Process for the preparation of triclabendazole

Abstract

The application discloses a synthesis method of Triclabendazole, which comprises the following steps: starting from a compound of formula (11) and a compound of formula (10), a Pictet-Spengler reaction is performed, then intermolecular aldol condensation of a compound of formula (8) and a compound of formula (14) is performed, a fragment connection product of formula (15) is obtained through the reaction, then asymmetric ketal oxidation is performed to obtain a compound of formula (19-II), an intramolecular Stecker reaction is performed to obtain a compound of formula (5), then stereoselective decarboxylation protonation of palladium catalysis is performed to obtain a compound of formula (3), then a protecting group is removed, and an ethyl ester is reduced to obtain a compound of formula (26); then, the Triclabendazole shown in formula (A) is synthesized from the compound of formula (26). The method is mild in conditions, simple in operation, and raw materials are easy to obtain, and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of synthesis, in particular, the present application provides a preparation method of natural product trabectedin. BACKGROUND

[0002] Trabectedin (ET-743) is a complex marine natural product isolated from the Caribbean tunicate Ecteinascidia turbinata. Trabectedin was approved by the European Union and FDA in 2007, 2015 for the treatment of soft tissue sarcoma. As the first modern marine drug, its anti-tumor activity is 10-1000 times higher than that of the currently used first-line anticancer drug paclitaxel, and it is also considered as one of the best drugs for treating ovarian cancer. Spanish PharmaMar company also found that trabectedin has significant inhibitory effect on rectal cancer, breast cancer, lung cancer and melanoma.

[0003]

[0004] In the early stage, the source of trabectedin for activity research is mainly artificial extraction, but its content in nature is extremely low, only one ten millionth, so the chemical synthesis of trabectedin has always been the focus of chemists. As early as 1996, the Corey group realized the first total synthesis of trabectedin with the longest linear step of 36 steps and the total yield of 0.72% (J. Am. Chem. Soc. 1996, 118, 9202). The route involves asymmetric hydrogenation of noble metals, and the production cost is high. The steps of protection and deprotection in this route are 14 steps, accounting for 39% of the total route steps, which seriously affects the step economy of the route. Fuuyama group realized the total synthesis with linear 50 steps, total steps up to 63 steps and total yield of 0.56% (J. Am. Chem. Soc. 2002, 124, 6552), and the long synthesis route seriously restricts the application of the route. Zhu group, linear step 31 steps, total yield 1.7% (J. Am. Chem. Soc. 2006, 128, 87). Among them, C1 chiral exists chiral impurities, diastereoselectivity is 3:1, and the route economy is poor. At present, the source of the drug is to use safracin B obtained by fermentation as the starting material. After 22 steps, trabectedin is obtained with a total yield of only 1%. The raw material of this route is expensive, and toxic potassium cyanide or sodium cyanide is used in the reaction process, which is not conducive to labor protection. Therefore, it is urgent to develop a more concise and efficient route. SUMMARY

[0005] The present application provides a simple and efficient synthesis route of trabectedin of formula (A), which is simple in reaction operation and easy to scale up.

[0006] In the synthetic method of the present application, the compound (12) is obtained by intermolecular cyclization of the compound (11) with the compound (10) under acidic conditions, the compound (14) is obtained by hydroxyl and amino protection and ring opening of the compound (12), the compound (15) is prepared by intermolecular condensation reaction of (14) with (8), the compound (19-I) is obtained by removal of the protecting group and reductive amination of the compound (15), and then the compound (19-II) is obtained by intermolecular cyclization reaction of (19-I) with (6), and then the compound (26) is obtained by diastereoselective decarboxylation and removal of the protecting group. Then, the compound (29) is obtained by establishing a ten-membered sulfur-containing bridge ring from the compound (26), and finally the cyano protection is removed to obtain the trabectedin represented by formula (A).

[0007]

[0008] The reaction route of the method is as follows:

[0009]

[0010] In the synthetic method of the present application, the compound (12) is obtained by intermolecular cyclization of the compound (11) with the compound (10) under acidic conditions, the compound (12) is subjected to functional group transformation, and then intermolecular condensation reaction with 8 to prepare the compound (15), and then intermolecular cyclization reaction with 6 to obtain the compound (20), and then decarboxylation and functional group transformation to obtain the compound (3), so as to realize the synthesis of trabectedin.

[0011] Specifically, the synthetic method of the present application for trabectedin has the following reaction route:

[0012]

[0013] In specific embodiments, the compound of formula (26) is synthesized from the compounds of formula (11) and formula (10) as follows:

[0014] The left and right fragments (compounds 11 and 10) are connected by Pictet-Spengler reaction to construct the first tetrahydroisoquinoline ring as formula (12), and then intermolecular aldol condensation (compounds 8 and 14) to obtain the fragment connection product 15, and then reaction with the asymmetric ketal to obtain the compound 20, and then intramolecular Stecker reaction to construct the key five-ring skeleton shown in formula (5). Then, the palladium-catalyzed asymmetric decarboxylation constructs the compound shown in formula (3), and finally the protecting group is removed and the ester group is reduced to obtain the intermediate formula (26).

[0015]

[0016] Further specifically, the synthetic method of the present application comprises the following steps:

[0017] (a) in an acid, in a first solvent, compound 11 is reacted with compound 10 via Pictet-Spengler reaction to obtain compound 12;

[0018]

[0019] In step (a), the acid includes but is not limited to any one or more of acetic acid, formic acid, trifluoroacetic acid, oxalic acid; preferably, acetic acid.

[0020] In step (a), the first solvent includes but is not limited to any one or more of dichloromethane, trichloromethane, toluene, trifluoroethanol, hexafluoroisopropanol; preferably, trifluoroethanol and dichloromethane, wherein the volume ratio of dichloromethane DCM and trifluoroethanol TFE is 1:1-10; preferably, 1:7.

[0021] In step (a), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0022] In step (a), the time of the reaction is 2h-28h; preferably, 24h.

[0023] In step (a), the molar ratio of compound 11, compound 10 is 1:1-2; preferably, 1:1.1.

[0024] In a preferred example, in step (a), the reaction is carried out in an inert solvent (preferably DCM:TFE=7:1) in the presence of acetic acid and MS at room temperature to obtain compound 12.

[0025] (b) in an amino protecting agent, a base and a second solvent, compound 12 is reacted to obtain compound 12-I:

[0026]

[0027] In step (b), the amino protecting agent includes but is not limited to any one or more of chloroformic acid allyl ester, chloroformic acid isobutyl ester, chloroformic acid benzyl ester; preferably, chloroformic acid allyl ester.

[0028] In step (b), the base includes but is not limited to any one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate; preferably, sodium bicarbonate.

[0029] In step (b), the second solvent includes but is not limited to any one or more of dichloromethane, trichloromethane, acetonitrile; preferably, dichloromethane.

[0030] In step (b), the volume ratio of the second solvent to the saturated aqueous solution of base is 1:1-10; preferably, 1:1.

[0031] In step (b), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0032] In step (b), the time of the reaction is 1-24h; preferably, 24h.

[0033] In step (b), the molar ratio of compound 12 to the amino protecting agent is 1:(1.1-2.0); preferably, 1:1.1.

[0034] In a preferred embodiment, in step (b), the reaction is carried out in DCM / NaHCO3(aq.) with allyl chloroformate at room temperature to obtain compound 12-I.

[0035] (c) reacting with compound 12-I in a phenolic hydroxyl protecting agent, a base, an additive and a third solvent to obtain compound 12-II:

[0036]

[0037] In step (c), the phenolic hydroxyl protecting agent includes but is not limited to any one or more of allyl bromide, homoallyl bromide; preferably, allyl bromide.

[0038] In step (c), the third solvent includes but is not limited to any one or more of dichloromethane, trichloromethane, N,N-dimethylformamide; preferably, N,N-dimethylformamide.

[0039] In step (c), the base includes but is not limited to any one or more of cesium carbonate, sodium bicarbonate, sodium carbonate, sodium sulfate; preferably, cesium carbonate.

[0040] In step (c), the additive includes but is not limited to any one or more of sodium iodide, potassium iodide, etc.; preferably, sodium iodide.

[0041] In step (c), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0042] In step (c), the time of the reaction is 1-5h; preferably, 3h.

[0043] In step (c), the molar ratio of compound 12-I to the phenolic hydroxyl protecting agent, the base, the additive is 1:(1-3):(1-5):(0.05-0.1); preferably, 1:2:3:0.1.

[0044] In one preferred embodiment, the reaction in the step is carried out in N,N- dimethylformamide, cesium carbonate, allyl bromide, sodium iodide at room temperature to obtain compound 12-II.

[0045] (d) reacting compound 12-II with a protecting agent of alkyl alcohol, an activating agent, a base and a fourth solvent to obtain compound 13:

[0046]

[0047] In step (d), the protecting agent of alkyl alcohol includes, but is not limited to, one or more of acetic anhydride, TBSCl, benzoyl chloride; preferably, acetic anhydride.

[0048] In step (d), the base includes, but is not limited to, one or more of piperidine, pyridine, potassium carbonate; preferably, pyridine.

[0049] In step (d), the fourth solvent includes, but is not limited to, one or more of dichloromethane, chloroform, toluene; preferably, dichloromethane.

[0050] In step (d), the activating agent includes one or more of DMAP, potassium iodide, sodium iodide; preferably, DMAP.

[0051] In step (d), the reaction temperature is 10-50°C; preferably, 25°C.

[0052] In step (d), the reaction time is 10 min-1h; preferably, 20 min.

[0053] In step (d), the volume ratio of the protecting agent to the base is (1):(1-5); preferably, 1:2.

[0054] In one preferred embodiment, the reaction in step (d) is carried out in dichloromethane, pyridine, acetic anhydride, DMAP to obtain compound 13.

[0055] (e) reacting compound 13 with an acid under acidic conditions, a catalyst and a fifth solvent to obtain compound 14:

[0056]

[0057] In step (e), the acid includes, but is not limited to, one or more of boron trifluoride etherate, cerium trichloride, zirconium tetrachloride; preferably, cerium trichloride.

[0058] In step (e), the catalyst includes, but is not limited to, one or more of formic acid, acetic acid, oxalic acid; preferably, oxalic acid.

[0059] In step (e), the fifth solvent includes but is not limited to one or more of acetone, dichloromethane, acetonitrile; preferably, acetonitrile.

[0060] In step (e), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0061] In step (e), the time of the reaction is 1-10h; preferably, 2h.

[0062] In step (e), the molar ratio of compound 13 to acid to catalyst is 1:(1-10):(0.05-0.08); preferably, 0.05.

[0063] In a preferred embodiment, in step (e), the reaction is carried out in acetonitrile at room temperature with the addition of cerium chloride heptahydrate to obtain compound 14.

[0064] (f) performing Swern oxidation reaction on compound 14 in a sixth solvent under an activating reagent to obtain compound 14-I:

[0065]

[0066] In step (f), the activating reagent combination is oxalyl chloride / DMSO, trifluoroacetic anhydride / DMSO; preferably, oxalyl chloride / DMSO.

[0067] In step (f), the temperature of the reaction is -78°C-40°C; preferably, -60°C.

[0068] In step (f), the time of the reaction is 10min-1h; preferably, 30min.

[0069] In step (f), the sixth solvent includes but is not limited to one or more of dichloromethane, trichloromethane, toluene; preferably, dichloromethane.

[0070] In step (f), the molar ratio of compound 14 to activating reagent is 1:(1.5-6); preferably, 1:2.2.

[0071] In a preferred embodiment, the reaction is carried out in dichloromethane at -60°C with oxalyl chloride and DMSO to obtain compound 14-I.

[0072] (g) performing reaction on compound 14-I with compound 8 in a seventh solvent to obtain compound 15:

[0073]

[0074] In step (g), the seventh solvent includes but is not limited to dichloromethane / tetrahydrofuran, chloroform / tetrahydrofuran; preferably, dichloromethane / tetrahydrofuran.

[0075] In step (g), the ratio of compound 14-I to compound 8 is 1.5:1, 1:1.1, 1:2; preferably, 1:1.1.

[0076] In step (g), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0077] In step (g), the time of the reaction is 1h-24h; preferably, 15h.

[0078] In a preferred embodiment, in step (g), the reaction is carried out in a mixture of dichloromethane and tetrahydrofuran, the ratio of 14-I to 8 is 1:1.1, and the temperature is room temperature, to obtain compound 15.

[0079] (h) deprotection reaction with compound 15 in an eighth solvent, a catalyst, and a proton source to obtain compound 16:

[0080]

[0081] In step (h), the eighth solvent includes but is not limited to one or more of dichloromethane, chloroform, tetrahydrofuran; preferably, dichloromethane.

[0082] In step (h), the catalyst includes but is not limited to one or more of tetrakis triphenylphosphine palladium, dichlorobis triphenylphosphine palladium, palladium acetate; preferably, tetrakis triphenylphosphine palladium.

[0083] In step (h), the proton source is DBA, 1,3-DMBA; preferably, 1,3-DMBA.

[0084] In step (h), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0085] In step (h), the time of the reaction is 1h-10h; preferably, 6h.

[0086] In step (h), the molar ratio of compound 15, catalyst, and proton source is 1:(0.05-0.5):(1-3); preferably, 1:0.2:2.2.

[0087] In a preferred embodiment, in step (h), the reaction is carried out in dichloromethane, tetrakis triphenylphosphine palladium, 1,3-DMBA, to obtain compound 16.

[0088] (i) reacting compound 16 in a ninth solvent, a protecting agent and a base to obtain compound 17:

[0089]

[0090] In step (i), the protecting agent includes, but is not limited to, one or more of bromomethyl methyl ether, allyl chloroformate, allyl bromide; preferably, allyl bromide.

[0091] In step (i), the base includes, but is not limited to, one or more of cesium carbonate, potassium carbonate, sodium bicarbonate; preferably, potassium carbonate.

[0092] In step (i), the ninth solvent includes, but is not limited to, one or more of dichloromethane, toluene, acetone; preferably, acetone.

[0093] In step (i), the molar ratio of compound 16, the protecting agent and the base is 1: (1-5): (1-5); preferably, 1:2:2.5.

[0094] In step (i), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0095] In step (i), the time of the reaction is 1h-24h; preferably, 5h.

[0096] In a preferred embodiment, in step (i), the reaction is carried out in acetone, allyl bromide, potassium carbonate to obtain compound 17.

[0097] (j) dehydroxylating compound 17 in a tenth solvent, a reducing agent and an acid to obtain compound 18:

[0098]

[0099] In step (j), the reducing agent includes, but is not limited to, one or more of sodium borohydride, sodium cyanoborohydride, triethylsilane; preferably, sodium cyanoborohydride.

[0100] In step (j), the acid includes, but is not limited to, one or more of trifluoroacetic acid, boron trifluoride ether, etc.; preferably, boron trifluoride ether.

[0101] In step (j), the tenth solvent includes, but is not limited to, one or more of dichloromethane, chloroform, toluene; preferably, dichloromethane.

[0102] In step (j), the temperature of the reaction is 0-50°C; preferably, 25°C.

[0103] In step (j), the time of the reaction is 20min-2h; preferably, 0.5h.

[0104] In step (j), the molar ratio of compound 17, reducing agent and acid is 1 : (1-5) : (1-10); preferably, 1 : 5 : 2.

[0105] In a preferred embodiment, in step (j), the reaction is carried out in boron trifluoride diethyl ether complex, diethylsilane, dichloromethane at 0°C to obtain compound 18.

[0106] (k) methylating compound 18 with a methyl source in an eleventh solvent to obtain compound 19:

[0107]

[0108] In step (k), the methyl source used in the methylating reaction is formaldehyde solution (36%).

[0109] In step (k), the eleventh solvent includes but is not limited to one or more of methanol, acetonitrile, tetrahydrofuran, dichloromethane; preferably, tetrahydrofuran and acetonitrile.

[0110] In step (k), the reaction temperature is 10-50°C; preferably, 25°C.

[0111] In step (k), the reaction time is 30 min-2h; preferably, 1h.

[0112] In step (k), the molar ratio of compound 18 and methyl source is 1 : (1-10); preferably, 1 : 5.

[0113] In a preferred embodiment, in step (k), the reaction is carried out in a mixed solvent of acetonitrile and tetrahydrofuran, with formaldehyde solution, sodium cyanoborohydride, acetic acid to obtain compound 19.

[0114] (l) deprotecting compound 19 with an acid in a twelfth solvent to obtain compound 19-I:

[0115]

[0116] In step (l), the acid includes but is not limited to one or more of methanesulfonic acid, trifluoromethanesulfonic acid, hydrobromic acid; preferably, hydrobromic acid.

[0117] In step (l), the twelfth solvent includes but is not limited to one or more of acetic acid, dichloromethane, oxalic acid; preferably, dichloromethane.

[0118] In step (l), the reaction temperature is 0°C-50°C; preferably, 0°C.

[0119] The reaction in step (1) is carried out for 1 h to 10 h; preferably, for 5 h.

[0120] The volume ratio of the acid to the twelfth solvent in step (1) is 1 : (1-5); preferably, 1 : 1.

[0121] In a preferred embodiment, the reaction in step (1) is carried out in dichloromethane in hydrobromic acid to obtain 19-I.

[0122] (m) Pictet-Spengler reaction of compound 19-I with compound 6 in a thirteenth solvent to obtain compound 19-II:

[0123]

[0124] The thirteenth solvent in step (m) includes but is not limited to acetic acid, trifluoroacetic acid, a combination of acetic acid / trifluoroacetic acid; preferably, a combination of acetic acid / trifluoroacetic acid.

[0125] The reaction in step (m) is carried out at a temperature of 10-50 °C; preferably, at 25 °C.

[0126] The reaction in step (m) is carried out for 1 h to 10 h; preferably, for 8 h.

[0127] The molar ratio of compound 19-I to compound 6 in step (m) is 1 : (1:10); preferably, 1 :5.

[0128] In a preferred embodiment, the reaction in step (m) is carried out in acetic acid / trifluoroacetic acid at room temperature to obtain compound 19-II.

[0129] (n) phenolic hydroxyl protection reaction of compound 19-II in a fourteenth solvent to obtain compound 19-III:

[0130]

[0131] The protecting agent used in the phenolic hydroxyl protection reaction in step (n) includes but is not limited to one or more of bromomethyl methyl ether, chloromethyl methyl ether, chloroethoxy ethyl ether; preferably, bromomethyl methyl ether.

[0132] The fourteenth solvent in step (n) includes but is not limited to one or more of tetrahydrofuran, dichloromethane, trichloromethane; preferably, tetrahydrofuran.

[0133] The reaction in step (n) is carried out at a temperature of 10-50 °C; preferably, at 0 °C.

[0134] The reaction time in step (n) is 10 min to 1 h; preferably, 15 min.

[0135] The molar ratio of compound 19-II to the protecting agent in step (n) is 1 : (1-10); preferably, 1 : 8.

[0136] In a preferred embodiment, the reaction in step (n) is carried out in acetic acid / trifluoroacetic acid at room temperature to obtain compound 19-III.

[0137] (o) deprotection reaction with compound 19-III in the presence of a base in a fifteenth solvent to obtain compound 20:

[0138]

[0139] The base in step (o) includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, sodium bicarbonate; preferably, potassium carbonate.

[0140] The fifteenth solvent in step (o) includes, but is not limited to, one or more of methanol, ethanol, acetone; preferably, methanol.

[0141] The reaction temperature in step (o) is 10-50 °C; preferably, 25 °C.

[0142] The reaction time in step (o) is 1 h to 3 h; preferably, 2 h.

[0143] The molar ratio of compound 19-III to the base in step (o) is 1 : (1-3); preferably, 1 : 1.5.

[0144] In a preferred embodiment, the reaction in step (o) is carried out in methanol in the presence of potassium carbonate to obtain compound 20.

[0145] (p) Swern oxidation reaction with compound 20 to obtain compound 20-I:

[0146]

[0147] The combination of activating reagents for the Swern oxidation reaction in step (p) is oxalyl chloride / DMSO, trifluoroacetic anhydride / DMSO; preferably, oxalyl chloride / DMSO.

[0148] The molar ratio of compound 20 to the activating reagent in step (p) is 1 : (1-5); preferably, 1 : 2.

[0149] The reaction temperature in step (p) is -78 °C to 30 °C; preferably, -78 °C.

[0150] In step (p), the reaction time is 1-5 h; preferably, 1.5 h.

[0151] In a preferred embodiment, in step (p), the reaction is carried out at -78°C in oxalyl chloride / DMSO for 1.5 h to obtain compound 20-I.

[0152] (q) carrying out Strecker reaction with compound 20-I in a sixteenth solvent under the action of an activating agent to obtain compound 5:

[0153]

[0154] In step (q), the sixteenth solvent includes but is not limited to one or more of dichloromethane, trichloromethane, diethyl ether; preferably, dichloromethane.

[0155] In step (q), the molar ratio of compound 20-I to the activating agent is 1:1-10; preferably, 1:3.

[0156] In step (q), the reaction temperature is 10-50°C; preferably, 25°C.

[0157] In step (q), the reaction time is 1-5 h; preferably, 3 h.

[0158] In step (q), the activating agent includes but is not limited to one or more of zinc chloride, zinc iodide, zinc bromide; preferably, zinc chloride.

[0159] In a preferred embodiment, the reaction is carried out in DCM under the condition of TMSCN and zinc chloride to obtain compound 5.

[0160] (r) carrying out decarboxylation reaction with compound 5 in a seventeenth solvent under the action of a catalyst and a proton source to obtain compound 3:

[0161]

[0162] In step (r), the catalyst includes but is not limited to one or more of tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium acetate; preferably, tetrakis(triphenylphosphine)palladium.

[0163] In step (r), the proton source includes but is not limited to 1,3-DMBA, DBA, methanol; preferably, DBA.

[0164] In step (r), the seventeenth solvent includes but is not limited to one or more of dichloromethane, methanol, tetrahydrofuran; preferably, tetrahydrofuran.

[0165] In step (r), the temperature of the reaction is 10-50°C; preferably, 25°C.

[0166] In step (r), the reaction time is 1 h-3 h; preferably, 3 h.

[0167] In step (r), the molar ratio of compound 5, catalyst and proton source is 1 : (0.05-0.5) : (1-10); preferably, 1 : 0.2 : 5.

[0168] In a preferred embodiment, in step (r), the reaction is carried out in tetrahydrofuran, with tetrakis triphenylphosphine palladium, dimethyl ketone to obtain compound 3.

[0169] (s) deprotection reaction with compound 3 in the presence of an additive in an eighteenth solvent to obtain compound 3-I:

[0170]

[0171] In step (s), the additive is one or more of, but not limited to, zirconium tetrachloride, p-toluenesulfonic acid, trifluoroacetic acid; preferably, zirconium tetrachloride.

[0172] In step (s), the temperature of the reaction is 0°C-50°C; preferably, 0°C.

[0173] In step (s), the reaction time is 1 h-3 h; preferably, 1 h.

[0174] In step (s), the eighteenth solvent includes, but is not limited to, one or more of dichloromethane, trichloromethane, tetrahydrofuran; preferably, dichloromethane.

[0175] In step (s), the molar ratio of compound 3 to additive is 1 : (1-3); preferably, 1 : 2.

[0176] In a preferred embodiment, in step (s), the reaction is carried out in dichloromethane, zirconium tetrachloride, at 0°C to obtain compound 3-I.

[0177] (t) reduction reaction with compound 3-I in the presence of a reducing agent and an additive in a nineteenth solvent to obtain compound 26:

[0178]

[0179] In step (t), the reducing agent includes, but is not limited to, one or more of sodium borohydride, lithium borohydride, lithium aluminum hydride; preferably, lithium borohydride.

[0180] In step (t), the additive includes but is not limited to one or more of methanol, ethanol; preferably, methanol.

[0181] In step (t), the temperature of the reaction is 0-50℃; preferably, 25℃.

[0182] In step (t), the time of the reaction is 1-5h; preferably, 3h.

[0183] In step (t), the nineteenth solvent includes but is not limited to one or more of tetrahydrofuran, toluene, 1,4-dioxane; preferably, tetrahydrofuran.

[0184] In step (t), the molar ratio of the compound 3-I, the reducing agent, the additive is 1:(1-20):(1-20); preferably, 1:10:10.

[0185] In a preferred embodiment, the reaction is carried out at room temperature with lithium borohydride, methanol, tetrahydrofuran.

[0186] In a specific embodiment, the route for synthesizing Triciribine starting from the intermediate compound of formula (26) is as follows:

[0187]

[0188] Starting from compound (26), referring to the method reported by Ma (Angew. Chem. Int. Ed. 2019, 58, 3972), oxidation generates compound 28 connected with the side chain of cysteine, and the de-sulfur alcohol protection constructs a ten-membered bridge ring. Finally, the Pictet-Spengler reaction is used to construct the tetrahydroisoquinoline ring shown in formula (34), and the cyano group is hydrolyzed to complete the synthesis of Triciribine shown in formula (A).

[0189] The present application also provides a series of new intermediate compounds, the structures of which are shown in the following formula (I), (I-1), (I-2), (I-3), (I-4), (I-5) respectively, which can be applied to the preparation of Triciribine according to the present application:

[0190]

[0191] wherein, R1 is selected from H, Allyl; R2 is selected from H, Me, Alloc, MOM; R3 is selected from H, Ac; R is selected from H, OH.

[0192] Preferably, the intermediate structure includes, but is not limited to, compounds represented by the following formula (12), (12-I), (12-II), (13), (14), (15), (16), (17), (18), (19), (19-II), (19-III), (20), (5), (3), (3-I), and specifically as shown below:

[0193]

[0194] As can be seen above, among the intermediate compounds, general formula (I) includes formula (12), formula (12-I), formula (12-II), and formula (13); general formula (I-1) includes formula (14); general formula (I-2) includes formula (15), formula (16), formula (17), formula (18), and formula (19); general formula (I-3) includes formula (19-II), formula (19-III), and formula (20); general formula (I-4) includes formula (5); and general formula (I-5) includes formula (3-I) and formula (3).

[0195] The present application also provides use of the intermediate compounds in a method for preparing Triciribine.

[0196] The present application has the following beneficial effects: the reaction conditions of the present application are mild, raw materials are easy to obtain, the method is simple and efficient, suitable for large-scale production, the synthesis reaction is simple to operate and easy to scale up, for example, the five-ring intermediate represented by formula (5) can be prepared in gram scale, and the intermediate represented by formula (14) can be prepared in ten gram scale, efficiently solving the problem of large-scale synthesis of raw materials. The construction of C1 chiral center is single selective, avoiding the over-functionalization of the substrate leading to a long route. DETAILED DESCRIPTION

[0197] The present application will be further described below in conjunction with specific examples, which should be understood as merely illustrating the present application and not limiting the scope of the present application. The experimental methods in the following examples, if not specified, are generally carried out under conventional conditions. The present application provides a synthesis method of Triciribine. Compared with the prior art, the present application adopts a direct Pictet-Spengler cyclization reaction in the construction of the key B ring, and a palladium-catalyzed asymmetric decarboxylation reaction in the construction of C1 chirality, avoiding the influence of excessive modification of the substrate on the reaction atom economy and step economy. The late-stage assembly of the five-ring skeleton makes it easier to obtain skeleton analogs in this route to achieve the discovery of potential drug molecules. In addition, the reagents and raw materials used in the route are low in price, easy to obtain, and easy to scale up.

[0198] The synthetic reaction route of the present application specifically comprises the following: firstly, starting from the compound of formula (11) and the compound of formula (10), the intermediate compound of formula (26) is synthesized; then, starting from the compound of formula (26), the target product triclabendazole represented by formula (A) is synthesized.

[0199]

[0200]

[0201] Example 1, synthesis of compound 12

[0202]

[0203] Compound 11 (11.3 g, 53.44 mmol) was dissolved in a mixed solvent of dichloromethane and trifluoroethanol (7:1, 231 mL / 33 mL), and then aldehyde 10 (16.9 g, 64.13 mmol), glacial acetic acid (7.64 mL, 133.6 mmol), molecular sieves (11.3 g) were added, and the reaction was carried out at room temperature for 24 h, and the reaction was monitored by TLC, and then filtered through diatomite, concentrated under reduced pressure, and column chromatography (DCM:MeOH 20:1) to obtain light yellow foam 12 (22.9 g, 94%). Compound 11 (11.3 g, 53.44 mmol) was dissolved in a mixed solvent of dichloromethane and trifluoroethanol (7:1, 231 mL / 33 mL), and then aldehyde 10 (16.9 g, 64.13 mmol), glacial acetic acid (7.64 mL, 133.6 mmol), molecular sieves (11.3 g) were added, and the reaction was carried out at room temperature for 24 h, and the reaction was monitored by TLC, and then filtered through diatomite, concentrated under reduced pressure, and column chromatography (DCM:MeOH 20:1) to obtain light yellow foam 12 (22.9 g, 94%). 1 H NMR (400 MHz, CDCl3) δ 7.49-7.24 (m, 5H), 6.44 (s, 1H), 5.27-5.07 (m, 2H), 4.91 (m, 2H), 3.89-3.60 (m, 6H), 3.52 (d, J = 4.7 Hz, 1H), 2.94 (d, J = 17.4 Hz, 1H), 2.61 (dd, J = 27.4, 14.5 Hz, 1H), 2.47 (dd, J = 15.3, 2.7 Hz, 1H), 2.23 (s, 3H), 1.68 (d, J = 40.7 Hz, 3H), 1.47 (d, J = 30.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 153.5, 152.8, 146.1, 145.6, 143.8, 143.4, 136.5, 136.0, 132.9, 132.3, 129.0, 128.5, 128.4, 128.2, 128.0, 127.7, 122.1, 121.9, 119.7, 119.3, 95.0, 94.3, 67.3, 66.5, 65.8, 64.9, 64.3, 60.6, 60.5, 60.3, 58.8, 53.2, 52.1, 32.3, 26.2, 25.2, 24.4, 23.1, 15.5. HRMS (ESI, m / z): calcd for C 25 H32 N2O6[M+H] + 457.2260, found 457.2260.

[0204] Example 2, synthesis of compound 13

[0205]

[0206] Compound 12 (19.85 g, 43.5 mmol) synthesized in Example 1 of the present application was dissolved in dichloromethane (174 mL), saturated sodium bicarbonate solution (174 mL) was added, followed by the addition of allyl chloroformate (5.1 mL, 47.86 mmol), and the reaction was allowed to proceed at room temperature for 1 h, after which the reaction was monitored by TLC, diluted with dichloromethane, extracted, and the organic phase was separated, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined and washed with water, then saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed (PE:EA 2:1) to give white solid 12-I (20.6 g, 88%). 1 H NMR (400 MHz, CDC13) δ 7.40 - 7.22 (m, 3H), 7.11 (m, 2H), 6.56 (s, 1H), 6.22 (s, 1H), 6.05 - 5.69 (m, 2H), 5.57 - 5.12 (m, 2H), 4.92 (m, 1H), 4.72 - 4.38 (m, 3H), 4.17 (d, J = 9.2 Hz, 1H), 4.05 - 3.85 (m, 3H), 3.85 - 3.75 (m, 1H), 3.75 - 3.60 (m, 5H), 3.39 (m, H), 2.88 (d, J = 8.5 Hz, 1H), 2.63 (d, J = 9.1 Hz, 1H), 2.23 (d, J = 17.7 Hz, 3H), 1.83 (d, J = 42.4 Hz, 3H), 1.48 (d, J = 34.3 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 156.7, 152.4, 145.1, 143.7, 135.9, 132.0, 131.3, 128.9, 127.8, 127.7, 127.6, 120.4, 116.6, 95.2, 66.1, 65.3, 65.1, 60.3, 59.0, 58.2, 55.0, 51.2, 29.3, 26.1, 22.8, 15.4. HRMS (ESI, m / z): calcd for C 29 H 36 N2O8[M+H] + 541.2472, found 541.2477.

[0207] The white solid 12-I (18.22 g, 33.73 mmol) from previous step was dissolved in DMF (135 mL), potassium carbonate (9.3 g, 67.46 mmol), sodium iodide (506 mg, 3.37 mmol), allyl bromide (8.76 mL, 101.2 mmol) were added successively and stirred at room temperature for 3 h, TLC monitored the completion of the reaction, quenched the reaction with water, diluted with ethyl acetate, extracted, combined the organic phase, washed with water three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography (PE:EA 2:1) to give pale yellow oil 12-II (16.5 g, 85%). 1 H NMR (400 MHz, CDC13) δ 7.34 - 7.23 (m, 3H), 7.21 - 7.03 (m, 2H), 6.57 (d, 1H), 6.06 (d, J = 6.2 Hz, 1H), 5.92 (ddd, J = 15.8, 10.2, 5.0 Hz, 1H), 5.70 (d, J = 10.1 Hz, 1H), 5.53 - 5.13 (m, 4H), 4.97 - 4.74 (m, 1H), 4.74 - 4.44 (m, 3H), 4.42 - 4.21 (m, 2H), 4.11 (d, J = 9.2 Hz, 1H), 3.94 (m, 2H), 3.87 (dd, J = 10.9, 3.6 Hz, 1H), 3.83 - 3.69 (m, 3H), 3.63 (m, 1H), 3.03 - 2.68 (m, 2H), 2.60 (dd, J = 15.4, 6.6 Hz, 1H), 2.20 (d, 3H), 1.80 (d, 3H), 1.44 (d, 3H). 13 C NMR (100 MHz, CDC13) δ 157.0, 153.4, 152.2, 149.5, 149.3, 147.9, 136.1, 134.2, 134.1, 132.1, 131.2, 131.0, 130.7, 128.4, 128.1, 127.9, 127.7, 124.6, 117.9, 117.8, 95.6, 95.1, 74.3, 66.8, 66.6, 66.3, 65.5, 65.3, 60.3, 59.8, 58.8, 58.0, 55.3, 52.5, 52.1, 29.8, 29.5, 27.0, 26.3, 24.4, 22.9, 15.7, 15.6. HRMS (ESI, m / z): calcd for C 32 H 40 N2O8[M+H] + 581.2785, found 581.2786.

[0208] The yellow oil 12-II (19.8 g, 34.1 mmol) from the previous step was dissolved in dichloromethane (134 mL), pyridine (26 mL), DMAP (205 mg), and acetic anhydride (13 mL) were added successively. After the reaction was completed by TLC monitoring at room temperature for 20 min, 1 N hydrochloric acid solution was added to adjust the pH to 1-2, dichloromethane was added for extraction, the organic phase was separated, the aqueous phase was extracted with dichloromethane three times, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA 4:1) was performed to obtain a light yellow oil 13 (20.8 g, 97%). 1 H NMR (400 MHz, CDC13) δ 7.34 - 7.26 (m, 3H), 7.21 - 7.01 (m, 2H), 6.56 (d, 1H), 6.06 (s, 1H), 5.99 - 5.83 (m, 1H), 5.69 (s, 1H), 5.54 - 5.10 (m, 4H), 4.99 - 4.74 (m, 1.42H), 4.72-4.45 (m, 3.58H), 4.42 - 4.20 (m, 4H), 4.10 (m, 2H), 3.94 (dd, J = 9.0, 5.1 Hz, 1H), 3.85 - 3.67 (m, 3H), 3.63 (s, 1H), 3.24 (t, J = 13.8 Hz, 0.28H), 2.93 - 2.66 (m, 1H), 2.52 (dd, J = 15.4, 6.7 Hz, 1H), 2.20 (m, 3H), 2.06 (m, 3H), 1.80 (m, 3H), 1.45 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 170.4, 170.3, 155.8, 153.4, 152.1, 149.7, 147.9, 136.1, 136.0, 134.2, 134.0, 132.1, 130.9, 130.6, 128.3, 128.1, 127.9, 127.8, 127.7, 124.4, 118.0, 117.69, 95.6, 95.1, 74.4, 66.7, 66.4, 66.2, 65.5, 65.3, 60.3, 59.8, 58.8, 58.1, 52.4, 52.0, 29.4, 27.0, 26.2, 24.3, 22.8, 20.8, 20.7, 15.7, 15.6. HRMS (ESI, m / z): calcd for C 34 H 42 N2O9[M+H] + 623.2890, found 623.8995.

[0209] Example 3, synthesis of compound 14

[0210]

[0211] Compound 13 (21 g, 33.75 mmol) synthesized in Example 2 was dissolved in acetonitrile (135 mL), oxalic acid (231 mg, 1.69 mmol), cerium trichloride heptahydrate (25.15 g, 67.5 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed as determined by TLC, the reaction solution was cooled to 0 °C, and sodium bicarbonate was added. After 15 min, diatomite was added for filtration, and the filtrate was concentrated under reduced pressure. Column chromatography (PE:EA 2:1) gave compound 14 (18.5 g, 94%) as a colorless oil. 1 HNMR (400 MHz, CDC13) δ 7.34 - 7.22 (m, 3H), 7.19 - 7.06 (m, 2H), 6.60-6.78 (d, 1H), 6.07 (ddd, J = 16.2, 10.7, 5.4 Hz, 1H), 5.92 (ddd, J = 16.2, 10.7, 5.4 Hz, 1H), 5.73 (t, J = 11.7 Hz, 1H), 5.30 (m, 4H), 4.92 - 4.80 (m, 2H), 4.67 (m, 3H), 4.56 - 4.36 (m, 2H), 4.28 (d, J = 11.2 Hz, 1H), 4.16 (m, 1H), 4.02 (t, J = 10.5 Hz, 1H), 3.92 (dd, J = 12.1, 1.8 Hz, 1H), 3.88 - 3.66 (m, 2H), 3.60 (s, 3H), 3.19 (dd, J = 15.0, 12.7 Hz, 1H), 2.80 (dd, J = 15.5, 6.4 Hz, 1H), 2.25 (d, 3H), 2.14 (s, 2.76H), 1.89 (s, 0.36H). 13 C NMR (100 MHz, CDC13) δ 170.6, 157.6, 155.9, 149.4, 147.6, 136.5, 133.7, 131.9, 131.7, 129.3, 128.2, 128.0, 127.7, 127.4, 126.6, 124.7, 118.6, 117.9, 73.6, 67.2, 66.1, 65.3, 61.6, 59.7, 54.5, 52.1, 49.7, 29.3, 20.7, 15.7. HRMS (ESI, m / z): calcd for C 31 H 38 N2O9[M+H] + 584.2577, found 584.2579.

[0212] Example 4, synthesis of compound 15

[0213]

[0214] Add oxalyl chloride (6.1 mL, 12.27 mmol) to dichloromethane (120 mL), slowly add dimethyl sulfoxide (10.3 mL, 144.54 mmol) to the reaction at -60 °C, react for 15 min at -60 °C, slowly add a solution of compound 14 (19.2 g, 32.9 mmol) synthesized in Example 3 of the present invention in dichloromethane (30 mL) to the reaction, then warm to -40 °C and react for 30 min, then add triethylamine (20.55 mL, 147.8 mmol) and stir for 10 min at room temperature. Quench the reaction by adding water, dilute with dichloromethane, extract, separate the organic phase, extract the aqueous phase with dichloromethane three times, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 14-I, which is used directly in the next step without purification.

[0215] Dissolve the white solid 8 (369 mg, 2.4 mmol) in tetrahydrofuran (5 mL), slowly add a solution of methyl magnesium bromide in tetrahydrofuran (3 M, 807 μL, 2.4 mmol), after stirring for 15 min at room temperature, slowly add a solution of aldehyde 14-I (1.3 g, 2.2 mmol) in dichloromethane (6 mL) to the reaction, react for 15 h at room temperature, monitor the reaction by TLC, when the reaction is complete, quench the reaction by adding saturated ammonium chloride, dilute with dichloromethane, extract, separate the organic phase, extract the aqueous phase with dichloromethane three times, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (PE:EA 4:1) to obtain yellowish foam 15 (1.3 g, 77%). 1H NMR (500 MHz, CDC13) δ 8.45 (s, 1H), 7.23 (m, 5H), 7.04 - 6.93 (m, 2H), 6.77 (s, 1H), 6.47 (s, 1H), 6.12 - 6.01 (m, 1H), 5.99 - 5.87 (m, 1H), 5.81 (dd, J = 20.6, 9.3 Hz, 3H), 5.50 (d, J = 11.2 Hz, 2H), 5.39 (dd, J = 17.2, 1.3 Hz, 1H), 5.32 (d, J = 17.3 Hz, 1H), 5.24 (dd, J = 19.9, 10.3 Hz, 3H), 4.81 (d, J = 12.7 Hz, 1H), 4.71 - 4.63 (m, 3H), 4.59 (dd, J = 12.5, 5.3 Hz, 1H), 4.52 - 4.41 (m, 2H), 4.35 (ddd, J = 16.7, 10.8, 4.3 Hz, 2H), 4.15 (d, J = 10.6 Hz, 1H), 3.55 (s, 3H), 3.19 (t, J = 13.9 Hz, 1H), 2.82 (dd, J = 15.5, 6.1 Hz, 1H), 2.22 (s, 3H), 2.09 (s, 3H), 2.01 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 171.0, 158.4, 156.1, 150.0, 149.4, 148.0, 145.8, 139.7, 136.5, 133.9, 132.0, 131.7, 129.4, 128.2, 127.6, 127.3, 126.0, 124.6, 119.0, 117.8, 114.1, 108.4, 103.4, 100.6, 73.5, 71.8, 67.6, 66.1, 65.8, 59.7, 56.6, 52.4, 51.2, 29.3, 20.8, 15.8, 8.7. HRMS (ESI, m / z): calcd for C 39 H 44 N2O 12 [M+H] + 733.7830, found 733.7838.

[0216] Example 5, synthesis of compound 16

[0217]

[0218] Compound 15 (13.9 g, 19 mmol) synthesized in Example 4 was dissolved in dichloromethane (95 mL), and tetrakis triphenylphosphine palladium (4.39 g, 3.8 mmol), 1,3-DMBA (6.5 g, 41.8 mmol) were added successively, and the reaction was allowed to proceed at room temperature for 6 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate was added to quench the reaction, and the reaction was diluted with dichloromethane, and extracted, and the organic phase was separated, and the aqueous phase was extracted with dichloromethane three times, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and column chromatography (PE:EA 3:1) was performed to obtain yellow foam 16 (9.8 g, 85%). 1 H NMR (500 MHz, CDC13) δ 7.34 - 7.23 (m, 5H), 6.51 (s, 1H), 6.08 (s, 1H), 5.98 (d, J = 5.2 Hz, 1H), 5.80 (s, 2H), 5.04 (m, 2H), 4.91 (m, 2H), 4.31 (dd, J = 11.4, 3.2 Hz, 1H), 3.97 (dd, J = 11.4, 7.0 Hz, 1H), 3.76 (s, 3H), 3.18 - 3.04 (m, 1H), 2.81 - 2.65 (m, 1H), 2.58 (dd, J = 15.4, 2.1 Hz, 1H), 2.27 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 170.8, 156.7, 150.3, 145.9, 145.7, 144.1, 139.8, 136.3, 131.1, 129.7, 128.3, 127.9, 127.7, 122.3, 117.4, 114.3, 108.6, 102.6, 100.5, 74.8, 67.1, 66.7, 60.7, 56.8, 56.1, 51.3, 32.1, 20.7, 15.6, 8.6. HRMS (ESI, m / z): calcd for C 32 H 36 N2O 10 [M+H] + 609.2370, found 609.2374.

[0219] Example 6, synthesis of compound 17

[0220]

[0221] Compound 16 synthesized in Example 5 (3.76 g, 6.2 mmol) was dissolved in anhydrous acetone (31 ml), and potassium carbonate (2.57 g, 15.6 mmol), allyl bromide (1.1 ml, 12.4 mmol) were added successively, and stirred at room temperature for 5 h, filtered, and the filtrate was concentrated under reduced pressure, and column chromatography (PE:EA 4:1) was performed to obtain 17 (3.21 g, 80%) as a yellow oil.1H NMR (500 MHz, CDCl3) δ 7.37 - 7.24 (m, 1H), 6.73 (s, 1H), 6.28 (s, 1H), 6.06 (s, 1H), 5.88 (d, J = 6.9 Hz, 1H), 5.82 (s, 1H), 5.34 (d, J = 16.7 Hz, 1H), 5.23 (d, J = 9.0 Hz, 1H), 5.13 - 5.05 (m, 1H), 4.98 (d, J = 6.9 Hz, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.54 (s, 1H), 4.34 (dd, J = 11.4, 3.2 Hz, 1H), 3.96 (dd, J = 11.2, 7.4 Hz, 1H), 3.83 (s, 1H), 3.17 - 3.07 (m, 1H), 3.17 - 3.08 (m, 1H), 2.78 - 2.68 (m, 1H), 2.60 (dd, J = 15.4, 2.2 Hz, 1H), 2.25 (s, 1H), 2.10 (s, 1H), 2.06 (s, 1H). 13 C NMR (125 MHz, CDCl3) δ 170.7, 156.4, 150.3, 148.8, 145.7, 139.8, 136.4, 134.2, 131.6, 130.5, 128.4, 127.9, 127.6, 126.4, 125.0, 118.3, 114.3, 108.6, 102.6, 100.5, 75.2, 74.1, 67.1, 66.5, 60.2, 57.0, 56.9, 51.2, 32.1, 20.8, 15.6, 8.6. HRMS (ESI, m / z): calcd for C 35 H 40 N2O 10 [M+H] + 649.2683, found 649.2685.

[0222] Example 7, synthesis of compound 18

[0223]

[0224] Compound 17 (3.4 g, 5.2 mmol) synthesized in Example 7 was dissolved in dichloromethane (104 mL), triethylsilane (4.15 mL, 26 mmol) was added at 0 °C, and boron trifluoride etherate (790 μL, 10.4 mmol) was added dropwise slowly. After 0.5 h, the reaction was stirred at room temperature for 24 h. TLC monitoring showed that the reaction was completed. The reaction was quenched with saturated sodium bicarbonate solution, diluted with dichloromethane, and the organic phase was separated. The aqueous phase was extracted with dichloromethane three times, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (PE:EA 4:1) gave 18 as a light yellow foam (2.61 g, 81%). 1 H NMR (500 MHz, CDC13) δ 7.35 - 7.20 (m, 5H), 6.68 (s, 1H), 6.28 (s, 1H), 5.96 - 5.86 (m, 1H), 5.83 (s, 2H), 5.40 (d, J = 5.9 Hz, 1H), 5.13 (dd, J = 18.1, 15.0 Hz, 2H), 5.02 (q, J = 12.3 Hz, 2H), 4.60 (s, 1H), 4.54 (dd, J = 12.2, 5.5 Hz, 1H), 4.36 - 4.24 (m, 3H), 4.17 (dd, J = 11.1, 7.7 Hz, 1H), 3.64 (s, 3H), 3.21 (dt, J = 11.7, 4.5 Hz, 1H), 2.91 (d, J = 13.6 Hz, 1H), 2.78 - 2.61 (m, 3H), 2.19 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H). 13 CNMR (125 MHz, CDC13) δ 170.9, 156.0, 149.5, 149.2, 148.3, 145.5, 139.7, 136.4, 133.9, 131.1, 130.3, 128.4, 128.0, 127.9, 127.0, 126.0, 117.7, 113.6, 108.9, 107.6, 100.4, 73.7, 67.6, 66.5, 59.9, 54.2, 53.8, 51.5, 31.4, 30.5, 20.9, 15.6, 9.2. HRMS (ESI, m / z): calcd for C 35 H 40 N2O9[M+H] + 633.2734, found 633.2734.

[0225] Example 8, synthesis of compound 19

[0226]

[0227] Yellow foam 18 (1.54 g, 2.4 mmol) synthesized in Example 7 was dissolved in a mixture of tetrahydrofuran / acetonitrile (1:3, 20 mL), and aqueous formaldehyde (36%, 1 mL, 12 mmol), sodium cyanoborohydride (377 mg, 6 mmol) were added successively. After stirring at room temperature for 15 min, glacial acetic acid (326 μL, 6 mmol) was added, and the reaction was continued for another 1 h. TLC monitoring showed that the reaction was completed. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate three times. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (PE:EA 4:1) gave white foam 19 (1.27 g, 82%). 1 HNMR (500 MHz, CDC13) δ 9.00 (s, 1H), 7.38 - 7.27 (m, 3H), 7.25 - 7.16 (m, 2H), 6.79 (s, 1H), 6.50 (s, 1H), 5.96 - 5.87 (m, 2H), 5.83 - 5.71 (m, 1H), 5.49 (d, J = 8.4 Hz, 1H), 5.15 - 5.05 (m, 2H), 4.98 (dd, J = 29.5, 12.5 Hz, 2H), 4.63 (dd, J = 12.8, 5.2 Hz, 1H), 4.34 (dd, J = 11.1, 7.3 Hz, 1H), 4.25 - 4.16 (m, 2H), 4.13 (dd, J = 10.9, 8.8 Hz, 1H), 3.58 (m, 4H), 3.29 (dd, J = 14.6, 3.3 Hz, 1H), 2.96 - 2.84 (m, 2H), 2.78 (dd, J = 15.4, 6.4 Hz, 1H), 2.73 - 2.64 (m, 1H), 2.26 (s, 6H), 2.22 (s, 6H). 13 CNMR (125 MHz, CDC13) δ 170.9, 155.6, 149.2, 149.0, 148.6, 145.4, 139.9, 136.5, 133.6, 131.3, 129.3, 128.3, 127.8, 127.5, 126.2, 125.3, 117.2, 114.6, 109.1, 107.1, 100.4, 73.5, 67.3, 66.2, 60.5, 60.2, 59.6, 54.7, 48.7, 32.4, 28.0, 20.8, 15.7, 9.2. HRMS (ESI, m / z): calcd for C 36 H 42 N2O9[M+H] + 647.2890, found 647.2890.

[0228] Example 9, synthesis of compound 20

[0229]

[0230] Compound 19 (3.32 g, 5.14 mmol) synthesized in Example 8 was dissolved in dichloromethane (8 mL), and a solution of hydrobromic acid in acetic acid (33% in AcOH, 8 mL) was slowly added dropwise at 0 °C. The reaction solution was reacted at 0 °C for 5 h, and the reaction was completed as monitored by TLC. The reaction solution was slowly poured into a saturated sodium bicarbonate solution, and the pH was adjusted to >7. After dilution with dichloromethane, extraction was performed, and the organic phase was separated. The aqueous phase was extracted with dichloromethane three times, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain brownish black oil 19-I, which was used in the next step without further purification.

[0231] The oil 19-I was dissolved in a mixed solution of trifluoroacetic acid and acetic acid (4:1, 30 mL), and ketal (5.2 g, 25.7 mmol) was added to the reaction solution. After reaction at room temperature for 8 h, the reaction was completed as monitored by TLC. The reaction solution was slowly poured into a saturated sodium bicarbonate solution, and diluted with ethyl acetate. Extraction was performed, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (PE:EA 4:1) was performed to obtain yellowish oil 19-II mixed with ketal, which was used in the next step without further purification.

[0232] The above yellowish oil 19-II was dissolved in tetrahydrofuran (26 mL), and sodium hydride (2.1 g, 51.4 mmol) was added at 0 °C and reacted for 10 min. Bromomethyl methyl ether (3.36 mL, 41.1 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 0 °C for 15 min. The reaction was completed as monitored by TLC, and the reaction was quenched with saturated ammonium chloride. Ethyl acetate was added to dilute the reaction solution, and extraction was performed after separation of the layers. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (PE:EA 4:1) was performed to obtain yellowish oil 19-III mixed with ketal, which was used in the next step without further purification.

[0233] Dissolve the yellow oil 19-III from the previous step in methanol (26 mL), add potassium carbonate (1.1 g, 7.7 mmol), and stir at room temperature for 2 h. Monitor the reaction by TLC until completion. Adjust the pH to neutral with 10% citric acid, extract with ethyl acetate, separate the organic phase, extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (PE:EA 2:1 / DCM:MeOH 50:1) to obtain 20 as a colorless oil (1.8 g, 51% over four steps). HRMS (ESI, m / z): calcd for C 36 H 46 N2O 11 [M+H] + 683.3102, found 683.3102.

[0234] Example 10, synthesis of compound 5

[0235]

[0236] Dissolve oxalyl chloride (442 μL, 5.2 mmol) in dichloromethane (20 mL) at -78 °C, and slowly add dimethyl sulfoxide (739 μL, 10.4 mmol) dropwise. After stirring at -78 °C for 15 min, add compound 20 (1.78 g, 2.6 mmol) synthesized in Example 9 of the present invention in dichloromethane (5 mL) slowly dropwise. After 4 h, add triethylamine (2.9 mL) and stir at -78 °C for 30 min, then warm to 0 °C and stir for 1 h. Quench the reaction with water, dilute with dichloromethane, separate the layers and extract, extract the aqueous phase with dichloromethane three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 20-I, which is used directly in the next step.

[0237] Dissolve the oil 20-I from the previous step in dichloromethane (26 mL), and add TMSCN (976 μL, 7.8 mmol) and a solution of zinc chloride (1 M in THF, 7.8 mL, 7.8 mmol) sequentially. Stir the reaction at room temperature for 3 h, monitor the reaction by TLC until completion, quench with water, extract, separate the organic phase, extract the aqueous phase with dichloromethane three times and wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (PE:EA 4:1) to obtain 5 as a light yellow oil (1.2 g, 65%). HRMS (ESI, m / z): calcd for C 37 H 43 N3O 10 [M+H] + 690.2948, found 690.2949.

[0238] Example 11, synthesis of compound 3

[0239]

[0240] A reaction vial containing tetraphenylphosphine palladium (37 mg, 0.032 mmol) and DBA (113 mg, 0.8 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 min, then a solution of compound 20 (110 mg, 0.16 mmol) synthesized in Example 10 of the present invention in tetrahydrofuran (1 mL) was added to the reaction vial and the reaction was allowed to proceed at room temperature for 3 h, monitored by TLC, then quenched by the addition of saturated aqueous sodium bicarbonate solution, the layers were separated and the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, then purified by column chromatography (PE:EA 3:1) to give 3 (70 mg, 72%) as a light yellow foam. 1 HNMR (400 MHz, CDC13) δ 6.59 (s, 1H), 6.04 (dq, J = 10.8, 5.7 Hz, 1H), 5.85 (d, J = 19.2 Hz, 2H), 5.36 (d, J = 17.1 Hz, 1H), 5.19 (d, J = 10.3 Hz, 1H), 4.84 (d, J = 5.5 Hz, 1H), 4.76 (d, J = 5.6 Hz, 1H), 4.41 (s, 1H), 4.31 - 4.18 (m, 2H), 4.07 (s, 1H), 3.99 (dq, J = 14.2, 7.1 Hz, 1H), 3.87 (dq, J = 14.4, 7.1 Hz, 1H), 3.75 (s, 3H), 3.56 (s, 3H), 3.30 (d, J = 6.9 Hz, 1H), 3.24 - 3.14 (m, 2H), 2.98 (dd, J = 17.8, 8.1 Hz, 1H), 2.45 (d, J = 17.8 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.90 (dd, J = 15.3, 12.5 Hz, 1H), 0.96 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 170.1, 149.4, 148.4, 146.8, 144.2, 139.9, 134.0, 130.3, 129.9, 124.4, 123.1, 120.8, 117.4, 112.9, 109.5, 101.2, 99.2, 73.3, 60.9, 60.8, 56.0, 59.7, 57.6, 56.8, 56.7, 55.1, 41.5, 26.3, 25.3, 15.4, 13.5, 9.6. HRMS (ESI, m / z): calcd for C 33 H39 N3O8[M+H] + 606.2737, found 606.2737.

[0241] Example 12, synthesis of compound 26

[0242]

[0243] The compound 3 (270 mg, 0.45 mmol) synthesized in Example 11 of the present application was dissolved in dichloromethane (4 mL) at 0 °C, and zirconium tetrachloride (208 mg, 0.89 mmol) was added, and the reaction was maintained at 0 °C for 1 h. The reaction was quenched with saturated sodium bicarbonate, diluted with dichloromethane, extracted, and the organic phase was separated. The aqueous phase was extracted with dichloromethane three times, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-I, which was used directly in the next step.

[0244] The deprotection product 3-I (651 mg, 1.16 mmol) from the previous step was dissolved in tetrahydrofuran (12 mL), and methanol (469 μL, 11.6 mmol) was added. A solution of LiBH4 in tetrahydrofuran (11.6 mmol, 2 M in THF, 5.8 mL) was added slowly dropwise to the reaction tube. The reaction was maintained at room temperature for 3 h, and TLC was used to determine that the reaction was complete. The reaction was quenched slowly by adding saturated brine to the system, and dichloromethane was added to extract the product. The aqueous phase was extracted with dichloromethane three times, and the organic phases were combined, dried, and concentrated. Column chromatography (PE:EA 2:1) gave compound 26 (460 mg, 75%). 1 HNMR (500 MHz, CDC13) δ 6.67 (s, 1H), 6.09 (ddt, J = 16.2, 10.7, 5.5 Hz, 1H), 5.84 (d, J = 22.2 Hz, 2H), 5.43 (d, J = 17.2 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.81 (s, 1H), 4.70 (dd, J = 12.8, 5.3 Hz, 1H), 4.42 (dd, J = 12.7, 5.7 Hz, 1H), 4.15 (s, 1H), 4.06 (s, 1H), 3.96 (s, 1H), 3.76 (s, 3H), 3.63 (d, J = 11.1 Hz, 1H), 3.43 (dd, J = 14.5, 6.2 Hz, 1H), 3.34 (t, J = 7.5 Hz, 2H), 3.07 (dd, J = 17.9, 8.0 Hz, 2H), 2.50 (d, J = 18.0 Hz, 1H), 2.33 (s, 3H), 2.20 (s, 3H), 2.05 (s, 3H), 1.85 (dd, J = 15.4, 11.9 Hz, 1H). 13C NMR (125 MHz, CDC13) δ 149.5, 149.1, 145.0, 144.4, 136.5, 134.2, 131.5, 129.2, 124.8, 123.0, 117.7, 117.5, 113.1, 113.0, 106.1, 100.9, 73.4, 63.8, 60.2, 60.0, 58.0, 57.3, 56.5, 55.3, 41.7, 26.0, 25.4, 15.8, 8.8. HRMS (ESI, m / z): calcd for C 29 H 33 N3O6[M+H] + 520.2369, found 520.2369.

[0245] Example 13, synthesis of compound 27

[0246]

[0247] Compound 26 (463 mg, 0.892 mmol) synthesized in example 12 was dissolved in DCM (18 mL), seleninic anhydride (321 mg, 0.892 mmol) was added in portions at -10 °C, the reaction was monitored by TLC after 10 min, the reaction was complete, sodium bicarbonate saturated solution was added to quench the reaction. The organic phase was separated, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to give compound 27, which was used in the next step without purification.

[0248] Example 14, synthesis of compound 28

[0249]

[0250] The crude 27 was dissolved in dichloromethane (11 mL), EDCI (511.6 mg, 2.67 mmol), DMAP (327 mg, 2.67 mmol), cysteine derivative (683 mg, 1.784 mmol) were added in sequence. The reaction was carried out at room temperature for 2 h, the reaction was monitored by TLC, water was added to separate the layers, the organic phase was separated, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, the crude was purified by column chromatography (PE:EA 2:1) to give compound 28 (546 mg, 68% over two steps). major: 1H NMR (500 MHz, CDC13) δ 7.74 (d, J = 7.5 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.30 (td, J = 7.3, 3.1 Hz, 2H), 6.54 (s, 1H), 5.94 (dddd, J = 38.8, 22.4, 10.7, 5.7 Hz, 2H), 5.70 (s, 1H), 5.62 (s, 1H), 5.30 (t, J = 17.1 Hz, 2H), 5.24 - 5.18 (m, 2H), 4.69 (d, J = 12.7 Hz, 1H), 4.55 (dd, J = 13.4, 5.6 Hz, 4H), 4.44 - 4.34 (m, 1H), 4.30 (dd, J = 12.3, 6.0 Hz, 1H), 4.11 (t, J = 6.5 Hz, 1H), 4.09 - 4.04 (m, 1H), 4.01 (s, 1H), 3.90 (s, 1H), 3.90 (s, 1H), 3.78 (d, J = 11.3 Hz, 1H), 3.67 (s, 3H), 3.41 (s, 1H), 3.16 (d, J = 6.3 Hz, 2H), 3.01 - 2.83 (m, 4H), 2.46 (d, J = 17.0 Hz, 1H), 2.25 (s, 3H), 2.17 (s, 3H), 2.14 - 2.08 (m, 1H), 1.77 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 200.1, 170.5, 160.0, 155.8, 149.4, 148.7, 145.6, 145.5, 141.0, 138.6, 133.9, 132.4, 131.0, 129.6, 127.7, 127.1, 124.8, 124.8, 124.6, 119.9, 118.0, 116.5, 111.3, 104.9, 101.0, 73.2, 72.1, 66.0, 63.7, 59.9, 57.9, 56.7, 56.3, 56.0, 55.1, 54.0, 46.8, 41.6, 41.3, 37.1, 35.2, 25.7, 15.9, 7.1.minor 1H NMR (500 MHz, CDC13) δ 7.75 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.8 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 6.62 (s, 1H), 6.04 - 5.95 (m, 1H), 5.95 - 5.84 (m, 1H), 5.73 (d, J = 14.9 Hz, 1H), 5.52 (d, J = 7.2 Hz, 1H), 5.32 (d, J = 17.0 Hz, 2H), 5.21 (dd, J = 17.4, 10.5 Hz, 2H), 4.70 (dd, J = 12.5, 5.4 Hz, 1H), 4.57 (dd, J = 12.6, 6.4 Hz, 2H), 4.47 (s, 1H), 4.40 - 4.33 (m, 1H), 4.22 - 4.15 (m, 1H), 4.14 - 4.03 (m, 3H), 3.97 (s, 1H), 3.87 (s, 1H), 3.23 (m, 1H), 3.09 (d, J = 6.0 Hz, 3H), 2.93 (ddd, J = 39.3, 14.3, 5.0 Hz, 3H), 2.47 - 2.28 (m, 5H), 2.21 (s, 4H), 1.82 (t, J = 4.7 Hz, 1H), 1.79 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 198.5, 170.3, 158.1, 155.5, 149.3, 149.2, 145.6, 142.5, 141.0, 141.0, 133.8, 132.3, 127.7, 127.1, 124.8, 124.7, 124.6, 119.9, 118.2, 104.7, 101.6, 73.5, 70.4, 66.6, 66.1, 60.4, 57.2, 56.0, 55.1, 53.9, 46.9, 41.5, 37.1, 37.0, 35.3, 22.7, 15.8, 7.4. HRMS (ESI, m / z): calcd for C 50 H 52 N4O 10 S[M+H] + 901.3404, found 901.3408.

[0251] Example 15, synthesis of compound 29

[0252]

[0253] A solution of triflic anhydride (10.5 μL, 0.062 mmol) in dichloromethane (2 mL) was added to the reaction tube at -78 °C, dimethylsulfoxide (11 μL, 0.156 mmol) was added slowly dropwise, the reaction was stirred at -78 °C for 15 min, then a solution of compound 28 (28 mg, 0.031 mmol) synthesized in Example 14 was added slowly dropwise to the reaction, then the temperature was slowly increased to -78 °C and the reaction was allowed to proceed for 40 min. Then DIPEA (43.4 μL, 0.25 mmol) was added, the temperature was increased to 0 °C and the reaction was allowed to proceed for 30 min. Then tert-butanol (12 μL, 0.13 mmol) was added, the temperature was maintained at 0 °C for 15 min, then tert-butylguanidine (44 μL, 0.22 mmol) was added dropwise and the reaction was allowed to warm to room temperature and proceed for 40 min. Finally, acetic anhydride (29 μL, 0.31 mmol) was added and the stirring was continued for 1 h, then the reaction was quenched with saturated ammonium chloride, the organic phase was separated, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined and washed with saturated brine, dried, concentrated and purified by column chromatography (PE:EA 4:1) to give compound 29 (14.2 mg, 51%). 1 H NMR (500 MHz, CDC13) δ 6.78 (s, 1H), 6.13 - 6.04 (m, 2H), 6.00 (s, 1H), 5.93 (ddd, J = 16.4, 11.1, 5.8 Hz, 1H), 5.45 (d, J = 17.1 Hz, 1H), 5.32 (d, J = 17.2 Hz, 1H), 5.25 (dd, J = 10.3, 2.3 Hz, 2H), 5.02 (d, J = 11.7 Hz, 1H), 4.81 (d, J = 9.3 Hz, 2H), 4.59 - 4.45 (m, 3H), 4.37 - 4.28 (m, 2H), 4.27 - 4.20 (m, 2H), 4.17 (d, J = 10.0 Hz, 2H), 3.79 (s, 3H), 3.48 - 3.39 (m, 2H), 2.99 - 2.86 (m, 2H), 2.42 - 2.32 (m, 1H), 2.27 (s, 6H), 2.22 (s, 3H), 2.17 - 2.11 (m, 1H), 2.03 (s, 3H). 13C NMR (125 MHz, CDC13) δ 170.4, 168.6, 155.4, 150.8, 148.9, 145.8, 140.9, 140.4, 134.5, 132.8, 131.8, 129.8, 124.7, 120.1, 118.0, 117.9, 116.7, 113.6, 113.3, 102.0, 72.9, 65.9, 61.3, 60.4, 59.3, 59.3, 59.1, 55.1, 54.6, 53.9, 41.6, 41.6, 32.8, 23.9, 20.5, 15.8, 9.6. HRMS (ESI, m / z): calcd for C 38 H 42 N4O 10 S[M+H] + 747.2622, found 747.2622.

[0254] Example 16, synthesis of compound 30

[0255]

[0256] Compound 29 (61 mg, 0.082 mmol) synthesized in example 15 was dissolved in dichloromethane (2 mL), tetrakis triphenylphosphine palladium (19 mg, 0.016 mmol), acetic acid (28 μL, 0.492 mmol), tributyltin hydride (66 μL, 0.246 mmol) were added successively, the reaction was carried out at room temperature for 1 h, TLC monitoring showed that the reaction was completed, the pH was adjusted to basic with saturated sodium bicarbonate solution, diluted with dichloromethane, the organic phase was separated, the aqueous phase was extracted with dichloromethane three times, the organic phase was combined and washed with saturated brine, dried, concentrated, and column chromatography (DCM:MeOH 20:1) to obtain compound 30 (43 mg, 85%). 1 HNMR (500 MHz, CDC13) δ 6.54 (s, 1H), 6.08 (s, 1H), 5.99 (s, 1H), 5.02 (d, J = 11.6 Hz, 1H), 4.53 (s, 1H), 4.28-4.22 (m, 2H), 4.16 (m, 2H), 3.80 (s, 3H), 3.64 (s, 1H), 3.47 (s, 1H), 3.44-3.38 (m, 2H), 2.90 (d, J = 5.1 Hz, 2H), 2.30 (s, 6H), 2.24 (d, J = 14.6 Hz, 2H), 2.18 (d, J = 5.5 Hz, 3H), 2.03 (s, 3H). 13C NMR (125 MHz, CDC13) δ 174.3, 168.6, 148.1, 145.9, 143.1, 141.1, 140.3, 130.5, 129.7, 120.8, 120.0, 118.1, 118.0, 113.5, 102.0, 61.4, 60.5, 60.4, 59.2, 54.6, 42.0, 41.5, 23.8, 20.6, 15.7, 9.6. HRMS (ESI, m / z): calcd for C 31 H 34 N4O8S [M+H] + 623.2097, found 623.2097.

[0257] Example 17, synthesis of compound 31

[0258]

[0259] Pyridine benzenesulfonate (107 mg, 0.383 mmol) was dissolved in dry DMF (3.25 mL), and a solution of compound 30 (34 mg, 0.055 mmol) synthesized in Example 16 of the present invention in dichloromethane (3.25 mL) was added slowly dropwise, and stirred at room temperature for 4 h. Subsequently, the reaction was moved to 0 °C, and a solution of DBU (20.5 μL, 0.137 mmol) in dichloromethane was added slowly dropwise to the reaction, and after 20 min at this temperature, saturated sodium bicarbonate solution was added to adjust the pH. Ethyl acetate was added to dilute, and the organic phase was separated and extracted with ethyl acetate three times, and the combined organic phase was washed with saturated brine twice, dried and concentrated, and column chromatography (PE:EA 2:1) was performed to obtain compound 31 (17 mg, 52%). 1 H NMR (500 MHz, CDC13) δ 6.49 (s, 1H), 6.11 (d, J = 0.9 Hz, 1H), 6.02 (d, J = 0.9 Hz, 1H), 5.71 (s, 1H), 5.09 (d, J = 11.4 Hz, 1H), 4.66 (s, 1H), 4.39 (s, 1H), 4.29 (d, J = 4.6 Hz, 1H), 4.24 - 4.18 (m, 1H), 4.17 (d, J = 2.0 Hz, 1H), 3.76 (s, 2H), 3.56 (d, J = 4.6 Hz, 1H), 3.44 (d, J = 9.0 Hz, 1H), 2.95 - 2.80 (m, 2H), 2.71 (d, J = 17.8 Hz, 1H), 2.56 (d, J = 13.0 Hz, 1H), 2.33 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H). 13C NMR (125 MHz, CDC13) δ 186.7, 168.5, 160.5, 147.2, 146.4, 143.1, 141.7, 140.7, 130.3, 130.0, 121.7, 120.0, 117.7, 116.8, 113.5, 102.3, 61.7, 61.4, 60.3, 59.7, 58.8, 54.6, 43.2, 41.6, 36.9, 24.3, 20.3, 15.8, 9.7. HRMS (ESI, m / z): calcd for C 31 H 31 N3O9S[M+H] + 622.1782, found 622.1782.

[0260] Example 18, Synthesis of compound 34

[0261]

[0262] Compound 31 (8 mg, 0.0129 mmol) synthesized in example 17 of the present application was dissolved in ethanol (0.5 mL), 4-methoxydopamine hydrochloride 32 (26.3 mg, 0.129 mmol), sodium acetate (12 mg, 0.142 mmol) were added successively, the reaction was carried out at room temperature for 5 h, TLC monitoring showed that the reaction was completed, ethanol was removed by concentration, diluted with ethyl acetate, water was added to separate the organic phase, the aqueous phase was extracted with ethyl acetate three times, the organic phase was combined and washed with saturated brine, concentrated, dried, column chromatography (DCM:MeOH 20:1) to obtain compound 34 (9 mg, 92%)

[0263] 1H NMR (500 MHz, CDC13) δ 6.60 (s, 1H), 6.46 (d, J = 13.0 Hz, 2H), 6.05 (s, 1H), 5.97 (s, 1H), 5.75 (s, 1H), 5.43 (s, 1H), 5.02 (d, J = 11.5 Hz, 1H), 4.57 (s, 1H), 4.33 (s, 1H), 4.28 (d, J = 4.4 Hz, 1H), 4.18 (d, J = 2.3 Hz, 1H), 4.15 - 4.09 (m, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 3.51 (d, J = 4.5 Hz, 1H), 3.42 (d, J = 5.7 Hz, 1H), 3.10 (t, J = 8.5 Hz, 1H), 2.98 - 2.88 (m, 2H), 2.78 (d, J = 10.2 Hz, 1H), 2.60 (d, J = 5.6 Hz, 1H), 2.47 (d, J = 15.9 Hz, 1H), 2.35 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 2.14 (m, 1H), 2.04 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 172.6, 168.2, 147.8, 145.3, 144.5, 144.3, 143.1, 141.3, 140.1, 130.8, 129.4, 129.1, 125.7, 121.2, 120.7, 118.1, 118.1, 114.1, 113.4, 109.8, 101.8, 64.6, 61.1, 60.3, 60.0, 59.6, 59.5, 55.2, 54.7, 54.6, 42.2, 41.8, 41.6, 39.6, 28.8, 24.2, 20.4, 15.8, 9.7. HRMS (ESI, m / z): calcd for C 40 H 42 N4O 10 S[M+H] + 771.2622, found 771.2622.

[0264] Example 19, synthesis of trabectedin 1

[0265]

[0266] Compound 34 (12 mg, 0.0156 mmol) synthesized in example 18 of the present application was dissolved in acetonitrile (1.2 mL), H2O (0.8 mL), silver nitrate (53 mg, 0.3117 mmol) was added, the reaction was monitored by TLC at room temperature for 24 h, saturated solution of sodium chloride (0.8 mL) and saturated solution of sodium bicarbonate (0.8 mL) were added, after 15 min of stirring at room temperature, saturated solution of sodium chloride and saturated solution of sodium bicarbonate were added again, 18 mL each, extracted with ethyl acetate, the organic phase was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, column chromatography (DCM:MeOH 20:1) to obtain the natural product Trabectedin (10.7 mg, 90%). 1 HNMR (500 MHz, CDC13) δ 6.61 (s, 1H), 6.46 (d, J = 13.4 Hz, 2H), 6.02 (d, J = 1.1 Hz, 1H), 5.94 (d, J = 1.1 Hz, 1H), 5.74 (s, 1H), 5.13 (d, J = 11.2 Hz, 1H), 4.83 (s, 1H), 4.50 (s, 2H), 4.20 (s, 1H), 4.05 (dd, J = 11.3, 2.3 Hz, 1H), 3.80 (s, 3H), 3.62 (d, J = 3.0 Hz, 4H), 3.25 (s, 1H), 3.13 (d, J = 7.0 Hz, 1H), 2.95 - 2.80 (m, 3H), 2.61 (d, J = 6.6 Hz, 1H), 2.48 (d, J = 15.9 Hz, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 2.19 (s, 4H), 2.03 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 172.5, 168.4, 147.7, 145.2, 144.5, 144.3, 143.0, 141.3, 140.5, 131.4, 129.4, 129.1, 126.0, 121.7, 121.0, 117.8, 115.9, 114.1, 109.8, 101.7, 82.1, 64.7, 61.4, 60.4, 57.9, 57.6, 55.9, 55.2, 55.0, 42.2, 42.2, 41.4, 39.7, 28.8, 24.1, 20.5, 15.8, 9.7. HRMS (ESI, m / z): calcd for C 39 H 43 N3O 11 S[M-OH] + 744.2591, found 744.2596.

[0267] The protection scope of the present application is not limited to the above-mentioned embodiments. Changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the present application are included in the present application and are protected by the appended claims.

Claims

1. A method of synthesizing a compound of formula 26, characterized by, The reaction route of the method is as follows: ； The synthesis method is as follows: a compound of formula 11 and a compound of formula 10 are subjected to a Pictet-Spengler reaction, then subjected to an intermolecular aldol condensation of a compound of formula 8 and a compound of formula 14 to obtain a fragment connection product of formula 15, then subjected to an asymmetric ketal oxidation reaction to obtain a compound of formula 20, subjected to an intramolecular Strecker reaction to obtain a compound of formula 5, then subjected to a palladium-catalyzed stereoselective decarboxylation protonation to obtain a compound of formula 3, then subjected to a protection group removal, and then subjected to a reduction of an ethyl ester to obtain a compound of formula 26, wherein (a) under acidic conditions, in a first solvent, compound 11 and compound 10 are subjected to a Pictet-Spengler reaction to obtain compound 12; (b) compound 12 is subjected to a reaction in an amino protecting agent, a base, and a second solvent to obtain compound 12-I: ； (c) compound 12-I is subjected to a reaction in a phenolic hydroxyl protecting agent, a base, an additive, and a third solvent to obtain compound 12-II: ； (d) compound 12-II is subjected to a reaction in an alkyl alcohol protecting agent, an activating agent, a base, and a fourth solvent to obtain compound 13; (e) under acidic conditions, in a catalyst and a fifth solvent, compound 13 is subjected to a reaction to obtain compound 14; (f) compound 14 is subjected to a Swern oxidation reaction in an activating agent and a sixth solvent to obtain compound 14-I: ； (g) compound 14-I is subjected to a reaction with compound 8 in a seventh solvent to obtain compound 15; (h) compound 15 is subjected to a deprotection reaction in an eighth solvent, a catalyst, and a proton source to obtain compound 16; (i) compound 16 is subjected to a reaction in a ninth solvent, a protecting agent, and a base to obtain compound 17; (j) compound 17 is subjected to a dehydroxylation reaction in a tenth solvent, a reducing agent, and an acid to obtain compound 18; (k) compound 18 is subjected to a methylation reaction in an eleventh solvent to obtain compound 19; (l) compound 19 is subjected to a deprotection reaction with an acid in a twelfth solvent to obtain compound 19-I: ； (m) compound 19-I is subjected to a Pictet-Spengler reaction with compound 6 in a thirteenth solvent to obtain compound 19-II; (n) compound 19-II is subjected to a phenolic hydroxyl protection reaction in a fourteenth solvent to obtain compound 19-III: ； (o) compound 19-III is subjected to a deprotection reaction under the action of a base in a fifteenth solvent to obtain compound 20; (p) Swern oxidation with compound 20 to give compound 20-I: ; (q) compound 20-I is subjected to a Strecker reaction under the action of an activating agent in a sixteenth solvent to obtain compound 5; (r) compound 5 is subjected to a decarboxylation reaction under the action of a catalyst and a proton source in a seventeenth solvent to obtain compound 3; (s) compound 3 is subjected to a deprotection reaction under the action of an additive in an eighteenth solvent to obtain compound 3-I; (t) compound 3-I is subjected to a reduction reaction under the action of a reducing agent and an additive in a nineteenth solvent to obtain compound 26.

2. A method of synthesis of Triclabendazole characterized in that, The reaction route of the method is as follows: ； ； The compound of formula 26 is synthesized by the method of claim 1; then, starting from the compound of formula 26, an ortho-hydroxyquinone is oxidized to be connected with a cysteine side chain to obtain a compound of formula 28, a de-thiol protection is constructed to form a ten-membered bridge ring, and a Pictet-Spengler reaction is performed to synthesize the trazodone shown in formula (A); Formula (A).

3. The method of claim 1, wherein, In step (a), the acid includes any one or more of acetic acid, formic acid, trifluoroacetic acid, and oxalic acid; the first solvent includes any one or more of dichloromethane, chloroform, toluene, trifluoroethanol, and hexafluoroisopropanol; the reaction temperature is 10-50°C; and the molar ratio of the compound 11 to the compound 10 is 1: (1-2); In step (b), the amino protecting agent includes any one or more of allyl chloroformate, isobutyl chloroformate, and benzyl chloroformate; the base includes any one or more of potassium carbonate, sodium carbonate, cesium carbonate, and sodium bicarbonate; the second solvent includes any one or more of dichloromethane, chloroform, and acetonitrile; the reaction temperature is 10-50°C; the molar ratio of the compound 12 to the amino protecting agent is 1: (1.1-2.0); and the volume ratio of the saturated aqueous solution of the second solvent to the base is 1: (1-10); In step (c), the phenolic hydroxyl protecting agent includes allyl bromide and homoallyl bromide; the third solvent is any one or more of dichloromethane, chloroform, and N,N-dimethylformamide; the base includes any one or more of cesium carbonate, sodium bicarbonate, sodium carbonate, and sodium sulfate; the additive includes any one or both of sodium iodide and potassium iodide; the reaction temperature is 10-50°C; and the molar ratio of the compound 12-I to the phenolic hydroxyl protecting agent, the base, and the additive is 1: (1-3): (1-5): (0.05-0.1); In step (d), the alkyl alcohol protecting agent includes any one or more of acetic anhydride, TBSCl, and benzoyl chloride; the base includes any one or more of piperidine, pyridine, and potassium carbonate; the activating agent includes any one or more of DMAP, potassium iodide, and sodium iodide; the fourth solvent is any one or more of dichloromethane, chloroform, and toluene; the reaction temperature is 10-50°C; and the volume ratio of the alkyl alcohol protecting agent to the base is (1): (1-5).

4. The method of claim 1, wherein, In step (e), the acid includes any one or more of boron trifluoride diethyl ether, cerium trichloride, and zirconium tetrachloride; the fifth solvent includes any one or more of acetone, dichloromethane, and acetonitrile; the catalyst includes any one or more of formic acid, acetic acid, and oxalic acid; the reaction temperature is 10-50°C; and the molar ratio of the compound 13 to the acid and the catalyst is 1: (1-10): (0.05-0.08). And / or, in step (f), the combination of the activating agent is oxalyl chloride / DMSO, trifluoroacetic anhydride / DMSO; the temperature of the reaction is -78℃-40℃; the sixth solvent includes one or more of dichloromethane, chloroform, toluene; the molar ratio of compound 14 to activating agent is 1:(1.5-6); And / or, in step (g), the seventh solvent includes one or more of dichloromethane / tetrahydrofuran, chloroform / tetrahydrofuran; the ratio of compound formula 14-I to compound 8 is 1.5:1, 1:1.1, 1:2; the temperature of the reaction is 10-50℃; And / or, in step (h), the eighth solvent includes one or more of dichloromethane, chloroform, tetrahydrofuran; the catalyst includes one or more of tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium acetate; the proton source includes one or both of DBA, 1,3-DMBA; the temperature of the reaction is 10-50℃; the molar ratio of compound 15, catalyst and proton source is 1:(0.05-0.5):(1-3).

5. The method of claim 1, wherein, In step (i), the protecting agent includes one or more of bromomethyl methyl ether, allyl chloroformate, allyl bromide; the base includes one or more of cesium carbonate, potassium carbonate, sodium bicarbonate; the ninth solvent includes one or more of dichloromethane, toluene, acetone; the temperature of the reaction is 10-50℃; the molar ratio of compound 16 to protecting agent, base is 1:(1-5):(1-5); And / or, in step (j), the reducing agent includes one or more of sodium borohydride, sodium cyanoborohydride, triethylsilane; the acid includes one or both of trifluoroacetic acid, boron trifluoride ether; the tenth solvent includes one or more of dichloromethane, chloroform, toluene; the temperature of the reaction is 0℃-50℃; the molar ratio of compound 17, reducing agent and acid is 1:(1-5):(1-10); And / or, in step (k), the methyl source used in the methylation reaction is a 36% formaldehyde solution; the eleventh solvent includes one or more of methanol, acetonitrile, tetrahydrofuran, dichloromethane; the temperature of the reaction is 10-50℃; the molar ratio of compound 18 and methyl source is 1:(1-10); And / or, in step (l), the acid includes one or more of methanesulfonic acid, trifluoromethanesulfonic acid, hydrobromic acid; the twelfth solvent includes one or more of acetic acid, dichloromethane, oxalic acid; the temperature of the reaction is 0℃-50℃; the volume ratio of the acid to the twelfth solvent is 1:(1-5).

6. The method of claim 1, wherein, In step (m), the thirteenth solvent includes one or both of acetic acid, trifluoroacetic acid; the temperature of the reaction is 10-50℃; the molar ratio of compound 19-I to compound 6 is 1:(1-10); And / or, in step (n), the protecting agent used in the phenolic hydroxyl protection reaction includes one or more of bromomethyl methyl ether, chloromethyl methyl ether, chloroethoxy ether; the fourteenth solvent includes one or more of tetrahydrofuran, dichloromethane, trichloromethane; the reaction temperature is 10-50℃; the molar ratio of compound 19-II to protecting agent is 1:(1-10); And / or, in step (o), the base includes one or more of sodium carbonate, potassium carbonate, sodium bicarbonate; the fifteenth solvent includes one or more of methanol, ethanol, acetone; the reaction temperature is 10-50℃; the molar ratio of compound 19-III to base is 1:(1-3); And / or, in step (p), the Swern oxidation reaction uses a combination of activating reagents oxalyl chloride / DMSO, trifluoroacetic anhydride / DMSO; the molar ratio of compound 20 to activating reagent is 1:(1-5); the reaction temperature is -78℃~30℃.

7. The method of claim 1, wherein, In step (q), the Strecker reaction, the sixteenth solvent includes one or more of dichloromethane, trichloromethane, diethyl ether; the reaction temperature is 10℃-50℃; the activating agent is one or more of zinc chloride, zinc iodide, zinc bromide; the molar ratio of compound 20-I to activating agent is 1:1-10; And / or, in step (r), the catalyst includes one or more of palladium tetraphenylphosphine, dichlorobis-triphenylphosphine palladium, palladium acetate; the proton source includes one or more of 1,3-DMBA, DBA, methanol; the seventeenth solvent includes one or more of dichloromethane, methanol, tetrahydrofuran; the reaction temperature is 10-50℃; the molar ratio of compound 5, catalyst to proton source is 1:(0.05-0.5):(1-10); And / or, in step (s), the additive includes one or more of zirconium tetrachloride, p-toluenesulfonic acid, trifluoroacetic acid; the reaction temperature is 0℃-50℃; the eighteenth solvent includes one or more of dichloromethane, trichloromethane, tetrahydrofuran; the molar ratio of compound 3 to additive is 1:(1-3); And / or, in step (t), the reducing agent includes one or more of sodium borohydride, lithium borohydride, lithium tetrahydroaluminate; the additive includes one or more of methanol, ethanol; the reaction temperature is 0℃-50℃; the nineteenth solvent includes one or more of tetrahydrofuran, toluene, 1,4-dioxane; the molar ratio of compound 3-I, reducing agent, additive is 1:(1-20):(1-20).

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