WO2022167002A1 - 含二氢苯并呋喃结构的1,4-硫桥多环化合物、其制备方法及用途 - Google Patents
含二氢苯并呋喃结构的1,4-硫桥多环化合物、其制备方法及用途 Download PDFInfo
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- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical group C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 title claims abstract description 17
- -1 polycyclic compound Chemical class 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000003054 catalyst Substances 0.000 claims abstract description 38
- RSZMTXPFGDUHSE-UHFFFAOYSA-N 2-nitro-1-benzofuran Chemical compound C1=CC=C2OC([N+](=O)[O-])=CC2=C1 RSZMTXPFGDUHSE-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000002808 molecular sieve Substances 0.000 claims abstract description 26
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910052786 argon Inorganic materials 0.000 claims abstract description 24
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- JUYAMZBWGRADBA-UHFFFAOYSA-N 2,5-dihydro-1,3-thiazole 1-oxide Chemical compound O=S1CC=NC1 JUYAMZBWGRADBA-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 125000003367 polycyclic group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000758 substrate Substances 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 63
- 238000003786 synthesis reaction Methods 0.000 abstract description 26
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 39
- 238000012360 testing method Methods 0.000 description 23
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- 239000013078 crystal Substances 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- JLPUISACQXFVRC-UHFFFAOYSA-N 2,5-dihydro-1,3-thiazole Chemical compound C1SCN=C1 JLPUISACQXFVRC-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- HCGYMSSYSAKGPK-UHFFFAOYSA-N 2-nitro-1h-indole Chemical compound C1=CC=C2NC([N+](=O)[O-])=CC2=C1 HCGYMSSYSAKGPK-UHFFFAOYSA-N 0.000 description 1
- JIZRGGUCOQKGQD-UHFFFAOYSA-N 2-nitrothiophene Chemical compound [O-][N+](=O)C1=CC=CS1 JIZRGGUCOQKGQD-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 102220612388 Mitogen-activated protein kinase kinase kinase 1_C15S_mutation Human genes 0.000 description 1
- 102220623959 Putative uncharacterized protein IBA57-DT_C2S_mutation Human genes 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 102220231685 rs1064797227 Human genes 0.000 description 1
- 102220260185 rs202005786 Human genes 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen 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 three hetero rings
- C07D513/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to the field of organic synthesis, in particular to a 1,4-sulfur bridged polycyclic compound containing a dihydrobenzofuran structure, a preparation method and application thereof.
- Bridged polycyclic compounds widely exist in natural products and drug molecules, have a wide range of biological activities, and are an important source for the development of new drugs.
- Morphine a clinically important potent analgesic, is a bridged polycyclic drug with a dihydrobenzofuran structure.
- the synthesis of bridged polycyclic compounds containing dihydrobenzofuran structures is of great scientific interest.
- combining two or more pharmacodynamic functional groups into one molecule may produce unexpected biological activities, which has very important application value.
- Asymmetric dearomatization is a difficult point in the field of organic synthesis.
- the main research direction is electron-rich aromatic compounds, such as indole, naphthol, etc., which mainly utilize the inherent nucleophilicity of these compounds.
- asymmetric dearomatization of nitroheteroaromatics such as nitroindole, nitrobenzofuran, and nitrothiophene, has also attracted extensive interest among organic chemists.
- One of the objects of the present invention is to provide a new class of bridged polycyclic compounds containing dihydrobenzofuran structure to solve the above problems.
- the technical scheme adopted in the present invention is as follows: the 1,4-sulfur bridged polycyclic compound containing the dihydrobenzofuran structure has the structure shown in the following structural formula (I):
- Ar is a variety of substituted aromatic rings, heteroaromatic rings, etc.
- R 1 group is a single substituent or a multi-substituted group, and the substituent is selected from hydrogen, alkyl, alkoxy, nitro or halogen.
- R 2 group is one of methyl, ethyl and benzyl.
- the present invention discloses for the first time a new class of chiral bridged polycyclic compounds containing dihydrobenzofuran structure. and drug screening to provide more candidate molecules.
- the second purpose of the present invention is to provide a kind of preparation method of the above-mentioned bridged polycyclic compound containing dihydrobenzofuran structure, the technical scheme adopted is: 2-nitrobenzofuran (II), 5H-thiazole Ketone (III) is dissolved in organic solvent, then molecular sieve and chiral catalyst are added, and the reaction is stirred at room temperature under the protection of argon. Cyclic compound (I), wherein,
- the 2-nitrobenzofuran (II) has the following structure:
- the 5H-thiazolone (III) has the following structure:
- 5H-thiazolone as a good sulfur-containing nucleophile is widely used in organic synthesis, but current research mainly focuses on the nucleophilic addition reaction at the C5 position, while the nucleophilicity at the C5 position and the C2 position are utilized. There are few reports of electrophilic construction of 1,4-sulfur bridged rings. Therefore, the inventors of the present application selected a suitable catalytic system through a large number of experiments, using the substrates 2-nitrobenzofuran and 5H-thiazolone to undergo Michael addition reaction first, and then further Mannich reaction, one-step construction containing two A bridged polycyclic compound with four consecutive chiral centers of the hydrobenzofuran structure, as follows:
- the reaction solvent is selected from one of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4-dioxane, chlorobenzene or Various mixes.
- the chiral catalyst is a chiral tertiary amine-thiourea bifunctional catalyst or a chiral tertiary amine-squaramide bifunctional catalyst.
- the chiral tertiary amine-thiourea catalyst has the structure of the following formula A or B or C or D, that is, the catalyst used is preferably one of the following:
- Catalyst D is further preferred because of the high yield and good stereoselectivity of the reaction.
- the third object of the present invention is to provide the use of the above-mentioned compounds in the preparation of antitumor drugs.
- the application value of the above-mentioned compounds disclosed in the present invention is as follows: through preliminary cell activity experiments, it is shown that these compounds have a good killing effect on human leukemia cells K562 and human lung cancer cells A549, and the cell activity research results are shown in the table. 1. Therefore, through further research, this type of compound is expected to become the leading compound of anti-tumor drugs.
- the present invention Compared with the prior art, the present invention has the advantages that: the present invention discloses for the first time a series of compounds containing both dihydrobenzofuran and Bridged polycyclic compounds with 1,4-sulfur bridged piperidinone substructure, which have four consecutive chiral centers and easily functionalized groups, are convenient for derivatization and synthesis of other chiral polycyclic compounds; at the same time, through preliminary The cell activity study of the present invention shows that this kind of compound has a good inhibitory effect on human leukemia cell K562 and human lung cancer cell A549, and is expected to become the leading compound of anti-tumor drugs; moreover, the method of the invention has mild reaction conditions, raw materials and catalysts It is easy to obtain, easy to operate, and has excellent stereoselectivity (>20:1dr, 98%ee).
- Fig. 1 is the hydrogen spectrogram of the I-ea obtained in Example 5;
- Fig. 2 is the carbon spectrogram of the I-ea obtained in Example 5;
- FIG. 3 is a single crystal diagram of I-ea prepared in Example 5.
- the raw materials, solvents, catalysts, molecular sieves, etc. used in the present invention are all commercially available.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明公开了一类含二氢苯并呋喃结构的1,4-硫桥多环化合物，属于有机合成领域，其具有如式(Ⅰ)所示的结构；还公开了其制备方法为将2-硝基苯并呋喃(Ⅱ)和5H-噻唑酮(Ⅲ)溶解在有机溶剂中，然后加入分子筛和手性催化剂，在氩气保护下室温搅拌反应，待反应完毕后，分离纯化得到含二氢苯并呋喃结构的1,4-硫桥多环化合物；本发明所提供的多环化合物，具有二氢苯并呋喃和1,4-硫桥哌啶酮亚结构；还公开了该类化合物在制备用于抗肿瘤药物中的用途，其在抗肿瘤药物研究中具有很好的潜在价值；而且本发明的制备方法具有新颖、简捷、操作简单、反应条件温和、收率高、立体选择性高等优点。
Description
本发明涉及有机合成领域，尤其涉及一种含二氢苯并呋喃结构的1,4-硫桥多环化合物、其制备方法及用途。
桥多环化合物广泛存在于天然产物和药物分子中，具有广泛的生物活性，是开发新药的重要来源。吗啡，作为临床上非常重要的强效镇痛药，就是一种二氢苯并呋喃结构的桥多环药物。鉴于苯并呋喃结构重要的生物活性以及桥多环化合物广泛的药理性质，合成含二氢苯并呋喃结构的桥多环化合物具有非常重要的科学意义。同时，从药物设计的角度来看，组合两个或多个药效官能团到一个分子中，可能会产生意想不到的生物活性，具有非常重要的应用价值。
不对称去芳构化是有机合成领域的一个难点，目前主要的研究方向为富电子芳香化合物，例如吲哚、萘酚等，主要利用这类化合物固有的亲核性。近些年，硝基杂芳烃类化合物的不对称去芳构化反应也引起了有机化学家广泛的兴趣，例如硝基吲哚、硝基苯并呋喃和硝基噻吩。然而，通过文献调研我们发现，硝基杂芳烃类化合物参与的不对称反应主要用于构建手性多环并环化合物和手性多环螺环化合物，而用于构建桥多环化合物的报道很少。构建桥多环化合物以丰富化合物种类并从中筛选具有良好生物活性的化合物是本领域一直的追求。
发明内容
本发明的目的之一，就在于提供一类新的含二氢苯并呋喃结构的桥多环化合物，以解决上述问题。
为了实现上述目的，本发明采用的技术方案是这样的：含二氢苯并呋喃结构的1,4-硫桥多环化合物，具有如下结构式(Ⅰ)所示的结构：
上述结构式中，Ar为各种取代的芳环、杂芳环等；R
1基为单取代基或多取代基，所述取代基选自氢，烷基，烷氧基，硝基或卤素中的一种；R
2基为甲基、乙基、苄基中的一种。
本发明首次公开了一类新的手性含二氢苯并呋喃结构的桥多环化合物，该化合物具有二氢苯并呋喃和1,4-硫桥哌啶酮亚结构，可以为新药的研发及药物的筛选提供更多候选分子。
本发明的目的之二，在于提供一种上述的含二氢苯并呋喃结构的桥多环化合物的制备方法，采用的技术方案为：将2-硝基苯并呋喃(Ⅱ)、5H-噻唑酮(Ⅲ)溶解在有机溶剂中，然后加入分子筛和手性催化剂，在氩气保护下室温搅拌反应，待反应完毕后，分离纯化得到含二氢苯并呋喃结构的1,4-硫桥多环化合物(Ⅰ)，其中，
所述2-硝基苯并呋喃(Ⅱ)具有如下结构：
所述5H-噻唑酮(Ⅲ)具有如下结构：
其反应式为：
5H-噻唑酮作为一种很好的含硫的亲核试剂广泛由于有机合成中，但目前的研究主要集中在C5位的亲核加成反应，而利用C5位的亲核性和C2位的亲电性构建1,4-硫桥环的报道很少。因此，本申请的发明人通过大量试验，选择合适的催化体系，采用底物2-硝基苯并呋喃和5H-噻唑酮先发生迈克尔加成反应，然后进一步曼尼希反应，一步构建含二氢苯并呋喃结构的具有四个连续的手性中心的桥多环化合物，如下式：
作为优选的技术方案：所述反应溶剂选自甲苯、均三甲苯、二氯甲烷、氯仿、四氢呋喃、乙醚、乙腈、乙醇、甲醇、1,4-二氧六环、氯苯中的一种或者多种混合。
进一步优先二氯甲烷，因为反应的收率最高，立体选择性最好。
作为优选的技术方案：所述手性催化剂为手性叔胺-硫脲双官能团催化剂或手性叔胺-方酰胺双官能团催化剂。
更为优选的，所述手性叔胺-硫脲催化剂手性叔胺-方酰胺催化剂具有如下式A或B或C或D的结构，即所使用的催化剂优选自下述的其中之一：
进一步优选催化剂D，因为反应的收率高，立体选择性好。
作为优选的技术方案：所述反应底物的摩尔比为n
Ⅱ:n
Ⅲ＝2:1～1:2。
进一步优选的：所述反应底物的摩尔比为n
Ⅱ:n
Ⅲ＝1:1.3。因为反应收率更高。
本发明的目的之三，在于提供上述的化合物在制备抗肿瘤药物中的用途。
具体而言，本发明公开的上述化合物的应用价值在于：通过初步的细胞活性实验，表明该类化合物对人白血病细胞K562和人肺癌细胞A549就有很好的杀害作用，细胞活性研究结果见表1。因此，通过进一步的研究，这类化合物有望成为抗肿瘤药物的先导化合物。
具体实验操作：将5000个人白血病细胞K562和人肺癌细胞A549分别接种到96孔细胞培养板中，并让其生长24小时。然后分别加入一定浓度的上述合成的化合物，以抗肿瘤药物顺铂作为对照，作用48h。然后测定所有化合物的平均50％的抑制浓度(IC
50)。每个浓度至少重复3次，所有实验重复3次，得到的平均结果见表1。
表1：细胞活性测定结果
从表1可以看出，本发明的化合物，具有与顺铂相当甚至更好的抑制K562和A549活性的作用。
与现有技术相比，本发明的优点在于：本发明通过2-硝基苯并呋喃的不对称去芳构化[4+2]反应，首次公开了一系列同时含有二氢苯并呋喃和1,4-硫桥哌啶酮亚结构的桥多环化合物，该类化合物具有四个连续的手性中心且含有易官能化基团，便于衍生合成其他手性多环化合物；同时，通过初步的细胞活性研究，表明该类化合物对人白血病细胞K562和人肺癌细胞A549都有很好的抑制作用，有望成为抗肿瘤药物的先导化合物；而且，本发明的方法具有反应条件温和，原料与催化剂易得，操作简单，立体选择性非常好(>20:1dr,98％ee)等优点。
图1为实施例5制得的I-ea的氢谱图；
图2为实施例5制得的I-ea的碳谱图；
图3为实施例5制得的I-ea的单晶图。
下面将结合附图对本发明作进一步说明。
本发明所用的原料、溶剂、催化剂、分子筛等等，均为市购。
实施例1：合成化合物Ⅰ-aa
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮Ⅲ-a 0.26 mmol，5A分子筛100mg和手性催化剂A/B/C/D，然后加入2.0mL溶剂，在氩气保护下室温反应，反应完全后，粗产品经柱色谱分离纯化得化合物I-aa，不同的反应条件如表2所示，具体反应过程如下：
表2不同的反应条件
| 序号 | 催化剂 | x | 溶剂 | 时间(h) | 分子筛 | Ar | 收率(％) | dr | ee(％) |
| 1 | A | 20 | CHCl 3 | 20 | 无 | 无 | 40 | >20:1 | 73 |
| 2 | B | 20 | CHCl 3 | 20 | 无 | 无 | 41 | >20:1 | 61 |
| 3 | C | 20 | CHCl 3 | 10 | 无 | 无 | 39 | >20:1 | 64 |
| 4 | D | 20 | CHCl 3 | 24 | 无 | 无 | 33 | >20:1 | 85 |
| 5 | D | 20 | CH 2Cl 2 | 24 | 无 | 无 | 31 | >20:1 | 93 |
| 6 | D | 20 | (CH 2Cl) 2 | 24 | 无 | 无 | 30 | >20:1 | 93 |
| 7 | D | 20 | CH 2Cl 2 | 24 | 有 | 无 | 60 | >20:1 | 91 |
| 8 | D | 20 | CH 2Cl 2 | 24 | 有 | 有 | 85 | >20:1 | 94 |
| 9 | D | 10 | CH 2Cl 2 | 48 | 有 | 有 | 83 | >20:1 | 94 |
| 10 | D | 5 | CH 2Cl 2 | 72 | 有 | 有 | 78 | >20:1 | 93 |
表1中，“x”是指所用催化剂的百分摩尔比。
从表1中可见，采用催化剂D 20mol％、二氯甲烷作溶剂、加入分子筛和氩气保护下反应，是更为优选的方案。
所得化合物I-aa为白色固体，经HPLC检测纯度为>99％；>20:1dr,94％ee；[α]
D
20＝-182.6(c 1.0,CH
2Cl
2)；m.p.163.1-164.0℃；其中，ee值的测定采用HPLC法： Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；保留时间t
major＝15.79min,t
minor＝10.01min；
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.20(s,1H),7.62–7.53(m,2H),7.53–7.44(m,4H),7.44–7.34(m,1H),7.23–7.10(m,2H),4.81(s,1H),1.60(s,3H).
13C NMR(75MHz,DMSO-d
6)δ206.1,176.2,160.0,130.4,129.9,129.2,128.7,127.1,126.1,125.8,123.2,123.0,110.3,81.6,62.5,59.5,11.8.HRMS(ESI-TOF)Calcd.for C
18H
15N
2O
4S[M+H]
+:355.0747；found:355.0747。
测定结果如图3所示，表明化合物1-a的绝对构型为(C2R,C15S,C16S,C17R)。以此类推，本发明的化合物均为该构型。
实施例2：合成化合物I-ba
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-b 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ba；淡黄色固体；收率为87％；>20:1dr,94％ee；m.p.178.5-179.5℃,[α]
D
25＝-425.5(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相95/5hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝21.78min,t
minor＝12.01min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.23(s,1H),7.59–7.53(m,2H),7.51–7.45(m,3H),7.37(dd,J＝8.1,2.4Hz,1H),7.26–7.18(m,2H),4.83(s,1H),1.61(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.5,159.6,157.2,156.7,130.5,129.1,128.1(d,J＝266.6Hz,1C),127.6,125.3(d,J＝9.1Hz,1C),117.3(d,J＝25.2Hz,1C),113.7(d,J＝26.3Hz,1C),111.6(d,J＝9.0Hz,1C),82.1,62.8,60.0,12.3.HRMS(ESI-TOF)Calcd.for C
18H
13FN
2NaO
4S[M+Na]
+:395.0472；found:395.0466。
实施例3：合成化合物I-ca
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-c 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ca；淡黄色固体；收率为95％；>20:1dr,90％ee；m.p.138.2-139.1℃,[α]
D
25＝-538.6(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝23.51min,t
minor＝14.52min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.28(s,1H),7.58(dd,J＝6.8,3.0Hz,2H),7.55–7.47(m,3H),7.43–7.29(m,2H),7.21–7.11(m,1H),4.94(s,1H),1.61(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.4,146.7(d,J＝11.1Hz,1C)146.5(d,J＝247.4Hz,1C),130.6,129.2,127.5,127.4,126.6,124.5(d,J＝5.0Hz,1C),122.4,122.3,117.9(d,J＝16.2Hz,1C),82.2,62.9,60.4,55.4,12.3.HRMS(ESI-TOF)Calcd.for C
18H
13FN
2NaO
4S[M+Na]
+:395.0472；found:395.0465。
实施例4：合成化合物I-da
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-d 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-da；淡黄色固体；收率为90％；>20:1dr,84％ee；m.p.144.3-145.2℃,[α]
D
25＝-345.6(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相95/5hexane/
iPr-OH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝9.46min,t
minor＝7.60min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.34(s,1H),7.60–7.54(m,2H),7.54–7.48(m,3H),7.47–7.41(m,1H),7.22(dd,J＝11.6,8.1Hz,2H),4.86(s,1H),1.66(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.2,161.4,132.7,130.8,130.6,129.2,129.1,127.6,125.7,124.5,122.4,110.1,81.9,64.8,60.1,14.8.HRMS (ESI-TOF)Calcd.for C
18H
13ClN
2NaO
4S[M+Na]
+:411.0177；found:411.0159。
实施例5：合成化合物I-ea
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-e 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ea；白色固体；收率为90％；>20:1dr,93％ee；m.p.155.3-156.2℃,[α]
D
25＝-419.1(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝11.11min,t
minor＝7.89min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)(见图1)δ10.25(s,1H),7.61–7.54(m,3H),7.53–7.47(m,3H),7.45(dd,J＝8.6,2.3Hz,1H),7.23(d,J＝8.6Hz,1H),4.85(s,1H),1.62(s,3H).
13C NMR(101MHz,DMSO-d
6)(见图2)δ176.4,159.3,130.7,130.5,129.3,129.2,127.5,127.3,126.5,126.4,126.0,112.3,82.1,62.8,59.8,12.3.HRMS(ESI-TOF)Calcd.for C
18H
13ClN
2NaO
4S[M+Na]
+:411.0177；found:411.0161。
单晶衍衍射实验：
单晶培养：将实施例1中得到的主要组分化合物I-a(40mg)溶于20mL二氯甲烷和乙醇的混合液中(V
二氯甲烷:V
二氯甲烷＝1:10)中，于室温下静置7天，有单晶析出，收集单晶进行单晶衍射测试。测试参数如表3所示：
表3单晶测试参数
测定结果如图3所示，表明化合物I-ea的绝对构型为(C2S,C3R,C4R,C5S)。以此类推，本发明的化合物均为该构型。
实施例6：合成化合物I-fa
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-f 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-fa；白色固体；收率为86％；>20:1dr,92％ee；m.p.149.3-150.3℃,[α]
D
25＝-444.4(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝10.66min,t
minor＝8.61min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.25(s,1H),7.68(d,J＝2.1Hz,1H),7.61–7.54(m,3H),7.53–7.45(m,3H),7.18(d,J＝8.6Hz,1H),4.86(s,1H), 1.61(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.4,159.8,133.5,130.5,129.3,129.2,129.1,127.6,126.5,126.4,114.9,112.8,82.1,62.8,59.8,12.3.HRMS(ESI-TOF)Calcd.for C
18H
13
79BrN
2NaO
4S[M+Na]
+:454.9672；found:454.9653；For C
18H
13
81BrN
2NaO
4S[M+Na]
+:456.9651；found:454.9630。
实施例7：合成化合物I-ga
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-g 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ga；白色固体；收率为86％；>20:1dr,92％ee；m.p.161.8-162.8℃,[α]
D
25＝-597.1(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝28.17min,t
minor＝15.67min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.24(s,1H),7.60–7.54(m,2H),7.53–7.47(m,4H),7.43(d,J＝8.1Hz,1H),7.35(dd,J＝8.0,1.8Hz,1H),4.81(s,1H),1.59(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.4,161.2,130.5,129.3,129.1,128.0,127.6,126.5,126.4,123.5,123.0,114.1,82.1,62.8,59.5,12.2.HRMS(ESI-TOF)Calcd.for C
18H
13
79BrN
2NaO
4S[M+Na]
+:454.9672；found:454.9662；For C
18H
13
81BrN
2NaO
4S[M+Na]
+:456.9651；found:454.9642。
实施例8：合成化合物I-ha
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-h 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ha；黄色固体；收率为80％；>20:1dr,88％ee；m.p.222.8-223.5℃,[α]
D
25＝-47.9(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相70/30hexane/EtOH；流速:1.0 mL/min；检测波长λ＝220nm；t
major＝9.73min,t
minor＝10.65min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.33(s,1H),8.43–8.27(m,2H),7.58–7.54(m,2H),7.54–7.48(m,3H),7.45(d,J＝8.9Hz,1H),5.75(s,1H),1.66(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.2,164.8,143.8,130.7,129.7,129.2,129.0,128.4,127.7,127.5,126.7,125.9,122.6,111.4,82.3,62.9,59.2,12.1.HRMS(ESI-TOF)Calcd.for C
18H
13N
3NaO
6S[M+Na]
+:422.0417；found:422.0403。
实施例9：合成化合物I-ia
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-i 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ia；白色固体；收率为78％；>20:1dr,89％ee；m.p.140.2-140.9℃,[α]
D
25＝-284.3(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝10.12min,t
minor＝7.33min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.18(s,1H),7.58(dd,J＝6.8,3.0Hz,2H),7.53–7.45(m,3H),7.35(d,J＝7.7Hz,1H),7.01(s,1H),6.96(d,J＝7.7Hz,1H),4.74(s,1H),2.34(s,3H),1.58(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.7,160.8,141.0,130.4,129.7,129.1,127.5,126.5,126.1,124.1,120.7,111.2,82.0,63.0,59.8,21.6,12.3.HRMS(ESI-TOF)Calcd.for C
19H
16N
2NaO
4S[M+Na]
+:391.0723；found:391.0710。
实施例10：合成化合物I-ja
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-j 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ja；白色固体；收率为 78％；>20:1dr,88％ee；m.p.188.7-189.5℃,[α]
25＝-219.5(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝12.69min,t
minor＝9.04min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.16(s,1H),7.57(dd,J＝6.8,3.0Hz,2H),7.52–7.46(m,3H),7.35(d,J＝8.4Hz,1H),6.84(d,J＝2.3Hz,1H),6.70(dd,J＝8.4,2.3Hz,1H),4.70(s,1H),3.78(s,3H),1.57(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.7,162.0,161.8,130.4,129.6,129.1,127.5,127.0,126.7,115.2,109.7,97.0,81.9,63.1,59.6,56.2,12.2.HRMS(ESI-TOF)Calcd.for C
19H
16N
2NaO
5S[M+Na]
+:407.0672；found:407.0656。
实施例11：合成化合物I-ka
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-k 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ka；白色固体；收率为70％；>20:1dr,89％ee；m.p.177.4-178.3℃,[α]
D
25＝-214.1(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相95/5hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝11.02min,t
minor＝8.88min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.19(s,1H),7.62–7.55(m,2H),7.49(dd,J＝4.3,2.3Hz,4H),7.41(dd,J＝8.5,2.1Hz,1H),7.09(d,J＝8.6Hz,1H),4.76(s,1H),1.61(s,3H),1.30(s,9H).
13C NMR(101MHz,DMSO-d
6)δ176.7,158.5,146.1,130.4,129.9,129.7,129.1,127.6,127.5,126.6,123.4,123.3,109.9,81.9,62.9,60.1,34.8,31.8,12.4.HRMS(ESI-TOF)Calcd.for C
22H
22N
2NaO
5S[M+Na]
+:433.1192；found:433.1181。
实施例12：合成化合物I-la
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-l 0.2mmol，5H-噻唑酮III-a 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-la；白色固体；收率为94％；>20:1dr,91％ee；m.p.156.9-157.7℃,[α]
D
25＝-285.5(c 1.0,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相95/5hexane/
iPrOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝32.45min,t
minor＝39.30min。
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.22(s,1H),7.58–7.45(m,5H),7.33–7.22(m,2H),4.85(s,1H),3.87(s,3H),1.59(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.6,148.7,144.4,130.4,130.0,129.6,129.1,129.0,127.6,126.5,124.8,124.2,118.0,114.3,82.0,62.9,60.5,56.4,12.4.HRMS(ESI-TOF)Calcd.for C
19H
15
79BrN
2NaO
5S[M+Na]
+:484.9777；found:484.9764；For C
19H
15
81BrN
2NaO
5S[M+Na]
+:486.9757；found:486.9739。
实施例13：合成化合物I-ab
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-b 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ab；白色固体；收率为60％；>20:1dr,89％ee；m.p.160.7-161.5℃,[α]
25＝-171.5(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝23.50min,t
minor＝14.23min。
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.05(s,1H),7.56(dd,J＝14.6,7.4Hz,2H),7.47(d,J＝7.7Hz,1H),7.41–7.31(m,3H),7.17–7.10(m,2H),4.80(s,1H),1.59(s,3H).
13C NMR(151MHz,DMSO-d
6)δ176.2,160.6(d,J＝250.7Hz,1C),160.5,133.2(d,J＝9.1Hz,1C),130.8,130.4(d,J＝3.0Hz,1C),126.5,125.7,125.2(d,J＝4.5Hz,1C),123.7,123.4,117.2(d,J＝22.6Hz,1C),116.5(d,J＝10.6Hz.1C),110.7,79.8(d,J＝3.0Hz,1C),62.4,59.9,12.2.HRMS(ESI-TOF)Calcd.for C
18H
14FN
2O
4S[M+H]
+:373.0653；found:373.0652。
实施例14：合成化合物I-ac
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-c 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ac；白色固体；收率为72％；>20:1dr,93％ee；m.p.173.4-174.1℃,[α]
D
25＝-64.2(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相80/20hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝11.64min,t
minor＝16.50min。
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.16(s,1H),7.53–7.44(m,3H),7.43–7.35(m,1H),7.20–7.11(m,2H),7.06–7.01(m,2H),4.79(s,1H),1.58(s,3H).
13C NMR(151MHz,DMSO-d
6)δ176.6,163.3(d,J＝249.2Hz,1C),160.4,130.8,130.0(d,J＝9.1Hz,2C),126.6,126.2,126.0(d,J＝3.0Hz,1C),123.6,123.5,116.2(d,J＝22.6Hz,2C),110.7,81.3,63.1,59.8,12.3.HRMS(ESI-TOF)Calcd.for C
18H
14FN
2O
4S[M+H]
+:373.0653；found:373.0662。
实施例15：合成化合物I-ad
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-d 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ad；白色固体；收率为78％；>20:1dr,98％ee；m.p.186.0-186.7℃,[α]
D
25＝-389.3(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝13.93min,t
minor＝8.09min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.25(s,1H),7.66–7.56(m,4H),7.53–7.46(m,1H),7.45–7.37(m,1H),7.22–7.12(m,2H),4.85(s,1H),1.60(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.6,160.5,135.3,130.9,129.5,129.2,128.7,126.6,126.2,123.6,123.5,110.8,81.2,63.1,59.8,12.3.HRMS(ESI-TOF)Calcd.for C
18H
14ClN
2O
4S[M+H]
+:389.0357；found:389.0364。
实施例16：合成化合物I-ae
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-e 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ae；白色固体；收率为72％；>20:1dr,96％ee；m.p.175.7-176.6℃,[α]
D
25＝-37.8(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝11.44min,t
minor＝9.76min。
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.25(s,1H),7.79–7.67(m,2H),7.58–7.45(m,3H),7.44–7.35(m,1H),7.22–7.08(m,2H),4.84(s,1H),1.59(s,3H).
13C NMR(75MHz,DMSO-d
6)δ176.4,160.2,131.9,130.6,129.4,128.8,126.3,125.9,123.8,123.3,123.2,110.5,81.0,62.9,59.5,12.0.HRMS(ESI-TOF)Calcd.for C
18H
14
79BrN
2O
4S[M+H]
+:432.9858；found:432.9852；For C
18H
14
81BrN
2O
4S[M+H]
+:434.9833；found:434.9843。
实施例17：合成化合物I-af
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-f 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保 护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-af；白色固体；收率为75％；>20:1dr,90％ee；m.p.224.0-224.8℃,[α]
D
25＝-112.3(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相80/20hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝32.08min,t
minor＝17.18min。
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.08(s,1H),7.99–7.82(m,1H),7.62–7.54(m,1H),7.47(d,J＝7.1Hz,1H),7.42–7.35(m,1H),7.34–7.26(m,1H),7.19–7.10(m,2H),4.82(s,1H),1.60(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.1,160.5,156.7(d,J＝253.5Hz,1C),136.3,130.9,129.9,126.6,126.4(d,J＝4.0Hz,1C),125.7,123.6(d,J＝8.1Hz,1C),118.5(d,J＝13.1Hz,1C),110.8,110.3(d,J＝22.2Hz,1C),79.4,79.4,62.7,59.9,12.2.HRMS(ESI-TOF)Calcd.for C
18H
13
79BrFN
2O
4S[M+H]
+:450.9783；found:450.9758；For C
18H
13
81BrFN
2O
4S[M+H]
+:452.9739；found:452.9712。
实施例18：合成化合物I-ag
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-g 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ag；黄色固体；收率为83％；>20:1dr,81％ee；m.p.134.3-135.1℃,[α]
D
25＝-86.6(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝24.80min,t
minor＝14.80min。
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.23(s,1H),7.94–7.80(m,1H),7.47(d,J＝7.5Hz,1H),7.43–7.35(m,1H),7.24–7.09(m,2H),6.85(d,J＝3.5Hz,1H),6.60(dd,J＝3.5,1.8Hz,1H),4.81(s,1H),1.57(s,3H).
13C NMR(75MHz,DMSO-d
6)δ175.3,160.2,145.2,142.3,130.4,126.1,125.1,123.1,123.0,111.4,111.2,110.4,75.9,63.1,58.9,11.9.HRMS(ESI-TOF)Calcd.for C
16H
12N
2O
5S[M+Na]
+:367.0359；found:367.0360。
实施例19：合成化合物I-ah
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-h 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ah；白色固体；收率为75％；>20:1dr,80％ee；m.p.221.9-222.7℃,[α]
D
25＝-60.3(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝19.62min,t
minor＝16.90min。
结构鉴定：
1H NMR(400MHz,DMSO-d
6)δ10.19(s,1H),8.62–8.55(m,1H),8.13–8.02(m,2H),7.92–7.83(m,1H),7.78–7.66(m,2H),7.55-7.48(m,1H),7.44–7.35(m,1H),7.20–7.12(m,2H),4.86(s,1H),1.64(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.0,160.6,149.0,146.8,138.3,131.2,130.8,129.5,128.5,128.4,128.3,126.6,125.8,123.7,123.4,119.9,110.9,83.4,63.5,60.0,12.5.HRMS(ESI-TOF)Calcd.for C
21H
16N
2O
4S
2[M+H]
+:406.0856；found:406.0864。
实施例20：合成化合物I-ai
在一根干燥的反应试管中加入2-硝基苯并呋喃Ⅱ-a 0.2mmol，5H-噻唑酮III-i 0.26mmol，5A分子筛100mg和手性催化剂D 0.02mmol，然后加入2.0mL二氯甲烷，氩气保护下室温反应；反应完全后，粗产品经柱色谱分离纯化得化合物I-ai；白色固体；收率为70％；>20:1dr,82％ee；m.p.182.6-183.5℃,[α]
D
25＝-113.2(c 0.5,CH
2Cl
2)；其中，ee值的测定采用HPLC法：Chiralpak IC色谱柱；流动相90/10hexane/EtOH；流速:1.0mL/min；检测波长λ＝220nm；t
major＝35.00min,t
minor＝28.40min。
结构鉴定：
1H NMR(300MHz,DMSO-d
6)δ10.14(s,1H),8.69–8.61(m,1H), 8.05–7.93(m,1H),7.56(dd,J＝8.2,4.2Hz,2H),7.47(d,J＝7.5Hz,1H),7.42–7.31(m,1H),7.13(dd,J＝8.0,5.7Hz,2H),4.77(s,1H),1.59(s,3H).
13C NMR(101MHz,DMSO-d
6)δ176.2,160.6,149.6,148.5,137.9,130.7,126.5,125.7,125.6,123.8,123.3,123.0,110.8,83.5,62.9,60.1,12.4.HRMS(ESI-TOF)Calcd.for C
17H
14N
3O
4S[M+H]
+:356.0700；found:356.0694。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (8)
- 含二氢苯并呋喃结构的1,4-硫桥多环化合物，其特征在于，具有如下结构式(Ⅰ)所示的结构：
上述结构式中，Ar为各种取代的芳环、杂芳环等；R 1基为单取代基或多取代基，所述取代基选自氢，烷基，烷氧基，硝基或卤素中的一种；R 2基为甲基、乙基、苄基中的一种。 - 权利要求1所述的含二氢苯并呋喃结构的1,4-硫桥多环化合物的制备方法，其特征在于：将反应底物2-硝基苯并呋喃(Ⅱ)和5H-噻唑酮(Ⅲ)溶解在有机溶剂中，然后加入分子筛和手性催化剂，在氩气保护下室温搅拌反应，待反应完毕后，分离纯化得到含二氢苯并呋喃结构的1,4-硫桥多环化合物(Ⅰ)，其中，所述2-硝基苯并呋喃(Ⅱ)具有如下结构：
所述5H-噻唑酮(Ⅲ)具有如下结构：
- 根据权利要求2所述的制备方法，其特征在于：所述有机溶剂选自甲苯、均三甲苯、二氯甲烷、氯仿、四氢呋喃、乙醚、乙腈、乙醇、甲醇、1,4-二氧六环、氯苯中的一种或者多种混合。
- 根据权利要求3所述的制备方法，其特征在于：所述有机溶剂为二氯甲烷。
- 根据权利要求2所述的制备方法，其特征在于：所述手性催化剂为手性叔胺-硫脲催化剂或叔胺-方酰胺催化剂。
- 根据权利要求2所述的制备方法，其特征在于：所述反应底物的摩尔比为n Ⅱ:n Ⅲ＝2:1～1:2。
- 根据权利要求6所述的制备方法，其特征在于：所述反应底物的摩尔比为n Ⅱ:n Ⅲ＝1:1.3。
- 权利要求1所述的含二氢苯并呋喃结构的1,4-硫桥多环化合物在制备用于抗肿瘤的 药物中的用途。
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