WO2023020531A1 - 5,8-二氨基-3,4-二氢-2h-1-萘酮的合成方法以及其中采用的中间体化合物 - Google Patents

5,8-二氨基-3,4-二氢-2h-1-萘酮的合成方法以及其中采用的中间体化合物 Download PDF

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WO2023020531A1
WO2023020531A1 PCT/CN2022/112985 CN2022112985W WO2023020531A1 WO 2023020531 A1 WO2023020531 A1 WO 2023020531A1 CN 2022112985 W CN2022112985 W CN 2022112985W WO 2023020531 A1 WO2023020531 A1 WO 2023020531A1
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amino
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synthetic method
acid
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徐辉
周伟
王珍珍
谭小钉
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江苏迈威康新药研发有限公司
迈威(上海)生物科技股份有限公司
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  • the present invention relates to the field of preparation of pharmaceutical intermediates, in particular, the present invention relates to the synthesis method and the Intermediate compounds used in this synthetic method.
  • Campotothecin (CPT) compounds as topoisomerase I inhibitors, can specifically inhibit DNA topoisomerase I, hinder the closure of DNA chains, cause DNA single-strand breaks that cannot be reconnected, and eventually lead to cell death. It is an important class of antitumor drugs.
  • ADC antibody-drug conjugates
  • camptothecin compounds as part of small-molecule drugs exerting anti-tumor activity, are coupled with antibodies or antibody-like ligands to form targeted therapeutic drugs.
  • IMMU-132 Sacituzumab govitecan
  • DS-0821 Enhertu
  • camptothecin compound CPT-1 has the following structure:
  • these routes all include nitration reaction, which will lead to the appearance of isomers, and multi-step column chromatography is required for purification, which makes the whole process complicated. , and there is a certain risk when enlarging the production scale; at the same time, the above synthetic route also needs post-processing operations, or requires relatively high equipment, which is not suitable for industrial production.
  • the technical problem to be solved in the present invention is to avoid 5,8-diamino-3,4-dihydro-2H-1-naphthalenone (compound I) in the existing synthetic routes of nitration, oxidation, etc., which are not suitable for scale-up production reactions and Operation, to provide a new synthetic method of compound I, which can realize the industrial production of compound I, so as to better provide raw materials for the synthesis of camptothecin compound CPT-1, and even the preparation of ADC.
  • the purpose of the present invention is to provide an intermediate compound with a novel chemical structure for the synthesis of compound I, and then to synthesize the camptothecin compound CPT-1; in addition, using the intermediate compound as a raw material, provide A new synthetic method for compound I.
  • the present invention provides a synthesis method of 5,8-diamino-3,4-dihydro-2H-1-naphthone, that is, compound I, the synthesis method comprising: making 2,5-di Protected aminobenzenebutyric acid undergoes Friedel-Crafts reaction for ring closure, and then removes the protecting group on the amino group to obtain compound I,
  • P 1 and P 2 are amino protecting groups.
  • P1 and P2 are independently selected from acetyl, benzoyl, benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc); more preferably, P1 and P2 are the same; further preferably, P 1 and P2 are both acetyl groups.
  • the Friedel-Crafts ring-closing reaction is carried out under the catalysis of polyphosphoric acid; or, the Friedel-Crafts ring-closing reaction is carried out by combining 2,5-diprotected aminobenzenebutyric acid shown in formula III with oxalyl chloride or chlorinated
  • the reaction of sulfone to produce acid chloride intermediate is carried out under the catalysis of aluminum oxide.
  • 2,5-diprotected aminobenzenebutyric acid shown in formula III is provided by the following synthetic route 1 (zinc reagent palladium catalyzed coupling method):
  • X and Y are independently nitro, amino or P1 or P2 protected amino;
  • R is C1 to C6 alkyl or benzyl, preferably selected from methyl, ethyl , isopropyl, tert-butyl and benzyl, more preferably methyl or ethyl.
  • the palladium catalyst is selected from palladium acetate, palladium chloride, dppf palladium dichloride and tetrakistriphenylphosphine palladium, more preferably palladium acetate.
  • the phosphine ligand is selected from BINAP, S-PHOS and X-PHOS, more preferably S-PHOS.
  • the synthetic route 1 includes:
  • 2,5-diprotected aminobenzenebutyric acid represented by formula III is provided by the following synthetic route 2 (amide hydrolysis method):
  • Z is nitro, amino or P1 or P2 protected amino;
  • R is C1 to C6 alkyl or benzyl, preferably selected from methyl, ethyl, isopropyl , tert-butyl and benzyl, more preferably methyl or ethyl.
  • the acid is selected from sulfuric acid, hydrogen chloride, thionyl chloride and p-toluenesulfonic acid, more preferably sulfuric acid.
  • the synthetic route 2 includes:
  • the present invention also provides intermediate compounds used in the synthesis method of 5,8-diamino-3,4-dihydro-2H-1-naphthone, namely compound I, including:
  • the present invention provides compounds represented by formula V,
  • P 1 and P 2 are amino protecting groups; R is C 1 to C 6 alkyl or benzyl.
  • P1 and P2 are independently selected from acetyl, benzoyl, benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc); more preferably, P1 and P2 are the same; further preferably, P 1 and P2 are both acetyl groups.
  • R is selected from methyl, ethyl, isopropyl, t-butyl and benzyl, more preferably methyl or ethyl.
  • the compound represented by formula V is compound D:
  • the present invention provides the compound shown in formula III:
  • P 1 and P 2 are amino protecting groups.
  • P1 and P2 are independently selected from acetyl, benzoyl, benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc); more preferably, P1 and P2 are the same; further preferably, P 1 and P2 are both acetyl groups.
  • the compound represented by formula III is compound E:
  • the present invention provides the use of the compound represented by formula V and/or the compound represented by formula III in the preparation of compound I, camptothecin compounds and/or antibody-drug conjugates.
  • the present invention provides a new synthetic method of compound I, which uses the compound shown in the formula V provided by the invention and the compound shown in the formula III as intermediate compounds.
  • the synthesis route realizes the synthesis of compound I with a high yield; and, this synthesis method avoids reactions and operations that are not suitable for scale-up production such as nitration and oxidation in the existing synthesis route of compound I, and is more suitable for the industrialized production of compound I, thereby being more It is good to provide raw material compounds for the synthesis of camptothecin compound CPT-1.
  • the present invention also provides intermediate compounds used in the synthesis method, providing more optional raw materials for the synthesis or preparation of compound I, camptothecin compounds, and even antibody-drug conjugates.
  • step 1 of Example 1 2,5-diaminobromobenzene was acetylated to obtain 2,5-diacetamidobromobenzene as a light yellow solid with a yield of 93%.
  • Zinc reagent (4-ethoxy-4-oxobutyl zinc bromide) was prepared according to the method in step 2 of Example 1.
  • reaction solution was cooled to room temperature, and ammonium chloride solution (15 mL) was added to the reaction solution to quench the reaction. Pour the reaction solution into 1L of water, add 400 mL of ethyl acetate, separate the layers, and extract the aqueous phase with ethyl acetate (400 mL*2).
  • Zinc reagent (4-ethoxy-4-oxobutyl zinc bromide) was prepared according to the method in step 2 of Example 1.
  • reaction solution was cooled to room temperature, and ammonium chloride solution (15 mL) was added to the reaction solution to quench the reaction. Pour the reaction solution into 1L of water, add 400 mL of ethyl acetate, separate the layers, and extract the aqueous phase with ethyl acetate (400 mL*2).
  • the raw material intermediate F (3.75 g) was suspended in 19% hydrochloric acid (30 mL).
  • the reaction system was heated to 90° C. (internal temperature) for 3 hours.
  • the reaction of the raw materials was detected by TLC, the temperature of the ice-salt bath was lowered to below 5°C, the pH was adjusted to 10 by adding 4M NaOH solution (45mL, 30eq) dropwise, the aqueous phase was extracted with ethyl acetate (80mL*5), the organic phases were combined, and washed with saturated chlorine Sodium chloride solution (50 mL) was washed once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.45 g of a crude product.
  • the crude product was purified by column chromatography with DCM as the eluent to obtain a yellow solid (Compound I), 1.93 g, with a yield of 76%.
  • Dissolve intermediate E (13.9, 0.05mol) in dichloromethane (200ml) in a 250mL three-neck flask, control the temperature in an ice bath at 5-10°C, add DMF (1ml), dropwise add oxalyl chloride (7.62g, 0.06mol, 1.2eq), after dripping, keep warm for 2 hours, take a sample and add methanol for TLC detection, the reaction of raw materials is complete. The organic solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (50 ml) and evaporated to dryness under reduced pressure again, repeating twice. 16.2 g of the crude acid chloride was obtained, which was directly reacted in the next step.

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Abstract

5，8-二氨基-3，4-二氢-2H-1-萘酮(化合物I)的合成方法，包括：使2,5-二保护氨基苯丁酸经傅克反应关环，再脱去氨基上的保护基，得到化合物I。

Description

5,8-二氨基-3,4-二氢-2H-1-萘酮的合成方法以及其中采用的中间体化合物
相关申请的交叉引用
本专利申请要求于2021年8月17日提交的申请号为CN202110943248.1的中国发明专利申请的优先权权益，在此将其全部内容引入作为参考。
技术领域
本发明涉及药物中间体制备领域，具体而言，本发明涉及用于制备喜树碱类化合物的原料5,8-二氨基-3,4-二氢-2H-1-萘酮的合成方法以及在该合成方法中采用的中间体化合物。
背景技术
喜树碱(campotothecin，CPT)类化合物作为拓扑异构酶I抑制剂，能够特异性抑制DNA拓扑异构酶I，阻碍DNA链的闭合，导致DNA单链断裂不能再度连接，最终导致细胞死亡，是一类重要的抗肿瘤药物。
同时，这类化合物还广泛用于制备抗体偶联药物(Antibody-drug conjugate，ADC)。在ADC中，喜树碱类化合物作为发挥抗肿瘤活性的小分子药物部分，与抗体或抗体类配体偶联形成靶向治疗药。例如，喜树碱类化合物SN38与抗Trop-2抗体偶联形成的Sacituzumab govitecan(IMMU-132)，Exatecan与Trastuzumab偶联形成的Enhertu(DS-0821)等。
在专利公开文件WO2020200880A1中报道了如下结构的ADC：
Figure PCTCN2022112985-appb-000001
其中采用的喜树碱类化合物CPT-1具有如下结构：
Figure PCTCN2022112985-appb-000002
在该WO2020200880A1与文献(Journal of Medicinal Chemistry,1998,vol.41,#13,p.2308-2318)报道中报道了CPT-1可由5,8-二氨基-3,4-二氢-2H-1-萘酮(化合物I)与化合物II缩合得到：
Figure PCTCN2022112985-appb-000003
然而，需要经过以下路线提供合成CPT-1的原料化合物I：
合成路线1(反应总收率为24.2％)：
Figure PCTCN2022112985-appb-000004
合成路线2(反应总收率为15.6％)：
Figure PCTCN2022112985-appb-000005
合成路线3(反应总收率为33.2％)：
Figure PCTCN2022112985-appb-000006
如上所示，除了上述合成路线的反应总收率均比较低之外，这些路线均包括硝化反应，硝化反应会导致异构体出现，需利用多步柱层析进行纯化，造成整个过程操作复杂，而且放大生产规模时具有一定的危险性；同时上述合成路线还需要进行后处理操作，或者对设备要求比较高，不适合工业化生产。
发明内容
本发明要解决的技术问题是，规避5,8-二氨基-3,4-二氢-2H-1-萘酮(化合物I)已有合成路线中硝化、氧化等不适合放大生产的反应与操作，提供一种化合物I的新的合成方法，该合成方法可实现化合物I的工业化生产，从而更好地为合成喜树碱类化合物CPT-1、甚至制备ADC提供原料化合物。
为了解决上述技术问题，本发明的目的是，提供用于合成化合物I、进而合成喜树碱类化合物CPT-1的具有新型化学结构的中间体化合物；另外，以该中间体化合物作为原料，提供化合物I的新的合成方法。
本发明的技术方案如下。
一方面，本发明提供5,8-二氨基-3,4-二氢-2H-1-萘酮即化合物I的合成方法，所述合成方法包括，使式III所示的2,5-二保护氨基苯丁酸经傅克反应关环，再脱去氨基上的保护基，得到化合物I，
Figure PCTCN2022112985-appb-000007
其中，P 1和P 2为氨基保护基。
优选地，P 1和P 2独立地选自乙酰基、苯甲酰基、苄氧羰基(Cbz)和芴甲氧羰基(Fmoc)；更优选地，P 1和P 2相同；进一步优选地，P 1和P 2均为乙酰基。
其中，所述傅克关环反应在多聚磷酸催化下进行；或者，所述傅克关环反应经由将式III所示的2,5-二保护氨基苯丁酸与草酰氯或氯化亚砜反应制成酰氯中间体后再在三氧化铝催化下进行。
在本发明提供的合成方法中，式III所示的2,5-二保护氨基苯丁酸通过以下合成路线1(锌试剂钯催化偶联法)提供：
合成路线1：
Figure PCTCN2022112985-appb-000008
所述合成路线1中，X和Y独立地为硝基、氨基或P 1或P 2保护的氨基；R为C 1至C 6的烷基或苄基，优选地选自甲基、乙基、异丙基、叔丁基和苄基，更优选为甲基或乙基。
优选地，钯催化剂选自醋酸钯、氯化钯、dppf二氯化钯和四三苯基膦钯等，更优选为醋酸钯。优选地，膦配体选自BINAP、S-PHOS和X-PHOS，更优选为S-PHOS。
根据本发明的具体实施方式，所述合成路线1包括：
1)X为氨基、Y为硝基时：
Figure PCTCN2022112985-appb-000009
2)X、Y均为氨基时：
Figure PCTCN2022112985-appb-000010
3)X为硝基、Y为氨基时：
Figure PCTCN2022112985-appb-000011
或者，式III所示的2,5-二保护氨基苯丁酸通过以下合成路线2(酰胺水解法)提供：
合成路线2：
Figure PCTCN2022112985-appb-000012
所述合成路线2中，Z为硝基、氨基或P 1或P 2保护的氨基；R为C 1至C 6的烷基或苄基，优选地选自甲基、乙基、异丙基、叔丁基和苄基，更优选为甲基或乙基。
优选地，酸选自硫酸、氯化氢、氯化亚砜和对甲苯磺酸，更优选为硫酸。
根据本发明的具体实施方式，所述合成路线2包括：
1)Z为氨基时：
Figure PCTCN2022112985-appb-000013
2)Z为硝基时：
Figure PCTCN2022112985-appb-000014
或
Figure PCTCN2022112985-appb-000015
另一方面，本发明还提供在5,8-二氨基-3,4-二氢-2H-1-萘酮即化合物I的合成方法中采用的中间体化合物，包括：
本发明提供式V所示的化合物，
Figure PCTCN2022112985-appb-000016
其中，P 1和P 2为氨基保护基；R为C 1至C 6的烷基或苄基。
优选地，P 1和P 2独立地选自乙酰基、苯甲酰基、苄氧羰基(Cbz)和芴甲氧羰基(Fmoc)；更优选地，P 1和P 2相同；进一步优选地，P 1和P 2均为乙酰基。
优选地，R选自甲基、乙基、异丙基、叔丁基和苄基，更优选为甲基或乙基。
根据本发明的具体实施方式，式V所示的化合物为化合物D：
Figure PCTCN2022112985-appb-000017
本发明提供式III所示的化合物：
Figure PCTCN2022112985-appb-000018
其中，P 1和P 2为氨基保护基。
优选地，P 1和P 2独立地选自乙酰基、苯甲酰基、苄氧羰基(Cbz)和芴甲氧羰基(Fmoc)；更优选地，P 1和P 2相同；进一步优选地，P 1和P 2均为乙酰基。
根据本发明的具体实施方式，式III所示的化合物为化合物E：
Figure PCTCN2022112985-appb-000019
又一方面，本发明提供式V所示的化合物和/或式III所示的化合物在制备化合物I、喜树碱类化合物和/或抗体偶联药物中的应用。
与现有技术相比，本发明提供了一种化合物I的新的合成方法，该合成方法以本发明提供的式V所示的化合物、式III所示的化合物为中间体化合物，经过新的合成路线，以高收率实现化合物I的合成；并且，该合成方法规避了化合物I已有合成路线中硝化、氧化等不适合放大生产的反应与操作，更适合化合物I的工业化生产，从而更好地为合成喜树碱类化合物CPT-1提供原料化合物。此外，本发明还提供了该合成方法中采用的中间体化合物，为化合物I、喜树碱类化合物、甚至抗体偶联药物的合成或制备提供了更多可选原料。
附图说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1：化合物D的 1H NMR(d 6-DMSO)。
图2：化合物E的 1H NMR(d 6-DMSO)。
图3：化合物I的 1H NMR(d 6-DMSO)。
图4：化合物I的质谱。
实施发明的最佳方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的原料、试剂材料等，如无特殊说明，均为市售购买产品。
实施例1中间体D的合成(合成路线1—锌试剂钯催化偶联法)
Figure PCTCN2022112985-appb-000020
(1)中间体A的合成
在500mL烧瓶中加入3-溴-4-硝基苯胺(25.00g，0.12mol)和200mL醋酸，缓慢滴加50mL乙酸酐，室温下反应16小时。TLC检测原料反应完全后，将反应液过滤，反应液减压浓缩除去醋酸，合并滤饼用200mL MTBE打浆，过滤干燥的黄色固体(中间体A)27.6g。收率92％。LC-MS(ESI):m/z259(M+H) +。
(2)4-乙氧基-4-氧代丁基溴化锌的制备
在一个250mL三口烧瓶中(温度计，回流冷凝管，橡胶塞)加入活化过的锌粉(19.0g,0.29mol，2.00eq)，置换氮气后加入无水DMF(145mL)，再次置换氮气，室温下加入碘单质(1.86g,0.015mol，0.1eq)，可观察到溶液由无色变为棕红色，再逐渐变为淡黄色最后恢复无色(2-3min)，然后加入4-溴丁酸乙酯(28.6g,0.15mol，1.00eq)，升温至80℃(内温)反应4～5小时，TLC检测反应完全后，将反应液静置，冷却至室温待用，上清液呈淡黄色，浓度为1mol/L。
(3)中间体B的合成
500mL反应瓶中加入无水DMF(120mL)和中间体A(25.0g,1.00eq)， 置换氮气后加入醋酸钯(433mg,0.02eq)，置换氮气室温下搅拌10min后加入S-PHOS(1.6g,0.04eq)，再次置换氮气，搅拌20min后室温(25-30℃)滴加上述步骤中制备的4-乙氧基-4-氧代丁基溴化锌(145mL,1.50eq)，加完后保持25-30℃反应16小时。TLC检测(DCM:EA＝5:1)原料反应完全后，将反应液冷却至室温，向反应液中加入氯化铵溶液(15mL)淬灭反应。将反应液倒入1L水中，加入400mL乙酸乙酯，分液，布氏漏斗过滤，水相用乙酸乙酯(400mL*2)萃取，有机相用水(500mL)洗涤两遍，饱和氯化钠溶液(500mL)洗涤一遍，无水硫酸钠干燥，减压浓缩，得红棕色油状液体(中间体B)37.0g，收率130％。粗产品不用进一步纯化，直接用于下一步反应。LC-MS(ESI):m/z 295(M+H) +。
(4)中间体C的合成
3L三口反应瓶中加入中间体B(37.0g,1.0eq)和乙醇(1.5L)，原料完全溶解。反应体系冷却至5℃，加入5％Pd/C(5.7g,1.0eq)，氢气氛围下(常压)升温至25℃反应16小时。TLC检测(DCM:EA＝5:1)反应完毕，反应体系在硅藻土下过滤，有机相浓缩得粗产品(中间体C)33.0g,收率130％。粗产品不用进一步纯化，直接用于下一步反应。LC-MS(ESI):m/z 265(M+H) +。
(5)中间体D的合成
在1L烧瓶中加入中间体C(33.0g，1.00eq)和260mL醋酸，缓慢滴加46mL乙酸酐，室温下反应2小时。TLC检测(DCM:MeOH＝10:1)原料反应完全后，将反应液过滤，反应液减压浓缩除去醋酸，加入250mL水，水相用乙酸乙酯(400mL*2)萃取，有机相用水(500mL)洗涤两遍，饱和氯化钠溶液(500mL)洗涤一遍，无水硫酸钠干燥，减压浓缩，得粗产品32g。粗产品用400mL MTBE打浆，过滤干燥的淡黄色固体(中间体D)27.0g，收率91％。四步反应总收率为83.7％。
LC-MS(ESI):m/z 307(M+H) +。
1H NMR(400MHz,DMSO)δ9.87(s,1H),9.19(s,1H),7.41(s,1H),7.37(d,J＝8.7Hz,1H),7.20(d,J＝8.5Hz,1H),4.06(q,J＝7.0Hz,2H),2.52(d,J＝8.5Hz,2H),2.29(t,J＝7.3Hz,2H),2.02(s,6H),1.79–1.64(m,2H),1.18(t,J＝7.1Hz,3H).
1H NMR谱图见图1。
实施例2中间体D的合成(合成路线1—锌试剂钯催化偶联法)
Figure PCTCN2022112985-appb-000021
按实施例1步骤1中类似的方法将2,5-二氨基溴苯经乙酰化得到2,5-二乙酰氨基溴苯，为淡黄色固体，收率93％。
锌试剂(4-乙氧基-4-氧代丁基溴化锌)按照实施例1步骤2中的方法制备得到。
500mL反应瓶中加入无水DMF(120mL)和2,5-二乙酰氨基溴苯(26.1g,96.5mmol，1.00eq)，置换氮气后加入醋酸钯(433mg,1.93mmol，0.02eq)，置换氮气室温下搅拌10min后加入S-PHOS(1.6g，3.85mmol，0.04eq)，再次置换氮气，搅拌20min后室温(25-30℃)滴加上述步骤中制备的4-乙氧基-4-氧代丁基溴化锌(145mL,145mmol，1.50eq)，加完后保持65～70℃反应16小时。TLC检测原料反应完全后，将反应液冷却至室温，向反应液中加入氯化铵溶液(15mL)淬灭反应。将反应液倒入1L水中，加入400mL乙酸乙酯，分液，水相用乙酸乙酯(400mL*2)萃取。合并有机相，用水(500mL)洗涤两遍，饱和氯化钠溶液(500mL)洗涤一遍，无水硫酸钠干燥，抽滤，减压浓缩，粗产品经柱层析纯化，洗脱剂DCM：MeOH＝50:1～30:1，得中间体D为淡黄色固体，13.8g，收率46.7％。两步反应总收率43.4％。LC-MS(ESI):m/z 307(M+H) +。
实施例3中间体D的合成(合成路线1—锌试剂钯催化偶联法)
Figure PCTCN2022112985-appb-000022
按实施例1步骤1类似的方法将2-氨基-5-硝基溴苯乙酰化得到2-乙酰氨基-5-硝基溴苯，黄色固体，收率90％。
锌试剂(4-乙氧基-4-氧代丁基溴化锌)按照实施例1步骤2中的方法制备得到。
(1)中间体B3的合成
500mL反应瓶中加入无水DMF(120mL)和2-乙酰氨基-5-硝基溴苯(25.0g,96.5mmol，0.1mol)，置换氮气后加入醋酸钯(433mg,1.93mmol，0.02eq)，置换氮气室温下搅拌10min后加入S-PHOS(1.6g,3.85mmol，0.04eq)，再次置换氮气，搅拌20min后室温(25-30℃)滴加上述步骤中制备的4-乙氧基-4-氧代丁基溴化锌(145mL,145mmol，1.50eq)，加完后保持65～70℃反应16小时。TLC检测原料反应完全后，将反应液冷却至室温，向反应液中加入氯化铵溶液(15mL)淬灭反应。将反应液倒入1L水中，加入400mL乙酸乙酯，分液，水相用乙酸乙酯(400mL*2)萃取。合并有机相，用水(500mL)洗涤两遍，饱和氯化钠溶液(500mL)洗涤一遍，无水硫酸钠干燥，抽滤，减压浓缩，粗产品经柱层析纯化，洗脱剂DCM：MeOH＝50:1～30:1，得中间体B3黄色固体，10.3g，收率36.5％。LC-MS(ESI):m/z 295(M+H)+。
(2)中间体C3的合成
500ml反应瓶中将中间体B3(10.3g,)和乙醇(250ml)混合。反应体系冷却至5℃，加入5％Pd/C(1.5g，15％w)，氢气氛围下(常压)升温至25℃反应16小时。TLC检测(DCM:EA＝5:1)反应完毕，反应体系在硅藻土下过滤，有机相浓缩得粗产品(中间体C3)9.4g。粗产品不经纯化，按理论量直接用于下一步反应。LC-MS(ESI):m/z 265(M+H)+.
(3)中间体D的合成
在1L烧瓶中加入中间体C3(9.4g，1.00eq)和260mL醋酸，缓慢滴加46mL乙酸酐，室温下反应2小时。TLC检测(DCM:MeOH＝10:1)原料反应完全后，将反应液过滤，反应液减压浓缩除去醋酸，加入150mL水，水相用乙酸乙酯(100mL*2)萃取，有机相用水(100mL)洗涤两遍，饱和氯化钠溶液(100mL)洗涤一遍，无水硫酸钠干燥，减压浓缩，得粗产品，粗产品用200mL MTBE打浆，过滤干燥的淡黄色固体(中间体D)9.6g，收率89％。四步反应总收率为29.2％。LC-MS(ESI):m/z 307(M+H)+。
实施例4中间体D的合成(合成路线2—酰胺水解法)
Figure PCTCN2022112985-appb-000023
于500ml三口烧瓶中，将7-氨基-4,5-二氢-1H-苯并[b]氮杂卓-2(3H)-酮(17.6g，0.1moml)，乙醇(250ml)，98％硫酸(5ml)混合，加热回流反应24小时。取样检测，待反应完全后，将反应液减压浓缩至干。残留物加入二氯甲烷(200ml)和水(100ml)，冰浴降温至10℃以下，用1N氢氧化钠水溶液调节pH7～8，搅拌分液，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压蒸馏，蒸除有机溶剂，得到二氨基乙酯中间体C4粗品，25g，直接下一步反应。
中间体C4溶于二氯甲烷(200ml)中，加入三乙胺(20.2g，0.2mol，2eq)，冰浴降温至10℃以下，滴加乙酸酐(25.5g，0.25mol，2.5eq)。滴毕，保温反应1小时，取样检测，待反应完全后，将反应液倒入冰的1N盐酸中，搅拌15分钟，分液，水相二氯甲烷(50ml*3)萃取，合并有机相，无水硫酸钠干燥，抽滤，减压蒸馏，蒸除有机溶剂，粗产品用400mL MTBE打浆，过滤干燥得中间体D为淡黄色固体，26.9g。两步反应总收率87.8％。LC-MS(ESI):m/z 307(M+H) +。
实施例5中间体E的合成
Figure PCTCN2022112985-appb-000024
500mL三口反应瓶中加入中间体D(27.0g,88mmol，1.0eq)，水(100mL)和四氢呋喃(200mL)，原料完全溶解。室温条件下加入一水合氢氧化锂(18.5g,441mmol，5.0eq)，反应体系维持室温继续反应3小时。TLC检测反应完毕，减压蒸出大部分四氢呋喃，残留物加入300mL水，水相用EA萃取(2×100mL)，弃去有机相。水相在冰浴下用6N盐酸调pH至4，有 固体析出，过滤得中间体E为白色固体，19.1g，收率78％。
1H NMR(400MHz,DMSO)δ12.09(s,1H),9.86(s,1H),9.18(s,1H),7.38(d,J＝15.5Hz,2H),7.23(d,J＝8.5Hz,1H),2.51(d,J＝8.1Hz,2H),2.23(t,J＝7.1Hz,2H),2.02(s,6H),1.76–1.61(m,2H).
1H NMR谱图见图2。
实施例6化合物I的合成(多聚磷酸关环)
Figure PCTCN2022112985-appb-000025
250mL反应瓶中加入多聚磷酸40ml，加热至90℃，分批加入中间体E(5.0g，17.97mmol)，内温保持95-100℃反应5小时。TLC检测反应完毕，撤去加热，体系降温至50-60℃，向反应体系中滴加15mL 4M HCl(aq)(温度会升至100℃)淬灭反应，滴毕，冰浴下滴加600mL 4M NaOH水溶剂调pH到10。水相用乙酸乙酯(50mL*3)萃取，合并有机相，用饱和氯化钠溶液(50mL)洗涤一遍，无水硫酸钠干燥，减压浓缩，得黄色固体(中间体F)3.75g，收率80.5％。不经纯化直接下一步反应。LC-MS(ESI):m/z 261(M+H)+。
250mL三口反应瓶中将原料中间体F(3.75g)悬浮于19％盐酸(30mL)中。反应体系加热至90℃(内温)反应3小时。TLC检测原料反应完毕，冰盐浴降温至5℃以下，滴加4M NaOH溶液(45mL,30eq)调pH到10，水相用乙酸乙酯(80mL*5)萃取，合并有机相，用饱和氯化钠溶液(50mL)洗涤一遍，无水硫酸钠干燥，减压浓缩，得粗产品2.45g。粗产品柱层析纯化，洗脱剂为DCM，得黄色固体(化合物I)，1.93g，收率76％。两步反应总收率61.2％。
MS(ESI):m/z 177(M+H)+.
1H NMR(400MHz,DMSO)δ6.76(d,J＝8.7Hz,1H),6.68(s,2H),6.42(d,J＝8.7Hz,1H),4.17(s,2H),2.55(t,J＝5.9Hz,2H),2.46(t,J＝6.2Hz,2H),2.00–1.80(m,2H).
1H NMR谱图和质谱分别见图3和图4。
实施例7化合物I的合成(分步关环)
Figure PCTCN2022112985-appb-000026
250mL三口烧瓶中将中间体E(13.9，0.05mol)溶于二氯甲烷(200ml)中，冰浴控温5～10℃，加入DMF(1ml)，滴加草酰氯(7.62g，0.06mol，1.2eq)，滴毕，保温反应2小时，取样加甲醇后TLC检测，原料反应完全。减压蒸出有机溶剂，残留物用二氯甲烷(50ml)溶解后再次减压蒸干，重复2次。得酰氯粗品16.2g，直接下一步反应。
于250ml三口烧瓶中，将二氯甲烷(200ml)和三氯化铝(8g，0.06mol，1.2eq)混合搅拌，冰浴冷却至5～10℃，滴加上述酰氯的二氯甲烷溶液(16.2g粗品溶于100ml二氯甲烷中)，滴毕，保温反应5小时。TLC检测反应完毕，将反应液倒入冰的1N盐酸(300ml)中，搅拌15分钟，分液，水相用二氯甲烷(100ml*3)萃取，合并有机相，饱和氯化钠溶液(80mL)洗涤一遍，无水硫酸钠干燥，减压浓缩，得中间体F粗品10g，含部分掉乙酰基产物，可不经纯化直接用于下一步反应。LC-MS(ESI):m/z 261(M+H) +。
中间体F粗品与盐酸反应，与实施例6相同，得到化合物I，2.3g，三步总收率26.1％。
LC-MS(ESI):m/z 177(M+H) +.
化合物I合成的总收率如表1所示。
表1化合物I合成的总收率
Figure PCTCN2022112985-appb-000027
*实施例1中的收率
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可 以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。

Claims (14)

  1. 5,8-二氨基-3,4-二氢-2H-1-萘酮(化合物I)的合成方法，所述合成方法包括，使式III所示的2,5-二保护氨基苯丁酸经傅克反应关环，再脱去氨基上的保护基，得到化合物I，
    Figure PCTCN2022112985-appb-100001
    其中，P 1和P 2为氨基保护基。
  2. 根据权利要求1所述的合成方法，其特征在于，P 1和P 2独立地选自乙酰基、苯甲酰基、苄氧羰基(Cbz)和芴甲氧羰基(Fmoc)；
    优选地，P 1和P 2相同；
    进一步优选地，P 1和P 2均为乙酰基。
  3. 根据权利要求1或2所述的合成方法，其特征在于，所述关环反应在多聚磷酸催化下进行；或者，
    所述关环反应经由将式III所示的2,5-二保护氨基苯丁酸与草酰氯或氯化亚砜反应制成酰氯中间体后再在三氧化铝催化下进行。
  4. 根据权利要求1至3中任一项所述的合成方法，其特征在于，所述合成方法中，式III所示的2,5-二保护氨基苯丁酸通过以下合成路线1提供：
    合成路线1：
    Figure PCTCN2022112985-appb-100002
    其中，X和Y独立地为硝基、氨基或P 1或P 2保护的氨基；R为C 1至C 6的烷基或苄基，优选地选自甲基、乙基、异丙基、叔丁基和苄基，更优选为甲基或乙基；
    优选地，钯催化剂选自醋酸钯、氯化钯、dppf二氯化钯和四三苯基膦钯等，更优选为醋酸钯；
    优选地，膦配体选自BINAP、S-PHOS和X-PHOS，更优选为S-PHOS。
  5. 根据权利要求4所述的合成方法，其特征在于，所述合成路线1包括：
    1)X为氨基、Y为硝基时：
    Figure PCTCN2022112985-appb-100003
    2)X、Y均为氨基时：
    Figure PCTCN2022112985-appb-100004
    3)X为硝基、Y为氨基时：
    Figure PCTCN2022112985-appb-100005
  6. 根据权利要求1至3中任一项所述的合成方法，其特征在于，所述合成方法中，式III所示的2,5-二保护氨基苯丁酸通过以下合成路线2提供：
    合成路线2：
    Figure PCTCN2022112985-appb-100006
    其中，Z为硝基、氨基或P 1或P 2保护的氨基；R为C 1至C 6的烷基或苄基，优选地选自甲基、乙基、异丙基、叔丁基和苄基，更优选为甲基或乙基；
    优选地，酸选自硫酸、氯化氢、氯化亚砜和对甲苯磺酸，更优选为硫酸。
  7. 根据权利要求6所述的合成方法，其特征在于，所述合成路线2包括：
    1)Z为氨基时：
    Figure PCTCN2022112985-appb-100007
    2)Z为硝基时：
    Figure PCTCN2022112985-appb-100008
    Figure PCTCN2022112985-appb-100009
  8. 式V所示的化合物，
    Figure PCTCN2022112985-appb-100010
    其中，P 1和P 2为氨基保护基；R为C 1至C 6的烷基或苄基。
  9. 根据权利要求8所述的化合物，其特征在于，P 1和P 2独立地选自乙酰基、苯甲酰基、苄氧羰基(Cbz)和芴甲氧羰基(Fmoc)；更优选地，P 1和P 2相同；进一步优选地，P 1和P 2均为乙酰基；
    优选地，R选自甲基、乙基、异丙基、叔丁基和苄基，更优选为甲基或乙基。
  10. 根据权利要求8或9所述的化合物，其特征在于，式V所示的化合物为化合物D：
    Figure PCTCN2022112985-appb-100011
  11. 式III所示的化合物：
    Figure PCTCN2022112985-appb-100012
    其中，P 1和P 2为氨基保护基。
  12. 根据权利要求11所述的化合物，其特征在于，P 1和P 2独立地选自乙酰基、苯甲酰基、苄氧羰基(Cbz)和芴甲氧羰基(Fmoc)；更优选地，P 1和P 2相同；进一步优选地，P 1和P 2均为乙酰基。
  13. 根据权利要求10或11所述的化合物，其特征在于，式III所示的化合物为化合物E：
    Figure PCTCN2022112985-appb-100013
  14. 权利要求8至10中任一项所述的式V所示的化合物和/或权利要求11至13中任一项所述的式III所示的化合物在制备化合物I、喜树碱类化合物和/或抗体偶联药物中的应用。
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