CN103896943A - Varenicline salt and preparing method thereof - Google Patents
Varenicline salt and preparing method thereof Download PDFInfo
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- CN103896943A CN103896943A CN201210572501.8A CN201210572501A CN103896943A CN 103896943 A CN103896943 A CN 103896943A CN 201210572501 A CN201210572501 A CN 201210572501A CN 103896943 A CN103896943 A CN 103896943A
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- methanopyrazino
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- tartrate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/08—Bridged systems
Abstract
The invention relates to varenicline hemitartrate and a preparing method thereof. The salt has a structure shown as the formula II. The varenicline hemitartrate is good in stability, low in moisture adsorption and high in safety. The preparing method is simple in operation and good in 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 formula 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 radical-6H-pyrazine is [2,3-h] [3] benzazepine also, is researched and developed by Pfizer.In May, 2006 and September, 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h tartrate is respectively by U.S. FDA and European EMEA approval listing.
Conventionally, use the pharmacy acceptable salt of medicinal compound, for example formula I compound of antagonism nicotine addiction medicine is also so, and this pharmacy acceptable salt that makes to prepare this compounds is particularly important.To this, forefathers have also done certain work in this respect.
Patent CN100370987 discloses tri-kinds of crystal formations of A, B, C of the L-TARTARIC ACID salt of formula I compound.
Patent CN101851236 discloses tri-kinds of crystal formations of D, E, F of the L-TARTARIC ACID salt of formula I compound.
Patent WO2009109651 discloses maleate, fumarate, adipate, mucate and the malate of formula I compound.
Patent WO2011140431 discloses tosilate, vitriol, acetate and the hydrobromate of formula I compound.
Patent CZ201008461 discloses the benzene sulfonate of formula I compound.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h tartrate is used in medicament production, although tartrate is the medicinal acid ion of I class, but its toxicity is being concerned (WHO FOOD ADDITIVES SERIES NO. 12 always, by the Joint FAO/WHO 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 disclose a large amount of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt in numerous patents, the performance of various salt all do not provided to detailed evaluation and test as solvability, thermostability etc.Above-mentioned character is said quite important to pharmacy acceptable salt, the pharmacy acceptable salt that therefore continues searching novel type is still quite important.
Summary of the invention
In order to make up prior art deficiency, obtain the well behaved pharmaceutically acceptable 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt that can be sure of, we have screened various acid, find that 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h can become with tartrate half salt.The invention provides this new 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt and preparation method thereof.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, has the structure shown in formula II:
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.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, in the X-ray powder diffraction spectrum of use Cu-K α radiation detection, 2 θ values are 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, locate diffraction peak for 25.49,27.59,28.82 ± 0.2 °.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, hydrogen spectrum data are as follows:
1hNMR 400MHz (DMSO-d
6) 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).
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention, TGA spectrogram shows that weightlessness is that 4.166 ± 0.2%, DSC spectrogram shows at 74.54 DEG C, has located endotherm(ic)peak for 191.07 DEG C and 229.30 DEG C.
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.
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.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound of the present invention has shown in accompanying drawing 3
1hNMR 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: 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h and tartrate are reacted in the mixed solvent of organic solvent and water in the ratio of 1:0.4～0.6, temperature of reaction is 0～100 DEG C, reaction times is 1～24 hour, then from reaction solution, collects 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate.
Described organic solvent is selected from single solvent or mixed solvent in methyl alcohol, ethanol, Virahol, n-propyl alcohol, acetone, acetonitrile, tetrahydrofuran (THF); The amount of organic solvent is advisable to dissolve 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h.The ratio of organic solvent and water is 10:0.5～5.
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate compound stability provided by the invention is good, have higher water-soluble, security, and its preparation method is simple to operate, favorable reproducibility.7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt compound of the present invention, and salt of the prior art relatively has the following advantages:
Solubleness comparison (g/ml) in water:
| 25℃ | 35℃ | 45℃ | |
| 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate | 0.83 | 0.91 | 0.95 |
| 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h tartrate | 0.47 | 0.52 | 0.60 |
Thermostability comparison:
Trial-product is placed under 50 DEG C of vacuum, detected its different period purity and change.
| 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% |
Brief description of the drawings
Accompanying drawing 1 is the X ray powder diffraction spectrogram of embodiment 1 gained 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate.
Embodiment
Further illustrate technical scheme of the present invention with specific embodiment below, but protection scope of the present invention is not limited to this.
Analyzing and testing condition of the present invention is as follows:
1, DSC-TGA is measured by the SDT Q600 of TA company of the U.S., and test condition is 120ml/min N2,10 DEG C/min of heat-up rate.
2, X-ray powder diffraction data are to use X ' Pert Pro MPD (Multi-Purpose Diffractometer) to measure, light pipe type: Empyrean XRD tube Cu LFF HR; Electric current and voltage: 45 kV, 40 mA; The vertical goniometer of goniometer: PW3050/60, radius 240mm; Slit: DS=2 °, SS=1/2 °, mask=15mm, RS=5.0mm; The super detector of detector: X ' Celerator; Scan pattern: continuous sweep; Sweep limit: 3 ° of-40 ° of 2 θ; Every step gate time: 20s; Scanning total time: 6min.
3, hydrogen spectrum is detected by Bruker 400 instruments.
Embodiment 1
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 25ml ethanol, 1.02g tartrate is dissolved in 10ml ethanol, under stirring, the ethanolic soln of L-TARTARIC ACID is slowly added in the ethanolic soln of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finish, be warming up to 70 DEG C, add 4.5ml water to just clarification, maintain this thermotonus 10min, leave standstill, separate out a large amount of off-white color solids, suction filtration, vacuum-drying obtains 2.8g off-white color solid, yield 68.9%.
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 20ml acetone, 1.02g tartrate is dissolved in 5ml water, under stirring, the aqueous solution of L-TARTARIC ACID is 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 clarification, maintain this thermotonus 10min, leave standstill, separate out a large amount of off-white color solids, suction filtration, vacuum-drying obtains 3.3g off-white color solid, yield 81.2%.
3g 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is dissolved in 20ml methyl alcohol, 1.02g tartrate is dissolved in 5ml methyl alcohol, under stirring, the methanol solution of L-TARTARIC ACID is slowly added in the methanol solution of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finish, be warming up to 65 DEG C, add 1.5ml water to just clarification, maintain this thermotonus 10min, leave standstill, separate out a large amount of off-white color solids, suction filtration, vacuum-drying obtains 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 tartrate is dissolved in 8ml tetrahydrofuran (THF), under stirring, the tetrahydrofuran solution of L-TARTARIC ACID is slowly added in the acetone soln of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finish, be warming up to 65 DEG C, add 10 ml water to just clarification, maintain this thermotonus 10min, leave standstill, separate out a large amount of off-white color solids, suction filtration, vacuum-drying obtains 2.2g off-white color 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 tartrate is dissolved in 10ml acetonitrile, under stirring, the acetonitrile solution of L-TARTARIC ACID is slowly added in the acetonitrile solution of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, finish, be warming up to 80 DEG C, add 3.2ml water to just clarification, maintain this thermotonus 10min, leave standstill, separate out a large amount of off-white color solids, suction filtration, vacuum-drying obtains 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-TARTARIC ACID salt.
3. according to claim 1, in the X-ray powder diffraction spectrum that it is characterized in that expressing with 2 θ with Cu-K α radiation detection, 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, locate diffraction peak for 25.49,27.59,28.82 ± 0.2 °.
4. according to claim 1, it is characterized in that, in DSC spectrogram, at 74.54 DEG C, located endotherm(ic)peak for 191.07 DEG C and 229.30 DEG C.
5. the preparation method of a 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt compound claimed in claim 1, its feature comprises: 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h and tartrate are reacted in the mixed solvent of organic solvent and water in the ratio of 1:0.4～0.6, temperature of reaction is 0～100 DEG C, reaction times is 1～24 hour, then from reaction solution, collects 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h half tartrate.
6. according to claim 5, it is characterized in that, described organic solvent is selected from single solvent or mixed solvent in methyl alcohol, ethanol, Virahol, n-propyl alcohol, acetone, acetonitrile, tetrahydrofuran (THF).
7. according to claim 5, it is characterized in that, the ratio of organic solvent and water is 10:0.5～5.
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| CN201210572501.8A CN103896943B (en) | 2012-12-25 | 2012-12-25 | A kind of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt and preparation method thereof |
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| CN201210572501.8A CN103896943B (en) | 2012-12-25 | 2012-12-25 | A kind of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h salt and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11602537B2 (en) | 2022-03-11 | 2023-03-14 | Par Pharmaceutical, Inc. | Varenicline compound and process of manufacture thereof |
| EP4241775A1 (en) | 2022-03-11 | 2023-09-13 | Par Pharmaceutical, Inc. | Tablet comprising varenicline and process of preparation thereof |
Family Cites Families (1)
| 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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11602537B2 (en) | 2022-03-11 | 2023-03-14 | Par Pharmaceutical, Inc. | Varenicline compound and process of manufacture thereof |
| US11717524B1 (en) | 2022-03-11 | 2023-08-08 | Par Pharmaceutical, Inc. | Varenicline compound and process of manufacture thereof |
| EP4241775A1 (en) | 2022-03-11 | 2023-09-13 | Par Pharmaceutical, Inc. | Tablet comprising varenicline and process of preparation thereof |
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| CN103896943B (en) | 2016-09-07 |
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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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