Scopolamine analogs, methods of making and use thereof in the treatment of depression

Abstract

This invention discloses scopolamine analogues, their preparation methods, and their applications in antidepressant treatment, belonging to the field of medicinal chemistry. The aforementioned scopolamine analogues have the following general structural formula and are obtained through two different methods. These scopolamine analogues can be used to protect against, alleviate, or treat depression.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to scopolamine analogues, their preparation methods, and their application in antidepressants. Background Technology

[0002] According to a World Health Organization report, an estimated 322 million people worldwide suffer from depression, accounting for 4.4% of the world's population, making it the fourth leading cause of disease prevalence globally. Scopolamine is a hyoscyamine-type alkaloid, primarily found in plants of the Solanaceae family, such as belladonna and datura, and is the main alkaloid in datura, hyoscyamine, and henbane. Currently, the supply of scopolamine is mainly met through large-scale field cultivation. Clinical studies show that intravenous injection of scopolamine can achieve rapid antidepressant effects within one day, with the antidepressant effect lasting 1-2 weeks. Repeated administration can prolong the effective time in patients with drug resistance.

[0003] Although the antidepressant properties of scopolamine can compensate for the shortcomings of current antidepressant treatments, there are still problems in its synthesis and application. Research on the antidepressant effects of scopolamine has been focused on clinical trials of scopolamine itself or its combination with other drugs.

[0004] To date, there have been no reports on the antidepressant activity of scopolamine analogues. Summary of the Invention

[0005] To overcome the above-mentioned technical defects, the present invention aims to provide a fluoroscopolamine analogue and optimize the preparation method, which is obtained by two different methods; the scopolamine analogue can be used to protect against, alleviate or treat depression, etc.

[0006] The scopolamine analogue described in this invention has the following general structural formula:

[0007] Wherein: X is selected from F, Cl, Br, I, OH, OTs, N3; R is selected from phenyl or substituted phenyl, benzyl or substituted benzyl, alkyl, allyl, wherein the substituent in the substituted phenyl or substituted benzyl is one or more of alkyl, haloalkyl, alkoxy, nitrile, nitro, halogen, hydroxyl, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and the alkyl is C1-C20 straight chain, branched chain, or cyclic alkyl.

[0008] Under further optimized conditions, the specific structure of the scopolamine analogue described in Formula I is as follows:

[0009]

[0010]

[0011]

[0012] The present invention also provides a method for synthesizing the above-mentioned scopolamine analogue, comprising the following steps:

[0013] Method A:

[0014]

[0015] Method B:

[0016]

[0017] The present invention also provides the use of the above-mentioned scopolamine analogue in the preparation of antidepressant drugs.

[0018] Furthermore, in the above technical solution, the antidepressant is an anticorticosterone-induced HT22 cell damage.

[0019] The present invention also provides the use of pharmaceutically acceptable salts of the above-mentioned scopolamine analogues in the preparation of antidepressant drugs.

[0020] Furthermore, in the above technical solution, the pharmaceutically acceptable salt is a salt formed by the compound of formula (I) and an acid.

[0021] Furthermore, in the above technical solution, the acid is selected from hydrochloric acid, hydrobromic acid, aminosulfonic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, ascorbic acid palmitic acid, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, or leucine. Attached image description:

[0022] Figure 1 This is a screening chart of corticosterone concentration for modeling in Example 4. Specific Implementation

[0023] Example 1

[0024]

[0025] Add 50 mL of THF to a 250 mL round-bottom flask, and add 10 mmol of tert-butyl malonate methyl ester and 10 mmol of NaH at 0 °C. The mixture was stirred at 0°C for 15 min. 10 mmol of compound a was dissolved in 50 mL of THF and slowly added dropwise to the above reaction solution. The reaction was carried out at room temperature for 8 h. After quenching with water, the mixture was extracted with EA and evaporated to dryness before column chromatography to obtain compound b. Subsequently, compound b was dissolved in 50 mL of THF at 0°C, 10 mmol of NaH was added, and the mixture was stirred for 15 min. Then, 10 mmol of NFSI was added, and the reaction was carried out at room temperature for 8 h to obtain compound c. Compound c was then dissolved in 40 mL of THF, and 20 mmol of lithium aluminum tritert-butoxyhydride was added at -78°C. After reacting for 1 h, the reaction was quenched with water, and column chromatography was used to obtain compound d. Compound d was dissolved in DCM, and 8 mmol of imidazole, 1 mmol of DMAP, and 10 mmol of TBSCl were added. The reaction was carried out at room temperature for 8 h, and evaporated to dryness before column chromatography to obtain compound e. Compound e was dissolved in THF, and 7 mmol of sodium borohydride was added. The reaction was carried out at room temperature for 8 h, quenched with water, extracted with EA, evaporated to dryness, and column chromatography was used to obtain compound f. Compound f was dissolved in 30 mmol of TCM. In THF, 6 mmol of hyoscyamine was added, followed by 6 mmol of DCC and 0.6 mmol of DMAP. The reaction was carried out at room temperature for 8 h, and the product was obtained by rotary evaporation and column chromatography with dry pressure. Compound g was dissolved in 20 mL of DCM, and 20 mL of 1% HCl was added. The reaction was carried out at room temperature for 8 h, quenched with saturated sodium bicarbonate, and extracted with EA. The product TM was obtained by rotary evaporation and column chromatography with dry pressure.

[0026] Compound 1: 1 H NMR (400MHz, CDCl3) δ7.53-7.31(m,5H),5.06(t,J=5.9Hz,1H),4.31(ddt,J=30.3,12.7,2.6Hz,1H),3.99(ddt,J=15.2,12.7,2.5Hz,1H),3.42( dt,J=29.4,2.9Hz,2H),3.19-3.03(m,2H),2.83(s,1H),2.49(t,J=2.6H z,3H),2.11(dddt,J=15.5,9.6,6.7,3.1Hz,2H),1.57(t,J=18.2Hz,2H). 13 C NMR (31MHz, CDCl3) δ168.1,167.8,134.9,134.7,129.3,128.9,124.7,124.6,98.4,96.5,68.8,67.3,67.1,58.0,56.5,56.4,42.6,31.2,31.1. 19 F NMR (377MHz, CDCl3) δ -170.91.

[0027] Compound 2: 1 H NMR(400MHz, CDCl3)δ7.51(td,J=7.7,1.8Hz,1H),7.43-7.36(m,1H),7.22(td,J=7.6,1.2H z,1H),7.10(ddt,J=10.6,8.3,1.1Hz,1H),5.10(t,J=5.5Hz,1H),4.42(ddd,J=27.6,12.7,1 .4Hz,1H),4.17(ddd,J=17.5,12.7,0.8Hz,1H),3.30(d,J=3.0Hz,1H),3.26(d,J=3.0Hz,1H) ,3.11(dt,J=4.0,1.9Hz,2H),2.49(s,3H),2.13(dq,J=15.4,4.5Hz,2H),1.63-1.52(m,2H). 13 C NMR (101MHz, CDCl3) δ167.2,166.9,160.5,160.5,158.1,158.0,131.6,131.5,127.7,127.6,127.6,127.5,124.9,124.8,12 3.0,122.8,122.7,122.6,116.5,116.3,96.1,96.0,94.2,94.2,68.9,65.5,65.4,65.2,65.2,57.9,56.3,56.2,42.5,31.0. 19 F NMR (377MHz, CDCl3) δ-112.65,-164.53.

[0028] Compound 3: 1 H NMR (400MHz, CDCl3) δ7.70-7.51(m,1H),7.48-7.30(m,3H),5.12(t,J=5.6Hz,1H),4.56-4.35(m,1H),4.18(dd,J=22.0,12.8Hz,1H),3. 11(t,J=3.2,1H),3.05(dt,J=11.6,4.0,2.0Hz,2H),2.91(d,J=2.8Hz,1H),2.45(d,J=2.0Hz,3H),2.22-2.03(m,2H),1.66-1.46(m,2H). 13C NMR (101MHz, CDCl3) δ166.8,166.5,133.9,133.7,131.0,131.0,130.7,127.9,127.8, 127.4,127.4,96.9,95.1,68.7,64.8,64.6,58.0,57.9,56.2,56.1,42.5,31.1,30.9. 19 F NMR (377MHz, CDCl3) δ -163.90.

[0029] Compound 4: 1 H NMR (600MHz, CDCl3) δ7.45 (dd, J=7.8, 1.7Hz, 1H), 7.36 (td, J=7.8, 1.7Hz, 1H), 7.02 (t, J=7.5Hz, 1 H),6.91(d,J=8.3Hz,1H),5.08(t,J=5.4Hz,1H),4.35(dd,J=26.9,12.7Hz,1H),4.10(dd,J=19.6,1 2.7Hz,1H),3.80(s,3H),3.16(d,J=2.9Hz,1H),3.06(ddd,J=17.4,4.0,2.0Hz,2H),2.94(d,J=3.0 Hz,1H),2.46(s,3H),2.10(dt,J=15.3,4.8Hz,2H),1.54(d,J=15.2Hz,1H),1.45(d,J=15.2Hz,1H). 13 C NMR (151MHz, CDCl3) δ167.6,167.4,155.6,155.6,130.6,126.7,126.7,124.4,124.2,12 1.1,111.0,96.0,94.7,67.6,65.1,65.0,57.9,57.8,56.2,56.0,55.5,42.3,30.9,30.8. 19 F NMR (565MHz, CDCl3) δ -165.48.

[0030] Compound 5: 11H NMR (600 MHz, CDCl3) δ 7.43 - 7.30 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.18 (dt, J = 9.6, 2.4 Hz, 1H), 7.07 - 6.98 (td, J = 8.4, 2.4 Hz, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.23 (dd, J = 30.6, 12.6 Hz, 1H), 3.94 (dd, J = 15.6, 12.6 Hz, 1H), 3.50 (d, J = 3.0 Hz, 1H), 3.47 (d, J = 3.0 Hz, 1H), 3.14 (dd, J = 4.2, 2.4 Hz, 1H), 3.10 (dd, J = 4.2, 2.4 Hz, 1H), 2.47 (s, 3H), 2.20 - 2.05 (m, 2H), 1.59 (d, J = 15.6 Hz, 1H), 1.55 (d, J = 15.6 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 167.7, 167.5, 163.7, 162.0, 137.3, 137.3, 137.2, 137.1, 130.5, 130.5, 120.4, 120.4, 120.4, 120.3, 116.3, 116.2, 112.4, 112.3, 112.2, 112.2, 97.7, 96.4, 68.9, 67.2, 67.0, 57.8, 56.4, 56.2, 42.1, 30.7. 19 19F NMR (565 MHz, CDCl3) δ -111.17, -170.44.

[0031] Compound 6: 1 1H NMR (600 MHz, CDCl3) δ 7.29 (t, J = 8.3 Hz, 1H), 7.01 - 6.97 (m, 2H), 6.90 - 6.86 (m, 1H), 5.03 (t, J = 5.4 Hz, 1H), 4.26 (dd, J = 31.1, 12.6 Hz, 1H), 3.95 (dd, J = 15.4, 12.6 Hz, 1H), 3.78 (s, 3H), 3.46 (d, J = 3.0 Hz, 1H), 3.43 (d, J = 3.0 Hz, 1H), 3.12 (dd, J = 4.0, 1.9 Hz, 1H), 3.09 (dd, J = 4.0, 2.0 Hz, 1H), 2.47 (s, 3H), 2.11 (tdd, J = 15.4, 5.5, 4.0 Hz, 2H), 1.57 (t, J = 16.3 Hz, 2H). 13C NMR (151MHz, CDCl3) δ167.9,167.7,159.9,136.3,136.2,129.9,116.8,116.8,114 .5,110.7,110.7,98.1,96.8,68.6,67.1,67.0,57.9,56.4,56.3,55.4,42.3,30.8. 19 F NMR (565MHz, CDCl3) δ-170.28.

[0032] Compound 7: 1 H NMR (400MHz, CDCl3) δ7.68-7.36(m,2H),7.19-6.95(m,2H),5.08(t,J=5.5Hz,1H) ,4.28(dd,J=30.1,12.6Hz,1H),3.97(dd,J=15.2,12.6Hz,1H),3.52(d,J=2.9Hz,1 H),3.44(d,J=2.9Hz,1H),3.16(dd,J=4.0,2.0Hz,1H),3.12(dd,J=4.0,2.0Hz,1H) ,2.51(s,3H),2.19-2.08(m,2H),1.65-1.59(m,1H),1.55(dq,J=15.4,1.5Hz,1H). 13 CNMR (101MHz, CDCl3) δ168.0,167.7,164.5,162.0,130.7,130.7,130.5,130.4,126.8,126.8,126.7,1 16.1,115.9,98.1,96.2,83.7,75.5,74.5,69.0,67.4,67.2,58.0,56.6,56.4,42.7,31.2,31.2,27.8. 19 F NMR (377MHz, CDCl3) δ-111.89,-170.33.

[0033] Compound 8: 11H NMR (400 MHz, CDCl3) δ 7.44 - 7.36 (m, 4H), 5.08 (t, J = 5.4 Hz, 1H), 4.27 (dd, J = 29.5, 12.6 Hz, 1H), 3.97 (dd, J = 15.4, 12.6 Hz, 1H), 3.53 (d, J = 2.9 Hz, 1H), 3.43 (d, J = 2.9 Hz, 1H), 3.16 (dd, J = 4.0, 1.9 Hz, 1H), 3.12 (dd, J = 4.0, 1.9 Hz, 1H), 2.51 (s, 3H), 2.13 (ddt, J = 15.2, 9.7, 4.9 Hz, 2H), 1.66 - 1.51 (m, 7H). 13 13C NMR (101 MHz, CDCl3) δ 135.6, 133.1, 129.2, 126.3, 126.2, 98.0, 96.1, 69.2, 67.4, 67.2, 58.2, 58.1, 56.6, 56.4, 42.8, 31.4. 19 19F NMR (377 MHz, CDCl3) δ -171.39 (dd, J = 29.5, 15.3 Hz).

[0034] Compound 9: 1 1H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 5.​​​​​​​​H NMR (600MHz, CDCl3) δ7.48-7.29(m,4H),5.06(t,J=5.4Hz,1H),4.30(dd,J=30.6,12.6Hz,1H),4.00(dd,J=15.0,12.6Hz,1H),3.52-3 .38(m,2H),3.13(ddd,J=18.9,4.1,1.9Hz,2H),2.51(s,3H),2.12(tdd,J=15.2,5.4,4.0Hz,2H),1.61(t,J=16.4Hz,2H),1.31(s,9H). 13 C NMR (151MHz, CDCl3) δ168.1,167.9,152.4,131.7,131.5,125.7,124.4,124.3 ,98.0,96.8,68.6,67.2,67.1,57.9,56.4,56.3,42.5,34.7,31.2,31.2,31.1. 19 F NMR (565MHz, CDCl3) δ -170.38.

[0036] Compound 11: 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=8.4Hz2H),7.69(d,J=8.4Hz2H),5.80-5.66(m,1H),4.89(t,J=5.6Hz,1H),4.36-4.13(dq J=31.2,12.5,6.7Hz,1H),4.23(ddd,J=31.2,12.4,6.4Hz,1H),3.95-3.84(m,1H),3.61(d,J=2.8Hz,1H),3.44(d, J=2.8Hz,1H),3.12-3.02(m,2H),2.40(s,3H),2.13-1.90(m,2H),1.54(d,J=15.2Hz,1H),1.43(d,J=15.2Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ166.7,166.5,140.3,140.1,132.5,126.2,126.1,118.3 ,111.8,98.0,96.1,68.8,65.1,64.9,57.6,57.5,55.9,55.7,42.9,31.1,31.0. 19 F NMR(377MHz,DMSO-d6)δ-167.04.

[0037] Compound 12: 11H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.02 - 6.79 (m, 2H), 5.14 - 5.04 (m, 1H), 4.29 (ddd, J = 29.9, 12.5, 3.3 Hz, 1H), 4.00 (ddd, J = 14.5, 12.4, 3.5 Hz, 1H), 3.82 (s, 3H), 3.52 - 3.34 (m, 2H), 3.13 (ddt, J = 11.8, 4.2, 2.1 Hz, 2H), 2.51 (s, 3H), 2.13 (ddt, J = 15.4, 10.4, 5.2 Hz, 2H), 1.61 (d, J = 19.1 Hz, 5H). 13 13C NMR (101 MHz, CDCl3) δ 167.2, 166.9, 145.4, 132.6, 132.5, 130.4, 130.0, 128.6, 128.0, 127.8, 95.7, 93.7, 71.1, 70.9, 68.7, 57.9, 57.8, 56.2, 56.1, 42.7, 39.7, 39.5, 31.4, 31.3, 21.7. 19 19F NMR (377 MHz, CDCl3) δ -169.08 (dd, J = 29.9, 14.6 Hz).

[0038] Compound 13: 1 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 5.11 (t, J = 5.6 Hz, 1H), 4.39 (dd, J = 24.0, 13.2 Hz, 1H), 4.16 (dd, J = 22.4, 12.8 Hz, 1H), 3.22 (d, J = 2.8 Hz, 1H), 3.12 - 3.05 (m, 2H), 3.04 (d, J = 2.8 Hz, 1H), 2.47 (s, 3H), 2.16 - 2.05 (m, 2H), 1.63 - 1.48 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 166.4, 166.2, 136.1, 132.6, 132.3, 131.9, 131.8, 130.5, 129.0, 128.9, 127.7, 127.7, 96.7, 94.9, 69.0, 64.6, 64.4, 58.0, 57.9, 56.3, 56.2, 42.6, 31.2, 31.0. 19 19F NMR (377 MHz, CDCl3) δ -163.01.

[0039] Compound 14:1 1H NMR (400 MHz, CDCl3) δ 6.97 - 6.93 (m, 2H), 6.86 - 6.82 (m, 1H), 5.04 (t, J = 5.2 Hz, 1H), 4.26 (dd, J = 30.4, 12.4 Hz, 1H), 3.96 (dd, J = 15.2, 12.8 Hz, 1H), 3.85 (s, 6H), 3.46 (t, J = 3.6 Hz, 1H), 3.10 (ddd, J = 11.2, 4.0, 1.9 Hz, 2H), 2.48 (s, 3H), 2.16 - 2.05 (m, 2H), 1.60 - 1.52 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 168.2, 168.0, 149.8, 149.3, 127.3, 127.0, 117.3, 117.2, 111.2, 108.2, 108.1, 98.3, 96.4, 68.6, 67.2, 67.0, 58.0, 56.5, 56.4, 56.×, 56.0, 42.5, 31.1. 19 19F NMR (377 MHz, CDCl3) δ -168.75.

[0040] Compound 15: 1 1H NMR (600 MHz, CDCl3) δ 7.33 - 7.27 (m, 3H), 7.22 - 7.18 (m, 2H), 4.98 (t, J = 5.4 Hz, 1H), 3.96 (dd, J = 25.8, 12.0 Hz, 1H), 3.85 (dd, J = 13.8, 12.6 Hz, 1H), 3.47 (d, J = 3.0 Hz, 1H), 3.17 - 3.05 (m, 3H), 3.03 (d, J = 3.× Hz, 1H), 2.97 (dd, J = 4.2, 1.8 Hz, 1H), 2.47 (s, 3H), 2.11 - 2.04 (m, ×H), 2.00 - 1.94 (m, 1H), 1.51 (d, J = 15.0 Hz, 1H), 1.19 (d, J = 15.0 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 169.0, 168.9, 133.8, 130.5, 128.6, 127.6, 98.3, 97.1, 68.2, 66.6, 66.4, 58.0, 58.0, 56.5, 56.3, 42.7, 39.8, 39.7, 31.3. 19 19F NMR (565 MHz, CDCl3) δ -172.33.

[0041] Compound 16: 11H NMR (400 MHz, CDCl3) δ 5.70 - 5.81 (m, 7.2 Hz, 1H), 5.21 - 5.13 (m, 2H), 5.09 (t, J = 5.6 Hz, 1H), 3.87 (d, J = 12.4 Hz, 1H), 3.83 - 3.80 (m, 1H), 3.68 (d, J = 3.2 Hz, 1H), 3.63 (d, J = 2.8 Hz, 1H), 3.18 (td, J = 4.0, 2.0 Hz, 2H), 2.60 - 2.50 (m, 6H), 2.11 - 2.21 (m, 2H), 1.61 - 1.68 (m, 2H). 13 13C NMR (151 MHz, CDCl3) δ 168.8, 168.7, 129.9, 129.8, 120.4, 97.9, 96.6, 68.4, 66.4, 66.3, 58.2, 58.2, 56.7, 56.6, 42.8, 38.0, 37.9, 31.5. 19 19F NMR (376 MHz, CDCl3) δ -172.92.

[0042] Compound 17: 1 1H NMR (600 MHz, CDCl3) δ 7.33 - 7.27 (m, 3H), 7.22 - 7.18 (m, 2H), 4.98 (t, J = 5.4 Hz, 1H), 3.96 (dd, J = 25.8, 12.0 Hz, 1H), 3.85 (dd, J = 13.8, 12.6 Hz, 1H), 3.47 (d, J = 3.0 Hz, 1H), 3.17 - 3.05 (m, 3H), 3.03 (d, J = 3.0 Hz, 1H), 2.97 (dd, J = 4.2, 1.8 Hz, 1H), 2.47 (s, 3H), 2.11 - 2.04 (m, 1H), 2.00 - 1.94 (m, 1H), 1.51 (d, J = 15.0 Hz, 1H), 1.19 (d, J = 15.0 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 169.0, 168.9, 133.8, 130.5, 128.6, 127.6, 98.3, 97.1, 68.2, 66.6, 66.4, 58.0, 56.5, 56.3, 42.7, 39.8, 39.7, 31.3. 19 19F NMR (565 MHz, CDCl3) δ -172.33.

[0043] Compound 18: 11H NMR (600 MHz, CDCl3) δ 7.19 - 7.07 (m, 4H), 4.96 (t, J = 5.4, 1H), 3.96 (dd, J = 27.0, 12.0 Hz, 1H), 3.82 (dd, J = 14.4, 12.6 Hz, 1H), 3.42 (d, J = 3.0 Hz, 1H), 3.15 (s, 1H), 3.11 (d, J = 5.4 Hz, 1H), 3.09 - 3.06 (m, 1H), 3.02 (d, J = 3.0 Hz, 1H), 2.97 - 2.94 (m, 1H), 2.44 (s, 3H), 2.29 (s, 3H), 2.06 (dt, J = 15.0, 4.8 Hz, 1H), 1.96 (dt, J = 15.0, 4.8 Hz, 1H), 1.48 (d, J = 15.6 Hz, 1H), 1.22 (d, J = 15.6 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 169.4, 169.1, 137.7, 132.5, 131.0, 130.7, 127.6, 125.9, 99.3, 97.4, 68.0, 66.6, 66.3, 57.9, 56.3, 56.1, 42.3, 36.3, 36.1, 31.0, 30.9, 19.9. 19 19F NMR (565 MHz, CDCl3) δ -171.26.

[0044] Compound 19: 1 1H NMR (400 MHz, CDCl3) δ 7.23 (q, J = 8.2, 5.8 Hz, 3H), 7.05 (dt, J = 21.9, 8.2 Hz, 2H), 5.02 (t, J = 5.4 Hz, 1H), 4.04 - 3.77 (m, 2H), 3.50 (d, J = 3.0 Hz, 1H), 3.30 (d, J = 3.0 Hz, 1H), 3.24 - 3.04 (m, 4H), 2.50 (s, 3H), 2.15 (s, 4H), 1.55 (d, J = 15.4 Hz, 1H), 1.42 (d, J = 15.6 Hz, 1H). 19 19F NMR (377 MHz, CDCl3) δ -116.34 (d, J = 6.9 Hz), -171.22 (d, J = 6.8 Hz). 1313C NMR (101 MHz, CDCl3) δ 168.69, 168.43, 162.64, 160.18, 132.68, 132.64, 129.64, 129.55, 124.34, 124.31, 120.98, 120.83, 115.71, 115.48, 98.14, 96.24, 58.22, 56.39, 56.20, 42.72, 32.49, 32.26, 31.26, 31.18.

[0045] Compound 20: 1 1H NMR (600 MHz, CDCl3) δ 7.40 - 7.36 (m, 1H), 7.34 - 7.30 (m, 1H), 7.25 - 7.20 (m, 2H), 5.03 (t, J = 5.5 Hz, 1H), 4.00 (dd, J = 28.2, 12.4 Hz, 1H), 3.82 (dd, J = 13.9, 12.4 Hz, 1H), 3.47 (d, J = 2.9 Hz, 1H), 3.39 - 3.27 (m, 3H), 3.12 (dd, J = 3.9, 2.0 Hz, 1H), 3.07 (dd, J = 4.0, 2.0 Hz, 1H), 2.49 (s, 3H), 2.09 (dddd, J = 24.6, 15.4, 5.6, 4.0 Hz, 2H), 1.55 - 1.43 (m, 2H). 13 13C NMR (151 MHz, CDCl3) δ 168.60, 168.43, 134.90, 132.25, 131.92, 129.70, 128.93, 126.89, 97.86, 96.59, 68.35, 66.02, 65.87, 57.88, 56.38, 56.18, 42.37, 36.11, 35.96, 31.01, 30.98. 19 19F NMR (565 MHz, CDCl3) δ -170.12.

[0046] Compound 21: 1 1H NMR (400 MHz, CDCl3) δ 7.65 - 7.52 (m, 1H), 7.37 - 7.10 (m, 4H), 5.05 (s, 1H), 4.02 (dd, J = 28.0, 12.4 Hz, 1H), 3.81 (t, J = 12.9 Hz, 1H), 3.52 - 3.28 (m, 4H), 3.16 - 2.95 (m, 2H), 2.50 (s, 3H), 2.20 - 2.02 (m, 3H), 1.51 (dd, J = 26.3, 15.4 Hz, 2H). 13C NMR (101MHz, CDCl3) δ168.72,168.46,133.84,133.20,132.25,129.27,127.67,125.74 ,98.24,96.34,68.56,66.16,65.93,58.05,56.53,56.32,42.59,38.79,38.57,31.22. 19 F NMR (377MHz, CDCl3) δ -170.02.

[0047] Compound 22: 1 H NMR(600MHz, CDCl3) δ7.28(td,J=8.2,6.1Hz,1H),6.99(td,J=8.0,7.5,4.1Hz,2H),6.93(dt,J=10.0,2.1Hz ,1H),4.99(t,J=5.4Hz,1H),3.94(dd,J=26.4,12.3Hz,1H),3.84(dd,J=14.3,12.3Hz,1H),3.52(d,J=2.9Hz ,1H),3.17(d,J=3.0Hz,1H),3.15-3.10(m,2H),3.09(d,J=3.1Hz,1H),3.03(dd,J=4.0,2.0Hz,1H),2.48(s, 3H), 2.11(ddd,J=15.3,5.6,4.0Hz,1H),2.05-1.99(m,1H),1.54(d,J=15.3Hz,1H),1.25(d,J=15.3Hz,1H). 13 C NMR (151MHz, CDCl3) δ168.7,168.6,163.5,161.9,136.2,136.1,130.0,129.9,126.0,126.0,117.3 ,117.2,114.5,114.4,98.1,96.8,68.3,66.3,66.2,57.9,57.8,56.4,56.2,42.4,39.3,39.1,31.1. 19 F NMR (565MHz, CDCl3) δ-112.93,-172.16.

[0048] Compound 23: 11H NMR (600 MHz, CDCl3) δ 8.17 (dt, J = 8.3, 1.6 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 5.00 (t, J = 5.4 Hz, 1H), 3.96 (dd, J = 25.6, 12.3 Hz, 1H), 3.88 (dd, J = 14.4, 12.3 Hz, 1H), 3.56 (d, J = 2.9 Hz, 1H), 3.31 - 3.24 (m, 2H), 3.23 (d, J = 2.9 Hz, 1H), 3.16 (dd, J = 4.1, 2.0 Hz, 1H), 3.06 (dd, J = 4.1, 2.0 Hz, 1H), 2.50 (s, 3H), 2.14 (ddd, J = 15.4, 5.5, 4.0 Hz, 1H), 2.05 (dt, J = 15.5, 4.7 Hz, 1H), 1.60 (d, J = 15.4 Hz, 1H), 1.30 (d, J = 15.4 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 168.36, 168.19, 148.26, 136.44, 135.80, 129.50, 124.92, 122.61, 97.77, 96.49, 68.81, 66.25, 66.09, 57.91, 57.85, 56.42, 56.20, 42.58, 38.98, 38.84, 31.28, 31.24. 19 19F NMR (565 MHz, CDCl3) δ -172.40.

[0049] Compound 24: 1 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.9 Hz, 1H), 6.87 - 6.70 (m, 3H), 5.00 (t, J = 5.4 Hz, 1H), 4.02 - 3.83 (m, 2H), 3.79 (s, 3H), 3.49 (d, J = 2.9 Hz, 1H), 3.13 (d, J = 3.2 Hz, 2H), 3.06 (d, J = 2.8 Hz, 1H), 3.00 (dd, J = 4.0, 2.0 Hz, 1H), 2.48 (s, 3H), 2.09 (ddd, J = 15.3, 5.5, 4.0 Hz, 1H), 2.04 - 1.95 (m, 1H), 1.53 (d, J = 15.3 Hz, 1H), 1.27 (d, J = 15.2 Hz, 1H). 19 19F NMR (377 MHz, CDCl3) δ -171.91.

[0050] Compound 25:1 1H NMR (400 MHz, CDCl3) δ 7.68 - 7.36 (m, 2H), 7.19 - 6.95 (m, 2H), 5.08 (t, J = 5.2 Hz, 1H), 4.28 (dd, J = 30.0, 12.8 Hz, 1H), 3.97 (dd, J = 14.8, 12.4 Hz, 1H), 3.52 (d, J = 3.2 Hz, 1H), 3.44 (d, J = 3.2 Hz, 1H), 3.16 (dd, J = 4.0, 2.0 Hz, 1H), 3.12 (dd, J = 4.0, 1.9 Hz, 1H), 2.51 (s, 3H), 2.18 - 2.09 (m, 2H), 1.65 - 1.52 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 167.9, 167.6, 164.4, 161.9, 130.6, 130.5, 130.3, 130.3, 126.7, 126.6, 126.5, 116.0, 115.8, 98.0, 96.1, 83.6, 68.9, 67.3, 67.1, 57.9, 56.5, 56.3, 42.5, 31.1. 19 19F NMR (377 MHz, CDCl3) δ -111.89, -170.33.

[0051] Compound 26: 1 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 4.98 (t, J = 5.2, 1H), 3.99 - 3.77 (m, 2H), 3.52 (d, J = 2.8 Hz, 1H), 3.22 (d, J = 3.2 Hz, 1H), 3.13 (t, J = 2.8, 1H), 3.08 (d, J = 8.0 Hz, 1H), 3.06 - 3.00 (m, 2H), 2.49 (s, 3H), 2.11 (dt, J = 15.2, 4.8 Hz, 1H), 2.02 (dt, J = 15.2, 4.8 Hz, 1H), 1.53 (d, J = 15.6 Hz, 1H), 1.22 (d, J = 15.6 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 168.8, 168.6, 132.8, 132.1, 131.7, 121.7, 98.4, 96.5, 68.4, 66.4, 66.2, 58.1, 58.0, 56.5, 56.3, 42.7, 39.1, 38.9, 31.4, 31.3. 19 19F NMR (377 MHz, CDCl3) δ -172.3.

[0052] Compound 27: 1 H NMR(600MHz,CDCl3)δ7.57(d,J=7.8Hz,2H),7.32(d,J=7.9Hz,2H),4.96(t,J=5.5Hz,1H),3.94(dd,J=26.1,12.3Hz,1H),3.84(dd,J=14.3,12.4Hz,1H),3.50(d,J=2.9Hz,1H),3.20 - 3.13(m,3H),3.13 - 3.10(m,1H),3.01 - 2.96(m,1H),2.47(s,3H),2.10(dt,J=15.5,4.8Hz,1H),1.99(dt,J=15.6,4.9Hz,1H),1.51(d,J=15.3Hz,1H),1.14(d,J=15.3Hz,1H). 13 C NMR(151MHz,CDCl3)δ168.7,168.5,138.0,130.8,130.3,130.1,129.9,129.7,128.9,126.9,125.5,125.5,125.4,125.4,125.1,123.3,98.1,96.8,68.4,66.4,66.2,57.9,57.8,56.4,56.2,42.5,39.4,39.3,31.2,31.1. 19 F NMR(565MHz,CDCl3)δ - 62.58.

[0053] Compound 28: 1 H NMR(600MHz,CDCl3)δ7.22 - 6.99(m,4H),4.97(t,J=5.5Hz,1H),4.03 - 3.72(m,2H),3.48(d,J=2.9Hz,1H),3.15 - 2.95(m,5H),2.46(s,3H),2.32(s,3H),2.07(dt,J=15.4,4.8Hz,1H),1.98(dt,J=15.4,4.8Hz,1H),1.51(d,J=15.3Hz,1H),1.24(d,J=15.3Hz,1H). 13 C NMR(151MHz,CDCl3)δ169.0,168.9,137.2,130.6,130.2,129.2,98.5,97.3,77.4,77.2,76.9,68.0,66.5,66.3,57.9,56.4,56.2,42.4,39.3,39.2,31.1,21.2. 19FNMR (565 MHz, CDCl3) δ -172.18.

[0054] Compound 29: 1 HNMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 7.8, 1.7 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 4.83 (t, J = 5.4 Hz, 1H), 4.04 (dd, J = 26.1, 12.3 Hz, 1H), 3.90 (dd, J = 14.5, 12.3 Hz, 1H), 3.63 (d, J = 5.6 Hz, 1H), 3.59 (s, 1H), 3.20 (d, J = 3.0 Hz, 1H), 2.96 (dd, J = 4.1, 2.0 Hz, 1H), 2.81 (dd, J = 4.1, 2.0 Hz, 1H), 2.72 (d, J = 3.0 Hz, 1H), 2.38 (s, 3H), 1.90 (ddd, J = 15.3, 5.6, 4.0 Hz, 1H), 1.78 (dt, J = 15.5, 4.6 Hz, 1H), 1.15 (d, J = 15.3 Hz, 1H), 0.81 (d, J = 15.4 Hz, 1H). 13 CNMR (151 MHz, CDCl3) δ 169.13, 168.96, 133.82, 132.62, 130.26, 128.99, 128.72, 128.29, 126.34, 125.92, 125.27, 124.14, 124.12, 98.36, 97.08, 67.97, 66.44, 66.29, 57.68, 56.17, 55.88, 42.24, 35.81, 35.67, 30.70, 30.67. 19 FNMR (565 MHz, CDCl3) δ -168.40.

[0055] Compound 30: 11H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.17 - 7.12 (m, 2H), 5.03 (t, J = 5.5 Hz, 1H), 3.93 - 3.78 (m, 2H), 3.70 (d, J = 2.9 Hz, 1H), 3.61 (d, J = 2.9 Hz, 1H), 3.18 (s, 2H), 2.81 (ddd, J = 13.9, 10.6, 5.8 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.52 (s, 3H), 2.21 - 2.03 (m, 4H), 1.66 (d, J = 15.4 Hz, 1H), 1.56 (d, J = 15.4 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 169.07, 168.80, 140.29, 128.61, 128.34, 126.42, 98.71, 96.84, 68.21, 66.78, 66.55, 57.93, 57.91, 56.52, 56.40, 42.33, 35.19, 34.97, 31.14, 31.10, 29.12, 29.09. 19 19F NMR (377 MHz, CDCl3) δ -173.95.

[0056] Compound 31: 1 1H NMR (400 MHz, CDCl3) δ 7.28 (q, J = 5.8, 4.1 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.14 (d, J = 7.4 Hz, 2H), 5.08 (t, J = 5.5 Hz, 1H), 3.82 (d, J = 6.5 Hz, 1H), 3.77 (s, 1H), 3.59 (d, J = 3.0 Hz, 1H), 3.41 (d, J = 3.0 Hz, 1H), 3.18 - 3.08 (m, 2H), 2.68 (dt, J = 13.9, 6.8 Hz, 1H), 2.58 (q, J = 6.7 Hz, 1H), 2.52 (s, 3H), 2.13 (dt, J = 15.4, 4.8 Hz, 2H), 1.87 - 1.70 (m, 3H), 1.66 - 1.43 (m, 3H). 13 13C NMR (101 MHz, CDCl3) δ 169.07, 168.80, 140.29, 128.61, 128.34, 126.42, 98.71, 96.84, 68.21, 66.78, 66.55, 57.93, 57.91, 56.52, 56.40, 42.33, 35.19, 34.97, 31.14, 31.10, 29.12, 29.09. 19F NMR (377MHz, CDCl3) δ -173.63.

[0057] Compound 32: 1 H NMR (400MHz, CDCl3) δ8.26 (d, J = 7.7Hz, 1H), 7.90 (t, J = 5.2Hz, 2H), 7.60-7.42 (m, 4H) ,5.05(t,J=5.4Hz,1H),4.69-4.43(m,2H),2.97(dd,J=4.2,2.1Hz,1H),2.89(d,J=3.0 Hz,1H),2.84-2.76(m,1H),2.37(s,3H),2.21(d,J=2.9Hz,1H),2.05(dt,J=15.5,4.8 Hz,1H),1.94(dt,J=15.4,4.7Hz,1H),1.47(d,J=15.4Hz,1H),1.18(d,J=15.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ168.40,168.13,134.14,130.77,130.59,130.42,129.24,127.20,126.31,124.74,124.47 ,124.41,124.28,124.20,97.89,96.05,68.59,66.13,65.90,57.69,57.56,55.96,55.66,42.37,31.02,30.92. 19 F NMR (377MHz, CDCl3) δ -159.44. Example 2: Synthesis of fluoroscopolamine analogs (X = Cl, Br, I).

[0058]

[0059] 5 mmol of compound d was dissolved in 20 mL of THF, 5 mmol of triphenylphosphine and 5 mmol of NCS were added, and the mixture was reacted at room temperature for 8 h. After drying, the product was obtained by column chromatography. Compound h was dissolved in 20 mL of THF, 4 mL of 2M sodium hydroxide was added, and the mixture was reacted at room temperature for 4 h. The pH was adjusted to 1 with 6M HCl, and the mixture was extracted with EA. After drying, the crude product i was obtained. Compound i was dissolved in 20 mL of THF, 4 mmol of DCC and 0.4 mmol of DMAP were added, and the mixture was reacted at room temperature for 8 h. After drying, the product TM-1 was obtained by column chromatography.

[0060] 5 mmol of compound d was dissolved in 20 mL of THF, 5 mmol of triphenylphosphine and 5 mmol of NBS were added, and the reaction was carried out at room temperature for 8 h. After rotary evaporation and column chromatography, compound j was obtained. Compound j was dissolved in 20 mL of THF, 4 mL of 2M sodium hydroxide was added, and the reaction was carried out at room temperature for 4 h. The pH was adjusted to 1 with 6M HCl, and the mixture was extracted with EA and rotary evaporation to obtain crude product k. Compound k was dissolved in 20 mL of THF, 3.5 mmol of DCC and 0.35 mmol of DMAP were added, and the reaction was carried out at room temperature for 8 h. After rotary evaporation and column chromatography, product TM-2 was obtained.

[0061] 5 mmol of compound d was dissolved in 20 mL of THF, and 5 mmol of triphenylphosphine, 5 mmol of imidazole, and 5 mmol of iodine were added. The mixture was reacted at 80 °C for 8 h, and the product was obtained by rotary evaporation and column chromatography. Compound 1 was dissolved in 20 mL of THF, and 4 mL of 2 M sodium hydroxide was added. The mixture was reacted at room temperature for 4 h, and the pH was adjusted to 1 with 6 M HCl. The mixture was extracted with EA and the product was obtained by rotary evaporation and column chromatography. Compound 2 was dissolved in 20 mL of THF, and 3 mmol of DCC and 0.3 mmol of DMAP were added. The mixture was reacted at room temperature for 8 h, and the product was obtained by rotary evaporation and column chromatography.

[0062] Compound 33: 1 H NMR (600MHz, CDCl3) δ7.53-7.44(m,2H),7.44-7.30(m,3H),5.08(t,J=6.0,1H) ,4.28(dd,J=28.8,12.0Hz,1H),3.87(t,J=12.6,1H),3.55(d,J=3.0Hz,1H),3. 36(d,J=3.0Hz,1H),3.14(dd,J=4.2,2.4Hz,1H),3.08(dd,J=4.2,2.4Hz,1H),2 .49(s,3H),2.17-2.06(m,2H),1.65(d,J=15.6Hz,1H),1.50(d,J=15.6Hz,1H). 13 C NMR (151MHz, CDCl3) δ167.0,166.9,135.1,135.0,129.7,129.0,124.5,124.5,96.0 ,94.7,77.4,77.2,76.9,69.3,58.0,57.9,56.5,56.3,48.1,48.0,42.7,31.4,31.1. 19 F NMR (565MHz, CDCl3) δ -167.47.

[0063] Compound 34: 11H NMR (600 MHz, CDCl3) δ 7.36 - 7.28 (m, 3H), 7.23 - 7.18 (m, 2H), 5.00 (t, J = 5.4 Hz, 1H), 3.93 (dd, J = 25.8, 12.0 Hz, 1H), 3.74 (t, J = 11.4 Hz, 1H), 3.51 (d, J = 3.0 Hz, 1H), 3.23 - 3.14 (m, 2H), 3.13 - 3.09 (m, 1H), 3.08 - 3.05 (d, J = 2.4 Hz, 1H), 3.01 - 2.97 (m, 1H), 2.48 (s, 3H), 2.08 (d, J = 15.0 Hz, 1H), 1.98 (d, J = 15.0 Hz, 1H), 1.54 (d, J = 15.6 Hz, 1H), 1.15 (d, J = 15.0 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 168.0, 167.7, 133.2, 130.5, 128.7, 127.9, 96.8, 94.8, 68.8, 58.2, 58.1, 56.5, 56.3, 47.4, 47.1, 43.0, 41.7, 41.5, 31.7, 31.5. 19 19F NMR (565 MHz, CDCl3) δ -167.05.

[0064] Compound 35: 1 1H NMR (600 MHz, CDCl3) δ 7.18 (dt, J = 9.1, 5.4 Hz, 2H), 7.12 (d, J = 4.0 Hz, 2H), 5.01 (t, J = 5.5 Hz, 1H), 3.97 (dd, J = 26.7, 12.0 Hz, 1H), 3.75 (t, J = 11.5 Hz, 1H), 3.49 (d, J = 2.9 Hz, 1H), 3.28 - 3.15 (m, 2H), 3.09 (dd, J = 3.9, 2.0 Hz, 1H), 3.03 (d, J = 2.9 Hz, 1H), 2.97 (dd, J = 4.0, 2.0 Hz, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 2.07 (dt, J = 15.3, 4.7 Hz, 1H), 1.97 (dt, J = 15.3, 4.7 Hz, 1H), 1.53 (d, J = 15.3 Hz, 1H), 1.17 (d, J = 15.3 Hz, 1H). 13C NMR (151MHz, CDCl3) δ168.1,168.0,137.9,131.7,131.1,130.9,127.9,126.0,97.1 ,95.7,68.7,58.0,57.9,56.4,56.2,47.6,47.4,42.7,38.2,38.0,31.5,31.3,20.0. 19 FNMR (565MHz, CDCl3) δ -166.64.

[0065] Compound 36: 1 H NMR (600MHz, CDCl3) δ7.45(d,J=7.8Hz,2H),7.11(d,J=7.8Hz,2H),5.00(t,J=5.4Hz,1H ),3.89(dd,J=25.8,12.0Hz,1H),3.71(t,J=11.4Hz,1H),3.55(d,J=3.0Hz,1H),3.23(d ,J=3.0Hz,1H),3.18-3.09(m,3H),3.07-3.03(m,1H),2.50(s,3H),2.10(dt,J=15.6,4. 8Hz,1H),2.01(dt,J=15.6,4.8Hz,1H),1.56(d,J=15.0Hz,1H),1.16(d,J=15.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ167.6,167.3,132.1,132.0,131.7,121.9,96.4,94. 4,68.9,58.0,57.9,56.4,56.2,46.9,46.7,42.9,40.8,40.5,31.6,31.4. 19 F NMR (565MHz, CDCl3) δ -166.92.

[0066] Compound 37: 11H NMR (600 MHz, CDCl3) δ 7.12 (d, J = 7.7 Hz, 2H), 7.08 (d, J = 7.7 Hz, 2H), 5.01 (t, J = 5.5 Hz, 1H), 3.90 (dd, J = 26.2, 12.0 Hz, 1H), 3.71 (t, J = 11.7 Hz, 1H), 3.51 (d, J = 2.9 Hz, 1H), 3.18 - 3.07 (m, 4H), 3.00 (dd, J = 4.1, 2.0 Hz, 1H), 2.48 (s, 3H), 2.33 (s, 3H), 2.08 (dt, J = 15.4, 4.8 Hz, 1H), 1.99 (dt, J = 15.3, 4.7 Hz, 1H), 1.54 (d, J = 15.3 Hz, 1H), 1.21 (d, J = 15.3 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 168.0, 167.7, 137.6, 130.3, 130.0, 129.3, 96.8, 94.8, 68.7, 58.1, 58.1, 56.5, 56.3, 47.3, 47.0, 42.9, 41.2, 41.0, 31.6, 31.4, 21.2. 19 19F NMR (565 MHz, CDCl3) δ -166.88.

[0067] Compound 38: 1 1H NMR (600 MHz, CDCl3) δ 7.57 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 4.96 (t, J = 5.5 Hz,1H), 3.94 (dd, J = 26.1, 12.3 Hz, 1H), 3.84 (dd, J = 14.3, 12.4 Hz, 1H), 3.50 (d, J = 2.9 Hz, 1H), 3.20 - 3.13 (m, 3H), 3.13 - 3.10 (m, 1H), 3.01 - 2.96 (m, 1H), 2.47 (s, 3H), 2.10 (dt, J = 15.5, 4.8 Hz, 1H), 1.99 (dt, J = 15.6, 4.9 Hz, 1H), 1.51 (d, J = 15.3 Hz, 1H), 1.14 (d, J = 15.3 Hz, 1H). 13C NMR (151MHz, CDCl3) δ168.7,168.5,138.0,130.8,130.3,130.1,129.9,129.7,128.9,126.9,125.5,125.5,12 5.4,125.4,125.1,123.3,98.1,96.8,68.4,66.4,66.2,57.9,57.8,56.4,56.2,42.5,39.4,39.3,31.2,31.1. 19 F NMR(565MHz, CDCl3)δ-62.58,-172.20.

[0068] Compound 39: 1 H NMR (600MHz, CDCl3) δ5.11 (t, J=5.4Hz, 1H), 3.80 (dd, J=28.2, 12.0Hz, 1H), 3.69 (dd, J=12.0,10.8Hz,1H),3.65(d,J=3.0Hz,1H),3.62(d,J=3.0Hz,1H),3.17(td,J=4.2,1 .8Hz,2H),2.51(s,3H),2.15(dt,J=15.6,4.2Hz,2H),1.90-1.74(m,2H),1.62(dd,J= 15.0,9.0Hz,2H),1.45(m,1H),1.30(m,2H),1.24-1.16(m,1H),0.87(t,J=7.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ168.1,168.0,96.5,95.2,68.6,58.1,58.1,56.6,56.5,47.5,47.4,42.8,35.3,35.2,31.7,31.6,25.2,25.2,22.5,13.8. 19 F NMR (565MHz, CDCl3) δ -168.76.

[0069] Compound 40: 11H NMR (600 MHz, CDCl3) δ 5.76 (ddt, J = 17.3, 10.3, 7.2 Hz, 1H), 5.25 - 5.18 (m, 2H), 5.13 (t, J = 5.5 Hz, 1H), 3.85 (dd, J = 26.8, 12.1 Hz, 1H), 3.75 (t, J = 11.7 Hz, 1H), 3.70 - 3.65 (m, 2H), 3.19 (dd, J = 4.1, 1.9 Hz, 2H), 2.70 - 2.61 (m, 2H), 2.54 (s, 3H), 2.17 (ddt, J = 15.6, 5.4, 3.8 Hz, 2H), 1.66 (t, J = 1.4 Hz, 1H), 1.63 (d, J = 1.6 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 167.58, 167.41, 129.24, 129.21, 120.94, 95.74, 94.43, 68.83, 58.06, 56.53, 56.45, 46.90, 46.74, 42.82, 39.77, 39.63, 31.62, 31.56. 19 19F NMR (565 MHz, CDCl3) δ -167.56.

[0070] Compound 41: 1 1H NMR (600 MHz, CDCl3) δ 7.52 - 7.46 (m, 2H), 7.45 - 7.37 (m, 3H), 5.09 (t, J = 5.4, 1H), 4.15 (dd, J = 30.0, 11.4 Hz, 1H), 3.73 (t, J = 11.4 Hz, 1H), 3.59 (d, J = 3.0 Hz, 1H), 3.42 - 3.36 (d, J = 2.9 Hz, 1H), 3.15 (dd, J = 4.2, 1.8 Hz, 1H), 3.09 (dd, J = 4.2, 1.8 Hz, 1H), 2.50 (s, 3H), 2.19 - 2.06 (m, 2H), 1.67 (d, J = 15.6, 1H), 1.51 (d, J = 15.6, 1H). 13 13C NMR (151 MHz, CDCl3) δ 167.2, 167.0, 135.6, 135.5, 129.8, 129.1, 124.6, 124.5, 94.1, 69.4, 58.1, 58.0, 56.6, 56.4, 42.8, 35.6, 35.4, 31.5, 31.2. 19 19F NMR (565 MHz, CDCl3) δ -163.82.

[0071] Compound 42: 11H NMR (400 MHz, CDCl3) δ 7.38 - 7.27 (m, 3H), 7.24 - 7.16 (m, 2H), 5.00 (s, 1H), 3.86 - 3.72 (m, 1H), 3.63 - 3.48 (m, 2H), 3.30 - 3.13 (m, 2H), 3.13 - 3.05 (m, 2H), 2.98 (s, 1H), 2.51 - 2.43 (m, 3H), 2.13 - 1.89 (m, 2H), 1.56 (d, J = 15.2 Hz, 1H), 1.14 (d, J = 15.2 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 168.0, 167.8, 133.3, 130.5, 128.7, 127.9, 96.2, 94.2, 68.8, 58.1, 58.1, 56.5, 56.3, 42.9, 42.5, 42.3, 34.8, 34.6, 31.7, 31.4. 19 19F NMR (377 MHz, CDCl3) δ -163.42.

[0072] Compound 43: 1 1H NMR (600 MHz, CDCl3) δ 7.50 - 7.45 (m, 2H), 7.44 - 7.36 (m, 3H), 5.08 (t, J = 6.0 Hz, 1H), 4.02 (dd, J = 30.6, 10.8 Hz, 1H), 3.62 - 3.54 (m, 2H), 3.36 (s, 1H), 3.16 (s, 1H), 3.10 (s, 1H), 2.51 (s, 3H), 2.17 - 2.06 (m, 2H), 1.69 (d, J = 15.0 Hz, 1H), 1.50 (d, J = 15.6 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 167.4, 167.1, 136.3, 136.1, 129.6, 129.1, 124.5, 124.4, 95.6, 93.6, 69.4, 58.2, 58.1, 56.6, 56.5, 42.9, 31.6, 31.3, 8.5, 8.2. 19 19F NMR (565 MHz, CDCl3) δ -157.16.

[0073] Compound 44: 11H NMR (400 MHz, CDCl3) δ 7.79 - 7.70 (m, 2H), 7.43 - 7.36 (m, 5H), 7.36 - 7.30 (m, 2H), 5.04 (t, J = 5.6, 1H), 4.72 (dd, J = 40.0, 11.2 Hz, 1H), 4.34 (dd, J = 15.2, 11.2 Hz, 1H), 3.43 (d, J = 2.8 Hz, 1H), 3.31 - 3.23 (d, J = 2.9 Hz, 1H), 3.09 (dd, J = 4.0, 2.0 Hz, 1H), 3.06 (dd, J = 4.0, 2.0 Hz, 1H), 2.49 (s, 3H), 2.44 (s, 3H), 2.14 - 2.01 (m, 2H), 1.57 (d, J = 15.6 Hz, 1H), 1.47 (d, J = 15.6 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 166.5, 166.3, 145.4, 133.4, 133.2, 132.6, 130.1, 129.8, 129.0, 128.1, 124.7, 124.6, 95.3, 93.3, 71.7, 71.5, 69.5, 58.1, 58.0, 56.4, 56.3, 42.8, 31.4, 31.1, 21.8. 19 19F NMR (377 MHz, CDCl3) δ -169.6.

[0074] Compound 45: 1 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.45 - 7.29 (m, 7H), 5.04 (t, J = 5.5 Hz, 1H), 4.72 (dd, J = 28.1, 11.0 Hz, 1H), 4.33 (dd, J = 15.2, 11.1 Hz, 1H), 3.43 (d, J = 2.9 Hz, 1H), 3.27 (d, J = 2.9 Hz, 1H), 3.10 (dd, J = 4.0, 2.0 Hz, 1H), 3.06 (dd, J = 4.1, 2.0 Hz, 1H), 2.49 (s, 3H), 2.44 (s, 3H), 2.08 (dddd, J = 15.4, 12.9, 5.5, 4.0 Hz, 2H), 1.57 (d, J = 15.4 Hz, 1H), 1.47 (d, J = 15.4 Hz, 1H). 13C NMR (101MHz, CDCl3) δ166.5,166.3,145.4,133.4,133.2,132.6,130.1,129.8,129.0,128.1 ,124.7,124.6,95.3,93.3,71.7,71.5,69.5,58.1,58.0,56.4,56.3,42.8,31.4,31.1,21.8. 19 F NMR (377MHz, CDCl3) δ -169.60.

[0075] Compound 46: 1 H NMR (400MHz, CDCl3) δ7.34-7.28(m,3H),7.22-7.16(m,2H),4.99(t,J=5.6Hz,1H),3.65 -3.61(m,1H),3.60-3.55(m,1H),3.49-3.46(d,J=2.8Hz,1H),3.16(s,1H),3.10(d,J=4 .4Hz,2H),3.00(d,J=3.2Hz,1H),2.96(dd,J=4.0,2.0Hz,1H),2.47(s,3H),2.11-2.04( m,1H),2.00-1.92(m,1H),1.67(s,1H),1.53(d,J=15.2Hz,1H),1.14(d,J=15.2Hz,1H). 13 C NMR (101MHz, CDCl3) δ168.3,168.0,133.3,130.5,128.7,127.9,98.0,96. 0,68.7,58.1,58.0,56.5,56.3,56.1,55.9,42.9,41.1,40.9,31.6,31.5. 19 F NMR (377MHz, CDCl3) δ -167.45.

[0076] Example 3: Neuronal cell protection experiment:

[0077] Corticosterone (CORT)-induced damage to HT22 (mouse hippocampal neurons) is a commonly used cell model for screening antidepressant drugs and studying their mechanisms. Using CORT-damaged HT22 cells as a model, cell viability was measured by the CCK8 assay to screen the neuroprotective activity of synthesized fluoroscopolamine analogs.

[0078] Example 4: Screening of corticosterone concentration for modeling:

[0079] Mouse neural cell line (HT22) culture medium consisted of 89% DMEM high-glucose medium, 3% fetal bovine serum, and 1% penicillin-streptomycin mixture. The cells were cultured in a 37℃ / 5% CO2 incubator, with medium changes every 2 days. Cells were passaged at a density of 80% after two passages. Once cells reached the logarithmic growth phase, the cell density was adjusted to 25,000 cells / mL, and 100 μL was seeded into 96-well plates (6 replicates per group). After 24 hours of culture until complete adhesion, the culture medium was discarded, and 100 μL of different concentrations of corticosterone solution were added. After 8 hours of culture, 10 μL of CCK-8 assay solution was added to each well. Cell viability was measured at 450 nm after 1 hour.

[0080] Figure 1 The results showed 100-1500 μM·L -1 CORT showed a dose-dependent inhibitory effect on HT22 cell viability at 600 μM·L⁻¹. -1 Under CORT treatment, the survival rate of HT22 cells was 50% (P<0.01), therefore, the cell survival rate of approximately 50% was used as the modeling condition.

[0081] Example 5

[0082] Protective experiment of fluoroscopolamine against corticosterone-induced HT22 cell damage:

[0083] The cell plating procedure is the same as above. Culture for 24 hours until fully adherent, then aspirate the culture medium and add 600 μM·L⁻¹. -1 CORT medium and medium solutions containing different concentrations of fluoroscopolamine were cultured for another 24 hours. The culture medium was then discarded, and 100 μL of CCK8 assay solution was added. Cell viability was measured at 450 nm after 1 hour. The experimental results are shown in Table 1 below.

[0084] Table 1

[0085]

[0086]

[0087] Cell protection experiments showed that compounds 1, 3, 4, 5, 8, 9, 10, 11, 12, 14, 17, 18, 21, 23, 24, 25, 26, 27, 28, 29, 33, 34, 35, 37, 41, 43, 45, and 46 all had varying degrees of protective effects against corticosterone-induced cell damage in the range of 12.5-50 μmM. Compounds 2, 6, 7, 13, 15, 16, 19, 20, 22, 30, 31, 32, 36, 39, 40, and 42 did not damage cells.

[0088] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A scopolamine analogue, characterized in that, Its analogues have the following chemical structures: ， ， ， ， ， 。 2. The method for synthesizing the scopolamine analogue as described in claim 1, characterized in that, Includes the following steps: Method A: ， Method B: ， Wherein: Formula I corresponds to chemical structures 1, 3-5, 8-12, 14-15, 17-18, 21, 23, 26, 28 in claim 1; Formula II corresponds to chemical structures 33-35, 41, 43, 45 in claim 1.

3. The use of the scopolamine analogue as described in claim 1 in the preparation of antidepressant drugs.

4. The use of a pharmaceutically acceptable salt of the scopolamine analogue as described in claim 1 in the preparation of an antidepressant.

5. The use of the pharmaceutically acceptable salt of the scopolamine analogue according to claim 4 in the preparation of antidepressant drugs, characterized in that: The pharmaceutically acceptable salt is a salt formed by scopolamine analogues and acids.

6. The use of a pharmaceutically acceptable salt of the scopolamine analogue according to claim 5 in the preparation of an antidepressant, characterized in that: The acid is selected from hydrochloric acid, hydrobromic acid, aminosulfonic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, ascorbic acid, palmitic acid, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, or leucine.

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