CN111233815B - Preparation method of isoargentine formin - Google Patents
Preparation method of isoargentine formin Download PDFInfo
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- CN111233815B CN111233815B CN202010070854.2A CN202010070854A CN111233815B CN 111233815 B CN111233815 B CN 111233815B CN 202010070854 A CN202010070854 A CN 202010070854A CN 111233815 B CN111233815 B CN 111233815B
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- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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Abstract
The invention relates to a preparation method of isoargentine formin, which comprises the following steps: (1) reacting a compound 1:4, 7-dimethyl-1, 4a,5,6, 7a hexahydrocyclopentopyran is taken as a raw material, benzyl alcohol, trichloroacetonitrile and a silicon reagent are sequentially added into a solvent for nucleophilic addition reaction, and a compound 2 is obtained; (2) Removing benzyl from the compound 2 and a palladium reagent in a solvent through hydrogen to prepare a compound 3; (3) And (3) adding N-methylmorpholine oxide, perruthenate tetrapropylamine salt and a molecular sieve into the compound 3 in a solvent in sequence, and oxidizing to obtain the isoargentine formin. Compared with the prior art, the method has the advantages of simple operation process, mild reaction conditions, relative greenness, no use of highly toxic substances, high yield, large-scale production and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of isoargentina ant.
Background
Isoargentin formin (4R, 4aS,7S, 7aR) -isoiridomyrmin, a compound with a cyclic ether terpenoid structure, is an important insect semiochemical that can be used as a signaling molecule between flat spotted clerodendron and certain butterflies. The iso-argentine ant extract can be used for comparison and some biological assays with natural ant extracts.
In 2010, hofferberth.j.e topic groups were protected by catalytic hydrogenation and by protecting the aminal by disulfide followed by liberation of the primary alcohol as benzyl ether. The disulfide protection is then removed by treatment with CAN and NaBH 4 Reducing the free aldehyde. The newly formed primary alcohol is then protected by acetylation, the benzyl protection is removed, and the resulting primary alcohol is oxidized to the carboxylic acid. Finally, the ester exchange is carried out by TsOH to obtain the isoargentine formin. The method has the advantages of complex process, harsh reaction and lower yield.
In 2013, the subject group develops a new synthetic route. They adopt a hydromercurization reduction method to synthesize a key hemiacetal intermediate, and further oxidize the hemiacetal intermediate to obtain the isoargentine formin. The final yield of the method is only 30%, the selectivity, the conversion rate and the yield are not high, and the synthesis route is as follows:
although the method is greatly simplified compared with the prior synthetic process, the heavy metal mercury reagent used in the key conversion process is extremely unfriendly to the environment, and the mass production of the mercury reagent is limited.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of the iso-argentine formide, which has the advantages of simple operation process, mild reaction conditions, relative greenness, no use of highly toxic substances, high yield and suitability for large-scale production.
The purpose of the invention can be realized by the following technical scheme:
a preparation method of isoargentine formin comprises the following synthetic route:
the method specifically comprises the following steps:
(1) Taking a compound 1,4, 7-dimethyl-1, 4a,5,6, 7a hexahydro cyclopentopyran as a raw material, and sequentially adding benzyl alcohol, trichloroacetonitrile and a silicon reagent into a solvent for nucleophilic addition reaction to obtain a compound 2;
(2) Removing benzyl from the compound 2 and a palladium reagent in a solvent through hydrogen to prepare a compound 3;
(3) Adding the compound 3 into a solvent, sequentially adding N-methylmorpholine oxide, perruthenate tetrapropylamine salt and a molecular sieve, and oxidizing to obtain the isoargentina ant.
Further, the solvent comprises one or more of an alcohol solvent, an ester solvent, a halogenated hydrocarbon solvent or an ether solvent.
Further, the alcohol solvent comprises one or more of methanol, ethanol or isopropanol, the ester solvent comprises ethyl acetate or isopropyl acetate, the halogenated hydrocarbon solvent comprises dichloromethane or trichloromethane, and the ether solvent comprises one or more of diethyl ether, tetrahydrofuran or 1, 4-dioxane.
Further, the silicon reagent comprises one or more of TMSCl, TESCl or TBSCl.
Further, the palladium reagent comprises one or more of palladium carbon, palladium hydroxide or platinum oxide.
Further, the molar ratio of the compound 1, the benzyl alcohol, the trichloroacetonitrile, the silicon reagent and the solvent in the step (1) is 1.0 (1.0-2.0): 10.0-20.0: (0.1-0.2): 200.0-300.0, the temperature of the nucleophilic addition reaction is 15-35 ℃, and the time is 12-48h.
Further, the molar ratio of the compound 2 to the palladium reagent in the step (2) is 1.0 (0.05-0.20), the flow rate of the hydrogen is 0.2-2ml/min, the temperature for removing the benzyl is 15-35 ℃, and the time is 12-48h.
Furthermore, the mol ratio of the N-methylmorpholine oxide, the perruthenate tetrapropylamine salt, the molecular sieve and the solvent in the step (3) is 1.0 (0.05-0.20): (0.1-1.0): (20-50), the oxidation temperature is 15-35 ℃, and the time is 2-4h.
The methyl on the 9 th carbon position of the isoargentina ant formide prepared by the invention can rotate, so that the isoargentina ant formide is divided into two diastereoisomers of an R type and an S type, and the R type isomer is the most desired target product of the invention, in the prior art, the R type isomer of the isoargentina ant formide only has about 30 percent of content, and in the isoargentina ant formide obtained by the method, the R type isomer can reach 70-80 percent.
Compared with the prior art, the invention has the following advantages:
(1) The operation process is simple, the reaction conditions are mild, all reactions can be completed at room temperature, heating is not needed, and heating equipment and heat are saved;
(2) The method is relatively green and free of highly toxic substances, and a benzyl protection and palladium hydroxide debenzylation method is used for replacing a mercury acetate reagent mercury hydroxide oxidation reduction method in the prior art, so that a green method for realizing the oxidation reduction of double bonds into hydroxyl groups without a mercury reagent which has great harm to the environment and human bodies is realized;
(3) The yield is high, and the method can be used for large-scale production, and the yield of the target compound is improved from 30% in the prior art to 60-71%.
Drawings
FIG. 1 is an NMR hydrogen spectrum of isoargentine formin.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments.
Example 1
A method for preparing isoargentine formin,
(1) Compound 1:4,7-dimethyl-1,4a, 5,6,7,7a hexahydrocyclopentopyran (1.52 g), benzyl alcohol (1.3 g), trichloroacetonitrile (20.5 g), TMSCl (0.2 g) were mixed in dichloromethane (15 mL) and reacted overnight at room temperature for 24 hours. Passing through diatomite, removing solvent, and separating with chromatographic column (10% ethyl acetate in petroleum ether) to obtain compound 2 (1.9g, 72%);
(2) Compound 2 (1.3 g) was dissolved in ethyl acetate (10 ml), palladium on carbon (100 mg) was added, and reaction was carried out under hydrogen atmosphere at room temperature for 24 hours. Purifying with Celite, removing solvent, and chromatography (40% ethyl acetate in petroleum ether) to obtain compound 3 (0.76g, 90%);
(3) Compound 3 (0.5 g), N-methylmorpholine oxide (0.4 g) and molecular sieve (0.3 g) were mixed in dichloromethane and reacted at room temperature for 5min, tetrapropylamine perruthenate (0.05 g) was added and reacted at room temperature for 3h, and then recrystallized through celite and ethyl acetate petroleum ether to give isoargentina formin (0.45g, 92%). The final yield of the three steps is 66%.
Example 2
A method for preparing isoargentine formin,
(1) Compound 1:4,7-dimethyl-1,4a, 5,6,7,7a hexahydrocyclopentopyran (3.04 g), benzyl alcohol (2.6 g), trichloroacetonitrile (40.2 g), TMSCl (0.4 g) were mixed under ethyl acetate (25 mL) and reacted overnight at room temperature for 36 hours. Passing through diatomaceous earth, removing solvent, and separating with chromatography column (10% ethyl acetate in petroleum ether) to obtain compound 2 (4.0 g, 77%);
(2) Compound 2 (2.6 g) was dissolved in methanol (20 ml), palladium on carbon (200 mg) was added, and the reaction was carried out under hydrogen at room temperature for 18 hours. Purifying with diatomaceous earth, removing solvent, and chromatography column (40% ethyl acetate in petroleum ether) to obtain compound 3 (1.6 g, 92%);
(3) Mixing compound 3 (1.0 g), N-methylmorpholine oxide (0.8 g) and molecular sieve (1 g) in ethyl acetate, reacting at room temperature for 5min, adding tetrapropylamine perruthenate (0.1 g), reacting at room temperature for 3h, passing through diatomite, and recrystallizing with ethyl acetate petroleum ether to obtain the final product. The final yield of the three steps is 67%.
Example 3
A method for preparing isoargentine formin,
(1) Compound 1:4,7-dimethyl-1,4a, 5,6,7,7a hexahydrocyclopentopyran (4.56 g), benzyl alcohol (4.0 g), trichloroacetonitrile (65.0 g), TMSCl (1.0 g) were mixed in chloroform (50 mL) and reacted overnight at room temperature for 48 hours. Passing through diatomaceous earth, removing solvent, and separating with chromatography column (10% ethyl acetate in petroleum ether) to obtain compound 2 (6.1g, 78%);
(2) Compound 2 (2.6 g) was dissolved in ethanol (20 ml), and palladium hydroxide (180 mg) was added to the solution, followed by reaction with hydrogen at room temperature for 48 hours. Purifying with diatomaceous earth, removing solvent, and chromatography column (40% ethyl acetate in petroleum ether) to obtain compound 3 (1.6 g, 93%);
(3) Compound 3 (1.5 g), N-methylmorpholine oxide (1.3 g) and molecular sieve (1.2 g) were mixed in tetrahydrofuran and reacted at room temperature for 5min, tetrapropylamine perruthenate (0.18 g) was added and reacted at room temperature for 3h, and then celite and ethyl acetate petroleum ether were recrystallized to yield isoargentina formin (1.4 g, 95%). The final yield of the three steps is 69%.
Example 4
A method for preparing isoargentine formin,
(1) Compound 1:4,7-dimethyl-1,4a, 5,6,7,7a hexahydrocyclopentopyran (1.52 g), benzyl alcohol (1.3 g), trichloroacetonitrile (20.5 g), TBSCl (0.3 g) were mixed in dichloromethane (15 mL) and reacted overnight at room temperature for 18 hours. Passing through diatomaceous earth, removing solvent, and separating with chromatography column (10% ethyl acetate in petroleum ether) to obtain compound 2 (2.1g, 81%);
(2) Compound 2 (1.5 g) was dissolved in isopropanol (10 ml), palladium hydroxide (90 mg) was added, and the reaction was carried out under hydrogen at room temperature for 18h. After passing through celite, the solvent was removed and the column (40% ethyl acetate in petroleum ether) was purified to give compound 3 (0.9 g, 91%);
(3) Mixing compound 3 (0.5 g), N-methylmorpholine oxide (0.4 g) and molecular sieve (0.5 g) in 1, 4-dioxane, reacting at room temperature for 5min, adding tetrapropylamine perruthenate (0.05 g), reacting at room temperature for 3h, passing through diatomite, and recrystallizing with ethyl acetate petroleum ether to obtain isoargentina formin (0.47g, 96%). The final yield of the three steps is 71 percent.
Example 5
A method for preparing isoargentine formin,
(1) Compound 1:4,7-dimethyl-1,4 a,5,6,7,7a hexahydrocyclopentopyran (4.56 g), benzyl alcohol (4.0 g), trichloroacetonitrile (65.0 g), TBSCl (1.0 g) were mixed under ethyl acetate (50 mL) and reacted overnight at room temperature for 40 hours. Passing through diatomaceous earth, removing solvent, and separating with chromatography column (10% ethyl acetate in petroleum ether) to obtain compound 2 (6.2g, 79%);
(2) Compound 2 (2.6 g) was dissolved in tetrahydrofuran (20 ml), palladium on carbon (200 mg) was added, and the reaction was carried out by introducing hydrogen at room temperature for 48 hours. Passing through diatomaceous earth, removing solvent, and purifying with chromatography column (40% ethyl acetate in petroleum ether) to obtain compound 3 (1.6 g, 93%);
(3) Compound 3 (1.5 g), N-methylmorpholine oxide (1.3 g) and molecular sieve (1.2 g) were mixed in isopropanol and reacted at room temperature for 5min, then tetrapropylamine perruthenate (0.17 g) was added and reacted at room temperature for 3h, and then the mixture was recrystallized through celite and ethyl acetate petroleum ether to obtain isoargentina ant formin ant (1.41g, 95%). The final yield of the three steps is 70 percent.
NMR hydrogen spectra of isoargentina formin: 1 H NMR(500MHz，CDCl 3 )δ4.36(dd,J＝11.2,1H),3.95(t,1H),2.30(m,1H),2.12-2.03(m,3H),1.89(m,1H),1.65(m,1H),1.31(m,2H0,1.19(d,3H),1.04(d,3H)。
example 6
A method for preparing isoargentine formin,
(1) Taking a compound 1, namely 4, 7-dimethyl-1, 4a,5,6, 7a hexahydrocyclopentopyran as a raw material, sequentially adding benzyl alcohol, trichloroacetonitrile and a silicon reagent TMSCl into a solvent methanol for nucleophilic addition reaction to obtain a compound 2, wherein the molar ratio of the compound 1 to the benzyl alcohol to the trichloroacetonitrile to the silicon reagent TMSCl to the solvent methanol is 1.0;
(2) Removing benzyl from the compound 2 and palladium hydroxide serving as a palladium reagent in a solvent by hydrogen to prepare a compound 3, wherein the molar ratio of the compound 2 to the palladium hydroxide serving as the palladium reagent is 1.0.05, the flow rate of hydrogen is 0.2-2ml/min, the temperature for removing benzyl is 15-35 ℃, and the time is 12 hours;
(3) Adding N-methylmorpholine oxide, tetrapropylamine perruthenate and a molecular sieve into ethanol serving as a solvent in sequence, and oxidizing to obtain the isoargentina ant formic acid, wherein the molar ratio of the N-methylmorpholine oxide to the tetrapropylamine perruthenate to the molecular sieve to the ethanol serving as the solvent is 1.0-0.1.
Example 7
A method for preparing isoargentine formin,
(1) Taking a compound 1,4, 7-dimethyl-1, 4a,5,6, 7a hexahydrocyclopentopyran as a raw material, sequentially adding benzyl alcohol, trichloroacetonitrile and a silicon reagent TBSCl into solvent ethyl ether for nucleophilic addition reaction to obtain a compound 2, wherein the molar ratio of the compound 1, the benzyl alcohol, the trichloroacetonitrile, the silicon reagent TBSCl and the solvent ethyl ether is (1.0);
(2) Removing benzyl from the compound 2 and palladium carbon serving as a palladium reagent in a solvent by hydrogen to prepare a compound 3, wherein the molar ratio of the compound 2 to the palladium carbon serving as the palladium reagent is 1.0.20, the flow rate of the hydrogen is 0.2-2ml/min, the temperature for removing the benzyl is 15-35 ℃, and the time is 48h;
(3) Adding N-methylmorpholine oxide, tetrapropylamine perruthenate and a molecular sieve into a solvent 1, 4-dioxane in sequence, and oxidizing to obtain the isoargentina ant formin, wherein the molar ratio of the N-methylmorpholine oxide to the tetrapropylamine perruthenate to the solvent 1, 4-dioxane is 1.0.
Claims (8)
1. A preparation method of iso-argentine formin is characterized by comprising the following steps:
(1) Taking a compound 1,4, 7-dimethyl-1, 4a,5,6,7 a-hexahydro cyclopentopyran as a raw material, and sequentially adding benzyl alcohol, trichloroacetonitrile and a silicon reagent into a solvent for nucleophilic addition reaction to obtain a compound 2;
(2) Removing benzyl from the compound 2 and a palladium reagent in a solvent through hydrogen to prepare a compound 3;
(3) Adding N-methylmorpholine oxide, perruthenate tetrapropylamine salt and a molecular sieve into a solvent in turn to obtain the isoargentine formin through oxidation, wherein the synthetic route is as follows:
2. the method of claim 1, wherein the solvent is one or more of an alcohol solvent, an ester solvent, a halogenated hydrocarbon solvent, or an ether solvent.
3. The method according to claim 2, wherein the alcoholic solvent is one or more of methanol, ethanol or isopropanol, the ester solvent is ethyl acetate or isopropyl acetate, the halogenated hydrocarbon solvent is dichloromethane or chloroform, and the ether solvent is one or more of diethyl ether, tetrahydrofuran or 1, 4-dioxane.
4. The method of claim 1, wherein the silicon reagent is one or more of TMSCl, TESCl, or TBSCl.
5. The method of claim 1, wherein the palladium reagent is palladium on carbon or palladium hydroxide.
6. The method of claim 1, wherein the molar ratio of the compound 1, the benzyl alcohol, the trichloroacetonitrile, the silicon reagent and the solvent in the step (1) is 1.0 (1.0-2.0): (10.0-20.0): (0.1-0.2): (200.0-300.0), the temperature of the nucleophilic addition reaction is 15-35 ℃, and the time is 12-48h.
7. The method for preparing iso-argentine formin as claimed in claim 1, wherein the mole ratio of compound 2 to palladium reagent in step (2) is 1.0 (0.05-0.20), the flow rate of hydrogen is 0.2-2ml/min, the temperature for removing benzyl is 15-35 ℃ and the time is 12-48h.
8. The method of claim 1, wherein the molar ratio of N-methylmorpholine oxide, tetrapropylamine perruthenate, molecular sieve and solvent in step (3) is 1.0 (0.05-0.20) (0.1-1.0) (20-50), the oxidation temperature is 15-35 ℃ and the time is 2-4h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017205269A1 (en) * | 2016-05-24 | 2017-11-30 | Glycomimetics, Inc. | Haloalkyl fucose-containing selectin antagonists |
| TW201930269A (en) * | 2018-01-12 | 2019-08-01 | 美商賽吉醫療公司 | Compositions and methods for treating CNS disorders |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017205269A1 (en) * | 2016-05-24 | 2017-11-30 | Glycomimetics, Inc. | Haloalkyl fucose-containing selectin antagonists |
| TW201930269A (en) * | 2018-01-12 | 2019-08-01 | 美商賽吉醫療公司 | Compositions and methods for treating CNS disorders |
Non-Patent Citations (3)
| Title |
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| Chemical Synthesis and Biological Evaluation of the Englerin Analogues;Kok Ping Chan et al;《ChemMedChem》;20110307;第6卷(第3期);第420-423页 * |
| Diastereoselective Synthesis of b-Ether Derivatives of Artemisinin,an Antimalarial Drug: The Effect of Nitrile on Stereoselectivity;Hemender R. Chand et al;《Asian Journal of Organic Chemistry》;20160228;第5卷(第2期);第201-206页 * |
| Divergent Diastereoselective Synthesis of Iridomyrmecin, Isoiridomyrmecin, Teucrimulactone, and Dolicholactone from Citronellol;Clara J. Fischman et al;《The Journal of Organic Chemistry》;20130621;第78卷(第14期);第7318-7323页 * |
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