CN104130212B - A kind of applicable hydrobromic acid irrigates the synthetic method for western spit of fland industrialized production - Google Patents
A kind of applicable hydrobromic acid irrigates the synthetic method for western spit of fland industrialized production Download PDFInfo
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- CN104130212B CN104130212B CN201410305506.3A CN201410305506A CN104130212B CN 104130212 B CN104130212 B CN 104130212B CN 201410305506 A CN201410305506 A CN 201410305506A CN 104130212 B CN104130212 B CN 104130212B
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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 kind of hydrobromic acid and irrigate the new preparation process for Xi Ting, belong to technical field of medicine synthesis.The method with adjacent fluoroaniline as initiation material, by Boc protection, condensation, deprotection condensation, cyclization etc. 4 step reaction prepared and meet the medicinal hydrobromic acid of clinic and irrigate and replace Xi Ting.Raw material of the present invention is easy to get, cheap, synthetic operation simple, and reaction condition is gentle, easily controllable, and without high pressure, good reaction selectivity, yield is high, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of method producing antidepressants, relate in particular to a kind of industrialized production antidepressants hydrogen
Bromic acid irrigates the method for Xi Ting, relates to a kind of hydrobromic acid and irrigates the synthetic method for Xi Tingxin, belongs to technical field of medicine synthesis.
Background technology
Major depressive disorder is a kind of crippling mental sickness, is characterized in change of being in a bad mood, disturb work, impact to sleep,
Daily routines are had no interest by study, diet and amusement, insomnia or hypersomnia, uneasy, exciting, tired, guilt feeling or useless
Sense, thinking or attention concentrate difficulty, suicidal thought etc., but patients symptomatic is incomplete same.Based on patient's reaction to medicine
Difference, has multi-medicament to be available for it and selects.6 randomized clinical trials that the U.S. and other countries are carried out show, fertile for Xi Ting with
Placebo group comparison major depressive disorder has obvious curative effects.
Hydrobromic acid is fertile for Xi Ting (vortioxetine hydrobromide), chemical entitled 1-[2-[(2,4-diformazans
Base phenyl) sulfydryl] phenyl]-piperazine hydrobromide, it is the inhibitor of serotonin transporter, and its receptor is carried out activity
Regulation, by Ling Bei (Lundbeck) and military field (Takeda) cooperative research and development, in JIUYUE, 2013 obtains in U.S. FDA approval
City, trade name Brintellix, it is clinically used for treating major depressive disorder and generalized anxiety disorder.
The chemical structural formula that hydrobromic acid is irrigated for Xi Ting is as follows:
About the preparation method of (I), according to disclosed document, can be largely classified into following several method:
Method one, hydrobromic acid are fertile to be replaced in western spit of fland WO 2003029232 patent with N-bromo phenyl-N-protected base (pg) piperazine
For initiation material, with 2, the reaction of 4-dimethyl sulfydryl benzene obtains replacing Xi Ting with the fertile of protection group, then obtains mesh by deprotection
Mark compound (I).
In the domestic nothing of the method initiation material, and synthesis, catalyst is expensive, is not easy to obtain.
Method two, hydrobromic acid are fertile to be replaced in western spit of fland WO 2007144005 and WO 2010094285 patent with bromobenzene propyl ether
For initiation material, react with the piperazine of monosubstituted protection, obtain replacing Xi Ting with the fertile of protection group, then obtain mesh by deprotection
Mark compound (I).
In the domestic nothing of the same initiation material of the method, and synthesis, catalyst is expensive, is not easy to obtain, and exists in simultaneous reactions
Many competition side reactions.
Method three, hydrobromic acid are irrigated and are disclosed a kind of improvement for western spit of fland W0 2007144005 and W02013 102573 patent
The fertile preparation method for Xi Ting, the most directly by three functional compounds, under certain catalyst action, by treating different things alike
Method prepare fertile for Xi Ting (I).
The method needs not move through protection and the deprotection of piperazine, but the method the most fundamentally solves the competing of double halogen
Strive side reaction, thus the purity of the product of real income only has about 90%.If so using the method, need also exist for solving
Follow-up issues of purification, it addition, the method use expensive catalyst, cost is high, difficult recovery so that the work of the method
Industry difficulty increases.
Method four, hydrobromic acid are fertile to be disclosed for western spit of fland CN 103788019A with 2-nitro thiophenol or 2-amido phenylmercaptan.
And 2,4-dimethyl halogeno-benzene is initiation material, occurs condensation reaction to generate 2-(2,4-dimethylphenylsulfanyl) Nitrobenzol
Or 2-(2,4-dimethylphenylsulfanyl) aniline, 2-(2,4-dimethylphenylsulfanyl) aniline is in the basic conditions with two
(2-Y replacement) ethamine generation ring-closure reaction obtains fertile for Xi Ting (I).
Though the method is improved further, but reaction needs to use substantial amounts of reproducibility iron powder during reduction, and precious metal is urged
Agent, complex operation, cost is high, and yield is low.
Method four, hydrobromic acid are fertile for Xi Ting (Chinese Journal of Pharmaceuticals, 2014,45(4), 301～302), with adjacent fluorine nitre
Base benzene is initiation material, prepares fertile for Xi Ting (I) through 4 step reactions.
The method is relatively above greatly improved, but still complex operation, and yield is low, and produce needs high pressure simultaneously, unfavorable
In industrialized production (Chinese Journal of Pharmaceuticals, 2014,45(4), 301～302).
Summary of the invention
On the basis of the basis of comprehensive previous work and experiment, the invention provides synthesis and reach hydrobromic acid and irrigate for Xi Ting's
A kind of new method.
The goal of the invention of the present invention is to realize with step by the following technical programs:
A, the preparation of II:
Adjacent fluoroaniline and Boc anhydride react at 40～100 DEG C in suitable organic solvent and reach terminal, react complete cold
But to room temperature, being concentrated to dryness, add ether solvent stirring 10～20min, incline ether solvent, concentrates and i.e. obtains in colorless oil
Mesosome II；
B, the preparation of III:
Intermediate II and 2,4-thiophenol dimethyl benzene reacts at 60～140 DEG C in the basic conditions in DMF solvent and reaches
Terminal, cooling, through extraction after adding water, washing, concentrate and i.e. obtain colorless oil intermediate III；
C, the preparation of IV:
Intermediate III and trifluoroacetic acid react at 10～40 DEG C in suitable organic solvent and reach terminal, are then passed through dilute
Release, alkalization, extracting and washing, be dried the post processing such as concentration and obtain colorless oil intermediate IV；
D, the preparation of I:
Intermediate IV and double (2-bromoethyl) amine hydrobromate react at 100～230 DEG C in suitable organic solvent and reach
To terminal, cooling crystallization, centrifugal, crude product methanol or methanol-water mixed solvent refine that i.e. to obtain clinical medicinal hydrobromic acid fertile for western
Spit of fland.
Additionally, the present invention also proposes following attached technical scheme:
When preparing intermediate II, the mol ratio of adjacent fluoroaniline and Boc anhydride is 1:1.2～2, preferably 1:1.5；Adopted
Suitable organic solvent be oxolane, DMF, N,N-dimethylacetamide, dichloromethane, preferably four
Hydrogen furan；Preferably reaction temperature is reflux temperature；The ethers that post processing adds is diisopropyl ether, petroleum ether, preferably petroleum ether.
When preparing intermediate III, this step alkalescence condition is carried out in the presence of referring to organic base or inorganic base, Qi Zhongwu
Machine alkali is selected from that potassium bicarbonate, potassium carbonate, carbonic acid is gorgeous, sodium carbonate, sodium bicarbonate；Organic base be selected from pyridine, DMAP, DIPEA,
DBU, triethylamine, most preferred alkali is DIPEA(N, N-diisopropylethylamine)；Reaction temperature preferably 80～90 DEG C, locates after reaction
Reason extractant ethyl acetate.
When preparing intermediate IV, the suitable organic solvent used is dichloromethane, oxolane, chloroform, second
Acetoacetic ester, preferably dichloromethane；Reaction temperature preferably 20～30 DEG C, the preferred dichloromethane of diluent, basifier preferably 0.1～1M
Sodium hydroxide solution.
When preparing hydrobromic acid and irrigating for western spit of fland, the mol ratio of intermediate IV and double (2-bromoethyl) amine hydrobromates is 1:
1.05～1.2, preferably 1:1.1；The suitable organic solvent used is diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethyl
Glycol monobutyl ether, ethylene carbonate. diethylene glycol acetas, preferably diethylene glycol monomethyl ether；Preferably reaction temperature is
130～220 DEG C.
When preparing hydrobromic acid and irrigating for western spit of fland, time refined, mixed solvent methanol is 10:1～2 with the volume ratio of water, preferably
10:1。
Advantages of the present invention:
This invention is that synthesis hydrobromic acid is irrigated and provided a kind of new thinking and method for Xi Ting, the method operation and letter thereof
Just, reaction condition is gentle, good reaction selectivity, and yield is higher, without high pressure, simple to operate, be easy to purification, be suitable for industrial metaplasia
Produce.
Detailed description of the invention
The present invention can be conducted further description by the following examples, but, these embodiments should not be used as this
The restriction of invention scope.
Embodiment one:
A, the preparation of intermediate II:
Adjacent fluoroaniline 111g(1.0mol) and Boc anhydride 327g(1.5mol) stir in dry oxolane 2200ml
Backflow 48h, thin layer identification terminal (developing solvent: dichloromethane-pentane=1:4), reacts complete, is cooled to room temperature, mistake
Filter, filtrate is concentrated to dryness, and residue adds petroleum ether 1500ml, strong agitation 30min, stands, and incline supernatant, and residue concentrates
205g colorless oil intermediate II, yield 97.1% is i.e. obtained to doing.
1H NMR(500MHz, CDCl3/ 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).
B, the preparation of intermediate III:
Intermediate II 190g(0.90mol), 2,4-thiophenol dimethyl benzene 125g(0.90mol) and DMF 1500ml, DIPEA
(DIPEA) 149ml(0.91mol)；Stirring 30h at 85～90 DEG C, thin layer identification terminal (launches
Agent: dichloromethane-pentane=1:3), react complete, be cooled to room temperature, add ethyl acetate 3000ml and deionized water
500ml, stirs 20min, stratification, and organic layer saturated nacl aqueous solution 300ml × 2 are washed, and anhydrous sodium sulfate is dried, mistake
Filtering desiccant, filtrate is concentrated to dryness to obtain 270g colorless oil intermediate III, yield 91.2%.
1H NMR(500MHz, CDCl3/ 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).
C, the preparation of intermediate IV:
Intermediate III 264g(0.80mol) and trifluoroacetic acid 1600ml in dichloromethane 1800ml, at what 25～30 DEG C
Stirring reaction 2h, thin layer identification terminal (developing solvent: dichloromethane-pentane=1:2), reacts complete, adds dichloromethane
3000ml, with the sodium hydroxide solution regulation pH value of 1M to 9～10, stratification, water layer dichloromethane 600ml × 2 extract,
Merging organic layer, anhydrous sodium sulfate is dried, and is filtered to remove desiccant, and filtrate is concentrated to dryness to obtain 174g colorless oil intermediate
IV, yield 95.1%；
1H NMR(500MHz, CDCl3/ TMS, ppm):
δ 7.38 (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, hydrobromic acid irrigate the preparation for Xi Ting:
Intermediate IV 172g(0.75mol and diethylene glycol monomethyl ether 2000ml, heated and stirred to 100～110 DEG C, divide 5 times
Add double (2-bromoethyl) amine hydrobromate 257g(0.82mol), add complete, be warming up to 170～180 DEG C, stirring reaction 9h,
Thin layer identification terminal (developing solvent: n-butyl alcohol-glacial acetic acid-water=10:2:1), reacts complete, is cooled to room temperature crystallize, stands
5h, centrifugal, it is fertile for Xi Ting, yield 89.6% that crude product recrystallizing methanol i.e. obtains 253g off-white color solid hydrogen bromic acid.HPLC content
99.1%。
1H NMR(500MHz, CDCl3/ TMS, ppm): totally 21 hydrogen signals
δ 7.31 (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 two:
A, the preparation of intermediate II:
Adjacent fluoroaniline 111g(1.0mol) and Boc anhydride 327g(1.5mol) stir in dry oxolane 2000ml
Backflow 48h, thin layer identification terminal (developing solvent: dichloromethane-pentane=1:4), reacts complete, is cooled to room temperature, mistake
Filter, filtrate is concentrated to dryness, and residue adds petroleum ether 2000ml, strong agitation 30min, stands, and incline supernatant, and residue concentrates
201g colorless oil intermediate II, yield 96.3% is i.e. obtained to doing.
B, the preparation of intermediate III:
Intermediate II 190g(0.90mol), 2,4-thiophenol dimethyl benzene 125g(0.90mol) and DMF 2000ml, DIPEA
(DIPEA) 149ml(0.91mol)；Stirring 36h at 80～85 DEG C, thin layer identification terminal (launches
Agent: dichloromethane-pentane=1:3), react complete, be cooled to room temperature, add ethyl acetate 3000ml and deionized water
500ml, stirs 20min, stratification, and organic layer saturated nacl aqueous solution 300ml × 2 are washed, and anhydrous sodium sulfate is dried, mistake
Filtering desiccant, filtrate is concentrated to dryness to obtain 273g colorless oil intermediate III, yield 91.6%.
C, the preparation of intermediate IV:
Intermediate III 264g(0.80mol) and trifluoroacetic acid 1800ml in dichloromethane 1800ml, at what 20～25 DEG C
Stirring reaction 2.5h, thin layer identification terminal (developing solvent: dichloromethane-pentane=1:2), reacts complete, adds dichloromethane
Alkane 3000ml, with the sodium hydroxide solution regulation pH value of 1M to 9～10, stratification, water layer dichloromethane 600ml × 2 extract
Taking, merge organic layer, anhydrous sodium sulfate is dried, and is filtered to remove desiccant, filtrate be concentrated to dryness in the middle of 177g colorless oil
Body IV, yield 95.5%；
D, hydrobromic acid irrigate the preparation for Xi Ting:
Intermediate IV 172g(0.75mol and diethylene glycol monomethyl ether 2000ml, heated and stirred to 110～120 DEG C, divide 5 times
Add double (2-bromoethyl) amine hydrobromate 257g(0.82mol), add complete, be warming up to 160～170 DEG C, stirring reaction
11h, thin layer identification terminal (developing solvent: n-butyl alcohol-glacial acetic acid-water=10:2:1), react complete, be cooled to room temperature crystallize,
Standing 5h, centrifugal, it is fertile for Xi Ting, yield that crude product methanol-water (10:1) recrystallization i.e. obtains 245g white solid hydrobromic acid
89.1%.HPLC content 99.8%.
Claims (9)
1. preparing the fertile method for Xi Ting (I) of hydrobromic acid, its structural formula is:
It is characterized in that with adjacent fluoroaniline as initiation material, prepare hydrobromic acid through 4 step reactions fertile for Xi Ting, synthetic route is:
Reactions steps is:
A, the preparation of II:
Adjacent fluoroaniline and Boc anhydride react at 40～100 DEG C in suitable organic solvent and reach terminal, react complete and are cooled to
Room temperature, is concentrated to dryness, and adds ether solvent stirring 10～20min, and incline ether solvent, concentrates and i.e. obtains colorless oil intermediate
Ⅱ；
B, the preparation of III:
Intermediate II and 2,4-thiophenol dimethyl benzene is in DMF solvent, in the presence of DIPEA at 60～140 DEG C
Reaction reaches terminal, cooling, through extraction after adding water, and washing, concentrate and i.e. obtain colorless oil intermediate III；
C, the preparation of IV:
Intermediate III and trifluoroacetic acid react at 10～40 DEG C in suitable organic solvent and reach terminal, are then passed through dilution,
Alkalization, extracting and washing, the dry post processing concentrated obtain colorless oil intermediate IV；
D, the preparation of I:
Intermediate IV and double (2-bromoethyl) amine hydrobromate react at 100～230 DEG C in suitable organic solvent and reach eventually
Point, cooling crystallization, centrifugal, crude product methanol or methanol-water mixed solvent refine and i.e. obtain that clinical medicinal hydrobromic acid is fertile replaces Xi Ting.
A kind of hydrobromic acid of preparing the most according to claim 1 irrigates the method for Xi Ting, it is characterised in that preparation intermediate II
Time, the mol ratio of adjacent fluoroaniline and Boc anhydride is 1:1.2～2；The suitable organic solvent used is oxolane；Reaction
Temperature is reflux temperature；The ethers that post processing adds is petroleum ether.
A kind of hydrobromic acid of preparing the most according to claim 2 irrigates the method for Xi Ting, it is characterised in that preparation intermediate II
Time, the mol ratio of adjacent fluoroaniline and Boc anhydride is 1:1.5.
A kind of hydrobromic acid of preparing the most according to claim 1 irrigates the method for Xi Ting, it is characterised in that prepare intermediate III
Time, reaction temperature is 80～90 DEG C, and post-reaction treatment extractant is ethyl acetate.
A kind of hydrobromic acid of preparing the most according to claim 1 irrigates the method for Xi Ting, it is characterised in that prepare intermediate IV
Time, the suitable organic solvent used is dichloromethane；Reaction temperature is 20～30 DEG C, and diluent is dichloromethane, basifier
It it is the sodium hydroxide solution of 0.1～1M.
A kind of hydrobromic acid of preparing the most according to claim 1 irrigates the method for Xi Ting, it is characterised in for preparing hydrobromic acid and irrigates
During for western spit of fland, the mol ratio of intermediate IV and double (2-bromoethyl) amine hydrobromate is 1:1.05～1.2；Used is suitable
Organic solvent is diethylene glycol monomethyl ether；Reaction temperature is 130～220 DEG C.
A kind of hydrobromic acid of preparing the most according to claim 6 irrigates the method for Xi Ting, it is characterised in for preparing hydrobromic acid and irrigates
During for western spit of fland, the mol ratio of intermediate IV and double (2-bromoethyl) amine hydrobromate is 1:1.1.
A kind of hydrobromic acid of preparing the most according to claim 7 irrigates the method for Xi Ting, it is characterised in for preparing hydrobromic acid and irrigates
During for western spit of fland, time refined, mixed solvent methanol is 10:1～2 with the volume ratio of water.
A kind of hydrobromic acid of preparing the most according to claim 8 irrigates the method for Xi Ting, it is characterised in for preparing hydrobromic acid and irrigates
During for western spit of fland, time refined, mixed solvent methanol is 10:1 with the volume ratio of water.
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN104447622B (en) * | 2014-11-28 | 2017-01-04 | 郑州大明药物科技有限公司 | Hydrobromic acid irrigates the preparation method for western spit of fland beta crystal |
| 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 |
| CN105348220B (en) * | 2015-11-10 | 2017-08-25 | 山东川成医药股份有限公司 | A kind of synthetic method of hydrobromic acid Vortioxetine |
| CN107843656B (en) * | 2016-09-21 | 2021-02-26 | 成都弘达药业有限公司 | Detection method of 2, 4-dimethylthiophenol related substances |
| 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 |
| 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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| WO2013026455A1 (en) * | 2011-08-24 | 2013-02-28 | Aarhus Universitet | Permanently positively charged antidepressants |
| CN103788019A (en) * | 2014-01-22 | 2014-05-14 | 苏州明锐医药科技有限公司 | Preparation method of vortioxetine |
| CN103788020A (en) * | 2014-01-22 | 2014-05-14 | 苏州明锐医药科技有限公司 | Preparation method of vortioxetine |
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| WO2013026455A1 (en) * | 2011-08-24 | 2013-02-28 | Aarhus Universitet | Permanently positively charged antidepressants |
| CN103788019A (en) * | 2014-01-22 | 2014-05-14 | 苏州明锐医药科技有限公司 | Preparation method of vortioxetine |
| CN103788020A (en) * | 2014-01-22 | 2014-05-14 | 苏州明锐医药科技有限公司 | Preparation method of vortioxetine |
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Effective date of registration: 20190820 Address after: Five road 230000 Anhui city in Hefei Province, Baohe Industrial District No. fifteen weft Patentee after: Anhui Heal Star Pharmaceutical Co.,Ltd. Address before: Yanan Lu, Baohe Industrial District of Hefei City, Anhui Province, No. 15 230051 Patentee before: Anhui Province Yi Xinming Pharmaceutical Technology Co., Ltd |
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