CN105061364A - Vortioxetine hydrobromide preparation method - Google Patents
Vortioxetine hydrobromide preparation method Download PDFInfo
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- CN105061364A CN105061364A CN201510502904.9A CN201510502904A CN105061364A CN 105061364 A CN105061364 A CN 105061364A CN 201510502904 A CN201510502904 A CN 201510502904A CN 105061364 A CN105061364 A CN 105061364A
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- 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
Abstract
The invention provides a vortioxetine hydrobromide preparation method. The vortioxetine hydrobromide preparation method comprises the following steps: a reaction is performed between o-bromoiodobenzene and 2,4-dimethylbenzenethiol in a protonic solvent under the action of a cuprous catalyst, glycol and inorganic base to obtain 2-(2,4-dimethylthiophenyl) bromobenzene (a compound IV); the compound IV in an aprotic solvent is coupled with piperazine under the action of a palladium catalyst, a phosphine ligand and organic base; finally, salifying is performed with hydrobromic acid to obtain vortioxetine hydrobromide. Compared with the prior art, the vortioxetine hydrobromide preparation method has the advantages that competition side reactions of dual halogens are avoided, by-products are reduced, the total yield and product purity are high, and the process operation is simple, and suitable for amplification and industrialized production.
Description
Technical field
The invention belongs to organic synthesis field, particularly relate to formula (I) compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] preparation method of piperazine hydrobromide, it is a kind of newly-developed antidepressant for Xi Ting that this compound has another name called Hydrogen bromide fertile.
Background technology
Hydrogen bromide is fertile for Xi Ting (Vortioxetinehydrobromide, I) be that commodity are called Brintellix by a kind of newly-developed antidepressant of Ling Bei drugmaker of Denmark (Lundbeck) and Japan military field drug company (TakedaPharmaceutical) cooperative research and development.Obtain FDA (Food and Drug Adminstration) (FDA) in September, 2013 to ratify this medicine and be used for the treatment of grownup's major depressive disorder (MDD).Its structural formula is as follows:
No. WO200714405th, Ling Bei drugmaker of Denmark patent, No. WO2013102573 report, with adjacent bromo-iodobenzene, 2,4-thiophenol dimethyl benzene, piperazine or 2-bromo thiophenol, 2,4-dimethyl iodobenzenes, piperazine are that raw material is at two (dibenzalacetone) palladium (Pddba
2) and 1,1 '-dinaphthalene-2-2 '-bis-diphenyl phosphine (BINAP) catalysis under to carry out obtained Hydrogen bromide through a step or multistep method fertile for Xi Ting, its synthetic method is as follows:
In method (1), bromothiophenol expensive starting materials, apparent availability is little, is not suitable for suitability for industrialized production; No matter above-mentioned three kinds of methods are single stage method or two-step approach, actual obtained product purity is low, and amount of impurities is many, and make subsequent purification difficulty, industrialization difficulty increases, and contriver traces it to its cause, and thinks the competition side reaction because all solving two halogen.
No. CN103788019th, the bright and sharp patent in Suzhou report, replace Xi Ting as starting raw material through obtained the irrigating such as condensation, hydro-reduction, ring-closure reaction using nitro thiophenol or aminothiophenol, its synthetic route is as follows:
The method route is long, formed at two (2-chloroethyl) amine hydrochlorate in the process of piperazine ring and inevitably produce mono-substituted products and two 2-(2,4-dimethyl benzene sulfenyl) by product that aniline and one two (2-bromotrifluoromethane) amine linearly replace, cause yield not high.
Benevolence to it is said etc. with 2,4-thiophenol dimethyl benzenes, 2-bromo-iodobenzene and piperazine be raw material choose cuprous iodide, that ethylene glycol (EG) catalysis adopts " treating different things alike " method to obtain Hydrogen bromide is fertile for Xi Ting, synthetic route is as follows:
The method is that catalyzer adopts " treating different things alike " method obtained fertile for Xi Ting with cuprous iodide, produces, find that the method reaction yield is not high through contriver's practical study though step is simple and easy to amplify.
In sum, current Hydrogen bromide is fertile numerous for western spit of fland synthetic method, but mostly has problems, or yield is on the low side, purity is poor, purification difficult, or the long step of route is many, is all not suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is for existing technological deficiency, provide one to have raw material and be easy to get, concise in technology, yield is high, purity good, impurity is few and preparation method for Xi Ting irrigated by applicable industrialized Hydrogen bromide.The method comprises two steps: first 2,4-thiophenol dimethyl benzenes and adjacent bromo-iodobenzene carry out coupling and generate 2-(2,4-dimethyl benzene sulfenyl) bromobenzene (compound IV) under cuprous class catalyst action; Then, compound (IV) and piperazine coupling under palladium class catalyst action obtain Hydrogen bromide again with Hydrogen bromide salify fertile for Xi Ting (formula I), the method step compared with method of " treating different things alike " in prior art increases, but contriver surprisingly finds technical scheme of the present invention, become after two-step approach from single stage method, while solving two halogen competition side reaction, greatly reduce the generation of by product, total recovery is high, good product purity, technological operation is simply applicable to amplifying and suitability for industrialized production.
The invention provides the preparation method of 1-[2-(2, the 4-dimethylphenylsulfanyl)-phenyl] piperazine hydrobromide shown in a kind of formula (I), described preparation method comprises:
Step 1) in protic organic solvent, under cuprous class catalyzer, ethylene glycol and mineral alkali effect, 2-(2, the 4-dimethyl benzene sulfenyl) bromobenzene shown in adjacent bromo-iodobenzene and 2,4-thiophenol dimethyl benzene reaction production (IV);
Step 2) in non-proton organic solvent, under palladium class catalyzer, Phosphine ligands and organic bases effect, compound (IV) and piperazine coupling, more fertile for Xi Ting with the Hydrogen bromide shown in Hydrogen bromide salify production (I).Its reaction formula is as follows:
Specifically, preparation method provided by the invention comprises the following steps:
Protic solvent, adjacent bromo-iodobenzene, 2,4-thiophenol dimethyl benzenes, cuprous class catalyzer, ethylene glycol and mineral alkali are added in reactor and stirs;
Vacuumized by reactor in above-mentioned steps, pass into nitrogen, under nitrogen protection, reacting by heating is to complete;
Remove solvent under reduced pressure, in residue, add methylene dichloride and water stirs, diatomite filtration, separatory removing aqueous phase, methylene dichloride washed through salt, wash, anhydrous magnesium sulfate drying, underpressure distillation obtains 2-(2,4-dimethyl benzene sulfenyl) bromobenzene (IV);
Non-proton organic solvent, compound (IV), piperazine, palladium class catalyzer, Phosphine ligands and organic bases are added in reactor and stirs;
Vacuumized by reactor, pass into nitrogen, under nitrogen protection, reacting by heating is to complete;
Be down to room temperature, add water, stir, diatomite filtration in reactor, separatory removing aqueous phase, toluene is washed through salt, wash, anhydrous sodium sulfate drying, and mistake filters anhydrous sodium sulphate, adds gac, reflux 1h in organic phase;
Heat filtering removing gac, organic phase is cooled to 40 DEG C and adds Hydrogen bromide, stirred at ambient temperature crystallization;
Filtration obtains solid, obtains Hydrogen bromide fertile for Xi Ting with toluene and ethyl acetate washing.
In preparation method of the present invention, described protic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, n-propyl alcohol, isopropylcarbinol, propyl carbinol, preferred Virahol;
Described cuprous class catalyzer is red copper oxid (Cu
2o), cuprous chloride (CuCl), cuprous bromide (CuBr), the sub-ketone (CuI) of iodate, preferred cuprous iodide (CuI);
Described mineral alkali is salt of wormwood (K
2cO
3), Tripotassium phosphate (K
3pO
4), cesium carbonate (Se
2cO
3), preferably phosphoric acid tripotassium (K
3pO
4);
Described non-protonic solvent is toluene, dimethylbenzene, dioxane, dimethyl formamide, methyl-sulphoxide, preferred toluene;
Described palladium class catalyzer is palladium (Pd), palladium (Pd (OAc)
2), Palladous chloride (PdCl
2), tetrakis triphenylphosphine palladium (Pd [P (Ph)
3]
4), two (triphenylphosphine) palladium (Pd (PPh of dichloro
3)
2cl
2), 1,1 '-bis-(diphenylphosphine) ferrocene palladium chloride or three (dibenzalacetone) two palladium (Pd
2(dba)
3), two (dibenzalacetone) palladium (Pd (dba)
2), preferably three (dibenzalacetone) two palladium (Pd
2(dba)
3);
Described Phosphine ligands is 2,2 '-bis-diphenylphosphanyl-[1,1 '] dinaphthalene (rac-BINAP), 1,1 '-bis-(diphenylphosphino) ferrocene (DPPF), two-(2-diphenylphosphinophenyl) ether (DPEphos), preferably 2,2 '-bis-diphenylphosphanyl-[1,1 '] dinaphthalene (rac-BINAP);
Described organic bases is sodium tert-butoxide ((CH
3)
3cONa), potassium tert.-butoxide ((CH
3)
3cOK), preferred tertiary sodium butylate ((CH
3)
3cONa).
The adjacent bromo-iodobenzene (II) of described reaction Raw, 2, the molar ratio of 4-thiophenol dimethyl benzene (III), cuprous class catalyzer, ethylene glycol and mineral alkali is 1:0.8-1.2:0.03-0.1:1.5-2.5:1.5-2.5, preferred 1:1.1:0.05:2.0:2.0; Temperature of reaction is 60-90 DEG C, preferred 80-90 DEG C.
The molar ratio of the compound (IV) in described reaction, piperazine and palladium class catalyzer, Phosphine ligands, organic bases is 1:2.0-4.0:0.002-0.005:0.005-0.01:2.0-4.0, preferred 1:3.0:0.004:0.008:3.0.Temperature of reaction is 80-120 DEG C, preferred 105-115 DEG C.
According to the specific embodiment of the present invention, described protic solvent is Virahol, and non-protonic solvent is toluene, and copper class catalyzer is cuprous iodide, and palladium class catalyzer is three (dibenzalacetone) two palladium, and reaction formula is:
Compared with prior art, tool of the present invention has the following advantages:
1) under the effect of cuprous class catalyzer, the bromine in adjacent bromo-iodobenzene does not react with thiophenol, and iodine and thiophenol generation linked reaction generate compound IV, solves the competition side reaction problem of two halogen, by product is reduced greatly;
2) catalytic capability of cuprous iodide is more weak, in second step reaction, adopt the palladium class catalyzer that catalytic capability is stronger, make high-purity compound IV then obtain with HBr salify again with piperazine coupling Hydrogen bromide fertile for western spit of fland yield and purity very high, amount of impurities obviously reduces, and reduces difficulty to follow-up purification work.
Accompanying drawing illustrates:
Fig. 1 is that the Hydrogen bromide that embodiment 1 is synthesized is fertile for western spit of fland 1HMR collection of illustrative plates.
Fig. 2 is that the Hydrogen bromide that embodiment 1 is synthesized is fertile for western spit of fland HPLC collection of illustrative plates.
Fig. 3 is that the Hydrogen bromide of the 2-in-1 one-tenth of embodiment is fertile for western spit of fland HPLC collection of illustrative plates
Fig. 4 is that the Hydrogen bromide that embodiment 3 is synthesized is fertile for western spit of fland HPLC collection of illustrative plates
Fig. 5 is that the Hydrogen bromide that embodiment 4 is synthesized is fertile for western spit of fland HPLC collection of illustrative plates
Fig. 6 is that the Hydrogen bromide that comparative example 1 is synthesized is fertile for western spit of fland HPLC collection of illustrative plates
Embodiment
Following embodiment is to describe the present invention in detail, and unrestricted the present invention.
Embodiment 1
The synthesis of the first step: 2-(2,4-dimethyl benzene sulfenyl) bromobenzene (compound IV)
To in 2L single port bottle, add adjacent bromo-iodobenzene 127.5g (0.45mol) successively, 2, 4-thiophenol dimethyl benzene 68.4g (0.5mol), sub-ketone 4.3g (22.5mmol) of iodate, ethylene glycol 56.0g (0.9mol), Virahol 1.1L, Tripotassium phosphate 191.0g (0.9mol), atmospheric pressure at room passes into nitrogen under stirring, vacuumize displacement three times, 80-90 DEG C of reaction 7-8h, stop heating, after question response liquid is cooled to room temperature, mother liquor is spin-dried for obtain oily matter by 60-70 DEG C, methylene dichloride 1.5L is added in oily matter, add water 1L, stirred at ambient temperature 10-20min, diatomite filtration, by mother liquor separatory, 15% sodium-chlor washing 1L × 2 time, washing 1L × 1 time, more than anhydrous magnesium sulfate drying 4h, DCM is spin-dried for give light yellow oil 132.2g (yield: 100%).
The synthesis of second step: 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide (Compound I)
Sodium tert-butoxide 129.7g (1.35mol) is added successively, Pd in 3L mono-bottle
2(dba)
31.56g (1.70mmol) and rac-BINAP2.15g (3.45mmol), compound (IV) 132.2g (0.45mol), piperazine 116.3g (1.35mol), toluene 1.0L, under atmospheric pressure at room stirs, pass into nitrogen protection, be heated to 105-115 DEG C, reaction times 7-8h, be cooled to room temperature, water 0.3L is added in reaction solution, stir 10-20min, diatomite filtration, mother liquor 15% sodium-chlor water washing 1.0L × 5 time, washing 0.7L × 2 time, organic phase anhydrous sodium sulfate drying, filter, in organic phase, add gac 10.9g be heated to the 1h that refluxes, heat filtering.Filtrate is cooled to about 40 DEG C and adds 48%HBr75.8g, then stirred at ambient temperature crystallization, filtering solids, use 200ml toluene, 200ml n-hexane successively, at 45 DEG C, dried overnight obtains off-white color solid 153.9g, yield: 90.2%, HPLC purity 99.9%.
1H-NMR(CHCl
3-d6，400MHz)δ：7.31-7.36(d，1H)，7.20-7.25(d，1H)，7.14-7.18(t，2H)，7.05-7.10(d，1H)，6.91-6.98(t，1H)，3.40-3.51(dd，8H)，2.26-2.31(s，3H)，2.33-2.36(s，3H)。ESI-MS(m/z)：298.9[M+H]
+.
Embodiment 2
The synthesis of the first step: 2-(2,4-dimethyl benzene sulfenyl) bromobenzene (compound IV)
To in 1L single port bottle, add adjacent bromo-iodobenzene 28.3g (0.1mol) successively, 2, 4-thiophenol dimethyl benzene 16.6g (0.12mol), sub-ketone 1.9g (10mmol) of iodate, ethylene glycol 12.4g (0.2mol), Virahol 250ml, Tripotassium phosphate 42.4g (0.2mol), atmospheric pressure at room passes into nitrogen under stirring, vacuumize displacement three times, 80-90 DEG C of reaction 7-8h, stop heating, after question response liquid is cooled to room temperature, mother liquor is spin-dried for obtain oily matter by 60-70 DEG C, methylene dichloride 300ml is added in oily matter, add water 200ml, stirred at ambient temperature 10-20min, diatomite filtration, by mother liquor separatory, 15% sodium-chlor washing 200ml × 2 time, washing 200nl × 1 time, more than anhydrous magnesium sulfate drying 4h, DCM is spin-dried for give light yellow oil 30.1g (yield: 100%).
The synthesis of second step: 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide (Compound I)
Sodium tert-butoxide 28.8g (0.3mol) is added successively, Pd in 500ml mono-bottle
2(dba)
30.46g (0.5mmol) and rac-BINAP0.62g (1mmol), compound (IV) 30.1g (0.1mol), piperazine 34.4g (0.4mol), toluene 200ml, under atmospheric pressure at room stirs, pass into nitrogen protection, be heated to 105-115 DEG C, reaction times 7-8h, be cooled to room temperature, water 0.1L is added in reaction solution, stir 10-20min, diatomite filtration, mother liquor 15% sodium-chlor water washing 200ml × 5 time, washing 160ml × 2 time, organic phase anhydrous sodium sulfate drying, filter, in organic phase, add gac 2.5g be heated to the 1h that refluxes, heat filtering.Filtrate is cooled to about 40 DEG C and adds 48%HBr17.0g, then stirred at ambient temperature crystallization, filtering solids, use 50ml toluene, 50ml n-hexane successively, at 45 DEG C, dried overnight obtains off-white color solid 33.7g, yield: 88.9%, HPLC purity 99.6%.
Embodiment 3
The synthesis of the first step: 2-(2,4-dimethyl benzene sulfenyl) bromobenzene (compound IV)
To in 1L single port bottle, add adjacent bromo-iodobenzene 28.3g (0.1mol) successively, 2, 4-thiophenol dimethyl benzene 11.1g (0.08mol), sub-ketone 0.6g (3mmol) of iodate, ethylene glycol 9.3g (0.15mol), Virahol 250ml, Tripotassium phosphate 31.8g (0.15mol), atmospheric pressure at room passes into nitrogen under stirring, vacuumize displacement three times, 60-70 DEG C of reaction 10h, stop heating, mother liquor is spin-dried for obtain oily matter, methylene dichloride 300ml is added in oily matter, add water 200ml, stirred at ambient temperature 10-20min, diatomite filtration, by mother liquor separatory, 15% sodium-chlor washing 200ml × 2 time, washing 200nl × 1 time, more than anhydrous magnesium sulfate drying 4h, DCM is spin-dried for give light yellow oil 24.5g (yield: 100%).
The synthesis of second step: 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide (Compound I)
Sodium tert-butoxide 15.4g (0.16mol) is added successively, Pd in 500ml mono-bottle
2(dba)
30.15g (0.16mmol) and rac-BINAP0.25g (0.4mmol), compound (IV) 24.5g (0.08mol), piperazine 13.8g (0.16mol), toluene 200ml, under atmospheric pressure at room stirs, pass into nitrogen protection, be heated to 80-90 DEG C, reaction times 10h, be cooled to room temperature and add water 40ml in reaction solution, stir 10-20min, diatomite filtration, mother liquor 15% sodium-chlor water washing 200ml × 5 time, washing 150ml × 2 time, organic phase anhydrous sodium sulfate drying, filter, in organic phase, add gac 2.0g be heated to the 1h that refluxes, heat filtering.Filtrate is cooled to about 40 DEG C and adds 48%HBr13.6g, then stirred at ambient temperature crystallization, filtering solids, use 50ml toluene, 50ml n-hexane successively, at 45 DEG C, dried overnight obtains off-white color solid 18.6g, yield: 61.3%, HPLC purity 99.5%.
Embodiment 4
The synthesis of the first step: 2-(2,4-dimethyl benzene sulfenyl) bromobenzene (compound IV)
To in 500ml single port bottle, add adjacent bromo-iodobenzene 14.3g (0.05mol) successively, 2, 4-thiophenol dimethyl benzene 6.9g (0.05mol), cuprous bromide 0.36g (2.5mmol), ethylene glycol 7.5g (0.12mol), Virahol 125ml, Tripotassium phosphate 25.5g (0.12mol), atmospheric pressure at room passes into nitrogen under stirring, vacuumize displacement three times, 80-90 DEG C of reaction 8h, stop heating, after question response liquid is cooled to room temperature, mother liquor is spin-dried for obtain oily matter by 60-70 DEG C, methylene dichloride 150ml is added in oily matter, add water 200ml, stirred at ambient temperature 10-20min, diatomite filtration, by mother liquor separatory, 15% sodium-chlor washing 200ml × 2 time, washing 200nl × 1 time, more than anhydrous magnesium sulfate drying 4h, DCM is spin-dried for give light yellow oil 15.2g (yield: 100%).
The synthesis of second step: 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide (Compound I)
Sodium tert-butoxide 19.2g (0.2mol) is added successively, Pd (OAC) in 250ml mono-bottle
20.05g (0.2mmol) and triphenylphosphine 0.1g (0.4mmol), compound (IV) 15.2g (0.05mol), piperazine 12.9g (0.15mol), toluene 100ml, under atmospheric pressure at room stirs, pass into nitrogen protection, be heated to 105-115 DEG C, reaction times 7h, in reaction solution, water 40ml is added after being cooled to room temperature, stir 10-20min, diatomite filtration, mother liquor 15% sodium-chlor water washing 100ml × 5 time, washing 80ml × 2 time, organic phase anhydrous sodium sulfate drying, filter, in organic phase, add gac 1.0g be heated to the 1h that refluxes, heat filtering.Filtrate is cooled to about 40 DEG C and adds 48%HBr8.5g, then stirred at ambient temperature crystallization, filtering solids, use 25ml toluene, 25ml n-hexane successively, at 45 DEG C, dried overnight obtains off-white color solid 15.8g, yield: 83.5%, HPLC purity 98.7%.
Comparative example 1 (with reference to patent CN102617513A, embodiment 23)
To in 100ml single port bottle, by sodium tert-butoxide 4.08g (42.4mmol), piperazine 4.2g (49.0mmol), Pd (dba)
20.03g (0.05mmol) and rac-BINAP0.07g (0.1mmol), toluene 20ml stirs 50min together, then by adjacent bromo-iodobenzene 4.2g (14.8mmol), add in above-mentioned mixed solution with 8ml toluene and stir 30min, by 2,4-thiophenol dimethyl benzene 1.95g (14.1mmol) and 8ml toluene add the suspension of gained to add to be hankered to backflow, and continue backflow 5h, by reaction solution cool overnight, add water 10ml and stir 1h, filtering, the organic phase salt water washing of 3 × 10ml, then, by the methylbenzene extraction of the aqueous phase 10ml of merging.By the toluene heat phase to 70 DEG C merged, then add 1.7ml48%HBr and water 0.8ml.Mixture is cooled to room temperature overnight.By collecting by filtration end product, and vacuum-drying (60 DEG C), obtain 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide (Compound I) 3.86g off-white color solid, yield 68.9%.HPLC purity 91.7%.
Claims (4)
1. a fertile preparation method for Xi Ting, it is characterized in that, this preparation method comprises the steps:
Step 1) adjacent bromo-iodobenzene and 2,4-thiophenol dimethyl benzene in protic solvent, under cuprous class catalyzer, ethylene glycol and mineral alkali effect, obtain 2-(2,4-dimethyl benzene sulfenyl) bromobenzene (compound IV);
Step 2) compound IV is in non-protonic solvent, and with piperazine coupling under palladium class catalyzer, Phosphine ligands and organic bases effect, it is fertile for Xi Ting that last and Hydrogen bromide salify obtains Hydrogen bromide, and its reaction formula is as follows:
2. preparation method as claimed in claim 1, is characterized in that, the cuprous class catalyzer in described step 1 reaction is red copper oxid (Cu
2o), cuprous chloride (CuCl), cuprous bromide (CuBr), the sub-ketone (CuI) of iodate, preferred cuprous iodide (CuI); Mineral alkali is salt of wormwood (K
2cO
3), Tripotassium phosphate (K
3pO
4), cesium carbonate (Se
2cO
3), preferably phosphoric acid tripotassium (K
3pO
4); Protic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, n-propyl alcohol, isopropylcarbinol, propyl carbinol, preferred Virahol;
Palladium class catalyzer in described step 2 reaction is palladium (Pd), palladium (Pd (OAc)
2), Palladous chloride (PdCl
2), tetrakis triphenylphosphine palladium (Pd [P (Ph)
3]
4), two (triphenylphosphine) palladium (Pd (PPh of dichloro
3)
2cl
2), 1,1 '-bis-(diphenylphosphine) ferrocene palladium chloride or three (dibenzalacetone) two palladium (Pd
2(dba)
3), two (dibenzalacetone) palladium (Pd (dba)
2), preferably three (dibenzalacetone) two palladium (Pd
2(dba)
3); Phosphine ligands is 2,2 '-bis-diphenylphosphanyl-[1,1 '] dinaphthalene (rac-BINAP), 1,1 '-bis-(diphenylphosphino) ferrocene (DPPF), two-(2-diphenylphosphinophenyl) ether (DPEphos), preferably 2,2 '-bis-diphenylphosphanyl-[1,1 '] dinaphthalene (rac-BINAP); Non-protonic solvent is toluene, dimethylbenzene, dioxane, dimethyl formamide, methyl-sulphoxide, preferred toluene; Organic bases is sodium tert-butoxide ((CH
3)
3cONa), potassium tert.-butoxide ((CH
3)
3cOK), preferred tertiary sodium butylate ((CH
3)
3cONa).
3. preparation method as claimed in claim 1 or 2, it is characterized in that, adjacent bromo-iodobenzene (II), 2 in step 1, the molar ratio of 4-thiophenol dimethyl benzene (III), cuprous class catalyzer, ethylene glycol and mineral alkali is 1:0.8-1.2:0.03-0.1:1.5-2.5:1.5-2.5, preferred 1:1.1:0.05:2.0:2.0;
The molar ratio of the compound (IV) in described step 2, piperazine and palladium class catalyzer, Phosphine ligands, organic bases is 1:2.0-4.0:0.002-0.005:0.005-0.01:2.0-4.0, preferred 1:3.0:0.004:0.008:3.0.
4., as the preparation method as described in arbitrary in claim 1-3, it is characterized in that, in step 1, temperature of reaction is 60-90 DEG C, preferred 80-90 DEG C; In step 2, temperature of reaction is 80-120 DEG C, preferred 105-115 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106380455A (en) * | 2016-08-31 | 2017-02-08 | 安徽省润生医药股份有限公司 | Synthetic method and application of vortioxetine hydrobromide |
| CN110804027A (en) * | 2019-10-11 | 2020-02-18 | 杭州和康药业有限公司 | Vortioxetine impurity 1- [3- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine and application thereof |
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