阅读说明：本技术 一种手性吲哚并氧杂七元环化合物及其合成方法 (Chiral indolo-oxa-heptatomic ring compound and synthesis method thereof ) 是由 石枫 张家毅 谭伟 张宇辰 于 2021-10-18 设计创作，主要内容包括：本发明公开了一种手性吲哚并氧杂七元环化合物及其合成方法,该化合物的结构式如式3所示；以2,3-二取代吲哚甲醇衍生物与2-萘酚衍生物作为反应原料,以苯及其衍生物作为反应溶剂,手性磷酸作为催化剂,在室温条件下搅拌反应,TLC跟踪反应至完全,过滤、浓缩、纯化即得。本发明通过生物活性测试,显示该类化合物对Hela癌细胞具有一定的细胞毒活性。本合成方法反应过程温和,产物的对映选择性高、收率高,适宜工业化生产。(The invention discloses a chiral indolo-oxa-heptatomic ring compound and a synthesis method thereof, wherein the structural formula of the compound is shown as a formula 3; the method comprises the following steps of taking a 2, 3-disubstituted indole methanol derivative and a 2-naphthol derivative as reaction raw materials, taking benzene and the derivative thereof as reaction solvents, taking chiral phosphoric acid as a catalyst, stirring for reaction at room temperature, tracking and reacting by TLC until the reaction is complete, filtering, concentrating and purifying to obtain the product. The compounds have certain cytotoxic activity on Hela cancer cells through biological activity tests. The synthesis method has the advantages of mild reaction process, high enantioselectivity and high yield of the product, and is suitable for industrial production.)

1. A chiral indolocarbaxepin is characterized in that the chemical structure of the chiral indolocarbaxepin is shown as formula 3:

in the formula, R¹Selected from hydrogen, C1-C3 alkyl,One of C1-C3 alkoxy and halogen; r²One selected from hydrogen, C1-C3 alkyl and halogen; r³One selected from hydrogen, C1-C3 alkyl and halogen; r⁴Is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, aryl and halogen.

2. A method for synthesizing the chiral indolo-oxa-heptatomic ring compound of claim 1, which comprises the following steps:

taking a 2, 3-disubstituted indole methanol derivative and a 2-naphthol derivative as reaction raw materials, taking benzene and the derivative thereof as reaction solvents, taking chiral phosphoric acid as a catalyst, stirring for reaction at room temperature, tracking and reacting by TLC (thin layer chromatography) until the reaction is complete, and filtering, concentrating and purifying to obtain a compound shown in a formula 3;

wherein the reaction molar ratio of the 2, 3-disubstituted indole methanol derivative to the 2-naphthol derivative is 1:1.2 to 2: 1;

the structural formula of the 2, 3-disubstituted indole methanol derivative is shown in the specificationIn the formula, R¹One selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen; r²One selected from hydrogen, C1-C3 alkyl and halogen; r³One selected from hydrogen, C1-C3 alkyl and halogen;

the structural formula of the 2-naphthol derivative is shown in the specificationIn the formula, R⁴One selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, aryl and halogen;

the chiral phosphoric acid is selected from one or two of binaphthyl skeleton derivatives, octahydrobinaphthyl skeleton derivatives and spiro skeleton derivatives; the structural formula of the binaphthyl skeleton derivative is shown in the specificationWherein G is selected from 9-anthryl, 9-phenanthryl, 2,4, 6-triOne of isopropylphenyl, triphenylsilyl, 2-naphthyl or 1-naphthyl; the structural formula of the octahydrobinaphthyl skeleton derivative is shown in the specificationWherein G' is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, triphenylsilicon base, 2-naphthyl or 1-naphthyl; the structural formula of the spiro skeleton derivative is shown in the specificationWherein G' is selected from one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, triphenylsilicon base, 2-naphthyl or 1-naphthyl.

3. The method for synthesizing chiral indolo-oxa-heptatomic ring compound according to claim 2, wherein the chiral phosphoric acid has a structural formula ofWherein G is selected from 2,4, 6-triisopropylphenyl.

4. The method for synthesizing chiral indolo-oxa-heptatomic ring compound according to claim 2, wherein the benzene and its derivatives are selected from one of toluene, o-xylene, m-xylene, mesitylene, fluorobenzene, bromobenzene and chlorobenzene.

5. A method of synthesizing a chiral indolocarbaxeheptatomic ring compound according to claim 4, wherein the benzene and its derivatives are selected from mesitylene.

6. The method for synthesizing a chiral indolocarbaxeheptatomic ring compound according to claim 2, wherein the reaction molar ratio of the 2, 3-disubstituted indolocarballyl alcohol derivative to the 2-naphthol derivative is 1: 1.2.

7. the method for synthesizing the chiral indolo-oxa-heptatomic ring compound according to claim 2, wherein the purification is performed by silica gel column chromatography, and the eluent is a compound having a volume ratio of 10:1 in the form of a petroleum ether/ethyl acetate mixture.

Technical Field

The invention relates to the technical field of organic chemical synthesis, in particular to a chiral indolo-oxa-heptatomic ring compound and a synthesis method thereof.

Background

The chiral indolo-oxa-heptatomic ring compound has wide application prospect in the field of life science, and meanwhile, as the chiral indolo-oxa-heptatomic ring compound plays a role in biological activity in drug molecules and is often an enantiomer in a racemate, people urgently need to design a novel chiral indolo-oxa-heptatomic ring compound and develop a method for efficiently synthesizing the chiral indolo-oxa-heptatomic ring compound. At present, the research on the cytotoxic activity of the chiral indolo-oxa-heptatomic ring compound on Hela cancer cells in the prior art is not sufficient, and the chiral indolo-oxa-heptatomic ring compound is almost in a blank stage; and when the chiral indolo-oxa-heptatomic ring compound is synthesized, the reaction condition is harsh, the misoperation is easy, even safety accidents are caused, and the problems of high cost, low yield, low enantioselectivity and the like are indirectly caused.

Disclosure of Invention

The invention aims to provide a chiral indolocarbaxeptatomic ring compound which has certain cytotoxic activity on Hela cancer cells.

The invention also aims to provide a synthesis method of the chiral indolocarbaxeptatomic ring compound, which has the advantages of mild reaction conditions, low cost and high yield.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

in one aspect, the invention provides a chiral indolocarbaxepin-heptatomic ring compound, which has a chemical structure shown in formula 3:

in the formula, R¹One selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen; r²One selected from hydrogen, C1-C3 alkyl and halogen; r³One selected from hydrogen, C1-C3 alkyl and halogen; r⁴Is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, aryl and halogen.

On the other hand, the invention also provides a synthesis method of the chiral indolocarbaxeptatomic ring compound, which comprises the following specific steps:

taking a 2, 3-disubstituted indole methanol derivative and a 2-naphthol derivative as reaction raw materials, taking benzene and the derivative thereof as reaction solvents, taking chiral phosphoric acid as a catalyst, stirring for reaction at room temperature, tracking and reacting by TLC (thin layer chromatography) until the reaction is complete, and filtering, concentrating and purifying to obtain a compound shown in a formula 3;

wherein the reaction molar ratio of the 2, 3-disubstituted indole methanol derivative to the 2-naphthol derivative is 1:1.2 to 2: 1;

the structural formula of the 2, 3-disubstituted indole methanol derivative is shown in the specificationIn the formula, R¹One selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen; r²One selected from hydrogen, C1-C3 alkyl and halogen; r³One selected from hydrogen, C1-C3 alkyl and halogen;

the structural formula of the 2-naphthol derivative is shown in the specificationIn the formula, R⁴One selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, aryl and halogen;

the chiral phosphoric acid is selected from one or two of binaphthyl skeleton derivatives, octahydrobinaphthyl skeleton derivatives and spiro skeleton derivatives; the structural formula of the binaphthyl skeleton derivative is shown in the specificationWherein G is selected from one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, triphenylsilicon base, 2-naphthyl or 1-naphthyl; the structural formula of the octahydrobinaphthyl skeleton derivative is shown in the specificationWherein G' is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, triphenylsilicon base, 2-naphthyl or 1-naphthyl; the structural formula of the spiro skeleton derivative is shown in the specificationWherein G' is selected from one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, triphenylsilicon base, 2-naphthyl or 1-naphthyl.

The reaction route is as follows:

preferably, the chiral phosphoric acid has the structural formulaWherein G is selected from 2,4, 6-triisopropylphenyl.

Preferably, the benzene and its derivatives are selected from one of toluene, o-xylene, m-xylene, mesitylene, fluorobenzene, bromobenzene and chlorobenzene.

More preferably, the benzene and its derivatives are selected from mesitylene.

Preferably, the reaction molar ratio of the 2, 3-disubstituted indole methanol derivative to the 2-naphthol derivative is 1: 1.2.

preferably, the purification is silica gel column chromatography, and the eluent is petroleum ether/ethyl acetate mixed liquor with the volume ratio of 10: 1.

Compared with the prior art, the invention has the following beneficial effects:

1. the chiral indolo-oxa-heptatomic ring compound disclosed by the invention is shown to have certain cytotoxic activity on Hela cancer cells through biological activity tests, and the chiral indolo-oxa-heptatomic ring compound synthesized by the invention has application value in research and development of novel antitumor drugs.

2. According to the synthesis method of the chiral indolo-oxa-heptatomic ring compound, chiral phosphoric acid is used as a catalyst, so that high enantioselectivity can be obtained; in the synthesis method, the product has high enantioselectivity, high yield and mild reaction process, and is suitable for industrial production; a wide variety of substrates can be used as reactants to obtain products of structural diversity and complexity.

Detailed Description

The present invention will be described in further detail with reference to specific examples.

In the examples described below, unless otherwise indicated, the experimental procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer.

The starting 2, 3-disubstituted indolylmethanol derivatives (i.e. compounds of formula 1) used in the following examples are according to the literature: org.chem.Front.2018,5(18),2657-2667, and the remaining starting materials or reagents are commercially available.

Example 1

The synthetic route of the chiral indolocarbaxeheptatomic ring compound 3aa is shown as follows:

in the above reaction, the catalyst chiral phosphoric acid has the following structural formula:

adding 0.1 mmol of 2, 3-disubstituted indole methanol derivative 1a and 0.12 mmol of 2-naphthol compound 2a as reactants and 0.01 mmol of chiral phosphoric acid (namely a compound shown in a formula 4) as a catalyst into 1 ml of mesitylene, stirring and reacting at room temperature for 12 hours, tracking and reacting by TLC until the reaction is finished, and separating by silica gel column chromatography (eluent is mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10: 1) to obtain chiral indole oxaheptatomic ring compound 3 aa.

The structural characterization data for product 3aa in example 1 is as follows:

yield 90% (46.3 mg); a white solid; the melting point is 250.1-251.0 ℃; [ alpha ] to]_D ²⁰＝+97.8(c＝0.42,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ8.57–8.51(m,1H),7.96–7.90(m,1H),7.79–7.73(m,1H),7.64 –7.57(m,2H),7.47–7.41(m,1H),7.40–7.27(m,8H),7.26–7.13(m,9H),7.11–6.98(m,2H), 6.62(s,1H),6.44(d,J＝8.8Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ151.40,145.11,144.75, 140.68,135.74,135.52,135.42,132.01,131.61,131.17,130.60,130.12,128.80,128.70,128.52, 128.29,128.09,127.78,127.65,127.54,127.31,126.96,126.49,125.88,125.39,124.69,123.26, 122.59,122.46,120.14,118.53,114.11,110.96,87.00, 37.05; IR (KBr) 2360,2343,1260,795, 748,699,668,633,618,606,591,530,517, 452; enantiomeric excess (ee) 92%, HPLC (Daicel Chiralpak OD-H, n-hexane/isopropanol 98:2, flow rate 1.0mL/min, T30 ℃,254 nm); t is t_R＝8.846min (minor),t_R＝11.366min(major).

Examples 2 to 8

The reaction synthetic route is shown as follows:

the reaction raw materials and yields are shown in table 1:

TABLE 1^*Reaction raw materials and yields of examples 2 to 8

0.1 mmol of the compound of formula 1 and 0.12 mmol of the compound of formula 2a as reactants, 0.0l mmol of the compound of formula 4 as catalyst and 1 ml of mesitylene as solvent.

Examples 9 to 17

The reaction synthetic route is shown as follows:

the reaction raw materials and yields are shown in table 2:

TABLE 2^*Reaction starting materials and yields for examples 19-24

0.1 mmol of the compound of formula 1a and 0.12 mmol of the compound of formula 2 as reactants, 0.0l mmol of the compound of formula 4 as catalyst and 1 ml of mesitylene as solvent.

As can be seen from tables 1 and 2, the method of the present invention not only allows the synthesis of chiral indolo-oxaheptatomic ring compounds to be achieved in a single step with high atom economy and environmental friendliness, but also allows the desired chiral indolo-oxaheptatomic ring compounds to be obtained in excellent yields, high enantioselectivity, and diversity. In addition, the reaction raw materials are easy to obtain, the operation is simple and safe, the condition is mild, and the post-treatment is simple, so that the method has higher implementation value and potential social and economic benefits.

The chiral indolocarbaxeheptacyclic compounds synthesized in examples 1-15 and example 17 were also tested for cytotoxic activity against Hela cancer cells by the MTT method, which is a method conventional in the art, and the results are shown in Table 3. The result shows that the compound synthesized by the invention has certain cytotoxic activity on Hela cancer cells.

TABLE 3 cytotoxic Activity of the Compounds of the present invention on Hela cancer cells

The prepared chiral indolocarbaoxheptatomic ring compound is subjected to biological activity test, and the result shows that the chiral indolocarbaoxheptatomic ring compound has certain cytotoxic activity on Hela cancer cells, so that the compound is a potential drug lead compound in the research and development of novel antitumor drugs and has considerable application and research values.