CN106349132B - Vortioxetine intermediate impurities and its production and use - Google Patents
Vortioxetine intermediate impurities and its production and use Download PDFInfo
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- CN106349132B CN106349132B CN201610753292.5A CN201610753292A CN106349132B CN 106349132 B CN106349132 B CN 106349132B CN 201610753292 A CN201610753292 A CN 201610753292A CN 106349132 B CN106349132 B CN 106349132B
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- CZUVZIQYUDJRDB-UHFFFAOYSA-N CC(C)(C)OC(N(CC(O)=O)CO)=O Chemical compound CC(C)(C)OC(N(CC(O)=O)CO)=O CZUVZIQYUDJRDB-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses Vortioxetine impurity, i.e. Vortioxetine impurity 1, impurity 2, impurity 3, impurity 4, impurity 5, impurity 6；Above-mentioned six kinds of impurity is the noval chemical compound found first, in addition, also disclosing its preparation method.The purposes of reference substance of the Vortioxetine related impurities provided by the invention as Vortioxetine intermediate, bulk drug and its compound preparation quality research, basis is tamped for the quality research of Vortioxetine.
Description
Technical field
The invention belongs to technical field of medicine synthesis, is related to Vortioxetine related impurities and its preparation technology.
Background technology
Major depressive disorder (MDD) is a kind of mental illness, and its feature is emotional change, changes of weight, do not feel like eating, insomnia
Or drowsiness (hypersomnia), fidgety, sense of fatigue increase, compunction or petty and low sense enhancing, slowness of thinking or notice do not collect
In, have a strong impact on the work and life of people.The breaking-out of depression often with all one's life of people, causes greatly to personal and family
Pain.
World-leading pharmacy is studied with health care problem and consulting firm --- Decision Resource company Decision
Resources issued address prediction before day：Emerging antidepressants Vortioxetine the U.S., France, Germany, Italy, Spain,
Weight pound antidepressant will be turned into Britain, Japanese market.Data shows at present, and Vortioxetine is curative for effect, side effect
Smaller, Vortioxetine is expected to turn into most successful new drug in anti-depression drug.
The Vortioxetine synthetic route of patent CN1561336 reports is ground according to original：
Vortioxetine impurity production is as follows：
Above-mentioned impurity 1, impurity 2, impurity 3, impurity 4, impurity 5, no relevant report, are novel substances, and available for fertile for west
Spit of fland Related product quality research.
By controlled syntheses target impurity, establish the detection method of target impurity, to Vortioxetine intermediate, bulk drug and
The quality of its preparation, which control effectively, to have great importance.
The content of the invention
The present inventor have developed five kinds of novel substances first：Vortioxetine impurity 1, impurity 2, impurity 3 and impurity 4, impurity 5
And preparation method thereof, it control effectively for the quality of Vortioxetine bulk drug and tamped basis.
It is an object of the invention to provide the impurity compound of Vortioxetine.
It is a further object to provide the preparation method of above-mentioned impurity compound.
Third object of the present invention there is provided the purposes of above-mentioned impurity compound.
Specifically, in embodiments of the invention, the invention provides five kinds of Vortioxetine impurity, i.e. impurity 1, miscellaneous
Matter 2, impurity 3 and impurity 4, impurity 5, its chemical structural formula are as follows
Second aspect, the invention provides the preparation method of five kinds of impurity of Vortioxetine；Wherein, impurity 1, impurity 3, impurity
5 preparation method, comprises the following steps：
A) preparation of impurity 1
By 1- tert-butoxycarbonyls -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazines, matter is added
In subclass organic solvent, the aqueous solution of inorganic base, 40~50 DEG C of hydrolysis are instilled, reaction is completed, and obtains impurity 1；
B) preparation of impurity 3
Impurity 1 carries out reduction reaction with diborane, and ethanol is quenched, and obtains impurity 3；
C) preparation of impurity 5
Impurity 3 carries out removing the reaction of BOC protection groups with inorganic acid, obtains impurity 5；
In a preferred embodiment of the invention, the invention provides Vortioxetine impurity --- and it is impurity 1, impurity 3, miscellaneous
The preparation method of matter 5, comprises the following steps：
A) preparation of impurity 1
By 1- tert-butoxycarbonyls -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazines, matter is added
In subclass organic solvent, the aqueous solution of inorganic base is instilled, 40~50 DEG C of reactions are organic through evaporated under reduced pressure, ethers after the completion of reaction
Solvent is beaten to obtain impurity 1；
B) preparation of impurity 3
Impurity 1 is dissolved in aprotic organic solvent, is slowly added to diborane, after the completion of reaction, ethanol is quenched, and decompression is steamed
Do, ethyl acetate/2N salt acid extractions, evaporated under reduced pressure organic layer, proton class organic solvent is recrystallized to give impurity 3；
C) preparation of impurity 5
Impurity 3 is added in proton class organic solvent, the inorganic acid of addition, after the completion of reaction, evaporated under reduced pressure solvent, proton
Class solvent recrystallization obtains impurity 5.
In provided by the invention, preferable Vortioxetine impurity --- impurity 1, impurity 3, impurity 5 preparation method in, its
In, step a), wherein, proton class organic solvent is ethanol, and inorganic base is sodium hydroxide, and sodium hydroxide mole dosage is the tertiary fourths of 1-
1.2~the 1.3eq of Epoxide carbonyl -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazine mole dosages, beats
Ether solvent used in slurry is isopropyl ether.
In provided by the invention, preferable Vortioxetine impurity --- impurity 1, impurity 3, impurity 5 preparation method in, its
In, step b), the ether solvent of dissolved impurity 1 is tetrahydrofuran, diborane mole dosage for the mole dosage of impurity 1 3.0~
3.1eq, it is methanol to recrystallize proton class solvent used.
In provided by the invention, preferable Vortioxetine impurity --- impurity 1, impurity 3, impurity 5 preparation method in, its
In, step c), wherein, the proton class solvent of dissolved impurity 3 is isopropanol, and inorganic acid is hydrobromic acid, and hydrobromic acid mole dosage is
1.5~1.6eq of the mole dosage of impurity 3, it is isopropanol to recrystallize proton class solvent used.
In embodiments of the invention, the invention provides the preparation method of Vortioxetine impurity 2, impurity 4, including such as
Lower step：
I) condensation reaction is occurred into for N-Boc- iminodiacetic acids (SM3) and 3- (2,4- dimethyl benzene sulfenyl) aniline, obtained
To impurity 2；
Ii) impurity 2 carries out reduction reaction with diborane, obtains impurity 4；
In a preferred embodiment of the invention, the invention provides the preparation method of Vortioxetine impurity 2, impurity 4, bag
Include：
I) N-Boc- iminodiacetic acids (SM3) are put into halogenated alkanes solvents, adds condensing agent, room temperature reaction
30~40min；Instilled after 3- (2,4- dimethyl benzenes sulfenyl) aniline (intermediate B) is dissolved in into dichloromethane.After reaction completely, subtract
Pressure is evaporated, ethyl acetate/2N salt acid extractions, evaporated under reduced pressure organic layer, is crossed silicagel column purifying, is obtained impurity 2；
Ii) impurity 2 is dissolved in ether solvent by, is slowly added to diborane, after reaction completely, adds ethanol and reaction is quenched,
Evaporated under reduced pressure, ethyl acetate, 2N salt acid extractions, evaporated under reduced pressure, proton class solvent recrystallization obtain impurity 4；
In provided by the invention, preferable Vortioxetine impurity --- impurity 2, impurity 4 preparation method in, step i),
Wherein, halogenated alkanes solvents are dichloromethane, and N-Boc- iminodiacetic acids dosage is 3- (2,4- dimethyl benzene sulfenyl) benzene
1.0~1.1eq of amine；Condensing agent is dicyclohexylcarbodiimide (DCC), and dosage is 3- (2,4- dimethyl benzene sulfenyl) aniline
2.5~2.6eq.
In provided by the invention, preferable Vortioxetine impurity --- in impurity 2, the preparation method of impurity 4, step ii), its
In, ether solvent is tetrahydrofuran, and diborane dosage is 3.0~3.1eq, and proton class solvent is methanol.
The third aspect, the invention provides Vortioxetine impurity 1, impurity 2, impurity 3, impurity 4, impurity 5, as fertile for west
The purposes of spit of fland intermediate, bulk drug or the reference substance of its single-activity component preparation or compound preparation, here, active component is
Vortioxetine.
The beneficial outcomes of the present invention are：
Vortioxetine impurity 1, impurity 2, impurity 3 and impurity 4 are provided first, method prepared by impurity 5；Synthesize first
Novel substance：Vortioxetine impurity 1, impurity 2, impurity 3, impurity 4, impurity 5, gained compound can be used for Vortioxetine intermediate,
The quality research of bulk drug and its compound preparation.
Brief description of the drawings
What Fig. 1 .1 were represented is the hydrogen spectrum of Vortioxetine impurity 1
What Fig. 1 .2 were represented is the mass spectrum of Vortioxetine impurity 1
What Fig. 2 .1 were represented is the hydrogen spectrum of Vortioxetine impurity 2
What Fig. 2 .2 were represented is the mass spectrum of Vortioxetine impurity 2
What Fig. 3 .1 were represented is the hydrogen spectrum of Vortioxetine impurity 3
What Fig. 3 .2 were represented is the mass spectrum of Vortioxetine impurity 3
What Fig. 4 .1 were represented is the hydrogen spectrum of Vortioxetine impurity 4
What Fig. 4 .2 were represented is the mass spectrum of Vortioxetine impurity 4
What Fig. 5 .1 were represented is the hydrogen spectrum of Vortioxetine impurity 5
What Fig. 5 .2 were represented is the mass spectrum of Vortioxetine impurity 5
Embodiment
Embodiment of the present invention is specifically described below by the embodiment of the present invention.
The analysis of impurity nucleus magnetic hydrogen spectrum and mass spectral analysis condition are as follows obtained by the embodiment of the present invention:
Nmr analysis：Instrument：Agilent 600DD2 (600MHz) high resolution NMR instrument
Test condition：Solvent C DCl3；
30 DEG C of temperature.
Mass spectral analysis：Instrument：Waters Acquity SQ Detector
Soure mode:ESI
Polarity+
Calibration Dynamic 1
Capillary(kV) 2.50
Cone(V) 30.00
Extractor(V) 0.00
RF(V) 0.00
Source Temperature(℃) 100
Desolvation Temperature(℃) 350
Cone Gas Flow(L/Hr) 55
Desolvation Gas Flow(L/Hr) 550
The preparation of the Vortioxetine impurity 1 of embodiment 1
By 1- tert-butoxycarbonyls -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazines (20g,
46.9mmol), add in 150ml ethanol, the 10ml aqueous solution of 20~30 DEG C of instillation 2.34g sodium hydroxides, 40~50 DEG C of reactions
30min, evaporated under reduced pressure, the extraction of the watery hydrochloric acid of ethyl acetate 150ml, 50ml 3%, evaporated under reduced pressure organic layer, added into residue
120ml isopropyl ethers, 60~65 DEG C, insulated and stirred 30min are warming up to, are cooled to 0~5 DEG C, insulated and stirred 1.5h, obtain 15.1g
The yield of impurity 1：72.6%.H1- NMR (600HZ, CDCl3):8.81 (1H, s), 8.35 (1H, d), 7.41 (2H, d), 7.16
(2H, d), 6.67 (2H, t), 6.88 (2H, t), 6.71 (1H, d), 4.03 (2H, s), 3.79 (2H, d), 2.37 (3H, s),
2.27 (3H, s), 1.45 (9H, s)；MS(ESI):[M+H]+445.44。
The preparation of the Vortioxetine impurity 3 of embodiment 2
12g impurity 1 (27.0mmol) is dissolved in 50ml tetrahydrofurans, 0~5 DEG C is slowly added to diborane 82.3ml
(1mol/L), 20~30 DEG C reaction, 50ml ethanol, which is slowly dropped into, to be quenched, 35~45 DEG C of evaporated under reduced pressure, 100ml ethyl acetate and
100ml2N salt acid extractions, 40~50 DEG C of evaporated under reduced pressure organic layers, 60ml recrystallizing methanols obtain 7.65g impurity 3, yield：
68.0%.H1- NMR (600HZ, CDCl3):7.37 (1H, d), 7.29 (2H, t), 6.98 (1H, s), 6.82 (1H, d), 6.76
(1H, d), 6.70 (1H, t), 6.62 (1H, d), 4.98 (1H, s), 3.31~3.43 (8H, m), 2.93 (1H, s), 2.37
(3H, s), 2.25 (3H, s), 1.45 (9H, s)；MS(ESI):[M+H]+417.50。
The preparation of the Vortioxetine impurity 5 of embodiment 3
5g impurity 3 (12mmol) is added in 25ml isopropanols, add 46% hydrobromic acid (3.23g,
18.6mmol), after the completion of reaction, 50~60 DEG C of evaporated under reduced pressure isopropanols add 30ml isopropanols into residue, and heating is molten
Clearly, 0~5 DEG C is cooled to, is filtered, 45~50 DEG C are dried under reduced pressure 12h, obtain 3.02g impurity 5, yield：79.5%.H1-NMR
(600HZ, CDCl3):8.68 (2H, s), 7.32 (3H, t), 6.97 (1H, s), 6.90 (1H, d), 6.80 (1H, t), 6.75
(1H, d), 6.62 (1H, d), 3.88 (2H, t), 3.80 (2H, t), 3.20 (2H, s), 3.07 (2H, s), 2.36 (3H, s),
2.23 (3H, s)；MS(ESI):[M+H]+317.40。
The preparation of the Vortioxetine impurity 2 of embodiment 4
N-Boc- iminodiacetic acids (SM3) (20.2g, 87.2mmol) are put into 300ml dichloromethane, slowly added
Enter dicyclohexylcarbodiimide (45.9g, 214.7mmol), react at room temperature 30~40min；By 3- (2,4- dimethyl benzenes sulfenyl)
Aniline (intermediate B) (20g, 87.2mmol) instills after being dissolved in 50ml dichloromethane, after room temperature reaction completely, 35~40 DEG C of decompressions
It is evaporated, 200ml ethyl acetate/200ml2N salt acid extractions, evaporated under reduced pressure organic layer.Silicagel column purifying is crossed, obtains 12.3g impurity
2, yield：43.0%.H1- NMR (600HZ, CDCl3):8.88 (1H, s), 8.62 (1H, s), 8.32 (2H, dd), 7.39 (4H,
T), 7.12 (2H, d), 7.09 (2H, m), 6.86 (2H, d), 6.72 (2H, dd), 3.79 (4H, d), 2.36 (3H, d), 2.26
(3H, d), 1.41 (9H, s)；
MS(ESI):[M+H]+656.53。
The preparation of the Vortioxetine impurity 4 of embodiment 5
Impurity 2 (10g, 15.2mmol) is dissolved in tetrahydrofuran, is slowly added to (46.5ml, 46.5mmol) diborane,
After room temperature reaction completely, it is slowly added to 30ml ethanol and reaction, 40~45 DEG C of evaporated under reduced pressure, ethyl acetate 150nl, 2N hydrochloric acid is quenched
100ml is extracted, and 40~45 DEG C of evaporated under reduced pressure, 70ml recrystallizing methanols obtain 8.19g impurity 4, yield：85.6%.H1-NMR
(600HZ, CDCl3):7.35 (2H, s), 7.25 (2H, d), 6.96 (2H, d), 6.77 (2H, s), 6.67 (4H, d), 6.58
(2H, d), 5.03 (1H, s), 4.89 (1H, s), 3.26 (8H, d), 2.35 (6H, s), 2.22 (6H, s), 1.43 (9H, s)；MS
(ESI):[M+H]+628.56。
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 embodiments 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 (11)
1. a kind of Vortioxetine impurity 1, its structure are as follows：
2. a kind of Vortioxetine impurity 2, its structure are as follows：
3. a kind of Vortioxetine impurity 3, its structure are as follows：
4. a kind of Vortioxetine impurity 4, its structure are as follows：
5. a kind of Vortioxetine impurity 5, its structure are as follows：
6. the preparation method of Vortioxetine impurity 1 described in claim 1：Comprise the following steps：
A) preparation of impurity 1
By 1- tert-butoxycarbonyls -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazines, proton class is added
In organic solvent, the aqueous solution of inorganic base, 40~50 DEG C of hydrolysis are instilled, reaction is completed, and obtains impurity 1；
7. the preparation method of Vortioxetine impurity 3 described in claim 3：Comprise the following steps：
A) preparation of impurity 1
By 1- tert-butoxycarbonyls -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazines, proton class is added
In organic solvent, the aqueous solution of inorganic base, 40~50 DEG C of hydrolysis are instilled, reaction is completed, and obtains impurity 1；
B) preparation of impurity 3
Impurity 1 carries out reduction reaction with diborane, and ethanol is quenched, and obtains impurity 3；
8. the preparation method of claim 5 Vortioxetine impurity 5：Comprise the following steps：
A) preparation of impurity 1
By 1- tert-butoxycarbonyls -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazines, proton class is added
In organic solvent, the aqueous solution of inorganic base, 40~50 DEG C of hydrolysis are instilled, reaction is completed, and obtains impurity 1；
B) preparation of impurity 3
Impurity 1 carries out reduction reaction with diborane, and ethanol is quenched, and obtains impurity 3；
C) preparation of impurity 5
Impurity 3 carries out removing the reaction of BOC protection groups with inorganic acid, obtains impurity 5；
9. the preparation method of Vortioxetine impurity 2 described in claim 2：Comprise the following steps：
I) condensation reaction is occurred into for N-Boc- iminodiacetic acids and 3- (2,4- dimethyl benzene sulfenyl) aniline, obtains impurity 2；
10. the preparation method of Vortioxetine impurity 4 described in claim 4：Comprise the following steps：
I) condensation reaction is occurred into for N-Boc- iminodiacetic acids and 3- (2,4- dimethyl benzene sulfenyl) aniline, obtains impurity 2；
Ii) impurity 2 carries out reduction reaction with diborane, obtains impurity 4；
11. Vortioxetine impurity is as Vortioxetine intermediate, bulk drug as any one of claim 1-5 or its is single
The purposes of active agent preparation or the reference substance of compound preparation quality research, here, described active component are Vortioxetine.
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Citations (2)
| 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 |
| WO2016079751A2 (en) * | 2014-11-17 | 2016-05-26 | Megafine Pharma (P) Ltd. | A process for preparation of vortioxetine and polymorphs thereof |
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Patent Citations (2)
| 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 |
| WO2016079751A2 (en) * | 2014-11-17 | 2016-05-26 | Megafine Pharma (P) Ltd. | A process for preparation of vortioxetine and polymorphs thereof |
Non-Patent Citations (1)
| Title |
|---|
| 氢溴酸沃替西汀的合成;郭培良 等;《化学研究与应用》;20160131;第28卷(第1期);第124-128页 * |
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