CN101851165B - Glutamate of O-demethyl-venlafaxine and preparation method thereof - Google Patents
Glutamate of O-demethyl-venlafaxine and preparation method thereof Download PDFInfo
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- CN101851165B CN101851165B CN 200910129272 CN200910129272A CN101851165B CN 101851165 B CN101851165 B CN 101851165B CN 200910129272 CN200910129272 CN 200910129272 CN 200910129272 A CN200910129272 A CN 200910129272A CN 101851165 B CN101851165 B CN 101851165B
- Authority
- CN
- China
- Prior art keywords
- demethyl
- venlafaxine
- free alkali
- glutaminate
- pidolidone
- 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.)
- Expired - Fee Related
Links
- 229960004688 venlafaxine Drugs 0.000 title claims abstract description 31
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 229930195712 glutamate Natural products 0.000 title abstract 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 229960002989 glutamic acid Drugs 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 239000003937 drug carrier Substances 0.000 abstract description 4
- 239000000935 antidepressant agent Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 229940005513 antidepressants Drugs 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000008194 pharmaceutical composition Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000024732 dysthymic disease Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229920001684 low density polyethylene Polymers 0.000 description 2
- 239000004702 low-density polyethylene Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical group C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical class C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to glutamate of new O-demethyl-venlafaxine and a preparation method thereof, as well as a medicine composition containing the glutamate and pharmaceutically acceptable carriers and application thereof in preparing antidepressants.
Description
Technical field
The present invention relates to new O-demethyl-Venlafaxine glutaminate and preparation method thereof, this salt and pharmaceutical composition pharmaceutically acceptable carrier.The glutaminate of O-demethyl-Venlafaxine is the pharmaceutically useful salt that is used for the treatment of the O-demethyl-Venlafaxine of various dysthymia disorders.
Background technology
O-demethyl-Venlafaxine is the major metabolite of Venlafaxine, is serotonin and NRI, is used for the treatment of various dysthymia disorders, and its chemical name is 4-[2-dimethylamino-1-(1-hydroxy-cyclohexyl) ethyl] phenol.U.S. Patent No. 4,535,186 have enumerated its fumarate; U.S. Patent No. 2004044241 discloses its succinate; U.S. Patent No. 2003236309 discloses its formate.
Suitable salt can be on the basis that does not change basic chemical structure by the physico-chemical property that changes medicine and then affect it as the appropriateness of medicine.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides the new salt of O-demethyl-Venlafaxine, i.e. O-demethyl-Venlafaxine glutaminate.The structural formula of O-demethyl-Venlafaxine glutaminate is as follows:
Wherein:
O-demethyl-Venlafaxine comprises racemic mixture and the pure form of stereoisomerism thereof.
L-glutamic acid comprises D-Glu, Pidolidone mixture and the pure form of stereoisomerism thereof.
O-demethyl-Venlafaxine glutaminate has the suitable character that is particularly suitable for as medicine, comprises being difficult for suction to make things convenient for preparation, good solubility, perviousness and bioavailability.
The present invention also provides pharmaceutical composition, and described pharmaceutical composition comprises the glutaminate of O-demethyl-Venlafaxine as activeconstituents and pharmaceutically acceptable carrier.
The present invention also provides the method for preparing O-demethyl-Venlafaxine glutaminate, can contact to prepare with O-demethyl-Venlafaxine free alkali by making stoichiometric L-glutamic acid, and described contact is carried out in ethanol, propyl alcohol, water at 50-80 ℃.
Further, the purposes of the glutaminate that the present invention relates to O-demethyl-Venlafaxine in the preparation antidepressant drug also relates to the glutaminate that comprises O-demethyl-Venlafaxine as the purposes of pharmaceutical composition in the preparation antidepressant drug of activeconstituents and pharmaceutically acceptable carrier.
Embodiment
O-demethyl-Venlafaxine glutaminate can prepare by the following examples, but is not limited to following method.
Embodiment 1
O-demethyl-Venlafaxine free alkali (8.146g, 30.93mmol) is dissolved in the ethanol (160ml) of heat.Pidolidone (4.778g, 32.47mmol) is joined in the purified water (100ml), be heated to 80 ℃, add the hot ethanol solution of above-mentioned O-demethyl-Venlafaxine free alkali, be stirred to whole dissolvings, continue to stir 15 minutes, be chilled to room temperature, the filtering insolubles, removal of solvent under reduced pressure adds ethanol (80ml), stir, filter, a small amount of washing with alcohol of filter cake, vacuum-drying gets O-demethyl-Venlafaxine-Pidolidone salt: 10.7g.
Fusing point: 182.5～183.5 ℃ (melting is decomposed simultaneously).
1HNMR(400MHz，DMSO-d
6)：δ＝9.2～8.8(bs，2H)，7.00～6.97(d，2H)，6.67～6.64(d，2H)，3.27～3.24(t，1H)，3.05～2.99(dd，1H)，2.75～2.71(t，2H)，2.43～2.33(m，2H)，2.17(s，6H)，1.6～0.8(m，12H)
Embodiment 2
O-demethyl-Venlafaxine free alkali (8.146g, 30.93mmol) is dissolved in the acetone (200ml) of heat.Pidolidone (4.778g, 32.47mmol) is joined in the purified water (100ml), be heated to 50 ℃, the hot acetone solution that adds above-mentioned O-demethyl-Venlafaxine free alkali, be stirred to whole dissolvings, continue to stir 15 minutes, be chilled to room temperature, the filtering insolubles, removal of solvent under reduced pressure adds ethanol (100ml), stirs, filter, vacuum-drying gets O-demethyl-Venlafaxine-Pidolidone salt: 9.4g.
Embodiment 3
The O-demethyl prepared according to embodiment 1-Venlafaxine glutaminate is carried out solvability, Stability Determination, contrast simultaneously O-demethyl-Venlafaxine succinate (according to the CN1501909 preparation) and detect relevant nature.
1, solubleness
Press two note on the use tests of Chinese Pharmacopoeia version in 2005.
Take by weighing the trial-product that is ground into fine powder, place the solvent of 25 ℃ ± 2 ℃ of certain capacities, powerful jolting was 30 seconds every 5 minutes; Observe the dissolving situation in 30 minutes, as when cannot see particles of solute, namely be considered as dissolving fully.The results are shown in following table 1.
Table 1: solvability detected result
| The name of an article | O-demethyl-Venlafaxine succinate | O-demethyl-Venlafaxine-Pidolidone salt |
| Water (solute: solvent) | Dissolving (1: 29) | Yi Rong (1: 9) |
Conclusion: the compounds of this invention O-demethyl-Venlafaxine-Pidolidone salt is better than the solvability of O-demethyl-Venlafaxine succinate.
2, stability test
Accelerated test
This product is placed the particular envelope material, and (two-layer medicinal Low Density Polyethylene bag is distinguished heat sealing, adds siccative, the outer sealing with the SP compound membrane bag packed) in, in (40 ℃ RH75%) were placed 1 month under the condition, detect its related substance, measurement result sees Table 2.
Test of long duration
This product is placed the particular envelope material, and (two-layer medicinal Low Density Polyethylene bag is distinguished heat sealing, adds siccative, the outer sealing with the SP compound membrane bag packed) in, in (25 ℃, RH60%) the long-term placement, 1 month, detect its related substance, measurement result sees Table 2.
Table 2: stability test result
Conclusion: 1 month data of acceleration, long-term stable experiment show that O-demethyl-Venlafaxine of the present invention-Pidolidone salt is highly stable, substantially without degraded.
Claims (1)
1. be prepared as follows the method for the glutaminate of the O-demethyl-Venlafaxine shown in the formula, by stoichiometric L-glutamic acid is contacted with O-demethyl-Venlafaxine free alkali, it is characterized in that, with O-demethyl-Venlafaxine free alkali 8.146g, 30.93mmol is dissolved among the ethanol 160ml of heat; With Pidolidone 4.778g, 32.47mmol joins among the purified water 100ml, is heated to 80 ℃, add the hot ethanol solution of above-mentioned O-demethyl-Venlafaxine free alkali, be stirred to whole dissolvings, continue to stir 15 minutes, be chilled to room temperature, filtering insolubles, removal of solvent under reduced pressure, add ethanol 80ml, stir, filter a small amount of washing with alcohol of filter cake, vacuum-drying gets O-demethyl-Venlafaxine-Pidolidone salt: 10.7g
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910129272 CN101851165B (en) | 2009-04-03 | 2009-04-03 | Glutamate of O-demethyl-venlafaxine and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910129272 CN101851165B (en) | 2009-04-03 | 2009-04-03 | Glutamate of O-demethyl-venlafaxine and preparation method thereof |
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| Publication Number | Publication Date |
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| CN101851165A CN101851165A (en) | 2010-10-06 |
| CN101851165B true CN101851165B (en) | 2013-09-18 |
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| CN 200910129272 Expired - Fee Related CN101851165B (en) | 2009-04-03 | 2009-04-03 | Glutamate of O-demethyl-venlafaxine and preparation method thereof |
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| CN103483210B (en) * | 2012-06-13 | 2016-01-13 | 成都弘达药业有限公司 | A kind of new compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101074200A (en) * | 2006-05-16 | 2007-11-21 | 北京海步国际医药科技发展有限公司 | Aspartic acid salt of O-demethyl-Venlafacin |
| CN101959846A (en) * | 2008-01-29 | 2011-01-26 | 力奇制药公司 | Novel salts of O-desmethyl-venlafaxine |
-
2009
- 2009-04-03 CN CN 200910129272 patent/CN101851165B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101074200A (en) * | 2006-05-16 | 2007-11-21 | 北京海步国际医药科技发展有限公司 | Aspartic acid salt of O-demethyl-Venlafacin |
| CN101959846A (en) * | 2008-01-29 | 2011-01-26 | 力奇制药公司 | Novel salts of O-desmethyl-venlafaxine |
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| CN101851165A (en) | 2010-10-06 |
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