阅读说明：本技术 一类多并杂环螺羟吲哚类化合物的合成方法 (Synthesis method of polyatomic heterocyclic spiro oxindole compound ) 是由 任海 潘卫东 宋俊蓉 李志遥 于 2019-10-10 设计创作，主要内容包括：本发明涉及一类多并杂环螺羟吲哚类化合物的合成方法。该类化合物在有机溶剂中,在绿色环保、廉价的铁催化剂作用下一步反应得到。得到的部分化合物是临床二期开发药物NITD609及其类似物或者重要的药物中间体。同时本发明的制备方法反应收率高,催化剂绿色环保,催化剂用量少,水是唯一副产物,绿色无污染,适用取代基范围广,操作简单,有望实现工业化应用前景。(The invention relates to a synthesis method of a polyatomic heterocyclic spiro oxindole compound. The compound is obtained by one-step reaction in an organic solvent under the action of a green, environment-friendly and cheap iron catalyst. The obtained partial compound is a clinical second-stage development medicament NITD609 and analogues thereof or important medicament intermediates. Meanwhile, the preparation method disclosed by the invention is high in reaction yield, the catalyst is green and environment-friendly, the using amount of the catalyst is small, water is the only byproduct, the preparation method is green and pollution-free, the applicable substituent range is wide, the operation is simple, and the industrial application prospect is expected to be realized.)

1. A synthetic method of a kind of polyatomic heterocyclic spiro oxindole compound is characterized in that: reacting compound 1 with compound 2 in the presence of a catalytic amount of iron salt in tetrahydrofuran as a solvent to form compound a:

in the above formulae, R¹、R²、R³And R⁴Each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, substituted or unsubstituted C₆-C₁₅Aryl, alkoxy or benzyloxy;

R⁵is H, substituted or unsubstituted C₁-C₁₅Alkyl of (2), substituted or unsubstituted C₆-C₁₅Aryl, acyl;

R⁶and R⁷Each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, substituted or unsubstituted C₆-C₁₅Aryl, alkoxy or benzyloxy or a linker ring forms a polycyclic ring system of the formula B in which R is¹⁰、R¹¹、R¹²And R¹³Each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, substituted or unsubstituted C₆-C₁₅Aryl, alkoxy or benzyloxy;

R⁸、R⁹each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, alkoxy or benzyloxy; x, Y are each independently O, S, NR¹⁴Wherein R is¹⁴Is H, substituted or unsubstituted C₁-C₁₅Alkyl of (a), substituted or unsubstituted benzyl, substituted or unsubstituted C₆-C₁₅Aryl, acyl.

2. The method for synthesizing a polyatomic heterocyclic spirooxindole compound according to claim 1, wherein the molar ratio of the compound 1 to the compound 2 in the reaction formula is 1:1, and the mass fraction of the added iron salt serving as a catalyst is 0.01% -1%.

3. The method for synthesizing polyaheterocycle spirooxindole compounds according to claim 1 or 2, wherein the reaction temperature is 25-60 ℃.

Technical Field

The invention belongs to the field of generation processes of medicines and medicine intermediates, and particularly relates to a synthesis method of a polyatomic heterocyclic spiro oxindole compound.

Background

Polyatomic heterocyclic spirooxindoles, as an important core building block, are widely present in natural products and numerous molecules with biological activity (a) peddibotla, s.curr.bioact.compact.2009, 5,20.(b) Trost, b.m.; brennan, m.k.synthesis 2009,2009,3003.(c) Christensen, m.k.; erichsen, k.d.; Trojel-Hansen, C.; tjornelund, j.; nielsen, s.j.; frydenvang, K.; johansen, t.n.; nielsen, b.; secured, m.; jensen, p.b.; ikaunieks, m.; zaichenko, a.; loza, e.; kalvinsh, i.; bjorkling, f.j.med.chem.2010,53,7140. (d) Sharma, i.; tan, d.s.nat.chem.2013,5,157.(e) Cao, z. -y.; zhou, f.; the research on how to efficiently construct the structural derivative of the polyatomic heterocyclic spirooxindole has been a hotspot difficulty in the field of organic synthesis.

In 2010, Diagana et al reported on Top journal Science that tetrahydro- β -carboline spirooxindole molecule NITD609 (formula 1) showed excellent antimalarial activity (IC50 ═ 0.9 nM). More notably, this molecule differs from the mechanism of action of the existing antimalarial drugs mefloquine (mefloquine) and artemisinin (artemisinine), by modulating the P-type atpase (PfATP4) and thereby rapidly inhibiting the synthesis of proteins in the parasite. The research provides a brand new relieving way for the problem of severe drug resistance of the current antimalarial drugs. Currently, Nowa company is conducting phase II clinical trials on it. In 2014, the existing compound NITD609 of McLeod and the like has the anti-plasmodium activity, also shows good pharmacological activity on toxoplasma tachyzoite, and the IC of the compound in an in vitro cell experiment₅₀The value was 1. mu.M. In addition, the compound has high safety and no damage to normal cells of human body even if the dosage is more than 10 μ M. (a) Rottmann, m.; McNamara, c.; yeung, b.k.; lee, m.c.; zuo, b.; russell, b.; seitz, p.; plouffe, d.m.; dharia, n.v.; tan, j.; cohen, s.b.; spencer, k.r.; Gonzalez-Paez, g.e.; lakshminarayana, s.b.; goh, a.; suwanarusk, r.; jegla, t.; schmitt, e.k.; beck, h.p.; brun, r.; nonsten, f.; renia, l.; dartois, v.; keller, t.h.; fidock, d.a.; winzeler, e.a.; diagana, t.t.science 2010,329,1175.

Formula 1: antimalarial drug molecule NITD609

Has great application value and prospect. Taking an example of synthesis of NITD609 parent nucleus tetrahydro-beta-carboline spirooxindole skeleton structure, scientists have conducted a great deal of research and obtained a series of important research results (a) Zheng, H.; liu, x.; xu, c.; xia, y.; lin, l.; feng, x.angelw.chem.int.ed.2015, 54,10958, (b) Yeung, b.k.s.; zuo, b.; rottmann, m.; lakshminarayana, s.b.; ang, s.h.; leong, s.y.; tan, j.; wong, j.; Keller-Maerki, S.; fischli, c.; goh, a.; schmitt, e.k.; krastel, p.; francotte, e.; kuhen, k.; plouffe, D.; henson, k.; wagner, t.; winzeler, e.a.; petersen, f.; brun, r.; dartois, v.; diagana, t.t.; keller, t.h.j.med.chem.2010, 53,5155.(c) von xiaoming, zheng haifeng, liu xianhua, linlili. chinese patent: CN 104926813A. Conventionally, it has been found through literature studies that a spiro structural derivative containing structural units such as oxoheterocyclic spirooxindole and thiethylspirooxindole and corresponding to the parent nucleus of tetrahydro- β -carboline spirooxindole has not been reported (formula 2). It is worth mentioning that no synthesis of such structures can be achieved by any of the reported strategies and methods.

Formula 2: molecular analogous structure of antimalarial drug

In conclusion, a synthetic method which is simple and convenient in reaction operation, short in synthetic steps, wide in applicable substituent range and capable of synthesizing various heterocyclic spiro oxindoles including the NITD609 parent nucleus in an industrial system is not available in the field, and the current situation needs to be solved urgently.

Disclosure of Invention

The invention aims to provide a method for synthesizing multi-type multi-heterocyclic spiro oxindole, which solves the problems of single type of reaction products, limited substrate compatibility, expensive catalyst and the like in the synthesis method in the prior art.

As is well known, iron in nature is abundant in resource, and is one of trace elements of human body. Iron catalysis has the obvious advantages of low price, safety, environmental protection and the like, such as FeCl₃Is a common sewage and wastewater treating agent. The iron catalyst is applied to the high-efficiency construction of the compound with pharmacological activity and the industrial production thereof is realizedHas important value and significance.

The invention provides a synthesis method of a poly heterocyclic spiro oxindole, which comprises the following steps of reacting a compound shown in a formula 1 with a compound shown in a formula 2 in an inert solvent under the catalysis of a trace amount of iron salt to form a compound shown in a formula A, wherein the chemical formula is as follows:

in the above formulae, R¹、R²、R³And R⁴Each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, substituted or unsubstituted C₆-C₁₅Aryl, alkoxy or benzyloxy;

R⁵is H, substituted or unsubstituted C₁-C₁₅Alkyl of (2), substituted or unsubstituted C₆-C₁₅Aryl, acyl;

R⁶and R⁷Each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, substituted or unsubstituted C₆-C₁₅Aryl, alkoxy or benzyloxy or a linker ring forms an aromatic system represented by structure (B), wherein R is¹⁰、R¹¹、R¹²And R¹³Each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, substituted or unsubstituted C₆-C₁₅Aryl, alkoxy or benzyloxy.

R⁸、R⁹Each independently is H, substituted or unsubstituted C₁-C₁₅Alkyl, halogen, alkoxy or benzyloxy;

x, Y are each independently O, S, NR¹⁴Wherein R is¹⁴Is H, substituted or unsubstituted C₁-C₁₅Alkyl of (2), substituted or unsubstituted C₆-C₁₅Aryl, acyl;

the molar ratio of the compound of formula 1 to the compound of formula 2 is 1:1 to 1: 1.5;

preferably, the catalyst iron salt is FeCl₃，Fe(ClO₄)₃.6H₂O，Fe(OTf)₃，FeCl₂；

Preferably, the dosage of the catalyst iron salt is 0.01-1%;

preferably, the reaction temperature is between 25 and 60 ℃, and more preferably, the reaction temperature is between 30 and 50 ℃.

Preferably, the inert solvent is selected from the group consisting of N, N-dimethylamide, dimethylsulfoxide, tetrahydrofuran, or combinations thereof.

The working principle of the invention is as follows: through long-term intensive and systematic research, the inventor of the invention discovers a brand-new synthesis method of polyatomic heterocyclic spirooxindole, and the compound shown in the formula 1 and the compound shown in the formula 2 are reacted in an inert solvent under the catalysis of trace iron salt, so that polyatomic heterocyclic spirooxindole compounds with various structures are obtained. The method has the advantages of simple and easily-obtained raw materials, green and environment-friendly catalyst, wide substrate application range, simple and convenient operation, high reaction efficiency, green and less pollution and the like, and water is the only byproduct. On this basis, the inventors have completed the present invention. The prepared polyatomic heterocyclic spiro oxindole compound has very important application prospect in the biomedical fields of malaria resistance, antibiosis and the like.

Detailed Description

The invention will be further elucidated with reference to specific embodiments. It should be understood that these examples are only for illustrating the present invention and are not to be construed as limiting the scope of the present invention. In the following examples, the experimental methods in which specific conditions are indicated generally follow conventional conditions or conditions recommended by the manufacturer, and unless the reaction temperature is indicated, the reaction is carried out at room temperature. Unless otherwise indicated, percentages and parts amine weight are calculated.

The following examples were all purified by a method of post-treatment which is conventional in the art.