CN107935866A - The preparation method of dapoxetine hydrochloride impurity - Google Patents
The preparation method of dapoxetine hydrochloride impurity Download PDFInfo
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- CN107935866A CN107935866A CN201711242398.XA CN201711242398A CN107935866A CN 107935866 A CN107935866 A CN 107935866A CN 201711242398 A CN201711242398 A CN 201711242398A CN 107935866 A CN107935866 A CN 107935866A
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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
- 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
- C07C269/04—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 from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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Abstract
The invention discloses the similar impurity of 3 structures of dapoxetine hydrochloride：(S) 3 (1 epoxide of naphthalene) 1 phenyl propyl, 1 amine (compound ii), 1 amine (compound III) of (S) N methyl 3 (1 epoxide of naphthalene) 1 phenyl propyl and (S) N, the preparation method of 1 amine (compounds Ⅳ) of N-dimethyl 3 (2 epoxide of naphthalene) 1 phenyl propyl.Using 3 phenyl propyl of (S) 3 amido, 1 alcohol (VII) as starting material, dapoxetine hydrochloride impurity compound II, compound III and compounds Ⅳ are made respectively by multistep reactions such as amido protecting, hydroxy activated, substitution, amino deprotections.The syntheti c route starting material is easy to get；Reaction condition is gentle, high selectivity；It can be obtained by the sample of higher degree (more than 98%) by conventional post-processing approach, can be as the reference substance of dapoxetine hydrochloride impurity compound II, compound III and compounds Ⅳ, the quality control for dapoxetine hydrochloride study on the synthesis.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to the similar impurity of 3 structures of dapoxetine hydrochloride (I),
(S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine (II), (S)-N- methyl -3- (naphthalene -1- epoxides) -1- phenyl propyls -1-
The preparation method of amine (III) and (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine (IV).
Background technology
Dapoxetine hydrochloride (Dapoxetine Hydrochloride, I), entitled (S)-(+)-N, the N- dimethyl of chemistry-
3- (1- naphthoxys) phenylpropyl alcohol amine hydrochlorate, is a kind of new serotonin reuptake inhibitor class medicine, is had fast in human body
The pharmacokinetics feature such as speed absorption and removing, becomes the first oral medicine for needing type for being approved for treatment prospermia of males (PE)
(tablet), so far more than 50 state approval listings in the world.
The chemical constitution of dapoxetine hydrochloride (I) impurity II, III, IV similar with 3 structures is as follows：
Impurity research is the important content of study of pharmacy, directly related with the security and validity of medicine.Compound ii,
III and IV in document Australian Public Assessment Report for Dapoxetine and state food medicine
Addressed in Surveillance Authority import registered standard JX 20090323, three has similar to dapoxetine hydrochloride bulk pharmaceutical chemicals
Structure, both comprising degradation impurity, further include the potential impurity of technique.EP2168947 relate to the preparating example of impurity III.But
Research is found：By EP2168947 literature methods, during intermediate V bromination reactions, due to the ether tool of the naphthalene nucleus 1 of intermediate V
There is activation, it is easier to which 4 in naphthalene nucleus occur nucleophilic bromo-reaction.Except a small amount of VI in product, further comprises more
VI a and VI b, this mixture continue with methylamine react, finally only obtain containing a small amount of target product III and be difficult to separated
Mixture.
The content of the invention
Based on above the deficiencies in the prior art, technical problem solved by the invention be to provide a kind of high selectivity, into
The preparation method of this relatively low, mild condition dapoxetine hydrochloride impurity II, III and IV, obtaining the sample of higher degree can make
For the reference substance of impurity II, III and IV, for inspection of the dapoxetine hydrochloride in relation to material.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
The present invention provides a kind of preparation method of dapoxetine hydrochloride impurity, and the structure of compound ii is：Chemical name is (S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine；
The preparation method of the compound ii includes the following steps：
The structure of the compound Ⅸ is:
Wherein, R1For one kind in methane sulfonyl, p-toluenesulfonyl, benzenesulfonyl or trifyl.
As the preferred of above-mentioned technical proposal, the preparation method of dapoxetine hydrochloride impurity provided by the invention is further wrapped
Include the part or all of of following technical characteristic：
As the improvement of above-mentioned technical proposal, the preparation method of dapoxetine hydrochloride impurity II provided by the invention includes such as
Lower step：
Step 1: under base catalysis, compound VII (S) -3- amido -3- phenyl propyl -1- alcohol is mixed with phthalic anhydride
With or be dissolved in organic solvent, heating obtain compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- bis-
Ketone；
It is Step 2: the hydroxyl of compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone is activated
Compound Ⅸ is obtained, is dissolved under base catalysis, then by compound Ⅸ and 1- naphthols in organic solvent, is heated and obtained by substitution reaction
To compound Ⅹ (S) -2- (3- (naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone；
Step 3: in organic solvent, under heating condition, reagent is removed by (the S) -2- of compound Ⅹ (3- with protection group
(naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone benzyl bit amino protection group remove to obtain compound ii (S) -
3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine.
As the improvement of above-mentioned technical proposal, the molar ratio of VII compound of formula and phthalic anhydride is 1:1-3；Step
The catalyst that base catalysis process described in rapid one uses is DMAP (4-dimethylaminopyridine), DBN (1,5- diazabicyclos
[4.3.0] -5- nonenes), one kind in DBU (11 carbon -7- alkene of 1,8- diazabicylos [5.4.0])；Heating reaction temperature is
80~140 DEG C；The organic solvent is benzene,toluene,xylene, ethylo benzene, chlorobenzene or without using solvent；
In step 2, organic solvent used in the substitution reaction be selected from ethyl acetate, acetonitrile, toluene, tetrahydrofuran,
Any one of DMF or acetone or at least two mixed solvent；Alkali used in the substitution reaction is organic base or nothing
Machine alkali, is preferably potassium carbonate or potassium hydroxide；Heating-up temperature is 60~100 DEG C；
In step 3, the organic solvent is selected from any one of acetonitrile, methanol, ethanol, tetrahydrofuran, DMF or water
Or at least two mixed solvent；The protection group removes reagent as one kind in methylamine, ethamine or hydrazine hydrate, the guarantor
The molar ratio for protecting base removing reagent and Formula Ⅹ is 1:1-10；The heating reaction temperature is 60~90 DEG C.
As the improvement of above-mentioned technical proposal, the preparation method of the dapoxetine hydrochloride impurity, it is characterised in that also
Preparation method including compound III, the structure of the compound III are：
Chemical name is (S)-N- methyl -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine；
The preparation method of the compound III includes the following steps：Compound ii described in claim 1 is passed through into acid amides
To change reaction and obtain compound Ⅺ, the reduction of compound Ⅺ obtains compound III,
The structure of the compound Ⅺ is shown below:
Wherein, R2Including but not limited to C1~C4Alkyl, benzyl or fluorene methyl.
As the improvement of above-mentioned technical proposal, compound ii (S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine first leads to
Superamide reacts to obtain compound Ⅺ, then compound Ⅺ is dissolved in organic solvent, under heating condition, occurs also with reducing agent
Original reaction obtains compound III.
As the improvement of above-mentioned technical proposal, organic solvent used is selected from ether, Isosorbide-5-Nitrae-dioxa in the reduction reaction
Any one of hexamethylene, toluene, tetrahydrofuran or 2- methyltetrahydrofurans or at least two mixed solvent；Reduction reaction
Used reducing agent is selected from BH3、LiBH4、ZnBH4、NaBH4/AlCl3Or LiAlH4。
As the improvement of above-mentioned technical proposal, the preparation method of the dapoxetine hydrochloride impurity, it is characterised in that also
Preparation method including compounds Ⅳ, the structure of the compounds Ⅳ are：
Chemical name is (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine；
The preparation method of the compounds Ⅳ includes the following steps：
As the improvement of above-mentioned technical proposal, the preparation method of the dapoxetine hydrochloride impurity IV is：
Step 1: under base catalysis, compound VII (S) -3- amido -3- phenyl propyl -1- alcohol is mixed with phthalic anhydride
With or be dissolved in organic solvent, heating obtain compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- bis-
Ketone；
It is Step 2: the hydroxyl of compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone is activated
Compound Ⅸ is obtained, is dissolved under base catalysis, then by compound Ⅸ and beta naphthal in organic solvent, is heated and obtained by substitution reaction
To compound Ⅹ a (S) -2- (3- (naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone；
Step 3: in organic solvent, under heating condition, reagent is removed by compound Ⅹ a (S) -2- (3- with protection group
(naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone benzyl bit amino protection group remove to obtain compound ii a (S) -
3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine；
Step 4: compound ii a (S) -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine and methylation reaction reagent reacting
Compounds Ⅳ (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine is made.
As the improvement of above-mentioned technical proposal, the molar ratio of VII compound of formula and phthalic anhydride is 1:1-3；Step
The catalyst that base catalysis process described in rapid one uses is DMAP (4-dimethylaminopyridine), DBN (1,5- diazabicyclos
[4.3.0] -5- nonenes), one kind in DBU (11 carbon -7- alkene of 1,8- diazabicylos [5.4.0])；Heating reaction temperature is
80~140 DEG C；The organic solvent is benzene,toluene,xylene, ethylo benzene, chlorobenzene or without using solvent；
In step 2, organic solvent used in the substitution reaction be selected from ethyl acetate, acetonitrile, toluene, tetrahydrofuran,
Any one of DMF or acetone or at least two mixed solvent；Alkali used in the substitution reaction is organic base or nothing
Machine alkali, is preferably potassium carbonate or potassium hydroxide；Heating-up temperature is 60~100 DEG C；
In step 3, the organic solvent is selected from any one of acetonitrile, methanol, ethanol, tetrahydrofuran, DMF or water
Or at least two mixed solvent；The protection group removes reagent as one kind in methylamine, ethamine or hydrazine hydrate, the guarantor
It is 1 that base removing reagent, which is protected, with Ⅹ a molar ratios of Formula:1-10；The heating reaction temperature is 60~90 DEG C；
In step 4, the methylating reagent is selected from dimethyl suflfate, dimethyl carbonate, iodomethane, thionyl chloride/first
One kind in alcohol, formaldehyde/formic acid or paraformaldehyde/formic acid；Preferably formaldehyde/formic acid, methylation reaction solvent for use are selected from C1
~C4Any one of alkylol or water or at least two mixed solvent.
Compared with prior art, technical scheme has the advantages that：Impurity II, III and IV is synthesized to use
Starting material it is identical with the starting material of synthetic hydrochloric acid Dapoxetine hydrochloride bulk pharmaceutical chemicals, raw material is easy to get；Reaction condition is gentle, selectivity
It is high；It can be obtained by the sample of higher degree (more than 98%) by conventional post-processing approach, Bo Xi can be reached as hydrochloric acid
The reference substance of spit of fland impurity II, III and IV, for inspection of the dapoxetine hydrochloride in relation to material.
Described above is only the general introduction of technical solution of the present invention, in order to better understand the technological means of the present invention,
And can be practiced according to the content of specification, and in order to allow the above and other objects, features and advantages of the present invention can
Become apparent, below in conjunction with preferred embodiment, describe in detail as follows.
Brief description of the drawings
In order to illustrate the technical solution of the embodiments of the present invention more clearly, will simply it be situated between to the attached drawing of embodiment below
Continue.
Attached drawing 1 is syntheti c route figure of the present invention on dapoxetine hydrochloride impurity II, III and IV；
Attached drawing 2 is the LC/ of embodiment 1 (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone (compound VIII)
MS collection of illustrative plates；
Attached drawing 3 is embodiment 1 (S) -2- (3- (naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (compounds
Ⅹ) LC/MS collection of illustrative plates；
Attached drawing 4 is embodiment 1 (S) -2- (3- (naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (compounds
Ⅹ) nuclear magnetic resonance map；
Attached drawing 5 is the LC/MS collection of illustrative plates of embodiment 1 (S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine (compound ii)；
Attached drawing 6 is the nuclear magnetic resonance figures of embodiment 1 (S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine (compound ii)
Spectrum；
Attached drawing 7 is embodiment 2 (S)-N- methyl -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- ammonium salt hydrochlorate (compounds
III) nuclear magnetic resonance map；
Attached drawing 8 is embodiment 3 (S) -2- (3- (naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (compounds
Ⅹ LC/MS collection of illustrative plates a)；
Attached drawing 9 is embodiment 3 (S) -2- (3- (naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (compounds
Ⅹ nuclear magnetic resonance map a)；
Attached drawing 10 is embodiment 3 (S) -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine (LC/MS figures of compound ii a)
Spectrum；
Attached drawing 11 is embodiment 3 (S) -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine (nuclear magnetic resonance of compound ii a)
Collection of illustrative plates；
Attached drawing 12 is that embodiment 3 (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- ammonium salts hydrochlorate (is changed
Compound IV) LC/MS collection of illustrative plates；
Attached drawing 13 is that embodiment 3 (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- ammonium salts hydrochlorate (is changed
Compound IV) nuclear magnetic resonance map.
Embodiment
The following detailed description of the present invention embodiment, its as part of this specification, by embodiment come
Illustrate the principle of the present invention, other aspects of the present invention, feature and its advantage will become apparent by the detailed description.
Attached drawing 1 is syntheti c route figure of the present invention on dapoxetine hydrochloride impurity II, III and IV.
The synthesis of 1 dapoxetine hydrochloride impurity II of embodiment
(S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone (compound VIII)
By compound VII (18.1g, 0.12mol) and phthalic anhydride (17.8g, 0.12mol), 4-dimethylaminopyridine
(1.5g, 0.012mol) is uniformly mixed, and being heated in 140 DEG C of oil baths melts reactant, and insulation reaction 3h, naturally cools to room
Temperature, reactant ethyl acetate (120ml) dissolve, then successively with 1mol/L dilute hydrochloric acid (50ml), 10% aqueous sodium carbonate
(50ml) is washed.Dry, filtering, filtrate decompression concentration, obtains pale yellow oil, is compound VIII (27.2g, 80.4%).
Attached drawing 2 is the LC/ of embodiment 1 (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone (compound VIII)
MS collection of illustrative plates.LC/MS(m/s):282.2[M+H]+, 304.1 [M+Na]+。
(S) -3- (1,3- dioxy iso-indoles -2- bases) -3- phenyl propyl -4- toluenesulfonic acids esters (compound Ⅸ)
Under ice bath cooling, compound VIII (16.8g, 0.06mol) and triethylamine (12.1g, 0.12mol) are dissolved in dichloromethane
In alkane (170ml), paratoluensulfonyl chloride (11.4g, 0.06mol) is added, reacts at room temperature 24h.Reaction solution is dilute with 1mol/L successively
Hydrochloric acid (80ml), 10% aqueous sodium carbonate (80ml) washing.Dry, filtering, filtrate decompression concentration, obtains pale yellow oil,
For compound Ⅸ (24.1g, 92.2%).Without being further purified, it is directly used in and reacts in next step.
(S) -2- (3- (naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (compound Ⅹ)
Anhydrous potassium carbonate (12.4g, 0.09mol) and 1- naphthols (4.3g, 0.03mol) are put into acetone (80ml),
2h is reacted in 70 DEG C of oil baths.It is another to take compound Ⅸ (13.1g, 0.03mol) to add above-mentioned mixing with after acetone (50ml) dissolving
In thing, back flow reaction is overnight.Reaction solution is filtered under diminished pressure after being cooled to room temperature, and filtrate is concentrated to dryness.Gained crude product is through column chromatography (stone
Oily ether: ethyl acetate=15: 1) purify, obtain yellow-brown solid, be compound Ⅹ (7.4g, 60.6%).
Attached drawing 3 is embodiment 1 (S) -2- (3- (naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (compounds
Ⅹ) LC/MS collection of illustrative plates；Attached drawing 4 is embodiment 1 (S) -2- (3- (naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone
The nuclear magnetic resonance map of (compound Ⅹ).LC/MS(m/s):430.1[M+Na]+；1H NMR(400MHz,CDCl3)δ:2.97~
3.05 (m, 1H), 3.22~3.31 (m, 1H), 4.24 (t, J=5.8Hz, 2H), 5.87 (dd, J=9.0,7.0Hz, 1H), 6.74
(d, J=7.6Hz, 1H), 7.28~7.51 (m, 7H), 7.65~7.69 (m, 4H), 7.77~7.81 (m, 3H), 8.25 (d, J=
7.6Hz,1H)。
(S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine (dapoxetine hydrochloride impurity II)
85% hydrazine hydrate (4ml) is added in ethanol (100ml) suspension of compound Ⅹ (5.5g, 0.013mol),
Back flow reaction 3h.It is filtered under diminished pressure after being cooled to room temperature, filtrate decompression obtains pale tan oil after being concentrated to dryness, and is compound ii
(3.5g, 97.1%).
Attached drawing 5 is the LC/MS collection of illustrative plates of embodiment 1 (S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine (compound ii)；
Attached drawing 6 is the nuclear magnetic resonance map of embodiment 1 (S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine (compound ii).LC/MS
(m/s):278.2[M+H]+；1H NMR(400MHz,CDCl3)δ:2.24~2.41 (m, 2H), 4.08~4.13 (m, 1H), 4.22
~4.26 (m, 1H), 4.39 (t, J=7.0Hz, 1H), 6.78 (d, J=7.4Hz, 1H), 7.27~7.56 (m, 9H), 7.81~
7.86 (m, 1H), 8.28~8.32 (m, 1H).
The synthesis of 2 dapoxetine hydrochloride impurity III of embodiment
(S)-tert-butyl group (3- (naphthalene -1- epoxides) -1- phenyl propyls) carbamate (compound Ⅺ)
Under ice bath cooling, di-tert-butyl dicarbonate (4.4g, 0.020mol) is dissolved in dichloromethane (20ml), is added drop-wise to
In the dichloromethane solution of compound ii (5.0g, 0.018mol) and triethylamine (2.1g, 0.021mol).Drop finishes, and is warmed to room temperature
Reaction is overnight.Washed with water (2 × 40ml), organic phase is dried with anhydrous magnesium sulfate, filtering, filtrate decompression be concentrated to dryness class is white
Color solid, is compound Ⅺ (7.9g).Without being further purified, it is directly used in and reacts in next step.
(S)-N- methyl -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- ammonium salts hydrochlorate (salt of dapoxetine hydrochloride impurity III
Hydrochlorate)
At room temperature, tetrahydrofuran (30ml) solution of compound Ⅺ (6.0g, 0.016mol) is added drop-wise to Lithium Aluminium Hydride
In tetrahydrofuran (30ml) suspension of (3g, 0.079mol).Drop finishes, and is warming up to back flow reaction 2h.After dropping to room temperature, water is added dropwise
Reaction is quenched, 30% sodium hydrate aqueous solution (20ml), diatomite (10g) are sequentially added into reaction bulb.It is filtered under diminished pressure, filters
Liquid evaporated under reduced pressure, residue are extracted with ethyl acetate (2 × 50ml), add concentrated hydrochloric acid (6ml), evaporated under reduced pressure, residue is with different
Propyl alcohol is recrystallized to give off-white powder, is the hydrochloride (3.1g, 59.1%) of compound III.
Attached drawing 7 is embodiment 2 (S)-N- methyl -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- ammonium salt hydrochlorate (compounds
III) nuclear magnetic resonance map.1H NMR(400MHz,CDCl3)δ:2.55 (s, 3H), 2.71~2.80 (m, 1H), 3.18~
3.27 (m, 1H), 3.71~3.78 (m, 1H), 4.06~4.11 (m, 1H), 4.46 (bs, 1H), 6.53 (d, J=7.4Hz, 1H),
7.22~7.51 (m, 7H), 7.60~7.63 (m, 2H), 7.75~7.79 (m, 1H), 8.16~8.19 (m, 1H), 10.09 (bs,
1H),10.53(bs,1H)。
The synthesis of 3 dapoxetine hydrochloride impurity IV of embodiment
(S) -2- (3- (naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (Ⅹ a of compound)
Anhydrous potassium carbonate (24.8g, 0.18mol) and beta naphthal (8.6g, 0.06mol) are put into N, N- dimethyl formyls
In amine (200ml), 2h is reacted in 90 DEG C of oil baths.Compound Ⅸ (26.1g, 0.06mol) is dissolved in N, N- dimethyl formyls again
After amine (120ml), add in said mixture, react 3h in 90 DEG C.Reaction solution is depressurized after being cooled to room temperature and filtered, filtrate decompression
Concentration steams 1/2 N,N-dimethylformamide.Water (400ml) and ethyl acetate (200ml) are added into residue, was depressurized
Filter, obtains off-white powder, is Ⅹ a of compound (13.1g, 53.6%).
Attached drawing 8 is embodiment 3 (S) -2- (3- (naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone (compounds
Ⅹ LC/MS collection of illustrative plates a)；Attached drawing 9 is embodiment 3 (S) -2- (3- (naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone
The nuclear magnetic resonance map of (Ⅹ a of compound).LC/MS(m/s):430.2[M+Na]+；1H NMR(400MHz,CDCl3)δ:2.83~
2.89 (m, 1H), 3.13~3.22 (m, 1H), 4.14 (t, J=5.9Hz, 2H), 5.74 (dd, J=9.4,6.6Hz, 1H), 6.99
~7.02 (m, 2H), 7.26~7.42 (m, 5H), 7.59~7.74 (m, 7H), 7.76~7.82 (m, 2H).
(S) -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine (compound ii a)
85% hydrazine hydrate (8ml) is added to ethanol (200ml) suspension of Ⅹ a of compound (10.1g, 0.025mol)
In, back flow reaction 3h.Cooled to room temperature, is filtered under diminished pressure removing insoluble solid.Filtrate decompression obtains light after being concentrated to dryness
Yellow oil, is compound ii a (6.8g, 98.2%).
Attached drawing 10 is embodiment 3 (S) -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine (LC/MS figures of compound ii a)
Spectrum；Attached drawing 11 is embodiment 3 (S) -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine (nuclear magnetic resonance maps of compound ii a).
LC/MS(m/s):278.3[M+H]+；
1H NMR(400MHz,CDCl3)δ:2.17~2.25 (m, 2H), 4.00~4.08 (m, 1H), 4.12~4.20 (m,
1H), 4.27 (t, J=6.9Hz, 1H), 7.08 (d, J=2.5Hz, 1H), 7.15 (dd, J=8.9,2.5Hz, 1H), 7.22~
7.47 (m, 7H), 7.69 (dd, J=8.2Hz, 1H), 7.76 (t, J=9.2Hz, 2H).
(S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- ammonium salts hydrochlorate (dapoxetine hydrochloride impurity IV
Hydrochloride)
By 37~40% formalin (7.1g, 0.090mol) be added to compound ii a (6.1g, 0.022mol),
In 88% formic acid solution (9.4g, 0.180mol) and the suspension of 40ml water, after back flow reaction 7h, room temperature is down to, to reaction
20% sodium hydroxide (50ml) is added in liquid, is extracted with ethyl acetate (3*100ml), merges organic pressure of subtracting each other and is evaporated, to surplus
The dilute hydrochloric acid (50ml) of 3moL/L, again with toluene (100ml) washing, liquid separation are added in excess.After water phase evaporated under reduced pressure, residue
Off-white powder is obtained with recrystallisation from isopropanol again, is the hydrochloride (3.4g, 45.2%) of compounds Ⅳ.
Attached drawing 12 is that embodiment 3 (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- ammonium salts hydrochlorate (is changed
Compound IV) LC/MS collection of illustrative plates；Attached drawing 13 is embodiment 3 (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyls -1-
The nuclear magnetic resonance map of ammonium salt hydrochlorate (compounds Ⅳ).
LC/MS(m/s):306.3[M+H]+；1H NMR(400MHz,CDCl3) δ 2.60 (d, J=4.9Hz, 3H), 2.76
(m, 1H), 2.94 (d, J=4.9Hz, 3H), 2.96~3.07 (m, 1H), 3.60 (td, J=10.0,3.4Hz, 1H), 4.10
(ddd, J=9.1,4.9,3.5Hz, 1H), 4.32 (ddd, J=11.0,6.6,3.6Hz, 1H), 6.90 (d, J=2.5Hz, 1H),
7.03 (dd, J=8.9,2.5Hz, 1H), 7.24~7.49 (m, 5H), 7.56~7.66 (m, 3H), 7.72 (dd, J=12.1,
8.5Hz,2H),12.85(s,1H)。
Each raw material cited by the present invention, and bound, the section value of each raw material of the present invention, and technological parameter
Bound, the section value of (such as temperature, time) can realize the present invention, embodiment numerous to list herein.
The above is the preferred embodiment of the present invention, cannot limit the right model of the present invention with this certainly
Enclose, it is noted that for those skilled in the art, without departing from the principle of the present invention, may be used also
To make some improvement and variation, these are improved and variation is also considered as protection scope of the present invention.
Claims (9)
1. a kind of preparation method of dapoxetine hydrochloride impurity, it is characterised in that the structure of compound ii is：
Chemical name is (S) -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine；
The preparation method of the compound ii includes the following steps：
The structure of the compound Ⅸ is:
Wherein, R1For one kind in methane sulfonyl, p-toluenesulfonyl, benzenesulfonyl or trifyl.
2. the preparation method of dapoxetine hydrochloride impurity as claimed in claim 1, it is characterised in that comprise the following steps：
Step 1: under base catalysis, compound VII (S) -3- amido -3- phenyl propyl -1- alcohol and phthalic anhydride are mixed or
Person is dissolved in organic solvent, and heating obtains compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone；
Step 2: obtain the hydroxyl of compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone is activated
Compound Ⅸ, is dissolved in organic solvent, heating passes through substitution reaction under base catalysis, then by compound Ⅸ and 1- naphthols
Compound Ⅹ (S) -2- (3- (naphthalene -1- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone；
Step 3: in organic solvent, under heating condition, reagent is removed by compound Ⅹ (S) -2- (3- (naphthalene -1- with protection group
Epoxide) -1- phenyl propyls) iso-indoles -1,3- diketone benzyl bit amino protection group remove to obtain compound ii (S) -3- (naphthalene -
1- epoxides) -1- phenyl propyl -1- amine.
3. the preparation method of dapoxetine hydrochloride impurity as claimed in claim 2, it is characterised in that：VII compound of formula and
The molar ratio of phthalic anhydride is 1:1-3；The catalyst that base catalysis process described in step 1 uses is DMAP (4- diformazans
Aminopyridine), DBN (1,5- diazabicyclos [4.3.0] -5- nonenes), DBU (11 carbon of 1,8- diazabicylos [5.4.0] -
7- alkene) in one kind；It is 80~140 DEG C to heat reaction temperature；The organic solvent is benzene,toluene,xylene, ethylo benzene, chlorine
Benzene or without using solvent；
In step 2, organic solvent used in the substitution reaction be selected from ethyl acetate, acetonitrile, toluene, tetrahydrofuran, DMF or
Any one of acetone or at least two mixed solvent；Alkali used in the substitution reaction is organic base or inorganic base,
Preferably potassium carbonate or potassium hydroxide；Heating-up temperature is 60~100 DEG C；
In step 3, the organic solvent is selected from any one of acetonitrile, methanol, ethanol, tetrahydrofuran, DMF or water or extremely
Mixed solvent two kinds few；The protection group removes reagent as one kind in methylamine, ethamine or hydrazine hydrate, the protection group
The molar ratio for removing reagent and Formula Ⅹ is 1:1-10；The heating reaction temperature is 60~90 DEG C.
4. the preparation method of dapoxetine hydrochloride impurity as claimed in claim 1, it is characterised in that further include compound III
Preparation method, the structure of the compound III are：
Chemical name is (S)-N- methyl -3- (naphthalene -1- epoxides) -1- phenyl propyl -1- amine；
The preparation method of the compound III includes the following steps：Compound ii described in claim 1 is anti-by amidatioon
Compound Ⅺ should be obtained, the reduction of compound Ⅺ obtains compound III,
The structure of the compound Ⅺ is shown below:
Wherein, R2Including but not limited to C1~C4Alkyl, benzyl or fluorene methyl.
5. the preparation method of dapoxetine hydrochloride impurity as claimed in claim 4, it is characterised in that：Compound ii (S) -3-
(naphthalene -1- epoxides) -1- phenyl propyl -1- amine first passes through amidation process and obtains compound Ⅺ, then compound Ⅺ is dissolved in organic
In solvent, under heating condition, reduction reaction occurs with reducing agent and obtains compound III.
6. the preparation method of dapoxetine hydrochloride impurity as claimed in claim 5, it is characterised in that：Institute in the reduction reaction
Any one of ether, 1,4- dioxanes, toluene, tetrahydrofuran or 2- methyltetrahydrofurans are selected from organic solvent
Or at least two mixed solvent；Reducing agent used in reduction reaction is selected from BH3、LiBH4、ZnBH4、NaBH4/AlCl3Or
LiAlH4。
7. a kind of preparation method of dapoxetine hydrochloride impurity, it is characterised in that the structure of compounds Ⅳ is：Chemical name is (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine；
The preparation method of the compounds Ⅳ includes the following steps：
8. the preparation method of dapoxetine hydrochloride impurity as claimed in claim 7, it is characterised in that：The system of the compounds Ⅳ
Preparation Method is,
Step 1: under base catalysis, compound VII (S) -3- amido -3- phenyl propyl -1- alcohol and phthalic anhydride are mixed or
Person is dissolved in organic solvent, and heating obtains compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone；
Step 2: obtain the hydroxyl of compound VIII (S) -2- (3- hydroxyl -1- phenyl propyls) iso-indoles -1,3- diketone is activated
Compound Ⅸ, is dissolved in organic solvent, heating passes through substitution reaction under base catalysis, then by compound Ⅸ and beta naphthal
Compound Ⅹ a (S) -2- (3- (naphthalene -2- epoxides) -1- phenyl propyls) iso-indoles -1,3- diketone；
Step 3: in organic solvent, under heating condition, reagent is removed by compound Ⅹ a (S) -2- (3- (naphthalene -2- with protection group
Epoxide) -1- phenyl propyls) iso-indoles -1,3- diketone benzyl bit amino protection group remove to obtain compound ii a (S) -3- (naphthalene -
2- epoxides) -1- phenyl propyl -1- amine；
Step 4: compound ii a (S) -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine is made with methylation reaction reagent reacting
Compounds Ⅳ (S)-N, N-dimethyl -3- (naphthalene -2- epoxides) -1- phenyl propyl -1- amine.
9. the preparation method of dapoxetine hydrochloride impurity as claimed in claim 8, it is characterised in that：VII compound of formula and
The molar ratio of phthalic anhydride is 1:1-3；The catalyst that base catalysis process described in step 1 uses is DMAP (4- diformazans
Aminopyridine), DBN (1,5- diazabicyclos [4.3.0] -5- nonenes), DBU (11 carbon of 1,8- diazabicylos [5.4.0] -
7- alkene) in one kind；It is 80~140 DEG C to heat reaction temperature；The organic solvent is benzene,toluene,xylene, ethylo benzene, chlorine
Benzene or without using solvent；
In step 2, organic solvent used in the substitution reaction be selected from ethyl acetate, acetonitrile, toluene, tetrahydrofuran, DMF or
Any one of acetone or at least two mixed solvent；Alkali used in the substitution reaction is organic base or inorganic base,
Preferably potassium carbonate or potassium hydroxide；Heating-up temperature is 60~100 DEG C；
In step 3, the organic solvent is selected from any one of acetonitrile, methanol, ethanol, tetrahydrofuran, DMF or water or extremely
Mixed solvent two kinds few；The protection group removes reagent as one kind in methylamine, ethamine or hydrazine hydrate, the protection group
It is 1 that reagent, which is removed, with Ⅹ a molar ratios of Formula:1-10；The heating reaction temperature is 60~90 DEG C；
In step 4, the methylating reagent be selected from dimethyl suflfate, dimethyl carbonate, iodomethane, thionyl chloride/methanol,
One kind in formaldehyde/formic acid or paraformaldehyde/formic acid；Preferably formaldehyde/formic acid, methylation reaction solvent for use are selected from C1~C4
Any one of alkylol or water or at least two mixed solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110937984A (en) * | 2018-09-21 | 2020-03-31 | 苏州科伦药物研究有限公司 | Dapoxetine hydrochloride related substance, preparation method and application thereof |
| CN113072466A (en) * | 2021-04-01 | 2021-07-06 | 湖南普道医药技术有限公司 | Synthetic method of dapoxetine impurity |
-
2017
- 2017-11-30 CN CN201711242398.XA patent/CN107935866B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| SASIKUMAR, M.等: "Simple and efficient synthesis of (S)-dapoxetine", 《 SYNTHETIC COMMUNICATIONS》 * |
| 戴蓉等: "盐酸达泊西汀的合成", 《中国新药杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110937984A (en) * | 2018-09-21 | 2020-03-31 | 苏州科伦药物研究有限公司 | Dapoxetine hydrochloride related substance, preparation method and application thereof |
| CN110937984B (en) * | 2018-09-21 | 2022-05-03 | 苏州科伦药物研究有限公司 | Dapoxetine hydrochloride related substance, preparation method and application thereof |
| CN113072466A (en) * | 2021-04-01 | 2021-07-06 | 湖南普道医药技术有限公司 | Synthetic method of dapoxetine impurity |
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