CN103483210B - A kind of new compound and preparation method thereof - Google Patents
A kind of new compound and preparation method thereof Download PDFInfo
- Publication number
- CN103483210B CN103483210B CN201210193978.5A CN201210193978A CN103483210B CN 103483210 B CN103483210 B CN 103483210B CN 201210193978 A CN201210193978 A CN 201210193978A CN 103483210 B CN103483210 B CN 103483210B
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction
- solvent
- phenyl
- impurity
- 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.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of new compound and preparation method thereof, this compound is the new impurity of Venlafaxine, it is specially (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin, this compound with and preparation method thereof be the impurity controlled more accurately in Venlafaxine, obtain Venlafaxine that is more safe and reliable, determined curative effect and provide support.
Description
Background technology
Any material affecting pharmaceutical purity is referred to as impurity.Assorted Quality Research is an important content of drug research and development.It comprises selects suitable analytical procedure, differentiates exactly and measures the content of impurity and the reasonable limit of the result determination impurity of comprehensive pharmacy, toxicity and clinical study.This research is through the whole process of drug research and development.The untoward reaction produced in Clinical practice due to medicine, except outside the Pass having with the pharmacologically active of medicine itself, also has much relations with the impurity that exists in medicine sometimes.Such as, the macromolecule impurities such as the polymer in the microbiotic such as penicillin cause irritated major cause.So specification ground carries out assorted Quality Research, and controlled within a safety, reasonably limits, will quality and the security [technical director's principle of version chemicals impurity research in 2005] of marketed products be directly connected to.Medicine is absolutely necessary for people, how to control the safe and reliable of medicine, become vital problem in society's today, supervision department also or enterprise all have a responsibility for improving the quality of medicine, along with more and more higher to the requirement of drug quality, in medicine, impurity research also becomes more and more important.In impurity, organic impurity mainly comprises the impurity and degraded product etc. introduced in technique, may be known or the unknown, volatile or non-volatility.Chemical structure due to this kind of impurity is general and activeconstituents is similar or tool original relationship, therefore usually can be referred to as related substance again, and more seems particularly important for the control of related substance.
Dysthymia disorders, as " by product " of modern economy high speed development, affects the life of people more and more widely.Have data to show, the people of China 70% is in sub-health state, and the Disease relevant to psychology accounts for crowd's 5% ~ 10%, and mental disease and psychological disorders have become frequently-occurring disease, common disease." World Health Report " display that the World Health Organization (WHO) delivers, dysthymia disorders has become the fourth-largest illness in the world, may become be only second to cardiopathic second largest disease to the year two thousand twenty dysthymia disorders.Venlafaxine (Venlafaxine) is that a kind of serotonin (5-HT) of being developed by Wyeth of the U.S. and norepinephrine (NE) double back receive blocker, is clinically used for the treatment of dysthymia disorders and generalized anxiety disorder.Current VENLAFAXINE HCL has become antidepressant clinical choice drug, but it also exists a lot of untoward reaction, such as common appetite decline, constipation, Nausea and vomiting; Hypertension, vasodilation (mostly being flush); Serum cholesterol increases, lose weight; Dreamland is abnormal, sexual desire declines, dizzy, dry, muscle spasm, insomnia, nervous, paresthesia, calmness, tremble; Yawn; Perspire (comprising sweat at night); Eye dysregulation, platycoria, ocular disorders; Ejaculation exception/abnormal climax (male sex), sexy forfeiture, erective dysfunction, urinary function impaired (mostly being misnicturition) etc.
In order to improve the quality standard of Venlafaxine, in the world through years of researches, the following three kinds of synthetic routes (WO2008038146) of the synthesis technique summary and induction for Venlafaxine:
Route 1:
Route 2:
Route 3:
Research for the reaction conditions of above-mentioned route has a lot of reports, but about the research of each step reaction impurities, and the impurity research existed in the finished product is then reported less, wherein WO2007049302 clearly reports the following by product of structural formula:
Listed the impurity being numbered A-G in the quality standard of the VENLAFAXINE HCL of European Pharmacopoeia 7.0 in, its structural formula is as follows respectively:
The existence that Saravanan etc. disclose related compound and impurity in active pharmaceutical ingredient may have larger impact to the quality of medicine and security, therefore, the all impurity of comprehensive research in active medicine are necessary, the document disclose in detail six impurity in Venlafaxine, with and preparation method thereof and structural characterization, these six compound structures are respectively impurity F in impurity 2(and European Pharmacopoeia), impurity G in impurity 3(and European Pharmacopoeia), impurity D in impurity 5(and European Pharmacopoeia), impurity E in impurity 6(and European Pharmacopoeia), impurity in impurity 7(WO2007049302), impurity A in impurity 8(and European Pharmacopoeia) [SyntheticCommunications, 40:1881-1886, 2010].
Summary of the invention
One aspect of the present invention provides a kind of compound, and it has following structure:
The present invention additionally provides the preparation method of above-claimed cpd on the other hand, it comprises following steps: take p methoxy phenyl acetonitrile as starting raw material, through hydrolysis, reduction, esterification, with 1-[2-amino-1-(4-methoxyl group) phenyl] ethyl cyclohexanol condensation, formaldehyde carboxylic acid methyl after obtain product;
Hydrolysis reaction described in above-mentioned preparation method has and preferably utilizes mineral acid or mineral alkali to be hydrolyzed, and described hydrolysising solvent is preferably water or the solvent miscible with water; Wherein said mineral acid most preferably strong acid, more preferably hydrochloric acid; Described mineral alkali is basic metal mineral alkali most preferably, more preferably sodium hydroxide; The described solvent miscible with water most preferably lower alcohols, more preferably ethanol; The temperature of reaction of described hydrolysis is preferably reflux temperature.
In reduction reaction described in above-mentioned preparation method, reductive agent is preferably sodium borohydride and boron trifluoride diethyl etherate, and solvent is preferably tetrahydrofuran (THF).
In esterification described in above-mentioned preparation method, solvent is preferably aprotic solvent, and alkali is preferably trimethylamine, and acylating reagent is preferably methane sulfonyl chloride; Wherein said aprotic solvent is more preferably methylene dichloride, and described trimethylamine is more preferably triethylamine.
In condensation reaction described in above-mentioned preparation method, solvent is preferably acetonitrile or toluene, and alkali is preferably basic metal mineral alkali, wherein said basic metal inorganic salt more preferably sodium bicarbonate or salt of wormwood;
In methylation reaction described in above-mentioned preparation method, solvent is preferably water, and methylating reagent and reductive agent are preferably formaldehyde and formaldehyde.
The present invention still further provides the preparation method in above-claimed cpd, take p methoxy phenyl acetonitrile as starting raw material, through sodium hydroxide hydrolysis, borane reduction, methane sulfonyl chloride esterification, with 1-[2-amino-1-(4-methoxyl group) phenyl] ethyl cyclohexanol condensation, formaldehyde carboxylic acid methyl after obtain product; Reductive agent in wherein said borane reduction is preferably sodium borohydride and boron trifluoride diethyl etherate.
Invention still further provides the crystal formation containing the X powder diffraction spectrogram containing following peak:
Invention still further provides above-claimed cpd is under the condition of 10 DEG C/minute in rate of heating, and it has the thermogravimetric amount identical with Fig. 5 with Fig. 6 endothermic curve identical with differential thermal analysis endothermic curve.
The present invention provides the purposes of above-claimed cpd as Venlafaxine defects inspecting reference substance on the other hand.
Know through the large quantity research of contriver, in hydrolysis reaction of the present invention, employing p methoxy phenyl acetonitrile is raw material, and preferably water or the solvent miscible with water are hydrolyzed as solvent, mineral acid or mineral alkali; The preferred lower alcohols of wherein miscible with water solvent, more preferably ethanol; The preferred strong acid of mineral acid, more preferably hydrochloric acid; Mineral alkali preferred as alkali mineral alkali, more preferably sodium hydroxide; Temperature of reaction is preferably the lower temperature of backflow.
In reduction reaction, be preferably solvent with tetrahydrofuran (THF), be reductive agent by sodium borohydride and boron trifluoride diethyl etherate, react, add suitable quantity of water after completion of the reaction, sodium hydroxide solution is adjusted to alkalescence, and extraction, washing, drying, organic phase concentrating under reduced pressure obtains nearly colorless oil to anisole ethanol.
In the esterification reaction, solvent is preferably aprotic solvent, is more preferably methylene dichloride; Preferred trimethylamine does alkali; be more preferably triethylamine, methane sulfonyl chloride is that acylating reagent reacts, and reacts complete diluted acid and adjusts pH to neutral; extraction, washing, separatory, organic phase concentrating under reduced pressure obtains pale yellow oil 2-(4-methoxyl group-phenyl)-ethanol methanesulfonates.
In the condensation reaction, be preferably solvent with acetonitrile or toluene, alkali is preferably basic metal mineral alkali, more preferably sodium bicarbonate or solution of potassium carbonate are alkali, react, add suitable quantity of water after completion of the reaction, separatory, extraction, washing, organic phase concentrating under reduced pressure, obtains slightly pale yellow oil, normal hexane or normal hexane, the making beating of ethyl acetate mixtures reflux, cooling stirring and crystallizing, filter, dry, obtain white solid (±)-1-{2-[(4-methoxyphenethyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin.
In methylation reaction, preferably use water as solvent, formaldehyde, formic acid, as methylating reagent and reductive agent, react, reacting complete sodium hydroxide solution adjusts pH to alkalescence, extraction, washing, separatory, organic phase concentrating under reduced pressure, obtains pale yellow oil, add alcohol and dissolve stirring and crystallizing, filter, washing, drying obtains white solid (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin.
The present invention is by studying in great detail Venlafaxine impurity, not only obtain a kind of new impurity, also (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyl has successfully been prepared) ethyl } hexalin, qualitative examination for Venlafaxine impurity provides more comprehensive and accurate information, also for more impurity can be controlled accurately, obtain more safe and reliable, the Venlafaxine of determined curative effect provides new direction, invention also provides the preparation method of VENLAFAXINE HCL impurity I, for the quality of control VENLAFAXINE HCL better provides impurity reference substance, and synthetic route is simple and easy to control, raw material sources are convenient, simple to operate, yield is high.
Accompanying drawing explanation
Fig. 1 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } the LC-MS figure of hexalin
Fig. 2-1 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin
1h-NMR spectrogram
Fig. 2-2 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyls) ethyl } hexalin
1the partial enlarged drawing of H-NMR spectrogram
Fig. 3-1 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin
13c-NMR spectrogram
Fig. 3-2 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyls) ethyl } hexalin
13the partial enlarged drawing of C-NMR spectrogram
Fig. 4 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } the X-ray diffraction spectrogram of hexalin
Fig. 5-1 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } the TG spectrogram of hexalin
Fig. 5-2 is (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyls) ethyl } the DAT spectrogram of hexalin
Fig. 6 is the HPLC spectrogram of the mixture of Venlafaxine and impurity reference substance thereof
The HPLC spectrogram of Fig. 7 to be lot number be Venlafaxine of 20120201
The HPLC spectrogram of Fig. 8 to be lot number be Venlafaxine of 20120202
The HPLC spectrogram of Fig. 9 to be lot number be Venlafaxine of 20120203
Embodiment:
Embodiment, only for illustration of method of the present invention, includes but not limited to the method for embodiment.
Embodiment one (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } preparation of hexalin
1, the preparation of homoanisic acid
By p-methoxybenzeneacetonitrile (60.0g, 408mmol), sodium hydroxide (80.0g, 2.0mol) water (300ml) solution and ethanol 60ml add in reaction flask, heating reflux reaction, adjust pH to acid after completion of the reaction, add water stirring and crystallizing, filter, washing, drying obtains white-yellowish solid homoanisic acid 59.0g, yield 87.1%.
2, to the preparation of anisole ethanol
Homoanisic acid (90.0g, 542mmol), tetrahydrofuran (THF) (700ml), sodium borohydride (31.0g, 819mmol) with boron trifluoride diethyl etherate (108.5g, 894mmol) add in reaction flask, stirring at room temperature is reacted, and adds suitable quantity of water after completion of the reaction, adjust pH alkalescence, extraction, washing, drying, organic phase concentrating under reduced pressure obtains nearly colorless oil to anisole ethanol (81.0g), yield 98.3%.
3,2-(4-methoxyl group-phenyl) preparation of-ethanol methanesulfonates
To anisole ethanol (64.1g, 420mmol), methylene dichloride (530ml), triethylamine (85.2g, 840mmol) with methylsulfonyl chloride (57.9g, 505mmol) add in reaction flask, stirring at room temperature is reacted, and reacts complete tune pH to neutral, extraction, washing, separatory, organic phase concentrating under reduced pressure obtains pale yellow oil 2-(4-methoxyl group-phenyl)-ethanol methanesulfonates (90.6g), yield 93.4%.
4-1, (±)-1-{2-[(4-methoxyphenethyl) amino]-1-(4-p-methoxy-phenyl) ethyl } preparation method 1 of hexalin
2-(4-methoxyl group-phenyl)-ethanol methanesulfonates (70.6g, 306mmol), 1-[2-amino-1-(4-methoxyl group) phenyl] ethyl cyclohexanol (91.7g, 368mmol), acetonitrile (600ml), sodium bicarbonate (113.3g, 1.35mol) and 200ml water join in reaction flask, heating reflux reaction, add suitable quantity of water after completion of the reaction, separatory, extraction, washing, organic phase concentrating under reduced pressure, obtain slightly pale yellow oil, normal hexane, ethyl acetate mixtures reflux is pulled an oar, cooling stirring and crystallizing, filter, dry, obtain white solid (±)-1-{2-[(4-methoxyphenethyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin (72.3g), yield 61.5%.
4-2(±)-1-{2-[(4-methoxyphenethyl) amino]-1-(4-p-methoxy-phenyl) ethyl } preparation method 2 of hexalin
2-(4-methoxyl group-phenyl)-ethanol methanesulfonates (20.0g, 87mmol), 1-[2-amino-1-(4-methoxyl group) phenyl] ethyl cyclohexanol (26.0g, 104mmol), toluene (100ml), salt of wormwood (36.1g, 261mmol) and 50ml water join in reaction flask, heating reflux reaction, add suitable quantity of water after completion of the reaction, separatory, extraction, washing, organic phase concentrating under reduced pressure, obtain pale yellow oil, normal hexane backflow making beating, stirring at room temperature crystallization, filter, dry, obtain white solid (±)-1-{2-[(4-methoxyphenethyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin (20.4g), yield 61.2%.
5, (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } preparation of hexalin
(±)-1-{2-[(4-methoxyphenethyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin (60.0g, 156mmol), formaldehyde (15.2g, 187mmol), formic acid (18.6g, 343mmol) add in reaction flask with 120ml water, heating reflux reaction, react complete tune pH to alkalescence, extraction, washing, separatory, organic phase concentrating under reduced pressure, obtain pale yellow oil, add alcohol and dissolve stirring and crystallizing, filter, washing, drying obtains white solid (±)-1-{2-[(4-methoxyphenethyl) (methyl) is amino]-1-(4-p-methoxy-phenyl) ethyl } hexalin (47.0g), yield 75.6%.mp85-86℃。HPLC99.46%。Embodiment two, (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } LC-MS of hexalin detects
1, determining instrument, condition and measuring unit
Determining instrument: AgilentInfnity1290 (CA, USA) and FinniganLTQIonTrapMassSpectrometer (SanJose, CA, USA) coupling, software is respectively AgilentChemstation and Xcalibur.
2, liquid phase chromatogram condition
Chromatographic column: EclipsePlusC8,5um, 250 × 4.6mm, SN:USHXJ01301, Agilent
Moving phase: mobile phase A: water (0.1% formic acid, 20mM ammonium acetate)
Mobile phase B: acetonitrile, carries out gradient elution, in table 1.
Flow velocity: 0.8ml/min
Column temperature: 35 DEG C
Determined wavelength: 260nm
Table 1 gradient elution program
3, Mass Spectrometry Conditions
From UV-detector solution out through shunting, entering mass spectrometric flow velocity is 0.2ml/min.Electron spray ionisation, positive ion mode detects, and nitrogen is as sheath gas, assisted gas and sweep gas.Spray voltage 4.5kV: sheath gas is 20arb, assisted gas is 5arb, and sweep gas is 2arb; Capillary temperature: 275 DEG C, capillary voltage is 25V.Sweep limit: 150-1000amu.
4, detected result
Detected result is shown in Fig. 1, and LC-MS detects this compound molecule quasi-molecular ions is m/z398.33
Embodiment three, (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl hexalin proton nmr spectra (
1h-NMR) spectrogram
1, chemical structural formula and hydrogen atom numbering:
2, determining instrument, condition and measuring unit
INSTRUMENT MODEL: nuclear magnetic resonance analyser BrukerAV II-400MHzNMR
Test condition: TMS is interior mark, CDCl
3for test solvent
3, result: hydrogen nuclear magnetic resonance modal data is in table 2, and accompanying drawing 2-1,2-2.
Table 2
1h-NMR data and ownership
Embodiment three, (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl hexalin carbon-13 nmr spectra (
13c-NMR) spectrogram
1, Venlafaxine impurity I chemical structural formula and carbon atoms numbered
2, determining instrument, condition and measuring unit
INSTRUMENT MODEL: nuclear magnetic resonance analyser BrukerAV II-400MHzNMR
Test condition: TMS is interior mark, CDCl
3for test solvent
3, test result: carbon-13 nmr spectra data in table 3, accompanying drawing 3-1,3-2.
Table 3
13c-NMR data and ownership
| 13C sequence number | Sample separation chemical shift (ppm) |
| C-1 | 158.28 |
| C-2 | 158.04 |
| C-3 | 132.84 |
| C-4 | 131.84 |
| C-5、C-6 | 130.15 |
| C-7、C-8 | 129.58 |
| C-9、C-10 | 113.95 |
| C-11、C-12 | 113.33 |
| C-13 | 74.17 |
| C-14 | 60.39 |
| C-15 | 59.85 |
| C-16 | 55.29 |
| C-17 | 55.20 |
| C-18 | 51.58 |
| C-25 | 41.93 |
| C-19 | 38.11 |
| C-20 | 32.72 |
| C-21 | 31.27 |
| C-22 | 26.00 |
| C-23 | 21.59 |
| C-24 | 21.35 |
Embodiment four, (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } powder diffractogram of hexalin
1, determining instrument
INSTRUMENT MODEL: X ' pertProMPDX x ray diffractometer x
2, detected result is in table 4, accompanying drawing 4
Table 4X ray powder diffraction data
| 2 θ angles (°) | Spacing d value | Relative intensity (%) | 2 θ angles (°) | Spacing d value | Relative intensity (%) |
| 7.60585 | 13.48642 | 21.66 | 25.10824 | 4.11519 | 61.34 |
| 9.67326 | 10.60886 | 18.34 | 25.52778 | 4.04865 | 76.02 |
| 11.33106 | 9.06072 | 24.62 | 26.15110 | 3.95377 | 36.13 |
| 11.73533 | 8.74963 | 22.04 | 26.30574 | 3.93094 | 48.32 |
| 12.68090 | 8.09958 | 92.41 | 27.77486 | 3.72679 | 18.64 |
| 15.20583 | 6.76069 | 13.15 | 28.28822 | 3.66050 | 15.78 |
| 18.28021 | 5.63103 | 60.26 | 29.96924 | 3.45949 | 23.46 |
| 19.37925 | 5.31448 | 14.45 | 30.19198 | 3.43456 | 26.73 |
| 20.08702 | 5.12905 | 34.26 | 30.65536 | 3.38386 | 13.24 |
| 20.26907 | 5.08345 | 45.22 | 31.33387 | 3.31236 | 15.96 |
| 20.94328 | 4.92155 | 100.00 | 32.54027 | 3.19269 | 14.60 |
| 22.66772 | 4.55149 | 21.26 | 34.41704 | 3.02344 | 10.20 |
| 24.06889 | 4.29010 | 52.87 |
Embodiment five, (±)-1-{2-[(4-methoxyphenethyl) (methyl) amino]-1-(4-p-methoxy-phenyl) ethyl } the TG-DTA spectrogram of hexalin
1, determining instrument and testing conditions
INSTRUMENT MODEL: NSK company thermal analyzer EXSTA6000TG/DTA6300 analyser.
Test condition: rate of heating 10 DEG C/min, N
2flow velocity is 100ml/min.
2, measurement result
TG data are shown in Fig. 5-1; DTA data are shown in Fig. 5-2
Embodiment 6, Venlafaxine defects inspecting
1, detecting instrument and testing conditions
Detecting instrument: Shimadzu LC-2010C
Chromatographic condition and system: be weighting agent with octyl silane group silica gel; Acetonitrile-buffer solution system (25:75) (buffered soln: 17g primary ammonium phosphate is dissolved in 1490ml water, phosphoric acid regulates pH4.4) is moving phase, and determined wavelength is 225nm, column temperature 30 DEG C, flow velocity: 1.2ml/min.
2, reference substance
VENLAFAXINE HCL lot number: 100543-200401 originates: Nat'l Pharmaceutical & Biological Products Control Institute
VENLAFAXINE HCL known impurities A lot number: Lot.No.393.02.08.01
VENLAFAXINE HCL known impurities B lot number: Lot.No.393.07.08.01
VENLAFAXINE HCL known impurities C lot number: Lot.No.393.08.07.01
VENLAFAXINE HCL known impurities D lot number: Lot.No.393.04.07.01
VENLAFAXINE HCL known impurities F lot number: Lot.No.393.03.08.01
VENLAFAXINE HCL known impurities G lot number: Lot.No.2497
Above-mentioned impurity raw material all derives from Britain LGC laboratory
VENLAFAXINE HCL known impurities H(lot number: 120409, purity is 99.1%, self-control)
VENLAFAXINE HCL impurity I(lot number: 20120112, purity is 97.7%, self-control)
2, sample preparation: get VENLAFAXINE HCL, impurity reference substance is appropriate, add moving phase and make the about hydrochloric Venlafaxine 1mg of every 1ml, each impurity 50 μ g mixing solutions, as system suitability solution.Get 20 μ l injection liquid chromatographies, record color atlas, impurity and VENLAFAXINE HCL resolution must not be less than 1.5, and number of theoretical plate calculates should be not less than 2000 by VENLAFAXINE HCL peak.
3, detected result:
Detected result is shown in Fig. 6, and its concrete data are in table 5
Each substance data in table 5HPLC spectrogram
Embodiment 7, Venlafaxine spectrogram detect HPLC and detect
Detecting instrument and testing conditions are with embodiment 6.
Sample preparation: get VENLAFAXINE HCL sample appropriate, add moving phase and make the about hydrochloric Venlafaxine 1mg of every 1ml, it can be used as system suitability solution.Get 20 μ l injection liquid chromatographies, record color atlas.
Present inventor synthesizes Venlafaxine sample according to route in WO2008038146 2 and CN1225356A, and detects three batches of Venlafaxine samples that different time is produced, and the results are shown in accompanying drawing 7-9 and table 6-8.
In the spectrogram of table 6 accompanying drawing 7, each material detects data
In the spectrogram of table 7 accompanying drawing 8, each material detects data
In the spectrogram of table 8 accompanying drawing 9, each material detects data
Claims (18)
1. compound and a pharmacy acceptable salt thereof, is characterized in that having following structure:
2. the preparation method of compound described in claim 1 and pharmacy acceptable salt thereof, it is characterized in that described preparation method comprises following steps: take p methoxy phenyl acetonitrile as starting raw material, through hydrolysis reaction, reduction reaction, esterification, with 1-[2-amino-1-1 (4-methoxyl group) phenyl] ethyl cyclohexanol condensation, after formaldehyde, carboxylic acid methyl, obtain product; Concrete route is as follows:
3. preparation method according to claim 2, is characterized in that described hydrolysis reaction is under mineral acid or mineral alkali exist, carries out in water or the solvent miscible with water.
4. preparation method according to claim 3, is characterized in that described mineral acid is strong acid.
5. preparation method according to claim 4, is characterized in that described mineral acid is hydrochloric acid.
6. preparation method according to claim 3, is characterized in that described mineral alkali is basic metal mineral alkali.
7. preparation method according to claim 6, is characterized in that described mineral alkali is sodium hydroxide.
8. preparation method according to claim 3, is characterized in that the described solvent miscible with water is ethanol.
9. preparation method according to claim 3, is characterized in that the temperature of reaction of described hydrolysis is reflux temperature.
10. preparation method according to claim 2, it is characterized in that described reduction reaction with sodium borohydride and boron trifluoride diethyl etherate for reductive agent, take tetrahydrofuran (THF) as reaction solvent.
11. preparation methods according to claim 2, is characterized in that described esterification take aprotic solvent as reaction solvent, react under existing at trimethylamine, methane sulfonyl chloride.
12. preparation methods according to claim 11, it is characterized in that described aprotic solvent is methylene dichloride, described trimethylamine is triethylamine.
13. preparation methods according to claim 2, is characterized in that described condensation reaction with acetonitrile or toluene for reaction solvent, react under basic metal mineral alkali exists.
14. preparation methods according to claim 13, is characterized in that described basic metal mineral alkali is sodium bicarbonate or salt of wormwood.
15. preparation methods according to claim 2, is characterized in that described methylation reaction take water as solvent, are respectively methylating reagent and reductive agent with formaldehyde and formic acid.
16. preparation methods according to any one of claim 2-15, it is characterized in that comprising in the step of described preparation method: take p methoxy phenyl acetonitrile as starting raw material, through sodium hydroxide hydrolysis, borane reduction, methane sulfonyl chloride esterification, with 1-[2-amino-1-(4-methoxyl group) phenyl] ethyl cyclohexanol condensation, after formaldehyde, carboxylic acid methyl, obtain product; Reductive agent in wherein said borane reduction is sodium borohydride and boron trifluoride diethyl etherate.
17. compound according to claim 1 and pharmacy acceptable salts thereof, is characterized in that containing following peak in its X powder diffraction spectrogram:
Compound described in 18. claims 1 and pharmacy acceptable salt thereof are as the purposes of Venlafaxine defects inspecting reference substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210193978.5A CN103483210B (en) | 2012-06-13 | 2012-06-13 | A kind of new compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210193978.5A CN103483210B (en) | 2012-06-13 | 2012-06-13 | A kind of new compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103483210A CN103483210A (en) | 2014-01-01 |
| CN103483210B true CN103483210B (en) | 2016-01-13 |
Family
ID=49823866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210193978.5A Active CN103483210B (en) | 2012-06-13 | 2012-06-13 | A kind of new compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103483210B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107721955B (en) * | 2016-11-30 | 2019-10-11 | 内蒙古京东药业有限公司 | Darifenacin intermediate 2, the novel preparation method of 3- dihydro -5- benzofuranacetic acid |
| CN107721954B (en) * | 2016-11-30 | 2020-02-14 | 内蒙古京东药业有限公司 | Novel preparation method of darifenacin intermediate 2, 3-dihydro-5-benzofuran acetic acid |
| CN111675671A (en) * | 2020-07-15 | 2020-09-18 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine impurity E |
| CN112778143A (en) * | 2021-01-29 | 2021-05-11 | 合肥华方医药科技有限公司 | Preparation method of venlafaxine amine impurity |
| CN115650863A (en) * | 2022-09-05 | 2023-01-31 | 上海博纳赛恩医药研发有限公司 | Method for preparing venlafaxine hydrochloride |
| CN116354835A (en) * | 2023-03-02 | 2023-06-30 | 浙江普洛家园药业有限公司 | Preparation method of venlafaxine hydrochloride EP impurity H |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007049302A2 (en) * | 2005-10-28 | 2007-05-03 | Ind-Swift Laboratories Limited | An improved process for the preparation of pure venlafaxine |
| CN101092366A (en) * | 2000-10-19 | 2007-12-26 | 特瓦制药工业有限公司 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof |
| WO2009095431A1 (en) * | 2008-01-29 | 2009-08-06 | Lek Pharmaceuticals D.D. | Novel salts of o-desmethyl-venlafaxine |
| CN101851165A (en) * | 2009-04-03 | 2010-10-06 | 连云港恒邦医药科技有限公司 | Glutamate of O-demethyl-venlafaxine and preparation method thereof |
-
2012
- 2012-06-13 CN CN201210193978.5A patent/CN103483210B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092366A (en) * | 2000-10-19 | 2007-12-26 | 特瓦制药工业有限公司 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof |
| WO2007049302A2 (en) * | 2005-10-28 | 2007-05-03 | Ind-Swift Laboratories Limited | An improved process for the preparation of pure venlafaxine |
| WO2009095431A1 (en) * | 2008-01-29 | 2009-08-06 | Lek Pharmaceuticals D.D. | Novel salts of o-desmethyl-venlafaxine |
| CN101851165A (en) * | 2009-04-03 | 2010-10-06 | 连云港恒邦医药科技有限公司 | Glutamate of O-demethyl-venlafaxine and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸文拉法辛的合成;俞慧萍等;《中国医药工业杂志》;20061231;第37卷(第6期);第373-374页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103483210A (en) | 2014-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103483210B (en) | A kind of new compound and preparation method thereof | |
| US9908841B2 (en) | Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure | |
| CN102702008B (en) | Agomelatine sulfuric acid composition and preparation method thereof | |
| CN105510459A (en) | Method for detecting febuxostat raw material | |
| CN104910239B (en) | Pentacyclic triterpenoid and preparation method thereof, pharmaceutical composition and purposes | |
| JPH06211867A (en) | Fluorescent compound | |
| CN104080777B (en) | As the morpholinyl-derivatives of MOGAT-2 inhibitor | |
| CN102702041B (en) | Agomelatine benzenesulfonic acid compound and preparation method thereof | |
| CN108047155A (en) | A kind of orientation Preparation method and use of the isoxazole compound of double aryl substitutions | |
| Korach et al. | Diethylstilbestrol metabolites and analogs: stereochemical probes for the estrogen receptor binding site | |
| CN112409257A (en) | Preparation method of deuterium-labeled higenamine stable isotope compound | |
| CN102924295B (en) | Bromhexine hydrochloride crystal as well as preparation method and application of crystal | |
| CN112110897B (en) | Preparation method of deuterated crizotinib and derivative thereof | |
| CN108947946B (en) | Brain injury resistant deuterated compound and medical application thereof | |
| US20120244546A1 (en) | Antibodies specific to carbamazepine | |
| Ge et al. | Chemical synthesis, microbial transformation and biological evaluation of tetrahydroprotoberberines as dopamine D1/D2 receptor ligands | |
| CN100410254C (en) | Preparation process of thiatro bromoaminium anhydrous compound | |
| EP0569490A1 (en) | Haptens, tracers, immunogens and antibodies for immunoassays for cotinine | |
| CN112724102A (en) | Pramipexole related compound and preparation method and application thereof | |
| CN112358446B (en) | Synthetic method of stable isotope labeled tritoquinol hydrochloride | |
| CN109096316B (en) | Deuterated 3-nitrophenylboronic acid and preparation method and application thereof | |
| CN113156021A (en) | Detection method for cantharidin in cantharis extraction stock solution | |
| CN108373488B (en) | Catalpol 6-caffeic acid ester derivative and preparation method and application thereof | |
| WO2023208233A1 (en) | Diazo compound, preparation method therefor and use thereof | |
| CN105330563B (en) | For the reference compound in the control of Kukoamine B quality |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 637500 No. 66, Jinghua East Road, Hexi Town, Jialing District, Nanchong City, Sichuan Province Patentee after: Sichuan Hongyuan Pharmaceutical Co.,Ltd. Address before: 611930 No.89 Hualong Road, Tianpeng Town, Pengzhou City, Chengdu City, Sichuan Province Patentee before: CHENGDU HONGDA PHARMACEUTICAL Co.,Ltd. |