CN105777667A - Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine - Google Patents
Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine Download PDFInfo
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Abstract
The invention relates to a preparation method of an anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine (VI). The method comprises the following steps: condensing an initial raw material 2,4-dimethylthiophenol (I) and t-butyl 2-X halogenated phenyl carbamate (II) to generate t-butyl 2-(2,4-dimethylphenylthioalkyl) phenyl carbamate (III), carrying out Boc group removal on the t-butyl 2-(2,4-dimethylphenylthioalkyl) phenyl carbamate (III) in a proper organic solvent solution of hydrogen chloride to obtain 2-(2,4-dimethylphenylthioalkyl)aniline hydrochloride (IV), and carrying out ring closing on the 2-(2,4-dimethylphenylthioalkyl)aniline hydrochloride (IV) and bis(2-chloroethyl)amine hydrochloride (V) to generate 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine (VI). The preparation method has the advantages of concise technology, economy, environmental protection, and suitableness 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 route A and B are shown in Fig. 1, Fig. 2.
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), and synthetic route C is shown in Fig. 3.
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 D is shown in Fig. 4.
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 following (synthetic route chart of the present invention is shown in Fig. 5):
(A) with 2,4-thiophenol dimethyl benzene (I) is initiation material, 2-(2 is generated with 2-halogeno-benzene t-butyl carbamate (II) condensation, 4-dimethylphenylsulfanyl) the carbanilic acid tert-butyl ester ((III), (B) 2-(2,4-dimethylphenylsulfanyl) ((III) obtains 2-(2 through de-Boc base to the carbanilic acid tert-butyl ester under the suitable organic solvent solution of hydrogen chloride, 4-dimethylphenylsulfanyl) anilinechloride (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 the reaction of step (A) (namely, with 2,4-thiophenol dimethyl benzene (I) is initiation material, 2-(2 is generated with 2-halogeno-benzene t-butyl carbamate (II) condensation, 4-dimethylphenylsulfanyl) the carbanilic acid tert-butyl ester (III)) in, reaction carries out under the existence of phase transfer catalyst and alkali, wherein, molar ratio of material (I): (II): alkali: phase transfer catalyst=1:1.1 ~ 2.0:1.1 ~ 2.0:0.01 ~ 0.2, it is preferred to 1:1.1:1.2:0.05.Additionally, reaction preferably carries out in the presence of the solvent, solvent can be selected from one or more in polar solvent and non-polar solven, it it is such as hydro carbons (such as hexane, toluene, benzene etc.), alcohols (such as ethanol, propanol, butanol etc.), ethers (such as ether, propyl ether, oxolane etc.), ketone (such as acetone, butanone etc.), nitrile (such as acetonitrile etc.), amide-type (such as N, dinethylformamide etc.) one or more among solvent etc., solvent for use is preferably acetonitrile, oxolane, dimethyl sulfoxide, N, dinethylformamide, toluene；Or the mixed solvent of any one in water, methanol, ethanol, isopropanol and the arbitrary solvent in acetonitrile, oxolane, dimethyl sulfoxide, N,N-dimethylformamide, toluene.And more preferably at toluene and water (weight ratio toluene: water=1 ~ 3:1 ~: 3, more preferably 1 ~ 2:1 ~ 2) mixed solvent in carry out.Preferred reaction condition is: reaction temperature: 10 ~ 60 DEG C, it is preferable that 25 ~ 50 DEG C；Response time: 12 ~ 30h, it is preferable that 18 ~ 24h.Alkali can be potassium hydroxide, sodium hydroxide, Feldalat NM, Feldalat KM, Sodium ethylate or sodium hydride, it is preferred to potassium hydroxide or Feldalat NM.
Phase transfer catalyst such as can be selected from following among one or more:
A, polyethers: chain Polyethylene Glycol: H (OCH2CH2)nOH, chain dialkylethers: R (OCH2CH2)nOR；
B, cyclic crown ether class: 18 hat 6,15 hats 5, cyclodextrin etc.；
C, quaternary ammonium salt: benzyltriethylammoinium chloride, tetrabutyl ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride etc.；
D, tertiary amine: R3N such as tri-n-butylamine etc.；
E, quaternary ammonium base: R4NOH etc.；
F, season phosphonium salt.
2,4-thiophenol dimethyl benzene (I) generates 2-(2 with 2-X halogeno-benzene t-butyl carbamate (II) condensation, 4-dimethylphenylsulfanyl) the carbanilic acid tert-butyl ester (III), 2-X halogeno-benzene t-butyl carbamate (II) is 2-chloroanilino t-butyl formate, 2-bromoanilino t-butyl formate or 2-fluoroanilino t-butyl formate, being preferably 2-chloroanilino t-butyl formate and 2-fluoroanilino t-butyl formate, phase transfer catalyst used is preferably tetrabutylammonium chloride, tetrabutyl ammonium bromide；Alkali used is preferably potassium hydroxide or Feldalat NM.Phase transfer catalysis dosage is preferably: 0.05eq, and the mol ratio of (I), (II) and alkali is preferably: 1:1.1:1.2.Solvent for use is preferably the mixed solvent of toluene and water.
Step (B) reaction (namely, 2-(2, 4-dimethylphenylsulfanyl) ((III) is under the suitable organic solvent solution of hydrogen chloride for the carbanilic acid tert-butyl ester, 2-(2 is obtained through de-Boc base, 4-dimethylphenylsulfanyl) anilinechloride (IV)) in, elimination Boc group, agents useful for same is the organic solvent solution of hydrogen chloride, organic solvent is, ether solvent is (such as 1, 4-dioxane, oxolane, ether etc.), ketones solvent (such as acetone, methyl ethyl ketone etc.), esters solvent (such as ethyl acetate, iso-propyl acetate, methyl acetate etc.), alkane solvent (such as dichloromethane, toluene, petroleum ether etc.), alcohols solvent (such as methanol, ethanol etc.), it is preferably ethyl acetate or oxolane.The reaction of step (B) carries out under the organic solvent solution of hydrogen chloride, and its concentration is 1-10M, it is preferred to 2-4M；(III) the reaction mol ratio with the organic solvent solution of hydrogen chloride is 1:1.1 ~ 3.0, preferred 1:1.2 ~ 1.5；Temperature is preferably 20-40 DEG C；Response time is 1-5h, it is preferred to 2.5h.
Step (C) reaction (namely, 2-(2,4-dimethylphenylsulfanyl) anilinechloride (IV) generates 1-[2-(2 with double; two (2-chloroethyl) amine hydrochlorate (V) cyclizations, 4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI)) in, intermediate (IV): mol ratio=1:0.9 ~ 2 of double; two (2-chloroethyl) amine hydrochlorate (V), preferred 1:1.1 ~ 1.5, more preferably 1:1.1.Reaction preferably carries out in the presence of the solvent under reflux, and solvent is triethylamine, N-methylmorpholine, DIPEA, N-Methyl pyrrolidone, it is preferred to DIPEA, N-Methyl pyrrolidone.Reaction is preferably performed 5 ~ 15 hours, it is preferable that 6 ~ 8 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.
Accompanying drawing illustrates:
Fig. 1: synthetic route A；
Fig. 2: synthetic route B；
Fig. 3: synthetic route C；
Fig. 4: synthetic route D；
Fig. 5: synthetic route chart of the present invention.
Detailed description of the invention
Example below, only for further illustrating the present invention, does not limit the present invention in any form.
Embodiment 1
The preparation of 2-(2,4-dimethylphenylsulfanyl) the carbanilic acid tert-butyl ester (III)
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (56.3g, 0.40mol), adjacent chloroanilino t-butyl formate (II) (100.0g, 0.44mol), 200mL toluene, tetrabutyl ammonium bromide (5.2g, 0.016mol), it is then used by 200mL dissolved hydrogen water potassium oxide (26.9g, 0.48mol), and is dropped in reaction bulb, after dropwising, react 24-26 hour at 45 DEG C.Stopped reaction, adds 1L ethyl acetate and 300mL water, separates organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merges organic facies with 1L saturated common salt water washing once, and anhydrous sodium sulfate dries and dewaters, rotation is steamed solvent and is obtained colorless oil (III) 121.0g, productivity 92%.
1HNMR(400MHz,CD3Cl) δ: 1.40(s, 9H) 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),9.91(s,1H)。
Embodiment 2
The preparation of 2-(2,4-dimethylphenylsulfanyl) the carbanilic acid tert-butyl ester (III)
1L reaction bulb adds 2,4-thiophenol dimethyl benzenes (I) (56.3g, 0.40mol), adjacent chloroanilino t-butyl formate (II) (100.0g, 0.44mol), 200mL toluene, tetrabutyl ammonium bromide (12.9g, 0.040mol), it is then used by 200mL dissolved hydrogen water potassium oxide (26.9g, 0.48mol), and is dropped in reaction bulb, after dropwising, react 24-26 hour at 45 DEG C.Stopped reaction, adds 1L ethyl acetate and 300mL water, separates organic facies, aqueous phase 500mL extraction into ethyl acetate twice, merges organic facies with 1L saturated common salt water washing once, and anhydrous sodium sulfate dries and dewaters, rotation is steamed solvent and is obtained colorless oil 121.8g, productivity 92.5%.
Embodiment 3
The preparation of 2-(2,4-dimethylphenylsulfanyl) anilinechloride (IV)
In 1L reaction bulb, add intermediate (III) IV (98.7g, 0.30mol), the tetrahydrofuran solution (90.0mL, 36mol) of 4N hydrogen chloride, join in reaction bulb, at 25 DEG C, reaction 2.5h, filters, vacuum drying, obtain light yellow solid powder 77.5g, productivity 97.5%.
1HNMR (400MHz, CD3Cl) δ: 2.52 (s, 3H), 2.68 (s, 3H), 4.44 (s, 3H), 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 4
The preparation of 2-(2,4-dimethylphenylsulfanyl) anilinechloride (IV)
In 1L reaction bulb, add intermediate (III) IV (98.7g, 0.30mol), the ethyl acetate solution (90.0mL, 36mol) of 4N hydrogen chloride, join in reaction bulb, at 25 DEG C, reaction 2.5h, filters, vacuum drying, obtain light yellow solid powder 77.9g, productivity 98%.
Embodiment 5
The preparation of 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI)
In 1L two neck bottle, add intermediate (IV) (79.5g, 0.3mol), double, two (2-chloroethyl) amine hydrochlorate (58.4g, 0.33mol) and N, N-diisopropylethylamine (70ml), under nitrogen protection, heating is to refluxing, react 10～12 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) 79.0g after filter cake is dried, productivity: 93.1%.
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 6
The preparation of 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI)
In 100ml two neck bottle, add intermediate (IV) (79.5g, 0.30mol), double, two (2-chloroethyl) amine hydrochlorate (58.4g, 0.33mol) with N-Methyl pyrrolidone (70ml), under nitrogen protection, heating is to 150 DEG C, react 10～12 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) 76.0g after filter cake is dried, productivity: 89.5%.
Claims (9)
1. the preparation method of antidepressant 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine (VI):
It is characterized in that including being made by step: (A) is with 2, 4-thiophenol dimethyl benzene (I) is initiation material, 2-(2 is generated with 2-X halogeno-benzene t-butyl carbamate (II) condensation, 4-dimethylphenylsulfanyl) the carbanilic acid tert-butyl ester (III), (B) 2-(2, 4-dimethylphenylsulfanyl) the carbanilic acid tert-butyl ester (III) obtains 2-(2 through de-Boc base under the suitable organic solvent solution of hydrogen chloride, 4-dimethylphenylsulfanyl) anilinechloride (IV), (C) 2-(2, 4-dimethylphenylsulfanyl) anilinechloride (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=1:1.1 ~ 2.0:1.1 ~ 2.0:0.01 ~ 0.2, it is preferred to 1:1.1:1.2:0.05.
3. preparation method according to claim 2, it is characterised in that the reaction of step (A) carries out in the presence of the solvent, solvent for use is acetonitrile, oxolane, dimethyl sulfoxide, DMF, N,N-dimethylacetamide, toluene；Or 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, it is preferable that 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 25 ~ 40 DEG C；Response time 12 ~ 30h, it is preferable that 18 ~ 30h.
5. the preparation method according to any one of claim 1-4, it is characterised in that alkali is potassium hydroxide, sodium hydroxide, Feldalat NM, Feldalat KM, Sodium ethylate or sodium hydride, it is preferred to potassium hydroxide or Feldalat NM；
Phase transfer catalyst example be chosen from following among one or more:
A, polyethers: chain Polyethylene Glycol: H (OCH2CH2) nOH, chain dialkylethers: R (OCH2CH2) nOR；
B, cyclic crown ether class: 18 hat 6,15 hats 5, cyclodextrin etc.；
C, quaternary ammonium salt: benzyltriethylammoinium chloride, tetrabutyl ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride etc.；
D, tertiary amine: R3N such as tri-n-butylamine etc.；
E, quaternary ammonium base: R4NOH etc.；
F, season phosphonium salt.
6. the preparation method according to any one of claim 1-5, it is characterized in that, in the reaction of step (B), elimination Boc group, agents useful for same is the organic solvent solution of hydrogen chloride, organic solvent is, ether solvent is (such as 1, 4-dioxane, oxolane, ether etc.), ketones solvent (such as acetone, methyl ethyl ketone etc.), esters solvent (such as ethyl acetate, isopropyl acetate, methyl acetate etc.), alkane solvent (such as dichloromethane, toluene, petroleum ether etc.), alcohols solvent (such as methanol, ethanol etc.), it is preferably ethyl acetate or oxolane.
7. the preparation method according to any one of claim 1-6, it is characterised in that the reaction of step (B) carries out under the organic solvent solution of hydrogen chloride, and its concentration is 1-10M, it is preferred to 2-4M；(III) the reaction mol ratio with the organic solvent solution of hydrogen chloride is 1:1.1 ~ 3.0, preferred 1:1.2 ~ 1.5；Reaction temperature is preferably 20-40 DEG C；Response time is 1-5h, it is preferred to 2.5h.
8. the preparation method according to any one of claim 1-7, it is characterised in that in the reaction of step (C), intermediate (IV): mol ratio=1:0.9 ~ 2 of double; two (2-chloroethyl) amine hydrochlorate, it is preferable that 1:1.1 ~ 1.5, more preferably 1:1.1.
9. the preparation method according to any one of claim 1-8, it is characterised in that the reaction of step (C) carries out in the presence of the solvent under reflux, solvent is preferably triethylamine, N-methylmorpholine, DIPEA, N-Methyl pyrrolidone；It is more preferably DIPEA or N-Methyl pyrrolidone；This reaction carries out 5 ~ 15 hours, it is preferable that 10 ~ 12 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111320592A (en) * | 2018-12-17 | 2020-06-23 | 天津理工大学 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
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| WO2007144005A1 (en) * | 2006-06-16 | 2007-12-21 | H. Lundbeck A/S | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment |
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| CN111320592A (en) * | 2018-12-17 | 2020-06-23 | 天津理工大学 | Preparation method of 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl ] piperazine |
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Application publication date: 20160720 |