CN103553940A - Preparation method of new crystal form tapentadol hydrochloride - Google Patents
Preparation method of new crystal form tapentadol hydrochloride Download PDFInfo
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- CN103553940A CN103553940A CN201310549387.1A CN201310549387A CN103553940A CN 103553940 A CN103553940 A CN 103553940A CN 201310549387 A CN201310549387 A CN 201310549387A CN 103553940 A CN103553940 A CN 103553940A
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Abstract
The invention discloses a preparation method of new crystal form tapentadol hydrochloride, which comprises the following steps of (1) converting (2R, 3R)-3-(3-methoxyphenyl)-N,N,2-trimethyl-amylamine hydrochloride by use of a demethylation reagent into the formula (III): (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylphenyl)phenol; (2) salifying the compound of formula (III) with hydrochloric acid in a mixed solvent of acetonitrile and isopropyl alcohol to obtain a compound of formula (I): (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylphenyl)phenol hydrochloride. By adopting the method disclosed by the invention, stable new crystal form tapentadol hydrochloride can be obtained; moreover, the process conditions are mild, the after-treatment is simple, the purity is high, the reaction cost is low, and industrial production is easy to realize.
Description
Technical field
The invention belongs to chemicals synthesis technical field, relate to the preparation method of a kind of new crystal of tapentadol hydrochloride (tapentadol hydrochloride).
Background technology
Tapentadol hydrochloride (Imatinib Mesylate), chemistry tapentadol hydrochloride by name, structural formula is as follows:
Tapentadol hydrochloride is developed by U.S. Johnson & Johnson company, it is a kind of central analgesics of the novel dual mode of action, it is mu opioid receptor excitomotor, again that norepinephrine heavily absorbs Depressant, several animal models to acute, inflammatory and chronic neuropathic pain model has analgesic activity, its usefulness between morphine and tramadol, intravenous injection or orally all can reach satisfied Plasma Concentration, and well-tolerated.
The synthetic method of tapentadol hydrochloride is a lot, and the method summary of related documents report is as follows:
(1) in Tetrahedron:Asymmetry23 (2012) the 577-582 document, the experiment route of synthetic hydrochloric acid tapentadol hydrochloride is as follows:
This route experimental procedure is longer, and reacts the low-temp reaction that relates to-78 ℃, and the harsher suitability for industrialized production that is not suitable for of experiment condition, is used lithium aluminum hydride in reaction process, inflammable and explosive.
(2) Chinese patent CN102936205A discloses that to take 1-dimethylamino-2-methyl-propione be starting raw material, through reduction, halogenating reaction, obtain the bromo-N of 3-, N-2-trimethylammonium penta-1-amine, under the catalysis of transition metal, obtain 3-(3-p-methoxy-phenyl)-N, N-2-trimethylammonium penta-1-amine, then passes through demethylation and fractionation, obtains tapentadol hydrochloride.In this patent, on the starting raw material market of the synthetic method of tapentadol hydrochloride, easily obtain, but step is longer, yield is lower, is not suitable for suitability for industrialized production.
(2) in PCT patent WO 2011/107876A2, prepare the method for tapentadol hydrochloride as follows:
The method is with (2R, 3R)-3-(3-p-methoxy-phenyl)-N, N, 2-trimethylammonium-amylamine hydrochloride is starting raw material, through demethylation, one-tenth hydrochloride, finally generates target product tapentadol hydrochloride, and this route steps is short, simple to operate, aftertreatment is simple, and yield is higher.
Less for the document of tapentadol hydrochloride crystal formation research in prior art, relate to new crystal tapentadol hydrochloride preparation technology's document still less, therefore, by researching and developing a kind of preparation method safe and manageable new crystal tapentadol hydrochloride, be very important.
Summary of the invention
In view of the deficiencies in the prior art, it is shorter that technical problem to be solved by this invention is to provide a kind of synthesis step, be easy to purifying, simple to operate, the preparation method of the tapentadol hydrochloride of the applicable suitability for industrialized production that yield is higher (tapentadol hydrochloride) new crystal.
The invention provides a kind of method of the tapentadol hydrochloride new crystal of preparing, in the present invention, its X-ray powder diffraction pattern of tapentadol hydrochloride new crystal is about 10.09(8.7 at reflection angle 2 θ), 16.7(5.3), 16.9(5.2), 18.0(4.9), 19.5, (4.5), 21.9(4.1), 27.7(3.6) 30.3(2.9) located characteristic absorbance.
In the present invention, the mensuration of 2 θ values is used Cu-K α light source, and precision is ± 0.2 °,
In order to realize object of the present invention, the inventor studies by lot of experiments, has finally obtained following technical scheme:
A preparation method for new crystal tapentadol hydrochloride, comprises the following steps:
(1) by formula II (2R, 3R)-3-(3-p-methoxy-phenyl)-N, N, 2-trimethylammonium-amylamine hydrochloride is converted into formula III with demethylation reagent: (-)-(1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenol
(2) formula III compound and hydrochloric acid salify obtain formula I compound: (-)-(1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenolate hydrochlorate
After gained formula I compound crystallization, it is a kind of new crystal tapentadol hydrochloride.
Preferably, the preparation method of above-mentioned new crystal tapentadol hydrochloride, wherein the temperature of reaction of step (1) is 80-120 ℃, and the reaction times is 4-8 hour, and demethylation reagent agent is selected from aqueous solution of hydrogen bromide, aqueous solution of hydrogen iodide, a kind of in methylsulfonic acid;
Further preferably, the preparation method of above-mentioned new crystal tapentadol hydrochloride, wherein the demethylation reagent in step (1) is Hydrogen bromide.
Preferably, the preparation method of above-mentioned new crystal tapentadol hydrochloride, wherein the reaction times of step (2) is 4-6 hour, recrystallization temperature is-10-10 ℃,, reaction solvent is selected from one or more in tetrahydrofuran (THF), Virahol, ethanol, acetonitrile and acetone; Crystallization solvent is selected from sherwood oil, isopropyl ether, normal hexane, one or more in normal heptane.
Further preferably, the preparation method of above-mentioned new crystal tapentadol hydrochloride, wherein the reaction solvent in step (2) is the mixed solvent of acetonitrile and Virahol, crystallization solvent is isopropyl ether.
Again further preferably, the preparation method of above-mentioned new crystal tapentadol hydrochloride, wherein the reaction solvent in step (2) is acetonitrile: mixed solvent Virahol=1:4(v:v), the consumption of mixed solvent is 10-15 times (v/w) of compound (III) weight.
Tapentadol hydrochloride has multiple crystal formation, is mainly wherein A crystal formation and B crystal formation.The inventor, in research process, has found a kind of novel method of preparing new crystal tapentadol hydrochloride.Compared with the conventional method, it is shorter that the method has synthesis step, simple to operate, is easy to purifying, and yield is high, and new crystal is stable and purity is higher.In addition, the present invention has effectively avoided using inflammable, deadly poisonous compound, has greatly dwindled reactions steps, thereby has reduced reaction difficulty, and then simplified aftertreatment, improved yield and significantly reduced reaction cost simultaneously, is beneficial to industrialized production.
Embodiment
Form is described in further detail foregoing of the present invention again by the following examples, but this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology realizing based on foregoing of the present invention all belong to scope of the present invention.
The preparation of embodiment tapentadol hydrochloride new crystal
(1) synthesizing of (-)-(1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenol (formula III)
Take 100g (2R, 3R)-3-(3-p-methoxy-phenyl)-N, N, 2-trimethylammonium-amylamine hydrochloride joins in 1L there-necked flask, measure 200mlHBr(48%) join in reaction flask, thermometer is installed, reflux condensing tube, open mechanical stirring, be heated to 90-95 ℃, stirring reaction 6 hours, cools the temperature to room temperature, add 300ml ethyl acetate, under stirring, slowly add 400ml saturated sodium bicarbonate to regulate pH to 8-9, separatory is isolated organic layer, and organic layer is spin-dried for, obtaining tapentadol hydrochloride, is micro-yellow oil.Weigh, 76g, yield 93%.
(2) synthesizing of (-)-(1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenolate hydrochlorate (formula I)
The tapentadol hydrochloride obtaining (oily matter) 76g is dissolved in the mixed solvent (V/V:1:4) of 800ml acetonitrile and Virahol, under stirring at room, pass into 300ml hydrochloric acid Virahol (1mol/L), stirring at room 1 hour, add 500ml isopropyl ether, be cooled to 0-10 ℃, stir 2 hours, the solid that suction filtration obtains is placed air dry oven, and 60 ℃ of forced air dryings are spent the night.Obtain hydrochloride tapentadol hydrochloride new crystal.Weigh, 73g, yield 83%.
Relevant physico-chemical property, the spectroscopy data of compound (formula I) are as follows:
Fusing point: 199-202 ℃;
1h NMR(300MHz, DMSO) δ (ppm): 10.2 (s, 1H), 9.37-9.41 (m, 1H); 7.07-7.12 (m, 1H), 6.6-6.66 (m, 3H), 2.81-2.84 (m; 3H), 2.73-2.77 (m, 3H), 2.60-2.61 (m; 3H), 2.29-2.36 (m, 1H), 2.05-2.09 (m; 1H) 1.67-1.74 (m, 1H), 1.49-1.57 (m, 1H); 1.03-1.05 (d, 3H), 0.64-0.71 (m, 3H); MS (ES) m/z222.3 ([M-HCl+H]
+). compound (formula I) X-ray diffracting spectrum is that its refraction angle of new crystal characteristic peak 2 θ are as follows: 10.09(8.7), and 16.7(5.3), 16.9(5.2), 18.0(4.9), 19.5, (4.5), 21.9(4.1), 27.7(3.6) 30.3(2.9) located characteristic absorbance.
The instrument and the reagent that in the various embodiments described above, adopt are as follows:
X-4 type micro-meldometer; Varian Mercury plus-500MHz type nuclear magnetic resonance analyser, AGILENTLC-MSD-Trap-SL mass spectrograph, D
8x-ray diffractometer (German Bruker-axs company).
Other reagent used is commercially available analytical pure or chemical pure, not purified before use.
Claims (7)
1. a preparation method for new crystal tapentadol hydrochloride, is characterized in that comprising the following steps:
(1) by formula II (2R, 3R)-3-(3-p-methoxy-phenyl)-N, N, 2-trimethylammonium-amylamine hydrochloride is converted into formula III with demethylation reagent: (-)-(1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenol
(2) formula III compound and hydrochloric acid salify obtain formula I compound: (-)-(1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenolate hydrochlorate
After gained formula I compound crystallization, it is a kind of new crystal tapentadol hydrochloride.
2. the preparation method of new crystal tapentadol hydrochloride according to claim 1, it is characterized in that: the new crystal tapentadol hydrochloride obtaining in step (2), it is characterized in that using its X-ray powder diffraction pattern of Cu-K α light source to be about 10.09(8.7 at reflection angle 2 θ), 16.7(5.3), 16.9(5.2), 18.0(4.9), 19.5, (4.5), 21.9(4.1), 27.7(3.6) 30.3(2.9) located characteristic absorbance.
3. the preparation method of new crystal tapentadol hydrochloride according to claim 1, it is characterized in that: the temperature of reaction of step (1) is 80-120 ℃, the reaction times is 4-8 hour, and demethylation reagent agent is selected from aqueous solution of hydrogen bromide, aqueous solution of hydrogen iodide, a kind of in methylsulfonic acid;
4. the preparation method of new crystal tapentadol hydrochloride according to claim 3, is characterized in that: the demethylation reagent in step (1) is Hydrogen bromide.
5. the preparation method of new crystal tapentadol hydrochloride according to claim 1, it is characterized in that: the reaction times of step (2) is 4-6 hour, recrystallization temperature is-10-10 ℃,, reaction solvent is selected from one or more in tetrahydrofuran (THF), Virahol, ethanol, acetonitrile and acetone; Crystallization solvent is selected from sherwood oil, isopropyl ether, normal hexane, one or more in normal heptane
6. the preparation method of new crystal tapentadol hydrochloride according to claim 5, is characterized in that: the reaction solvent in step (2) is the mixed solvent of acetonitrile and Virahol, and crystallization solvent is isopropyl ether.
7. the preparation method of new crystal tapentadol hydrochloride according to claim 6, it is characterized in that: the reaction solvent in step (2) is acetonitrile: mixed solvent Virahol=1:4(v:v), the consumption of mixed solvent is 10-15 times (v/w) of compound (III) weight.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503619A (en) * | 2015-12-31 | 2016-04-20 | 江苏尚莱特医药化工材料有限公司 | Preparation method of 3,3minute-dihydroxy-4,4minute-benzidine |
| WO2017085734A1 (en) * | 2015-11-17 | 2017-05-26 | Msn Laboratories Private Limited | Crystalline forms of tapentadol salts and process for preparation thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008012047A1 (en) * | 2006-07-24 | 2008-01-31 | Grünenthal GmbH | Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
| US20090326271A1 (en) * | 2006-07-24 | 2009-12-31 | Gruenenthal Gmbh | Preparation of 3-[(1R,2R)-3-(Dimethylamino)-1Ethyl-2-Methylpropyl]phenol |
| WO2011080736A1 (en) * | 2009-12-29 | 2011-07-07 | Mapi Pharma Hk Limited | Intermediate compounds and processes for the preparation of tapentadol and related compounds |
| CN103193659A (en) * | 2013-03-15 | 2013-07-10 | 北京润德康医药技术有限公司 | Novel crystal form of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008012047A1 (en) * | 2006-07-24 | 2008-01-31 | Grünenthal GmbH | Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
| US20090326271A1 (en) * | 2006-07-24 | 2009-12-31 | Gruenenthal Gmbh | Preparation of 3-[(1R,2R)-3-(Dimethylamino)-1Ethyl-2-Methylpropyl]phenol |
| WO2011080736A1 (en) * | 2009-12-29 | 2011-07-07 | Mapi Pharma Hk Limited | Intermediate compounds and processes for the preparation of tapentadol and related compounds |
| CN103193659A (en) * | 2013-03-15 | 2013-07-10 | 北京润德康医药技术有限公司 | Novel crystal form of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017085734A1 (en) * | 2015-11-17 | 2017-05-26 | Msn Laboratories Private Limited | Crystalline forms of tapentadol salts and process for preparation thereof |
| CN105503619A (en) * | 2015-12-31 | 2016-04-20 | 江苏尚莱特医药化工材料有限公司 | Preparation method of 3,3minute-dihydroxy-4,4minute-benzidine |
| CN105503619B (en) * | 2015-12-31 | 2018-01-19 | 江苏尚莱特医药化工材料有限公司 | The preparation method of the benzidine of 3,3 ' dihydroxy 4,4 ' |
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Application publication date: 20140205 |