CN112094230A - Synthesis method of venlafaxine hydrochloride related substances - Google Patents
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- QYRYFNHXARDNFZ-UHFFFAOYSA-N venlafaxine hydrochloride Chemical compound [H+].[Cl-].C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 QYRYFNHXARDNFZ-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960002416 venlafaxine hydrochloride Drugs 0.000 title claims abstract description 47
- 239000000126 substance Substances 0.000 title claims abstract description 41
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- SUQHIQRIIBKNOR-UHFFFAOYSA-N N,N-didesmethylvenlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 SUQHIQRIIBKNOR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 26
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 13
- 235000019253 formic acid Nutrition 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229960004688 venlafaxine Drugs 0.000 description 4
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960002748 norepinephrine Drugs 0.000 description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- PACGLQCRGWFBJH-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetonitrile Chemical compound COC1=CC=C(CC#N)C=C1 PACGLQCRGWFBJH-UHFFFAOYSA-N 0.000 description 1
- APRBBNCMOUWDJD-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-2-(4-methoxyphenyl)ethanamine Chemical compound C1(=CCCCC1)C(CN)C1=CC=C(C=C1)OC APRBBNCMOUWDJD-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229940125436 dual inhibitor Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000001962 neuropharmacologic effect Effects 0.000 description 1
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- 229940053544 other antidepressants in atc Drugs 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
Abstract
The invention discloses a synthesis method of venlafaxine hydrochloride related substances, which relates to the technical field of medicine organic synthesis, and is characterized in that 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is used as an initial raw material, and the venlafaxine hydrochloride impurities are prepared through acid dehydration reaction and cyclization reaction.
Description
The technical field is as follows:
the invention relates to the technical field of organic synthesis of medicaments, in particular to a method for synthesizing venlafaxine hydrochloride related substances.
Background art:
depression, a by-product of the rapid development of modern economies, has increasingly affected the lives of people. The data show that 70% of people in China are in sub-health state, the patients with diseases related to psychology account for about 5% -10% of the population, and mental diseases and mental disorders become frequently encountered diseases and common diseases. The World Health Organization (WHO) published the world health report that depression has become the fourth disease in the world, and by 2020 depression may become the second disease after heart disease.
Venlafaxine (VENLAFAXINE, VEN) is a phenethylamine derivative, is a bicyclic atypical antidepressant, is developed by Wyeth-Ayerst company in the United states, is firstly marketed in the United states in 4 months in 1994, and is applied to China in 1997. Venlafaxine is the first dual inhibitor of 5-hydroxytryptamine (5-HT) and Norepinephrine (NE) reuptake (SNRIs), a novel antidepressant with a unique chemical structure and neuropharmacological activity, distinct from other antidepressant drugs. Venlafaxine exists in a racemic form, and has pharmacological activities of the left and right enantiomers different from each other, and when the dextroisomer mainly inhibits 5-HT, the levoisomer simultaneously inhibits reuptake of 5-HT and NE. It has no obvious affinity to adrenergic, M1 cholinergic and histamine H1 receptors, so it has less untoward effect and fast effect owing to its fast down regulation to beta receptor. Compared with other antidepressants, the traditional Chinese medicine composition has obvious advantages and becomes a first-line medicine for treating depression.
Venlafaxine hydrochloride, chemically (±) -1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl ] cyclohexanol hydrochloride, having the following structure:
through literature search, the venlafaxine hydrochloride is prepared by taking p-methoxyphenylacetonitrile and cyclohexanone as starting materials through condensation, reduction, methylation and salification, and the synthetic route is as follows:
in the preparation process of venlafaxine hydrochloride, the system in the reduction step is acidic, hydroxyl is easy to remove to form a double bond, 2- (1-cyclohexenyl) -2- (4-methoxyphenyl) -ethylamine is obtained, and then the venlafaxine hydrochloride reacts with formaldehyde and formic acid to generate venlafaxine hydrochloride related substances I, wherein the structural formula is as follows:
the related substance I is not collected in the standards of European pharmacopoeia and United states pharmacopoeia venlafaxine hydrochloride, and domestic and foreign documents and patents do not report the synthesis method of the related substance I, so that no reference substance of the related substance I is supplied in the domestic and foreign venlafaxine hydrochloride synthesis processes.
At present, a self-contrast method is adopted, but the accuracy of qualitative and quantitative determination is poor, and the risk of clinical medication is increased. In order to improve the quality of raw materials and preparations in venlafaxine hydrochloride and reduce the risk of clinical medication, more detailed research and control on related substances in the raw materials and preparations in the venlafaxine hydrochloride synthesis process are needed, so that the technical problem which needs to be solved at present is to provide a synthesis method which can quickly, simply and efficiently obtain a work reference substance of the related substances.
The invention content is as follows:
the technical problem to be solved by the invention is to provide a synthesis method of venlafaxine hydrochloride related substances, wherein the purity of the venlafaxine hydrochloride related substances prepared by the method is more than 95%, and the venlafaxine hydrochloride related substances can be used as impurity reference substances for researching the venlafaxine hydrochloride related substances.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
a synthesis method of venlafaxine hydrochloride related substances takes 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol as a reaction raw material, an intermediate II is prepared by dehydration reaction under the catalysis of acid, and the intermediate II, formic acid and formaldehyde are subjected to cyclization reaction to prepare venlafaxine hydrochloride related substances I;
the synthetic route is as follows:
the mol ratio of the 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol to the acid is 1: 1-3.
The acid is one of concentrated sulfuric acid, glacial acetic acid, concentrated hydrochloric acid and p-toluenesulfonic acid, and preferably concentrated sulfuric acid.
The reaction solvent for the dehydration reaction is one of toluene, ethyl acetate and dichloromethane, and dichloromethane is preferred.
The reaction temperature of the dehydration reaction is 0-100 DEG C
The molar ratio of the intermediate II to the formic acid to the formaldehyde is 1:5-10: 3-8.
The formaldehyde is 37% formaldehyde aqueous solution.
The formic acid is 88% formic acid aqueous solution.
The reaction solvent of the cyclization reaction is one or more of solvent-free solvent, water, isopropanol and ethanol.
The reaction temperature of the cyclization reaction is 80-110 ℃.
The invention has the beneficial effects that: the invention takes 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol as the initial raw material, prepares the Venlafaxine hydrochloride impurity through acid dehydration reaction and cyclization reaction, has the advantages of easily obtained raw materials in the whole synthesis route, mild reaction conditions, simple and easy post-treatment separation and purification operation, good repeatability of the preparation method, and can prepare the Venlafaxine hydrochloride impurity with high yield and high purity, thereby being suitable for being used as the impurity reference substance of the Venlafaxine hydrochloride.
Description of the drawings:
FIG. 1 shows venlafaxine hydrochloride related substance I1H-NMR hydrogen spectrum;
FIG. 2 shows venlafaxine hydrochloride related substance I13C-NMR carbon spectrum；
FIG. 3 is an MS spectrum of venlafaxine hydrochloride related substance I;
FIG. 4 is an HPLC chromatogram of venlafaxine hydrochloride related substance I.
The specific implementation mode is as follows:
in order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments and the drawings.
Example 1
Synthesis of intermediate II:
adding 5.0g (0.02mol) of 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol, 100mL of dichloromethane and 2.0g (0.02mol) of triethylamine into a reaction bottle, stirring for dissolving, cooling to 0-5 ℃, slowly dropwise adding 1.1mL (0.02mol) of concentrated sulfuric acid, keeping the temperature for reaction, slowly dropwise adding 50mL of saturated potassium carbonate solution after the reaction is finished, separating an organic layer, washing with 50mL of water and 50mL of saturated sodium chloride respectively, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, crystallizing the residue dichloromethane n-hexane, filtering and drying to obtain an intermediate II, wherein 4.0g of a white solid is obtained, the yield is 85.9%, and mp: 182.8-183.7 ℃.
Example 2
Synthesis of intermediate II:
adding 5.0g (0.02mol) of 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol, 50mL (toluene) and 2.0g (0.02mol) of triethylamine into a reaction bottle, stirring for dissolving, adding 10.3g (0.06mol) of p-toluenesulfonic acid, heating to reflux, dividing water in a water separator, reacting for 3 hours under the temperature, cooling to room temperature after the reaction is finished, slowly dropwise adding a saturated potassium carbonate solution to adjust the pH to 9-10, dividing the solution, adding 50mL of ethyl acetate into an organic layer, washing with 50mL of water and 50mL of saturated sodium chloride respectively, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, crystallizing residual dichloromethane n-hexane, filtering, and drying to obtain an intermediate II, 3.8g of a white solid, wherein the yield is 81.6%.
Example 3
Synthesis of intermediate II:
adding 5.0g (0.02mol) of 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol, 100mL of dichloromethane and 2.0g (0.02mol) of triethylamine into a reaction bottle, stirring for dissolving, cooling to 0-5 ℃, slowly dropwise adding 1.32mL (0.024mol) of concentrated sulfuric acid, keeping the temperature for reaction, slowly dropwise adding 50mL of saturated potassium carbonate solution after the reaction is finished, separating an organic layer, washing with 50mL of water and 50mL of saturated sodium chloride respectively, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, crystallizing the residue dichloromethane n-hexane, filtering and drying to obtain an intermediate II, wherein the white solid is 3.8g, and the yield is 81.6%.
Example 4
Synthesis of venlafaxine hydrochloride related substance I:
adding 2.3g (0.01mol) of the intermediate II, 5mL of 50% ethanol solution, 12mL of 88% formic acid and 7mL of 37% formaldehyde aqueous solution into a reaction bottle, refluxing for 15h, stopping the reaction, cooling to room temperature, extracting 2 times with ethyl acetate, adjusting the pH of the aqueous phase to 9-10 with 10% sodium hydroxide aqueous solution, extracting 50mL multiplied by 2 times with ethyl acetate, washing with 50mL of water and 50mL of saturated sodium chloride respectively, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and carrying out n-hexane column chromatography on the residue with ethyl acetate to obtain a venlafaxine hydrochloride related substance I, wherein the white solid is 1.7g, the yield is 60.5%, and the HPLC purity is 99.4%.
Example 5
Synthesis of venlafaxine hydrochloride related substance I:
2.3g (0.01mol) of the intermediate II, 5mL of water, 23mL of 88% formic acid and 18.4mL of 37% formaldehyde aqueous solution are added into a reaction bottle, reflux reaction is carried out for 10h, the reaction is stopped, after the temperature is reduced to room temperature, ethyl acetate is extracted for 2 times, the pH of an aqueous phase is adjusted to 9-10 by 10% sodium hydroxide aqueous solution, ethyl acetate is used for extracting for 50mL multiplied by 2 times, water and 50mL of saturated sodium chloride are respectively used for washing once, an organic layer is dried by anhydrous sodium sulfate, filtration is carried out, filtrate is concentrated under reduced pressure, and the residual ethyl acetate n-hexane column chromatography is carried out to obtain the venlafaxine hydrochloride related substance I, 1.6g of white solid, and the yield is 56.9%.
Example 6
Synthesis of venlafaxine hydrochloride related substance I:
2.3g (0.01mol) of the intermediate II, 5mL of water, 16.1mL of 88% formic acid and 11.5mL of 37% aqueous formaldehyde solution are added into a reaction bottle, reflux reaction is carried out for 20h, the reaction is stopped, the reaction solution is cooled to room temperature, ethyl acetate is extracted for 2 times, the pH of an aqueous phase is adjusted to 9-10 by 10% aqueous sodium hydroxide solution, ethyl acetate is used for extraction for 50mL multiplied by 2 times, water and 50mL of saturated sodium chloride are respectively used for washing once, an organic layer is dried by anhydrous sodium sulfate, filtration is carried out, filtrate is concentrated under reduced pressure, and the residual ethyl acetate n-hexane column chromatography is carried out to obtain the venlafaxine hydrochloride related substance I, 1.78g of white solid, and the yield is 63.3%.
Example 7
Synthesis of venlafaxine hydrochloride related substance I:
adding 2.3g (0.01mol) of intermediate II, 12mL of 88% formic acid and 7mL of 37% formaldehyde aqueous solution into a reaction bottle, refluxing for 15h, stopping the reaction, cooling to room temperature, extracting with ethyl acetate for 2 times, adjusting the pH of the aqueous phase to 9-10 with 10% sodium hydroxide aqueous solution, extracting with ethyl acetate for 50mL × 2 times, washing with 50mL of water and 50mL of saturated sodium chloride respectively, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing column chromatography on the residue with ethyl acetate and n-hexane to obtain venlafaxine hydrochloride related substance I, 1.9g of white solid and 68.4% yield.
Structural characterization data of venlafaxine hydrochloride related substance I:
ESI-MS:m/z＝276.3[M+H]+.
1H-NMR(400MHz,CDCl3)7.12(d,J＝8.6Hz,2H),6.87(d,J＝8.7Hz,2),3.81(s,3H),3.01(m,1H),2.86(m,1H),2.70(m,1H),2.37(s,3H),2.11-1.96(m,2H),1.85-1.74(m,2H),1.57-1.43(m,3H),1.42-1.26(m,4H).
13C-NMR(100MHz,CDCl3)158.75,130.64,130.51,113.71,71.99,58.48,58.39,55.39,53.76,46.21,41.54,27.14,25.53,21.27,21.12.
the foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. A synthesis method of venlafaxine hydrochloride related substances is characterized by comprising the following steps: taking 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol as a reaction raw material, carrying out dehydration reaction under the catalysis of acid to prepare an intermediate II, and carrying out cyclization reaction on the intermediate II, formic acid and formaldehyde to prepare a venlafaxine hydrochloride related substance I;
the synthetic route is as follows:
2. the method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the mol ratio of the 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol to the acid is 1: 1-3.
3. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the acid is one of concentrated sulfuric acid, glacial acetic acid, concentrated hydrochloric acid and p-toluenesulfonic acid, and preferably concentrated sulfuric acid.
4. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the reaction solvent for the dehydration reaction is one of toluene, ethyl acetate and dichloromethane, and dichloromethane is preferred.
5. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the reaction temperature of the dehydration reaction is 0-100 ℃.
6. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the molar ratio of the intermediate II to the formic acid to the formaldehyde is 1:5-10: 3-8.
7. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the formaldehyde is 37% formaldehyde aqueous solution.
8. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the formic acid is 88% formic acid aqueous solution.
9. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the reaction solvent of the cyclization reaction is one or more of solvent-free solvent, water, isopropanol and ethanol.
10. The method for synthesizing venlafaxine hydrochloride related substances according to claim 1, wherein: the reaction temperature of the cyclization reaction is 80-110 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010046808A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for the preparation of venlafaxine hydrochloride |
| CN103382159A (en) * | 2013-08-16 | 2013-11-06 | 成都倍特药业有限公司 | Venlafaxine hydrochloride preparation method |
| CN106866434A (en) * | 2017-02-14 | 2017-06-20 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of VENLAFAXINE HCL intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010046808A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for the preparation of venlafaxine hydrochloride |
| CN103382159A (en) * | 2013-08-16 | 2013-11-06 | 成都倍特药业有限公司 | Venlafaxine hydrochloride preparation method |
| CN106866434A (en) * | 2017-02-14 | 2017-06-20 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of VENLAFAXINE HCL intermediate |
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