Preparation method of viltrabutine hydrochloride

Abstract

The invention provides a preparation method of viltrabutine hydrochloride, and relates to the technical field of medicine synthesis. The invention relates to a preparation method of viltrobutine hydrochloride, which comprises the following steps: (1) in the presence of a catalyst, reacting 3, 4-dimethoxybenzaldehyde with tert-butyl sulfinamide to obtain a compound VC-1; (2) reacting the compound VC-1 with (3-phenyl propyl) magnesium bromide to obtain a compound VC-2; (3) reacting the compound VC-2 with acid, and neutralizing to obtain a compound VC-3; (4) reacting the compound VC-3 with formaldehyde in the presence of a reducing agent to obtain free viltrabutine; and (5) reacting the free viltrabutine with hydrogen chloride to obtain the viltrabutine hydrochloride. The invention provides a viltrabutine hydrochloride synthesis process which is high in purity, high in yield and simple and convenient to operate, the operation process is simplified, and industrial production is convenient to realize.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of vertibutin hydrochloride. Background Art

[0002] During the parturition of sows, the phenomenon of stillbirth is a common problem in the breeding industry, which has a direct negative impact on reproductive efficiency and economic benefits. The normal parturition interval should be 15 to 30 minutes per sow. If the parturition process exceeds 4 hours, the risk of fetal death due to intrauterine hypoxia will increase significantly. Excessive use of oxytocin may cause the uterus to contract too strongly, compress the placental blood vessels, block the channels for the mother to deliver oxygen and nutrients to the fetus, and thus increase the stillbirth rate. Too strong uterine contractions may also cause the umbilical cord to be squeezed in the birth canal, directly cutting off the oxygen supply to the fetus. Since piglets have extremely low tolerance to hypoxia, irreversible brain damage may occur within the first 5 minutes after the umbilical cord ruptures, or lead to insufficient vitality of the delivered piglets. Improper handling of dystocia sows may induce endometritis, resulting in long-term infertility and thus causing significant economic losses.

[0003] As a selective β2-adrenergic receptor agonist, vertibutin hydrochloride effectively relieves uterine or gastrointestinal spasms by regulating the contraction and relaxation of smooth muscles. In the application of sows, it specifically binds to β2-adrenergic receptors in parts such as the uterus and intestine, reduces the binding of myosin and actin, and reduces the contractility of smooth muscles. The activation of β2-adrenergic receptors can also promote the opening of ATP-sensitive potassium channels (KATP), resulting in cell membrane hyperpolarization, reducing the opening of voltage-dependent calcium channels, and further inhibiting contraction, thereby achieving the effect of expanding the birth canal. This mechanism has a positive impact on the parturition of sows, especially in cases of insufficient cervical dilation, high cervical osmolarity, reduced spasm state, and uterine vasodilation, which helps to improve fetal oxygenation. In addition, this drug can also eliminate the spasms of uterine muscles after difficult parturition and reduce the risk of uterine prolapse.

[0004] Vertibutin hydrochloride was developed by Boehringer (Merial) and is commercially available as Monzal. Monzal has been approved for use in bitches and sows, and its function is to dilate the soft part of the birth canal and coordinate uterine contractions to relieve and shorten the parturition process.

[0005] Boehringer described a synthesis method of vertibutin hydrochloride in the 1964 patent (US3133967). In this route, 3-phenylbromopropane reacts with magnesium in an anhydrous ether solution to synthesize a Grignard reagent, and then the Grignard reagent is added to an anhydrous ether solution of 2-(3,4-dimethoxyphenyl)-2-dimethylamino-acetonitrile to obtain free vertibutin, and finally it is salted with ethereal hydrogen chloride to obtain the finished product vertibutin hydrochloride. The specific route is as follows:

[0006]

[0007] This synthetic route has at least the following major defects:

[0008] (1) The starting material 2-(3,4-dimethoxyphenyl)-2-dimethylamino-acetonitrile in this route is a non-standard chemical product and cannot be purchased on the market. It is usually prepared by the Mannich reaction of veratraldehyde, dimethylamino hydrochloride, and sodium cyanide, and sodium cyanide is a highly toxic substance. The specific reaction formula is as follows:

[0009]

[0010] (2) Anhydrous diethyl ether with a low boiling point is used as a solvent in the synthesis process of this route, which is not suitable for large-scale production;

[0011] (3) During the reaction of Grignard reagent with 2-(3,4-dimethoxyphenyl)-2-dimethylamino-acetonitrile, in addition to the target product, side reactions will also occur with the cyano group, resulting in many by-products and difficult separation and purification;

[0012] (4) Through repeated verification of the original literature, the yield of the target product is low, and the yield of free vilazodone is less than 20%.

[0013] Therefore, there is an urgent need to develop a synthetic process for vilazodone hydrochloride with high purity, high yield and simple operation, which has significant economic value and practical significance for the market.

[0014] In view of this, the present invention is specifically proposed. Summary of the Invention

[0015] The purpose of the present invention is to provide a preparation method of vilazodone hydrochloride. The reaction yield of the preparation method is significantly improved, and the intermediate does not require additional purification steps, and the purity of the final product is extremely high.

[0016] In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:

[0017] A preparation method of vilazodone hydrochloride according to the present invention, the preparation method of vilazodone hydrochloride comprises the following steps:

[0018] (1) In the presence of a catalyst, 3,4-dimethoxybenzaldehyde reacts with tert-butylsulfinamide to obtain compound VC-1; the reaction formula is as follows:

[0019]

[0020] (2) Compound VC-1 reacts with (3-phenylpropyl)magnesium bromide to obtain compound VC-2; the reaction formula is as follows:

[0021]

[0022] (3) After the compound VC-2 reacts with an acid and then undergoes a neutralization treatment, the compound VC-3 is obtained; the reaction formula is as follows:

[0023]

[0024] (4) In the presence of a reducing agent, the compound VC-3 reacts with formaldehyde to obtain free viloxazine; the reaction formula is as follows:

[0025]

[0026] (5) The free viloxazine reacts with hydrogen chloride to obtain viloxazine hydrochloride; the reaction formula is as follows:

[0027]

[0028] Preferably, in step (1), the molar ratio of the 3,4-dimethoxybenzaldehyde to the tert-butylsulfinamide is 1:(1 - 1.5).

[0029] Preferably, in step (1), the catalyst is selected from any one or a combination of at least two of pyrrolidine, morpholine, piperidine or piperazine.

[0030] Preferably, in step (1), the molar ratio of the 3,4-dimethoxybenzaldehyde to the catalyst is 1:(0.1 - 0.5).

[0031] Preferably, in step (1), the reaction is carried out in a solvent, and the solvent is dichloromethane.

[0032] Preferably, in step (1), the temperature of the reaction is 20 - 40 °C, and the reaction time is 4 - 24 h.

[0033] Preferably, in step (1), after the reaction, the following post-treatment steps are further included:

[0034] The reaction solution obtained from the reaction is concentrated, a pulping solvent is added, then a pulping treatment is carried out, and after filtration and drying, the compound VC-1 is obtained.

[0035] Preferably, in step (1), the pulping solvent is selected from any one or a combination of at least two of methyl tert-butyl ether, isopropyl ether, ether, petroleum ether, n-hexane, cyclohexane or n-heptane.

[0036] Preferably, in step (1), the temperature of the pulping treatment is 10 - 30 °C, and the pulping treatment time is 0.5 - 2 h.

[0037] Preferably, the preparation steps of the (3-phenylpropyl)magnesium bromide include:

[0038] 3-phenylpropyl bromide, magnesium, and iodine undergo a Grignard reaction in tetrahydrofuran to obtain a Grignard reagent containing (3-phenylpropyl)magnesium bromide.

[0039] Preferably, the molar ratio of the 3-phenylpropyl bromide to magnesium is 1:(1 - 2).

[0040] Preferably, the addition amount of iodine is 0.1 - 0.2% of the mass of the 3-phenylpropyl bromide.

[0041] Preferably, the temperature of the Grignard reaction is 50 - 60 °C, and the time of the Grignard reaction is 20 - 60 min.

[0042] Preferably, the concentration of (3-phenylpropyl)magnesium bromide in the Grignard reagent is 0.5 - 2 mol / mL.

[0043] Preferably, in step (2), the preparation steps of the (3-phenylpropyl)magnesium bromide include:

[0044] Mix 3-phenylpropyl bromide and tetrahydrofuran to obtain a 3-phenylpropyl bromide tetrahydrofuran solution; mix magnesium, iodine, and tetrahydrofuran to obtain a mixed solution; add part of the 3-phenylpropyl bromide tetrahydrofuran solution to the mixed solution, start the Grignard reaction, and continuously add the remaining 3-phenylpropyl bromide tetrahydrofuran solution. After the addition is completed, continue the Grignard reaction to obtain a Grignard reagent containing (3-phenylpropyl)magnesium bromide.

[0045] Preferably, the molar ratio of the 3-phenylpropyl bromide to magnesium is 1:(1 - 2).

[0046] Preferably, the addition amount of iodine is 0.1 - 0.2% of the mass of the 3-phenylpropyl bromide.

[0047] Preferably, the volume ratio of the part of the 3-phenylpropyl bromide tetrahydrofuran solution to the remaining 3-phenylpropyl bromide tetrahydrofuran solution is 1:(40 - 60).

[0048] Preferably, the temperature of the Grignard reaction is 50 - 60 °C.

[0049] Preferably, the time for adding the remaining 3-phenylpropyl bromide tetrahydrofuran solution is 0.5 - 3 h.

[0050] Preferably, the time for continuing the Grignard reaction is 20 - 60 min.

[0051] Preferably, the concentration of (3-phenylpropyl)magnesium bromide in the Grignard reagent is 1 - 1.5 mol / mL.

[0052] Preferably, in step (2), the steps of the reaction between compound VC-1 and (3-phenylpropyl)magnesium bromide include:

[0053] Mix compound VC-1 and tetrahydrofuran, and dropwise add a Grignard reagent containing (3-phenylpropyl)magnesium bromide to obtain a reaction solution containing compound VC-2.

[0054] Preferably, in step (2), the molar ratio of compound VC-1 to the one containing (3-phenylpropyl)magnesium bromide is 1:(1 - 2).

[0055] Preferably, in step (2), the temperature of the reaction is below 0 °C, and the reaction time is 0.5 - 2 h.

[0056] Preferably, in step (2), after the reaction, the following post-treatment steps are further included:

[0057] Quench the reaction solution obtained from the reaction, perform the first liquid separation to obtain organic phase I; extract the organic layer of the tetrahydrofuran phase, perform the second liquid separation to obtain organic phase II, and then perform drying, filtration and concentration to obtain the compound VC-2.

[0058] Preferably, the reagent used for quenching is a saturated ammonium chloride solution.

[0059] Preferably, the reagents used for extraction are ethyl acetate and water.

[0060] Preferably, in step (3), the molar ratio of compound VC-2 to the acid is 1:(1 - 3).

[0061] Preferably, in step (3), the acid is selected from hydrogen chloride solution and / or trifluoroacetic acid.

[0062] Preferably, in step (3), the hydrogen chloride solution includes any one or a combination of at least two of hydrogen chloride methanol solution, hydrogen chloride ethanol solution, hydrogen chloride ethyl acetate solution, hydrogen chloride dichloromethane solution or hydrogen chloride ether solution.

[0063] Preferably, in step (3), the reaction is carried out in a solvent selected from any one or a combination of at least two of dichloromethane, ethyl acetate, acetonitrile or toluene.

[0064] Preferably, in step (3), the temperature of the reaction is 10 - 40 °C, and the reaction time is 0.5 - 5 h.

[0065] Preferably, in step (3), the neutralization treatment is to adjust the reaction solution to neutral with a base.

[0066] Preferably, in step (3), the base used for neutralization treatment is selected from any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, ammonia water, or triethylamine.

[0067] Preferably, in step (3), the base is a 20 - 30 wt% base solution.

[0068] Preferably, in step (4), the molar ratio of the compound VC - 3 to formaldehyde is 1:(2 - 4).

[0069] Preferably, in step (4), the reducing agent is selected from any one or a combination of at least two of sodium triacetoxyborohydride, sodium borohydride, or sodium cyanoborohydride.

[0070] Preferably, in step (4), the molar ratio of the compound VC - 3 to the reducing agent is 1:(2 - 4).

[0071] Preferably, in step (4), the reaction is carried out in a solvent, and the solvent is water.

[0072] Preferably, in step (4), during the addition of the reducing agent, the system temperature is controlled to be < 15 °C.

[0073] Preferably, in step (4), the temperature of the reaction is 0 - 30 °C, and the reaction time is 6 - 18 h.

[0074] Preferably, in step (4), after the reaction, the following post - treatment steps are further included:

[0075] The reaction solution obtained from the reaction is adjusted to a pH of 9 - 10, and after liquid separation and drying, an organic phase containing free vilazodone is obtained.

[0076] Preferably, the reagent for adjusting the pH is a saturated base solution; wherein, the base is selected from any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, ammonia water, or triethylamine.

[0077] Preferably, in step (5), the molar ratio of free vilazodone to hydrogen chloride is 1:(1 - 2).

[0078] Preferably, in step (5), the reaction is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of ethyl acetate, dichloromethane, acetone, acetonitrile, toluene, methanol, ethanol, isopropanol, propanol, tetrahydrofuran, ether, isopropyl ether, or methyl tert - butyl ether.

[0079] Preferably, in step (5), the temperature of the reaction is 10 - 40 °C, and the reaction time is 2 - 8 h.

[0080] Preferably, in step (5), after the reaction is completed, the following post-treatment steps are further included:

[0081] Filter the reaction solution obtained from the reaction to obtain crude vilazodone hydrochloride; dissolve the crude vilazodone hydrochloride in acetone for recrystallization, and then dry it to obtain pure vilazodone hydrochloride.

[0082] Among them, the purity of the crude vilazodone hydrochloride is above 90.0%, and the purity of the pure vilazodone hydrochloride is above 99.90%.

[0083] Compared with the prior art, the present invention has the following beneficial effects:

[0084] (1) The starting materials used in the preparation method of the present invention are all commercially available common chemical raw materials, with low cost and easy availability;

[0085] (2) Compared with the traditional synthesis route, the preparation method of the present invention avoids the use of highly toxic cyanides and realizes green and safe chemical synthesis;

[0086] (3) Compared with the traditional synthesis route, the preparation method of the present invention has a significantly improved reaction yield, and the intermediate does not require additional purification steps, and the purity and yield of the final product are both significantly improved;

[0087] (4) The last two reaction steps in the preparation method of the present invention can be carried out continuously, and the reaction solution of intermediate VC-3 can be directly used for the next reaction, simplifying the operation process and facilitating industrial production. Description of the Drawings

[0088] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0089] Figure 1 It is the HPLC chromatogram of the pure vilazodone hydrochloride prepared in Example 1.

[0090] Figure 2 It is the 1H NMR spectrum of the pure vilazodone hydrochloride prepared in Example 1.

[0091] Figure 3 It is the 13C NMR spectrum of the pure vilazodone hydrochloride prepared in Example 1. Detailed Embodiments

[0092] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by one of ordinary skill in the art. The meanings and scopes of the terms should be clear. However, in any case of potential ambiguity, the definitions provided herein shall prevail over any dictionary or extrinsic definition. In this application, unless otherwise specified, the use of "or" means "and / or". In addition, the use of the term "comprising" and other forms is non-restrictive.

[0093] It should be noted that specific details are set forth in the following description to facilitate a thorough understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0094] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0095] A preparation method of vibrotine hydrochloride of the present invention, the preparation method of vibrotine hydrochloride comprises the following steps:

[0096] (1) In the presence of a catalyst, 3,4-dimethoxybenzaldehyde reacts with tert-butylsulfinamide to obtain compound VC-1; the reaction formula is as follows:

[0097]

[0098] (2) Compound VC-1 reacts with (3-phenylpropyl)magnesium bromide to obtain compound VC-2; the reaction formula is as follows:

[0099]

[0100] (3) After compound VC-2 reacts with an acid and then undergoes neutralization treatment, compound VC-3 is obtained; the reaction formula is as follows:

[0101]

[0102] (4) In the presence of a reducing agent, compound VC-3 reacts with formaldehyde to obtain free vibrotine; the reaction formula is as follows:

[0103]

[0104] (5) Free vibrotine reacts with hydrogen chloride to obtain vibrotine hydrochloride; the reaction formula is as follows:

[0105]

[0106] In the present invention, the starting materials used in the preparation method of the present invention are all commercially available common chemical raw materials (such as 3,4-dimethoxybenzaldehyde, tert-butylsulfinamide, 3-phenylbromopropane, etc.), which are low in cost and easy to obtain; and the synthesis route of the present invention avoids the use of highly toxic cyanides, realizing green and safe chemical synthesis; the total yield of repeating the synthesis path in the original literature is only about 10%, and the reaction yield of the synthesis route of the present invention is significantly improved, which can be increased to more than 60%, and the intermediate does not require additional purification steps, and the purity of the final product is significantly improved, which can be increased to more than 99.9%; in particular, the last two reaction steps can be carried out continuously, and the reaction solution of intermediate VC-3 can be directly used for the next reaction, simplifying the operation process and facilitating industrial production.

[0107] As an optional implementation manner, in step (1), the specific steps of the reaction include:

[0108] Mix 3,4-dimethoxybenzaldehyde, tert-butylsulfinamide, a catalyst and a solvent, and carry out a reaction to obtain a reaction solution containing compound VC-1.

[0109] As an optional implementation manner, in step (1), the molar ratio of 3,4-dimethoxybenzaldehyde to tert-butylsulfinamide is 1:(1-1.5), for example, it can be 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0110] As an optional implementation manner, in step (1), the catalyst is selected from any one or a combination of at least two of pyrrolidine, morpholine, piperidine or piperazine.

[0111] As a preferred implementation manner, in step (1), the catalyst is pyrrolidine.

[0112] As an optional implementation manner, in step (1), the molar ratio of 3,4-dimethoxybenzaldehyde to the catalyst is 1:(0.1-0.5), for example, it can be 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, etc.

[0113] As an optional implementation manner, in step (1), the reaction is carried out in a solvent, and the solvent is any one or a combination of at least two of dichloromethane, tetrahydrofuran, acetonitrile or toluene.

[0114] As a preferred implementation manner, in step (1), the reaction is carried out in a solvent, and the solvent is dichloromethane.

[0115] As an alternative embodiment, in step (1), the temperature of the reaction is 20 to 40 °C, for example, it can be 20 °C, 22 °C, 25 °C, 28 °C, 30 °C, 32 °C, 35 °C, 38 °C, 40 °C, etc., and the reaction time is 4 to 24 h, for example, it can be 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 24 h, etc.

[0116] As an alternative embodiment, in step (1), after the reaction, the following post-treatment steps are further included:

[0117] The reaction solution containing compound VC-1 obtained from the reaction is concentrated, after adding a pulping solvent, pulping treatment is carried out, and then it is dried after filtration to obtain the compound VC-1.

[0118] As an alternative embodiment, in step (1), the pulping solvent is selected from any one or a combination of at least two of methyl tert-butyl ether, isopropyl ether, ethyl ether, petroleum ether, n-hexane, cyclohexane or n-heptane.

[0119] As a preferred embodiment, in step (1), the pulping solvent is methyl tert-butyl ether.

[0120] As an alternative embodiment, in step (1), the temperature of the pulping treatment is 10 to 30 °C, for example, it can be 10 °C, 12 °C, 15 °C, 18 °C, 20 °C, 22 °C, 25 °C, 28 °C, 30 °C, etc., and the pulping treatment time is 0.5 to 2 h, for example, it can be 0.5 h, 0.6 h, 0.8 h, 1 h, 1.2 h, 1.5 h, 1.6 h, 1.8 h, 2 h, etc.

[0121] As an alternative embodiment, the preparation steps of the (3-phenylpropyl)magnesium bromide include:

[0122] 3-phenylpropyl bromide, magnesium and iodine carry out a Grignard reaction in tetrahydrofuran to obtain a Grignard reagent containing (3-phenylpropyl)magnesium bromide; the reaction formula is as follows:

[0123]

[0124] As an alternative embodiment, the molar ratio of the 3-phenylpropyl bromide to magnesium is 1:(1 to 2), for example, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0125] As an alternative embodiment, the addition amount of iodine is 0.1-0.2% of the mass of 3-phenylbromopropane, and can be, for example, 0.1%, 0.12%, 0.14%, 0.15%, 0.16%, 0.18%, 0.2%, etc.

[0126] As an alternative embodiment, the temperature of the Grignard reaction is 50-60 °C, and can be, for example, 50 °C, 52 °C, 54 °C, 55 °C, 56 °C, 58 °C, 60 °C, etc., and the time of the Grignard reaction is 20-60 min, and can be, for example, 20 min, 22 min, 24 min, 25 min, 26 min, 28 min, 30 min, 32 min, 34 min, 35 min, 36 min, 38 min, 40 min, 45 min, 50 min, 55 min, 60 min, etc.

[0127] As an alternative embodiment, the concentration of (3-phenylpropyl)magnesium bromide in the Grignard reagent is 0.5-2 mol / mL, and can be, for example, 0.5 mol / mL, 0.6 mol / mL, 0.7 mol / mL, 0.8 mol / mL, 0.9 mol / mL, 1 mol / mL, 1.2 mol / mL, 1.4 mol / mL, 1.6 mol / mL, 1.8 mol / mL, 2 mol / mL, etc.

[0128] As an alternative embodiment, the preparation steps of the Grignard reagent containing (3-phenylpropyl)magnesium bromide specifically include:

[0129] Mix 3-phenylbromopropane and tetrahydrofuran to obtain a 3-phenylbromopropane tetrahydrofuran solution; mix magnesium chips, iodine and tetrahydrofuran to obtain a magnesium-containing raw material solution; add part of the 3-phenylbromopropane tetrahydrofuran solution to the magnesium-containing raw material solution, and after the Grignard reaction starts, continuously add the remaining 3-phenylbromopropane tetrahydrofuran solution; after the addition is completed, continue the Grignard reaction to obtain a Grignard reagent containing (3-phenylpropyl)magnesium bromide.

[0130] As an alternative embodiment, in the process of preparing the Grignard reagent containing (3-phenylpropyl)magnesium bromide, the molar ratio of 3-phenylbromopropane to magnesium is 1:(1-2), and can be, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0131] As an alternative embodiment, during the preparation of the Grignard reagent containing (3-phenylpropyl)magnesium bromide, the addition amount of iodine is 0.1-0.2% of the mass of 3-phenylpropyl bromide, for example, it can be 0.1%, 0.12%, 0.14%, 0.15%, 0.16%, 0.18%, 0.2%, etc.

[0132] As an alternative embodiment, the volume ratio of the partial 3-phenylpropyl bromide tetrahydrofuran solution to the remaining 3-phenylpropyl bromide tetrahydrofuran solution is 1:(40-60), for example, it can be 1:40, 1:45, 1:50, 1:55, 1:60, etc.

[0133] As an alternative embodiment, the temperature of the Grignard reaction is 50-60°C, for example, it can be 50°C, 52°C, 54°C, 55°C, 56°C, 58°C, 60°C, etc.

[0134] As an alternative embodiment, the time for dropping the remaining 3-phenylpropyl bromide tetrahydrofuran solution is 0.5-3 h, for example, it can be 0.5 h, 0.6 h, 0.8 h, 1 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h, 2 h, etc.

[0135] As an alternative embodiment, the time for continuously carrying out the Grignard reaction is 20-60 min, for example, it can be 20 min, 22 min, 24 min, 25 min, 26 min, 28 min, 30 min, 32 min, 34 min, 35 min, 36 min, 38 min, 40 min, 45 min, 50 min, 55 min, 60 min, etc.

[0136] As an alternative embodiment, the partial 3-phenylpropyl bromide tetrahydrofuran solution accounts for 1-3% of the total volume of the 3-phenylpropyl bromide tetrahydrofuran solution, for example, it can be 1%, 1.2%, 1.4%, 1.5%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.5%, 2.6%, 2.8%, 3%, etc.

[0137] As a preferred embodiment, the concentration of (3-phenylpropyl)magnesium bromide in the Grignard reagent is 1-1.5 mol / mL, for example, it can be 1 mol / mL, 1.1 mol / mL, 1.2 mol / mL, 1.3 mol / mL, 1.4 mol / mL, 1.5 mol / mL, etc.

[0138] As an alternative embodiment, in step (2), the steps of the reaction between the compound VC-1 and (3-phenylpropyl)magnesium bromide include:

[0139] Mix compound VC-1 with tetrahydrofuran, and dropwise add a Grignard reagent containing (3-phenylpropyl)magnesium bromide to obtain a reaction solution containing compound VC-2.

[0140] As an alternative embodiment, in step (2), the molar ratio of compound VC-1 to the one containing (3-phenylpropyl)magnesium bromide is 1:(1 - 2), for example, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0141] As an alternative embodiment, in step (2), the temperature of the reaction is below 0°C, for example, it can be -10°C, -8°C, -6°C, -5°C, -4°C, -2°C, -1°C, 0°C, etc., and the reaction time is 0.5 - 2 h, for example, it can be 0.5 h, 0.6 h, 0.7 h, 0.8 h, 0.9 h, 1 h, 1.2 h, 1.4 h, 1.5 h, 1.6 h, 1.8 h, 2 h, etc.

[0142] As an alternative embodiment, in step (2), after the reaction, the following post-treatment steps are further included:

[0143] Quench the reaction solution obtained from the reaction, perform the first liquid separation to obtain organic phase I; extract the tetrahydrofuran phase of the organic layer, perform the second liquid separation to obtain organic phase II, and then perform drying, filtration, and concentration to obtain compound VC-2.

[0144] As an alternative embodiment, the quenching reagent is a saturated ammonium chloride solution.

[0145] As an alternative embodiment, the extraction reagents are ethyl acetate and water.

[0146] As an alternative embodiment, in step (3), after compound VC-2 reacts with an acid, the specific steps for neutralization treatment include:

[0147] Dissolve compound VC-2 in an organic solvent, then add an aqueous solution of the acid and conduct the reaction; after the reaction is completed, adjust the pH of the system to neutral to obtain a post-treatment solution containing VC-3.

[0148] As an alternative embodiment, in step (3), the molar ratio of compound VC-2 to the acid is 1:(1 - 3), for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.

[0149] As an alternative embodiment, in step (3), the acid is selected from hydrochloric acid solution and / or trifluoroacetic acid.

[0150] As an alternative embodiment, in step (3), the acid is a hydrogen chloride solution.

[0151] As an alternative embodiment, in step (3), the hydrogen chloride solution includes any one or a combination of at least two of a hydrogen chloride methanol solution, a hydrogen chloride ethanol solution, a hydrogen chloride ethyl acetate solution, a hydrogen chloride dichloromethane solution, or a hydrogen chloride ether solution.

[0152] As an alternative embodiment, in step (3), the solvent is selected from any one or a combination of at least two of dichloromethane, ethyl acetate, acetonitrile, or toluene.

[0153] As a preferred embodiment, in step (3), the reaction is carried out in an organic solvent, and the organic solvent is dichloromethane.

[0154] As an alternative embodiment, in step (3), the temperature of the reaction is 10 to 40 °C, for example, it can be 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, etc., and the reaction time is 0.5 to 5 h, for example, it can be 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, etc.

[0155] As an alternative embodiment, in step (3), the neutralization treatment is to adjust the reaction solution to neutral with a base.

[0156] As an alternative embodiment, in step (3), the base is selected from any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, ammonia water, or triethylamine.

[0157] As an alternative embodiment, in step (3), the base is a 20 to 30 wt% (for example, it can be 20 wt%, 22 wt%, 24 wt%, 25 wt%, 26 wt%, 28 wt%, 30 wt%, etc.) base solution.

[0158] As an alternative embodiment, in step (4), the specific steps of the reaction between compound VC-3 and formaldehyde include:

[0159] Adding an aqueous solution of formaldehyde to the post-treatment solution containing VC-3, and adding a reducing agent in batches. After the addition is completed, carry out the reaction to obtain a reaction solution containing compound VC-3.

[0160] As an alternative embodiment, in step (4), the molar ratio of the compound VC-3 to formaldehyde is 1:(2 - 4), for example, it can be 1:2, 1:2.2, 1:2.4, 1:2.5, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.5, 1:3.6, 1:3.8, 1:4, etc.

[0161] As a preferred embodiment, in step (4), the reducing agent is selected from any one or a combination of at least two of sodium triacetoxyborohydride, sodium borohydride, or sodium cyanoborohydride.

[0162] As a preferred embodiment, in step (4), the reducing agent is sodium triacetoxyborohydride.

[0163] As an alternative embodiment, in step (4), the molar ratio of the compound VC-3 to the reducing agent is 1:(2 - 4), for example, it can be 1:2, 1:2.2, 1:2.4, 1:2.5, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.5, 1:3.6, 1:3.8, 1:4, etc.

[0164] As an alternative embodiment, in step (4), the reaction is carried out in a solvent, and the solvent is water.

[0165] As an alternative embodiment, in step (4), during the addition of the reducing agent, the system temperature is controlled at <15°C, for example, it can be 15°C, 13°C, 12°C, 11°C, 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, 1°C, 0°C, etc.

[0166] As an alternative embodiment, in step (4), the reaction temperature is 0 - 30°C, for example, it can be 0°C, 2°C, 4°C, 5°C, 6°C, 8°C, 10°C, 12°C, 14°C, 15°C, 16°C, 18°C, 20°C, 25°C, 30°C, etc., and the reaction time is 6 - 18 h, for example, it can be 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, etc.

[0167] As an alternative embodiment, after step (4), the following post-treatment steps are further included:

[0168] The reaction solution containing the compound VC-3 obtained from the reaction is adjusted to a pH of 9 - 10, and after liquid separation and drying, an organic phase containing free vilazodone is obtained.

[0169] As an alternative embodiment, the reagent for adjusting the pH is an alkaline solution; wherein, the alkali is selected from any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, ammonia water or triethylamine.

[0170] As an alternative embodiment, in step (5), the step of reacting the free viloxazine with hydrogen chloride specifically comprises:

[0171] Adding a solution of hydrogen chloride to the organic phase containing free viloxazine, carrying out the reaction, precipitating a solid, and filtering to obtain a crude product of viloxazine hydrochloride.

[0172] As an alternative embodiment, in step (5), the molar ratio of the free viloxazine to hydrogen chloride is 1:(1 - 2), for example, it can be 1:1, 1:1.2, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2, etc.

[0173] As an alternative embodiment, in step (5), the reaction is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of ethyl acetate, dichloromethane, acetone, acetonitrile, toluene, methanol, ethanol, isopropanol, propanol, tetrahydrofuran, ether, isopropyl ether or methyl tert - butyl ether.

[0174] As a preferred embodiment, in step (5), the reaction is carried out in a solvent, and the solvent is ethyl acetate.

[0175] As an alternative embodiment, in step (5), the temperature of the reaction is 10 - 40°C, for example, it can be 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc., and the reaction time is 2 - 8 h, for example, it can be 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, etc.

[0176] As an alternative embodiment, after the reaction in step (5), the following post - treatment steps are further included:

[0177] Filtering the reaction solution obtained from the reaction to obtain a crude product of viloxazine hydrochloride; dissolving the crude product of viloxazine hydrochloride in acetone for recrystallization, and then drying to obtain a pure product of viloxazine hydrochloride.

[0178] As an alternative embodiment, the purity of the crude product of viloxazine hydrochloride is above 90.0%, and the purity of the pure product of viloxazine hydrochloride is above 99.90%.

[0179] The present invention will be further illustrated by the following examples. Unless otherwise specified, the materials in the examples are prepared according to the existing methods or directly purchased from the market.

[0180] Example 1

[0181] This example provides a method for preparing vertibutin hydrochloride. The method for preparing vertibutin hydrochloride specifically includes the following steps:

[0182] (1) In a 5 L round-bottom flask, add 265.6 g (1.6 mol) of 3,4-dimethoxybenzaldehyde, 217.8 g (1.8 mol) of tert-butylsulfinamide, 35.5 g (0.5 mol) of pyrrolidine, and 2.5 L of dichloromethane. After the addition is completed, start stirring and heat under reflux, and react at 40 °C for 12 h. After the reaction is completed, concentrate by vacuum distillation to obtain a yellow solid. Subsequently, add 1.5 L of methyl tert-butyl ether and perform pulping treatment at 25 °C for 1 h. After filtration and drying, 391.7 g of light yellow powder VC-1 is obtained, with a yield of 91% and a purity of 96%.

[0183] (2) Weigh 376.2 g (1.9 mol) of 3-phenylbromopropane and mix it with 500 mL of anhydrous tetrahydrofuran to obtain a 3-phenylbromopropane tetrahydrofuran solution for standby. Weigh 57.6 g (2.4 mol) of magnesium chips, 0.5 g of iodine, and 1.5 L of anhydrous tetrahydrofuran and place them in a 5 L round-bottom flask. Start stirring under a nitrogen atmosphere and add 10 mL of the 3-phenylbromopropane tetrahydrofuran solution at 25 °C. After the Grignard reaction starts, continuously and slowly add the 3-phenylbromopropane tetrahydrofuran solution while controlling the reaction temperature within 55 °C, and control the addition time within 2 h. After the addition is completed, reflux at 66 °C for 30 min, and then cool to room temperature to obtain a Grignard reagent (0.95 mol / L) for standby.

[0184] Weigh 391.7 g (1.5 mol) of VC-1 and place it in a 5 L round-bottom flask together with 1 L of anhydrous tetrahydrofuran. Then, under a nitrogen atmosphere, place the flask in a low-temperature bath and cool it to an internal temperature of -8 °C to obtain a VC-1 solution. Slowly add 1900 mL of the prepared Grignard reagent (0.95 mol / L) to the VC-1 solution, ensuring that the addition temperature is maintained below 0 °C. After the addition is completed, restore to 25 °C and continue the reaction for 3 h until the raw material VC-1 completely reacts.

[0185] After the reaction is completed, cool the reaction system below 0 °C, quench the reaction with 500 mL of saturated ammonium chloride solution, and separate the organic layer to obtain a tetrahydrofuran solution. Subsequently, add 1 L of ethyl acetate and 500 mL of water, stir and then separate again. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to finally obtain 509.8 g of a light yellow solid compound VC-2, with a yield of 90% and a purity of 93%.

[0186] (3) Weigh 509.8 g (1.3 mol) of VC-2, dissolve it in 2 L of dichloromethane, and place it in a 5 L round-bottom flask. Subsequently, add 260 g (2.6 mol) of concentrated hydrochloric acid and 1000 g of water, and stir and react at 25 °C for 3 h until the raw material VC-2 completely reacts. After the reaction is completed, adjust the pH to neutral with 25 wt% sodium hydroxide solution to obtain the post-treatment solution of VC-3 for direct use in subsequent reactions.

[0187] (4) Weigh 263.5 g (3.3 mol) of 37 wt% aqueous formaldehyde solution and add it to the post-treatment solution of VC-3. Add 689 g (3.3 mol) of sodium triacetoxyborohydride in batches, and control the internal temperature during the feeding process not to exceed 15 °C. After the feeding is completed, restore the reaction temperature to 25 °C and react for 12 h, and monitor the raw material VC-3 until it completely reacts. After the reaction is completed, adjust the pH to 9.5 with saturated sodium carbonate solution, perform liquid separation, and dry the organic layer with anhydrous sodium sulfate to obtain the organic phase containing free vilazodone.

[0188] (5) Add 500 mL (2 mol) of 4 mol / L hydrogen chloride in ethyl acetate solution to the organic phase containing free vilazodone, stir at room temperature for 5 h, and white solid precipitates. After filtration, 379.5 g of crude vilazodone hydrochloride is obtained, with a yield of 83% and a purity of 98%. The crude product is recrystallized with acetone and dried to finally obtain 341.5 g of pure vilazodone hydrochloride, with a purity reaching 99.9% (as Figure 1 shown), and the yield is 90%. The structure is characterized by NMR, and the structure determination results (as Figure 2 and Figure 3 shown).

[0189] Calculated, the total yield of Example 1 from the raw material feeding in step (1) to (5) is 61.2%.

[0190] Example 2

[0191] This example provides a method for preparing vilazodone hydrochloride, and the method for preparing vilazodone hydrochloride specifically includes the following steps:

[0192] (1) Prepare compound VC-1:

[0193] In a 20 L (glass reactor), add 1062.4 g (6.4 mol) of 3,4-dimethoxybenzaldehyde, 871.2 g (7.2 mol) of tert-butylsulfinamide, 142 g (2 mol) of pyrrolidine, and 10 L of dichloromethane; after the feeding is completed, start stirring and heat under reflux, and react at 40 °C for 14 h; after the reaction is completed, concentrate by vacuum distillation to obtain a yellow solid, then add 6 L of methyl tert-butyl ether, and carry out pulping treatment at 25 °C for 1 h. After filtration and drying, 1583.9 g of light yellow powder VC-1 is obtained, with a yield of 92% and a purity of 95%.

[0194] (2) Weigh 1504.8 g (7.6 mol) of 3-phenylbromopropane and mix it with 1.6 L of anhydrous tetrahydrofuran to obtain a 3-phenylbromopropane tetrahydrofuran solution for standby; weigh 230.4 g (9.6 mol) of magnesium chips, 3 g of iodine and 6 L of anhydrous tetrahydrofuran and place them in a 20 L reactor. Start stirring under a nitrogen atmosphere and add 100 mL of the 3-phenylbromopropane tetrahydrofuran solution at 25 °C; after the Grignard reaction starts, continuously and slowly add the 3-phenylbromopropane tetrahydrofuran solution while controlling the reaction temperature within the range of 55 °C, and control the dropping time within 2 h; after the dropping is completed, reflux and react at 66 °C for 30 min, and then cool to room temperature to obtain a Grignard reagent (1 mol / L) for standby.

[0195] Weigh 1583.9 g (5.9 mol) of VC-1 and place it in a 20 L reactor together with 4 L of anhydrous tetrahydrofuran. Under a nitrogen atmosphere, cool down to an internal temperature of -8 °C to obtain a VC-1 solution; slowly add 6.7 L of the prepared Grignard reagent (1 mol / L) to the VC-1 solution to ensure that the dropping temperature is maintained below 0 °C; after the dropping is completed, restore to 25 °C and continue to react for 3 h until the raw material VC-1 is completely reacted.

[0196] After the reaction is completed, cool the reaction system to below 0 °C, use 2 L of saturated ammonium chloride solution to quench the reaction, and separate to obtain an organic layer of tetrahydrofuran solution. Then add 4 L of ethyl acetate and 2 L of water, stir and separate again. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Finally, 2084.3 g of light yellow solid compound VC-2 is obtained, with a yield of 91% and a purity of 94%.

[0197] (3) Weigh 2084.3 g (5.4 mol) of VC-2 and dissolve it in 8 L of dichloromethane, and place it in a 20 L reactor; then add 1080 g (10.8 mol) of concentrated hydrochloric acid and 4 Kg of water, and stir and react at 25 °C for 3 h until the raw material VC-2 is completely reacted. After the reaction is completed, adjust the pH to neutral with 25 wt% sodium hydroxide solution to obtain a post-treatment solution of VC-3 for direct use in subsequent reactions.

[0198] (4) Weigh 1054 g (13.2 mol) of 37 wt% aqueous formaldehyde solution and add it to the post-treatment solution of VC-3. Add 2756 g (13.2 mol) of sodium triacetoxyborohydride in batches, and control the internal temperature during the feeding process not to exceed 15 °C. After the feeding is completed, restore the reaction temperature to 25 °C and react for 12 h, and monitor the raw material VC-3 until the reaction is complete. After the reaction is completed, adjust the pH to 9.5 with saturated sodium carbonate solution, carry out liquid separation, and dry the organic layer with anhydrous sodium sulfate to obtain an organic phase containing free viloxazine.

[0199] (5) Add 2 L (8 mol) of ethyl acetate solution of 4 mol / L hydrogen chloride to the organic phase containing free viloxazine, stir at room temperature for 5 h, and white solid precipitates. After filtration, 1552.1 g of crude viloxazine hydrochloride is obtained, with a yield of 83% and a purity of 98%. The crude product is recrystallized with acetone and dried to finally obtain 1381.4 g of pure viloxazine hydrochloride, with a purity of 99.9% and a yield of 89%.

[0200] Calculated, the total yield of Example 2 from the raw material feeding in step (1) to (5) is 61.8%.

[0201] Example 3

[0202] This example provides a method for preparing viloxazine hydrochloride. The difference from Example 1 is only that in step (1), pyrrolidine is replaced with an equimolar amount of piperazine, and the other steps are the same as those in Example 1.

[0203] The results show that: in step (1), 282.7 g of light yellow powder VC-1 is obtained, with a yield of 65% and a purity of 95%; in step (5), 245.7 g of pure viloxazine hydrochloride is finally obtained after purification, with a purity of 99.9%.

[0204] Calculated, the total yield of Example 3 from the raw material feeding in step (1) to (5) is 44%.

[0205] Example 4

[0206] This example provides a method for preparing viloxazine hydrochloride. The difference from Example 1 is only that in step (1), the reaction solvent is replaced with tetrahydrofuran and the reaction is carried out at 70 °C for 1 h, and the other steps are the same as those in Example 1.

[0207] The results show that: in step (1), 396 g of light yellow powder VC-1 is obtained, with a yield of 92% and a purity of 84%; in step (5), 307.1 g of pure viloxazine hydrochloride is finally obtained after purification, with a purity of 98.7%.

[0208] After calculation, the total yield of Example 4 from the raw material feeding in step (1) to step (5) is 55%.

[0209] Example 5

[0210] This example provides a method for preparing vertabutin hydrochloride. The difference from Example 1 is only that in step (1), the solvent for pulping treatment is replaced with 1.5 L of isopropyl ether, and the other steps are the same as those in Example 1.

[0211] The results show that: in step (1), 383.1 g of light yellow powder VC-1 is obtained, with a yield of 89% and a purity of 94%; in step (5), 312.7 g of pure vertabutin hydrochloride is finally obtained by purification, and its purity is 99.9%.

[0212] After calculation, the total yield of Example 5 from the raw material feeding in step (1) to step (5) is 56%.

[0213] Example 6

[0214] This example provides a method for preparing vertabutin hydrochloride. The difference from Example 1 is only that in step (3), concentrated hydrochloric acid is replaced with an equimolar amount of trifluoroacetic acid, and the other steps are the same as those in Example 1.

[0215] The results show that: in step (5), 301.5 g of pure vertabutin hydrochloride is finally obtained by purification, and its purity is 97.8%.

[0216] After calculation, the total yield of Example 6 from the raw material feeding in step (1) to step (5) is 54%.

[0217] Example 7

[0218] This example provides a method for preparing vertabutin hydrochloride. The difference from Example 1 is only that in step (4), sodium triacetoxyborohydride is replaced with an equimolar amount of sodium borohydride, and the other steps are the same as those in Example 1;

[0219] The results show that: in step (5), 173.1 g of pure vertabutin hydrochloride is finally obtained by purification, and its purity is 67.3%.

[0220] After calculation, the total yield of Example 7 from the raw material feeding in step (1) to step (5) is 31%.

[0221] Example 8

[0222] This example provides a method for preparing vertabutin hydrochloride. The difference from Example 1 is only that in step (4), the ethyl acetate solution of hydrogen chloride is replaced with the dichloromethane solution of hydrogen chloride, and the other steps are the same as those in Example 1;

[0223] The results showed that: in step (5), 311.3 g of pure viloxazine hydrochloride was finally obtained, with a purity of 99.9%, and the yield of step (5) was 82%.

[0224] After calculation, the total yield of Example 8 from the raw material feeding in step (1) to step (5) was 55.7%.

[0225] Comparative Example 1

[0226] This comparative example provides a method for preparing viloxazine hydrochloride, and the method for preparing viloxazine hydrochloride includes the following steps:

[0227] (1) Weigh 400 g (2.41 mol) of veratraldehyde and dissolve it in 1400 g of methanol. Cool the temperature to 0 - 5 °C, and dropwise add 1360 g (12.1 mol) of 40% dimethylamine solution. After the dropping is completed, react at low temperature for 30 min. Control the internal temperature at 0 - 5 °C and slowly add 471 g (9.6 mol) of sodium cyanide in several portions. After the addition is completed, slowly raise the temperature to 25 °C and react for 16 h. Monitor the reaction by TLC. After the reaction is completed, dropwise add 2 L of 10 wt% sodium hydroxide solution, extract with 2.5 L × 2 of ethyl acetate, and then wash twice with 1 L × 2 of saturated brine. After desolvation, slurry with petroleum ether, filter and dry to obtain 872 g of product, with a yield of 82.2%.

[0228] (2) Dissolve 290 g (1.3 mol) of the product prepared in the first step in 2 L of anhydrous tetrahydrofuran, and slowly drop it into the tetrahydrofuran solution of 3 - phenylpropylmagnesium bromide (1.97 mol) that has been cooled to 0 - 5 °C. After the dropping is completed, restore to room temperature and react for 2 h. Monitor the reaction by TLC. After the reaction is completed, add 800 mL of 1N hydrochloric acid solution, and distill off tetrahydrofuran. Extract with 1000 mL × 2 of ethyl acetate, adjust the pH = 8 - 9, dry with anhydrous sodium sulfate, and desolvate to obtain crude viloxazine. After column chromatography, the purity of viloxazine is less than 90%. After purification by a preparative column, 190 g of free viloxazine is obtained, and hydrochloric acid in ethyl acetate is added to form a salt. After filtration, 169.7 g of viloxazine hydrochloride finished product is obtained, with a yield of 12.24% and a purity of 99.5%.

[0229] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A preparation method of vertibutin hydrochloride, characterized in that, The preparation method of viltrumite hydrochloride comprises the following steps: (1) In the presence of a catalyst, 3,4-dimethoxybenzaldehyde reacts with tert-butylsulfinamide to obtain compound VC-1; the reaction formula is as follows: (2) Compound VC-1 reacts with (3-phenylpropyl)magnesium bromide to obtain compound VC-2; the reaction formula is as follows: (3) After compound VC-2 reacts with an acid and then undergoes neutralization treatment, compound VC-3 is obtained; the reaction formula is as follows: (4) In the presence of a reducing agent, compound VC-3 reacts with formaldehyde to obtain free viltrumite; the reaction formula is as follows: (5) Free viltrumite reacts with hydrogen chloride to obtain viltrumite hydrochloride; the reaction formula is as follows:

2. The preparation method of verticabine hydrochloride according to claim 1, characterized in that, In step (1), the molar ratio of 3,4-dimethoxybenzaldehyde to tert-butylsulfinamide is 1:(1-1.5); And / or, in step (1), the catalyst is selected from any one or a combination of at least two of pyrrolidine, morpholine, piperidine or piperazine; And / or, in step (1), the molar ratio of 3,4-dimethoxybenzaldehyde to the catalyst is 1:(0.1-0.5); And / or, in step (1), the reaction is carried out in a solvent, and the solvent is any one or a combination of at least two of dichloromethane, tetrahydrofuran, acetonitrile or toluene; And / or, in step (1), the reaction temperature is 20-40°C, and the reaction time is 4-24 h.

3. The preparation method of vertibutin hydrochloride according to claim 1, characterized in that, In step (1), after the reaction is completed, the following post-treatment steps are further included: The reaction solution obtained from the reaction is concentrated, a pulping solvent is added, pulping treatment is carried out, and then it is filtered and dried to obtain compound VC-1; And / or, in step (1), the pulping solvent is selected from any one or a combination of at least two of methyl tert-butyl ether, isopropyl ether, ether, petroleum ether, n-hexane, cyclohexane or n-heptane; And / or, in step (1), the temperature of the pulping treatment is 10-30°C, and the time of the pulping treatment is 0.5-2 h.

4. The preparation method of vertibutin hydrochloride according to claim 1, characterized in that, In step (2), the preparation steps of (3-phenylpropyl)magnesium bromide include: 3-phenylbromopropane, magnesium and iodine carry out a Grignard reaction in tetrahydrofuran to obtain a Grignard reagent containing (3-phenylpropyl)magnesium bromide; And / or, the molar ratio of 3-phenylbromopropane to magnesium is 1:(1-2); And / or, the addition amount of iodine is 0.1-0.2% of the mass of 3-phenylbromopropane; And / or, the temperature of the Grignard reaction is 50-60°C, and the time of the Grignard reaction is 20-60 min; And / or, the concentration of (3-phenylpropyl)magnesium bromide in the Grignard reagent is 0.5-2 mol / mL.

5. The preparation method of vertibutin hydrochloride according to claim 1, characterized in that, In step (2), the molar ratio of compound VC-1 to (3-phenylpropyl)magnesium bromide is 1:(1-2); And / or, in step (2), the reaction temperature is below 0°C, and the reaction time is 0.5-2 h.

6. The preparation method of vertibutin hydrochloride according to claim 1 or 5, characterized in that, In step (2), after the reaction is completed, the following post-treatment steps are further included: Quench the reaction solution obtained from the reaction. After the first liquid separation, an organic phase I is obtained; extract the tetrahydrofuran phase of the organic layer, and after the second liquid separation, an organic phase II is obtained. Then, through drying, filtration, and concentration, the compound VC-2 is obtained. And / or, the quenching reagent is a saturated ammonium chloride solution; And / or, the extraction reagent is ethyl acetate and water.

7. The preparation method of vertibutin hydrochloride according to claim 1, characterized in that, In step (3), the molar ratio of the compound VC-2 to the acid is 1:(1 - 3); And / or, in step (3), the acid is selected from hydrogen chloride solution and / or trifluoroacetic acid; And / or, in step (3), the hydrogen chloride solution includes any one or a combination of at least two of hydrogen chloride methanol solution, hydrogen chloride ethanol solution, hydrogen chloride ethyl acetate solution, hydrogen chloride dichloromethane solution, or hydrogen chloride ether solution; And / or, in step (3), the reaction is carried out in a solvent selected from any one or a combination of at least two of dichloromethane, ethyl acetate, acetonitrile, or toluene; And / or, in step (3), the reaction temperature is 10 - 40 °C, and the reaction time is 0.5 - 5 h; And / or, in step (3), the neutralization treatment is to adjust the reaction solution to neutral with a base; And / or, in step (3), the base is selected from any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, ammonia water, or triethylamine; And / or, in step (3), the base is a 20 - 30 wt% base solution.

8. The preparation method of vertibutin hydrochloride according to claim 1, characterized in that, In step (4), the molar ratio of the compound VC-3 to formaldehyde is 1:(2 - 4); And / or, in step (4), the reducing agent is selected from any one or a combination of at least two of sodium triacetoxyborohydride, sodium borohydride, or sodium cyanoborohydride; And / or, in step (4), the molar ratio of the compound VC-3 to the reducing agent is 1:(2 - 4); And / or, in step (4), the reaction is carried out in a solvent, and the solvent is water; And / or, during the addition of the reducing agent in step (4), the system temperature is controlled < 15 °C; And / or, in step (4), the reaction temperature is 0 - 30 °C, and the reaction time is 6 - 18 h.

9. The preparation method of vertibutin hydrochloride according to claim 1 or 8, characterized in that, In step (4), after the reaction, the following post-treatment steps are further included: Adjust the pH of the reaction solution obtained from the reaction to 9 - 10. After liquid separation and drying, an organic phase containing free vilazodone is obtained; And / or, the reagent for adjusting the pH is a saturated base solution; wherein, the base is selected from any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, ammonia water, or triethylamine.

10. The preparation method of vertibutin hydrochloride according to claim 1, characterized in that, In step (5), the molar ratio of free vilazodone to hydrogen chloride is 1:(1 - 2); And / or, in step (5), the reaction is carried out in a solvent selected from any one or a combination of at least two of ethyl acetate, dichloromethane, acetone, acetonitrile, toluene, methanol, ethanol, isopropanol, propanol, tetrahydrofuran, ether, isopropyl ether, or methyl tert-butyl ether; And / or, in step (5), the temperature of the reaction is 10 to 40 °C, and the time of the reaction is 2 to 8 h; And / or, in step (5), after the reaction, the following post-treatment steps are further included: Filter the reaction solution obtained from the reaction to obtain the crude product of vilazodone hydrochloride; dissolve the crude product of vilazodone hydrochloride in acetone for recrystallization, and then dry it to obtain the pure product of vilazodone hydrochloride; Among them, the purity of the crude product of vilazodone hydrochloride is above 90.0%, and the purity of the pure product of vilazodone hydrochloride is above 99.90%.

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