43,84.37,81.13,80.27,79.73,61.77,59.78,57.65,57.07,56.17,54.17,38.70,37.18,34.41,30.51,25.95,19.09,18.27,17.45,12.33,-4.54,-4.76.
Preparation example 49:
the product of preparation 48 (2 g,2.88 mmol) was dissolved in anhydrous dichloromethane (29 mL), dimethylsulfoxide (2.74 mL,21.26 mmol) and diisopropylethylamine (3.5 mL,20.16 mmol) were added, argon was purged, the temperature was lowered to 0℃and the pyridine-sulfur trioxide complex (917 mg,5.76 mmol) was added in portions and the reaction at 0℃was continued for 1 hour. TLC was used to monitor completion of the reaction, water quenching was added to the reaction solution, extraction was performed with methylene chloride, the organic phase was washed with 10% aqueous citric acid, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give a colorless oily aldehyde compound (1.93 g, 97%).
18-crown-6 (3.69 g,13.95 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), argon shielded, cooled to-78deg.C, and potassium bis (trimethylsilyl) amide (4.2 mL,4.2 mmol) was added dropwise and reacted for 15 min. Methyl bis (2, 2-trifluoroethyl) phosphonoacetate P (1.18 mL,5.58 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), and the reaction was continued for 30 minutes after the completion of the dropwise addition. The aldehyde (1.93 g,2.79 mmol) was dissolved in dry tetrahydrofuran (8 mL), added dropwise, the reaction was continued for 1.5 hours after the dropwise addition, TLC monitored the completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried, and the crude product was flash column chromatographed (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (1.9 g, 91%). 1 H NMR(400MHz,CDCl 3 )δ6.91(t,J＝7.7Hz,1H),6.83(dd,J＝7.6,1.5Hz,1H),6.77(dd,J＝7.9,1.5Hz,1H),6.00–5.88(m,2H),5.74(ddt,J＝16.6,10.2,6.4Hz,2H),5.22–5.06(m,7H),4.88(dd,J＝8.9,5.7Hz,1H),4.83(d,J＝6.5Hz,1H),4.59(d,J＝6.5Hz,1H),4.02(d,J＝5.6Hz,1H),3.69(d,J＝6.2Hz,4H),3.66(s,3H),3.59–3.55(m,4H),3.38(s,3H),3.29(s,3H),3.26(s,3H),3.22(d,J＝10.5Hz,1H),2.67(dd,J＝13.4,5.7Hz,1H),2.55(dd,J＝13.4,9.1Hz,1H),2.47(dtt,J＝13.0,9.2,4.7Hz,1H),2.05–1.96(m,1H),1.75(ddd,J＝14.0,10.6,3.1Hz,1H),1.62(s,3H),1.21–1.12(m,1H),1.03(d,J＝6.6Hz,3H),0.87(s,9H),0.74(d,J＝6.6Hz,3H),0.03(s,3H),-0.00(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.31,149.25,146.98,143.27,135.75,135.54,135.09,130.92,124.75,123.46,122.14,119.54,117.51,98.28,97.45,81.27,81.25,79.74,79.51,57.62,57.56,56.88,56.16,54.15,51.35,38.75,36.89,34.44,30.49,25.95,19.02,18.39,17.68,12.85,-4.61,-4.69.
Preparation example 50:
the product of preparation 49 (1.83 g,2.45 mmol) was dissolved in anhydrous dichloromethane (25 mL), argon was purged, cooled to-78℃and diisobutylaluminum hydride (6.12 mL,6.12 mmol) was added dropwise, and the reaction was continued for 1 hour. The reaction mixture was stirred vigorously at room temperature until a clear layer was formed, with ethyl acetate (50 mL) and the mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and flash column chromatographed (petroleum ether/ethyl acetate: 5/1) to give the product as a colourless oil (1.66 g, 94%). 1 H NMR(400MHz,CDCl 3 )δ6.92(t,J＝7.7Hz,1H),6.83(dd,J＝7.6,1.5Hz,1H),6.77(dd,J＝7.8,1.6Hz,1H),5.86–5.70(m,3H),5.28–5.23(m,1H),5.16–5.08(m,7H),4.82(d,J＝6.6Hz,1H),4.60(d,J＝6.6Hz,1H),4.22–4.11(m,2H),4.04(d,J＝6.3Hz,1H),3.91(dd,J＝8.5,6.8Hz,1H),3.70(d,J＝6.3Hz,4H),3.56(s,4H),3.38(s,3H),3.29(d,J＝2.5Hz,6H),3.27–3.24(m,1H),2.68(dd,J＝13.4,5.7Hz,1H),2.58–2.42(m,2H),2.20(t,J＝5.9Hz,1H),2.03(brs,1H),1.75(ddd,J＝14.0,10.6,3.3Hz,1H),1.56(s,3H),1.17(ddd,J＝14.0,10.3,1.9Hz,1H),1.03(d,J＝6.7Hz,3H),0.89(s,9H),0.77(d,J＝6.6Hz,3H),0.07(s,3H),0.03(s,3H). 13 C NMR(101MHz,CDCl 3 )δ149.27,143.29,135.69,135.09,134.43,133.17,131.64,129.57,124.74,123.52,119.61,117.55,98.33,97.42,81.12,80.67,79.94,58.87,57.67,56.99,56.91,56.20,54.18,38.65,36.97,34.50,30.51,26.02,19.06,18.49,17.68,12.79,-4.63.
Preparation example 51:
dimethyl sulfoxide (477 μl,212.6 mmol) was dissolved in anhydrous dichloromethane (8 mL), protected by argon, cooled to-78deg.C, oxalyl chloride (379 μl,4.48 mmol) was dissolved in anhydrous dichloromethane (4 mL), added dropwise, reacted for 30 min after the addition, the product of preparation 50 (1.61 g,2.24 mmol) was dissolved in anhydrous dichloromethane (4 mL), added dropwise after the addition, reacted for 1 h, triethylamine (1.87 mL,13.43 mmol) was dissolved in anhydrous dichloromethane (2 mL), added dropwise, the addition was completed, the reaction was continued at room temperature for 30 min after the addition, TLC was monitored to completion, saturated aqueous ammonium chloride solution was added to quench, dichloromethane extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give colorless oily aldehyde compound (1.59 g, 99%).
Aldehyde (1.59 g,2.22 mmol) was directly dissolved in anhydrous toluene (44 mL), under argon protection, ylide reagent S (1.61 g,4.44 mmol) was added and reacted at 80℃for 1 hour, TLC monitored complete reaction, reaction liquid was directly spin-dried, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (1.74 g, 98%). 1 H NMR(400MHz,CDCl 3 )δ7.51(dt,J＝12.1,1.3Hz,1H),6.91(t,J＝7.7Hz,1H),6.79(ddd,J＝18.1,7.7,1.6Hz,2H),6.45(t,J＝11.7Hz,1H),5.74(ddt,J＝16.5,10.2,6.4Hz,2H),5.47(t,J＝10.5Hz,1H),5.17–5.08(m,7H),4.81(d,J＝6.6Hz,1H),4.58(d,J＝6.5Hz,1H),4.21(q,J＝7.1Hz,2H),4.11(dd,J＝9.8,6.7Hz,1H),4.01(d,J＝6.6Hz,1H),3.69(d,J＝6.2Hz,4H),3.57–3.54(m,4H),3.37(s,3H),3.29(s,3H),3.26(s,3H),3.22–3.19(m,1H),2.66(dd,J＝13.4,5.8Hz,1H),2.54(dd,J＝13.4,8.9Hz,1H),2.44(dtd,J＝9.6,6.7,3.1Hz,1H),2.00(dddd,J＝15.8,12.0,7.6,4.6Hz,1H),1.88(d,J＝1.2Hz,3H),1.73(ddd,J＝14.0,10.7,3.1Hz,1H),1.54(d,J＝1.2Hz,3H),1.30(t,J＝7.1Hz,3H),1.17–1.10(m,1H),1.02(d,J＝6.6Hz,3H),0.88–0.86(m,9H),0.72(d,J＝6.6Hz,3H),0.08(s,3H),0.03(s,3H). 13 CNMR(101MHz,CDCl 3 )δ168.36,149.26,143.29,135.70,135.10,134.77,134.72,132.16,131.75,129.63,127.62,124.75,123.47,119.58,117.52,98.29,97.43,81.37,81.23,80.18,79.75,60.81,57.62,56.99,56.87,56.16,54.17,38.79,36.88,34.42,30.49,25.95,19.18,18.38,17.62,14.45,12.79,12.55,-4.54,-4.70.
Preparation example 52:
The product of preparation 51 (1.67 g,2.08 mmol) was dissolved in acetonitrile (73 mL), pyridine/hydrogen fluoride pyridine solution/acetonitrile (1/1/2.5) (73 mL) was added dropwise at room temperature, the reaction was completed for 60 hours, TLC was monitored for completion, the reaction solution was placed in an ice bath, saturated aqueous sodium bicarbonate solution was added dropwise for quenching, ethyl acetate extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the product as a colourless oil (1.4 g, 98%). 1 H NMR(400MHz,CDCl 3 )δ7.47(d,J＝12.4Hz,1H),6.91(t,J＝7.7Hz,1H),6.78(ddd,J＝13.3,7.7,1.4Hz,2H),6.54(t,J＝11.7Hz,1H),5.78–5.69(m,2H),5.49(t,J＝10.5Hz,1H),5.34(d,J＝10.1Hz,1H),5.15–5.09(m,6H),4.77(d,J＝6.6Hz,1H),4.57(d,J＝6.6Hz,1H),4.23–4.13(m,3H),3.90(dd,J＝7.7,1.8Hz,1H),3.69(d,J＝6.3Hz,4H),3.55(s,3H),3.52(dd,J＝8.5,1.9Hz,1H),3.37(s,3H),3.30(s,3H),3.28(s,3H),3.17(d,J＝10.3Hz,1H),2.84(d,J＝2.0Hz,1H),2.65(dd,J＝13.3,5.9Hz,1H),2.55–2.45(m,2H),2.01–1.95(m,1H),1.89(s,3H),1.69(ddd,J＝14.2,10.6,3.3Hz,1H),1.60(s,3H),1.29(t,J＝7.1Hz,3H),1.14(ddd,J＝14.0,10.5,1.8Hz,1H),1.03(d,J＝6.7Hz,3H),0.72(d,J＝6.6Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ168.12,149.25,143.29,135.64,135.08,133.46,133.45,132.68,131.39,130.57,129.00,124.77,123.47,119.61,117.54,98.29,97.41,81.13,80.18,80.05,78.90,60.92,57.62,56.96,56.65,56.13,54.16,38.80,37.09,34.42,30.54,19.18,17.42,14.41,12.95,12.59.
Preparation example 53:
the product of preparation 52 (1.1 g,1.6 mmol) was dissolved in anhydrous dichloromethane (69 mL), N-dimethylbarbituric acid (999 mg,6.4 mmol) and tetrakis triphenylphosphine palladium (370 mg,0.32 mmol) were added sequentially at room temperature, the reaction was completed under argon, the reaction was refluxed for 5 hours, the reaction solution was washed with 0.5N aqueous sodium hydroxide solution, dichloromethane was extracted, the organic phase was dried over sodium sulfate, filtered, dried soon, the crude product was dissolved in methanol/tetrahydrofuran/water (2/2/1) (70.4 mL), lithium hydroxide (958 mg,40 mmol) was added at room temperature, the reaction was completed overnight, sodium dihydrogen phosphate (10% wt,70 mL) was added to the reaction solution, the aqueous phase was adjusted to saturation with solid sodium chloride, the dichloromethane was extracted, the organic phase was dried over sodium sulfate, filtered, dried soon, directly dissolved in anhydrous toluene (702 mL), diisopropylethylamine (2.57 mL) and 2-3 mmol of bis (2-oxo-3 mmol) were added sequentially at room temperature, the aqueous solution was dried over ethyl phosphate (700.4 mL), the aqueous phase was added to dry, the aqueous solution was quenched by saturated aqueous phase was saturated aqueous phase, the aqueous phase was saturated aqueous phase was quenched with diethyl ether (700 mL), the aqueous phase was saturated with water, the aqueous phase was quenched, the aqueous phase was saturated with sodium hydroxide solution was saturated with water, and saturated aqueous phase was concentrated at room temperature, and saturated aqueous phase was filtered. 1/1) to give a pale yellow solid product (745 mg, 83%), the conformational isomerism of the ring-closure product was severe and was directly fed to the next reaction.
The ring-closed product (745 mg,1.327 mmol) was dissolved in anhydrous dichloromethane (33 mL), argon was used to protect, trichloroacetyl isocyanate (307. Mu.L, 2.654 mmol) was added dropwise, after the addition was completed, the reaction was continued for 1 hour, TLC was monitored to complete the reaction, anhydrous methanol (33 mL), potassium carbonate (844 mg,6.1 mmol) was added to the reaction solution, the reaction was shifted to room temperature for 1 hour, TLC was monitored to complete the reaction, water was added to the reaction solution to clarify, dichloromethane extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-drying, crude flash column chromatography (petroleum ether/ethyl acetate: 3/2) to give the pale yellow solid product 16a (788 mg, 84%).
Aluminum trichloride (317 mg,2.68 mmol) was suspended in anhydrous dichloromethane (24 mL), argon was purged, the temperature was lowered to-78 ℃, anisole (29.97 mL,275.7 mmol) was added dropwise, after the addition was completed, the reaction was continued for 5 minutes, and the pale yellow solid product (60 mg,0.099 mmol) was dissolved in anhydrous dichloromethane (3.5 mL) and added dropwiseAfter the completion of the dropwise addition, the reaction mixture was warmed to room temperature over 2 hours, the reaction was continued for 1 hour, TLC was monitored to complete the reaction, the reaction mixture was quenched with 0.5N hydrochloric acid solution and saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, and crude product was flash column chromatographed (petroleum ether/ethyl acetate: 1/1) to give GA-H (35 mg, 69%) as a pale yellow solid product. 1 H NMR(400MHz,DMSO-d6,100℃)δ8.74(s,1H),8.48(brs,1H),7.52(d,J＝7.6Hz,1H),6.81–6.72(m,3H),6.47(t,J＝11.4Hz,1H),6.11(s,2H),5.56–5.46(m,2H),4.90(d,J＝3.7Hz,1H),4.21(dd,J＝9.3,3.6Hz,1H),3.77(s,1H),3.48–3.45(m,1H),3.29(s,3H),3.14(s,4H),2.80(dd,J＝13.3,5.2Hz,1H),2.59–2.52(m,1H),2.40(dd,J＝13.3,6.8Hz,1H),1.96(s,4H),1.56(s,3H),1.53(t,J＝4.7Hz,1H),1.44–1.39(m,1H),0.91(d,J＝6.7Hz,3H),0.88(d,J＝6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6,100℃)δ169.04,155.63,145.92,134.58,132.63,132.26,131.74,128.23,127.78,126.47,126.15,125.00,119.51,118.83,80.71,79.95,78.63,72.70,55.92,55.45,38.51,33.05,32.57,28.27,20.66,13.86,12.24,11.96
Preparation example 54:
5-methyl salicylaldehyde (25 g,183.6 mmol) was dissolved in glacial acetic acid (550 mL), concentrated nitric acid (62 mL) was diluted with glacial acetic acid (62 mL), added dropwise, reacted at room temperature for 1 hour after the addition was completed, TLC monitored the reaction was complete, the reaction solution was directly poured into an ice-water mixture (1L), left to stand for 15 minutes, filtered, the filter cake was washed with a large amount of ice water, the filter cake was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, and spun dry to give a yellow solid product (30.19 g, 91%). 1 H NMR(400MHz,CDCl 3 )δ11.21(s,1H),10.37(s,1H),8.14(s,1H),7.91(s,1H),2.40(s,3H). 13 C NMR(101MHz,CDCl 3 )δ189.43,154.76,137.76,134.99,131.34,130.03,125.28,20.29.
Preparation example 55:
the product of preparation 54 (21 g,116 mmol) was dissolved in anhydrous tetrahydrofuran (928 mL), protected by argon, sodium borohydride (6.96 g,174 mmol) was slowly added, the reaction was carried out at room temperature for 30 min after the addition was completed, bromomethyl ether (18.9 mL,232 mmol) was added dropwise, after the addition was completed, the reaction was continued for 3 h, TLC was monitored for completion, the reaction system was cooled in ice bath, saturated aqueous sodium bicarbonate solution was added dropwise, extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, dried, the crude product was dissolved in tetrahydrofuran (580 mL), sodium borohydride (4.39 g,116 mmol) was slowly added at room temperature, the addition was completed, the reaction was monitored for 1 h, the reaction solution was quenched with acetone, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, dried, and the crude product was flash column chromatographed (petroleum ether/ethyl acetate: 4/1), to give the white solid compound (22.9 g, 87%). 1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝2.2Hz,1H),7.45(d,J＝2.2Hz,1H),5.09(s,2H),4.64(d,J＝6.8Hz,2H),3.62(s,3H),3.25(t,J＝6.8Hz,1H),2.37(s,3H). 13 C NMR(101MHz,CDCl 3 )δ147.49,137.52,135.44,125.13,101.69,60.36,57.89,20.72.
Preparation 56:
the product of preparation 55 (8.8 g,38.75 mmol) was dissolved in dichloromethane (230 mL), argon was used to protect, the temperature was reduced to 0 ℃,2, 6-lutidine (16.25 mL,139.5 mmol) was added, tert-butyldimethyl triflate (26.72 mL,116.25 mmol) was added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 2 hours, TLC was monitored to completion, the reaction solution was washed with 10% aqueous citric acid, dichloromethane was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the compound as a colourless oil (11.5 g, 87%). 1 H NMR(400MHz,CDCl 3 )δ7.53(d,J＝5.5Hz,2H),5.03(s,2H),4.84(s,2H),3.54(s,3H),2.38(s,3H),0.95(s,9H),0.13(s,6H). 13 C NMR(101MHz,CDCl 3 )δ145.62,137.76,134.79,133.10,123.87,101.68,60.14,57.76,26.04,20.99,18.53,-5.21.
Preparation example 57:
the product of preparation 56 (15 g,43.97 mmol) was dissolved in methanol (220 mL), palladium on carbon (1.5 g,10% wt) was added, hydrogen was introduced, the reaction was monitored overnight at room temperature, TLC was complete, the reaction solution was filtered with celite, dried by spinning, the crude product was directly dissolved in anhydrous N, N-dimethylformamide (176 mL), argon was purged, sodium hydride (10.6 g,263.82 mmol) was slowly added, allyl bromide (15.2 mL,175.76 mmol) was added dropwise, after the addition was completed, the reaction was allowed to proceed to room temperature for 4 hours, TLC was monitored to completion, the reaction solution was placed in an ice bath, quenched with saturated aqueous ammonium chloride, extracted with petroleum ether, the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the colorless oily compound (12.6 g, 73%). 1 H NMR(400MHz,CDCl 3 )δ6.97(d,J＝1.2Hz,1H),6.65(d,J＝1.7Hz,1H),5.75(ddt,J＝16.5,10.2,6.3Hz,2H),5.18–5.11(m,6H),4.85(s,2H),3.70(d,J＝6.3Hz,4H),3.55(s,3H),2.29(s,3H),0.97(s,9H),0.13(s,6H). 13 C NMR(101MHz,CDCl 3 )δ144.93,142.46,135.53,135.06,133.38,121.76,121.08,117.49,98.51,60.62,57.63,54.14,26.17,21.55,18.63,-5.14.
Preparation example 58:
the product of preparation 57 (9.4 g,24 mmol) was dissolved in tetrahydrofuran (430 mL), tetrabutylammonium fluoride (28.8 mL,28.8 mmol) was added dropwise at room temperature, the reaction was stirred for 1 hour, TLC monitored for completion, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash columnChromatography (petroleum ether/ethyl acetate: 4/1) gave the compound as a colourless oil (5.99 g, 90%). 1 H NMR(500MHz,CDCl 3 )δ6.80(s,1H),6.71(s,1H),5.79–5.71(m,2H),5.18–5.10(m,6H),4.59(d,J＝6.3Hz,2H),3.70(d,J＝6.2Hz,4H),3.55(s,3H),3.15(t,J＝6.4Hz,1H),2.27(s,3H). 13 C NMR(126MHz,CDCl 3 )δ147.20,142.98,135.32,134.92,134.07,124.30,122.46,117.58,98.79,61.59,57.58,54.10,21.25.
Preparation example 59:
the product of preparation 58 (8.4 g,30.31 mmol) was dissolved in anhydrous dichloromethane (303 mL), displaced by argon, cooled to 0deg.C, triphenylphosphine (11.9 g,45.46 mmol) and N-bromosuccinimide (8.1 g,45.46 mmol) were added sequentially, the reaction was turned to room temperature after the addition was completed for 1 hour, TLC monitored the reaction was complete, the reaction was quenched with copious amounts of water, dichloromethane extracted, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 95/5) to give the compound as a colourless oil (8.74 g, 85%). 1 H NMR(500MHz,CDCl 3 )δ6.85(s,1H),6.69(s,1H),5.79–5.71(m,2H),5.19–5.12(m,6H),4.60(s,2H),3.71(d,J＝6.2Hz,4H),3.62(s,3H),2.26(s,3H). 13 CNMR(126MHz,CDCl 3 )δ146.39,143.35,134.77,133.82,132.04,125.09,123.27,117.75,98.28,57.89,54.02,29.45,21.21.
Preparation example 60:
evans prosthetic group H (5.04 g,21.6 mmol) was dissolved in anhydrous tetrahydrofuran (44 mL), argon was used to protect it, bis (trimethylsilyl) sodium amide (10.8 mL,21.6 mmol) was added dropwise at-78deg.C, the reaction was completed for 30 min, the product of preparation 59 (3.66 g,10.8 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), the dropwise addition was completed, the reaction was continued for 4H, TLC was monitored to be complete, the reaction was completed Saturated aqueous ammonium chloride was added to the solution, quenched until clear, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, the crude product was directly dissolved in tetrahydrofuran/water (3/1) (51 mL), protected by argon, cooled to 0 ℃, sodium borohydride (2.45, 64.8 mmol) was slowly added, the addition was completed, overnight reaction was monitored by TLC, the reaction solution was quenched dropwise with saturated aqueous ammonium chloride until clear, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, and crude product was purified by flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the product as a colourless oil (2.51 g, 73%). 1 H NMR(500MHz,CDCl 3 )δ6.62(d,J＝7.2Hz,2H),5.75(ddt,J＝12.4,10.1,6.4Hz,2H),5.17–5.11(m,6H),3.70(d,J＝6.2Hz,4H),3.57(s,3H),3.41–3.32(m,2H),2.75(dd,J＝13.3,8.0Hz,1H),2.56(dd,J＝13.3,6.1Hz,1H),2.49(s,1H),2.24(s,3H),1.95–1.89(m,1H),0.98(d,J＝6.8Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ146.60,142.91,134.95,134.19,133.34,125.59,120.69,117.59,98.78,66.45,57.97,54.24,37.35,33.55,21.28,17.24.
Preparation example 61:
triphenylphosphine (26.3 g,100.32 mmol) was dissolved in anhydrous dichloromethane (250 mL), argon was used to protect it, imidazole (8.5 g,125.4 mmol) and iodine (28.6 g,112.86 mmol) were added sequentially, the product of preparation 60 (26.7 g,83.6 mmol) was dissolved in anhydrous dichloromethane (84 mL), added dropwise, the reaction was allowed to proceed to room temperature for 1 hour after the dropwise addition, TLC was monitored to complete and the reaction was dried directly as a colorless oily product (31 g, 86%) by flash column chromatography (petroleum ether/ethyl acetate: 95/5). 1 H NMR(500MHz,CDCl 3 )δ6.63(d,J＝11.0Hz,2H),5.76(ddt,J＝16.6,10.3,6.3Hz,2H),5.16–5.07(m,6H),3.70(d,J＝6.3Hz,4H),3.57(s,3H),3.28(dd,J＝9.6,4.2Hz,1H),3.12(dd,J＝9.5,6.4Hz,1H),2.67–2.59(m,2H),2.25(s,3H),1.91–1.85(m,1H),1.01(d,J＝6.5Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ146.90,143.06,135.08,133.89,133.04,125.22,120.85,117.52,98.49,57.75,54.15,37.64,35.84,21.30,21.03,18.11.
Preparation example 62:
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the product of preparation 61 (30 g,69.9 mmol) was dissolved in N, N-dimethylformamide (350 mL), sodium salt of benzene sulfinate (23 g,139.8 mmol) was added and reacted overnight at room temperature, TLC monitored a small amount of starting material remaining, quenched with water, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spinning, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (27.4 g, 88%). 1 H NMR(500MHz,CDCl 3 )δ7.81(d,J＝7.6Hz,2H),7.59(t,J＝7.1Hz,1H),7.49(t,J＝7.0Hz,2H),6.57(s,1H),6.44(s,1H),5.72(dq,J＝16.1,7.2,6.1Hz,2H),5.14–5.09(m,4H),5.00(d,J＝4.8Hz,2H),3.64(d,J＝5.0Hz,4H),3.48(s,3H),3.15(d,J＝14.2Hz,1H),2.92(dd,J＝13.5,9.8Hz,1H),2.63(dt,J＝20.1,11.0Hz,2H),2.35(s,1H),2.18(s,3H),1.13(d,J＝5.3Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ146.83,143.04,140.15,134.94,133.40,133.19,132.85,129.21,127.89,124.94,121.01,117.58,98.44,61.50,57.64,54.09,37.57,30.22,21.27,20.18.
Preparation example 63:
diisopropylamine (2.8 mL,20.22 mmol) was dissolved in anhydrous tetrahydrofuran (162 mL), argon was used to protect the reaction, n-butyllithium (8.43 mL,20.22 mmol) was added dropwise to the reaction mixture, the reaction was carried out for 30 min, the product of preparation 62 (8.96 g,20.22 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), the product of preparation 15 (6.8 g,13.48 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and added dropwise to the reaction mixture, the reaction was continued for 1 h after the dropwise addition, TLC was monitored to completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with diethyl ether, the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-on, and the crude product was purified by flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give a colorless oily product (11.32 g, 89%).
Preparation example 64:
the product of preparation 63 (12 g,12.72 mmol) was dissolved in dichloromethane (127 mL), argon protected, cooled to 0deg.C, sodium bicarbonate (4.27 g,50.88 mmol) and Dess-Martin oxidant (5.4 g,19.08 mmol) were added sequentially, the reaction was allowed to proceed to room temperature for 1 h, TLC monitored to completion, the reaction was quenched with saturated aqueous sodium thiosulfate, extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to afford the product as a colourless oil (9.6 g, 80%).
Preparation example 65:
the product of preparation 64 (8.96 g,9.48 mmol) was dissolved in anhydrous methanol/anhydrous tetrahydrofuran (3/2) (76 mL), argon protected, cooled to-78deg.C, samarium iodide (200 mL) was added dropwise until the reaction became green, TLC monitored the reaction was complete, the reaction was quenched with a large amount of saturated aqueous potassium sodium tartrate solution, stirred vigorously at room temperature for 1 hour, extracted with diethyl ether, the organic phase dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give the product as a colourless oil (6 g, 83%). 1 H NMR(500MHz,CDCl 3 )δ6.62(s,1H),6.58(s,1H),5.74(ddt,J＝12.4,10.0,6.2Hz,2H),5.32–5.07(m,7H),4.56(d,J＝6.7Hz,2H),3.93(dd,J＝13.1,6.2Hz,1H),3.80–3.73(m,1H),3.68(d,J＝6.1Hz,4H),3.59–3.53(m,4H),3.47–3.40(m,4H),3.33(d,J＝19.9Hz,3H),3.14(ddt,J＝20.6,6.1,3.4Hz,1H),2.85–2.76(m,1H),2.62–2.50(m,3H),2.43–2.29(m,2H),2.22(s,3H),1.64(s,3H),0.93(d,J＝6.7Hz,3H),0.89(d,J＝6.6Hz,21H),0.05–0.04(m,9H),-0.02(s,3H). 13 C NMR(101MHz,CDCl 3 )δ210.54,146.86,143.00,136.31,135.08,134.47,132.95,128.67,125.16,120.54,117.51,100.07,98.42,97.12,86.47,85.89,78.78,63.81,60.29,57.66,56.28,54.10,45.78,37.50,34.68,29.86,26.05,25.98,21.29,20.19,18.39,18.34,15.37,12.48,-4.64,-4.80,-5.12,-5.18.
Preparation example 66:
the product of preparation 65 (5.2 g,6.46 mmol) was dissolved in anhydrous diethyl ether (84 mL), argon was purged to 0deg.C, cyclohexene (5.24 mL,51.68 mmol), 2-methoxypropene (4.72 mL,51.68 mmol) was added sequentially, then zinc borohydride (16.15 mL,16.15 mmol) was added dropwise, the reaction was allowed to proceed to room temperature for 3 hours after the dropwise addition, TLC monitored to completion, saturated aqueous ammonium chloride was added dropwise to the reaction solution to quench the reaction, diethyl ether was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 5/1) to give the product as a colourless oil (3.34 g, 64%). 1 H NMR(400MHz,CDCl 3 )δ6.64(s,1H),6.55(s,1H),5.74(ddt,J＝16.7,10.3,6.3Hz,2H),5.20–5.02(m,7H),4.70(d,J＝6.8Hz,1H),4.58(d,J＝6.8Hz,1H),4.01(d,J＝5.6Hz,1H),3.68(d,J＝6.3Hz,4H),3.64(dd,J＝11.1,3.4Hz,1H),3.56(s,3H),3.47–3.42(m,4H),3.26–3.22(m,1H),3.20(s,3H),3.15(td,J＝10.1,8.3,4.5Hz,2H),2.58(d,J＝7.2Hz,2H),2.52(td,J＝9.7,6.6Hz,1H),2.21(s,3H),2.18–2.09(m,1H),1.64(s,3H),1.60–1.52(m,1H),1.14–1.03(m,1H),0.97(d,J＝6.5Hz,3H),0.88(s,21H),0.05(s,3H),0.04(s,6H),0.00(s,3H). 13 C NMR(101MHz,CDCl 3 )δ146.93,142.98,135.46,135.27,135.15,132.68,129.37,125.25,120.16,117.43,99.40,98.36,92.17,85.73,77.81,69.57,63.30,59.83,57.57,55.86,54.12,38.98,37.63,34.83,30.01,26.04,26.01,21.28,19.63,18.37,18.36,17.73,12.99,-4.57,-4.77,-5.11,-5.15.
Preparation 67:
the product of preparation 66 (365 mg,0.452 mmol) was dissolved in anhydrous dichloromethane (7.7 mL), 1, 8-bis-dimethylaminonaphthalene (581 mg, 2.719mmol) and trimethyloxonium tetrafluoroborate (200 mg,1.356 mmol) were added sequentially under argon at room temperature, the reaction was stirred for 3 hours, TLC was monitored to complete, the reaction was filtered through celite, the organic phase was dried sequentially with 0.5N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated brine, anhydrous sodium sulfate, filtered, dried, and crude flash column chromatography (petroleum ether/ethyl acetate: 9/1) gave the product as a colorless oil (315 mg, 85%). 1 H NMR(400MHz,CDCl 3 )δ6.64(s,1H),6.56(s,1H),5.75(ddt,J＝16.7,10.1,6.3Hz,2H),5.19–5.04(m,7H),4.84(d,J＝6.6Hz,1H),4.60(d,J＝6.6Hz,1H),4.01(d,J＝5.7Hz,1H),3.69(d,J＝6.1Hz,4H),3.64–3.58(m,2H),3.56(s,3H),3.45(s,3H),3.45–3.43(m,1H),3.39(s,3H),3.29(s,3H),3.22(d,J＝10.5Hz,1H),3.16(td,J＝7.2,3.3Hz,1H),2.62(dd,J＝13.3,5.6Hz,1H),2.55–2.48(m,2H),2.22(s,3H),2.01(tdt,J＝12.1,9.5,4.0Hz,1H),1.77(ddd,J＝13.8,10.7,2.9Hz,1H),1.63(s,3H),1.21–1.14(m,1H),1.04(d,J＝6.6Hz,3H),0.88(d,J＝6.8Hz,18H),0.77(d,J＝6.5Hz,3H),0.07(s,3H),0.03(s,6H),0.01(s,3H). 13 C NMR(101MHz,CDCl 3 )δ146.81,142.93,135.40,135.25,135.21,132.71,130.02,125.23,120.16,117.41,98.31,97.51,85.96,81.29,79.77,77.83,63.52,59.97,57.59,56.95,56.18,54.10,38.75,36.95,34.47,30.53,26.03,26.02,21.32,19.11,18.37,18.34,17.76,13.02,-4.54,-4.75,-5.08,-5.13.
Preparation example 68:
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the product of preparation 67 (315 mg,0.383 mmol) was dissolved in methanol/dichloromethane (1/1) (6.9 mL), camphorsulfonic acid (93.5 mg,0.403 mmol) was added and the reaction was stirred at room temperature for 30 min, monitored by TLC to complete the reaction, triethylamine (319. Mu.L, 2.298 mmol) was added to the reaction solution and the reaction was continued for 15 min and the reaction solution was dried directly by flash chromatography (petroleum ether/ethyl acetate: 4/1) to give the product as a colourless oil (210 mg, 77%). 1 H NMR(400MHz,CDCl 3 )δ6.64(d,J＝1.6Hz,1H),6.56(d,J＝1.9Hz,1H),5.80–5.69(m,2H),5.22–5.05(m,7H),4.81(d,J＝6.6Hz,1H),4.60(d,J＝6.6Hz,1H),4.04(d,J＝7.2Hz,1H),3.69(d,J＝6.3Hz,4H),3.59–3.53(m,5H),3.50(s,3H),3.39(s,3H),3.37–3.32(m,1H),3.30(s,3H),3.23(ddt,J＝8.8,7.0,3.0Hz,2H),2.62(dd,J＝13.3,5.7Hz,1H),2.53(qd,J＝9.6,9.2,7.1Hz,2H),2.22(s,3H),2.20–2.15(m,1H),2.05–1.96(m,1H),1.75(ddd,J＝14.1,10.6,3.4Hz,1H),1.61(d,J＝1.1Hz,3H),1.18(ddd,J＝14.1,10.4,1.9Hz,1H),1.05(d,J＝6.7Hz,3H),0.89(s,9H),0.79(d,J＝6.6Hz,3H),0.08(s,3H),0.02(s,3H). 13 C NMR(101MHz,CDCl 3 )δ146.79,142.93,135.20,135.19,134.61,132.75,131.22,125.26,120.21,117.42,98.32,97.44,84.36,81.16,80.27,79.75,61.77,59.78,57.63,57.07,56.17,54.11,38.66,37.28,34.41,30.64,25.95,21.31,19.05,18.28,17.46,12.32,-4.54,-4.76.
Preparation example 69:
the product of preparation 68 (1.86 g,2.63 mmol) was dissolved in anhydrous dichloromethane (26 mL), dimethylsulfoxide (2.5 mL,212.6 mmol) and diisopropylethylamine (3.2 mL,18.41 mmol) were added, argon was purged, the temperature was lowered to 0℃and the pyridine-trioxide complex (837 mg,5.26 mmol) was added in portions and the reaction was continued at 0℃for 1 hour. TLC was used to monitor completion of the reaction, water quenching was added to the reaction solution, extraction was performed with methylene chloride, the organic phase was washed with 10% aqueous citric acid, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate: 9/1) to give a colorless oily aldehyde compound (1.84 g, 99%).
18-crown-6 (3.45 g,13.04 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), argon shielded, cooled to-78deg.C, and potassium bis (trimethylsilyl) amide (3.9 mL,3.9 mmol) was added dropwise and reacted for 15 min. Methyl bis (2, 2-trifluoroethyl) phosphonoacetate P (1.1 mL,5.22 mmol) was dissolved in anhydrous tetrahydrofuran (7 mL), and the reaction was continued for 30 minutes after the completion of the dropwise addition. The aldehyde compound (1.84 g,2.61 mmol) was dissolved in anhydrous tetrahydrofuran The reaction was continued for 1.5 hours after the dropwise addition of the pyran (7 mL), and the TLC was monitored to completion, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude product as a colorless oily product (1.85 g, 93%) by flash column chromatography (petroleum ether/ethyl acetate: 9/1). 1 H NMR(400MHz,CDCl 3 )δ6.64(d,J＝1.8Hz,1H),6.56(d,J＝1.7Hz,1H),5.99–5.89(m,2H),5.74(ddt,J＝16.6,10.2,6.4Hz,2H),5.21–5.05(m,7H),4.88(dd,J＝8.9,5.6Hz,1H),4.84(d,J＝6.6Hz,1H),4.59(d,J＝6.5Hz,1H),4.02(d,J＝5.5Hz,1H),3.69–3.67(m,4H),3.66(s,3H),3.60–3.57(m,1H),3.55(s,3H),3.39(s,3H),3.30(s,3H),3.27(s,3H),3.22(d,J＝10.9Hz,1H),2.61(dd,J＝13.3,5.6Hz,1H),2.54–2.45(m,2H),2.22(s,3H),1.98(ttd,J＝9.3,4.6,3.9,1.9Hz,1H),1.75(ddd,J＝14.2,10.8,3.3Hz,1H),1.62(d,J＝1.2Hz,3H),1.17(ddd,J＝14.3,10.4,1.7Hz,1H),1.03(d,J＝6.6Hz,3H),0.87(s,9H),0.73(d,J＝6.6Hz,3H),0.03(s,3H),0.00(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.32,146.99,146.79,142.93,135.54,135.31,135.19,132.71,130.91,125.22,122.14,120.14,117.41,98.30,97.45,81.29,81.24,79.76,79.52,57.60,57.56,56.89,56.16,54.09,51.35,38.71,36.98,34.45,30.62,25.95,21.31,18.97,18.39,17.68,12.85,-4.61,-4.69.
Preparation example 70:
the product of preparation 69 (1.78 g,2.34 mmol) was dissolved in anhydrous dichloromethane (23 mL), argon shielded, cooled to-78deg.C, diisobutylaluminum hydride (5.85 mL,5.85 mmol) was added dropwise, and the reaction was continued for 1 hour after the addition. TLC was used to monitor the completion of the reaction, and the reaction mixture was stirred vigorously at room temperature with a large amount of saturated aqueous potassium sodium tartrate and ethyl acetate (50 mL) until the layers became clear, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and spun-dried to give the crude product as a colourless oil by flash column chromatography (petroleum ether/ethyl acetate: 5/1) (1.58 g, 92%). 1 H NMR(400MHz,CDCl 3 )δ6.64(d,J＝1.6Hz,1H),6.56(d,J＝1.6Hz,1H),5.87–5.80(m,1H),5.78–5.70(m,2H),5.28–5.23(m,1H),5.16–5.04(m,7H),4.83(d,J＝6.6Hz,1H),4.61(d,J＝6.6Hz,1H),4.16(d,J＝4.0Hz,1H),4.04(d,J＝6.2Hz,1H),3.93–3.89(m,1H),3.68(d,J＝5.7Hz,4H),3.60–3.56(m,1H),3.56(s,3H),3.39(s,3H),3.30(s,3H),3.29(s,3H),3.27–3.24(m,1H),2.62(dd,J＝13.3,5.5Hz,1H),2.54–2.45(m,2H),2.22(s,3H),2.05–1.96(m,1H),1.76(ddd,J＝14.1,10.7,3.3Hz,1H),1.66(s,1H),1.56(d,J＝1.2Hz,3H),1.17(ddd,J＝14.0,10.5,1.9Hz,1H),1.03(d,J＝6.6Hz,3H),0.89(s,9H),0.77(d,J＝6.5Hz,3H),0.07(s,3H),0.03(s,3H). 13 C NMR(101MHz,CDCl 3 )δ146.80,142.94,135.25,135.18,134.44,133.19,132.79,131.62,129.54,125.20,120.22,117.45,98.34,97.42,81.13,80.66,79.93,58.87,57.64,56.98,56.91,56.19,54.12,38.61,37.05,34.49,30.62,26.02,21.32,19.01,18.48,17.69,12.77,-4.63
Preparation example 71:
dimethyl sulfoxide (439 μl,6.18 mmol) was dissolved in anhydrous dichloromethane (8 mL), argon was used to protect, the temperature was reduced to-78 ℃, oxalyl chloride (349 μl,4.12 mmol) was dissolved in anhydrous dichloromethane (4 mL), dropwise added, the reaction was completed for 30 minutes, the product of preparation 70 (1.51 g,2.06 mmol) was dissolved in anhydrous dichloromethane (4 mL), dropwise added, after the completion of the reaction for 1 hour, triethylamine (1.25 mL,12.36 mmol) was dissolved in anhydrous dichloromethane (2 mL), dropwise added, the dropwise addition was completed, the reaction was continued at room temperature for 30 minutes, TLC was monitored to completion the reaction, saturated aqueous ammonium chloride solution was added to quench, dichloromethane extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and flash column chromatography (petroleum ether/ethyl acetate: 9/1) was performed to obtain colorless oily aldehyde compound (1.45 g, 96%).
Aldehyde (1.45 g,1.98 mmol) was directly dissolved in anhydrous toluene (40 mL), under the protection of argon, ylide reagent S (1.44 g,3.96 mmol) was added, the reaction was completed by TLC monitoring the reaction at 80℃and the reaction solution was directly spin-dried, crude flash column chromatography (Petroleum ether/ethyl acetate: 9/1) was obtained withoutThe product was obtained as an oil (1.54 g, 96%). 1 H NMR(500MHz,CDCl 3 )δ7.51(d,J＝12.0Hz,1H),6.63(s,1H),6.56(s,1H),6.45(t,J＝11.6Hz,1H),5.79–5.71(m,2H),5.47(t,J＝10.5Hz,1H),5.18–5.05(m,7H),4.82(d,J＝6.5Hz,1H),4.59(d,J＝6.4Hz,1H),4.21(q,J＝7.1Hz,2H),4.12–4.09(m,1H),4.01(d,J＝6.5Hz,1H),3.68(d,J＝5.7Hz,4H),3.56(d,J＝9.5Hz,4H),3.38(s,3H),3.30(s,3H),3.26(s,3H),3.22–3.18(m,1H),2.61(dd,J＝13.2,5.4Hz,1H),2.52–2.42(m,2H),2.22(s,3H),2.00–1.96(m,1H),1.88(s,3H),1.76–1.71(m,1H),1.54(s,3H),1.30(t,J＝7.1Hz,3H),1.16–1.11(m,1H),1.02(d,J＝6.5Hz,3H),0.87(s,9H),0.72(d,J＝6.5Hz,3H),0.08(s,3H),0.03(s,3H). 13 C NMR(126MHz,CDCl 3 )δ168.36,146.83,142.96,135.28,135.22,134.77,134.75,132.71,132.20,131.78,129.63,127.60,125.24,120.20,117.39,98.33,97.45,81.40,81.29,80.24,79.85,60.81,57.59,57.00,56.89,56.16,54.14,38.79,37.01,34.44,30.63,25.97,21.31,19.18,18.39,17.61,14.45,12.80,12.53,-4.52,-4.67.
Preparation example 72:
the product of preparation 71 (1.48 g,1.815 mmol) was dissolved in acetonitrile (64 mL), pyridine/hydrogen fluoride pyridine solution/acetonitrile (1/1/2.5) (64 mL) was added dropwise at room temperature, the reaction was completed for 60 hours, TLC was monitored for completion, the reaction solution was placed in an ice bath, saturated aqueous sodium bicarbonate solution was added dropwise for quenching, ethyl acetate extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-on, crude flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give the product as a colourless oil (1.17 g, 92%). 1 H NMR(400MHz,CDCl 3 )δ7.47(d,J＝12.1Hz,1H),6.67–6.47(m,3H),5.81–5.67(m,2H),5.49(t,J＝10.5Hz,1H),5.34(d,J＝10.6Hz,1H),5.15–5.03(m,6H),4.77(d,J＝6.5Hz,1H),4.57(d,J＝6.5Hz,1H),4.23–4.13(m,3H),3.90(dd,J＝7.7,1.8Hz,1H),3.68(d,J＝6.3Hz,4H),3.55–3.51(m,4H),3.37(s,3H),3.30(s,3H),3.28(s,3H),3.18(dt,J＝10.4,1.9Hz,1H),2.84(d,J＝2.0Hz,1H),2.62–2.45(m,3H),2.22(t,J＝0.6Hz,3H),1.95(s,1H),1.89(d,J＝1.2Hz,3H),1.69(ddd,J＝13.9,10.4,3.2Hz,1H),1.60(d,J＝1.3Hz,3H),1.29(t,J＝7.1Hz,3H),1.13(ddd,J＝14.1,10.5,2.0Hz,1H),1.03(d,J＝6.7Hz,3H),0.71(d,J＝6.6Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ168.11,146.79,142.94,135.20,135.17,133.46,133.44,132.70,132.68,131.39,130.54,128.99,125.25,120.21,117.42,98.29,97.40,81.14,80.18,80.05,78.91,60.91,57.58,56.95,56.64,56.11,54.09,38.77,37.17,34.41,30.64,21.29,19.13,17.42,14.40,12.92,12.56.
Example 73:
the product of preparation 71 (1.3 g,1.85 mmol) was dissolved in anhydrous dichloromethane (80 mL), N-dimethylbarbituric acid (1.16 g,7.41 mmol) and tetrakis triphenylphosphine palladium (428 mg,0.37 mmol) were sequentially added at room temperature, the reaction was monitored by TLC for 5 hours under the protection of argon, the reaction solution was washed with 0.5N aqueous sodium hydroxide solution, dichloromethane was extracted, the organic phase was dried over sodium sulfate, filtered, dried by spin-drying, the crude product was dissolved in methanol/tetrahydrofuran/water (2/2/1) (81 mL), lithium hydroxide (1.11 g,46.25 mmol) was added at room temperature, the reaction was monitored by TLC for completion, sodium dihydrogen phosphate (10% wt,80 mL) was added to the reaction solution, the aqueous phase was adjusted to saturation with solid sodium chloride, the dichloromethane was extracted, the organic phase was dried over sodium sulfate, filtered, dried by spin-drying, directly dissolved in anhydrous toluene (812 mL), diisopropylethylamine (2.972 ℃ C) and bis (2.97 mL) were sequentially added at room temperature, the aqueous phase was added to dry, the aqueous phase was directly quenched by dry-phase was saturated aqueous solution (800.97 mL), the aqueous phase was directly added to water-soluble solution was saturated with water (800 mL), the aqueous phase was saturated solution was directly quenched by dry phase, the aqueous phase was saturated solution was saturated with water, the aqueous phase was saturated solution was distilled, and saturated aqueous solution was directly added to be distilled at room temperature, and saturated aqueous phase was added to water, and saturated solution was saturated.
The ring-closed product (1 g,1.74 mmol) was dissolved in anhydrous dichloromethane (44 mL), argon protected, cooled to 0deg.C, trichloroacetyl isocyanate (403 μL,3.48 mmol) was added dropwise, after the addition was completed, the reaction was continued for 1 hour, TLC monitored to complete the reaction, anhydrous methanol (44 mL), potassium carbonate (1.11 mg,8.0 mmol) was added to the reaction solution, the reaction was shifted to room temperature for 1 hour, TLC monitored to complete the reaction, water was added to the reaction solution until clear, dichloromethane extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spin-drying, crude flash column chromatography (petroleum ether/ethyl acetate: 3/2) to give pale yellow solid product (882 mg, 82%).
Aluminum trichloride (450 mg,3.375 mmol) was suspended in anhydrous dichloromethane (30 mL), argon was used to protect it, anisole (37.8 mL,0.864 mmol) was added dropwise, after the addition was completed, the reaction was continued for 5 min, pale yellow solid product (80 mg,0.125 mmol) was dissolved in anhydrous dichloromethane (4.8 mL), added dropwise, the reaction solution was warmed to room temperature over 2 hours after the addition was completed, the reaction was continued for 1 hour, TLC was monitored to complete the reaction, the reaction solution was quenched with 0.5N hydrochloric acid solution and saturated ammonium chloride solution, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying, crude flash column chromatography (petroleum ether/ethyl acetate: 1/1) to obtain pale yellow solid product GA-Me (50 mg, 71%). 1 H NMR(400MHz,DMSO-d6,100℃)δ8.64(s,1H),8.12(brs,1H),7.26(s,1H),6.65(d,J＝11.3Hz,1H),6.57(d,J＝1.7Hz,1H),6.40(t,J＝11.3Hz,1H),6.05(s,2H),5.47–5.37(m,2H),4.84(d,J＝4.4Hz,1H),4.12(dd,J＝9.4,4.1Hz,1H),3.65(brs,1H),3.41(t,J＝5.4Hz,1H),3.24(s,3H),3.09(s,3H),3.06(q,J＝5.8Hz,1H),2.72(dd,J＝13.3,5.5Hz,1H),2.49–2.44(m,1H),2.31(dd,J＝13.3,6.4Hz,1H),2.15(s,3H),1.91(s,4H),1.47(s,4H),1.30(ddd,J＝14.1,7.0,3.5Hz,1H),0.87–0.81(m,6H). 13 C NMR(101MHz,DMSO-d6,100℃)δ169.25,155.60,143.76,134.72,132.39,132.16,131.43,127.95,127.67,127.50,127.12,126.34,124.61,120.04,80.59,79.97,78.63,72.60,55.88,55.41,38.37,32.67,28.22,20.37,19.90,14.16,12.30,11.69.
Example 74: and (3) screening the in vitro anti-tumor cell activity of the geldanamycin derivative.
The testing method comprises the following steps: the antiproliferative activity of geldanamycin derivatives against common human tumor cell lines was examined using the MTT method. Taking logarithmic growth phasePancreatic enzyme digestion of tumor cells to form a single cell suspension. Counted with blood platelets and diluted to a cell concentration of 6x10 4 Each ml was inoculated into 96-well cell culture plates, 80. Mu.l per well, and 3 wells of cell-free, empty control with the same volume of medium alone for instrument zeroing were additionally provided. Placing at 37deg.C, 5% CO 2 Is incubated for 24 hours, and then 20. Mu.L of the sample diluted with the cell culture medium is added. Meanwhile, 20. Mu.L of diluted geldanamycin was added to the positive control wells, and the negative control wells and the blank control wells were added with the same dilutions of dimethyl sulfoxide and 20. Mu.L of medium, respectively. After further culturing for 72h, the same volume of fresh cell culture medium was replaced. mu.L of MTT solution at a concentration of 5mg/mL was added to each well, and incubated at 37℃for 3 hours, and 100. Mu.L of MTT-stop solution (10% SDS-0.01mol/L HC 1) was added to each well and dissolved overnight. Colorimetric assay by a microplate reader (assay wavelength 590 nm). Inhibition results were according to the formula [ (0 Dc (blank control group) -0Dt (dosing group))]The calculation was performed at 0Dc (blank) x100%, and the specific results are shown in Table 1.
TABLE 1 inhibitory Activity of geldanamycin derivatives against different tumor cell lines
The results shown in Table 1 indicate that the compounds GA-H, GA-Me and GA-Cl all show strong inhibition activity on 6 tumor cells. The activity of the compound GA-H, GA-Me and GA-Cl on A549 is superior to that of geldanamycin, and the activity of the compound GA-H and GA-Cl on U251 is similar to that of geldanamycin.
In conclusion, the compounds GA-H, GA-Me and GA-Cl have remarkable inhibition effect on human lung cancer A549 cells and glioma U251 cells, and have good drug properties.

Claims (7)

1. A geldanamycin compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein: r is hydrogen or halogen, C1-C6 alkyl,
2. the geldanamycin compound of claim 1 or a pharmaceutically acceptable salt thereof,
the method is characterized in that:
r is hydrogen or halogen, C1-C6 saturated alkyl, halogen selected from fluorine, chlorine, bromine and iodine.
3. Geldanamycin derivatives as claimed in claim 2, characterized in that:
r is hydrogen, chlorine or methyl.
4. A geldanamycin derivative according to claim 3 characterized in that: the geldanamycin compound is as follows: 18-deoxyhydroquinone geldanamycin GA-H, 18-chlorohydroquinone geldanamycin GA-Cl and 18-methylhydroquinone geldanamycin GA-Me
5. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a geldanamycin-like compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers.
6. Use of geldanamycin compounds or pharmaceutically acceptable salts thereof as defined in any one of claims 1-5 for the preparation of antitumor drugs.
7. The use according to claim 6, wherein the anti-tumour is selected from lung cancer or human glioma.
CN202211185487.6A 2022-09-26 2022-09-26 Geldanamycin derivatives and application thereof Pending CN117800913A (en)

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