Preparation method of chiral three-membered ring compound

Abstract

The invention relates to a preparation method of a chiral three-membered ring compound. The compound is an important chiral intermediate for preparing camptothecin compounds. According to the method disclosed by the invention, the chiral three-membered ring compound can be simply and efficiently prepared at high yield and low cost.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to a preparation method of a chiral three-membered ring compound, which is an important common intermediate of camptothecin compounds. Background Art

[0002] Camptothecin is a quinoline alkaloid with a five-membered ring, which was initially isolated from the wood and bark of Camptotheca acuminata by Wall et al. (J. Am. Chem. Soc., 1966, 88(16), 388). Due to its significant anti-tumor activity shown in in vivo and in vitro animal experiments, it has become one of the focuses of anti-tumor drug research.

[0003] The synthesis and modification of camptothecin is another important field of camptothecin research. For the modification of camptothecin, it is usually carried out on the A / B ring. Among many synthetic strategies, the Friedlander condensation method uses the A ring and a chiral three-membered ring for condensation to obtain camptothecin, which has unique advantages in the structural modification of camptothecin. Therefore, the camptothecin chiral three-membered ring compound is an important common intermediate for preparing camptothecin analogs with high yield and high purity, and is also the research focus of the synthesis of camptothecin compounds. IN315162B discloses a preparation method of the chiral three-membered ring compound (S)-triketone (14). This method uses acetone and diethyl oxalate as raw materials, through a series of reactions, and finally obtains (S)-triketone (14) (i.e., the chiral three-membered ring compound) through chiral resolution.

[0004]

[0005] However, this method requires chiral resolution in the last step, which increases the process cost and is not conducive to industrial production.

[0006] Therefore, there is still a need for a specific preparation method of chiral three-membered ring compounds with high yield, low cost, high purity and low impurities. Summary of the Invention

[0007] The inventors of the present invention found that by improving the synthetic idea, the chiral three-membered ring compound can be prepared simply and efficiently with high yield and low cost. The chiral resolution process is placed at the first step of the whole process route, and the present invention is completed on this basis.

[0008] An object of the present invention is to provide a preparation method of a chiral three-membered ring compound.

[0009] According to an embodiment of the present invention, the method includes:

[0010]

[0011] XY-331-CDE10

[0012] (S11) The compound XY-331-CDE10 reacts with an acid to obtain the chiral ternary ring compound XY-331-CDEring.

[0013] In step (S11), the acid is selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, and combinations thereof.

[0014] Preferably:

[0015] (S11) The compound XY-331-CDE10 reacts with an acid by refluxing in toluene for 2 - 10 hours, then a solvent is added, and the chiral ternary ring compound XY-331-CDEring is obtained by filtration.

[0016] In step (S11), the acid is selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, and combinations thereof;

[0017] The solvent is selected from ethyl acetate, ethanol, methanol, methyl tert-butyl ether, and combinations thereof.

[0018] According to an embodiment of the present invention, the method further includes

[0019]

[0020] (S10) The compound XY-331-CDE9 reacts with tert-butyl acrylate to obtain the compound XY-331-CDE10.

[0021] Preferably,

[0022] (S10) The compound XY-331-CDE9 reacts with tert-butyl acrylate in the presence of a solvent and a base at 50 - 100 °C for 8 - 30 hours, then hydrochloric acid and water are added, and extraction is performed with an extractant. The organic phases are combined and concentrated to obtain the compound XY-331-CDE10.

[0023] In step (S10), the solvent is selected from DMSO, DMF, DMA, NMP, and combinations thereof.

[0024] The base is selected from cesium carbonate, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and combinations thereof.

[0025] The extractant is selected from toluene, ethyl acetate, dichloromethane, and combinations thereof.

[0026] According to an embodiment of the present invention, the method further includes

[0027]

[0028] (S9) The compound XY-331-CDE8 reacts with an ethyl acetate solution of hydrogen chloride, a dioxane solution of hydrogen chloride, concentrated hydrochloric acid, a dichloromethane solution of sodium iodide, or a dichloromethane solution of TMSCl to obtain the compound XY-331-CDE9.

[0029] Preferably,

[0030] (S9) The compound XY-331-CDE8 reacts with an ethyl acetate solution of hydrogen chloride at 30 - 50 °C for 10 - 30 hours, and then is filtered to obtain the compound XY-331-CDE9, or

[0031] using a dioxane solution of hydrogen chloride, concentrated hydrochloric acid, or a dichloromethane solution of sodium iodide or TMSCl to replace the ethyl acetate solution of hydrogen chloride, reacting it with the compound XY-331-CDE8 at 30 - 50 °C for 1 - 3 hours, and then filtering to obtain the compound XY-331-CDE9.

[0032] According to an embodiment of the present invention, the method further includes

[0033]

[0034] (S8) The compound XY-331-CDE7 reacts with methanesulfonic acid to obtain the compound XY-331-CDE8.

[0035] Preferably,

[0036] (S8) The compound XY-331-CDE7 reacts with methanesulfonic acid in a solvent at 20 - 50 °C for 2 - 4 hours, then water is added, and it is extracted with dichloromethane. The organic phases are combined, washed, dried, and concentrated to obtain the compound XY-331-CDE8,

[0037] In step (S8), the solvent is selected from dichloromethane, chloroform, tetrahydrofuran, and combinations thereof.

[0038] According to an embodiment of the present invention, the method further includes

[0039]

[0040] (S7) The compound XY-331-CDE6 reacts with 2-methyl-2-butene under the action of sodium dihydrogen phosphate dihydrate, acetonitrile, and water, and then sodium hypochlorite is added to react to obtain the compound XY-331-CDE7.

[0041] Preferably,

[0042] (S7) Compound XY-331-CDE6 reacts with 2-methyl-2-butene in the presence of sodium dihydrogen phosphate dihydrate, acetonitrile and water at 20 - 40 °C for 0.5 - 1 hour, then sodium hypochlorite is added and the reaction proceeds for 4 - 8 hours. It is extracted with dichloromethane, and the organic phases are combined, dried and concentrated to obtain compound XY-331-CDE7.

[0043] According to one embodiment of the present invention, the method further comprises

[0044]

[0045] (S6) Compound XY-331-CDE5 reacts with sodium periodate to obtain compound XY-331-CDE6.

[0046] Preferably,

[0047] (S6) Compound XY-331-CDE5 reacts with sodium periodate in the presence of acetonitrile and water at 20 - 40 °C for 1 - 3 hours, then sodium periodate salt is added and the reaction proceeds for 4 - 8 hours. It is extracted with ethyl acetate, and the organic phases are combined, dried and concentrated to obtain compound XY-331-CDE6.

[0048] According to one embodiment of the present invention, the method further comprises

[0049]

[0050] (S5) Compound XY-331-CDE4 reacts with ethanol in the presence of an acid to obtain compound XY-331-CDE5,

[0051] In step (S5), the acid is selected from concentrated hydrochloric acid, sulfuric acid, trifluoroacetic acid and combinations thereof.

[0052] Preferably,

[0053] (S5) Compound XY-331-CDE4 reacts with ethanol in the presence of an acid at 20 - 40 °C for 2 - 4 hours, neutralized, then extracted with an extractant, and the organic phases are combined, dried and concentrated to obtain compound XY-331-CDE5,

[0054] In step (S5), the acid is selected from concentrated hydrochloric acid, sulfuric acid, trifluoroacetic acid and combinations thereof,

[0055] The extractant is selected from dichloromethane, ethanol, tetrahydrofuran and combinations thereof.

[0056] According to one embodiment of the present invention, the method further comprises

[0057]

[0058] (S4) React the compound XY-331-CDE3 with a palladium catalyst, a ligand, a base, and absolute ethanol to obtain the compound XY-331-CDE4.

[0059] In step (S4), the palladium catalyst is selected from Pd(OAc) 2 ; Pd(dba) 2 ; PdCl 2 ; Pd(dppf)Cl 2 ; Pd(PPh 3 )Cl 2 ; Pd 2 (dba) 3 ;

[0060] The ligand is selected from dppf; dppp; PPh 3 ; and BINAP;

[0061] The base is selected from TEA; sodium carbonate; potassium carbonate; sodium acetate; potassium phosphate and combinations thereof.

[0062] Preferably,

[0063] (S4) React the compound XY-331-CDE3 dissolved in anhydrous DMF with a palladium catalyst, a ligand, a base, and absolute ethanol in a carbon monoxide atmosphere at 25 - 100 °C for 10 - 30 hours, neutralize, and then extract with petroleum ether. The organic phases are combined, dried, and concentrated to obtain the compound XY-331-CDE4.

[0064] In step (S4), the palladium catalyst is selected from Pd(OAc) 2 ; Pd(dba) 2 ; PdCl 2 ; Pd(dppf)Cl 2 ; Pd(PPh 3 )Cl 2 ; Pd 2 (dba) 3 ;

[0065] The ligand is selected from dppf; dppp; PPh 3 ; and BINAP;

[0066] The base is selected from TEA; sodium carbonate; potassium carbonate; sodium acetate; potassium phosphate and combinations thereof.

[0067] According to one embodiment of the present invention, the method further comprises

[0068]

[0069] (S3) React the compound XY-331-CDE2 with a base, tetrabutylammonium iodide to obtain the compound XY-331-CDE3.

[0070] In step (S3), the base is selected from potassium tert-butoxide, sodium ethoxide, sodium hydride, and combinations thereof.

[0071] Preferably,

[0072] (S3) React the compound XY-331-CDE2 with a base, tetrabutylammonium iodide, and anhydrous THF under a nitrogen atmosphere at 60 - 80 °C for 1 - 3 hours, cool to 20 - 40 °C, add benzyl bromide, reflux for 10 - 30 hours, cool, and then extract with ethyl acetate. The organic phases are combined, dried, and concentrated to obtain the compound XY-331-CDE3.

[0073] In step (S3), the base is selected from potassium tert-butoxide, sodium ethoxide, sodium hydride, and combinations thereof.

[0074] According to one embodiment of the present invention, the method further comprises

[0075]

[0076] (S2) React the compound XY-331-CDE1 with lithium chloride and a reducing agent to obtain the compound XY-331-CDE2.

[0077] In step (S2), the reducing agent is selected from potassium borohydride, lithium borohydride, lithium aluminum hydride, and combinations thereof.

[0078] Preferably,

[0079] (S2) Stir lithium chloride, a reducing agent, and anhydrous tetrahydrofuran under a nitrogen atmosphere at 50 - 70 °C for 1 - 3 hours, cool to 20 - 40 °C, add the compound XY-331-CDE1 dissolved in anhydrous tetrahydrofuran, react at 40 - 60 °C for 10 - 30 hours, cool, and then extract with ethyl acetate. The organic phases are combined, dried, and concentrated to obtain the compound XY-331-CDE2.

[0080] In step (S2), the reducing agent is selected from potassium borohydride, lithium borohydride, lithium aluminum hydride, and combinations thereof.

[0081] According to one embodiment of the present invention, the method further comprises

[0082]

[0083] (S1) React the compound SM-1 with 2,2,6,6-tetramethylpiperidine to obtain the compound XY-331-CDE1.

[0084] (S1) Cool 2,2,6,6 - tetramethylpiperidine and anhydrous tetrahydrofuran to -78 °C and react for 0.5 - 1 hour. Dropwise add a solution of n - butyllithium in tetrahydrofuran, react at 20 - 40 °C for 0.5 - 2 hours, cool to -78 °C and add a solution of compound SM - 1 in anhydrous tetrahydrofuran, react for 0.5 - 2 hours, wash, extract, filter, and recrystallize with n - propanol to obtain compound XY - 331 - CDE1.

[0085] According to one embodiment of the present invention, the method includes:

[0086]

[0087] Beneficial effects

[0088] According to the method of the present invention, chiral three - membered ring compounds can be prepared simply, efficiently, with high yield and low cost. Detailed implementation manners

[0089] To enable those with ordinary knowledge in the art to understand the features and effects of the present invention, the following provides a general description and definition of the terms and phrases mentioned in the specification and the scope of the patent application. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art for the present invention. In case of conflict, the definition in this specification shall prevail.

[0090] In the present invention, unless otherwise stated, all raw materials used are purchased from Shanghai Titan Scientific Co., Ltd., and the instruments used are purchased from Shanghai Titan Scientific Co., Ltd.

[0091] The meanings of the terms used herein are as follows:

[0092] DMSO: Dimethyl sulfoxide

[0093] DMF: N,N - Dimethylformamide

[0094] DMA: N,N - Dimethylacetamide

[0095] NMP: N - Methylpyrrolidone

[0096] TMSCl: Trimethylchlorosilane

[0097] DPPP: 1,3 - Bis(diphenylphosphino)propane

[0098] DPPF: 1,1'-Bis(diphenylphosphino)ferrocene

[0099] BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0100] DBA: Dibenzylideneacetone

[0101] The present invention will be described below by way of examples, but the present invention is not limited to the following examples.

[0102] Example 1:

[0103] 1. Preparation of XY-331-CDE1

[0104]

[0105] Under anhydrous conditions, 67.5 mL of 2,2,6,6-tetramethylpiperidine was added to a 3 L three-necked flask, 500 mL of anhydrous tetrahydrofuran was added, the temperature of the system was lowered to -78 °C, and the reaction was carried out for 30 minutes. 214 mL of a 2.5 M solution of n-butyllithium in tetrahydrofuran was added dropwise, and the reaction was carried out at room temperature for 1 hour. Subsequently, the temperature of the system was lowered to -78 °C. After dissolving 25 g of compound SM-1 in 250 mL of anhydrous tetrahydrofuran, it was added dropwise to the system, and the reaction was carried out for 1 hour. After dissolving 63.3 g of glycerone in 125 mL of anhydrous tetrahydrofuran, it was added to the system, and the reaction was carried out for 1 hour. After detecting the completion of the reaction by TLC, 1700 mL of water was added to the reaction solution, 300 mL of 2 M hydrochloric acid was added to the aqueous phase, and it was extracted 3 times with 200 mL of ethyl acetate. The organic phases were combined, washed 3 times with 500 mL of saturated sodium bicarbonate, washed 1 time with 500 mL of water, washed 1 time with 500 mL of saturated brine, and dried over anhydrous sodium sulfate. After the system was concentrated under vacuum, it was slurried with PE:EA = 20:1 and then filtered. The mother liquor was collected and recrystallized with n-propanol, and 7.31 g of a white solid was obtained by filtration. The yield was 17%.

[0106] 1 HNMR(400MHz,CDCl 3 )δ6.99(s,1H),4.07(d,J=2.0Hz,3H),4.06 - 3.96(m,3H),2.15 - 1.89(m,2H),1.37(s,3H),1.25(s,3H),0.59(t,J=7.4Hz,3H); 13 CNMR(101MHz,CDCl 3 )δ165.90,160.60,154.36,111.18,110.67,107.98,88.22,78.32,64.99,55.23,25.92,24.40,6.63; MS(EI)m / z=327; HRMS(EI)m / z calculated: C 15 H 18 ClNO 5 [M]+328.09, found: 328.03.

[0107] 2. Preparation of XY-331-CDE2

[0108]

[0109] Under anhydrous conditions, 2.8 g of lithium chloride and 3.6 g of potassium borohydride were added to a 250 mL three-necked flask. Nitrogen was evacuated and replaced three times, and 50 mL of anhydrous tetrahydrofuran was added. The mixture was stirred at an internal temperature of 60 °C for 2 hours. After the reaction solution was cooled to room temperature, the raw material XY-331-CDE1 dissolved in 50 mL of anhydrous tetrahydrofuran was added, and the reaction was carried out overnight at an internal temperature of 50 °C. After the reaction was completed as detected by TLC, the reaction solution was cooled to room temperature, and the reaction was quenched with 50 mL of saturated ammonium chloride solution. The layers were separated, and the organic phase was collected. The aqueous phase was extracted 4 times with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 7.5 g of a yellow oil. The product was triturated with petroleum ether and ethyl acetate to obtain 6.2 g of a white solid. Yield: 83%.

[0110] 1 HNMR(400MHz,CDCl 3 )δ7.28(d,J=2.7Hz,1H),6.83(s,1H),4.84(dd,J=28.4,12.2Hz,2H),4.53(t,J=6.9Hz,1H),4.00(s,3H),3.79(t,J=7.5Hz,1H),3.59(t,J=7.9Hz,1H),2.10-1.86(m,2H),1.47(d,J=28.4Hz,6H),0.82(t,J=7.4Hz,3H); 13 CNMR(101MHz,DMSO)δ163.10,156.29,146.51,120.46,115.88,109.53,80.71,77.72,64.99,54.76,31.19,26.49,25.84,8.29;MS(EI)m / z=331;HRMS(EI)m / z calculated:C 15 H 22 ClNO 5 [M]+332.1,found:332.1.

[0111] 3. Preparation of XY-331-CDE3

[0112]

[0113] Add 6.2 g of XY-331-CDE2, 3.0 g of sodium hydride, and 0.7 g of tetrabutylammonium iodide to a 250 mL three-necked flask. Add 70 mL of anhydrous THF, and reflux and stir at an internal temperature of 70 °C for 2 hours. After the reaction solution cools to room temperature, add 8.8 mL of benzyl bromide, and reflux and react at an internal temperature of 70 °C overnight. After detecting the completion of the reaction by TLC, wait for the reaction to cool to room temperature, dropwise add 15 mL of saturated ammonium chloride solution to quench the reaction, separate the liquid, collect the organic phase, extract the aqueous phase three times with 30 mL of ethyl acetate, combine the organic phases, wash once with 50 ml of saturated sodium bicarbonate, wash once with 50 ml of water, wash once with 50 ml of saturated brine, and dry over anhydrous sodium sulfate. Rotavapor to obtain 11 g of a yellow oil, yield: 92%.

[0114] 1 HNMR(400MHz,CDCl 3 )δ7.26(ddd,J=32.3,18.8,5.9Hz,10H),7.17(s,1H),4.87-4.70(m,2H),4.64(dd,J=15.2,10.5Hz,2H),4.45(d,J=9.1Hz,1H),4.43(d,J=6.5Hz,2H),3.99(d,J=7.9Hz,1H),3.95(s,3H),3.85(t,J=7.7Hz,1H),2.32-2.10(m,2H),1.39-1.23(m,6H),0.85(t,J=7.3Hz,3H); 13 CNMR(101MHz,CDCl 3 )δ164.04,154.19,148.36,138.55,138.37,128.41,128.27,128.04,127.62,127.44,127.27,117.92,116.19,109.91,82.44,80.38,76.86,73.38,65.89,65.35,63.57,54.56,26.72,26.10,24.64,8.73;MS(EI)m / z=511;HRMS(EI)m / z calculated: C 29 H 34 ClNO 5 [M]+512.2, found: 512.2.

[0115] 4. Preparation of XY-331-CDE4

[0116]

[0117] Add 1.2 g of palladium diacetate, 2.2 g of DPPP, and 4.5 g of potassium carbonate into a 500 mL three-necked flask. After displacing nitrogen, add XY-331-CDE3 dissolved in 110 mL of anhydrous DMF. Displace carbon monoxide three times, then add 110 mL of anhydrous ethanol, and stir at an internal temperature of 80 °C overnight. After detecting that the reaction is complete by TLC, adjust the reaction solution to neutral with 4 M hydrochloric acid, add 100 mL of water, and extract with 100 mL of petroleum ether 5 times. Combine the organic phases, wash once with 50 ml of saturated sodium bicarbonate, once with 50 ml of water, and once with 50 ml of saturated brine, and dry over anhydrous sodium sulfate. Rotavapor to obtain 9.1 g of a yellow oil, yield: 80%.

[0118] 1 H NMR(400MHz,CDCl 3 )δ7.99(s,1H),7.43-7.25(m,10H),4.83(t,J=7.2Hz,1H),4.78-4.59(m,2H),4.53(d,J=11.2Hz,1H),4.45(dd,J=13.0,5.7Hz,4H),4.15-4.04(m,3H),3.94(dt,J=15.4,8.0Hz,2H),2.31(ddq,J=22.3,14.9,7.4Hz,2H),1.45(t,J=7.0Hz,3H),1.38(d,J=8.9Hz,3H),1.33(d,J=13.1Hz,3H),0.93(t,J=7.3Hz,3H); 13 C NMR(101MHz,CDCl 3 )δ165.41,164.35,151.58,144.55,138.60,138.45,128.33,128.20,127.95,127.52,127.33,127.20,124.27,118.32,109.83,82.58,80.40,73.44,65.65,65.41,63.94,61.60,54.16,26.78,26.07,24.83,14.29,8.61;MS(EI)m / z=549;HRMS(EI)m / z calculated:C 32 H 39 NO 7 [M]+550.2,found:550.2.

[0119] 5. Preparation of XY-331-CDE5

[0120]

[0121] Dissolve 9.1 g of XY-331-CDE4 in 100 mL of ethanol, add it to a 250 mL single-necked flask, slowly add 30 mL of concentrated hydrochloric acid with stirring, and react for 3 hours. After detecting the completion of the reaction by TLC, adjust the reaction solution to neutral with saturated sodium bicarbonate solution. After the solution no longer produces a large amount of gas, extract it 3 times with 30 mL of dichloromethane, combine the organic phases, and dry over anhydrous sodium sulfate. Rotavapor to obtain 8.3 g of a yellow oil, yield: 82%.

[0122] 1 H NMR(400MHz,CDCl 3 )δ7.73(s,1H),7.46 - 7.21(m,10H),5.30(s,1H),5.01 - 4.97(m,1H),4.94(d,J=9.7Hz,1H),4.72(dd,J=23.4,10.1Hz,2H),4.52(d,J=10.4Hz,1H),4.46 - 4.30(m,4H),4.13(d,J=4.5Hz,1H),4.01(s,3H),3.71(s,1H),3.59 - 3.25(m,2H),2.49 - 2.16(m,2H),1.40(t,J=7.1Hz,3H),0.87(t,J=7.2Hz,3H); 13 C NMR(101MHz,CDCl 3 )δ165.36,164.28,152.09,144.40,138.15,137.71,128.51,128.31,128.07,127.89,127.80,127.72,123.50,118.27,85.39,73.12,65.23,63.86,63.17,61.74,54.26,25.36,14.28,8.07;MS(EI)m / z=509;HRMS(EI)m / z calculated:C 29 H 35 NO 7 [M]+510.2,found:510.2.

[0123] 6.Preparation of XY-331-CDE6

[0124]

[0125] Dissolve 8.3 g of XY-331-CDE5 in 60 mL of acetonitrile and 7.5 mL of water, then add it to a 250 mL single-necked flask. Stir and add 5.1 g of sodium periodate and react for 2 hours. A white solid precipitate of sodium periodate salt is formed. After TLC detection shows that the reaction is complete, add 80 mL of water to the reaction solution to dissolve the formed sodium periodate salt. Extract the solution with 30 mL of ethyl acetate three times, combine the organic phases, and dry over anhydrous sodium sulfate. Rotavapor to obtain 5.7 g of a yellow oil, yield: 87%.

[0126] 1 H NMR(400MHz,CDCl 3 )δ9.71(s,1H),7.98(s,1H),7.40-7.29(m,10H),4.63(s,2H),4.52-4.42(m,4H),4.33(dd,J=53.8,11.1Hz,2H),4.08(s,3H),2.48-2.28(m,2H),1.45(t,J=7.1Hz,3H),0.98(t,J=7.3Hz,3H); 13 CNMR(101MHz,CDCl 3 )δ199.06,165.07,163.53,154.30,149.01,145.21,137.70,137.38,128.48,128.32,128.10,127.82,127.75,127.51,122.92,117.85,85.54,72.96,65.32,62.98,61.75,54.28,25.83,14.30,7.11;MS(EI)m / z=477;HRMS(EI)m / z calculated: C 28 H 31 NO 6 [M]+478.2, found: 478.2.

[0127] 7. Preparation of XY-331-CDE7

[0128]

[0129] Dissolve 5.7 g of XY-331-CDE6 in 60 mL of acetonitrile and 20 mL of water, then add it to a 250 mL single-necked flask. Stir and add 6.1 g of sodium dihydrogen phosphate dihydrate and 11 mL of 2-methyl-2-butene and react at room temperature for 30 minutes. Subsequently, add 4.5 g of sodium hypochlorite and react for 6 hours. After TLC detection shows that the reaction is complete, extract the solution with 30 mL of dichloromethane three times, combine the organic phases, and dry over anhydrous sodium sulfate. Rotavapor to obtain 6.2 g of a yellow oil, yield: 90%.

[0130] 11H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, 1H), 7.18 (ddd, J = 19.0, 9.8, 6.2 Hz, 4H), 5.71 (s, 1H), 4.70 - 4.51 (m, 1H), 4.38 - 4.24 (m, 1H), 4.23 (d, J = 6.6 Hz, 1H), 3.90 (s, 1H), 2.38 (q, J = 7.3 Hz, 1H), 1.30 (t, J = 7.0 Hz, 1H), 0.81 (t, J = 7.3 Hz, 1H); 13 13C NMR (101 MHz, DMSO) δ 172.55, 169.80, 164.83, 163.75, 151.52, 145.07, 144.68, 138.70, 138.30, 128.73, 128.62, 128.11, 127.93, 122.78, 117.50, 83.29, 73.13, 65.51, 62.93, 61.72, 60.23, 56.84, 55.35, 54.44, 26.67, 20.15, 14.56, 7.82; MS (EI) m / z = 493; HRMS (EI) m / z calcd: C 28 H 31 NO 7 [M]+ 494.2, found: 494.2.

[0131] 8. Preparation of XY - 331 - CDE8

[0132]

[0133] Dissolve 6.2 g of XY - 331 - CDE7 in 120 mL of dichloromethane and add it to a 250 - mL single - necked flask. Stir and add 24 mL of methanesulfonic acid and stir for 3 hours. After TLC detection shows that the reaction is complete, add 100 mL of water to the reaction solution, separate the layers, collect the organic phase. Extract the aqueous phase three times with 30 mL of dichloromethane each time. Combine the organic phases, wash once with 50 mL of saturated sodium bicarbonate and once with 50 mL of water, dry over anhydrous sodium sulfate, and rotary evaporate to obtain 5.8 g of a yellow oil, yield: 96%.

[0134] 1 1H NMR (400 MHz, CDCl 3)δ 7.87 (d, J = 3.0 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.53 (d, J = 16.2 Hz, 1H), 5.24 (d, J = 9.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 15.1 Hz, 3H), 1.74 (q, J = 7.4 Hz, 2H), 1.34 (dd, J = 17.8, 10.6 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 )δ 173.63, 164.55, 158.64, 149.03, 146.17, 115.33, 114.95, 72.84, 65.66, 61.85, 54.22, 32.04, 14.27, 7.61; MS (EI) m / z = 295; HRMS (EI) m / z calcd: C 14 H 17 NO 6 [M]+ 296.2, found: 296.2.

[0135] 9. Preparation of XY - 331 - CDE9

[0136]

[0137] Dissolve 5.8 g of XY - 331 - CDE8 in 30 mL of 4 M hydrogen chloride ethyl acetate solution, add it to a 100 - mL single - necked flask, stir overnight at 40 °C. After the reaction is completed, a white solid precipitates directly. Filter to obtain 1.3 g of white solid, and the liquid chromatography - mass spectrometry monitoring shows it is the desired pure product. Yield: 60%.

[0138] 1 H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.11 (s, 1H), 6.46 (s, 1H), 5.38 - 5.24 (m, 2H), 4.33 (d, J = 7.1 Hz, 2H), 1.84 - 1.69 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, DMSO) δ 172.46, 161.34, 159.13, 149.08, 135.76, 124.49, 107.05, 72.21, 65.79, 62.56, 31.13, 14.37, 8.07; MS (EI) m / z = 281; HRMS (EI) m / z calcd: C 13 H 15 NO 6[M] + 282.2, measured: 282.2.

[0139] Preparation of 10.XY - 331 - CDE10

[0140]

[0141] Add 1.3 g of XY - 331 - CDE9 and 3 g of cesium carbonate into a 100 mL three - necked flask. After evacuating and replacing with nitrogen three times, add 30 mL of anhydrous DMSO to dissolve the raw materials. Then add 6.8 mL of tert - butyl acrylate and stir at 50 °C for 21 hours. After detecting the completion of the reaction by TLC, cool the mixture to room temperature, and add 2 mL of concentrated hydrochloric acid and 20 mL of water. Extract 4 times with a total of 100 mL of 4:1 (v / v) toluene / ethyl acetate. Combine the organic phases, wash the organic phases with water (3×20 mL), and then evaporate to an oily substance. Add toluene (20 mL), and concentrate the solution to obtain 1.5 g (86%) of XY - 331 - CDE10 (toluene solventate), which is a light yellow crystalline solid: Yield: 74%.

[0142] 1 H NMR (300 MHz, CDCl 3 ) δ 0.92 (t, 7.4 Hz, 3H), 1.50 (s, 9H), 1.71 - 1.79 (m, 2H), 2.28 (s, 3H), 4.59 (s, 2H), 5.16 (d, J) 17.8 Hz, 1H), 5.61 (d, J) 17.8 Hz, 1H), 6.94 (s, 1H), 7.0 - 7.2 (m, 5H); 13 C NMR (75 MHz, CDCl 3 ) δ 7.6, 21.4, 28.2, 31.4, 49.3, 66.1, 72.5, 83.5, 97.8, 105.7, 118.6, 125.2, 128.1, 128.9, 137.8, 143.8, 149.5, 156.8, 159.3, 166.0, 173.6; MS (EI) m / z = 363; HRMS (EI) m / z calculated: C 18 H 21 NO 7 [M] + 364.1.2, measured: 364.1.

[0143] 11. Preparation of XY - 331 - CDE cyclic compound

[0144]

[0145] Dissolve 1.5 g of XY-331-CDE10 in 15 mL of toluene and 3 mL of trifluoroacetic acid and add it to a single-necked flask. Reflux the reaction mixture at 110 °C for 2 hours. After the reaction is complete as detected by TLC (DCM:MeOH = 10:1), cool the mixture to room temperature. Rotate the reaction solution to about 4 mL and recrystallize with ethyl acetate. Filter to obtain 0.87 g of an off-white solid: Yield: 93%.

[0146] 1 1H NMR (400 MHz, DMSO) δ 6.86 (s, 1H), 6.50 (s, 1H), 5.47 - 5.31 (m, 2H), 4.13 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 1.84 - 1.74 (m, 1H), 0.80 (t, J = 7.3 Hz, 3H); 13 13C NMR (101 MHz, DMSO) δ 198.48, 172.57, 157.54, 149.62, 140.76, 124.40, 99.05, 72.49, 65.79, 43.11, 34.29, 30.92, 8.09. MS (EI) m / z = 263; HRMS (EI) m / z calculated: C 13 H 13 NO 5 [M]+ 264.2, found: 264.2.

Claims

1. A method for preparing a chiral ternary ring compound, the method comprises: (S11) Reacting compound XY-331-CDE10 with an acid to obtain a chiral ternary ring compound, In step (S11), the acid is selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid and combinations thereof.

2. The preparation method according to claim 1, the method further comprises (S10) Reacting compound XY-331-CDE9 with tert-butyl acrylate to obtain compound XY-331-CDE10.

3. The preparation method according to claim 2, the method further comprises (S9) Reacting compound XY-331-CDE8 with an ethyl acetate solution of hydrogen chloride, a dioxane solution of hydrogen chloride, concentrated hydrochloric acid, a dichloromethane solution of sodium iodide, or a dichloromethane solution of TMSCl to obtain compound XY-331-CDE9.

4. The preparation method according to claim 3, the method further comprises (S8) Reacting compound XY-331-CDE7 with methanesulfonic acid to obtain compound XY-331-CDE8.

5. The preparation method according to claim 4, the method further comprises (S7) Reacting compound XY-331-CDE6 with 2-methyl-2-butene under the action of sodium dihydrogen phosphate dihydrate, acetonitrile and water, and then adding sodium hypochlorite to react to obtain compound XY-331-CDE7.

6. The preparation method according to claim 5, the method further comprises (S6) Reacting compound XY-331-CDE5 with sodium periodate to obtain compound XY-331-CDE6.

7. The preparation method according to claim 6, the method further comprises (S5) Reacting compound XY-331-CDE4 with ethanol under the action of an acid to obtain compound XY-331-CDE5, In step (S5), the acid is selected from concentrated hydrochloric acid, sulfuric acid, trifluoroacetic acid and combinations thereof.

8. The preparation method according to claim 7, the method further comprises (S4) Reacting compound XY-331-CDE3 with a palladium catalyst, a ligand, a base, and absolute ethanol to obtain compound XY-331-CDE4, In step (S4), the palladium catalyst is selected from Pd(OAc) 2 ; Pd(dba) 2 ; PdCl 2 ; Pd(dppf)Cl 2 ; Pd(PPh 3 )Cl 2 ; Pd 2 (dba) 3 ; The ligand is selected from dppf; dppp; PPh 3 ; and BINAP; The base is selected from TEA; sodium carbonate; potassium carbonate; sodium acetate; potassium phosphate and combinations thereof.

9. The preparation method according to claim 8, the method further comprises (S3) Reacting compound XY-331-CDE2 with a base and tetrabutylammonium iodide to obtain compound XY-331-CDE3, In step (S3), the base is selected from potassium tert-butoxide, sodium ethoxide, sodium hydride and combinations thereof.

10. The preparation method according to claim 9, the method further comprises (S2) Reacting compound XY-331-CDE1 with lithium chloride and a reducing agent to obtain compound XY-331-CDE2, In step (S2), the reducing agent is selected from potassium borohydride, lithium borohydride, lithium aluminum hydride and combinations thereof.

11. The preparation method according to claim 10, the method further comprises (S1) Reacting compound SM-1 with 2,2,6,6-tetramethylpiperidine to obtain compound XY-331-CDE1.

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