CN107473977A - Intermediate and the preparation method of Dapoxetine hydrochloride prepared by a kind of Dapoxetine hydrochloride - Google Patents
Intermediate and the preparation method of Dapoxetine hydrochloride prepared by a kind of Dapoxetine hydrochloride Download PDFInfo
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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
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The intermediate and the preparation method of Dapoxetine hydrochloride prepared the present invention relates to a kind of Dapoxetine hydrochloride; pass through preparation path provided by the invention; by sulfonylation, with 1 how phenol occur to slough Boc blocking groups in the basic conditions in substitution reaction, acid system, the step such as the compound Dapoxetine hydrochloride that is converted into Formula II under reducing agent effect with formalin, the dapoxetine hydrochloride of high-optical-purity can be obtained.Preparation method reaction condition of the present invention is gentle, and operation is simple, and optical purity and chemical purity are high, are mass produced suitable for industrialization.
Description
Technical field
The present invention relates to the preparation method of medicine technical field of organic synthesis, more particularly to Dapoxetine hydrochloride.
Background technology
Dapoxetine hydrochloride（Dapoxetine）, wherein science of culture title：(+)-(S)-N, N- dimethyl-（α）-[2-（1- naphthalene oxygen
Base）Ethyl]-benzene methanamine.
Cas. No. 119356-11-3, its structural formula：
Dapoxetine hydrochloride (dapoxetine) is a kind of chemicals, as a kind of new quick SSRI, half-life short, belongs to choosing
Selecting property serotonin reuptake inhibithors (SSRI), for treating prospermia of males and erectile dysfunction, effective percentage is 98%, should
Medicine is by Li Lai drugmakers（Eli Lilly）Develop, listed first in Sweden and Finland in 2009, trade name must sharp strength
（Priligy）, its hydrochloride form for using on clinical application, Dapoxetine hydrochloride absorbs fast, can quickly reach effective blood concentration；
Tissue distribution is wide, and drug concentration and the blood concentration of nerve fiber approach, and the medicine is first mouth ratified for PE in the world
Take prescription drug.
Prior art discloses the preparation method of several Dapoxetine hydrochlorides：
Route one：
The conjunction that Li Lai companies have applied for 1- phenyl -3- (1- naphthoxys) propanamine derivatives series compound is disclosed in EP288188
Into route.
This route raw material is although cheap and easy to get, but dangerous very using red aluminum solution, hydrogenation sodium reagent, pyroreaction etc. in technique
High reagent or reaction condition are not easy to be amplified batch production.Dapoxetine hydrochloride is obtained using method for splitting in addition, splits and receives
Rate is relatively low, and the difficult control of isomers.
Route two：
The following syntheti c route of Yuan Yan house journals is also disclosed in EP0288188：
Raw materials used reagent is relatively cheap in the route, but uses carbon tetrachloride anti-as solvent progress bromination in technique
Should, yield is very low, and selectivity ratios are poor, produces multiple aromatic ring bromo accessory substances, meanwhile, carbon tetrachloride is a kind of toxic solvents,
Forbid to be used in medicine production.Chemical resolution method obtains Dapoxetine hydrochloride, and yield is very low, and the difficult control of isomers.
Route three：Following syntheti c route is disclosed in application for a patent for invention WO2008035358A：
The route is more succinct, but elimination impurity is relatively more during dimethylamine nucleophilic substitution, the difficult control of technics comparing.
Route four：Org. following syntheti c route is disclosed in Process Res. Dev. 2012,16,710 713：
This method is further optimized on the basis of route three, using Corey Itsuno reduction reactions, utilizes Cbs- borines
Chirality control reduction structure chiral centre, but side reaction is eliminated when the route still has dimethylamino substitution reaction and is compared
The defects of serious, cause low yield, purifying products complex process.
Route five：
Chinese patent CN103396320 is disclosed using chirality (R) -1- phenyl -1,3-PD as raw material, chosen property esterification,
Condensation, resterification and methylamine obtain end-product.This process route is succinct, and the synthesis of selective of compound 2 is difficult to control, chemical combination
Thing 4 easily produces and eliminates impurity, and methylamine is not thorough.
As can be seen here, the preparation method at present on dapoxetine hydrochloride is relatively more, but these preparation methods have it is various
The shortcomings that various kinds, chiral resolution is carried out if desired for intermediate or product, causes yield relatively low, using high-risk reagent, eliminated
Impurity is difficult to remove；Overall route is long, cumbersome, reduces the gross production rate etc. of product.Therefore, it is more simple to seek a kind of operation
Just, the high Dapoxetine hydrochloride preparation method of purity is very necessary.
The content of the invention
In order to overcome, production procedure needs to use high-risk reagent, high poison to the present invention among Dapoxetine hydrochloride in the prior art
Property solvent, optical purity is difficult to control, and eliminates the defects of impurity is difficult to remove, there is provided a kind of new prepares in Dapoxetine hydrochloride
Mesosome and the method for preparing Dapoxetine hydrochloride.Preparation method reaction condition of the present invention is gentle, and operation is simple, and optical purity and chemistry are pure
Degree is high, suitable for industrialized production.
To achieve these goals, the present invention provides a kind of intermediate of the Dapoxetine hydrochloride shown in Formula V, has following structure
Formula：
（V）,
Wherein R is methyl, phenyl, p-methylphenyl, 3- nitrobenzophenones or 4- nitrobenzophenones.Methyl is in related experiment of the present invention
Being represented with Va, phenyl is represented in related experiment of the present invention with Vb, and p-methylphenyl is represented in related experiment of the present invention with Vc,
3- nitrobenzophenones represent that 4- nitrobenzophenones are represented in related experiment of the present invention with Ve in related experiment of the present invention with Vd.
The present invention uses following synthetic route：
Specifically include following reactions steps：
a）The hydroxyl of compound shown in Formula IV and suitable sulfonylation agent are subjected to sulfonylation and obtain Formula V compound；
b）How substitution reaction occurs in the basic conditions for phenol forms compound shown in formula IV by compound shown in Formula V and 1-；
c）Formula IV compound sloughs Boc blocking groups in acid system, and obtains III compounds with excessive acid with alkali；
d）Compound shown in formula III is converted into the compound Dapoxetine hydrochloride of Formula II with formalin under reducing agent effect.
Preferably, after Step d, also e）Step, Formula II compound and hydrogen chloride organic solution reaction shape
Into compound dapoxetine hydrochloride shown in Formulas I.
Preferably, the preparation method described in step a, its sulfonylation agent refer to methylsufonyl chloride, phenylSulphon
Chlorine, p-methyl benzene sulfonic chloride, 2- nitrobenzene sulfonyl chlorides, 3- nitrobenzene sulfonyl chlorides, 4- nitrobenzene sulfonyl chlorides and pyrovinic acid acid anhydride,
P-methyl benzenesulfonic acid acid anhydride etc., preferably methylsufonyl chloride and 3- nitrobenzene sulfonyl chlorides.
Preferably, the preparation method described in step a, the alkali used in sulfonylation are selected from triethylamine, diisopropyl
Base ethamine, pyridine, 2,6- lutidines, potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, cesium carbonate etc., preferably three second
Amine and diisopropylethylamine.
Preferably, the preparation method described in step b, the alkali that its substitution reaction uses be selected from potassium carbonate, sodium carbonate,
Cesium carbonate, potassium phosphate etc., preferably potassium carbonate and potassium phosphate.
Preferably, the preparation method described in step b, the solvent that its substitution reaction uses are selected from acetone, butanone, second
Nitrile, dichloromethane, tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes, N,N-dimethylformamide, N, N- bis-
The one or more combination of methylacetamide, 1-METHYLPYRROLIDONE etc., preferably acetone and acetonitrile.
Preferably, the preparation method described in step c, the III compounds are free state, used deprotection
Base acid is selected from trifluoroacetic acid, the suitable organic solution of debita spissitudo hydrogen chloride, debita spissitudo aqueous hydrochloric acid solution etc., preferably trifluoro
Acetic acid and hydrochloric acid acetone soln.
Preferably, the preparation method described in step d, it is characterised in that the reducing agent is selected from triacetyl boron hydrogen
Change sodium, preferably sodium cyanoborohydride, Sodium triacetoxyborohydride.
Preferably, the preparation method described in step d, it is characterised in that the reduction reaction solvent is selected from dichloromethane
One or more of groups of alkane, methanol, ethanol, isopropanol, tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes etc.
Close, preferably dichloromethane and methanol solution.
Preferably, the preparation method described in step e, it is characterised in that described salt-forming reaction solvent is selected from second
Acetoacetic ester, isopropyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes, toluene,
The one or more combination of methanol, ethanol, isopropanol etc., preferably isopropyl acetate.
Overcome technical scheme using the present invention, production procedure among Dapoxetine hydrochloride in the prior art can be overcome to need to use
High-risk reagent, high toxicity solvent, optical purity are difficult to control, and eliminate the defects of impurity is difficult to remove.Preparation method of the present invention
Reaction condition is gentle, and operation is simple, and optical purity and chemical purity are high, suitable for industrialized production.
Embodiment：
It is noted that described further below is all exemplary, it is intended to provides further instruction to the application.It is not used to limit
The system present invention, for those skilled in the art, the present invention can have various modifications and variations.All spirit in the present invention
Within principle, any modification, equivalent substitution and improvements made etc., it should be included in the scope of the protection.
It should be noted that term used herein above is merely to describe embodiment, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singulative
It is also intended to include plural form, term " first ", " second " in the description and claims of this application etc. are to be used for area
Not similar object, without for describing specific order or precedence.It should be appreciated that the data so used are appropriate
In the case of can exchange, so as to presently filed embodiment described herein for example can with except it is described here those with
Outer order is implemented.Additionally, it should be understood that when using term "comprising" and/or " comprising " in this manual, its
Indicate existing characteristics, step, operation, device, component and/or combinations thereof.
Embodiment given below illustrates the present invention, but the present invention is by any restriction of these embodiments.
Embodiment 1
Dapoxetine hydrochloride is synthesized using following route：
Specifically include following reactions steps：
a）The hydroxyl of compound shown in Formula IV and suitable sulfonylation agent are subjected to sulfonylation and obtain Formula V compound；
Preparation method described in step a, its sulfonylation agent refer to methylsufonyl chloride, phenylsulfonylchloride, p-methyl benzene sulfonic chloride,
2- nitrobenzene sulfonyl chlorides, 3- nitrobenzene sulfonyl chlorides, 4- nitrobenzene sulfonyl chlorides and pyrovinic acid acid anhydride, p-methyl benzenesulfonic acid acid anhydride etc.,
It is preferred that methylsufonyl chloride and 3- nitrobenzene sulfonyl chlorides.
Alkali used in sulfonylation be selected from triethylamine, diisopropylethylamine, pyridine, 2,6- lutidines, potassium carbonate,
Sodium carbonate, saleratus, sodium acid carbonate, cesium carbonate etc., preferably triethylamine and diisopropylethylamine.
b）How substitution reaction occurs in the basic conditions for phenol forms compound shown in formula IV by compound shown in Formula V and 1-；
Preparation method described in step b, the alkali that its substitution reaction uses are selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate etc.,
It is preferred that potassium carbonate and potassium phosphate.The solvent that its substitution reaction uses be selected from acetone, butanone, acetonitrile, dichloromethane, tetrahydrofuran,
2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N- methylpyrroles
The one or more combination of alkanone etc., preferably acetone and acetonitrile.
c）Formula IV compound sloughs Boc blocking groups in acid system, and obtains formula III chemical combination with excessive acid with alkali
Thing；Preparation method described in step c, the formula III compound are free state, and used Deprotection acid is selected from trifluoro second
Acid, the suitable organic solution of debita spissitudo hydrogen chloride, debita spissitudo aqueous hydrochloric acid solution etc., preferably trifluoroacetic acid and hydrochloric acid acetone
Solution.
d）The compound that compound shown in formula III is converted into Formula II with formalin under reducing agent effect reaches Bo Xi
Spit of fland；
Preparation method described in step d, reducing agent are selected from Sodium triacetoxyborohydride, preferably sodium cyanoborohydride, triacetyl
Sodium borohydride.Reduction reaction solvent is selected from dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, 2- methyltetrahydrofurans, 1,
The one or more combination of 2- dimethoxy-ethanes etc., preferably dichloromethane and methanol solution.
e）Formula II compound reacts to form compound dapoxetine hydrochloride shown in Formulas I with hydrogen chloride organic solution.
Preparation method described in step e, salt-forming reaction solvent is selected from ethyl acetate, isopropyl acetate, methyl tertbutyl
One kind or several of ether, tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes, toluene, methanol, ethanol, isopropanol etc.
Kind combination, preferably isopropyl acetate.
The preparation experiment of the dapoxetine hydrochloride of embodiment 2
S-1-N-Boc-3- aminophenylpropyl alcohols used produce for company oneself in experiment.
Step 1：Sulfonylation
By S-1-N-Boc-3- aminophenylpropyl alcohols VI（2.51 kg, 10.0 mole）It is dissolved in 25kg dichloromethane, controls in kettle
Temperature is less than 10 degree, and triethylamine is added dropwise（1.51kg, 15.0 mole）, methylsufonyl chloride is added dropwise into reaction system（1.35kg
12.0 mole）, stirring 1 hour is added dropwise, TLC monitoring reactions are complete, and watery hydrochloric acid is added into reaction system, makes reactant
System is in weakly acidic pH, is stood, liquid separation, and water layer is extracted twice with dichloromethane, merges organic phase, organic phase saturated nacl aqueous solution
It washed once, anhydrous sodium sulfate drying, be concentrated to dryness to obtain intermediate Va（3.12 kg, yield 95%）
Step 2：Substitution reaction
By Va（3.12 kg, 9.5 mole）It is dissolved in acetone（30kg）, add 1- naphthols（1.45 kg, 10.0 mole）, nitrogen guarantor
Shield is lower to add potassium carbonate（3.27kg 23.5mole）, back flow reaction 24-48 hours are warming up to, TLC shows the conversion of Va intermediates
Completely.Interior temperature is cooled to less than 30 degree, filtering, filter cake is eluted with 5kg acetone, is merged solution, is concentrated to dryness to obtain intermediate compound IV
（3.6kg, 100% yield）, crude product directly carries out next step reaction.
Step 3：De- Boc reactions
Previous step is obtained into intermediate compound IV（3.6kg）It is dissolved in 15kg dichloromethane, is cooled to 0 degree Celsius, 1kg trifluoros is added dropwise
Acetic acid, stirring reaction 5-10 hours, TLC detection reactions are complete, and heating is concentrated to dryness, and by concentrate solution water, add methyl
Tertbutyl ether（2kg）Extracting impurities, after being extracted twice, addition 1N sodium hydroxide solutions in aqueous phase, condition system pH 10-12,
Add dichloromethane 10kg to be extracted twice, merge organic phase, add saturated aqueous common salt and washed once, add sodium sulphate and dry, mistake
Filter, filter cake are washed with 2kg dichloromethane, merging filtrate, are concentrated to dryness, and isopropyl acetate is added in concentrate（15kg）, cooling
To 0-10 degree, hydrogen chloride is passed through（2.0kg）, led to hydrogen chloride gas, insulation reaction 2 hours, be warming up to 25-35 degree, continued anti-
Answer 2-5 hours, TLC monitoring intermediate compound IV reactions are complete, add methyl tertiary butyl ether(MTBE)（15kg）, stirring and crystallizing 10 hours, filtering,
Filter cake washed once with methyl tertiary butyl ether(MTBE), be dried to obtain off-white powder III hydrochloride（2.53 kg, yield 85%）.
Step 4：Dimethylaminoization is reacted
Dichloromethane (25.0kg) is sequentially added into 50L reactors, intermediate II (2.50 kg 9.98mol) obtained by upper step,
Stirring, 10~25 DEG C of temperature is maintained, 5% sodium hydroxide solution is added dropwise, 0.5~1.0h is added dropwise, stirred completely clear to solution
After clear, static liquid separation, dichloromethane layer is separated, dichloromethane (5.0kg), stirring, static liquid separation are added to water layer.Merge dichloro
Methane phase, washed with purified water (5.0kg), static liquid separation obtains dichloromethane solution.Dichloromethane solution is transferred to 50L reactions
In kettle, methanol (0.38kg, 12.0mol) is added, formalin (9.70kg), opens nitrogen protection, at 20~30 DEG C, slowly
Sodium triacetoxy borohydride (12.0kg, 56.50mol) is added, 2.0~3.0h is added.It is anti-at 20~30 DEG C after addition
Answer 1.5~3.0h.Purified water (30.0kg) is added, 5~20 DEG C of temperature is maintained, 20% sodium hydroxide solution is added dropwise into system, when
System pH stops being added dropwise, stirs 20~30min at 9.0~11.0.Static liquid separation, separates dichloromethane layer, into water layer
Add dichloromethane (10.0kg), stirring, static liquid separation.Combined dichloromethane layer, go in 100L reactors, add purified water
(30.0kg) is stirred.Dichloromethane layer is separated, then, combined dichloromethane layer, to purified water (150.0kg) repeated washing once
Anhydrous magnesium sulfate (2.0kg) is added in dichloromethane layer and dries 3.0~5.0h.Filtering, solid are washed twice with dichloromethane, often
Secondary to use 2.0kg, collection obtains the dichloromethane solution of diaminourea compound.The removing solvent that is concentrated under reduced pressure obtains crude free base.It is molten
In 10kg isopropyl acetates, hydrogen chloride gas (1.6~2.0kg) is passed through, stops being passed through, system gradually separates out solid, stirring
3.0~4.0h.Filtering, obtains dapoxetine hydrochloride crude product 2.8kg, yield 85%.
Step 5：Crude product refines
Isopropanol (15.0kg), dapoxetine hydrochloride crude product 2.8kg are sequentially added into 20L reactors, is stirred, it is warming up to 60~
70 DEG C, after system all dissolving clarification, filter off while hot except mechanical admixture, cooling are controlled at 35~45 DEG C, stirring 1.0~
2.0h, then 20~30 DEG C are cooled to, 3.0~4.0h of stirring and crystallizing.It is filtrated to get 2.38kg sterlings, yield 85%.
Structure elucidation：
Mass spectrum Ms
Mass spectrograph：Agilent TOF 6224
Ion gun：ESI+
Condition determination:Solvent：Methanol;Scanning range:290 to 330.
Mass spectrometric data and parsing are shown in Table 1：
The dapoxetine hydrochloride high resolution mass spectrum data of table 1 and parsing
| m/e | Quasi-molecular ion peak | Remarks |
| 306.1859 | [M +H]+ | Dapoxetine hydrochloride captures the quasi-molecular ions of a proton |
Parsing:In the ESI/MS high resolution mass spectrums of sample, dapoxetine hydrochloride free alkali molecular weight is 306.1856, for capture
The quasi-molecular ions of one proton.It thus is seen that the electrospray ionization mass spectrum data of sample are consistent with the molecular weight of dapoxetine hydrochloride.
NMR spectrum：
Use NMR spectrum obtain compound structure for：
It is consistent with dapoxetine hydrochloride.
Hydrogen nuclear magnetic resonance spectrum (1H-NMR)
1. INSTRUMENT MODEL and test condition
INSTRUMENT MODEL：The type nuclear magnetic resonance chemical analysers of Bruker Advance 400
Test condition：Solvent-deuterochloroform（CDCl3）, 30 DEG C of temperature
2. hydrogen modal data and analysis result are shown in Table 2：
The dapoxetine hydrochloride highly finished product hydrogen nuclear magnetic resonance modal data of table 2 and analysis result
bIn heavy water exchanges spectrogram, this several groups of hydrogen disappear, and it is active hydrogen to illustrate these hydrogen.
Nuclear magnetic resonance of carbon spectrum (13C-NMR, DEPT-135)
1. INSTRUMENT MODEL and test condition
（a）INSTRUMENT MODEL：The type nuclear magnetic resonance chemical analysers of Bruker Advance 400
（b）Test condition：Solvent-deuterochloroform, 30 DEG C of temperature
2. carbon modal data and analysis result are shown in Table 3：
The carbon of table 3 is composed and DEPT modal datas and parsing
Claims (11)
1. a kind of intermediate for preparing Dapoxetine hydrochloride, it is characterised in that there is following structural formula
,
Wherein R is methyl, phenyl, p-methylphenyl, 3- nitrobenzophenones or 4- nitrobenzophenones.
2. a kind of preparation method of Dapoxetine hydrochloride, it is characterised in that comprise the steps of：
a）The hydroxyl of compound shown in Formula IV and suitable sulfonylation agent are subjected to sulfonylation and obtain Formula V compound；
b）How substitution reaction occurs in the basic conditions for phenol forms compound shown in formula IV by compound shown in Formula V and 1-；
c）Formula IV compound sloughs Boc blocking groups in acid system, and obtains III compounds with excessive acid with alkali；
d）Compound shown in formula III is converted into the compound Dapoxetine hydrochloride of Formula II with formalin under reducing agent effect.
3. preparation method according to claim 2, it is characterised in that after Step d, also e）Step, Formula II chemical combination
Thing reacts to form compound dapoxetine hydrochloride shown in Formulas I with hydrogen chloride organic solution.
4. preparation method according to claim 2, it is characterised in that the preferred methylsufonyl chloride of sulfonylation agent in step a,
Phenylsulfonylchloride, p-methyl benzene sulfonic chloride, 2- nitrobenzene sulfonyl chlorides, 3- nitrobenzene sulfonyl chlorides, 4- nitrobenzene sulfonyl chlorides and first
Base sulphonic acid anhydride, p-methyl benzenesulfonic acid acid anhydride, more preferably methylsufonyl chloride and 3- nitrobenzene sulfonyl chlorides.
5. preparation method according to claim 2, it is characterised in that the alkali preferably three in step a used in sulfonylation
Ethamine, diisopropylethylamine, pyridine, 2,6- lutidines, potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, cesium carbonate,
More preferably triethylamine and diisopropylethylamine.
6. preparation method according to claim 2, it is characterised in that the preferred carbonic acid of alkali that substitution reaction uses in step b
Potassium, sodium carbonate, cesium carbonate, potassium phosphate, more preferably potassium carbonate and potassium phosphate.
7. preparation method according to claim 2, it is characterised in that the solvent that substitution reaction uses in step b preferably third
Ketone, butanone, acetonitrile, dichloromethane, tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes, N, N- dimethyl formyls
Amine, DMA, the more preferably one or more combination of 1-METHYLPYRROLIDONE, acetone and acetonitrile.
8. preparation method according to claim 2, it is characterised in that III compounds described in step c are free state, are made
It is water-soluble that Deprotection acid is preferable over trifluoroacetic acid, the suitable organic solution of debita spissitudo hydrogen chloride, debita spissitudo hydrochloric acid
Liquid, more preferably trifluoroacetic acid and hydrochloric acid acetone soln.
9. preparation method according to claim 2, it is characterised in that the preferred triacetyl boron hydrogen of reducing agent described in step d
Change sodium, more preferably sodium cyanoborohydride, Sodium triacetoxyborohydride.
10. preparation method according to claim 2, it is characterised in that the preferred dichloro of reduction reaction solvent described in step d
The one or more of methane, methanol, ethanol, isopropanol, tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes etc.
Combination, preferably dichloromethane and methanol solution.
11. preparation method according to claim 3, it is characterised in that the salt-forming reaction solvent described in step e is preferable over
Ethyl acetate, isopropyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dimethoxy-ethanes, first
Benzene, methanol, ethanol, the preferably one or more combination of isopropanol, isopropyl acetate.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369424A (en) * | 2018-07-09 | 2019-02-22 | 华控创新（北京）药物研究院有限公司 | A kind of purification process of dapoxetine hydrochloride |
| CN110078632A (en) * | 2019-04-17 | 2019-08-02 | 淮阴工学院 | A kind of biological synthesis method and its intermediate of Dapoxetine hydrochloride intermediate |
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application 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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| CN106397227A (en) * | 2016-08-19 | 2017-02-15 | 山东省药学科学院 | Preparation method of dapoxetine hydrochloride |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369424A (en) * | 2018-07-09 | 2019-02-22 | 华控创新（北京）药物研究院有限公司 | A kind of purification process of dapoxetine hydrochloride |
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN110903203B (en) * | 2018-09-14 | 2022-11-18 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN110078632A (en) * | 2019-04-17 | 2019-08-02 | 淮阴工学院 | A kind of biological synthesis method and its intermediate of Dapoxetine hydrochloride intermediate |
| 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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Application publication date: 20171215 |