CN106748825A - A kind of synthesis of Dapoxetine hydrochloride, resolving and purifying and salifying method - Google Patents

A kind of synthesis of Dapoxetine hydrochloride, resolving and purifying and salifying method Download PDF

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CN106748825A
CN106748825A CN201611068686.3A CN201611068686A CN106748825A CN 106748825 A CN106748825 A CN 106748825A CN 201611068686 A CN201611068686 A CN 201611068686A CN 106748825 A CN106748825 A CN 106748825A
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propylamine
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孙彬
李腾
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Liaocheng University
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    • 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
    • C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • 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
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • 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
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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Abstract

The invention provides a kind of new Dapoxetine hydrochloride synthesis, gradient resolving and purifying and salifying method.The synthetic route is with cheap and easily-available benzaldehyde as initiation material, whole reaction condition is relatively mild, synthetic route is shorter, and in the absence of it is hypertoxic, explosive the shortcomings of, the route also solves the problems, such as chiral resolution well simultaneously, and the purifying of product has been carried out during fractionation, finally select the hydrogen chloride methyl tertiary butyl ether(MTBE) that has no toxic side effect into salt, save substantial amounts of human and material resources and time, effectively reduce production cost, whole synthetic route is not required to particular facility, equipment, easy to operate, therefore with good industrialized production and application prospect.

Description

A kind of synthesis of Dapoxetine hydrochloride, resolving and purifying and salifying method
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of synthesis of Dapoxetine hydrochloride, gradient resolving and purifying and Salifying method.
Background technology
The chemical name of Dapoxetine hydrochloride is (S)-N, N- dimethyl -3- (naphthyl -1- epoxides)-phenylpropyl alcohol amido hydrochloride. English name is：(S)-N, N-dimethyl-3-(naphthalen-1-yloxy)-1-phenyl propan-1-amine hydrochloride。
Chemical structural formula：
Molecular formula：C21H23NO.HCl；Molecular weight：341.88；No. CAS：[129938-20-1]；([119356-77-3] for not into The Dapoxetine hydrochloride of salt, molecular weight 305.4134)；Chemistry is pure：≥98.5%；Optical voidness：≥98.5%
Mp: 175-177℃；Optically-active：+128°±3(C=1, CH3OH)。
Dapoxetine hydrochloride is a kind of selective serotonin reuptake inhibithors（SSRI）, this kind of medicine is widely used in treatment to be pressed down The strongly fragrant and related disturbance of emotion, and male premature ejaculation (premature ejaculation, PE) problem, achieve good Effect, the premature ejaculation (premature ejaculation, PE) of male is most common male sexual disfunction, current its hair Sick rate 30% or so, in all of medicine classification, it has been determined that SSRIs treatment PE curative effect it is optimal.It is wherein newer The effect of SSRIs preparations it is rapider, half-life period is shorter, and incidence of side effects is lower, and curative effect is more prominent.Clinical test shows, Dapoxetine hydrochloride can effectively extend the latent time (IELT) of the intravaginal ejaculation of PE patient, improve sexual function, and without serious Adverse reaction, its mechanism is probably using serotonin reuptake inhibithors（SSRI）To disturb during control intracerebral control ejaculation Between the serotonin that exists of sexual desire center and dopamine etc neurotransmitter, so as to reach the purpose for the treatment of premature ejaculation.
In 166 random patients（Average age 23 ~ 64 years old）In, 130 complete research.Average baselining before medication IELT is 1.01 minutes.IELT is 2.94 minutes after 60 milligrams of dosage treatments, and 100 milligrams of dosage are 3.20 minutes, and placebo is 2.05 minutes, difference was obvious.Most common adverse reaction is nausea.10 patients that treatment is interrupted because of adverse reaction have 9 people It is to receive 100 milligrams of treatments.This research it was concluded that being passed through in initial dose using the Dapoxetine hydrochloride treatment of two weeks by a definite date IELT is evaluated and can be just obviously improved PE.There is more preferable security and tolerance compared with traditional SSRIs.This product is possible into To improve first new drug of PE from now on.Bad thing is produced there is presently no the interaction about Dapoxetine hydrochloride and other drugs The report of part.
Although FD A not yet ratify, application Dapoxetine hydrochloride is used to treat the report of PE within 2004, however, this grade have can Can turn into several years from now on improves first new drug of male PE.
Hong Kong has been introduced by listing.China's Mainland has also listed in December, 2013.
On N, N- dimethyl -1- phenyl -3-（1- naphthoxys）The preparation of propylamine, existing method report is as follows：
1st, it is raw material that the route uses cinnamyl alcohol, and target product is solved through epoxidation, red aluminium reducing, esterification, amine.
Nucl Med Bio digests
2nd, it is raw material to use 2- naphthoxy ethyl chlorides, with phenylacetic acid condensation, reset through Azide, be acidified, methylating obtains target Product；
3rd, it is raw material that the route uses 3- phenylpropanols, through thionyl chloride chlorination, is etherified with 1- naphthols；NBS bromos, dimethylamine amine solution Purpose product is obtained, or bromination product first passes through sodium azide and carries out substitution reaction, then hydrogenate obtaining purpose product.
European patent Ep0288188;Chinese patent CN88102018A
4th, the route, with the condensation of 1- naphthols, is obtained with the chloro- 1- propiophenones of 3- as initiation material through amination, reduction, methylation reaction Target product
Chinese patent 101367739A
5th, be raw material using cinnamate, through Sharpless Asymmetrical dihydroxylations, Barton-McCombie deoxidations and The classical reaction such as Mitsunobu, but step is tediously long, it is cumbersome.
Tetrahedron ：Asymmetry 2007,18 (17)
In these routes, mostly use synthetic route it is more long, and exist raw material it is hypertoxic, explosive, source or accessory substance be difficult to The problems such as control, be not a kind of optimal synthesis method, needs further improvement.
The content of the invention
The technical problems to be solved by the invention are to overcome above-mentioned deficiency, optimize reaction condition.Inventor is big in Liaocheng Learn doctor's scientific research initial funding（318051519）Subsidy under, research and design go out advantageously in industrialized production (S)-（+）- The method of N, N- dimethyl -3- (naphthyl -1- epoxides)-phenylpropyl alcohol amido hydrochloride, this synthesis route is short, and cost of material is just Preferably, and in the absence of it is hypertoxic, explosive the shortcomings of.
The invention provides a kind of new Dapoxetine hydrochloride synthesis, gradient resolving and purifying and the method into salt, the method is selected Benzaldehyde cheap and easy to get is initiation material, and whole reaction scheme contains 6 steps altogether, first through Knoevenagel condensations, reduction, amine first Crude product N, N- dimethyl -1- phenyl -3- can be prepared after base and nucleophilic displacement of fluorine（1- naphthoxys）Propylamine, then by (D)- (-) tartaric acid, is split under the ethanol-water system of graded, is purified, finally using hydrogen chloride methyl tertbutyl Ether solvents are converted into Dapoxetine hydrochloride.
A kind of preparation method of new Dapoxetine hydrochloride, synthetic route is as follows：
The preparation method is with benzaldehyde as initiation material, by Knoevenagel condensation reactions, carboxyl reduction, amine-methylated Can preparation N, N- dimethyl -1- phenyl -3- with after nucleophilic displacement of fluorine（1- naphthoxys）Propylamine, then use（D）-（-）- tartaric acid into Salt, is processed according to the method for Solvent Gradient resolving and purifying, finally with hydrochloride methyl tertbutyl ether into salt, that is, is synthesized target product and is reached Bo Xi spits of fland.
Foregoing preparation method, specific steps include：
（1）, solvent made with absolute ethyl alcohol, benzaldehyde, malonic acid and ammonium acetate are reacted in the solvent of absolute ethyl alcohol, 3- amido -3- phenylpropionic acids are obtained after reaction completely（Formula 2）；
（2）, first by 3- amido -3- phenylpropionic acids, NaBH4It is dissolved in tetrahydrofuran solvent, under the conditions of 0 DEG C -10 DEG C, slowly Instill iodine solution, reaction completely after, be quenched, solvent is evaporated off, with alkaline matter for processing after, extract to obtain reduzate 3- amido -3- benzene Base propyl alcohol（Formula 3）；
（3）, reduzate 3- amido -3- phenyl propanols are dissolved in formic acid solvent, add formalin, 85 DEG C -95 DEG C are returned Stream, alkaline matter for processing is used after reaction completely, and key intermediate 3- dimethylamino -3- phenyl propanols are obtained after extraction（Formula 4）；
（4）, the product 3- dimethylamino -3- phenyl propanols for methylating are dissolved in dry DMF solvent, add sodium hydride, 55 DEG C - After 65 DEG C are reacted 1 hour, 1- fluoronaphthalenes are added, react to obtain crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 5）；
（5）, from (D)-(-)-winestone acid treatment crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 5） Tartrate white solid, three recrystallizations are carried out with ethanol-water system graded, and dichloromethane washing after dissociation, obtains right Rotation product（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 6）；
（6）, by dextrorotation product（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine is in hydrochloric acid-methyl tertiary butyl ether(MTBE) Into salt in solvent, then use isopropanol：N-hexane system obtains final product white end-product after being recrystallized again（Formula 1）.
Described preparation method, preferred scheme is：The step（1）Benzaldehyde：Malonic acid：Ammonium acetate is 1:1.0- 1.5:1.0-1.5 mol ratios.
Described preparation method, preferred scheme is：The step（2）3- amido -3- phenylpropionic acids（Formula 2）:Boron hydrogen Change sodium:Iodine is 1:1.0-1.5:1.0-1.5 mol ratios（Preferably, step（2）The alkaline matter is 10% potassium hydroxide or hydrogen Sodium hydroxide solution）.
Described preparation method, preferred scheme is：Step（3）3- amido -3- phenyl propanols（Formula 3）：Formaldehyde：Formic acid It is 1:2.5-3.0:2.5-3.0 mol ratios（Preferably, the alkaline matter is one kind of NaOH or potassium hydroxide）.
Described preparation method, preferred scheme is：Step（4）3- dimethylamino -3- phenyl propanols（Formula 4）：Hydrogenation Sodium：1- fluoronaphthalenes are=1:1.5-2.0:1.1-1.2 mol ratios（Preferably, charging sequence is first under conditions of 0 DEG C -10 DEG C, to incite somebody to action Compound 3- dimethylamino -3- phenyl propanols are added in DMF solvent, add sodium hydride, are warming up to 55 DEG C -65 DEG C, and stirring 1 is small Shi Hou, adds 1- fluoronaphthalenes）.
Described preparation method, preferred scheme is：Step（5）Middle N, N- dimethyl -1- phenyl -3-（1- naphthoxys） Propylamine with（D）- tartaric acid is 1:1.5-2.0 mol ratios（Preferably, step（5）The ratio of recrystallization solvent absolute ethyl alcohol and water 1:1.5-2.5；More preferred, three graded ratio difference 1 of recrystallization solvent:2-3:4-5）.
Described preparation method, preferred scheme is：Step（6）Recrystallization solvent isopropanol and n-hexane ratio are 1: 1。
Present invention also offers the method for resolving and purifying of the Dapoxetine hydrochloride, be using crude product N, N- dimethyl -1- phenyl - 3-（1- naphthoxys）Propylamine（Formula 5）With levotartaric acid into salt, white solid, then the ethanol-water system for passing through graded are obtained Three recrystallizations are carried out to reach the purpose for splitting and purifying.Step is as follows：By crude product N, the N- dimethyl -1- phenyl of gained - 3-（1- naphthoxys）Propylamine（Formula 5）It is dissolved in absolute ethyl alcohol, under room temperature condition, is slowly dropped into dissolved with D-（-）The distillation of-tartaric acid In water, there is a small amount of solid to separate out, be stirred overnight under the conditions of 0 DEG C, there is substantial amounts of solid to separate out, the yellowish solid of gained is used Dichloromethane is washed, and removes impurity, then is recrystallized twice with the ethanol-water system of graded, by resulting winestone 2 M NaOH of hydrochlorate are neutralized to and are produced without white precipitate, ethyl acetate extraction, dry, and sterling is obtained after concentration（+）-N,N- Dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine.
Advantages of the present invention：
（1）It is initiation material that the present invention uses cheap and easily-available benzaldehyde, greatly reduces initial cost, is passed through Knoevenagel condensations directly connect amido, and raw material or the explosive and play of use are made using expensive chiral material so as to avoid Poisonous substance product.
（2）In the course of reaction of 3- amido -3- phenylpropionic acids reduction, from NaBH4-I2System replaces LiAlH4, improve The feasibility and security of whole piece process route.
（3）It is former as reaction from formaldehyde cheap and easy to get, formic acid in 3- amido -3- phenyl propanol methylation procedures Material, further reduces reaction cost.
（4）In the course of reaction of 3- dimethylamino -3- phenyl propanol nucleophilic displacement of fluorine, from sodium hydride, fluoronaphthalene as original Material obtains crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine so that whole byproduct of reaction is relatively low.
（5）Graded recrystallization is carried out using resolution solvent, the purpose for improving optical purity has both been reached, purifying is reached again The purpose of product, simplifies operation.
（6）Traditional hydrogen chloride-ether into the method for salt is changed, from hydrogen chloride-methyl tertiary butyl ether(MTBE) into salt, is reduced The toxic and side effect and volatility of ether, promote the security and operability of W-response, further to improve industrialization The feasibility of production.
On the whole, compared with prior art, Dapoxetine hydrochloride preparation technology of the present invention has the following advantages that：This technique has Have synthetic route short, easy to operate, raw material is cheap and easily-available, and in the absence of it is hypertoxic, explosive the advantages of.
Specific embodiment：
The present invention is described in detail below by embodiment, but protection domain is not limited by this.
Embodiment 1：A kind of preparation method of Dapoxetine hydrochloride, comprises the following steps：
Step（1）By benzaldehyde, malonic acid and ammonium acetate in 75-85 DEG C of anhydrous ethanol solvent（It is preferred that 78 DEG C）Middle reaction, reaction Cooling is stood after completely, suction filtration obtains white solid 3- amido -3- phenylpropionic acids（Formula 2）；
Step（2）By 3- amido -3- phenylpropionic acids, NaBH4It is dissolved in tetrahydrofuran solvent, under condition of ice bath, temperature control 0 DEG C -10 DEG C, iodine solution is slowly dropped into, after reaction completely, be quenched, remove solvent under reduced pressure, with alkaline matter for processing, must reduced after extraction Product 3- amido -3- phenyl propanols（Formula 3）；
Step（3）Reduzate 3- amido -3- phenyl propanols are dissolved in formic acid solvent, formalin, 85 DEG C -95 is added DEG C backflow, reaction completely after use alkaline matter for processing, after extraction key intermediate 3- dimethylamino -3- phenyl propanols（Formula 4）；
Step（4）The product 3- dimethylamino -3- phenyl propanols for methylating are dissolved in dry DMF solvent, sodium hydride, 55 is added After DEG C of -65 DEG C reactions 1 hour, 1- fluoronaphthalenes are added, react to obtain crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine （Formula 5）；
Step（5）With (D)-(-)-winestone acid treatment crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine obtains tartaric acid Salt white solid, dichloromethane washing carries out three recrystallizations with the ethanol-water system comprising graded, after dissociation, Obtain dextrorotation product（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 6）；
Step（6）Will（S）-（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine is molten in hydrochloric acid-methyl tertiary butyl ether(MTBE) Into salt in agent, then use isopropanol：N-hexane system obtains final product white end-product after being recrystallized again（Formula 1）.
Step（1）Described in initiation material benzaldehyde, malonic acid and ammonium acetate mole dosage ratio be 1:1.0-1.5: 1.0-1.5.Step（2）Described in 3- amido -3- phenylpropionic acids, sodium borohydride and iodine mole dosage ratio be 1:1.0-1.5: 1.0-1.5.Step（2）Described in the alkaline matter be 15% potassium hydroxide or sodium hydroxide solution.Step（3）Described in The 3- amido -3- phenyl propanols of synthesis, formaldehyde and formic acid mole dosage ratio be 1:2.5-3.0:2.5-3.0 mol ratios.Step Suddenly（3）Described in the alkaline matter be NaOH or one kind of potassium hydroxide.Step（4）Described in compound 3- Dimethylamino -3- phenyl propanols, sodium hydride and 1- fluoronaphthalene mole dosages ratio are 1:1.5-2.0:1.1-1.2.Step（4）Middle institute The charging sequence stated be first under condition of ice bath, by compound 3- dimethylamino -3- phenyl propanols add DMF solvent in, then add Enter sodium hydride, be warming up to 55 DEG C -65 DEG C stirring 1 hour after, add 1- fluoronaphthalenes.Step（5）Described in compound N, N- diformazans Base -1- phenyl -3-（1- naphthoxys）Propylamine is 1 with (D)-(-)-tartaric acid mole dosage ratio:1.5-2.0.Step（5）Middle institute The recrystallization solvent absolute ethyl alcohol and water ratio stated are 1:1.5-2.5.Step（5）Described in three gradients of recrystallization solvent Change ratio is 1:2-3:4-5.Step（6）Described in recrystallization solvent isopropanol and n-hexane ratio be 1:1.
Embodiment 2：A kind of preparation method of Dapoxetine hydrochloride, step is as follows：
At 75-85 DEG C（It is preferred that 78 DEG C）, with absolute ethyl alcohol as solvent, sequentially add benzaldehyde, malonic acid, ammonium acetate（Benzaldehyde: Malonic acid：Ammonium acetate is 1:1.0-1.5:1.0-1.5 mol ratios）, after reaction completely, room temperature being cooled to, suction filtration obtains white solid 3- amido -3- phenylpropionic acids.
Under condition of ice bath, sodium borohydride, 3- amido -3- phenylpropionic acids are dissolved in THF solvents, are slowly added dropwise and are dissolved in THF Iodine solution（3- amido -3- phenylpropionic acids:Sodium borohydride:Iodine is 1:1.0-1.5:1.0-1.5 mol ratios）, keep the temperature of reaction solution Not higher than 10 DEG C of degree, after gas is released completely, 62 DEG C -68 DEG C（It is preferred that 65 DEG C）Backflow, after reaction completely, absolute methanol is quenched Go out, solvent is evaporated off, add 40% NaOH or potassium hydroxide solution to be adjusted to 13,45 DEG C of stirring 4h of pH, extraction is dried, is evaporated off Solvent, obtains white crude product 3- amidos -3- phenyl propanols.
By product 3- amido -3- phenyl propanols under condition of ice bath, 90% aqueous formic acid is added, stirring is to being completely dissolved Afterwards, 37% formalin is added（3- amido -3- phenyl propanols：Formaldehyde：Formic acid is 1:2.5-3.0:2.5-3.0 mol ratios）, reaction 85 DEG C -95 DEG C of temperature（It is preferred that 90 DEG C）, after reaction completely, but to room temperature, under condition of ice bath, reinforcing body NaOH adjusts pH to cold system =13, extraction is dried, and solvent is evaporated off, and obtains pale yellow transparent crude oil 3- dimethylamino -3- phenyl propanols.
Compound 3- dimethylamino -3- phenyl propanols are dissolved in dry DMF solvent, quality is dividedly in some parts under condition of ice bath The NaH of fraction 60%, after being released without gas, is warming up to 55 DEG C -65 DEG C（It is preferred that 60 DEG C）After reaction 1h.Add 1- fluoronaphthalenes（3- bis- Methylamino -3- phenyl propanols：Sodium hydride：1- fluoronaphthalenes are=1:1.5-2.0:1.1-1.2 mol ratios）, then 90-110 DEG C（It is preferred that 100℃）After reaction completely, it is poured into water, ethyl acetate is extracted, dries, remove solvent under reduced pressure, obtains pale tan oil N, N- bis- Methyl isophthalic acid-phenyl -3-（1- naphthoxys）Propylamine.
By crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine is dissolved in absolute ethyl alcohol, D-（-）- tartaric acid is molten Yu Shuizhong（N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine：（D）-（-）- tartaric acid=1:1.5-2.0 mol ratios）, room It is slowly dropped in ethanol solution under temperature, ice bath overnight, has substantial amounts of solid to separate out, and filters to obtain yellowish solid, and dichloromethane is washed Filter cake is washed, then the solid of gained is carried out into three subgradients change recrystallization, wherein absolute ethyl alcohol with ethanol-water solution system：Water Ratio is 1:1.5-2.5, three times the graded ratio of recrystallization solvent is 1:2-3:4-5.The winestone that will be obtained after recrystallization 2 M NaOH of hydrochlorate are neutralized to white solid disappearance, and extraction is dried, and decompression obtains faint yellow solid except solvent（+）- N, N- diformazan Base -1- phenyl -3-（1- naphthoxys）Propylamine.
By compound（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine is dissolved in methyl tertiary butyl ether(MTBE), Xiang Rong Hydrogen chloride-t-butyl methyl ether solution is added dropwise in liquid to be produced to there is no white solid, white powder is filtered to obtain, then use isopropyl Alcohol：N-hexane system is recrystallized（Isopropanol：N-hexane=1:1）, obtain sterling Dapoxetine hydrochloride.
Reaction equation of the invention is：
Hereinafter, actual process of the invention is illustrated by example, it is necessary to what is illustrated is：Example as described below is a portion Experiment, and not comprising all experimentss of the invention.
Embodiment 3：A kind of preparation method of Dapoxetine hydrochloride, step is：
With 140 ml absolute ethyl alcohols it is solvent in 250 ml three-necked bottles, sequentially adds 22.13 g malonic acid（0.21 mol）, vinegar Sour ammonium 16.35g（0.21 mol）, the g of benzaldehyde 15.0（0.14 mol）, 78 DEG C of temperature is controlled, condensing reflux reacts 6h, warp TLC is monitored, and is shown without raw material, after the completion of reaction, is cooled to room temperature, is filtered, absolute ethanol washing, obtains 16.0 g whites solid Body 3- amido -3- phenylpropionic acids, mp 213.0-213.6 DEG C, MS m/z:166[M+H]+。
Under condition of ice bath, by the g of sodium borohydride 1.38 (0.036mol), the g of compound 3- amido -3- phenylpropionic acids 4 (0.024 mol) and THF（65 ml）Add in 250 ml three-necked bottles, after 10 min of stirring, be slowly added dropwise from constant pressure funnel It is dissolved in THF（30 ml）Iodine（6.16 g, 0.024mol）, keep the temperature of reaction solution to be not higher than 10 DEG C, release substantial amounts of hydrogen The color of gas, about 30 min completion of dropping, and solution becomes clarification, after hydrogen emitting rate slows down, 65 DEG C of back flow reaction 7h.It is cold But absolute methanol to reaction solution is slowly added dropwise to room temperature, under condition of ice bath to clarify, decompression removes solvent after 30 min are stirred at room temperature, plus Enter 15% potassium hydroxide solution（30 ml）13,45 DEG C of stirring 1h of pH are adjusted, ethyl acetate is used（30 ml×3）Extract, merge organic Phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is evaporated, and obtains white crude product 3- amidos -3- phenyl propanols（3.34g, 91%）, MS m/z:151[M+H]+。
90% formic acid（2.0 ml, 0.05 mol）, 10 ml distilled water are added in 100 ml three-necked bottles, under condition of ice bath in batches Add compound 3- amido -3- phenyl propanols（3 g, 0.02 mol）, 37% formalin is added after stirring to dissolving（3.9 ml, 0.05 mol）, 90 DEG C of oil bath stirring reaction 10h are cooled to room temperature, and reinforcing body NaOH adjusts pH=13, acetic acid under condition of ice bath Ethyl ester（30 ml×3）Extract, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is steamed It is dry, obtain pale yellow transparent crude oil 3- dimethylamino -3- phenyl propanols（3.50 g, 98%）, MS m/z:180[M+H]+。
By compound 3- dimethylamino -3- phenyl propanols（3.0 g, 0.017 mol）Add in 100 ml three-necked bottles, add 40 ml dry DMFs, stirring dissolves it.Under condition of ice bath, the NaH of mass fraction 60% is dividedly in some parts（0.87 g, 0.034mol）, until after gas is released slowly, being warming up to 60 DEG C of reactions, solution colour gradually turns yellow.After 1h, 1- fluorine is added dropwise to Naphthalene（2.7 g, 0.019 mol）, then 100 DEG C of oil bath stirring reaction 9h.Room temperature is cooled to, add water 400 ml, ethyl acetate （100 ml×3）Extract, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is evaporated, obtains Pale tan oil N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（4.61 g, 90.2%）, MS m/z: 306[M+H ]+。
Primary recrystallization：By the crude Compound 5 of gained（2.0 g, 0.007 mol）It is dissolved in 4ml absolute ethyl alcohols, will 1.2 g D-（-）- tartaric acid is dissolved in 8 ml water, is slowly added drop-wise in ethanol solution at room temperature, continues to stir, and has a small amount of consolidating Body is separated out, and ice bath is stirred overnight, and has substantial amounts of solid to separate out, and filters to obtain the yellowish solids of 2.43 g, and filter cake washs 2-3 with dichloro It is secondary；Secondary recrystallization：The yellowish solid of gained is carried out into secondary recrystallization with 36ml absolute ethyl alcohols-aqueous systems, ice bath is stirred Mix overnight, there is substantial amounts of solid to separate out, filter to obtain the yellowish solids of 2.43 g, filter cake is washed 2-3 times with dichloro；Three recrystallizations： The yellowish solid of gained is stirred overnight with three recrystallizations, ice bath is carried out in 48ml absolute ethyl alcohols-aqueous systems, there is substantial amounts of Solid is separated out, and filters to obtain the yellowish solids of 2.43 g, and filter cake is washed 2-3 times with dichloro, finally gives 1.10 g white solids.Will To tartrate be neutralized to pH 10 with 2 M NaOH, ethyl acetate extraction merges organic phase, anhydrous sodium sulfate drying, decompression Except solvent obtains 0.73 g faint yellow solids（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine, yield 37%.
By compound 6（1.0 g, 0.015 mol）It is dissolved in 10 ml anhydrous methyl tertbutyl ethers, to chlorine is added dropwise in solution The t-butyl methyl ether solution for changing hydrogen is produced to there is no white solid, filters to obtain the g of pale powder 1.10（Yield 97.7%）, By the compound of gained with 22 times amount isopropanols：N-hexane（1:1）Recrystallized, obtained 0.85 g white powders 1（Yield 85%）,+130.9 ° of [α] 25 D=（C=1%, methyl alcohol）, mp 179.1-180.2 DEG C.
Embodiment 4：The fractionation of Dapoxetine hydrochloride, purification process, using crude product N, N- dimethyl -1- phenyl -3-（1- naphthalene oxygen Base）Propylamine（Formula 5）With levotartaric acid into salt, white solid is obtained, then three weights are carried out by the ethanol-water system of graded Crystallize to reach the purpose for splitting and purifying.Step is as follows：By crude product N, the N- dimethyl -1- phenyl -3- of gained（1- naphthalene oxygen Base）Propylamine（Formula 5）It is dissolved in absolute ethyl alcohol, under room temperature condition, is slowly dropped into dissolved with D-（-）In the distilled water of-tartaric acid, there is few The solid of amount is separated out, and is stirred overnight under the conditions of 0 DEG C, has substantial amounts of solid to separate out, by the yellowish solid dichloromethane of gained Washing, removes impurity, then is recrystallized twice with the ethanol-water system of graded, by 2 M of resulting tartrate NaOH is neutralized to and is produced without white precipitate, ethyl acetate extraction, dries, and sterling is obtained after concentration（+）- N, N- dimethyl -1- Phenyl -3-（1- naphthoxys）Propylamine.

Claims (10)

1. a kind of preparation method of Dapoxetine hydrochloride, it is characterised in that：It is condensed by Knoevenagel by initiation material of benzaldehyde N, N- dimethyl -1- phenyl -3- can be prepared after reaction, carboxyl reduction, amine-methylated and nucleophilic displacement of fluorine（1- naphthoxys）Propylamine, Use again（D）-（-）- tartaric acid, is processed according to the method for Solvent Gradient resolving and purifying, finally uses hydrochloride methyl tertbutyl ether Into salt, synthesize target product Dapoxetine hydrochloride.
2. preparation method according to claim 1, it is characterised in that：Specific steps include：
（1）, solvent made with absolute ethyl alcohol, benzaldehyde, malonic acid and ammonium acetate are reacted in the solvent of absolute ethyl alcohol, 3- amido -3- phenylpropionic acids are obtained after reaction completely（Formula 2）；
（2）, first by 3- amido -3- phenylpropionic acids, NaBH4It is dissolved in tetrahydrofuran solvent, under the conditions of 0 DEG C -10 DEG C, slow drop Enter iodine solution, after reaction completely, be quenched, solvent is evaporated off, with alkaline matter for processing after, extract to obtain reduzate 3- amido -3- phenyl Propyl alcohol（Formula 3）；
（3）, reduzate 3- amido -3- phenyl propanols are dissolved in formic acid solvent, add formalin, 85 DEG C -95 DEG C are returned Stream, alkaline matter for processing is used after reaction completely, and key intermediate 3- dimethylamino -3- phenyl propanols are obtained after extraction（Formula 4）；
（4）, the product 3- dimethylamino -3- phenyl propanols for methylating are dissolved in dry DMF solvent, add sodium hydride, 55 DEG C - After 65 DEG C are reacted 1 hour, 1- fluoronaphthalenes are added, react to obtain crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 5）；
（5）, from (D)-(-)-winestone acid treatment crude product N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 5） Tartrate white solid, three recrystallizations are carried out with ethanol-water system graded, and dichloromethane washing after dissociation, obtains right Rotation product（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 6）；
（6）, by dextrorotation product（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine is in hydrochloric acid-methyl tertiary butyl ether(MTBE) Into salt in solvent, then use isopropanol：N-hexane system obtains final product white end-product after being recrystallized again（Formula 1）.
3. preparation method according to claim 2, it is characterised in that：The step（1）Benzaldehyde：Malonic acid：Ammonium acetate is 1: 1.0-1.5:1.0-1.5 mol ratios.
4. preparation method according to claim 2, it is characterised in that：The step（2）3- amido -3- phenylpropionic acids（Formula 2）:Boron Sodium hydride:Iodine is 1:1.0-1.5:1.0-1.5 mol ratios（Preferably, step（2）The alkaline matter be 10% potassium hydroxide or Sodium hydroxide solution）.
5. preparation method according to claim 2, it is characterised in that：Step（3）3- amido -3- phenyl propanols（Formula 3）：Formaldehyde： Formic acid is 1:2.5-3.0:2.5-3.0 mol ratios（Preferably, the alkaline matter is one kind of NaOH or potassium hydroxide）.
6. preparation method according to claim 2, it is characterised in that：Step（4）3- dimethylamino -3- phenyl propanols（Formula 4）：Hydrogen Change sodium：1- fluoronaphthalenes are=1:1.5-2.0:1.1-1.2 mol ratios（Preferably, charging sequence be first under conditions of 0 DEG C -10 DEG C, By in compound 3- dimethylamino -3- phenyl propanols addition DMF solvent, sodium hydride is added, be warming up to 55 DEG C -65 DEG C, stirring 1 After hour, 1- fluoronaphthalenes are added）.
7. preparation method according to claim 2, it is characterised in that：Step（5）Middle N, N- dimethyl -1- phenyl -3-（1- naphthalene oxygen Base）Propylamine with（D）- tartaric acid is 1:1.5-2.0 mol ratios（Preferably, step（5）The ratio of recrystallization solvent absolute ethyl alcohol and water Example 1:1.5-2.5；More preferred, three graded ratio difference 1 of recrystallization solvent:2-3:4-5）.
8. preparation method according to claim 2, it is characterised in that：Step（6）Dextrorotation product（+）- N, N- dimethyl -1- benzene Base -3-（1- naphthoxys）Propylamine is in hydrochloric acid-methyl tert-butyl ether solvent into salt, recrystallization solvent isopropanol and n-hexane ratio It is 1:1.
9. fractionation, the purification process of any Dapoxetine hydrochlorides of claim 1-8, it is characterized by：Using crude product N, N- dimethyl- 1- phenyl -3-（1- naphthoxys）Propylamine（Formula 5）With D-（-）- tartaric acid, obtains white solid, then the second for passing through graded Alcohol-water system carries out three recrystallizations to reach the purpose for splitting and purifying.
10. the fractionation of Dapoxetine hydrochloride described in claim 9, purification process, it is characterized by：Step is as follows：By the crude product N of gained, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine（Formula 5）It is dissolved in absolute ethyl alcohol, under room temperature condition, is slowly dropped into dissolved with D- （-）In the distilled water of-tartaric acid, there is a small amount of solid to separate out, be stirred overnight under the conditions of 0 DEG C, there is substantial amounts of solid to separate out, by institute The yellowish solid for obtaining is washed with dichloromethane, removes impurity, then weighed twice with the ethanol-water system of graded Crystallization, resulting tartrate is neutralized to 2 M NaOH and is produced without white precipitate, ethyl acetate extraction, is dried, concentration Sterling is obtained afterwards（+）- N, N- dimethyl -1- phenyl -3-（1- naphthoxys）Propylamine.
CN201611068686.3A 2016-11-29 2016-11-29 A kind of synthesis of Dapoxetine hydrochloride, resolving and purifying and salifying method Pending CN106748825A (en)

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CN110845369A (en) * 2019-11-28 2020-02-28 浙江工业大学 Synthetic method of dapoxetine and intermediate thereof
CN112159328A (en) * 2020-06-28 2021-01-01 石家庄市度智医药科技有限公司 Resolution method of dapoxetine
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CN115636760A (en) * 2022-10-28 2023-01-24 河北常山凯库得生物技术有限公司 Preparation method of dapoxetine hydrochloride intermediate

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CN110845369A (en) * 2019-11-28 2020-02-28 浙江工业大学 Synthetic method of dapoxetine and intermediate thereof
CN110845369B (en) * 2019-11-28 2022-03-18 浙江工业大学 Synthetic method of dapoxetine and intermediate thereof
CN113801027A (en) * 2020-06-16 2021-12-17 扬子江药业集团江苏紫龙药业有限公司 Synthesis process of dapoxetine hydrochloride
CN112159328A (en) * 2020-06-28 2021-01-01 石家庄市度智医药科技有限公司 Resolution method of dapoxetine
CN115636760A (en) * 2022-10-28 2023-01-24 河北常山凯库得生物技术有限公司 Preparation method of dapoxetine hydrochloride intermediate

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