阅读说明：本技术 一种天然产物6-hhc的合成方法 (Synthetic method of natural product 6-HHC ) 是由 覃双林 慧斯文 闵清 陈新 王诗 彭瑞 熊思博 姜梦娇 于 2021-07-16 设计创作，主要内容包括：本发明公开了一种化合物6-hydroxyethyldihydrochelerythrine的合成方法,包括如下步骤：S1：将式1化合物在室温下溶于N,N-二甲基甲酰胺溶剂中,在室温下依次加入无水磷酸氢二钠、溴乙酸乙酯、Ir(ppy)-(2)(dtbbpy)PF-(6),在氮气的保护下,搅拌10分钟混匀,用灯照射,室温搅拌24 h,得到式2化合物；S2：将式2化合物溶于四氢呋喃溶剂中,0℃加入氢化铝锂,0℃条件下搅拌6h,得到标的物。本发明为天然产物6-hydroxyethyldihy drochelerythrine(6-HHC)的首次合成报道,路线设计独特新颖,反应条件温和,催化效率高,路线短,副反应少,操作简便。(The invention discloses a method for synthesizing a compound 6-hydroxytetrahydrochylerythrine, which comprises the following steps: s1: dissolving the compound of formula 1 in water at room temperature N,N To a dimethylformamide solvent, anhydrous disodium hydrogenphosphate, ethyl bromoacetate, Ir (ppy) were added in this order at room temperature 2 (dtbbpy)PF 6 Stirring for 10 minutes and uniformly mixing under the protection of nitrogen, irradiating by using a lamp, and stirring for 24 hours at room temperature to obtain a compound shown in a formula 2; s2: dissolving the compound shown in the formula 2 in a tetrahydrofuran solvent, adding lithium aluminum hydride at 0 ℃, and stirring for 6 hours at 0 ℃ to obtain a target substance. The invention is the first synthesis report of the natural product 6-hydroxytetrahydrochylerythronine (6-HHC), and has the advantages of unique and novel route design, mild reaction conditions, high catalytic efficiency, short route, less side reactions and simple and convenient operation.)

1. A synthetic method of a compound 6-hydroxytetrahydrochelerythrine is characterized by comprising the following steps:

s1 dissolving the compound of formula 1 in N, N-dimethylformamide solvent at room temperature, and sequentially adding anhydrous disodium hydrogen phosphate, ethyl bromoacetate, Ir (ppy)₂(dtbbpy)PF₆Stirring for 10 minutes and uniformly mixing under the protection of nitrogen, irradiating by using a lamp, and stirring for 24 hours at room temperature to obtain a compound shown in a formula 2;

s2, dissolving the compound of the formula 2 in a tetrahydrofuran solvent, adding lithium aluminum hydride at 0 ℃, and stirring for 6 hours at 0 ℃ to obtain a compound of the formula 3;

2. the method for synthesizing 6-hydroxytetrahydrochylerythrine according to claim 1, wherein: in step S1), the reaction conditions are: adding anhydrous disodium hydrogen phosphate, ethyl bromoacetate, Ir (ppy) into N, N-dimethylformamide solvent of the compound of the formula 1 at room temperature under the protection of nitrogen₂(dtbbpy)PF₆Stirring for 10 minutes, irradiating with a lamp, stirring at room temperature for 24 hours, and purifying to obtain the compound of formula 2.

3. The method for synthesizing 6-hydroxytetrahydrochylerythrine according to claim 1, wherein: in step S2), the reaction conditions are: adding lithium aluminum hydride into a tetrahydrofuran solvent of the compound of the formula 2 at 0 ℃ under the protection of nitrogen, stirring for 6 hours at 0 ℃, and purifying to obtain the compound of the formula 3.

Technical Field

The invention relates to a natural product synthesis technology, in particular to a synthesis method of a natural product 6-hydroxytetrahydrochelerythrine (6-HHC).

Background

6-Hydroxypropyldihydrochelerythrine (6-HHC) was isolated from the medicinal plant Macleaya cordata in 2017 by Zeng's task group, and its structure was determined by spectroscopic analysis and classified into dihydrobenzophenanthridine alkaloids. The dihydrobenzophenanthridine alkaloids are important bioactive components in nature, and have wide biological activities of resisting tumors, viruses, inflammation, bacteria and the like;

the natural source of 6-hydroxytetrahydrochylerythronine is very limited, and the Zeng subject group only extracts 21.6 mg from hundreds of kilograms of fresh macleaya cordata leaves, which limits the further research and development of 6-hydroxyyhydrochelrythrone. So far, no report on the synthesis of 6-hydroxytetrahydrochylerythronine is found, and the development of a high-efficiency synthesis route of 6-hydroxyyhydrochelrythronine is helpful for further research and development of the natural product.

Disclosure of Invention

The invention aims to solve the problems of very limited natural source, low extraction rate and the like of the natural product 6-hydroxytetrahydrochytridythrane and develop an efficient synthesis method of the 6-hydroxyyhydrochytridythrane.

The technical scheme of the invention is as follows:

a synthetic method of a compound 6-hydroxytetrahydrochelerythrine comprises the following steps:

s1 dissolving the compound of formula 1 in water at room temperatureN,NTo a dimethylformamide solvent, anhydrous disodium hydrogenphosphate, ethyl bromoacetate, Ir (ppy) were added in this order at room temperature₂(dtbbpy)PF₆Stirring for 10 minutes and uniformly mixing under the protection of nitrogen, irradiating by using a lamp, and stirring for 24 hours at room temperature to obtain a compound shown in a formula 2;

s2, dissolving the compound of the formula 2 in a tetrahydrofuran solvent, adding lithium aluminum hydride at 0 ℃, and stirring for 6 hours at 0 ℃ to obtain a compound of the formula 3;

preferably, in the step S1), the reaction conditions are as follows: to the compound of formula 1 at room temperature under the protection of nitrogenN,NAdding anhydrous disodium hydrogen phosphate, ethyl bromoacetate, Ir (ppy) to dimethylformamide solvent₂(dtbbpy)PF₆Stirring for 10 minutes, irradiating with a lamp, stirring at room temperature for 24 hours, and purifying to obtain the compound of formula 2.

Preferably, in the step S2), the reaction conditions are as follows: adding lithium aluminum hydride into a tetrahydrofuran solvent of the compound of the formula 2 at 0 ℃ under the protection of nitrogen, stirring for 6 hours at 0 ℃, and purifying to obtain the compound of the formula 3.

The invention has the beneficial effects that:

1. the design of the whole synthesis route is unique and novel, the obtained 6-hydroxytetrahydrochylerythronine is synthesized in a single selective way, the side reaction is relatively less, and the product yield is high;

2. the synthesis route has simple and reasonable design, simple and convenient operation process, mild reaction conditions in each step, less linear steps and suitability for industrial preparation.

Drawings

FIG. 1 is a flow diagram of the reaction of the present invention.

Detailed Description

In order to better explain the present invention, the present invention is further described in detail with reference to the following specific examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Example 1

As described in the specification and attached figure 1

1) Synthesis of Compound of formula 2

The compound of formula 1 (0.27 g, 0.77 mmol, 1.0 eq.) was dissolved in 2.6 ml under nitrogen protectionN,NDimethylformamide solvent, to which anhydrous disodium hydrogenphosphate (0.33 g, 2.31 mmol, 3.0 eq.) and Ir (ppy) were added in that order₂(dtbbpy)PF₆(15 mg, 0.015 mmol, 0.02 eq.), ethyl bromoacetate (0.39 g, 2.31 mmol, 3.0 eq.), stirring at room temperature (25 ℃) for 10 minutes, irradiating with a lamp under the protection of nitrogen, reacting at room temperature (25 ℃) for 24 hours, then clarifying the solution from light yellow to brown-yellow turbidity, after the reaction is completed by TLC, adding an aqueous solution (50 mL) to the mixed system at room temperature (25 ℃), extracting with ethyl acetate (3X 30 mL), washing the combined organic phases with an aqueous solution of sodium chloride (3X 30 mL), combining the resulting organic phases, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the organic solvent, and separating and purifying the resulting crude product by flash column chromatography (ethyl acetate: petroleum ether = 1: 5) to obtain a pale yellow solid, namely the compound of formula 2 (0.28 g, 85%).¹H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 8.6 Hz, 1H), 7.54 (t, J = 4.3 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.02 (s, 2H), 5.00 (dd, J = 10.8, 4.6 Hz, 1H), 4.21–4.09 (m, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 2.65 (s, 3H), 2.41–2.23 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl3) δ 171.8, 152.2, 148.1, 147.6, 145.9, 139.5, 131.2, 128.1, 127.7, 125.0, 123.9, 123.2, 119.9, 118.9, 111.7, 104.4, 101.1, 101.0, 61.1, 60.4, 55.9, 55.2, 43.0, 39.3, 14.3.

2) Synthesis of Compounds of formula 3

Dissolving a compound (0.10 g, 0.23 mmol, 1.0 eq.) in a tetrahydrofuran solvent at 0 ℃ under the protection of nitrogen, adding lithium aluminum hydride (2.5 mol/L) (0.92 mL, 2.30 mmol, 10 eq.) into the tetrahydrofuran solvent, reacting for 6 hours, adding an aqueous solution (15 mL) into the mixed system at 0 ℃ for quenching, washing with an aqueous solution of sodium chloride, extracting with ethyl acetate (3X 30 mL), combining the obtained organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure to remove the organic solvent, purifying the obtained crude product by flash column chromatography (ethyl acetate: petroleum ether = 1: 3) to obtain a white solid,i.e. the compound of formula 3 (0.75 g, 83%).¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 8.5 Hz, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.11 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.04 (dd, J = 7.9, 1.3 Hz, 2H), 4.65 (dd, J = 9.4, 5.4 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.77 (ddd, J = 12.4, 9.3, 3.6 Hz, 1H), 3.69 (dt, J = 11.0, 4.7 Hz, 1H), 3.44 (s, 1H), 2.68 (s, 3H), 1.78 (dtd, J = 13.9, 9.3, 4.5 Hz, 1H), 1.48 (dtd, J = 14.1, 5.1, 3.6 Hz, 1H). ¹³C NMR (101 MHz, CDCl3) δ 152.3, 148.5, 147.7, 145.7, 139.3, 131.3, 128.7, 127.2, 124.7, 124.3, 123.9, 120.0, 119.4, 111.3, 104.7, 101.3, 100.1, 61.9, 61.0, 57.1, 56.0, 42.1, 35.7.

The whole route of the invention has unique and novel design, mild reaction conditions in each step, high catalytic efficiency, short route, less side reaction and simple and convenient operation.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.