CN103373931A - Industrial preparation method of apoxetine and intermediate of apoxetine - Google Patents
Industrial preparation method of apoxetine and intermediate of apoxetine Download PDFInfo
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Abstract
The invention relates to an industrial preparation method of apoxetine and an intermediate of apoxetine. According to the method, methylation, condensation and salt forming reaction are carried out on 3-amino-3-phenyl propanol serving as a starting raw material to obtain the apoxetine and the intermediate of apoxetine. The method overcomes the deficiencies in the prior art, comprises simple and short reaction steps and is convenient and fast to operate and suitable for industrial production; moreover, the raw materials are simple and easily available.
Description
Technical field:
The invention belongs to medicine and chemical field, be specifically related to the industrialized process for preparing of a kind of dapoxetine and intermediate thereof.
Background technology:
Dapoxetine hydrochloride (dapoxetine hydrochloride), chemical name is S-(+)-N, N-dimethyl-1-phenyl-3-(1-naphthyloxy) propylamin hydrochloride (as shown in the formula), be a kind of selective serotonin reuptake inhibitor (SSRI), can effectively treat prospermia of males and sexual dysfunction.In February, 2009 is as the medicine (Priligy for the treatment of prospermia of males (PE)
TM) at first at Finland and Sweden two countries listing (Johnson ﹠amp; Johnson), 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 that is used for the treatment of this indication in the world.
Dapoxetine hydrochloride
Dapoxetine is the free alkali form of dapoxetine hydrochloride, 1 chiral centre is arranged in the molecular structure, asymmetric synthesis technique relative complex, cost is higher, dapoxetine adopts conventional salify technology just can make easily dapoxetine hydrochloride, therefore, the preparation of industrialization of dapoxetine seems particularly crucial.
European patent EP 0288188(patent families CN88102018A and US5135947A) a kind of preparation method (reaction formula is as follows) of dapoxetine disclosed, the method is take phenyl aldehyde as raw material, successively through the Knoevenagel condensation, methylate, esterification, reduce, be condensed into ether and get the dapoxetine raceme, again through L-(+)-tartrate splits to get target compound, but because the method adopts hydrogenating reduction when methylation reaction, be unfavorable for producing and amplify; Adopt expensive reagent two (2-methoxy ethoxy) sodium alanate (being commonly called as red aluminium) during the ester reduction; Condensation gained dapoxetine raceme adopts the high pressure lipuid chromatography (HPLC) separation and purification, is unfavorable for producing; Need during the dapoxetine mesotomy just can reach medicinal requirements through recrystallization repeatedly, complex operation, yield is low.So the whole yield of this route is low, cost is high, and unsuitable suitability for industrialized production.
Chinese patent CN1709859 discloses a kind of preparation method (reaction formula is as follows) of dapoxetine, the method is take phenyl aldehyde as raw material, at first prepare the beta-amino phenylpropionic acid through the Knoevenagel condensation, again through L-(+)-tartrate fractionation preparation dextrorotation beta-amino phenylpropionic acid, then get target compound through amination, reduction, condensation, salify successively.The method splits the loss that can reduce optical isomer at beta-amino phenylpropionic acid place, relatively improved the yield of reaction scheme, but because the method is carried out the separation of optical isomer by the control reacting liquid pH value when splitting, its operating process is very loaded down with trivial details, and can't guarantee the optical purity of sample, unsuitable suitability for industrialized production.
World patent WO2008035358 discloses a kind of preparation method (reaction formula is as follows) of dapoxetine; take benzene as raw material; at first prepare the 3-chloro-benzene acetone through friedel-crafts acylation; get the dapoxetine raceme through reduction, condensation, sulphonyl esterification, amination successively again, then through D-(+)-fractionation of methyldiphenyl formyl tartrate, salify are got target compound.CN1821212A prepares the dapoxetine raceme through reduction, condensation, sulphonyl esterification, amination, again through L-(+ successively then directly take the 3-chloro-benzene acetone as raw material)-tartrate splits, salify gets target compound.Two pieces of patents all adopt the 1-naphthols to become ether when condensation, and (it easily changes into the coloring matters such as quinones; be difficult for purifying); when sulphonyl esterification and amination, adopt in addition the highly toxic product Methanesulfonyl chloride; and its reaction times is tediously long; yield is low; the waste liquid that produces also is unfavorable for environment protection, more unsuitable suitability for industrialized production.
Wear Rong; guilt is along woods; Gu Fei; " dapoxetine hydrochloride synthetic " literary composition (reaction formula is as follows) that Wang Yucheng delivers at " Chinese Journal of New Drugs " the 17th volume 24 phase 2119-2121 page or leaf in 2008; the employing phenyl aldehyde is raw material; successively through Knoevenagel condensation, reduction, amido protecting and the esterification of hydroxyl sulphonyl, condensation, Deprotection, Bo Xi spit of fland raceme methylates to get; again through D-(-)-tartrate splits, salify gets target compound; the method is because route is tediously long; need continuous disassemble at twice during fractionation, operate numerous
Trivial, yield is low, unsuitable suitability for industrialized production.
Zhang Derong; Ren Yuhong; Huang Lei; Wei Dongzhi is at " biological process synthesizes a dapoxetine " literary composition (reaction formula is as follows) of " biological processing " the 8th volume the 2nd phase 13-16 page or leaf in 2010; the employing phenyl aldehyde is raw material, successively through Knoevenagel condensation, amino phenyl acetyl, immobilization penicillin acylated enzyme catalysis split, reduce, methylate, condensation gets target compound.The document adopts biological catalysis to carry out chiral separation, but because catalysis needs strict control pH value scope when splitting, and the enzyme that uses is expensive, should not reclaim preservation, and gained sample optical purity is difficult to reach medicinal requirements; Methylating of compound (S)-3-amino-3-phenyl propanol adopted 90 ℃～100 ℃ oil temperature reactions 8 hours that directly heat up in addition, the formaldehyde loss is more, its reaction conditions is violent, product is complicated, need further column chromatographic isolation and purification, yield lower (seeing comparative example 3) is so be difficult for realizing suitability for industrialized production.
Koizumi, the people such as Toru are at Journal of Organic Chemistry 1982,47,20,4004-4005 discloses a kind of take (S)-beta-amino phenylpropionic acid ethyl ester as raw material, successively through Lithium Aluminium Hydride reduction, the methylate cyclization and Lithium Aluminium Hydride-(S)-β-(reaction formula is as follows for (dimethyl-amino) phenylpropyl alcohol for the preparation of aluminum chloride reduction system of formaldehyde formic acid
)The document methylates it and carries out stepwise reaction, uses Lithium Aluminium Hydride-aluminum chloride system to reduce, and has used inflammable and explosive solvent ether for twice, has increased reactions steps, and aftertreatment is relatively loaded down with trivial details, and yield is relatively low, is difficult for realizing suitability for industrialized production.
In addition, for compound (S)-3-methyl 4-phenyl-1, the preparation of 3-oxazine and open loop, the people such as Matthias Dhooghe are at Journal of Medicinal Chemistry 2009,52,13, introduced another preparation method among the 4058-4062, with (2S, 3R)-2-benzyloxy-3-isobutyl amino-3-(4-aminomethyl phenyl)-the 1-propyl alcohol is raw material, through the formalin Bei oxazine processed analogue of cyclization in tetrahydrofuran (THF) (4R, 5S)-5-(benzyl)-3-isobutyl--4-(4-aminomethyl phenyl)-1, the 3-oxazine, get corresponding substituted-amino alcohol (reaction formula is as follows) through sodium borohydride reductive ring open in methyl alcohol again, the method operates relative simple than Lithium Aluminium Hydride-aluminum chloride reduction system, and empirical tests 3-methyl 4-phenyl-1, but the open loop of 3-oxazine gets 3-dimethylamino phenylpropyl alcohol, but reaction not exclusively, and yield lower (seeing comparative example 2) also is difficult for realizing suitability for industrialized production.
In above disclosed dapoxetine preparation method, all because of some deficiency factor, should not realize suitability for industrialized production, be necessary so seek the industrialized process for preparing that a kind of simple to operate, safety and environmental protection, yield and purity are high, production cost is low.The present invention finishes for this reason.
Summary of the invention:
The industrialized process for preparing that the object of the invention is to a kind of dapoxetine and intermediate thereof, the method has overcome the weak point that prior art exists, it is advantageous that simple to operate, safety and environmental protection, yield and purity are high, save cost (open loop need not the reductive agents such as Lithium Aluminium Hydride-aluminum chloride or sodium borohydride), production cost is low, is particularly suitable for suitability for industrialized production.
For realizing purpose of the present invention, provide following embodiment.
In one embodiment, the industrialized process for preparing of a kind of dapoxetine intermediate (formula IV compound) comprises formula V compound ring-opening reaction in formic acid is obtained formula IV compound,
Wherein, the ring-opening reaction temperature is 95 ℃～105 ℃, preferred 100 ℃～105 ℃.
In the above-described embodiment, described V formula compound is to carry out methylation reaction with formaldehyde and get in formic acid through formula VI compound, wherein, the methylation reaction temperature is 0 ℃～40 ℃, preferred 20 ℃～30 ℃, described formaldehyde is selected from Paraformaldehyde 96 or formalin, preferred formalin; The mol ratio of described formula VI compound and formaldehyde is 1:2～5.
In another embodiment, the industrialized process for preparing of a kind of dapoxetine intermediate (formula IV compound), comprise that the VI compound is carried out methylation reaction with formaldehyde gets formula V compound in formic acid, wherein, the methylation reaction temperature is 0 ℃～40 ℃, preferred 20 ℃～30 ℃, again formula V compound ring-opening reaction in formic acid is obtained formula IV compound, wherein, the ring-opening reaction temperature is 95 ℃～105 ℃, preferred 100 ℃～105 ℃.
In the above-described embodiment, described formaldehyde is selected from Paraformaldehyde 96 or formalin, preferred formalin; The mol ratio of described formula VI compound and formaldehyde is 1:2～5.
In yet another embodiment, the invention provides the industrialized process for preparing of the dapoxetine of a kind of formula I, comprising:
(1) will carry out condensation reaction by formula IV compound and the 1-fluoronaphthalene of the method gained of above-mentioned two kinds of embodiments, get the formula III compound,
(2) with the formula III compound of D-(-)-tartrate splitting step (1) gained, get formula II compound,
；
(3) with the formula II compound alkaline purification of step (2) gained, get dapoxetine,
(4) optional, dapoxetine is obtained dapoxetine hydrochloride with hydrogen chloride gas or the solution-treated that contains hydrogenchloride.
In the above-described embodiment, the industrialized process for preparing of dapoxetine of the present invention, step (1)～(4) all can be realized by prior art, but preferred, in step (2), further comprise a kind of resolution solvent, this resolution solvent is 5～75% aqueous ethanolic solutions, preferred 10～30% aqueous ethanolic solutions, further comprise formula II compound is carried out crystallisation step at 10～50% aqueous ethanolic solution, preferred 15～30% aqueous ethanolic solution, formula III compound and D-(-)-tartaric mol ratio is 1:0.5～2.0; In step (3), the mol ratio of formula II compound and alkali is 1:1～5, and described alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, yellow soda ash or sodium bicarbonate, preferred sodium hydroxide or potassium hydroxide.
In one embodiment, the industrialized process for preparing of the dapoxetine of a kind of formula I of the present invention comprises:
(1) formula V compound is got formula IV compound through ring-opening reaction; Perhaps formula VI compound is carried out methylation reaction with formaldehyde in formic acid, get formula V compound, formula V compound gets formula IV compound through ring-opening reaction;
(2) formula IV compound and the 1-fluoronaphthalene with step (1) gained carries out condensation reaction, gets the formula III compound;
(3) with the formula III compound of D-(-)-tartrate splitting step (2) gained, get formula II compound;
(4) with the formula II compound alkaline purification of step (3) gained, obtain dapoxetine (formula I);
(5) optional, dapoxetine is obtained dapoxetine hydrochloride with hydrogen chloride gas or the solution-treated that contains hydrogenchloride.
In above-mentioned specific embodiments, the industrialized process for preparing of dapoxetine of the present invention (formula I), in its process, step (2)～(5) all can be realized by prior art.
Preferably, in above-mentioned specific embodiments, the industrialized process for preparing of dapoxetine of the present invention, wherein, in the methylation reaction of step (1), 3-amino-3-phenyl propanol (formula VI compound) carries out preferred 20 ℃～30 ℃ with the methylation reaction of formaldehyde under 0 ℃～40 ℃ temperature; 3-methyl 4-phenyl-1, the ring-opening reaction of 3-oxazine (formula V compound) is at 95 ℃～105 ℃, finishes under preferred 100 ℃～105 ℃ condition, gets N, N-dimethyl-3-amino-3-phenyl propanol (formula IV compound).
In above-mentioned specific embodiments, the industrialized process for preparing of dapoxetine of the present invention, wherein, in the methylation reaction of step (1), described formaldehyde is selected from Paraformaldehyde 96 or formalin, preferred formalin; The mol ratio of described formula VI compound and formaldehyde is 1:2～5.
In above-mentioned specific embodiments, the industrialized process for preparing of dapoxetine of the present invention, in step (3), also comprise a kind of resolution solvent, preferred 5～75% aqueous ethanolic solutions of this resolution solvent, more preferably 10～30% aqueous ethanolic solutions, the mass volume ratio of formula III compound and aqueous ethanolic solution is 1:10～50, and dapoxetine (formula III compound) is 1:0.5～2.0 with D-(-)-tartaric mol ratio.
In above-mentioned specific embodiments, the industrialized process for preparing of dapoxetine of the present invention, in step (3), further comprise crystallisation step, i.e. (S)-N, N-dimethyl-1-phenyl-3-(1-naphthyloxy) propylamine tartrate (formula II compound) is crystallization and isolate crystalline solid in 10～50% the aqueous ethanolic solution at recrystallization solvent, and preferred 15～30% aqueous ethanolic solution, the mass volume ratio of formula II compound and aqueous ethanolic solution are 1:10～30; Recrystallization temperature is 0 ℃～60 ℃, preferred 0 ℃～45 ℃.
In above-mentioned specific embodiments, the industrialized process for preparing of dapoxetine of the present invention, in step (4), the mol ratio of formula II compound and alkali is 1:1～5; Its said alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, yellow soda ash or sodium bicarbonate, preferred sodium hydroxide or potassium hydroxide.
The advantage of the inventive method, be that the inventive method cut off conventional column chromatography purification mode in step (1) and (2), particularly in ring-opening reaction, do not adopt expensive reagent and the inflammable and explosive ether such as Lithium Aluminium Hydride-aluminum chloride, sodium borohydride, and yield and purity are all higher, can be directly used in next step reaction.Simplified conventional repeatedly the fractionation or the operation steps of recrystallization repeatedly in step (3), and resolving agent is cheap and easy to get, the product chiral purity is high, and yield is higher.In step (5), the dapoxetine salify of step (4) gained is namely got qualified dapoxetine hydrochloride, omitted the conventional step that also needs further recrystallization.The inventive method is take 3-amino-3-phenyl propanol as starting raw material in addition, simplified the operation sequence step, the disclosed stepwise reactions of people such as Koizumi and Matthias Dhooghe have been abandoned, omitted such as the esterif iotacation step among the patent CN88102018A, and avoided the use of the red aluminium of expensive reagent, got rid of amino the protection and the step of deprotection in " dapoxetine hydrochloride synthetic " literary composition such as Dai Rong, and the use of methane sulfonyl chloride; And industrialization is implemented easily.
In a word, raw material of the present invention is simple and easy to, and is easy to operation, production safety, and yield is higher, and three-waste pollution is few, suitability for industrialized production.
Compound 3-amino-3-phenyl propanol can be prepared with reference to method that " preparation of 3-dimethylin-3-phenyl propanol " literary composition that the people such as Liao Xiangwei, Wu Xiaofeng deliver at Chinese Journal of Pharmaceuticals 37 volumes, 3 phase 152-153 page or leaf in 2006 is introduced, and introduces in full reference of the present invention.
Further specify by the following examples and explain the industrialized process for preparing of dapoxetine of the present invention.But do not limit the scope of the invention.
Embodiment:
Embodiment 1
1.1 N, the preparation of N-dimethyl-3-amino-3-phenyl propanol (IV)
Compound vi (80g, 0.529mol) is dissolved in the 800ml anhydrous formic acid under the ice bath cooling, stirs the formalin (128.8g, 1.587mol) of lower adding 37%, at 20 ℃～30 ℃ lower stirring reactions, the TLC detection reaction gets compound V fully.
Reaction solution is continued to be heated to 95 ℃～100 ℃ reactions, the TLC detection reaction is complete, stopped reaction, be cooled to room temperature, 75 ℃ of reclaim under reduced pressure aqueous formic acids, residue is bathed under the cooling at cryosel, slowly drip 50% aqueous sodium hydroxide solution and regulate pH=7, the 1500ml methylene dichloride divides three extractions, and water is continued to regulate pH=13 with 50% aqueous sodium hydroxide solution, and the 2000ml ethyl acetate is divided four extractions, anhydrous sodium sulfate drying, filter, 45 ℃ of reclaim under reduced pressure ethyl acetate of filtrate get light yellow oil compound IV 71.6g(HPLC purity〉95%, yield 75%).
Dimethyl-1-phenyl-3-(1-naphthyloxy) preparation of propylamine (III)
With compound IV (105g; 0.586mol) under nitrogen protection, be dissolved in 1050ml N; in the dinethylformamide, add 60% sodium hydride (46.9g, 1.172mol) in batches; be heated to 65 ℃ of reaction 1h under stirring; be cooled to room temperature and add 1-fluoronaphthalene (94.2g, 0.644mol), be warming up to again 120 ℃ of reaction 10h; the TLC detection reaction is complete; stopped reaction, cryosel are bathed the lower 500ml of the dropping shrend of cooling and are gone out, and use 6N hydrochloric acid conditioned reaction liquid pH=1 again; 80 ℃ are evaporated to dried; add 1000ml water dissolution residue, the 1500ml ethyl acetate is divided three extractions, and water is regulated pH=13 with 50% aqueous sodium hydroxide solution; the 1800ml ethyl acetate is divided three extractions; merge organic phase, three washings of 1500ml salt moisture, drying; 40 ℃ of concentrating under reduced pressure get compound III brown color oily matter 131g(HPLC〉95%, yield 73.2 %).
1.3 the preparation of dapoxetine tartrate (II)
With compound III crude product (23g, 68.8mmol) be dissolved in the 69ml dehydrated alcohol, slowly drip D-(-)-tartrate (11.3g under the stirring at room, 75.3mmol) the aqueous solution (391ml), dripping to finish has a large amount of white solids to separate out, place ice-water bath to cool off, filter, vacuum-drying gets Compound I I crude product off-white color solid 15.0g.
15.0g Compound I I crude product is added in 180ml 25% aqueous ethanolic solution, be heated to 80 ℃ of back flow reaction under stirring, the dissolving clarification, stopped reaction, leave standstill and be cooled to 60 ℃, insulation crystallization 2 hours, leave standstill again be cooled to 40 ℃ of insulation crystallizatioies and get Compound I I off-white color solid 9.75g(ee value 99%, yield 31%).
Fusing point: 98～102 ℃
1.4(S)-preparation of dapoxetine (I)
With Compound I I(9.3g, 20.4mmol) be dissolved in the 93ml distilled water, lower potassium hydroxide (the 4.5g that slowly drips of ice-water bath cooling, 68.2mmol) the aqueous solution (20ml), stirring reaction 0.5h, the 150ml ethyl acetate is divided three extractions, drying, 40 ℃ of concentrating under reduced pressure get Compound I light yellow oil 6.1g(ee value〉99%, yield 97.8%).
Specific optical rotation:
=+79.6 ° of (c=1 gmL
-1, CHCl
3)
Embodiment 2
2.1 N, the preparation of N-dimethyl-3-amino-3-phenyl propanol (IV)
Compound vi (30g, 0.198mol) is dissolved in the 300ml anhydrous formic acid under the ice bath cooling, stirs the formalin (64.4g, 0.793mol) of lower adding 37%, at 10 ℃～20 ℃ about 4h of lower stirring reaction, the TLC detection reaction gets compound V fully.
Reaction solution is continued to be heated to 100 ℃～105 ℃ reactions, the TLC detection reaction is complete, stopped reaction, be cooled to room temperature, 75 ℃ of reclaim under reduced pressure aqueous formic acids are to about 200ml, bathe under the cooling at cryosel, slowly drip 50% aqueous sodium hydroxide solution and regulate pH=7, the 900ml methylene dichloride divides three extractions, and water is continued to regulate pH=13 with 50% aqueous sodium hydroxide solution, and the 1200ml ethyl acetate is divided four extractions, anhydrous sodium sulfate drying, filter, 45 ℃ of reclaim under reduced pressure ethyl acetate of filtrate get compound IV light yellow oil 32.3g(HPLC purity〉90%, yield 90.8%).
Dimethyl-1-phenyl-3-(1-naphthyloxy) preparation of propylamine (III)
Implement with reference to example 1 step 2.
Dimethyl-1-phenyl-3-(1-naphthyloxy) preparation of propylamine tartrate (II)
With compound III crude product (22g, 66.5mmol) and D-(-)-tartrate (10.8g, 72.0mmol) be dissolved in the 110ml dehydrated alcohol, be heated to 80 ℃ of dissolving clarifications under stirring, filtered while hot, again filtrate is cooled to room temperature, stir the lower 44ml water that slowly drips, drip and finish, place the ice bath cooling to separate out a large amount of white solids, filter, vacuum-drying gets Compound I I crude product 13.5g off-white color solid.
13.5g Compound I I crude product is added in 162ml 25% aqueous ethanolic solution, be heated to 80 ℃ of back flow reaction under stirring, dissolving clarification, stopped reaction, leave standstill be cooled to 40 ℃ the insulation crystallizatioies get Compound I I off-white color solid 7.93g(ee value 99%, yield 26.2%).
2.4 (S)-preparation of dapoxetine (I)
With Compound I I(7.5g, 16.5mmol) be dissolved in the 93ml distilled water, lower sodium hydroxide (the 2.0g that slowly drips of ice-water bath cooling, 50.0mmol) the aqueous solution (10ml), stirring reaction 1h, the 150ml ethyl acetate is divided three extractions, drying, 40 ℃ of concentrating under reduced pressure get Compound I light yellow oil 4.8g(ee value〉99%, yield 95.4%).
Embodiment 3
3.1 3-methyl 4-phenyl-1, the preparation of 3-oxazine (V)
With compound vi (10g, 0.066mol) under the ice bath cooling, be dissolved in the 100ml anhydrous formic acid, stir the formalin (26.8g of lower adding 37%, 0.330mol), at 0 ℃～10 ℃ about 3h of lower stirring reaction, the TLC detection reaction is complete, stopped reaction, slowly drip 50% aqueous sodium hydroxide solution and regulate pH=8, the 400ml ethyl acetate is divided four extractions, anhydrous sodium sulfate drying, filter, 45 ℃ of reclaim under reduced pressure ethyl acetate of filtrate, column chromatography (eluent: ethyl acetate/petroleum ether=1:1) separation and purification gets compound V yellow oil 9.8g(HPLC purity〉95%, yield 83.6%).
The preparation of dimethyl-3-amino-3-phenyl propanol (IV)
With compound V(9g, 0.051mol) under ice bath cooling, slowly be dissolved in the formalin (8.2g of 100ml anhydrous formic acid and 37%, 0.101mol) in, be heated to 100 ℃～105 ℃ reactions, the TLC detection reaction is complete, stopped reaction, be cooled to room temperature, 75 ℃ of reclaim under reduced pressure aqueous formic acids, bathe under the cooling at cryosel, slowly drip 50% aqueous sodium hydroxide solution and regulate pH=7, the 300ml methylene dichloride divides three extractions, water is continued to regulate pH=13 with 50% aqueous sodium hydroxide solution, the 400ml ethyl acetate is divided four extractions, and anhydrous sodium sulfate drying filters, 45 ℃ of reclaim under reduced pressure ethyl acetate of filtrate get compound IV light yellow oil 7.8g(HPLC purity〉90%, yield 85.7%).
Embodiment 4
4.1 the preparation of dapoxetine hydrochloride
Compound I (6.0g, 0.020mol) is dissolved in the 60ml isopropyl ether, passes into hydrogen chloride gas to separating out without solid, filter, vacuum-drying gets dapoxetine hydrochloride off-white color solid 5.9g(ee value〉99%, yield 87.8%).
1H NMR:（300 MHz，DMSO-d
6）δ 11.25~11.20（s，1H，HCl），δ 8.06~8.04（d，1H，Ar-H），δ 7.83~8.82（d，1H，Ar-H），δ 7.63~7.28（m，9H，Ar-H）, δ 6.73~6.72（m，1H，Ar-H），δ 4.72~4.70（m，1H，OCH
2），δ 4.72~4.70（m，1H，Ph-CH）, δ 4.12~4.11（m，1H，OCH
2）, δ 3.69~3.68（m，1H，OCH
2）, δ 2.90（m，1H，CH
CH 2CH
2O）,δ 2.83（s，1H，N(CH
3)
2）,δ 2.72~2.67（m，1H，CH
CH 2CH
2O）, δ 2.57（s，1H，N(CH
3)
2）；
13C NMR: （300 MHz，DMSO-d
6）δ153.6，133.9，132.6，129.8，129.5，128.9，127.3，126.4，126.0，125.2，124.7，121.7，120.1，104.8，67.1，64.4，41.3，29.5。
Specific optical rotation:
=+128.4 ° of (c=1 gmL
-1, CH
3OH), fusing point: 179.0～181.5 ℃.
4.2 the preparation of dapoxetine hydrochloride
Compound I (4.8g, 0.016) is dissolved in the 48ml isopropyl ether, slowly drips the isopropyl ether solution of hydrogenchloride to separating out without solid, filter, vacuum-drying gets dapoxetine hydrochloride off-white color solid 5.0g(ee value〉99%, yield 93.0%).
Specific optical rotation:
=+131.2 ° of (c=1 gmL
-1, CH
3OH)
Fusing point: 180.6～182.9 ℃
4.3 the preparation of dapoxetine hydrochloride
Compound I (10g, 0.033) is dissolved in the 20ml acetone, and the lower concentrated hydrochloric acid that slowly drips of ice bath cooling filters to separating out without solid, and vacuum-drying gets dapoxetine hydrochloride off-white color solid 9.1g(ee value〉99%, yield 81.3%).
Specific optical rotation:
=+130.5 ° of (c=1 gmL
-1, CH
3OH), fusing point: 179.7～182.1 ℃.
The comparative example 1
N, the preparation of N-dimethyl-3-amino-3-phenyl propanol (IV)
Compound vi (23g, 0.152mol) is dissolved in the 230ml anhydrous formic acid under the ice bath cooling, stirs the formalin (37g, 0.456mol) of lower adding 37%, at 30 ℃～40 ℃ stirring reactions, the TLC detection reaction gets formula V compound fully.
Reaction solution is continued to be heated to about 20 hours of 80 ℃ of reactions, stopped reaction, be cooled to room temperature, 75 ℃ of reclaim under reduced pressure aqueous formic acids are bathed residue under the cooling at cryosel, slowly drip 50% aqueous sodium hydroxide solution and regulate pH=13, the 300ml ethyl acetate is divided three extractions, anhydrous sodium sulfate drying filters, and 45 ℃ of reclaim under reduced pressure ethyl acetate of filtrate get compound IV crude product light yellow oil 30.9g.
Light yellow oil is adopted silica gel column chromatography (eluent: ethyl acetate/methanol=25:1) separation and purification gets compound IV light yellow oil 12.2g(yield 44.7%), and unreacted is compound V yellow oil 13.0g completely.
The comparative example 2
N, the preparation of N-dimethyl-3-amino-3-phenyl propanol (IV)
With compound V(33g, 0.186mol) be dissolved in the 330ml anhydrous methanol the lower NaBH that slowly adds of ice bath cooling
4(17.6g, 0.465mol), be warming up to 70 ℃ of about 18h of back flow reaction, still have the raw material unreacted complete, stopped reaction, ice bath is cooled to 0 ℃～5 ℃, slowly dripping the 110ml shrend goes out, 40 ℃ of concentrating under reduced pressure reclaim methyl alcohol, and the 660ml ethyl acetate is divided three extractions, anhydrous sodium sulfate drying, filter, 45 ℃ of reclaim under reduced pressure ethyl acetate of filtrate, column chromatography (eluent: ethyl acetate/methanol=25:1) separation and purification gets compound IV light yellow oil 8.7g(yield 26.1%), unreacted is compound V yellow oil 21.3g completely.
The comparative example 3
N, the preparation of N-dimethyl-3-amino-3-phenyl propanol (IV)
With compound vi (30g, 0.198mol) under the ice bath cooling, be dissolved in the 50g anhydrous formic acid, stir the formalin (36.2g of lower adding 37%, 0.446mol), direct heating is warming up to 96 ℃～100 ℃ about 8h, TLC detection reaction system is more assorted, stopped reaction is bathed reaction solution under the cooling at cryosel, slowly drips the 6mol/L aqueous sodium hydroxide solution and regulates pH=13, add the dilution of 200ml water, the 450ml ethyl acetate is divided three extractions, and anhydrous sodium sulfate drying filters, 50 ℃ of reclaim under reduced pressure ethyl acetate of filtrate get compound IV crude product light yellow oil 34.5g(HPLC purity 85.4%, yield 97%).
Find out that from comparative example's result the open loop temperature is excessively low, compound V reaction not exclusively; Stepwise reaction prepares compound IV, and it is incomplete that compound V also reacts.
The front has been described the present invention in detail, comprises its preferred embodiment.But, should be understood that and consider content disclosed by the invention, those skilled in the art can change the present invention in the spiritual scope of following claims and/or improve, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. the method for a preparation formula IV compound comprises formula V compound ring-opening reaction in formic acid is obtained formula IV compound,
2. method according to claim 1, wherein, described V formula compound is to carry out methylation reaction with formaldehyde and get in formic acid through formula VI compound,
3. the industrialized process for preparing of the dapoxetine of a formula I comprises:
(1) formula IV compound and the 1-fluoronaphthalene of method gained carry out condensation reaction as claimed in claim 1, get the formula III compound,
(2) with the formula III compound of D-(-)-tartrate splitting step (1) gained, get formula II compound,
(3) with the formula II compound alkaline purification of step (2) gained, get dapoxetine,
(4) optional, dapoxetine is obtained dapoxetine hydrochloride with hydrogen chloride gas or the solution-treated that contains hydrogenchloride.
4. method according to claim 1, the ring-opening reaction temperature is 95 ℃～105 ℃.
5. method according to claim 4, the ring-opening reaction temperature is 100 ℃～105 ℃.
6. method according to claim 2 is characterized in that described formaldehyde is Paraformaldehyde 96 or formalin.
7. method according to claim 6 is characterized in that described formaldehyde is formalin.
8. method according to claim 2, wherein, the mol ratio of formula VI compound and formaldehyde is 1:2～5.
9. method according to claim 2, wherein, the methylation reaction temperature is 0 ℃～40 ℃.
10. method according to claim 9, wherein, the methylation reaction temperature is 20 ℃～30 ℃.
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| CN103664659A (en) * | 2013-12-04 | 2014-03-26 | 苏州永健生物医药有限公司 | Dapoxetine hydrochloride crystal form and preparation method thereof |
| CN106748825A (en) * | 2016-11-29 | 2017-05-31 | 聊城大学 | A kind of synthesis of Dapoxetine hydrochloride, resolving and purifying and salifying method |
| CN109879766A (en) * | 2019-03-02 | 2019-06-14 | 台州保灵药业有限公司 | A kind of synthetic method of 3- (NN- dimethyl) amino butanol |
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Cited By (4)
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| CN103664659A (en) * | 2013-12-04 | 2014-03-26 | 苏州永健生物医药有限公司 | Dapoxetine hydrochloride crystal form and preparation method thereof |
| CN103664659B (en) * | 2013-12-04 | 2016-01-06 | 苏州永健生物医药有限公司 | A kind of Dapoxetine hydrochloride crystal form and preparation method thereof |
| CN106748825A (en) * | 2016-11-29 | 2017-05-31 | 聊城大学 | A kind of synthesis of Dapoxetine hydrochloride, resolving and purifying and salifying method |
| CN109879766A (en) * | 2019-03-02 | 2019-06-14 | 台州保灵药业有限公司 | A kind of synthetic method of 3- (NN- dimethyl) amino butanol |
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