阅读说明：本技术 一种盐酸达泊西汀消旋体的制备方法 (Preparation method of dapoxetine hydrochloride racemate ) 是由 徐云根 张飞皇 高玲莉 孙芩 姚硕蔚 朱启华 于 2020-06-15 设计创作，主要内容包括：本发明公开了一种盐酸达泊西汀消旋体的制备方法,本发明使用1-(3-苯丙氧基)萘为原料,经卤代、胺化、氢化脱卤等得到盐酸达泊西汀消旋体(V)。本发明方法的收率高、后处理方便,更适合工业化生产。<Image he="462" wi="492" file="DDA0002539132460000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of dapoxetine hydrochloride racemate, which uses 1- (3-phenylpropoxy) naphthalene as a raw material to obtain the dapoxetine hydrochloride racemate (V) through halogenation, amination, hydrogenation dehalogenation and the like. The method has high yield and convenient post-treatment, and is more suitable for industrial production.)

1. A preparation method of dapoxetine hydrochloride racemate with a structure shown as a general formula (V) is characterized in that:

wherein: x represents Cl, Br or I;

the process comprises the following steps: halogenating the compound II with a halogenating agent to obtain a compound III, reacting the compound III with dimethylamine to obtain a compound IV, and carrying out hydrogenation dehalogenation reaction on the compound IV to obtain a compound V.

2. The method for preparing the dapoxetine hydrochloride racemate having the structure of general formula (V) according to claim 1, wherein: the catalyst used in the preparation of the compound III from the compound II is benzoyl peroxide or Azobisisobutyronitrile (AIBN), and the solvent used is one of dichloromethane, acetonitrile or carbon tetrachloride or a mixture of any two of the dichloromethane, the acetonitrile and the carbon tetrachloride.

3. The method for preparing the dapoxetine hydrochloride racemate having the structure of general formula (V) according to claim 1, wherein: the halogenating agent is N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS), liquid bromine, chlorine, iodine, 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-triketone or dibromohydantoin.

4. The method for preparing the dapoxetine hydrochloride racemate having the structure of general formula (V) according to claim 1, wherein: the hydrochloride of the dapoxetine hydrochloride racemate is as follows: n, N-dimethylamino-3- (naphthyl-1-oxy) -1-phenylpropan-1-amine hydrochloride (I).

5. The method for preparing the dapoxetine hydrochloride racemate having the structure of general formula (V) according to claim 1, wherein: the dapoxetine hydrochloride racemate is as follows: 1-chloro-4- (3-chloro-3-phenylpropoxy) naphthalene.

6. The process for preparing a dapoxetine hydrochloride racemate having the structure of any one of claims 1 to 3, wherein: when X is Br, the compound II is used for preparing the compound III, the halogenating agent is N-bromosuccinimide (NBS), liquid bromine, 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-triketone or dibromohydantoin, the catalyst is benzoyl peroxide or Azobisisobutyronitrile (AIBN), and the solvent is one or a mixture of any two of dichloromethane, acetonitrile or carbon tetrachloride.

7. The process for preparing a dapoxetine hydrochloride racemate having the structure of any one of claims 1 to 3, wherein: when X ═ Cl, the halogenating agent used in preparing compound III from compound II is N-chlorosuccinimide (NCS), chlorine, the catalyst is benzoyl peroxide or Azobisisobutyronitrile (AIBN), and the solvent is one of dichloromethane, acetonitrile or carbon tetrachloride or a mixture of any two of them.

8. The process for preparing a dapoxetine hydrochloride racemate having the structure of any one of claims 1 to 3, wherein: when X is equal to I, the halogenating agent used for preparing the compound III by the compound II is N-iodosuccinimide (NIS) and iodine, the catalyst is benzoyl peroxide or Azobisisobutyronitrile (AIBN), and the solvent is one of or a mixture of any two of dichloromethylene, acetonitrile or carbon tetrachloride.

9. The method for preparing the dapoxetine hydrochloride racemate having the structure of general formula (V) according to claim 1, wherein: and (3) reacting the compound III with dimethylamine to prepare a compound IV, wherein the solvent is one or a mixture of any two of acetone, ethanol, methanol, isopropanol, tetrahydrofuran or 1, 4-dioxane.

10. The method for preparing the dapoxetine hydrochloride racemate having the structure of general formula (V) according to claim 1, wherein: when the compound V is prepared from the compound IV, the used solvent is one or the mixture of any two of ethyl acetate, methanol, ethanol, glacial acetic acid or cyclohexane, and the used catalyst is 5-10% Pd/C or Raney nickel.

Technical Field

The invention relates to the field of pharmaceutical chemistry, and particularly relates to a preparation method of dapoxetine hydrochloride racemate.

Background

Dapoxetine is chemically known as (+) -S- (N, N-dimethylamino) -3- (naphthyl-1-oxy) -1-phenylpropane and is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI). The traditional Chinese medicine is the first oral medicine approved for treating premature ejaculation in the world, has the characteristics of short half-life, small adverse reaction and the like, is firstly marketed in Europe in 2009 and is more and more valued by people.

The dapoxetine molecule contains a chiral center, and the synthesis method mainly has two ideas, namely an achiral synthesis method, namely obtaining racemate dapoxetine or an intermediate thereof, and then splitting to obtain dapoxetine with a single configuration; the other is an asymmetric synthesis method, i.e. the target compound with optical purity can be obtained without chiral resolution, but the synthesis method has the problems of long steps, complex operation, high cost and the like, and is not suitable for industrial production.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide a preparation method of the dapoxetine hydrochloride racemate.

The technical scheme is as follows: the invention provides a preparation method of dapoxetine hydrochloride racemate with a structure of a general formula (V), which is characterized by comprising the following steps:

wherein: x represents Cl, Br or I;

the process comprises the following steps: halogenating the compound II with a halogenating agent to obtain a compound III, reacting the compound III with dimethylamine to obtain a compound IV, and carrying out hydrogenation dehalogenation reaction on the compound IV to obtain a compound V.

Further, when the compound II is used for preparing the compound III, the catalyst is benzoyl peroxide or Azobisisobutyronitrile (AIBN), and the solvent is one or a mixture of any two of dichloromethane, acetonitrile or carbon tetrachloride.

Further, the halogenating agent is N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS), liquid bromine, chlorine gas, iodine, 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-trione, or dibromohydantoin.

Further, the hydrochloride of the dapoxetine hydrochloride racemate is as follows: n, N-dimethylamino-3- (naphthyl-1-oxy) -1-phenylpropan-1-amine hydrochloride (I).

Further, the dapoxetine hydrochloride racemate is as follows: 1-chloro-4- (3-chloro-3-phenylpropoxy) naphthalene.

Further, when X is Br, the compound (I) of the present invention can be prepared by the following method:

in the preparation of compound III-1 from II, the halogenating agent used is N-bromosuccinimide (NBS), liquid bromine, 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-trione or dibromohydantoin, preferably NBS; the catalyst used is benzoyl peroxide or Azobisisobutyronitrile (AIBN), preferably benzoyl peroxide; the solvent is one or a mixture of any two of dichloromethane, acetonitrile or carbon tetrachloride, preferably carbon tetrachloride; the preferred molar ratio of the compound II to the halogenating agent is 1: 1-1: 3.

When the compound III-1 is reacted with dimethylamine to prepare the compound IV-1, the solvent is one or a mixture of any two of acetone, ethanol, methanol, isopropanol, tetrahydrofuran or 1, 4-dioxane, preferably acetone; the preferable molar ratio of the compound III-1 to the dimethylamine is 1: 1-1: 10.

When the compound V is prepared from the compound IV-1 through catalytic hydrogenation and dehalogenation, the solvent is one or a mixture of any two of ethyl acetate, methanol, ethanol, glacial acetic acid or cyclohexane, and preferably a mixed solvent of methanol and glacial acetic acid; the catalyst is 5-10% Pd/C or Raney nickel, preferably 10% palladium carbon.

When the compound V is used for preparing the compound I, the acid is a hydrogen chloride saturated ethyl acetate solution or a hydrogen chloride saturated dichloromethane solution, and the hydrogen chloride saturated ethyl acetate solution is preferred; the solvent is one or a mixture of any two of ethyl acetate, dichloromethane or toluene, preferably ethyl acetate.

Further, when X is Cl, the compound (V) of the present invention can be prepared by the following method:

in the preparation of compound III-2 from II, the halogenating agent used is N-chlorosuccinimide (NCS), chlorine, preferably NCS; the catalyst used is benzoyl peroxide or Azobisisobutyronitrile (AIBN), preferably benzoyl peroxide; the solvent is one or a mixture of any two of dichloromethane, acetonitrile or carbon tetrachloride, preferably carbon tetrachloride; the preferred molar ratio of the compound II to the halogenating agent is 1: 1-1: 3.

Preparing a compound IV-2 by reacting a compound III-2 with dimethylamine, wherein the solvent is one or a mixture of any two of acetone, ethanol, methanol, isopropanol, tetrahydrofuran or 1, 4-dioxane, preferably acetone; the preferable molar ratio of the compound III to the dimethylamine is 1: 1-1: 10.

When the compound V is prepared from the compound IV-2 through catalytic hydrogenation and dehalogenation, the solvent is one or a mixture of any two of ethyl acetate, methanol, ethanol, glacial acetic acid or cyclohexane, and preferably a mixed solvent of methanol and glacial acetic acid; the catalyst is 5-10% Pd/C or Raney nickel, preferably 10% palladium carbon.

Further, when X is I, the compound (V) of the present invention can be prepared by the following method:

when preparing compound III-3 from II, the halogenating agent used is N-iodosuccinimide (NIS), iodine, preferably NIS; the catalyst used is benzoyl peroxide or Azobisisobutyronitrile (AIBN), preferably benzoyl peroxide; the solvent is one or a mixture of any two of dichloromethane, acetonitrile or carbon tetrachloride, preferably carbon tetrachloride; the preferred molar ratio of the compound II to the halogenating agent is 1: 1-1: 3.

Preparing a compound IV-3 by reacting the compound III-3 with dimethylamine, wherein the solvent is one or a mixture of any two of acetone, ethanol, methanol, isopropanol, tetrahydrofuran or 1, 4-dioxane, preferably acetone; the preferable molar ratio of the compound III to the dimethylamine is 1: 1-1: 10.

When the compound V is prepared from the compound IV-3 through catalytic hydrogenation and dehalogenation, the solvent is one or a mixture of any two of ethyl acetate, methanol, ethanol, glacial acetic acid or cyclohexane, and preferably a mixed solvent of methanol and glacial acetic acid; the catalyst is 5-10% Pd/C or Raney nickel, preferably 10% palladium carbon.

Further, compound IV is prepared by reacting compound III with dimethylamine, and the solvent used is one of acetone, ethanol, methanol, isopropanol, tetrahydrofuran or 1, 4-dioxane or a mixture of any two of the acetone, the ethanol, the methanol, the isopropanol, the tetrahydrofuran or the 1, 4-dioxane.

Further, when the compound V is prepared from the compound IV, the solvent used is one of ethyl acetate, methanol, ethanol, glacial acetic acid or cyclohexane or a mixture of any two of the ethyl acetate, the methanol, the ethanol, the glacial acetic acid or the cyclohexane, and the catalyst used is 5-10% Pd/C or Raney nickel.

Has the advantages that: the invention uses 1- (3-phenylpropyloxy) naphthalene as a raw material, and obtains dapoxetine hydrochloride racemate (I) through halogenation, amination, hydrodehalogenation and salt forming reaction. The method has high yield and convenient post-treatment, and is more suitable for industrial production.

Detailed Description