CN113045568A - Method for preparing gamma-eudiosmin U - Google Patents
Method for preparing gamma-eudiosmin U Download PDFInfo
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- CN113045568A CN113045568A CN202110345849.2A CN202110345849A CN113045568A CN 113045568 A CN113045568 A CN 113045568A CN 202110345849 A CN202110345849 A CN 202110345849A CN 113045568 A CN113045568 A CN 113045568A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the technical field of medicines, and discloses a simple method for preparing gamma-eudiosmin U. The method takes 4-piperidone and phenylhydrazine as starting materials to synthesize the gamma-eudiosmin U through three-step reaction. The reagent used in the method is a reagent commonly used in a laboratory, and the coupling reaction of the key step can be completed at room temperature. Therefore, the method has the advantages of easily available required materials, low cost, simple reaction operation and easy treatment, and can obtain a large amount of gamma-eudiosmin U for medicine research and development.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing gamma-eudiosmin U.
Background
The various marine alkaloids have wide biological activity and are good starting points for searching new medicaments. Eudistomin marine alkaloids are tryptophan metabolites containing beta carboline skeleton structure. Wherein, eudiosmin U and isoeudiosmin U and related derivatives have high DNA binding capacity and antibacterial, antimalarial, anticancer and antioxidant activities. Gamma-Eudistomin U is an isomer compound of Eudistomin U, and is different from Eudistomin U in that it is a derivative belonging to a gamma carboline skeleton structure. By taking 4-piperidone and phenylhydrazine as starting materials, gamma-Eudistomin U can be quickly obtained through three-step simple reaction and can be used for medicine research and development.
Disclosure of Invention
The invention aims to provide a method for preparing gamma-eudiosmin U, which can quickly and simply obtain a sample for biological medicine research.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for preparing gamma-eudiosmin U is characterized in that 4-piperidone and phenylhydrazine are used as starting raw materials, and the gamma-eudiosmin U is obtained through a one-pot two-step method.
The method comprises the following steps:
1) reacting 4-piperidone with phenylhydrazine and then reacting with p-toluenesulfonyl chloride to obtain a tetrahydro gamma-carboline raw material;
2) 2-methyltetrahydrofuran is used as a solvent, added with tetrahydro gamma-carboline, slowly added with tert-butyl hypochlorite, reacted for a few minutes, added with indole, uniformly mixed for a period of time and then treated to obtain 2-indole substituted tetrahydro gamma-carboline;
3) finally, the final product gamma-eudiosmin U is obtained by the protection of p-toluenesulfonyl removal and oxidative dehydrogenation reaction under the condition of potassium persulfate.
The method comprises the following specific steps: step (1): the molar ratio of the 4-piperidone to the phenylhydrazine hydrochloride is 1:1-1: 1.5;
step (2): the mol ratio of the tetrahydro gamma-carboline raw material to the tert-butyl ester hypochlorite is 1:1-1: 1.5; the reaction solvent is 2-methyltetrahydrofuran.
And (3): indole substitution products with Me4NCl and K2S2O8In a molar ratio of 1:0.1: 2.
The invention has the advantages that: compared with the prior art, the method has the advantages of simple synthetic route, easily obtained raw materials, low cost, simple reaction operation, easy treatment and higher yield, and can obtain a large amount of gamma-eudiosmin U for medicine research and development.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Solvent: AcOH (acetic acid); CH (CH)2Cl2(dichloromethane); EtOAc (ethyl acetate); PE (petroleum ether); DMSO (dimethyl sulfoxide); MeOH (methanol).
Reagent: TsCl (p-toluenesulfonyl chloride); et (Et)3N (triethylamine);t-BuOCl (tert-butyl hypochlorite); na (Na)2SO4(sodium sulfate); me4NCl (tetramethylammonium chloride); k2S2O8(potassium persulfate); CDCl3(deuterated chloroform); DMSO-d 6(deuterated dimethyl sulfoxide).
Radical abbreviation: me (methyl); ts (tosyl).
Example 1:
a method of preparing gamma-eudiosmin U, comprising the steps of:
step (1):
after adding phenylhydrazine hydrochloride (1.59 g, 11 mmol) to a solution of 4-piperidone (1.49 g, 11 mmol) in AcOH (10 mL), the reaction was stirred at 70 ℃ for 4 hours; after dilution with 100 mL of water and stirring for 10 minutes. The crude product was collected by filtration (1.51 g, 79%); the obtained product (500 mg, 2.9 mmol) was suspended in dichloromethane (5 mL) and TsCl (536 mg, 3 mmol) and Et were added slowly at a temperature of 0 deg.C3N (400 mg, 4 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then the solvent was removed under reduced pressure to give a crude product, which was added to 50 mL of water to give a yellow solid as a starting tetrahydro γ -carboline (680 mg, reaction yield 75%).
yellow solid.
Melting Point: 110.9‐111.8 ℃.
TLC: Rf = 0.47 (CH2Cl2).
1H NMR (400 MHz, DMSO‐d 6) δ 10.90 (s, 1H), 7.74 (d, J = 6.6 Hz, 2H), 7.47 – 7.36 (m, 3H), 7.28 (d, J = 7.4 Hz, 1H), 7.08 – 6.92 (m, 2H), 4.26 (s, 2H), 3.42 – 3.38 (m, 2H), 2.80 – 2.84 (m, 2H), 2.37 (s, 3H).
13C NMR (101 MHz, DMSO‐d 6) δ 143.90, 136.31, 134.22, 132.19, 130.29, 127.78, 125.43, 121.28, 119.09, 117.64, 111.41, 104.59, 43.94, 43.47, 23.61, 21.45.
HRMS (ESI): calcd for C18H18N2O2S [M + H]+ m/z 327.1162, found 327.1173。
Step (2):
the tetrahydro gamma-carboline starting material (1.63 g, 5 mmol) was dissolved in 2-methyltetrahydrofuran (30 mL) and tert-butyl hypochlorite (597 mg, 5.5 mmol) was added at room temperature. After the reaction mixture was stirred at room temperature for 2 minutes, indole (878 mg, 7.5 mmol) was added to the mixture. After stirring for another 10 min, the reaction mixture was diluted with EtOAc (80 mL) and then saturated NaHCO3Aqueous solution (80 mL). Anhydrous Na for organic layer2SO4Drying, filtering and concentrating under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EtOAc =3:1, vol) to give the indole-substituted product as a white solid (1.65 g, reaction yield 75%).
white solid.
Melting Point: 84.2-84.6 ℃.
TLC: Rf= 0.45 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.76 – 7.67 (m, 3H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.13 – 7.05 (m, 4H), 6.96 (d, J = 10.8 Hz, 2H), 4.87 (d, J = 13.6 Hz, 1H), 4.62 (s, 1H), 4.19 (d, J = 13.7 Hz, 1H), 4.16 – 4.10 (m, 1H), 3.10 (t, J = 10.6 Hz, 1H), 2.40 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 143.48, 136.25, 135.68, 134.08, 133.78, 129.62, 127.34, 125.94, 125.18, 123.31, 122.27, 121.68, 119.74, 119.54, 118.68, 117.54, 112.74, 111.46, 110.98, 105.89, 50.14, 43.21, 33.05, 21.34.
HRMS (ESI): calcd for C26H23N3O2S [M + H]+ m/z 442.1584, found 442.1587。
And (3):
me was added to a solution of indole-substituted product (441 mg, 1.0 mmol) dissolved in DMSO (8 mL)4NCl (11 mg, 0.1 mmol) and K2S2O8(540 mg, 2.0 mmol). The reaction mixture was stirred at 90 ℃ for 0.5 h. Then saturated NaHCO was used3Basification of the reaction mixture to pH 8 and addition of CH2Cl2MeOH =10:1 (40 mL, volume ratio) extraction. The combined organic layer was washed with saturated brine, and anhydrous Na2SO4Drying, filtration, concentration under reduced pressure to give the crude product, chromatography on silica gel (DCM/MeOH =50:1 to CH)2Cl2MeOH =20:1, volume ratio) to obtain the final product (190 mg, 67% reaction yield) as a pink solid, i.e., γ -eudiosmin U, with a purity of more than 97%.
pink solid.
Melting Point: >230 ℃.
TLC: Rf= 0.42 (DCM/MeOH = 10:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.66 (s, 1H), 11.53 (s, 1H), 9.32 (s, 1H), 8.63 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H).
13C NMR (101 MHz, DMSO-d 6) δ 143.73, 142.14, 140.65, 140.57, 137.08, 126.94, 126.28, 125.44, 122.26, 121.54, 121.02, 120.53, 120.20, 119.53, 112.51, 112.48, 109.60.
HRMS (ESI): calcd for C19H13N3 [M + H]+ m/z 284.1182, found 284.1172。
Example 2:
step (1): to a solution of 4-piperidone (6.8 g, 50 mmol) in AcOH (100 mL) was added phenylhydrazine hydrochloride (7.3 g, 50 mmol). The reaction was mixed and stirred for 5 hours at 70 ℃. The mixture was diluted with water (300 mL) and stirred for 30 min. Filtration gave the crude product (8.2 g, 95%). The product obtained (8.2 g, 47.6 mmol) was suspended in dichloromethane (500 mL) and TsCl (8.6 g, 48 mmol) and Et were added slowly at a temperature of 0 deg.C3N (5.0 g, 50 mmol). After the addition was complete, it was allowed to come to room temperature and stirred for 4 hours, then the solvent was rotary evaporated to give the crude product which was added to water (500 mL) to give the tetrahydro γ -carboline starting material (12.5 g, 84%) as a yellow solid.
Step (2): the tetrahydro gamma-carboline starting material (16.3 g, 50 mmol) was dissolved in tetrahydrofuran (200 mL) and tert-butyl hypochlorite (5.4 g, 50 mmol) was added at room temperature. After the reaction mixture was stirred at 0 ℃ for 5 minutes, indole (5.9 g, 51 mmol) was added to the mixture. After stirring for another 1 h, the reaction mixture was diluted with EtOAc (80 mL) and then saturated NaHCO3Aqueous solution (80 mL). Organic layer in anhydrous Na2SO4Dried, filtered and then concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography (PE/EtOAc =3:1, vol) to afford the indole-substituted product as a white solid (20.5 g, 93%).
And (3): indole substitution product (4.41 g, 10 mmol) was dissolved in DMSMe was added to a solution in O (50 mL)4NCl (110 mg, 1 mmol) and K2S2O8(5.4 g, 20 mmol). The reaction mixture was stirred at 90 ℃ for 1 hour. Then saturated NaHCO was used3Basifying the reaction mixture to pH 8-9 and adding CH2Cl2MeOH =10:1 (500 mL, volume ratio) extraction. The combined organic layer was washed with saturated brine, and anhydrous Na2SO4Drying, filtration, concentration under reduced pressure to give the crude product, chromatography on silica gel (DCM/MeOH =50:1 to CH)2Cl2MeOH =20:1, volume ratio) to give the final product (2.1 g, reaction yield 74%) as a pink solid, γ -eudiosmin U, with a purity of over 97%.
pink solid.
Melting Point: >230℃.
TLC: Rf= 0.42 (DCM/MeOH = 10:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.66 (s, 1H), 11.53 (s, 1H), 9.32 (s, 1H), 8.63 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H).
13C NMR (101 MHz, DMSO-d 6) δ 143.73, 142.14, 140.65, 140.57, 137.08, 126.94, 126.28, 125.44, 122.26, 121.54, 121.02, 120.53, 120.20, 119.53, 112.51, 112.48, 109.60.
HRMS (ESI): calcd for C19H13N3 [M + H]+ m/z 284.1182, found 284.1172。
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (3)
1. A method for preparing gamma-eudiosmin U, which is characterized by comprising the following steps: 4-piperidone and phenylhydrazine are used as initial raw materials, and gamma-eudiosmin U is obtained through three-step reaction.
2. The method of claim 1, wherein the method comprises the steps of: the method comprises the following steps:
1) reacting 4-piperidone with phenylhydrazine and then reacting with p-toluenesulfonyl chloride to obtain a tetrahydro gamma-carboline raw material;
2) 2-methyltetrahydrofuran is used as a solvent, added with tetrahydro gamma-carboline, slowly added with tert-butyl hypochlorite, added with indole after reaction, mixed uniformly for a period of time and then treated to obtain 2-indole substituted tetrahydro gamma-carboline;
3) finally, the final product gamma-eudiosmin U is obtained by the protection of p-toluenesulfonyl removal and oxidative dehydrogenation reaction under the condition of potassium persulfate.
3. A process for preparing γ -eudiosmin U according to claim 1, wherein:
step (1): the molar ratio of the 4-piperidone to the phenylhydrazine hydrochloride is 1:1-1: 1.5;
step (2): the mol ratio of the tetrahydro gamma-carboline raw material to the tert-butyl ester hypochlorite is 1:1-1: 1.5; the reaction solvent is 2-methyltetrahydrofuran;
and (3): indole substitution products with Me4NCl and K2S2O8In a molar ratio of 1:0.1: 2.
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102093338A (en) * | 2010-12-08 | 2011-06-15 | 华东师范大学 | N-acyl cyclic urea derivative and preparation method thereof |
CN103130802A (en) * | 2013-01-22 | 2013-06-05 | 天津大学 | Tetrahydro-gamma-carboline derivative synthesis method |
CN104892510A (en) * | 2015-07-03 | 2015-09-09 | 中国科学院兰州化学物理研究所 | Preparation method of isocorydaline |
CN107311948A (en) * | 2017-06-16 | 2017-11-03 | 福州大学 | A kind of key intermediates of MI 2 and preparation method thereof |
CN108440550A (en) * | 2018-06-05 | 2018-08-24 | 福州大学 | A kind of isochroman diindyl derivative and preparation method thereof |
CN108727399A (en) * | 2018-07-03 | 2018-11-02 | 福州大学 | A kind of benzo dioxane indole derivatives and its preparation method and application |
CN110698474A (en) * | 2019-11-14 | 2020-01-17 | 福州大学 | Alpha-substituted tetrahydro-gamma-carboline compound and preparation method and application thereof |
CN112574198A (en) * | 2021-01-25 | 2021-03-30 | 福州大学 | Indolated derivative of tetrahydro-beta-carboline and preparation and application thereof |
-
2021
- 2021-03-31 CN CN202110345849.2A patent/CN113045568A/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102093338A (en) * | 2010-12-08 | 2011-06-15 | 华东师范大学 | N-acyl cyclic urea derivative and preparation method thereof |
CN103130802A (en) * | 2013-01-22 | 2013-06-05 | 天津大学 | Tetrahydro-gamma-carboline derivative synthesis method |
CN104892510A (en) * | 2015-07-03 | 2015-09-09 | 中国科学院兰州化学物理研究所 | Preparation method of isocorydaline |
CN107311948A (en) * | 2017-06-16 | 2017-11-03 | 福州大学 | A kind of key intermediates of MI 2 and preparation method thereof |
CN108440550A (en) * | 2018-06-05 | 2018-08-24 | 福州大学 | A kind of isochroman diindyl derivative and preparation method thereof |
CN108727399A (en) * | 2018-07-03 | 2018-11-02 | 福州大学 | A kind of benzo dioxane indole derivatives and its preparation method and application |
CN110698474A (en) * | 2019-11-14 | 2020-01-17 | 福州大学 | Alpha-substituted tetrahydro-gamma-carboline compound and preparation method and application thereof |
CN112574198A (en) * | 2021-01-25 | 2021-03-30 | 福州大学 | Indolated derivative of tetrahydro-beta-carboline and preparation and application thereof |
Non-Patent Citations (2)
Title |
---|
DEKANG XU ET AL.: "Manipulation of Water for Diversified Functionalization of Tetrahydro-β-carbolines (THβCs) with Indoles", 《ORGANIC LETTER》 * |
JINXIANG YE ET AL.: "Biomimetic Oxidative Coupling Cyclization Enabling Rapid Construction of Isochromanoindolenines", 《ORGANIC LETTERS》 * |
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