WO2019114704A1 - 天然产物Trabectedin的制备 - Google Patents

天然产物Trabectedin的制备 Download PDF

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WO2019114704A1
WO2019114704A1 PCT/CN2018/120340 CN2018120340W WO2019114704A1 WO 2019114704 A1 WO2019114704 A1 WO 2019114704A1 CN 2018120340 W CN2018120340 W CN 2018120340W WO 2019114704 A1 WO2019114704 A1 WO 2019114704A1
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compound
reaction
mmol
give
reacting
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PCT/CN2018/120340
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马大为
何卫明
张志高
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中国科学院上海有机化学研究所
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Priority to JP2020552086A priority Critical patent/JP7221548B2/ja
Priority to US16/772,888 priority patent/US11339179B2/en
Priority to EP18888627.9A priority patent/EP3725792A4/en
Publication of WO2019114704A1 publication Critical patent/WO2019114704A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to the field of synthesis, and in particular, the present invention provides a process for the preparation of the natural product Trabectedin.
  • Trabectedin (ecteinascidi-743, Et-743) is an extremely complex marine natural product from the structure of the marine tunicate red sea squirt Ecteinascidia turbinata. Since its approval in the European Union for the treatment of advanced soft tissue tumors in 2007, Trabectedin has achieved hundreds of millions of dollars in sales due to its remarkable efficacy. As the first modern marine drug, the anti-tumor activity of Trabectedin is 1-3 orders of magnitude higher than that of currently available anti-tumor drugs. It is also currently considered to be the best drug for the treatment of ovarian cancer. And the Zeltia Pharma company in Spain found that the compound has significant effects on rectal cancer, breast cancer, lung cancer, melanoma and the like.
  • the current drug source is obtained by semi-synthesis of cyanosafracin B obtained by fermentation of Pseudomonas fluorescens. Even if semi-synthesis still requires 22 steps, the total yield is only 1.0%. Such an acquisition method makes the production cost of Trabectedin very high.
  • the reaction in the step (b), is carried out in a mixed solvent of (1) CH 3 CN/THF under the conditions of HCHO, NaBH 3 CN, AcOH, and (2)
  • the reaction with AllylBr in the presence of K 2 CO 3 in the presence of K 2 CO 3 gave Compound 19.
  • the reaction in the step (c), is reacted under (1) Swern oxidation conditions, reacted with compound 19 with DIPEA in DCM, and then reacted with TMSCN to obtain compound 20. .
  • the reaction in the step (d), is carried out in DCM at -80 ° C with compound 20 and BCl 3 and then with TMSCN to give compound 21.
  • step (e) compound 21 is reacted with (PhSeO) 2 O in DCM at -10 ° C to give compound 22.
  • step (f) in the step (f), in the presence of EDCI and DMAP in dichloromethane, compound 22 is used.
  • the reaction gave Compound 24.
  • the reaction is sequentially carried out in (1) DMSO solvent with compound 24 and Tf 2 O; (2) at 0 ° C, with DIPEA; (3) reacting with tBuOH at 0 ° C; (4) at room temperature, with Reaction; and (5) reaction with Ac 2 O at room temperature to give compound 25.
  • the reaction is sequentially carried out in (1) DMSO solvent with compound 24 and Tf 2 O; (2) at 0 ° C, with DIPEA; (3) reacting with tBuOH at 0 ° C; (4) at room temperature, with Reaction; and (5) reaction with Ac 2 O at room temperature to give compound 25.
  • the preparation method comprises the following steps:
  • the step is carried out by reacting Pd(PPh 3 ) 4 and Bu 3 SnH with compound 25 in DCM in the presence of AcOH to give compound 26.
  • the preparation method further comprises the following steps:
  • the step comprises: (1) using a compound in DMF at room temperature Reaction with compound 25, (2) reaction with DBU, and (3) reaction with oxalic acid give compound 28.
  • the preparation method further comprises the following steps:
  • the step comprises (1) reacting compound 28 with compound 29 in anhydrous ethanol in the presence of NaOAc to provide compound 30.
  • the preparation method further comprises the following steps:
  • the step comprises: (1) reacting compound 30 with AgNO 3 in an acetonitrile/water mixed solvent to obtain compound 31.
  • an Et-743 intermediate compound selected from the group consisting of:
  • R 1 is selected from the group consisting of H, Bn-, allyl,
  • R 2 is selected from the group consisting of H, Bn-, and allyl
  • R 3 is selected from the group consisting of H, Ac;
  • R 4 is selected from the group consisting of Cbz,
  • R is selected from the group consisting of H, OH.
  • a process for the preparation of a compound of formula 15 which comprises the steps of: (i) reacting with compound 10 to give compound 11:
  • the method comprises: reacting with the compound 10 in an inert solvent (preferably THF) under blue light to obtain the compound 11.
  • an inert solvent preferably THF
  • the method comprises: reacting with BnBr in the presence of K 2 CO 3 to obtain a compound 12; preferably, the reaction is at 55-65 It was carried out in an acetone solvent at °C.
  • the method comprises: (1) reacting in a MeOH solvent in the presence of NaOH at 100 ° C; (2) presenting NEt 3 in a DCM solvent Next, with Reaction; (3) reacting with AcCl in the presence of NEt 3 to give compound 13.
  • the method comprises: (1) carrying out the reaction at 80 ° C in CH 3 CN in the presence of POCl 3 ; (2) at 0 ° C The reaction with NaBH 4 gave Compound 14.
  • the method comprises: reacting with (Boc) 2 O in the presence of NEt 3 to obtain a compound 15.
  • the method comprises: oxidizing the compound 15 in the presence of a Swern oxidizing agent to obtain a compound 16.
  • the process is carried out in the presence of AcOH at 0 ° C in the presence of 4 A molecular sieves.
  • the method comprises: reacting Boc 2 O with compound 32 in an inert solvent (preferably DCM) in the presence of NEt3 to obtain a compound 33.
  • an inert solvent preferably DCM
  • the method comprises: reacting with the compound 33 with a Salcomine oxidizing agent and oxygen in an inert solvent (preferably CH 3 CN) to obtain a compound 34.
  • the method comprises: reacting with compound 34 in an inert solvent (preferably THF) under blue light to obtain compound 35.
  • an inert solvent preferably THF
  • the method comprises: reacting with a compound 35 in an inert solvent (preferably acetone) at 65 ° C to obtain a compound 15; preferably, the The reaction is carried out in the presence of BnBr and K 2 CO 3 .
  • an inert solvent preferably acetone
  • the method further includes the steps of:
  • the reaction comprises: oxidizing compound 8 with Salcomine reagent / O 2 in CH 3 CN at room temperature to obtain compound 10.
  • the compound 8 is prepared using tyrosine as a starting material.
  • the inert solvent is selected from the group consisting of Et 2 O, MeCN, toluene, t-BuOH, THF, DMF, acetone, or a combination thereof.
  • the blue light is light having a wavelength in the range of 400-500 nm.
  • a process for the preparation of a compound of formula 35 comprising the steps of:
  • the inert solvent is selected from the group consisting of Et 2 O, MeCN, toluene, t-BuOH, THF, DMF, acetone, or a combination thereof.
  • the blue light is light having a wavelength in the range of 400-500 nm.
  • the reaction in the step (a), is carried out in the presence of a catalyst (preferably selected from the group consisting of TFA, BF 3 ⁇ OEt 2 , HCOOH, TsOH, AcOH, Yb(OTf) 3 ).
  • a catalyst preferably selected from the group consisting of TFA, BF 3 ⁇ OEt 2 , HCOOH, TsOH, AcOH, Yb(OTf) 3 .
  • the catalyst is AcOH.
  • step (a) is carried out in the presence of 4A molecular sieve.
  • reaction is carried out at 40-60 °C.
  • the reaction is carried out at 60-80 °C.
  • a ninth aspect of the invention there is provided a method of preparing a compound 20, the method comprising the steps of:
  • the method comprises: after the reaction under Swern oxidation conditions, the ring closure is carried out in the presence of TFA, DCM, TMSCN.
  • the reaction comprises:
  • the present inventors After long-term and intensive research, the present inventors have obtained a method for synthesizing Trabectedin, which uses tyrosine as a starting substrate, can be synthesized after 26 steps of reaction, and the raw materials and reagents used in the synthetic route. Both are relatively easy to obtain, the reaction conditions are mild, and large-scale preparation can be achieved. Based on the above findings, the inventors completed the present invention.
  • the current drug source is obtained by semi-synthesis of cyanosafracin B obtained by fermentation of Pseudomonas fluorescens. Even if semi-synthesis still requires 22 steps, the total yield is only 1.0%. Such an acquisition method makes the production cost of Trabectedin very high.
  • the invention provides a novel synthetic route, starting from tyrosine and a natural chiral source, closing the five-membered ring by a simple and efficient photocatalytic reaction, and constructing the first tetrahydroisoquinoline ring by Bischler-Napieralski reaction. Or use the Pictet-Spengler reaction to close the first tetrahydroisoquinoline ring and then use a highly efficient photocatalytic reaction to close the five-membered ring.
  • the Pictet-Spengler reaction connects the left and right fragments to form a second tetrahydroisoquinoline ring in the molecular skeleton, the intramolecular Strecker reaction, and closes the piperazine ring in the molecular skeleton structure, thereby completing the molecular five-ring skeleton. Construction. Subsequent deprotection operation, condensation on the upper cysteine side chain, close the ten-membered thiolactone ring, and the second Pictet-Spengler reaction is connected to the last tetrahydroisoquinoline structure to complete the synthesis of the molecule. jobs. The route adopts a convergent synthesis strategy.
  • the shortest linear step can complete the complete synthesis of Et-743 in 26 steps, and the raw materials and reagents used in the synthetic route are relatively easy to obtain.
  • the reaction conditions are also mild, and large-scale preparation can be achieved.
  • the novel route of the present invention can separately synthesize compounds 9 and 16 from tyrosine, which synthesize key intermediate 18 by PS reaction, and then obtain compound 25 through multiple steps, which are all new synthetic routes, followed by compound 25 After deprotection, it is converted into an existing advanced intermediate, and Et-743 is synthesized by the previously reported route.
  • compound 8 was synthesized from L-tyrosine by 6 steps according to the known literature (R. Chen, D. Zhu, Z. Hu, Z. Zheng, X. Chen, Tetrahedron: Asymmetry, 2010, 21, 39-42.)
  • Compound 9 is obtained by hydrogenation of compound 8 to remove a protecting group.
  • the photocatalytic reaction of the compound 11 prepared from the compound 10 is a relatively key and novel reaction, and the method can be completed in one step, which is conventionally required to be completed in three steps, and has a good yield and a simple reaction condition, and is suitable for large-scale preparation.
  • Compound 16 can also be prepared from compound 9 by the following route, and then prepared from compound 15:
  • the inventors have optimized the two-step photoreaction of Compound 11 for the preparation of Compound 11 and Compound 34 for the preparation of Compound 35, and the results are as follows:
  • the preferred source is the blue light
  • the solvent is screened for DMF, acetone, acetonitrile, tert-butanol, toluene, etc., preferably the solvent is THF.
  • the two left and right fragments (compounds 9 and 16) were linked by a Pictet-Spengler reaction to construct a second tetrahydroisoquinoline ring in the molecular skeleton, and then the intramolecular Strecker reaction was used to close the pipe in the molecular skeleton structure.
  • the azine ring completes the construction of the molecular pentacyclic skeleton (Compound 19 to prepare compound 20).
  • Subsequent deprotection operation affords compound 22, condensed to the upper cysteine side chain to give compound 24, and the ten-membered thiolactone ring to give compound 25:
  • R 1 is selected from the group consisting of H, Bn-, allyl
  • R 2 is selected from the group consisting of H, Bn-, and allyl
  • R 3 is selected from the group consisting of H, Ac;
  • R 4 is selected from the group consisting of Cbz,
  • R is selected from the group consisting of H, OH.
  • the compound 18 can also be synthesized by using the following intermediates having different protecting groups.
  • the synthetic route of the present invention is inspired by the Et 743 source pathway, and an important starting substrate of the readily available natural chiral source tyrosine is used to rapidly and efficiently construct an important five-ring skeleton intermediate and synthesized.
  • the raw materials and reagents used in the route are relatively easy to obtain and the cost is low;
  • reaction conditions of each step of the synthesis method of the invention are relatively mild, and the photocatalytic ring-closing reaction is green and efficient, and is suitable for large-scale preparation;
  • Compound 8 was synthesized from L-tyrosine by 6 steps according to known literature (R. Chen, D. Zhu, Z. Hu, Z. Zheng, X. Chen, Tetrahedron: Asymmetry, 2010, 21, 39). -42.)
  • the raw material 8 (6.0 g, 17.38 mmol) was charged with oxygen, dissolved in a solvent of acetonitrile under an oxygen atmosphere, and the catalyst salcomine (0.56 g, 1.74 mmol) was added thereto, and the reaction was stirred under an oxygen atmosphere at room temperature, and the mixed system was black, and the reaction was complete for 2 hours.
  • the obtained crude product was dissolved in 150 mL of anhydrous methanol, and NaBH 4 (3.18 g, 84.15 mmol) was added portionwise at 0 ° C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was applied to the next step.
  • the optimum condition is AcOH, 50 °C.
  • the crude product was dissolved in 50 mL of acetone, K 2 CO 3 (4.68 g, 33.95 mmol) and allyl bromide (4.11 g, 33.95 mmol) were added, and the reaction was refluxed at 65 ° C for 4 hours. After the reaction was completed, the mixture was evaporated under reduced pressure. Acetone solvent, water and dichloromethane were extracted three times, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated. The step yield was 89%.
  • Compound 15 can also be synthesized from compound 9 according to the following optimized route.
  • the specific operation examples and compound data are as follows:

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Abstract

本发明提供了一种天然产物Trabectedin的制备方法，具体地，本发明提供了一种Et-743的制备方法，所述方法以酪氨酸为起始底物，经过26步反应即可完成合成，且合成路线中采用的原料和试剂都较易获得，反应条件也比较温和，可实现大规模的制备。

Description

天然产物Trabectedin的制备 技术领域
本发明涉及合成领域，具体地，本发明提供了一种天然产物Trabectedin的制备方法。
背景技术
Trabectedin(ecteinascidi-743，Et-743)是从海洋被囊动物红树海鞘Ecteinascidia turbinata的结构极为复杂的海洋天然产物。Trabectedin自2007年在欧盟批准上市用于晚期软组织肿瘤的治疗以来，由于其疗效显著，已经取得数亿美元的销售额。作为第一个现代海洋药物，Trabectedin抗肿瘤活性比目前临床广泛使用的抗肿瘤药物的作用活性高1-3个数量级。目前也被认为是治疗卵巢癌疗效最好的药物。而且西班牙的Zeltia Pharma公司研究发现该化合物对直肠癌、乳腺癌、肺癌、黑色素瘤等有显著的疗效。
Figure PCTCN2018120340-appb-000001
研究发现从海鞘中提取的Trabectedin(Et-743)最高获取量为0.0001％。这使得从自然界直接获得该化合物作为药源的可能性很低。目前已经有几条合成路线报道，主要都是从芝麻酚或其衍生物出发，如美国E.J.Corey教授发展的路线总长43步，收率0.53％(J.Am.Chem.Soc,1996,118,9202-9203.)；日本Fukuyama教授发展的路线总长45步，收率0.78％，由于步骤长，总产率低，部分步骤的可操作性差，这些合成路线被应用于生产的可能性也极为有限。
Figure PCTCN2018120340-appb-000002
Figure PCTCN2018120340-appb-000003
目前的药物来源是利用荧光假单孢菌通过发酵的方法获得的cyanosafracin B为原料经过半合成而得到的。即使半合成仍需要22步反应，总收率仅为1.0％。这样一种获得方式使得Trabectedin的生产成本非常高。
综上所述，本领域尚缺乏一种低成本，高效率制备Trabectedin的方法。
发明内容
本发明的目的是提供一种低成本，高效率制备Trabectedin的方法。
本发明的第一方面，提供了一种Et-743的制备方法：
Figure PCTCN2018120340-appb-000004
其特征在于，包括步骤：
(a)用化合物9与化合物16反应，得到化合物18：
Figure PCTCN2018120340-appb-000005
(b)用化合物18反应，得到化合物19：
Figure PCTCN2018120340-appb-000006
(c)用化合物19反应，得到化合物20：
Figure PCTCN2018120340-appb-000007
(d)用化合物20反应，得到化合物21：
Figure PCTCN2018120340-appb-000008
(e)用化合物21反应，得到化合物22：
Figure PCTCN2018120340-appb-000009
(f)用化合物22与
Figure PCTCN2018120340-appb-000010
反应，得到化合物24：
Figure PCTCN2018120340-appb-000011
(g)用化合物24反应，得到化合物25：
Figure PCTCN2018120340-appb-000012
和
用化合物25制备得到Et-743。
在另一优选例中，所述的步骤(a)中，所述的反应在惰性溶剂(优选为甲苯:DCM:TFE＝2.7:1:1)中，在AcOH和4A MS存在下，在70℃下进行，得到化合物18。
在另一优选例中，所述的步骤(b)中，所述的反应在(1)CH 3CN/THF混合溶剂中，在HCHO、NaBH 3CN、AcOH条件下反应后，在(2)丙酮溶剂中，在K 2CO 3存在下，回流条件下与AllylBr进行反应，得到化合物19。
在另一优选例中，所述的步骤(c)中，所述的反应在(1)Swern氧化条件下反应后，在DCM中，用DIPEA与化合物19反应，然后与TMSCN反应，得到化合物20。
在另一优选例中，所述的步骤(d)中，所述的反应在DCM中，于-80℃下用化合物20与BCl 3反应，然后与TMSCN反应，得到化合物21。
在另一优选例中，所述的步骤(e)中，在-10℃下，在DCM中，用化合物21与(PhSeO) 2O反应，得到化合物22。
在另一优选例中，所述的步骤(f)中，在二氯甲烷中，EDCI和DMAP存在下，用化合物22与
Figure PCTCN2018120340-appb-000013
反应，得到化合物24。
在另一优选例中，所述的步骤(g)中，所述的反应依次在(1)DMSO溶剂中，用化合物24与Tf 2O反应；(2)在0℃下，与DIPEA反应；(3)在0℃下，与tBuOH反应；(4)在室温下，与
Figure PCTCN2018120340-appb-000014
反应；和(5)在室温下，与Ac 2O进行反应，得到化合物25。
本发明的第二方面，提供了一种Et-743的制备方法：
Figure PCTCN2018120340-appb-000015
其特征在于，包括步骤：
(g)用化合物24反应，得到化合物25：
Figure PCTCN2018120340-appb-000016
和
用化合物25制备得到Et-743。
在另一优选例中，所述的步骤(g)中，所述的反应依次在(1)DMSO溶剂中，用化合物24与Tf 2O反应；(2)在0℃下，与DIPEA反应；(3)在0℃下，与tBuOH反应；(4)在室温下，与
Figure PCTCN2018120340-appb-000017
反应；和(5)在室温下，与Ac 2O进行反应，得到化合物25。
在另一优选例中，所述的制备方法包括如下步骤：
用化合物25进行脱保护反应，得到化合物26：
Figure PCTCN2018120340-appb-000018
优选地，所述的步骤在DCM中，在AcOH存在下，用Pd(PPh 3) 4和Bu 3SnH与化合物25反应，得到化合物26。
在另一优选例中，所述的制备方法还包括如下步骤：
用化合物26进行氧化反应，得到化合物28：
Figure PCTCN2018120340-appb-000019
优选地，所述的步骤包括(1)在DMF中，室温下，用化合物
Figure PCTCN2018120340-appb-000020
与化合物25反应，(2)用DBU继续反应，和(3)用草酸进行反应，得到化合物28。
在另一优选例中，所述的制备方法还包括如下步骤：
用化合物28与化合物29反应，得到化合物30：
Figure PCTCN2018120340-appb-000021
优选地，所述的步骤包括(1)在无水乙醇中，在NaOAc存在下，用化合物28与化合物29反应，得到化合物30。
在另一优选例中，所述的制备方法还包括如下步骤：
用化合物30反应，得到化合物31(Et-743)：
Figure PCTCN2018120340-appb-000022
优选地，所述的步骤包括(1)在乙腈/水混合溶剂中，用化合物30与AgNO 3反应，得到化合物31。
本发明的第三方面，提供了一种选自下组的Et-743中间体化合物：
Figure PCTCN2018120340-appb-000023
其中，
R 1选自下组：H、Bn-、烯丙基、
Figure PCTCN2018120340-appb-000024
R 2选自下组：H、Bn-、烯丙基；
R 3选自下组：H、Ac；
R 4选自下组：Cbz、
Figure PCTCN2018120340-appb-000025
R选自下组：H、OH。
本发明的第四方面，提供了一种式16化合物的制备方法，所述方法包括步骤：
(vi)用化合物15反应，得到化合物16：
Figure PCTCN2018120340-appb-000026
本发明的第五方面，提供了一种式15化合物的制备方法，所述方法包括步骤：(i)用化合物10反应，得到化合物11：
Figure PCTCN2018120340-appb-000027
(ii)用化合物11反应，得到化合物12：
Figure PCTCN2018120340-appb-000028
(iii)用化合物12反应，得到化合物13：
Figure PCTCN2018120340-appb-000029
(iv)用化合物13反应，得到化合物14：
Figure PCTCN2018120340-appb-000030
(v)用化合物14反应，得到化合物15：
Figure PCTCN2018120340-appb-000031
或所述的方法包括以下步骤：
(i-a)用化合物9反应，得到化合物32：
Figure PCTCN2018120340-appb-000032
(ii-a)用化合物32反应，得到化合物33：
Figure PCTCN2018120340-appb-000033
(iii-a)用化合物33反应，得到化合物34：
Figure PCTCN2018120340-appb-000034
(iv-a)用化合物34反应，得到化合物35：
Figure PCTCN2018120340-appb-000035
(v-a)用化合物35反应，得到化合物15：
Figure PCTCN2018120340-appb-000036
在另一优选例中，在所述步骤(i)中，所述的方法包括：在惰性溶剂中(优选为THF)，蓝光条件下，用化合物10反应，得到化合物11。
在另一优选例中，在所述步骤(ii)中，所述的方法包括：在K 2CO 3存在下，用BnBr进行 反应，得到化合物12；优选地，所述的反应在55-65℃下，在丙酮溶剂中进行。
在另一优选例中，在所述步骤(iii)中，所述的方法包括：(1)在NaOH存在下，在MeOH溶剂中，100℃反应；(2)在DCM溶剂中，NEt 3存在下，与
Figure PCTCN2018120340-appb-000037
反应；(3)在NEt 3存在下，与AcCl反应，得到化合物13。
在另一优选例中，在所述步骤(iv)中，所述的方法包括：(1)在POCl 3存在下，在CH 3CN中，于80℃下进行反应；(2)在0℃下，与NaBH 4反应，得到化合物14。
在另一优选例中，在所述步骤(v)中，所述的方法包括：在NEt 3存在下，与(Boc) 2O进行反应，得到化合物15。
在另一优选例中，在所述步骤(vi)中，所述的方法包括：在Swern氧化剂存在下对化合物15进行氧化，得到化合物16。
在另一优选例中，在所述步骤(i-a)中，所述的方法包括：在惰性溶剂中(优选为DCM/TFE＝7:1)，用BnOCH 2CHO与化合物9反应，得到化合物32。优选地，所述的方法在AcOH存在下，在0℃下，4A分子筛存在下进行。
在另一优选例中，在所述步骤(ii-a)中，所述的方法包括：在惰性溶剂中(优选为DCM)，在NEt3存在下，用Boc 2O与化合物32反应，得到化合物33。
在另一优选例中，在所述步骤(iii-a)中，所述的方法包括：在惰性溶剂中(优选为CH 3CN)，用Salcomine氧化剂和氧气与化合物33反应，得到化合物34。
在另一优选例中，在所述步骤(iv-a)中，所述的方法包括：在惰性溶剂中(优选为THF)，蓝光条件下，用化合物34反应，得到化合物35。
在另一优选例中，在所述步骤(v-a)中，所述的方法包括：在惰性溶剂中(优选为丙酮)，65℃下，用化合物35反应，得到化合物15；优选地，所述的反应在BnBr和K 2CO 3存在下进行。
在另一优选例中，所述的方法还包括步骤：
用化合物8反应，得到化合物10：
Figure PCTCN2018120340-appb-000038
在另一优选例中，所述的反应包括：在CH 3CN中，在室温下，用Salcomine试剂/O 2对化合物8进行氧化，得到化合物10。
在另一优选例中，所述的化合物8用酪氨酸作为原料进行制备。
本发明的第六方面，提供了一种式11化合物的制备方法，所述方法包括步骤：
在惰性溶剂中，在蓝光下，用化合物10进行光化学反应，得到式11化合物；
Figure PCTCN2018120340-appb-000039
在另一优选例中，所述的惰性溶剂选自下组：Et 2O、MeCN、甲苯、t-BuOH、THF、DMF、丙酮，或其组合。
在另一优选例中，所述的蓝光为波长范围在400-500nm的光。
本发明的第七方面，提供了一种式35化合物的制备方法，所述方法包括步骤：
在惰性溶剂中，在蓝光下，用化合物34进行光化学反应，得到化合物35：
Figure PCTCN2018120340-appb-000040
在另一优选例中，所述的惰性溶剂选自下组：Et 2O、MeCN、甲苯、t-BuOH、THF、DMF、丙酮，或其组合。
在另一优选例中，所述的蓝光为波长范围在400-500nm的光。
本发明的第八方面，提供了一种式18化合物的制备方法，所述方法包括步骤：
(a)用化合物9与化合物16反应，得到化合物18：
Figure PCTCN2018120340-appb-000041
在另一优选例中，所述的步骤(a)中，所述的反应在催化剂(优选为选自TFA、BF 3·OEt 2、HCOOH、TsOH、AcOH、Yb(OTf) 3)存在下进行，优选地，所述的催化剂为AcOH。
在另一优选例中，所述的步骤(a)在4A分子筛存在下进行。
在另一优选例中，所述的反应在40-60℃下进行。
在另一优选例中，所述的反应在选自下组的溶剂中进行：甲苯、DCM、TFE，或其组合；优选地，所述的反应在DCM：TFE＝1-10:1(优选为3-7:1)(v:v)的混合溶剂中进行。
在另一优选例中，所述的步骤(a)中，所述的反应在60-80℃下进行。
在另一优选例中，所述的反应在甲苯：DCM：TFE＝1-5：0.8-1.2：1(v:v:v))溶剂中进行。
本发明的第九方面，提供了一种化合物20的制备方法，所述方法包括步骤：
(c)用化合物19反应，得到化合物20：
Figure PCTCN2018120340-appb-000042
在另一优选例中，所述的步骤(c)中，所述的方法包括：在Swern氧化条件下反应后，在TFA、DCM、TMSCN存在下进行关环。
本发明的第十方面，提供了一种化合物25的制备方法，所述方法包括步骤：
(g)用化合物24反应，得到化合物25：
Figure PCTCN2018120340-appb-000043
在另一优选例中，所述的步骤(g)中，所述的反应包括：
化合物24依次在(1)Tf 2O,DMSO；(2)DIPEA,0℃；(3)tBuOH,室温；(4)
Figure PCTCN2018120340-appb-000044
和(5)Ac 2O,室温条件下反应，得到化合物25。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，得到了一种Trabectedin的合成方法，所述方法以酪氨酸为起始底物，经过26步反应即可完成合成，且合成路线中采用的原料和试剂都较易获得，反应条件也比较温和，可实现大规模的制备。基于上述发现，发明人完成了本发明。
Trabectedin的合成
目前的药物来源是利用荧光假单孢菌通过发酵的方法获得的cyanosafracin B为原料经过半合成而得到的。即使半合成仍需要22步反应，总收率仅为1.0％。这样一种获得方式使得Trabectedin的生产成本非常高。
本发明提供一条全新的合成路线，以酪氨酸为起始底物和天然手性源，通过简洁高效的光催化反应关上五元环，Bischler-Napieralski反应构建第一个四氢异喹啉环，或者利用Pictet-Spengler反应关上第一个四氢异喹啉环，再利用高效的光催化反应关上五元环。Pictet-Spengler反应将左右两个片段关环连接，构建分子骨架中的第二个四氢异喹啉环，分子内的Strecker反应，关上分子骨架结构中的哌嗪环，从而完成分子五环骨架的构建。随后进行脱保护基操作，缩合连接上半胱氨酸边链，关上十元硫杂内酯环，第二个Pictet-Spengler反应接上最后一个四氢异喹啉结构，从而完成该分子的合成工作。该路线采用汇聚式合成策略，从易得的天然手性源酪氨酸出发，最短线性步骤26步即可完成Et-743的全合成，而且合成路线中采用的原料和试剂都较易获得，反应条件也比较温和，可实现大规模的制备。
合成路线概览
本发明的新路线可从酪氨酸出发分别合成化合物9和16，这两个化合物通过P-S反应合成关键中间体18，再经过多步转化得到化合物25，此前都是新合成路线，随后化合物25经过脱保护转化为已有的高级中间体，并采用此前报道的路线合成Et-743。其中化合物8根据已知文献报道，从L-酪氨酸出发，经6步合成(R.Chen,D.Zhu,Z.Hu,Z.Zheng,X.Chen,Tetrahedron:Asymmetry,2010,21,39-42.)
Figure PCTCN2018120340-appb-000045
(1)化合物9的合成
化合物9由化合物8氢化脱除保护基而得。
Figure PCTCN2018120340-appb-000046
(2)化合物16的合成
从化合物8出发经多步反应通过化合物10、11、12、13、14、15制备。其中各个新化合物均通过 1H NMR， 13C NMR，MS确定结构，化合物15通过Noesy确定顺反结构。
Figure PCTCN2018120340-appb-000047
其中，由化合物10制备化合物11这一步光催化反应为比较关键和新颖的反应，该方法可以将常规需要3步完成的转化一步完成，且收率良好，反应条件简单，适合大规模制备。
化合物16也可以通过以下途径，由化合物9制备化合物15，再由化合物15制备得到：
Figure PCTCN2018120340-appb-000048
发明人对于化合物10制备化合物11，以及化合物34制备化合物35的这两步光反应进行了条件优化，结果如下：
Figure PCTCN2018120340-appb-000049
Figure PCTCN2018120340-appb-000050
Figure PCTCN2018120340-appb-000051
[a]反应条件:化合物10或34(0.5mmol),溶剂(5mL),RT,2h.
[b]产率根据 1H NMR(使用CH 2Br 2作为内标)分析计算.
由上述结果筛选得到优选光源为蓝光，对DMF，丙酮，乙腈，叔丁醇，甲苯等进行溶剂的筛选，优选溶剂为THF。
(3)化合物25的合成
通过Pictet-Spengler反应将左右两个片段(化合物9和16)关环连接，构建分子骨架中的第二个四氢异喹啉环，然后通过分子内的Strecker反应，关上分子骨架结构中的哌嗪环，从而完成分子五环骨架的构建(化合物19制备化合物20)。随后进行脱保护基操作得到化合物22，缩合连接上半胱氨酸边链得到化合物24，关上十元硫杂内酯环得到化合物25：
Figure PCTCN2018120340-appb-000052
Figure PCTCN2018120340-appb-000053
(4)Et-743的合成
从化合物25出发，参照之前Corey报道的方法合成(J.Am.Chem.Soc,1996,118,9202-9203)，通过Pictet-Spengler反应接上最后一个四氢异喹啉结构，从而完成Et-743分子的合成工作
Figure PCTCN2018120340-appb-000054
Et-743中间体化合物
在本发明方法中，得到了一系列可以用于制备Et-743的中间体化合物：
Figure PCTCN2018120340-appb-000055
Figure PCTCN2018120340-appb-000056
其中，
R 1选自下组：H、Bn-、烯丙基、
Figure PCTCN2018120340-appb-000057
R 2选自下组：H、Bn-、烯丙基；
R 3选自下组：H、Ac；
R 4选自下组：Cbz、
Figure PCTCN2018120340-appb-000058
R选自下组：H、OH。
优选的中间体结构如下：
Figure PCTCN2018120340-appb-000059
其中，化合物18也可以采用以下几个具有不同保护基的中间体进行合成。
Figure PCTCN2018120340-appb-000060
与现有技术相比，本发明的主要优点包括：
(1)本发明的合成路线从Et 743生源途径得到启发，以易得的天然手性源酪氨酸为唯一的起始底物出发，快速高效地构建重要的五环骨架中间体，且合成路线中采用的原料和试剂都较易获得，成本低廉；
(2)本发明合成方法的各步反应条件皆比较温和，光催化的关环反应绿色高效，适合大规模的制备；
(3)本发明方法合成路线短，26步即可完成Et-743的全合成，制备简单。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
化合物8根据已知文献报道，从L-酪氨酸出发，经6步合成(R.Chen,D.Zhu,Z.Hu,Z.Zheng,X.Chen,Tetrahedron:Asymmetry,2010,21,39-42.)
实施例1、化合物9的合成
Figure PCTCN2018120340-appb-000061
将化合物8(6.7g，19.4mmol)溶于甲醇中，称量0.67g的10％Pd/C于250ml的烧瓶中，氩气保护下注射甲醇，加入到体系中，氢气充换气3次，1个大气压下常温反应6小时，TLC板(DCM:MeOH＝10:1)上原料点反应完全，用硅藻土过滤掉Pd/C，减压蒸馏除去溶剂，得到4.0g化合物9，收率98％。
化合物9： 1H NMR(400MHz,CD 3OD)δ6.60(d,J＝1.9Hz,1H),6.55(d,J＝1.5Hz,1H),3.73(s,3H),3.63(dd,J＝11.3,3.9Hz,1H),3.45(dd,J＝11.2,6.6Hz,1H),3.22(td,J＝11.0,6.9Hz,1H),2.72(dd,J＝13.6,7.3Hz,1H),2.62(dd,J＝13.2,7.5Hz,1H),2.22(s,3H).
13C NMR(100MHz,CD 3OD)δ151.21,146.30,134.10,132.93,123.44,116.04,63.73,60.41,55.65,37.81,15.95.
HRMS(ESI):calcd.for C 11H 18NO 3[M+H] +212.1287；found 212.1291
实施例2、化合物10的合成
Figure PCTCN2018120340-appb-000062
将原料8(6.0g,17.38mmol)充换氧气，在氧气的气氛下加入溶剂乙腈溶解，加入催化剂salcomine(0.56g，1.74mmol)，室温氧气气氛下搅拌反应，混合体系呈黑色，2h反应完全，用硅藻土过滤除掉黑色催化剂，减压蒸馏除去溶剂，快速柱层析纯化(EA:PE＝1:2)，得到5.6g亮黄色固体10，收率91％。
化合物10： 1H NMR(400MHz,CDCl 3)δ7.35-7.25(m,5H),6.48(s,1H),5.45-5.43(d,J＝8.68Hz,1H),5.07-4.97(m,2H),4.00(s,3H),3.90-3.80(m,1H),3.67-3.51(m,2H),3.11-3.00(m,1H),2.77-2.65(m,1H),2.60-2.47(m,1H),1.93(s,3H)
13C NMR(100MHz,CDCl 3)δ188.7,188.3,156.4,155.6,145.3,136.3,132.8,128.7,128.6,128.2,128.0,66.8,64.2,60.9,52.6,31.3,9.0
HRMS(ESI):calcd.for C 19H 22NO 6[M+H] +360.1447；found 360.1451
实施例3、化合物11的合成
Figure PCTCN2018120340-appb-000063
将黄色化合物10(8.0g，22.3mmol)溶解在220mL无水THF溶剂中，氩气保护，在蓝光照射下室温搅拌反应，8h后反应完全。减压蒸馏除去THF溶剂。快速柱层析纯化(EA:PE＝1:2),得到6.6g白色固体产物11，收率82％。:
化合物11： 1H NMR(400MHz,CDCl 3)δ7.43-7.30(m,5H),6.41(s,1H),5.86(s,2H),5.54-5.52(d,J＝7.24Hz,1H),5.11(s,2H),3.79-3.31(m,4H),2.90-2.67(m,2H),2.13(s,3H)
13C NMR(100MHz,CDCl 3)δ157.1,148.3,145.7,140.3,136.1,128.6,128.3,128.2,114.4,108.8,107.0,100.7,67.2,62.4,53.7,31.9,9.2
HRMS(ESI):calcd.for C 19H 22NO 6[M+H] +360.1447；found 360.1452
实施例4、化合物12的合成
Figure PCTCN2018120340-appb-000064
将化合物11(6.6g,18.38mmol)溶于180mL丙酮中，加入K 2CO 3(5.07g,36.77mmol)和BnBr(3.27mL,27.57mmol)，65℃条件下回流反应两小时，点板监测反应已经完全，减压蒸馏除掉丙酮，加水，用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸馏除去溶剂，快速柱层析(EA：PE＝3:1)，得到产品7.67g。收率93％。
化合物12： 1H NMR(400MHz,CDCl 3)δ7.46–7.29(m,10H),6.57(s,1H),5.94(s,2H),5.37(d,J＝7.6Hz,1H),5.08(s,2H),4.78(dd,J＝34.5,11.0Hz,2H),3.80–3.68(m,1H),3.43(d,J＝2.7Hz,2H),2.75(d,J＝7.3Hz,2H),2.22(s,3H).
13C NMR(101MHz,CDCl 3)δ156.44,150.12,145.82,143.67,136.59,136.38,128.82,128.58,128.51,128.05,128.03,127.96,122.74,113.45,107.28,101.26,76.07,66.62,63.31,54.23,31.56,9.80.
HRMS(ESI):calcd.for C 26H 27NO 6[M+H] +450.1917；found 450.1918
实施例5、化合物13的合成
Figure PCTCN2018120340-appb-000065
将化合物12(2.54g,5.66mmol)溶解在50mL的甲醇中，加入2M的NaOH水溶液30mL，此时混合液呈浑浊状，升温至100℃回流，体系逐渐变澄清。2小时后反应完全，减压蒸馏除去甲醇，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压蒸馏除去溶剂，得到的粗品溶解在50mL的无水二氯甲烷中，加入NEt 3(3.13mL,22.64mmol),0℃条件下缓慢滴加溶于10mL二氯甲烷的苄氧基乙酰氯(0.8mL,5.1mmol),15min滴加完毕，反应完全，加入(Ac) 2O(1.07mL,11.32mmol),室温下反应2小时。反应完毕后，二氯甲烷萃取三次，合并有机相，减压蒸馏除去溶剂，快速柱层析(EA：PE＝1:3)，得到2.3g白色固体化合物13，两步收率81％。
化合物13： 1H NMR(400MHz,CDCl 3)δ7.46–7.29(m,8H),7.27–7.23(m,2H),6.95(d,J＝8.2Hz,1H),6.52(s,1H),5.93(d,J＝0.6Hz,2H),4.83–4.68(m,2H),4.46(d,J＝6.7Hz,2H),4.40–4.28(m,1H),4.13–3.99(m,2H),3.87(d,J＝13.8Hz,2H),2.17(s,3H),1.94(s,3H).
13C NMR(100MHz,CDCl 3)δ170.8,169.5,150.5,145.8,143.3,137.2,137.0,128.58,128.55,127.75,127.69,122.35,113.6,107.0,101.2,75.4,73.4,69.4,65.1,49.2,31.8,20.7,9.8.
HRMS(ESI):calcd.for C 29H 32NO 7[M+H] +506.2179；found 506.2183
实施例6、化合物14的合成
Figure PCTCN2018120340-appb-000066
氩气保护条件下，将化合物13(8.5g,16.83mmol)溶解在170mL无水乙腈中，加入POCl 3(3.14mL,33.66mmol),升温至80℃回流反应3小时，反应完全后，加入饱和的NaHCO 3溶液至反应液中性，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏除掉溶剂，抽干。将所得的粗产品溶解于150mL的无水甲醇中，0℃分批加入NaBH 4(3.18g,84.15mmol),反应4小时。反应完全后，减压蒸馏除去溶剂，得到的粗产品用于下步反应。
化合物14a： 1H NMR(400MHz,CDCl 3)δ7.46–7.26(m,10H),5.83(s,1H),4.81(d,J＝11.2Hz,1H),4.69(d,J＝11.2Hz,1H),4.55(q,J＝12.0Hz,1H),4.28(d,J＝4.5Hz,1H),4.12(dd,J＝9.3,2.9Hz,1H),3.85(dd,J＝9.3,6.6Hz,1H),3.78(dd,J＝10.9,3.7Hz,1H),3.53(dd,J＝10.9,7.5Hz,1H),2.97–2.85(m,1H),2.81(dd,J＝15.9,2.8Hz,1H),2.32(dd,J＝15.5,11.4Hz,1H),2.15(s,1H).
13C NMR(100MHz,CDCl 3)δ149.65,144.39,139.49,138.31,137.37,128.56,128.31,128.09,127.85,127.77,127.62,121.95,115.17,112.22,100.70,74.58,73.27,71.53,65.94,54.42,54.09,26.70,9.46.
HRMS(ESI):calcd.for C 27H 30NO 5[M+H] +448.2124；found 448.2120
化合物14b： 1H NMR(400MHz,CDCl 3)δ7.44–7.22(m,10H),5.83(dd,J＝10.4,1.4Hz,2H),4.77(d,J＝11.2Hz,1H),4.66(dt,J＝11.1,5.7Hz,2H),4.52–4.44(m,2H),3.79(ddd,J＝13.7,10.8,2.9Hz,2H),3.61(dd,J＝19.2,9.7Hz,2H),3.22–3.12(m,1H),2.74(dd,J＝16.6,3.8Hz,1H),2.53(dd,J＝16.6,11.1Hz,1H),2.12(s,3H).
13C NMR(100MHz,CDCl 3)δ149.60,144.45,139.57,137.89,137.26,128.55,128.43,128.11,127.93,127.82,127.78,119.97,112.75,112.30,101.23,74.42,73.11,68.32,64.73,51.03,49.57,25.17,9.44
HRMS(ESI):calcd.for C 27H 30NO 5[M+H] +448.2124；found 448.2120
实施例7、化合物15的合成
Figure PCTCN2018120340-appb-000067
.将上步得到的化合物14粗产品溶解在150mL二氯甲烷中，加入(Boc) 2O(11.02g,50.49mmol)和NEt 3(6.98mL,50.49mmol),室温搅拌反应4小时。反应完全后，加入100mL的水，二氯甲烷萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(EA:PE＝6:1),得到4.69g无色油状化合物15，三步收率51％。
化合物15:
Figure PCTCN2018120340-appb-000068
(c＝1.0,CHCl 3) 1H NMR(400MHz,CDCl 3)δ7.45–7.25(m,10H),5.86(t,J＝5.4Hz,2H),5.77–5.42(m,1H),4.73(s,2H),4.71–4.57(m,1H),4.52(d,J＝11.8Hz,1H),4.28(d,J＝37.5Hz,1H),3.93–3.68(m,3H),3.57–3.19(m,2H),2.99–2.69(m,2H),2.18(s,3H),1.46(s,9H).
化合物15: 13C NMR(100MHz,CDCl 3)δ155.84,149.26,144.52,139.33,137.68,137.12,128.60,128.34,128.23,128.02,127.76,127.74,80.53,75.22,72.89,70.58,64.36,52.52,49.88,48.51,28.42,23.44,9.50.
HRMS(ESI):calcd.for C 32H 37NO 7Na[M+Na] +570.2468；found 570.2472
实施例8、化合物16的合成
Figure PCTCN2018120340-appb-000069
将(COCl) 2(0.9mL,10.97mmol)溶解于2mL的无水二氯甲烷中，氩气保护，-78℃条件下缓慢滴加溶于2mL二氯甲烷的DMSO(1.56mL,21.94mmol),保持该温度反应30min，随后将化合物15(1.5g,2.74mmol)溶于26mL的二氯甲烷中，缓慢滴加入到体系中。保持-78℃反应。1小时后，加入DIPEA(4.77mL,27.42mmol),-78℃反应30min。反应完全后，加入10mL的饱和氯化铵溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(EA:PE＝1:5)，得到1.43g化合物16，收率95％。
化合物16: 1H NMR(400MHz,CDCl 3)δ9.46(d,J＝1.6Hz,0.44H),9.41(d,J＝2.7Hz,0.59H),7.45–7.14(m,10H),5.88(d,J＝10.3Hz,2H),5.52(t,J＝4.6Hz,0.52H),5.28(t,J＝4.7Hz,0.45H),4.80–4.68(m,2H),4.56–4.43(m,2H),4.26(t,J＝6.8Hz,0.38H),4.01–3.91(m,0.52H),3.84–3.59(m,2H),3.04–2.67(m,2H),2.18(s,3H),1.48(s,4H),1.43(s,5H).
13C NMR(101MHz,CDCl 3)δ200.30,199.82,155.62,154.78,149.10,148.73,145.00,144.85,139.54,139.35,138.13,137.93,137.09,136.90,128.61,128.26,128.18,127.59,118.59,118.30,114.50,113.88,112.95,112.79,101.37,101.26,81.87,81.49,75.64,75.56,72.96,72.30,71.99,60.66,59.62,50.34,49.48,28.34,28.25,22.16,21.81,9.52.
HRMS(ESI):calcd.for C 32H 35NO 7Na[M+Na] +568.2311；found 568.2310
实施例9、化合物18的合成
Figure PCTCN2018120340-appb-000070
氩气保护下，将化合物16(3.92g,7.19mmol)和化合物9(2.28g,10.79mmol),4A 分子筛(3.9g)混合，溶于40mL/15mL/15mL＝Toluene:DCM:TFE混合溶剂中，加入AcOH(2.06mL，35.96mmol)，70℃条件下过夜反应。反应完全后，硅藻土过滤除去分子筛，减压蒸馏除去溶剂，快速柱层析(EA:PE＝1:2),得到3.58g化合物18，收率67％。
化合物18：
Figure PCTCN2018120340-appb-000071
(c＝1.0,CHCl 3) 1H NMR(400MHz,CDCl 3)δ7.35–7.19(m,8H),7.05(d,J＝6.4Hz,2H),6.44(s,1H),5.99(s,0.48H),5.85(s,2H),5.64(s,0.52H),5.24(s,1H),5.04(s,1H),4.81–4.29(m,6H),4.01(d,J＝49.6Hz,1H),3.67(d,J＝7.0Hz,3H),3.57–3.35(m,3H),3.10–2.92(m,1.52H),2.72–2.57(m,1.42H),2.50–2.32(m,2H),2.26(s,3H),2.16(s,13H),1.53(s,9H).
13C NMR(100MHz,CDCl 3)δ177.04,156.82,148.77,148.58,146.83,146.17,144.36,143.58,139.24,138.16,137.71,136.67,132.61,131.94,128.54,128.36,122.23,121.54,120.99,119.38,115.03,114.74,112.76,112.46,101.35,81.28,80.77,75.94,75.61,72.14,71.78,66.66,66.19,60.46,60.23,57.67,55.28,54.73,53.88,53.55,52.84,49.91,48.65,32.84,22.57,20.96,20.00,15.86,9.40.
HRMS(ESI):calcd.for C 43H 50N 2O 9[M+H] +739.3595；found 739.3599
对于上述反应，发明人对溶剂体系，以及酸进行了条件筛选：筛选结果如下：
对酸以及反应温度进行筛选：
Figure PCTCN2018120340-appb-000072
最优条件为AcOH，50℃。
对反应溶剂以及酸的当量进行条件筛选：
Figure PCTCN2018120340-appb-000073
Figure PCTCN2018120340-appb-000074
优选条件为：反应溶剂为DCM/TFE＝5:1，AcOH当量为3当量，反应温度为50℃。
实施例10、化合物19的合成
Figure PCTCN2018120340-appb-000075
氩气保护下，将化合物18(3.58g,4.85mmol)溶于CH 3CN/THF(40mL:10mL)混合溶剂中，加入37％的甲醛溶液(3.93g,48.5mmol)，室温下搅拌反应20分钟，后加入NaBH 3CN(0.76g,12.13mmol)，室温下搅拌反应20分钟，加入AcOH(0.69mL,12.13mmol)，室温下搅拌反应90分钟，反应完全后，减压蒸馏除去溶剂，加饱和碳酸氢钠溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂得到粗产品。将粗产品溶于50mL的丙酮中，加入K 2CO 3(4.68g,33.95mmol)和烯丙基溴(4.11g,33.95mmol)，65℃回流反应4小时，反应完全后，减压蒸馏除去丙酮溶剂，加水，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(EA:PE＝1:3),得3.42g化合物19，两步收率89％。
化合物19： 1H NMR(400MHz,CDCl 3)δ7.42–7.21(m,8H),7.08(s,2H),6.72(s,1H),6.37(s,1H),5.90–5.84(m,2H),5.60(s,1H),5.44–5.01(m,3H),4.65–4.48(m,4H),4.43(s,1H),4.31(s,1H),4.12(dd,J＝14.2,7.1Hz,1H),3.94–3.69(m,3H),3.60(s,3H),3.48(d,J＝11.0Hz,1H),3.13–2.64(m,4H),2.59–2.32(m,5H),2.23(s,3H),2.14(s,3H),1.48(s,9H).
13C NMR(100MHz,CDCl 3)δ171.20,155.76,149.88,148.59,148.27,144.26,139.41,138.39,136.76,134.88,133.13,130.37,128.53,128.37,128.18,128.15,127.67,127.39,124.66,120.93,118.42,112.25,101.13,79.97,75.82,74.49,72.50,64.06,62.45,59.97,51.12,45.34,33.31,21.09,15.90,14.23,9.36.
HRMS(ESI):calcd.for C 47H 57N 2O 9[M+H] +793.4064；found 793.4068
实施例11、化合物20的合成
Figure PCTCN2018120340-appb-000076
将(COCl) 2(1.21mL,14.75mmol)溶解于3mL的无水二氯甲烷中，氩气保护，-78℃条件下缓慢滴加溶于3mL二氯甲烷的DMSO(2.10mL,29.52mmol),保持该温度反应30min，随后将化合物19(2.92g,3.69mmol)溶于30mL的二氯甲烷中，缓慢滴加入到体系中。保持-78℃反应。1小时后，加入DIPEA(4.50mL,25.83mmol),-78℃反应30min。 反应完全后，加入15mL的饱和氯化铵溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，得到的粗品溶于40mL DCM/TFA＝4:1的混合溶剂中，室温下搅拌反应2小时，加入TMSCN(1.83g,18.45mmol)，室温下搅拌反应2小时，缓慢加入饱和碳酸氢钠溶液，二氯甲烷萃取三次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(EA/PE＝1:3)，得到2.22g化合物20，两步收率86％。
化合物20： 1H NMR(400MHz,CDCl 3)δ7.54–7.21(m,10H),6.65(s,1H),6.01(ddt,J＝16.4,10.4,6.0Hz,1H),5.89(dd,J＝19.3,1.3Hz,2H),5.31(dd,J＝17.1,1.4Hz,1H),5.12(d,J＝10.3Hz,1H),4.68(dd,J＝11.5,6.4Hz,2H),4.55–4.43(m,3H),4.38–4.26(m,2H),4.18(dd,J＝8.5,2.1Hz,1H),4.10(d,J＝2.2Hz,1H),3.69(s,3H),3.55(dd,J＝9.2,2.5Hz,1H),3.32(dd,J＝15.4,2.2Hz,1H),3.28–3.12(m,3H),2.94(dd,J＝17.7,8.1Hz,1H),2.61(d,J＝17.7Hz,1H),2.28(s,3H),2.24(s,3H),2.12(s,3H),1.92(dd,J＝15.3,11.6Hz,1H).
13C NMR(101MHz,CDCl 3)δ149.67,148.70,148.20,144.36,139.37,138.39,137.13,134.28,130.77,130.23,128.58,128.39,128.36,128.25,127.52,127.37,124.66,124.06,121.47,118.79,117.95,112.80,112.21,101.13,76.43,75.21,73.83,73.39,61.96,59.99,57.33,57.25,57.01,55.53,41.78,26.40,25.51,15.89,9.33.
HRMS(ESI):calcd.for C 43H 46N 3O 6[M+H] +700.3387；found 700.3390
实施例12、化合物21的合成
Figure PCTCN2018120340-appb-000077
氩气保护下，将化合物20(0.5g,0.715mmol)溶解在10mL的无水二氯甲烷中，冷却至-80℃，缓慢滴加1M的BCl 3的二氯甲烷溶液(5.01mL,5.01mmol),维持该温度反应1小时，反应完全后，-80℃条件下加入5mL的甲醇淬灭，减压蒸馏除去溶剂，加入饱和碳酸氢钠溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(DCM/MeOH＝20:1),得到0.30g化合物21，收率为81％。
化合物21: 1H NMR(400MHz,CDCl 3)δ6.68(s,1H),6.10(ddd,J＝16.1,10.8,5.7Hz,1H),5.85(d,J＝21.2Hz,2H),5.43(dd,J＝17.2,1.5Hz,1H),5.26(dd,J＝10.4,1.0Hz,1H),4.96(s,1H),4.71(dd,J＝12.6,5.5Hz,1H),4.41(ddt,J＝12.7,5.8,1.2Hz,1H),4.14(d,J＝2.0Hz,1H),4.05(d,J＝2.5Hz,1H),3.97(t,J＝3.0Hz,1H),3.77(s,3H),3.63(dd,J＝11.1,3.5Hz,1H),3.43(d,J＝10.2Hz,1H),3.39–3.30(m,2H),3.13–2.98(m,2H),2.51(d,J＝18.1Hz,1H),2.33(s,3H),2.21(s,3H),2.07(s,3H),1.81(dd,J＝15.4,11.9Hz,1H).
化合物21: 13C NMR(100MHz,CDCl 3)δ149.58,149.10,145.14,144.40,136.49,134.18,131.21,129.56,124.95,123.59,117.80,117.68,113.36,113.09,106.29,100.87,73.58,63.71,60.21,60.17,58.08,57.20,56.62,55.37,41.78,25.80,25.65,15.80,8.82.
HRMS(ESI):calcd.for C 29H 34N 3O 6[M+H] +520.2448；found 520.2450
实施例13、化合物22的合成
Figure PCTCN2018120340-appb-000078
氩气保护下，将化合物21(0.6g,1.16mmol)溶解在30mL的无水二氯甲烷中，冷却至-10℃，将(PhSeO) 2O(0.37g,1.16mmol)溶解在10mL的二氯甲烷中，缓慢加入到反应体系中，在-10℃条件下反应10分钟，反应完全后，加入饱和的碳酸氢钠溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(EA/PE＝1:1)，得到0.53g化合物22，收率为86％。
化合物22isomer 1： 1H NMR(400MHz,CDCl 3)δ6.62(s,1H),5.99(ddt,J＝16.3,10.4,5.8Hz,1H),5.86(s,1H),5.76(s,1H),5.29(dd,J＝17.1,1.5Hz,1H),5.20(dd,J＝10.4,1.3Hz,1H),4.56(ddt,J＝12.5,5.6,1.3Hz,1H),4.29(ddt,J＝12.5,6.1,1.2Hz,1H),4.24(d,J＝2.8Hz,1H),4.09(dd,J＝13.4,1.2Hz,1H),4.03–3.94(m,2H),3.75(dt,J＝11.9,2.8Hz,1H),3.68(s,3H),3.62(d,J＝2.7Hz,1H),3.39(d,J＝8.7Hz,1H),3.03–2.84(m,2H),2.54(d,J＝17.9Hz,1H),2.22(s,3H),2.20(s,3H),2.12(dd,J＝14.0,2.8Hz,1H),1.80(s,3H).
13C NMR(101MHz,CDCl 3)δ200.47,159.83,149.49,148.70,137.64,134.05,130.63,130.12,124.74,123.84,117.81,116.66,113.61,105.04,100.80,73.26,72.25,59.94,58.33,57.27,56.71,56.65,56.04,55.21,41.55,41.48,25.49,15.92,7.16.
HRMS(ESI):calcd.for C 29H 34N 3O 7[M+H] +536.2397；found 536.2400
化合物22isomer 2： 1H NMR(400MHz,CDCl 3)δ6.69(s,1H),6.01(ddt,J＝16.5,10.4,5.8Hz,1H),5.85(d,J＝0.7Hz,2H),5.32(dd,J＝17.1,1.5Hz,1H),5.18(dd,J＝10.3,1.3Hz,1H),4.72(dd,J＝12.6,5.5Hz,1H),4.33(dd,J＝12.6,6.1Hz,1H),4.09(d,J＝2.6Hz,1H),4.01(d,J＝2.3Hz,1H),3.96(s,3H),3.87(t,J＝3.4Hz,1H),3.78(dd,J＝11.6,4.0Hz,1H),3.61(dd,J＝11.7,2.9Hz,1H),3.30(dd,J＝12.9,5.1Hz,2H),3.01(dd,J＝18.0,7.9Hz,1H),2.60(d,J＝17.9Hz,1H),2.29(s,3H),2.23(s,3H),2.19(dd,J＝10.7,4.8Hz,1H),1.98(dd,J＝15.4,8.1Hz,1H),1.80(s,3H).
13C NMR(100MHz,CDCl 3)δ198.75,158.94,149.31,149.24,140.37,134.11,131.27,130.14,125.10,122.64,117.80,116.96,111.09,104.36,101.64,73.73,70.32,61.58,60.64,58.42,57.96,57.31,55.24,55.20,41.85,36.37,25.66,15.83,7.32.
HRMS(ESI):calcd.for C 29H 34N 3O 7[M+H] +536.2397；found 536.2400
实施例14、化合物24的合成
Figure PCTCN2018120340-appb-000079
氩气保护下，将化合物22(180mg,0.336mmol)，化合物23(387mg,1.01mmol)，EDCI(321mg,1.68mmol)和DMAP(205mg,1.68mmol)混合溶解在30mL的无水二氯甲烷中，室温下搅拌反应5小时，反应完全后，加入饱和的氯化铵溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(EA/PE＝1:2)得到261mg化合物24，收率85％。
化合物24： 1H NMR(400MHz,CDCl 3)δ7.74(d,J＝7.5Hz,2H),7.66(d,J＝7.4Hz,2H),7.41–7.35(m,2H),7.34–7.27(m,2H),6.54(d,J＝11.7Hz,1H),6.03–5.84(m,2H),5.71–5.58(m,3H),5.37–5.13(m,5H),4.68(d,J＝12.5Hz,1H),4.60–4.47(m,4H),4.39(dd,J＝12.7,5.0Hz,1H),4.28(dd,J＝12.5,6.1Hz,1H),4.11(t,J＝6.0Hz,1H),3.95(dd,J＝9.1,6.3Hz,1H),3.87(d,J＝2.5Hz,1H),3.71(s,1H),3.67(s,1H),3.27(t,J＝8.5Hz,1H),3.15(d,J＝6.3Hz,1H),2.97(d,J＝3.0Hz,1H),2.84(dd,J＝17.9,8.4Hz,1H),2.39(d,J＝17.8Hz,1H),2.19(s,1H),2.16(d,J＝4.1Hz,1H),1.77(d,J＝6.9Hz,1H).
13C NMR(101MHz,CDCl 3)δ200.23,170.52,160.06,155.82,149.48,148.68,145.62,145.59,145.54,141.11,141.07,138.54,138.49,134.04,132.44,130.67,129.97,127.69,127.14,124.84,124.80,124.62,123.72,119.93,118.01,117.79,116.82,111.54,104.87,101.04,73.22,72.25,66.02,63.77,59.92,58.11,56.61,56.56,56.09,55.20,54.02,46.95,46.88,41.81,41.44,35.95,35.23,31.91,29.29,25.52,22.68,7.12.
HRMS(ESI):calcd.for C 50H 53N 4O 10S[M+H] +901.3482；found 901.3484
实施例15、化合物25的合成
Figure PCTCN2018120340-appb-000080
将Tf 2O(34μL,0.2mmol)加入干燥的氩气保护的反应瓶中，-78℃条件下缓慢滴加溶于4.5mL干燥二氯甲烷的DMSO(36μL,0.5mmol),保持该温度反应20min，随后将化合物24(90mg,0.1mmol)溶解在1.5mL的无水二氯甲烷中，保持-78℃温度缓慢加入到体系中，加完后升温至-40℃，反应40min，随后缓慢滴加DIPEA(139μL,0.8mmol),升温至0℃，反应45min，加入 tBuOH(29μL,0.3mmol)，0℃条件下反应40min，反应完毕后，移至室温，加入(MeN) 2C＝N- tBu(141μL,0.7mmol)，室温下反应40min，加入(Ac) 2O(38μL,0.4mmol)，室温下搅拌反应15min，反应完全后，加入饱和氯化铵溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压蒸馏除去溶剂，快速柱层析(EA/PE＝1:3)，得到36mg化合物25，收率为49％。
化合物25： 1H NMR(400MHz,CDCl 3)δ6.78(s,1H),6.15–5.88(m,4H),5.45(d,J＝17.1Hz,1H),5.32(d,J＝17.2Hz,1H),5.25(d,J＝10.4Hz,2H),5.02(d,J＝11.6Hz,1H),4.81(d,J＝9.7Hz,2H),4.65–4.44(m,3H),4.39–4.27(m,2H),4.26–4.12(m,4H),3.80(s,3H),3.46–3.35(m,2H),2.98–2.88(m,J＝12.3Hz,2H),2.27(s,6H),2.20(s,3H),2.13(d,J＝15.7Hz,1H),2.03(s,3H).
13C NMR(100MHz,CDCl 3)δ170.41,168.60,155.43,150.85,148.87,145.77,140.92,140.38,134.53,132.88,131.72,129.97,124.71,124.62,120.22,118.02,118.00,116.64,113.54,113.38,102.02,72.92,65.86,61.34,60.50,59.45,59.28,59.20,55.08,54.60,53.89,41.68,41.58,32.81,23.76,20.46,15.78,9.62.
HRMS(ESI):calcd.for C 38H 43N 4O 10S[M+H] +747.2700；found 747.2704
实施例16、化合物26的合成
Figure PCTCN2018120340-appb-000081
氩气保护下，将化合物25(108mg,0.145mmol)和Pd(PhPPh 3) 4(66.84mg,0.058mmol)，溶解于5mL的二氯甲烷中，加入Bu 3SnH(0.12ml,0.434mmol)和AcOH(0.05ml,0.868mmol)，室温下搅拌反应3小时，反应完全后，加入饱和碳酸氢钠溶液，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(DCM/MeOH＝10:1)，得到76mg的化合物26，收率85％。
化合物26： 1H NMR(400MHz,CDCl 3)δ6.51(s,1H),6.07(d,J＝1.3Hz,1H),5.98(d,J＝1.3Hz,1H),5.01(d,J＝11.5Hz,1H),4.52(s,1H),4.25(d,J＝4.7Hz,2H),4.18(d,J＝2.5Hz,1H),4.13(dd,J＝11.6,1.8Hz,1H),3.78(s,2H),3.43-3.38(m,2H),3.32(s,1H),2.92-2.87(m,2H),2.30(s,3H),2.28(s,3H),2.22(m,2H),2.18(s,3H),2.03(s,3H).
13C NMR(100MHz,CDCl 3)δ174.11,168.65,147.91,145.69,142.97,141.02,140.34,130.51,129.41,120.80,120.44,118.25,118.17,113.71,113.38,101.95,61.39,60.24,60.12,59.35,59.15,54.68,54.62,53.98,41.78,41.52,34.22,23.83,20.60,15.70,9.64.
HRMS(ESI):calcd.for C 31H 35N 4O 8S[M+H] +623.2176；found 623.2180
实施例17、化合物28的合成
Figure PCTCN2018120340-appb-000082
氩气保护下，将化合物27(44mg,0.157mmol)溶解在1.5mL的无水DMF中，将溶解在1.5mL DCM中的化合物26(14mg,0.0225mmol)加入到体系中，室温下搅拌反应4小时，随后将DBU(8.6mg,0.0562mmol)溶于0.5mL的无水DCM中，0℃条件下缓慢加入到体系中，此时反应液呈黑色。反应20分钟后，0℃加入1mL的草酸饱和溶液，放置室温反应45min，反应完全后，0℃加入碳酸氢钠溶液，用乙醚萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(EA/PE＝1:2)，得到8.0mg化合物28，收率为57％。
化合物28: 1H NMR(400MHz,CDCl 3)δ6.49(s,1H),6.11(d,J＝1.3Hz,1H),6.02(d, J＝1.3Hz,1H),5.78(s,1H),5.09(d,J＝11.4Hz,1H),4.66(s,1H),4.39(s,1H),4.28(d,J＝5.0Hz,1H),4.21(dd,J＝11.4,1.8Hz,1H),4.16(d,J＝1.9Hz,1H),3.75(s,3H),3.55(d,J＝5.0Hz,1H),3.43(d,J＝8.3Hz,1H),2.92(d,J＝9.6Hz,1H),2.82(s,1H),2.70(d,J＝17.8Hz,1H),2.56(d,J＝13.9Hz,1H),2.32(s,3H),2.24(s,3H),2.15(s,3H),2.04(s,3H).
13C NMR(100MHz,CDCl 3)δ186.71,168.56,160.52,147.21,146.40,143.01,141.67,140.70,130.41,129.90,121.69,120.04,117.89,117.12,113.50,113.39,102.25,61.76,61.40,60.33,59.80,58.93,54.61,43.24,41.63,36.88,24.16,20.36,15.81,9.68.
HRMS(ESI):calcd.for C 31H 32N 3O 9S[M+H] +622.1859；found 622.1862
实施例18、化合物30的合成
Figure PCTCN2018120340-appb-000083
氩气保护下，将化合物28(29mg,0.0467mmol)，化合物29(95mg,0.467mmol)和NaOAc(43mg,0.514mmol)混合溶解于5mL的无水乙醇中，室温下搅拌反应5小时，反应完全后，减压蒸馏除去溶剂，加水，用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(DCM/MeOH＝20:1)，得到33mg化合物30，收率为92％。
化合物30: 1H NMR(400MHz,CDCl 3)δ6.60(s,1H),6.48(s,1H),6.42(s,1H),6.05(s,1H),5.98(s,1H),5.84(s,1H),5.02(d,J＝11.5Hz,1H),4.58(s,1H),4.34(s,1H),4.28(d,J＝4.8Hz,1H),4.18(d,J＝2.4Hz,1H),4.13(d,J＝9.7Hz,1H),3.78(d,J＝14.4Hz,3H),3.62(s,3H),3.51(d,J＝4.5Hz,1H),3.44–3.40(m,1H),3.20–3.10(m,1H),2.94(d,J＝5.1Hz,2H),2.88(s,1H),2.68(s,1H),2.50(d,J＝15.4Hz,1H),2.36(d,J＝17.7Hz,1H),2.33(s,3H),2.27(s,3H),2.20(s,3H),2.04(s,3H).
13C NMR(100MHz,CDCl 3)δ172.55,168.21,147.86,145.33,144.60,144.36,143.07,141.34,140.13,130.78,129.42,129.07,125.62,121.15,120.73,118.17,118.14,114.14,114.07,113.43,109.80,101.87,64.62,61.12,60.37,60.06,59.67,59.57,55.19,54.71,54.62,42.16,41.87,41.62,39.67,28.72,24.18,20.45,15.84,9.74.
HRMS(ESI):calcd.for C 40H 43N 4O 10S[M+H] +771.2700；found 771.2703
实施例19、Et-743的合成
Figure PCTCN2018120340-appb-000084
氩气保护下，将化合物29(7.7mg,0.01mmol)溶于1mL按比例配制的乙腈，水的混合溶剂中，加入AgNO 3(32.3mg,0.19mmol)，室温下搅拌反应24h，分别加入1mL的饱和氯化钠和饱和碳酸氢钠溶液搅拌10min，用乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，快速柱层析(DCM/MeOH＝20:1),得到7.2mg的化合物31(Et-743)。收率为95％。
1H NMR(400MHz,CDCl 3)δ6.63(s,1H),6.48(s,1H),6.43(s,1H),6.03(d,J＝1.1Hz,1H),5.95(d,J＝1.1Hz,1H),5.85(s,1H),5.12(d,J＝11.4Hz,2H),4.89(s,1H),4.54(d,J＝25.4Hz,2H),4.06(dd,J＝11.4,2.1Hz,2H),3.82(s,3H),3.62(s,3H),3.46–3.31(m,2H),3.25–3.09(m,2H),3.03–2.78(m,4H).2.35(s,3H),2.27(s,3H),2.16(s,3H),2.03(s,3H).
HRMS(ESI):calcd.for C 39H 42N 3O 10S[M-OH] +744.2591；found 744.2594
化合物15也可以以化合物9为原料，按照以下优化的路线合成，具体操作实例以及化合物数据如下：
实施例20、化合物32的合成
Figure PCTCN2018120340-appb-000085
氩气保护下，将化合物9(10.1g，47.86mmol)溶解在DCM(175ml),TFE(25ml)的混合溶剂中，加入苄氧基乙醛(9.3g，62.22mmol)和4AMS(10.1g)，-10℃下缓慢滴加AcOH(0.72g,12.0mmol),保持-10oC下反应4小时，随后升温至0度继续反应4小时。反应完全后，用硅藻土过滤除去分子筛，加入饱和的碳酸氢钠溶液，二氯甲烷萃取三次，合并有机相，减压蒸馏除去溶剂，快速柱层析(DCM/MeOH＝20:1),得到14.6g白色固体化合物32，收率89％。
化合物32： 1H NMR(400MHz,CDCl 3)δ7.36–7.26(m,5H),6.46(s,1H),4.54(q,J＝12.1Hz,2H),4.44(t,J＝4.8Hz,1H),3.99(dd,J＝9.2,4.3Hz,1H),3.80(dd,J＝9.2,5.9Hz,1H),3.76(s,3H),3.72(dd,J＝10.8,3.8Hz,1H),3.50(dd,J＝10.8,7.0Hz,1H),2.98–2.90(m,1H),2.55–2.47(m,2H),2.24(s,3H).
13C NMR(100MHz,CDCl 3)δ146.21,143.90,138.10,132.60,128.68,128.36,127.76,127.65,122.26,120.70,73.73,73.23,66.18,60.57,54.04,53.28,32.56,15.64.
HRMS(ESI):calcd.for C 20H 26NO 4[M+H] +344.1862；found 344.1864
实施例21、化合物33的合成
Figure PCTCN2018120340-appb-000086
氩气保护下，将化合物32(1.2g，3.5mmol)溶解在35ml的无水DCM中，加入(Boc) 2O(0.92 g,4.2mmol)和NEt 3(0.97ml,7.0mmol)，室温下搅拌反应5小时。反应完全后，加入50ml的水，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压蒸馏除去溶剂，快速柱层析(EA/PE＝1:4),得到1.5g白色泡沫状产物33，收率97％。
化合物33： 1H NMR(400MHz,CDCl 3)δ7.33–7.25(m,5H),6.53(s,1H),6.24(d,J＝27.2Hz,1H),5.90(d,J＝110.2Hz,1H),4.89–4.62(m,1H),4.55(d,J＝11.7Hz,1H),4.23(d,J＝23.1Hz,1H),3.96(d,J＝16.5Hz,1H),3.76(s,1H),3.67(dd,J＝21.7,12.9Hz,2H),3.61–3.30(m,2H),3.11–2.69(m,2H),2.26(s,3H),1.45(s,9H).
13C NMR(100MHz,CDCl 3)δ155.90(s),145.20,143.87,137.72,130.57,130.51,129.72,128.35,127.69,121.44,119.82,80.48,72.66,71.74,71.01,65.87,64.64 60.66,53.43,49.57,48.10,28.42,15.72.
HRMS(ESI):calcd.for C 25H 33NO 6Na[M+Na] +466.2206；found 466.2205
实施例22、化合物34的合成
Figure PCTCN2018120340-appb-000087
将化合物33(5.0g，11.3mmol)溶解在100ml无水乙腈中，加入salcomine催化剂(0.36g，1.1mmol)，充换气3次，使其在氧气的气氛下反应1小时，反应完全后，过滤掉黑色固体催化剂，减压蒸馏除去乙腈，快速柱层析(EA/PE＝1:4)，目标产物在柱子上显现黄色，得到4.4g黄色产物34，收率为85％。
化合物34： 1H NMR(400MHz,CDCl 3)δ7.24–7.11(m,5H),5.20(d,J＝74.0Hz,1H),4.44(s,2H),4.34(d,J＝11.8Hz,1H),3.80(s,3H),3.77–3.64(m,2H),3.59(d,J＝7.1Hz,1H),3.45(m,1H),3.34(m,1H),2.59(d,J＝19.0Hz,1H),2.46(ddd,J＝19.1,7.5,2.0Hz,1H),1.82(s,3H),1.35(s,9H).
13C NMR(101MHz,CDCl 3)δ186.29,181.04,155.60,155.05,140.33,137.07,136.74,136.30,128.38,127.87,127.84,80.80,73.31,72.39,65.03,60.69,50.12,49.22,48.41,28.29,22.84,8.63.
HRMS(ESI):calcd.for C 25H 31NO 7Na[M+Na] +480.1998；found 480.2003
实施例23、化合物35的合成
Figure PCTCN2018120340-appb-000088
氩气保护下，将化合物34(2.0g,4.38mmol)溶解在44ml的无水四氢呋喃中，在蓝光照射下室温搅拌反应2小时，反应完全后，减压蒸馏除去溶剂，快速柱层析(EA/PE＝1:2),得到 1.5g化合物白色泡沫状固体35，收率为75％。
化合物35： 1H NMR(400MHz,CDCl 3)δ7.36–7.22(m,5H),5.80(d,J＝10.0Hz,2H),5.63(s,1H),5.45(d,J＝22.8Hz,1H),4.75–4.37(m,3H),3.95–3.69(m,4H),3.54(s,1H),2.78(d,J＝35.5Hz,2H),2.08(s,3H),1.45(s,9H).
13C NMR(100MHz,CDCl 3)δ155.88,146.22,144.13,137.54,136.75,128.33,127.81,127.76,113.06,112.48,106.86,100.72,80.68,72.98,71.21,70.72,67.99,65.66,64.67,28.40,22.96,8.90.
HRMS(ESI):calcd.for C 25H 33NO 6Na[M+Na] +480.1998；found 480.1999
实施例24、化合物15的合成
Figure PCTCN2018120340-appb-000089
将化合物35(1.5g,3.28mmol)溶解在30ml的丙酮中，加入BnBr(1.12g,6.56mmol)和K 2CO 3(0.91g,6.56mmol),65℃下回流反应5小时。反应完全后，减压蒸馏除去溶剂，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压旋蒸除去溶剂，快速柱层析(EA/PE＝1:4),得到1.68g粘稠状化合物15，收率为94％。
化合物15:
Figure PCTCN2018120340-appb-000090
(c＝1.0,CHCl 3) 1H NMR(400MHz,CDCl 3)δ7.45–7.25(m,10H),5.86(t,J＝5.4Hz,2H),5.77–5.42(m,1H),4.73(s,2H),4.71–4.57(m,1H),4.52(d,J＝11.8Hz,1H),4.28(d,J＝37.5Hz,1H),3.93–3.68(m,3H),3.57–3.19(m,2H),2.99–2.69(m,2H),2.18(s,3H),1.46(s,9H).
13C NMR(100MHz,CDCl 3)δ155.84,149.26,144.52,139.33,137.68,137.12,128.60,128.34,128.23,128.02,127.76,127.74,80.53,75.22,72.89,70.58,64.36,52.52,49.88,48.51,28.42,23.44,9.50.
HRMS(ESI):calcd.for C 32H 37NO 7Na[M+Na] +570.2468；found 570.2472
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (11)

  1. 一种Et-743的制备方法：
    Figure PCTCN2018120340-appb-100001
    其特征在于，包括步骤：
    (a)用化合物9与化合物16反应，得到化合物18：
    Figure PCTCN2018120340-appb-100002
    (b)用化合物18反应，得到化合物19：
    Figure PCTCN2018120340-appb-100003
    (c)用化合物19反应，得到化合物20：
    Figure PCTCN2018120340-appb-100004
    (d)用化合物20反应，得到化合物21：
    Figure PCTCN2018120340-appb-100005
    (e)用化合物21反应，得到化合物22：
    Figure PCTCN2018120340-appb-100006
    (f)用化合物22与
    Figure PCTCN2018120340-appb-100007
    反应，得到化合物24：
    Figure PCTCN2018120340-appb-100008
    (g)用化合物24反应，得到化合物25：
    Figure PCTCN2018120340-appb-100009
    用化合物25制备得到Et-743。
  2. 一种Et-743的制备方法：
    Figure PCTCN2018120340-appb-100010
    其特征在于，包括步骤：
    (g)用化合物24反应，得到化合物25：
    Figure PCTCN2018120340-appb-100011
    用化合物25制备得到Et-743。
  3. 一种选自下组的Et-743中间体化合物：
    Figure PCTCN2018120340-appb-100012
    其中，
    R 1选自下组：H、Bn-、烯丙基、
    Figure PCTCN2018120340-appb-100013
    R 2选自下组：H、Bn-、烯丙基；
    R 3选自下组：H、Ac；
    R 4选自下组：Cbz、
    Figure PCTCN2018120340-appb-100014
    R选自下组：H、OH。
  4. 一种式16化合物的制备方法，其特征在于，包括步骤：
    (vi)用化合物15反应，得到化合物16：
    Figure PCTCN2018120340-appb-100015
  5. 一种式15化合物的制备方法，其特征在于，包括步骤：
    (i)用化合物10反应，得到化合物11：
    Figure PCTCN2018120340-appb-100016
    (ii)用化合物11反应，得到化合物12：
    Figure PCTCN2018120340-appb-100017
    (iii)用化合物12反应，得到化合物13：
    Figure PCTCN2018120340-appb-100018
    (iv)用化合物13反应，得到化合物14：
    Figure PCTCN2018120340-appb-100019
    (v)用化合物14反应，得到化合物15：
    Figure PCTCN2018120340-appb-100020
    或所述的方法包括以下步骤：
    (i-a)用化合物9反应，得到化合物32：
    Figure PCTCN2018120340-appb-100021
    (ii-a)用化合物32反应，得到化合物33：
    Figure PCTCN2018120340-appb-100022
    (iii-a)用化合物33反应，得到化合物34：
    Figure PCTCN2018120340-appb-100023
    (iv-a)用化合物34反应，得到化合物35：
    Figure PCTCN2018120340-appb-100024
    (v-a)用化合物35反应，得到化合物15：
    Figure PCTCN2018120340-appb-100025
  6. 如权利要求3所述的方法，其特征在于，所述的方法还包括步骤：
    用化合物8反应，得到化合物10：
    Figure PCTCN2018120340-appb-100026
  7. 一种式11化合物的制备方法，其特征在于，包括步骤：
    在惰性溶剂中，在蓝光下，用化合物10进行光化学反应，得到式11化合物；
    Figure PCTCN2018120340-appb-100027
  8. 一种式35化合物的制备方法，其特征在于，包括步骤：
    在惰性溶剂中，在蓝光下，用化合物34进行光化学反应，得到化合物35：
    Figure PCTCN2018120340-appb-100028
  9. 一种式18化合物的制备方法，其特征在于，包括步骤：
    (a)用化合物9与化合物16反应，得到化合物18：
    Figure PCTCN2018120340-appb-100029
  10. 一种化合物20的制备方法，其特征在于，包括步骤：
    (c)用化合物19反应，得到化合物20：
    Figure PCTCN2018120340-appb-100030
  11. 一种化合物25的制备方法，其特征在于，包括步骤：
    (g)用化合物24反应，得到化合物25：
    Figure PCTCN2018120340-appb-100031
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