Preparation method of phenylephrine hydrochloride intermediate impurity
A method for preparing N-benzyl-2-(3-hydroxyphenyl)-N-(2-(3-hydroxybenzene)-2-oxoethyl)-N-methyl-2-oxoethylamine bromide as an intermediate impurity addresses the lack of synthesis methods for such impurities, achieving high yield and purity for use as a reference substance in phenylephrine hydrochloride synthesis, ensuring drug safety and effectiveness.
Patent Information
- Application Number
- CN202411327160.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-23
- Publication Date
- 2024-12-27
AI Technical Summary
Current methods for synthesizing phenylephrine hydrochloride do not address the preparation of intermediate impurities, which are necessary for controlling drug quality and ensuring safety and effectiveness.
A method is developed to prepare N-benzyl-2-(3-hydroxyphenyl)-N-(2-(3-hydroxybenzene)-2-oxoethyl)-N-methyl-2-oxoethylamine bromide as an intermediate impurity by reacting 3-hydroxyacetophenone with copper bromide, followed by subsequent reactions with N-methylbenzylamine and sodium bicarbonate, and purification using column chromatography and specific solvents.
The method achieves high yield and purity of the intermediate impurity, allowing it to serve as a reference substance for controlling impurity levels in phenylephrine hydrochloride synthesis, thereby ensuring drug safety and efficacy.
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Figure CN119192003A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing a phenylephrine hydrochloride intermediate impurity. Background Art
[0002] Phenylephrine hydrochloride is an α-adrenaline receptor agonist, a sympathomimetic amine that acts directly on the receptor, but sometimes it also works indirectly by promoting the release of phenylephrine from the storage site. Specifically, phenylephrine hydrochloride acts on α receptors (especially the skin, mucous membranes, internal organs, etc.), causing vasoconstriction, increased peripheral resistance, and increased systolic and diastolic blood pressure; it can reflexively excite the vagus nerve, slow the heart rate, and have a short-term mydriasis effect; it is generally used clinically to prevent and treat hypotension caused by spinal anesthesia, general anesthesia, and the use of chlorpromazine, and is also used for supraventricular tachycardia and mydriasis examinations. Based on this, phenylephrine hydrochloride has good safety and reliable efficacy, and has a good prospect for clinical use.
[0003] Many impurities are generated during the synthesis of phenylephrine hydrochloride. For example, an impurity is found during the synthesis of phenylephrine hydrochloride in the present invention. It is confirmed that the chemical structure of this impurity is as shown in formula (I). This impurity can further derive other impurities.
[0004]
[0005] In order to ensure the safety and effectiveness of the drug, it is necessary to study this impurity and its derivatives to facilitate the subsequent control of the drug quality of phenylephrine hydrochloride. First, it is necessary to prepare this impurity as an impurity reference.
[0006] However, the current patents related to phenylephrine hydrochloride, such as CN103772215A, CN102040529A, and US1954389, mainly disclose a synthesis process of "using 3-hydroxyacetophenone or m-hydroxybenzaldehyde as a starting material, and obtaining phenylephrine hydrochloride through chemical synthesis, chiral reduction, and dynamic resolution". No reports have been seen on the synthesis of the phenylephrine hydrochloride intermediate impurities of the present invention. Summary of the invention
[0007] The technical problem to be solved by the present invention is to provide a method for preparing impurities of an intermediate of phenylephrine hydrochloride.
[0008] The present invention adopts the following technical solutions to solve the above technical problems:
[0009] A method for preparing an impurity of an intermediate of phenylephrine hydrochloride, wherein the impurity is N-benzyl-2-(3-hydroxyphenyl)-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-N-methyl-2-oxoethylamine bromide, and the structure is shown in the following formula I:
[0010]
[0011] The preparation method of the impurity is as follows:
[0012] S1, using 3-hydroxyacetophenone as a raw material, brominating it with copper bromide to obtain a 2-bromo-3'-hydroxyacetophenone solution;
[0013] S2, reacting the 2-bromo-3'-hydroxyacetophenone solution obtained in step S1 with N-methylbenzylamine to obtain 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride, i.e., intermediate I;
[0014] S3, adding the intermediate I obtained in step S2 to the 2-bromo-3'-hydroxyacetophenone solution, and adding sodium bicarbonate, and obtaining the target impurity after the reaction;
[0015] S4. The obtained target impurity is separated by column chromatography, or after separation, it is purified by a purification solvent to obtain a purified target impurity.
[0016] Furthermore, in step S1, the molar ratio of 3-hydroxyacetophenone to copper bromide is 1:(1.1-1.5). In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the molar ratio of 3-hydroxyacetophenone to copper bromide is preferably 1:1.5.
[0017] Furthermore, in step S1, the reaction temperature of 3-hydroxyacetophenone and copper bromide is 55-65° C. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction temperature of 3-hydroxyacetophenone and copper bromide is preferably 60-65° C.
[0018] Furthermore, in step S1, the reaction time of 3-hydroxyacetophenone and copper bromide is 5 to 7 hours. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction time of 3-hydroxyacetophenone and copper bromide is preferably 6 hours.
[0019] Furthermore, in the step S1, a reaction solvent is added to the reaction of 3-hydroxyacetophenone and copper bromide; the reaction solvent is selected from one or more of ethyl acetate, butyl acetate, and chloroform. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction solvent of 3-hydroxyacetophenone and copper bromide is preferably ethyl acetate.
[0020] Furthermore, in step S2, the molar ratio of 2-bromo-3'-hydroxyacetophenone to N-methylbenzylamine is 1:(2.0-2.5). In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the molar ratio of 2-bromo-3'-hydroxyacetophenone to N-methylbenzylamine is preferably 1:2.2.
[0021] Furthermore, in step S2, N-methylbenzylamine is added dropwise to the 2-bromo-3'-hydroxyacetophenone solution at a temperature of 0 to 20° C. In order to obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, it is preferred that the temperature of N-methylbenzylamine added dropwise to the 2-bromo-3'-hydroxyacetophenone solution is 10 to 20° C.
[0022] Furthermore, in step S2, the reaction temperature of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is 30-50° C. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction temperature of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is preferably 40-50° C.
[0023] Furthermore, in step S2, the reaction time of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is 1 to 2 hours. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction time of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is preferably 2 hours.
[0024] Furthermore, in step S3, the molar ratio of intermediate I to 2-bromo-3'-hydroxyacetophenone is 1:(1.3-2.0). In order to better obtain the target impurity of phenylephrine hydrochloride intermediate with a higher yield, the molar ratio of intermediate I to 2-bromo-3'-hydroxyacetophenone is preferably 1:1.5.
[0025] Furthermore, in step S3, the molar ratio of intermediate I to sodium bicarbonate is 1:(1.5-2.0). In order to obtain the target impurity of phenylephrine hydrochloride intermediate with a higher yield, the molar ratio of intermediate I to sodium bicarbonate is preferably 1:1.8.
[0026] Furthermore, in step S3, the reaction temperature of the intermediate I and 2-bromo-3'-hydroxyacetophenone is 50-100° C. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction temperature of the intermediate I and 2-bromo-3'-hydroxyacetophenone is preferably 50-60° C.
[0027] Furthermore, in step S3, the reaction time of the intermediate I and 2-bromo-3'-hydroxyacetophenone is 2 to 3 hours. In order to obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction time of the intermediate I and 2-bromo-3'-hydroxyacetophenone is preferably 2 hours.
[0028] Furthermore, in step S3, a reaction solvent is added to the reaction of intermediate I with 2-bromo-3'-hydroxyacetophenone; the reaction solvent is selected from one or more of ethyl acetate, acetonitrile, dichloromethane, toluene, and tetrahydrofuran. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the reaction solvent of intermediate I with 2-bromo-3'-hydroxyacetophenone is preferably acetonitrile.
[0029] Furthermore, in step S4, the purification solvent is selected from one or more of methanol, ethanol, n-butanol, isopropanol, acetonitrile, and ethyl acetate. In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the preferred purification solvents for the target impurity of the phenylephrine hydrochloride intermediate are methanol and isopropanol.
[0030] Furthermore, in step S4, when isopropanol and isopropanol are selected as the purification solvent, the volume ratio of methanol to isopropanol is 1:(3-5). In order to better obtain the target impurity of the phenylephrine hydrochloride intermediate with a higher yield, the preferred volume ratio of methanol to isopropanol is 1:4.
[0031] The advantages of the present invention compared to the prior art are:
[0032] (1) The preparation method of the present invention is simple and easy to implement, with ideal yield and purity, and the intermediate impurity can be prepared in large quantities; the impurity is used as an impurity reference substance in the synthesis process of phenylephrine hydrochloride, and the impurity situation in the synthesis of phenylephrine hydrochloride can be reasonably and effectively controlled, and ultimately the safety and effectiveness of phenylephrine hydrochloride drugs can be ensured;
[0033] (2) The present invention finally obtains an exclusive synthesis method of N-benzyl-2-(3-hydroxyphenyl)-N-(2-(3-hydroxybenzene)-2-oxoethyl)-N-methyl-2-oxoethylamine bromide. The prepared product has a maximum purity of 100% and can be used as a reference substance. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] Figure 1 is a synthetic route diagram of the phenylephrine hydrochloride intermediate impurity in Examples 1 to 8;
[0035] Figure 2 is the IHPLC chart of the phenylephrine hydrochloride intermediate I in Experimental Example 1;
[0036] Figure 3 is the HPLC chart of the target impurity after column chromatography elution in Experimental Example 1;
[0037] Figure 4 is the IHPLC chart of phenylephrine hydrochloride intermediate I in Experimental Example 2;
[0038] Figure 5 is the HPLC chart of the crude target impurity after column chromatography elution in Experimental Example 2;
[0039] Figure 6 is the HPLC chart of the refined product of the target impurity after purification with methanol and isopropanol in Experimental Example 2;
[0040] Figure 7 is the mass spectrum of the refined product of the target impurity in Experimental Example 2;
[0041] Figure 8 is the H of the target impurity refined product in Experimental Example 2 1 NMR spectra;
[0042] Fig. 9 yes Figure 8 A magnified view of the local map. DETAILED DESCRIPTION
[0043] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.
[0044] The target impurity in the following embodiments of the present invention is N-benzyl-2-(3-hydroxyphenyl)-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-N-methyl-2-oxoethylamine bromide, and its structure is shown in the following formula (I):
[0045]
[0046] Meanwhile, the raw materials, reagents, equipment and experimental methods used in the following examples, unless otherwise specified, are conventional raw materials, reagents, equipment and methods in the art and will not be described in detail.
[0047] Example 1
[0048] A preparation method of a phenylephrine hydrochloride intermediate impurity in this embodiment (synthesis route diagram is shown in Figure 1 ):
[0049] S1. Add 3-hydroxyacetophenone (10 g), copper bromide (24.6 g), and ethyl acetate (60 g) to a 100 mL reaction bottle, stir and heat at 62 °C for 6 h; cool to room temperature and filter, wash the filter cake with 30 mL of ethyl acetate, wash the filtrate once with 20 mL of water, and then wash once with 20 mL of saturated sodium chloride; separate the organic phase, which is 2-bromo-3'-hydroxyacetophenone ethyl acetate solution.
[0050] S2. Take 5 g (30 g solution weight) of 2-bromo-3'-hydroxyacetophenone after conversion into a 100 mL reaction bottle; stir and cool to 10°C, add 6.3 g of N-methylbenzylamine dropwise, add the mixture after about 30 minutes, heat to 45°C for 2 hours, cool to 0°C and stir for 1 hour to precipitate a large amount of white solid; filter with suction, and charge the filtrate into a 100 mL reaction bottle; add isopropanol hydrochloride dropwise at room temperature to precipitate solid, stir at room temperature for 2 hours, filter with suction, and wash with 12 mL of ethyl acetate to obtain 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I).
[0051] S3. Take 3.8 g of 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I) in a 100 mL reaction bottle, add 23 mL of acetonitrile and stir to dissolve, add 2 g of sodium bicarbonate and then dropwise add 4.2 g (solution weight 26 g) of 2-bromo-3'-hydroxyacetophenone ethyl acetate solution, heat to 55° C. and react for 2 h; stop the reaction, concentrate to dryness and then add 20 mL of dichloromethane to dissolve; wash once with 20 mL of water and once with 100 mL of saturated brine to obtain the target impurity solution of the phenylephrine hydrochloride intermediate.
[0052] S4. Add silica gel to the target impurity solution of the phenylephrine hydrochloride intermediate and mix the sample, and then perform column chromatography to obtain the purified target impurity of the brown-yellow phenylephrine hydrochloride intermediate.
[0053] Example 2
[0054] The method for preparing a phenylephrine hydrochloride intermediate impurity in this embodiment is basically the same as that in Example 1, except that:
[0055] In step S1, the molar ratio of 3-hydroxyacetophenone to copper bromide is 1:1.1. The reaction temperature of 3-hydroxyacetophenone and copper bromide is 55° C., and the reaction time is 7 hours. In the reaction of 3-hydroxyacetophenone and copper bromide, butyl acetate is used as the reaction solvent.
[0056] In the step S2, the molar ratio of 2-bromo-3'-hydroxyacetophenone to N-methylbenzylamine is 1:2.0. The dropping temperature is 0° C. The reaction temperature of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is 30° C., and the reaction time is 2 hours.
[0057] In step S3, the molar ratio of intermediate I, 2-bromo-3'-hydroxyacetophenone and sodium bicarbonate is 1:1.3:1.5. The reaction temperature of intermediate I and 2-bromo-3'-hydroxyacetophenone is 50°C, and the reaction time is 3h. In the reaction of intermediate I and 2-bromo-3'-hydroxyacetophenone, ethyl acetate is used as the reaction solvent.
[0058] Example 3
[0059] The method for preparing a phenylephrine hydrochloride intermediate impurity in this embodiment is basically the same as that in Example 1, except that:
[0060] In step S1, the molar ratio of 3-hydroxyacetophenone to copper bromide is 1:1.3. The reaction temperature of 3-hydroxyacetophenone and copper bromide is 60° C., and the reaction time is 6 hours. In the reaction of 3-hydroxyacetophenone and copper bromide, chloroform is used as the reaction solvent.
[0061] In the step S2, the molar ratio of 2-bromo-3'-hydroxyacetophenone to N-methylbenzylamine is 1:2.1. The dropping temperature is 4° C. The reaction temperature of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is 40° C., and the reaction time is 1.5 h.
[0062] In step S3, the molar ratio of intermediate I, 2-bromo-3'-hydroxyacetophenone and sodium bicarbonate is 1:1.4:1.6. The reaction temperature of intermediate I and 2-bromo-3'-hydroxyacetophenone is 60°C, and the reaction time is 2.5h. In the reaction of intermediate I and 2-bromo-3'-hydroxyacetophenone, dichloromethane is used as the reaction solvent.
[0063] Example 4
[0064] The method for preparing a phenylephrine hydrochloride intermediate impurity in this embodiment is basically the same as that in Example 1, except that:
[0065] In step S1, the molar ratio of 3-hydroxyacetophenone to copper bromide is 1:1.4. The reaction temperature of 3-hydroxyacetophenone and copper bromide is 65° C., and the reaction time is 5 hours. Chloroform is used as the reaction solvent.
[0066] In the step S2, the molar ratio of 2-bromo-3'-hydroxyacetophenone to N-methylbenzylamine is 1:2.5. The dropping temperature is 20° C. The reaction temperature of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is 50° C., and the reaction time is 1 hour.
[0067] In step S3, the molar ratio of intermediate I, 2-bromo-3'-hydroxyacetophenone and sodium bicarbonate is 1:2.0:2.0. The reaction temperature of intermediate I and 2-bromo-3'-hydroxyacetophenone is 100° C., and the reaction time is 2 hours. In the reaction of intermediate I and 2-bromo-3'-hydroxyacetophenone, tetrahydrofuran is used as the reaction solvent.
[0068] Example 5
[0069] A preparation method of a phenylephrine hydrochloride intermediate impurity in this embodiment (synthesis route diagram is shown in Figure 1 ):
[0070] S1. Add 3-hydroxyacetophenone (50 g), copper bromide (123 g), and ethyl acetate (300 g) to a 1000 mL reaction bottle, stir and heat at 62 °C for 6 h; cool to room temperature and filter, wash the filter cake with 50 mL of ethyl acetate, wash the filtrate once with 100 mL of water, and then wash once with 100 mL of saturated sodium chloride; separate the organic phase, which is 2-bromo-3'-hydroxyacetophenone ethyl acetate solution.
[0071] S2. Take 30 g (solution weight 206 g) of 2-bromo-3'-hydroxyacetophenone after conversion into a 1000 mL reaction bottle, stir and cool to 10°C, add 37.4 g of N-methylbenzylamine dropwise, add the mixture over a period of about 30 minutes, heat to 40-50°C, react for 2 hours, cool to 0°C, stir for 1 hour, and a large amount of white solid precipitates; filter with suction, put the filtrate into a 1000 mL reaction bottle, add isopropanol hydrochloride dropwise at room temperature, and solid precipitates; stir at room temperature for 2 hours, filter with suction, and wash with 100 mL of ethyl acetate to obtain 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I).
[0072] S3. Take 20 g of 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I) in a 500 mL reaction bottle, add 120 mL of acetonitrile and stir to dissolve, add 10.4 g of sodium bicarbonate and then dropwise add 22 g (solution weight 151 g) of 2-bromo-3'-hydroxyacetophenone ethyl acetate solution, heat to 55° C. and react for 2 h, stop the reaction, concentrate to dryness and then add 200 mL of dichloromethane to dissolve; wash once with 100 mL of water and once with 100 mL of saturated brine to obtain the target impurity solution of the phenylephrine hydrochloride intermediate.
[0073] S4. Add silica gel to the target impurity solution of the intermediate of phenylephrine hydrochloride, and mix the sample. Elute by column chromatography to obtain a brown-yellow crude target impurity of the intermediate of phenylephrine hydrochloride; add the crude target impurity of the intermediate of phenylephrine hydrochloride into a 250mL reaction bottle, add methanol and isopropanol in a volume ratio of 1:4, 84mL, heat to reflux to dissolve, cool to 15°C, stir and crystallize for 3h, and filter to obtain the purified target impurity.
[0074] Example 6
[0075] The method for preparing a phenylephrine hydrochloride intermediate impurity in this embodiment is basically the same as that in Example 5, the main difference is that in step S4, ethanol is selected as the purification solvent.
[0076] Example 7
[0077] The method for preparing a phenylephrine hydrochloride intermediate impurity in this embodiment is basically the same as that in Example 5, the main difference is that in step S4, n-butanol is selected as the purification solvent.
[0078] Example 8
[0079] The method for preparing a phenylephrine hydrochloride intermediate impurity in this embodiment is basically the same as that in Example 5, the main difference is that in step S4, acetonitrile is selected as the purification solvent.
[0080] Experimental Example 1
[0081] This experimental example takes Example 1 as an example to verify the feasibility of the method of the present invention:
[0082] (1) Add 3-hydroxyacetophenone (10 g), copper bromide (24.6 g), and ethyl acetate (60 g) to a 100 mL reaction bottle, stir and heat at 62° C. to react for 6 h; cool to room temperature and filter, wash the filter cake with 30 mL of ethyl acetate, wash the filtrate once with 20 mL of water, and then wash once with 20 mL of saturated sodium chloride; separate the organic phase, which is 2-bromo-3'-hydroxyacetophenone ethyl acetate solution (total weight: 74 g, purity 76%), and the converted 2-bromo-3'-hydroxyacetophenone is 12 g.
[0083] (2) 5 g of 2-bromo-3'-hydroxyacetophenone (solution weight 30 g) was added to a 100 mL reaction bottle; stirred and cooled to 10° C., 6.3 g of N-methylbenzylamine was added dropwise, and the temperature was raised to 45° C. for about 30 minutes after the addition was completed, and the reaction was continued for 2 hours. The temperature was then lowered to 0° C. and stirred for 1 hour to cause a large amount of white solid to precipitate; suction filtration was performed, and the filtrate was charged into a 100 mL reaction bottle; hydrochloric acid isopropanol was added dropwise at room temperature to cause solid to precipitate, and the mixture was stirred at room temperature for 2 hours, suction filtered, and washed with 12 mL of ethyl acetate to obtain 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I), about 3.8 g, with a yield of 56% and a purity of 97.495%. Figure 2 .
[0084] (3) 3.8 g of 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I) was added to a 100 mL reaction bottle, 23 mL of acetonitrile was added, and the mixture was stirred to dissolve. 2 g of sodium bicarbonate was added, and 4.2 g of 2-bromo-3'-hydroxyacetophenone ethyl acetate solution (the solution weighed 26 g) was added dropwise. The mixture was heated to 55° C. and reacted for 2 h. The reaction was stopped, the mixture was concentrated to dryness, and 20 mL of dichloromethane was added to dissolve the mixture. The mixture was washed once with 20 mL of water and once with 100 mL of saturated brine to obtain a target impurity solution of the intermediate of phenylephrine hydrochloride.
[0085] (4) The target impurity solution of the intermediate of phenylephrine hydrochloride was mixed with silica gel and eluted by column chromatography to obtain the purified target impurity of the intermediate of phenylephrine hydrochloride in brown yellow color, 1.3 g, with a purity of 91.567%. Figure 3 .
[0086] Experimental Example 2
[0087] This experimental example takes Example 5 as an example to verify the feasibility of the method of the present invention:
[0088] (1) Add 3-hydroxyacetophenone (50 g), copper bromide (123 g), and ethyl acetate (300 g) to a 1000 mL reaction bottle, stir and heat at 62° C. to react for 6 h; cool to room temperature and filter, wash the filter cake with 50 mL of ethyl acetate, wash the filtrate once with 100 mL of water, and then wash once with 100 mL of saturated sodium chloride; separate the organic phase, which is 2-bromo-3'-hydroxyacetophenone ethyl acetate solution (total weight: 405 g, purity 75%), and the converted 2-bromo-3'-hydroxyacetophenone is 59 g.
[0089] (2) 30 g of 2-bromo-3'-hydroxyacetophenone (solution weight 206 g) was added to a 1000 mL reaction bottle, stirred and cooled to 10° C., 37.4 g of N-methylbenzylamine was added dropwise, and the temperature was raised to 40-50° C. for about 30 minutes after the addition was completed, and the reaction was continued for 2 hours. The temperature was then lowered to 0° C. and stirred for 1 hour to precipitate a large amount of white solid. The filtrate was filtered by suction, and the filtrate was placed in a 1000 mL reaction bottle. Hydrochloric acid isopropanol was added dropwise at room temperature to precipitate solid. The mixture was stirred at room temperature for 2 hours, filtered by suction, and washed with 100 mL of ethyl acetate to obtain 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I), about 24.9 g, with a yield of 61% and a purity of 96.413%. Figure 4 .
[0090] (3) 20 g of 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride (i.e., intermediate I) was placed in a 500 mL reaction bottle, 120 mL of acetonitrile was added and stirred to dissolve, 10.4 g of sodium bicarbonate was added and 22 g of ethyl acetate solution of 2-bromo-3'-hydroxyacetophenone (the weight of the solution was 151 g) was added dropwise, the temperature was raised to 55° C. and the reaction was allowed to proceed for 2 h. The reaction was stopped, the mixture was concentrated to dryness, and 200 mL of dichloromethane was added to dissolve the mixture; the mixture was washed once with 100 mL of water and once with 100 mL of saturated brine to obtain a target impurity solution of the intermediate of phenylephrine hydrochloride.
[0091] (4) Silica gel was added to the target impurity solution of the intermediate of phenylephrine hydrochloride, and the sample was eluted by column chromatography to obtain 12 g of a brown-yellow crude product of the target impurity of the intermediate of phenylephrine hydrochloride, with a purity of 91.001%. Figure 5 ; Add 12g of the target impurity crude product of the intermediate of phenylephrine hydrochloride into a 250mL reaction bottle, add methanol and isopropanol in a volume ratio of 1:4, 84mL, heat to reflux to dissolve, cool to 15℃, stir and crystallize for 3h, filter and obtain 8.7g of off-white solid, with a yield of 72.5% and a purity of 100% (see Figure 6 ), MS detection (see Figure 7 ), H 1 NMR (see Figure 8 , 9 ).
[0092] In summary, the preparation method of the present invention is simple and easy, with ideal yield and purity, and the intermediate impurity can be prepared in large quantities; the impurity is used as an impurity reference substance in the synthesis process of phenylephrine hydrochloride, and the impurity situation in the synthesis of phenylephrine hydrochloride can be reasonably and effectively controlled, and ultimately the safety and effectiveness of the phenylephrine hydrochloride drug can be ensured.
[0093] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for preparing an impurity of a phenylephrine hydrochloride intermediate, characterized in that: The impurity is N-benzyl-2-(3-hydroxyphenyl)-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-N-methyl-2-oxoethylamine bromide, and its structure is shown in the following formula I: The preparation method of the impurity is as follows: S1, using 3-hydroxyacetophenone as a raw material, brominating it with copper bromide to obtain a 2-bromo-3'-hydroxyacetophenone solution; S2, reacting the 2-bromo-3'-hydroxyacetophenone solution obtained in step S1 with N-methylbenzylamine to obtain 1-(3-hydroxyphenyl)-2-[methyl(benzyl)amino]-ethanone hydrochloride, i.e., intermediate I; S3, adding the intermediate I obtained in step S2 to the 2-bromo-3'-hydroxyacetophenone solution, and adding sodium bicarbonate, and obtaining the target impurity after the reaction; S4. The obtained target impurity is separated by column chromatography, or after separation, it is purified by a purification solvent to obtain a purified target impurity.
2. The method for preparing the phenylephrine hydrochloride intermediate impurity according to claim 1, characterized in that: In the step S1, the molar ratio of 3-hydroxyacetophenone to copper bromide is 1:(1.1-1.5).
3. The method for preparing the phenylephrine hydrochloride intermediate impurity according to claim 1, characterized in that: In the step S1, the reaction temperature of 3-hydroxyacetophenone and copper bromide is 55-65° C., and the reaction time is 5-7 hours.
4. The method for preparing the phenylephrine hydrochloride intermediate impurity according to claim 1, characterized in that: In the step S1, a reaction solvent is further added to the reaction between 3-hydroxyacetophenone and copper bromide; the reaction solvent is selected from one or more of ethyl acetate, butyl acetate, and chloroform.
5. The method for preparing the phenylephrine hydrochloride intermediate impurity according to claim 1, characterized in that: In the step S2, the molar ratio of 2-bromo-3'-hydroxyacetophenone to N-methylbenzylamine is 1:(2.0-2.5).
6. The method for preparing phenylephrine hydrochloride intermediate impurities according to claim 1, characterized in that: In the step S2, the reaction temperature of 2-bromo-3'-hydroxyacetophenone and N-methylbenzylamine is 30-50° C., and the reaction time is 1-2 hours.
7. The method for preparing phenylephrine hydrochloride intermediate impurities according to claim 1, characterized in that: In the step S3, the molar ratio of the intermediate I, 2-bromo-3'-hydroxyacetophenone and sodium bicarbonate is 1:(1.3-2.0):(1.5-2.0).
8. The method for preparing phenylephrine hydrochloride intermediate impurities according to claim 1, characterized in that: In the step S3, the intermediate I reacts with 2-bromo-3'-hydroxyacetophenone at a reaction temperature of 50 to 100° C. and a reaction time of 2 to 3 hours.
9. The method for preparing phenylephrine hydrochloride intermediate impurities according to claim 1, characterized in that: In the step S3, a reaction solvent is further added to the reaction of the intermediate I and 2-bromo-3'-hydroxyacetophenone; the reaction solvent is selected from one or more of ethyl acetate, acetonitrile, dichloromethane, toluene, and tetrahydrofuran.
10. The method for preparing phenylephrine hydrochloride intermediate impurities according to claim 1, characterized in that: In step S4, the purification solvent is selected from one or more of methanol, ethanol, n-butanol, isopropanol, acetonitrile, and ethyl acetate.