A method of preparing prilocaine

Abstract

The application discloses a preparation method of pramoxine, which comprises the following steps: taking 1,4-p-dibromobenzene and n-butanol as raw materials, and adopting cheap and easily obtained nickel salt as a catalyst, and under the action of catalytic amount of silane reagent, a ligand and an organic base, 1-bromo-4-butoxybenzene is synthesized through C-O coupling reaction; then, 1-bromo-4-butoxybenzene and 3-(4-morpholinyl)-1-propanol are subjected to C-O coupling reaction through the same method to obtain pramoxine. The preparation method has the characteristics of mild conditions, all the raw materials are commercially available and low in price, simple synthesis steps, high yield, high atom economy and the like, and is expected to realize industrialized production of pramoxine.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical organic synthesis, and particularly relates to a preparation method of pramoxine. BACKGROUND

[0002] Pramoxine, with a molecular formula of C 17 H 27 NO3, has a chemical name of 4-(3-(4-butoxyphenoxy)propyl)morpholine, is a topical anesthetic, and is clinically used in the form of hydrochloride, has the effects of anesthesia, analgesia and antipruritic. A structural formula is as follows:

[0003]

[0004] A synthesis route of pramoxine mainly includes the following:

[0005] Route one: morpholine, 1,3-dichloropropane and 4-n-butoxyphenol are reacted under the catalysis of a base and a halide to obtain pramoxine.

[0006]

[0007] Route two: 4-n-butoxyphenol is obtained by selective hydroxylation at a para position of phenyl n-butyl ether in the presence of a catalyst and an oxidant, and then 4-(3-chloropropyl)morpholine is reacted under alkaline conditions to obtain pramoxine.

[0008]

[0009] Route three: 1-iodobutane, 4-iodophenol and 3-(4-morpholinyl)-1-propanol are reacted under the catalysis of a base to obtain pramoxine.

[0010]

[0011] The existing traditional synthesis method is mainly to synthesize pramoxine by using 4-n-butoxyphenol and 4-(3-chloropropyl)morpholine, or 1-butoxy-4-iodobenzene and 3-(4-morpholinyl)-1-propanol under the action of a base. The method has limitations such as complicated steps, complex operation, harsh reaction conditions such as the use of a strong base and high temperature, and low yield. SUMMARY

[0012] The technical problem to be solved by the present application is to provide a preparation method of pramoxine, which is easy to obtain raw materials, simple in operation process, mild in conditions, high in yield, and suitable for industrial production.

[0013] The preparation method of prilocaine provided by the present application comprises two steps, the first step is to react 1,4-dibromobenzene with n-butanol to obtain 1-bromo-4-butoxybenzene, and the second step is to react 1-bromo-4-butoxybenzene with 3-(4-morpholine)-1-propanol to obtain prilocaine. The specific synthesis route and preparation method are as follows:

[0014]

[0015] Step 1: under an inert gas atmosphere, 1,4-dibromobenzene and n-butanol are added into an organic solvent, and then a nickel salt, a ligand, an organic base and a silane reagent are sequentially added, and stirring reaction is carried out at 80-120℃ for 20-24 hours, and after the reaction is completed, separation and purification are carried out to obtain 1-bromo-4-butoxybenzene.

[0016] Step 2: under an inert gas atmosphere, 1-bromo-4-butoxybenzene and 3-(4-morpholine)-1-propanol are added into an organic solvent, and then a nickel salt, a ligand, an organic base and a silane reagent are sequentially added, and stirring reaction is carried out at 80-120℃ for 20-24 hours, and after the reaction is completed, separation and purification are carried out to obtain prilocaine.

[0017] Preferably, in the above step 1, the molar ratio of 1,4-dibromobenzene, n-butanol, nickel salt, ligand, organic base, silane reagent is 1.0:1.5-4.0:0.05-0.1:0.05-0.1:1.0-2.5:0.2-0.3.

[0018] Preferably, in the above step 2, the molar ratio of 1-bromo-4-butoxybenzene, 3-(4-morpholine)-1-propanol, nickel salt, ligand, organic base, silane reagent is 1.0:1.5-4.0:0.05-0.1:0.05-0.1:1.0-2.5:0.2-0.3.

[0019] Preferably, the above nickel salt is any one of nickel bromide, nickel chloride, nickel bromide trihydrate.

[0020] Preferably, the above ligand is any one of 4,4-dimethoxybipyridine, 4,4-di-tert-butylbipyridine, 5,5-dimethylbipyridine.

[0021] Preferably, the above silane reagent is any one of phenylsilane, triphenylsilane, diethylsilane.

[0022] Preferably, the above organic base is any one of tetramethylguanidine, 1,8-diazobis-spiro[5.4.0]undec-7-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0023] Preferably, the above organic solvent is any one of toluene, 1,4-dioxane, N,N-dimethylformamide.

[0024] The beneficial effects of the present application are as follows:

[0025] The present application takes 1,4-p-dibromobenzene and n-butanol as raw materials, uses cheap and easily available nickel salt as catalyst, and under the action of catalytic amount of silane reagent, ligand and organic base, 1-bromo-4-butoxybenzene is first synthesized by C-O coupling reaction; then using the same method, 1-bromo-4-butoxybenzene and 3-(4-morpholinyl)-1-propanol are subjected to C-O coupling reaction to obtain prilocaine. The preparation method has the characteristics of mild conditions, all the raw materials are commercially available and low in price, simple synthesis steps, high yield, high atom economy, etc., and is expected to realize the industrialized production of prilocaine. DETAILED DESCRIPTION

[0026] The present application will be further described in detail below in combination with examples, but the protection scope of the present application is not limited to these examples.

[0027] Example 1

[0028] Step 1: Under nitrogen atmosphere, 1,4-p-dibromobenzene (0.5 mmol), n-butanol (1.0 mmol), 4,4-dimethoxy-2,2'-bipyridine (0.025 mmol), nickel bromide (0.025 mmol), tetramethylguanidine (0.75 mmol), phenylsilane (0.15 mmol), toluene (1.0 mL) and magnetic son were added into a reaction tube, and the reaction was stirred in an oil bath at 100°C for 20 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by reduced pressure distillation to obtain a crude product, which was purified by column chromatography with petroleum ether and ethyl acetate as eluent to obtain 1-bromo-4-butoxybenzene with a yield of 81%, and the structure characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 3.92 (t, J = 6.8 Hz, 2H), 1.79-1.72 (m, 2H), 1.53-1.44 (m, 2H), 0.98 (t, J = 3.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 158.4, 132.3, 116.4, 112.7, 68.1, 31.3, 19.3, 13.9; HRMS (ESI) m / z C 10 H 14 BrO[M+H] + : Theoretical value 229.0223, found value 229.0224.

[0029] Step 2: In a reaction tube, 1-bromo-4-butoxybenzene (0.5 mmol), 3-(4- morpholin)-1-propanol (1.0 mmol), 4,4-dimethoxy-2,2'-bipyridine (0.025 mmol), nickel bromide (0.025 mmol), tetramethylguanidine (0.75 mmol), phenylsilane (0.15 mmol), toluene (1.0 mL) and a magnetic stir bar were added and stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the reaction was cooled to room temperature and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using dichloromethane and methanol as eluents to obtain pumocaine in a yield of 76% with the following structural characterization data: 1 H NMR (400 MHz, CDC13) δ 6.81 (s, 4H), 3.96 (t, J = 6.4 Hz, 2H), 3.89 (t, J = 6.8 Hz, 2H), 3.71 (t, J = 4.8 Hz, 4H), 2.53-2.44 (m, 6H), 1.97-1.90 (m, 2H), 1.77-1.70 (m, 2H), 1.52-1.43 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 153.4, 153.1, 115.5, 115.4, 68.4, 67.1, 66.8, 55.7, 53.8, 31.5, 26.7, 19.4, 13.9; HRMS (ESI) m / z C 17 H 28 NO3[M+H] + : Theoretical value 294.2064, actual value 294.2062.

[0030] Example 2

[0031] 1. In a reaction tube, 1,4-p-dibromobenzene (0.5 mmol), n-butanol (1.0 mmol), 4,4-di-tert-butyl-2,2'-bipyridine (0.025 mmol), nickel bromide trihydrate (0.025 mmol), 1,8-diazobicyclo[5.4.0]undec-7-ene, phenylsilane (0.15 mmol), toluene (1.0 mL) and a magnetic stir bar were added and stirred in an oil bath at 120 °C for 24 h. After the reaction was completed, the reaction was cooled to room temperature and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using petroleum ether and ethyl acetate as eluents to obtain 1-bromo-4-butoxybenzene in a yield of 87%.

[0032] 2. In an argon atmosphere, 1-bromo-4-butoxybenzene (0.5 mmol), 3-(4- morpholinyl)-1-propanol (1.0 mmol), 5,5-dimethylpyridine (0.025 mmol), nickel chloride (0.025 mmol), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.75 mmol), phenylsilane (0.15 mmol), 1,4-dioxane (1.0 mL) and a magnetic stirrer were added to a reaction tube, and the reaction was stirred in an oil bath at 80°C for 24 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using petroleum ether and ethyl acetate as eluents to obtain 1-bromo-4-butoxybenzene in a yield of 69%.

[0033] Example 3

[0034] 1. In an argon atmosphere, 1,4-p-dibromobenzene (0.5 mmol), n-butanol (1.0 mmol), 5,5-dimethylpyridine (0.025 mmol), nickel chloride (0.025 mmol), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.75 mmol), phenylsilane (0.15 mmol), 1,4-dioxane (1.0 mL) and a magnetic stirrer were added to a reaction tube, and the reaction was stirred in an oil bath at 80°C for 24 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using petroleum ether and ethyl acetate as eluents to obtain 1-bromo-4-butoxybenzene in a yield of 69%.

[0035] 2. In an argon atmosphere, 1-bromo-4-butoxybenzene (0.5 mmol), 3-(4-morpholinyl)-1-propanol (1.0 mmol), 5,5-dimethylpyridine (0.025 mmol), nickel chloride (0.025 mmol), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.75 mmol), phenylsilane (0.15 mmol), 1,4-dioxane (1.0 mL) and a magnetic stirrer were added to a reaction tube, and the reaction was stirred in an oil bath at 80°C for 24 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using dichloromethane and methanol as eluents to obtain prilocaine in a yield of 63%.

[0036] Example 4

[0037] 1. In an argon atmosphere, 1,4-p-dibromobenzene (0.5 mmol), n-butanol (1.0 mmol), 4,4-di-tert-butylbipyridine (0.025 mmol), nickel bromide trihydrate (0.025 mmol), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.75 mmol), phenylsilane (0.15 mmol), N,N-dimethylformamide (1.0 mL) and a magnetic stirrer were added to a reaction tube, and the reaction was stirred in an oil bath at 100°C for 24 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using petroleum ether and ethyl acetate as eluents to obtain 1-bromo-4-butyloxybenzene at a yield of 74%.

[0038] 2. In an argon atmosphere, 1-bromo-4-butyloxybenzene (0.5 mmol), 3-(4-morpholin)-1-propanol (1.0 mmol), 4,4-di-tert-butylbipyridine (0.025 mmol), nickel bromide trihydrate (0.025 mmol), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.75 mmol), phenylsilane (0.15 mmol), N,N-dimethylformamide (1.0 mL) and a magnetic stirrer were added to a reaction tube, and the reaction was stirred in an oil bath at 100°C for 24 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using dichloromethane and methanol as eluents to obtain prilocaine at a yield of 68%.

[0039] Example 5

[0040] 1. In an argon atmosphere, 1,4-p-dibromobenzene (0.5 mmol), n-butanol (1.0 mmol), 4,4-di-tert-butylbipyridine (0.025 mmol), nickel bromide trihydrate (0.025 mmol), 1,8-diazobis-spiro[5.4.0]undec-7-ene (0.75 mmol), phenylsilane (0.15 mmol), toluene (1.0 mL) and a magnetic stirrer were added to a reaction tube, and the reaction was stirred in an oil bath at 120°C for 24 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using petroleum ether and ethyl acetate as eluents to obtain 1-bromo-4-butyloxybenzene at a yield of 84%.

[0041] 2. In an argon atmosphere, 1-bromo-4-butoxybenzene (0.5 mmol), 3-(4- morpholin)-1-propanol (1.0 mmol), 4,4-di-tert-butylbipyridine (0.025 mmol), nickel bromide trihydrate (0.025 mmol), 1,8-diazobicyclo[5.4.0]undec-7-ene (0.75 mmol), phenylsilane (0.15 mmol), toluene (1.0 mL) and a magnetic stirrer were added to a reaction tube, and the reaction was stirred in an oil bath at 120°C for 24 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by column chromatography using dichloromethane and methanol as eluents to obtain prilocaine at a yield of 73%.

Claims

1. A method for preparing promocaine, characterized in that... Includes the following steps: Step 1: In an inert gas atmosphere, 1,4-dibromobenzene and n-butanol are added to an organic solvent, followed by the addition of nickel salt, ligand, organic base and silane reagent. The mixture is stirred at 80-120°C for 20-24 hours. After the reaction is complete, the mixture is separated and purified to obtain 1-bromo-4-butoxybenzene. Step 2: In an inert gas atmosphere, 1-bromo-4-butoxybenzene and 3-(4-morpholino)-1-propanol are added to an organic solvent, followed by the addition of nickel salt, ligand, organic base and silane reagent. The mixture is stirred at 80-120°C for 20-24 hours. After the reaction is complete, the mixture is separated and purified to obtain promocaine. The nickel salt is any one of nickel bromide, nickel chloride, and nickel bromide trihydrate; The organic base is any one of tetramethylguanidine, 1,8-diazobispiro[5.4.0]undec-7-ene, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene; The ligand is any one of 4,4-dimethoxybipyridine, 4,4-di-tert-butylbipyridine, and 5,5-dimethylbipyridine. The silane reagent is any one of benzylsilane, triphenylsilane, or diethylsilane.

2. The method for preparing promocaine according to claim 1, characterized in that: In step 1, the molar ratio of 1,4-dibromobenzene to n-butanol, nickel salt, ligand, organic base, and silane reagent is 1.0 : 1.5-4.0 : 0.05-0.1 : 0.05-0.1 : 1.0-2.5 : 0.2-0.

3.

3. The method for preparing promocaine according to claim 1, characterized in that: In step 2, the molar ratio of 1-bromo-4-butoxybenzene to 3-(4-morpholine)-1-propanol, nickel salt, ligand, organic base, and silane reagent is 1.0 : 1.5~4.0 : 0.05~0.1 : 0.05~0.1 : 1.0~2.5 : 0.2~0.

3.

4. The method for preparing promocaine according to claim 1, characterized in that: The organic solvent is any one of toluene, 1,4-dioxane, and N,N-dimethylformamide.

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