CN106397227A - Preparation method of dapoxetine hydrochloride - Google Patents

Preparation method of dapoxetine hydrochloride Download PDF

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Publication number
CN106397227A
CN106397227A CN201610695061.3A CN201610695061A CN106397227A CN 106397227 A CN106397227 A CN 106397227A CN 201610695061 A CN201610695061 A CN 201610695061A CN 106397227 A CN106397227 A CN 106397227A
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reaction
compound
formula
dapoxetine
preparation
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CN106397227B (en
Inventor
张宁
付丙月
刘宪华
段崇刚
孔祥雨
孙晋瑞
赵思太
邓玉晓
任业明
崔新强
于治见
冯光玲
马新成
李丹
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Shandong Academy of Pharmaceutical Sciences
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Shandong Academy of Pharmaceutical Sciences
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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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • 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
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a preparation method of dapoxetine hydrochloride. The preparation method comprises that 3-chloropropiophenone and naphthol as initial raw materials and (S)-tert-butanesulfinyl amide undergo a condensation reaction in a solvent, the intermediate is reduced through a reducer BH3 and then is further subjected to deprotection, the reaction product undergoes a methylation reaction and the reaction product undergoes a salification reaction to produce dapoxetine hydrochloride. The preparation method has mild conditions, can be operated simply, realizes a low cost, is free of resolution or use of an expensive heavy metal catalyst, has a simple aftertreatment process, has a high product yield, produces the product with high chemical purity and optical purity and is suitable for industrial production.

Description

A kind of preparation method of dapoxetine hydrochlorate
Technical field
The present invention relates to a kind of preparation method of dapoxetine hydrochlorate.
Background technology
Dapoxetine hydrochloride (dapoxetine hydrochloride), chemical entitled S- (+)-N, N- dimethyl -1- benzene Base -3- (1- naphthoxy) propylamin hydrochloride, structural formula is as follows：
It is a kind of selective serotonin reuptake inhibitor (SSRI), by Lilly drugmaker (Eli Lilly) develop, 2009 in Europe listing, trade name Priligy, for treating prospermia of males (PE), be in the world first Plant the peroral administration prescription drugss going through to treat PE.At the beginning of 2009, Johson ＆ Johnson announces：Dapoxetine hydrochloride (dapoxetine hydrochloride) is used as new drug of PE treatment, has passed through the approval of Finland of European countries and Sweden, and 18 , as applicable crowd, this medicine half-life short, untoward reaction are little, effect is significant for～64 years old male.Dapoxetine is in European market List and greatly inspire to researcher, the current U.S. has 60 units carrying out dapoxetine as treatment male The clinical research of PE medicine, if obtaining FDA approval, the market scale of dapoxetine will reach 20～5,000,000,000 dollars.So, Dapoxetine market prospect is very wide.
Synthesis with regard to dapoxetine hydrochloride mainly has following several method at present：
Route one：[Dai Rong etc., Chinese Journal of New Drugs, 2008,17 (24), 2119-2121] disclose with benzaldehyde for rise The synthetic method of beginning raw material：
Route two：It is raw material that Chinese patent CN1821212 selects 3- chlorophenyl acetone cheap and easy to get and 1- naphthols, through also Former, condensation, N-methyl, recycle tartaric acid to split, as follows：
Route three：Tetrahedron：Asymmetry 2007,18 (17), 2099-2103, are former using cinnamate Material, through Sharpless Asymmetrical dihydroxylation, the classical reaction such as Barton-McCombie deoxidizer Mitsunobu, but step Tediously long, complex operation.
Route four：Tetrahedron 2009,65 (12), 2605-2609, react through seven steps from 3- hydroxyazetidinium ketone Obtain (S) -3- dimethylamino -3- phenyl-1-propanol, dapoxetine is being further converted to according to document.
Route five：Chinese patent CN101875666 adopts chiral reagent sulfenamide, first with 3- tertiary butyl dimethyl Si Propionic aldehyde reacts, and obtains Chiral Amine, then with grignard reagent reacting, obtains chiral intermediate, then reaches through series reaction acquisition Bo Xi spit of fland.
As can be seen here, the preparation method with regard to dapoxetine hydrochloride is relatively more at present, but these preparation methoies have various The shortcoming of various kinds, carries out chiral separation if desired for intermediate or product, leads to yield relatively low；Overall route is long, loaded down with trivial details, fall Low gross production rate of product etc..Therefore, seek a kind of more easy, high income the preparation method of operation very necessary.
The present invention by inventor's long-term experiment provide a kind of easy and simple to handle, route is short, post processing is simple, yield and pure Spend high dapoxetine hydrochloride preparation method, the method is suitable for industrialized production.
Content of the invention
The present invention needs using fractured operation, receipts in the middle production procedure of dapoxetine to overcome in prior art Rate is not high or the not high defect of optical purity, and provides a kind of new dapoxetine preparation method.The preparation method bar of the present invention Part is gentle, simple to operate, it is simple using fractured operation, post processing not need, and product yield, chemical purity, optical purity are high, fit Together in industrialized production.
The present invention adopts following synthetic method：
Specifically include the steps：
1) Formula IV compound and Formula V compound are dissolved in dry anhydrous organic solvent, add solid base, heating is anti- Should, after Formula IV compound reacts completely, it is cooled to room temperature, add anhydrous CuSO4(S)-t-butyl sulfonamide, stirring Under, add condensing agent Ti (OEt)4, reacting by heating, after reaction terminates, separate and obtain intermediate compound IV；
2) by step 1) intermediate compound IV for preparing is dissolved in anhydrous THF, maintains temperature below 0 DEG C, be dividedly in some parts Reducing agent, finishes, and continues stirring reaction, after reaction terminates below 0 DEG C；Add HCl ethanol solution, stirring reaction at room temperature 0.5-2h, concentrating under reduced pressure, residue adds diisopropyl ether stirring, filters, and filter cake is soluble in water, adjusts pH with alkali liquor and is more than or equal to 7, then it is extracted with ethyl acetate, be dried, be concentrated to give intermediate compound III；
3) formula III compound is carried out methylation reaction, obtaining Formula II compound is dapoxetine；
4) by Formula II compound through salt-forming reaction, obtain dapoxetine hydrochloride；
As preferred scheme, organic solvent of the present invention refer to DMF, THF, dioxane, in methyl tertiary butyl ether(MTBE) One or more, preferably THF, dioxane.
As preferred scheme, step 1) described in solid base be selected from NaOH, KOH, NaHCO3、KHCO3、Na2CO3、K2CO3 In at least one.
Further, step 2) described in reducing agent be selected from KBH4, NaBH4、BH3One of many or multiple, preferably BH3, It is highly preferred that BH3With BH3Tetrahydrofuran complex form uses.
Preferably, step 2) in alkali liquor be selected from：NaOH、KOH、NaHCO3、KHCO3、Na2CO3、K2CO3Aqueous solution.
As preferred scheme, step 3) described in methylation reaction carry out as follows：Formula III compound is dissolved in CH2Cl2In, add triethylamine, be cooled to less than 0 DEG C, Deca CH3I, drips and finishes, and reacts 4-6h at room temperature, is prepared into arrival pool Xi Ting.
Further, step 4) described in salt-forming reaction carry out as follows：Formula II compound is dissolved in ethyl acetate In, then pass to hydrogen chloride gas, separate out a large amount of solids, filter, gained solid recrystallisation from isopropanol obtains dapoxetine hydrochloride.
Preferably, step 1) described in heat, refer to be heated to 50 DEG C～120 DEG C, preferably 65 DEG C～85 DEG C.
It is further preferred that step 1) described in isolate and purify be to pour reactant liquor in ethyl acetate and saline solution into, point From organic layer, aqueous layer with ethyl acetate is repeatedly extracted, and merges organic layer, is concentrated into grease, adds diisopropyl ether, stirring analysis Go out faint yellow solid.
Room temperature of the present invention refers to 20-30 DEG C.
The method of the present invention has following good effect：
1) in step 1) condensation reaction in, add anhydrous CuSO4, on the one hand the water of reaction generation is removed, really Protect condensation reagent Ti (OEt)4It is not destroyed, be conducive to the carrying out of condensation reaction；On the other hand, anhydrous CuSO4Itself also can conduct Condensing agent concerted catalysis condensation reaction；Improve reaction yield；
2) the preparation method mild condition of the present invention, simple to operate, low cost, do not need using fractured operation or using high Precious metal catalyst, post processing are simple, and product yield is higher, and chemical purity and optical purity are high, are suitable for industrialized production.
Specific embodiment
Embodiment 1
16.85g Formula IV compound and 14.51g Formula V compound are dissolved in the oxolane that 150mL is dried, add 5.60g solid KOH, is heated to 60 DEG C of reactions, TLC monitors, and after reacting completely to Formula IV compound, is cooled to room temperature, adds 20g Anhydrous CuSO4With 14.52g (S)-t-butyl sulfonamide, under stirring, add 27.36g condensing agent Ti (OEt)4, back flow reaction, After reaction terminates, reactant liquor is poured in ethyl acetate and saline solution, separate organic layer, aqueous layer with ethyl acetate is repeatedly extracted Take, merge organic layer, be concentrated into grease, add diisopropyl ether, it is formula IV intermediate 34.5g that stirring separates out faint yellow solid, receive Rate 91.0%, purity 95% (HPLC area normalization method).
MS(ES+)m/z：402[M+Na]+.1H-NMR(CDCl3)δ：1.37(s,9H)；3.71-4.06(m,2H)；4.46- 4.59(m,2H)；6.83(d,1H)；7.26-7.52(m,8H)；7.77(m,1H)；8.12(m,1H).
Embodiment 2
18.8g formula IV compound is dissolved in the anhydrous THF of 150mL, is cooled to less than 0 DEG C, be dividedly in some parts reducing agent BH3Four Hydrogen furan complex (50mL, 1eq), finishes, and continues stirring reaction below 0 DEG C, and reaction 3h terminates；Add HCl at room temperature Ethanol solution (3eq), to reactant liquor, stirring reaction 0.5-2h, concentrating under reduced pressure, adds diisopropyl ether stirring, filters, filter cake is dissolved in In water, it is slowly added dropwise 10%NaOH aqueous solution, adjust pH and be more than or equal to 7, then use ethyl acetate (90mL × 2) to extract, be dried, Concentrate, obtain formula III intermediate 12.6g, yield 91.9%, purity 98% (HPLC area normalization method), 99%ee.
MS(ES+)m/z：278[M+H]+.1H-NMR(CDCl3)δ：2.33(m,2H)；4.10(m,1H)；4.21(m,1H)； 4.33(m,1H)；6.73(d,1H)；7.26-7.49(m,8H)；7.78(m,1H)；8.23(m,1H).
Embodiment 3
10g formula III compound is dissolved in 80mL CH2Cl2In, add 12mL triethylamine, be cooled to less than 0 DEG C, by 6mL CH3I is dissolved in 20mL CH2Cl2, then it is slowly dropped into, drip and finish, room temperature reaction 5h, after reaction terminates, add Na2SO3Aqueous solution stirs Mix, standing, separate organic layer, be dried, be evaporated that to obtain 9.8g Formula II compound be dapoxetine, yield 89.1%, purity 94% (HPLC area normalization method).
Embodiment 4
5g Formula II compound is dissolved in 50mL ethyl acetate, under ice bath, is passed through excess chlorination hydrogen 1.5h, separate out big Amount solid, is stirred at room temperature 1.5h, filters, and gained solid recrystallisation from isopropanol obtains 5.05g dapoxetine hydrochloride, yield 90.1%, purity 99.8% (HPLC area normalization method), 99%ee, m.p.179～181 DEG C, [α]23 D=+131 (c=1%, MeOH).
Comparative example 5
Method according to embodiment 1 is carried out, but is added without anhydrous CuSO4, 16.85g Formula IV compound obtains 30g formula IV, I.e. yield is 80% about, and HPLC purity is 88%.

Claims (8)

1. a kind of preparation method of dapoxetine hydrochlorate, comprises the steps：
1) Formula IV compound and Formula V compound are dissolved in dry anhydrous organic solvent, add solid base, reacting by heating, treat After Formula IV compound reacts completely, it is cooled to room temperature, add anhydrous CuSO4(S)-t-butyl sulfonamide, under stirring, adds Condensing agent Ti (OEt)4, reacting by heating, after reaction terminates, separate and obtain intermediate compound IV；
2) by step 1) intermediate compound IV for preparing is dissolved in anhydrous THF, maintains temperature below 0 DEG C, be dividedly in some parts reduction Agent, finishes, and continues stirring reaction, after reaction terminates below 0 DEG C；Add HCl ethanol solution, stirring reaction 0.5- at room temperature 2h, concentrating under reduced pressure, residue adds diisopropyl ether stirring, filters, and filter cake is soluble in water, adjusts pH with alkali liquor and is more than or equal to 7, so After be extracted with ethyl acetate, be dried, be concentrated to give intermediate compound III；
3) formula III compound is carried out methylation reaction, obtaining Formula II compound is dapoxetine；
4) by Formula II compound through salt-forming reaction, obtain dapoxetine hydrochloride；
Reaction scheme is as follows：
2. the preparation method described in claim 1 it is characterised in that：Step 1) described in organic solvent be selected from DMF, THF, dioxy One or more of six rings, methyl tertiary butyl ether(MTBE).
3. the method described in any one of claim 1-2 it is characterised in that：Step 1) described in solid base be selected from NaOH, KOH, NaHCO3、KHCO3、Na2CO3、K2CO3In at least one.
4. the method any one of claim 1-3 it is characterised in that：Step 2) described in reducing agent be selected from KBH4、 NaBH4、BH3One of many or multiple, preferably BH3.
5. the method described in claim 4 it is characterised in that：BH3With BH3Tetrahydrofuran complex form uses.
6. the method any one of claim 1-4 it is characterised in that：Step 3) described in methylation reaction press as lower section Method is carried out：Formula III compound is dissolved in CH2Cl2In, add triethylamine, be cooled to less than 0 DEG C, Deca CH3I, drips and finishes, in room temperature Lower reaction 4-6h, prepares dapoxetine.
7. the method any one of claim 1-5 it is characterised in that：Step 4) described in salt-forming reaction as follows Carry out：Formula II compound is dissolved in ethyl acetate, then passes to hydrogen chloride gas, separate out a large amount of solids, filter, gained solid Obtain dapoxetine hydrochloride with recrystallisation from isopropanol.
8. the method any one of claim 1-7 it is characterised in that：Step 2) described in alkali liquor be selected from：NaOH、KOH、 NaHCO3、KHCO3、Na2CO3、K2CO3Aqueous solution.
CN201610695061.3A 2016-08-19 2016-08-19 A kind of preparation method of Dapoxetine hydrochloride hydrochloride Active CN106397227B (en)

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Cited By (3)

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CN107473977A (en) * 2017-09-21 2017-12-15 成都海杰亚医药科技有限公司 Intermediate and the preparation method of Dapoxetine hydrochloride prepared by a kind 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
CN111763700A (en) * 2020-06-23 2020-10-13 南京欧信医药技术有限公司 Biosynthesis method of dapoxetine intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107473977A (en) * 2017-09-21 2017-12-15 成都海杰亚医药科技有限公司 Intermediate and the preparation method of Dapoxetine hydrochloride prepared by a kind 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
CN111763700A (en) * 2020-06-23 2020-10-13 南京欧信医药技术有限公司 Biosynthesis method of dapoxetine intermediate
CN111763700B (en) * 2020-06-23 2023-07-04 南京欧信医药技术有限公司 Biosynthesis method of dapoxetine intermediate

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