A process for the preparation of dezocin

Abstract

The present application provides a preparation method of dezocine. The base used in the method of the present application is some cheap and readily available base, which is mild and safe, avoiding strong corrosion. The present application adopts a specific phase transfer catalyst in the presence of an aqueous solution of alkali metal carbonate, selects a specific resolution process, and / or selects a specific catalyst in the step of reducing ketoxime. The catalyst used has high yield, less impurities, convenient application, economy, and is suitable for industrial production. In addition, the chiral resolving agent used has high resolution efficiency, economy, low price, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, and specifically relates to a method for preparing dezocine. Background Technology

[0002] Dezocine, scientifically known as [5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methylenebenzocyclodecene-3-phenol, is a typical opioid alkaloid analgesic developed by AstraZeneca. These drugs exert their effects by stimulating opioid receptors. Dezocine has a stronger analgesic effect than pentazocine and is a κ-receptor agonist and μ-receptor antagonist. Dezocine has a low addictive potential and is suitable for treating moderate to severe postoperative pain, visceral colic, and pain in patients with advanced cancer. Due to its good tolerability and safety profile, dezocine is gaining increasing acceptance in the medical market, leading to growing clinical demand and making it a promising opioid alkaloid analgesic.

[0003] Currently available literature indicates that the synthesis of dezocine involves numerous steps, is complex, has a long cycle, requires stringent reaction conditions, and carries some safety risks, resulting in high costs for both raw materials and formulations, thus leading to higher medication costs for patients. To provide milder reaction conditions, improve process safety, reduce the cost of dezocine raw materials, and offer patients a high-quality, affordable product, the inventors conducted in-depth research on its synthesis process and designed and discovered a highly efficient method for synthesizing dezocine.

[0004] 1-(5-Bromopentyl)-7-methoxy-1-methyl-tetrahydronaphthone is an important intermediate in the synthesis of dezocine. Currently, the relevant dezocine synthesis process (US4001331) is relatively cumbersome and uses expensive raw materials. It uses 7-methoxy-1-methyl-2-tetrahydronaphthone as the starting material, 1,5-dichloropentane as the alkylating agent, and sodium hydride as the base to produce 1-(5-Bromopentyl)-7-methoxy-1-methyl-tetrahydronaphthone. Sodium hydride is expensive and chemically very reactive, readily reacting violently with air and water in the solvent. Therefore, the transportation and storage conditions of sodium hydride and the reaction system require stringent conditions. Furthermore, the reaction with sodium hydride is quite vigorous, making reaction control during production difficult.

[0005] Patent CN102503840B discloses a method for preparing dezocine. Sodium hydroxide solution is used in the α-carbon alkylation of the carbonyl group. Sodium hydroxide solution is highly corrosive, not mild enough, and expensive, making it unsuitable for large-scale production, and the yield is low. Furthermore, in the resolution of racemic intermediates, the chiral compound resolution efficiency is low, and the resolution reagent is expensive. In the reduction of ketoxime step, the inventors found that Raney nickel catalyst has a lower hydrogen absorption rate than palladium on carbon, and the reaction yield is also lower; moreover, it is toxic. Furthermore, Raney nickel is flammable and cannot be reused, failing to meet the requirements of economy, environmental protection, safety, and high efficiency. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a new and improved method for preparing dezocine.

[0007] The technical solution of this invention is a method for preparing dezocine, comprising the following reaction steps:

[0008] (1) Using the compound 7-methoxy-3,4-dihydro-1-naphthone shown in structural formula I as the starting material, the intermediate shown in structural formula II was prepared by reaction, and the reaction formula is as follows:

[0009]

[0010] (2) The intermediate with structural formula III was prepared by reacting intermediate II obtained in step (1) as follows:

[0011]

[0012] (3) The intermediate with structural formula IV was prepared by reacting intermediate III obtained in step (2), and the reaction formula is as follows:

[0013]

[0014] (4) The intermediate with structural formula V was prepared by reacting intermediate IV obtained in step (3) as follows:

[0015]

[0016] (5) The intermediate V obtained in step (4) is reacted to prepare the intermediate with the structure shown in formula VI. The reaction formula is as follows:

[0017]

[0018] (6) The intermediate VI obtained in step (5) is reacted to prepare the intermediate shown in structural formula VII, and the reaction formula is as follows:

[0019]

[0020] (7) The intermediate with structural formula VIII was prepared by reacting intermediate VII obtained in step (6) as follows:

[0021]

[0022] (8) The intermediate VIII obtained in step (7) was used to prepare dezocine with the structure shown in formula IX. The reaction formula is as follows:

[0023]

[0024] In step (2), the oxidant in the reaction formula is selected from one or more of the following: peroxyformic acid, peracetic acid, perpropionic acid, peroxybutyric acid, peroxybenzoic acid, m-chloroperoxybenzoic acid, peroxyphenylacetic acid, peroxyethanol, peroxypropanol, peroxybutanol or hydrogen peroxide.

[0025] In step (2), the reaction solvent is selected from dichloromethane, trichloromethane, 1,2-dichloroethane or 1,1-dichloroethane;

[0026] In step (3), the haloalkane in the reaction formula is 1,5-dihalopentane, wherein the halogen atom is selected from fluorine, chlorine, bromine or iodine;

[0027] In step (3), the reaction solvent is selected from benzene, toluene, xylene, o-xylene, m-xylene, or p-xylene;

[0028] The phase transfer catalyst in step (3) is a quaternary ammonium salt.

[0029] In step (7), the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or tert-butanol.

[0030] More preferably, the phase transfer catalyst is one or more of tetrabutylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, or trioctylmethylammonium chloride.

[0031] Preferably, the alkaline environment in step (3) refers to the environment in which an aqueous solution of alkali metal carbonate is added.

[0032] More preferably, the alkali metal carbonate in step (3) refers to one or more of potassium carbonate, sodium carbonate, or lithium carbonate.

[0033] Preferably, the alkaline environment in step (3) refers to the addition of 40-60% by weight of an aqueous solution of potassium carbonate.

[0034] More preferably, the potassium carbonate aqueous solution is a 50% potassium carbonate aqueous solution.

[0035] Preferably, the alkaline environment in step (3) refers to the environment in which an aqueous solution of alkali metal bicarbonate is added.

[0036] Preferably, the alkali metal bicarbonate refers to one or more of sodium bicarbonate, lithium bicarbonate, or potassium bicarbonate.

[0037] More preferably, the alkaline environment in step (3) refers to the addition of 40-60% by weight of an aqueous solution of potassium bicarbonate.

[0038] Preferably, the phase transfer catalyst is tetrabutylammonium chloride. The alkaline environment in step (3) refers to a 50% potassium carbonate aqueous solution.

[0039] Preferably, the solvent in step (6) is anhydrous ethanol and glacial acetic acid.

[0040] Preferably, a method for preparing dezocine comprises one or more of the following reaction steps:

[0041] (1) Using the compound 7-methoxy-3,4-dihydro-1-naphthone shown in structural formula I as the starting material, the intermediate shown in formula II was prepared by reaction, as follows:

[0042]

[0043] (2) The intermediate with structural formula III was prepared by reacting intermediate II obtained in step (1) as follows:

[0044]

[0045] (3) The intermediate with structural formula IV was prepared by reacting intermediate III obtained in step (2), and the reaction formula is as follows:

[0046]

[0047] (4) The intermediate with structural formula V was prepared by reacting intermediate IV obtained in step (3) as follows:

[0048]

[0049] (5) The intermediate V obtained in step (4) is reacted to prepare the intermediate with the structure shown in formula VI. The reaction formula is as follows:

[0050]

[0051] (6) The intermediate VI obtained in step (5) is reacted to prepare the intermediate shown in structural formula VII, and the reaction formula is as follows:

[0052]

[0053] (7) The intermediate with structural formula VIII was prepared by reacting intermediate VII obtained in step (6) as follows:

[0054]

[0055] (8) The intermediate VIII obtained in step (7) was used to prepare dezocine with the structure shown in formula IX. The reaction formula is as follows:

[0056]

[0057] Preferably, in step (2), the oxidant in the reaction formula is m-chloroperoxybenzoic acid.

[0058] Preferably, in step (2), the reaction solvent is selected from dichloromethane.

[0059] Preferably, in step (3), the halogenated hydrocarbon in the reaction formula is 1,5-dibromopentane.

[0060] Preferably, in step (3), the reaction solvent is toluene.

[0061] Preferably, in step (7), the reaction solvent is methanol.

[0062] Preferably, a method for preparing dezocine includes the following reaction steps: preparing the compound represented by structural formula IV from the compound represented by structural formula III, as shown in the following reaction formula:

[0063]

[0064] Preferably, a method for preparing dezocine includes the following reaction steps: preparing the compound represented by structural formula VII from the compound represented by structural formula VI, as shown in the following reaction formula:

[0065]

[0066] Preferably, a method for preparing dezocine includes the following reaction steps: preparing the compound represented by structural formula VIII from the compound represented by structural formula VII, as shown in the following reaction formula:

[0067]

[0068] Preferably, a method for preparing dezocine includes the following reaction steps: preparing the compound represented by structural formula IX from the compound represented by structural formula VIII, as shown in the following reaction formula:

[0069] Detailed Implementation

[0070] The technical solution of the present invention will be described in detail below.

[0071] Comparative Example

[0072] β-tricyclic amine intermediates were prepared by hydrogenation of Raney nickel with 10% palladium on carbon. The results are shown in Table 1.

[0073] Table 1 Catalyst Selection

[0074]

[0075] As shown in Table 1, the palladium-on-carbon catalyst exhibits faster hydrogen absorption and a more complete reaction, but its yield is lower than that of palladium-on-carbon, and it is also toxic. Compared to Raney nickel, palladium-on-carbon catalysts offer advantages. Furthermore, Raney nickel is flammable and cannot be reused, failing to meet the requirements of economy, environmental protection, safety, and high efficiency. Therefore, in the following examples, a palladium-on-carbon catalyst is used for the preparation of the β-tricyclic amine intermediate.

[0076] Example 1 Preparation of 1-(5-bromopentyl)-7-methoxy-1-methyl-tetrahydronaphthone (compound IV)

[0077] Add 260L of toluene to the reaction vessel, then add 40kg of 7-methoxy-1-methyl-2-tetrahydronaphthone and start stirring. After dissolving, add 145.6kg of 1,5-dibromopentane and 6.76kg of tetrabutylammonium chloride. After the addition is complete, cool to 5-10℃. Prepare 144kg of 50% anhydrous potassium carbonate solution and cool to 20-30℃. Then, add the anhydrous potassium carbonate solution dropwise to the reaction solution, controlling the temperature at 5-10℃ during the dropwise addition. After the dropwise addition is complete, raise the temperature to 55-65℃ and maintain the temperature for 16h. Start TLC monitoring. The reaction is complete when the starting material spots have basically disappeared. After the reaction was completed, the mixture was allowed to stand and separated. The aqueous layer was extracted with toluene, and the toluene layer was washed with a prepared 10% hydrochloric acid solution until the pH was 1-2. Then, it was washed with a prepared 10% sodium chloride solution until the pH was about 6. The organic layer was collected and concentrated under reduced pressure at a temperature of 70-80°C until no toluene was detected. The concentrate was then transferred to a reaction vessel and heated to 130-145°C. The concentrate was further concentrated under reduced pressure until dry, yielding 62.5 kg of a brown oily substance with an HPLC purity of 75% and a yield of 65.8%. This substance was then directly used for the next reaction.

[0078] Example 2 Preparation of 5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methylenebenzocyclodecen-13-one (compound V)

[0079] Under nitrogen protection, 208 L of N,N-dimethylformamide was added to a reaction vessel and dissolved by stirring at 15–25 °C. Then, 10.6 kg of N,N-dimethylformamide and sodium hydride were added to the reaction vessel, and the mixture was stirred at 25–30 °C for 20 min. DMF was then added dropwise, and the temperature was slowly raised to 90–100 °C after the addition was complete. This temperature was maintained for the reaction, and TLC monitoring was started after 5 h. The reaction was considered complete when the starting material of 1-(5-bromopentyl)-7-methoxy-1-methyl-tetrahydronaphthone essentially disappeared. The solvent was concentrated under reduced pressure at 60–90 °C. After concentration, the temperature was lowered to 15–25 °C, and water was slowly added dropwise to the reaction vessel. After the addition was complete, ethyl acetate was added, and the mixture was stirred for 10–20 min. The layers were separated, and the aqueous layer was extracted once with ethyl acetate. The combined ethyl acetate layers were washed with 10% hydrochloric acid solution until pH 1–2, and then washed twice with drinking water. The organic phase was dried over anhydrous sodium sulfate for 1 h. The organic layer was concentrated to dryness under reduced pressure at a temperature of 40–80°C. The resulting brown oily substance was then directly used in the next reaction.

[0080] Example 3 Preparation of β-tricyclic ketoxime (compound VI)

[0081] 104 kg of hydroxylamine hydrochloride and 280 L of pyridine were added to a reaction vessel. The temperature was raised to 40–50 °C and maintained for 5 h. The temperature was then raised to reflux and the reaction was carried out for 24 h. TLC monitoring was started, with ethyl acetate:petroleum ether as the developing solvent at a ratio of 1:5,5,6,7,8,9,10,11,12-octahydro-3-methoxy-5-methyl-5,11-methylenebenzocyclodecen-13-one. The starting material spot essentially disappeared, indicating complete reaction. The mixture was concentrated to dryness under reduced pressure at 70–80 °C. After concentration, ethyl acetate and water were added and stirred for 15 min to dissolve the mixture. The layers were separated, and the aqueous layer was extracted once more with ethyl acetate. The organic phases were combined. The organic layer was concentrated under reduced pressure to remove some of the solvent at 40–50 °C. Crystallization was carried out at 0-10℃, centrifuged, and the filter cake was recrystallized from isopropanol to obtain 18.8 kg of off-white solid with an HPLC purity of 98.5%. The yield was 32.2% based on 7-methoxy-1-methyl-2-tetrahydronaphthone up to the β-tricyclic ketoxime step.

[0082] Example 4 Preparation of β-tricyclic amine hydrochloride (compound VII)

[0083] 18.8 kg of β-tricyclic ketoxime, 4.7 kg of palladium on carbon, 150 L of anhydrous ethanol, and 75 L of glacial acetic acid were added to a reaction vessel. The mixture was purged with nitrogen three times, then hydrogen was introduced. The reaction was maintained at 65–70 °C with stirring. TLC monitoring was initiated after 48 h of reaction, using petroleum ether:ethyl acetate = 2:1 as the developing solvent. The reaction proceeds were essentially eliminated, indicating complete reaction. The reaction solution was filtered into the reaction vessel and concentrated to dryness under reduced pressure at 60–70 °C. Anhydrous ethanol was added to dissolve the solution, and concentrated hydrochloric acid was added dropwise, resulting in the precipitation of a large amount of crystals. The solution was heated to reflux for 1 h, cooled to 0–5 °C, stirred for 2 h, centrifuged, filtered, and dried at 60–70 °C for 12–16 h, yielding 14.8 kg of a white solid powder with an HPLC purity of 99% and a yield of 74.0%.

[0084] Example 5 Preparation of L-β-tricyclic amine dibenzoyl-tartrate (compound VIII)

[0085] 14.8 kg of β-tricyclic amine hydrochloride, 74 L of water, and 74 L of ethyl acetate were added to a reaction vessel. Stirring was started, and ammonia was added dropwise until the pH reached 9. The mixture was stirred for 15 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and returned to the reaction vessel, where they were washed twice with water. The organic layer was concentrated under reduced pressure at 40–50 °C to remove ethyl acetate, yielding a free base. 20 L of methanol was added to the free base to dissolve it, and the mixture was directly used for the next reaction step.

[0086] 12.6 kg of D(+)-dibenzoyl-tartaric acid and 148 L of methanol were added to a reaction vessel. The mixture was heated to 60–70 °C and stirred until dissolved. A free base methanol solution was then slowly added, maintaining the temperature at 60–70 °C. The reaction vessel was then washed with methanol, and the solution was added back into the methanol solution. The mixture was then stirred and refluxed for 3 h. The mixture was cooled to 20–30 °C and allowed to crystallize for 23–25 h. After centrifugation, the centrifuged filter cake and 445 L of methanol were heated to 60–70 °C and stirred for 4.5–5.5 h. The mixture was then cooled to -5–5 °C and stirred for 1.5–2.5 h. After centrifugation, the filter cake was dried under reduced pressure at 60–65 °C for 12–14 h. After drying, 14.4 kg of L-β-tricyclic amine dibenzoyl-tartaric acid was obtained, with an HPLC purity of 99.7% and a yield of 47.1%.

[0087] Example 6 Preparation of dezocine (compound IX)

[0088] Hydrobromic acid was added to an 83.5L reactor, followed by 14.4 kg of levorotatory β-tricyclic amine dibenzoyl-tartrate. The mixture was refluxed and stirred under nitrogen protection. After 2 hours of reaction, TLC monitoring was initiated, using methanol:dichloromethane as the developing solvent (1:1). Approximately 2% glacial acetic acid was added dropwise. The levorotatory β-tricyclic amine tartrate starting material spot essentially disappeared, indicating complete reaction. Hydrobromic acid was removed by vacuum concentration. Water was added to the concentrate, and after complete dissolution by heating, 4% activated carbon was added. The mixture was refluxed for 30 minutes. The solution was filtered, washed with water, and dried. The filtrate was stirred at 2–6℃ for 4 hours to crystallize, and then filtered to obtain wet dezocine hydrobromide. 90 L of ethyl acetate was added, and the mixture was stirred at 55–65℃ for 2 hours. After cooling to 20–30℃, the mixture was centrifuged to obtain a filter cake. Water and the filter cake were added to the reactor and stirred until completely dissolved. Ammonia was added dropwise to the reaction solution until pH 9, and the mixture was stirred for 15 minutes to maintain a constant pH. The filter cake was washed with water and dried under vacuum to obtain crude wet dezocine. The crude wet dezocine was then placed in a drying oven and dried under reduced pressure at 60–65°C for 4–6 hours. After drying, 2.7 kg of crude dezocine was obtained, with an HPLC purity of 99.5%, and a yield of 47.0% for this step.

[0089] It should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the scope of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing dezocine, comprising the following reaction steps: (1) Using the compound 7-methoxy-3,4-dihydro-1-naphthone shown in structural formula I as the starting material, the intermediate shown in structural formula II was prepared by reaction, and the reaction formula is as follows: (2) The intermediate with structural formula III was prepared by reacting intermediate II obtained in step (1) as follows: (3) The intermediate with structural formula IV was prepared by reacting intermediate III obtained in step (2), and the reaction formula is as follows: (4) The intermediate with structural formula V was prepared by reacting intermediate IV obtained in step (3) as follows: (5) The intermediate V obtained in step (4) is reacted to prepare the intermediate with the structure shown in formula VI. The reaction formula is as follows: (6) The intermediate VI obtained in step (5) is reacted to prepare the intermediate shown in structural formula VII, and the reaction formula is as follows: (7) The intermediate with structural formula VIII was prepared by reacting intermediate VII obtained in step (6) as follows: (8) The intermediate with structural formula IX was prepared by reacting intermediate VIII obtained in step (7) as follows: Its features are, In step (2), the oxidant in the reaction formula is selected from one or more of peroxyformic acid, peracetic acid, perpropionic acid, peroxybutyric acid, peroxybenzoic acid, m-chloroperoxybenzoic acid, peroxyphenylacetic acid, peroxyethanol, peroxypropanol, peroxybutanol or hydrogen peroxide. In step (2), the reaction solvent is selected from dichloromethane, trichloromethane, 1,2-dichloroethane or 1,1-dichloroethane; In step (3), the haloalkane in the reaction formula is 1,5-dihalopentane, wherein the halogen atom is selected from fluorine, chlorine, bromine or iodine; In step (3), the reaction solvent is selected from benzene, toluene, xylene, o-xylene, m-xylene, or p-xylene; The phase transfer catalyst in step (3) is tetrabutylammonium chloride; the alkaline environment in step (3) refers to the environment in which potassium carbonate aqueous solution is added, wherein the potassium carbonate aqueous solution is a 50% potassium carbonate aqueous solution; and / or In step (7), the reaction solvent is methanol. After heating to 60-70°C and stirring to dissolve, free alkali methanol solution is slowly added dropwise while maintaining the temperature at 60-70°C. The mixture is stirred and refluxed for 3 hours, then cooled to 20-30°C and crystallized for 23-25 ​​hours. After centrifugation, the centrifuged filter cake and methanol are heated to 60-70°C and stirred for 4.5-5.5 hours. Then, the mixture is cooled to -5-5°C and stirred for 1.5-2.5 hours. After centrifugation, the filter cake is dried under reduced pressure at a temperature of 60-65°C for 12-14 hours.

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