CN104356092A - Preparation method for vortioxetine - Google Patents
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- CN104356092A CN104356092A CN201410509736.1A CN201410509736A CN104356092A CN 104356092 A CN104356092 A CN 104356092A CN 201410509736 A CN201410509736 A CN 201410509736A CN 104356092 A CN104356092 A CN 104356092A
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention relates to the field of medicament synthesis, in particular to a novel preparation method for an antidepressant medicament intermediate vortioxetine. The method comprises the following steps of reacting 2,4-dimethylthiophenol with 2-halogen chlorobenzene to obtain an intermediate 2-(2,4-dimethylthiophenyl) chlorobenzene, and reacting the intermediate with piperazine to obtain vortioxetine. According to the method, the total yield can reach 68 to 75 percent, the method has the advantages of starting materials are low in cost and easy to obtain, the process is simple, and the requirements of large-scale production are met.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, irrigate the novel preparation method for Xi Ting in particular to a kind of antidepressant drug intermediate.
Background technology
Fertile for Xi Ting, English Vortioxetine, CAS accession number: 508233-74-7 by name, be the medicine being used for the treatment of major depressive disorder adult patient by Takeda Pharmaceutical Company Limited of the U.S. and Ling Bei drugmaker of U.S. joint development, its chemical structural formula is as follows:
U.S. FDA ratifies Brintellix (Vortioxetine in September, 2013, fertile for Xi Ting) listing, in addition, on December 27th, 2013, Brintellix (vortioxetine) also obtain final approval in European Union, is also delivered to State Bureau Yao Shen center in June, 2014 at the import application for registration Hydrogen bromide Wo Saiting sheet of this medicine of China.
World-leading pharmacy and health care problem are studied and consulting firm---and Decision Resource company (Decision Resources) once issued address prediction, by 2022, new antidepressant Brintellix will be expected to into a pound medicine of attaching most importance in the U.S., France, Germany, Italy, Spain, Britain, Japanese market.According to the data obtained so far, in view of it is on the positive impact of cognition and the side effect attribute that can tolerate, Brintellix estimates to become the most successful new drug in unipolar depression market.
At present, the fertile document for western spit of fland synthetic method of report is also few, grinds except a series of patents that clever northern pharmacy apply in China except former, and domestic also have minority to be different from former new synthetic method of grinding patent to report.
The former synthetic method reported in world patent WO2003029232, WO2007144005, WO2010094285 of clever northern pharmaceutical applications of grinding is as follows:
With 2 in this route; 4-thiophenol dimethyl benzene, adjacent bromo-iodobenzene are that starting raw material synthesizes 2-(2; 4-3,5-dimethylphenyl sulfenyl) bromobenzene; and then there is Buchwald-Hartwig linked reaction with the piperazine that single Boc protects; obtain replacing Xi Ting with the fertile of protecting group; the adjacent bromo-iodobenzene used in this route is expensive; cause process costs higher; in addition; the protection of piperazinyl and deprotection too increase the complexity of operational path; virtually also make the cycle of research and development lengthen, too increase the cost of technique simultaneously to a certain extent.
In addition, another synthetic route reported in the patent CN02819025 that clever northern pharmacy is applied in China is as follows:
In this route in the process of reduction nitro, employ iron powder and make reductive agent, the iron mud that meeting by-product is a large amount of, cause product to be wrapped absorption, affect yield; In addition, in the reduction process of carbonyl, need to use the larger borine of toxicity, be unfavorable for the large production in workshop, therefore, in making this route not be suitable for commercially producing.
The disclosed synthetic method of world patent WO2007144005 (route 2) and WO201302573 (route 3) is a kind of one pot reaction after improving, three starting raw materials directly add in same catalystic converter system by the method, and direct reaction obtains fertile for Xi Ting.
These two routes improved and Yuan Yan company earlier application method compared with, be kept to single step reaction by original two to three-step reaction, decrease postprocessing working procedures, while also significantly can shorten reaction time, but shortcoming is also apparent.In one pot reaction, owing to phenyl ring there being two different halogens, outside reacting with 2,4-thiophenol dimethyl benzene, also simultaneously can with piperazine generation competing reaction, synthesize fertile for while Xi Ting, also create much side reaction impurity, these impurity are close with the fertile polarity for Xi Ting, are difficult to purifying, make the purity of the finished product be difficult to reach medicinal requirements, also can cause the significantly reduction of yield simultaneously.In addition, be exactly all need in these two lines to use expensive iodo thing, make process costs higher, these all constrain the application of this route in actual production.
The synthetic route that Chinese patent CN201410166305 (route 4) and CN201410028213 (route 5) report is as follows respectively:
From these two Research idea of report, roughly the same, all with 2,4-thiophenol dimethyl benzene, 2-halogen oil of mirbane are starting raw material, obtain fertile for Xi Ting through condensation, reduction, cyclization, and the method is not used and formerly ground expensive 2-bromo-iodobenzene in patent, therefore more former to grind route cost low for cost, but will use the reductive agents such as hydrazine hydrate, iron powder, tin protochloride or hydrogen in the reduction step of nitro, hydrazine hydrate belongs to anakinetomer, there is potential safety hazard in use procedure; And with iron powder or tin protochloride for reductive agent time, there is aftertreatment difficulty, the defects such as product absorption is serious, product yield can be had a strong impact on; Hydrogenation needs under high pressure to carry out, and higher to equipment requirements, these factors are all unfavorable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of fertile new preparation process for Xi Ting, this operational path is brief, do not relate to harsh reaction conditions and the use of high toxogen material, also the more former process costs grinding clever northern pharmacy is low for cost simultaneously, can better adapt to industrial requirement.
The present invention irrigates the preparation method for Xi Ting, comprising:
Step 1) 2,4-thiophenol dimethyl benzenes and 2-halogen chlorobenzene by condensation reaction obtain intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene and
Step 2) intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene and piperazine obtain fertile for Xi Ting by linked reaction.
The present invention irrigates in the preparation method for Xi Ting, described step 1) 2, the condensation reaction of 4-thiophenol dimethyl benzene and 2-halogen chlorobenzene is copper, cuprous bromide or cuprous iodide at condensation catalyst, solvent is toluene, dimethylbenzene, N, dinethylformamide or dimethyl sulfoxide (DMSO), alkali is reacting by heating 10-20 hour under the inert atmosphere of sodium tert-butoxide.
The mol ratio of described 2,4-thiophenol dimethyl benzenes and 2-halogen chlorobenzene is preferably 1:1.0 ~ 1:2.0.
Described 2-halogen chlorobenzene is preferably orthodichlorobenzene, 2-bromochlorophene or 2-iodine chlorobenzene, most preferably is orthodichlorobenzene.
The consumption of described sodium tert-butoxide is 2 ~ 4 times of 2,4-thiophenol dimethyl benzene molar weight.
Described condensation catalyst add-on is 1% ~ 10% of 2,4-thiophenol dimethyl benzene molar weight, is preferably 3%-6%.
The present invention irrigates in the preparation method for Xi Ting, described step 2) intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) linked reaction of chlorobenzene and piperazine is copper, cuprous bromide or cuprous iodide at coupling catalyst, solvent is toluene, dimethylbenzene, N, dinethylformamide or dimethyl sulfoxide (DMSO), alkali is back flow reaction 3-8 hour under the inert atmosphere of sodium tert-butoxide; The consumption of described sodium tert-butoxide is 2 ~ 4 times of intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene molar weight.
The molar ratio of described intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene and piperazine is preferably 1:1.0 ~ 1:3.0, most preferably is 1:2.0 ~ 1:2.2.
Described coupling catalyst add-on is 1% ~ 10% of 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene molar weight, is preferably 3%-6%.
A kind of operational path meeting industrialization production requirements of the present invention, concrete adopts following synthetic route:
Step 1) reacted after, by reaction mixture cool, washing filtering, filtrate is used saturated common salt water washing, methylbenzene extraction aqueous phase, concentrating under reduced pressure toluene phase, obtain refining oil product 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene, productive rate more than 85%.
Step 2) react completely after, reaction mixture is cooled, washing filtering, uses saturated common salt water washing by filtrate, methylbenzene extraction aqueous phase, to toluene mutually in add concentrated hydrochloric acid and water, stir stratification, collect aqueous phase, adjusting PH with base value 7 ~ 8 under ice bath, dichloromethane extraction, merge organic phase, saturated common salt water washing, layering, organic phase is concentrated obtains off-white powder, dehydrated alcohol recrystallization, the white solid powder finished product namely obtaining refining is fertile for Xi Ting, and productive rate is more than 79%, M.p:116 ~ 118 DEG C, HPLC purity is not less than 99.58%.
Compared with the existing technology, be not difficult to find, the orthodichlorobenzene that the present invention adopts, 2-bromochlorophene or 2-iodine chlorobenzene, the o-dibromobenzene used in patent is ground than former, 2-bromo-iodobenzene price is low, simultaneously, take cuprous iodide as catalyzer, do not need to use expensive palladium catalyst and racemization 1, 1 '-dinaphthalene-2, 2-' diphenyl phosphine (BINAP) part, thus significantly reduce the fertile production cost for Xi Ting, in the present invention, the fertile total recovery for Xi Ting can reach 68% ~ 75%, this novel process has raw material and is easy to get, the advantage of with low cost and concise in technology, meet large requirement of producing completely, finally realize suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 be the fertile proton nmr spectra for Xi Ting (
1h NMR) spectrogram.
Fig. 2 is the fertile HPLC liquid chromatogram for Xi Ting.
Embodiment
Following embodiment further illustrates using as the explaination to the technology of the present invention content for content of the present invention; but flesh and blood of the present invention is not limited in described in following embodiment, those of ordinary skill in the art can and should know any simple change based on connotation of the present invention or replace all should belong to protection domain of the presently claimed invention.
Embodiment 1
1. the synthesis of 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene:
By 2 of 14g, the NaOtBu (304.2mmol) of the orthodichlorobenzene (202.8mmol) of 6-thiophenol dimethyl benzene (101.4mmo1), 29.8g, the CuI (5.1mmol) of 965mg and 29.2g adds in the Yue benzene of 210mL successively, opens and stirs.By whole reaction system nitrogen replacement 3 times (reaction needed is carried out under nitrogen protection), outer temperature oil bath temperature is risen to 120 DEG C, keep reaction system to be in reflux state, insulation reaction 16 hours at such a temperature.Reaction mixture is cooled, adds the water of 50mL, and stir l hour, then by the mixture of filter aid gained.Filtrate is washed with saturated aqueous common salt (3*100mL).Then, by the methylbenzene extraction of the aqueous phase 200ml of merging.Then, by the toluene phase concentrating under reduced pressure merged, 21.4g oily matter (productive rate is 86%) is obtained.
2. the fertile synthesis for Xi Ting and purifying:
By the above-mentioned gained oily matter 2-(2 of 21.4g, 4-3,5-dimethylphenyl sulfenyl) chlorobenzene (86mmo1), the piperazine (172mmol) of 14.8g, the CuI (4.3mmol) of 819mg and 24.8g NaOtBu (258mmol) add successively in the toluene of 300mL, open stir.By whole reaction system nitrogen replacement 3 times (reaction needed is carried out under nitrogen protection), outer temperature oil bath temperature is risen to 120 DEG C, keep reaction system to be in reflux state, insulation reaction 5 hours at such a temperature.Reaction mixture is cooled, adds the water of 70mL, and stir l hour, then by the mixture of filter aid gained.Filtrate is washed with saturated aqueous common salt (3*150mL).Then, by the Yue benzene extraction of the aqueous phase 300ml of merging.Merge organic phase, add 20mL concentrated hydrochloric acid and 100mL water wherein, stir 1 hour, stratification.Collect aqueous phase, 2mol/L sodium hydroxide solution adjust ph to 7 ~ 8 are slowly added under condition of ice bath, with dichloromethane extraction (2*100mL), merge organic phase, saturated common salt water washing, layering, organic phase is concentrated obtains 22g off-white powder, recrystallization in dehydrated alcohol, obtains 20.3g white solid powder (productive rate is 79%).M.p:116 ~ 118 DEG C, HPLC purity 99.65%, as Fig. 2.
1h NMR (400MHz, DMSO-d6), δ (ppm): 7.33 (1H, d, J=9.6Hz), 7.17 (s, 1H), 7.17 ~ 7.09 (m, 3H), 6.99 ~ 6.43 (m, 1H), 6.41 (1H, d, J=7.2Hz), 3.19 ~ 3.14 (dd, 8H), 2.245 (s, 3H), 2.329 (s, 3H), as Fig. 1.
Embodiment 2
3. the synthesis of 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene:
By 2 of 14g, the NaOtBu (304.2mmol) of the 2-bromochlorophene (152.1mmol) of 6-thiophenol dimethyl benzene (101.4mmo1), 29.1g, the CuI (5.1mmol) of 965mg and 29.2g adds in the Yue benzene of 210mL successively, opens and stirs.By whole reaction system nitrogen replacement 3 times (reaction needed is carried out under nitrogen protection), outer temperature oil bath temperature is risen to 120 DEG C, keep reaction system to be in reflux state, insulation reaction 16 hours at such a temperature.Reaction mixture is cooled, adds the water of 50mL, and stir l hour, then by the mixture of filter aid gained.Filtrate is washed with saturated aqueous common salt (3*100mL).Then, by the Yue benzene extraction of the aqueous phase 200ml of merging.Then, by the Yue benzene phase concentrating under reduced pressure merged, 22.9g oily matter (productive rate is 91%) is obtained.
4. the fertile synthesis for Xi Ting and purifying:
By the above-mentioned gained oily matter 2-(2 of 22.9g, 4-3,5-dimethylphenyl sulfenyl) chlorobenzene (92mmo1), the piperazine (193.2mmol) of 16.6g, the CuI (4.6mmol) of 876mg and 26.5g NaOtBu (276mmol) add successively in the toluene of 300mL, open stir.By whole reaction system nitrogen replacement 3 times (reaction needed is carried out under nitrogen protection), outer temperature oil bath temperature is risen to 120 DEG C, keep reaction system to be in reflux state, insulation reaction 5 hours at such a temperature.Reaction mixture is cooled, adds the water of 70mL, and stir l hour, then by the mixture of filter aid gained.Filtrate is washed with saturated aqueous common salt (3*150mL).Then, by the Yue benzene extraction of the aqueous phase 300ml of merging.Merge organic phase, add 20mL concentrated hydrochloric acid and 100mL water wherein, stir 1 hour, stratification.Collect aqueous phase, 2mol/L sodium hydroxide solution adjust ph to 7 ~ 8 are slowly added under condition of ice bath, with dichloromethane extraction (2*100mL), merge organic phase, saturated common salt water washing, layering, organic phase is concentrated obtains 24g off-white powder, recrystallization in dehydrated alcohol, obtains 22.2g white solid powder (productive rate is 81%).M.p:116 ~ 118 DEG C, HPLC purity 99.58%.
1H NMR(400MHz,DMSO-d6),δ(ppm):7.33(1H,d,J＝9.6Hz),7.17(s,1H),7.17～7.09(m,3H),6.99～6.43(m,1H),6.41(1H,d,J＝7.2Hz),3.19～3.14(dd,8H),2.245(s,3H),2.329(s,3H).
Embodiment 3
5. the synthesis of 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene:
By 2 of 14g, the NaOtBu (304.2mmol) of the 2-iodine chlorobenzene (106.5mmol) of 6-thiophenol dimethyl benzene (101.4mmo1), 25.4g, the CuI (5.1mmol) of 965 mg and 29.2g adds in the Yue benzene of 210mL successively, opens and stirs.By whole reaction system nitrogen replacement 3 times (reaction needed is carried out under nitrogen protection), outer temperature oil bath temperature is risen to 120 DEG C, keep reaction system to be in reflux state, insulation reaction 16 hours at such a temperature.Reaction mixture is cooled, adds the water of 50mL, and stir l hour, then by the mixture of filter aid gained.Filtrate is washed with saturated aqueous common salt (3*100mL).Then, by the Yue benzene extraction of the aqueous phase 200ml of merging.Then, by the Yue benzene phase concentrating under reduced pressure merged, 22.7g oily matter (productive rate is 90%) is obtained.
6. the fertile synthesis for Xi Ting and purifying:
By the above-mentioned gained oily matter 2-(2 of 22.7g, 4-3,5-dimethylphenyl sulfenyl) chlorobenzene (91.2mmo1), the piperazine (200.6mmol) of 17.2g, the CuI (4.6mmol) of 876mg and 26.3g NaOtBu (274mmol) add successively in the toluene of 300mL, open stir.By whole reaction system nitrogen replacement 3 times (reaction needed is carried out under nitrogen protection), outer temperature oil bath temperature is risen to 120 DEG C, keep reaction system to be in reflux state, insulation reaction 5 hours at such a temperature.Reaction mixture is cooled, adds the water of 70mL, and stir l hour, then by the mixture of filter aid gained.Filtrate is washed with saturated aqueous common salt (3*150mL).Then, by the Yue benzene extraction of the aqueous phase 300ml of merging.Merge organic phase, add 20mL concentrated hydrochloric acid and 100mL water wherein, stir 1 hour, stratification.Collect aqueous phase, 2mol/L sodium hydroxide solution adjust ph to 7 ~ 8 are slowly added under condition of ice bath, with dichloromethane extraction (2*100mL), merge organic phase, saturated common salt water washing, layering, organic phase is concentrated obtains 24.3g off-white powder, recrystallization in dehydrated alcohol, obtains 22.5g white solid powder (productive rate is 83%).M.p:116 ~ 118 DEG C, HPLC purity 99.58%.
1H NMR(400MHz,DMSO-d6),δ(ppm):7.33(1H,d,J＝9.6Hz),7.17(s,1H),7.17～7.09(m,3H),6.99～6.43(m,1H),6.41(1H,d,J＝7.2Hz),3.19～3.14(dd,8H),2.245(s,3H),2.329(s,3H)。
Claims (10)
1. the fertile preparation method for Xi Ting, comprise: step 1) 2,4-thiophenol dimethyl benzene and 2-halogen chlorobenzene obtain intermediate 2-(2 by condensation reaction, 4-3,5-dimethylphenyl sulfenyl) chlorobenzene and step 2) intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene and piperazine obtain fertile for Xi Ting by linked reaction.
2. irrigate the preparation method for Xi Ting as claimed in claim 1, it is characterized in that, described step 1) 2, the condensation reaction of 4-thiophenol dimethyl benzene and 2-halogen chlorobenzene is copper, cuprous bromide or cuprous iodide at condensation catalyst, solvent is toluene, dimethylbenzene, N, dinethylformamide or dimethyl sulfoxide (DMSO), alkali is reacting by heating 10-20 hour under the inert atmosphere of sodium tert-butoxide.
3. irrigate the preparation method for Xi Ting as claimed in claim 2, it is characterized in that, the mol ratio of described 2,4-thiophenol dimethyl benzenes and 2-halogen chlorobenzene is 1:1.0 ~ 1:2.0.
4. the fertile preparation method for Xi Ting as described in Claims 2 or 3, it is characterized in that, described 2-halogen chlorobenzene is orthodichlorobenzene, 2-bromochlorophene or 2-iodine chlorobenzene.
5. irrigate the preparation method for Xi Ting as claimed in claim 4, it is characterized in that, the consumption of described sodium tert-butoxide is 2 ~ 4 times of 2,4-thiophenol dimethyl benzene molar weight.
6. irrigate the preparation method for Xi Ting as claimed in claim 2, it is characterized in that, described condensation catalyst add-on is 1% ~ 10% of 2,4-thiophenol dimethyl benzene molar weight.
7. irrigate the preparation method for Xi Ting as claimed in claim 1, it is characterized in that, described step 2) intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) linked reaction of chlorobenzene and piperazine is copper, cuprous bromide or cuprous iodide at coupling catalyst, solvent is toluene, dimethylbenzene, N, dinethylformamide or dimethyl sulfoxide (DMSO), alkali is back flow reaction 3-8 hour under the inert atmosphere of sodium tert-butoxide; The consumption of described sodium tert-butoxide is intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) 2 ~ 4 times of chlorobenzene molar weight.
8. the fertile preparation method for Xi Ting as claimed in claim 7, is characterized in that, described intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) molar ratio of chlorobenzene and piperazine is 1:1.0 ~ 1:3.0.
9. the fertile preparation method for Xi Ting as claimed in claim 8, is characterized in that, described intermediate 2-(2,4-3,5-dimethylphenyl sulfenyl) molar ratio of chlorobenzene and piperazine is 1:2.0 ~ 1:2.2.
10. the fertile preparation method for Xi Ting as claimed in claim 7, it is characterized in that, described coupling catalyst add-on is 2-(2,4-3,5-dimethylphenyl sulfenyl) chlorobenzene molar weight 1% ~ 10%.
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| CN109912538A (en) * | 2019-01-22 | 2019-06-21 | 安徽赛乐普制药有限公司 | A kind of preparation method of antidepressants Vortioxetine |
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| CN104829557A (en) * | 2015-04-23 | 2015-08-12 | 济南百诺医药科技开发有限公司 | Novel compound 1-[2-(2,4-dimethylphenylthio)phenyl]-2-oxopiperazine and its preparation method and use in vortixetine synthesis |
| CN104829557B (en) * | 2015-04-23 | 2017-06-27 | 山东百诺医药股份有限公司 | A kind of noval chemical compound 1 [2（2,4 3,5-dimethylphenyl sulfenyls）Phenyl] 2 oxygen piperazines and preparation method thereof and the application in Vortioxetine synthesis |
| CN105330615A (en) * | 2015-12-08 | 2016-02-17 | 齐鲁天和惠世制药有限公司 | Preparation method of Vortioxetine |
| CN105330615B (en) * | 2015-12-08 | 2017-08-11 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of Vortioxetine |
| CN107843656A (en) * | 2016-09-21 | 2018-03-27 | 成都弘达药业有限公司 | A kind of detection method of 2,4 thiophenol dimethyl benzene about material |
| CN106568862A (en) * | 2016-11-04 | 2017-04-19 | 万全万特制药江苏有限公司 | Method for separation and determination of vortioxetine hydrobromide intermediate related substances by liquid chromatography |
| CN109912538A (en) * | 2019-01-22 | 2019-06-21 | 安徽赛乐普制药有限公司 | A kind of preparation method of antidepressants Vortioxetine |
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