Synthesis method of trabectedine pentacyclic core skeleton

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a synthesis method of a trabectedin five-ring core skeleton. According to the synthesis method of the trabectedin five-ring core skeleton, connection of an AE ring system is completed through a condensation reaction, then a D ring is constructed through a Pictet-Spengler reaction, then a C ring is subjected to an aza-Michael reaction, and finally a B ring is constructed through an SOMO small organic molecule catalytic reaction, so that large-scale preparation of the trabectedin five-ring core skeleton is realized, construction sites of derivative rings are reserved, and the synthesis method has the advantages that the synthesis method is simple and convenient, and the synthesis cost is low. A more convenient preparation method is provided for total synthesis of trabectedin and derivatives thereof, and a material construction basis is provided for activity research of the medicine.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical chemistry, and in particular to a method for synthesizing a five-ring core skeleton of trabectedin. Background Art

[0002] Ecteinascidin 743 is a tetrahydroisoquinoline alkaloid isolated from Caribbean sea squirts. It has excellent anti-tumor activity. In 2007, as the first anti-tumor drug derived from the ocean, it was approved by the European Union for the second-line treatment of advanced soft tissue sarcomas. In 2015, it was approved by the U.S. Food and Drug Administration (FDA) for the second-line treatment of unresectable or metastatic liposarcoma or leiomyosarcoma. At present, the application of ecteinascidin has been extended to the treatment of recurrent ovarian cancer sensitive to platinum drugs. The yield of ecteinascidin extracted from natural sources is extremely low. Only 1 gram of ecteinascidin can be extracted from each ton of sea squirts, which is far from meeting the market demand. At present, the source of ecteinascidin is mainly obtained by semi-synthesis. However, even if it is semi-synthesized, it takes 21 steps of reaction to obtain ecteinascidin with a total yield of 1.0%, which makes ecteinascidin very expensive. Therefore, it is very urgent to develop a new and efficient synthesis method of ecteinascidin, which also has important application value.

[0003]

[0004] Trabectedin includes five core rings (A, B, C, D, E) and derivative rings (F, G, H). The construction strategy of the five core rings determines the efficiency of the total synthesis. From the perspective of molecular structure, the A and B rings are fully substituted tetrahydroisoquinoline ring systems, and there is a cross-ring ten-membered thiolactone ring on the B ring, which is a major difficulty in synthesis. The CDE ring system contains an aza[3.3.1] bridge ring system. Stereoscopically, the DE ring is in a state that is almost parallel to the F ring, which is another major difficulty in synthesis. Therefore, when developing the method, it is necessary not only to consider the construction of the five rings, but also to provide active sites for further generating derivative rings.

[0005] Since the A and E rings in the pentacyclic ring are mainly substituted benzene rings, almost all reported syntheses are started from the corresponding commercially available benzene ring compounds as starting materials. The five-ring construction methods reported so far include: Corey group (JACS, 1996, 118, 9202-9203): A→AB→ABE→ABCDE; Fukuyama group first generation (JACS, 2002, 124, 6552-6554): A→AE→ACE→ACDE→ABCDE; Fukuyama group second generation (JACS2013, 135, 13684-13687): A→ACDE→ABCDCE; Zhu group (JACS, 2006, 128, 87-89): A→ADE→ACDE→ABCDE; Ma group (ACIEE2019, 58, 3972-3975): A→AB→ABDE→ABCDE; Danishefsky group (ACIEE, 2006, 45, 1754-1759): A→AB→ABE→ABCDE; Williams group (JOC 2008, 73, 9594-9600): A→AB→ABE→ABCDE. All of the above synthetic routes introduce a ten-membered thiolactone bridge ring (F ring) and G ring and H ring at the end. The main difference is how to synthesize the ABCDE five-ring skeleton structure. The above synthetic routes still need to be further simplified, and the overall yield needs to be further improved.

[0006] Based on this, the technical solution of this application is specially proposed. Summary of the invention

[0007] In order to further simplify the synthesis route, the present application proposes a method for synthesizing the five-ring core skeleton of Trabectedin. The synthesis method realizes the large-scale preparation of the ABCDE five-ring skeleton of Trabectedin, the synthesis steps can be shortened to ten steps, and the yield can reach 12.5%.

[0008] The technical solution of this application includes the following contents:

[0009] A method for synthesizing a five-ring core skeleton of trabectedin comprises the following steps:

[0010]

[0011] Compound I and compound II are subjected to a condensation reaction to obtain compound III;

[0012] The compound III is dehydrated by removing the Boc group in an acid solution to obtain a compound IV;

[0013] After the compound IV is dissolved in a mixed solution of dichloromethane and trifluoroethanol, tert-butyldimethylsilyl acetaldehyde, acetic acid and The molecular sieves were mixed and stirred for 3 h to 5 h to obtain compound V;

[0014] The compound V and di-tert-butyl dicarbonate are subjected to an amino protection reaction to obtain a compound VI;

[0015] The compound VI and 3-bromopropylene are subjected to a hydroxyl protection reaction to obtain a compound VII;

[0016] Detaching the TBS group of the compound VII in a tetrabutylammonium fluoride solution to obtain a compound VIII;

[0017] The compound VIII is oxidized to obtain the compound IX;

[0018] The compound IX and (formylmethylene)triphenylphosphine are mixed, and stirred at 30° C. to 40° C. for 10 h to 20 h to obtain a compound X;

[0019] The compound X is dissolved in tetrahydrofuran, and a lithium bis(trimethylsilyl)amide solution is added at -80°C to -70°C, and the mixture is stirred at 20°C to 40°C for 10h to 20h to obtain a compound XI;

[0020] The compound XI is dissolved in ethylene glycol dimethyl ether, and then (2R, 5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone, trifluoroacetic acid, cerium ammonium nitrate and water are added at -80°C to -70°C, and then stirred at 20°C to 40°C for 10h to 20h to obtain compound XII.

[0021] In some embodiments, compound I and compound II are subjected to a condensation reaction to obtain compound III, comprising:

[0022] The compound I and the compound II are dissolved in tetrahydrofuran, and N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are added and mixed, and then stirred for 10 hours to 20 hours to obtain the compound II;

[0023] Optionally, the molar ratio of the compound I to the compound II is 1:(1-1.5);

[0024] Optionally, the molar ratio of the compound I to the N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(2-3):(1-1.3):(1-1.3).

[0025] In some embodiments, the compound III is dehydrated by removing the Boc group in an acid solution to obtain compound IV, comprising:

[0026] Adding a dioxane solution of hydrogen chloride to a methanol solution of the compound III at -5°C to 5°C, heating to 20°C to 40°C and stirring for 10h to 20h after the addition is complete, to obtain the compound IV;

[0027] Optionally, the molar concentration of the dioxane solution of hydrogen chloride is 3M to 5M;

[0028] Optionally, the molar ratio of the compound III to the hydrogen chloride is 1:(5-6).

[0029] In some embodiments, the volume ratio of the dichloromethane to the trifluoroethanol is (6-8):1; and / or,

[0030] The molar ratio of the compound IV to the tert-butyldimethylsilyl acetaldehyde is 1:(1-1.5); and / or,

[0031] The molar ratio of the compound IV to the acetic acid is 1:(0.2-0.4); and / or,

[0032] The The mass volume ratio of the molecular sieve to the mixed solution of dichloromethane and trifluoroethanol is 5-15 g:100 mL.

[0033] In some embodiments, the compound V and di-tert-butyl dicarbonate are subjected to an amino protection reaction to prepare compound VI, comprising:

[0034] The compound V is dissolved in dichloromethane, and N,N-diisopropylethylamine and di-tert-butyl dicarbonate are added and mixed, and then stirred for 10 hours to 20 hours to obtain the compound VI;

[0035] Optionally, the molar ratio of the compound V to the di-tert-butyl dicarbonate is 1:(1.5-2);

[0036] Optionally, the molar ratio of the compound V to the N,N-diisopropylethylamine is 1:(1-1.5).

[0037] In some embodiments, the compound VI and 3-bromopropylene are subjected to a hydroxyl protection reaction to obtain compound VII, comprising:

[0038] The compound VI and cesium carbonate are dissolved in acetonitrile, and the 3-bromopropylene is added, mixed, and stirred at 30° C. to 40° C. for 10 h to 20 h to obtain the compound VII;

[0039] Optionally, the molar ratio of the compound VI to the cesium carbonate is 1:(1-1.5);

[0040] Optionally, the molar ratio of the compound VI to the 3-bromopropylene is 1:(1-1.5).

[0041] In some embodiments, the compound VII is depolymerized with TBS in a tetrabutylammonium fluoride solution to obtain a compound VIII, comprising:

[0042] Adding a tetrahydrofuran solution of tetrabutylammonium fluoride to a tetrahydrofuran solution of the compound VII, stirring at 20° C. to 40° C. for 1 h to 3 h after the addition is complete, to obtain the compound VIII;

[0043] Optionally, the molar ratio of the compound VII to the tetrabutylammonium fluoride is 1:(1.2-1.6);

[0044] Optionally, the molar concentration of the tetrabutylammonium fluoride tetrahydrofuran solution is 0.5M to 1.5M.

[0045] In some embodiments, the compound VIII is subjected to a hydroxyl oxidation reaction to prepare a compound IX, comprising:

[0046] The compound VIII is dissolved in dichloromethane, iodobenzene diacetic acid and 9-azabicyclo[3.3.1]nonane-N-oxide are added and mixed, and then stirred at 20° C. to 40° C. for 10 h to 20 h to obtain the compound IX;

[0047] Optionally, the molar ratio of the compound VIII, the iodophenyldiacetic acid and the 9-azabicyclo[3.3.1]nonane-N-oxide is 1:(1.5-2):(0.1-0.12).

[0048] In some embodiments, the compound IX and (formylmethylene)triphenylphosphine are subjected to a Wittig addition reaction to prepare a compound X, comprising:

[0049] The compound IX is dissolved in acetonitrile, (formylmethylene)triphenylphosphine is added and mixed, and then stirred at 30° C. to 40° C. for 10 h to 20 h to obtain the compound X;

[0050] The molar ratio of the compound IX to the (formylmethylene)triphenylphosphine is 1:(1-1.5).

[0051] In some embodiments, the solution of lithium bis(trimethylsilyl)amide comprises a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran; and / or,

[0052] The molar concentration of the tetrahydrofuran solution of lithium bistrimethylsilylamide is 0.5M to 1.5M; and / or,

[0053] The molar ratio of the compound X to the lithium bis(trimethylsilyl)amide is 1:(1.5-2.5); and / or,

[0054] The molar ratio of the compound XI, the (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone, the trifluoroacetic acid, the ammonium cerium nitrate and the water is 1:(0.15-0.25):(0.15-0.25):(1.5-2.5):(1.5-2.5).

[0055] The synthesis method of the five-ring skeleton of trabectedin of the present application realizes the synthesis of the five-ring skeleton according to the construction sequence of the ring system A→AE→ADE→ACDE→ABCDE. The specific synthesis strategy is, after the large-scale synthesis of the A-ring and E-ring fragments, the connection of the AE ring system is completed by an EDCI-mediated condensation reaction, followed by the Pictet-Spengler reaction to construct the D ring, and then the C ring by the aza-Michael reaction, and finally the B ring is constructed by the SOMO organic small molecule catalytic reaction, thereby realizing the large-scale preparation of the ABCDE five-ring skeleton of trabectedin and reserving the construction site of the derivative ring, providing a more convenient preparation method for the total synthesis of trabectedin and its derivatives, and providing a material construction basis for the activity research of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0057] Figure 1 A synthetic route map for constructing the five-ring skeleton of trabectedin is provided for one embodiment of the present application. DETAILED DESCRIPTION

[0058] The present application will be further described below in conjunction with the embodiments and examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. In addition, it should be understood that after reading the content taught in the present application, those skilled in the art may make various changes or modifications to the present application, and these equivalent forms also fall within the protection scope of the claims attached to the present application.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0060] the term

[0061] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0062] The term "and / or" used in this article includes any one of two or more related listed items, and also includes any and all combinations of related listed items, and the arbitrary and all combinations include any two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0063] Herein, "preferred", "preferable", "better", etc. are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute limitations on the scope of protection of this application.

[0064] In the present application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0065] In the present application, the terms "first", "second", "third", "fourth", etc. in "the first aspect", "the second aspect", "the third aspect", "the fourth aspect", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0066] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0067] In the present application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges included therein.

[0068] The temperature parameters in this application, unless otherwise specified, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±1°C, ±0.8°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed.

[0069] In the present application, weight may be μg, mg, g, kg or other mass units known in the chemical industry.

[0070] In this application, the concentration unit M refers to mol / L. For example, a 1M sodium chloride solution means that 1 mole of sodium chloride is dissolved in 1 liter of the solution.

[0071] One or more embodiments of the present application provide a method for synthesizing the five-ring skeleton of trabectedin, which realizes the preparation of the ABCDE five-ring skeleton of trabectedin in only ten steps, and reserves the construction site of the derivative ring, thereby providing a more convenient preparation method for the total synthesis of trabectedin and its derivatives, and providing a material construction basis for the activity research of the drug.

[0072] Among them, the synthesis method of the trabectedin five-ring skeleton comprises the following steps:

[0073]

[0074] S1: condensing compound I and compound II to obtain compound III;

[0075] S2: removing the Boc group from the compound III in an acid solution to obtain compound IV;

[0076] S3: After dissolving the compound IV in a mixed solution of dichloromethane and trifluoroethanol, tert-butyldimethylsilyl acetaldehyde, acetic acid and The molecular sieves were mixed and stirred for 3 h to 5 h to obtain compound V;

[0077] S4: subjecting the compound V and di-tert-butyl dicarbonate to an amino protection reaction to obtain a compound VI;

[0078] S5: subjecting the compound VI and 3-bromopropylene to a hydroxyl protection reaction to obtain a compound VII;

[0079] S6: removing the TBS group from the compound VII in a tetrabutylammonium fluoride solution to obtain a compound VIII;

[0080] S7: subjecting the compound VIII to a hydroxyl oxidation reaction to obtain a compound IX;

[0081] S8: subjecting the compound IX to a Wittig addition reaction with (formylmethylene)triphenylphosphine to obtain a compound X;

[0082] S9: dissolving the compound X in tetrahydrofuran, adding a solution of lithium bis(trimethylsilylamide) at -80°C to -70°C, mixing, and stirring at 20°C to 40°C for 10h to 20h to obtain compound XI;

[0083] S10: After dissolving the compound XI in ethylene glycol dimethyl ether, add (2R, 5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone, trifluoroacetic acid, ammonium cerium nitrate and water at -80°C to -70°C, and stir at 20°C to 40°C for 10h to 20h to obtain compound XII.

[0084] refer to Figure 1 The synthesis method of the trabectedin five-ring skeleton of the present application realizes the synthesis of the five-ring skeleton according to the construction sequence of the ring system A→AE→ADE→ACDE→ABCDE. The specific synthesis strategy is to synthesize the A ring and E ring fragments on a large scale, and then use a condensation reaction to complete the connection of the AE ring system (refer to step S1), and then use the Pictet-Spengler reaction to construct the D ring after a suitable group protection strategy (refer to steps S2~S3), and then use the aza-Michael reaction to construct the C ring after a suitable group protection strategy and chain extension strategy (refer to steps S4~S9), and finally construct the B ring through a SOMO organic small molecule catalytic reaction (refer to S10).

[0085] Here is a detailed description of each step:

[0086] Step S1: In this step, compound I and compound II are subjected to a condensation reaction to obtain compound III.

[0087] In one embodiment, compound I and compound II are subjected to a condensation reaction to obtain compound III, comprising:

[0088] The compound I and the compound II are dissolved in tetrahydrofuran, and N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are added and mixed, and then stirred for 10 hours to 20 hours to obtain the compound II;

[0089] Optionally, the molar ratio of the compound I to the compound II is 1:(1-1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc. Optionally, the molar ratio of the compound I to the N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(2-3):(1-1.3):(1-1.3); for example, 1:2:1:1, 1:2.5:1.2:1.2, 1:3:1.2:1.2, etc.

[0090] Step S2: In this step, the Boc group of the compound III is removed in an acid solution to obtain the compound IV;

[0091] In one embodiment, the Boc group of the compound III is removed in an acid solution to obtain the compound IV, comprising:

[0092] Adding a dioxane solution of hydrogen chloride to a methanol solution of the compound III at -5°C to 5°C, heating to 20°C to 40°C and stirring for 10h to 20h after the addition is complete, to obtain the compound IV;

[0093] Optionally, the molar concentration of the dioxane solution of hydrogen chloride is 3M to 5M;

[0094] Optionally, the molar ratio of the compound III to the hydrogen chloride is 1:(5-6); for example, 1:5, 1:5.5, 1:6, etc.

[0095] Step S3: In this step, the D ring is constructed by Pictet-Spengler reaction.

[0096] In one embodiment, the compound IV is dissolved in a mixed solution of dichloromethane and trifluoroethanol, and tert-butyldimethylsilyl acetaldehyde, acetic acid and The molecular sieves were mixed and stirred for 3 h to 5 h to obtain compound V.

[0097] Optionally, the volume ratio of the dichloromethane to the trifluoroethanol is (6-8):1; for example, 6:1, 7:1, 8:1, etc.

[0098] Optionally, the molar ratio of the compound IV to the tert-butyldimethylsiloxyacetaldehyde is 1:(1-1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0099] Optionally, the molar ratio of the compound IV to the acetic acid is 1:(0.2-0.4); for example, 1:0.2, 1:0.3, 1:0.4, etc.

[0100] Optionally, the The mass volume ratio of the molecular sieve to the mixed solution of dichloromethane and trifluoroethanol is 5-15g:100mL; for example, 5g:100mL, 8g:100mL, 10g:100mL, 12g:100mL, 15g:100mL, etc.

[0101] Step S4: In this step, the compound V and di-tert-butyl dicarbonate are subjected to an amino protection reaction to obtain compound VI.

[0102] In one embodiment, the compound V and di-tert-butyl dicarbonate are subjected to an imino protection reaction to obtain compound VI, comprising:

[0103] The compound V is dissolved in dichloromethane, and N,N-diisopropylethylamine and di-tert-butyl dicarbonate are added and mixed, and then stirred for 10 hours to 20 hours to obtain the compound VI;

[0104] Optionally, the molar ratio of the compound V to the di-tert-butyl dicarbonate is 1:(1.5-2); for example, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0105] Optionally, the molar ratio of the compound V to the N,N-diisopropylethylamine is 1:(1-1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0106] Step S5: In this step, the compound VI and 3-bromopropylene are subjected to a hydroxyl protection reaction to obtain compound VII.

[0107] In one embodiment, the compound VI and 3-bromopropylene are subjected to a hydroxyl protection reaction to obtain the compound VII, comprising:

[0108] The compound VI and cesium carbonate are dissolved in acetonitrile, and the 3-bromopropylene is added, mixed, and stirred at 30° C. to 40° C. for 10 h to 20 h to obtain the compound VII;

[0109] Optionally, the molar ratio of the compound VI to the cesium carbonate is 1:(1-1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0110] Optionally, the molar ratio of the compound VI to the 3-bromopropylene is 1:(1-1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0111] Step S6: In this step, the compound VII is depolymerized with TBS in a tetrabutylammonium fluoride solution to obtain compound VIII.

[0112] In one embodiment, the compound VII is depolymerized with TBS in a tetrabutylammonium fluoride solution to obtain a compound VIII, comprising:

[0113] Adding a tetrahydrofuran solution of tetrabutylammonium fluoride to a tetrahydrofuran solution of the compound VII, stirring at 20° C. to 40° C. for 1 h to 3 h after the addition is complete, to obtain the compound VIII;

[0114] Optionally, the molar ratio of the compound VII to the tetrabutylammonium fluoride is 1:(1.2-1.6); for example, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, etc.;

[0115] Optionally, the molar concentration of the tetrabutylammonium fluoride tetrahydrofuran solution is 0.5M to 1.5M.

[0116] Step S7: In this step, the compound VIII is subjected to a hydroxyl oxidation reaction to obtain a compound IX.

[0117] In one embodiment, the compound VIII is subjected to a hydroxyl oxidation reaction to obtain a compound IX, comprising:

[0118] The compound VIII is dissolved in dichloromethane, iodobenzene diacetic acid and 9-azabicyclo[3.3.1]nonane-N-oxide are added and mixed, and then stirred at 20° C. to 40° C. for 10 h to 20 h to obtain the compound IX;

[0119] Optionally, the molar ratio of the compound VIII, the iodophenyldiacetic acid and the 9-azabicyclo[3.3.1]nonane-N-oxide is 1:(1.5-2):(0.1-0.12); for example, 1:1.5:0.1, 1:1.8:0.11, 1:2:0.12, etc.

[0120] Step S8: In this step, the compound IX and (formylmethylene)triphenylphosphine are subjected to a Wittig addition reaction to obtain a compound X.

[0121] In one embodiment, the compound IX and (formylmethylene)triphenylphosphine are subjected to a Wittig addition reaction to obtain a compound X, comprising:

[0122] The compound IX is dissolved in acetonitrile and (formylmethylene)triphenylphosphine is added and mixed, and then stirred at 30° C. to 40° C. for 10 h to 20 h to obtain the compound X;

[0123] The molar ratio of the compound IX to the (formylmethylene)triphenylphosphine is 1:(1-1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0124] Step S9: In this step, an aza-Michael reaction is performed on the C ring to obtain compound XI.

[0125] In one embodiment, the compound X is dissolved in tetrahydrofuran, and a solution of lithium bis(trimethylsilyl)amide is added at -80°C to -70°C, and then stirred at 20°C to 40°C for 10h to 20h to obtain compound XI.

[0126] Optionally, the molar ratio of the compound X to the lithium bis(trimethylsilyl)amide is 1:(1.5-2.5); for example, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, etc.

[0127] Optionally, the molar concentration of the tetrahydrofuran solution of lithium bis(trimethylsilylamide) is 0.5M to 1.5M.

[0128] Step S10: In this step, the B ring is constructed by a SOMO organic small molecule catalytic reaction to obtain compound XII.

[0129] In one embodiment, the compound XI is dissolved in ethylene glycol dimethyl ether, and then (2R, 5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone, trifluoroacetic acid, cerium ammonium nitrate and water are added at -80°C to -70°C, and then stirred at 20°C to 40°C for 10h to 20h to obtain compound XII.

[0130] Optionally, the molar ratio of the compound XI, the (2R, 5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone, the trifluoroacetic acid, the ammonium cerium nitrate and the water is 1:(0.15-0.25):(0.15-0.25):(1.5-2.5):(1.5-2.5); for example, 1:0.15:0.15:1.5:1.5, 1:0.2:0.2:2:2, 1:0.25:0.25:2.5:2.5, etc.

[0131] The following are some specific embodiments.

[0132] For experimental parameters not specified in the following specific embodiments, reference is made to the instructions given in the present application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by manufacturers.

[0133] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources, or can be prepared by those skilled in the art according to known methods.

[0134] Example 1

[0135] 1. Synthesis of Compound 2

[0136]

[0137] Substrate 1 (30 g, 169.5 mmol, 1.0 equiv.) and potassium carbonate (46.8 g, 338.9 mmol, 2.0 equiv.) were dissolved in DMF (200 mL), 3-bromopropylene (16.1 mL, 186.4 mmol, 1.1 equiv.) was added at room temperature, stirred overnight, and then quenched by adding saturated ammonium chloride solution (200 mL). Then, the organic phase was removed by rotary evaporation under reduced pressure, and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed once with saturated brine (300 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to obtain a light yellow solid 2 (34.6 g, yield 94%).

[0138] R f =0.6 (petroleum ether / ethyl acetate=8 / 1); 1 H NMR (400MHz, CDCl3) δ6.34 (s, 1H), 6.05 (s, 2H), 6.09–5.93 (m, 1H), 5.41 (dq, J = 17.3 ,1.6Hz,1H),5.30(dq,J=10.6,1.5Hz,1H),4.46(dt,J=5.1,1.6Hz,2H),2.14(s,3H);13 C NMR (101MHz, CDCl3) δ152.47,147.49,144.53,132.63,117.71,115.79,115.18,104.08,102.52,88.84,69.77,9.30.

[0139] 2. Synthesis of Compound 3

[0140]

[0141] Substrate 2 (30 g, 138.2 mmol, 1.0 equiv.) was dissolved in dichloromethane (200 mL), and a 1.5 M diisobutylaluminum hydride toluene solution (110.6 mL, 165.8 mmol, 1.2 equiv.) was added at 0°C. After stirring for 2 hours, a saturated sodium potassium tartrate solution (200 mL) was added at this temperature to quench the mixture, and the mixture was warmed to room temperature and stirred overnight until the system was clear. Then, the mixture was extracted with dichloromethane (200 mL × 3), and the combined organic phases were washed once with saturated brine (300 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude product from the concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to obtain a light yellow solid 3 (27.7 g, yield 91%).

[0142] R f =0.6 (petroleum ether / ethyl acetate=8 / 1); 1 H NMR(600MHz, CDCl3)δ10.07(s,1H),6.65(s,1H),6.08(s,2H),6.02-6.07(m,1H),5.42(dq, J=17.3,1.7Hz,1H),5.29(dq,J=10.5,1.5Hz,1H),4.52(dt,J=5.1,1.6Hz,2H),2.18(s,3H); 13 C NMR (151MHz, CDCl3) δ191.0,152.5,149.4,143.9,130.5,125.2,118.7,104.1,103.5,89.3,70.1,9.8.

[0143] 3. Synthesis of compound 4

[0144]

[0145] Substrate 3 (30.0 g, 136.3 mmol, 1.0 equiv.) and S-tert-butylsulfenamide (19.8 g, 163.6 mmol, 1.2 equiv.) were dissolved in tetrahydrofuran (200 mL), tetraethyl titanate (57.2 mL, 272.6 mmol, 2.0 equiv.) was added at room temperature, stirred overnight, quenched with saturated ammonium chloride solution (200 mL), the organic phase was removed by rotary evaporation under reduced pressure, and extracted with ethyl acetate (200 mL×3), the combined organic phase was washed once with saturated brine (300 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to obtain a light yellow solid 4 (41.0 g, yield 93%).

[0146] R f =0.3 (petroleum ether / ethyl acetate=8 / 1); 1 H NMR(600MHz, CDCl3)δ9.17(s,1H),7.79(s,1H),6.63–6.53(m,3H),5.96(dq,J=17.3,1.7Hz ,1H),5.81(dq,J=10.5,1.5Hz,1H),5.04(dt,J=5.2,1.6Hz,2H),2.69(s,3H),1.78(s,9H); 13 C NMR (151MHz, CDCl3) δ157.17,152.52,147.48,142.70,133.23,117.32,114.54,112.88,102.00,100.51,69.60,57.72,22.56,9.32.

[0147] 4. Synthesis of Compound 6

[0148]

[0149] Substrate 5 (15.0 mL, 54.1 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (100 mL), and a 2M solution of lithium diisopropylamide in tetrahydrofuran / n-heptane / ethylbenzene (29.7 mL, 59.5 mmol, 1.1 equiv.) was added at 0°C. After stirring for 1 hour, the mixture was cooled to -78°C. BOMCl (8.7 mL, 59.5 mmol, 1.1 equiv.) was then added, and the mixture was stirred and heated naturally. After 4 hours, a saturated ammonium chloride solution (100 mL) was added to quench the mixture. The organic phase was removed by rotary evaporation under reduced pressure, and then extracted with ethyl acetate (100 mL×3). The combined organic phases were washed once with saturated brine (300 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure was performed to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (pure petroleum ether) to obtain a light yellow liquid 6 (16.0 g, yield 72%).

[0150] R f =0.7 (pure petroleum ether); 1 H NMR(600MHz, CDCl3)δ7.31–7.17(m,5H),4.35(s,2H),3.68(s,

[0151] 2H),1.51–1.37(m,6H),1.27-1.19(m,6H),0.93–0.77(m,15H); 13 C NMR (151MHz, CDCl3) δ138.91,128.18,127.50,127.28,77.20,61.48,29.13,27.31,13.70,8.98.

[0152] 5. Synthesis of Compound 7

[0153]

[0154] Substrate 6 (17.9 g, 40.2 mmol, 2.6 equiv.) was dissolved in tetrahydrofuran (100 mL), and 2.5 M n-butyl lithium in n-hexane solution (14.2 mL, 35.6 mmol, 2.3 equiv.) was added at -78 °C, and stirred for 1.5 hours. At this temperature, substrate 4 (5 g, 15.5 mmol, 1.0 equiv., dissolved in 50 mL tetrahydrofuran) was slowly added, and stirred for 4 hours. At this temperature, saturated ammonium chloride solution (100 mL) was added to quench and warm to room temperature. The organic phase was removed by vacuum rotary evaporation, and then extracted with ethyl acetate (100 mL×3). The combined organic phases were washed once with saturated brine (300 mL), dried over Na2SO4, filtered, and vacuum rotary evaporation to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to obtain a yellow liquid (R)-7 (5.3 g, yield 77%).

[0155] R f =0.4 (petroleum ether / ethyl acetate=2 / 1); 1 H NMR (600MHz, CDCl3) δ7.38–7.19(m,5H),6.53(s,1H),6.07(m,1H),5.91(s,2H),5.42(dd,J=17.3,1.8Hz,1H) ,5.22(dd,J=10.6,1.7Hz,1H),4.67(m,1H),4.53(s,2H)4.47(d,2H),3.74(m,2H),2.07(s,6H),1.16(s,9H); 13 CNMR (151MHz, CDCl3) δ152.2,146.3,138.7,134.1,128.3,128.1,127.8,127.4,127.3,1 19.0,116.2,108.1,103.5,101.0,73.1,72.5,69.5,55.6,54.1,22.0,8.11; HRMS(ESI)C 24 H 32 NO5S + [M+H] + Calculated molecular weight: 446.1996; Measured molecular weight: 446.1993.

[0156] 6. Synthesis of Compound 10

[0157]

[0158] Substrate 7 (6.5 g, 14.6 mmol, 1.0 equiv.) was dissolved in methanol (300 mL), and 4 M hydrogen chloride in dioxane solution (14.6 mL, 58.4 mmol, 4.0 equiv.) was added at 0°C, and stirred for 1 hour. After removing the organic phase by vacuum rotary evaporation, ethyl acetate (100 mL) and 10% sodium hydroxide solution (100 mL) were added, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed once with 10% sodium hydroxide solution (300 mL), dried over Na2SO4, filtered, and vacuum rotary evaporation was performed to obtain a crude brown-yellow liquid (R)-8 after the organic phase was concentrated. The crude product was not purified.

[0159] The crude product 8 (1.0 equiv.) and substrate (S)-9 (5.7 g, 17.6 mmol, 1.2 equiv.) were dissolved in tetrahydrofuran (200 mL), and DIPEA (7.7 mL, 44.0 mmol, 3.0 equiv.), HOBt (2.4 g, 17.6 mmol, 1.2 equiv.) and EDCI (3.4 g, 17.6 mmol, 1.2 equiv.) were added at room temperature. After stirring overnight, saturated ammonium chloride solution (100 mL) was added to quench the mixture. The organic phase was removed by rotary evaporation under reduced pressure, and then extracted with ethyl acetate (100 mL×3). The combined organic phases were washed once with saturated sodium chloride solution (300 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure was performed to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to obtain a yellow solid (R,R)-10 (8.5 g, 2-step yield 89%).

[0160] R f =0.8 (petroleum ether / ethyl acetate=1 / 1); 1H NMR (600MHz, CDCl3) δ9.52 (s, 1H), 8.73 (d, J = 9.5Hz, 1H), 7.31-7.23 (m, 5H), 6.76 (s, 1H), 6.46 (s, 1H), 6.40 (s,1H),6.17-6.10(m,1H),5.90(dd,J=12.7,1.5Hz,2H),5.54–5.44(m,1H),5.44–5.39(m,2H),5.31–5.23( m,2H),4.74–4.61(m,2H),4.61–4.54(m,2H),4.51–4.40(m,2H),4.11–3.96(m,1H),3.85(s,3H),3.84–3.73 (m,2H),3.04(dd,J=15.3,5.1Hz,1H),2.50(dd,J=15.3,5.1Hz,1H),2.28(s,3H),2.12(s,3H),1.17(s,9H); 13 C NMR (151MHz, CDCl3) δ152.35,148.76,148.71,146.54,144.31,138.25,137.92,133.89,133.59,129.90,129.47,128.30,128.28,127.63,123. 29,116.94,116.54,113.86,109.12,103.32,100.94,72.85,69.83,60. 48,38.17,29.31,28.26,27.21,22.68,15.63,14.11,8.74; HRMS(ESI)C 36 H 45 N2O9 + [M+H] + Calculated molecular weight: 649.3120; measured molecular weight: 649.3116; chiral purity 99% ee.

[0161] 7. Synthesis of Compound 12

[0162]

[0163] The substrate 10 (5.9 g, 9.1 mmol, 1.0 equiv.) was dissolved in methanol (300 mL), and a 4 M solution of hydrogen chloride in dioxane (11.4 mL, 45.5 mmol, 5.0 equiv.) was added at 0°C, and the temperature was naturally raised and stirred overnight. The organic phase was removed by rotary evaporation under reduced pressure, and ethyl acetate (100 mL) and 10% sodium hydroxide solution (100 mL) were added, and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed once with 10% sodium hydroxide solution (300 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure was performed to obtain the crude product 11 by concentrating the organic phase.

[0164] The crude product 11 (1.0 equiv.) was dissolved in a dichloromethane / trifluoroethanol mixed solvent (50 mL, 7:1), and tert-butyldimethylsilyl acetaldehyde (12.0 mL, 11.0 mmol, 1.2 equiv.), acetic acid (0.15 mL, 2.8 mmol, 0.3 equiv.) and Molecular sieves (5g, 100% wt.), stirred for 4 hours, quenched with saturated sodium carbonate solution (50mL) at this temperature and warmed to room temperature, extracted with dichloromethane (50mL×3), the combined organic phase was washed once with saturated sodium chloride solution (200mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (dichloroethane: ethyl acetate 7:1) to obtain a yellow solid (1R, 11S, 13S)-12 (5.2g, 2-step yield of 81%).

[0165] R f =0.3 (dichloromethane / methanol=10 / 1); 1 H NMR(600MHz, CDCl3)δ7.30(d,J=9.3Hz,1H),7.21–7.13(m,5H),6.42(s,1H),6.23(s,1H),5.97–5.9 3(m,1H),5.87–5.79(m,2H),5.55–5.49(m,1H),5.32(dq,J=17.3,1.7Hz,1H),5.17(dq,J=10.6,1.5H z,1H),4.45(s,2H),4.36(dt,J=5.5,1.6Hz,2H),4.08–4.03(m,1H),3.86(d,J=5.1Hz,2H),3.78–3.7 1(m,2H),3.70(s,3H),3.67–3.58(m,2H),2.96–2.87(m,2H),2.19(s,3H),2.03(s,3H),1.07(s,9H); 13C NMR (151MHz, CDCl3) δ172.40,154.57,151.32,145.77,144.15,143.20,13 7.66,137.14,132.46,128.83,128.26,127.18,126.43,125.34,119.61,11 9.27,116.19,115.98,108.23,103.51,99.90,80.11,71.60,70.76,68.98, 65.17,57.56,51.09,30.64,26.71,24.95,17.62,14.70,7.70; HRMS(ESI)C 39 H 53 N2O8Si + [M+H] + Calculated molecular weight: 705.3566; measured molecular weight: 705.3559; chiral purity 99% ee.

[0166] 8. Synthesis of Compound 13

[0167]

[0168] The substrate 12 (5 g, 7.1 mmol, 1.0 equiv.) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (1.5 mL, 8.5 mmol, 1.2 equiv.) and di-tert-butyl dicarbonate (2.5 mL, 10.6 mmol, 1.5 equiv.) were added at room temperature. After stirring overnight, the organic phase was concentrated and evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to obtain a yellow solid 13 (5.3 g, yield 93%).

[0169] R f =0.7 (petroleum ether / ethyl acetate=2 / 1); 1H NMR(600MHz, CDCl3)δ7.30(d,J=9.3Hz,1H),7.21–7.13(m,5H),6.42(s,1H),6.23(s,1H),5.97–5.93(m,1H ),5.87–5.79(m,2H),5.55–5.49(m,1H),5.32(dq,J=17.3,1.7Hz,1H),5.17(dq,J=10.6,1.5Hz,1H),4.45(s ,2H),4.36(dt,J=5.5,1.6Hz,2H),4.08–4.03(m,1H),3.86(d,J=5.1Hz,2H),3.78–3.71(m,2H),3.70(s,3H ),3.67–3.58(m,2H),2.96–2.87(m,2H),2.19(s,3H),2.03(s,3H),1.07(s,9H),0.74(s,9H),-0.10(s,6H); 13 C NMR (151MHz, CDCl3) δ172.40,154.57,151.32,145.77,144.15,143.20,137.66,13 7.14,132.46,128.83,128.26,127.18,126.43,125.34,119.61,119.27,116.19,1 15.98,108.23,103.51,99.90,80.11,71.60,70.76,68.98,65.17,59.57,51.09,5 0.58,48.63,30.64,26.71,24.95,17.62,14.70,7.70,-1.03,-6.57.; HRMS(ESI)C 44 H 61 N2O 10 Si + [M+H] + Calculated molecular weight: 805.4090; measured molecular weight: 805.4086; chiral purity 99% ee.

[0170] 9. Synthesis of Compound 14

[0171]

[0172] Substrate 13 (5 g, 6.2 mmol, 1.0 equiv.) and cesium carbonate (2.5 g, 7.4 mmol, 1.2 equiv.) were dissolved in acetonitrile (50 mL), 3-bromopropylene (0.7 mL, 7.4 mmol, 1.2 equiv.) was added at room temperature, the temperature was raised to 35°C, stirred at this temperature overnight and then cooled to room temperature, saturated ammonium chloride solution (50 mL) was added to quench, the organic phase was removed by rotary evaporation under reduced pressure, and then extracted with ethyl acetate (50 mL×3), the combined organic phases were washed once with saturated brine (150 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to obtain yellow solid 14 (3.9 g, yield 73%).

[0173] R f =0.7 (petroleum ether / ethyl acetate=3 / 1); 1 H NMR(600MHz, CDCl3)δ7.43(d,J=9.5Hz,1H),7.22–7.12(m,5zzzH),6.63(s,1H),6.27(s,1H),6.08–6.00( m,1H),6.00–5.93(m,1H),5.81(d,J=28.1Hz,2H),5.55(s,1H),5.32(dq,J=17.3,1.7Hz,2H),5.20–5.11( m,2H),4.57–4.50(m,1H),4.45(s,2H),4.36(d,J=5.2Hz,2H),4.07(s,1H),3.87(d,J=10.4Hz,1H),3.71( s,3H),3.68–3.59(m,2H),2.97(s,2H),2.16(s,3H),2.03(s,3H),1.06(s,9H),0.74(s,9H),-0.07(s,6H); 13C NMR (151MHz, CDCl3) δ172.69,154.59,151.30,148.58,146.77,137.22,133.17,132.50, 130.48,128.93,127.16,126.46,126.38,125.96,123.44,116.69,116.29,115.96,108.2 7,103.85,99.85,79.86,72.87,71.53,70.48,69.08,65.42,59.02,57.63,51.37,48.50, 30.60,28.67,26.67,25.04,21.66,17.69,14.69,13.09,7.70,-1.04,-6.46; HRMS(ESI)C 47 H 65 N2O 10 Si + [M+H] + Calculated molecular weight: 845.4403; measured molecular weight: 845.4394; chiral purity 99% ee.

[0174] 10. Synthesis of Compound 15

[0175]

[0176] The substrate 14 (3 g, 3.5 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (30 mL), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (5.0 mL, 5.0 mmol, 1.4 equiv.) was added at room temperature. After stirring for 2 hours, the organic phase was concentrated and evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 2:1) to obtain a yellow solid 15 (2.34 g, yield 90%).

[0177] R f =0.3 (petroleum ether / ethyl acetate=3 / 1); 1H NMR (600MHz, CDCl3) δ7.74(d,J=9.0Hz,1H),7.31-7.23(m,5H),6.71(s,1H),6.32(d,J=17.9Hz,1H),6.14–6.07(m,1H) ,6.07–6.00(m,1H),5.92–5.83(m,2H),5.79–5.59(m,1H),5.44–5.36(m,2H),5.24(ddd,J=10.4,8.3,1.7Hz,2H),4.64– 4.54(m,2H),4.54–4.47(m,2H),4.47–4.38(m,2H),4.28–3.85(m,1H),3.79(s,3H),3.78-3.70(m,2H),3.45(d,J=13.8 Hz,1H),3.21(d,J=13.8Hz,1H),3.11(d,J=13.7Hz,1H),2.92(d,J=13.9Hz,1H),2.23(s,3H),2.10(s,3H),1.21(s,9H); 13 C NMR (151MHz, CDCl3) δ173.60,156.21,152.50,149.77,147.91,146.62,138.67,138. 01,134.03,133.63,131.87,129.06,128.31,127.73,127.67,126.77,124.84,118.0 0,116.94,116.75,109.17,103.50,100.98,81.30,74.11,72.96,71.96,69.83,64.7 9,60.07,57.72,51.39,48.67,31.03,29.71,28.35,27.88,15.74,8.77; HRMS(ESI)C 41 H 51 N2O 10 + [M+H] + Calculated molecular weight: 731.3538; measured molecular weight: 731.3530; chiral purity 99% ee.

[0178] 11. Synthesis of Compound 16

[0179]

[0180] Substrate 15 (2 g, 2.7 mmol, 1.0 equiv.) was dissolved in dichloromethane (20 mL), and iodophenyl diacetic acid (1.3 g, 4.1 mmol, 1.5 equiv.) and ABNO (0.04 g, 0.3 mmol, 0.1 equiv.) were added at room temperature. After stirring overnight, saturated sodium sulfite solution (20 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed once with saturated sodium chloride solution (80 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to obtain yellow solid 16 (1.4 g, yield 69%).

[0181] R f =0.4 (petroleum ether / ethyl acetate=3 / 1); 1 H NMR (600MHz, CDCl3) δ9.52 (s, 1H), 8.73 (d, J = 9.5Hz, 1H), 7.23-7.31 (m, 5H), 6.76 (s, 1H), 6.46 (s, 1H), 6.40 (s, 1 H),6.17-6.10(m,1H),6.09-6.03(m,1H),5.90(dd,J=12.7,1.5Hz,2H),5.54–5.44(m,1H),5.44–5.39(m,2H),5. 31–5.23(m,2H),4.74–4.61(m,2H),4.61–4.54(m,2H),4.51–4.40(m,2H),4.11–3.96(m,1H),3.85(sf,3H),3.84 –3.73(m,2H),3.04(dd,J=15.3,5.1Hz,1H),2.50(dd,J=15.3,5.1Hz,1H),2.28(s,3H),2.12(s,3H),1.17(s,9H); 13 C NMR (151MHz, CDCl3) δ197.57,172.31,154.96,152.35,149.91,148.03,146.58,138. 74,138.32,133.57,133.49,133.45,130.65,128.07,127.56,127.49,127.26,124.7 5,120.65,118.68,116.84,116.82,108.90,103.45,100.95,81.89,72.69,71.95,69 .64,60.23,60.04,59.17,48.52,31.78,28.01,27.55,15.78,8.70,8.64; HRMS(ESI)C41 H 49 N2O 10 + [M+H] + Calculated molecular weight: 729.3382; measured molecular weight: 729.3378; chiral purity 99% ee.

[0182] 12. Synthesis of Compound 17

[0183]

[0184] Substrate 16 (2 g, 2.7 mmol, 1.0 equiv.) was dissolved in acetonitrile (20 mL), (formylmethylene)triphenylphosphine (1.0 g, 3.3 mmol, 1.2 equiv.) was added at room temperature, the temperature was raised to 35°C, stirred overnight and then cooled to room temperature, saturated ammonium chloride solution (20 mL) was added to quench, the organic phase was removed by rotary evaporation under reduced pressure, and then extracted with ethyl acetate (20 mL×3), the combined organic phases were washed once with saturated brine (60 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure to obtain a crude product of concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to obtain yellow solid 17 (1.7 g, yield 81%).

[0185] R f =0.4 (petroleum ether / ethyl acetate=3 / 1); 1 H NMR (600MHz, CDCl3) δ9.40(s,1H),8.10(s,1H),7.34–7.23(m,5H),7.01(d,J=8.7Hz,1H),6.95(dd,J=15.6 ,5.3Hz,1H),6.76(s,1H),6.45(s,1H),6.27-6.18(m,1H),6.06-6.0z(m,1H),5.92(dd,J=12.7,1.5Hz,2H) ,5.39(dq,J=17.2,1.7Hz,1H),5.36(s,2H),5.27–5.19(m,4H),4.67-4.48(m,2H),4.44-4.42(m,2H),3.80 (s,3H),3.79-3.71(m,2H),3.65(s,2H),2.91(s,1H),2.73(s,1H),2.25(s,3H),2.10(s,3H),1.25(s,9H); 13C NMR (151MHz, CDCl3) δ193.61,155.68,154.99,152.48,150.00,147.75,146.81,138. 51,137.88,133.77,133.45,132.54,132.23,131.90,129.07,128.36,128.28,127.65 ,124.78,118.28,117.00,109.35,103.61,101.02,100.86,81.78,74.00,72.97,72. 37,72.21,69.80,60.13,58.63,48.95,31.49,29.68,22.68,15.79,8.74; HRMS(ESI)C 43 H 51 N2O 10 + [M+H] + Calculated molecular weight: 755.3538; measured molecular weight: 755.3539; chiral purity 99% ee.

[0186] 13. Synthesis of Compound 18

[0187]

[0188] The substrate 17 (2 g, 2.7 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (20 mL), and a 1 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (5.3 mL, 5.3 mmol, 2.0 equiv.) was added at -78 °C, and the mixture was naturally heated and stirred overnight, and then a saturated ammonium chloride solution (20 mL) was added to quench the mixture, and the organic phase was removed by rotary evaporation under reduced pressure, and then extracted with ethyl acetate (20 mL×3). The combined organic phases were washed once with saturated brine (60 mL), dried over Na2SO4, filtered, and rotary evaporation under reduced pressure was performed to obtain a crude product of the concentrated organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 2:1) to obtain a yellow solid diastereomer 18 (1.5 g, yield 76%, dr=1:1).

[0189] R f =0.5 (petroleum ether / ethyl acetate=3 / 1); 1H NMR(600MHz,CDCl3)δ9.68–9.56(m,1H),7.42–7.05(m,5H),6.57–6.47(m,1H),6.24–6.13(m,1H),6.12(d,J=7.0Hz,1H),6.04–5.96(m,1H),5.84–5.79(m,2H),5.41–5.36(m,2H),5.36–5.27(m,1H),5.25(dt,J=9.0,1.5Hz,2H),5.24–5.16(m,1H),4.91–4.77(m,1H),4.71–4.61(m,1H),4.59–4.47(m,1H),4.32–4.26(m,2H),4.25(s,1H),4.20(s,1H),3.67(d,J=7.2Hz,3H),3.65–3.52(m,2H),3.15–3.02(m,1H),2.97(dd,J=16.3,1.7Hz,1H),2.73–2.61(m,1H),2.38–2.21(m,1H),2.11(d,J=2.4Hz,3H),2.04(d,J=1.2Hz,3H),1.48–1.37(m,9H); 13C NMR (151MHz, CDCl3) δ198.90,198.78,168.88,168.74,153.12,152.65,152.58,149 .45,149.36,147.96,147.55,146.41,146.19,139.84,139.61,138.10,138.08,134 .34,134.06,133.44,133.42,131.98,131.87,129.20,128.77,128.54,128.17,128.14,127.62,127.41,127.39,127.36,127.29,126.95,126.07,125.83,125.43,125. 25,118.30,117.68,116.99,116.97,113.82,113.35,109.88,109.75,104.23,104.10,100.87,100.78,81.14,81.02,73.85,73.58,72.74,72.69,69.60,69.58,68.40, 68.34,65.35,59.88,59.83,56.51,56.26,55.18,54.91,53.72,52.18,50.25,49.2 5,47.16,47.05,32.72,32.28,29.67,28.30,28.23,15.71,15.70,8.75; HRMS(ESI)C 43 H 51 N2O 10 + [M+H] + Calculated molecular weight: 755.3538; measured molecular weight: 755.3537; diastereoisomer dr = 1:1.

[0190] 14. Synthesis of Compound 19

[0191]

[0192] The substrate 18 (1 g, 1.33 mmol, 1.0 equiv.) was dissolved in ethylene glycol dimethyl ether (10 mL), and (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone (0.065 g, 0.27 mmol, 0.2 equiv.), trifluoroacetic acid (0.02 mL, 0.27 mmol, 0.2 equiv.), cerium ammonium nitrate (1.41 g, 2.65 mmol, 2.0 equiv.) and water (0.05 mL, 2.65 mmol, 2.0 equiv.) were added at -78 °C. After naturally warming and stirring overnight, saturated ammonium chloride solution (10 mL) was added to quench the mixture. The organic phase was removed by rotary evaporation under reduced pressure, and then extracted with ethyl acetate (10 mL×3). The combined organic phases were washed once with saturated brine (30 mL), dried over Na2SO4, filtered, and rotary evaporated under reduced pressure to obtain a crude organic phase. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 3:1) to give yellow solid diastereomer 19 (0.67 g, yield 67%, dr = 3:3:1:1).

[0193] R f =0.5 (petroleum ether / ethyl acetate=3 / 1); 1 H NMR (600MHz, CDCl3) δ9.62–9.46(m,1H),7.25–7.02(m,5H),6.49–6.40(m,1H),6.18–6.07(m,1H),6.04(s, 1H),5.94(ddq,J=16.0,10.5,5.8Hz,2H),5.86–5.81(m,1H),5.73(s,2H),5.32(d,J=17.8Hz,2H),5.27–5. 15(m,4H),4.87–4.67(m,1H),4.65–4.38(m,3H),4.27–4.00(m,6H),3.60(s,3H),3.49(dd,J=11.3,5.0Hz, 2H),3.10–2.94(m,2H),2.90(d,J=16.4Hz,1H),2.67–2.53(m,1H),2.04(s,3H),1.97(s,3H),1.36(s,9H); 13C NMR (151MHz, CDCl3) δ197.92,197.78,167.88,152.12,151.59,148.45,146.96,145.42,137.09,133. 35,133.06,132.43,130.87,128.21,127.18,127.05,126.39,126.29,125.08,125.07,124.26,117.32 ,116.68,116.00,112.33,108.88,103.22,99.79,80.15,76.20,72.86,72.58,71.70,68.59,67.39,5 8.84,55.50,55.24,54.18,53.89,51.18,49.25,46.17,28.68,27.31,27.24,14.72,7.76; HRMS(ESI)C 43 H 49 N2O 10 + [M+H] + Calculated molecular weight: 755.3382; measured molecular weight: 755.3383; diastereoisomer dr = 3:3:1:1.

[0194] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited with all contents and all purposes. When the cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0195] The technical features of the above-mentioned implementation modes and examples can be combined in any appropriate manner. To make the description concise, not all possible combinations of the technical features in the above-mentioned implementation modes and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0196] The above-described embodiments only express several implementation methods of the present application, but they cannot be understood as limiting the scope of the patent application. It should be pointed out that, for those of ordinary skill in the art, without departing from the concept of the present application, several variations and improvements can also be made, which all belong to the protection scope of the present application. In addition, it should be understood that after reading the above-mentioned teaching content of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by those skilled in the art on the basis of the technical solutions provided in the present application through logical analysis, reasoning or limited experiments are all within the protection scope of the claims attached to the present application. Therefore, the protection scope of the patent of the present application shall be based on the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A method for synthesizing a five-ring skeleton of trabectedin, characterized in that: The steps include: Compound I and compound II are subjected to a condensation reaction to obtain compound III; The compound III is dehydrated by removing the Boc group in an acid solution to obtain a compound IV; After the compound IV is dissolved in a mixed solution of dichloromethane and trifluoroethanol, tert-butyldimethylsilyl acetaldehyde, acetic acid and The molecular sieves were mixed and stirred for 3 h to 5 h to obtain compound V; The compound V and di-tert-butyl dicarbonate are subjected to an amino protection reaction to obtain a compound VI; The compound VI and 3-bromopropylene are subjected to a hydroxyl protection reaction to obtain a compound VII; Detaching the TBS group of the compound VII in a tetrabutylammonium fluoride solution to obtain a compound VIII; The compound VIII is subjected to a hydroxyl oxidation reaction to obtain a compound IX; The compound IX and (formylmethylene)triphenylphosphine are subjected to a Wittig addition reaction to obtain a compound X; The compound X is dissolved in tetrahydrofuran, and a solution of lithium bis(trimethylsilylamide) is added at -80°C to -70°C, and then stirred at 20°C to 40°C for 10h to 20h to obtain a compound XI; The compound XI is dissolved in ethylene glycol dimethyl ether, and then (2R, 5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone, trifluoroacetic acid, cerium ammonium nitrate and water are added at -80°C to -70°C, and then stirred at 20°C to 40°C for 10h to 20h to obtain compound XII.

2. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1, characterized in that: Compound I and compound II are subjected to a condensation reaction to obtain compound III, comprising: The compound I and the compound II are dissolved in tetrahydrofuran, and N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride are added and mixed, and then stirred for 10 hours to 20 hours to obtain the compound II; Optionally, the molar ratio of the compound I to the compound II is 1:(1-1.5); Optionally, the molar ratio of the compound I to the N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(2-3):(1-1.3):(1-1.3).

3. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1 or 2, characterized in that: The compound III is subjected to de-Boc treatment in an acid solution to obtain a compound IV, comprising: Adding a dioxane solution of hydrogen chloride to a methanol solution of the compound III at -5°C to 5°C, heating to 20°C to 40°C and stirring for 10h to 20h after the addition is complete, to obtain the compound IV; Optionally, the molar concentration of the dioxane solution of hydrogen chloride is 3M to 5M; Optionally, the molar ratio of the compound III to the hydrogen chloride is 1:(5-6).

4. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1, characterized in that: The volume ratio of the dichloromethane to the trifluoroethanol is (6-8):1; and / or, The molar ratio of the compound IV to the tert-butyldimethylsilyl acetaldehyde is 1:(1-1.5); and / or, The molar ratio of the compound IV to the acetic acid is 1:(0.2-0.4); and / or, The The mass volume ratio of the molecular sieve to the mixed solution of dichloromethane and trifluoroethanol is 5-15 g:100 mL.

5. The method for synthesizing the trabectedin pentacyclic skeleton according to any one of claims 1, 2 and 4, characterized in that: The compound V and di-tert-butyl dicarbonate are subjected to an amino protection reaction to prepare the compound VI, comprising: The compound V is dissolved in dichloromethane, and N,N-diisopropylethylamine and di-tert-butyl dicarbonate are added and mixed, and then stirred for 10 hours to 20 hours to obtain the compound VI; Optionally, the molar ratio of the compound V to the di-tert-butyl dicarbonate is 1:(1.5-2); Optionally, the molar ratio of the compound V to the N,N-diisopropylethylamine is 1:(1-1.5).

6. The method for synthesizing the trabectedin pentacyclic skeleton according to any one of claims 1, 2 and 4, characterized in that: The compound VI and 3-bromopropylene are subjected to a hydroxyl protection reaction to obtain a compound VII, comprising: The compound VI and cesium carbonate are dissolved in acetonitrile, and the 3-bromopropylene is added, mixed, and stirred at 30° C. to 40° C. for 10 h to 20 h to obtain the compound VII; Optionally, the molar ratio of the compound VI to the cesium carbonate is 1:(1-1.5); Optionally, the molar ratio of the compound VI to the 3-bromopropylene is 1:(1-1.5).

7. The method for synthesizing the trabectedin pentacyclic skeleton according to any one of claims 1, 2 and 4, characterized in that: The compound VII is desorbed from the TBS group in a tetrabutylammonium fluoride solution to obtain a compound VIII, comprising: Adding a tetrahydrofuran solution of tetrabutylammonium fluoride to a tetrahydrofuran solution of the compound VII, stirring at 20° C. to 40° C. for 1 h to 3 h after the addition is complete, to obtain the compound VIII; Optionally, the molar ratio of the compound VII to the tetrabutylammonium fluoride is 1:(1.2-1.6); Optionally, the molar concentration of the tetrabutylammonium fluoride tetrahydrofuran solution is 0.5M to 1.5M.

8. The method for synthesizing the trabectedin pentacyclic skeleton according to claims 1, 2 and 4, characterized in that: The compound VIII is subjected to a hydroxyl oxidation reaction to obtain a compound IX, comprising: The compound VIII is dissolved in dichloromethane, iodobenzene diacetic acid and 9-azabicyclo[3.3.1]nonane-N-oxide are added and mixed, and then stirred at 20° C. to 40° C. for 10 h to 20 h to obtain the compound IX; Optionally, the molar ratio of the compound VIII, the iodophenyldiacetic acid and the 9-azabicyclo[3.3.1]nonane-N-oxide is 1:(1.5-2):(0.1-0.12).

9. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1, characterized in that: The compound IX and (formylmethylene)triphenylphosphine are subjected to a Wittig addition reaction to obtain a compound X, comprising: The compound IX is dissolved in acetonitrile and (formylmethylene)triphenylphosphine is added and mixed, and then stirred at 30° C. to 40° C. for 10 h to 20 h to obtain the compound X; The molar ratio of the compound IX to the (formylmethylene)triphenylphosphine is 1:(1-1.5).

10. According to the method for synthesizing the pentacyclic skeleton of trabectedin according to any one of claims 1, 2, 4 and 9, the solution of lithium bistrimethylsilylamide comprises a tetrahydrofuran solution of lithium bistrimethylsilylamide; and / or, The molar concentration of the tetrahydrofuran solution of lithium bistrimethylsilylamide is 0.5M to 1.5M; and / or, The molar ratio of the compound X to the lithium bis(trimethylsilyl)amide is 1:(1.5-2.5); and / or, The molar ratio of the compound XI, the (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone, the trifluoroacetic acid, the ammonium cerium nitrate and the water is 1:(0.15-0.25):(0.15-0.25):(1.5-2.5):(1.5-2.5).

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