CN107915685A - A kind of preparation method of hydrobromic acid Vortioxetine intermediate - Google Patents
A kind of preparation method of hydrobromic acid Vortioxetine intermediate Download PDFInfo
- Publication number
- CN107915685A CN107915685A CN201711306443.3A CN201711306443A CN107915685A CN 107915685 A CN107915685 A CN 107915685A CN 201711306443 A CN201711306443 A CN 201711306443A CN 107915685 A CN107915685 A CN 107915685A
- Authority
- CN
- China
- Prior art keywords
- preparation
- solvent
- dosage
- condensing agent
- hydrobromic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Abstract
The invention discloses a kind of preparation method for hydrobromic acid Vortioxetine intermediate, which includes：With intermediate B i.e. 2（2,4 3,5-dimethylphenyl sulfenyls）Aniline is raw material, with N Boc iminodiacetic acids, in non-proton class solvent, is reacted under the action of condensing agent, concentrated after the completion of reaction, is extracted, and is concentrated, and refines, obtains high-purity, 1 tert-butoxycarbonyl 4 [2 in high yield（2,4 3,5-dimethylphenyl sulfenyls）Phenyl] 3,5 dioxopiperazines, that is, intermediate C.The whole synthesis technique of the present invention, has the advantages that the cost of raw material is cheap, solvent toxicity is low, the reaction time is short, product yield high quality is good, is adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, is related to a kind of hydrobromic acid Vortioxetine intermediate 1- tert-butoxy carbonyls
Base -4- [2-（2,4- 3,5-dimethylphenyl sulfenyls）Phenyl] -3,5- dioxopiperazines preparation method, which irrigates for hydrobromic acid
For the important intermediate products of Xi Ting.
Background technology
Major depressive disorder is by genetic system in individual patients（Gene）There are exception, or caused by the great change of acquired environment
A kind of mood sex dysfunction, with it is lasting spontaneous it is depressed based on a series of depressive symptoms.The disease can threaten people
Life security, induce body illness, make one to produce negative emotions, deprive the social function of people.Pole is caused to personal and society
Big burden.
Hydrobromic acid Vortioxetine is developed jointly by Japanese military field pharmacy with Denmark Lundbeck pharmacy, and indication is severe adult's suppression
Strongly fragrant disease (MDD) and generalized anxiety disorder (GAD), in September, 2013 are ratified to list in the U.S..Clinical test shows that hydrobromic acid is irrigated for west
The effect of spit of fland is for major depressive disorder is definite, Small side effects, is expected to the medicine as most successful major depressive disorder.Cause
This, which has good market prospects.
At present, the synthetic route of hydrobromic acid Vortioxetine mainly has following two：
Route one：Patent WO2014161976A1 is reported
Route two：Patent WO2013102573A1 is reported
Here, one raw material of route is easy to get, cheap, but employs double (2- chloroethyls) amine, which has carcinogenesis,
It is unfavorable for the quality control of product.The extremely difficult acquisition of raw material that route two uses, and it is expensive.
Patent CN1561336A is reported, devises following route：
It is condensing agent that patent CN1561336A middle fingers, which go out using carbonyl dimidazoles, in tetrahydrofuran, by intermediate B and N-Boc-
Iminodiacetic acid is condensed, generation intermediate C.When the reaction time is 72 small, reaction time length, reaction is not exclusively；And react
Temperature is high, is unfavorable for safety and environmental protection；Product is not refined at the same time, poor product quality.
The content of the invention
The present inventor has found exist using condensing agent and catalyst during hydrobromic acid Vortioxetine synthetic test
Under, in non-proton class solvent, in 20 ~ 30 DEG C of temperature ranges, using intermediate B as raw material, with N-Boc- iminodiacetic acids
Intermediate C reaction solutions are condensed to yield, reaction solution recrystallizes through extracting, concentrating, obtains the intermediate C of high-purity.In addition, this hair
The bright yield for obtaining product is 80% ~ 90%, can obtain the intermediate C that purity is more than 99%.The present invention compared with patent CN1561336A and
Speech, shortens the reaction time, reduces reaction temperature, and making intermediate B, the reaction was complete, obtains the intermediate C of high-purity high-yield,
Be conducive to safety and environmental protection, industrialized production preferably.
The object of the present invention is to provide it is a kind of be prepared in hydrobromic acid Vortioxetine intermediate C i.e. 1- tert-butoxycarbonyls-
4-[2-（2,4- 3,5-dimethylphenyl sulfenyls）Phenyl] -3,5- dioxopiperazines new method, this method can make that the reaction was complete, together
When shorten the production cycle, reduce safety and environmental protection risk, improve product quality, industrialized production preferably.
Reaction according to the present invention, can be stated with following equation：
Intermediate B intermediate C
Specifically, the present invention provides a kind of new method for being used to prepare hydrobromic acid Vortioxetine intermediate C, it includes following
Step：
A. in the presence of condensing agent and catalyst, in non-proton class organic solvent, in 20 ~ 30 DEG C of temperature ranges, with such as
Lower intermediate B is raw material, and intermediate C reaction solutions are obtained with N-Boc- iminodiacetic acid condensation reactions；
Intermediate B intermediate C
B. the reaction solution that step a is obtained is recrystallized through extracting, concentrating, obtains the intermediate C of high-purity.
In embodiments of the invention, wherein, the condensing agent is dicyclohexylcarbodiimide, double isopropyl carbon two
Imines, 3- ethyls -1-（3- dimethyl propyls）Carbodiimide；The dosage of the condensing agent is 2.5 ~ 3.5 equivalents of intermediate B
（Molar ratio）.
In embodiments of the invention, the catalyst is 4-dimethylaminopyridine；Dosage is the 0.05 of intermediate B
~ 0.1 equivalent（Molar ratio）.
In embodiments of the invention, the non-proton class solvent is dichloromethane, ethyl acetate, or toluene；It is described
Non-proton class solvent dosage is 8 ~ 13 times of intermediate B quality（Unit is ml/g）.
In embodiments of the invention, the N-Boc- iminodiacetic acids dosage is 1.2 ~ 1.8 equivalents of intermediate B
（Molar ratio）.
In embodiments of the invention, the recrystallization solvent includes ethanol, methanol, isopropanol, normal propyl alcohol, the use
Measure 15 ~ 20 times of (unit ml/g for intermediate B quality）.
The beneficial outcomes of the present invention are：1- tert-butoxycarbonyls -4- [2- provided by the invention（2,4- 3,5-dimethylphenyls
Sulfenyl）Phenyl] -3,5- dioxopiperazines（That is intermediate C）The method of preparation, it is with short production cycle, it can obtain the centre of high quality
Body C, makes product quality controllable, while reduces safety and environmental protection risk, industrialized production preferably.
Brief description of the drawings
Fig. 1 shows be 1 product of embodiment purity.
What Fig. 2 was represented is the hydrogen spectrum of 1 product of embodiment.
What Fig. 3 was represented is the mass spectrum (adding sodium) of 1 product of embodiment.
Embodiment
Embodiment of the present invention is specifically described below by the embodiment of the present invention.
1 1- tert-butoxycarbonyl -4- [2- of embodiment（2,4- 3,5-dimethylphenyl sulfenyls）Phenyl] -3,5- dioxopiperazines
（Intermediate C）Preparation
By dicyclohexylcarbodiimide 233.9g, 4-dimethylaminopyridine 4.26g, 500ml dichloromethane puts into 3L there-necked flasks
In, 20 ~ 30 DEG C of stirring 30min, intermediate B 100g are dissolved in the dichloromethane of 600ml, 20 ~ 30 DEG C of temperature control slowly drips
Entering, drop finishes, and reacts 60 ~ 70min, after the reaction was complete, adds 2N hydrochloric acid 1000ml and washs, the washing of 1000ml saturated sodium bicarbonates,
Evaporated under reduced pressure organic layer, adds 1500ml ethanol, is warming up to 73 ~ 80 DEG C, stirs 15 ~ 25min, is cooled to 0 ~ 5 DEG C, filters, 40
DEG C it is dried under reduced pressure to obtain off-white color crystalline powder 160.3g, purity 99.354%, yield 86.18%.
Efficient liquid phase testing conditions
2 1- tert-butoxycarbonyl -4- [2- of embodiment（2,4- 3,5-dimethylphenyl sulfenyls）Phenyl] -3,5- dioxopiperazines（In
Mesosome C）Preparation
By double diisopropylcarbodiimide 145g, 4-dimethylaminopyridine 4.50g, 500ml ethyl acetate is put into 3L there-necked flasks,
20 ~ 30 DEG C of stirring 30min, intermediate B 106g are dissolved in the ethyl acetate of 600ml, 20 ~ 30 DEG C of temperature control is slowly dropped into three mouthfuls
In bottle, drop finishes, and reacts 60 ~ 70min, after the reaction was complete, sequentially adds 2N hydrochloric acid 1000ml washings, 1000ml saturated sodium bicarbonates
Washing, evaporated under reduced pressure organic layer, adds 1600ml methanol, is warming up to 60 ~ 65 DEG C, stirs 15 ~ 25min, is cooled to 0 ~ 5 DEG C, takes out
Filter, 40 DEG C are dried under reduced pressure to obtain off-white color crystalline powder 165.8g, purity 99.318%, yield 89.14%.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although passing through ginseng
According to the preferred embodiment of the present invention, invention has been described, it should be appreciated by those of ordinary skill in the art that can
, as various changes, to be limited in the form and details to it without departing from appended claims of the invention
Spirit and scope.
Claims (10)
1. a kind of preparation method of hydrobromic acid Vortioxetine intermediate C, it comprises the following steps：
Intermediate B intermediate C
A. in the presence of condensing agent and catalyst, in non-proton class solvent, in 20 ~ 30 DEG C of temperature ranges, in following
Mesosome B is raw material, and intermediate C reaction solutions are obtained with N-Boc- iminodiacetic acid condensation reactions；
B. reaction solution step a obtained is concentrated, extracted, concentrating, is refined, obtains intermediate C.
2. preparation method according to claim 1, wherein, the condensing agent is dicyclohexylcarbodiimide, double isopropyls
Base carbodiimide, 3- ethyls -1-3-（3- dimethyl propyls）Diimine.
3. preparation method according to claim 2, wherein, the dosage of the condensing agent is worked as the 2.5 ~ 3.5 of intermediate B
Amount（Molar ratio）.
4. preparation method according to claim 1, wherein, the catalyst is 4-dimethylaminopyridine.
5. preparation method according to claim 4, wherein, the catalyst amount is worked as the 0.05 ~ 0.1 of intermediate B
Amount（Molar ratio）.
6. preparation method according to claim 1, wherein, the non-proton class solvent is dichloromethane, ethyl acetate, or
Toluene.
7. preparation method according to claim 6, wherein, the non-proton class solvent dosage for intermediate B quality 8 ~
13 times, unit ml/g.
8. preparation method according to claim 1, wherein, the N-Boc- iminodiacetic acids dosage is intermediate B
1.2 ~ 1.8 equivalents（Molar ratio）.
9. preparation method according to claim 1, wherein, recrystallization solvent includes ethanol, methanol, isopropanol,
Or normal propyl alcohol.
10. preparation method according to claim 9, wherein, the recrystallization is with 15 that solvent dosage is intermediate B quality
~ 20 times, unit ml/g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711306443.3A CN107915685A (en) | 2017-12-11 | 2017-12-11 | A kind of preparation method of hydrobromic acid Vortioxetine intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711306443.3A CN107915685A (en) | 2017-12-11 | 2017-12-11 | A kind of preparation method of hydrobromic acid Vortioxetine intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107915685A true CN107915685A (en) | 2018-04-17 |
Family
ID=61893157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711306443.3A Pending CN107915685A (en) | 2017-12-11 | 2017-12-11 | A kind of preparation method of hydrobromic acid Vortioxetine intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107915685A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912538A (en) * | 2019-01-22 | 2019-06-21 | 安徽赛乐普制药有限公司 | A kind of preparation method of antidepressants Vortioxetine |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004022536A1 (en) * | 2002-09-04 | 2004-03-18 | Glenmark Pharmaceuticals Limited | New heterocyclic amide compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them |
| CN1561336A (en) * | 2001-10-04 | 2005-01-05 | H·隆德贝克有限公司 | Phenyl-piperazine derivatives as serotonin reuptake inhibitors |
| WO2007019867A1 (en) * | 2005-08-17 | 2007-02-22 | H. Lundbeck A/S | Novel 2,3-dihydroindole compounds |
| CN106349132A (en) * | 2016-08-30 | 2017-01-25 | 重庆植恩药业有限公司 | Vortioxetine intermediate impurities and preparing method and use thereof |
-
2017
- 2017-12-11 CN CN201711306443.3A patent/CN107915685A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561336A (en) * | 2001-10-04 | 2005-01-05 | H·隆德贝克有限公司 | Phenyl-piperazine derivatives as serotonin reuptake inhibitors |
| WO2004022536A1 (en) * | 2002-09-04 | 2004-03-18 | Glenmark Pharmaceuticals Limited | New heterocyclic amide compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them |
| WO2007019867A1 (en) * | 2005-08-17 | 2007-02-22 | H. Lundbeck A/S | Novel 2,3-dihydroindole compounds |
| CN106349132A (en) * | 2016-08-30 | 2017-01-25 | 重庆植恩药业有限公司 | Vortioxetine intermediate impurities and preparing method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| C. C. KRUSE ET AL.: "Single-step conversion of aliphatic, aromatic and heteroaromatic primary amines into piperazine-2,6-diones", 《RECUEIL DES TRAVAUX CHIMIQUES DES PAYS-BAS》 * |
| 胡宏纹: "《有机化学 下册》", 31 May 2006, 高等教育出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912538A (en) * | 2019-01-22 | 2019-06-21 | 安徽赛乐普制药有限公司 | A kind of preparation method of antidepressants Vortioxetine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105367557B (en) | A kind of preparation method of epoxy quinoline | |
| CN106995439B (en) | Deuterium replaces 3- (mesyl)-L-phenylalanine derivative and its pharmaceutical composition, pharmaceutical preparation and purposes | |
| WO2014066799A2 (en) | Modulators of resistant androgen receptor | |
| CN106220576B (en) | A kind of synthetic method of Clozapine key intermediate | |
| CN104961781B (en) | The O benzyls β D glucopyranoses of 2 deoxidation, 2 isothiocyanates 1,3,4,6 4 and synthetic method and purposes | |
| CN107915685A (en) | A kind of preparation method of hydrobromic acid Vortioxetine intermediate | |
| CN105949153B (en) | A kind of Ta Simeiqiong synthetic method | |
| CN108358966B (en) | Targeting-mitochondrial function enhancing drug Mito-VB3 and preparation method and application thereof | |
| CN107200707B (en) | Preparation method of pimavanserin | |
| CN101143852A (en) | Method for preparing cyclodipeptide cyclo(L-Asp-L-Pro) | |
| CN103864889B (en) | Epoxy ketone compound, preparation method thereof and preparation method of kyprolis | |
| CN101979376B (en) | Method for preparing glycinamide hydrochloride | |
| CN106588753B (en) | Pimanerin preparation method | |
| CN107266390A (en) | A kind of new technique for synthesizing of hydrobromic acid Vortioxetine | |
| CN116621810A (en) | Process for preparing 2-methyl nicotine | |
| CN105968037A (en) | N-acyl-1,2-cyclo-nitrogen-p-menthane, as well as preparation method and herbicidal activity application thereof | |
| CN108863822A (en) | A method of purification isoprenaline hydrochloride | |
| CN102146046A (en) | New method for preparing N-[2-(7- anisyl-1-naphthyl)ethide] acetamide | |
| CN105175355B (en) | A kind of preparation method of 2- cyano-phenothiazines | |
| WO2022017317A1 (en) | Method for large-scale synthesis of tetrodotoxin | |
| CN112375017A (en) | Synthesis method of important intermediate 4-fluoro-3-nitrobenzenesulfonamide of antiviral drug 0994 | |
| CN115215817B (en) | 2-aminothiazole-4-acetic acid derivative and preparation method and application thereof | |
| CN103113243A (en) | Synthetic method of 2-(7-methoxyl-1-naphthyl) ethylamine hydrochloride | |
| JPS5970692A (en) | Novel organic silicon compound, its non-toxic salt, its preparation and antitumor agent containing said compound as active component | |
| CN106632145B (en) | Novel preparation method of vortioxetine hydrobromide crystal form alpha |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: Room 1-6, Jinfeng biomedical industrial park, No. 28, Gaoxin Avenue, Jiulongpo District, Chongqing Applicant after: Zhien Biotechnology Co.,Ltd. Address before: 400039 10th floor, building B3, Erlang International Students Pioneer Park, Jiulongpo District, Chongqing Applicant before: Chongqing Zen Pharmaceutical Co.,Ltd. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180417 |