A kind of preparation method of fluoxetine hydrochloride

Abstract

The present invention relates to the technical field of organic synthesis, and more particularly to a method for preparing fluoxetine hydrochloride. The main innovative points and scheme contents of the method include: N-methyl-amphetamine in dichloromethane under the conditions of chlorine and ultraviolet light, a free radical reaction of α-carbon on the aromatic ring side chain of N-methyl-amphetamine occurs, and N-methyl-3-chloro-3-phenylpropylamine is formed. This is a reaction not reported in the existing literature for preparing fluoxetine. After the disappearance of the starting raw materials of this reaction, no separation and purification is required, and 4-hydroxybenzotrifluoride and potassium carbonate are directly added. After the TLC detection reaction ends, the reduced pressure concentration after filtration, fluoxetine is added to methanol, and concentrated hydrochloric acid is added with stirring to obtain the hydrochloride of fluoxetine. The whole reaction process is continuous and uninterrupted. This invention fills the gap of preparing fluoxetine by one-pot method, and also invents a new method for the side chain halogenation of Ph-CH2-(CH2)n-CH2NMe(n=1-5) compounds. The whole preparation process has simple method, mild conditions and high product yield.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing fluoxetine hydrochloride. Background Art

[0002] Fluoxetine, also known as Prozac, is an antidepressant drug that belongs to the class of selective serotonin reuptake inhibitors (SSRIs). Its main function is to prevent serotonin in neurons from being recycled, thereby increasing the serotonin content between neurons, thereby achieving the effect of treating depression and other related mental disorders. Fluoxetine has shown good efficacy in treating mild to moderate depression and other affective disorders. In addition, it is also widely used to treat diseases such as obsessive-compulsive disorder, social phobia, and post-traumatic stress disorder.

[0003] Fluoxetine is a selective 5-hydroxytryptamine reuptake inhibitor that can selectively act on neurotransmitter receptors. Compared with traditional tricyclic and tetracyclic antidepressants, it has the characteristics of good efficacy, mild and few adverse reactions, and high safety. Therefore, since the drug was launched on the market, people have paid great attention to the preparation of this drug. At present, there are more than ten synthetic routes reported in the literature, but each synthetic route has at least three steps, such as Figure 2 As shown, the preparation steps are long and a variety of organic solvents are used.

[0004] A comparative example of two current synthetic routes for fluoxetine hydrochloride is described below.

[0005] For example, comparative case 1 discloses the preparation of fluoxetine using acetophenone as a raw material, such as Figure 3 As shown, acetophenone is used as the starting material, and fluoxetine hydrochloride is synthesized through 6 steps of Mannich reaction, reduction, etherification, demethylation, hydrolysis, and salt formation, and the total yield of fluoxetine hydrochloride is 41.9%;

[0006] For example, comparative case 2 discloses the preparation of fluoxetine using acetophenone as a raw material, such as Figure 4As shown, acetophenone is first carboxylated under catalytic high pressure, and reacts with ethanol to generate ethyl benzoyl acetate, which is reduced by a microbial catalytic method to obtain (S)-1-hydroxy-1-phenylpropionic acid ethyl ester, and the reaction yield of this step is 76%, and the enantiomeric amount of the obtained product is 99%. (S)-1-hydroxy-1-phenylpropionylethanol is then decomposed by methylamine to obtain (S)-1-hydroxy-1-phenylpropionylmethylamine, which is then reduced by lithium aluminum hydride to obtain (S)-3-methylamino-1-phenylpropanol, which is then subjected to etherification reaction and salt formation reaction with p-trifluoromethylchlorobenzene to obtain (S)-fluoxetine hydrochloride. This preparation method was published in the 11th issue of the 16th volume of the Chinese Journal of New Drugs in 2007. The preparation method includes the carboxylation reaction of acetophenone; the reduction reaction of ethyl benzoyl acetate; the synthesis of (S)-1-hydroxy-1-phenylpropanol, including the aminolysis and reduction reaction of methylamine; and the etherification reaction and salt formation reaction with trifluoromethylchlorobenzene to obtain (S)-fluoxetine hydrochloride. The preparation of fluoxetine was completed in four steps, and a variety of organic solvents were used. Summary of the invention

[0007] 1. Technical issues to be solved

[0008] The object of the present invention is to provide a method for preparing fluoxetine hydrochloride to solve the problems raised in the above background technology.

[0009] (II) Technical solution

[0010] To achieve the above-mentioned purpose, the present invention provides the following technical scheme: a method for preparing fluoxetine hydrochloride, comprising the following steps: adding dichloromethane and compound 1 into a reaction container, introducing chlorine gas at room temperature, irradiating with ultraviolet light for 1 hour, adding 4-hydroxytrifluorotoluene after the reaction is detected, and then adding potassium carbonate, reacting at room temperature for 2 hours, filtering to obtain a filtrate after the reaction is detected, and distilling the solvent under reduced pressure to obtain fluoxetine, adding fluoxetine to methanol, adding concentrated hydrochloric acid with stirring, stirring at room temperature for 1 hour, and filtering and drying to obtain fluoxetine hydrochloride.

[0011] Compound 1 (N-methyl-amphetamine) undergoes a free radical reaction on the aromatic ring side chain of N-methyl-amphetamine in dichloromethane under the conditions of chlorine and ultraviolet light to form N-methyl-3-chloro-3-phenylpropylamine. After the starting material compound 1 disappears, there is no need to separate and purify it. 4-hydroxytrifluorotoluene and potassium carbonate are directly added. After the reaction is detected, it is filtered and concentrated under reduced pressure. Fluoxetine is added to methanol, and concentrated hydrochloric acid is added with stirring to obtain fluoxetine hydrochloride. The entire reaction process is continuous without interruption.

[0012] Based on the above technical solution, the present invention can also be improved as follows.

[0013] Further, compound 1 is N-methyl-amphetamine.

[0014] Further, the feeding mass ratio of N-methyl-amphetamine to dichloromethane is 1.0:6.0-7.0.

[0015] Furthermore, the molar ratio of N-methyl-amphetamine to potassium carbonate to 4-hydroxytrifluorotoluene is 1:1.00-1.05:1.00-1.05.

[0016] Further, the feeding mass ratio of N-methyl-amphetamine to methanol is 1.0:2.6-2.7.

[0017] In addition, compound 1 can also be: Ph-CH2-(CH2)n-CH2NMe (n=1), and finally fluoxetine hydrochloride is obtained. The present invention expands the new method of side chain α-carbon halogenation of Ph-CH2-(CH2)n-CH2NMe (n=1-5) compounds.

[0018] (III) Beneficial effects

[0019] Compared with the prior art, the present invention provides a method for preparing fluoxetine hydrochloride, which has the following beneficial effects:

[0020] 1. One-step preparation of fluoxetine. The preparation steps are greatly shortened, and the entire reaction process is continuous without interruption, filling the gap in the one-pot preparation of fluoxetine.

[0021] 2. The yield is high, and the total yield is about 72%. A higher yield can reduce the possibility of impurities, thereby improving the purity and quality of the product, saving costs and improving production efficiency.

[0022] 3. This preparation method does not require a high temperature and high pressure environment while shortening the number of steps, and is suitable for large-scale industrial production and laboratory synthesis.

[0023] 4. This preparation method does not produce any high-risk chemicals while shortening the number of steps.

[0024] 5. Only two organic solvents are used in the reaction. Using two organic solvents can reduce the demand for equipment and costs, reduce the generation of waste, reduce the risk of environmental pollution, and use only two organic solvents, making the reaction more controllable and stable.

[0025] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention in conjunction with the accompanying drawings. The specific implementation of the present invention is given in detail by the following embodiments and their accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The drawings described herein are used to provide further understanding of the present invention and constitute a part of this application. The illustrative embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0027] In the attached picture:

[0028] Figure 1 Schematic diagram of the synthesis route of the present invention;

[0029] Figure 2 This is a schematic diagram of the current synthetic route of fluoxetine hydrochloride;

[0030] Figure 3 Schematic diagram of the synthetic route of comparative case 1;

[0031] Figure 4 Schematic diagram of the synthetic route for comparative case 2. DETAILED DESCRIPTION

[0032] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention. The present invention is described in more detail by way of example with reference to the accompanying drawings in the following paragraphs. The advantages and features of the present invention will become clearer according to the following description and claims. It should be noted that the drawings are all in a very simplified form and are not in precise proportions, and are only used to conveniently and clearly assist in explaining the purpose of the embodiments of the present invention.

[0033] like Figure 1 As shown, the embodiments provided by the present invention are:

[0034] Embodiment 1

[0035] 500 ml of dichloromethane was added to a 2000 ml three-necked flask, and then N-methyl-amphetamine was added. After chlorine was introduced under ultraviolet irradiation at room temperature for 1 hour, the introduction of chlorine was stopped. After the reaction was detected, 109 g of 4-hydroxytrifluorotoluene was added, and then 93 g of potassium carbonate was added. The reaction was reacted at room temperature for 2 hours. After the reaction was detected, the filtrate was obtained by filtration, and the dichloromethane was distilled off under reduced pressure to obtain 170 g of fluoxetine, with a yield of 82% and a purity of 98%.

[0036] The characterization data of the obtained product are:

[0037] 1H NMR (400MHz, DMSO-d6): σ7.56(d,J=7.2Hz,2H),7.4(dd,J=7.6Hz,2H),7.38-7.25(m ,3H),7.1(d,J=8.8Hz,2H),5.6(m,1H),2.6(m,2H),2.2-1.9(m,2H),2.18(s,3H)ppm;

[0038] ESI-MS: m / z: 310.2 ([M+H] + ).

[0039] 170 g of fluoxetine was added to 340 ml of methanol, and 58.5 g of concentrated hydrochloric acid was added with stirring. The mixture was stirred at room temperature for 1 h, and filtered and air-dried to obtain 167 g of a white solid with a yield of 88% and a purity of 99%.

[0040] The characterization data of the obtained product are:

[0041] 1H NMR (200MHz, DMSO-d6): δppm 2.54(s,3H),9.32(s,NH),3.01(t,J=7.16Hz,3H),2.24-2.29(m,2H),5.74(d, J=4.9,2.8,1H),7.1(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.2-7.5(5H); 13C NMR (125MHz, DMSO-d6): δppm32.4,34.2,45.23,76.55,116.37,126.02,121.57, 126.02,116.37,124.39,140.07,126.67,128.72,128;MS:calcdforC17H18F3NO 309.1340(M+), found 310.1354(M+H+).

[0042] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any ordinary technician in the industry can smoothly implement the present invention as shown in the drawings and described above. However, any equivalent changes, modifications and evolutions made by technicians familiar with the profession without departing from the scope of the technical solution of the present invention using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing fluoxetine hydrochloride, characterized in that: The method comprises the following steps: adding dichloromethane and compound 1 into a reaction container, introducing chlorine gas at room temperature, irradiating with ultraviolet light for 1 hour, adding 4-hydroxybenzotrifluoride after the detection reaction is completed, and then adding potassium carbonate, reacting at room temperature for 2 hours, filtering to obtain a filtrate after the detection reaction is completed, distilling the solvent under reduced pressure to obtain fluoxetine, adding fluoxetine to methanol, adding concentrated hydrochloric acid with stirring, stirring at room temperature for 1 hour, filtering with suction and drying to obtain fluoxetine hydrochloride, wherein the compound 1 is N-methyl-amphetamine, and the synthesis route of fluoxetine hydrochloride of the present invention is as follows: 。 2. A method for preparing fluoxetine hydrochloride according to claim 1, characterized in that: The feeding mass ratio of the N-methyl-amphetamine to dichloromethane is 1.0:6.0-7.

0.

3. A method for preparing fluoxetine hydrochloride according to claim 1, characterized in that: The molar ratio of the N-methyl-amphetamine to potassium carbonate to 4-hydroxybenzotrifluoride is 1: 1.00-1.05:1.00-1.

05.

4. A method for preparing fluoxetine hydrochloride according to claim 1, characterized in that: The feeding mass ratio of the N-methyl-amphetamine to methanol is 1.0:2.6-2.7.

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