CN105669594A - Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) - Google Patents
Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) Download PDFInfo
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Abstract
The invention relates to a preparation method of an anti-depression drug 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI). The preparation method comprises the following steps: using 2,4-dimethyl thiophenol (I) as the initial raw material; condensing the 2,4-dimethyl thiophenol (I) with 2-halogenated nitrobenzene (II) to obtain 2-(2,4-dimethylphenylsulfanyl)nitrobenzene (III); reducing the 2-(2,4-dimethylphenylsulfanyl)nitrobenzene (III) to obtain 2-(2,4-dimethylphenylsulfanyl)aniline (IV); and performing loop closing on the 2-(2,4-dimethylphenylsulfanyl)aniline (IV) and bis-(2-chloroethyl)amine hydrochloride (V), so that the 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (VI) is prepared. The preparation method disclosed by the invention has the following advantages: the raw materials are low in costs and easy to obtain, the technology is simple, and the preparation method is economical and environmental-friendly as well as suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field. The preparation method being particularly used for medicine 1-[2-(the 2,4-aminomethyl phenyl sulfenyl) phenyl] piperazine of novel anti-severe depression.
Background technology
1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI) is by the novel anti-severe depression disease drug of one of Ling Bei drugmaker of Denmark (Lundbeck) and Japan's Takeda Pharmaceutical Company Limited (TakedaPharmaceutical) cooperative research and development. This medicine of in JIUYUE, 2013 obtains the listing approval of FDA (Food and Drug Adminstration) (FDA), and commodity are called Brintellix.
1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI) is the newly-developed antidepressant with selectivity 5-hydroxy tryptamine reuptake inhibitor, 5-HT3A acceptor inhibitor, 5-HT7 acceptor inhibitor and part 5-HT1B receptor stimulating agent multiple action, compared with existing antidepressants, there is onset time, less toxic and side effects and better antidepressant activity faster.
At present, the relevant fertile synthesis for Xi Ting mainly has several as follows both at home and abroad:
The former international monopoly of grinding being mainly seen in Ling Bei drugmaker of Denmark (Lundbeck) is WO2003029232, WO2007144005, WO2010094285. Its two main synthetic routes are as follows:
Article 1, route is obtained by reacting 1-[2-(2, the 4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine with protection base with raw material A for initiation material and 2,4-dimethyl sulfydryl benzene, obtains target compound (VI) again through deprotection.
Article 2 route, with bromobenzene thioether (B) for raw material, reacts with the piperazine of monosubstituted protection, then obtains target compound (VI) again through deprotection.
Prepared by the step of the substantially not enough protection and deprotection being just the increase in piperazinyl of above two method, complex operation, palladium chtalyst coupling yield is not high and cost is also high. Analyse in depth this synthetic route, no matter being all non-common industrial chemicals of Article 1 route or Article 2 route, raw material A or raw material B, its preparation process is respectively present the competition side reaction of double; two halogen and piperazine secondary amine or sulfydryl, make it prepare difficulty to strengthen, and purity is not high.
Former patent WO2007144005 and the WO2013102573 that grinds also discloses the method for " treating different things alike " and prepares 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI)
Although the method enormously simplify reactions steps, but side reaction is more, and purity is not high, and purification post processing is complicated, and uses expensive palladium catalyst, and cost increases, and is unfavorable for industrialized production.
Lundbeck company is at China issued patents CN1561336, and synthetic route is as follows:
This route reaction complex steps, yield is not high yet.
Summary of the invention
Present invention aim to overcome that weak point of the prior art, research design one cheaper starting materials is easy to get, easy and simple to handle, and reaction yield is high, economic and environment-friendly applicable industrialized 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI) preparation method.
The preparation method of the present invention is as follows:
(A) with 2,4-thiophenol dimethyl benzene (I) is initiation material, 2-(2 is generated with 2-halogenated nitrobenzene (II) condensation, 4-dimethylphenylsulfanyl) Nitrobenzol (III), (B) 2-(2,4-dimethylphenylsulfanyl) Nitrobenzol (III) through reduction obtain 2-(2,4-dimethylphenylsulfanyl) aniline (IV), (C) again with double; two (2-chloroethyl) amine hydrochlorate (V)Cyclization generates 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI).
In 2-halogenated nitrobenzene (II), halogen X is fluorine, chlorine, bromine, iodine.
According to the first embodiment of the present invention, it is provided that the preparation method of antidepressant 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI), the method comprises the following steps:
(A) with 2,4-thiophenol dimethyl benzenes (I) for initiation material, 2-(2,4-dimethylphenylsulfanyl) Nitrobenzol (III) is generated with 2-halogenated nitrobenzene (II) condensation,
(B) 2-(2,4-dimethylphenylsulfanyl) Nitrobenzol (III) reduces through reducing agent, obtains 2-(2,4-dimethylphenylsulfanyl) aniline (IV), and
(C) 2-(2,4-dimethylphenylsulfanyl) aniline (IV) again with double; two (2-chloroethyl) amine hydrochlorate (V) cyclization generate 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI).
Here, in step (A) halogen (i.e. X) of " halo " be fluorine, chlorine, bromine, iodine.
Preferably, the reaction of step (A) carries out under the existence of phase transfer catalyst and alkali. Preferably, molar ratio of material (I): (II): alkali: phase transfer catalyst=1:1～2.0:1～2.0:0.01～0.25, it is preferably 1:1.05～1.9:1.05～1.9:0.015～0.2, it is more preferably 1:1.08～1.8:1.08～1.8:0.02～0.18, it is preferably 1:1.1～1.7:1.1～1.7:0.025～0.16, more preferably 1:1.1:1.2:0.05.
Additionally, the reaction of step (A) is usually and carries out in the presence of the solvent. In step (A), solvent for use is acetonitrile, oxolane, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, toluene; Or solvent for use is any one in water, methanol, ethanol, isopropanol and acetonitrile, oxolane, dimethyl sulfoxide, N, dinethylformamide, N, the mixed solvent of the arbitrary solvent in N-dimethyl acetylamide, toluene, it is more preferably the mixed solvent of toluene and water, weight ratio toluene: water=1～3:1～3, more preferably 1～2:1～2.
Preferably, the reaction condition of step (A) is: reaction temperature 10～60 DEG C, it is preferable that 20～50 DEG C, more preferably 25～40 DEG C; Response time 12～30h, it is preferable that 15-26h, it is preferable that 18～24h.
It addition, the alkali used in step (A) is preferably potassium hydroxide, sodium hydroxide, Feldalat NM, Feldalat KM, Sodium ethylate or sodium hydride, it is preferred to potassium hydroxide or Feldalat NM.
Preferably, above-described phase transfer catalyst example is chosen from one or more among following substances:
A, polyethers, for instance: linear or chain Polyethylene Glycol: H (OCH2CH2) nOH, or, linear or chain dialkylethers: R (OCH2CH2)nOR, or, linear or chain polyalkylene glycol monoalkyl ether: H (OCH2CH2) nOR, wherein R=C1-C6 alkyl, it is preferable that R=C2-C4 alkyl;Generally, n=5-700, it is preferable that 10-500, more preferably 15-300;
B, cyclic crown ether class, for instance: 18 hat 6,15 hat 5 or cyclodextrin;
C, quaternary ammonium salt, for instance: benzyltriethylammoinium chloride, tetrabutyl ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride;
D, tertiary amines, for instance: R3N, wherein R=C1-C7 alkyl; Such as tri-n-butylamine, tripropylamine or triethylamine;
E, quaternary ammonium bases, for instance: R4NOH, wherein R=C1-C7 alkyl, C4-C6 cycloalkyl, phenyl or benzyl;
F, season phosphonium salt class.
Preferably, the reducing agent in the reaction of step (B) is hydrazine hydrate, ferrum, zinc, stannum, sodium hydrosulfite, hydrogen, azanol or sodium hydride, it will be preferred that hydrazine hydrate.
Preferably, the reaction of this step (B) is to carry out in the presence of a catalyst, and this catalyst is ferric chloride/activated carbon, ammonium chloride, hydrochloric acid or sulphuric acid. More preferably, catalyst is activated carbon and Iron(III) chloride hexahydrate, wherein molar ratio of material intermediate (III): activated carbon: Iron(III) chloride hexahydrate: mol ratio=1:1.1～3:0.05～0.5:8～20 of reducing agent (preferred hydrazine hydrate), it is preferably 1:1.4～2.6:0.07～0.4:10～18, preferred 1:1.8～2.2:0.08～0.3:11～15, it is preferable that 1:2:0.1:12.
Preferably, the reaction of step (B) is at alcohols solvent (such as methanol, ethanol), nitrile solvents (such as acetonitrile, propionitrile) or amide solvent (N, dinethylformamide, N, N-diethylformamide etc.) in carry out under reflux. The reaction of step (B) generally carries out 1～10 hour, it is preferable that 3～8 hours, more preferably 4～6 hours.
Moreover it is preferred that in the reaction of step (C), intermediate (IV): mol ratio=1:0.8～2 of double; two (2-chloroethyl) amine hydrochlorate (V), it is preferable that 1:1.0～1.5, more preferably 1:1.1.
Generally, the reaction of step (C) is to carry out under reflux in the presence of the solvent. Preferably, this solvent is triethylamine, N-methylmorpholine, DIPEA, N-Methyl pyrrolidone; It is more preferably DIPEA, N-Methyl pyrrolidone. This reaction of step (C) carries out 5～15 hours, it is preferable that 6～12 hours, more preferably 7～9 hours.
The preparation method raw material of the present invention is cheap to be easy to get, concise in technology, industrialized production economic and environment-friendly, applicable.
Detailed description of the invention
Embodiment 1
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (47g, 0.341mol), o-chloronitrobenzene (II) (58.9g, 0.375mol), 200mL toluene, tetrabutyl ammonium bromide (4.8g, 0.015mol), it is then used by 200mL dissolved hydrogen water potassium oxide (23g, 0.411mol), and is dropped in reaction bulb, after dropwising, react 24 hours at 40 DEG C. Stopped reaction, add 1L ethyl acetate and 300mL water, separate organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merging organic facies with 1L saturated common salt water washing once, anhydrous sodium sulfate dries and dewaters, and revolves steaming solvent and obtains faint yellow solid crude product, 200mL absolute ethanol washing is used to obtain faint yellow needle-like solid (III) 74.8g, productivity 85%.
1HNMR(400MHz,CD3Cl) δ: 2.18 (s, 3H), 2.28 (s, 3H), 6.60 (d, J=8,1H), 7.01 (d, J=8,1H), 7.04～7.08 (m, 2H), 7.15 (s, 1H), 7.20 (d, J=8,1H), 8.12 (d, J=8,1H).
Embodiment 2
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (47g, 0.341mol), o-fluoronitrobenzene (II) (52.9g, 0.375mol), 200mL toluene, tetrabutyl ammonium bromide (4.8g, 0.015mol), it is then used by 200mL dissolved hydrogen water potassium oxide (23g, 0.411mol), and is dropped in reaction bulb, after dropwising, react 24 hours at 40 DEG C. Stopped reaction, add 1L ethyl acetate and 300mL water, separate organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merging organic facies with 1L saturated common salt water washing once, anhydrous sodium sulfate dries and dewaters, and revolves steaming solvent and obtains faint yellow solid crude product, 200mL absolute ethanol washing is used to obtain faint yellow needle-like solid (III) 76.8g, productivity 87%.
Embodiment 3
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (47g, 0.341mol), o-chloronitrobenzene (II) (58.9g, 0.375mol), 200mL toluene, tetrabutyl ammonium bromide (11.0g, 0.034mol), it is then used by 200mL dissolved hydrogen water potassium oxide (23g, 0.411mol), and is dropped in reaction bulb, after dropwising, react 24 hours at 40 DEG C. Stopped reaction, add 1L ethyl acetate and 300mL water, separate organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merging organic facies with 1L saturated common salt water washing once, anhydrous sodium sulfate dries and dewaters, and revolves steaming solvent and obtains faint yellow solid crude product, 200mL absolute ethanol washing is used to obtain faint yellow needle-like solid (III) 74.8g, productivity 85%.
Embodiment 4
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (47g, 0.341mol), o-chloronitrobenzene (II) (64.2g, 0.409mol), 200mL toluene, tetrabutyl ammonium bromide (4.8g, 0.015mol), it is then used by 200mL dissolved hydrogen water potassium oxide (23g, 0.411mol), and is dropped in reaction bulb, after dropwising, react 24 hours at 40 DEG C. Stopped reaction, add 1L ethyl acetate and 300mL water, separate organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merging organic facies with 1L saturated common salt water washing once, anhydrous sodium sulfate dries and dewaters, and revolves steaming solvent and obtains faint yellow solid crude product, 200mL absolute ethanol washing is used to obtain faint yellow needle-like solid (III) 75.5g, productivity 85.5%.
Embodiment 5
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (47g, 0.341mol), o-chloronitrobenzene (II) (58.9g, 0.375mol), 200mL toluene, tetrabutyl ammonium bromide (4.8g, 0.015mol), it is then used by 200mL dissolved hydrogen water potassium oxide (28.7g, 0.512mol), and is dropped in reaction bulb, after dropwising, react 24 hours at 40 DEG C. Stopped reaction, add 1L ethyl acetate and 300mL water, separate organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merging organic facies with 1L saturated common salt water washing once, anhydrous sodium sulfate dries and dewaters, and revolves steaming solvent and obtains faint yellow solid crude product, 200mL absolute ethanol washing is used to obtain faint yellow needle-like solid (III) 74.6g, productivity 84.5%.
Embodiment 6
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (47g, 0.341mol), o-chloronitrobenzene (II) (59g, 0.375mol), 200mL toluene, tetrabutyl ammonium bromide (4.7g, 0.015mol), it is then used by 200mL methanol and dissolves Feldalat NM (23g, 0.411mol), and dropped in reaction bulb, after dropwising, react 24 hours at 40 DEG C.Stopped reaction, add 1L ethyl acetate and 300mL water, separate organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merging organic facies with 1L saturated common salt water washing once, anhydrous sodium sulfate dries and dewaters, and revolves steaming solvent and obtains faint yellow solid crude product, 200mL absolute ethanol washing is used to obtain faint yellow needle-like solid (III) 73.7g, productivity 83.5%.
Embodiment 7
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (47g, 0.341mol), o-chloronitrobenzene (II) (52.9g, 0.375mol), 200mL toluene, tetrabutylammonium chloride (4.2g, 0.015mol), it is then used by 200mL dissolved hydrogen water potassium oxide (23g, 0.411mol), and is dropped in reaction bulb, after dropwising, react 24 hours at 40 DEG C. Stopped reaction, add 1L ethyl acetate and 300mL water, separate organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merging organic facies with 1L saturated common salt water washing once, anhydrous sodium sulfate dries and dewaters, and revolves steaming solvent and obtains faint yellow solid crude product, 200mL absolute ethanol washing is used to obtain faint yellow needle-like solid (III) 75.9g, productivity 86%.
Embodiment 8
In 1L reaction bulb, add intermediate (III) IV (79g, 0.305mol) with methanol 200mL, add activated carbon (1g, 0.62mol) with ferric chloride (8g, 0.030mol), heating is to refluxing, hydrazine hydrate (250ml) is dripped in solution, reaction 3 hours is continued after dropwising, stopped reaction, it is cooled to room temperature, add suction filtered through kieselguhr, revolve nor-alcohol, extract by ethyl acetate (400ml × 3), merge organic layer, saturated common salt water washing, anhydrous sodium sulfate dries 20min, sucking filtration, it is spin-dried for solvent and obtains pale yellow oil (VI) 67g, productivity: 95.9%. other impurity it is substantially free of by the analysis of liquid phase and nuclear magnetic spectrogram.1HNMR (400MHz, CD3Cl) δ: 2.52 (s, 3H), 2.68 (s, 3H), 4.44 (s, 2H), 6.93 (d, J=8,1H), 6.99～7.09 (m, 2H), 7.30 (d, J=8,1H), 7.44 (s, 1H), 7.50 (d, J=8,1H), 7.65 (d, J=8,1H).
Embodiment 9
In 1L two neck bottle, add intermediate (IV) (68g, 0.297mol), double, two (2-chloroethyl) amine hydrochlorate (58g, 0.325mol) and N, N-diisopropylethylamine (70ml), under nitrogen protection, heating is to refluxing, react 6～8 hours (TLC detects terminal: petroleum ether: ethyl acetate=10:1), stop heating, it is cooled to room temperature, add ethyl acetate 70ml, it is cooled to 0 DEG C, precipitate out a large amount of khaki solid, sucking filtration, methanol washs, sucking filtration obtains obtaining khaki solid (VI) 78.7g after filter cake is dried, productivity: 79%.
1HNMR (400MHz, DMSO) δ: 2.25 (s, 3H), 2.32 (s, 3H), 3.20～3.30 (m, 8H), 6.41 (d, J=8,1H), 7.00 (d, J=8,1H), 7.11～7.20 (m, 2H), 7.25 (s, 1H), 7.30 (d, J=8,1H), 7.41 (d, J=8,1H), 8.75 (s, 1H).
Embodiment 10
In 100ml two neck bottle, add intermediate (IV) (68g, 0.297mol), double, two (2-chloroethyl) amine hydrochlorate (58g, 0.325mol) with N-Methyl pyrrolidone (70ml), under nitrogen protection, heating is to 150 DEG C, react 6～8 hours (TLC detects terminal: petroleum ether: ethyl acetate=10:1), stop heating, it is cooled to room temperature, add ethyl acetate 70ml, it is cooled to 0 DEG C, precipitate out a large amount of khaki solid, sucking filtration, methanol washs, sucking filtration obtains obtaining khaki solid (VI) 74.4g after filter cake is dried, productivity: 75%.
Comparative example 1
According to the method for the embodiment 20 of CN101472906B, 2, the 4-thiophenol dimethyl benzenes (424mmol) of 1, the 2-dibromo-benzene (424mmol) of 100g and 58.6g are dissolved in the toluene of 800mlL. Gained solution nitrogen is purged, is subsequently adding 4.6gPddba2(8mmol; 2mol-%) with 13.1grac-BINAP (21mmol; 5mol-%). Being stirred 5 minutes by reactant mixture, in this process, color is become orange from peony. Add 61gNaOBut(636mmol) with 200ml toluene, mixture heterogeneous is formed immediately. Suspension is heated under a nitrogen to 80 DEG C. After 10 hours, mixture is cooled to 60 DEG C,
It is subsequently adding the Boc-piperazine (551mmol) of 102.6g and the NaOBu of other 61gt(636mmol) slurry in 500ml toluene. Reactant mixture nitrogen is purged, is subsequently adding the 4.6gPddba of another part2(8mmol; 2mol-%) with 13.1grac-BINAP (21mmol; 5mol-%). Now, other 6 hour that mixture heating (110 DEG C) is refluxed, or until HPLC shows to convert completely. By reactant mixture cooled on ice 2 hours, then pass through one layer of celite and filter this mixture. The toluene of the filter cake 2x200ml of gained is washed, and the filtrate of merging is evaporated to the red oil of 242g. Being dissolved in the MeOH of 1000mL by this grease, and be slowly added to the HBr (aq.) of 115ml48wt%, be then heated to backflow 2 hours, hereafter, HPLC detects complete deprotection. This mixture is cooled down, adds 1000mLEtOAc, and remove MeOH by evaporating. Add the Et of 1000ml2O, thus produces precipitation. It is continuously stirred at room temperature 2 hours, then gained slurry is placed in refrigerator (-18 DEG C) overnight. Filter, and with the Et of 200ml2O washes twice, and after dry in the vacuum at 40 DEG C, produces the brown solid of 172g. By this brown solid 1500mL H seethed with excitement2O processes 1 hour, is subsequently cooled to room temperature and keeps 2 hours again. Filter, and at 40 DEG C dried in vacuum overnight, thus generating 1-[2-(2, the 4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide of 98g.
From above comparative example it can be seen that this comparative example needs to use precious metal palladium reagent and part, expensive, cause that preparation cost increases.
It is pointed out that above-described embodiment is only the technology design and feature that the present invention is described, its object is to allow person skilled in the art will appreciate that present disclosure and to implement according to this, can not limit the scope of the invention with this. All equivalences made according to spirit of the invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. the preparation method of 1-[2-(2, the 4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine of formula (VI), the method comprises the following steps:
(A) with 2,4-thiophenol dimethyl benzenes (I) for initiation material, 2-(2,4-dimethylphenylsulfanyl) Nitrobenzol (III) is generated with 2-halogenated nitrobenzene (II) condensation,
(B) 2-(2,4-dimethylphenylsulfanyl) Nitrobenzol (III) reduces through reducing agent, obtains 2-(2,4-dimethylphenylsulfanyl) aniline (IV), and
(C) 2-(2,4-dimethylphenylsulfanyl) aniline (IV) again with double; two (2-chloroethyl) amine hydrochlorate (V) cyclization generate 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI).
2. preparation method according to claim 1, it is characterised in that the reaction of step (A) carries out under the existence of phase transfer catalyst and alkali;Preferably, molar ratio of material (I): (II): alkali: phase transfer catalyst=1:1～2.0:1～2.0:0.01～0.25, it is preferably 1:1.05～1.9:1.05～1.9:0.015～0.2, it is more preferably 1:1.08～1.8:1.08～1.8:0.02～0.18, it is preferably 1:1.1～1.7:1.1～1.7:0.025～0.16, more preferably 1:1.1:1.2:0.05.
3. preparation method according to claim 2, it is characterized in that, the reaction of step (A) is to carry out in the presence of the solvent, and solvent for use is acetonitrile, oxolane, dimethyl sulfoxide, N, dinethylformamide, N,N-dimethylacetamide, toluene; Or solvent for use is any one in water, methanol, ethanol, isopropanol and acetonitrile, oxolane, dimethyl sulfoxide, N, dinethylformamide, N, the mixed solvent of the arbitrary solvent in N-dimethyl acetylamide, toluene, it is more preferably the mixed solvent of toluene and water, weight ratio toluene: water=1～3:1～3, more preferably 1～2:1～2.
4. the preparation method according to any one of claim 1-3, it is characterised in that the reaction condition of step (A) is: reaction temperature 10～60 DEG C, it is preferable that 20～50 DEG C, more preferably 25～40 DEG C; Response time 12～30h, it is preferable that 15-26h, it is preferable that 18～24h.
5. the preparation method according to any one of claim 2-4, it is characterised in that the alkali used in step (A) is potassium hydroxide, sodium hydroxide, Feldalat NM, Feldalat KM, Sodium ethylate or sodium hydride, it is preferred to potassium hydroxide or Feldalat NM; And/or
Phase transfer catalyst example is chosen from one or more among following substances:
A, polyethers, for instance: linear or chain Polyethylene Glycol: H (OCH2CH2) nOH, or, linear or chain dialkylethers: R (OCH2CH2)nOR, or, linear or chain polyalkylene glycol monoalkyl ether: H (OCH2CH2) nOR, wherein R=C1-C6 alkyl;
B, cyclic crown ether class, for instance: 18 hat 6,15 hat 5 or cyclodextrin;
C, quaternary ammonium salt, for instance: benzyltriethylammoinium chloride, tetrabutyl ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride;
D, tertiary amines, for instance: R3N, wherein R=C1-C7 alkyl; Such as tri-n-butylamine, tripropylamine or triethylamine;
E, quaternary ammonium bases, for instance: R4NOH, wherein R=C1-C7 alkyl, C4-C6 cycloalkyl, phenyl or benzyl;
F, season phosphonium salt class.
6. the preparation method according to any one of claim 1-5, it is characterised in that in the reaction of step (B), reducing agent is hydrazine hydrate, ferrum, zinc, stannum, sodium hydrosulfite, hydrogen, azanol or sodium hydride, it will be preferred that hydrazine hydrate.
7. the preparation method in any of the one of claim 1-6, wherein the reaction of this step (B) is to carry out in the presence of a catalyst, and this catalyst is ferric chloride/activated carbon, ammonium chloride, hydrochloric acid or sulphuric acid; Preferably, catalyst is activated carbon and Iron(III) chloride hexahydrate, wherein molar ratio of material intermediate (III): activated carbon: Iron(III) chloride hexahydrate: mol ratio=1:1.1～3:0.05～0.5:8～20 of reducing agent (preferred hydrazine hydrate), it is preferably 1:1.4～2.6:0.07～0.4:10～18, preferred 1:1.8～2.2:0.08～0.3:11～15, it is preferable that 1:2:0.1:12.
8. the preparation method according to any one of claim 1-7, it is characterized in that, the reaction of step (B) is at alcohols solvent (such as methanol, ethanol), nitrile solvents (such as acetonitrile, propionitrile) or amide solvent (N, dinethylformamide, N, N-diethylformamide etc.) in carry out under reflux, reaction carries out 1～10 hour, it is preferable that 3～8 hours, more preferably 4～6 hours.
9. the preparation method according to any one of claim 1-8, it is characterized in that, in the reaction of step (C), intermediate (IV): mol ratio=1:0.8～2 of double; two (2-chloroethyl) amine hydrochlorate (V), preferred 1:1.0～1.5, more preferably 1:1.1.
10. the preparation method according to any one of claim 1-9, it is characterised in that the reaction of step (C) is to carry out under reflux in the presence of the solvent; Preferably, this solvent is triethylamine, N-methylmorpholine, DIPEA, N-Methyl pyrrolidone; It is more preferably DIPEA, N-Methyl pyrrolidone; This reaction carries out 5～15 hours, it is preferable that 6～12 hours, more preferably 7～9 hours.
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