Synthesis method of compound with cephalotaxine tetracyclic skeleton

Abstract

The invention discloses a synthesis method of a compound with a cephalotaxine tetracyclic skeleton, and belongs to the technical field of organic synthesis. According to the method, a compound shown in a formula (4) is obtained by taking a formula (1) with a cephalotaxine tetracyclic skeleton as a starting raw material through three-step conversion of carbonyl enol methylation, allylic oxidation and alcohol oxidation, so that efficient conversion of a cephalotaxine D-ring functional group is realized. The method is simple to operate, the used reagents are cheap and easy to obtain, the total yield of three steps can reach 34%, and large-scale production is facilitated.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a compound having a tetracyclic skeleton of cephalotaxine, and belongs to the technical field of organic synthesis. Background Art

[0002] Cephalotaxine was first isolated by Puadler et al. from the branches and leaves of Torreya grandis (Paudler, W. Wetal. J. Org. Chem. 1963, 28, 2194). Its main structural feature is that it is composed of a 6 / 7 / 5 / 5 fused tetracyclic skeleton with three consecutive chiral centers (one of which is an nitrogen-containing quaternary carbon center). It is worth noting that the D-ring structural unit contains all the chiral centers and functional group substitutions of cephalotaxine. Cephalotaxine itself has no biological activity, but a number of ester base derivatives derived from cephalotaxine as the core skeleton have significant anti-tumor activity (Powell, R. G. et al. J. Pharm. Sci. 1972, 61, 1227). Since the 1970s, homoharringtonine has been used in my country to treat cancer, acute myeloid leukemia, and other related diseases, with remarkable results. It is now listed in the 1990 edition of the Chinese Pharmacopoeia (Pharmacopoeia Committee of Ministry of Health Chinese Pharmacopoeia, 1990 Edition II, People's Health Pub House, Beijing, 1990, pp. 588-590 (in Chinese)). In 2012, the U.S. Food and Drug Administration (FDA) approved homoharringtonine for the treatment of chronic myeloid leukemia.

[0003]

[0004] Currently, cephalotaxine and its ester-base derivatives are primarily extracted from the branches, leaves, and seeds of Cephalotaxus plants. However, due to the slow growth of Cephalotaxus plants, limited resources, and the fact that some plants are endangered, as well as the extremely low content of ester alkaloids with anti-cancer activity, the isolation and extraction of these ester-base derivatives is far from meeting clinical needs. To address this issue, one feasible approach is to first synthesize the core skeleton of the active ester-base, cephalotaxine, through chemical synthesis, and then to obtain cephalotaxine ester alkaloids on a large scale by assembling ester side chains.

[0005] At present, there are many literature reports on the synthesis of chiral (-)-cephalotaxine ((a) Pérard-Viret, J.; Quteishat, L.; Alsalim, R.; Royer, J.; Dumas, F. The Alkaloids: Chemistry and Biology 2017, 78, 205; (b) Li, W.-DZ et al. Chin. J. Org. Chem. 2017, 37, 1885). Formula (1a) is one of the classic intermediates for the synthesis of cephalotaxine (Tetrahedron Lett. 1986, 27, 2023; Chem. Pharm. Bu11. 1988, 36, 422; Org. Lett. 2002, 4, 885; Org. Lett. 2018, 20, 1050; J. Am. Chem. Soc. 2023, 145, 9233). The synthesis of cephalotaxine via formula (1a) is generally achieved through three steps: trivalent iodine oxidation, amide reduction, and removal of methanol by p-toluenesulfonic acid. However, trivalent iodine oxidation conditions often produce regional isomer products, which need to be removed by column chromatography. The conditions for removing methanol by p-toluenesulfonic acid cannot be scaled up, and the reaction time needs to be precisely controlled. If the time is too long, product decomposition occurs.

[0006]

[0007] Therefore, for the transformation of the D-ring functional group of cephalotaxine, a new method with simple operation, low cost and suitable for industrial production is urgently needed.

[0008] The present invention is based on the chiral cephalotaxine tetracyclic skeleton (ZL 202310188141.X), and hopes to provide a new method for efficiently transforming the D-ring functional group of cephalotaxine. Summary of the Invention

[0009] In order to solve the above technical problems existing in the prior art, the purpose of the present invention is to provide a method for synthesizing a compound having a tetracyclic skeleton structure of cephalotaxine as shown in formula (4), which has achieved efficient conversion of the D-ring functional group of cephalotaxine.

[0010] In order to achieve the above object, the present invention adopts the following technical means:

[0011] The present invention provides a method for synthesizing a compound having a tetracyclic skeleton of cephalotaxine represented by formula (4), comprising the following steps:

[0012] Step 1, carbonyl enol methyl etherification: dissolving the compound represented by formula (1) in an organic solvent 1, adding an acidic reagent, and reacting at a certain temperature to obtain a compound represented by formula (2);

[0013] Step 2, allylic oxidation: the compound represented by formula (2) is dissolved in an organic solvent 2, an oxidizing agent 1 is added, and the mixture is reacted at a certain temperature to obtain a compound represented by formula (3);

[0014] Step 3, hydroxyl group oxidation: the compound represented by formula (3) is dissolved in an organic solvent 3, an oxidizing agent 2 is added, and the mixture is reacted at a certain temperature to obtain a compound represented by formula (4);

[0015]

[0016] Among them, R 1 ,R 2 ,R 3 and R 4 may be the same or different and are each independently selected from the group consisting of: hydrogen, amino, hydroxy, mercapto, cyano, nitro, halogen, trihalomethyl, benzyl, C6-C 14 Aryl or heteroaryl, unsubstituted, monosubstituted or polysubstituted C1-C 18 Alkyl, unsubstituted, monosubstituted or polysubstituted C1-C 18 Alkoxy; wherein the substituent is selected from: amino, hydroxyl, mercapto, cyano, nitro, halogen or trihalomethyl; the halogen is selected from fluorine, chlorine, bromine or iodine;

[0017] Or, R 2 ,R 3 It can also form a full carbocyclic ring or a heteroatom carbocyclic ring with an adjacent group, and the ring system is selected from:

[0018]

[0019] Among them, preferably, the compound represented by formula (1) is selected from the following compounds:

[0020]

[0021] Among them, preferably, the compound represented by formula (2) is selected from the following compounds:

[0022]

[0023] Among them, preferably, the compound represented by formula (3) is selected from the following compounds:

[0024]

[0025] Among them, preferably, the compound represented by formula (4) is selected from the following compounds:

[0026]

[0027] Wherein, preferably, in step 1, the organic solvent 1 is one or a mixture of two of methanol, chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, trimethyl orthoformate, methyl tert-butyl ether, and acetonitrile;

[0028] The acidic reagent is one or a mixture of two of p-toluenesulfonic acid, benzenesulfonic acid, Amberlyst 15, camphorsulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and trichloroacetic acid;

[0029] The certain temperature is 25°C to 120°C.

[0030] Preferably, in step 1, the molar ratio of the compound represented by formula (1) to the acidic reagent is 1:0.1-2.

[0031] Wherein, preferably, in step 2, the organic solvent 2 is one or a mixture of two of 1,2-dichloroethane, 1,4-dioxane, 2-methyltetrahydrofuran, chlorobenzene, toluene, and acetonitrile;

[0032] The oxidizing agent 1 is selenium dioxide, selenium dioxide / hydrogen peroxide, selenium dioxide / pyridine nitrogen oxide, phenylselenous anhydride, chromium trioxide, manganese acetate or cuprous bromide / tert-butyl peroxide;

[0033] The certain temperature is 0°C to 130°C.

[0034] Preferably, in step 2, the molar ratio of the compound represented by formula (2) to the oxidizing agent 1 is 1:1-3.

[0035] Wherein, preferably, in step 3, the organic solvent 3 is one or a mixture of two of dichloromethane, 1,2-dichloroethane, chloroform, 1,4-dioxane, chlorobenzene, toluene, 2-methyltetrahydrofuran, and acetonitrile;

[0036] The oxidizing agent 2 is chromium trioxide, pyridinium chlorochromate, pyridinium dichromate, tetrapropylammonium perruthenate / nitromethylmorpholine oxide, dimethyl sulfoxide / oxalyl chloride or dimethyl sulfoxide / trifluoroacetic anhydride;

[0037] The certain temperature is -78℃~60℃

[0038] Preferably, in step 3, the molar ratio of the compound represented by formula (3) to the oxidizing agent 2 is 1:0.1-3.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] The present invention discloses a method for synthesizing a compound having a tetracyclic skeleton of cephalotaxine, which achieves efficient conversion of the D-ring functional group of cephalotaxine. The present invention uses the tetracyclic skeleton of cephalotaxine represented by formula (1) as a starting material and obtains the compound represented by formula (4) through three steps of carbonyl enol methylation, allylic oxidation, and alcohol oxidation. The method of the present invention is simple to operate, the reagents used are inexpensive and readily available, the total yield of the three steps can reach 34%, and it is easy to scale up production. DETAILED DESCRIPTION

[0041] The present invention will be further described below by way of specific examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions.

[0042] Experimental raw materials

[0043] 1a-1l were obtained by referring to the prior art literature (J.Am.Chem.Soc.2023,145,9233)

[0044] p-Toluenesulfonic acid was purchased from Bidex Pharmaceutical Co., Ltd. with a purity of 95%

[0045] Selenium dioxide was purchased from Bid Pharmaceutical Co., Ltd. with a purity of 98%

[0046] Tetrapropylammonium perruthenate was purchased from Aikon Pharmaceutical Co., Ltd. with a purity of 95%

[0047] N-Methylmorpholine oxide was purchased from Aikon Pharmaceutical Co., Ltd. with a purity of 95%

[0048] Example: The overall synthetic route of the present invention for preparing the compound of formula (4) from the compound of formula (1) is as follows:

[0049] The molecular formula of the compound represented by formula (1) is as follows:

[0050]

[0051] The molecular formulas of the compounds represented by formula (2), formula (3) and formula (4) are as follows:

[0052]

[0053] Example 1: Preparation of Compound 2a from Compound 1a

[0054] Compound 1a (5.0 g, 16.7 mmol) and trimethyl orthoformate (20 mL) were mixed, p-toluenesulfonic acid (5.7 g, 33.4 mmol) was added, and the mixture was heated under reflux at 100°C for 6 hours. After the reaction system cooled to room temperature, saturated sodium bicarbonate was added to quench the reaction. The reaction mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure and vacuum drying, the yellow solid product 2a (4.7 g, 90% yield) was obtained. Spectral data: 1 H NMR (CDCl3, 600MHz): δ = 6.61 (s, 1H), 6.59 (s, 1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.44 (s, 1H), 4.06–3.96 (m, 1H), 3.70 (s, 3H), 3.45–3.36 (m, 1H), 3.10–2.99(m,1H),2.84(dd,J=24.0,12.0Hz,1H),2.62(dd,J=12.0,6.0Hz,1H),2.57–2.51(m,1H),2.26–2.11(m,3H),2.06–2.00(m,1H)ppm; 13 C NMR (150MHz, CDCl3) δ = 174.3, 163.0, 146.6, 146.0, 133.1, 129.9, 111.0, 110.6, 100.9, 97.1, 73.3, 57.2, 52.5, 38.8, 38.0, 37.9, 30.1, 29.7ppm.

[0055] Example 1-1: Preparation of Compounds 2b-2l from Compounds 1b-1l

[0056] The preparation process is similar to that of Example 1.

[0057] The spectral data of compounds 2b-2l are as follows:

[0058] 2b: 1 H NMR (400MHz, CDCl3): δ=6.65(s,1H),6.64(s,1H),4.32-4.12(m,5H),3.70(s,3H),3.49(t,J=10.5Hz,1H),3.03-2.71(m,5H),2.35-2.10(m,4H)ppm; 13 C NMR (100MHz, CDCl3): δ=174.2,142.8,141.8,130.0,128.5,120.3,119.5,97.2,67.4,64.3,64.2,52.4,49.5,43.6,35.6,30.5,29.8ppm.

[0059] 2c: 1 H NMR(600MHz,CDCl3):δ=6.56(s,1H),4.81–4.64(m,1H),4.64–4.45(m,3H),3.98–3.74(m,3H),3.59(s,7H),3.20(t,J=7.0Hz,2H),2.88(td,J=7.0,1.0Hz,4H),2.81–2.56(m,4H),2.45(td,J=7.1,1.6Hz,3H),1.99(dt,J=15.8,7.1Hz,3H)ppm; 13 C NMR(150MHz,CDCl3):δ=172.5,162.3,157.2,134.2,133.6,125.4,125.2,114.0,108.7,73.9,70.3,55.2,51.9,42.3,40.9,32.1,31.1,30.8,30.2ppm.

[0060] 2d: 1 H NMR(600MHz,CDCl3):δ=7.03(d,J=7.9Hz,1H),6.72-6.65(m,2H),5.47(s,1H),4.34-4.25(m,1H),3.76(s,3H),3.70(s,3H),3.58(t,J=10.5Hz,1H),3.14-3.04(m,1H),3.03-2.92(m,2H),2.88-2.73(m,2H),2.34-2.24(m,1H),2.20-2.08(m,3H)ppm; 13 C NMR(150MHz,CDCl3):δ=174.1,159.3,137.1,131.9,128.9,117.4,111.8,97.2,67.6,55.1,52.3,49.6,43.6,35.3,34.7,29.7ppm.

[0061] 2e: 1 H NMR(400 MHz,CDCl3):δ=7.08(dd,J=8.0,5.9 Hz,1H),6.92-6.80(m,2H),5.40(s,1H),4.36-4.22(m,1H),3.70(s,3H),3.62(t,J=10.5 Hz,1H),3.16-2.92(m,3H),2.91-2.69(m,2H),2.34-2.24(m,1H),2.21-2.05(m,3H)ppm; 13C NMR(100 MHz,CDCl3):δ=174.0,162.3(d,J=245.6 Hz),138.0(d,J=7.6 Hz),132.8(d,J=3.1 Hz),132.3(d,J=8.0 Hz),118.5(d,J=21.5 Hz),113.5(d,J=2.9Hz),97.0,67.3,52.3,49.5,43.4,35.1,34.7,29.6 ppm.

[0062] 2f: 1 H NMR(400 MHz,CDCl3):δ=7.11(d,J=7.5 Hz,1H),6.80(d,J=1.5 Hz,1H),6.71(d,J=7.5 Hz,1H),4.65(t,J=1.9 Hz,1H),3.84(d,J=7.2 Hz,1H),3.72(dd,J=1.8,0.7 Hz,1H),3.59(s,2H),2.93(d,J=16.3 Hz,1H),2.77(dd,J=12.5,7.0 Hz,1H),2.67(dd,J=12.3,7.0 Hz,1H),2.43(t,J=7.0 Hz,2H),2.01(t,J=7.2Hz,2H)ppm; 13 C NMR(100 MHz,CDCl3):δ=172.3,162.3,158.3,137.3,128.8,128.2,114.0,112.4,112.3,73.9,55.6,55.2,52.0,42.5,40.9,32.2,31.6,31.2 ppm.

[0063] 2g: 1 H NMR(400 MHz,CDCl3):δ=7.13(d,J=7.5 Hz,1H),7.07–7.01(m,2H),6.99–6.92(m,2H),4.65(dd,J=1.9,0.9 Hz,2H),3.98–3.66(m,5H),3.59(s,4H),3.11–2.90(m,1H),2.83(dtd,J=12.5,7.2,1.0 Hz,2H),2.75(m,2H),2.64(dd,J=12.4,7.1 Hz,2H),2.44(t,J=7.1 Hz,2H),2.32(s,4H),2.09–1.90(m,4H)ppm; 13C NMR(100 MHz,CDCl3):δ=172.5,162.3,136.4,136.2,131.9,128.1,127.6,127.3,113.2,73.9,55.2,52.1,42.1,40.9,32.2,31.6,31.1,21.1 ppm.

[0064] 2h: 1 H NMR(400 MHz,CDCl3):δ=7.48(dd,J=7.3,1.6 Hz,1H),7.17(t,J=7.4Hz,1H),7.13–7.06(m,1H),4.72–4.55(m,1H),3.92–3.66(m,3H),3.59(s,2H),3.05–2.71(m,3H),2.64(dd,J=12.4,7.1 Hz,1H),2.44(t,J=7.1 Hz,2H),1.99(t,J=12.3 Hz,2H)ppm. 13 C NMR(100 MHz,CDCl3):δ=172.5,162.3,140.9,134.7,131.6,128.1,126.2,125.6,113.2,73.9,55.2,51.8,41.7,40.9,32.2,31.6,30.7 ppm.

[0065] 2i: 1 H NMR(400 MHz,CDCl3):δ=7.43(d,J=7.5 Hz,1H),7.33(d,J=1.3 Hz,1H),7.18(d,J=7.5 Hz,1H),5.42(d,J=1.8 Hz,1H),4.72(td,J=6.7,1.0 Hz,1H),3.77(td,J=7.1,2.5 Hz,3H),3.73(s,1H),3.52(d,J=6.6 Hz,1H),2.85(dd,J=18.6,12.4 Hz,2H),2.44(t,J=7.1 Hz,3H),2.18–1.94(m,3H)ppm; 13 C NMR(100 MHz,CDCl3):δ=172.3,159.7,137.0,135.5,130.3,129.8,127.6,120.7,103.5,75.7,73.6,57.3,56.7,42.5,32.2,32.0,30.7 ppm.

[0066] 2j: 1H NMR(400 MHz,CDCl3):δ=7.35–7.17(m,1H),7.08(td,J=7.6,1.5Hz,1H),6.81(d,J=8.1Hz,1H),4.71–4.60(m,1H),3.95–3.70(m,3H),3.59(s,2H),2.93–2.84(m,1H),2.65(dd,J=12.4,7.0Hz,1H),2.44(t,J=7.1Hz,2H),2.09–1.86(m,2H)ppm. 13 C NMR(100MHz,CDCl3):δ=172.5,163.0,162.3,161.0,136.4,136.3,134.9,134.9,127.5,127.4,115.4,115.3,114.1,113.9,113.2,74.0,55.2,52.4,42.4,41.0,32.2,31.6,30.1,30.1ppm.

[0067] 2k: 1 H NMR(400MHz,CDCl3):δ=7.27(d,J=7.5Hz,1H),7.21–7.16(m,1H),7.08(q,J=1.1Hz,1H),4.65(dd,J=1.9,0.9Hz,1H),4.10–3.69(m,3H),3.59(s,2H),2.99–2.81(m,2H),2.74(dd,J=12.3,7.0Hz,1H),2.63(dd,J=12.4,7.0Hz,1H),2.44(t,J=7.1Hz,2H),2.05–1.84(m,2H)ppm. 13 C NMR(100MHz,CDCl3):δ=172.5,162.3,136.4,136.3,132.3,127.1,126.8,126.5,113.2,74.0,55.2,52.6,42.5,40.9,32.2,31.4,30.8ppm.

[0068] 2l: 1H NMR (400MHz, CDCl3): δ=7.33–7.27(m,1H),7.25(d,J=7.5Hz,1H),7.15(d,J=7.5Hz,1H),4.75–4.52(m,1H),3.97–3.70(m,3H), 3.59(s,2H),3.11–2.82(m,2H),2.80–2.73(m,1H),2.64(dd,J=12.4,7.1Hz,1H),2.44(t,J=7.1Hz,2H),2.12–1.85(m,2H).ppm; 13 C NMR (100MHz, CDCl3): δ=172.5,162.8,140.2,133.7,132.5,127.6,127.1,127.0,113.2,73.9,55.2,51.9,42.5,40.9,32.2,31.6,31.4ppm.

[0069] Example 2: Preparation of Compound 3a from Compound 2a

[0070] Compound 2a (3.0 g, 9.6 mmol) was dissolved in 1,4-dioxane, and selenium dioxide (1.6 g, 14.4 mmol) was added. The mixture was heated at reflux at 120°C for 2 hours. The solvent was evaporated, and the resulting mixture was diluted with dichloromethane. The organic phase was washed sequentially with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography to obtain a yellow solid 3a (1.7 g, 54% yield). Spectral data: 1 H NMR (CDCl3, 600MHz): δ = 6.66 (s, 1H), 6.60 (s, 1H), 5.89, 5.88 (ABq, J = 6.0Hz, 2H), 4.75 (d, J = 4.8Hz, 1H), 4.57 (s, 1H), 4.04 –3.96(m,1H),3.73(s,3H),3.10(d,J=4.8Hz,1H),2.99–2.85(m,2H),2.53(dd,J=12.0,6.0Hz,1H),2.22–2.05(m,3H)ppm; 13 C NMR (151MHz, CDCl3) δ=174.7,162.9,146.9,146.2,131.2,129.7,111.3,110.9,100.9,99.4,79.2,70.5,63.7,57.5,37.6,37.5,30.0,29.6ppm.

[0071] Example 2-1: Preparation of Compounds 3b-3l from Compounds 2b-2l

[0072] The preparation process is similar to that of Example 2.

[0073] The spectral data of compounds 3b-3l are as follows:

[0074] 3b: 1 H NMR (400MHz, CDCl3): 6.83(s,1H),6.64(s,1H),5.45(d,J=1.8Hz,1H),4.74(dd,J=7.3,6.6Hz,1H),4.26(s,4H),3.83(td,J=7.0,3.6H z,2H),3.45(d,J=6.4Hz,1H),2.96(dd,J=12.3,7.0Hz,1H),2.80(td,J=12.4,7.1Hz,1H),2.45(t,J=7.1Hz,2H),2.23–1.96(m,2H)ppm. 13 C NMR (150MHz, CDCl3): δ=172.2,159.8,145.5,145.2,130.1,129.6,112.6,1 12.2,102.9,75.6,73.5,64.5,64.1,57.3,56.3,42.5,32.0,31.9,30.3ppm.

[0075] 3c: 1 H NMR (400MHz, CDCl3): δ=7.40–7.03(m,1H),6.58(s,1H),5.42(dd,J=1.8,0.9Hz,1H),4.74(dd,J=7.3,6.6Hz,1H),4.54(td,J=7.1,1.8Hz,2H ),3.95–3.78(m,2H),3.55(d,J=6.6Hz,1H),3.20(td,J=7.1,3.1Hz,2H),2.95–2.72(m,2H),2.45(t,J=7.1Hz,2H),2.05(t,J=7.1Hz,2H)ppm. 13 C NMR (100MHz, CDCl3): δ=172.2,159.9,157.3,132.9,129.3,125.7,125.3,1 09.2,103.2,75.8,73.2,70.9,57.3,56.6,42.2,32.2,31.9,30.6,30.3ppm.

[0076] 3d: 1H NMR(600MHz,CDCl3):δ=7.12(t,J=7.9Hz,1H),6.81(d,J=8.2Hz,1H),6.73(d,J=7.5Hz,1H),5.42(s,1H),4.20(dt,J=14.3,8.4Hz,1H),3.79(s,3H),3.70(s,3H),3.69-3.58(m,2H),3.06-2.96(m,1H),2.92-2.73(m,2H),2.58-2.50(m,1H),2.34-2.12(m,4H)ppm; 13 C NMR(150MHz,CDCl3):δ=174.0,157.9,138.7,127.4,124.1,123.3,110.2,97.4,67.2,55.6,53.2,49.5,44.3,35.9,29.8,22.1ppm.

[0077] 3e: 1 H NMR(600MHz,CDCl3):δ=7.03(d,J=7.9Hz,1H),6.72-6.65(m,2H),5.47(s,1H),4.34-4.25(m,1H),3.76(s,3H),3.70(s,3H),3.58(t,J=10.5Hz,1H),3.14-3.04(m,1H),3.03-2.92(m,2H),2.88-2.73(m,2H),2.34-2.24(m,1H),2.20-2.08(m,3H)ppm; 13 C NMR(150MHz,CDCl3):δ=174.1,159.3,137.1,131.9,128.9,117.4,111.8,97.2,67.6,55.1,52.3,49.6,43.6,35.3,34.7,29.7ppm.

[0078] 3f: 1 H NMR(400MHz,CDCl3):δ=7.02(d,J=7.9Hz,1H),6.70-6.62(m,2H),5.47(s,1H),4.34-4.25(m,1H),3.76(s,3H),3.70(s,3H),3.51(t,J=10.5Hz,1H),3.12-3.04(m,1H),3.03-2.90(m,2H),2.88-2.77(m,2H),2.35-2.24(m,1H),2.12-2.08(m,3H)ppm; 13C NMR(100MHz,CDCl3):δ=174.1,159.3,137.1,131.9,128.9,117.4,111.8,97.1,67.6,55.1,52.3,49.6,43.6,35.4,34.3,29.7ppm.

[0079] 3g: 1 H NMR(400 MHz,CDCl3):δ=7.09–7.06(m,1H),7.05–7.02(m,1H),7.00–6.95(m,1H),5.45(dd,J=1.8,0.9 Hz,1H),4.77(dd,J=7.3,6.6 Hz,1H),3.88–3.77(m,2H),3.69(dd,J=7.0,1.9 Hz,1H),3.42(d,J=6.4 Hz,1H),3.09–2.71(m,3H),2.44(t,J=7.1Hz,3H),2.33(s,3H),2.13–1.87(m,3H)ppm. 13 C NMR(100MHz,CDCl3):δ=172.2,159.7,136.4,134.6,132.6,128.1,127.8,126.4,103.5,76.0,73.5,57.3,56.4,42.5,32.2,31.9,31.5,21.1 ppm.

[0080] 3h: 1 H NMR(400 MHz,CDCl3):δ=7.45(dd,J=7.3,1.6 Hz,1H),7.22(d,J=7.4Hz,1H),7.20–7.15(m,1H),5.45(dd,J=1.8,0.9 Hz,1H),4.75(td,J=6.7,0.9Hz,1H),3.77(t,J=7.1 Hz,2H),3.73(s,3H),3.42(d,J=6.4 Hz,1H),3.13(qt,J=12.3,7.0 Hz,2H),2.44(t,J=7.1 Hz,2H),2.29–1.90(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ=172.1,159.7,139.1,133.5,131.8,128.4,126.3,125.5,103.5,75.7,73.5,57.3,54.8,41.8,32.2,32.0,30.7 ppm.

[0081] 3i:1 H NMR(400 MHz,CDCl3):δ=7.43(dd,J=7.5,1.5 Hz,1H),7.33(d,J=1.3Hz,1H),7.18(dd,J=7.5,0.7 Hz,1H),5.42(dd,J=1.8,0.9 Hz,1H),4.72(td,J=6.7,1.0Hz,1H),3.85–3.75(m,3H),3.73(s,3H),3.52(d,J=6.6 Hz,1H),2.85(ddd,J=38.6,12.4,7.1 Hz,2H),2.44(t,J=7.1 Hz,2H),2.20–1.87(m,2H). 13 C NMR(100 MHz,CDCl3):δ=172.3,159.7,137.0,135.5,130.3,129.8,127.6,120.7,103.5,75.7,73.6,57.3,56.7,42.5,32.2,32.0,30.7 ppm.

[0082] 3j: 1 H NMR(400 MHz,CDCl3):δ=7.36–7.19(m,1H),7.08(td,J=7.8,1.5Hz,1H),6.84(d,J=7.9 Hz,1H),5.42(dd,J=1.8,0.9 Hz,1H),4.72(td,J=6.7,1.0Hz,1H),3.77(td,J=7.1,1.5 Hz,2H),3.55(d,J=6.6 Hz,1H),3.16–2.71(m,2H),2.44(t,J=7.1 Hz,2H),2.20–1.92(m,2H)ppm; 13 C NMR(100 MHz,CDCl3):δ=172.2,163.1,161.1,159.7,136.1,136.0,132.7,132.6,127.5,127.5,115.4,115.2,114.4,114.3,103.5,76.2,73.6,57.3,56.1,42.4,32.2,31.6,30.2,30.2 ppm.

[0083] 3k: 1H NMR (400 MHz, CDCl3): δ = 7.24 (dd, J = 7.5, 1.5 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.09 (q, J = 1.1 Hz, 1H), 5.42 (d, J = 1.8 Hz, 1H), 4.73 (td, J = 6.7, 0.9 Hz,1H),3.78(t,J=7.1 Hz,2H),3.73(s,3H),3.52(d,J=6.6 Hz,1H),3.26–2.77(m,2H),2.44(t,J=7.1 Hz,2H),2.17–1.92(m,2H)ppm. 13 C NMR (100 MHz, CDCl3): δ=172.2,159.7,135.5,135.2,132.7,127.8,127.5,127.1,103.5,76.2,73.6,57.3,56.4,42.4,32.2,31.6,30.4ppm.

[0084] 3l: 1 H NMR (400MHz, CDCl3): δ=7.23 (dd, J=7.5, 1.5Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 7.19 (q, J=1.1Hz, 1H), 5.43 (dd, J=1.8, 0.9Hz, 1H), 4.75 (td, J= 6.7,0.9Hz,1H),3.78(t,J=7.1Hz,2H),3.73(s,3H),3.52(d,J=6.6Hz,1H),3.25–2.74(m,2H),2.44(t,J=7.1Hz,2H),2.12–1.90(m,2H)ppm. 13 C NMR (100MHz, CDCl3): δ=172.2,159.8,135.6,135.2,132.2,127.4,127.1,127.1,103.5,76.1,73.6,57.2,56.4,42.4,32.1,31.5,30.3ppm.

[0085] Example 3: Preparation of Compound 4a from Compound 3a

[0086] Compound 3a (2.0 g, 6.1 mmol) was dissolved in dichloromethane, followed by the addition of tetrapropylammonium perruthenate (0.2 g, 0.6 mmol) and N-methylmorpholine oxide (1.1 g, 9.1 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure and vacuum drying, the crude product was washed with petroleum ether to obtain a yellow solid product 4a (1.4 g, 70% yield). Spectral data: 1 H NMR (CDCl3, 600MHz): δ = 6.67 (s, 1H), 6.62 (s, 1H), 6.08 (s, 1H), 5.93 (s, 1H), 5.92 (s, 1H), 4.16–4. 09(m,1H),3.85(s,3H),3.50(s,1H),2.97–2.90(m,1H),2.55–2.43(m,2H),2.39–2.18(m,4H)ppm; 13 C NMR (151MHz, CDCl3) δ=199.0,174.3,159.2,147.8,146.7,129.4,127.1,123.3,112.1,110.8,101.2,65.9,62.8,57.7,37.9,34.6,30.8,29.6ppm.

[0087] Example 3-1: Preparation of Compounds 4b-4l from Compounds 3b-3l

[0088] The preparation process is similar to that of Example 3.

[0089] The spectral data of compounds 4b-4l are as follows:

[0090] 4b: 1 H NMR (400MHz, CDCl3): δ = 6.95 (d, J = 0.6Hz, 1H), 6.69 (t, J = 0.9Hz, 1H), 5.96 (d, J = 1.8Hz, 1H), 4.52 (d, J = 1.9Hz, 1H), 4.26(s,4H),3.81(t,J=7.1Hz,2H),2.89(dd,J=12.3,7.0Hz,2H),2.45(t,J=7.1Hz,2H),2.07(t,J=7.1Hz,2H)ppm. 13 C NMR (100MHz, CDCl3): δ=203.6,171.8,156.8,145.9,145.0,129.7,128.6,12 2.4,113.7,112.0,70.6,64.5,64.1,59.9,56.1,42.3,32.0,31.4,30.2ppm.

[0091] 4c: 1 H NMR(400MHz,CDCl3):δ=7.32(q,J=0.9Hz,1H),6.67(d,J=1.0Hz,1H),5.98(d,J=1.6Hz,1H),4.53(td,J=7.1,4.2Hz,2H),4.48–4.27(m,1H),3.81(dd,J=12.4,7.1Hz,1H),3.78(s,3H),3.20(td,J=7.1,2.4,Hz,2H),2.95–2.76(m,2H),2.46(t,J=7.1Hz,2H),2.22–1.96(m,2H)ppm. 13 C NMR(100MHz,CDCl3):δ=203.8,171.7,157.5,156.7,134.0,128.8,126.0,125.6,122.4,109.03,70.6,70.2,60.0,56.1,42.2,32.1,31.4,30.6,30.2 ppm.

[0092] 4d: 1 H NMR(400 MHz,CDCl3):δ=7.22(t,J=7.5 Hz,1H),6.93(dd,J=7.6,1.5Hz,1H),6.74(dd,J=7.5,1.5 Hz,1H),6.28(d,J=1.8 Hz,1H),4.47–4.29(m,1H),3.83(s,2H),3.78(s,3H),3.74(t,J=7.0 Hz,1H),3.23–2.83(m,2H),2.44(t,J=7.1 Hz,2H),2.07(t,J=7.1 Hz,2H)ppm. 13 C NMR(100 MHz,CDCl3):δ=203.6,171.7,160.3,156.7,135.2,127.2,125.5,122.7,121.6,110.6,70.6,59.0,56.1,55.6,42.1,32.1,31.4,27.1 ppm.

[0093] 4e: 1H NMR(400 MHz,CDCl3):δ=7.35–7.01(m,1H),6.73(dd,J=7.5,1.6Hz,1H),6.66(d,J=1.3 Hz,1H),5.98(d,J=1.6 Hz,1H),4.41–4.21(m,1H),3.80(d,J=17.8 Hz,6H),3.00–2.82(m,2H),2.45(t,J=7.1 Hz,2H),2.23–1.94(m,2H)ppm. 13 C NMR(100 MHz,CDCl3):δ=203.7,171.7,158.0,156.7,135.2,127.2,126.8,122.4,113.1,111.5,70.6,60.1,56.1,55.3,42.3,32.1,31.4,30.1 ppm.

[0094] 4f: 1 H NMR(400 MHz,CDCl3):δ=7.15–7.03(m,1H),6.88(dd,J=1.5,0.6Hz,1H),6.71(dd,J=7.5,1.5 Hz,1H),6.28(d,J=1.8 Hz,1H),4.40–4.32(m,1H),3.82(s,5H),3.78(s,3H),2.92(d,J=7.1 Hz,3H),2.44(t,J=7.1 Hz,3H),2.07(t,J=7.1 Hz,3H)ppm. 13 C NMR(100 MHz,CDCl3):δ=203.6,171.0,158.5,156.7,132.4,128.4,127.9,122.4,112.5,112.3,70.6,59.1,56.1,55.6,42.3,32.1,31.4,31.4 ppm.

[0095] 4g: 1 H NMR(400 MHz,CDCl3):δ=7.17(t,J=0.6 Hz,1H),7.11–7.06(m,2H),7.05–6.96(m,2H),5.99(d,J=1.6 Hz,2H),4.31(d,J=1.9 Hz,2H),3.80(s,5H),3.78–3.63(m,4H),3.02–2.74(m,4H),2.45(t,J=7.1 Hz,4H),2.35(s,5H),2.20–1.92(m,4H)ppm. 13C NMR(100 MHz,CDCl3):δ=203.6,171.7,156.7,136.0,132.1,130.6,128.1,128.1,127.4,122.4,70.6,60.31,56.2,42.5,32.2,31.5,30.9,21.0 ppm.

[0096] 4h: 1 H NMR(400 MHz,CDCl3):δ=7.46(dd,J=7.3,1.6 Hz,1H),7.30–7.06(m,2H),6.28(d,J=1.8 Hz,1H),4.50(dd,J=1.8,0.6 Hz,1H),3.78(s,3H),3.74–3.65(m,1H),3.34–2.96(m,2H),2.45(t,J=7.0 Hz,2H),2.29–1.90(m,2H)ppm. 13 C NMR(100 MHz,CDCl3):δ=203.6,172.4,154.4,134.4,133.2,131.8,128.3,126.4,126.3,123.4,70.6,58.6,56.1,41.6,32.2,31.7,30.6 ppm.

[0097] 4i: 1 H NMR(400 MHz,CDCl3):δ=7.43(dd,J=7.5,1.5 Hz,1H),7.34(d,J=1.4Hz,1H),7.24(dd,J=7.5,0.6 Hz,1H),5.99(d,J=1.6 Hz,1H),4.53(d,J=1.9Hz,1H),3.78(s,3H),3.08–2.72(m,2H),2.45(t,J=7.1 Hz,2H),2.23–1.88(m,2H)ppm. 13 C NMR(100MHz,CDCl3):δ=203.7,172.0,154.4,135.0,132.6,130.1,129.6,127.4,123.4,121.2,70.6,60.0,56.1,42.4,32.2,31.7,30.6 ppm.

[0098] 4k: 1H NMR(400 MHz,CDCl3):δ=7.39–7.21(m,1H),7.08(td,J=7.8,1.5Hz,1H),6.84(d,J=7.9 Hz,1H),5.98(d,J=1.6 Hz,1H),4.48–4.09(m,1H),3.80(s,3H),3.79–3.59(m,2H),2.80(t,J=7.2 Hz,2H),2.44(t,J=7.0 Hz,2H),2.07(td,J=7.1,2.3 Hz,2H)ppm. 13 C NMR(100 MHz,CDCl3):δ=203.70,171.70,163.05,161.03,156.79,135.86,135.8,129.6,129.6,127.6,127.9,122.4,115.4,115.3,114.3,114.1,70.6,60.1,56.2,42.3,32.2,31.5,30.1,30.0 ppm.

[0099] 4l: 1 H NMR(400 MHz,CDCl3):δ=7.31–7.19(m,1H),7.12(d,J=1.1 Hz,

[0100] 1H),5.99(d,J=1.6 Hz,1H),4.47(d,J=1.7 Hz,1H),3.79(s,2H),3.10–2.80(m,

[0101] 1H),2.45(t,J=7.1 Hz,1H),2.06(d,J=7.1 Hz,1H)ppm. 13 C NMR(100 MHz,CDCl3):δ=203.7,171.7,156.7,135.1,132.5,131.3,127.9,127.1,126.9,122.4,70.6,59.9,56.1,42.3,32.2,31.4,29.8 ppm.

Claims

1. A method for synthesizing a compound having a tetracyclic skeleton of cephalotaxine represented by formula (4), characterized in that: The following steps are involved: Step 1, carbonyl enol methyl etherification: dissolving the compound represented by formula (1) in an organic solvent 1, adding an acidic reagent, and reacting at a certain temperature to obtain a compound represented by formula (2); Step 2, allylic oxidation: the compound represented by formula (2) is dissolved in an organic solvent 2, an oxidizing agent 1 is added, and the mixture is reacted at a certain temperature to obtain a compound represented by formula (3); Step 3, hydroxyl group oxidation: the compound represented by formula (3) is dissolved in an organic solvent 3, an oxidizing agent 2 is added, and the mixture is reacted at a certain temperature to obtain a compound represented by formula (4); Among them, R 1 ,R 2 ,R 3 and R 4 may be the same or different and are each independently selected from the group consisting of: hydrogen, amino, hydroxy, mercapto, cyano, nitro, halogen, trihalomethyl, benzyl, C6-C 14 Aryl or heteroaryl, unsubstituted, monosubstituted or polysubstituted C1-C 18 Alkyl, unsubstituted, monosubstituted or polysubstituted C1-C 18 Alkoxy; wherein the substituent is selected from: amino, hydroxyl, mercapto, cyano, nitro, halogen or trihalomethyl; the halogen is selected from fluorine, chlorine, bromine or iodine; Or, R 2 ,R 3 It can also form a full carbocyclic ring or a heteroatom carbocyclic ring with an adjacent group, and the ring system is selected from:

2. The synthesis method according to claim 1, wherein The compound represented by formula (1) is selected from the following compounds: The compound represented by formula (2) is selected from the following compounds: The compound represented by formula (3) is selected from the following compounds: The compound represented by formula (4) is selected from the following compounds:

3. The synthesis method according to claim 1, wherein In step 1, the organic solvent 1 is one or a mixture of two of methanol, chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, trimethyl orthoformate, methyl tert-butyl ether, and acetonitrile; The acidic reagent is one or a mixture of two of p-toluenesulfonic acid, benzenesulfonic acid, Amberlyst 15, camphorsulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and trichloroacetic acid; The certain temperature is 25°C to 120°C.

4. The synthesis method according to claim 1, wherein In step 1, the molar ratio of the compound represented by formula (1) to the acidic reagent is 1:0.1-2.

5. The synthesis method according to claim 1, wherein In step 2, the organic solvent 2 is one or a mixture of two of 1,2-dichloroethane, 1,4-dioxane, 2-methyltetrahydrofuran, chlorobenzene, toluene, and acetonitrile; The oxidizing agent 1 is selenium dioxide, selenium dioxide / hydrogen peroxide, selenium dioxide / pyridine nitrogen oxide, phenylselenous anhydride, chromium trioxide, manganese acetate or cuprous bromide / tert-butyl peroxide; The certain temperature is 0°C to 130°C.

6. The synthesis method according to claim 1, wherein In step 2, the molar ratio of the compound represented by formula (2) to the oxidizing agent 1 is 1:1-3.

7. The synthesis method according to claim 1, wherein In step 3, the organic solvent 3 is one or a mixture of two of dichloromethane, 1,2-dichloroethane, chloroform, 1,4-dioxane, chlorobenzene, toluene, 2-methyltetrahydrofuran, and acetonitrile; The oxidizing agent 2 is chromium trioxide, pyridinium chlorochromate, pyridinium dichromate, tetrapropylammonium perruthenate / nitromethylmorpholine oxide, dimethyl sulfoxide / oxalyl chloride or dimethyl sulfoxide / trifluoroacetic anhydride; The certain temperature is -78°C to 60°C.

8. The synthesis method according to claim 1, wherein In step 3, the molar ratio of the compound represented by formula (3) to the oxidizing agent 2 is 1:0.1-3.

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