Veltioxetine long-acting prodrug derivative as well as pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a votioxetine long-acting prodrug derivative as well as a pharmaceutical composition and application of the votioxetine long-acting prodrug derivative. The vosulfur oxetine long-acting prodrug derivative comprises a compound with a structure as shown in a formula (I). The povitioxetine long-acting prodrug derivative generates povitioxetine through enzyme metabolism in vivo, so that the blood concentration fluctuation of povitioxetine is small, the effective blood concentration maintenance time is long, the administration frequency can be reduced, and the patient compliance and the disease treatment effect can be improved. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a long-acting prodrug derivative of vortioxetine, a drug compound thereof and use thereof in preparing a drug for preventing or treating diseases related to 5-hydroxytryptamine receptors. Background Art

[0002] Depression is a common, persistent and severe mental illness in clinical practice. It is a disease caused by various reasons with low mood or state of mind and lack of interest as the core symptoms. It may be accompanied by slow thinking, sleep disorders, executive dysfunction and abnormal social function. In more severe cases, suicidal ideation may be seen.

[0003] Vortioxetine is a new type of selective serotonin reuptake inhibitor and an antidepressant with multiple mechanisms. It not only acts on the 5-HT transporter, but also can bind to multiple 5-HT receptors. It is a 5-HT1A agonist, a 5-HT1B partial agonist, and an antagonist of 5-HT1D, 5-HT7 and 5-HT3. It exerts its pharmacological effects by binding to the corresponding transporters and receptors.

[0004] The Chinese invention patent with publication number CN109851573B discloses a vortioxetine amino acid amide compound and its preparation method and application. This type of amidated modified compound is stable in gastric juice and intestinal juice, and can reduce the promoting effect of vortioxetine on gastrointestinal motility, thereby reducing the incidence of adverse reactions such as nausea and vomiting. The PCT invention patent application with publication number WO2017162536A1 discloses a series of vortioxetine amide derivatives and alkyl carbonate derivatives, with the purpose of enhancing the lipid solubility of vortioxetine, improving the blood-brain barrier passage rate, and prolonging its metabolic time.

[0005] The treatment of depression usually requires a long-term process. As the only antidepressant drug that can significantly improve patients' cognitive function, if its long-acting drug can be developed, the dosing interval can be greatly extended, thereby improving the treatment effect of depression. Summary of the invention

[0006] In view of the deficiencies in the above-mentioned prior art, the present invention synthesized a series of long-acting prodrug derivatives of vortioxetine with diverse structures, and conducted pharmacokinetic screening on them in rats, and found compounds that can maintain stable release of vortioxetine in the body for a longer period of time, which can significantly extend the dosing interval of vortioxetine.

[0007] The specific technical solutions are as follows: The first object of the present invention is to provide a long-acting prodrug derivative of vortioxetine, comprising a compound having a structure shown in formula (I):

[0008] Wherein, R1 is selected from the following groups: or

[0009] wherein R2 is independently selected from methyl, trifluoromethyl or cyano, and m is selected from an integer of 0-2; X is selected from an oxygen atom or a sulfur atom; R3 is selected from aryl or heteroaryl, and the aryl is independently substituted by halogen, cyano, trifluoromethyl, nitro, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, amino or C1-C4 alkylamino, and the number of substituents is 0-3. When X is selected from oxygen atom, the aryl cannot be phenyl without any substitution; the heteroaryl is independently substituted by hydroxyl or C1-C4 alkoxy, and the number of substituents is 0-1.

[0010] The vortioxetine long-acting prodrug derivative of the present invention is metabolized by enzymes in vivo to produce vortioxetine, so that the blood concentration of vortioxetine fluctuates little, and the effective blood concentration is maintained for a long time, thereby reducing the number of drug administrations and improving patient compliance.

[0011] Further, R1 is selected from the following groups: , , , , .

[0012] Further, R1 is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0013] Specifically, the representative compound structures of the compounds of formula (I) of the present invention are shown in Table 1: Table 1 Representative structures of compounds of formula (I)

[0014] Furthermore, the long-acting prodrug derivative of vortioxetine also includes a pharmaceutically acceptable salt of the compound having the structure shown in formula (I).

[0015] Pharmaceutically acceptable salts refer to inorganic and organic acid salts that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment and have no excessive toxicity, irritation, or allergic reaction. Inorganic acids that form salts with the amino group of the compound of formula (I) include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, boric acid, nitric acid, and the like. Organic acids that form salts with the amino group of the compound of formula (I) include, but are not limited to, formic acid, acetic acid, butyric acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, lactic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, benzoic acid, fumaric acid, glycerophosphoric acid, gluconic acid, malic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, oxalic acid, oleic acid, palmitic acid, pamoic acid, and the like.

[0016] The second object of the present invention is to provide a pharmaceutical composition, which comprises the long-acting prodrug derivative of vortioxetine as described above.

[0017] Furthermore, the pharmaceutical composition is administered parenterally.

[0018] Furthermore, the pharmaceutical composition is administered by injection.

[0019] Furthermore, the pharmaceutical composition is administered in the form of intramuscular injection or subcutaneous injection.

[0020] The third object of the present invention is to provide a use of the long-acting prodrug derivative of vortioxetine as described above in the preparation of a drug for preventing or treating diseases related to 5-hydroxytryptamine receptors.

[0021] Furthermore, the present invention provides a use of the long-acting prodrug derivative of vortioxetine as described above in the preparation of a drug for preventing or treating depression-related diseases.

[0022] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention synthesized a series of long-acting prodrug derivatives of vortioxetine with diverse structures and conducted in vivo pharmacokinetic screening on them in rats, and found compounds that can maintain stable release of vortioxetine in vivo for a long time, thereby extending the dosing interval; (2) The long-acting prodrug derivative of vortioxetine provided by the present invention is metabolized by enzymes in the body to produce vortioxetine, which reduces the fluctuation of the blood concentration of vortioxetine and maintains the effective blood concentration for a long time, thereby reducing the number of dosing times and improving patient compliance and disease treatment effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The blood drug concentration-time curve of vortioxetine produced by the metabolism of compounds 1, 3, and 4 in vivo; Figure 2 This is the blood concentration-time curve of vortioxetine produced by the metabolism of compounds 14, 24, 41, and 45 in vivo. DETAILED DESCRIPTION

[0024] The principles and features of the present invention are described below in conjunction with examples, which are only used to explain the present invention and are not intended to limit the scope of the present invention in any form. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and may be made including but not limited to changes and modifications related to the chemical structures, substituents, derivatives, formulations and / or methods of the present invention without departing from the spirit of the present invention and the scope of the appended claims.

[0025] Example 1: Preparation of Compound 1

[0026] In the reaction flask, 1.0 g of vortioxetine, 0.97 g of benzoyl peroxide, 1.2 g of disodium hydrogen phosphate, and 20 g of DMF were added. The mixture was stirred at 35°C overnight. After the reaction, 50 g of water was added, and 100 g of dichloromethane was extracted. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to (transition to) petroleum ether / ethyl acetate 65 / 35, V / V) to obtain 0.82 g of solid, i.e., compound 1.

[0027] HPLC purity 97.53%. mp: 109.2-110.7℃. ESI-MS (m / z): 441.18 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 8.06 – 8.00 (m, 2H), 7.60 – 7.53 (m, 1H), 7.49 – 7.42 (m,2H), 7.38 (d, J = 7.9 Hz, 1H), 7.20 – 7.13 (m, 1H), 7.12 – 7.05 (m, 2H), 7.04– 6.99 (m, 1H), 6.88 (ddd, J = 8.0, 6.3, 2.5 Hz, 1H), 6.54 – 6.50 (m, 1H), 3.71 – 3.36 (m, 4H), 3.35 – 3.08 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 2: Preparation of Compound 2

[0028] 8.0 g of compound 1 was added with 80 mL of methanol and 9.67 g of potassium carbonate, and the mixture was reacted at room temperature overnight. The solvent was removed under reduced pressure, and 30 g of dichloromethane and 30 g of water were added for separation. The organic phase was purified by column chromatography (the elution ratio of the eluent was dichloromethane to ethyl acetate / dichloromethane 10 / 90, V / V) to obtain 5.6 g of off-white solid N-hydroxyvortioxetine.

[0029] 0.63 g of N-hydroxyvortioxetine was added with 0.45 g of 2,4-dimethylbenzoic acid, 0.29 g of DMAP, and 30 mL of dichloromethane, and 0.62 g of DCC was added under stirring, and the temperature was raised to 40°C for reaction for 4 h. After the reaction, the solvent was removed and purified by column chromatography (the elution ratio of the eluent was petroleum ether~ethyl acetate / petroleum ether 5 / 95, V / V), to obtain 0.70 g of an off-white solid, namely compound 2.

[0030] HPLC purity 96.20%. mp: 124.5-125.7℃. ESI-MS (m / z): 469.14 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.21 –7.16 (m, 2H), 7.13 – 7.04 (m, 4H), 6.92 – 6.87 (m, 1H), 6.38 (dd, J = 8.0, 1.2Hz, 1H), 3.56 – 3.38 (m, 2H), 3.30 – 3.27 (m, 2H), 3.15 – 2.94 (m, 4H), 2.44(s, 3H), 2.28 (s, 6H), 2.21 (s, 3H). Example 3: Preparation of Compound 3

[0031] 0.78 g of N-hydroxyvortioxetine, 0.71 g of 4-trifluoromethylbenzoic acid, 0.37 g of DMAP, and 20 mL of dichloromethane were added with stirring to 0.77 g of DCC. After the addition, the temperature was raised to 40°C and the reaction was continued for 4 hours. After the reaction was completed, the temperature was lowered and filtered, and the filtrate was concentrated and purified by column chromatography (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 5 / 95, V / V), to obtain 0.80 g of a light yellow solid, namely compound 3.

[0032] HPLC purity 96.37%. mp: 122.3-123.5℃. ESI-MS (m / z): 509.31 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) d 8.13 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.31 (d, J =7.6 Hz, 1H), 7.22 – 7.17 (m, 2H), 7.12 – 7.04 (m, 2H), 6.93 – 6.87 (m, 1H), 6.38 (dd, J= 7.8, 1.2 Hz, 1H), 3.59 – 3.39 (m, 2H), 3.37 – 3.29 (m, 2H), 3.20 – 2.96 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H). Example 4: Preparation of Compound 4

[0033] 0.7 g N-hydroxyvortioxetine, 0.46 g p-methylbenzoic acid, 0.69 g DCC, and 0.33 g DMAP were added to 20 g dichloromethane. The mixture was stirred overnight at 35°C. After the reaction, 20 g water was added, the mixture was separated, and the organic phase was purified by column chromatography (the elution ratio of the eluent was dichloromethane to dichloromethane / methanol 95 / 5, V / V). The obtained oil was added with 20 mL of n-hexane and stirred vigorously to obtain 0.50 g of a white solid, i.e., compound 4.

[0034] HPLC purity 97.31%. mp: 122.5-123.4℃. ESI-MS (m / z): 455.16 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.95 – 7.90 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.26 – 7.23(m, 2H), 7.15 (s, 1H), 7.12 – 7.06 (m, 2H), 7.06 – 7.01 (m, 1H), 6.88 (ddd, J= 8.4, 6.3, 2.4 Hz, 1H), 6.56 – 6.48 (m, 1H), 3.66 – 3.35 (m, 4H), 3.34 –3.17 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H). Example 5: Preparation of Compound 5

[0035] 0.7 g N-hydroxyvortioxetine, 0.46 g 4-cyanobenzoic acid, 0.69 g DCC, and 0.33 g DMAP were added to 20 g dichloromethane. The mixture was stirred at 35°C overnight. After the reaction, 30 g water was added, the mixture was separated, and the organic phase was purified by column chromatography (the elution ratio of the eluent was dichloromethane to dichloromethane / methanol 95 / 5, V / V). The obtained oil was added with 20 mL of n-hexane to slurry to obtain 0.48 g of a white solid, namely compound 5.

[0036] HPLC purity 97.46%. mp: 103.3-104.4℃. ESI-MS (m / z): 466.17 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 8.20 – 8.07 (m, 2H), 7.79 – 7.71 (m, 2H), 7.37 (d, J = 7.8Hz, 1H), 7.15 (s, 1H), 7.11 – 7.06 (m, 2H), 7.03 (d, J = 7.9 Hz, 1H), 6.92 –6.84 (m, 1H), 6.52 (d, J = 7.6 Hz, 1H), 3.66 – 3.37 (m, 4H), 3.35 – 3.18 (m,4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 6: Preparation of Compound 6

[0037] 0.70 g triphosgene and 20 g dichloroethane were added to the reaction flask. 0.31 g 4-methylphenol was added at 0-5°C, and 0.75 g triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 min, and then the temperature was raised to 50°C and stirred overnight.

[0038] 0.80 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction, 50 g of water was added, the liquids were separated, and the organic layer was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.80 g of colorless oil, i.e., compound 6.

[0039] HPLC purity 96.73%. ESI-MS (m / z): 455.22 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ7.40 (d, J = 7.8 Hz, 1H), 7.19 – 7.15 (m, 3H), 7.14 – 7.09 (m, 1H), 7.04 –7.03 (m, 2H), 7.01 – 7.00 (m, 2H), 6.95 – 6.90 (m, 1H), 6.58 (dd, J = 7.9,1.3 Hz, 1H), 3.95 – 3.70 (m, 4H), 3.12 (s, 4H), 2.38 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H). Example 7: Preparation of Compound 7

[0040] 0.70 g of triphosgene was added to 20 g of dichloroethane, the temperature was lowered to 0-5°C, 0.31 g of 4-isopropylphenol was added, and 0.75 g of triethylamine was added dropwise. After the addition, the mixture was stirred for 30 minutes, and then the temperature was raised to 50°C and stirred overnight.

[0041] 0.80 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 20 g of water was added, the liquids were separated, and the organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V). 0.82 g of an oily substance was obtained, namely compound 7.

[0042] HPLC purity 96.89%. ESI-MS (m / z): 483.21 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ7.39 (d, J = 7.8 Hz, 1H), 7.29 – 7.19 (m, 3H), 7.17 (s, 1H), 6.94 – 6.89 (m,1H), 6.75 – 6.73 (m, 4H), 6.57 (d, J = 7.8 Hz, 1H), 3.87 – 3.78 (m, 4H), 3.12(s, 4H), 2.91 – 2.81 (m, 1H), 2.38 (s, 3H), 2.34 (s, 3H), 1.26 (s, 3H), 1.24(s, 3H). Example 8: Preparation of Compound 8

[0043] 0.70g triphosgene, 20g dichloroethane, 0.76g 4-chlorophenol, 0.75g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 minutes in an ice-water bath, and then heated to 50°C and stirred overnight.

[0044] 0.80 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added, and the liquid was separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.44 g of a white solid, namely compound 8.

[0045] HPLC purity 97.89%. mp: 95.6-96.6℃. ESI-MS (m / z): 475.15 [M+Na] + .1 H NMR(400MHz, CDCl3) δ 7.39 (d, J = 7.8 Hz, 1H), 7.29 – 7.19 (m, 2H), 7.17 (s,1H), 7.12 – 7.07 (m, 3H), 7.06 – 7.03 (m, 2H), 6.94 – 6.89 (m, 1H), 6.57 (d,J = 7.8 Hz, 1H), 3.82 (s, 4H), 3.12 (s, 4H) 2.38 (s, 3H), 2.34 (s, 3H). Example 9: Preparation of Compound 9

[0046] 0.70g triphosgene, 20g dichloroethane, 0.67g 4-fluorophenol, and 0.75g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 minutes in an ice-water bath, and then heated to 50°C and stirred overnight.

[0047] 0.80 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.33 g of a white solid, i.e., compound 9.

[0048] HPLC purity 96.15%. mp: 107.6-108.4℃. ESI-MS (m / z): 459.24 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.37 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.12 – 7.07 (m,3H), 7.07 –7.02 (m, 4H), 6.90 (ddd, J = 8.0, 7.1, 1.6 Hz, 1H), 6.55 (dd, J =7.9, 1.3 Hz, 1H), 3.91 – 3.69 (m, 4H), 3.15 – 3.06 (m, 4H), 2.36 (s, 3H), 2.33 (s, 3H). Example 10: Preparation of Compound 10

[0049] 0.80g triphosgene, 20g dichloroethane, 0.94g 2-fluorophenol, and 0.85g triethylamine were slowly added dropwise at 0-5°C. After the addition was complete, the mixture was stirred for 30 minutes in an ice-water bath, and then heated to 50°C and stirred overnight.

[0050] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.58 g of a white solid, i.e., compound 10.

[0051] HPLC purity 94.23%. mp: 108.5-109.3℃. ESI-MS (m / z): 459.18 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.26 – 7.20 (m, 1H), 7.19 – 7.14(m, 3H), 7.14 – 7.11 (m, 1H), 7.11 – 7.02 (m, 3H), 6.93 – 6.87 (m, 1H), 6.56 (d, J = 7.9 Hz, 1H), 3.96 – 3.70 (m, 4H), 3.18 – 3.08 (m, 4H), 2.37 (s, 3H), 2.33 (s, 3H). Example 11: Preparation of Compound 11

[0052] 0.70 g triphosgene, 20 g dichloroethane, 0.70 g 4-cyanophenol, and 0.75 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to 50°C and stirred overnight.

[0053] 0.8 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.58 g of a white solid, i.e., compound 11.

[0054] HPLC purity 98.27%. mp: 120.2-120.9℃. ESI-MS (m / z): 466.19 [M+Na] + . 1H NMR(400MHz, CDCl3) δ 7.70 – 7.65 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.32 – 7.25(m, 2H), 7.15 (s, 1H), 7.11 – 7.06 (m, 1H), 7.06 – 7.01 (m, 2H), 6.90 (ddd, J= 7.9, 7.1, 1.6 Hz, 1H), 6.54 (dd, J = 7.9, 1.4 Hz, 1H), 3.90 – 3.70 (m, 4H), 3.16 – 3.06 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 12: Preparation of Compound 12

[0055] 0.80g triphosgene, 20g dichloroethane, 1.2g 2-naphthol, and 0.85g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, stirring was continued in an ice-water bath for 30 minutes, and then the temperature was raised to 50°C and stirred overnight.

[0056] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.76 g of a white solid, i.e., compound 12.

[0057] HPLC purity 94.44%. mp: 88.3-89.5℃. ESI-MS (m / z): 491.22 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.74 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.63 –7.58 (m, 2H), 7.49 – 7.44 (m, 2H), 7.41 – 7.37 (m, 2H), 7.34 – 7.29 (m, 2H),7.17 (s, 1H), 7.14 – 7.09 (m, 1H), 6.95 – 6.87 (m, 1H), 6.59 – 6.54 (m, 1H),4.02 – 3.75 (m, 4H), 3.16 (s, 4H), 2.37 (s, 3H), 2.35 (s, 3H). Example 13: Preparation of Compound 13

[0058] 0.80 g triphosgene, 20 g dichloroethane, 0.8 g 4-hydroxypyridine, and 0.85 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to 50°C and stirred overnight.

[0059] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.34 g of a white solid, i.e., compound 13.

[0060] HPLC purity 95.88%. mp: 121.8-122.3℃. ESI-MS (m / z): 420.32 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.39 – 8.33 (m, 1H), 7.75 – 7.71 (m, 1H), 7.36 (d, J = 7.8Hz, 1H), 7.19 – 7.16 (m, 1H), 7.14 (s, 1H), 7.13 – 7.10 (m, 1H), 7.09 – 6.99 (m, 3H), 6.86 (ddd, J = 8.6, 6.7, 2.0 Hz, 1H), 6.52 (dd, J = 7.9, 1.0 Hz, 1H), 3.48 – 3.39 (m, 4H), 3.09 – 3.00 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H). Example 14: Preparation of Compound 14

[0061] 0.80 g triphosgene, 20 g dichloroethane, 0.8 g 2-hydroxypyridine, and 0.85 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to 50°C and stirred overnight.

[0062] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.74 g of a white solid, i.e., compound 14.

[0063] HPLC purity 96.21%. mp: 125.4-126.1℃. ESI-MS (m / z): 420.31[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.41 – 8.35 (m, 1H), 7.77 (ddd, J = 8.1, 7.4, 2.0 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.19 (ddd, J = 7.3, 4.9, 0.9 Hz, 1H), 7.16 – 7.12(m, 2H), 7.11 – 7.06 (m, 1H), 7.06 – 7.01 (m, 2H), 6.89 (ddd, J = 8.0, 7.1,1.6 Hz, 1H), 6.55 (dd, J = 7.9, 1.3 Hz, 1H), 3.92 – 3.71 (m, 4H), 3.18 – 3.05(m, 4H), 2.35 (s, 3H), 2.32 (s, 3H). Example 15: Preparation of Compound 15

[0064] 1.77g of compound 21, 35mL of tetrahydrofuran, 40mL of methanol, 0.20g of palladium carbon were added, and the mixture was replaced with a hydrogen balloon 3 times. The mixture was reacted at room temperature overnight. After the reaction was completed, the mixture was filtered and the filtrate was concentrated. Column chromatography was performed for purification (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 40 / 60, V / V) to obtain 0.58g of an off-white solid, i.e., compound 15.

[0065] HPLC purity 95.29%. mp: 164.6-166.2℃. ESI-MS (m / z): 434.48 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) d 7.32 (d, J = 7.6 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.16 – 7.13(m, 1H), 7.11 – 7.05 (m, 2H), 6.92 – 6.88 (m, 1H), 6.77 – 6.71 (m, 2H), 6.52– 6.46 (m, 2H), 6.37 (dd, J= 8.0, 1.2 Hz, 1H), 4.93 (s, 2H), 3.76 – 3.51 (m,4H), 3.03 – 2.97 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H). Example 16: Preparation of Compound 16

[0066] Vortioxetine 1.19 g, triethylamine 0.61 g, dichloromethane 20 mL, cooled to -10 ° C. Add p-methoxyphenyl chloroformate 0.82 g, dropwise, and react for 4 hours. After the reaction is completed, saturated NaHCO3 solution is used to quench the reaction, separate the liquids, concentrate the organic phase until there is no fraction, and purify by column chromatography (the elution ratio of the eluent is petroleum ether~ethyl acetate / petroleum ether 10 / 90, V / V), to obtain 1.71 g of white solid, i.e., compound 16.

[0067] HPLC purity 95.39%. mp: 135.6-136.4℃. ESI-MS(m / z): 471.30 [M+Na] + . 1 H NMR (400 MHz, Chloroform- d ) d 7.36 (d, J = 7.6 Hz, 1H), 7.16 – 7.14 (m, 1H), 7.13 –7.01 (m, 5H), 6.92 – 6.85 (m, 3H), 6.56 (d, J = 8.0 Hz, 1H), 3.91 – 3.82 (m,2H), 3.81 – 3.73 (m, 5H), 3.22 – 3.06 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 17: Preparation of Compound 17

[0068] 1.80g of compound 15, 40mL of dichloromethane, 3mL of acetone, 1mL of AcOH was added under stirring, nitrogen was replaced 3 times, and the temperature was raised to 40°C for reaction for 16h. The dichloromethane was removed by concentration, and 40mL of methanol, 1.74g of sodium triacetoxyborohydride, and 5 drops of acetic acid were added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the methanol was removed by concentration, 20mL of water and 20mL of ethyl acetate were added for separation, and the organic phase was concentrated under reduced pressure. Column chromatography purification (the elution ratio of the eluent was petroleum ether~ethyl acetate / petroleum ether 12 / 88, V / V) was obtained to obtain 0.58g of solid, i.e., compound 17.

[0069] HPLC purity 98.65%. mp: 155.6-156.3℃. ESI-MS (m / z): 476.40 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 – 8.13 (m, 1H), 7.44 – 7.30 (m, 2H), 7.23 – 7.20(m, 1H), 7.18 – 7.04 (m, 3H), 6.94 – 6.87 (m, 1H), 6.82 – 6.77 (m, 1H), 6.52– 6.45 (m, 1H), 6.43 – 6.34 (m, 1H), 5.26 (d, J = 8.8 Hz, 1H), 3.82 – 3.51(m, 4H), 3.52 – 3.40 (m, 1H), 3.12 – 2.91 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H), 1.08 (d, J = 6.4 Hz, 6H). Example 18: Preparation of Compound 18

[0070] 1.20g of compound 16, 40mL of dichloromethane, 0-5℃, 6mL of dichloromethane solution of boron tribromide (1M) was added dropwise. After the addition, the mixture was reacted at room temperature for 5h. After the reaction was completed, the reaction was quenched with saturated NaHCO3 solution, and the organic phase was concentrated until there was no fraction. Column chromatography was used for purification (the elution ratio of the eluent was petroleum ether~ethyl acetate / petroleum ether 30 / 70, V / V) to obtain 1.05g of off-white solid, i.e., compound 18.

[0071] HPLC purity 95.33%. mp: 180.4-181.1℃. ESI-MS (m / z): 457.39 [M+Na] + . 1 H NMR (400 MHz, Chloroform- d ) d 7.35 (d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.16 – 7.14 (m,1H), 7.12 – 7.08 (m, 1H), 7.02 (d, J= 2.0 Hz, 1H), 6.95 – 6.89 (m, 3H), 6.69 –6.65 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 5.77 (s, 1H), 3.94 – 3.75 (m, 4H), 3.26 – 3.08 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 19: Preparation of Compound 19

[0072] 0.80g triphosgene, 20g dichloroethane, 0.8g 3-hydroxypyridine, slowly add 0.85g triethylamine, continue stirring in an ice-water bath for 30 minutes after the addition is complete, then heat to 50°C and stir overnight.

[0073] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.64 g of a white solid, i.e., compound 19.

[0074] HPLC purity 96.91%. mp: 136.2-136.8℃. ESI-MS (m / z): 420.27 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.50 – 8.40 (m, 2H), 7.57 – 7.50 (m, 1H), 7.37 (d, J = 7.9Hz, 1H), 7.31 (ddd, J = 8.5, 4.8, 0.7 Hz, 1H), 7.15 (s, 1H), 7.13 – 6.94 (m,3H), 6.90 (ddd, J = 8.1, 7.0, 1.8 Hz, 1H), 6.55 (dd, J = 8.0, 1.6 Hz, 1H), 4.02 – 3.69 (m, 4H), 3.18 – 3.06 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 20: Preparation of Compound 20

[0075] 0.80g triphosgene, 20g dichloroethane, 0-5°C, add 1.2g 3-hydroxyquinoline, and slowly drop 0.85g triethylamine. After the dropwise addition, continue stirring in an ice-water bath for 30 minutes, then heat to 50°C and stir overnight.

[0076] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.64 g of a white solid, i.e., compound 20.

[0077] HPLC purity 96.11%. mp: 148.0-148.6℃. ESI-MS (m / z): 470.25 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.78 (d, J = 2.7 Hz, 1H), 8.15 – 8.09 (m, 1H), 7.99 (d, J =2.6 Hz, 1H), 7.84 – 7.76 (m, 1H), 7.68 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.55(ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.18 – 7.15 (m,1H), 7.13 – 7.02 (m, 3H), 6.91 (ddd, J = 8.0, 6.9, 1.8 Hz, 1H), 6.56 (dd, J =7.9, 1.3 Hz, 1H), 4.01 – 3.71 (m, 4H), 3.22 – 3.09 (m, 4H), 2.36 (s, 3H), 2.34 (s, 3H). Example 21: Preparation of Compound 21

[0078] Vortioxetine 1.19 g, triethylamine 0.61 g, dichloromethane 30 mL, cooled to -10 ° C. Add p-nitrophenyl chloroformate 0.89 g, keep warm for 5-10 min after addition, warm to room temperature and react for 4 h. After the reaction is completed, quench the reaction with saturated NaHCO3 solution, separate the liquids, and concentrate the organic phase until there is no fraction. Purify by column chromatography (the elution ratio of the eluent is petroleum ether~ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 1.80 g of light yellow solid, i.e., compound 21.

[0079] HPLC purity 96.36%. mp: 136.6-137.2℃. ESI-MS (m / z): 464.39 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) d 8.29 – 8.22 (m, 2H), 7.48 – 7.41 (m, 2H), 7.32 (d, J = 7.6Hz, 1H), 7.23 – 7.19 (m, 1H), 7.17 – 7.04 (m, 3H), 6.94 – 6.88 (m, 1H), 6.38(dd, J = 8.0, 1.2 Hz, 1H), 3.82 – 3.68 (m, 2H), 3.66 – 3.54 (m, 2H), 3.10 –2.96 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H). Example 22: Preparation of Compound 22

[0080] 0.45 g of triphosgene and 40 mL of dichloroethane were cooled in an ice-water bath. 0.90 g of p-trifluoromethylphenol was added, and 0.91 g of triethylamine was added dropwise. After the addition was completed, the mixture was kept warm for 5-10 min, and the temperature was raised to room temperature for reaction for 7 h. 1.46 g of vortioxetine was added, and the temperature was raised to 80 °C for reaction overnight. After the reaction was completed, the mixture was concentrated to no fraction, and purified by column chromatography (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 1.31 g of a white solid, namely compound 22.

[0081] HPLC purity 98.48%. mp: 87.7-88.2℃. ESI-MS (m / z): 509.21 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) d 7.75 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.22 – 7.05 (m, 1H), 7.18 – 7.05 (m, 3H), 6.95 – 6.88 (m, 1H), 6.42 – 6.36 (m, 1H), 3.81 – 3.67 (m, 2H), 3.64 – 3.50 (m, 2H), 3.08 – 2.98 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H). Example 23: Preparation of Compound 23

[0082] 0.71 g of triphosgene and 30 mL of dichloroethane were added and cooled in an ice-water bath. 1.09 g of 4-hydroxyquinoline was added and 1.52 g of triethylamine was added dropwise. After the addition was completed, the mixture was kept warm for 5-10 min and heated to room temperature for overnight reaction. Then, 0.90 g of vortioxetine was added and the mixture was heated to 80 °C for 8 h. After the reaction was completed, the mixture was concentrated until there was no fraction. Column chromatography was used for purification (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 20 / 80, V / V) to obtain 0.20 g of an off-white solid, i.e., compound 23.

[0083] HPLC purity 98.85%. mp: 178.6-179.2℃. ESI-MS (m / z): 470.40 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) d 8.88 (d, J = 4.8 Hz, 1H), 8.08 – 8.01 (m, 2H), 7.84 – 7.77(m, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 7.6 Hz,1H), 7.24 – 7.16 (m, 2H), 7.14 – 7.05 (m, 2H), 6.96 – 6.89 (m, 1H), 6.39 (dd, J = 8.0, 1.2 Hz, 1H), 3.98 – 3.83 (m, 2H), 3.72 – 3.57 (m, 2H), 3.17 – 3.01(m, 4H), 2.30 (s, 3H), 2.23 (s, 3H). Example 24: Preparation of Compound 24

[0084] 0.71 g of triphosgene and 30 mL of dichloroethane were cooled in an ice-water bath. 1.09 g of 2-hydroxyquinoline was added, and 1.52 g of triethylamine was added dropwise. After the addition was completed, the mixture was kept warm for 5-10 min, and the temperature was raised to room temperature for reaction overnight. 0.90 g of vortioxetine was added, and the temperature was raised to 80 ° C for reaction for 8 h. After the reaction was completed, the mixture was concentrated to no fraction, and purified by column chromatography (the elution ratio of the eluent was petroleum ether~ethyl acetate / petroleum ether 20 / 80, V / V) to obtain 0.32 g of an off-white solid, i.e., compound 24.

[0085] HPLC purity 96.89%. mp: 89.8-91.5℃. ESI-MS (m / z): 492.31 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) d 8.48 – 8.43 (m, 1H), 8.03 – 7.98 (m, 1H), 7.91 – 7.85 (m,1H), 7.80 – 7.73 (m, 1H), 7.64 – 7.54 (m, 1H), 7.34 (dd, J = 8.0, 6.4 Hz, 2H),7.24 – 7.16 (m, 2H), 7.14 – 7.06 (m, 2H), 6.95 – 6.89 (m, 1H), 6.39 (dd, J =8.0, 1.2 Hz, 1H), 3.85 – 3.69 (m, 2H), 3.68 – 3.52 (m, 2H), 3.11 – 3.00 (m,4H), 2.30 (s, 3H), 2.23 (s, 3H). Example 25: Preparation of Compound 25

[0086] 0.80g triphosgene, 20g dichloroethane, 0-5°C, add 1.2g 4-hydroxyisoquinoline, and slowly drop 0.85g triethylamine. After the dropwise addition, continue stirring in an ice-water bath for 30 minutes, then heat to 50°C and stir overnight.

[0087] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 1.1 g of a yellow solid, i.e., compound 25.

[0088] HPLC purity 96.65%. mp: 131.4-132.2℃. ESI-MS (m / z): 470.22 [M+H] + . 1 H NMR(400MHz, CDCl3) δ 9.14 (d, J = 0.5 Hz, 1H), 8.45 (s, 1H), 8.02 (dd, J = 8.2,0.9 Hz, 1H), 7.93 – 7.88 (m, 1H), 7.75 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.64(ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.18 – 7.15 (m,1H), 7.14 – 7.06 (m, 2H), 7.04 (ddd, J = 7.8, 1.4, 0.6 Hz, 1H), 6.91 (ddd, J= 8.0, 6.1, 2.6 Hz, 1H), 6.59 – 6.53 (m, 1H), 4.05 (s, 2H), 3.82 (s, 2H), 3.26 – 3.10 (m, 4H), 2.37 (s, 3H), 2.34 (s, 3H). Example 26: Preparation of Compound 26

[0089] 0.80g triphosgene, 20g dichloroethane, 1.1g 8-hydroxy-imidazo[1,2-A]pyridine, and 0.85g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 minutes in an ice-water bath, and then heated to 50°C and stirred overnight.

[0090] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.95 g of solid, i.e., compound 26.

[0091] HPLC purity 95.15%. mp: 163.5-165.1℃. ESI-MS (m / z): 459.22 [M+H] + . 1H NMR (400MHz, CDCl3) δ 8.00 (dd, J = 6.8, 1.0 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.16 – 7.12 (m, 1H), 7.12– 7.00 (m, 4H), 6.89 (ddd, J = 8.0, 6.7, 2.0 Hz, 1H), 6.79 – 6.72 (m, 1H), 6.56 (dd, J = 7.9, 1.1 Hz, 1H), 4.06 – 3.72 (m, 4H), 3.23 – 3.09 (m, 4H), 2.35 (s, 3H), 2.32 (s, 3H). Example 27: Preparation of Compound 27

[0092] 0.80g triphosgene, 20g dichloroethane, 1.5g 4-bromophenol, and 0.85g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 minutes in an ice-water bath, and then heated to 50°C and stirred overnight.

[0093] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.93 g of a white solid, i.e., compound 27.

[0094] HPLC purity 96.07%. mp: 100.9-101.6℃. ESI-MS (m / z): 519.07 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.55 – 7.50 (m, 2H), 7.49 – 7.44 (m, 2H), 7.36 (d, J = 7.8Hz, 1H), 7.11 – 7.06 (m, 1H), 7.04 – 7.00 (m, 3H), 6.89 (ddd, J = 8.0, 7.0,1.7 Hz, 1H), 6.54 (dd, J = 7.9, 1.4 Hz, 1H), 3.87 – 3.69 (m, 4H), 3.13 – 3.07(m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 28: Preparation of Compound 28

[0095] 0.80g triphosgene, 20g dichloroethane, 0.93g 2,3-dihydroxypyridine, and 0.85g triethylamine were slowly added dropwise at 0-5°C. After the addition was complete, the mixture was stirred in an ice-water bath for 30 minutes, and then heated to 50°C and stirred overnight.

[0096] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 1.1 g of a white solid, i.e., compound 28.

[0097] HPLC purity 95.41%. mp: 139.6-140.7℃. ESI-MS (m / z): 436.25 [M+H] + . 1 H NMR (400MHz, CDCl3) δ12.78 (s, 1H), 7.71 – 7.21 (m, 4H), 7.20 – 7.12 (m, 1H), 7.12 – 6.92 (m, 2H), 6.89 (ddd, J = 8.0, 6.8, 2.0 Hz, 1H), 6.63 – 6.43 (m,1H), 6.25 (dd, J = 7.4, 6.6 Hz, 1H), 4.47 – 3.50 (m, 4H), 3.50 – 2.76 (m,4H), 2.35 (s, 3H), 2.32 (s, 3H). Example 29: Preparation of Compound 29

[0098] 0.80 g triphosgene, 20 g dichloroethane, 1.0 g 5-methoxy-3-hydroxypyridine, and 0.85 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to 50°C and stirred overnight.

[0099] 1.0 g of vortioxetine was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.41 g of solid, i.e., compound 29.

[0100] HPLC purity 97.35%. mp: 146.3-147.1℃. ESI-MS (m / z): 450.24 [M+H]+ . 1 H NMR(400MHz, CDCl3) δ 8.15 (d, J = 2.6 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.34 –7.28 (m, 2H), 7.21 (s, 1H), 7.16 – 7.13 (m, 1H), 7.11 – 7.05 (m, 2H), 6.94 –6.88 (m, 1H), 6.38 (dd, J = 7.9, 1.4 Hz, 1H), 3.81 (s, 3H), 3.77 – 3.50 (m,4H), 3.03 (s, 4H), 2.29 (s, 3H), 2.21 (s, 3H). Example 30: Preparation of Compound 30

[0101] 0.35g triphosgene, 20g dichloromethane, 0.39g thiophenol, 0.72g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, stirring was continued in an ice-water bath for 30 minutes, and then the mixture was heated to room temperature and stirred overnight.

[0102] 0.7 g of vortioxetine was added and the reaction was carried out for 8 h. After the reaction was completed, 30 g of water was added and the mixture was separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V), and 20 mL of n-hexane was added and stirred vigorously to obtain 0.51 g of a white solid, i.e., compound 30.

[0103] HPLC purity 96.56%. mp: 132.6-133.2℃. ESI-MS (m / z): 457.13 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ7.56 – 7.49 (m, 2H), 7.43 – 7.37 (m, 3H), 7.36 (d, J = 7.8Hz, 1H), 7.15 (s, 1H), 7.11 – 7.06 (m, 1H), 7.05 – 7.00 (m, 2H), 6.89 (ddd, J= 7.9, 7.2, 1.5 Hz, 1H), 6.54 (dd, J = 7.9, 1.4 Hz, 1H), 3.79 (s, 4H), 3.10(s, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 31: Preparation of Compound 31

[0104] 0.35g triphosgene, 20g dichloromethane, add 0.45g p-fluorothiophenol at 0-5°C, and slowly add 0.72g triethylamine. After the addition is complete, continue stirring in an ice-water bath for 30 minutes, then warm to room temperature and stir overnight.

[0105] 0.7 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquid was separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.41 g of a white solid, i.e., compound 31.

[0106] HPLC purity 96.30%. mp: 164.7-165.5℃. ESI-MS (m / z): 474.98 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.53 – 7.43 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.16 (s,1H), 7.14 – 7.05 (m, 3H), 7.05 – 6.99 (m, 2H), 6.93 – 6.86 (m, 1H), 6.55 (dd,J = 8.1, 1.6 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 32: Preparation of Compound 32

[0107] 0.35g triphosgene, 20g dichloromethane, add 0.63g 4-(trifluoromethyl)thiophenol at 0-5°C, and slowly add 0.60g triethylamine. After the addition is complete, continue stirring in an ice-water bath for 30 minutes, then warm to room temperature and stir overnight.

[0108] 0.7 g of vortioxetine was added and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.32 g of a white solid, i.e., compound 32.

[0109] HPLC purity 94.95%. mp: 132.3-133.5℃. ESI-MS (m / z): 525.07 [M+Na] + . 1H NMR (400MHz, CDCl3) δ 7.35 – 7.31 (m, 2H), 7.27 – 7.24 (m, 2H), 7.14 (s, 1H), 7.08 – 7.05 (m, 2H), 7.04 – 7.02 (m, 2H), 6.89 – 6.84 (m, 1H), 6.50 (d, J =7.9 Hz, 1H), 3.49 – 3.29 (m, 4H), 3.21 – 3.07 (m, 4H), 2.35 (s, 3H), 2.30 (s,3H). Example 33: Preparation of Compound 33

[0110] 0.80 g triphosgene, 20 g dichloromethane, 0.68 g 4-mercaptobenzonitrile, and 0.82 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to room temperature and stirred overnight.

[0111] 1.0 g of vortioxetine was added and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.35 g of a white solid, i.e., compound 33.

[0112] HPLC purity 97.06%. mp: 163.3-164.1℃. ESI-MS (m / z): 482.07 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.64 – 7.59 (m, 2H), 7.35 (d, J = 8.0Hz, 1H), 7.15 (s, 1H), 7.11 – 6.94 (m, 3H), 6.92 – 6.84 (m, 1H), 6.54 (dd, J= 8.0, 1.6 Hz, 1H), 3.78 (s, 4H), 3.11 (s, 4H), 2.36 (s, 3H), 2.31 (s, 3H). Example 34: Preparation of Compound 34

[0113] 0.50 g of triphosgene and 20 g of dichloromethane were added at 0-5°C, and 0.50 g of 4-methyl-benzenethiol was slowly added dropwise, and 0.70 g of triethylamine was added dropwise. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to room temperature and stirred overnight.

[0114] 0.8 g of vortioxetine was added and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.40 g of a white solid, i.e., compound 34.

[0115] HPLC purity 95.21%. mp: 145.0-145.7℃. ESI-MS (m / z): 471.08 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.43 – 7.38 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.24 – 7.18(m, 2H), 7.16 (s, 1H), 7.12 – 7.06 (m, 1H), 7.06 – 7.00 (m, 2H), 6.93 – 6.87(m, 1H), 6.55 (dd, J = 7.9, 1.4 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H), 2.37 (s,3H), 2.36 (s, 3H), 2.32 (s, 3H). Example 35: Preparation of Compound 35

[0116] 0.49 g of triphosgene and 20 mL of dichloromethane were added, cooled in an ice-water bath, 1.00 g of vortioxetine was added, and 0.67 g of triethylamine was added dropwise. After the addition, the temperature was kept for 5-10 min, and the mixture was heated to room temperature and reacted overnight. 0.72 g of 2-chlorobenzenethiol was added, and the mixture was reacted at room temperature overnight. If there was an intermediate remaining, 0.5 mL of triethylamine was added, and the mixture was heated to 40 °C and reacted for 5 h. After the reaction was completed, the mixture was concentrated to no fraction, and purified by column chromatography (petroleum ether~ethyl acetate / petroleum ether 3 / 97, V / V) to obtain 0.85 g of a white solid, i.e., compound 35.

[0117] HPLC purity 96.38%. mp: 134.4-134.9℃. ESI-MS (m / z): 491.11 [M+Na] + . 1 H NMR (400 MHz, Chloroform- d ) d7.47 – 7.42 (m, 2H), 7.39 – 7.34 (m, 3H), 7.17 – 7.14(m, 1H), 7.11 – 7.06 (m, 1H), 7.06 – 7.00 (m, 2H), 6.94 – 6.87 (m, 1H), 6.55(dd, J = 8.0, 1.2 Hz, 1H), 3.88 – 3.66 (m, 4H), 3.20 – 3.01 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 36: Preparation of Compound 36

[0118] 0.80 g triphosgene, 20 g dichloromethane, 0.64 g 2-fluorothiophenol, and 0.82 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to room temperature and stirred overnight.

[0119] 1.0 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.45 g of a white solid, i.e., compound 36.

[0120] HPLC purity 98.75%. mp: 157.9-148.5℃. ESI-MS (m / z): 453.12 [M+H] + . 1 H NMR(400MHz, CDCl3) δ 7.66 – 7.60 (m, 1H), 7.52 (dd, J = 8.1, 1.8 Hz, 1H), 7.39 –7.33 (m, 2H), 7.32 – 7.24 (m, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.13 – 7.06 (m,1H), 7.06 – 6.95 (m, 2H), 6.94 – 6.87 (m, 1H), 6.55 (dd, J = 8.1, 1.7 Hz,1H), 3.90 – 3.73 (m, 4H), 3.10 (s, 4H), 2.35 (s, 3H), 2.31 (s, 3H). Example 37: Preparation of Compound 37

[0121] 0.70 g triphosgene, 20 g dichloromethane, 0.58 g 2-chlorothiophenol, and 0.75 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to room temperature and stirred overnight.

[0122] 0.80 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.42 g of a white solid, i.e., compound 37.

[0123] HPLC purity 98.16%. mp: 144.5-145.2℃. ESI-MS (m / z): 491.16 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ 7.63 (dd, J = 7.8, 2.0 Hz, 1H), 7.52 (dd, J = 8.1, 1.8 Hz, 1H), 7.48 – 7.22 (m, 3H), 7.16 (d, J = 1.6 Hz, 1H), 7.12 – 6.93 (m, 3H), 6.94– 6.84 (m, 1H), 6.55 (dd, J = 8.1, 1.7 Hz, 1H), 3.91 – 3.74 (m, 4H), 3.12 (s,4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 38: Preparation of Compound 38

[0124] 0.70 g triphosgene, 20 g dichloromethane, 0.76 g 4-bromobenzenethiol, and 0.75 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to room temperature and stirred overnight.

[0125] 0.80 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.75 g of a white solid, i.e., compound 38.

[0126] HPLC purity 98.30%. mp: 135.6-136.2℃. ESI-MS (m / z): 534.98 [M+Na] + . 1H NMR (400MHz, CDCl3) δ 7.55 – 7.49 (m, 2H), 7.41 – 7.34 (m, 3H), 7.16 (s, 1H), 7.12 – 7.06 (m, 1H), 7.05 – 7.00 (m, 2H), 6.94 – 6.86 (m, 1H), 6.55 (dd, J =7.9, 1.1 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 39: Preparation of Compound 39

[0127] 0.70g triphosgene, 20g dichloromethane, 0.64g naphthiophenol, and 0.75g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 minutes in an ice-water bath, and then heated to room temperature and stirred overnight.

[0128] 0.80 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.58 g of a white solid, i.e., compound 39.

[0129] HPLC purity 97.37%. mp: 148.3-149.7℃. ESI-MS (m / z): 485.11 [M+H] + . 1 H NMR(400MHz, CDCl3) δ 8.06 – 8.03 (m, 1H), 7.88 – 7.80 (m, 3H), 7.57 (dd, J = 8.5,1.8 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.12 – 7.06 (m, 1H), 7.06 – 7.00 (m, 2H), 6.90 (ddd, J = 7.9, 7.1, 1.6 Hz, 1H), 6.55 (dd, J = 7.9, 1.3 Hz, 1H), 3.86 – 3.76 (m, 4H), 3.12 (s, 4H), 2.36(s, 3H), 2.32(s, 3H). Example 40: Preparation of Compound 40

[0130] 0.70 g triphosgene, 20 g dichloromethane, 0.51 g 4-hydroxythiophenol, and 0.75 g triethylamine were slowly added dropwise at 0-5°C. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to room temperature and stirred overnight.

[0131] 0.80 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.47 g of solid, i.e., compound 40.

[0132] HPLC purity 94.76%. mp: 193.9-195.7℃. ESI-MS (m / z): 473.08 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ10.45 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.33 – 7.29 (m,1H), 7.29 – 7.25 (m, 2H), 7.15 (d, J = 0.7 Hz, 1H), 7.11 – 7.06 (m, 1H), 7.06– 7.00 (m, 2H), 6.93 – 6.87 (m, 1H), 6.74 – 6.70 (m, 1H), 6.55 (dd, J = 7.9,1.4 Hz, 1H), 3.81 (s, 4H), 3.11 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 41: Preparation of Compound 41

[0133] 0.46 g of triphosgene and 30 mL of dichloromethane were added in an ice-water bath, and 0.92 g of vortioxetine was added. 0.92 g of triethylamine was added dropwise. After the addition was completed, the mixture was kept warm for 5-10 min, and the mixture was heated to room temperature and reacted for 7 h. 0.38 g of 4-mercaptopyridine was added and the reaction was continued overnight. After the reaction was completed, the mixture was concentrated until there was no fraction. Column chromatography was used for purification (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 15 / 85, V / V) to obtain 0.32 g of an off-white solid, i.e., compound 41.

[0134] HPLC purity 96.38%. mp: 153.7-154.4℃. ESI-MS (m / z): 436.28 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) d 8.59 – 8.53 (m, 2H), 7.52 – 7.48 (m, 2H), 7.31 (d, J = 8.0Hz, 1H), 7.24 – 7.19 (m, 1H), 7.16 – 7.05 (m, 3H), 6.95 – 6.88 (m, 1H), 6.37(dd, J =8.0, 1.2 Hz, 1H), 3.72 – 3.60 (m, 4H), 3.06-2.96 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H). Example 42: Preparation of Compound 42

[0135] 0.50 g of triphosgene and 30 mL of dichloromethane were added, cooled in an ice-water bath, 1.00 g of vortioxetine was added, and 1.00 g of triethylamine was added dropwise. After the addition was completed, the temperature was kept at room temperature for 5-10 minutes, and the temperature was raised to room temperature for reaction for 7 hours. 0.77 g of 2,4,6-trichlorobenzenethiol was added, and the reaction was continued overnight. After the reaction was completed, the mixture was concentrated until there was no fraction. Column chromatography was used for purification (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 0.60 g of an off-white solid, i.e., compound 42.

[0136] HPLC purity 97.24%. mp: 173.5-174.7℃. ESI-MS (m / z): 559.14 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) d 7.84 (s, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.15 – 7.05 (m, 3H), 6.94 – 6.88 (m, 1H), 6.37 (dd, J = 8.0, 1.4 Hz, 1H), 3.76– 3.52 (m, 4H), 3.10 – 2.86 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H). Example 43: Preparation of Compound 43

[0137] 0.70 g of triphosgene and 20 g of dichloromethane were added at 0-5°C, and 0.56 g of 4-methoxythiophenol was slowly added dropwise, and 0.75 g of triethylamine was added dropwise. After the addition was completed, the mixture was stirred for 30 min in an ice-water bath, and then heated to room temperature and stirred overnight.

[0138] 0.80 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.46 g of a white solid, i.e., compound 43.

[0139] HPLC purity 99.18%. mp: 124.5-125.2℃. ESI-MS (m / z): 465.11 [M+H] + . 1 H NMR(400MHz, CDCl3) δ 7.46 – 7.40 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.19 – 7.13(m, 1H), 7.13 – 7.06 (m, 1H), 7.05 – 6.95 (m, 2H), 6.95 – 6.90 (m, 2H), 6.90– 6.85 (m, 1H), 6.55 (dd, J = 8.0, 1.6 Hz, 1H), 3.82 (s, 3H), 3.80 – 3.61 (m,4H), 3.10 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H). Example 44: Preparation of Compound 44

[0140] 0.50 g of triphosgene and 60 mL of dichloromethane were added in an ice-water bath, and 0.57 g of 6-mercaptopurine was added, and 1.04 g of triethylamine was added dropwise. After the addition was completed, the temperature was kept at room temperature for 5-10 min, and the temperature was raised to room temperature for reaction for 7 h. 1.00 g of vortioxetine was added, and the reaction was continued overnight. After the reaction was completed, the mixture was concentrated until there was no fraction. Column chromatography was used for purification (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 10 / 90, V / V) to obtain 0.44 g of an off-white solid, i.e., compound 44.

[0141] HPLC purity 95.74%. mp: 235.8-237.2℃. ESI-MS (m / z): 499.11 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) d13.93 (s, 1H), 8.48 (s, 1H), 8.24 (d, J = 3.6 Hz, 1H), 7.30(d, J = 7.6 Hz, 1H), 7.22 – 7.18 (m, 1H), 7.15 – 7.04 (m, 3H), 6.96 – 6.87 (m,1H), 6.37 (dd, J = 8.0, 1.2 Hz, 1H), 3.98 – 3.34 (m, 4H), 3.18 – 2.95 (m, 4H), 2.28 (s, 3H), 2.19 (s, 3H). Example 45: Preparation of Compound 45

[0142] 0.50 g of triphosgene and 30 mL of dichloromethane were added in an ice-water bath, and 1.00 g of vortioxetine was added. 1.00 g of triethylamine was added dropwise. After the addition was completed, the mixture was kept warm for 5-10 min, and the mixture was heated to room temperature for 7 h. 0.37 g of 2-mercaptopyridine was added, and the reaction was continued overnight. After the reaction was completed, the mixture was concentrated until there was no fraction. Column chromatography was used for purification (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 0.46 g of an off-white solid, i.e., compound 45.

[0143] HPLC purity 95.30%. mp: 135.8-137.2℃. ESI-MS (m / z): 458.19 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) d 8.57 – 8.48 (m, 1H), 7.87 – 7.79 (m, 1H), 7.68 – 7.64 (m,1H), 7.40 – 7.35 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.16– 7.04 (m, 3H), 6.94 – 6.86 (m, 1H), 6.37 (dd, J = 8.0, 1.2 Hz, 1H), 3.70 –3.56 (m, 4H), 3.08 – 2.89 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H). Example 46: Preparation of Compound 46

[0144] 0.50 g of triphosgene and 30 mL of dichloromethane were added in an ice-water bath, and 1.00 g of vortioxetine was added. 1.00 g of triethylamine was added dropwise. After the addition, the mixture was kept warm for 5-10 min, and the mixture was heated to room temperature for 7 h. 0.38 g of 2-mercaptothiophene was added, and the reaction was continued overnight. After the reaction was completed, the mixture was concentrated until there was no fraction. Column chromatography was used for purification (the elution ratio of the eluent was petroleum ether to ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 0.57 g of an off-white solid, i.e., compound 46.

[0145] HPLC purity 95.76%. mp: 123.8-125.2℃. ESI-MS (m / z): 463.19 [M+Na] + . 1 H NMR (400 MHz, DMSO- d 6) δ 7.80 (dd, J = 5.2, 1.2 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H),7.25 (dd, J = 3.6, 1.2 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.15 – 7.05 (m, 4H), 6.94– 6.88 (m, 1H), 6.37 (dd, J = 8.0, 1.2 Hz, 1H), 3.68 – 3.55 (m, 4H), 3.11 –2.91 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H). Example 47: Preparation of Compound 47

[0146] 0.70g triphosgene, 20g dichloromethane, add 0.47g p-isopropylthiophenol at 0-5°C, and slowly add 0.75g triethylamine. After the addition is complete, continue stirring in an ice-water bath for 30 minutes, then warm to room temperature and stir overnight.

[0147] 0.80 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the liquids were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.53 g of a white solid, i.e., compound 47.

[0148] HPLC purity: 96.41%. mp: 63.2-63.9℃. ESI-MS (m / z): 477.19 [M+H]+. 1H NMR(400MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.27 –7.24 (m, 2H), 7.15 (s, 1H), 7.11 – 7.06 (m, 1H), 7.05 – 7.00 (m, 2H), 6.92 –6.86 (m, 1H), 6.54 (dd, J = 7.9, 1.3 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H),2.91 (dq, J = 13.9, 6.9 Hz, 1H), 2.36 (s, 3H), 2.32 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H). Experiment: Pharmacokinetic behavior of vortioxetine derivatives in rats Experimental animals: Male SD rats, purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd., weighing 180-220 g, 3 rats in each group.

[0149] The oily or waxy prodrug compound is administered in the form of an oily solution. Preparation method of the oily solution: dissolve the oily or waxy vortioxetine prodrug derivative in soybean oil for injection to prepare an oily solution of 40 mg / mL (based on vortioxetine).

[0150] The crystalline solid is administered as an aqueous suspension. Preparation method of aqueous suspension: CMC-Na and Tween 20 are dissolved in ultrapure water to prepare an aqueous solution containing 1.5% CMC-Na and 0.4% Tween 20. After passing the solid vortioxetine prodrug derivative through a 200-mesh sieve, an appropriate amount is added to the above aqueous solution to prepare a 40 mg / mL (based on vortioxetine) suspension.

[0151] Each group of rats was intramuscularly injected with the above drugs at a dose of 20 mg / kg, and blood was collected from the eye sockets before and 15 minutes, 1 hour, 6 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 11 days, 14 days, 18 days, 21 days, 25 days, and 28 days after administration. 0.25 mL of blood was collected each time and placed in an EP tube pre-treated with heparin. The blood was centrifuged at 12000 rpm for 5 minutes, and the plasma was frozen at -80°C for detection.

[0152] Biological sample pretreatment: 50 μL of drug-containing plasma was added with 50 μL of internal standard (agomelatine, 2 ng / mL) and 150 μL of methanol, vortexed for 1 min, centrifuged at 12000 rpm for 5 min, and the supernatant was taken for sample analysis.

[0153] Testing instruments: Ultra-high performance liquid chromatography system: Ultimate3000 (Thermo Corporation, USA); Triple quadrupole tandem chromatograph: TSQ Quantiva (Thermo Corporation, USA); Data acquisition: Xcalibur (Thermo Corporation, USA); Mass spectrometry conditions: ion source: electrospray ionization source (ESI); ionization voltage: 5000 V; temperature: 500°C; sheath gas: 50 Arb; auxiliary gas: 50 Arb; positive ion mode detection, scan time: 200 ms.

[0154] The main pharmacokinetic parameters of vortioxetine produced by the metabolism of the prodrug compound in vivo are shown in Table 2.

[0155] Table 2 Main pharmacokinetic parameters of vortioxetine produced by the metabolism of prodrug compounds in vivo

[0156] Note: "~" indicates that "T1 / 2(d)" and "AUC" cannot be calculated because there is no downward trend in the concentration of vortioxetine over 28 days. 0-∞ ”.

[0157] As can be seen from Table 2, the half-life of vortioxetine free base in vivo is 2.09 days, and the half-life of vortioxetine produced by the metabolism of the prodrug compound of the present invention in vivo is greatly prolonged.

[0158] The first category, hydroxylamine compounds (compounds 1-5), release vortioxetine with a half-life of 6.06-19.34 days, with an average of 12.11 days. The drug concentrations of representative compounds 1, 3, and 4 produced by metabolism over time in vivo are shown in Table 3. The blood drug concentration-time curves of vortioxetine produced by their metabolism in vivo are shown in Figure 1 shown.

[0159] Table 3 Prodrug compounds 1, 3, 4 metabolized to produce vortioxetine drug concentration over time

[0160] Note: The drug concentration of each compound in the table is the average drug concentration in the blood of three rats.

[0161] From Table 3 and Figure 1It can be seen that compounds 1, 3, and 4 can achieve sustained release of vortioxetine (>1 ng / mL) in vivo for 21 days. The peak drug concentration of compound 1 is higher, and the concentration fluctuation is large in the early stage. The concentration fluctuation of vortioxetine in compounds 3 and 4 is small, and the stable release of vortioxetine can be achieved.

[0162] The second category is carbamates / thiocarbamates. Compounds 6 to 29 are carbamates, and the half-life of vortioxetine release is 2.30 to 196.97 days, with an average of 22.8 days. Compounds 30 to 47 are thiocarbamates, and the half-life of vortioxetine release is 4.23 to 1153.1 days, with an average of 97.6 days. The drug concentration of vortioxetine produced by the metabolism of representative compounds 14, 24, 41, and 45 over time in vivo is shown in Table 4, and the blood drug concentration-time curve of vortioxetine produced by its metabolism in vivo is shown in Figure 2 shown.

[0163] Table 4 Prodrug compounds 14, 24, 41, 45 metabolized to produce vortioxetine drug concentration over time

[0164] Note: The drug concentration of each compound in the table is the average drug concentration in the blood of three rats.

[0165] From Table 4 and Figure 2 It can be seen that compounds 14, 24, 41, and 45 can achieve sustained release of vortioxetine (>10 ng / mL) for >28 days in vivo, and the vortioxetine concentration fluctuates slightly and the drug release is stable.

[0166] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A long-acting prodrug derivative of vortioxetine, characterized in that: Including compounds having the structure shown in formula (I): Wherein, R1 is selected from the following groups: or wherein R2 is independently selected from methyl, trifluoromethyl or cyano, and m is selected from an integer of 0-2; X is selected from an oxygen atom or a sulfur atom; R3 is selected from aryl or heteroaryl, and the aryl is independently substituted by halogen, cyano, trifluoromethyl, nitro, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, amino or C1-C4 alkylamino, and the number of substituents is 0-3. When X is selected from oxygen atom, the aryl cannot be phenyl without any substitution; the heteroaryl is independently substituted by hydroxyl or C1-C4 alkoxy, and the number of substituents is 0-1.

2. The long-acting prodrug derivative of vortioxetine according to claim 1, characterized in that: R1 is selected from the following groups: ， ， ， ， 。 3. The long-acting prodrug derivative of vortioxetine according to claim 1, characterized in that: R1 is selected from the following groups: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 4. The long-acting prodrug derivative of vortioxetine according to claim 1, characterized in that: Also included are pharmaceutically acceptable salts of the compounds having the structure represented by formula (I).

5. A pharmaceutical composition, characterized in that The invention comprises the vortioxetine long-acting prodrug derivative as described in any one of claims 1 to 4.

6. The pharmaceutical composition according to claim 5, characterized in that Administer in parenteral form.

7. Use of the vortioxetine long-acting prodrug derivative according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating diseases related to 5-hydroxytryptamine receptors.

8. The use according to claim 7, characterized in that The diseases include depression.

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