CN113004307A - Novel double spiro-heterocyclic compound and preparation method thereof - Google Patents
Novel double spiro-heterocyclic compound and preparation method thereof Download PDFInfo
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- CN113004307A CN113004307A CN202110295060.0A CN202110295060A CN113004307A CN 113004307 A CN113004307 A CN 113004307A CN 202110295060 A CN202110295060 A CN 202110295060A CN 113004307 A CN113004307 A CN 113004307A
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- 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
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Abstract
The invention discloses a double spiro-heterocyclic compound, the structure of which is shown in chemical formula 1. The double spiro-heterocyclic compound disclosed by the invention contains four pharmacophores of rhodanine, pyrrolidine, oxindole and tetrahydroisoquinoline, and has a special spatial three-dimensional structure. Therefore, the compound has high protein affinity, is likely to become a biological targeting lead compound, and has high new drug development value. The invention also discloses a Lewis acid catalytic synthesis method of the double spiro-heterocyclic compound. The synthesis method is simple and efficient, and the product is easy to purify.
Description
Technical Field
The invention relates to a double spiro [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound with a novel structure and a synthesis method thereof, belonging to the field of organic chemistry.
Technical Field
Rhodanine, pyrrolidine, oxindole and tetrahydroisoquinoline are widely present as dominant structural skeletons in biologically active natural products and marketed drugs, and have become the pharmacophores of intense research by medicinal chemists. The compounds with the pharmacophores have excellent pharmacological activity in the aspects of cancer resistance, bacteria resistance, virus resistance, epilepsy resistance, hypertension resistance, hyperlipidemia resistance, inflammation resistance and the like. Nowadays, the pharmacophore superposition method has become a new drug development strategy widely accepted and effective in the industry. Therefore, it is possible to obtain an excellent lead compound by hybridizing the above four pharmacophores into one molecule. On the other hand, the spiro framework structure has stronger structural rigidity and spatial extensibility, so that the compound with the spiro framework structure has stronger target protein affinity. The introduction of a double helix loop in a hybrid mode of a four-drug cluster would likely further enhance the biological activity and the metabolic kinetics of the hybrid molecule.
Based on the assumption, four strong pharmacophores are hybridized by two connection modes of a spiro ring and a parallel ring, and a novel double spiro ring [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound 1 is designed. At present, no synthesis report of the compound is seen, so that a high-efficiency synthesis method is developed to construct the double spiro-heterocyclic compound with a complex structure, the development of an organic synthesis methodology can be promoted, and a high-quality prototype molecule can be provided for the development of a new drug.
Disclosure of Invention
The invention designs and synthesizes a novel double spiro [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound. Accordingly, the present invention includes two aspects, one is to provide a novel bis-spiro heterocyclic lead compound. The compound is formed by hybridizing four important pharmacophores and has a special spatial three-dimensional structure, so that the compound has high protein affinity and can become a biological target medicament. Secondly, a Lewis acid catalysis method is provided to efficiently synthesize the double spiro-heterocyclic compound with novel structure and potential pharmacological activity.
The technical scheme of the invention is as follows:
(1) a novel bis-spiro [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound 1 has the following chemical structural formula:
(2) synthesizing a double spiro [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound 1 by Lewis acid catalyzed cycloaddition reaction,
n-benzyl isatin 2, tetrahydroisoquinoline 3 and 5-ene rhodanine 4 are used as raw materials to perform 1, 3-dipolar [3+2] cycloaddition reaction under the catalysis of Lewis acid to synthesize the double-spiro [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound 1. The compound 2, the compound 3 and the compound 4 are known compounds, can be prepared by methods reported in literatures, and have the advantages of easily available raw materials and simple operation.
The lewis acid catalyst used is one of the following: ferric trichloride, gold trichloride, indium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, gadolinium trifluoromethanesulfonate. The amount of the catalyst is 1 to 20 mol%, preferably 10 mol%.
The solvent is one of toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, 1, 2-dichloroethane, tetrachloroethylene, 1, 4-dioxane, n-butyl ether and acetonitrile. Among these solvents, toluene, 1, 2-dichloroethane, n-butyl ether and acetonitrile are preferable. The addition volume of the solvent is in the range of 10 to 20 volumes (mL: mmol), preferably 20 volumes (mL: mmol) with respect to the amount of the compound of formula 2.
The molar ratio of the compound of formula 2 to the compound of formula 3 to the compound of formula 4 is 1:1:1 to 1:1.4:1.4, preferably 1:1: 1; the reaction temperature is in the range of 40-100 ℃, and preferably 50-90 ℃; the reaction time is 1 to 48 hours, preferably 2 to 8 hours.
The invention has the beneficial effects that: the 1, 3-dipolar [3+2] cycloaddition reaction of N-benzyl isatin, tetrahydroisoquinoline and 5-ene rhodanine is successfully realized through Lewis acid catalysis, and the double spiro [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound with a novel structure is efficiently synthesized. The compound is designed and successfully synthesized for the first time, so that the development of an organic synthesis methodology is promoted, and a precious prototype molecule is provided for the research and development of new drugs.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound of formula 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of a compound of formula 1;
FIG. 3 is a high resolution mass spectrum of the compound of formula 1.
Detailed Description
Example 1
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), ferric trichloride (3.2mg,10 mol%) and 4mL of n-butyl ether in that order, and the temperature was raised to 90 ℃ to react for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 90 ℃ for 8 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 45.4mg of the compound of formula 1 in 35% yield. A white solid; mp is 187.3-187.7 ℃;1H NMR(400MHz,CDCl3):δ7.49(t,J＝7.9Hz,2H),7.42-7.25(m,12H),7.21-7.00(m,5H),6.93(t,J＝6.6Hz,1H),6.75-6.68(m,2H),6.61-6.54(m,1H),5.74(d,J＝12.4Hz,1H),5.23(d,J＝17.6Hz,1H),4.72(d,J＝15.9Hz,1H),4.62-4.58(m.1H),3.11-3.02(m,1H),2.87(t,J＝10.5Hz,1H),2.71(t,J＝15.7Hz,2H)；13C{1H}NMR(100MHz,CDCl3):δ198.4,176.1,175.4,144.8,138.8,137.5,135.0,134.9,134.3,130.9,130.8,129.5,129.4,129.2,129.2,128.9,128.8,128.5,128.3,127.8,127.2,127.1,126.5,125.8,124.9,123.4,109.9,78.6,74.8,63.3,58.4,43.8,42.9,29.8；HRMS(ESI-TOF)m/z:[M+H]+calcd for C40H32N3O2S2:650.1930；found:650.1930.
example 2
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), gold trichloride (6.1mg,10 mol%) and 4mL of 1, 2-dichloroethane in this order, and the reaction was carried out at 80 ℃ for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 80 ℃ for 4 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 96.3mg of the compound of formula 1 in 74% yield.
Example 3
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), indium trichloride (4.4mg,10 mol%) and 4mL of n-butyl ether in that order, and the temperature was raised to 90 ℃ to react for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 90 ℃ for 8 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 41.6mg of the compound of formula 1 in 32% yield.
Example 4
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), indium trifluoromethanesulfonate (11.2mg,10 mol%) and 4mL of acetonitrile in this order, and the reaction was carried out at 50 ℃ for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 50 ℃ for 4 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 59.7mg of the compound of formula 1 in 46% yield.
Example 5
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), scandium trifluoromethanesulfonate (9.8mg,10 mol%) and 4mL of toluene in this order, and the reaction was carried out at 80 ℃ for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 80 ℃ for 2 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 114.5mg of the compound of formula 1, with a yield of 88%.
Example 6
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), ytterbium trifluoromethanesulfonate (12.4mg,10 mol%) and 4mL of toluene in this order, and the reaction was carried out at 80 ℃ for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 80 ℃ for 3 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 108.3mg of the compound of formula 1 in 83% yield.
Example 7
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), bismuth trifluoromethanesulfonate (13.1mg,10 mol%) and 4mL of 1, 2-dichloroethane in this order, and the reaction was carried out at 80 ℃ for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 80 ℃ for 6 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 68.6mg of the compound of formula 1 in 53% yield.
Example 8
A glass reaction tube was charged with the compound of formula 2 (47.5mg,0.2mmol), the compound of formula 3 (26.6mg,0.2mmol), gadolinium trifluoromethanesulfonate (12.1mg,10 mol%) and 4mL of acetonitrile in this order, and the reaction was carried out at 50 ℃ for 10 minutes. Then, the compound of formula 4 (59.5mg,0.2mmol) was added, the reaction was stirred at 50 ℃ for 4 hours, cooled to room temperature, and the reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 61.1mg of the compound of formula 1 in 47% yield.
Claims (6)
1. A novel bis-spiro heterocyclic compound characterized by the structural formula:
2. a process for the synthesis of novel bis-spiro-heterocyclic compounds according to claim 1, characterized in that:
n-benzyl isatin 2, tetrahydroisoquinoline 3 and 5-ene rhodanine 4 are used as raw materials to perform 1, 3-dipolar [3+2] cycloaddition reaction under the catalysis of Lewis acid to synthesize the double-spiro [ rhodanine-pyrrolidine-oxindole-tetrahydroisoquinoline ] compound 1.
3. A process for the synthesis of novel bis-spiro-heterocyclic compounds according to claim 2, characterized in that the lewis acid catalyst used in the synthesis is one of the following: ferric trichloride, gold trichloride, indium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, bismuth trifluoromethanesulfonate and gadolinium trifluoromethanesulfonate, wherein the amount of the catalyst is 1-20 mol%.
4. The method for synthesizing the novel bis-spiro-heterocyclic compound according to claim 2, wherein the solvent used in the synthesis method is one of toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, 1, 2-dichloroethane, tetrachloroethylene, 1, 4-dioxane, n-butyl ether and acetonitrile.
5. The synthesis method of the novel double spiro-heterocyclic compound according to claim 2, characterized in that the molar ratio of the compound of formula 2, the compound of formula 3 and the compound of formula 4 is 1:1: 1-1: 1.4: 1.4.
6. The synthesis method of the novel bis-spiro-heterocyclic compound according to claim 2, wherein the reaction temperature of the synthesis method is 40 to 100 ℃ and the reaction time is 1 to 48 hours.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440530A (en) * | 2018-04-19 | 2018-08-24 | 河南大学 | A kind of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440530A (en) * | 2018-04-19 | 2018-08-24 | 河南大学 | A kind of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| BOUDRIGA, SARRA: "Highly diastereoselective construction of novel dispiropyrrolo[2,1-a]isoquinoline derivatives via multicomponent 1,3-dipolar cycloaddition of cyclic diketones-based tetrahydroisoquinolinium N-ylides", 《RSC ADVANCES》 * |
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