CN105461573A - Preparation method of (S)-N-demethyl dapoxetine - Google Patents
Preparation method of (S)-N-demethyl dapoxetine Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- SCPPXXMPTQHFGC-IBGZPJMESA-N (1s)-n-methyl-3-naphthalen-1-yloxy-1-phenylpropan-1-amine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)NC)=CC=CC=C1 SCPPXXMPTQHFGC-IBGZPJMESA-N 0.000 title abstract description 3
- 229960005217 dapoxetine Drugs 0.000 claims abstract description 61
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 claims abstract description 58
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 39
- 239000012074 organic phase Substances 0.000 claims description 18
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 12
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- VFVBVEMVTNQIMZ-GOSISDBHSA-N (1r)-3-naphthalen-1-yloxy-1-phenylpropan-1-ol Chemical compound C1([C@@H](CCOC=2C3=CC=CC=C3C=CC=2)O)=CC=CC=C1 VFVBVEMVTNQIMZ-GOSISDBHSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000010410 layer Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000003908 quality control method Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 15
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 230000017858 demethylation Effects 0.000 abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000003814 drug Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 3
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 3
- JILHZKWLEAKYRC-UHFFFAOYSA-N 1-methoxy-2,2-dimethylpropane Chemical compound COCC(C)(C)C JILHZKWLEAKYRC-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VFVBVEMVTNQIMZ-SFHVURJKSA-N (1s)-3-naphthalen-1-yloxy-1-phenylpropan-1-ol Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)O)=CC=CC=C1 VFVBVEMVTNQIMZ-SFHVURJKSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 241000405119 Virga Species 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 238000012372 quality testing Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- -1 substituted-phenyl Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of (S)-N-demethyl dapoxetine (hereinafter referred to as a dapoxetine demethylation impurity). The dapoxetine demethylation impurity is obtained by removing one methyl group impurity from a dapoxetine nitrogen atom in a preparation process and is one of the main impurities of dapoxetine raw materials; the dapoxetine demethylation impurity can be used for analyzing and detecting HPLC (high performance liquid chromatography) purity of the dapoxetine raw materials, so that the quality of the dapoxetine raw materials is controlled.
Description
Technical field
The invention belongs to medicine and chemical technology field, be specifically related to (S)-N-demethylation dapoxetine, be i.e. the preparation method of (S)-N-methyl-(α)-[2-(1-naphthyloxy) ethyl] benzene methanamine.
Background technology
Dapoxetine (Dapoxetine), chemical name is (S)-N, N-dimethyl-(α)-[2-(1-naphthyloxy) ethyl] benzene methanamine, a kind of selective serotonin reuptake inhibitor (SSRI), it is unique medicine researched and developed for prospermia of males (PE) at present, also be the medicine uniquely obtaining the PE indication that State Food and Drug Administration (CFDA) ratifies, can effectively treat prospermia of males and sexual dysfunction.In February, 2009, first the medicine (priligy) as treatment PE went on the market in Sweden and two countries of Finland, get the Green Light in states such as Australia, Germany, Italy, Mexico, New Zealand, Portugal, Korea S and Spain subsequently, this medicine is the first oral prescription drugs being used for the treatment of this indication in the world.
Dapoxetine is specially for treating the New type of S SRI class medicine that premature ejaculation is researched and developed, find that it obviously can extend the ejaculation latent period (IELT) of PE patient through III phase Clinical controlled trial, promote the controllability to ejaculation, increase the sexual intercourse satisfaction of spouse both sides.The feature of its pharmacokinetics absorbs and drains rapidly, and the highest Plasma Concentration appears at 1h, and the transformation period is only 1.2h, is significantly shorter than antidepressant class SSRI medicine.In addition dapoxetine is through multipath metabolism, does not find to play cross reaction phenomenon with other drug in clinical study, and does not affect by diet, age, alcohol or Virga etc.Under normal circumstances, when PE patient treats with antidepressant class medicine, need medication in five or six hours in advance, some medicines also will adhere to that every day takes.And dapoxetine takes as required, as long as one and a half hours onset time, this is conducive to alleviating the infringement of medicine to health, and the toxicity of dapoxetine is less, and security is higher, has potential applicability in clinical practice widely.
(S) chemistry of-N-demethylation dapoxetine is called: (S)-N-methyl-(α)-[2-(1-naphthyloxy) ethyl] benzene methanamine, No. CAS: 147199-39-1, molecular formula: C
20h
21nO, molecular weight: 291.39, structural formula is as follows:
Dapoxetine is all more stable under acid, alkali, high temperature, can not produce obvious impurity.Under illumination destroys, produce a main degradation impurity dapoxetine demethyl impurity, its liquid phase retention time is 19.56min; The mass-to-charge ratio [M+H] of its molecular ion peak
+=292, mass spectrum (ESI+) records [M+H] of (S)-N-demethylation dapoxetine
+mass-to-charge ratio be 292, conform to the molecular weight of (S)-N-demethylation dapoxetine; The above results conforms to the structure of (S)-N-demethylation dapoxetine.
(S) 1H-NMR of-N-demethylation dapoxetine composes measurement result: 1H-NMR and provides 12 groups of peaks, its integration ratio (by low field to High-Field) is 2:1:1:2:7:1:1:1:1:1:1:3, totally 22 protons, consistent with proton number contained by (S)-N-demethylation dapoxetine, the hydrogeneous number of this product, type and chemical shift are all also consistent with (S)-N-demethylation dapoxetine.Related data is in table 1.
Table 1 (S)-N-demethylation dapoxetine
1h-NMR composes measurement result
(S) 13C-NMR of-N-demethylation dapoxetine composes measurement result: containing 20 C in this product molecule, wherein, there is symmetrical structure in substituted-phenyl, six C contained by it have four groups of coincidence peaks in carbon spectrum, therefore C contained by this product shows as 18 groups of peaks in carbon spectrum, and C number, type and chemical shift contained by this product are consistent with (S)-N-demethylation dapoxetine.Related data is in table 2.
Table 2 (S)-N-demethylation dapoxetine
13c-NMR composes measurement result
Because dapoxetine is in manufacture process, inevitably touch illumination, therefore the lower dapoxetine molecule of illumination destruction takes off methyl, produce (S)-N-demethylation dapoxetine, chemical equation is as follows:
According to above impurity research conditions, (S)-N-demethylation dapoxetine is present in dapoxetine and preparation thereof as impurity.Carrying out, in dapoxetine drug quality testing process, needing highly purified impurity product in contrast, for controlling the quality that may contain the medicine of this impurity.Therefore highly purified compound (S)-N-demethylation dapoxetine must be synthesized.
Synthesis and the method for existing (S)-N-demethylation dapoxetine have no report.Therefore be badly in need of the preparation problem solving (S)-N-demethylation dapoxetine, therefore the present invention produces.
Summary of the invention
The invention provides the preparation method of one (S)-N-demethylation dapoxetine (being called for short dapoxetine demethyl impurity), described method comprises:
(1) (S)-3-(1-naphthyloxy)-1-phenyl-1-propanol (formula III) is reacted with Methanesulfonyl chloride (MsCl), obtains formula II compound,
(2) step (1) formula II compound and Monomethylamine are reacted, obtain (S)-N-demethylation dapoxetine,
(S) preparation of-N-demethylation dapoxetine and method are specially:
A) in alcoholic solvent, add (R)-3-(1-naphthyloxy)-1-phenyl-1-propanol, drip Methanesulfonyl chloride reaction;
B) after dropwise reaction, Monomethylamine gas is passed into, until react completely;
C) after reacting completely, washing, and branch vibration layer;
D) using hcl acidifying by c) obtaining organic phase, dividing and removing organic layer;
E) using alkali lye alkalization by d) obtaining acid liquid, adding the extraction of organic ether solvent;
F) saturated common salt water washing is used, anhydrous sodium sulfate drying by e) obtaining organic phase;
G) organic phase f) will be obtained to filter, and be evaporated to and dryly obtain brown solid.
The mol ratio of step a) described (R)-3-(1-naphthyloxy)-1-phenyl-1-propanol and Methanesulfonyl chloride is 1:1 ~ 3; Organic ether kind solvent comprises methyl tertiary butyl ether, isopropyl ether.
Steps d) described alkali lye refers to the aqueous solution of sodium hydroxide, potassium hydroxide.
Show through the present inventor's research, by above-mentioned preparation and method, the product of purity more than 98.5% can be obtained, HPLC retention time 19.56min.From nuclear magnetic resonance spectrum and mass spectrum, the structured data of this compound is consistent with (S)-N-demethylation dapoxetine, can be used as contamination levels product or the impurity reference substance of bulk drug dapoxetine hydrochloride.
Testing conditions about related substance HPLC under dapoxetine raw material and preparation item is:
Chromatographic condition:
Chromatographic column: WatersXBridgeShieldRP18,150 × 4.6mm, 3.5 μm
Moving phase: the diethylamine aqueous solution of A:10mmol/L bicarbonate of ammonia and 6mmol/L;
B: acetonitrile (A: B=55: 45).
Determined wavelength: 293nm
Flow velocity: 0.6ml/min
Sample size: 10 μ l
Accompanying drawing explanation
Fig. 1 (S)-N-demethylation dapoxetine HPLC collection of illustrative plates, wherein 19.558min is this impurity.
Embodiment
With specific embodiment, technical scheme of the present invention is described further below, those skilled in the art can be made better to understand the present invention, but protection scope of the present invention is not limited thereto.
The preparation of embodiment 1 (S)-N-demethylation dapoxetine
Add 100ml methyl tertbutyl methyl ether, (R)-3-(1-naphthyloxy)-1-phenyl-1-propanol 5.0g in reaction flask, be cooled to 5 DEG C, slowly drip Methanesulfonyl chloride 4.1g, warm < 10 DEG C in keeping.Dropwise, stirring at room temperature 5-6h, TLC detect (ethyl acetate: sherwood oil=1:10).After reacting completely, be cooled to 10 DEG C, pass into Monomethylamine gas until react completely, TLC detects (ethyl acetate: sherwood oil=1:10).After reacting completely, wash 2 times, branch vibration layer, merge organic phase.Stirring is cooled to 5 DEG C-10 DEG C, in organic phase, add hcl acidifying, regulates pH=4-5, divides and removes organic layer, merges aqueous phase.Add methyl tertiary butyl ether in aqueous phase, stir and be cooled to 5 DEG C-10 DEG C, hydro-oxidation sodium water solution alkalizes, and regulates pH=9-10, separatory, merges organic phase.Wash 1 time, anhydrous sodium sulfate drying with saturated common salt, filter, filtrate reduced in volume is to dry, and obtain brown solid (S)-N-demethylation dapoxetine 3.0g, molar yield is 57.36%.
According to the testing conditions of related substance HPLC under dapoxetine raw material item, the detection collection of illustrative plates of (S)-N-demethylation dapoxetine is as Fig. 1.
The preparation of embodiment 2 (S)-N-demethylation dapoxetine
Add 100ml methyl tertbutyl methyl ether, (R)-3-(1-naphthyloxy)-1-phenyl-1-propanol 5.0g in reaction flask, be cooled to 5 DEG C, slowly drip Methanesulfonyl chloride 6.2g, warm < 10 DEG C in keeping.Dropwise, stirring at room temperature 5-6h, TLC detect (ethyl acetate: sherwood oil=1:10).After reacting completely, be cooled to 10 DEG C, pass into Monomethylamine gas until react completely, TLC detects (ethyl acetate: sherwood oil=1:10).After reacting completely, wash 2 times, branch vibration layer, merge organic phase.Stirring is cooled to 5 DEG C-10 DEG C, in organic phase, add hcl acidifying, regulates pH=4-5, divides and removes organic layer, merges aqueous phase.Add methyl tertiary butyl ether in aqueous phase, stir and be cooled to 5 DEG C-10 DEG C, hydro-oxidation aqueous solutions of potassium alkalizes, and regulates pH=9-10, separatory, merges organic phase.Wash 1 time, anhydrous sodium sulfate drying with saturated common salt, filter, filtrate reduced in volume is to dry, and obtain brown solid (S)-N-demethylation dapoxetine 3.3g, molar yield is 63.10%.
The preparation of embodiment 3 (S)-N-demethylation dapoxetine
Add 100ml isopropyl ether, (R)-3-(1-naphthyloxy)-1-phenyl-1-propanol 5.0g in reaction flask, be cooled to 5 DEG C, slowly drip Methanesulfonyl chloride 2.1g, warm < 10 DEG C in keeping.Dropwise, stirring at room temperature 5-6h, TLC detect (ethyl acetate: sherwood oil=1:10).After reacting completely, be cooled to 10 DEG C, pass into Monomethylamine gas until react completely, TLC detects (ethyl acetate: sherwood oil=1:10).After reacting completely, wash 2 times, branch vibration layer, merge organic phase.Stirring is cooled to 5 DEG C-10 DEG C, in organic phase, add hcl acidifying, regulates pH=4-5, divides and removes organic layer, merges aqueous phase.Add isopropyl ether in aqueous phase, stir and be cooled to 5 DEG C-10 DEG C, hydro-oxidation sodium water solution alkalizes, and regulates pH=9-10, separatory, merges organic phase.Wash 1 time, anhydrous sodium sulfate drying with saturated common salt, filter, filtrate reduced in volume is to dry, and obtain brown solid (S)-N-demethylation dapoxetine 2.9g, molar yield is 55.45%.
The preparation of embodiment 4 (S)-N-demethylation dapoxetine
Add 100ml isopropyl ether, (R)-3-(1-naphthyloxy)-1-phenyl-1-propanol 5.0g in reaction flask, be cooled to 5 DEG C, slowly drip Methanesulfonyl chloride 4.1g, warm < 10 DEG C in keeping.Dropwise, stirring at room temperature 5-6h, TLC detect (ethyl acetate: sherwood oil=1:10).After reacting completely, be cooled to 10 DEG C, pass into Monomethylamine gas until react completely, TLC detects (ethyl acetate: sherwood oil=1:10).After reacting completely, wash 2 times, branch vibration layer, merge organic phase.Stirring is cooled to 5 DEG C-10 DEG C, in organic phase, add hcl acidifying, regulates pH=4-5, divides and removes organic layer, merges aqueous phase.Add isopropyl ether in aqueous phase, stir and be cooled to 5 DEG C-10 DEG C, hydro-oxidation aqueous solutions of potassium alkalizes, and regulates pH=9-10, separatory, merges organic phase.Wash 1 time, anhydrous sodium sulfate drying with saturated common salt, filter, filtrate reduced in volume is to dry, and obtain brown solid (S)-N-demethylation dapoxetine 3.2g, molar yield is 61.19%.
Detail the present invention above, comprise its preferred embodiment.But it should be understood that and consider content disclosed by the invention, those skilled in the art can change the present invention and/or improve in the scope of described claims, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a preparation method of (S)-N-demethylation dapoxetine (formula I), described method comprises:
(1) (R)-3-(1-naphthyloxy)-1-phenyl-1-propanol (formula III) is reacted with Methanesulfonyl chloride (MsCl), obtains formula II compound,
；
(2) step (1) formula II compound and Monomethylamine are reacted, obtain (S)-N-demethylation dapoxetine,
。
2. preparation method according to claim 1, specifically comprises the steps:
(R)-3-(1-naphthyloxy is added in organic ether kind solvent)-1-phenyl-1-propanol, drip Methanesulfonyl chloride reaction;
After dropwise reaction, pass into Monomethylamine gas, until react completely;
After completion of the reaction, washing, and branch vibration layer;
Using hcl acidifying by c) obtaining organic phase, dividing and removing organic layer;
Using alkali lye alkalization by d) obtaining acid liquid, adding the extraction of organic ether solvent;
Saturated common salt water washing is used, anhydrous sodium sulfate drying by e) obtaining organic phase;
Organic phase f) will be obtained filter, and be evaporated to and dryly obtain brown solid.
3. preparation method according to claim 2, is characterized in that: (R)-3-(1-naphthyloxy) mol ratio of-1-phenyl-1-propanol and Methanesulfonyl chloride is 1:1 ~ 3.
4. alkali lye refers to the aqueous solution of sodium hydroxide, potassium hydroxide according to claim 2.
5. preparation method according to claim 2, is characterized in that: organic ether kind solvent comprises methyl tertiary butyl ether, isopropyl ether.
6. (S)-N-demethylation dapoxetine according to claim 1, is characterized in that: (S)-N-demethylation dapoxetine is used for the quality control of dapoxetine hydrochloride.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108610264A (en) * | 2016-12-09 | 2018-10-02 | 扬子江药业集团江苏紫龙药业有限公司 | Dapoxetine hydrochloride process contaminants, preparation and purposes |
| CN108663460A (en) * | 2018-08-03 | 2018-10-16 | 安徽省金楠医疗科技有限公司 | A kind of dapoxetine hydrochloride isomery body detecting method |
| CN113072466A (en) * | 2021-04-01 | 2021-07-06 | 湖南普道医药技术有限公司 | Synthetic method of dapoxetine impurity |
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| CN108610264A (en) * | 2016-12-09 | 2018-10-02 | 扬子江药业集团江苏紫龙药业有限公司 | Dapoxetine hydrochloride process contaminants, preparation and purposes |
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| CN113072466A (en) * | 2021-04-01 | 2021-07-06 | 湖南普道医药技术有限公司 | Synthetic method of dapoxetine impurity |
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