Process for the synthesis of isomeric derivatives of alvocidib

Abstract

The application belongs to the field of medicine synthesis, and specifically provides a synthesis method of alovudine isomer derivative. 4-nitro-1H-imidazole is used as raw material, substitution, elimination and reduction reaction are carried out to generate (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol; then 2-haloethylamine halide acid salt and phosphorus oxychloride are reacted to generate N,N'-bis(2-haloethyl) diaminophosphonic acid; finally, (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol, N,N'-bis(2-haloethyl) diaminophosphonic acid, triphenylphosphine and anhydrous tetrahydrofuran are added into a reaction bottle, the system is reduced to 0 DEG C, diisopropyl azodicarboxylate (DIAD) is added dropwise, the temperature is increased to 25 DEG C, reaction is carried out for 3h, and then the crude product is obtained through concentration under reduced pressure, and alovudine isomer derivative is obtained through purification through a silica gel column.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, and specifically provides a method for synthesizing isomer derivatives of evaphosphoramide. Background Technology

[0002] The vascular distribution in tumor tissue differs from that in normal tissue. It lacks clearly defined veins, arteries, and capillaries, exhibiting a disordered and disorganized vascular distribution with increased permeability. This results in a microenvironment containing both hypoxic and normoxic zones. In the relatively vascularized normoxic zones, tumor cells proliferate rapidly and are highly sensitive to conventional chemotherapy. In contrast, tumor cells in hypoxic zones remain dormant and resistant to standard chemotherapy and radiotherapy, becoming a major obstacle to tumor treatment. Research shows that tumor stem cells are key to the malignant evolution of tumors, including invasion, metastasis, and recurrence. Hypoxia plays a crucial role in the formation and evolution of the tumor-associated stroma microenvironment and the tumor stem cell microenvironment. Hypoxic regions of tumors contain abundant reductases, readily undergoing reduction reactions. Therefore, tumor cells in hypoxic regions are sensitive to reduction, making these regions excellent therapeutic targets. Thus, developing hypoxic-activated antitumor drugs that can kill tumor cells in a hypoxic microenvironment and combining them with standard cytotoxic chemotherapy or radiotherapy that effectively eliminates tumor cells in normoxic zones may improve tumor treatment efficacy, reduce recurrence rates, and prolong patient lifespan.

[0003] Evophosphatamide is a highly cytotoxic, selective hypoxia-activated DNA alkylating agent that selectively delivers cytotoxic or inhibitory drugs to hypoxic tumor cells, exhibiting low toxicity to normal tissues. Traditional evokinetic amide synthesis routes suffer from drawbacks such as high raw material costs, complex routes, and the inability to modify nitrogen groups on the parent ring. Furthermore, long-term use of the same evokinetic amide drug may lead to drug resistance in tumor cells. Therefore, structural modification of evokinetic amide is essential. The aim is to enhance the pharmacological activity of evokinetic amide through structural modification, thereby increasing its anticancer efficacy and reducing tumor drug resistance. Summary of the Invention

[0004] Traditional levonorgestrel fragments of levonorgestrel can only have methyl substitutions on the nitrogen atom, which is not conducive to drug modification. To modify the substituents on the nitrogen atom of the imidazole ring while changing the position of the nitro group in the imidazole ring, this invention designs a synthetic route for 4-nitro levonorgestrel isomer derivatives and synthesizes a series of 4-nitro levonorgestrel isomer derivatives to improve the bioreduction activity of levonorgestrel, laying the foundation for subsequent drug modification and synthesis.

[0005] The synthetic route for the isomer derivatives of evaphosphonamide is shown below:

[0006]

[0007] The specific synthesis method and steps are as follows:

[0008] (1) Iodination: The raw material 4-nitro-1H-imidazolium, anhydrous potassium carbonate and iodination reagents (iodomethane, deuterated iodomethane, iodoethane, 1-iodopropane, 2-iodopropane, iodobutane) were added to an acetonitrile solution in a molar ratio of 1:1.5:1. The mixture was heated to 65°C and stirred for 15 h. After the reaction was stopped, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Isopropanol was added, and the mixture was stirred for 5 min and then filtered. The filter cake was washed with isopropanol and air-dried to obtain 1-alkyl-4-nitro-1H-imidazolium.

[0009] (2) Dichloro substitution: Under anhydrous and oxygen-free conditions, potassium tert-butoxide, anhydrous DMF and anhydrous THF were added to the reaction flask, and the temperature was lowered to -60℃ and stirred vigorously for 10 min; in another reaction flask, 1-alkyl-4-nitro-1H-imidazolium obtained in step (1), anhydrous DMF and chloroform were added under nitrogen protection and stirred to dissolve; then, at -60℃, the mixed solution was added to the potassium tert-butoxide mixture, and the reaction was stirred at -60℃ for 1 min, and then acetic acid was added to quench the reaction; after the reaction was stopped, the temperature was raised to 20℃, and the acetic acid and tetrahydrofuran were removed by vacuum concentration. The mixture was diluted with H2O and extracted twice with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (eluents were petroleum ether and ethyl acetate) to obtain the product 5-(dichloromethyl)-1-alkyl-4-nitro-1H-imidazolium.

[0010] The molar ratio of 1-alkyl-4-nitro-1H-imidazolium, chloroform, and potassium tert-butoxide is 1:1.2:4.

[0011] (3) Elimination reaction: The 5-(dichloromethyl)-1-alkyl-4-nitro-1H-imidazolium obtained in step (2) and zinc chloride were dissolved in formic acid, heated to 100℃ and stirred for 16 h. After the reaction was stopped, the mixture was cooled to room temperature, concentrated under reduced pressure, diluted with sodium chloride aqueous solution, and extracted three times with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluents were petroleum ether and ethyl acetate) to obtain the product 1-alkyl-4-nitro-1H-imidazolium-5-carboxaldehyde.

[0012] The molar ratio of 5-(dichloromethyl)-1-alkyl-4-nitro-1H-imidazolium chloride to zinc chloride is 1:1.4.

[0013] (4) Reduction: Add methanol (MeOH) to the 1-alkyl-4-nitro-1H-imidazol-5-carboxaldehyde obtained in step (3), stir to dissolve, cool to 0°C, add NaBH4, heat to 20°C and stir for 30 min, stop the reaction, concentrate under reduced pressure to obtain crude product, and purify by column chromatography (eluents are petroleum ether and ethyl acetate) to obtain product (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol.

[0014] The molar ratio of 1-alkyl-4-nitro-1H-imidazol-5-carboxaldehyde to sodium borohydride is 1:1-1.2.

[0015] (5) Preparation of phosphoramide: Under nitrogen protection, 2-haloethylamine halide and anhydrous dichloromethane were added to the reaction flask. The temperature of the reaction system was cooled to -78°C. Phosphorus oxychloride was slowly added dropwise to the reaction flask. After the addition was complete, a mixed solution of triethylamine and dichloromethane was added dropwise to the reaction flask. After the addition was complete, the temperature was maintained at -78°C and the reaction was stirred for 1 hour. The temperature was then raised to 25°C and the reaction was stirred for 2 hours. After the reaction was stopped, the mixture was filtered. The filtrate was concentrated and ethyl acetate was added. The mixture was filtered again and the filtrate was concentrated under vacuum to a yellow viscous liquid. Tetrahydrofuran was added and sodium bromide aqueous solution was added dropwise at -2°C. After the addition was complete, the mixture was stirred at -2°C for 15 hours. Then the temperature was cooled to -20°C and the mixture was frozen to crystallize for 2 hours. The solid was filtered to obtain a white solid. After drying naturally at room temperature for 48 hours, N,N'-bis(2-haloethyl)diaminophosphonic acid was obtained.

[0016] 2-Haloethylamine haloate is or 2-chloroethylamine chlorate.

[0017] The molar ratio of phosphorus oxychloride and 2-haloethylamine halide is 1:2.5-2.7.

[0018] (6) Docking: The (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol obtained in step (4) and the N,N'-bis(2-haloethyl)diaminophosphonic acid obtained in step (5) were added to the reaction flask, followed by the addition of triphenylphosphine and anhydrous THF. The reaction system was cooled to 0°C, and diisopropyl azodicarbonate (DIAD) was added dropwise to the reaction flask. The temperature was raised to 25°C and reacted for 3 hours. After the reaction was stopped, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (eluents were petroleum ether and ethyl acetate) to obtain the product N,N'-bis(2-haloethyl)diaminophosphonic acid (1-alkyl-4-nitro-1H-imidazol-5-yl) methyl ester.

[0019] The molar ratio of (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol, N,N'-bis(2-haloethyl)diaminophosphonic acid, triphenylphosphine, and DIAD is 1:0.5:1:1.

[0020] The beneficial effects of this invention are:

[0021] Traditional levonorgestrel (EV) contains only a methyl substituent on the nitrogen atom of its 2-nitroimidazole fragment, which has significant limitations. To improve the bioreduction activity of EV, this invention modifies the position of the nitro group on the imidazole ring and modifies the substituents on the nitrogen atom of the imidazole ring. A synthetic route for 4-nitro EV isomer derivatives was designed, and a series of 4-nitro EV isomer derivatives were synthesized using this route. These derivatives can alter the reducing activity of the nitroimidazole moiety, laying the foundation for subsequent drug modification and synthesis.

[0022] On the one hand, the 4-nitro group has less steric hindrance than the 2-nitro group and is closer to the position where the hydroxyl group on the imidazole ring breaks at the later docking point, which may significantly improve the effect. On the other hand, the nitro group is an electron-withdrawing group. According to the electronic effect, the nitro group is farther away from the electron-donating alkyl group on the nitrogen, which is expected to improve the reactivity and enhance the drug resistance and efficacy of levophosphoramide. Detailed Implementation

[0023] The present invention will be further described below with reference to specific embodiments. These embodiments are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention.

[0024] Example 1

[0025] 5.0 g (44.2 mmol, 1.0 eq.) of 4-nitro-1H-imidazole, 60 mL of acetonitrile, 9.17 g (66.3 mmol, 1.5 eq.) of potassium carbonate, and 44.2 mmol (1.0 eq.) of iodomethane were added to a reaction flask. The mixture was heated to 65 °C and stirred for 15 h. After the reaction was stopped, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Isopropanol was added, and the mixture was stirred for 5 min and then filtered. The filter cake was washed with isopropanol and air-dried to obtain 1-methyl-4-nitro-1H-imidazole (1a). 98% yield; 1 H NMR(300MHz,DMSO-d6)δ:8.36(s,1H),7.81(s,1H),3.76(s,3H); 13 C NMR (75MHz, DMSO-d6) δ: 147.25, 138.49, 122.99, 34.75.

[0026] Example 2

[0027] Replacing iodomethane in Example 1 with deuterated iodomethane yields 1-deuterated methyl-4-nitro-1H-imidazolium (1b). Yield 97%; 1 H NMR(400MHz, DMSO-d6)δ:8.37(s,1H),7.82(s,1H); 13C NMR (75MHz, DMSO-d6) δ: 147.29, 138.46, 122.97.

[0028] Example 3

[0029] Replacing iodomethane with iodoethane in Example 1 yields 1-ethyl-4-nitro-1H-imidazolium (1c). 90% yield; 1 H NMR (300MHz, Chloroform-d) δ: 7.73 (s, 1H), 7.35 (s, 1H), 3.95 (q, J = 7.5Hz, 3H), 1.30 (t, J = 7.5Hz, 3H); 13 C NMR (75MHz, Chloroform-d) δ: 147.92, 135.70, 119.16, 43.33, 15.87.

[0030] Example 4

[0031] Replacing iodomethane in Example 1 with 2-iodopropane yields 1-isopropyl-4-nitro-1H-imidazolium (1d). Yield 82%; 1 H NMR (300MHz, Chloroform-d) δ: 7.79 (s, 1H), 7.46 (s, 1H), 4.46–4.33 (m, 1H), 1.51 (d, J = 6.6Hz, 6H); 13 C NMR (75MHz, Chloroform-d) δ: 147.99, 134.39, 117.41, 51.09, 23.48.

[0032] Example 5

[0033] Replacing iodomethane in Example 1 with 1-iodopropane yields 1-propyl-4-nitro-1H-imidazolium (1e).

[0034] Yield 85%; 1 H NMR(300MHz,Chloroform-d)δ:7.83(s,1H),7.46(s,1H),3.99(t,J=7.2Hz,2H),1.88–1.76(m,2H),0.88(t,J=7.5Hz,3H); 13 C NMR (75MHz, Chloroform-d) δ: 147.87, 136.18, 119.57, 49.95, 23.98, 10.80.

[0035] Example 6

[0036] Replacing iodomethane with iodobutane in Example 1 yields 1-butyl-4-nitro-1H-imidazolium (1f).

[0037] Yield 76%; 1 H NMR(300MHz,Chloroform-d)δ:7.77(s,1H),7.41(s,1H),4.01(t,J=7.2Hz,2H),1.84–1.74(m,2H),1.38–1.26(m,2H),0.92(t,J=7.2Hz,3H); 13 C NMR (75MHz, Chloroform-d) δ: 148.00, 136.04, 119.35, 48.17, 32.59, 19.56, 13.38.

[0038] Example 7

[0039] Under anhydrous and oxygen-free conditions, 2.77 g (24.7 mmol, 4.0 eq.) of potassium tert-butoxide, 10 mL of anhydrous DMF, and 20 mL of anhydrous THF were added to a reaction flask, and the mixture was cooled to -60 °C and stirred vigorously for 10 min. In a separate reaction flask, under nitrogen protection, 6.17 mmol (1.0 eq.) of 1-methyl-4-nitro-1H-imidazole, 8 mL of anhydrous DMF, and 0.59 mL (7.4 mmol, 1.2 eq.) of chloroform were added and stirred until dissolved. The mixture was then kept at -60 °C. The mixed solution was rapidly added to the potassium tert-butoxide mixture, and the reaction was stirred at -60°C for 1 min. Then, acetic acid (4 mL) was added to quench the reaction. After the reaction was stopped, the temperature was raised to 20°C, and the mixture was concentrated under reduced pressure to remove acetic acid and tetrahydrofuran. The mixture was diluted with H2O (10 mL), and then extracted twice with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 3 / 1] to obtain the product 5-(dichloromethyl)-1-methyl-4-nitro-1H-imidazolium. Yield 56%; 1 H NMR(300MHz,Chloroform-d)δ:7.91(s,1H),7.54(s,1H),4.12(s,3H); 13 C NMR (75MHz, Chloroform-d) δ: 141.80, 138.41, 127.13, 58.50, 34.76.

[0040] Example 8

[0041] Replacing 1-methyl-4-nitro-1H-imidazolium in Example 7 with 1-deuterated methyl-4-nitro-1H-imidazolium yielded the following result: Yield 66%; 1 H NMR(300MHz,Chloroform-d)δ:7.92(s,1H),7.53(s,1H); 13 CNMR (75MHz, Chloroform-d) δ: 140.38, 135.89, 126.05, 57.32, 41.65, 14.56.

[0042] Example 9

[0043] Replacing 1-methyl-4-nitro-1H-imidazol in Example 7 with 1-ethyl-4-nitro-1H-imidazol yielded the following result.

[0044] Yield 67%; 1 H NMR (300MHz, Chloroform-d) δ: 7.85 (s, 1H), 7.58 (s, 1H), 4.46 (q, J = 7.2Hz, 2H), 1.61 (t, J = 7.2Hz, 3H); 13 C NMR (75MHz, Chloroform-d) δ: 140.48, 135.66, 126.03, 57.31, 41.59, 14.55.

[0045] Example 10

[0046] Replacing 1-methyl-4-nitro-1H-imidazol in Example 7 with 1-isopropyl-4-nitro-1H-imidazol yielded the following result. Yield 71%; 1 H NMR (300MHz, DMSO-d6) δ: 8.42 (s, 1H), 8.04 (s, 1H), 5.12–4.99 (m, 1H), 1.59 (d, J = 6.6Hz, 6H); 13 C NMR (75MHz, Chloroform-d) δ: 140.85, 134.89, 126.62, 58.33, 50.25, 23.71.

[0047] Example 11

[0048] Replacing 1-methyl-4-nitro-1H-imidazol in Example 7 with 1-propyl-4-nitro-1H-imidazol yielded the following result.

[0049] Yield 76%; 1H NMR(300MHz,Chloroform-d)δ:7.87(s,1H),7.50(s,1H),4.32(t,J=7.5Hz,2H),2.06–1.94(m,2H),1.04(t,J=7.5Hz,3H); 13 CNMR(75MHz,Chloroform-d)δ:141.53,137.09,127.10,58.31,49.04,23.71,11.16.

[0050] Example 12

[0051] The 1-methyl-4-nitro-1H-imidazol in Example 7 was replaced with 1-butyl-4-nitro-1H-imidazol to obtain...

[0052] Yield 80%; 1 H NMR(300MHz,Chloroform-d)δ:7.87(s,1H),7.48(s,1H),4.34(t,J=7.5Hz,3H),2.02–1.86(m,2H),1.50–1.38(m,2H),0.97(t,J=7.5Hz,3H); 13 C NMR (75MHz, Chloroform-d) δ: 137.10, 127.07, 58.33, 47.35, 32.22, 19.95, 13.55.

[0053] Example 13

[0054] 5-(dichloromethyl)-1-methyl-4-nitro-1H-imidazolium (20.3 mmol, 1.0 eq.), formic acid (50 mL), and zinc chloride (8.5 g, 28 mmol, 1.4 eq.) were added to a reaction flask. The mixture was heated to 100 °C and stirred for 16 h. After the reaction was stopped, the mixture was cooled to room temperature, concentrated under reduced pressure, diluted with sodium chloride aqueous solution (25 mL), and extracted three times with ethyl acetate (25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 3 / 1] to obtain the product 1-methyl-4-nitro-1H-imidazolium-5-carboxaldehyde. Yield 82%; 1 H NMR(300MHz, DMSO-d6)δ:10.26(s,1H),8.12(s,1H),3.91(s,3H); 13 C NMR (75MHz, DMSO-d6) δ: 182.27, 150.24, 141.09, 126.12, 35.82.

[0055] Example 14

[0056] Replacing 5-(dichloromethyl)-1-methyl-4-nitro-1H-imidazolium in Example 13 with 5-(dichloromethyl)-1-deuterated methyl-4-nitro-1H-imidazolium yielded the following result: Yield 82%; 1 H NMR(300MHz,Chloroform-d)δ:10.49(s,1H),7.56(s,1H); 13 C NMR (75MHz, DMSO-d6) δ: 182.27, 150.19, 141.06, 126.11.

[0057] Example 15

[0058] Replacing 5-(dichloromethyl)-1-methyl-4-nitro-1H-imidazol in Example 13 with 5-(dichloromethyl)-1-ethyl-4-nitro-1H-imidazol yielded the following result: Yield 78%; 1 H NMR (300MHz, Chloroform-d) δ: 10.48 (s, 1H), 7.62 (s, 1H), 4.42 (q, J = 7.2Hz, 2H), 1.49 (t, J = 7.2Hz, 3H); 13 C NMR (75MHz, DMSO-d6) δ: 182.03, 150.75, 140.23, 125.28, 43.66, 16.15.

[0059] Example 16

[0060] Replacing 5-(dichloromethyl)-1-methyl-4-nitro-1H-imidazol in Example 13 with 5-(dichloromethyl)-1-isopropyl-4-nitro-1H-imidazol yielded the following result: Yield 72%; 1 H NMR (300MHz, Chloroform-d) δ: 10.51 (s, 1H), 7.77 (s, 1H), 5.37–5.24 (m, 1H), 1.56 (d, J = 6.6Hz, 6H); 13 C NMR (75MHz, DMSO-d6) δ: 182.33, 151.06, 137.81, 125.11, 50.82, 22.91.

[0061] Example 17

[0062] Replacing 5-(dichloromethyl)-1-methyl-4-nitro-1H-imidazol in Example 13 with 5-(dichloromethyl)-1-propyl-4-nitro-1H-imidazol yielded the following result: Yield 76%; 1 H NMR(300MHz,Chloroform-d)δ:10.48(s,1H),7.58(s,1H),4.33(t,J=7.2Hz,2H),1.90–1.78(m,2H),0.96(t,J=7.5Hz,3H); 13 C NMR (75MHz, DMSO-d6) δ: 182.12, 150.83, 140.75, 125.35, 49.62, 23.61, 10.94.

[0063] Example 18

[0064] Replacing 5-(dichloromethyl)-1-methyl-4-nitro-1H-imidazol in Example 13 with 5-(dichloromethyl)-1-butyl-4-nitro-1H-imidazol yielded the following result: Yield 72%; 1 H NMR (300MHz, Chloroform-d) δ: 10.49 (s, 1H), 7.57 (s, 1H), 4.36 (t, J = 7.2Hz, 2H), 1.83–1.73 (m, 2H), 1.43–1.30 (m, 2H), 0.96 (t, J = 7.2Hz, 3H); 13 C NMR (75MHz, DMSO-d6) δ: 182.06, 150.82, 140.69, 125.30, 47.94, 32.31, 19.45, 13.76.

[0065] Example 19

[0066] 1-Methyl-4-nitro-1H-imidazol-5-carboxaldehyde (1.93 mmol, 1.0 eq.) and methanol (MeOH 10 mL) were added to a reaction flask and stirred until dissolved. The mixture was cooled to 0 °C, and 74 mg of NaBH4 (1.96 mmol, 1.0 eq.) was added. The mixture was heated to 20 °C and stirred for 30 min. After the reaction was stopped, the crude product was concentrated under reduced pressure and purified by column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 1 / 3] to obtain the product (1-methyl-4-nitro-1H-imidazol-5-yl)methanol. Yield 46%; 1 H NMR (300MHz, DMSO-d6) δ: 7.78 (s, 1H), 5.48 (t, J = 5.7Hz, 1H), 4.85 (d, J = 5.7Hz, 2H), 3.75 (s, 3H); 13C NMR (75MHz, DMSO-d6) δ: 144.01, 137.35, 133.73, 52.04, 33.00.

[0067] Example 20

[0068] Replacing 1-methyl-4-nitro-1H-imidazol-5-carboxaldehyde in Example 19 with 1-deuterated methyl-4-nitro-1H-imidazol-5-carboxaldehyde yielded the following result: Yield 45%; 1 H NMR (300MHz, DMSO-d6)

[0069] δ:7.78(s,1H),5.48(t,J=5.7Hz,1H),4.85(d,J=5.7Hz,2H); 13 C NMR (75MHz,

[0070] DMSO-d6)δ:144.01,137.31,133.72,52.06.

[0071] Example 21

[0072] Replacing 1-methyl-4-nitro-1H-imidazol-5-carboxaldehyde in Example 19 with 1-ethyl-4-nitro-1H-imidazol-5-carboxaldehyde yielded the following result. Yield 43%; 1 H NMR (300MHz, DMSO-d6) δ: 7.90 (s, 1H), 5.66 (t, J = 5.1Hz, 1H), 4.86 (d, J = 5.1Hz, 2H), 4.16 (q, J = 7.2Hz, 2H), 1.39 (t, J = 7.2Hz, 3H); 13 C NMR (75MHz, DMSO-d6) δ: 148.78, 141.11, 137.94, 56.73, 46.00, 21.09.

[0073] Example 22

[0074] Replacing 1-methyl-4-nitro-1H-imidazol-5-carboxaldehyde in Example 19 with 1-isopropyl-4-nitro-1H-imidazol-5-carboxaldehyde yielded the following result. Yield 50%; 1 H NMR (300MHz, DMSO-d6) δ: 8.13 (s, 1H), 5.59 (t, J = 5.7Hz, 1H), 4.93 (d, J = 5.7Hz, 2H), 4.75–4.62 (m, 1H), 1.54 (d, J = 6.6Hz, 6H; 13C NMR (75MHz, DMSO-d6) δ: 134.21, 132.70, 51.82, 48.75, 23.40).

[0075] Example 23

[0076] Replacing 1-methyl-4-nitro-1H-imidazol-5-carboxaldehyde with 1-propyl-4-nitro-1H-imidazol-5-carboxaldehyde in Example 19 yielded the following result. Yield 45%; 1 H NMR (300MHz, DMSO-d6) δ: 7.87 (s, 1H), 5.66 (t, J = 5.1Hz, 1H), 4.85 (d, J = 5.4Hz, 2H), 4.08 (t, J = 7.2Hz, 2H), 1.80 (m, 2H), 0.87 (t, J = 7.5Hz, 3H); 13 C NMR (75MHz, DMSO-d6) δ: 144.10, 136.88, 133.29, 51.98, 47.52, 23.76, 11.25.

[0077] Example 24

[0078] Replacing 1-methyl-4-nitro-1H-imidazol-5-carboxaldehyde with 1-butyl-4-nitro-1H-imidazol-5-carboxaldehyde in Example 19 yielded the following result. Yield 45%; 1 H NMR (300MHz, DMSO-d6) δ: 7.86 (s, 1H), 5.51 (t, J = 5.7Hz, 1H), 4.85 (d, J = 5.7Hz, 2H), 4.11(t,J=7.5Hz,2H),1.82–1.72(m,2H),1.36–1.23(m,2H),0.91(t,J=7.2Hz,3H); 13 C NMR (75MHz, DMSO-d6) δ: 144.11, 136.83, 133.26, 52.02, 45.82, 32.42, 19.69, 13.88.

[0079] Example 25

[0080] Under nitrogen protection, 12.6 g (61.4 mmol, 2.5 eq.) of 2-bromoethylamine bromate and 50 mL of anhydrous dichloromethane were added to the reaction flask. The reaction system was cooled to -78 °C. 2.24 mL (24.5 mmol, 1.0 eq.) of phosphorus oxychloride was slowly added dropwise to the reaction flask. After the addition was complete, a mixed solution of triethylamine (9 mL) and dichloromethane (15 mL) was added dropwise to the reaction flask. After the addition was complete, the reaction was stirred while maintaining the temperature at -78 °C for 1 minute. The temperature was raised to 25°C, and the reaction was stirred for another 2 hours. After the reaction was stopped, the mixture was filtered, the filtrate was concentrated, ethyl acetate was added, and the mixture was filtered again. The filtrate was concentrated under vacuum to a yellow viscous liquid, tetrahydrofuran (8 mL) was added, and sodium bromide aqueous solution (5 g / 80 mL) was added dropwise at -2°C. After the addition was complete, the mixture was stirred at -2°C for 15 hours, then cooled to -20°C, and frozen to crystallize for 2 hours. The solid was filtered to obtain a white solid, which was then dried naturally at room temperature for 48 hours to obtain N,N'-bis(2-bromoethyl)diaminophosphonic acid.

[0081] Yield 56%; 1 H NMR (300MHz, DMSO-d6) δ: 5.89 (s, 3H), 3.42 (t, J = 7.2Hz, 4H), 3.11–3.02 (m, 4H); 13 C NMR (75MHz, DMSO-d6) δ: 43.46, 34.43.

[0082] Example 26

[0083] Under nitrogen protection, 12.6 g (108.6 mmol, 2.5 eq.) of 2-chloroethylamine chlorate and 50 mL of anhydrous dichloromethane were added to the reaction flask. The reaction system was cooled to -78 °C. 3.97 mL (43.5 mmol, 1.0 eq.) of phosphorus oxychloride was slowly added dropwise to the reaction flask. After the addition was complete, a mixed solution of triethylamine (7.5 mL) and dichloromethane (15 mL) was added dropwise to the reaction flask. After the addition was complete, the reaction was stirred while maintaining the temperature at -78 °C. The temperature was raised to 25°C and the reaction was stirred for another 2 hours. After the reaction was stopped, the mixture was filtered, the filtrate was concentrated, ethyl acetate was added, and the mixture was filtered again. The filtrate was concentrated under vacuum to a yellow viscous liquid, tetrahydrofuran (8 mL) was added, and sodium bromide aqueous solution (5 g / 80 mL) was added dropwise at -2°C. After the addition was complete, the mixture was stirred at -2°C for 15 hours, then cooled to -20°C and frozen to crystallize for 2 hours. The solid was filtered to obtain a white solid, which was then dried naturally at room temperature for 48 hours to obtain N,N'-bis(2-chloroethyl)diaminophosphonic acid. Yield 50%; 1 H NMR (300MHz, DMSO-d6) δ3.55 (t, J = 6.9 Hz, 1H), 3.01 (dt, J = 13.1, 6.9 Hz, 1H).

[0084] Example 27

[0085] Add (1-methyl-4-nitro-1H-imidazol-5-yl)methanol (0.95 mmol, 1.0 eq.), N,N'-bis(2-bromoethyl)diaminophosphonic acid 146 mg (0.47 mmol, 0.5 eq.), triphenylphosphine 249 mg (0.95 mmol, 1.0 eq.), and anhydrous tetrahydrofuran (15 mL) to the reaction flask. Cool the reaction system to 0 °C, add 0.2 mL (0.95 mmol, 1.0 eq.) of DIAD dropwise, and heat to 25 °C for 3 h. After stopping the reaction, concentrate under reduced pressure to obtain the crude product, which is then purified by silica gel column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 1 / 3] to obtain the product N,N'-bis(2-bromoethyl)diaminophosphonic acid (1-methyl-4-nitro-1H-imidazol-5-yl) methyl ester. Yield 46%; 1 H NMR(300MHz, DMSO-d6)δ:7.89(s,1H),5.26(d,J=8.1Hz,2H),5.08–5.01(m,3H),3.80(s,3H),3.41(t,J=6.9Hz,4H),3.14–3.16(m,4H); 13 C NMR (75MHz, DMSO-d6) δ: 144.91, 137.88, 129.26 (d, J = 7.8Hz), 54.74 (d, J = 3.9Hz), 43.13, 34.42 (d, J = 5.1Hz), 33.22.

[0086] Example 28

[0087] Add (1-methyl-4-nitro-1H-imidazol-5-yl)methanol (0.95 mmol, 1.0 eq.), N,N'-bis(2-chloroethyl)diaminophosphonic acid 104.2 mg (0.47 mmol, 0.5 eq.), triphenylphosphine 249 mg (0.95 mmol, 1.0 eq.), and anhydrous tetrahydrofuran (15 mL) to the reaction flask. Cool the reaction system to 0 °C, add 0.2 mL (0.95 mmol, 1.0 eq.) of DIAD dropwise, and heat to 25 °C for 3 h. After stopping the reaction, concentrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography [eluent: V(petroleum ether) / V(ethyl acetate) = 1 / 3] to obtain the product N,N'-bis(2-chloroethyl)diaminophosphonic acid (1-methyl-4-nitro-1H-imidazol-5-yl) methyl ester. Yield 50%; 1H NMR(300MHz,Chloroform-d)δ:7.38(s,1H),5.33(d,J=7.2Hz,2H),3.78(s,3H),3.54(t,J=5.4Hz,4H),3.27–

[0088] 3.18(m,4H),3.17–3.05(m,2H); 13 C NMR (101MHz, DMSO-d6) δ144.94,137.85,129.23,54.69,45.38,43.12,33.19.

[0089] Example 29

[0090] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol in Example 27 with (1-deuterated methyl-4-nitro-1H-imidazol-5-yl)methanol yielded the following result: Yield 50%; 1H NMR (400MHz, DMSO-d6) δ: 7.88 (s, 1H), 5.26 (d, J = 8.0Hz, 2H), 5.08–5.01 (m, 3H), 3.41 (t, J = 7.2Hz, 4H), 3.14–3.16 (m, 4H); 13 C NMR (75MHz, DMSO-d6) δ: 144.91, 137.85, 129.26 (d, J = 7.5Hz), 54.75 (d, J = 3.3Hz), 43.12, 34.41 (d, J = 4.8Hz).

[0091] Example 30

[0092] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol with (1-ethyl-4-nitro-1H-imidazol-5-yl)methanol yields the following result: Yield 48%; 1H NMR (300MHz, Chloroform-d) δ: 7.51 (s, 1H), 5.36 (d, J = 6.6Hz, 2H), 4.19 (q, J = 7.2Hz, 2H), 3.64–3.51 (m, 2H), 3.44 (t, J = 5.7Hz, 4H), 3.37–3.27 (m, 4H), 1.52 (t, J = 7.2Hz, 3H); 13 C NMR (75MHz, DMSO-d6) δ: 144.93, 136.89, 128.54 (d, J = 8.7Hz), 54.60 (d, J = 3.9Hz), 43.14, 41.38, 34.38 (d, J = 5.1Hz), 16.25.

[0093] Example 31

[0094] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol in Example 27 with (1-isopropyl-4-nitro-1H-imidazol-5-yl)methanol yields the following result: Yield 51%; 1H NMR (300MHz, Chloroform-d) δ: 7.54 (s, 1H), 5.34 (d, J = 6.2Hz, 2H), 4.66–4.53 (m, 1H), 3.41 (t, J = 3.9Hz, 4H), 3.34–3.26 (m, 4H), 1.53 (d, J = 6.6Hz, 6H); 13 C NMR (75MHz, Chloroform-d) δ: 145.35, 133.02, 126.29 (d, J = 9.6Hz), 54.51 (d, J = 3.6Hz), 49.09, 42.92, 34.47 (d, J = 5.2Hz), 23.69.

[0095] Example 32

[0096] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol in Example 27 with (1-propyl-4-nitro-1H-imidazol-5-yl)methanol yields the following result: Yield 52%; 1H NMR(300MHz,Chloroform-d)δ:7.48(s,1H),5.35(d,J=6.6Hz,2H),4.09(t,J=7.2Hz,2H),3.55– 3.48(m,2H),3.44(t,J=5.7Hz,4H),3.37–3.27(m,4H),1.93–1.80(m,2H),0.98(t,J=7.5Hz,3H); 13 C NMR (75MHz, Chloroform-d) δ: 145.59, 135.89, 126.84 (d, J = 9.3Hz), 54.60 (d, J = 3.6Hz), 48.05, 42.91, 34.52 (d, J = 5.4Hz), 24.15, 11.07.

[0097] Example 33

[0098] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol in Example 27 with (1-butyl-4-nitro-1H-imidazol-5-yl)methanol yields... Yield 58%; 1H NMR (400MHz, DMSO-d6) δ: 8.02 (s, 1H), 5.31 (d, J = 7.2Hz, 2H), 5.18–5.08 (m, 2H), 4.21 (t, J = 7.6Hz, 2H), 3.47 (t, J = 7.2Hz, 4H), 3.20–3.12 (m, 4H), 1.86–1.79 (m, 2H), 1.42–1.32 (m, 2H), 0.98 (t, J = 7.4Hz, 3H); 13 CNMR (75MHz, Chloroform-d) δ: 144.64, 134.72, 125.65 (d, J = 9.6Hz), 53.58 (d, J = 3.6Hz), 45.30, 41.87, 33.52 (d, J = 5.4Hz), 31.76, 18.80, 12.54.

[0099] Example 34

[0100] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol in Example 28 with (1-deuterated methyl-4-nitro-1H-imidazol-5-yl)methanol yielded the following result: Yield 45%;

[0101] 1 H NMR (300MHz, Chloroform-d) δ: 7.38 (s, 1H), 5.33 (d, J = 7.5Hz, 2H), 3.54 (t, J = 5.4Hz, 5H), 3.27–3.17 (m, 4H), 3.16–3.04 (m, 2H); 13 C NMR (101MHz, DMSO-d6) δ: 144.94, 137.85, 129.23, 54.69, 45.38, 43.12, 33.19.

[0102] Example 35

[0103] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol with (1-ethyl-4-nitro-1H-imidazol-5-yl)methanol yields the following result: Yield 50%;

[0104] 1H NMR(300MHz,Chloroform-d)δ:7.43(s,1H),5.31(d,J=6.6Hz,2H),4.05(t,J=7.2Hz,2H),3.54( t,J=5.7Hz,4H),3.43–3.35(m,2H),3.27–3.17(m,4H),1.89–1.77(m,2H),0.94(t,J=7.2Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ144.95,136.86,128.60,54.56,45.35,43.12,41.37,16.21.

[0105] Example 36

[0106] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol in Example 28 with (1-propyl-4-nitro-1H-imidazol-5-yl)methanol yields the following result: Yield 48%;

[0107] 1 H NMR(300MHz,Chloroform-d)δ:7.43(s,1H),5.31(d,J=6.6Hz,2H),4.05(t,J=7.2Hz,2H),3.54( t,J=5.7Hz,4H),3.43–3.35(m,2H),3.27–3.17(m,4H),1.89–1.77(m,2H),0.94(t,J=7.2Hz,3H); 13 C NMR (75MHz, Chloroform-d) δ132.90,126.11,54.53,49.04,45.79,42.99,23.68.

[0108] Example 37

[0109] Replacing (1-methyl-4-nitro-1H-imidazol-5-yl)methanol in Example 28 with (1-isopropyl-4-nitro-1H-imidazol-5-yl)methanol yields the following result: Yield 40%;

[0110] 1 H NMR(300MHz,Chloroform-d)δ:7.61(s,1H),5.41(d,J=6.3Hz,2H),4.74–4.61(m,1H) ,3.62(t,J=5.7Hz,4H),3.48–3.38(m,2H),3.35–3.25(m,4H),1.59(d,J=6.6Hz,6H); 13C NMR(75MHz,Chloroform-d)δ145.51,132.91,126.05,54.47,49.04,45.71,43.00,23.66。

Claims

1. A method for synthesizing an isomer derivative of evaphosphatidylcholine, characterized in that, The synthesis method steps are as follows: (1) Iodination: 4-nitro-1H-imidazolium, anhydrous K2CO3 and iodination reagent were added to acetonitrile solution, heated to 65℃ and stirred for 15h; after stopping the reaction, cooled to room temperature, filtered, concentrated the filtrate under reduced pressure, added isopropanol, stirred for 5min and filtered, the filter cake was washed with isopropanol and air-dried to obtain 1-alkyl-4-nitro-1H-imidazolium; The molar ratio of 4-nitro-1H-imidazolium, anhydrous potassium carbonate, and iodide reagent is 1:1.5:1; Iodinated reagents include iodomethane, iodoethane, 1-iodopropane, 2-iodopropane, and iodobutane; (2) Dichloro substitution: Under anhydrous and oxygen-free conditions, potassium tert-butoxide, anhydrous DMF and anhydrous THF were added to the reaction flask, and the temperature was lowered to -60℃ and stirred vigorously for 10 min; another reaction flask was taken, and 1-alkyl-4-nitro-1H-imidazolium obtained in step (1), anhydrous DMF and chloroform were added under nitrogen protection and stirred to dissolve; then, at -60℃, the mixed solution was added to the potassium tert-butoxide mixture, and the reaction was stirred at -60℃ for 1 min, and then acetic acid was added to quench the reaction; after the reaction was stopped, the temperature was raised to 20℃, and the acetic acid and tetrahydrofuran were removed by vacuum concentration, diluted with H2O, and extracted twice with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography to obtain the product 5-(dichloromethyl)-1-alkyl-4-nitro-1H-imidazolium; The molar ratio of 1-alkyl-4-nitro-1H-imidazolium, chloroform, and potassium tert-butoxide is 1:1.2:4; (3) Elimination reaction: The 5-(dichloromethyl)-1-alkyl-4-nitro-1H-imidazolium obtained in step (2) and zinc chloride were dissolved in formic acid, heated to 100℃ and stirred for 16 h. After the reaction was stopped, the mixture was cooled to room temperature, concentrated under reduced pressure, diluted with sodium chloride aqueous solution, and extracted three times with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 1-alkyl-4-nitro-1H-imidazolium-5-carboxaldehyde. The molar ratio of 5-(dichloromethyl)-1-alkyl-4-nitro-1H-imidazolium to zinc chloride is 1:1.4; (4) Reduction: MeOH was added to the 1-alkyl-4-nitro-1H-imidazol-5-carboxaldehyde obtained in step (3), and stirred to dissolve it. The mixture was cooled to 0°C, NaBH4 was added, and the mixture was heated to 20°C and stirred for 30 min. After the reaction was stopped, the crude product was concentrated under reduced pressure and purified by column chromatography to obtain the product (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol. The molar ratio of 1-alkyl-4-nitro-1H-imidazol-5-carboxaldehyde to sodium borohydride is 1:1-1.2; (5) Preparation of phosphoramide: Under nitrogen protection, 2-haloethylamine halide and anhydrous dichloromethane were added to the reaction flask. The temperature of the reaction system was cooled to -78°C. Phosphorus oxychloride was added dropwise to the reaction flask. After the addition was completed, a mixed solution of triethylamine and dichloromethane was added dropwise to the reaction flask. After the addition was completed, the temperature was maintained at -78°C and the reaction was stirred for 1 h. The temperature was raised to 25°C and the reaction was stirred for 2 h. After the reaction was stopped, the mixture was filtered. The filtrate was concentrated and ethyl acetate was added. The mixture was filtered again and the filtrate was concentrated under vacuum to a yellow viscous liquid. Tetrahydrofuran was added and sodium bromide aqueous solution was added dropwise at -2°C. After the addition was completed, the mixture was stirred at -2°C for 15 h. Then the mixture was cooled to -20°C and frozen to crystallize for 2 h. The mixture was filtered to obtain a white solid. After natural drying at room temperature, N,N'-bis(2-haloethyl)diaminophosphonic acid was obtained. The molar ratio of phosphorus oxychloride and 2-haloethylamine halide is 1:2.5-2.7; Docking: The (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol obtained in step (4) and the N,N'-bis(2-haloethyl)diaminophosphonic acid obtained in step (5) were added to the reaction flask, followed by the addition of triphenylphosphine and anhydrous THF. The reaction system was cooled to 0°C, and diisopropyl azodicarbonate was added dropwise to the reaction flask. The temperature was raised to 25°C and reacted for 3 hours. After the reaction was stopped, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product N,N'-bis(2-haloethyl)diaminophosphonic acid (1-alkyl-4-nitro-1H-imidazol-5-yl) methyl ester. The molar ratio of (1-alkyl-4-nitro-1H-imidazol-5-yl)methanol, N,N'-bis(2-haloethyl)diaminophosphonic acid, triphenylphosphine, and DIAD is 1:0.5:1:

1.

2. The method for synthesizing the isomer derivative of levonorgestrel as described in claim 1, characterized in that, In step (5), the 2-haloethylamine halide is 2-chloroethylamine chlorate or 2-bromoethylamine chlorate.

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