Total synthesis method of tylophorine and antofine

Abstract

The invention discloses a total synthesis method of tylophorine and antofine. The synthesis method comprises the following steps: respectively taking 3, 4-dimethoxyphenylacetylpyrrolidine acetic acid and 4-methoxyphenylacetylpyrrolidine acetic acid as initial raw materials, reacting in the presence of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-methylmorpholine to generate a Weinreb amide intermediate, and reacting with a Grignard reagent 3, 4-dimethoxyphenylacetylpyrrolidine acetic acid to generate the Weinreb amide intermediate. The preparation method comprises the following steps: carrying out Weinreb ketone reaction on 2, 4-dimethoxyphenyl magnesium bromide to generate tylophorine and antofen intermediates, further carrying out light cyclization dehydrogenation reaction under an illumination condition, and carrying out reduction reaction in the presence of lithium aluminum hydride to obtain tylophorine and antofen. The method for synthesizing tylophorine and antofine has the advantages of simple operation, short route, mild reaction conditions, low production cost and the like, no metal catalyst is used in the total synthesis route, the method is green and environment-friendly, the yield of each step is 70% or above, and the product yield is high.

Description

Technical Field

[0001] The invention belongs to the technical field of heterocyclic compound synthesis, and particularly relates to a total synthesis method of phenanthroindolizidine alkaloids. Background Art

[0002] Phenanthroindolizidine alkaloids are an important class of alkaloids, widely distributed in plants such as Asclepiadaceae, Moraceae, Acanthaceae and Lauraceae. This class of alkaloids not only has significant anti-tumor activity, but also has excellent biological activities such as antiviral, anti-inflammatory, and inhibition of biological protein synthesis. Valerianine and anthophen are representative compounds of phenanthroindolizidine alkaloids.

[0003] Ervatamia alkaloids are mainly found in Ervatamia ovata, Ervatamia indica, Ervatamia densiflora and Ervatamia tanaka. They were first isolated from Ervatamia indica and were initially used to treat asthma, diarrhea and other related diseases. Ervatamia alkaloids have excellent physiological effects. They not only have significant anti-tumor activity, but also have excellent biological activities such as anti-inflammatory, anti-leukemia, anti-microbial, anti-insect and antibacterial. Antophene is an alkaloid widely found in Cyperus rotundus in the arid sandy desert areas of northwest my country. It not only has a half inhibitory concentration (IC50) against common cancer cells (breast cancer, lung cancer, nasopharyngeal cancer, etc.), but also has a high inhibitory concentration (IC50) against common cancer cells (breast cancer, lung cancer, nasopharyngeal cancer, etc.). 50 ) is in the nanomolar range, and also maintains high cell inhibition activity against drug-sensitive nasopharyngeal carcinoma cell KB-3-1 and multi-drug resistant nasopharyngeal carcinoma cell KBV1. Antophane not only has good anti-cancer effect, but also has good anti-tobacco mosaic virus biological activity. The inhibition rate of 1ppm of anthophenes on tobacco mosaic virus is as high as 60%. At the same time, R-Anthophenes have good water solubility and antibacterial biological activity, and have good potential application prospects in the field of post-harvest preservation of fruits and vegetables.

[0004] At present, the main ways to obtain valerianine and anthophenes are separation from natural plants and artificial total synthesis. The total synthesis routes and methods of artificial total synthesis of valerianine and anthophenes can be mainly divided into two categories. One is the total synthesis route of first constructing the phenanthrene ring, which means first constructing the phenanthrene ring part of the phenanthene-indolizidine alkaloid, then extending the carbon chain, connecting it with a five-membered nitrogen-containing heterocycle, and finally closing the ring to form the target compound; the other is the total synthesis route of first constructing the indole ring, that is, first constructing the indole ring from a nitrogen-containing heterocycle, then connecting it with a polysubstituted benzene, and finally closing the ring to form the target compound. Both types of synthesis routes have their own advantages and disadvantages. The synthesis route starting from the phenanthrene ring is currently the mainstream method for synthesizing such compounds. Its raw materials are relatively economical and easy to obtain, but the general synthesis route is longer and more cumbersome; although the synthesis route starting from the indole ring generally has fewer steps, it usually requires the use of expensive transition metal catalysts and difficult-to-store VOF3 in the synthesis route to achieve the construction of the phenanthrene ring, and the economy and environmental protection are poor. In recent years, phytochemists have devoted themselves to the total synthesis of phenanthroindolizidine alkaloids and their derivatives and the study of their biological activities. How to efficiently construct the phenanthroindolizidine ring system has always been the direction of people's common efforts. Summary of the invention

[0005] The object of the present invention is to provide a method for the total synthesis of cypermethrin and anthophene with simple operation, short route, mild reaction conditions, low production cost and high product yield.

[0006] In view of the above purpose, the present invention uses 4-methoxyphenylacetylpyrrolidineacetic acid and 3,4-dimethoxyphenylacetylpyrrolidineacetic acid (compound 1) as starting materials, respectively, and synthesizes silanine and anthophenes through Weinreb ketone reaction, photocyclization dehydrogenation reaction, aldol condensation reaction and reduction reaction. Compound 1 is reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine to generate intermediate 2; intermediate 2 is reacted with 3,4-dimethoxyphenylmagnesium bromide to generate intermediate 3; intermediate 3 is subjected to aldol condensation reaction in the presence of NaOH to generate intermediate 4; intermediate 4 is dehydrogenated under argon protection and ultraviolet radiation to generate intermediate 5; intermediate 5 is subjected to reduction reaction in the presence of lithium aluminum hydride to obtain compound 6; the total synthesis route is as follows:

[0007]

[0008] Wherein R is a methoxy group or a hydrogen atom; wherein, when R is a methoxy group, compound 6 is ceramide; when R is a hydrogen atom, compound 6 is anthophenone.

[0009] In the above-mentioned total synthesis method, preferably under argon protection and -20 to -5°C, compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine are added to dichloromethane, stirred at room temperature for 1 to 3 hours, the reaction solution is acidified with a 10% hydrochloric acid aqueous solution, and then extracted and purified by column chromatography to obtain intermediate 2.

[0010] In the above-mentioned total synthesis method, the molar ratio of the compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine is preferably 1:1.5-2.5:1.5-2.5.

[0011] In the above-mentioned total synthesis method, preferably, under argon protection and -10 to 0°C, intermediate 2 and 3,4-dimethoxyphenylmagnesium bromide are added to tetrahydrofuran, and the reaction is stirred at 0 to 5°C for 12 to 20 hours. The reaction solution is quenched with a saturated aqueous ammonium chloride solution, and then extracted and purified by column chromatography to obtain intermediate 3.

[0012] In the above-mentioned total synthesis method, the molar ratio of the intermediate 2 to 3,4-dimethoxyphenylmagnesium bromide is preferably 1:1.5-2.

[0013] In the above-mentioned total synthesis method, it is preferred to dissolve intermediate 4 in an organic solvent and react for 15 to 20 hours under argon protection and 300 to 365 nm ultraviolet light radiation. After the reaction is completed, the reaction solution is distilled under reduced pressure and purified by column chromatography to obtain intermediate 5.

[0014] In the above-mentioned total synthesis method, the organic solvent is preferably any one of dichloromethane and dioxane or a mixed solvent of dichloromethane and methanol.

[0015] The beneficial effects of the present invention are as follows:

[0016] The invention adopts commercial 4-methoxyphenylacetylpyrrolidineacetic acid and 3,4-dimethoxyphenylacetylpyrrolidineacetic acid as starting materials, and fully synthesizes cypermethrin and anthophenanthrene alkaloids through Weinreb ketone reaction, photocyclization dehydrogenation reaction, aldol condensation reaction and reduction reaction. No metal catalyst is used in the full synthesis process. Compared with the existing method for synthesizing cypermethrin and anthophenanthrene alkaloids, both the indolizidine ring and the phenanthrene ring are constructed, and the yield of each method step is more than 70%. The invention has the advantages of short synthesis route, simple process, mild reaction conditions, low production cost, no need to use any transition metal catalyst, green environmental protection and high product yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the retention time of the hydrogen standard sample.

[0018] Figure 2 is the retention time of the photocyclization reaction gas sample. DETAILED DESCRIPTION

[0019] The present invention is further described in detail below in conjunction with the accompanying drawings and embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0020] Example 1

[0021] Synthetic cypermethrin

[0022]

[0023] Step 1: Add 30.7 g (0.1 mol) of 3,4-dimethoxyphenylacetylpyrrolidineacetic acid (Compound 1-1) and 1.0 L of dichloromethane to a reaction kettle, cool to -15 ° C under argon protection, then add 19.5 g (0.2 mol) of N, O-dimethylhydroxylamine hydrochloride, 38.3 g (0.2 mol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 19.5 g (0.2 mol) of N-methylmorpholine to the reaction kettle, and stir at room temperature. After reacting at room temperature for 2 hours, the reactor was cooled to 0°C, the reaction solution was acidified to pH = 6-7 with a 10% mass concentration of hydrochloric acid aqueous solution, and then 1.0L of distilled water was added for three extractions, the organic layer of the extract was dried over anhydrous sodium sulfate, the dried organic phase was distilled under reduced pressure to remove the solvent, and then separated and purified by silica gel column chromatography, using a mixed solvent of dichloromethane: methanol = 150:1 to 50:1 by volume as the eluent, and a white solid intermediate 2-1 was obtained after elution and separation, with a yield of 98%.

[0024] The structural characterization data of intermediate 2-1 are: 1 H NMR (400MHz, CDCl3) δ6.92-6.68(m,3H),4.57-4.34(m,1H),3.83(d,J=4.2Hz,6H),3.65(s,3H),3.5 6(d,J=11.6Hz,2H),3.51-3.37(m,2H),3.13(d,J=9.1Hz,3H),2.67-2.27(m,1H),2.18-1.71(m,5H); 13CNMR(400MHz, CDCl3)δ169.8(s),169.7(s),149.0(s),147.9(s),127.4(s),121.1(s),112.0(s),111.2(s), 61.2(s),55.9(s),54.6(s),54.3(s),47.3(s),42.1(s),32.0(s),31.3(s),23.9(s),21.5(s); HRMS(ESI)m / z C 18 H 21 The theoretical value of N2O5 is 351.1514, and the measured value is 351.1912.

[0025] Step 2: Add 33.6g (0.1mol) of intermediate 2-1 and 1.0L of anhydrous tetrahydrofuran to a dry reactor to dissolve the intermediate 2-1 completely, and cool the reaction system to -5°C. At the same time, cool 1.0L of tetrahydrofuran solution containing 48.0g (0.2mol) of 3,4-dimethoxyphenylmagnesium bromide to -5°C and slowly drop it into the reactor. After stirring and reacting at 0°C for 12 hours, add 50mL of saturated ammonium chloride aqueous solution to the reactor to quench the reaction, distill under reduced pressure to recover tetrahydrofuran, add 1L of distilled water to the concentrated product, extract three times with 1L of ethyl acetate respectively, combine and collect the organic phase, and distill under reduced pressure to remove ethyl acetate. Finally, the product is separated and purified by silica gel column chromatography, using a mixed solvent with a volume ratio of petroleum ether: ethyl acetate = 2.5:1 as the eluent to obtain a colorless oily liquid intermediate 3-1 with a yield of 76%.

[0026] The structural characterization data of intermediate 3-1 are: 1 H NMR (400MHz, CDCl3) δ7.91-7.80(m,1H),7.65-7.56(m,1H),6.90(d,J=8.3Hz,1H),6.85-6.74(m,3H),4.54(td,J=7.6,3.8Hz,1H),3.93(d,J=6.8 Hz, 6H), 3.86 (d, J=3.6Hz, 6H), 3.61 (s, 2H), 3.52 (dt, J=7.4, 4.6Hz, 1H), 3.45(t,J=7.7Hz,1H),2.59(dd,J=13.8,10.4Hz,1H),2.07-1.81(m,5H); 13CNMR(400MHz, CDCl3)δ170.1(s),153.5(s),149.2(s),149.1(s),148.0(s),129.9(s),127.2(s),123.9(s),121.2(s),112.2( s),111.3(s),110.4(s),110.3(s),56.1(s),56.0(s),55.5(s),47.6(s),42.1(s),29.8(s),29.3(s),24.0(s); HRMS(ESI)m / z C 16 H 21 NO5[M+H] + Theoretical value 428.2068, measured value 428.2075.

[0027] Step 3: According to the method reported in the literature [Bioorganic & Medicinal Chemistry Letters 2003, 13: 1679-1682.], 42.8g (0.1mol) of intermediate 3-1 and 8.0g (0.2mol) of sodium hydroxide were added to a dry reactor, and then 1L of anhydrous ethanol was added to react at 78°C for 24 hours. After the reaction was completed, it was cooled to room temperature, the excess sodium hydroxide was removed by suction filtration, and the solvent was removed by reduced pressure distillation, and the product was dissolved with 1L of dichloromethane, and extracted three times with 1L of distilled water. After the organic phase was dried with anhydrous sodium sulfate to remove water, the dichloromethane was recovered by reduced pressure distillation, and the product was separated and purified by silica gel column chromatography, and a mixed solvent of ethyl acetate: petroleum ether = 1.5:1 to 1:1 by volume was used as the eluent to obtain a white solid intermediate 4-1 with a yield of 93%.

[0028] The structural characterization data of intermediate 4-1 are: 1 H NMR (400MHz, CDCl3) δ6.73-6.69(m,3H),6.68(s,1H),6.65(dd,J=8.2,1.8Hz,1H),6.47(d,J= 1.8Hz,1H),3.94(ddt,J=14.5,10.1,5.1Hz,1H),3.81(d,J=4.7Hz,6H),3.69(s,3H),3.60(m, J=12.1,9.9,7.4Hz,1H),3.51(s,3H),2.86(dd,J=16.4,4.5Hz,1H),2.70(dd,J=16.4,13.8Hz ,1H),2.33-2.25(m,1H),2.13-2.04(m,1H),1.91-1.83(m,1H),1.72(dd,J=11.8,5.8Hz,2H); 13C NMR (400 MHz, CDCl3) δ 164.2 (s), 148.4 (s), 148.3 (s), 148.1 (s), 147.9 (s), 144.4 (s), 132.7 (s), 131.9 (s), 129.1 (s), 123.7 (s), 120.9 (s), 114.6 (s), 112.5 (s), 110.7 (s), 110.5 (s), 77.4 (s), 77.1 (s), 76.8 (s), 55.8 (s), 55.8 (s), 55.6 (s), 44.8 (s), 37.3 (s), 33.8 (s), 23.2 (s); HRMS (ESI) m / z theoretical value C 16 H 21 NO5[M+H] + 410.1962, measured value 410.1963.

[0029] Step 4: 40.9 g (0.1 mol) of intermediate 4-1 and 5 L of a mixed solvent of dichloromethane and methanol in a volume ratio of 1:9 were added to a photoreaction tube, and irradiated with 365 nm ultraviolet light for 15 hours under argon protection and stirring. After the reaction was completed, the reaction solution was distilled under reduced pressure and purified by column chromatography using a mixed solvent of dichloromethane: methanol in a volume ratio of 200:1 as the eluent to obtain a pure white solid intermediate 5-1 with a yield of 82%.

[0030] The structural characterization data of intermediate 5-1 are: 1 H NMR(400MHz, CDCl3)δ9.04(s,1H),7.82(s,1H),7.78(s,1H),7.34(s,1H),4.14(s,3H),4.12(s,3H),4.09(s,3H),4.06(s ,3H),3.79-4.01(m,3H),3.56-3.63(m,1H),2.70-2.99(m,1H),2.37-2.46(m,1H),2.12-2.22(m,1H),1.87-2.01(m,2H); 13C NMR (400MHz, CDCl3) δ164.8(s),150.4(s),149.0(s),148.9(s),148.8(s),133.2(s),126.8(s),124.5(s),124.4(s),123.3(s),122.6(s) ,108.1(s),104.9(s),103.2(s),102.4(s),76.7(s),56.0(s),55.9(s),55.3(s),45.4(s),33.9(s),32.7(s),23.6(s); HRMS(ESI)m / z C 24 H 25 NO5[M+H] + Theoretical value 408.1805, measured value 408.1803.

[0031] Step 5: According to the method reported in the literature [Org. Lett., 2013, 15 (20): 5334-5337.], 40g (0.1mol) of intermediate 5-1 was weighed and added to a dry reactor, and then 1L of dry tetrahydrofuran was added, and 0.8L of 0.25mol / L lithium aluminum hydride tetrahydrofuran solution was added at 0°C under argon protection and stirring, and then refluxed in a 68°C oil bath for 3 hours. After the reaction was completed, it was cooled to room temperature, 10mL of 6mol / L sodium hydroxide aqueous solution was slowly added dropwise to quench the reaction, the solvent was removed by reduced pressure distillation, and the reaction product was dissolved with 1L of ether, and extracted three times with 1L of distilled water. After the organic phase was dried with anhydrous sodium sulfate to remove water, the ether was recovered by reduced pressure distillation, and the reaction product was separated and purified by silica gel column chromatography, and a mixed solvent with a volume ratio of dichloromethane: methanol = 200: 1 was used as an eluent to obtain white solid cypermethrin, with a yield of 95%.

[0032] The structural characterization data of ergoline are: 1 H NMR (400MHz, CDCl3) δ7.82(d,J=2.3Hz,2H),7.30(s,1H),7.14(s,1H),4.63(d,J=14.7Hz,1H),4.15-4.09(m,6H),4.05(d,J=2.4Hz,6H),3.6 9(d,J=15.0Hz,1H),3.55-3.44(m,1H),3.40-3.32(m,1H),2.51(s,2H),2.38-2.15(m,1H),2.11-1.99(m,1H),1.95(m,1H),1.79(m,1H); 13C NMR (400MHz, CDCl3) δ148.7(s),148.5(s),148.4(s),126.2(s),125.8(s),124.3(s),123.6(s),123.4(s),103.9(s),103.4( s),103.3(s),103.1(s),60.2(s),56.0(s),56.0(s),55.9(s),55.9(s),55.1(s),31.2(s),29.7(s),21.6(s); HRMS(ESI)m / z C 24 H 27 NO4[M+H] + Theoretical value is 394.2013, measured value is 394.2014.

[0033] Example 2

[0034] In step 2 of this embodiment, 0.75L of tetrahydrofuran solution containing 36g (0.15mol) of 3,4-dimethoxyphenylmagnesium bromide was used to replace 1.0L of tetrahydrofuran solution containing 48g (0.2mol) of 3,4-dimethoxyphenylmagnesium bromide in step 2 of Example 1, and the other steps of this step were the same as those of Example 1, to obtain a colorless oily liquid intermediate 3-1 with a yield of 70%. In step 4 of this embodiment, 5L of dichloromethane was used to replace the mixed solvent of 5L of dichloromethane and methanol in a volume ratio of 1:9 in step 4 of Example 1, and the other steps of this step were the same as those of Example 1, to obtain a pure white solid intermediate 5-1 with a yield of 78%. Steps 1, 3, and 5 of this embodiment are the same as steps 1, 3, and 5 of Example 1.

[0035] Example 3

[0036] In step 2 of this embodiment, 1L of tetrahydrofuran solution containing 43.2g (0.18mol) of 3,4-dimethoxyphenylmagnesium bromide was used to replace 1.0L of tetrahydrofuran solution containing 48g (0.2mol) of 3,4-dimethoxyphenylmagnesium bromide in step 2 of embodiment 1, and the other steps of this step were the same as those of embodiment 1, to obtain a colorless oily liquid intermediate 3-1, with a yield of 73%. In step 4 of this embodiment, 5L of dioxane was used to replace the 5L of a mixed solvent of dichloromethane and methanol in a volume ratio of 1:9 in step 4 of embodiment 1, and 313nm ultraviolet light was irradiated for 20 hours under argon protection and stirring, and the other steps of this step were the same as those of embodiment 1, to obtain a pure white solid intermediate 5-1, with a yield of 80%. Steps 1, 3, and 5 of this embodiment are the same as steps 1, 3, and 5 of embodiment 1.

[0037] Example 4

[0038] Synthetic anthophenes

[0039]

[0040] Step 1: Substituting 4-methoxyphenylacetylpyrrolidineacetic acid for 3,4-dimethoxyphenylacetylpyrrolidineacetic acid in step 1 of Example 1, the other steps were the same as step 1 of Example 1 to obtain a colorless oily liquid intermediate 2-2 with a yield of 95%.

[0041] The structural characterization data of intermediate 2-2 are: 1 H NMR (400MHz, CDCl3) δ7.22-7.07(m,2H),6.82(m,2H),4.55-4.34(m,1H),3.75(d,J=5.6Hz,3H),3.66(s,3H) ,3.60(d,J=8.7Hz,1H),3.54(s,2H),3.51-3.35(m,2H),3.13(s,2H),2.64-2.25(m,1H),2.20-1.78(m,5H); 13 C NMR(400MHz, CDCl3)δ172.5(s),170.0(s),158.5(s),130.1(s),114.1(s),77.4(s),61.3(s) ,55.4(s),54.4(s),47.4(s),41.7(s),32.1(s),30.1(s),24.0(s),21.7(s); HRMS(ESI)m / zC 17 H 24 N2O4[M+H] + Theoretical value is 321.1809, measured value is 321.1815.

[0042] Step 2: Replace the intermediate 2-1 in step 2 of Example 1 with an equimolar amount of intermediate 2-2. The other steps are the same as step 2 of Example 1 to obtain a colorless oily liquid intermediate 3-2 with a yield of 80%.

[0043] The structural characterization data of intermediate 3-2 are: 1 H NMR (400MHz, CDCl3) δ7.88(dd,J=8.4,2.1Hz,1H),7.63(d,J=2.0Hz,1H),7.20(d,J=8.6Hz,2H),6.89(dd,J=14.3,8.5Hz,3H), 4.54(m,1H),3.94(d,J=7.0Hz,6H),3.80(s,3H),3.61(s,2H),3.52(m,1H),3.44(m,1H),2.60-2.52(m,1H),2.18-1.72(m,2H); 13C NMR (400MHz, CDCl3) δ197.7(s),170.1(s),158.5(s),153.4(s),149.0(s),130.0(s),129.9(s),126.8(s),123.8(s),114.1( s),110.4(s),110.3(s),56.1(s),55.4(s),55.3(s),47.4(s),42.1(s),41.6(s),29.7(s),29.2(s),24.0(s); HRMS(ESI)m / z C 23 H 27 NO5[M+H] + Theoretical value is 398.1962, measured value is 398.1960.

[0044] Step 3: Replace the intermediate 3-1 in step 3 of Example 1 with an equal molar amount of intermediate 3-2. The other steps are the same as step 3 of Example 1 to obtain a white solid intermediate 4-2 with a yield of 90%.

[0045] The structural characterization data of intermediate 4-2 are: 1 H NMR (400MHz, CDCl3) δ7.03 (d, J = 8.7Hz, 2H), 6.80-6.64 (m, 4H), 6.42 (d, J = 1.8Hz, 1H),3.97-3.62(m,1H),3.82(s,3H),3.73(s,3H),3.70-3.65(m,1H),3.59-3.57(m ,1H),3.48(s,3H),2.84(dd,J=16.3,4.5Hz,1H),2.70(dd,J=16.3,13.7Hz,1H),2. 35-2.22(m,1H),2.07(q,J=6.7,6.0Hz,1H),1.95-1.78(m,1H),1.75-1.65(m,1H); 13 C NMR (400MHz, CDCl3) δ164.4(s),158.4(s),148.3(s),147.9(s),144.1(s),132.7(s),132.2(s),131.9(s),128.9(s),120.8( s),113.3(s),112.8(s),110.4(s),55.8(s),55.6(s),55.5(s),55.2(s),44.8(s),37.3(s),33.8(s),23.2(s); HRMS(ESI)m / z C 23 H 25 NO4[M+H] +Theoretical value 380.1856, measured value 380.1856.

[0046] Step 4: Replace the intermediate 4-1 in step 4 of Example 1 with an equal molar amount of intermediate 4-2. The other steps are the same as step 4 of Example 1 to obtain a white solid intermediate 5-2 with a yield of 85%.

[0047] The structural characterization data of intermediate 5-2 are: 1 H NMR (400MHz, CDCl3) δ9.29(d,J=9.3Hz,1H),7.98-7.81(m,2H),7.33(s,1H),7.21(dd,J=22.9,2.5Hz,1H),4.12(s,3H),4.06(s,3H),4.01(s ,3H),3.97-3.70(m,2H),3.55(dd,J=15.5,4.1Hz,1H),2.91(t,J=14.4Hz,1H),2.50-2.38(m,1H),2.16(d,J=7.4Hz,1H),2.06-1.82(m,2H); 13 C NMR(400MHz, CDCl3)δ164.4(s),157.7(s),150.2(s),149.3(s),132.6(s),131.0(s),129.7(s),126.5(s),124.4(s),123.7(s),123.6( s),115.2(s),104.9(s),104.2(s),103.9(s),56.0(s),56.0(s),55.5(s),55.3(s),45.6(s),33.9(s),32.7(s),23.6(s); HRMS(ESI)m / z C 23 H 23 NO4[M+H] + Theoretical value is 378.1700, measured value is 378.1708.

[0048] Step 5: Intermediate 5-1 in step 5 of Example 1 was replaced by intermediate 5-2 in equal moles. The other steps were the same as step 5 of Example 1 to obtain anthophene as a white solid with a yield of 90%.

[0049] The structural characterization data of Anthophene are: 1H NMR (400MHz, CDCl3) δ8.00-7.87(m,2H),7.79(d,J=9.0Hz,1H),7.31(s,1H),7.2 1(dd,J=9.0,2.6Hz,1H),4.77(d,J=15.1Hz,1H),4.11(s,3H),4.06(s,3H),4 .02(s,3H),3.64(s,3H),3.39(d,J=15.7Hz,1H),3.04(s,1H),2.50(dt,J=9. 8,7.5Hz,2H),2.30(s,1H),2.12(d,J=6.3Hz,1H),2.01(q,J=7.1,6.4Hz,2H); 13 CNMR(400MHz, CDCl3)δ157.6(s),149.5(s),148.5(s),130.3(s),127.0(s),125.5(s),124.3(s),124.1(s),123.7(s),115.0( s),104.8(s),104.0(s),103.9(s),60.4(s),56.1(s),56.0(s),55.6(s),55.0(s),31.2(s),29.8(s),21.6(s); HRMS(ESI)m / z C 23 H 23 NO4[M+H] + Theoretical value: 364.1907, measured value: 364.1903.

[0050] Example 5

[0051] In step 2 of this embodiment, 0.75L of tetrahydrofuran solution containing 36g (0.15mol) of 3,4-dimethoxyphenylmagnesium bromide was used to replace 1.0L of tetrahydrofuran solution containing 48g (0.2mol) of 3,4-dimethoxyphenylmagnesium bromide in step 2 of embodiment 4, and the other steps of this step were the same as those of embodiment 4, to obtain a colorless oily liquid intermediate 3-2 with a yield of 75%. In step 4 of this embodiment, 5L of dichloromethane was used to replace the mixed solvent of 5L of dichloromethane and methanol in step 4 of embodiment 4 with a volume ratio of 1:9, and the other steps of this step were the same as those of embodiment 4, to obtain a pure white solid intermediate 5-2 with a yield of 80%. Steps 1, 3, and 5 of this embodiment are the same as steps 1, 3, and 5 of embodiment 4.

[0052] Example 6

[0053] In step 2 of this embodiment, 1L of tetrahydrofuran solution containing 43.2g (0.18mol) of 3,4-dimethoxyphenyl magnesium bromide was used to replace 1.0L of tetrahydrofuran solution containing 48g (0.2mol) of 3,4-dimethoxyphenyl magnesium bromide in step 2 of embodiment 4, and the other steps of this step were the same as those of embodiment 4, to obtain a colorless oily liquid intermediate 3-2 with a yield of 76%. In step 4 of this embodiment, 50L of dioxane was used to replace the 5L mixed solvent of dichloromethane and methanol in step 4 of embodiment 4 with a volume ratio of 1:9, and irradiated with 313nm ultraviolet light for 20 hours under argon protection and stirring, and the other steps of this step were the same as those of embodiment 4, to obtain a pure white solid intermediate 5-2 with a yield of 89%. Steps 1, 3, and 5 of this embodiment are the same as steps 1, 3, and 5 of embodiment 4.

[0054] In order to verify that the reaction in step 4 of the above embodiment is a photocyclization dehydrogenation reaction, the gas in the illumination tube is collected and detected by gas chromatography to verify whether hydrogen is generated. GC gas chromatography conditions: argon is used as the carrier gas, and a stainless steel column (column length 2m, column temperature 80°C) and a thermal conductivity detector (TCD, temperature 100°C) are used for gas chromatography analysis. Under the conditions of a gas flow rate of 0.3MPa and 75mL / min, 1mL is injected at room temperature for gas analysis. First, the hydrogen standard sample is subjected to gas chromatography detection, and the retention time of its signal peak value is obtained to be 2.543min (see Figure 1 ). The density of hydrogen is less than that of argon. If hydrogen is generated by the reaction, it will be concentrated in the upper layer of the gas phase in the light tube. Therefore, the upper layer of gas in the light tube was collected and analyzed by gas chromatography, and the following results were obtained: Figure 2 Results. By analyzing the gas chromatogram, the upper gas in the light tube has an obvious single signal peak in the gas chromatogram, and the retention time of the peak value of the signal is 2.583min, which is basically consistent with the retention time of the peak value of the signal of the hydrogen standard sample. Therefore, the gas chromatography confirmed that hydrogen was generated in the reaction, thus confirming that the reaction was a photocyclodehydrogenation reaction.

Claims

1. A method for the total synthesis of valerianine and anthophene, characterized in that: Compound 1 is reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine to generate intermediate 2; intermediate 2 is reacted with 3,4-dimethoxyphenylmagnesium bromide to generate intermediate 3 by Weinreb ketone reaction; intermediate 3 is subjected to aldol condensation reaction in the presence of NaOH to generate intermediate 4; intermediate 4 is dehydrogenated under argon protection and ultraviolet radiation to generate intermediate 5; intermediate 5 is subjected to reduction reaction in the presence of lithium aluminum hydride to obtain compound 6; the specific synthesis route is as follows: Wherein R is a methoxy group or a hydrogen atom. When R is a methoxy group, compound 6 is ceramide; when R is a hydrogen atom, compound 6 is anthophenone.

2. The method for the total synthesis of valerianine and anthophenes according to claim 1, characterized in that: Under argon protection and -20 to -5°C, compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine were added to dichloromethane, and the mixture was stirred at room temperature for 1 to 3 hours. The reaction solution was acidified with a 10% aqueous hydrochloric acid solution, and then purified by extraction and column chromatography to obtain intermediate 2.

3. The total synthesis method of valerianine and anthophen according to claim 2, characterized in that: The molar ratio of the compound 1, N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine is 1:1.5-2.5:1.5-2.

5.

4. The total synthesis method of valerianine and anthophen according to claim 1, characterized in that: Under argon protection and -10 to 0°C, intermediate 2 and 3,4-dimethoxyphenylmagnesium bromide were added to tetrahydrofuran, and the mixture was stirred at 0 to 5°C for 12 to 20 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution, and then extracted and purified by column chromatography to obtain intermediate 3.

5. The method for the total synthesis of valerianine and anthophenes according to claim 4, characterized in that: The molar ratio of the intermediate 2 to 3,4-dimethoxyphenylmagnesium bromide is 1:1.5-2.

6. The method for the total synthesis of valerianine and anthophenes according to claim 1, characterized in that: The intermediate 4 is dissolved in an organic solvent, and reacted for 15 to 20 hours under argon protection and 300 to 365 nm ultraviolet radiation. After the reaction is completed, the reaction solution is distilled under reduced pressure and purified by column chromatography to obtain the intermediate 5.

7. The method for the total synthesis of valerianine and anthophenes according to claim 6, characterized in that: The organic solvent is any one of dichloromethane and dioxane or a mixed solvent of dichloromethane and methanol.

Images