TWI443089B - The method for fabricating oxoaporphine alkaloids - Google Patents

Description

Method for preparing keto apophenin alkaloid

The present invention relates to a method for preparing a keto-apren alkaloid, and more particularly to a method for reducing a reaction step.

Oxoaporphine is an isoquinoline alkaloids. Since the first time that liriodenine was isolated from Atherospermaaceae ( Atherosperma moschatum Labill.) in 1956, it has been found that this nitrogen-containing tetracyclic skeleton has been found. Pu Fensheng alkaloids not only widely distributed in many plants [such as: Annonaceae (Annonaceae), Araceae (Araceae), hernandiaceae (hernandiaceae), Lauraceae (Lauraceae), lily family (Liliaceae), magnolia (Magnoliaceae) , Menispermaceae (Menispermaceae), poppy (Papaveraceae) and Ranunculaceae (Ranunculaceae)], and also demonstrates the diversity of biological activity.

Taking arbutin as an example: Clark et al first infected mice with lethal amount of Candida albicans NIH B311, and then administered different doses of scutellarin and its N-methyl iodide after seven hours. Tests, the results show that both have an antibacterial effect. Further, Nissanka et al tulip base was also tested in vitro Cladosporium fungus Cladosporium fungus (C.cladosporioides) and the lychee anthracnose pathogen (C.gloeosporioides) antifungal activity. At a dose of 2 mg (mg), the area of inhibition is 150 mm ² (mm ² ) and 100 mm ² , respectively, and the minimum lethal concentration is 200 mg (L/L) per liter, which can suppress 90%. The spores of the litchi anthracnose germinated, and the action time can reach six hours, showing strong antibacterial activity.

In 2000, Camacho et al. also tested the antiprotozoal activity of keto-aprefen, and the scutellarin and the compounds N- methylliriodendronine, 2-O, N- methylliriodendronine, dicentrinone and purpurin ( corydine) to facilitate even Leishmania (L. donovani) promastigotes (promastigotes) and amastigote (amastigotes) were poisoned activity assay, was sequentially IC50 values: 15 ± 0.15 / 72.4 ± 1.30 ; 18.6±0.14/36.1±0.11; 20.6±0.17/Toxic (at ≧30 μg/ml); 30.3±1.23/55.5±1.97 and 26.7±1.4890(μM), showing keto-abufen alkaloid compounds It also has the ability to be an antigenic worm.

In addition, some researchers have conducted experiments on whether keto-abufen compounds inhibit poliovirus, such as Boustie et al. using scutellaria, lysciamine and oxostephanine for poliovirus. The in vitro antiviral activity test was carried out, and the inhibitory effect of the ketoapacfen compound substituent on the virus was investigated. In addition, keto-aprefen compounds have anti-platelet aggregation, relaxation of smooth muscle cells and anti-corrosion.

In addition, Chia et al. found that aristolactams isolated from the genus Fissistigma balansae have anti-platelet aggregation activity; Cortes et al. from M.compressa 3-hydroxynornuciferine was found to have a relaxing effect on smooth muscle cells; Bhattacharya et al. isolated nuciferine from the plant of Nelumbo nucifera Gaertn . The efficacy of blood lipids; in addition, Rajsekhar et al. found that oxoanalobine alone in the plant of the genus Michelia has anti-corrosion effects.

In terms of anticancer activity: Yang et al. used the scutellarin isolated from plants to detect breast cancer cells (MCF-7), large cell lung cancer (NCI-H460) and central nervous cancer cells (SF-268). These three human cancer cells were tested for their anticancer activity, and the results showed that scorpion has a considerable degree of inhibitory effect on tumor activity in vitro, with an IC ₅₀ of 2.19 mg/L, 2.38 mg/L, and 3.19 mg/in order. L. Studies have also indicated that echinoin can reduce the cyclin D1 content in the G1 phase of the cell cycle and increase the cyclin B1 content in the G2 phase, thereby blocking the cell cycle in the G2/M phase. It causes apoptosis of tumor cells, so ligustrine inhibits growth and induces apoptosis of tumor cells.

In addition, Chen et al. further combines the obtained keto-aprefen compound with platinum (II), gold (III), silver (I) and cobalt to form respective metal complexes, such metal complexes. It exhibits stronger anticancer activity than the original compound.

It can be seen from the above that since the keto-aprefene alkaloid has antibacterial, anti-corrosive and anti-cancer activities, the synthesis method and route of the keto-apren alkaloid are more and more important, and the ketone group is prepared by the prior art. The method of apofen alkaloids is detailed below:

(I) via Pschorr cyclization

As shown in Scheme 1, Cava et al. used a quinoline to react with hydrazine and potassium cyanide to synthesize 1-mercapto-2-cyano-1,2-dihydroquinoline derivative 16 (1-acyl-2- Cyano-1,2-dihydroquinoline) (also known as Reissert compound), followed by alkylation and hydrolysis of the Resert compound 16 to give nitro-containing benzene Methyl isoquinoline, and then reduction of the nitro group to the corresponding amine compound by hydrogenation reaction, and finally the formation of C in the keto apophenin structure by the Pu'erl cyclization reaction The ring, which is oxidized by air, is further converted to a keto-abufen alkaloid. Or in the intramolecular condensation of the guanamine compound 20 by a cyclization reaction of Bischler-Napieralski, followed by dehydration, cyclization to form the imine 21, followed by dehydroaromatization and After the oxidation reaction, the compound 17b is obtained, and the nitro group is reduced to an amine group to obtain a cyclized precursor 18b. Finally, the keto-apren alkaloid of the tetracyclic skeleton can be obtained by cyclization with a Pupil reaction. .

In the process in which the Reesert compound 16 is alkylated, a portion of the Resert compound 16 is directly hydrolyzed to produce a 1-cyanoisoquinoline by-product, which causes difficulty in purification.

(II) via intermolecular cycloaddition reaction

As shown in Scheme 2, Saá et al. used intermolecular cycloaddition reaction of benzyne and 1-methyleneisoquinoline 22 to establish a tetracyclic skeleton of keto-abufen alkaloid. The strong oxidizing property of a compound such as aniline, phenol or benzoquinone can be effectively oxidized by using Fremy's salt, and further oxidized to a keto-aprefen compound 23.

A disadvantage of Scheme 2 is that the benzyne and the isoquinoline compound can only form a symmetric keto apophene compound.

As shown in Scheme 3, Nicolaides et al. used oxime derivative 24 and dimethyl acetylenedicarboxylate (DMAD) to react in a hot reflux environment of toluene for ten days for intermolecular [4+2] The cyclization reaction, when it is returned to room temperature, precipitates as yellow crystals, that is, ketone apofen compound 26 in which C-4 and C-5 are methyl ester groups.

Among them, the indole derivative 24 is not easy to synthesize, and the process of the third process not only has a long reaction time, but also the ester group (CO ₂ CH ₃ ) of the keto-apophene compound 26 which can be formed can only be attached to the ring B.

(III) via the intramolecular Friedel-Crafts reaction

As shown in Scheme 4, Gerecke et al. used the cyclization reaction of Bischler-Napieralski to carry out intramolecular condensation of oxamic ester 27, followed by dehydration. Cyclization produces the imine 28, first establishing the B ring structure, and then synthesizing the keto-apren alkaloid 29 under the intramolecular Friedel-Crafts reaction under polyphosphoric acid (PPA).

Among them, guanamine ethyl oxalate 27 is not easy to synthesize, and due to the structural relationship of guanamine ethyl oxalate 27 itself, the two benzene rings of guanamine ethyl oxalate 27 are difficult to have different substituents at the same time, and the synthesized ketone is also obtained. The Kiapfene alkaloid 29 cannot have different substituents at the same time.

(IV) Intramolecular condensation reaction of a primary amine with a ketone

As shown in Scheme 5, Seijas et al. heated a phenanthrene compound (9,10-phenanthrenedione) 30 containing an ethylamine side chain under basic conditions in methanol to remove the protecting group on the nitrogen and convert it to a primary amine. After condensation with the ketone group in the structure to form the B ring, the keto-apren alkaloid 31 can be obtained by dehydrogenation. However, the steps for synthesizing polysubstituted phenanthrene compounds containing ethylamine side chains are quite complicated. Therefore, the application value of this synthesis method is thus limited.

In view of the complicated steps in the synthesis method of the prior art apofen alkaloids, the inability to synthesize apofen alkaloids containing various different substituents, and the difficulty in producing by-products resulting in purification and separation, the object of the present invention is to provide a The preparation method for shortening the process and also eliminating the need to purify the keto-apren alkaloid.

In order to achieve the above object, the present invention provides a method for preparing a keto-apren alkaloid, which comprises the steps of: cyclizing a compound of the formula I under iodine catalysis to form a compound of the formula II;

The compound of the formula II is added to the compound of the formula III to carry out a nucleophilic aromatic substitution reaction (S _N Ar), and a compound of the formula IV is formed;

Oxidative dedecyanation of the compound of formula IV to convert to a compound of formula V;

A compound having the formula VI can be obtained by adding a reducing agent to the compound of the formula V and performing oxidative photocyclization.

Formula VI

Preferably, the step of cyclizing the compound of formula I to form a compound of formula II comprises, in sequence, a step of synthesizing an azide compound, a step of synthesizing an isoquinoline compound, and a step of synthesizing an iodoisoquinoline compound. .

More preferably, the step of synthesizing the azide compound comprises a hydrazine chlorination reaction and a one-azide reaction, wherein the ruthenium chlorination reaction is a mixture of ethanediamine dichloride and the compound of the formula I, The chlorine of dichloro is substituted for the hydroxyl group to form a monochloro compound; wherein the azide reaction is to combine the perylene chloride compound with an azo agent to form an azide compound.

More preferably, the azo agent is sodium azide (NaN ₃ ) or a trimethylsilylazide.

More preferably, the step of synthesizing the isoquinoline compound means that the azide compound is cyclized to form an isoquinoline compound under a catalyst and heat reflux conditions.

More preferably, the catalyst is iodine, mercury acetate {mercuric acetate, [Hg(OAc) ₂ ]} or triethylamine.

More preferably, the step of synthesizing the iodoisoquinoline compound comprises an esterification reaction and a nucleophilic substitution reaction, wherein the esterification reaction refers to the aforementioned isoquinoline compound and trifluoromethanesulfonic anhydride ( Trifluoromethanesulfonic anhydride, Tf ₂ O) esterification to form the corresponding trifluoromethanesulfonate; wherein the nucleophilic substitution reaction refers to the use of trifluoromethanesulfonic acid (TfOH) as a catalyst and the addition of sodium iodide (sodium iodide, NaI) to form a compound of formula II.

"Nucleophilic aromatic substitution reaction" as known to those skilled in the art means that a nucleophile is substituted for a leaving group on an aromatic ring; according to the invention, sodium amide (NaNH) is used. ₂ ) The bromophenylacetonitrile anion formed after deprotonation of the bromobenzeneacetonitrile compound is a nucleophilic reagent, and is gradually warmed to room temperature at 0 ° C, and the iodine atom is substituted to form a compound of the formula IV.

According to the present invention, "oxidative deacylation reaction" as used herein means that the α-carbon anion of the compound of the formula IV attacks an oxygen molecule to form an unstable tetracyclic intermediate, which is then subjected to ring opening to remove the isocyanate anion. ^{(- N = C = O)} , and the corresponding compound of formula V is formed.

According to the present invention, "oxidative photocyclization reaction" as used herein means that a compound of the formula V is reduced by a reducing agent to form an intermediate product, which is subjected to light to be reoxidized to form a compound of the formula VI. Compound.

Preferably, the reducing agent is sodium borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ) or lithium aluminum hydride (LiAlH ₄ ).

Preferably, the compound of formula I, wherein R is selected from the group consisting of hydrogen (H), 2-methoxy (methoxy), 3-methoxy, 4-methyl Oxyl, 2,3-dimethoxy and 3,4-dimethoxy.

Preferably, the compound of the formula II wherein R' is selected from the group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7'-methoxy , 5',6'-dimethoxy and 6',7'-methylenedioxy.

Preferably, the compound of the formula III, wherein R" is selected from the group consisting of hydrogen, 4", 5"-dimethoxy, 4", 5"-methylene oxygen And 5"-trifluoromethyl.

Preferably, the compound of the formula IV, wherein R' is selected from the group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7'-methoxy , 5',6'-dimethoxy and 6',7'-methylenedioxy; wherein R" is selected from the group consisting of hydrogen, 4", 5"-dimethoxy Base, 4", 5"-methylenedioxy and 5"-trifluoromethyl.

Preferably, the compound of the above formula V, wherein R' is selected from the group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7'-methoxy , 5',6'-dimethoxy and 6',7'-methylenedioxy; wherein R" is selected from the group consisting of hydrogen, 4", 5"-dimethoxy Base, 4", 5"-methylenedioxy and 5"-trifluoromethyl.

Preferably, the compound of the formula VI wherein R' is selected from the group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7'-methoxy , 5',6'-dimethoxy and 6',7'-methylenedioxy; wherein R" is selected from the group consisting of hydrogen, 4", 5"-dimethoxy Base, 4", 5"-methylenedioxy and 5"-trifluoromethyl.

The present invention further provides a compound of the formula II, which is prepared by the method for preparing a keto apophene alkaloid as described above, and wherein the R' of the compound of the formula II is selected from Group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7'-methoxy, 5',6'-dimethoxy and 6',7'-methylene Dioxy.

The invention further provides a compound of the formula IV, which is prepared by the method for preparing a keto apophenine alkaloid as described above, and wherein the R' of the compound of the formula IV is selected from a group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7'-methoxy, 5',6'-dimethoxy and 6',7'-methylenedioxy; R" is selected from the group consisting of hydrogen, 4", 5"-dimethoxy, 4", 5"-methylenedioxy And 5"-trifluoromethyl.

The present invention further provides a compound of the formula V wherein the R' of the compound of the formula V is selected from the group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7 '-Methoxy, 5',6'-dimethoxy and 6',7'-methylenedioxy; R" is selected from the group consisting of hydrogen, 4", 5" -Dimethoxy, 4",5"-methylenedioxy and 5"-trifluoromethyl.

The invention further provides a compound of formula VI, wherein the R' of the compound of formula VI is selected from the group consisting of hydrogen, 5'-methoxy, 6'-methoxy, 7 '-Methoxy, 5',6'-dimethoxy and 6',7'-methylenedioxy; R" is selected from the group consisting of hydrogen, 4", 5" -Dimethoxy, 4",5"-methylenedioxy and 5"-trifluoromethyl.

The invention utilizes a compound of the formula IV obtained by condensing a compound of the formula II with a compound of the formula III, which is converted into a compound of the formula V by an oxidative deacylation reaction, and can be directly reduced by photo-opticization without direct reduction. Further purification treatment can be carried out to synthesize a compound of the formula VI on the A ring and the D ring.

The invention is further illustrated by the following examples which are not intended to limit the invention. A person skilled in the art can make some modifications and modifications without departing from the scope of the invention.

Preparation Example 1 Materials and Methods

(1) Chemicals and reagents All solvents and reagents are commercially available and do not require further purification.

(2) Thin-Layer Chromatography Thin-layer chromatography was performed using a TLC sheet from Merck, Germany. The model of the TLC sheet was Art 5715, and the TLC sheet was passed through an aluminum film. Aluminium pre-coated silicone sheet (Silica gel 60 F ₂₅₄ plate) having a total of 25 sheets of 20 cm (cm) x 20 cm and a thickness of 0.2 mm (mm).

(3) Column chromatography is a filler of Merck's silica gel 60 in Germany, wherein the mesh of the silicone is between 230 and 400. .

(4) Nuclear magnetic resonance spectroscopy (NMR spectra) was determined by a Bruker AMX-400 FT-NMR spectrometer. Abbreviations used in the following systems: chemical shift in δ (ppm), and TMS (tetramethylsilane) δ =0. Ppm is an internal standard. Coupling constant (J) in Hz, absorption splitting mode: s represents singlet, d means doublet, dd means double-doublet, t Represents a triplet, q denotes a quartet, quintet denotes a quintet, septe denotes a septet, and m denotes a multiplet.

(5) Infrared spectrophotometer Infrared spectrum analysis was carried out by IRPrestige-21/FTIR-8400S, using potassium bromide (KBr) powder as a tableting diluent, and the spectral unit was cm ^-1 .

(6) Mass spectrum (MS spectra) was measured by a high resolution mass spectrometer (Finnigan/Thermo Quest MAT 95XL instrument).

(7) Melting point apparatus The melting point of the product of the experiment is a melting point measuring device (Yanaco The MP-500D) was determined to have a melting point ranging from 40 ° C to 300 ° C and the internal temperature was uncorrected.

(8) Element analyser The elements of carbon (C), hydrogen (H) and nitrogen (N) were measured by an elemental analyzer (Elementar vario EL III Heraeus CHNOS Rapid F002).

(9) X-ray diffraction was performed by X-ray single crystal diffractometer (Bruker AXS SMART-1000).

(10) UV equipment is a portable UV light (MODEL UVGAL-58) with 254 nm (nm) and 366 nm light source.

Example 1: General Scheme for Synthesis of Cinnamyl Azide Azides (Compounds 38a to 38f) by Compounds of Formula I (Compound 37a to Compound 37f) according to Reaction Scheme 1

The compound of formula I is a cinnamic acid compound, and 40.0 mmol (mmol) of cinnamic acid compound (compound 37a to compound 37f) is dissolved in 168 ml (mL) of dichloromethane or toluene solution, and then slowly dropped into 80.0 mmol. Ethylene dichloride [(COCl) ₂ ], at room temperature (or 80 ° C) for 5 hours, until the end of the reaction, and then the solvent is concentrated by concentration under reduced pressure, the obtained solid is a ruthenium chloride compound 40 Then, the ruthenium chloride compound was dissolved in 100 mL of anhydrous acetone, and then directly added to a suspension of 20 mL of anhydrous acetone and 120 mmol of sodium azide (NaN ₃ ) in an ice water bath, and the suspension was stirred at room temperature 2 After an hour, it was filtered, concentrated, and further purified by column chromatography (hexane/ethyl acetate = 10:1) to give the Cinnamyl azide compound (compound 38a to compound 38f), and the yield As shown in Table 1, the cinnamyl azide compound (compound 38a to compound 38f) was kept at 0 ° C to avoid further decomposition.

In the above hydrazine chlorination reaction, the ruthenium chloride compound 40 is easily hydrolyzed and returned to the compound of the formula I, so that almost all of the cinnamic acid compound can be completely 醯 after 5 hours of detection of the ruthenium chlorination reaction by ¹³ C NMR spectroscopy. Chlorination is the corresponding ruthenium chloride compound 40 (C=O of the general conjugate acid compound appears at δc 172, and after the cinnamic acid compound is completely ruthenium chloride, C=O of the ruthenium chloride compound appears at δc 167). After completion of the acyl chloride, acyl ethylene dichloride with excess solvent may be drained, without further purification, can be directly reacted with azide, sodium azide (NaN _3).

In the foregoing azidation reaction, since sodium azide is not dissolved in an organic solvent, a mixed solution of acetone and water or a phase transfer catalyst is usually used, but if water is present, the ruthenium chloride compound is easily hydrolyzed into acid Class, reducing the yield of the reaction. Therefore, we reacted a ruthenium chloride compound with sodium azide under anhydrous acetone, and a thiol azide compound (compound 38a to compound 38f) having a relatively high yield can be obtained.

Example 2: General procedure for the synthesis of isoquinoline compounds (compounds 39a to 39f) according to the cinnamyl azide compound (compound 38a to compound 38f) of Reaction Scheme 2

The 38.0 mmol cinnamyl acyl azide compound (Compound 38f to Compound 38a) was dissolved in 150 mL of o - dichlorobenzene (O -dichlorobenzene) and add 0.38 mmol of iodine as a catalyst, and heat at reflux over 15 hours After it is returned to room temperature, a solid precipitates, and the solid is retained by suction filtration, and then the solid is washed with n-hexane to obtain a heteroquinolinone compound (compound 39a to compound 39f) by cyclization rearrangement. The yields of the isoquinolinone compound (Compound 39a to Compound 39f) are shown in Table 2.

Example 3: General procedure for the synthesis of a compound of the general formula II (compound 32a to compound 32f) according to the isoquinoline compound of Reaction Scheme 3 (Compound 39a to Compound 39f)

10.0 mmol of the isoquinolinone compound (Compound 39a to Compound 39f) and 11.5 mmol of pyridine (pyride, py) were dissolved in 20 mL of acetonitrile, and 11.0 mmol of trifluoromethanesulfonic anhydride (Tf) was slowly added in an ice water bath. ₂ O), after two hours of reaction, it can be upgraded to the corresponding sulfonate compound 41 (sulfonate). 50 mmol of sodium iodide (NaI) was added to the sulfonate compound 41, and 11.0 mmol of trifluoromethanesulfonic acid (TfOH) was added dropwise thereto and stirring was continued vigorously for 15 hours. After the reaction is completed, wash into a conical flask with 35 mL of water and 45 mL of toluene. Add 10 M aqueous sodium hydroxide solution in an ice water bath, neutralize to alkaline, and then pour into liquid. In a funnel, rinse with 5%, 10 mL of aqueous sodium thiosulfate solution twice, 1 M, 10 mL of sodium hydride aqueous solution, and then wash the organic layer with 10 mL of saturated brine. Then, it is dried over anhydrous magnesium sulfate, concentrated, and further purified by a column chromatography (hexane/ethyl acetate = 10:1) to obtain a compound of the formula II, the compound of the formula II is 1- The yield of the iodoisoquinoline compound (Compound 32a to Compound 32f), the 1-iodoisoquinoline compound (Compound 32a to Compound 32f) is shown in Table 3.

Example 4: General procedure for the synthesis of a compound of the formula III (compound 33a and compound 33c) with a benzyl bromide derivative (compound 42a and compound 42c) according to Reaction Scheme 4

20.0 mmol of benzyl bromide compound (Compound 42a and Compound 42c) and 54.0 mmol of potassium cyanide (KCN) were dissolved in a mixture containing 15 mL of ethanol and 7 mL of water, and reacted under hot reflux for two hours. Back to room temperature After adding 50 mL of pure water and placing it in a low temperature environment, after solid precipitation, the solid is retained by suction filtration, and then the solid is washed with n-hexane to obtain a compound of the formula III, wherein the compound has The compound of the formula III is a 2-bromophenylacetonitrile compound (compound 33a and compound 33c) wherein the 2-bromophenylacetonitrile compound (compound 33b and compound 33d) is commercially available as a 2-bromophenylacetonitrile compound (compound 33a and compound 33c). The yields are shown in Table 4.

Example 5: General procedure for the synthesis of a compound of the formula IV (compounds 34a to 34x) by a compound of the formula II (compounds 32a to 32f) and a compound of the formula III (compound 33a and compound 33c) according to the reaction scheme 5

After dissolving 7.0 mmol of the compound of the formula II (compound 32a to compound 32f) and 8.8 mmol of the compound of the formula III (compound 33a to compound 33d) in 100 mL of tetrahydrofuran (THF), 43.8 mmol of sodium azide was added in an ice bath. (sodium amide, NaNH ₂ ), warmed to room temperature and passed overnight to form a reaction mixture. After the reaction was completed, the reaction mixture in a round bottom flask was washed with ethyl acetate and purified water. The mixture was washed three times with 100 mL of ethyl acetate, and all the ethyl acetate layers were combined, washed twice with 50 mL of water and once with saturated brine, then dried over anhydrous magnesium sulfate, concentrated, and Further purification (n-hexane/ethyl acetate = 5:1) provides a compound of the formula IV, which is a-cyano-1'-(2"-bromobenzyl) The yield of the quinoline compound (Compound 34a to Compound 34x), and the α-cyano-1'-(2"-bromobenzyl)isoquinoline compound (Compound 34a to Compound 34x) is shown in Table 5.

Example 6: General procedure for the synthesis of a compound of formula V (compound 35a to compound 35x) by a compound of formula IV (compound 34a to compound 34x) according to Scheme 6

1.5 mmol of the compound of the formula IV (compound 34a to compound 34x) was dissolved in 40 mL of tetrahydrofuran (THF), and 60%, 3.0 mmol of sodium hydride (NaH) was added; after hydrogen-free (H ₂ ) formation (about 1 Hour), a pure oxygen gas was passed through and allowed to stand at room temperature for 3 hours to form a reaction mixture. After the reaction was completed, the mixture was washed three times with 60 mL of ethyl acetate. After all the ethyl acetate layers were combined, the mixture was washed twice with 30 mL of pure water and once with saturated brine, and the reaction was carried out in a round bottom flask. The mixture is washed into a separatory funnel, followed by adding anhydrous magnesium sulfate to dryness, concentration, and chromatography on a silica gel column (hexane/ethyl acetate = 5:1) to obtain a compound of the formula V, wherein the formula The compound of V is a 1'-(2"-bromobenzoinyl)isoquinoline compound (compound 35a to compound 35x), and the 1'-(2"-bromobenzoinyl)isoquinoline compound (compound 35a to The yield of the compound 35x) is shown in Table 6.

As shown in Table 6, when a strong electron withdrawing group (CF ₃ ) is attached to the benzene ring, the α-carbon anion is stabilized, thereby making it difficult to react with oxygen molecules, so that the yield of the compound formed by the reaction is poor, such as compound 35d. , Compound 35h, Compound 35l, Compound 35p, Compound 35t, and Compound 35x.

Example 7: General procedure for the synthesis of a compound of the formula VI (compounds 36a to 36x) from a compound of the formula V (compound 35a to compound 35x) according to Scheme 7

After dissolving the compound of the general formula V (compound 35a to compound 35x) in 150 mL of neutral methanol, and adding the reducing agent sodium borohydride (NaBH ₄ ), the mixture was uniformly irradiated with a 450 watt (W) medium pressure mercury lamp. . After the reaction is completed, the 2.5 M methanol solution is washed into a round bottom bottle, a little pure water is added, and then methanol is removed by vacuum concentration, and then washed with dichloromethane and pure water into a separatory funnel to 200 mL. The methylene chloride was washed 8 times until the water layer had no UV absorption. Then, the dichloromethane layer extract was combined and washed once with 200 mL of water, and once with saturated brine, then dried over anhydrous magnesium sulfate, concentrated, and chromatographed (trichloromethane/methanol = 20:1) Carefully purified to obtain a compound of formula VI wherein the compound of formula VI is a keto apophene compound (compounds 36a to 36x).

As shown in Table 7, when a methoxy group of a push electron is attached to C-5 or C-7 of the isoquinoline ring, the electron cloud density of C-8 can be increased by the resonance effect, and thus the keto apophene compound 36e to keto apofen compound 36h (term 5 to 8) and keto apofen compound 36m to keto apophene compound The yield of 36p (Item 13 to Line 16) is higher, with a yield of at least 50%.

Conversely, when the methoxy group is attached to the C-6 of the isoquinoline ring, the electron cloud density of the C-8 to be cyclized is lowered by the induction effect of the oxygen atom, thereby deactivating the free radical cyclization reaction. The yield of the compound 36i to the compound 36l (the item 9 to the item 12) is about 50% or less; further, the compound 36m to the compound 36p (the item 13 to the item 16) and the compound 36q to the compound 36t (the item 17 to Item 20) In contrast, since the compound 36q to the compound 36t (the 17th to the 20th) isoquinoline ring has a methoxy group attached to the C-6, the yield is 36m to the compound 36p. The lowest from the 13th to the 16th); similar trends can also be seen in compound 36e to compound 36h (line 5 to 8) and compound 36u to compound 36x (line 21 to line 24), when compound 36u When the methoxy group is attached to the C-6 of the isoquinoline ring of the compound 36x (Item 21 to Item 24), the yield of the compound 36u to the compound 36x (Item 21 to the second) is lower than that of the compound 36e. Compound 36h (Item 5 to Line 8).

Claims (9)

A method for preparing a keto-apren alkaloid, comprising the steps of: cyclizing a compound of formula I under iodine catalysis to form a compound of formula II; The compound of the formula II is added to the compound of the formula III to carry out a nucleophilic aromatic substitution reaction (S _N Ar), and a compound of the formula IV is formed; Oxidative deacetylation of the compound of formula IV to form a compound of formula V; Adding a reducing agent to the compound of the formula V for oxidative photocyclization to obtain a compound of the formula VI, Wherein R is selected from the group consisting of hydrogen (-H), 2-methoxy (methoxy), 3-methoxy, 4-methoxy, 2,3-dimethoxy And 3,4-dimethoxy; R' is selected from the group consisting of: hydrogen, 5'-methoxy, 6'-methoxy, 7'-methoxy, 5' , 6'-dimethoxy and 6',7'-methylenedioxy;R" is selected from the group consisting of: hydrogen, 4", 5"-dimethoxy, 4 ", 5"-methylenedioxy and 5"-trifluoromethyl. The method for preparing a keto-apren alkaloid according to claim 1, wherein the reducing agent is sodium borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ) or lithium aluminum hydride (lithium). Aluminium hydride, LiAlH ₄ ). The method for producing a keto apophenin alkaloid according to claim 1, wherein the step of cyclizing the compound of the formula I to form a compound of the formula II comprises, in sequence, a step of synthesizing an azide compound, and synthesizing an isoquinoline. Compound steps and A step of synthesizing an iodoisoquinoline compound. The method for preparing a keto-apren alkaloid according to claim 3, wherein the step of synthesizing the azide compound comprises a hydrazine chlorination reaction and a nitridation reaction, wherein the ruthenium chlorination reaction is ethanediamine dichloride Mixing with a compound of formula I to form a ruthenium chloride compound; wherein the azidation reaction combines the ruthenium chloride compound with an azo agent to form an azide compound. The method for preparing a keto apoprofen alkaloid according to claim 3, wherein the step of synthesizing the isoquinoline compound means that the azide compound is cyclized to form an isoquinoline compound under a catalyst and a heat reflux condition. . The method for preparing a keto apoprofen alkaloid according to claim 3, wherein the step of synthesizing the iodoisoquinoline compound comprises an esterification reaction and a nucleophilic substitution reaction, wherein the esterification reaction is isoquinoline The compound is esterified with trifluoromethanesulfonic anhydride (Tf ₂ O) to form a corresponding trifluoromethanesulfonate; wherein the nucleophilic substitution reaction is trifluoromethanesulfonic acid (TfOH) As a catalyst, sodium iodide (NaI) is added to form a compound of the formula II. The method for producing a keto apophenine alkaloid according to claim 4, wherein the azo agent is sodium azide (NaN ₃ ) or a trimethylsilylazide. The method for producing a keto-apren alkaloid according to claim 5, wherein the catalyst is iodine, mercury acetate {mercuric acetate, [Hg(OAc) ₂ ]} or triethylamine. A compound of the formula IV as described in claim 1.