CN103373931B - The industrialized process for preparing of a kind of dapoxetine and intermediate thereof - Google Patents
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Abstract
The present invention relates to the industrialized process for preparing of a kind of dapoxetine and intermediate thereof, the method with 3-amino-3-phenyl propanol for starting raw material, through methylating, condensation, salt-forming reaction and get final product, the method overcome the deficiencies in the prior art, and raw material is simple and easy to get, reactions steps is brief, simple operation, is applicable to suitability for industrialized production.
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 (dapoxetinehydrochloride), 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) first in Finland and two countries of Sweden listing (Johnson & 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 being 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 had in molecular structure, asymmetric synthesis technique relative complex, cost is higher, dapoxetine adopts conventional salify technology just can obtain dapoxetine hydrochloride easily, therefore, the preparation of industrialization of dapoxetine seems particularly crucial.
European patent EP 0288188(patent families CN88102018A and US5135947A) disclose a kind of preparation method (reaction formula is as follows) of dapoxetine, the method take phenyl aldehyde as raw material, successively through Knoevenagel condensation, methylate, esterification, reduce, be condensed into ether and obtain dapoxetine raceme, again through L-(+)-tartrate splits to obtain target compound, but because the method adopts hydrogenating reduction when methylation reaction, be unfavorable for producing and amplify; Expensive reagent two (2-methoxy ethoxy) sodium alanate (being commonly called as red aluminium) is adopted during ester reduction; Condensation gained dapoxetine raceme adopts high pressure lipuid chromatography (HPLC) separation and purification, is unfavorable for producing; Just need can reach medicinal requirements, complex operation through repeatedly recrystallization during dapoxetine mesotomy, yield is low.Therefore the overall 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 take phenyl aldehyde as raw material, first beta-amino phenylpropionic acid is prepared through Knoevenagel condensation, again through L-(+)-tartrate fractionation preparation dextrorotation beta-amino phenylpropionic acid, then obtain target compound through amination, reduction, condensation, salify successively.The method carries out at beta-amino phenylpropionic acid place splitting the loss that can reduce optical isomer, relatively improve the yield of reaction scheme, but because the method carries out the separation of optical isomer by controlling reacting liquid pH value when splitting, its operating process is very loaded down with trivial details, and the optical purity of sample cannot be ensured, 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; first 3-chloro-benzene acetone is prepared through friedel-crafts acylation; dapoxetine raceme is obtained, then through D-(+ successively again through reduction, condensation, sulphonyl esterification, amination)-target compound is obtained to the fractionation of methyldiphenyl formyl tartrate, salify.CN1821212A then direct with 3-chloro-benzene acetone for raw material, prepare dapoxetine raceme through reduction, condensation, sulphonyl esterification, amination successively, then through L-(+)-tartrate splits, salify obtains target compound.Two sections of patents all adopt 1-naphthols to become ether when condensation, and (it easily changes into the coloring matters such as quinones; not easily purifying); highly toxic product Methanesulfonyl chloride is adopted in addition when sulphonyl esterification and amination; and its reaction times is tediously long; yield is low; the waste liquid produced also is unfavorable for environment protection, more unsuitable suitability for industrialized production.
Dai Rong; guilt is along woods; Gu Fei; " synthesis of dapoxetine hydrochloride " 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 in 2008; employing phenyl aldehyde is raw material; successively through Knoevenagel condensation, reduction, amido protecting and hydroxysulfonamide esterification, condensation, Deprotection, methylate to obtain Bo Xi spit of fland raceme; again through D-(-)-tartrate splits, salify obtains target compound; the method due to route tediously long; need continuous disassemble during fractionation at twice, operate numerous
Trivial, yield is low, unsuitable suitability for industrialized production.
Zhang Derong; Ren Yuhong; Huang Lei; Wei Dongzhi is at " biological process synthesis dapoxetine " literary composition (reaction formula is as follows) of " biological processing " the 8th volume the 2nd phase 13-16 page in 2010; employing phenyl aldehyde is raw material, splits successively, reduces, methylates, condensation obtains target compound through Knoevenagel condensation, amino phenyl acetyl, immobilization penicillin acylated enzyme catalysis.The document adopt biological catalysis carry out chiral separation, but due to when catalysis splits need strict control ph scope, and use the expensive of enzyme, should not reclaim preservation, gained sample optical purity is difficult to reach medicinal requirements; Methylating of compound (S)-3-amino-3-phenyl propanol adopts 90 DEG C ~ 100 DEG C oil temperatures that directly heat up to react 8 hours in addition, formaldehyde loss is more, its reaction conditions is violent, product is complicated, need further column chromatographic isolation and purification, yield lower (see comparative example 3), therefore not easily realize suitability for industrialized production.
Koizumi, the people such as Toru are at JournalofOrganicChemistry1982,47,20,4004-4005 discloses one with (S)-beta-amino phenylpropionic acid ethyl ester for raw material, successively through Lithium Aluminium Hydride reduction, the cyclization of formaldehyde carboxylic acid methyl and Lithium Aluminium Hydride-aluminum chloride reduction system preparation (S)-β-(dimethyl-amino) phenylpropyl alcohol (reaction formula is as follows).The document is methylated and is carried out stepwise reaction, and use Lithium Aluminium Hydride-aluminum chloride system to reduce, and employ inflammable and explosive solvent ether for twice, add reactions steps, aftertreatment is relatively loaded down with trivial details, and yield is relatively low, not easily realizes 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 MatthiasDhooghe are at JournalofMedicinalChemistry2009, 52, 13, another preparation method is described in 4058-4062, with (2S, 3R)-2-benzyloxy-3-i-butylamino-3-(4-aminomethyl phenyl)-1-propyl alcohol is raw material, through formalin cyclization Bei oxazine analogue (4R in tetrahydrofuran (THF), 5S)-5-(benzyl)-3-isobutyl--4-(4-aminomethyl phenyl)-1, 3-oxazine, corresponding substituted-amino alcohol (reaction formula is as follows) is obtained again through sodium borohydride reductive ring open in methyl alcohol, the method comparatively Lithium Aluminium Hydride-aluminum chloride reduction system, operation relative ease, and empirical tests 3-methyl 4-phenyl-1, 3-oxazine open loop can obtain 3-dimethylamino phenylpropyl alcohol, but reaction not exclusively, yield lower (see comparative example 2), also not easily suitability for industrialized production is realized.
In above disclosed dapoxetine preparation method, all because of some deficiency factor, should not suitability for industrialized production be realized, therefore find a kind of industrialized process for preparing simple to operate, that safety and environmental protection, yield and purity are high, production cost is low and be necessary.The present invention completes for this reason.
Summary of the invention:
The object of the invention is to the industrialized process for preparing of a kind of dapoxetine and intermediate thereof, the method overcome the weak point that prior art exists, it is advantageous that simple to operate, safety and environmental protection, yield and purity are high, cost-saving (open loop is without the need to Lithium Aluminium Hydride-reductive agent such as aluminum chloride or sodium borohydride), production cost is low, is particularly suitable for suitability for industrialized production.
For realizing object 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 and formula V compound ring-opening reaction in formic acid is obtained formula IV compound,
。
Wherein, ring-opening reaction temperature is 95 DEG C ~ 105 DEG C, preferably 100 DEG C ~ 105 DEG C.
In the above-described embodiment, described V formula compound in formic acid, carries out methylation reaction through formula VI compound with formaldehyde and obtains, wherein, methylation reaction temperature is 0 DEG C ~ 40 DEG C, preferably 20 DEG C ~ 30 DEG C, described formaldehyde is selected from paraformaldehyde or formalin, preferred formalin; The mol ratio of described formula VI compound and formaldehyde is 1:2 ~ 5.
。
In another embodiment, a kind of industrialized process for preparing of dapoxetine intermediate (formula IV compound), comprise and VI compound is carried out methylation reaction with formaldehyde in formic acid obtain formula V compound, wherein, methylation reaction temperature is 0 DEG C ~ 40 DEG C, preferably 20 DEG C ~ 30 DEG C, again formula V compound ring-opening reaction in formic acid is obtained formula IV compound, wherein, ring-opening reaction temperature is 95 DEG C ~ 105 DEG C, preferably 100 DEG C ~ 105 DEG C.
In the above-described embodiment, described formaldehyde is selected from paraformaldehyde 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) the formula IV compound of the method gained by above-mentioned two kinds of embodiments and 1-fluoronaphthalene are carried out condensation reaction, obtain formula III compound,
；
(2) with the formula III compound of D-(-)-tartrate splitting step (1) gained, formula II compound is obtained,
；
(3) by the formula II compound alkaline purification of step (2) gained, dapoxetine is obtained,
；
(4) optional, dapoxetine hydrogen chloride gas or the solution-treated containing hydrogenchloride are obtained dapoxetine hydrochloride.
In the above-described embodiment, the industrialized process for preparing of dapoxetine of the present invention, step (1) ~ (4) all can realize by prior art, but it is preferred, in step (2), comprise a kind of resolution solvent further, this resolution solvent is 5 ~ 75% aqueous ethanolic solutions, preferably 10 ~ 30% aqueous ethanolic solutions, comprise further by formula II compound 10 ~ 50% aqueous ethanolic solution carry out crystallisation step, the preferably aqueous ethanolic solution of 15 ~ 30%, formula III compound and D-(-)-tartaric mol ratio are 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, sodium carbonate 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, comprising:
(1) formula V compound is obtained formula IV compound through ring-opening reaction; Or formula VI compound is carried out methylation reaction with formaldehyde in formic acid, obtains formula V compound, formula V compound obtains formula IV compound through ring-opening reaction;
(2) the formula IV compound of step (1) gained and 1-fluoronaphthalene are carried out condensation reaction, obtain formula III compound;
(3) with the formula III compound of D-(-)-tartrate splitting step (2) gained, formula II compound is obtained;
(4) by the formula II compound alkaline purification of step (3) gained, dapoxetine (formula I) is obtained;
(5) optional, dapoxetine hydrogen chloride gas or the solution-treated containing hydrogenchloride are obtained dapoxetine hydrochloride.
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 realize 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 at 0 DEG C ~ 40 DEG C temperature with the methylation reaction of formaldehyde, preferably 20 DEG C ~ 30 DEG C; The ring-opening reaction of 3-methyl 4-phenyl-1,3-oxazine (formula V compound) is at 95 DEG C ~ 105 DEG C, completes, obtain N under the condition of preferably 100 DEG C ~ 105 DEG C, 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 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, also comprise a kind of resolution solvent in step (3), this resolution solvent is 5 ~ 75% aqueous ethanolic solutions preferably, 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) and D-(-)-tartaric mol ratio are 1:0.5 ~ 2.0.
In above-mentioned specific embodiments, the industrialized process for preparing of dapoxetine of the present invention, in step (3), comprise crystallisation step further, i.e. (S)-N, N-dimethyl-1-phenyl-3-(1-naphthyloxy) propylamine tartrate (formula II compound) is crystallization isolate crystalline solid, the preferably aqueous ethanolic solution of 15 ~ 30% in the aqueous ethanolic solution of 10 ~ 50% at recrystallization solvent, the mass volume ratio of formula II compound and aqueous ethanolic solution is 1:10 ~ 30; Recrystallization temperature is 0 DEG C ~ 60 DEG C, preferably 0 DEG C ~ 45 DEG C.
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, sodium carbonate or sodium bicarbonate, preferred sodium hydroxide or potassium hydroxide.
The advantage of the inventive method, be that the inventive method has cut off conventional column chromatography purification mode in step (1) and (2), in ring-opening reaction, particularly do not adopt Lithium Aluminium Hydride-expensive reagent such as aluminum chloride, sodium borohydride and inflammable and explosive ether, and yield and purity are all higher, next step reaction can be directly used in.Simplify conventional repeatedly fractionation or the operation steps of repeatedly recrystallization in step (3), and resolving agent is cheap and easy to get, product chiral purity is high, and yield is higher.In step (5), namely the dapoxetine salify of step (4) gained is obtained qualified dapoxetine hydrochloride, eliminate the conventional step also needing further recrystallization.In addition the inventive method with 3-amino-3-phenyl propanol for starting raw material, simplify operation sequence step, abandon stepwise reaction disclosed in the people such as Koizumi and MatthiasDhooghe, eliminate as the esterif iotacation step in patent CN88102018A, and avoid the use of the red aluminium of expensive reagent, get rid of the step of amino upper protection and the deprotection in " synthesis of dapoxetine hydrochloride " literary composition such as Dai Rong, and the use of methane sulfonyl chloride; And industrialization is easily implemented.
In a word, raw material of the present invention is simple and easy to get, easy to operation, production safety, and yield is higher, and three-waste pollution is few, and suitability for industrialized is produced.
Compound 3-amino-3-phenyl propanol can refer to " preparation of 3-dimethylin-3-phenyl propanol " that the people such as Liao Xiangwei, Wu Xiaofeng deliver at Chinese Journal of Pharmaceuticals 37 volume 3 phase 152-153 pages in 2006 one the method introduced of literary composition be prepared, introduce reference of the present invention in full.
Further illustrate and explain the industrialized process for preparing of dapoxetine of the present invention by the following examples.But do not limit the scope of the invention.
Embodiment:
Embodiment 1
The preparation of 1.1N, N-dimethyl-3-amino-3-phenyl propanol (IV)
Compound VI (80g, 0.529mol) be dissolved under ice cooling, 4 in 800ml anhydrous formic acid, add the formalin (128.8g, 1.587mol) of 37% under stirring, stirring reaction at 20 DEG C ~ 30 DEG C, TLC detection reaction obtains compound V completely.
Reaction solution is continued be heated to 95 DEG C ~ 100 DEG C reactions, TLC detection reaction is complete, stopped reaction, be cooled to room temperature, 75 DEG C of reclaim under reduced pressure aqueous formic acids, by residue under cryosel bath cooling, slow dropping 50% aqueous sodium hydroxide solution regulates pH=7, 1500ml methylene dichloride divides three extractions, aqueous phase is continued regulate pH=13 with 50% aqueous sodium hydroxide solution, 2000ml ethyl acetate divides four extractions, anhydrous sodium sulfate drying, filter, filtrate 45 DEG C of reclaim under reduced pressure ethyl acetate give light yellow oil compound IV 71.6g(HPLC purity >95%, yield 75%).
Dimethyl-1-phenyl-3-(1-naphthyloxy) preparation of propylamine (III)
By compound IV (105g, 0.586mol) be dissolved in 1050mlN under nitrogen protection, in dinethylformamide, add 60% sodium hydride (46.9g in batches, 1.172mol), 65 DEG C of reaction 1h are heated under stirring, be cooled to room temperature and add 1-fluoronaphthalene (94.2g, 0.644mol), be warming up to 120 DEG C of reaction 10h again, TLC detection reaction is complete, stopped reaction, cryosel bath cooling lower dropping 500ml shrend is gone out, reaction solution pH=1 is regulated again with 6N hydrochloric acid, 80 DEG C are evaporated to dry, add 1000ml water dissolution residue, 1500ml ethyl acetate divides three extractions, aqueous phase 50% aqueous sodium hydroxide solution regulates pH=13, 1800ml ethyl acetate divides three extractions, merge organic phase, three washings of 1500ml salt moisture, dry, 40 DEG C of concentrating under reduced pressure obtain compound III pale tan oil 131g(HPLC>95%, yield 73.2%).
1.3N, N-dimethyl-1-phenyl-3-(1-naphthyloxy) preparation of propylamine tartrate (II)
By compound III crude product (23g, 68.8mmol) be dissolved in 69ml dehydrated alcohol, D-(-)-tartrate (11.3g is slowly dripped under stirring at room temperature, the aqueous solution (391ml) 75.3mmol), dripping to finish has a large amount of white solid to separate out, be placed in ice-water bath to cool, filter, vacuum-drying obtains Compound II per crude product off-white color solid 15.0g.
15.0g Compound II per crude product is added in 180ml25% aqueous ethanolic solution, 80 DEG C of back flow reaction are heated under stirring, dissolve clarification, stopped reaction, leave standstill and be cooled to 60 DEG C, insulation crystallization 2 hours, then leave standstill be cooled to 40 DEG C of insulation crystallizatioies and obtain Compound II per off-white color solid 9.75g(ee value >99%, yield 31%).
Fusing point: 98 ~ 102 DEG C
The preparation of 1.4(S)-dapoxetine (I)
By Compound II per (9.3g, 20.4mmol) be dissolved in 93ml distilled water, potassium hydroxide (4.5g is slowly dripped under ice-water bath cooling, the aqueous solution (20ml) 68.2mmol), stirring reaction 0.5h, 150ml ethyl acetate divides three extractions, dry, 40 DEG C of concentrating under reduced pressure obtain Compound I light yellow oil 6.1g(ee value >99%, yield 97.8%).
Specific optical rotation:
=+79.6 ° of (c=1gmL
-1, CHCl
3)
Embodiment 2
The preparation of 2.1N, N-dimethyl-3-amino-3-phenyl propanol (IV)
Compound VI (30g, 0.198mol) be dissolved under ice cooling, 4 in 300ml anhydrous formic acid, add the formalin (64.4g, 0.793mol) of 37% under stirring, at 10 DEG C ~ 20 DEG C, stirring reaction is about 4h, and TLC detection reaction obtains compound V completely.
Reaction solution is continued be heated to 100 DEG C ~ 105 DEG C reactions, TLC detection reaction is complete, stopped reaction, be cooled to room temperature, 75 DEG C of reclaim under reduced pressure aqueous formic acids are to about 200ml, under cryosel bath cooling, slow dropping 50% aqueous sodium hydroxide solution regulates pH=7, 900ml methylene dichloride divides three extractions, aqueous phase is continued regulate pH=13 with 50% aqueous sodium hydroxide solution, 1200ml ethyl acetate divides four extractions, anhydrous sodium sulfate drying, filter, filtrate 45 DEG C of reclaim under reduced pressure ethyl acetate obtain 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)
By compound III crude product (22g, 66.5mmol) with D-(-)-tartrate (10.8g, 72.0mmol) be dissolved in 110ml dehydrated alcohol, be heated to 80 DEG C under stirring and dissolve clarification, filtered while hot, again filtrate is cooled to room temperature, stir lower slowly dropping 44ml water, drip and finish, be placed in ice bath cooling and separate out a large amount of white solid, filter, vacuum-drying obtains Compound II per crude product 13.5g off-white color solid.
13.5g Compound II per crude product is added in 162ml25% aqueous ethanolic solution, be heated to 80 DEG C of back flow reaction under stirring, dissolve clarification, stopped reaction, leave standstill be cooled to 40 DEG C insulation crystallizatioies obtain Compound II per off-white color solid 7.93g(ee value >99%, yield 26.2%).
The preparation of 2.4(S)-dapoxetine (I)
By Compound II per (7.5g, 16.5mmol) be dissolved in 93ml distilled water, sodium hydroxide (2.0g is slowly dripped under ice-water bath cooling, the aqueous solution (10ml) 50.0mmol), stirring reaction 1h, 150ml ethyl acetate divides three extractions, dry, 40 DEG C of concentrating under reduced pressure obtain Compound I light yellow oil 4.8g(ee value >99%, yield 95.4%).
Embodiment 3
The preparation of 3.13-methyl 4-phenyl-1,3-oxazine (V)
By compound VI (10g, 0.066mol) be dissolved under ice cooling, 4 in 100ml anhydrous formic acid, formalin (the 26.8g of 37% is added under stirring, 0.330mol), at 0 DEG C ~ 10 DEG C, stirring reaction is about 3h, TLC detection reaction is complete, stopped reaction, slow dropping 50% aqueous sodium hydroxide solution regulates pH=8, 400ml ethyl acetate divides four extractions, anhydrous sodium sulfate drying, filter, filtrate 45 DEG C of reclaim under reduced pressure ethyl acetate, column chromatography (eluent: ethyl acetate/petroleum ether=1:1) separation and purification obtains compound V yellow oil 9.8g(HPLC purity >95%, yield 83.6%).
The preparation of dimethyl-3-amino-3-phenyl propanol (IV)
By compound V(9g, 0.051mol) be slowly dissolved in the formalin (8.2g of 100ml anhydrous formic acid and 37% under ice cooling, 4, 0.101mol), be heated to 100 DEG C ~ 105 DEG C reactions, TLC detection reaction is complete, stopped reaction, be cooled to room temperature, 75 DEG C of reclaim under reduced pressure aqueous formic acids, under cryosel bath cooling, slow dropping 50% aqueous sodium hydroxide solution regulates pH=7, 300ml methylene dichloride divides three extractions, aqueous phase is continued regulate pH=13 with 50% aqueous sodium hydroxide solution, 400ml ethyl acetate divides four extractions, anhydrous sodium sulfate drying, filter, filtrate 45 DEG C of reclaim under reduced pressure ethyl acetate obtain compound IV light yellow oil 7.8g(HPLC purity >90%, yield 85.7%).
Embodiment 4
The preparation of 4.1 dapoxetine hydrochlorides
Compound I (6.0g, 0.020mol) be dissolved in 60ml isopropyl ether, pass into hydrogen chloride gas and separate out to without solid, filter, vacuum-drying obtains dapoxetine hydrochloride off-white color solid 5.9g(ee value >99%, yield 87.8%).
1HNMR:（300MHz，DMSO-d
6）δ11.25~11.20（s，1H，HCl），δ8.06~8.04（d，1H，Ar-H），δ7.83~8.82（d，1H，Ar-H），δ7.63~7.28（m，9H，Ar-H）,δ6.73~6.72（m，1H，Ar-H），δ4.72~4.70（m，1H，OCH
2），δ4.72~4.70（m，1H，Ph-CH）,δ4.12~4.11（m，1H，OCH
2）,δ3.69~3.68（m，1H，OCH
2）,δ2.90（m，1H，CH
CH 2CH
2O）,δ2.83（s，1H，N(CH
3)
2）,δ2.72~2.67（m，1H，CH
CH 2CH
2O）,δ2.57（s，1H，N(CH
3)
2）；
13CNMR:（300MHz，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=1gmL
-1, CH
3oH), fusing point: 179.0 ~ 181.5 DEG C.
The preparation of 4.2 dapoxetine hydrochlorides
Be dissolved in 48ml isopropyl ether by Compound I (4.8g, 0.016), the isopropyl ether solution slowly dripping hydrogenchloride is separated out to without solid, and filter, vacuum-drying obtains dapoxetine hydrochloride off-white color solid 5.0g(ee value >99%, yield 93.0%).
Specific optical rotation:
=+131.2 ° of (c=1gmL
-1, CH
3oH)
Fusing point: 180.6 ~ 182.9 DEG C
The preparation of 4.3 dapoxetine hydrochlorides
Be dissolved in 20ml acetone by Compound I (10g, 0.033), the lower concentrated hydrochloric acid that slowly drips of ice bath cooling is separated out to without solid, and filter, vacuum-drying obtains dapoxetine hydrochloride off-white color solid 9.1g(ee value >99%, yield 81.3%).
Specific optical rotation:
=+130.5 ° of (c=1gmL
-1, CH
3oH), fusing point: 179.7 ~ 182.1 DEG C.
Comparative example 1
The preparation of N, N-dimethyl-3-amino-3-phenyl propanol (IV)
Compound VI (23g, 0.152mol) be dissolved under ice cooling, 4 in 230ml anhydrous formic acid, add the formalin (37g, 0.456mol) of 37% under stirring, at 30 DEG C ~ 40 DEG C stirring reactions, TLC detection reaction obtains formula V compound completely.
Reaction solution is continued be heated to 80 DEG C of reactions about 20 hours, stopped reaction, be cooled to room temperature, 75 DEG C of reclaim under reduced pressure aqueous formic acids, by residue under cryosel bath cooling, slowly drip 50% aqueous sodium hydroxide solution and regulate pH=13,300ml ethyl acetate divides three extractions, anhydrous sodium sulfate drying, filter, filtrate 45 DEG C of reclaim under reduced pressure ethyl acetate obtain compound IV crude product light yellow oil 30.9g.
Silica gel column chromatography (eluent: ethyl acetate/methanol=25:1) separation and purification light yellow oil is adopted to obtain compound IV light yellow oil 12.2g(yield 44.7%), unreacted is compound V yellow oil 13.0g completely.
Comparative example 2
The preparation of N, N-dimethyl-3-amino-3-phenyl propanol (IV)
By compound V(33g, 0.186mol) be dissolved in 330ml anhydrous methanol, slowly add NaBH under ice bath cooling
4(17.6g, 0.465mol), be warming up to 70 DEG C of back flow reaction and be about 18h, still have raw material unreacted complete, stopped reaction, ice bath is cooled to 0 DEG C ~ 5 DEG C, slow dropping 110ml shrend is gone out, 40 DEG C of concentrating under reduced pressure reclaim methyl alcohol, and 660ml ethyl acetate divides three extractions, anhydrous sodium sulfate drying, filter, filtrate 45 DEG C of reclaim under reduced pressure ethyl acetate, column chromatography (eluent: ethyl acetate/methanol=25:1) separation and purification obtains compound IV light yellow oil 8.7g(yield 26.1%), unreacted is compound V yellow oil 21.3g completely.
Comparative example 3
The preparation of N, N-dimethyl-3-amino-3-phenyl propanol (IV)
By compound VI (30g, 0.198mol) be dissolved under ice cooling, 4 in 50g anhydrous formic acid, formalin (the 36.2g of 37% is added under stirring, 0.446mol), direct heating is warming up to 96 DEG C ~ 100 DEG C about 8h, TLC detection reaction system is more assorted, stopped reaction, by reaction solution under cryosel bath cooling, slow dropping 6mol/L aqueous sodium hydroxide solution regulates pH=13, add the dilution of 200ml water, 450ml ethyl acetate divides three extractions, anhydrous sodium sulfate drying, filter, filtrate 50 DEG C of reclaim under reduced pressure ethyl acetate obtain compound IV crude product light yellow oil 34.5g(HPLC purity 85.4%, yield 97%).
Find out from the result of comparative example, Open loop temperature is too low, and compound V reacts not exclusively; Stepwise reaction prepares compound IV, and compound V also reacts incomplete.
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 following claims, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a method for preparation formula IV compound, comprises and formula V compound ring-opening reaction in formic acid is obtained formula IV compound,
。
2. method according to claim 1, wherein, described formula V compound in formic acid, carries out methylation reaction through formula VI compound with formaldehyde and obtains,
。
3. method according to claim 1, ring-opening reaction temperature is 95 DEG C ~ 105 DEG C.
4. method according to claim 3, ring-opening reaction temperature is 100 DEG C ~ 105 DEG C.
5. method according to claim 2, is characterized in that described formaldehyde is paraformaldehyde or formalin.
6. method according to claim 5, is characterized in that described formaldehyde is preferred formalin.
7. method according to claim 2, wherein, the mol ratio of formula VI compound and formaldehyde is 1:2 ~ 5.
8. method according to claim 2, wherein, methylation reaction temperature is 0 DEG C ~ 40 DEG C.
9. method according to claim 8, wherein, methylation reaction temperature is 20 DEG C ~ 30 DEG C.
10. the dapoxetine of formula I or an industrialized process for preparing for its hydrochloride, comprising:
(1) method prepares formula IV compound as claimed in claim 1, carries out condensation reaction with 1-fluoronaphthalene, obtains formula III compound,
(2) with the formula III compound of D-(-)-tartrate splitting step (1) gained, formula II compound is obtained,
(3) by the formula II compound alkaline purification of step (2) gained, dapoxetine is obtained,
(4) optionally, dapoxetine hydrogen chloride gas or the solution-treated containing hydrogenchloride are obtained dapoxetine hydrochloride.
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| 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 |
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| CN102229538A (en) * | 2011-05-11 | 2011-11-02 | 中南大学 | Method for synthesizing dapoxetine |
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| CN102229538A (en) * | 2011-05-11 | 2011-11-02 | 中南大学 | Method for synthesizing dapoxetine |
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