CN106349132A - Vortioxetine intermediate impurities and preparing method and use thereof - Google Patents
Vortioxetine intermediate impurities and preparing method and use thereof Download PDFInfo
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- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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- C07C323/37—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to a carbon atom of a six-membered aromatic ring
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Abstract
The invention discloses the use of the wortioxetine impurities, i.e., the valerocetine impurity 1, the impurity 2, the impurity 3, the impurity 4, the impurity 5, and the impurity 6; the six kinds of impurities are the first new compounds found. The invention further discloses the preparing method thereof. The use of the wortioxetine impurities as the wortioxetine intermediate, active ingredient and the control product in the quality study of the compound preparation wherein lays a solid foundation for the quality study of the walcoxibine. (img file='dest_path_image001.TIF' wi='579' he='521' /).
Description
Technical field
The invention belongs to technical field of medicine synthesis, it is related to irrigate and replaces western spit of fland related impuritieses and its preparation technology.
Background technology
Major depressive disorder (mdd) is a kind of mental sickness, and its feature is emotion changes, body weight change, anorexia, insomnia
Or drowsiness (hypersomnia), fidgety, feeling of fatigue increases, compunction or petty and low sense enhancing, slowness of thinking or attention do not collect
In, have a strong impact on work and the life of people.The outbreak of depression often with all one's life of people, causes greatly to personal and family
Painful.
World-leading pharmacy and health care problem research and consulting firm Decision Resource public affairs decision
Before resources day issue address prediction: emerging antidepressants irrigate for Xi Ting the U.S., France, Germany, Italy, Spain,
In Britain, Japanese market, one-tenth is attached most importance to a pound antidepressant drug.Data shows at present, irrigates and replaces western spit of fland determined curative effect, side effect
Less, irrigate and be expected to become most successful new drug in anti-depression drug for Xi Ting.
According to the former fertile western spit of fland synthetic route of replacing grinding patent cn1561336 report:
Fertile as follows for western spit of fland impurity production:
| Impurity sequence number | Impurity 1 | Impurity 2 | Impurity 3 |
| Chemical constitution | |||
| Impurity sequence number | Impurity 4 | Impurity 5 | Impurity 6 |
| Chemical constitution |
Above-mentioned six kinds of impurity, no relevant report, is novel substance, and can be used for irrigating for the Related product quality research of western spit of fland.
By controlled syntheses target impurity, set up the detection method of target impurity, to fertile for western spit of fland intermediate, crude drug and
The quality of its preparation control effectively and has great importance.
Content of the invention
The present inventor have developed six kinds of novel substances first: fertile for western spit of fland impurity 1, impurity 2, impurity 3 and impurity 4, impurity 5,
Impurity 6 and preparation method thereof, control effectively for the fertile quality for western spit of fland crude drug and has tamped basis.
It is an object of the invention to provide the fertile impurity compound for Xi Ting.
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 six kinds fertile replace western spit of fland impurity, i.e. impurity 1, miscellaneous
Matter 2, impurity 3 and impurity 4, impurity 5, impurity 6, its chemical structural formula is as follows:
Second aspect, the invention provides the fertile preparation method for the six kinds of impurity in western spit of fland；Wherein, impurity 1, impurity 3, impurity 5
Preparation method, comprises the steps:
A) preparation of impurity 1
By 1- tert-butoxycarbonyl -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazine, add proton class
In organic solvent, instill the aqueous solution of inorganic base, 40 ~ 50 DEG C of hydrolysis, reaction completes, and obtains impurity 1；
B) preparation of impurity 3
Impurity 1 and diborane carry out reduction reaction, and ethanol is quenched, and obtains impurity 3；
C) preparation of impurity 5
Impurity 3 and mineral acid carry out removing boc protection group and react, and obtain impurity 5；
In a preferred embodiment of the invention, the invention provides fertile for western spit of fland Impurity Impurity 1, impurity 3, impurity 5
Preparation method, comprises the steps:
A) preparation of impurity 1
By 1- tert-butoxycarbonyl -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazine, add proton class
In organic solvent, instill the aqueous solution of inorganic base, 40 ~ 50 DEG C of reactions, after the completion of reaction, through evaporated under reduced pressure, ether organic solvent
Making beating obtains 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, evaporated under reduced pressure,
Ethyl acetate/2n salt acid extraction, 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 mineral acid of addition, after the completion of reaction, evaporated under reduced pressure solvent, proton class is molten
Agent is recrystallized to give impurity 5.
Replace in western spit of fland Impurity Impurity 1, impurity 3, the preparation method of impurity 5 present invention offer, preferably fertile, 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 fourth of 1-
1.2 ~ 1.3eq of Epoxide carbonyl -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazine mole dosage, beats
Ether solvent used by slurry is diisopropyl ether.
Replace in western spit of fland Impurity Impurity 1, impurity 3, the preparation method of impurity 5 present invention offer, preferably fertile, its
In, step b), the ether solvent of dissolved impurity 1 is oxolane, diborane mole dosage be impurity 1 mole dosage 3.0 ~
3.1eq, the proton class solvent used by recrystallization is methanol.
Replace in western spit of fland Impurity Impurity 1, impurity 3, the preparation method of impurity 5 present invention offer, preferably fertile, its
In, step c), wherein, the proton class solvent of dissolved impurity 3 is isopropanol, and mineral acid is hydrobromic acid, and hydrobromic acid mole dosage is
1.5 ~ 1.6eq of impurity 3 mole dosage, the proton class solvent used by recrystallization is isopropanol.
In embodiments of the invention, the invention provides fertile replace western spit of fland impurity 2, impurity 4, the preparation method of impurity 6,
Comprise the steps:
I) be there is condensation reaction with 3- (2,4- dimethyl benzene sulfenyl) aniline in n-boc- iminodiacetic acid (sm3), obtain miscellaneous
Matter 2；
Ii). impurity 2 and diborane carry out reduction reaction, obtain impurity 4；
Iii) impurity 4 and mineral acid carry out remove boc protection group react, obtain impurity 6；
In a preferred embodiment of the invention, the invention provides fertile replace western spit of fland impurity 2, impurity 4, the preparation method of impurity 6,
Including:
I) n-boc- iminodiacetic acid (sm3) is put in halogenated alkanes solvents, add condensing agent, room temperature reaction 30 ~
40min；By 3- (2,4- dimethyl benzene sulfenyl) aniline, (intermediate b) is dissolved in after dichloromethane and instilling.After reaction completely, decompression is steamed
Dry, ethyl acetate/2n salt acid extraction, evaporated under reduced pressure organic layer, cross silica column purification, obtain impurity 2；
Ii). impurity 2 is dissolved in ether solvent, is slowly added to diborane, after reaction completely, add ethanol that reaction is quenched, decompression
It is evaporated, ethyl acetate, 2n salt acid extraction, evaporated under reduced pressure, proton class solvent recrystallization obtains impurity 4；
Iii) impurity 4 is added in proton class solvent, the hydrobromic acid of addition, 30 ~ 40 DEG C of reactions, after the completion of reaction, evaporated under reduced pressure,
Proton class solvent recrystallization obtains impurity 6.
Present invention offer, preferably fertile in western spit of fland Impurity Impurity 2, impurity 4, the preparation method of impurity 6, walk
Suddenly i), wherein, halogenated alkanes solvents are dichloromethane, and n-boc- iminodiacetic acid consumption is 3- (2,4- dimethyl benzene sulfur
Base) aniline 1.0 ~ 1.1eq；Condensing agent is dicyclohexylcarbodiimide (dcc), and consumption is 3- (2,4- dimethyl benzene sulfenyl) benzene
2.5 ~ 2.6eq of amine.
Present invention offer, preferably fertile in western spit of fland Impurity Impurity 2, impurity 4, the preparation method of impurity 6, walk
Rapid ii), wherein, ether solvent is oxolane, and diborane consumption is 3.0 ~ 3.1eq, and proton class solvent is methanol.
Present invention offer, preferably fertile in western spit of fland Impurity Impurity 2, impurity 4, the preparation method of impurity 6, walk
Rapid iii), wherein, the proton class solvent of dissolved impurity 3 is ethanol, and mineral acid is hydrobromic acid, mole dosage be 3 moles of impurity with
1.5 ~ 1.6eq of amount, the proton class solvent used by recrystallization is ethanol.
The third aspect, the invention provides fertile replace western spit of fland impurity 1, impurity 2, impurity 3 and impurity 4, impurity 5, impurity 6 conduct
The purposes of the fertile reference substance becoming preparation or compound preparation for western spit of fland intermediate, crude drug or its single work.
The beneficial outcomes of the present invention are:
Provide the fertile method prepared for western spit of fland impurity 1, impurity 2, impurity 3 and impurity 4, impurity 5, impurity 6 first；Synthesize first
Novel substance: fertile replace western spit of fland impurity 1, impurity 2, impurity 3, impurity 4, impurity 5, impurity 6, gained compound can be used for fertile replacing Xi Ting
The quality research of intermediate, crude drug and its compound preparation.
Brief description
What Fig. 1 .1 represented is the fertile spectrum of the hydrogen for western spit of fland impurity 1.
What Fig. 1 .2 represented is the fertile mass spectrum for western spit of fland impurity 1.
What Fig. 2 .1 represented is the fertile spectrum of the hydrogen for western spit of fland impurity 2.
What Fig. 2 .2 represented is the fertile mass spectrum for western spit of fland impurity 2.
What Fig. 3 .1 represented is the fertile spectrum of the hydrogen for western spit of fland impurity 3.
What Fig. 3 .2 represented is the fertile mass spectrum for western spit of fland impurity 3.
What Fig. 4 .1 represented is the fertile spectrum of the hydrogen for western spit of fland impurity 4.
What Fig. 4 .2 represented is the fertile mass spectrum for western spit of fland impurity 4.
What Fig. 5 .1 represented is the fertile spectrum of the hydrogen for western spit of fland impurity 5.
What Fig. 5 .2 represented is the fertile mass spectrum for western spit of fland impurity 5.
What Fig. 6 .1 represented is the fertile spectrum of the hydrogen for western spit of fland impurity 6.
What Fig. 6 .2 represented is the fertile mass spectrum for western spit of fland impurity 6.
Specific embodiment
It is specifically described embodiment of the present invention below by the embodiment of the present invention.
The analysis of embodiment of the present invention gained impurity nucleus magnetic hydrogen spectrum and mass spectral analyses condition are as follows:
Nmr analysis: instrument: agilent 600dd2 (600mhz) high resolution NMR instrument
Test condition: solvent cdcl3；
30 DEG C of temperature.
Mass spectral analyses: 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 (°c) 100
desolvation temperature (°c) 350
cone gas flow (l/hr) 55
desolvation gas flow (l/hr) 550
Embodiment 1 irrigates the preparation for western spit of fland impurity 1
By 1- tert-butoxycarbonyl -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazine (20g,
46.9mmol), add in 150ml ethanol, the 10ml aqueous solution of 20 ~ 30 DEG C of instillation 2.34g sodium hydroxide, 40 ~ 50 DEG C of reactions
30min, evaporated under reduced pressure, ethyl acetate 150ml, 50ml 3% dilute hydrochloric acid extracts, evaporated under reduced pressure organic layer, adds in residue
120ml diisopropyl ether, is warming up to 60 ~ 65 DEG C, and insulated and stirred 30min is cooled to 0 ~ 5 DEG C, insulated and stirred 1.5h, obtains 15.1g miscellaneous
Matter 1 yield: 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.
Embodiment 2 irrigates the preparation for western spit of fland impurity 3
By 12g impurity 1(27.0mmol) it is dissolved in 50ml oxolane, 0 ~ 5 DEG C is slowly added to diborane 82.3ml(1mol/l),
20 ~ 30 DEG C of reactions, 50ml ethanol is slowly dropped into and is quenched, 35 ~ 45 DEG C of evaporated under reduced pressure, and 100ml ethyl acetate and 100ml2n hydrochloric acid extract
Take, 40 ~ 50 DEG C of evaporated under reduced pressure organic layers, 60ml recrystallizing methanol obtains 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.
Embodiment 3 irrigates the preparation for western spit of fland impurity 5
By 5g impurity 3(12mmol) it is added in 25ml isopropanol, add 46% hydrobromic acid (3.23g, 18.6mmol), reaction
After the completion of, 50 ~ 60 DEG C of evaporated under reduced pressure isopropanols, add 30ml isopropanol in residue, heat, molten clear, it is cooled to 0 ~ 5 DEG C,
Sucking filtration, 45 ~ 50 DEG C of drying 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.
Embodiment 4 irrigates the preparation for western spit of fland impurity 2
N-boc- iminodiacetic acid (sm3) (20.2g, 87.2mmol) is put in 300ml dichloromethane, is slowly added to two
Carbodicyclo hexylimide (45.9g, 214.7mmol), room temperature reaction 30 ~ 40min；By 3- (2,4- dimethyl benzene sulfenyl) aniline
(intermediate b) (20g, 87.2mmol) instills after being dissolved in 50ml dichloromethane, after room temperature reaction is complete, 35 ~ 40 DEG C of evaporated under reduced pressure,
200ml ethyl acetate/200ml2n salt acid extraction, evaporated under reduced pressure organic layer.Cross silica column purification, obtain 12.3g impurity 2, receive
Rate: 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.
Embodiment 5 irrigates the preparation for western spit of fland impurity 4
By impurity 2(10g, 15.2mmol) it is dissolved in oxolane, it is slowly added to (46.5ml, 46.5mmol) diborane, room temperature
After reaction completely, it is slowly added to 30ml ethanol and reaction is quenched, 40 ~ 45 DEG C of evaporated under reduced pressure, ethyl acetate 150nl, 2n hydrochloric acid 100ml
Extraction, 40 ~ 45 DEG C of evaporated under reduced pressure, 70ml recrystallizing methanol obtains 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.
Embodiment 6 irrigates the preparation for western spit of fland impurity 6
By impurity 4(5g, 7.96mmol) add 50ml isopropanol in, addition 46% hydrobromic acid (2.14g, 12.3mmol), 30
~ 40 DEG C of reactions, after the completion of reaction, evaporated under reduced pressure, 30ml ethyl alcohol recrystallization obtains 3.23g impurity 6, yield: 76.8%.h1-nmr
(600hz, cdcl3): 10.46 (3h, s), 7.94(2h, d), 7.23(2h, d), 7.18(4h, m), 6.98(2h, s), 6.90
(2h, d), 6.83(2h, d), 4.23(8h, d), 2.28(6h, s), 2.26(6h, s)；ms(esi):[m+h]+528.55.
Finally illustrate, above example only in order to technical scheme to be described and unrestricted, although by 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
Using in the form and details to it as various changes, the present invention's being limited without departing from claims
Spirit and scope.
Claims (10)
1. a kind of irrigating replaces western spit of fland impurity 1, and its structure is as follows:
.
2. a kind of irrigating replaces western spit of fland impurity 2, and its structure is as follows:
.
3. a kind of irrigating replaces western spit of fland impurity 3, and its structure is as follows:
.
4. a kind of irrigating replaces western spit of fland impurity 4, and its structure is as follows:
.
5. a kind of irrigating replaces western spit of fland impurity 5, and its structure is as follows:
.
6. a kind of irrigating replaces western spit of fland impurity 6, and its structure is as follows:
.
7. irrigate described in claim 1 and replace for fertile irrigating for western spit of fland impurity 3 or claim 5 described in western spit of fland impurity 1 or claim 3
The preparation method of western spit of fland impurity 5: comprise the steps:
A) preparation of impurity 1
By 1- tert-butoxycarbonyl -4- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] -3,5- dioxopiperazine, add proton class
In organic solvent, instill the aqueous solution of inorganic base, 40 ~ 50 DEG C of hydrolysis, reaction completes, and obtains impurity 1；
B) preparation of impurity 3
Impurity 1 and diborane carry out reduction reaction, and ethanol is quenched, and obtains impurity 3；
C) preparation of impurity 5
Impurity 3 and mineral acid carry out removing boc protection group and react, and obtain impurity 5；
.
8. irrigate described in claim 2 and replace for fertile irrigating for western spit of fland impurity 4 or claim 6 described in western spit of fland impurity 2 or claim 4
The preparation method of western spit of fland impurity 6: comprise the steps:
Comprise the steps:
I) be there is condensation reaction with 3- (2,4- dimethyl benzene sulfenyl) aniline in n-boc- iminodiacetic acid (sm3), obtain miscellaneous
Matter 2；
Ii). impurity 2 and diborane carry out reduction reaction, obtain impurity 4；
Iii) impurity 4 and mineral acid carry out remove boc protection group react, obtain impurity 6；
.
9. irrigate any one of claim 1-6 for western spit of fland impurity as fertile for western spit of fland intermediate, crude drug or its single work
Become the purposes of the reference substance of preparation or compound preparation.
10. irrigate as any one of claim 1-6 for western spit of fland impurity as fertile for western spit of fland intermediate, crude drug and its compound recipe
The purposes of the reference substance of quality of the pharmaceutical preparations research.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610753292.5A CN106349132B (en) | 2016-08-30 | 2016-08-30 | Vortioxetine intermediate impurities and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610753292.5A CN106349132B (en) | 2016-08-30 | 2016-08-30 | Vortioxetine intermediate impurities and its production and use |
Publications (2)
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| CN107915685A (en) * | 2017-12-11 | 2018-04-17 | 重庆植恩药业有限公司 | A kind of preparation method of hydrobromic acid Vortioxetine intermediate |
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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| 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 |
|---|
| 郭培良 等: "氢溴酸沃替西汀的合成", 《化学研究与应用》 * |
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| CN107915685A (en) * | 2017-12-11 | 2018-04-17 | 重庆植恩药业有限公司 | A kind of preparation method of hydrobromic acid Vortioxetine intermediate |
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