CN103896943B - A kind of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt and preparation method thereof - Google Patents
A kind of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt and preparation method thereof Download PDFInfo
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- CN103896943B CN103896943B CN201210572501.8A CN201210572501A CN103896943B CN 103896943 B CN103896943 B CN 103896943B CN 201210572501 A CN201210572501 A CN 201210572501A CN 103896943 B CN103896943 B CN 103896943B
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate and preparation method thereof, this salt has the structure of formula II.7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound stability is good for this, have relatively low moisture absorption, and safety is higher, and its preparation method is simple to operate, favorable reproducibility.
Description
Technical field
The present invention relates to anti-nicotine addiction medicine 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt and preparation method thereof.
Background technology
The compound of structure shown in Formulas I is the precursor structure of anti-nicotine addiction medicine 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, and chemical name is: 7,8,
9,10-tetrahydrochysene-6,10-methylene-6H-pyrazine also [2,3-h] [3] benzazepine, Pfizer research and develop.In May, 2006 and 9
Month, varenicline tartrate is respectively by U.S. FDA and Europe EMEA approval listing.
Generally, use the pharmaceutically acceptable salt of medicinal compound, resist nicotine addiction medicine such as Formulas I chemical combination
Also being such for thing, this makes the pharmaceutically acceptable salt preparing this compounds particularly important.To this, forefathers are at this
Aspect have also been made certain work.
Patent CN100370987 discloses tri-kinds of crystal formations of A, B, C of the L-TARTARIC ACID salt of compound of formula I.
Patent CN101851236 discloses tri-kinds of crystal formations of D, E, F of the L-TARTARIC ACID salt of compound of formula I.
Patent WO2009109651 discloses the maleate of compound of formula I, fumarate, adipate, mucate and
Malate.
Patent WO2011140431 discloses the tosilate of compound of formula I, sulfate, acetate and hydrobromic acid
Salt.
Patent CZ201008461 discloses the benzene sulfonate of compound of formula I.
Varenicline tartrate is used in drug products, although tartaric acid is the medicinal acid ion of I class, but it
Toxicity be concerned (WHO FOOD ADDITIVES SERIES NO. 12, by the Joint FAO/WHO always
Expert Committee on Food Additives* Geneva, 18-27 April 1977 and Gosselin R et
al. Clinical toxicology of commercial products, 5th ed. Williams and Wilkins,
Baltimore, MD, 1984, pg 200.).So half tartrate has less negative interaction than tartrate.Although
Numerous patents disclose substantial amounts of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt, but performance such as dissolubility, the heat stability etc. of various salt is not all given
Detailed evaluation and test.Pharmaceutically acceptable salt is said the most important by above-mentioned character, therefore continually looks for the medicine of new type
On, acceptable salt is the most important.
Summary of the invention
Not enough in order to make up prior art, obtain the of good performance pharmaceutically acceptable 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt that can be sure that,
We have screened various different acid, find that 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h can become half salt with tartaric acid.The invention provides this and new cut down human relations
Crin salt and preparation method thereof.
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, has a structure shown in formula II:
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, it is L-TARTARIC ACID salt.
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, at the X-ray powder diffraction using Cu-K α radiation detection
In spectrum, 2 θ values 6.95,11.61,12.07,13.52,15.63,17.05,17.67,18.16,18.89,
19.39,20.66,21.31,22.38,23.51,23.97,25.10,25.49,27.59,28 at .82 ± 0.2 °
There is diffraction maximum.
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, hydrogen modal data is as follows:1HNMR 400MHz (DMSO-d6)
8.88 (s, 1H), 7.90 (s,1H), 3.79(s, 1H), 3.40(br, 2H), 3.22(br,1H), 3.19(br,
1H), 3.01(br,1H), 2.98(br,1H), 2.51(m, 1H), 2.35(m, 1H)。
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, TGA spectrogram display weightlessness is 4.166 ± 0.2%, DSC spectrogram
Show, at 74.54 DEG C, at 191.07 DEG C and 229.30 DEG C, have endothermic peak.
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention has the XRPD spectrogram shown in accompanying drawing 1.
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention has the DSC-TGA spectrogram shown in accompanying drawing 2.
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention has shown in accompanying drawing 31HNMR spectrogram
The invention also discloses the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound, comprise the following steps: human relations will be cut down
Crin is reacted in the ratio of 1:0.4～0.6 with tartaric acid in the organic solvent mixed solvent with water, and reaction temperature is 0～100
DEG C, the response time is 1～24 hour, then collects 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate from reactant liquor.
Described organic solvent is single molten in methanol, ethanol, isopropanol, normal propyl alcohol, acetone, acetonitrile, oxolane
Agent or mixed solvent；The amount of organic solvent is advisable to dissolve 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h.Organic solvent is 10:0.5～5 with the ratio of water.
The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound stability that the present invention provides is good, have higher water solublity, safety,
And its preparation method is simple to operate, favorable reproducibility.The 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt compound of the present invention, and salt of the prior art compares tool
Have the advantage that
In water, dissolubility compares (g/ml):
| 25℃ | 35℃ | 45℃ | |
| 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate | 0.83 | 0.91 | 0.95 |
| Varenicline tartrate | 0.47 | 0.52 | 0.60 |
Heat stability compares:
Test sample is placed under 50 DEG C of vacuum, detects the change of its different periods purity.
| 1h | 3h | 6h | 10h | |
| 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate | 99.85% | 99.85% | 99.83% | 99.81% |
Accompanying drawing explanation
Accompanying drawing 1 is the X ray powder diffractogram of embodiment 1 gained 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate.
Accompanying drawing 2 is the DSC-TGA spectrogram of embodiment 1 gained 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate.
Accompanying drawing 3 is embodiment 1 gained 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate1HNMR spectrogram.
Detailed description of the invention
Further illustrate technical scheme with specific embodiment below, but protection scope of the present invention is not limited to
This.
The analysis testing conditions of the present invention is as follows:
1, DSC-TGA is to be measured by the SDT Q600 of TA company of the U.S., and test condition is 120ml/min N2, and heat up speed
10 DEG C/min of degree.
2, X-ray powder diffraction data is to use X ' Pert Pro MPD (Multi-Purpose
Diffractometer) measure, light pipe type: Empyrean XRD tube Cu LFF HR；Voltage x current: 45 kV, 40
mA；The vertical clinometer of clinometer: PW3050/60, radius 240mm；Slit: DS=2 °, SS=1/2 °, mask=15mm, RS=
5.0mm；Detector: the super detector of X ' Celerator；Scan pattern: scan continuously；Sweep limits: 3 ° of-40 ° of 2 θ；Often walk
Gate time: 20s；Scanning total time: 6min.
3, hydrogen spectrum is detected by Bruker 400 instrument.
Embodiment 1
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 25ml ethanol, 1.02g tartaric acid is dissolved in 10ml ethanol, by L-winestone under stirring
The ethanol solution of acid is slowly added in the ethanol solution of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finishes, is warming up to 70 DEG C, adds 4.5ml water to the most clear
Clearly, maintain this thermotonus 10min, stand, separate out a large amount of off-white color solid, sucking filtration, be vacuum dried to obtain 2.8g off-white color solid,
Yield 68.9%.
Embodiment 2
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 20ml acetone, 1.02g tartaric acid is dissolved in 5ml water, by L-TARTARIC ACID under stirring
Aqueous solution be slowly added in the acetone soln of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finish, be warming up to 55 DEG C, add 2.6ml water to just clarifying, dimension
Hold this thermotonus 10min, stand, separate out a large amount of off-white color solid, sucking filtration, be vacuum dried to obtain 3.3g off-white color solid, yield
81.2%。
Embodiment 3
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 20ml methanol, 1.02g tartaric acid is dissolved in 5ml methanol, by L-winestone under stirring
The methanol solution of acid is slowly added in the methanol solution of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finishes, is warming up to 65 DEG C, adds 1.5ml water to the most clear
Clearly, maintain this thermotonus 10min, stand, separate out a large amount of off-white color solid, sucking filtration, be vacuum dried to obtain 2.5g off-white color solid,
Yield 61.6%.
Embodiment 4
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 20ml acetone, 1.02g tartaric acid is dissolved in 8ml oxolane, by L-under stirring
Tartaric tetrahydrofuran solution is slowly added in the acetone soln of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finishes, and is warming up to 65 DEG C, adds 10 ml water
To just clarifying, maintain this thermotonus 10min, stand, separate out a large amount of off-white color solid, sucking filtration, be vacuum dried to obtain 2.2g class
White solid, yield 54.2%.
Embodiment 5
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 18ml acetonitrile, 1.02g tartaric acid is dissolved in 10ml acetonitrile, by L-winestone under stirring
The acetonitrile solution of acid is slowly added in the acetonitrile solution of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finishes, is warming up to 80 DEG C, adds 3.2ml water to the most clear
Clearly, maintain this thermotonus 10min, stand, separate out a large amount of off-white color solid, sucking filtration, be vacuum dried to obtain 3.1g off-white color solid,
Yield 76.3%.
Claims (7)
1. a 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound, described compound has the structure shown in formula II,
2. 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound as claimed in claim 1, is characterized by L-half tartrate.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound the most according to claim 1, it is characterised in that with Cu-K α radiation detection with
In the X-ray Powder Diffraction pattern that 2 θ express, 6.95,11.61,12.07,13.52,15.63,17.05,17.67,
18.16,18.89,19.39,20.66,21.31,22.38,23.51,23.97,25.10,25.49,27.59,28.82±0.2°
There is diffraction maximum at place.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound the most according to claim 1, it is characterised in that 74.54 in DSC spectrogram
DEG C, there is endothermic peak at 191.07 DEG C and 229.30 DEG C.
5. a preparation method for the 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt compound described in claim 1, its feature includes: by 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h and wine
Stone acid is reacted in the organic solvent mixed solvent with water in the ratio of 1:0.4～0.6, and reaction temperature is 0～100 DEG C, reaction
Time is 1～24 hour, then collects 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate from reactant liquor.
The preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt compound the most according to claim 5, it is characterised in that described organic solvent
Single solvent or mixed solvent in methanol, ethanol, isopropanol, normal propyl alcohol, acetone, acetonitrile, oxolane.
The preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt compound the most according to claim 5, it is characterised in that organic solvent and water
Ratio is 10:0.5～5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11779587B2 (en) | 2022-03-11 | 2023-10-10 | Par Pharmaceutical, Inc. | Vareniciline compound and process of manufacture thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP4241775A1 (en) | 2022-03-11 | 2023-09-13 | Par Pharmaceutical, Inc. | Tablet comprising varenicline and process of preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851236A (en) * | 2008-05-19 | 2010-10-06 | 美德（江西）生物科技有限公司 | Preparations of new polymorphic forms of varenicline tartrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851236A (en) * | 2008-05-19 | 2010-10-06 | 美德（江西）生物科技有限公司 | Preparations of new polymorphic forms of varenicline tartrate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11779587B2 (en) | 2022-03-11 | 2023-10-10 | Par Pharmaceutical, Inc. | Vareniciline compound and process of manufacture thereof |
| US11872234B2 (en) | 2022-03-11 | 2024-01-16 | Par Pharmaceutical, Inc. | Vareniciline compound and process of manufacture thereof |
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Inventor after: Wang Jubo Inventor after: Si Yongxing Inventor after: Fang Gan Inventor after: Gu Hong Inventor before: Wang Jubo Inventor before: Si Yongxing Inventor before: Fang Gan Inventor before: Wu Wenju Inventor before: Zhang Xini |
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