CN104130212A - Synthesis method suitable for industrialized production of vortioxetine hydrobromide - Google Patents
Synthesis method suitable for industrialized production of vortioxetine hydrobromide Download PDFInfo
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention provides a novel method for preparing vortioxetine hydrobromide, and belongs to the technical field of medicine synthesis. The method uses 2-fluoroaniline as a starting material to prepare the clinical medicinal vortioxetine hydrobromide by Boc protection, condensation, deprotection condensation, cyclization and other 4 steps of reaction. The method has the advantages of easy obtained raw material, low price, simple synthesis operation, mild reaction condition, easy control, no high pressure, good reaction selectivity, high yield and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of method of producing thymoleptic, relate in particular to a kind of fertile method for Xi Ting of suitability for industrialized production thymoleptic Hydrogen bromide, relate to the fertile synthetic method for Xi Tingxin of a kind of Hydrogen bromide, belong to technical field of medicine synthesis.
Background technology
Major depressive disorder is disabling property of one mental disorder, the change that is characterized in being in a bad mood, interference work; affect sleep, study, diet and amusement; daily routines are had no interest, insomnia or hypersomnia, uneasiness; exciting; tired, guilt feeling or sense of uselessness, thinking or attention are concentrated difficulty; suicidal thought etc., but patient's symptom is incomplete same.Reaction difference based on patient to medicine, has multi-medicament can supply its selection.6 randomized clinical trials that the U.S. and other countries carry out show, fertilely compare major depressive disorder for Xi Ting and placebo and have obvious curative effects.
Hydrogen bromide is fertile for Xi Ting (vortioxetine hydrobromide), chemistry 1-[2-[(2 by name, 4-3,5-dimethylphenyl) sulfydryl] phenyl]-piperazine hydrobromide, it is the inhibitor of serotonin transporter, and its acceptor is carried out to activity adjusting, by Ling Bei (Lundbeck) and military field (Takeda) cooperative research and development, obtain U.S. FDA approval listing in September, 2013, trade(brand)name Brintellix, clinical major depressive disorder and the generalized anxiety disorder of being used for the treatment of.
The fertile chemical structural formula for Xi Ting of Hydrogen bromide is as follows:
About the preparation method of (I), according to disclosed bibliographical information, mainly can be divided into following several method:
Method one, Hydrogen bromide are irrigated and are replaced in western spit of fland WO 2003029232 patents taking N-bromo phenyl-N-protected base (pg) piperazine as starting raw material; with 2; the reaction of 4-dimethyl sulfydryl benzene obtains the fertile Xi Ting of replacing with protecting group, then obtains target compound (I) by deprotection.
The domestic nothing of the method starting raw material, and in synthetic, catalyzer is expensive, is not easy to obtain.
Method two, Hydrogen bromide are irrigated and are replaced in western spit of fland WO 2007144005 and WO 2010094285 patents taking bromobenzene propyl ether as starting raw material; react with the piperazine of monosubstituted protection; obtain the fertile Xi Ting of replacing with protecting group, then obtain target compound (I) by deprotection.
The domestic nothing of the same starting raw material of the method, and in synthetic, catalyzer is expensive, is not easy to obtain, and has many competition side reactions in simultaneous reactions.
Method three, fertile western spit of fland W0 2007144005 and W02013 102573 patents replaced of Hydrogen bromide disclose a kind of improved fertile preparation method for Xi Ting, directly by three functional compounds, under certain catalyst action, prepare fertile for Xi Ting (I) by the method for the treatment of different things alike.
The method is without protection and deprotection through piperazine, but the method does not fundamentally solve the competition side reaction of two halogens, thereby the purity of the product of real income only has 90% left and right.If so use the method, need to solve equally follow-up issues of purification, in addition, the method has been used expensive catalyzer, and cost is high, and difficult recovery increases the industrialization difficulty of the method.
Method four, Hydrogen bromide are irrigated for western spit of fland CN 103788019A and are disclosed with 2-nitro thiophenol or 2-amido thiophenol and 2,4-dimethyl halogeno-benzene is starting raw material, there is condensation reaction and generate 2-(2,4-3,5-dimethylphenyl sulfanyl) oil of mirbane or 2-(2,4-3,5-dimethylphenyl sulfanyl) aniline, 2-(2,4-3,5-dimethylphenyl sulfanyl) aniline obtains fertile for Xi Ting (I) with two (2-Y replacement) ethamine generation ring-closure reaction under alkaline condition.
Though the method is further improved, when reaction needed reduction, use a large amount of reductibility iron powders, and precious metal catalyst, complex operation, cost is high, and yield is low.
method four, fertile Xi Ting (Chinese Journal of Pharmaceuticals, 2014,45(4), 301~302 of replacing of Hydrogen bromide), taking o-fluoronitrobenzene as starting raw material, make fertile for Xi Ting (I) through 4 steps reactions.
The method has significantly and improves above, but still complex operation, and yield is low, and need of production high pressure, is unfavorable for suitability for industrialized production (Chinese Journal of Pharmaceuticals, 2014,45(4), 301~302 simultaneously).
Summary of the invention
On the comprehensive basis of previous work and the basis of experiment, the invention provides the synthetic fertile a kind of novel method for Xi Ting of Hydrogen bromide that reaches.
Goal of the invention of the present invention is to realize with step by the following technical programs:
The preparation of a, II:
Adjacent fluoroaniline and Boc acid anhydrides in suitable organic solvent at 40~100 DEG C reaction reach terminal, react the complete room temperature that is cooled to, be concentrated into dryly, add ether solvent to stir 10~20min, the ether solvent that inclines, concentrates and obtains colorless oil intermediate II;
The preparation of b, III:
Intermediate II and 2,4-thiophenol dimethyl benzene react and reach terminal at 60~140 DEG C in DMF solvent under alkaline condition, cooling, and after adding water, through extraction, washing, concentrates and obtain colorless oil intermediate III;
The preparation of c, IV:
Intermediate III and trifluoroacetic acid in suitable organic solvent at 10~40 DEG C reaction reach terminal, then through dilution, alkalization, extracting and washing, the dry aftertreatment such as concentrated obtain colorless oil intermediate IV;
The preparation of d, I:
Intermediate IV and two (2-bromotrifluoromethane) amine hydrobromate react and reach terminal at 100~230 DEG C in suitable organic solvent, and cooling crystallization is centrifugal, and it is fertile for Xi Ting that clinical medicinal Hydrogen bromide is refined and obtained to crude product with methyl alcohol or methanol-water mixed solvent.
In addition, the present invention also proposes following attached technical scheme:
In the time preparing intermediate II, mole proportioning of adjacent fluoroaniline and Boc acid anhydrides is 1:1.2~2, preferably 1:1.5; The suitable organic solvent adopting is tetrahydrofuran (THF), DMF, N,N-dimethylacetamide, methylene dichloride, preferably tetrahydrofuran (THF); Preferred temperature of reaction is reflux temperature; The ethers that aftertreatment adds is isopropyl ether, sherwood oil, preferably sherwood oil.
In the time preparing intermediate III, this step alkaline condition refers to organic bases or mineral alkali to carry out under existing, wherein mineral alkali can be selected from that saleratus, salt of wormwood, carbonic acid are gorgeous, sodium carbonate, sodium bicarbonate; Organic bases can be selected from pyridine, DMAP, DIPEA, DBU, triethylamine, and most preferred alkali is DIPEA(N, N-diisopropylethylamine); Preferably 80~90 DEG C of temperature of reaction, post-reaction treatment extraction solvent ethyl acetate.
In the time preparing intermediate IV, the suitable organic solvent adopting is methylene dichloride, tetrahydrofuran (THF), trichloromethane, ethyl acetate, preferably methylene dichloride; Preferably 20~30 DEG C of temperature of reaction, the preferred methylene dichloride of thinner, basifier is the sodium hydroxide solution of 0.1~1M preferably.
To prepare Hydrogen bromide fertile during for western spit of fland, mole proportioning of intermediate IV and two (2-bromotrifluoromethane) amine hydrobromates is 1:1.05~1.2, preferably 1:1.1; The suitable organic solvent adopting be diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, ethylene carbonate. Diethylene Glycol acetic ester, preferably diethylene glycol monomethyl ether; Preferred temperature of reaction is 130~220 DEG C.
To prepare Hydrogen bromide fertile during for western spit of fland, when refining, mixed solvent methyl alcohol is 10:1~2 with the volume ratio of water, preferred 10:1.
Advantage of the present invention:
This invention provides a kind of new thinking and method for synthetic Hydrogen bromide is fertile for Xi Ting, the method operation and easy, and reaction conditions gentleness, good reaction selectivity, yield is higher, without high pressure, simple to operate, be convenient to purifying, be applicable to suitability for industrialized production.
Embodiment
The following examples can conduct further description the present invention, but these embodiment should not served as limitation of the scope of the invention.
embodiment mono-:
The preparation of a, intermediate II:
Adjacent fluoroaniline 111g(1.0mol) and Boc acid anhydrides 327g(1.5mol) stirring and refluxing 48h in dry tetrahydrofuran (THF) 2200ml, thin layer identification terminal (developping agent: methylene dichloride-Skellysolve A=1:4), reacts complete, is cooled to room temperature, filter, filtrate is concentrated into dry, and resistates adds sherwood oil 1500ml, violent stirring 30min, leave standstill, the supernatant liquor that inclines, resistates is concentrated into does and obtains 205g colorless oil intermediate II, yield 97.1%.
1H—NMR(500MHz,CDCl
3/TMS,ppm):
δ?8.13?(m,1?H),7.50?(m,?1?H),7.29?(m,1?H),7.00?(bs,1?H),6.89?(m,1?H),1.54?(s,9H)。
The preparation of b, intermediate III:
Intermediate II 190g(0.90mol), 2,4-thiophenol dimethyl benzene 125g(0.90mol) and DMF 1500ml, DIPEA(N, N-diisopropylethylamine) 149ml(0.91mol); At 85~90 DEG C, stir 30h, thin layer identification terminal (developping agent: methylene dichloride-Skellysolve A=1:3), reacts complete, is cooled to room temperature, add ethyl acetate 3000ml and deionized water 500ml, stir 20min, stratification, saturated nacl aqueous solution 300ml × 2 washing for organic layer, anhydrous sodium sulfate drying, remove by filter siccative, filtrate is concentrated into dry 270g colorless oil intermediate III, yield 91.2%.
1H—NMR(500MHz,CDCl
3/TMS,ppm):
δ?8.13?(m,1?H),?7.50?(bs,1?H),7.30(m,?2H),7.02?(m,1?H),6.99?(m,1?H),6.87(m,1?H),6.75?(m,1?H),2.41?(s,3H),2.29?(s,?3H,1.47?(s,9H)。
The preparation of c, intermediate IV:
Intermediate III 264g(0.80mol) and trifluoroacetic acid 1600ml in methylene dichloride 1800ml, stirring reaction 2h at 25~30 DEG C of whats, thin layer identification terminal (developping agent: methylene dichloride-Skellysolve A=1:2), react complete, add methylene dichloride 3000ml, with sodium hydroxide solution adjusting pH value to 9~10 of 1M, stratification, methylene dichloride 600ml × 2 extraction for water layer, merge organic layer, anhydrous sodium sulfate drying, removes by filter siccative, filtrate is concentrated into dry 174g colorless oil intermediate IV, yield 95.1%;
1H—NMR(500MHz,CDCl
3/TMS,ppm):
δ7.38?(m,1?H),7.25?(m,1?H),7.05?(s,1?H,6.89?(d,1?H,JJ=12.0?Hz),6.81(m,?2H),6.75?(d,1?H,JJ=12.0?Hz),4.24?(bs,2H),2.45?(s,?3H),?2.32?(s,3H)。
D, the fertile preparation for Xi Ting of Hydrogen bromide:
Intermediate IV 172g(0.75mol and diethylene glycol monomethyl ether 2000ml, heated and stirred to 100~110 DEG C, divide and add two (2-bromotrifluoromethane) amine hydrobromate 257g(0.82mol for 5 times), add complete, be warming up to 170~180 DEG C, stirring reaction 9h, thin layer identification terminal (developping agent: propyl carbinol-Glacial acetic acid-water=10:2:1), react complete, be cooled to room temperature crystallization, leave standstill 5h, centrifugal, it is fertile for Xi Ting that crude product obtains 253g off-white color solid hydrogen bromic acid by recrystallizing methanol, yield 89.6%.HPLC content 99.1%.
1h-NMR(500MHz, CDCl
3/ TMS, ppm): totally 21 hydrogen signals
δ7.31(?d,1H,?JJ=9.6?Hz),7.16(s,1H),7.11(d,2H,JJ=4.8?Hz),7.04(d,1H?,JJ=9.0?Hz),6.97~6.84(m,1H),?6.52(d,1H,JJ=9.6Hz),3.48(dd,?8H?,JJ=19.2),2.34(d,6H,JJ=32.6?Hz)。
MS:m/z?(M
+)299(100%)。
embodiment bis-:
The preparation of a, intermediate II:
Adjacent fluoroaniline 111g(1.0mol) and Boc acid anhydrides 327g(1.5mol) stirring and refluxing 48h in dry tetrahydrofuran (THF) 2000ml, thin layer identification terminal (developping agent: methylene dichloride-Skellysolve A=1:4), reacts complete, is cooled to room temperature, filter, filtrate is concentrated into dry, and resistates adds sherwood oil 2000ml, violent stirring 30min, leave standstill, the supernatant liquor that inclines, resistates is concentrated into does and obtains 201g colorless oil intermediate II, yield 96.3%.
The preparation of b, intermediate III:
Intermediate II 190g(0.90mol), 2,4-thiophenol dimethyl benzene 125g(0.90mol) and DMF 2000ml, DIPEA(N, N-diisopropylethylamine) 149ml(0.91mol); At 80~85 DEG C, stir 36h, thin layer identification terminal (developping agent: methylene dichloride-Skellysolve A=1:3), reacts complete, is cooled to room temperature, add ethyl acetate 3000ml and deionized water 500ml, stir 20min, stratification, saturated nacl aqueous solution 300ml × 2 washing for organic layer, anhydrous sodium sulfate drying, remove by filter siccative, filtrate is concentrated into dry 273g colorless oil intermediate III, yield 91.6%.
The preparation of c, intermediate IV:
Intermediate III 264g(0.80mol) and trifluoroacetic acid 1800ml in methylene dichloride 1800ml, stirring reaction 2.5h at 20~25 DEG C of whats, thin layer identification terminal (developping agent: methylene dichloride-Skellysolve A=1:2), react complete, add methylene dichloride 3000ml, with sodium hydroxide solution adjusting pH value to 9~10 of 1M, stratification, methylene dichloride 600ml × 2 extraction for water layer, merge organic layer, anhydrous sodium sulfate drying, removes by filter siccative, filtrate is concentrated into dry 177g colorless oil intermediate IV, yield 95.5%;
D, the fertile preparation for Xi Ting of Hydrogen bromide:
Intermediate IV 172g(0.75mol and diethylene glycol monomethyl ether 2000ml, heated and stirred to 110~120 DEG C, divide and add two (2-bromotrifluoromethane) amine hydrobromate 257g(0.82mol for 5 times), add complete, be warming up to 160~170 DEG C, stirring reaction 11h, thin layer identification terminal (developping agent: propyl carbinol-Glacial acetic acid-water=10:2:1), react complete, be cooled to room temperature crystallization, leave standstill 5h, centrifugal, it is fertile for Xi Ting that methanol-water for crude product (10:1) recrystallization obtains 245g white solid Hydrogen bromide, yield 89.1%.HPLC content 99.8%.
Claims (6)
1. a new method of preparing the fertile Xi Ting (I) of replacing of Hydrogen bromide, its structural formula is:
It is characterized in that taking adjacent fluoroaniline as starting raw material, make Hydrogen bromide through 4 step reactions fertile for Xi Ting, synthetic route is:
Reactions steps is:
The preparation of a, II:
Adjacent fluoroaniline and Boc acid anhydrides in suitable organic solvent at 40~100 DEG C reaction reach terminal, react the complete room temperature that is cooled to, be concentrated into dryly, add ether solvent to stir 10~20min, the ether solvent that inclines, concentrates and obtains colorless oil intermediate II;
The preparation of b, III:
Intermediate II and 2,4-thiophenol dimethyl benzene react and reach terminal at 60~140 DEG C in DMF solvent under alkaline condition, cooling, and after adding water, through extraction, washing, concentrates and obtain colorless oil intermediate III;
The preparation of c, IV:
Intermediate III and trifluoroacetic acid in suitable organic solvent at 10~40 DEG C reaction reach terminal, then through dilution, alkalization, extracting and washing, the dry aftertreatment such as concentrated obtain colorless oil intermediate IV;
The preparation of d, I:
Intermediate IV and two (2-bromotrifluoromethane) amine hydrobromate react and reach terminal at 100~230 DEG C in suitable organic solvent, and cooling crystallization is centrifugal, and it is fertile for Xi Ting that clinical medicinal Hydrogen bromide is refined and obtained to crude product with methyl alcohol or methanol-water mixed solvent.
2. a kind of new method of preparing the fertile Xi Ting of replacing of Hydrogen bromide according to claim 1, while it is characterized in that preparing intermediate II, mole proportioning of adjacent fluoroaniline and Boc acid anhydrides is 1:1.2~2, preferably 1:1.5; The suitable organic solvent adopting is tetrahydrofuran (THF), DMF, N,N-dimethylacetamide, methylene dichloride, preferably tetrahydrofuran (THF); Preferred temperature of reaction is reflux temperature; The ethers that aftertreatment adds is isopropyl ether, sherwood oil, preferably sherwood oil.
3. a kind of new method of preparing the fertile Xi Ting of replacing of Hydrogen bromide according to claim 1, while it is characterized in that preparing intermediate III, this step alkaline condition refers to organic bases or mineral alkali to carry out under existing, wherein mineral alkali can be selected from that saleratus, salt of wormwood, carbonic acid are gorgeous, sodium carbonate, sodium bicarbonate; Organic bases can be selected from pyridine, DMAP, DIPEA, DBU, triethylamine, and most preferred alkali is DIPEA(N, N-diisopropylethylamine); Preferably 80~90 DEG C of temperature of reaction, post-reaction treatment extraction solvent ethyl acetate.
4. a kind of new method of preparing the fertile Xi Ting of replacing of Hydrogen bromide according to claim 1, while it is characterized in that preparing intermediate IV, the suitable organic solvent adopting is methylene dichloride, tetrahydrofuran (THF), trichloromethane, ethyl acetate, preferably methylene dichloride; Preferably 20~30 DEG C of temperature of reaction, the preferred methylene dichloride of thinner, basifier is the sodium hydroxide solution of 0.1~1M preferably.
5. a kind of new method of preparing the fertile Xi Ting of replacing of Hydrogen bromide according to claim 1, it is characterized in that preparing Hydrogen bromide irrigates while replacing western spit of fland, mole proportioning of intermediate IV and two (2-bromotrifluoromethane) amine hydrobromates is 1:1.05~1.2, preferably 1:1.1; The suitable organic solvent adopting be diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, ethylene carbonate. Diethylene Glycol acetic ester, preferably diethylene glycol monomethyl ether; Preferred temperature of reaction is 130~220 DEG C.
6. a kind of new method of preparing the fertile Xi Ting of replacing of Hydrogen bromide according to claim 5, is characterized in that preparing Hydrogen bromide and irrigates while replacing western spit of fland, and when refining, the volume ratio of mixed solvent methyl alcohol and water is 10:1~2, preferably 10:1.
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Cited By (9)
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CN104447622A (en) * | 2014-11-28 | 2015-03-25 | 郑州大明药物科技有限公司 | Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form |
CN104725335A (en) * | 2014-11-28 | 2015-06-24 | 郑州大明药物科技有限公司 | Preparation method of high-purity vortioxetine hydrobromide |
CN105330614A (en) * | 2014-08-04 | 2016-02-17 | 上海诺星医药科技有限公司 | vortioxetine hydrobromide crystal and preparation method thereof |
CN105348220A (en) * | 2015-11-10 | 2016-02-24 | 山东川成医药股份有限公司 | Synthetic method for vortioxetine hydrobromide |
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CN105330614A (en) * | 2014-08-04 | 2016-02-17 | 上海诺星医药科技有限公司 | vortioxetine hydrobromide crystal and preparation method thereof |
CN104447622A (en) * | 2014-11-28 | 2015-03-25 | 郑州大明药物科技有限公司 | Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form |
CN104725335A (en) * | 2014-11-28 | 2015-06-24 | 郑州大明药物科技有限公司 | Preparation method of high-purity vortioxetine hydrobromide |
CN104725335B (en) * | 2014-11-28 | 2017-03-08 | 郑州大明药物科技有限公司 | High-purity hydrogen bromic acid irrigates the preparation method for Xi Ting |
CN105777667A (en) * | 2014-12-18 | 2016-07-20 | 康普药业股份有限公司 | Preparation method of anti-depression drug 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine |
CN106279066A (en) * | 2015-05-22 | 2017-01-04 | 天津药物研究院有限公司 | A kind of hydrobromic acid irrigates the purification process for western spit of fland crystal |
CN105348220A (en) * | 2015-11-10 | 2016-02-24 | 山东川成医药股份有限公司 | Synthetic method for vortioxetine hydrobromide |
CN107843656A (en) * | 2016-09-21 | 2018-03-27 | 成都弘达药业有限公司 | A kind of detection method of 2,4 thiophenol dimethyl benzene about material |
CN112125868A (en) * | 2020-09-25 | 2020-12-25 | 中山万远新药研发有限公司 | Crystal form of vortioxetine hydrobromide, preparation method, composition and application thereof |
CN112125868B (en) * | 2020-09-25 | 2021-08-03 | 中山万远新药研发有限公司 | Crystal form of vortioxetine hydrobromide, preparation method, composition and application thereof |
CN115181077A (en) * | 2022-07-27 | 2022-10-14 | 安徽峆一药业股份有限公司 | Synthetic method of vortioxetine with low impurity content |
CN115181077B (en) * | 2022-07-27 | 2024-03-29 | 安徽峆一药业股份有限公司 | Synthesis method of vortioxetine with low impurity content |
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