CN115368318A - Synthetic method and application of vortioxetine - Google Patents
Synthetic method and application of vortioxetine Download PDFInfo
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- CN115368318A CN115368318A CN202210711604.1A CN202210711604A CN115368318A CN 115368318 A CN115368318 A CN 115368318A CN 202210711604 A CN202210711604 A CN 202210711604A CN 115368318 A CN115368318 A CN 115368318A
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- vortioxetine
- reaction
- drying
- extracting
- piperazinyl
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- 229960002263 vortioxetine Drugs 0.000 title claims abstract description 50
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- WCHSYALJKNUPHT-UHFFFAOYSA-N 2-piperazin-1-ylbenzenethiol Chemical compound SC1=CC=CC=C1N1CCNCC1 WCHSYALJKNUPHT-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 12
- 229960004030 vortioxetine hydrobromide Drugs 0.000 claims abstract description 10
- VNGRUFUIHGGOOM-UHFFFAOYSA-N vortioxetine hydrobromide Chemical compound Br.CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 VNGRUFUIHGGOOM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 47
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 27
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 238000005406 washing Methods 0.000 claims description 21
- 239000012044 organic layer Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- 239000007810 chemical reaction solvent Substances 0.000 claims description 16
- 239000008213 purified water Substances 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 claims description 11
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical class ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 8
- ZQBVUULQVWCGDQ-UHFFFAOYSA-N propan-1-ol;propan-2-ol Chemical compound CCCO.CC(C)O ZQBVUULQVWCGDQ-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 18
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 238000000746 purification Methods 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 238000007086 side reaction Methods 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- BUNKQJAMHYKQIM-UHFFFAOYSA-N 1-iodo-2,4-dimethylbenzene Chemical compound CC1=CC=C(I)C(C)=C1 BUNKQJAMHYKQIM-UHFFFAOYSA-N 0.000 description 5
- AMNLXDDJGGTIPL-UHFFFAOYSA-N 2,4-dimethylbenzenethiol Chemical compound CC1=CC=C(S)C(C)=C1 AMNLXDDJGGTIPL-UHFFFAOYSA-N 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 125000004193 piperazinyl group Chemical group 0.000 description 5
- -1 4- [ (4-nitrophenoxy) carbonyloxymethyl ] phenoxymethyl Chemical group 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229910000859 α-Fe Inorganic materials 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- OIRHKGBNGGSCGS-UHFFFAOYSA-N 1-bromo-2-iodobenzene Chemical compound BrC1=CC=CC=C1I OIRHKGBNGGSCGS-UHFFFAOYSA-N 0.000 description 1
- KUFFULVDNCHOFZ-UHFFFAOYSA-N 2,4-xylenol Chemical compound CC1=CC=C(O)C(C)=C1 KUFFULVDNCHOFZ-UHFFFAOYSA-N 0.000 description 1
- MNVMYTVDDOXZLS-UHFFFAOYSA-N 4-methoxyguaiacol Natural products COC1=CC=C(O)C(OC)=C1 MNVMYTVDDOXZLS-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthetic method of vortioxetine, belonging to the technical field of chemical drug synthesis, comprising (1) synthesis of o-piperazinyl thiophenol, (2) synthesis of vortioxetine and (3) synthesis of vortioxetine hydrobromide, wherein the synthetic method has the following beneficial effects: the synthetic method of the Vortioxetine does not involve protection and deprotection of groups, can shorten the process flow, avoids side reactions, reduces the operation steps of later purification of the product, and is beneficial to industrial production.
Description
The technical field is as follows:
the invention belongs to the technical field of chemical drug synthesis, and particularly relates to a synthetic method of vortioxetine.
Background art:
vortioxetine is a novel drug developed by Lunabeck, a well-known pharmaceutical company in Denmark for the relief of major depressive disorders.
The mechanism of action of vortioxetine is believed to exert an antidepressant effect by inhibiting serotonin (5-HT) concentrations, which has little effect on norepinephrine and dopaminergic neurons compared to other inhibitors. A plurality of clinical tests show that the vortioxetine has a good effect on treating severe depression, and meanwhile, the research shows that the vortioxetine also has good performance in safety and tolerance.
According to the description of the original patent US7144884, 4- [ (4-nitrophenoxy) carbonyloxymethyl ] phenoxymethyl polystyrene is used as a starting material, coupled with a piperazine ring, then coupled with a ferrocene compound of o-dichlorobenzene, and finally removed with ferrocene and resin to obtain the product Voltamidin. The main synthetic route is as follows:
inevitably, the yield of the coupling reaction of 4- [ (4-nitrophenoxy) carbonyloxymethyl ] phenoxymethyl polystyrene and piperazine is low, and a large amount of compound 1 is formed.
Patent WO2013102573 discloses a one-pot synthesis route of vortioxetine, and a one-pot synthesis route of 2, 4-dimethylthiophenol, o-bromoiodobenzene and piperazine ring, but the reaction has the problem of double-halogen competition reaction of bromine and iodine, and expensive palladium catalyst and phosphorus ligand are used, which directly causes the problems of cost improvement of the reaction route, low reaction yield and the like.
In order to avoid the side reaction of the piperazine ring, the patent CN102617513A adopts Boc (tert-butoxycarbonyl) protection for the piperazine ring, so that the efficiency of the reaction of the compound 3 and the piperazine ring is higher, and the subsequent reaction step of removing Boc protection is added, which is troublesome in process and has a large influence on the yield of the final product.
Patent CN103936694A reports a synthetic method of vortioxetine, which uses o-nitrofluorobenzene and 2, 4-dimethylthiophenol as raw materials, and uses bis (2-chloroethyl) amine hydrochloride as cyclization reaction to obtain the product, but the product uses ferrite reduction, the reduction effect is poor, and the post-treatment is troublesome.
Recently, based on a synthetic method of vortioxetine reported in patent CN103936694A, some improvements were made: the o-nitrofluorobenzene is replaced by o-aminofluorobenzene and 2, 4-dimethylthiophenol as raw materials, and bis (2-chloroethyl) amine hydrochloride is used as a cyclization reaction in the middle to obtain a product, so that reduction of ferrite can be avoided, but the reaction effect of the o-aminofluorobenzene and the 2, 4-dimethylthiophenol is poor, a large number of side products are easily generated on reaction sites, and probably because the o-aminofluorobenzene can generate a self condensation reaction under the reaction condition of the o-aminofluorobenzene and 2, 4-dimethylphenol, and a halogen group can attack an ortho-position amino group under the reaction condition, so that the whole reaction process is influenced.
In the prior art, the synthetic methods of vortioxetine are various, but basically have various problems of difficult synthesis, more side reactions, poorer purity, lower yield or complicated purification process, difficult purification and the like.
The invention content is as follows:
in order to solve the problems and overcome the defects in the prior art, the invention provides a synthetic method of vortioxetine hydrobromide, which can effectively solve the problems.
The specific technical scheme for solving the technical problems comprises the following steps: the synthetic method of Vortioxetine is characterized by comprising the following steps:
step 1: adding o-aminothiophenol and bis (2-chloroethyl) amine hydrochloride into a reaction solvent I under the protection of nitrogen, and performing heating reflux reaction to generate a reaction solution I containing o-piperazinyl thiophenol;
step 2: extracting, purifying and drying reaction liquid I containing o-piperazinyl thiophenol to obtain o-piperazinyl thiophenol;
and step 3: adding 2, 4-dimethyl halogenated benzene and o-piperazinylthiophenol obtained in the step 2 into a reaction solvent II under the protection of nitrogen, adding an alkaline reagent, stirring and reacting at high temperature to generate a reaction liquid II containing the vortioxetine,
and 4, step 4: extracting, purifying and drying reaction liquid II containing the vortioxetine to obtain vortioxetine;
further, the reaction solvent I is ethanol or acetonitrile or dioxane or tetrahydrofuran;
further, the mol ratio of the o-aminothiophenol, the bis (2-chloroethyl) amine hydrochloride and the reaction solvent I is 1:1.0 to 1.5:20;
further, the extraction, purification and drying steps of step 2 comprise: adding purified water into a reaction solution I containing o-piperazinyl thiophenol for quenching reaction, adding an extracting agent for extraction and layering, washing an organic layer with a saturated saline solution, drying with anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and drying in vacuum at 55-65 ℃ to obtain o-piperazinyl thiophenol;
further, the reaction solvent II in the step 3 is DMF, DMSO or toluene, the reaction temperature is 110-130 ℃, the alkaline reagent is sodium tert-butoxide, sodium hydride or sodium ethoxide,
further, in the step 3, the molar ratio of the o-aminothiophenol, the bis (2-chloroethyl) amine salt, the reaction solvent II and the alkaline reagent is 1: (0.8-1.2): 20: (0.5 to 7.0);
further, the extracting, purifying and drying of the step 4 comprises: adding purified water into the reaction liquid II containing the vortioxetine to carry out quenching reaction, extracting by using an extracting agent, washing an organic layer by using saturated saline solution, decoloring by using activated carbon, filtering, combining the organic layers, evaporating the solvent under reduced pressure, and drying in vacuum to obtain the vortioxetine;
further, the volume ratio of the reaction solvent I to the purified water to the extracting agent in the step 2 is 1:1: (0.3-0.5); the molar ratio of the reaction solvent II to the purified water to the extracting agent in the step 4 is 1:1: (0.3-0.5), wherein the extracting agents in the step 2 and the step 4 are both ethyl acetate;
further, the vortioxetine is used for preparing vortioxetine hydrobromide, and the preparation method comprises the following steps: dissolving vortioxetine in an isopropanol solution, heating to 45 ℃, stirring for complete dissolution, slowly dripping a 45% hydrobromic acid solution, stirring for 30min when a solid is separated out, then adding the remaining 45% hydrobromic acid solution into the system, reacting for 1h at 50 ℃, filtering while hot, washing a filter cake by using a mixed solution of isopropanol and 45% hydrobromic acid, collecting the filter cake, adding methyl tert-butyl ether, controlling the temperature to be 25-30 ℃, stirring and pulping for 3h, continuously performing suction filtration when no filtrate is dripped, washing the filter cake by using a small amount of methyl tert-butyl ether, collecting the filter cake, and performing vacuum drying for 12h at 55 ℃ to obtain the vortioxetine hydrobromide;
further, W Vothioacitin :V Isopropyl alcohol :V 45% hydrobromic acid solution :V Washing water :V Methyl tert-butyl ether =(2~2.5g):10ml: 1ml:10ml:10ml。
The invention has the beneficial effects that:
does not involve protection and deprotection of groups, can shorten the process flow, avoids side reaction, reduces the operation steps of later purification of the product, and is beneficial to industrial production.
The specific implementation mode is as follows:
in the description of the invention, specific details are given only to enable a full understanding of the embodiments of the invention, but it should be understood by those skilled in the art that the invention is not limited to these details for the implementation. In other instances, well-known structures and functions have not been shown or described in detail to avoid obscuring aspects of embodiments of the invention. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
The specific implementation mode of the invention is as follows:
in order to better understand the present invention, the specific embodiments are specifically illustrated, and it is emphasized that the effects of the embodiments are not substantially different from the various embodiments within the scope of the present invention, and the effects described in the present invention and the above problems can be achieved;
example 1:
(1) Synthesis of o-piperazinyl thiophenols
2.48g of o-aminothiophenol (20 mmol) was dissolved in 25ml of ethanol under nitrogen atmosphere, 3.0g of bis (2-chloroethyl) amine hydrochloride was added, the mixture was heated under reflux at 80 ℃ and the progress of the reaction was monitored by TLC. After the reaction is finished, 20ml of purified water is added for quenching reaction, ethyl acetate (20 ml multiplied by 3) is added for extraction and layering, an organic layer is washed by saturated saline solution, dried by anhydrous magnesium sulfate, decompressed and evaporated to remove the solvent, and dried in vacuum at 60 ℃ to obtain 2.98g of white-like solid with the yield of 76.8%;
(2) Synthesis of vortioxetine
5.8g of sodium tert-butoxide (60 mmol) is added into DMF (15 ml) under the protection of nitrogen, 1.9g of o-piperazinylthiophenol (10 mmol) is added, and after stirring for 30min, 2, 4-dimethyliodobenzene (12 mmol) is added, the temperature is raised to 120 ℃, and the reaction is stirred overnight. Adding 15ml of purified water into the feed liquid for quenching reaction, extracting with ethyl acetate (30 ml) for three times, washing an organic layer with a saturated saline solution, decoloring with activated carbon, filtering, combining the organic layers, evaporating the solvent under reduced pressure, and drying in vacuum to obtain 2.42g of white powder with the yield of 81.5%;
(3) Synthesis of vortioxetine hydrobromide
Dissolving 1.2g of vortioxetine in 50ml of isopropanol solution, heating to 45 ℃, stirring for complete dissolution, slowly dripping 45% hydrobromic acid solution, stopping adding when solid is separated out, continuing stirring for 30min, then adding the remaining 45% hydrobromic acid solution into the system (5 ml in total), heating to 50 ℃, reacting for 1h, filtering while hot, and washing the filter cake with a mixed solution of 10ml of isopropanol and 45% hydrobromic acid (V isopropanol: 45% hydrobromic acid = 10). Collecting a filter cake, adding methyl tert-butyl ether, controlling the temperature to be 25-30 ℃, stirring and pulping for 3h, continuing to pump and filter for 15min when no filtrate drips, washing the filter cake with a small amount of methyl tert-butyl ether, collecting the filter cake, and vacuum-drying for 12h at 55 ℃ to obtain 1.32g of white crystalline powder, wherein the yield is 86.8% and the HPLC purity is 99.93%.
Example 2:
(1) Synthesis of o-piperazinyl thiophenols
Under the protection of nitrogen, 1.24g of o-aminothiophenol (10 mmol) is dissolved in 10ml of acetonitrile, 1.5g of bis (2-chloroethyl) amine hydrochloride is added, heating reflux is carried out at 80 ℃, and the reaction process is monitored by TLC. After the reaction, 5ml of purified water is added to quench the reaction, ethyl acetate (5 ml multiplied by 3) is added to extract and layer, an organic layer is washed by saturated saline solution, dried by anhydrous magnesium sulfate, decompressed and evaporated to remove the solvent, and dried in vacuum at 60 ℃ to obtain 1.45g of white-like solid with the yield of 75.1 percent,
(2) Synthesis of vortioxetine
Under the protection of nitrogen, 0.24g of sodium hydride (10 mmol) is added into DMSO (15 ml), then 1.9g of o-piperazinyl thiophenol (10 mmol) is added, stirring is carried out for 30min, then 2, 4-dimethyl iodobenzene (11 mmol) is added, the temperature is raised to 120 ℃, and the reaction is stirred overnight. Adding 5ml purified water into the solution to quench reaction, extracting with ethyl acetate (5 ml) for three times, washing the organic layer with saturated saline solution, decolorizing with activated carbon, filtering, combining the organic layers, evaporating the solvent under reduced pressure, and vacuum drying to obtain white powder 2.47g with yield of 82.8%.
(3) Synthesis of vortioxetine hydrobromide
Dissolving 2.0g vortioxetine in 100ml isopropanol solution, heating to 45 ℃, stirring for complete dissolution, slowly dropping 45% hydrobromic acid solution, stirring for 30min when solid is precipitated, then adding the remaining 45% hydrobromic acid solution into the system (10 ml in total), reacting for 1h at 50 ℃, filtering while hot, and washing the filter cake with 20ml isopropanol and 45% hydrobromic acid mixed solution (V isopropanol: 45% hydrobromic acid = 10. Collecting a filter cake, adding methyl tert-butyl ether, controlling the temperature to be 25-30 ℃, stirring and pulping for 3h, continuing to pump and filter for 15min when no filtrate drips, washing the filter cake with a small amount of methyl tert-butyl ether, collecting the filter cake, and vacuum-drying for 12h at 55 ℃ to obtain 2.18g of white crystalline powder, wherein the yield is 85.8%, and the HPLC purity is 99.93%.
Example 3:
(1) Synthesis of o-piperazinyl thiophenols
Under the protection of nitrogen, 2.51g of o-aminothiophenol (20 mmol) was dissolved in 35ml of dioxane, 2.6g of bis (2-chloroethyl) amine hydrochloride was added, heating reflux was carried out at 100 ℃, and the reaction progress was monitored by TLC. After the reaction, 15ml of purified water was added to quench the reaction, ethyl acetate (15 ml. Times.3) was added to extract and layer the mixture, the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, dried under vacuum at 60 ℃ to give 2.79g of an off-white solid with a yield of 71.9%,
(2) Synthesis of vortioxetine
Under the protection of nitrogen, 0.68g of sodium ethoxide (10 mmol) is put into toluene (25 ml), then 1.9g of o-piperazinyl thiophenol (10 mmol) is added, the mixture is stirred for 30min, then 2, 4-dimethyl iodobenzene (10 mmol) is added, the temperature is raised to 120 ℃, and the mixture is stirred for reaction overnight. Adding 5ml purified water into the solution to quench reaction, extracting with ethyl acetate (10 ml) for three times, washing the organic layer with saturated saline solution, decolorizing with activated carbon, filtering, combining the organic layers, evaporating the solvent under reduced pressure, and vacuum drying to obtain white powder 2.48g with yield 83.2%.
(3) Synthesis of vortioxetine hydrobromide
Dissolving 1.0g vortioxetine in 50ml isopropanol solution, heating to 45 ℃, stirring for complete dissolution, slowly dripping 45% hydrobromic acid solution, stirring for 30min when solid is precipitated, then adding the residual 45% hydrobromic acid solution into the system (5 ml in total), reacting for 1h at 50 ℃, filtering while hot, and washing a filter cake by using 10ml isopropanol and 45% hydrobromic acid mixed solution (V isopropanol: 45% hydrobromic acid = 10. Collecting a filter cake, adding methyl tert-butyl ether, controlling the temperature to be 25-30 ℃, stirring and pulping for 3h, continuing to pump and filter for 15min when no filtrate drips, washing the filter cake with a small amount of methyl tert-butyl ether, collecting the filter cake, and vacuum-drying for 12h at 55 ℃ to obtain 1.12g of white crystalline powder, wherein the yield is 88.2%, and the HPLC purity is 99.93%.
Example 4:
(1) Synthesis of o-piperazinyl thiophenols
1.86g of o-aminothiophenol (15 mmol) was dissolved in 25ml of tetrahydrofuran under nitrogen, 2.1g of bis (2-chloroethyl) amine hydrochloride was added, the mixture was refluxed at 60 ℃ and the progress of the reaction was monitored by TLC. After the reaction, adding 10ml of purified water to quench the reaction, adding ethyl acetate (10 ml multiplied by 3) to extract and separate layers, washing an organic layer by using saturated saline solution, drying by anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, drying in vacuum at 60 ℃ to obtain 2.15g of white-like solid with the yield of 73.8 percent,
(2) Synthesis of vortioxetine
Under the protection of nitrogen, 1.2g of sodium ethoxide (60 mmol) is put into DMF (15 ml), then 1.9g of o-piperazinyl thiophenol (10 mmol) is added, stirred for 30min, added with 2, 4-dimethyl iodobenzene (10 mmol), heated to 120 ℃, and stirred for reaction overnight. Adding 5ml purified water into the solution to quench reaction, extracting with ethyl acetate (5 ml) for three times, washing the organic layer with saturated saline solution, decolorizing with activated carbon, filtering, combining the organic layers, evaporating the solvent under reduced pressure, and vacuum drying to obtain white powder 2.51g with yield of 84.3%.
(3) Synthesis of vortioxetine hydrobromide
Dissolving 1.2g of vortioxetine in 50ml of isopropanol solution, heating to 45 ℃, stirring for complete dissolution, slowly dripping 45% hydrobromic acid solution, stirring for 30min when solid is separated out, then adding the residual 45% hydrobromic acid solution into the system (5 ml in total), reacting for 1h at 50 ℃, filtering while hot, and washing a filter cake with a mixed solution of 10ml of isopropanol and 45% hydrobromic acid (V isopropanol: 45% hydrobromic acid = 10). Collecting a filter cake, adding methyl tert-butyl ether, controlling the temperature to be 25-30 ℃, stirring and pulping for 3h, continuing to pump and filter for 15min when no filtrate drips, washing the filter cake with a small amount of methyl tert-butyl ether, collecting the filter cake, and vacuum-drying for 12h at 55 ℃ to obtain 1.33g of white crystalline powder, wherein the yield is 87.5 percent and the HPLC purity is 99.93 percent.
In order to more intuitively show the product advantages of the invention, the synthetic method of the vortioxetine is compared with the synthetic method of vortioxetine reported in comparative example 1 (according to the national invention patent CN103936694A, the synthetic method of the vortioxetine is used for producing the vortioxetine, which is introduced by reference),
comparative example 2:
the preparation method is the same as that of comparative example 1, except that: in the preparation process of the comparative example, o-nitrofluorobenzene is replaced by o-aminofluorobenzene; the step of reducing the ferrite can be avoided by replacing the initial raw material, but in the o-aminofluorobenzene, amino is a group with strong electron donor, halogen is a group with strong electron withdrawing, the amino and the halogen generate a push-pull electron effect to generate an intramolecular reaction, so that the reaction efficiency of the o-aminofluorobenzene and the 2, 4-dimethylthiophenol is influenced,
compared with amino, sulfhydryl group of o-amino thiophenol provided by the invention only shows very weak electron-donating effect, the strong electron-pushing effect of amino is utilized in the first step of reaction to preferentially react with bis (2-chloroethyl) amine hydrochloride to generate o-piperazinyl thiophenol, and then the o-piperazinyl thiophenol reacts with 2, 4-dimethyl iodobenzene to generate fostine, few byproducts are generated, and the reaction efficiency is greatly improved.
In summary, the following steps: the synthetic method of the Vortioxetine does not involve protection and deprotection of groups, can shorten the process flow, avoids side reactions, reduces the operation steps of later purification of the product, and is beneficial to industrial production.
Claims (10)
1. A synthetic method of Vortioxetine is characterized by comprising the following steps:
step 1: adding o-aminothiophenol and bis (2-chloroethyl) amine hydrochloride into a reaction solvent I under the protection of nitrogen, and performing heating reflux reaction to generate a reaction solution I containing o-piperazinyl thiophenol;
step 2: extracting, purifying and drying reaction liquid I containing o-piperazinyl thiophenol to obtain o-piperazinyl thiophenol;
and step 3: under the protection of nitrogen, adding 2, 4-dimethyl halogenated benzene and o-piperazinyl thiophenol obtained in the step 2 into a reaction solvent II, adding an alkaline reagent, stirring and reacting at a high temperature to generate a reaction solution II containing Voltamivir,
and 4, step 4: and extracting, purifying and drying the reaction liquid II containing the vortioxetine to obtain the vortioxetine.
2. The method for synthesizing Vortioxetine as claimed in claim 1, wherein the reaction solvent I is ethanol or acetonitrile or dioxane or tetrahydrofuran.
3. The method for synthesizing Vortioxetine according to claim 2, wherein the molar ratio of o-aminothiophenol, bis (2-chloroethyl) amine hydrochloride and reaction solvent I is 1:1.0 to 1.5:20.
4. the method for synthesizing Vortioxetine as claimed in claim 3, wherein the extracting, purifying and drying steps of step 2 comprise: adding purified water into the reaction liquid I containing the o-piperazinyl thiophenol to carry out quenching reaction, adding an extracting agent to extract and separate layers, taking an organic layer, washing the organic layer with a saturated saline solution, drying with anhydrous magnesium sulfate, distilling the solvent under reduced pressure, and drying in vacuum at 55-65 ℃ to obtain the o-piperazinyl thiophenol.
5. The method for synthesizing Vortioxetine as claimed in claim 1, wherein the reaction solvent II in step 3 is DMF, DMSO or toluene, the reaction temperature is 110-130 deg.C, and the alkaline reagent is sodium tert-butoxide, sodium hydride or sodium ethoxide.
6. The method for synthesizing Vortioxetine according to claim 5, wherein the molar ratio of o-aminothiophenol, bis (2-chloroethyl) amine salt, reaction solvent II and alkaline reagent in step 3 is 1: (0.8-1.2): 20: (0.5-7.0).
7. The method for synthesizing Vortioxetine according to claim 6, wherein the extracting, purifying and drying of step 4 comprises: adding purified water into the reaction liquid II containing the vortioxetine to quench the reaction, extracting by using an extracting agent, washing an organic layer by using saturated saline solution, decoloring by using activated carbon, filtering, combining the organic layers, evaporating the solvent under reduced pressure, and drying in vacuum to obtain the vortioxetine.
8. The method for synthesizing vortioxetine according to claim 4 or 7, wherein the volume ratio of the reaction solvent i to the purified water and the extracting agent in step 2 is 1:1: (0.3 to 0.5); the molar ratio of the reaction solvent II to the purified water to the extracting agent in the step 4 is 1:1: (0.3-0.5), wherein the extracting agents in the step 2 and the step 4 are both ethyl acetate.
9. The synthetic method of vortioxetine according to claim 1, characterized in that it is used for the preparation of vortioxetine hydrobromide, comprising: dissolving vortioxetine in an isopropanol solution, heating to 45 ℃, stirring to completely dissolve, slowly dropping 45% hydrobromic acid solution, stirring for 30min when solids are separated out, then adding the residual 45% hydrobromic acid solution into the system, reacting for 1h at 50 ℃, filtering while hot, washing a filter cake with a mixed solution of isopropanol and 45% hydrobromic acid, collecting the filter cake, adding methyl tert-butyl ether, controlling the temperature to be 25-30 ℃, stirring and pulping for 3h, performing suction filtration until no filtrate drops, continuing suction filtration, washing the filter cake with a small amount of methyl tert-butyl ether, collecting the filter cake, and performing vacuum drying for 12h at 55 ℃ to obtain the vortioxetine hydrobromide.
10. The method of synthesizing vortioxetine of claim 9, wherein W is W Vothiostatin :V Isopropanol (I-propanol) :V 45% hydrobromic acid solution :V Washing water :V Methyl tert-butyl ether =(2~2.5g):10ml:1ml:10ml:10ml。
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