A process improvement method for dapoxetine hydrochloride

Abstract

The present invention relates to a process improvement method for dapoxetine hydrochloride. The synthesis process of the present invention uses 3-nitro-5-trifluoromethyl salicylaldehyde as a racemization catalyst, can achieve crystallization-induced asymmetric transformation, and compared with the prior art, which simply splits the isomers (theoretically, the maximum yield that can be achieved is only 50%), the product purity is high, the yield is high, and the cost is saved. At the same time, the synthesis process of the present invention is simple to operate and easy to realize industrialization.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a process improvement method for dapoxetine hydrochloride. Background Art

[0002] Dapoxetine's chemical name is (+) -( S) -N,N-dimethyl-3-(naphthyl-1-oxy)-phenylalanine hydrochloride, CAS registration number is 119356-77-3, mp. 175~178 ℃. It is a selective serotonin reuptake inhibitor (SSRIs), similar in structure to fluoxetine, and also has antidepressant effects. Its hydrochloride is used clinically. The drug was used to treat depression and related affective disorders in the early stage, and was later used to treat male premature ejaculation. Studies have shown that the drug can quickly inhibit the reuptake of complex amines in the blood, has no direct effect on neuronal receptors and has a short half-life, which can effectively control the symptoms of premature ejaculation that often occur in young men. Compared with other SSRIs, dapoxetine has a faster effect, a shorter half-life, and a lower incidence of adverse reactions.

[0003] There have been a large number of literature reports on the synthesis of dapoxetine, which can be mainly summarized into two categories: the first category is the racemate resolution method; the second category is the asymmetric synthesis method. In the racemate resolution method, a chiral resolution agent is used to resolve the racemic intermediate or final product to obtain the required diastereomer, and then the resolution agent and the single isomer are separated to finally obtain the target chiral compound with high optical purity. Asymmetric synthesis is to convert the potential chiral unit into a chiral unit to generate unequal amounts of stereoisomer products. The biggest advantage of this method is that it can directly synthesize the target product with optical purity without the need for a resolution reaction, which not only reduces the loss of raw materials, but also meets the requirements of atomic economics and green chemistry.

[0004] Wheeler et al. (Journal of Labelled Compounds and Radiopharmaceuticals, 1992, 31(4): 305-315) found that using dimethylamine and methyl cinnamate as starting materials, a Michael addition reaction was first performed to generate the intermediate 3-N, N-dimethylammonium-3-phenylpropionic acid methyl ester, which was then reduced with the reducing agent LiAlH4 to generate the intermediate 3-N, N-dimethylammonium-3-phenylpropanol, which was then etherified with 1-fluoronaphthalene to generate the dapoxetine racemate compound, and finally a chiral resolution agent L-(+)-tartaric acid was used to resolve it, and finally the target product S-dapoxetine was obtained. The reaction formula is as follows:

[0005] .

[0006] Chen Fangjun et al. (CN20121026520.5) used acetophenone as the starting reaction material and carried out a condensation reaction with acetonitrile. After the carboxylation reaction, the intermediate 3-benzoylpropionic acid was generated, and then it was subjected to esterification reaction, hydroxyimination reaction, and reduction reaction to generate the intermediate 3-amino-3-phenylpropanol. Then, Boc was used to protect the amino group on the intermediate 3-amino-3-phenylpropanol, and then an etherification reaction and an aminomethylation reaction were carried out. Finally, tartaric acid was used as a resolving agent to perform a resolving reaction to obtain the target product S-dapoxetine. The reaction formula is as follows:

[0007] .

[0008] Yin Lingli et al. (Chinese Journal of Medicinal Chemistry, 2011, 1(1): 37-39) used 3-phenyl-1-propanol as the starting material, and firstly reacted it with 1-fluoronaphthalene to form the intermediate 3-phenyl-1-(naphthyloxy)-propane by Williamson reaction. Then, NBS was used to replace the hydrogen on the benzyl position of the phenyl ring of the intermediate 3-phenyl-1-(naphthyloxy)-propane, i.e., bromination was performed to form the intermediate 3-phenyl-3-bromo-1-(naphthyloxy)-propane. Then, the intermediate 3-phenyl-3-bromo-1-(naphthyloxy)-propane was reacted with dimethylamine to form the racemate of dapoxetine. Finally, the chiral resolution agent L-(+)-tartaric acid was used to resolve the racemate of dapoxetine, and finally the target product S-dapoxetine was obtained. The reaction formula is shown below:

[0009] .

[0010] Zhang Derong et al. (Bioprocess, 2010, 8(2): 13-17) used immobilized penicillin G acylase (PGA) to enzymatically decompose (±)-N-phenylacetyl-3-amino-3-phenylpropionic acid to obtain the intermediate (S)-3-amino-3-phenylpropionic acid for the synthesis of dapoxetine. The (S)-3-amino-3-phenylpropionic acid was subjected to multiple steps of chemical synthesis such as reduction, methylation, and condensation to obtain the final product dapoxetine. The reaction formula is as follows:

[0011] .

[0012] The use of chiral reagents to split racemates can obtain target compounds with higher ee values, but this splitting process usually requires multiple recrystallizations, and the splitting is performed at the final stage of the reaction, which wastes a lot of raw materials. The method of using asymmetric synthesis effectively avoids splitting and can effectively improve the ee value, but the route for synthesizing chiral intermediates is relatively cumbersome and complicated, and expensive chiral catalysts and toxic or explosive reagents are used in the synthesis process. Therefore, it is of great economic value to develop a process suitable for industrialization of dapoxetine hydrochloride. Summary of the invention

[0013] In order to solve the above technical problems existing in the prior art, the present invention provides a process improvement method for dapoxetine hydrochloride. The method of the present invention has simple reaction steps, does not require the use of expensive chiral catalysts, can reduce raw material losses, and is more suitable for industrial production.

[0014] The present invention provides a process improvement method for dapoxetine hydrochloride, comprising the following steps:

[0015] 1) subjecting 3-amino-3-phenylpropionic acid to a reduction reaction to obtain 3-amino-3-phenylpropanol;

[0016] 2) subjecting 3-amino-3-phenylpropanol to a crystal-induced asymmetric transformation reaction to obtain (S)-3-amino-3-phenylpropanol;

[0017] 3) subjecting (S)-3-amino-3-phenylpropanol to an amine methylation reaction to obtain (S)-3-dimethylamino-3-phenylpropanol;

[0018] 4) (S)-3-dimethylamino-3-phenylpropanol and 1-halonaphthalene are etherified to obtain dapoxetine;

[0019] 5) reacting S-dapoxetine with HCl to form a salt to obtain dapoxetine hydrochloride;

[0020] The reaction route is as follows:

[0021] ;

[0022] Wherein: X is a halogen;

[0023] The crystallization-induced asymmetric transformation reaction in step 2) is carried out in the presence of a racemization catalyst, a chiral organic acid auxiliary and a solvent, wherein the racemization catalyst is 3-nitro-5-trifluoromethyl salicylaldehyde.

[0024] Preferably, the reducing agent of the reduction reaction in step 1) is selected from NaBH4-I2, KBH4-I2, LiAlH4 or BH3.

[0025] Preferably, the chiral organic acid auxiliary in step 2) is in an optically pure form and is selected from one or more of tartaric acid, mandelic acid, dibenzoyltartaric acid, p-methyldibenzoyltartaric acid and camphorsulfonic acid, more preferably D-(-)-tartaric acid.

[0026] Preferably, the solvent in step 2) is selected from isopropanol, methanol, ethanol and isobutanol.

[0027] Preferably, in step 2), the molar ratio of the chiral organic acid auxiliary to 3-amino-3-phenylpropanol is (1-2):1.

[0028] Preferably, the reaction temperature of step 2) is 40°C to 80°C, more preferably 70°C to 75°C.

[0029] Preferably, the amine methylation reaction in step 3) is carried out in the presence of formaldehyde and formic acid.

[0030] Preferably, the 1-halonaphthalene in step 4) is 1-fluoronaphthalene.

[0031] Preferably, step 4) is carried out under alkaline conditions, and the base is selected from an organic base or an inorganic base.

[0032] Preferably, the salt-forming reaction in step 5) is carried out in the presence of a solvent.

[0033] Preferably, the reaction solvent in step 5) is selected from methanol, ethanol, propanol or butanol.

[0034] Optical resolution by crystallization is a classic method for separating enantiomers. It is simple and effective and is widely used in laboratories and industrial production. In the prior art, the synthesis of dapoxetine hydrochloride usually involves resolving the racemate using a resolving agent such as tartaric acid before the salt-forming reaction. However, the theoretical maximum yield of simply resolving the isomers is only 50%, which results in a huge waste. The application of crystallization-induced asymmetric transformation (CIAT) overcomes this defect. CIAT is a coupling of in situ racemization (or epimerization) and selective crystallization. A successful CIAT process needs to meet the following requirements: (1) Find an environment that allows the racemization (or epimerization) to proceed smoothly; (2) Find a stable and efficient resolution method (adding chiral catalysts, chiral auxiliary agents or enzymes) during the racemization process so that the conversion rate V between the isomers SMR and SMS is 1.5-2.0. RI ≠ V SI , and the conversion rate constant k RI With k SIcan be equal; (3) at least one isomer must be crystallized during the process; (4) they must be separated and operated in an environment where they will not be decomposed or degraded, and co-crystallization cannot occur between the enantiomers SMR and SMS. Usually the second point is the most critical and difficult part.

[0035] There have been many reports on the use of racemization (differential isomerization) via imines for chiral separation of amino acids. The principle is as follows:

[0036] .

[0037] However, there is no literature report on the chiral separation of amino alcohols by racemization in the form of imines. The inventors, through a lot of creative work, screened out the racemization catalyst 3-nitro-5-trifluoromethyl salicylaldehyde of the present invention, and found that it can achieve the crystallization-induced asymmetric transformation of (S)-3-amino-3-phenylpropanol with a high yield, and the product ee value is also high.

[0038] Compared with the prior art, the present invention has the following advantages:

[0039] 1) The synthesis process of the present invention uses 3-nitro-5-trifluoromethyl salicylaldehyde as a racemization catalyst, which can achieve crystallization-induced asymmetric transformation. Compared with the prior art which simply separates isomers (the theoretical maximum yield that can be achieved is only 50%), the product has high purity, high yield, and saves costs.

[0040] 2) The synthesis process of the present invention is simple to operate and can be easily industrialized. DETAILED DESCRIPTION

[0041] The following examples are provided to illustrate the present invention in detail. The following examples are provided to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0042] Therefore, before describing the present invention in detail, it should be understood that the present invention is not limited to the system or process parameters of specific examples which may vary of course. It should also be understood that the terms used herein are only for the purpose of describing a specific embodiment of the present invention, and are not intended to limit the scope of the present invention in any way. The examples used anywhere in this specification (including examples of any term discussed herein) are merely illustrative and in no way limit the scope and meaning of the present invention or any illustrative term. Similarly, the present invention is not limited to the various embodiments given in this specification. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. In the event of a conflict, this document (including definitions) shall prevail.

[0043] Example 1 Synthesis of 3-amino-3-phenylpropanol

[0044] 3-Amino-3-phenylpropionic acid (300 g, 1.82 mol) and 5 L of tetrahydrofuran were added to the reactor, and NaBH4 (152 g, 4.02 mol) was added under ice bath conditions and stirred for 20 min. The temperature was controlled at 0-5°C, and I2 (462 g, 1.82 mol) was dissolved in tetrahydrofuran (700 mL) and slowly added dropwise to the reactor. The addition was completed in about 1.5 h. After the release rate of H2 slowed down, the temperature was raised and refluxed for 18 h.

[0045] After stopping the reaction, the reaction mixture was cooled to room temperature, and 600 mL of anhydrous methanol was slowly added dropwise under an ice bath until the reaction solution was clear, stirred at room temperature for 60 min, and the solvent was evaporated under reduced pressure to obtain a white oily viscous substance. 3.5 L of 20% KOH was added, and stirred at room temperature for 3-4 h to precipitate a large amount of oil. Extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a white solid. 500 mL of n-hexane was added, stirred for 3 h, and filtered to obtain 253 g of a white solid, with a yield of 92.1% and a purity of 99.2% as determined by HPLC.

[0046] 1 HNMR (400MHz, CDCl3) δ: 1.83-1.91 (m, 2H, -CH2-); 2.80 (S, 3H, -NH2, -OH); 4.08-4.12 (m, 1H, N-CH); 3.72-3.80(m, 2H, -CH2-O); 7.24-7.35(m, 5H, Ar-H).

[0047] Example 2 Synthesis of (S)-3-amino-3-phenylpropanol

[0048] Add 30.2 g (0.20 mol) 3-amino-3-phenylpropanol and 150 mL isopropanol to a three-necked flask. After the 3-amino-3-phenylpropanol is completely dissolved under stirring, add 2.4 g (0.01 mol) 3-nitro-5-trifluoromethyl salicylaldehyde. Control the temperature to 70-75°C, and drop a mixed solution of 30.0 g (0.20 mol) D-(-)-tartaric acid and 150 mL isopropanol. Add the mixture in 1 h and keep the mixture warm for 2 h. Cool the reaction solution to room temperature, filter it, and rinse the solid with a small amount of isopropanol and dry it. Add 125 mL acetone to the dried solid, then add NaOH to adjust the pH of the solution to about 10, and filter to obtain 26.8 g of white solid (S)-3-amino-3-phenylpropanol with a yield of 88.7%. =-10.0 (c=1, MeOH), optical purity>99.5ee%.

[0049] Example 3 Effect of racemization catalyst on the preparation of (S)-3-amino-3-phenylpropanol

[0050] The same reaction conditions as in Example 2 were used, except that the racemization catalyst was different. The experimental results are as follows:

[0051]

[0052] It can be seen from Examples 2-3 that the use of the 3-nitro-5-trifluoromethyl salicylaldehyde of the present invention as a racemization catalyst has good resolution efficiency and high product purity.

[0053] Example 4 Synthesis of (S)-3-dimethylamino-3-phenylpropanol

[0054] Add 3-amino-3-phenylpropanol (20 g, 0.132 mol) to a three-necked flask, slowly drop 88% formic acid (36.5 g) under ice bath, after the drop is complete, wait for the solid to dissolve completely, slowly drop 36% formaldehyde (27.5 g, 0.33 mol), control the temperature at 0~5℃, and stir at 95~100℃ for 8~10 h after the drop is complete. After the reaction is completed, slowly drop 30% NaOH solution under ice bath until pH ≥ 13, precipitate oil, extract with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 20.5 g of light yellow oil, yield: 86.9%.

[0055] Example 5 Synthesis of (S)-dapoxetine

[0056] Add NaH (12.1 g, 0.3 mol) and 150 mL of dried N,N-dimethylformamide (DMF) to a three-necked flask equipped with a drying tube, a stirrer, and a nitrogen protection device, stir for about 30 min, slowly drop 3-dimethylamino-3-phenylpropanol (17.9 g, 0.10 mol) dissolved in 150 mL of DMF into the three-necked flask, place at 50-55°C for 2 h after the drop, then slowly drop 1-fluoronaphthalene (17.5 g, 0.12 mol), place at 100°C for 6 h after the drop. Stop the reaction, slowly add 600 mL of ice water in an ice bath, and extract with ethyl acetate three times. Combine the organic phases, dry over anhydrous sodium sulfate (anhydrous magnesium sulfate), and evaporate the solvent under reduced pressure to obtain a light yellow oil. Add 20 ml of petroleum ether, stir and grind to obtain 26.3 g of solid, with a yield of 86.2%. =+128.3°(c=1, methanol), ee%>99.8%, MS(m / z)=306.6(M+1).

[0057] 1 HNMR (400MHz, CDCl 3) δ: 2.26 [s, 6H, N-(CH3)2], 2.34-2.42 (m, 1H, CH2), 2.64-2.75 (m, 1H, CH2 ), 3.65-3.74 (m, 1H, Ar-CH), 3.97-4.01 (m, 1H, CH2O), 4.11-4.23 (m, 1H, CH 2 O), 6.72-6.78 (m, 1H, Ar), 7.32-7.48 (m, 7H, Ar), 7.58-7.72 (m, 2H, Ar), 7.81-7.91 (m, 1H, Ar).

[0058] Example 6 Preparation of Dapoxetine Hydrochloride

[0059] Place S-dapoxetine (4.0 g, 13.1 mmol) in a three-necked flask, add 50 mL of anhydrous ethanol, stir until dissolved, slowly add hydrochloric acid-ethanol solution dropwise to pH 3-4, stir for 15 min, evaporate the solvent under reduced pressure, add 60 mL of ethyl acetate to the residue, stir at 60 °C for 20 min, cool to room temperature, filter, wash the filter cake with a small amount of ethyl acetate, and dry to obtain 4.3 g of white powdery solid, yield: 96.0%.

[0060] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

Claims

1. A process improvement method for dapoxetine hydrochloride, characterized in that The steps include: 1) subjecting 3-amino-3-phenylpropionic acid to a reduction reaction to obtain 3-amino-3-phenylpropanol; 2) subjecting 3-amino-3-phenylpropanol to a crystal-induced asymmetric transformation reaction to obtain (S)-3-amino-3-phenylpropanol; 3) subjecting (S)-3-amino-3-phenylpropanol to an amine methylation reaction to obtain (S)-3-dimethylamino-3-phenylpropanol; 4) (S)-3-dimethylamino-3-phenylpropanol and 1-halonaphthalene are etherified to obtain dapoxetine; 5) reacting dapoxetine with HCl to form a salt to obtain dapoxetine hydrochloride; The reaction route is as follows: ； Wherein: X is a halogen; The crystallization-induced asymmetric transformation reaction in step 2) is carried out in the presence of a racemization catalyst, a chiral organic acid auxiliary and a solvent; the racemization catalyst is 3-nitro-5-trifluoromethyl salicylaldehyde; and the chiral organic acid auxiliary is D-(-)-tartaric acid.

2. The process improvement method according to claim 1, characterized in that: The reducing agent for the reduction reaction of step 1) is selected from NaBH4-I2, KBH4-I2, LiAlH4 and BH3.

3. The process improvement method according to claim 1, characterized in that: The solvent in step 2) is selected from isopropanol, methanol, ethanol and isobutanol.

4. The process improvement method according to claim 1, characterized in that: In step 2), the molar ratio of the chiral organic acid auxiliary to 3-amino-3-phenylpropanol is (1-2):1, and the reaction temperature of step 2) is 40°C to 80°C.

5. The process improvement method according to claim 1, characterized in that: The amine methylation reaction of step 3) is carried out in the presence of formaldehyde and formic acid.

6. The process improvement method according to claim 1, characterized in that: The 1-halonaphthalene in step 4) is 1-fluoronaphthalene; step 4) is carried out under alkaline conditions, and the base is selected from an organic base or an inorganic base.

7. The process improvement method according to claim 1, characterized in that: The salt-forming reaction in step 5) is carried out in the presence of a solvent.

8. The process improvement method according to claim 7, characterized in that: The reaction solvent in step 5) is selected from methanol, ethanol, propanol or butanol.

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