A method for synthesizing atipamezole hydrochloride

Abstract

The present application relates to the field of medicine preparation, in particular to a synthesis method of atipamezole hydrochloride. The method comprises the following steps: 4-cyanomethyl imidazole is subjected to acylation reaction, and a secondary amine group at position 1 of 4-cyanomethyl imidazole is subjected to acetyl protection to generate compound II; the compound II is subjected to two alkylations in sequence, and the cyanogen of the reaction product after the alkylation is hydrolyzed into a carboxyl group to generate compound III; under the catalysis of a Lewis acid, the compound III is subjected to intramolecular Friedel-Crafts acylation to generate compound IV; the carbonyl group of the compound IV is reduced into a methylene group to obtain a target product compound V; the method has the advantages of short synthesis route, mild reaction condition, low equipment requirement, convenient operation, high yield of reaction product, high yield of product obtained without complex purification method, and the like, and is easy to realize large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation, and in particular to a method for synthesizing atemexazole hydrochloride. Background Technology

[0002] Atipamezole hydrochloride, its English name is Atipamezole hydrochloride, and its molecular formula is: C 14 H 13 ClN2O2 is the hydrochloride salt form of an imidazole compound. It is a new drug developed and marketed by Orion-Farmos in the United States, primarily used to reverse the sedative effect induced by the α2-adrenergic receptor agonist medetomidine. Currently, this drug is mainly used in livestock or pets to recover from sedation and other effects caused by the anesthetic medetomidine after surgery. In human drug research, its functions are mainly focused on lowering blood sugar and blood pressure, but this is limited to the clinical research stage and has not yet achieved any breakthrough progress.

[0003] Wong WC (Synthesis, 1995, 2, 139-140) et al. reported a four-step synthetic route for atemetazole hydrochloride:

[0004] The first step involves using o-dibromobenzene and acetylacetone as starting materials to generate 2,2-diacetylindane under alkaline conditions. The second step involves the alkylation of 2-acetylindane with iodoethane under alkaline catalysis to generate 2-ethyl-2-acetylindane. The third step involves the reaction of 2-ethyl-2-acetylindane with LiHMDS in anhydrous THF at low temperature, followed by a liquid bromine reaction to generate 2-(2-bromoacetyl)-2-ethyl-indane. The fourth step involves reacting the product from the previous step with formamide to generate the target product. The synthetic route is shown below:

[0005]

[0006] The advantage of this route is that the raw materials are simple and readily available, but the disadvantages are: intermediate impurities are difficult to separate and the purification cost is high; the reaction uses liquid bromine, which is highly toxic and corrosive; the reaction is carried out at ultra-low temperatures, which requires high-end equipment, consumes a lot of energy, and is not easy to industrialize; and the yield of the ring-closing reaction is low.

[0007] Karjalainen, AJ (Eurpean Patent 183492), and others also reported a synthetic route using o-dibromobenzene as a starting material, the route being as follows.

[0008] The first step involves reacting the starting material with the sodium salt of methyl allyl ketone to generate 2-acetyl-2-vinyl-indenium; the second step involves bromination of the carbonyl α-carbon using liquid bromine to yield an α-haloketone; the third step involves the α-haloketone reacting with formamide to formamide to form an imidazole ring; and the fourth step involves hydrogenation reduction of the double bond to obtain the target product. The synthetic route is shown below:

[0009]

[0010] The disadvantages of this route are: sodium salts of methyl allyl ketones are not readily available; liquid bromine is also used as a raw material; and the yield of synthesizing imidazole rings from α-haloketones is low.

[0011] PCT international application publication number WO2009071584A1, with a publication date of June 11, 2009, also discloses a method for synthesizing atemetazole:

[0012] The first step involves the condensation reaction of phthalide with imidazolium aldehyde under the catalysis of sodium methoxide; the second step is alkylation to obtain the ethylated product; the third step is the removal of the triphenylmethyl protecting group under acidic conditions; and the fourth step is the hydrogenation reduction of the dicarbonyl group to obtain the target product. The route is shown below:

[0013]

[0014] The reagent used in this route, 1-triphenylmethylimidazol-4-carboxaldehyde, is expensive and has a low effective molecular weight, resulting in high costs. The reaction byproduct, triphenylmethanol, has strong ultraviolet absorption and is difficult to purify, affecting the purity of the product. The hydrogenation reduction of carbonyl under strongly acidic conditions requires special equipment to meet the requirements, making it difficult to achieve industrial-scale production.

[0015] Karjalainen, AJ (Eurpean Patent 247764) also disclosed a similar synthetic route:

[0016] The first step involves reacting 2-acetylindanone and bromoethane as starting materials in the presence of anhydrous potassium carbonate and DMF to generate 2-acetyl-2-ethylindanone. The second step involves reacting with liquid bromine to undergo a halogenation reaction of the carbonyl α-carbon. The third step involves a condensation reaction with formamide to close the imidazole ring. The fourth step involves reducing the carbonyl group with sodium borohydride to obtain an alcohol. The fifth step involves hydrogenation elimination reduction to obtain the target product. The reaction route is shown below:

[0017]

[0018] This route also involves preparing α-haloketones via liquid bromine; the yield of synthesizing imidazole rings is low; the conditions for reducing carbonyl groups are quite harsh, and hydrogenation needs to be carried out under strongly acidic conditions, which cannot be met by ordinary hydrogenation equipment, making it difficult to achieve industrial production. Summary of the Invention

[0019] To address the shortcomings of the prior art mentioned in the background section, this invention provides a method for synthesizing atemetazole hydrochloride, comprising the following steps:

[0020] The acylation reaction of 4-cyanomethylimidazolium and the acetyl protection of the secondary amino group at the 1-position of 4-cyanomethylimidazolium yielded compound II;

[0021] Compound II was subjected to two alkylation reactions in sequence, and the cyano group of the alkylation product was hydrolyzed to a carboxyl group to generate compound III;

[0022] Under the catalysis of Lewis acid, compound III undergoes an intramolecular Friedel-Crafts acylation reaction to generate compound IV;

[0023] The carbonyl group of compound IV is reduced to a methylene group to obtain the target product compound V.

[0024] The structural formula of the 4-cyanomethylimidazole is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows: The structural formula of compound IV is as follows: The structural formula of compound IV is as follows: The structural formula of the altemetazole hydrochloride is as follows:

[0025] In some embodiments, during the acylation reaction, 4-cyanomethylimidazole, an acylation reagent, and a hydroxyl group are added to a first aprotic solvent, and the acylation reaction is carried out under the action of a catalyst to produce compound II;

[0026] Wherein, the molar ratio of 4-cyanomethylimidazole to the acylation reagent is 1:(1-2); preferably 1:1.02; the molar ratio of 4-cyanomethylimidazole to the acetic acid agent is 1:(1.1-2); preferably 1:1.1; the acylation reaction temperature is (-10 to 10) °C, and the acylation reaction time is (4 to 12) h; preferably 0 °C.

[0027] In some embodiments, the acylation agent is one or more combinations of acetic anhydride, acetyl chloride, trifluoroacetyl chloride, and trifluoroacetic anhydride; the acetic acid agent is one or more combinations of triethylamine, diisopropylethylamine, and 1,8-diazobispirocyclo[5.4.0]undec-7-ene (DBU); the catalyst is 4-dimethylaminopyridine (DMAP); and the first aprotic solvent is one or more combinations of dichloromethane (DCM), tetrahydrofuran (THF), dioxane, and N,N-dimethylformamide (DMF).

[0028] In some embodiments, during the alkylation reaction, compound II and benzyl chloride are placed in a second aprotic solvent and subjected to a first alkylation reaction under the action of a base.

[0029] After the first alkylation reaction is completed, ethane halide is directly added to the reaction system to carry out the second alkylation reaction, generating the reactants;

[0030] After the second alkylation reaction is completed, water is added to the reaction system to carry out a hydrolysis reaction to hydrolyze the cyano group of the reactant into a carboxyl group, generating compound III.

[0031] In some embodiments, the molar ratio of compound II to benzyl chloride is 1:(1.0-1.1); the molar ratio of compound II to ethane halide is 1:(1.0-1.2); the molar ratio of compound II to base is 1:(2.0-4.0); preferably, the molar ratio of compound II, benzyl chloride, ethane halide, and base is 1:1:1:3.2.

[0032] The first alkylation reaction temperature is less than or equal to 0℃, and the reaction time is (2-6)h; the second alkylation reaction temperature is room temperature, and the reaction time is (4-12)h; the hydrolysis reaction temperature is (60-90)℃, and the reaction time is (8-12)h.

[0033] In some embodiments, the base is a strong organic base, which is one or more combinations of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium diisopropylamine, lithium diisopropylamine, sodium bis(trimethylsilyl)amino (NaHMDS), and lithium bistrimethylsilylamino (LiHMDS); the ethane halide is bromoethane and / or iodoethane; and the second aprotic solvent is one or more combinations of tetrahydrofuran (THF), dioxane, and N,N-dimethylformamide (DMF).

[0034] In some embodiments, under the catalysis of a Lewis acid, compound III is subjected to an intramolecular Friedel-Crafts acylation reaction in a third solvent to generate compound IV; wherein the temperature of the intramolecular Friedel-Crafts acylation reaction is 0–30°C, and the reaction time is 8–12 h until the raw material is consumed as monitored by TLC; preferably 10°C; the molar ratio of compound III to the Lewis acid is 1:(1–1.5), preferably 1:1.

[0035] In some embodiments, the Lewis acid is aluminum trichloride and / or ferric trichloride; the third solvent is one or more combinations of dichloromethane (DCM) and dichloroethane.

[0036] In some embodiments, the carbonyl group of compound IV is reduced to a methylene group using a hydrazine hydrate method or a hydrogenation reduction method to generate compound V.

[0037] In some embodiments, compound IV, potassium hydroxide, and hydrazine hydrate are heated under reflux in a fourth solvent for (2–4) h, and then the temperature is raised to (170–200) °C and kept at a constant temperature for (4–12) h to generate compound V.

[0038] In some embodiments, compound V is purified and salted to obtain atemexazole hydrochloride. In some embodiments, compound V is subjected to hydrochloric acid vapor-to-salt conversion, concentration, washing, and drying to obtain atemexazole hydrochloride.

[0039] Compared with existing technologies, the method for synthesizing atemetazole hydrochloride provided by this invention has the following advantages:

[0040] Beneficial effects:

[0041] The synthetic method of this invention is novel and unique, and its advantages are as follows:

[0042] 1. The synthetic route is short and the reaction conditions are mild;

[0043] 2. Low equipment requirements, easy operation, and easy to achieve industrialized production;

[0044] 3. The reaction yield is high, and high-yield products can be obtained without complicated purification methods. Attached Figure Description

[0045] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0046] Figure 1 This is a process route diagram for the synthesis of atemexazole hydrochloride provided in Example 1 of the present invention. Detailed Implementation

[0047] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0048] This invention provides an operational example of a method for synthesizing atemetazole hydrochloride:

[0049] (1) Add 4-cyanomethylimidazolium, acylation reagent and succinate to the first aprotic solvent and carry out acylation reaction under the action of catalyst to produce compound II;

[0050] Wherein, the molar ratio of 4-cyanomethylimidazole to the acylation reagent is 1:(1-2); the molar ratio of 4-cyanomethylimidazole to the acetic acid agent is 1:(1.1-2); the acylation reaction temperature is (-10-10)℃, optionally (0-5)℃, and the acylation reaction time is (4-12)h.

[0051] (2) Compound II was subjected to two alkylation reactions in sequence, and the cyano group of the alkylation product was hydrolyzed to a carboxyl group to generate compound III:

[0052] First, compound II and benzyl chloride are placed in a second aprotic solvent and subjected to a first alkylation reaction under the action of a base.

[0053] After the first alkylation reaction is completed, ethane halide is directly added to the reaction system to carry out the second alkylation reaction, generating the reactants;

[0054] After the second alkylation reaction is completed, water is added to the reaction system to carry out a hydrolysis reaction to hydrolyze the cyano group of the reactant into a carboxyl group, generating compound III.

[0055] Wherein, the molar ratio of compound II to benzyl chloride is 1:(1.0-1.1); the molar ratio of compound II to ethane halide is 1:(1.0-1.2); the molar ratio of compound II to base is 1:(2.0-4.0); the first alkylation reaction temperature is less than or equal to 0°C, and the reaction time is (2-6) h; the second alkylation reaction temperature is room temperature, and the reaction time is (4-12) h; the hydrolysis reaction temperature is (60-90)°C, and the reaction time is (8-12) h.

[0056] (3) Under the catalysis of Lewis acid, the compound III is subjected to an intramolecular Friedel-Crafts acylation reaction in a third solvent to generate compound IV;

[0057] The intramolecular Friedel-Crafts acylation reaction is carried out at a temperature of 0–30 °C for a duration of TLC until the raw material is consumed; the molar ratio of compound III to the Lewis acid is 1:(1–1.5).

[0058] (4) The carbonyl group of compound IV is reduced to a methylene group to obtain the target product compound V; optionally, the carbonyl group of compound IV is reduced to a methylene group by hydrazine hydrate or hydrogenation reduction to generate compound V.

[0059] (5) The compound V is purified and salted to obtain the atemexazole hydrochloride.

[0060] The structural formula of the 4-cyanomethylimidazole is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows: The structural formula of compound IV is as follows: The structural formula of compound V is as follows:

[0061] The present invention provides the following embodiments and comparative examples:

[0062] Example 1

[0063] like Figure 1 The synthesis process route diagram is shown below:

[0064] Step (I) Preparation of Compound II

[0065] In a 3L three-necked flask equipped with a constant-pressure dropping funnel, a thermometer, and a mechanical stirrer, add 1L of dichloromethane and 107g (1mol, 1eq) of cyanomethylimidazolium, 106g (1.05mol, 1.05eq) of triethylamine, 1.2g (0.01mol, 0.01eq) of 4-dimethylaminopyridine (DMAP) catalyst. Cool the system and control the internal temperature within the range of -5 to 0℃, and stir at a constant temperature for 10 min.

[0066] Acetic anhydride (104 g, 1.02 mol, 1.02 eq) was slowly added dropwise to the above reaction system, controlling the reaction temperature within the range of -5 to 0 °C. After the addition was complete, the mixture was allowed to cool naturally to room temperature. The reaction was monitored by TLC until it ended, with a reaction time of 4 h. The reaction solution was then poured into 2 L of water. The aqueous phase was acidified to pH 5 using 4 mol / L phosphoric acid, and then extracted with dichloromethane (500 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, and concentrated to give 146 g of compound II, with a yield of 98%. Compound II was used directly in the next reaction step.

[0067] Step (II) Preparation of Compound III

[0068] In a 3L reactor equipped with a thermometer, mechanical stirrer, and dropping funnel, compound II (146g, 0.98mol, 1eq) and 1.4L of THF were added. Stirring was started, and the system was cooled, maintaining the internal temperature between -5°C and 0°C. Then, potassium tert-butoxide (351g, 3.13mol, 3.2eq) was slowly added to the system, and the reaction was continued at 0°C for 30 minutes. Next, benzyl chloride (124g, 0.98mol, 1eq) was added dropwise to the system, maintaining the reaction temperature between -5°C and 0°C. After the addition was complete, the reaction was continued at this constant temperature for 4 hours.

[0069] After the reaction was monitored by TLC until it ended, 153 g of iodoethane (0.98 mol, 1 eq) was added dropwise to the above system, and the reaction temperature was controlled at 5–10 °C (not exceeding 10 °C). After the addition was completed, the temperature was naturally raised to room temperature and reacted at room temperature for 12 hours. The reaction was then shown to be complete by TLC.

[0070] 200 mL of water was slowly added dropwise to the above system, and the mixture was heated under reflux at 80 °C for 12 hours. After TLC showed complete hydrolysis of the cyano group, the reaction mixture was poured into 2 L of sodium chloride solution and extracted twice with ethyl acetate. The organic phase was discarded. The aqueous phase was then adjusted to pH 3-4 with 4 M hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with water, and dried to give compound III (202 g, 0.83 mol, overall yield 85%).

[0071] Step (III) Preparation of Compound IV

[0072] In a 3L reactor equipped with a thermometer, mechanical stirrer, and dropping funnel, compound III (202g, 0.83mol, 1eq) and 2L of DCM were added. Stirring was started, and the system was cooled, maintaining the internal temperature between 5 and 10°C. Then, aluminum trichloride (113g, 0.85mol, 1.02eq) was slowly added in portions. After the addition was complete, the reaction was kept at a constant temperature for 4 hours. The reaction was monitored by TLC until it ended. The reaction mixture was then slowly poured into 2000mL of ice water and stirred for 1 hour. The solution was neutralized to pH 12-14 with 20% sodium hydroxide solution, causing aluminum hydroxide solid to precipitate. The mixture was filtered, and the filter cake was washed with DCM. The combined organic phases were then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain compound IV (178g, 0.79mol, overall yield 95%).

[0073] Step (IV) Preparation of Atemexazole Hydrochloride

[0074] In a 3L reactor equipped with a thermometer, mechanical stirrer, and dropping funnel, compound IV (178g, 0.79mol, 1eq), potassium hydroxide (88g, 1.58mol, 2eq), 85% hydrazine hydrate (208g, 5.53mol, 7eq), and 1L of diethylene glycol were added. The mixture was heated to reflux in an oil bath and maintained at reflux for 1 hour. Then, the temperature inside the reactor was further increased to 190 degrees Celsius and maintained for 2 hours.

[0075] After the reaction was complete, the reaction system was cooled to room temperature and then poured into 3 L of ice water. It was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried, filtered, and transferred to a 5 L glass bottle. The mixture was cooled to 0°C, and hydrogen chloride gas was bubbled through it until the system was saturated, resulting in the precipitation of a large amount of solid. The filter cake was filtered, washed again with ethyl acetate, and dried to give atemexazole hydrochloride (156 g, 0.63 mol, overall yield 80%).

[0076] The synthesized product, atemetazole hydrochloride, was detected by nuclear magnetic resonance. 1 H-NMR spectrum and 13 C-NMR data confirm that it is atemetazole hydrochloride, and the specific data are as follows: 1 H NMR (400MHz, d6-DMSO): δ (ppm): 14.83 (b, 1H), 9.11 (d, 1H, J = 4.0Hz), 7.43 (d, 2H, J = 4.0Hz), 7.43 (dd, 2H, J = 3.6 ,5.2Hz),7.09-7.12(m,2H),3.25-2.29(m,2H),3.05-3.09(m,2H),1.89(q,2H,J=7.6Hz),0.65(t,3H,J=7.6Hz); 13C NMR (100MHz, d6-DMSO): δ (ppm): 141.72, 139.32, 134.77, 126.89, 124.88, 116.27, 47.52, 43.68, 32.21, 10.03.

[0077] Comparative Example 1

[0078] like Figure 1 The synthesis process route diagram is shown below:

[0079] Step (I) Preparation of Compound II

[0080] In a 3L three-necked flask equipped with a constant-pressure dropping funnel, a thermometer, and a mechanical stirrer, 11 g of cyanomethylimidazolium (0.1 mol, 1 eq), 11 g of triethylamine (0.105 mol, 1.05 eq), 0.12 g of 4-dimethylaminopyridine (DMAP) catalyst (0.001 mol, 0.01 eq), and 100 mL of dichloromethane were added. The system was cooled to an internal temperature of 5–10 °C and stirred at a constant temperature for 10 min.

[0081] Acetic anhydride (10.4 g, 0.102 mol, 1.02 eq) was slowly added dropwise to the above reaction system, controlling the reaction temperature within the range of 5–10 °C. After the addition was complete, the mixture was allowed to cool naturally to room temperature for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was poured into 200 mL of water. The aqueous phase was acidified to pH 5 using 4 mol / L phosphoric acid, and then extracted with dichloromethane (50 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to give 13.1 g of compound II, with a yield of 88%. Compound II was used directly in the next reaction step.

[0082] Step (II) Preparation of Compound III

[0083] In a 3L reactor equipped with a thermometer, mechanical stirrer, and dropping funnel, compound II (14.6g, 0.098mol, 1eq) and 140mL of THF were added. Stirring was started, and the system was cooled to an internal temperature of 5–10°C. Then, potassium tert-butoxide (35.1g, 0.313mol, 3.2eq) was slowly added to the system, and the reaction was carried out at 0°C for 30 min. Next, benzyl chloride (12.4g, 0.098mol, 1eq) was added dropwise to the system, controlling the reaction temperature to be between -5°C and 0°C. After the addition was complete, the reaction was maintained at this temperature for 1 h.

[0084] After the reaction was monitored by TLC until it ended, 15.3 g of iodoethane (0.098 mol, 1 eq) was added dropwise to the above system at room temperature, and the reaction was maintained at this temperature for 6 hours. TLC showed that the reaction was complete.

[0085] 20 mL of water was slowly added dropwise to the above system, and the mixture was heated under reflux at 80 °C for 12 hours. After TLC showed complete hydrolysis of the cyano group, the reaction mixture was poured into 200 mL of sodium chloride solution and extracted twice with ethyl acetate. The organic phase was discarded. The aqueous phase was then adjusted to pH 3-4 with 4 M hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with water, and dried to give compound III (15.2 g, 0.83 mol, overall yield 63%).

[0086] Step (III) Preparation of Compound IV

[0087] In a 3L reactor equipped with a thermometer, mechanical stirrer, and dropping funnel, compound III (10g, 0.41mol, 1eq) and 100mL of DCM were added. Stirring was started, and aluminum trichloride (5.7g, 0.42mol, 1.02eq) was slowly added in portions at room temperature. After the addition was complete, the reaction was kept at a constant temperature for 2 hours. The reaction was monitored by TLC until it was complete. The reaction mixture was then slowly poured into 100mL of ice water and stirred for 1 hour. The solution was neutralized to pH 12-14 with 20% sodium hydroxide solution, causing aluminum hydroxide solid to precipitate. The mixture was filtered, and the filter cake was washed with DCM. The combined organic phases were then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give compound IV (150g, 0.79mol, overall yield 67%).

[0088] Step (IV) Preparation of Atemexazole Hydrochloride

[0089] In a 300 mL reaction vessel equipped with a thermometer, mechanical stirrer, and dropping funnel, compound IV (17.8 g, 0.079 mol, 1 eq), potassium hydroxide (8.8 g, 0.158 mol, 2 eq), 85% hydrazine hydrate (20.8 g, 0.553 mol, 7 eq), and 100 mL of diethylene glycol were added. The mixture was heated to reflux in an oil bath and maintained at reflux for 1 hour. Then, the temperature inside the reaction vessel was further increased to 160 degrees Celsius and maintained for 12 hours.

[0090] After the reaction was complete, the reaction system was cooled to room temperature and then poured into 300 mL of ice water. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried, filtered, and transferred to a 500 mL glass bottle. The mixture was cooled to 0°C, and hydrogen chloride gas was bubbled through it until the system was saturated, resulting in the precipitation of a large amount of solid. The filter cake was filtered, washed again with ethyl acetate, and dried to give atemexazole hydrochloride (117 g, 0.47 mol, total yield 60%).

[0091] The prepared atemetazole hydrochloride product was characterized by nuclear magnetic resonance. 1 H-NMR spectrum and 13C-NMR data indicate that it is atemetazole. Only the relevant data from Example 1 are listed here. The spectra and testing procedures of other examples 2 will not be described here.

[0092] In summary, compared with the prior art, the present invention has the following beneficial effects:

[0093] 1. The synthetic route is short and the reaction conditions are mild:

[0094] This invention does not use highly toxic and corrosive liquid bromine as a reaction raw material; it does not require strong acid reaction conditions or ultra-low temperature reaction conditions, and it does not involve dangerous reagents such as liquid bromine or dangerous operations. The reaction temperature conditions are mild, the route is short, and it is easy to achieve large-scale industrial production.

[0095] 2. Low equipment requirements, easy operation, and easy to achieve industrialized production;

[0096] Its acylation, alkylation, hydrolysis, intramolecular Friedel-Crafts acylation, and carbonyl reduction reactions can all be carried out within the normal temperature range (without ultra-low or ultra-high temperature requirements) and without strong acid reaction conditions. This makes the equipment requirements for each step low, and the operation is convenient and less dangerous for operators, making it easy to achieve industrial production.

[0097] 3. The reaction yield is high, and high-yield products can be obtained without complicated purification methods. In the embodiments of the present invention, the total yield of the products in the embodiments reaches 80%.

[0098] It should be noted that:

[0099] In this article, “~” is used to represent the range of values, and the range of values ​​represented by this expression includes two endpoint values.

[0100] In addition to the actual choices shown in the specific embodiments above, preferably, the acid-absorbing agent can be an organic base such as triethylamine, diisopropylethylamine, 1,8-diazobisspirocyclic [5.4.0]undec-7-ene (abbreviated as DBU), including but not limited to the choices mentioned above;

[0101] In addition to the specific choices shown in the above embodiments, the first aprotic solvent may be any existing aprotic solvent, including but not limited to the specific selection of aprotic solvents such as dichloromethane, tetrahydrofuran, dioxane, and N,N-dimethylformamide.

[0102] In addition to the specific choices shown in the above embodiments, the base used in the alkylation reaction process can be an existing strong organic base, including but not limited to sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium diisopropylamine, sodium bis(trimethylsilyl)amino, lithium bistrimethylsilylamine, etc.

[0103] In addition to the specific choices shown in the above embodiments, the second aprotic solvent may be any existing aprotic solvent, including but not limited to tetrahydrofuran, dioxane, N,N-dimethylformamide, etc.

[0104] In addition to the actual selections shown in the specific embodiments above, the third solvent may be an existing organic solvent, including but not limited to organic solvents such as dichloromethane and dichloroethane.

[0105] This article describes the use of aluminum trichloride and / or ferric trichloride as Lewis acids. Based on the synthetic route design concept of this invention, the Lewis acids used in the present invention include, but are not limited to, aluminum trichloride and / or ferric trichloride. A Lewis acid is defined as an electron acceptor (i.e., having empty orbitals that can accept electron pairs), and can also be considered as a central body for forming coordinate bonds. Common Lewis acids include aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, and trifluoromethanesulfonates of lanthanides. This is common knowledge in the field and will not be elaborated further here.

[0106] This article describes the use of hydrazine hydrate and hydrogenation reduction to reduce the carbonyl group of compound IV to a methylene group. According to the synthetic route design concept of this invention, other methods for reducing the carbonyl group to a methylene group may also be used, including but not limited to the hydrazine hydrate method and the hydrogenation reduction method.

[0107] In summary, the specific parameters or some commonly used reagents or raw materials in the above embodiments are specific or preferred embodiments under the concept of this application, and not limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of this application.

[0108] In addition, unless otherwise specified, the raw materials used may be commercially available products in the field or prepared by conventional methods in the field; that is, the reagents and instruments used in this embodiment do not specify the manufacturer or other information, and are all conventional products that can be purchased from the market.

[0109] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing atemetazole hydrochloride, characterized in that, Includes the following steps: The acylation reaction of 4-cyanomethylimidazolium and the acetyl protection of the secondary amino group at the 1-position of 4-cyanomethylimidazolium yielded compound II; Compound II was subjected to two alkylation reactions in sequence, and the cyano group of the alkylation product was hydrolyzed to a carboxyl group to generate compound III; In the alkylation reaction, compound II and benzyl chloride are placed in a second aprotic solvent and subjected to a first alkylation reaction under the action of a base. After the first alkylation reaction is completed, ethane halide is directly added to the reaction system to carry out a second alkylation reaction to generate a reactant. After the second alkylation reaction is completed, water is added to the reaction system to carry out a hydrolysis reaction to hydrolyze the cyano group of the reactant into a carboxyl group to generate compound III. The molar ratio of compound II to benzyl chloride is 1:(1.0-1.1); the molar ratio of compound II to ethane halide is 1:(1.0-1.2); the molar ratio of compound II to base is 1:(2.0-4.0); the first alkylation reaction temperature is less than or equal to 0°C, and the reaction time is (2-6) h; the second alkylation reaction temperature is room temperature, and the reaction time is (4-12) h; the hydrolysis reaction temperature is (60-90)°C, and the reaction time is (8-12) h; Under the catalysis of Lewis acid, compound III undergoes an intramolecular Friedel-Crafts acylation reaction to generate compound IV; The carbonyl group of compound IV is reduced to a methylene group to obtain the target product compound V. The compound V was purified and salted to obtain the altemetazole hydrochloride. The structural formula of the 4-cyanomethylimidazole is as follows: The structural formula of compound II is as follows: The structural formula of compound III is as follows: The structural formula of compound IV is as follows: The structural formula of compound V is as follows: .

2. The method for synthesizing atemetazole hydrochloride according to claim 1, characterized in that: In the acylation reaction, 4-cyanomethylimidazole, acylation reagent, and acetic acid agent are added to the first aprotic solvent, and the acylation reaction is carried out under the action of a catalyst to produce compound II; Wherein, the molar ratio of 4-cyanomethylimidazole to the acylation reagent is 1:(1-2); the molar ratio of 4-cyanomethylimidazole to the acid-binding agent is 1:(1.1-2). The acylation reaction temperature is (-10 to 10) °C, and the acylation reaction time is (4 to 12) h.

3. The method for synthesizing atemetazole hydrochloride according to claim 2, characterized in that: The acylation reagent is one or more combinations of acetic anhydride, acetyl chloride, trifluoroacetyl chloride, and trifluoroacetic anhydride; The fusible acid agent is one or more combinations of triethylamine, diisopropylethylamine, and 1,8-diazobisspirocyclic [5.4.0]undec-7-ene; The catalyst is 4-dimethylaminopyridine; The first aprotic solvent is one or more combinations of dichloromethane, tetrahydrofuran, dioxane, and N,N-dimethylformamide.

4. The method for synthesizing atemetazole hydrochloride according to claim 1, characterized in that: The base is an organic strong base, which is one or a combination of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium diisopropylamine, sodium bis(trimethylsilyl)amino, and lithium bistrimethylsilylamine. The ethane halide is bromoethane and / or iodoethane; The second aprotic solvent is one or more combinations of tetrahydrofuran, dioxane, and N,N-dimethylformamide.

5. The method for synthesizing atemetazole hydrochloride according to claim 1, characterized in that: Under the catalysis of a Lewis acid, compound III was subjected to an intramolecular Friedel-Crafts acylation reaction in a third solvent to generate compound IV; The intramolecular Friedel-Crafts acylation reaction is carried out at a temperature of 0–30 °C and for a duration of time until the reaction is completed as monitored by TLC. The molar ratio of compound III to the Lewis acid is 1:(1 to 1.5).

6. The method for synthesizing atemetazole hydrochloride according to claim 5, characterized in that: The Lewis acid is aluminum trichloride and / or ferric trichloride; The third solvent is one or more combinations of dichloromethane and dichloroethane.

7. The method for synthesizing atemetazole hydrochloride according to claim 1, characterized in that: The carbonyl group of compound IV is reduced to a methylene group by using hydrazine hydrate or hydrogenation reduction to generate compound V.

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