阅读说明：本技术 达泊西汀的合成方法 (Synthetic method of dapoxetine ) 是由 肖稳定 胡俊 石笑弋 袁威冠 苏前锋 于 2021-08-06 设计创作，主要内容包括：本发明提供了一种达泊西汀的合成方法,包括以下步骤：S1、将(s)-3-氨基-3-苯基丙酸或其酯类化合物分散在溶剂中,在还原剂作用下进行回流反应,得到(s)-氨基-3-苯基丙醇；S2、将(s)-氨基-3-苯基丙醇溶解于甲酸水溶液中,加入多聚甲醛升温进行反应,得到(s)-3-二甲氨基-3-苯基丙醇；S3、将(s)-3-二甲氨基-3-苯基丙醇溶解在溶剂中,氮气保护下,在较高温度滴加到碱的溶液中反应,然后加入1-氟萘发生Williamson成醚反应,得到(s)-N,N-二甲基-3-(1-萘氧基)苯丙胺,即达泊西汀。本发明的达泊西汀的合成方法原料低廉易得,不使用有毒危险试剂,不会发生反应聚集喷料现象,工艺简单,适合工业化生产。(The invention provides a synthesis method of dapoxetine, which comprises the following steps: s1, dispersing (S) -3-amino-3-phenylpropionic acid or ester compounds thereof in a solvent, and carrying out reflux reaction under the action of a reducing agent to obtain (S) -amino-3-phenylpropanol; s2, dissolving (S) -amino-3-phenyl propanol in a formic acid aqueous solution, adding paraformaldehyde, heating and reacting to obtain (S) -3-dimethylamino-3-phenyl propanol; s3, dissolving (S) -3-dimethylamino-3-phenyl propanol in a solvent, dropwise adding the solution into the alkali solution at a higher temperature for reaction under the protection of nitrogen, and then adding 1-fluoronaphthalene for Williamson ether forming reaction to obtain (S) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, namely dapoxetine. The synthesis method of dapoxetine has the advantages of low-cost and easily-obtained raw materials, no use of toxic and dangerous reagents, no reaction aggregation and material spraying phenomenon, simple process and suitability for industrial production.)

1. A synthesis method of dapoxetine is characterized by comprising the following steps:

s1, dispersing (S) -3-amino-3-phenylpropionic acid or ester compounds thereof in a solvent, and carrying out reflux reaction under the action of a reducing agent to obtain (S) -amino-3-phenylpropanol;

s2, dissolving the (S) -amino-3-phenyl propanol obtained in the step S1 in a formic acid aqueous solution, adding paraformaldehyde, heating and reacting to obtain (S) -3-dimethylamino-3-phenyl propanol;

s3, dissolving the (S) -3-dimethylamino-3-phenylpropanol obtained in the step S2 in a solvent, dropwise adding the solution into an alkali solution at the temperature of more than 30 ℃ for reaction under the protection of nitrogen, and then adding 1-fluoronaphthalene to carry out Williamson ether forming reaction to obtain (S) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, namely dapoxetine.

2. The method for synthesizing dapoxetine according to claim 1,

in step S1, the reducing agent is borohydride and iodine, the reflux reaction time is 6-18 hours, and the solvent is one or more selected from tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dichloromethane, chloroform, and 1, 4-dioxane.

3. The method for synthesizing dapoxetine according to claim 2,

the borohydride is at least one selected from sodium borohydride, potassium borohydride and lithium borohydride.

4. A synthesis method of dapoxetine according to any of claims 1 to 3,

in step S1, (S) -3-amino-3-phenylpropionic acid or an esterified product thereof: borohydride compounds: the molar ratio of iodine is 1.0: (1.0-10.0): (0.4 to 3.0), preferably(s) -3-amino-3-phenylpropionic acid or an esterified product thereof: borohydride compounds: the molar ratio of iodine is 1.0: (1.0-2.0): (0.5 to 1.5).

5. A synthesis method of dapoxetine according to any of claims 1 to 3,

in step S1, after the reflux reaction is completed, the method further includes the steps of: quenching the reaction by using a quenching reagent, concentrating, adjusting the pH value to 10-13 by using an alkali solution, extracting, and concentrating an organic phase to obtain(s) -amino-3-phenylpropanol.

6. The method for synthesizing dapoxetine according to claim 1,

in the step S2, the heating reaction is carried out by heating to 70-105 ℃, stirring and reacting for 6-15 hours, adjusting the pH value of the alkali liquor to 10-13 after the reaction is finished, extracting, and concentrating the organic phase to obtain (S) -3-dimethylamino-3-phenylpropanol.

7. The method for synthesizing dapoxetine according to claim 1 or 6,

in step S2, (S) -3-amino-3-phenylpropanol: formic acid: the molar ratio of paraformaldehyde is 1.0: (3.0-6.0): (2.5-5.0); preferably(s) -3-amino-3-phenylpropanol: formic acid: the molar ratio of paraformaldehyde is 1.0: (3.0-4.0): (2.5-3.5).

8. The method for synthesizing dapoxetine according to claim 1,

step S3 specifically includes the following steps: dissolving the (S) -3-dimethylamino-3-phenylpropanol obtained in the step S2 in an anhydrous solvent, dropwise adding the solution into an alkali solution at 35-80 ℃ for reaction under the protection of nitrogen, then adding 1-fluoronaphthalene, reacting at 80-110 ℃, adding the reaction solution into water at the temperature of below 5 ℃ after the reaction is finished, stirring and crystallizing, centrifuging, and drying to obtain (S) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, namely dapoxetine.

9. The method for synthesizing dapoxetine according to claim 8,

the anhydrous solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and toluene, and the base is one or more of sodium hydride, sodium tert-butoxide, potassium hydride and sodium methoxide.

10. A synthesis method of dapoxetine according to claim 8 or 9,

the molar ratio of the(s) -3-dimethylamino-3-phenylpropanol to the base is 1.0: (1.0 to 5.0), preferably 1.0: (1.5-2.0).

11. The method for synthesizing dapoxetine according to claim 1,

step S3 is followed by: and(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine and alcohol-hydrogen chloride gas-ether are subjected to salt forming reaction, crystallization, centrifugation and drying to obtain dapoxetine hydrochloride.

12. The method for synthesizing dapoxetine according to claim 11,

the(s) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine: alcohol: the mass ratio of the ether is 1.0: (1.0-3.0): (6.0-20.0);

the(s) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine: the molar usage of hydrogen chloride gas is 1.0: (1.0-4.0).

13. A synthesis method of dapoxetine according to claim 11 or 12,

the salt-forming reaction crystallization is specifically operated as follows: adding(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine into alcohol at the temperature of-5-30 ℃, stirring, introducing hydrogen chloride gas, stirring until solid is clear, then adding an ether solution into the reaction liquid, and crystallizing at the temperature of-5 ℃.

14. The method for synthesizing dapoxetine according to claim 13,

and adding the ether solution at a constant speed, controlling the particle size of the precipitated product of the dapoxetine hydrochloride by controlling the adding time of the ether solution, wherein the longer the adding time of the ether solution is, the larger the particle size of the precipitated product is.

15. A synthesis method of dapoxetine according to claim 11 or 12,

the alcohol is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and ethylene glycol; the ether is selected from one or more of methyl tert-butyl ether, diethyl ether and ethylene glycol monomethyl ether.

Technical Field

The invention belongs to the technical field of medicine preparation, and particularly relates to a synthesis method of dapoxetine.

Background

Dapoxetine, chemical name: (S) -N, N-dimethyl-3- (naphthyl-1-oxy) -phenylpropylamino with the chemical structural formula: the chemical structural formula is as follows:

。

the dapoxetine hydrochloride is hydrochloride of (S) -N, N-dimethyl-3- (naphthyl-1-oxy) -phenylalanine, and in clinical test, the dapoxetine hydrochloride not only can be used as an antidepressant, but also has new application in controlling male premature ejaculation symptoms. Therefore, the dapoxetine hydrochloride serving as a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) has short half-life and small adverse reaction, is used for treating premature ejaculation of males, and has a remarkable effect.

The synthesis route of dapoxetine hydrochloride reported in the literature at present is as follows:

(1) a synthetic route for preparing dapoxetine hydrochloride from benzaldehyde and ethyl cinnamate as starting materials was published by the Tilia company in J.Label company radiopharmarm in 1992 (see patent CN 88102018A), and the specific route is as follows:

the route adopts flammable and explosive lithium aluminum hydride as a reducing reagent, and has high requirements on equipment. The benzaldehyde is used as a raw material, the line is long, and the L- (+) -tartaric acid is used for resolution to obtain an intermediate or a product with a known configuration, so that the product loss is large, the yield is low, the utilization rate of the raw material is low, and the production cost is increased.

(2) Chinese patent CN103664660A discloses a preparation method of dapoxetine hydrochloride, which takes(s) -3-amino-3-phenylpropionic acid as a starting material. The specific route is as follows:

the reaction route takes(s) -3-amino-3-phenylpropionic acid as a starting material, the(s) -3-amino-3-phenylpropanol is obtained by reduction under the action of a reducing agent and acid, and after treatment, reflux treatment is needed under an alkaline condition, so that partial product oxidation is easily caused, the purity is reduced, and the production cost is increased. And thirdly, adding alkali in batches, so that the operation is complicated, the reaction is difficult to control, the materials are easy to aggregate and spray, and the method is not suitable for industrial production. Hydrochloric acid gas cannot be quantitatively introduced to cause the precipitated product to be dissolved or become oily substances, so that the separation and purification are difficult, excessive hydrochloric acid gas is easy to overflow, and the requirements on operators and equipment are high.

(3) Chinese patent CN106883133A discloses a preparation method of dapoxetine hydrochloride, which uses(s) -3-amino-3-phenylpropionic acid or ester as a starting material. The specific route is as follows:

the reaction route takes(s) -3-amino-3-phenylpropionic acid or ester as a starting material, and the(s) -3-amino-3-phenylpropanol is obtained by reduction through the action of a reducing agent and a boron trifluoride complex, wherein boron trifluoride is a colorless gas with irritant odor, toxicity and corrosiveness, the reaction amount is difficult to control, and the reaction method is not suitable for industrial production. The sodium hydride is used for reaction, the batch addition operation is complicated, the aggregation and the material spraying are easy, and the method is not suitable for industrial production.

(4) Chinese patent CN105061230A discloses a preparation method of dapoxetine hydrochloride, which takes(s) -3-amino-3-phenylpropionate as a starting material. The specific route is as follows:

the reaction route takes(s) -3-amino-3-phenylpropionic acid ester as a starting material, and the intermediate of boron ether is directly obtained by quenching, filtering and concentrating after reduction through the action of a reduction system, the actual product contains a large amount of salt, the usage amount of paraformaldehyde and formic acid which are materials in the next step is increased, and the method is not suitable for industrial production. And thirdly, sodium hydride is used for forming ether, all materials are added, and then the temperature is raised, so that the reaction process is difficult to control, the materials are easy to aggregate and spray, and the method is not suitable for industrial production. And the crystal form is difficult to control by washing with dilute hydrochloric acid to form salt, and the monohydrate dapoxetine hydrochloride crystal form is easy to obtain.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides the synthesis method of dapoxetine, which is simple to operate, low in production cost, high in yield and suitable for industrial production.

According to one aspect of the invention, a method for synthesizing dapoxetine is provided, which comprises the following steps:

s1, dispersing (S) -3-amino-3-phenylpropionic acid or ester compounds thereof in a solvent, and carrying out reflux reaction under the action of a reducing agent to obtain (S) -amino-3-phenylpropanol;

s2, dissolving the (S) -amino-3-phenyl propanol obtained in the step S1 in a formic acid aqueous solution, adding paraformaldehyde, heating and reacting to obtain (S) -3-dimethylamino-3-phenyl propanol;

s3, dissolving the (S) -3-dimethylamino-3-phenylpropanol obtained in the step S2 in a solvent, dropwise adding the solution into a solution of alkali at a higher temperature of more than 30 ℃ for reaction under the protection of nitrogen, and then adding 1-fluoronaphthalene for Williamson ether forming reaction to obtain (S) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, namely dapoxetine.

Further, in step S1, the reducing agent is borohydride and iodine, the reflux reaction time is 6-18 hours, and the solvent is one or more selected from tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dichloromethane, chloroform, and 1, 4-dioxane.

Further, the borohydride is at least one selected from sodium borohydride, potassium borohydride and lithium borohydride.

Further, in step S1, (S) -3-amino-3-phenylpropionic acid or an esterified product thereof: borohydride compounds: the molar ratio of iodine is 1.0: (1.0-10.0): (0.4 to 3.0), preferably(s) -3-amino-3-phenylpropionic acid or an esterified product thereof: borohydride compounds: the molar ratio of iodine is 1.0: (1.0-2.0): (0.5 to 1.5).

Further, in step S1, after the reflux reaction is completed, the method further includes the steps of: quenching the reaction by using a quenching reagent, concentrating, adjusting the pH value to 10-13 by using an alkali solution, extracting, and concentrating an organic phase to obtain(s) -amino-3-phenylpropanol.

Further, in step S2, the heating is carried out by heating to 70-105 ℃, stirring and reacting for 6-15 hours, adjusting the pH value of the alkali liquor to 10-13 after the reaction is finished, extracting, and concentrating the organic phase to obtain (S) -3-dimethylamino-3-phenylpropanol.

Further, in step S2, (S) -3-amino-3-phenylpropanol: formic acid: the molar ratio of paraformaldehyde is 1.0: (3.0-6.0): (2.5-5.0); preferably(s) -3-amino-3-phenylpropanol: formic acid: the molar ratio of paraformaldehyde is 1.0: (3.0-4.0): (2.5-3.5).

Further, step S3 specifically includes the following steps: dissolving the (S) -3-dimethylamino-3-phenylpropanol obtained in the step S2 in an anhydrous solvent, dropwise adding the solution into an alkali solution at 35-80 ℃ for reaction under the protection of nitrogen, then adding 1-fluoronaphthalene, reacting at 80-110 ℃, adding the reaction solution into water at the temperature of below 5 ℃ after the reaction is finished, stirring and crystallizing, centrifuging, and drying to obtain (S) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, namely dapoxetine.

Further, the anhydrous solvent is selected from one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), Dimethylsulfoxide (DMSO) and toluene, and the base is one or more of sodium hydride, sodium tert-butoxide, potassium hydride and sodium methoxide.

Further, the molar ratio of the(s) -3-dimethylamino-3-phenylpropanol to the base is 1.0: (1.0 to 5.0), preferably 1.0: (1.5-2.0).

Further, step S3 is followed by: and(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine and alcohol-hydrogen chloride gas-ether are subjected to salt forming reaction, crystallization, centrifugation and drying to obtain dapoxetine hydrochloride.

Further, the(s) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine: alcohol: the mass ratio of the ether is 1.0: (1.0-3.0): (6.0-20.0);

the(s) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine: the molar usage of hydrogen chloride gas is 1.0: (1.0-4.0).

Further, the salt-forming reaction crystallization is specifically operated as follows: adding(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine into alcohol at the temperature of-5-30 ℃, stirring, introducing hydrogen chloride gas, stirring until solid is clear, then adding an ether solution into the reaction liquid, and crystallizing at the temperature of-5 ℃.

Further, the ether solution is added at a constant speed, the particle size of the precipitated product of the dapoxetine hydrochloride is controlled by controlling the adding time of the ether solution, and the particle size of the precipitated product is larger when the adding time of the ether solution is longer.

Further, the alcohol is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and ethylene glycol, preferably methanol, ethanol or isopropanol; the ether is selected from one or more of methyl tert-butyl ether, diethyl ether and ethylene glycol monomethyl ether.

The invention has the beneficial effects that:

(1) the synthesis method of dapoxetine uses chiral(s) -3-amino-3-phenylpropionic acid or an esterified substance thereof which is cheap and easily available in the market as a starting material, avoids the resolution of products, solves the problem of serious product loss caused by the resolution, and greatly saves the cost.

(2) The synthesis method of dapoxetine of the invention adopts the step of dropwise adding the intermediate(s) -3-dimethylamino-3-phenyl propanol into the alkali solution at a higher temperature during Williamson ether forming reaction, thereby avoiding the problems of reaction aggregation and material spraying and difficult process control.

(3) The synthesis method of dapoxetine adopts an alcohol-hydrogen chloride gas-ether system during the salt forming reaction, avoids the volatilization of hydrochloric acid gas, and can effectively control the particle size of the salt-formed precipitated product.

Drawings

FIG. 1 is a liquid phase diagram of the product testing of example 1;

FIG. 2 is a powder diffraction pattern of a crystal form assay of the product of example 1;

FIG. 3 is a particle size spectrum of the product of example 1;

FIG. 4 is a liquid phase diagram of the product testing of example 2;

FIG. 5 is a powder diffraction pattern of a crystal form assay of the product of example 2;

FIG. 6 is a particle size spectrum of the product of example 2;

FIG. 7 is a particle size spectrum of the product of example 3;

FIG. 8 is another particle size spectrum of the product of example 3.

Detailed Description

The synthesis method of dapoxetine comprises the following steps:

s1, dispersing (S) -3-amino-3-phenylpropionic acid or ester compounds thereof in a solvent, and carrying out reflux reaction under the action of a reducing agent to obtain (S) -amino-3-phenylpropanol;

s2, dissolving the (S) -amino-3-phenyl propanol obtained in the step S1 in a formic acid aqueous solution, adding paraformaldehyde, heating and reacting to obtain (S) -3-dimethylamino-3-phenyl propanol;

s3, dissolving the (S) -3-dimethylamino-3-phenylpropanol obtained in the step S2 in a solvent, dropwise adding the solution into a solution of alkali at a higher temperature of more than 30 ℃ for reaction under the protection of nitrogen, and then adding 1-fluoronaphthalene for Williamson ether forming reaction to obtain (S) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, namely dapoxetine.

The reaction process of the invention is as follows:

。

the synthesis method of dapoxetine uses chiral(s) -3-amino-3-phenylpropionic acid or an esterified substance thereof which is cheap and easily available in the market as a starting material, avoids the serious problem of product loss caused by product resolution, and greatly saves cost, wherein the esterified substance of(s) -3-amino-3-phenylpropionic acid is preferably(s) -3-amino-3-phenylpropionic acid methyl ester or(s) -3-amino-3-phenylpropionic acid ethyl ester. In the prior art, when Williamson ether forming reaction is carried out, a mode that an intermediate(s) -3-dimethylamino-3-phenylpropanol and an alkali (sodium hydride) are added into a solvent and then slowly heated is adopted, or a mode that the(s) -3-dimethylamino-3-phenylpropanol is added, the alkali (sodium hydride) is added in batches and then heated is adopted, however, the(s) -3-dimethylamino-3-phenylpropanol and the alkali (sodium hydride) react violently in the solvent, the heat release is difficult to control, hydrogen is generated, gas is accumulated in a reaction kettle, the pressure in the kettle is increased, in actual production operation, particularly in pilot scale production, the slow heating process is difficult to control, the accumulation reaction is easy to occur, the material flushing is caused, and the potential safety hazard exists. The invention adopts the method that the intermediate(s) -3-dimethylamino-3-phenylpropanol is dripped into the alkali solution at higher temperature, the amount of heat release and hydrogen generation is controlled by controlling the dripping speed, and the material flushing caused by gas aggregation is avoided.

In the invention, in step S1, the reducing agent adopts borohydride and iodine, the borohydride is at least one selected from sodium borohydride, potassium borohydride and lithium borohydride, the use of inflammable and explosive lithium aluminum hydride, highly toxic and expensive borane or a boron trifluoride complex compound with irritant odor and toxicity which have high requirements on equipment is avoided, the reaction safety is high, the method is green and environment-friendly, the borohydride and the iodine are easy to purchase, the price is low, the storage and the transportation are convenient, the safety is high, and the operation of the post-reaction treatment is simple and convenient.

In step S1, the reflux reaction is performed at the reflux temperature of the solvent for 6 to 18 hours, and the solvent is one or more selected from tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dichloromethane, chloroform, and 1, 4-dioxane. (s) -3-amino-3-phenylpropionic acid or an esterified product thereof: borohydride compounds: the molar ratio of iodine is 1.0: (1.0-10.0): (0.4 to 3.0), preferably(s) -3-amino-3-phenylpropionic acid or an esterified product thereof: borohydride compounds: the molar ratio of iodine is 1.0: (1.0-2.0): (0.5 to 1.5).

In the present invention, after the reflux reaction in step S1 is completed, the method further includes the steps of: quenching the reaction by using a quenching reagent, concentrating, adjusting the pH value to 10-13 by using an alkali solution, extracting, and concentrating an organic phase to obtain(s) -amino-3-phenylpropanol. The quenching reagent adopts alcohol, preferably one or more of methanol, ethanol, propanol and isopropanol, preferably methanol or ethanol, and the alkaline solution is selected from one of potassium hydroxide and sodium hydroxide.

In the invention, in step S2, the intermediate 1 reacts with formic acid and formaldehyde through Eschweiler-Clark reaction, and the specific operation steps are as follows: dissolving the intermediate 1(s) -3-amino-3-phenyl propanol in a solution of formic acid and water, adding paraformaldehyde, heating to 70-105 ℃, stirring for reacting for 6-15 hours, adjusting the pH value to 10-13 with an alkali solution after the reaction is finished, extracting, and concentrating an organic phase to obtain(s) -3-dimethylamino-3-phenyl propanol. Wherein(s) -3-amino-3-phenylpropanol: formic acid: the molar ratio of paraformaldehyde is 1.0: (3.0-6.0): (2.5-5.0); preferably(s) -3-amino-3-phenylpropanol: formic acid: the molar ratio of paraformaldehyde is 1: (3.0-4.0): (2.5-3.5). The alkali solution is selected from potassium hydroxide or sodium hydroxide.

In the present invention, step S3 specifically includes the following steps: dissolving the (S) -3-dimethylamino-3-phenylpropanol obtained in the step S2 in an anhydrous solvent, dropwise adding the solution into an alkali solution at 35-80 ℃ for reaction under the protection of nitrogen, then adding 1-fluoronaphthalene, reacting at 80-110 ℃, adding the reaction solution into water at the temperature of below 5 ℃ after the reaction is finished, stirring and crystallizing, centrifuging, and drying to obtain (S) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, namely dapoxetine. The anhydrous solvent is selected from one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO) and toluene, and the base is selected from one or more of sodium hydride, sodium tert-butoxide, potassium hydride and sodium methoxide. (s) -3-dimethylamino-3-phenylpropanol to base in a 1.0: (1.0 to 5.0), preferably 1.0: (1.5-2.0).

In the prior art, the intermediate(s) -3-dimethylamino-3-phenylpropanol and alkali (sodium hydride) are added into a solvent and then slowly heated when Williamson ether forming reaction is carried out, or the intermediate(s) -3-dimethylamino-3-phenylpropanol is added into the solvent and then the alkali (sodium hydride) is added in batches and then the temperature is raised. According to the invention,(s) -3-dimethylamino-3-phenylpropanol is dissolved in an anhydrous solvent, and is dripped into an alkali solution at a higher temperature of 35-80 ℃ for reaction under the protection of nitrogen, a temperature rise process is not required, and experiments prove that the method does not generate the phenomenon of aggregation and material spraying, so that the safety is greatly improved. After the reaction is finished, the reaction solution is added into water with the temperature of below 5 ℃ for quenching, stirring and crystallization, so that the residual alkali can be quenched, the phenomenon of flushing caused by aggregation reaction is avoided, products are separated out from the water, the extraction liquid separation operation is avoided, and the method is suitable for industrial production.

In the present invention, step S3 is followed by: carrying out salifying reaction on(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine and alcohol-hydrogen chloride gas-ether for crystallization, centrifuging and drying to obtain dapoxetine hydrochloride. The specific operation is as follows: adding(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine into alcohol at the temperature of-5-30 ℃, stirring, introducing hydrogen chloride gas, detecting the pH value of the solution to be about 1.0, stirring until the solid is clear, then adding an ether solution into the reaction solution, and crystallizing at the temperature of-5 ℃. Specifically,(s) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine: alcohol: the mass ratio of the ether is 1.0: (1.0-3.0): (6.0-20.0); (s) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine: the molar usage of hydrogen chloride gas is 1.0: (1.0-4.0). The alcohol is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and ethylene glycol, preferably methanol, ethanol or isopropanol; the ether is selected from one or more of methyl tert-butyl ether, diethyl ether and ethylene glycol monomethyl ether. And (4) continuing stirring for 2-4h after the addition of the ether is finished, and centrifugally drying to obtain the dapoxetine hydrochloride product.

In the prior art, the dapoxetine is salified by adopting a dry hydrochloric acid gas mode, or salified by quantitatively adding an alcoholic solution of hydrochloric acid, or salified by adopting an alcohol-acyl chloride or chloride method to obtain a target product of dapoxetine hydrochloride. The salifying operation process can not effectively control the particle size of the precipitated product, and the influence of the particle size of the raw material medicine on the preparationThe sound is loud. The particle size of the precipitated product of the dapoxetine hydrochloride can be controlled by controlling the addition time of the ether solution, the ether solution is added at a constant speed, and the longer the addition time of the ether is, the larger the particle size of the precipitated product is. One preferable ether solution adding mode is a dropwise adding mode, and specifically, when the ether dropwise adding time is 1-8 hours, the particle size range D of the obtained dapoxetine hydrochloride product can be controlled₅₀The particle size of the dapoxetine hydrochloride preparation is 20-160 mu m, the requirements of the dapoxetine hydrochloride preparation on bulk drugs are completely met, the particle size D50 of the dapoxetine hydrochloride preparation can be controlled strictly to be 29-35 mu m, the particle size is uniform, and the distribution range is narrow. The salification reaction device is simple and convenient, is simple to operate, has controllable dosage of hydrochloric acid gas, avoids harm to operators and pollution to the environment caused by the overflow of the hydrochloric acid gas, and can obtain the dapoxetine hydrochloride product with chemical purity and chiral purity of more than 99.9%.

The present application will be described in further detail with reference to specific examples. The following examples are intended to be illustrative of the present application only and should not be construed as limiting the present application.

The reagents and raw materials used in the invention are commercially available.

Example 1

Step S1, preparation of intermediate 1: (s) -3-amino-3-phenylpropanol.

Adding 20.2kg of tetrahydrofuran into a 200L reaction kettle at 0-10 ℃, stirring, adding 3.8kg of(s) -3-amino-3-phenylpropionic acid, adding 1.74kg of sodium borohydride, dropwise adding an iodine-tetrahydrofuran solution (5.9 kg of iodine is dissolved in 10.1kg of tetrahydrofuran solution and dropwise adding for 5-6 h) at 0-20 ℃, and finishing dropping. Heating to reflux (60-70 ℃) and reacting for 14-18 hours, wherein the medium-control raw materials are basically and completely reacted. And cooling to below 20 ℃, dropwise adding 9.0kg of methanol for quenching, wherein the dropwise adding time is 20-30 min. The organic solvent was distilled off under reduced pressure until no significant droplets flowed out, and a white oil was obtained. Adding 22.8kg of 20% (mass concentration) sodium hydroxide solution into the concentrate to adjust the pH value to 10-13, and stirring for 3h at 25-35 ℃. Adding dichloromethane for extraction, extracting twice, each time 20.0kg, combining organic layers of the two times, and removing an organic solvent through water bath reduced pressure distillation at 40-50 ℃ to obtain an intermediate 1: (s) -3-amino-3-phenylpropanol, as a pale yellow liquid 4.2kg, in a calculated yield of 120.6% and a checked purity of 94.6%.

Step S2, preparation of intermediate 2: (s) -3-dimethylamino-3-phenylpropanol.

4.2kg of water was charged into a 100L reactor at room temperature, stirred, and then 4.1kg of (S) -3-amino-3-phenylpropanol prepared in step S1 was added, 4.2kg of an aqueous formic acid solution (the mass concentration of formic acid was 88%) was added, and then 2.1kg of paraformaldehyde was added. Heating to 80-90 ℃, reacting for 11-13 h, cooling, monitoring by HPLC that the raw materials are basically reacted completely, and stopping the reaction. The pH of the reaction solution was adjusted to 10 to 13 with 8.2kg (2 times by mass) of a 20% aqueous sodium hydroxide solution, and the solution was extracted three times with 20.5kg of methylene chloride each time. The organic phases were combined and concentrated under reduced pressure until no significant droplets flowed out to give 4.4kg of a pale yellow liquid(s) -3-dimethylamino-3-phenylpropanol in a calculated yield of 90.5% and a purity of 95.6% by assay.

And step S3, preparing dapoxetine.

To a dry 200L reactor, 21.45kg of anhydrous N, N-dimethylformamide was added under stirring at room temperature. Under the protection of nitrogen, 1.9kg of sodium hydride was added. And (2) dropwise adding an N, N-dimethylformamide solution of (S) -3-dimethylamino-3-phenylpropanol at the temperature of 35-80 ℃ (preparation method is that 4.29kg of (S) -3-dimethylamino-3-phenylpropanol prepared in the step S2 is dissolved in 1.5 times of N, N-dimethylformamide (6.4 kg) in mass), and adding for about 2-3 hours. A solution of 1-fluoronaphthalene in N, N-dimethylformamide was added (preparation method: 3.3kg of 1-fluoronaphthalene was dissolved in 6.4kg of N, N-dimethylformamide), and the addition was completed for about 0.5 hour. And (3) raising the reaction temperature to 80-110 ℃, reacting for 9-11 h, monitoring the basic reaction of the raw materials by HPLC, and stopping the reaction. And adding the reaction solution into 84kg of water at the temperature of-5 ℃, quenching, stirring to separate out a solid product, and centrifuging to obtain the solid product. Drying to obtain 6.6kg of yellow solid dapoxetine(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, wherein the calculated yield is 90.4% and the detection purity is 90.7%.

And step S4, salt forming reaction.

Adding 9.75kg of methanol into a 100L reaction kettle at 0-30 ℃, adding 6.5kg of dapoxetine prepared in the step S3, stirring, introducing 1.62kg of hydrochloric acid gas, detecting the pH value to be about 1.0, and dissolving clearly. And cooling to 0 +/-5 ℃, dropwise adding 75kg of methyl tert-butyl ether, adding for 3 hours, keeping the temperature of 0 +/-5 ℃ after dropwise adding, stirring for 2-4 hours, and centrifuging to obtain the dapoxetine hydrochloride white solid. And (3) placing the mixture in a vacuum drying oven, controlling the temperature to be 45-55 ℃, and drying to obtain 5.45kg of white solid with the calculated yield of 75.0%.

The obtained dapoxetine hydrochloride white solid is detected and analyzed by HPLC, and the spectrum is shown in figure 1, so that the purity of the dapoxetine hydrochloride is 99.9%.

The crystal form detection and the particle size analysis of the dapoxetine hydrochloride product are respectively shown in fig. 2 and fig. 3, and it can be seen from the figure that the crystal form of the dapoxetine hydrochloride product prepared in the present example is the crystal form a, which is consistent with the original research, and the particle size D50 of the product is 119 μm.

Example 2

Step S1, preparation of intermediate 1: (s) -3-amino-3-phenylpropanol.

Adding 33.0kg of tetrahydrofuran into a 200L reaction kettle at 0-10 ℃, stirring, adding 6.2kg of(s) -3-amino-3-phenylpropionic acid methyl ester, adding 2.79kg of sodium borohydride, dropwise adding an iodine-tetrahydrofuran solution (9.5 kg of iodine is dissolved in 16.4kg of tetrahydrofuran solution and dropwise adding for 5-6 h) at 0-20 ℃, and finishing dropping. Heating to reflux (60-70 ℃) and reacting for 14-18 hours, wherein the medium-control raw materials are basically and completely reacted. And cooling to below 20 ℃, dropwise adding 14.7kg of methanol for quenching, wherein the dropwise adding time is 20-30 min. The organic solvent was distilled off under reduced pressure until no significant droplets flowed out, and a white oil was obtained. Adding 37.2kg of 20% sodium hydroxide (mass concentration) solution into the concentrate to adjust the pH value to 10-13, and stirring for 3h at 25-35 ℃. Adding dichloromethane for extraction, extracting twice, each time by 30kg, combining organic layers obtained in two times, and distilling in water bath at 40-50 ℃ under reduced pressure to remove an organic solvent to obtain an intermediate 1: (s) -3-amino-3-phenylpropanol, 6.4kg as a pale yellow liquid, in a calculated yield of 122.4% and a checked purity of 95.5%.

Step S2, preparation of intermediate 2: (s) -3-dimethylamino-3-phenylpropanol.

At room temperature, 5.5kg of water was charged into a 100L reactor, stirred, and then 6.2kg of (S) -3-amino-3-phenylpropanol prepared in step S1 was added, 6.6kg of an aqueous formic acid solution (the mass concentration of formic acid was 88%) was added, and then 3.1kg of paraformaldehyde was added. Heating to 80-90 ℃, reacting for 11-13 h, cooling, monitoring by HPLC that the raw materials are basically reacted completely, and stopping the reaction. The pH of the reaction solution was adjusted to 10 to 13 with 12.4kg (2 times by mass) of a 20% (mass concentration) aqueous solution of sodium hydroxide, and the mixture was extracted three times with 31kg of methylene chloride each time. The organic phases were combined and concentrated under reduced pressure until no significant droplets flowed out to give 6.9kg of a pale yellow liquid(s) -3-dimethylamino-3-phenylpropanol in a calculated yield of 93.8% and a purity of 97.1% by assay.

And step S3, preparing dapoxetine.

32.5kg of anhydrous N, N-dimethylformamide was added to a dry 200L reactor at room temperature, followed by stirring. Under the protection of nitrogen, 2.9kg of sodium hydride was added. And (2) dropwise adding an N, N-dimethylformamide solution of (S) -3-dimethylamino-3-phenylpropanol at the temperature of 35-80 ℃ (preparation method is that 6.5kg of (S) -3-dimethylamino-3-phenylpropanol prepared in the step S2 is dissolved in 1.5 times of N, N-dimethylformamide (9.8 kg) in mass), and adding for about 2-3 hours. A solution of 1-fluoronaphthalene in N, N-dimethylformamide was added (preparation method: 5.85kg of 1-fluoronaphthalene was dissolved in 9.8kg of N, N-dimethylformamide), and the addition was completed for about 0.5 hour. And (3) raising the reaction temperature to 80-110 ℃, reacting for 9-11 h, monitoring the basic reaction of the raw materials by HPLC, and stopping the reaction. And adding the reaction solution into 130kg of water at the temperature of-5 ℃, quenching, stirring to separate out a solid product, and centrifuging to obtain the solid product. Drying to obtain 9.75kg of yellow solid dapoxetine(s) -N, N-dimethyl-3- (1-naphthoxy) amphetamine, wherein the calculated yield is 88.1 percent and the detection purity is 96.1 percent.

And step S4, salt forming reaction.

Adding 14.4kg of methanol into a 100L reaction kettle at 0-30 ℃, adding 9.6kg of dapoxetine prepared in the step S3, stirring, introducing 4.8kg of hydrochloric acid gas, detecting the pH value to be about 1.0, and dissolving clearly. And cooling to 0 +/-5 ℃, dropwise adding 120kg of methyl tert-butyl ether, adding for 2 hours, keeping the temperature of 0 +/-5 ℃ after dropwise adding, stirring for 2-4 hours, and centrifuging to obtain the dapoxetine hydrochloride white solid. And (3) placing the mixture in a vacuum drying oven, controlling the temperature to be 45-55 ℃, and drying to obtain 8.42kg of white solid with the calculated yield of 78.5%.

The obtained dapoxetine hydrochloride white solid is detected and analyzed by HPLC, and the spectrum is shown in figure 4, so that the purity of the dapoxetine hydrochloride is 99.9%.

The crystal form detection and the particle size analysis of the dapoxetine hydrochloride product are respectively shown in fig. 5 and fig. 6, and it can be seen from the figures that the crystal form of the dapoxetine hydrochloride product prepared in the present example is the crystal form a, which is consistent with that of the original grinding, and the particle size D50 of the product is 86.2 μm.

Example 3

Steps S1 to S3 are the same as in example 1, and a yellow solid dapoxetine (S) -N, N-dimethyl-3- (1-naphthyloxy) amphetamine is prepared. In step S4, the ether dropping rate was changed for comparison.

At the temperature of 20 ℃, 7.5kg of methanol is added into a 100L reaction kettle, 5kg of dapoxetine prepared in the step S3 is added, stirring is carried out, 2.5kg of hydrochloric acid gas is introduced, the pH value is detected to be 0.8, and the solution is clear. And cooling to 0 +/-5 ℃, adding 65kg of methyl tert-butyl ether, adding for 1h, keeping the temperature of 0 +/-5 ℃ after dripping, stirring for 2-4h, and centrifuging to obtain the dapoxetine hydrochloride white solid. And (3) placing the mixture in a vacuum drying oven, controlling the temperature to be 45-55 ℃, drying, and analyzing the particle size of the dapoxetine hydrochloride product, wherein the particle size D50 of the product is 23.9 mu m as shown in figure 7.

At the temperature of 20 ℃, 7.5kg of methanol is added into a 100L reaction kettle, 5kg of dapoxetine prepared in the step S3 is added, stirring is carried out, 2.5kg of hydrochloric acid gas is introduced, the pH value is detected to be 0.8, and the solution is clear. And cooling to 0 +/-5 ℃, dropwise adding 65kg of methyl tert-butyl ether, adding for 6 hours, keeping the temperature of 0 +/-5 ℃ after dropwise adding, stirring for 2-4 hours, and centrifuging to obtain the dapoxetine hydrochloride white solid. And (3) placing the mixture in a vacuum drying oven, controlling the temperature to be 45-55 ℃, drying, and analyzing the particle size of the dapoxetine hydrochloride product, wherein the particle size D50 of the product is 159 mu m as shown in figure 8.

The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. For those skilled in the art to which the present application pertains, several simple deductions or substitutions may be made without departing from the concept of the present application, and all should be considered as belonging to the protection scope of the present application.