CN107935866B - Preparation method of dapoxetine hydrochloride impurity - Google Patents

Preparation method of dapoxetine hydrochloride impurity Download PDF

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CN107935866B
CN107935866B CN201711242398.XA CN201711242398A CN107935866B CN 107935866 B CN107935866 B CN 107935866B CN 201711242398 A CN201711242398 A CN 201711242398A CN 107935866 B CN107935866 B CN 107935866B
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phenylpropyl
naphthalene
dapoxetine hydrochloride
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CN107935866A (en
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王正雄
蔡泽宇
孟宪华
肖伟平
谢林霞
孙向阳
胡伟
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Hubei Hongyuan Pharmaceutical Technology Co ltd
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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
    • 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
    • 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
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • 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 invention discloses 3 impurities with similar structures of dapoxetine hydrochloride: (S) -3- (naphthalene-1-oxy) -1-phenylpropyl-1-amine (compound II), (S) -N-methyl-3- (naphthalene-1-oxy) -1-phenylpropyl-1-amine (compound III) and (S) -N, N-dimethyl-3- (naphthalene-2-oxy) -1-phenylpropyl-1-amine (compound IV). The dapoxetine hydrochloride impurity compound II, the compound III and the compound IV are respectively prepared by taking (S) -3-amido-3-phenylpropyl-1-alcohol (VII) as an initial raw material through multi-step reactions such as amino protection, hydroxyl activation, substitution, amino deprotection and the like. The initial raw materials of the preparation route are easy to obtain; the reaction condition is mild, and the selectivity is high; a sample with higher purity (more than 98 percent) can be obtained by a conventional post-treatment method, and the sample can be used as reference substances of dapoxetine hydrochloride impurity compounds II, III and IV for the quality control of dapoxetine hydrochloride synthesis research.

Description

Preparation method of dapoxetine hydrochloride impurity
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of 3 impurities with similar structures, (S) -3- (naphthalene-1-oxyl) -1-phenylpropyl-1-amine (II), (S) -N-methyl-3- (naphthalene-1-oxyl) -1-phenylpropyl-1-amine (III) and (S) -N, N-dimethyl-3- (naphthalene-2-oxyl) -1-phenylpropyl-1-amine (IV) of dapoxetine hydrochloride (I).
Background
Dapoxetine Hydrochloride (Dapoxetine Hydrochloride, I), the chemical name of which is (S) - (+) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine Hydrochloride, is a novel 5-hydroxytryptamine reuptake inhibitor drug, has the pharmacokinetic characteristics of rapid absorption and elimination in human bodies and the like, becomes the first required oral drug (tablet) approved for treating male Premature Ejaculation (PE), and has been approved to be marketed in more than 50 countries in the world so far.
The chemical structures of the dapoxetine hydrochloride (I) and 3 structurally similar impurities II, III and IV are as follows:
Figure BDA0001490157250000011
impurity research is an important content of pharmaceutical research and is directly related to the safety and effectiveness of drugs. The compounds II, III and IV are described in the literatures Australian Public Assessment Report for Dapoxetine and the national food and drug administration import registration standard JX 20090323, and have similar structures with Dapoxetine hydrochloride bulk drug, including degradation impurities and process potential impurities. EP2168947 relates to an example of the preparation of impurity iii. However, the research finds that: according to the method disclosed in EP2168947, when the intermediate V is brominated, nucleophilic bromination reaction is more likely to occur at the 4-position of naphthalene ring because the ether group at the 1-position of naphthalene ring of the intermediate V has activation effect. The product, which contains more VIa and VIb in addition to a small amount of VI, continues to react with methylamine, resulting in a mixture which contains only a small amount of the desired product III and is difficult to separate.
Figure BDA0001490157250000021
Figure BDA0001490157250000031
Disclosure of Invention
Based on the defects of the prior art, the technical problem solved by the invention is to provide the preparation method of the dapoxetine hydrochloride impurities II, III and IV, which has high selectivity, low cost and mild conditions, and the obtained sample with high purity can be used as a reference substance of the impurities II, III and IV and is used for checking related substances of the dapoxetine hydrochloride.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
Figure BDA0001490157250000032
the invention provides a preparation method of dapoxetine hydrochloride impurities, wherein a compound II has a structure as follows:
Figure BDA0001490157250000033
the chemical name is (S) -3- (naphthalene-1-oxyl) -1-phenyl propyl-1-amine;
the preparation method of the compound II comprises the following steps:
Figure BDA0001490157250000041
the compound IX has the structure:
Figure BDA0001490157250000042
wherein R is1Is one of methane sulfonyl, p-toluene sulfonyl, benzene sulfonyl or trifluoromethanesulfonyl.
As a preferred aspect of the above technical solution, the preparation method of dapoxetine hydrochloride impurity provided by the present invention further comprises a part or all of the following technical features:
as an improvement of the technical scheme, the preparation method of the dapoxetine hydrochloride impurity II comprises the following steps:
step one, mixing a compound VII (S) -3-amido-3-phenylpropyl-1-ol with phthalic anhydride or dissolving the mixture in an organic solvent under the catalysis of alkali, and heating to obtain a compound VIII (S) -2- (3-hydroxy-1-phenylpropyl) isoindole-1, 3-diketone;
step two, activating the hydroxyl of a compound VIII (S) -2- (3-hydroxyl-1-phenyl propyl) isoindole-1, 3-dione to obtain a compound IX, dissolving the compound IX and 1-naphthol in an organic solvent under the catalysis of alkali, heating and carrying out substitution reaction to obtain a compound X (S) -2- (3- (naphthalene-1-oxyl) -1-phenyl propyl) isoindole-1, 3-dione;
and step three, in an organic solvent, under the heating condition, removing the protecting group of the benzyl amino group of the compound X (S) -2- (3- (naphthalene-1-oxyl) -1-phenyl propyl) isoindole-1, 3-dione by using a protecting group removing reagent to obtain a compound II (S) -3- (naphthalene-1-oxyl) -1-phenyl propyl-1-amine.
As a modification of the technical scheme, the molar ratio of the compound shown in the formula VII to phthalic anhydride is 1: 1-3; the catalyst used in the base catalysis process in the first step is one of DMAP (4-dimethylaminopyridine), DBN (1, 5-diazabicyclo [4.3.0] -5-nonene) and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene); the heating reaction temperature is 80-140 ℃; the organic solvent is benzene, toluene, xylene, ethylbenzene, chlorobenzene or no solvent;
in the second step, the organic solvent used in the substitution reaction is selected from any one or a mixed solvent of at least two of ethyl acetate, acetonitrile, toluene, tetrahydrofuran, DMF and acetone; the alkali used in the substitution reaction is organic alkali or inorganic alkali, preferably potassium carbonate or potassium hydroxide; the heating temperature is 60-100 ℃;
in the third step, the organic solvent is selected from any one of acetonitrile, methanol, ethanol, tetrahydrofuran, DMF or water or a mixed solvent of at least two of the acetonitrile, the methanol, the ethanol, the tetrahydrofuran, the DMF or the water; the protecting group removing reagent is one of methylamine, ethylamine or hydrazine hydrate, and the molar ratio of the protecting group removing reagent to the compound X is 1: 1-10; the heating reaction temperature is 60-90 ℃.
As an improvement of the above technical solution, the preparation method of dapoxetine hydrochloride impurity is characterized by further comprising a preparation method of a compound iii, wherein the compound iii has a structure:
Figure BDA0001490157250000061
the chemical name is (S) -N-methyl-3- (naphthalene-1-oxyl) -1-phenylpropyl-1-amine;
the preparation method of the compound III comprises the following steps: subjecting the compound II as defined in claim 1 to amidation reaction to obtain a compound XI, reducing the compound XI to obtain a compound III,
Figure BDA0001490157250000062
the compound XI has the structure shown as the following formula:
Figure BDA0001490157250000063
wherein R is2Including but not limited to C1～C4Alkyl, benzyl or fluorenylmethyl.
As an improvement of the technical scheme, the compound II (S) -3- (naphthalene-1-oxyl) -1-phenylpropyl-1-amine is firstly subjected to amidation reaction to obtain a compound XI, and then the compound XI is dissolved in an organic solvent and subjected to reduction reaction with a reducing agent under the heating condition to obtain a compound III.
As an improvement of the above technical scheme, the organic solvent used in the reduction reaction is selected from any one of diethyl ether, 1, 4-dioxane, toluene, tetrahydrofuran or 2-methyltetrahydrofuran or a mixed solvent of at least two of the diethyl ether, the 1, 4-dioxane, the toluene, the tetrahydrofuran or the 2-methyltetrahydrofuran; the reducing agent used in the reduction is selected from BH3、LiBH4、ZnBH4、NaBH4/AlCl3Or LiAlH4。
As an improvement of the technical scheme, the preparation method of the dapoxetine hydrochloride impurity is characterized by further comprising a preparation method of a compound IV, wherein the compound IV has a structure as follows:
Figure BDA0001490157250000071
the chemical name is (S) -N, N-dimethyl-3- (naphthalene-2-oxyl) -1-phenylpropyl-1-amine;
the preparation method of the compound IV comprises the following steps:
Figure BDA0001490157250000072
as an improvement of the technical scheme, the preparation method of the dapoxetine hydrochloride impurity IV comprises the following steps:
step one, mixing a compound VII (S) -3-amido-3-phenylpropyl-1-ol with phthalic anhydride or dissolving the mixture in an organic solvent under the catalysis of alkali, and heating to obtain a compound VIII (S) -2- (3-hydroxy-1-phenylpropyl) isoindole-1, 3-diketone;
step two, activating the hydroxyl of a compound VIII (S) -2- (3-hydroxyl-1-phenyl propyl) isoindole-1, 3-diketone to obtain a compound IX, dissolving the compound IX and 2-naphthol in an organic solvent under the catalysis of alkali, heating and carrying out substitution reaction to obtain a compound Xa, (S) -2- (3- (naphthalene-2-oxyl) -1-phenyl propyl) isoindole-1, 3-diketone;
step three, in an organic solvent, under the heating condition, removing the protecting group of the benzyl amino group of the compound Xa (S) -2- (3- (naphthalene-2-oxyl) -1-phenyl propyl) isoindole-1, 3-diketone by using a protecting group removing reagent to obtain a compound IIA (S) -3- (naphthalene-2-oxyl) -1-phenyl propyl-1-amine;
step four, reacting the compound IIa (S) -3- (naphthalene-2-oxyl) -1-phenyl propyl-1-amine with a methylation reaction reagent to prepare the compound IV (S) -N, N-dimethyl-3- (naphthalene-2-oxyl) -1-phenyl propyl-1-amine.
As a modification of the technical scheme, the molar ratio of the compound shown in the formula VII to phthalic anhydride is 1: 1-3; the catalyst used in the base catalysis process in the first step is one of DMAP (4-dimethylaminopyridine), DBN (1, 5-diazabicyclo [4.3.0] -5-nonene) and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene); the heating reaction temperature is 80-140 ℃; the organic solvent is benzene, toluene, xylene, ethylbenzene, chlorobenzene or no solvent;
in the second step, the organic solvent used in the substitution reaction is selected from any one or a mixed solvent of at least two of ethyl acetate, acetonitrile, toluene, tetrahydrofuran, DMF and acetone; the alkali used in the substitution reaction is organic alkali or inorganic alkali, preferably potassium carbonate or potassium hydroxide; the heating temperature is 60-100 ℃;
in the third step, the organic solvent is selected from any one of acetonitrile, methanol, ethanol, tetrahydrofuran, DMF or water or a mixed solvent of at least two of the acetonitrile, the methanol, the ethanol, the tetrahydrofuran, the DMF or the water; the protecting group removing reagent is one of methylamine, ethylamine or hydrazine hydrate, and the molar ratio of the protecting group removing reagent to the compound formula Xa is 1: 1-10; the heating reaction temperature is 60-90 ℃;
in the fourth step, the methylating agent is selected from one of dimethyl sulfate, dimethyl carbonate, methyl iodide, thionyl chloride/methanol, formaldehyde/formic acid or paraformaldehyde/formic acid; preferably formaldehyde/formic acid, the solvent used in the methylation reaction being selected from C1～C4An alkyl alcohol or water, or a mixed solvent of at least two of them.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects: the starting materials for synthesizing the impurities II, III and IV are the same as those for synthesizing the dapoxetine hydrochloride bulk drug, and the raw materials are easy to obtain; the reaction condition is mild, and the selectivity is high; a sample with higher purity (more than 98%) can be obtained by a conventional post-treatment method, and the sample can be used as a reference substance of dapoxetine hydrochloride impurities II, III and IV and used for checking related substances of dapoxetine hydrochloride.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.
FIG. 1 is a schematic diagram of the preparation of dapoxetine hydrochloride impurities II, III and IV according to the present invention;
FIG. 2 is an LC/MS spectrum of (S) -2- (3-hydroxy-1-phenylpropyl) isoindole-1, 3-dione (Compound VIII) of example 1;
FIG. 3 is an LC/MS spectrum of (S) -2- (3- (naphthalene-1-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound X) of example 1;
FIG. 4 is a NMR spectrum of (S) -2- (3- (naphthalene-1-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound X) of example 1;
FIG. 5 is an LC/MS spectrum of (S) -3- (naphthalen-1-yloxy) -1-phenylpropyl-1-amine (compound II) of example 1;
FIG. 6 is a NMR spectrum of (S) -3- (naphthalen-1-yloxy) -1-phenylpropyl-1-amine (compound II) of example 1;
FIG. 7 is a NMR spectrum of (S) -N-methyl-3- (naphthalen-1-yloxy) -1-phenylpropyl-1-aminium hydrochloride (Compound III) of example 2;
FIG. 8 is an LC/MS spectrum of example 3(S) -2- (3- (naphthalene-2-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound Xa);
FIG. 9 is a NMR spectrum of example 3(S) -2- (3- (naphthalene-2-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound Xa);
FIG. 10 is an LC/MS spectrum of example 3(S) -3- (naphthalen-2-yloxy) -1-phenylpropyl-1-amine (compound IIa);
FIG. 11 is a NMR spectrum of (S) -3- (naphthalen-2-yloxy) -1-phenylpropyl-1-amine example 3 (compound IIa);
FIG. 12 is an LC/MS spectrum of example 3(S) -N, N-dimethyl-3- (naphthalen-2-yloxy) -1-phenylpropyl-1-aminium hydrochloride (Compound IV);
FIG. 13 is a NMR spectrum of (S) -N, N-dimethyl-3- (naphthalen-2-yloxy) -1-phenylpropyl-1-aminium hydrochloride (Compound IV) of example 3.
Detailed Description
Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.
FIG. 1 is a scheme showing the preparation of dapoxetine hydrochloride impurities II, III and IV.
Example 1 Synthesis of dapoxetine hydrochloride impurity II
(S) -2- (3-hydroxy-1-phenylpropyl) isoindole-1, 3-dione (Compound VIII)
The compound VII (18.1g, 0.12mol) is uniformly mixed with phthalic anhydride (17.8g, 0.12mol) and 4-dimethylamino pyridine (1.5g, 0.012mol), heated in oil bath at 140 ℃ to melt the reactant, kept warm for reaction for 3h, naturally cooled to room temperature, the reactant is dissolved by ethyl acetate (120ml), and then washed by 1mol/L diluted hydrochloric acid (50ml) and 10% sodium carbonate aqueous solution (50ml) in sequence. Drying, filtration and concentration of the filtrate under reduced pressure gave compound VIII as a pale yellow oil (27.2g, 80.4%).
FIG. 2 is an LC/MS spectrum of (S) -2- (3-hydroxy-1-phenylpropyl) isoindole-1, 3-dione (Compound VIII) of example 1. LC/MS (M/s) 282.2[ M + H]+，304.1[M+Na]+。
(S) -3- (1, 3-dioxoisoindol-2-yl) -3-phenylpropyl-4-methylbenzenesulfonate (Compound IX)
Compound VIII (16.8g, 0.06mol) and triethylamine (12.1g, 0.12mol) were dissolved in dichloromethane (170ml) under ice-cooling, p-toluenesulfonyl chloride (11.4g, 0.06mol) was added, and the reaction was carried out at room temperature for 24 hours. The reaction mixture was washed successively with 1mol/L dilute hydrochloric acid (80ml) and 10% aqueous sodium carbonate solution (80 ml). Drying, filtration and concentration of the filtrate under reduced pressure gave a light yellow oil as compound IX (24.1g, 92.2%). The product was used in the next reaction without further purification.
(S) -2- (3- (naphthalene-1-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound X)
Anhydrous potassium carbonate (12.4g, 0.09mol) and 1-naphthol (4.3g, 0.03mol) were put into acetone (80ml) and reacted in an oil bath at 70 ℃ for 2 hours. Further, after dissolving Compound IX (13.1g, 0.03mol) in acetone (50ml), the mixture was added thereto and refluxed overnight. The reaction solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated to dryness. The crude product was purified by column chromatography (petroleum ether: ethyl acetate 15: 1) to afford compound x (7.4g, 60.6%) as a tan solid.
FIG. 3 is an LC/MS spectrum of (S) -2- (3- (naphthalene-1-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound X) of example 1; FIG. 4 is a nuclear magnetic resonance spectrum of (S) -2- (3- (naphthalene-1-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound X) of example 1. LC/MS (M/s) 430.1[ M + Na ]]+；1H NMR(400MHz,CDCl3):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-oxy) -1-phenylpropyl-1-amine (dapoxetine hydrochloride impurity II)
85% hydrazine hydrate (4ml) was added to a suspension of Compound X (5.5g,0.013mol) in ethanol (100ml) and the reaction was refluxed for 3 h. After cooling to room temperature, filtration under reduced pressure was carried out, and the filtrate was concentrated to dryness under reduced pressure to give compound II (3.5g, 97.1%) as a brown-yellow oil.
FIG. 5 is an LC/MS spectrum of (S) -3- (naphthalen-1-yloxy) -1-phenylpropyl-1-amine (compound II) of example 1; FIG. 6 is a NMR spectrum of (S) -3- (naphthalene-1-yloxy) -1-phenylpropyl-1-amine (compound II) of example 1. LC/MS (M/s) 278.2[ M + H]+；1H NMR(400MHz,CDCl3):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)。
Example 2 Synthesis of dapoxetine hydrochloride impurity III
(S) -tert-butyl (3- (naphthalene-1-yloxy) -1-phenylpropyl) carbamate (Compound XI)
Di-tert-butyl dicarbonate (4.4g, 0.020mol) was dissolved in dichloromethane (20ml) under cooling in an ice bath, and added dropwise to a dichloromethane solution of compound II (5.0g, 0.018mol) and triethylamine (2.1g, 0.021 mol). After dropping, the temperature is raised to room temperature for reaction overnight. Washed with water (2X 40ml), the organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to dryness to give compound XI (7.9 g). The product was used in the next reaction without further purification.
(S) -N-methyl-3- (naphthalen-1-yloxy) -1-phenylpropyl-1-aminium hydrochloride (hydrochloride of dapoxetine hydrochloride impurity III)
A solution of the compound XI (6.0g, 0.016mol) in tetrahydrofuran (30ml) was added dropwise to a suspension of lithium aluminum hydride (3g, 0.079mol) in tetrahydrofuran (30ml) at room temperature. After dropping, the temperature is raised to reflux for 2 h. After cooling to room temperature, the reaction mixture was quenched dropwise with water, and 30% aqueous sodium hydroxide (20ml) and celite (10g) were added to the reaction flask in this order. Filtration under reduced pressure, evaporation of the filtrate to dryness under reduced pressure, extraction of the residue with ethyl acetate (2X 50ml), addition of concentrated hydrochloric acid (6ml), evaporation to dryness under reduced pressure, and recrystallization of the residue with isopropanol gave an off-white solid as the hydrochloride of compound III (3.1g, 59.1%).
FIG. 7 is a NMR spectrum of (S) -N-methyl-3- (naphthalen-1-yloxy) -1-phenylpropyl-1-aminium hydrochloride (Compound III) of example 2.1H NMR(400MHz,CDCl3):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)。
EXAMPLE 3 Synthesis of dapoxetine hydrochloride impurity IV
(S) -2- (3- (naphthalene-2-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound Xa)
Anhydrous potassium carbonate (24.8g, 0.18mol) and 2-naphthol (8.6g, 0.06mol) were put into N, N-dimethylformamide (200ml) and reacted in an oil bath at 90 ℃ for 2 hours. Then, compound IX (26.1g, 0.06mol) was dissolved in N, N-dimethylformamide (120ml), and the mixture was added to the reaction solution and reacted at 90 ℃ for 3 hours. The reaction solution was cooled to room temperature, then filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to distill out 1/2N, N-dimethylformamide. To the residue were added water (400ml) and ethyl acetate (200ml), and filtered under reduced pressure to give an off-white solid as compound Xa (13.1g, 53.6%).
FIG. 8 is an LC/MS spectrum of example 3(S) -2- (3- (naphthalene-2-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound Xa); FIG. 9 is a NMR spectrum of example 3(S) -2- (3- (naphthalene-2-yloxy) -1-phenylpropyl) isoindole-1, 3-dione (Compound Xa). LC/MS (M/s) 430.2[ M + Na ]]+；1H NMR(400MHz,CDCl3):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- (Naphthalen-2-yloxy) -1-phenylpropyl-1-amine (Compound IIa)
85% hydrazine hydrate (8ml) was added to a suspension of compound Xa (10.1g,0.025mol) in ethanol (200ml) and the reaction was refluxed for 3 h. Naturally cooling to room temperature, and filtering under reduced pressure to remove insoluble solids. The filtrate was concentrated to dryness under reduced pressure to give a pale yellow oil as compound IIa (6.8g, 98.2%).
FIG. 10 is an LC/MS spectrum of example 3(S) -3- (naphthalen-2-yloxy) -1-phenylpropyl-1-amine (compound IIa); FIG. 11 is a NMR spectrum of (S) -3- (naphthalene-2-yloxy) -1-phenylpropyl-1-amine (compound IIa) of example 3.
LC/MS(m/s):278.3[M+H]+；
1H NMR(400MHz,CDCl3):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- (naphthalen-2-yloxy) -1-phenylpropyl-1-aminium hydrochloride (hydrochloride of dapoxetine hydrochloride impurity IV)
Adding 37-40% formaldehyde aqueous solution (7.1g, 0.090moL) into a suspension of a compound IIa (6.1g,0.022moL), 88% formic acid solution (9.4g, 0.180moL) and 40ml of water, carrying out reflux reaction for 7 hours, cooling to room temperature, adding 20% sodium hydroxide (50ml) into a reaction solution, extracting with ethyl acetate (3 x 100ml), combining organic phases, evaporating to dryness under reduced pressure, adding 3moL/L dilute hydrochloric acid (50ml) into the residue, washing with toluene (100ml), and separating. After evaporation of the aqueous phase under reduced pressure, the residue was recrystallized from isopropanol to give an off-white solid as the hydrochloride salt of compound iv (3.4g, 45.2%).
FIG. 12 is an LC/MS spectrum of example 3(S) -N, N-dimethyl-3- (naphthalen-2-yloxy) -1-phenylpropyl-1-aminium hydrochloride (Compound IV); FIG. 13 is a NMR spectrum of (S) -N, N-dimethyl-3- (naphthalen-2-yloxy) -1-phenylpropyl-1-aminium hydrochloride (Compound IV) of example 3.
LC/MS(m/s):306.3[M+H]+；1H NMR(400MHz,CDCl3)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)。
The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.

Claims (6)

1. A preparation method of dapoxetine hydrochloride impurities is characterized in that,
the preparation method of the compound III comprises the following steps: amidation reaction of the compound II to obtain compound XI, reduction of the compound XI to obtain compound III,
Figure FDA0002575282390000011
wherein R is2Is C1～C4Alkyl, benzyl or fluorenylmethyl.
2. The process for preparing the dapoxetine hydrochloride impurity of claim 1, wherein: the compound II (S) -3- (naphthalene-1-oxyl) -1-phenylpropyl-1-amine is firstly subjected to amidation reaction to obtain a compound XI, and then the compound XI is dissolved in an organic solvent and subjected to reduction reaction with a reducing agent under the heating condition to obtain a compound III.
3. The process for preparing the dapoxetine hydrochloride impurity of claim 1, wherein: the preparation method of the compound II comprises the following steps:
Figure FDA0002575282390000012
wherein in the compound IX, R1Is one of methane sulfonyl, p-toluene sulfonyl, benzene sulfonyl or trifluoromethanesulfonyl.
4. The process for preparing the dapoxetine hydrochloride impurity of claim 3, wherein: the preparation method of the compound II comprises the following steps:
step one, mixing a compound VII (S) -3-amido-3-phenylpropyl-1-ol with phthalic anhydride or dissolving the mixture in an organic solvent under the catalysis of alkali, and heating to obtain a compound VIII (S) -2- (3-hydroxy-1-phenylpropyl) isoindole-1, 3-diketone;
step two, activating the hydroxyl of a compound VIII (S) -2- (3-hydroxyl-1-phenyl propyl) isoindole-1, 3-dione to obtain a compound IX, dissolving the compound IX and 1-naphthol in an organic solvent under the catalysis of alkali, heating and carrying out substitution reaction to obtain a compound X (S) -2- (3- (naphthalene-1-oxyl) -1-phenyl propyl) isoindole-1, 3-dione;
and step three, in an organic solvent, under the heating condition, removing the protecting group of the benzyl amino group of the compound X (S) -2- (3- (naphthalene-1-oxyl) -1-phenyl propyl) isoindole-1, 3-dione by using a protecting group removing reagent to obtain a compound II (S) -3- (naphthalene-1-oxyl) -1-phenyl propyl-1-amine.
5. The process for preparing the dapoxetine hydrochloride impurity of claim 4, wherein: the molar ratio of the compound shown in the formula VII to phthalic anhydride is 1: 1-3; the catalyst used in the base catalysis process in the first step is one of DMAP (4-dimethylaminopyridine), DBN (1, 5-diazabicyclo [4.3.0] -5-nonene) and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene); the heating reaction temperature is 80-140 ℃; the organic solvent is benzene, toluene, xylene, ethylbenzene, chlorobenzene or no solvent;
in the second step, the organic solvent used in the substitution reaction is selected from any one or a mixed solvent of at least two of ethyl acetate, acetonitrile, toluene, tetrahydrofuran, DMF and acetone; the alkali used in the substitution reaction is organic alkali or inorganic alkali; the heating temperature is 60-100 ℃;
in the third step, the organic solvent is selected from any one of acetonitrile, methanol, ethanol, tetrahydrofuran, DMF or water or a mixed solvent of at least two of the acetonitrile, the methanol, the ethanol, the tetrahydrofuran, the DMF or the water; the protecting group removing reagent is one of methylamine, ethylamine or hydrazine hydrate, and the molar ratio of the protecting group removing reagent to the compound X is 1: 1-10; the heating reaction temperature is 60-90 ℃.
6. The process for preparing the dapoxetine hydrochloride impurity of claim 2, wherein: the organic solvent used in the reduction reaction is any one or a mixed solvent of at least two of diethyl ether, 1, 4-dioxane, toluene, tetrahydrofuran and 2-methyltetrahydrofuran; the reducing agent used in the reduction is selected from BH3、LiBH4、ZnBH4、NaBH4/AlCl3Or LiAlH4。
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