A synthesis process of propranolol

Abstract

The present invention relates to a synthesis process of propranolol, belonging to the technical field of pharmaceutical synthesis. A synthesis process of propranolol is provided. The method includes reacting 1-naphthol with 1-bromo-3-hydroxyacetone in an organic solvent to form Compound 3, 1-hydroxy-3-(1-naphthyloxy)-2-propanone; reacting Compound 3 with isopropylamine in an organic solvent to form Compound 2, 1-isopropylamino-3-(1-naphthyloxy)-2-propanone; and subjecting Compound 2 to a reduction reaction under the action of a catalyst to form Compound 1, 1-isopropylamino-3-(1-naphthyloxy)-2-propanol. Overall, the present invention has the advantages of less generation of by-products and impurities, high product yield, high product purity, and simple post-treatment.

Description

Technical Field

[0001] The present invention relates to a synthesis process of propranolol, belonging to the field of preparation of pharmaceutical intermediates. Background Art

[0002] Propranolol is a β-blocker, which can reduce myocardial contractility, automaticity, conductivity and excitability, slow down the heart rate, reduce cardiac output and myocardial oxygen consumption, and is used to control hypertension, pheochromocytoma, myocardial infarction, arrhythmia, angina pectoris and hypertrophic cardiomyopathy. Propranolol has membrane-stabilizing properties but does not have intrinsic sympathomimetic activity.

[0003] Patent document CN107556203B discloses a preparation method of propranolol. In this method, 1-naphthol, epichlorohydrin and isopropylamine are added into a reaction kettle at one time for reaction. The reaction occurs under the action of a reaction solvent, a base and a phase transfer catalyst, and all reactions are completed in one step by a one-pot method to generate the final product propranolol, which simplifies the reaction steps. And water is used as the reaction solvent in the reaction, reducing the cost. However, although adding the three starting materials into the reaction kettle together can reduce the reaction operation steps, it is easy to produce side reactions, generate impurities, and reduce the product yield and product purity. The specific synthesis route is as follows:

[0004]

[0005] The publicly available literature Fine Chemicals and Intermediates Handbook · Volume II. Chemical Industry Press, 1510, Zhang Sigui, Zhang Wei. discloses a commonly used preparation method of propranolol hydrochloride. In this method, 1-naphthol and epichlorohydrin are first subjected to an etherification reaction to obtain an intermediate, and then the ring is opened with isopropylamine to obtain propranolol, and the final product propranolol hydrochloride is obtained after salification with hydrochloric acid. In this method, more than 3.5 times of isopropylamine is required, and the recovery of isopropylamine after the reaction is cumbersome and the recovery rate is low. Moreover, epichlorohydrin is very harmful to operators and the environment during the production process, and the post-treatment of the reaction is also difficult, and the product yield is not high, which is not conducive to large-scale industrial production. The specific synthesis route is as follows:

[0006]

[0007] It can be seen from the above publicly available patent documents and literature that the final product yield and product purity of the common propranolol synthesis routes are relatively low, and impurities are easily generated during the reaction process, which is easy to pollute the natural environment and the post-treatment is also difficult.

[0008] Therefore, there is an urgent need to find a preparation method with less impurity generation, higher product yield and higher product purity. Summary of the Invention

[0009] In view of the above-mentioned defects existing in the prior art, the present invention provides a synthesis process of propranolol, and the problem to be solved is to provide a preparation method for reducing the generation of impurities, increasing the product yield and product purity.

[0010] The object of the present invention is achieved through the following technical solutions. A synthesis process of propranolol, the synthesis process comprising the following steps:

[0011] S1: In an organic solvent, 1-naphthol is reacted with 1-bromo-3-hydroxyacetone to form Compound 3, 1-hydroxy-3-(1-naphthyloxy)-2-propanone;

[0012] S2: In an organic solvent, Compound 3 is reacted with isopropylamine to form Compound 2, 1-isopropylamino-3-(1-naphthyloxy)-2-propanone;

[0013] S3: After Compound 2 undergoes a reduction reaction under the action of a catalyst, Compound 1, 1-isopropylamino-3-(1-naphthyloxy)-2-propanol is formed.

[0014] In the present invention, by using 1-bromo-3-hydroxyacetone instead of epichlorohydrin to react with 1-naphthol to prepare Compound 3, the operation difficulty in the production process can be reduced, and at the same time, the environmental pollution can be reduced. Then, Compound 3 is reacted with isopropylamine to form Compound 2. The reaction can be carried out directly without ring opening, which can reduce the generation of by-products and increase the product yield. Finally, the carbonyl group in Compound 2 is reduced to a hydroxyl group to obtain the final product, Compound 1. The operation in this scheme is less difficult than the traditional production process, and at the same time, there are fewer by-products, higher product yield and higher product purity.

[0015] In the above synthesis process of propranolol, preferably, the organic solvent in the S1 step can be selected from one of ethanol, ether, alkaline solution, etc. Most preferably, when ethanol is used as the solvent, the substrate dissolution rate is larger and the reaction is milder.

[0016] In the above synthesis process of propranolol, preferably, the alkaline solution includes pyridine solution, sodium hydroxide solution, etc. Most preferably, when pyridine solution is used as the reaction environment, fewer by-products are generated.

[0017] In the above synthesis process of propranolol, preferably, the organic solvent in the S2 step can be selected from one of ethanol, ether or water, etc. Most preferably, when ethanol is used as the reaction solvent, the substrate dissolution rate is larger and the product purity is higher.

[0018] In the above-mentioned synthetic process of propranolol, preferably, the reaction temperature in step S2 is 30-45°C. Most preferably, when the reaction temperature is 35°C, the reaction rate is relatively high and energy is saved relatively more.

[0019] In the above-mentioned synthetic process of propranolol, preferably, the reaction environment in step S2 is an alkaline environment.

[0020] In the above-mentioned synthetic process of propranolol, preferably, one of triethylamine or N,N-diisopropylethylamine can be added to the alkaline environment in step S2. Most preferably, using triethylamine can reduce the generation of by-products and improve the product yield.

[0021] In the above-mentioned synthetic process of propranolol, preferably, after the reaction in step S2 is completed, the temperature is lowered to 0-10°C for crystallization.

[0022] In the above-mentioned synthetic process of propranolol, preferably, the catalyst selected in step S3 is aluminum isopropoxide and isopropanol. Most preferably, the combined use of aluminum isopropoxide and isopropanol makes the reaction milder and more selective.

[0023] In the above-mentioned synthetic process of propranolol, preferably, the reaction solvent selected in step S3 is methanol or a mixed solvent of absolute ethanol and dimethylformamide. Most preferably, when a mixed solvent of a methanol solution and a high-boiling solvent is used as the reaction solvent, the reaction efficiency can be accelerated by increasing the reaction temperature.

[0024] In summary, compared with the prior art, the present invention has the following advantages:

[0025] In the present invention, 1-bromo-3-hydroxyacetone is used to react with 1-naphthol instead of epichlorohydrin to prepare an intermediate compound. Compared with epichlorohydrin, 1-bromo-3-hydroxyacetone has less harm and pollution to personnel and the environment, and the generated product does not contain a carcinogenic ethylene oxide structure, reducing the post-treatment steps;

[0026] In the present invention, the reaction process is relatively mild, the generation of the product is relatively gentle, and the generation of impurities is less. Therefore, the product yield is relatively high. At the same time, 1-bromo-3-hydroxyacetone reacts more completely than epichlorohydrin, and the purity of the product is relatively high after purification and recrystallization. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is the synthetic route of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0028] The following are specific examples to further specifically illustrate the technical solutions of the present invention, but the present invention is not limited to these examples.

[0029] Example 1

[0030] Preparation of Compound of Formula 3, 1-Hydroxy-3-(1-naphthyloxy)-2-propanone:

[0031] Put 150 mL of ethanol into a beaker, add 14.42 g (0.1 mol) of 1-naphthol, stir until completely dissolved, dissolve 18.36 g (0.12 mol) of 1-bromo-3-hydroxyacetone in 50 mL of ethanol, slowly add it dropwise to the beaker, after the addition, raise the temperature to 40 °C and stir for 2 h. After the reaction is completed, cool to room temperature, add HCl solution to quench the reaction, remove the solvent under reduced pressure, add 100 mL of ethyl acetate for extraction 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, carry out recrystallization and then filter and dry to obtain 19.97 g of the compound of Formula 3, the product yield is 92.4%, and the product purity is 98.6%.

[0032] Example 2

[0033] Preparation of Compound of Formula 2, 1-Isopropylamino-3-(1-naphthyloxy)-2-propanone:

[0034] Put 150 mL of ethanol into a beaker, add 21.61 g (0.1 mol) of the compound of Formula 2, 1-bromo-3-(1-naphthyloxy)-2-propanone, stir until completely dissolved, add 10.12 g (0.1 mol) of triethylamine, add 16.89 mL (0.2 mol) of isopropylamine, raise the temperature to 35 °C, stir for 1 h. After the reaction is completed, cool to 0 - 10 °C for crystallization, add HCl solution to quench the reaction, remove the solvent under reduced pressure, add 100 mL of ethyl acetate for extraction 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, carry out recrystallization with toluene, filter and dry to obtain 23.09 g of the compound of Formula 2, the product yield is 89.8%, and the product purity is 99.2%.

[0035] Example 3

[0036] Preparation of Compound of Formula 1, 1-Isopropylamino-3-(1-naphthyloxy)-2-propanol:

[0037] Put 200 mL of methanol into a flask, add 25.71 g (0.1 mol) of the compound of Formula 2, after stirring until completely dissolved, add 50 mL of dimethylformamide, stir at room temperature for 20 min, add 24.51 g (0.12 mol) of aluminum isopropoxide and 7.5 mL (0.1 mol) of isopropyl alcohol, raise the temperature to 65 °C, control the temperature for reaction for 6 h, stop the reaction after the raw materials are exhausted, remove the solvent under reduced pressure, add 200 mL of ethyl acetate for extraction 3 times, combine the organic phases, wash with 200 mL of water 3 times, distill off the solvent under reduced pressure, carry out recrystallization and then filter and dry to obtain 24.13 g of the compound of Formula 1, the product yield is 93.1%, and the product purity is 99.4%.

[0038] Example 4

[0039] Preparation of the compound of Formula 3, 1-hydroxy-3-(1-naphthyloxy)-2-propanone:

[0040] Place 150 mL of diethyl ether in a beaker, add 14.42 g (0.1 mol) of 1-naphthol, stir until completely dissolved. Dissolve 18.36 g (0.12 mol) of 1-bromo-3-hydroxyacetone in 50 mL of diethyl ether, slowly add it dropwise to the beaker. After the addition is complete, raise the temperature to 40 °C and stir for 2 h. After the reaction is completed, cool to room temperature, add HCl solution to quench the reaction, remove the solvent under reduced pressure, extract with 100 mL of ethyl acetate three times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, recrystallize and filter and dry to obtain 19.55 g of the compound of Formula 3. The product yield is 90.5% and the product purity is 98.3%.

[0041] Example 5

[0042] Preparation of the compound of Formula 3, 1-hydroxy-3-(1-naphthyloxy)-2-propanone:

[0043] Place 150 mL of (1 mol / L) pyridine solution in a beaker, add 14.42 g (0.1 mol) of 1-naphthol, stir until completely dissolved. Dissolve 18.36 g (0.12 mol) of 1-bromo-3-hydroxyacetone in 50 mL of (1 mol / L) pyridine solution, slowly add it dropwise to the beaker. After the addition is complete, raise the temperature to 40 °C and stir for 2 h. After the reaction is completed, cool to room temperature, add HCl solution to quench the reaction, remove the solvent under reduced pressure, extract with 100 mL of ethyl acetate three times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, recrystallize and filter and dry to obtain 19 g of the compound of Formula 3. The product yield is 87.9% and the product purity is 98.5%.

[0044] Example 6

[0045] Preparation of the compound of Formula 3, 1-hydroxy-3-(1-naphthyloxy)-2-propanone:

[0046] Place 150 mL (1 mol / L) of sodium hydroxide solution in a beaker, add 14.42 g (0.1 mol) of 1-naphthol, stir until completely dissolved, dissolve 18.36 g (0.12 mol) of 1-bromo-3-hydroxyacetone in 50 mL (1 mol / L) of sodium hydroxide solution, slowly add it dropwise to the beaker, after dropping, raise the temperature to 40 °C and stir for 2 h. After the reaction is completed, cool it to room temperature, add HCl solution to quench the reaction, remove the solvent under reduced pressure, extract with 100 mL of ethyl acetate for 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, recrystallize and filter and dry to obtain 18.8 g of the compound of formula 3, the product yield is 87%, and the product purity is 98.4%.

[0047] Example 7

[0048] Preparation of the compound of formula 2, 1-isopropylamino-3-(1-naphthyloxy)-2-propanone:

[0049] Place 150 mL of diethyl ether in a beaker, add 21.61 g (0.1 mol) of the compound of formula 2, 1-bromo-3-(1-naphthyloxy)-2-propanone, stir until completely dissolved, add 10.12 g (0.1 mol) of triethylamine, add 16.89 mL (0.2 mol) of isopropylamine, raise the temperature to 35 °C, stir for 1 h. After the reaction is completed, cool it to 0 - 10 °C for crystallization, add HCl solution to quench the reaction, remove the solvent under reduced pressure, extract with 100 mL of ethyl acetate for 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, recrystallize with toluene, filter and dry to obtain 22.68 g of the compound of formula 2, the product yield is 88.2%, and the product purity is 99%.

[0050] Example 8

[0051] Preparation of the compound of formula 2, 1-isopropylamino-3-(1-naphthyloxy)-2-propanone:

[0052] Place 150 mL of water in a beaker, add 21.61 g (0.1 mol) of the compound of formula 2, 1-bromo-3-(1-naphthyloxy)-2-propanone, stir until completely dissolved, add 10.12 g (0.1 mol) of triethylamine, add 16.89 mL (0.2 mol) of isopropylamine, raise the temperature to 35 °C, stir for 1 h. After the reaction is completed, cool it to 0 - 10 °C for crystallization, add HCl solution to quench the reaction, remove the solvent under reduced pressure, extract with 100 mL of ethyl acetate for 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, recrystallize with toluene, filter and dry to obtain 21.78 g of the compound of formula 2, the product yield is 84.7%, and the product purity is 98.6%.

[0053] Example 9

[0054] Preparation of Compound 1 - isopropylamino - 3-(1 - naphthyloxy)-2 - propanone of Formula 2:

[0055] Put 150 mL of ethanol into a beaker, add 21.61 g (0.1 mol) of Compound 1 - bromo - 3-(1 - naphthyloxy)-2 - propanone of Formula 2, stir until completely dissolved, add 10.12 g (0.1 mol) of triethylamine, add 16.89 mL (0.2 mol) of isopropylamine, heat up to 30 °C, stir and react for 90 min. After the reaction is completed, cool down to 0 - 10 °C for crystallization, add HCl solution to quench the reaction, remove the solvent under reduced pressure, add 100 mL of ethyl acetate for extraction 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, perform recrystallization with toluene, filter and dry to obtain 22.24 g of the Compound of Formula 2. The product yield is 86.5% and the product purity is 99%.

[0056] Example 10

[0057] Preparation of Compound 1 - isopropylamino - 3-(1 - naphthyloxy)-2 - propanone of Formula 2:

[0058] Put 150 mL of ethanol into a beaker, add 21.61 g (0.1 mol) of Compound 1 - bromo - 3-(1 - naphthyloxy)-2 - propanone of Formula 2, stir until completely dissolved, add 10.12 g (0.1 mol) of triethylamine, add 16.89 mL (0.2 mol) of isopropylamine, heat up to 45 °C, stir and react for 40 min. After the reaction is completed, cool down to 0 - 10 °C for crystallization, add HCl solution to quench the reaction, remove the solvent under reduced pressure, add 100 mL of ethyl acetate for extraction 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, perform recrystallization with toluene, filter and dry to obtain 22.06 g of the Compound of Formula 2. The product yield is 85.8% and the product purity is 99%.

[0059] Example 11

[0060] Preparation of Compound 1 - isopropylamino - 3-(1 - naphthyloxy)-2 - propanone of Formula 2:

[0061] Place 150 mL of ethanol in a beaker, add 21.61 g (0.1 mol) of Compound 2 of Formula 2, 1-bromo-3-(1-naphthyloxy)-2-propanone, stir until completely dissolved, add 7.71 mL (0.1 mol) of triethylamine, add 16.89 mL (0.2 mol) of isopropylamine, raise the temperature to 35 °C, stir and react for 1 h. After the reaction is completed, cool to 0 - 10 °C for crystallization, add HCl solution to quench the reaction, remove the solvent under reduced pressure, extract with 100 mL of ethyl acetate 3 times, combine the organic phases, wash the organic phases with 200 mL of saturated brine, distill off the solvent under reduced pressure, recrystallize with toluene, filter and dry to obtain 22.53 g of Compound 2 of Formula 2. The product yield is 87.6% and the product purity is 99.1%.

[0062] Example 12

[0063] Preparation of Compound 1 of Formula 1, 1-isopropylamino-3-(1-naphthyloxy)-2-propanol:

[0064] Place 200 mL of anhydrous ethanol in a flask, add 25.71 g (0.1 mol) of Compound 2 of Formula 2, stir until completely dissolved, then add 50 mL of dimethylformamide, stir at room temperature for 20 min, add 24.51 g (0.12 mol) of aluminum isopropoxide and 7.5 mL (0.1 mol) of isopropyl alcohol, raise the temperature to 65 °C, control the temperature and react for 6 h. After the raw materials are exhausted, the reaction stops. Remove the solvent under reduced pressure, extract with 200 mL of ethyl acetate 3 times, combine the organic phases, wash with 200 mL of water 3 times, distill off the solvent under reduced pressure, recrystallize and then filter and dry to obtain 23.45 g of Compound 1 of Formula 1. The product yield is 90.5% and the product purity is 99.2%.

[0065] Comparative Example

[0066] Add naphthol (I) (144.2 g, 1 mol), epichlorohydrin (113.3, 1.1 mol), isopropylamine (90.5 g, 1.5 mol), tetrabutylammonium bromide (16.6 g, 0.05 mol) to a reaction flask, cool the temperature to about 0 °C, and then slowly add 10% aqueous sodium hydroxide solution (400 g) to the above reaction flask. After adding, react at 0 °C for 3 h, then raise the temperature to 100 °C and stir to react. Monitor by TLC. After 2 h, the reaction is completed. Cool the temperature to 0 °C, add 10% aqueous sodium hydroxide solution (400 g), stir for 1 h, filter, wash the filter cake with water and pump it dry, dry under reduced pressure, and recrystallize with n-hexane to obtain 233.4 g of propranolol (TM). The yield is 90.0% and the purity is 99.5%.

[0067] Comparing with the synthesis method in the present invention, this comparative example needs to catalyze the reaction at high temperature, and a large amount of energy is consumed during the reaction process, which increases the production cost.

[0068] The embodiments of the present invention are not limited to those described in the above embodiments. Without departing from the spirit and scope of the present invention, those of ordinary skill in the art can make various changes and improvements in form and detail, and all of these are considered to fall within the protection scope of the present invention.

Claims

1. A synthetic process of propranolol, characterized in that, The synthesis process comprises the following steps: S1: React 1-naphthol with 1-bromo-3-hydroxyacetone in a solvent to form Compound 3, 1-hydroxy-3-(1-naphthyloxy)-2-propanone; S2: React Compound 3 with isopropylamine in a solvent to form Compound 2, 1-isopropylamino-3-(1-naphthyloxy)-2-propanone; S3: After the reduction reaction of Compound 2 under the action of a catalyst, Compound 1, 1-isopropylamino-3-(1-naphthyloxy)-2-propanol is formed; In step S3, the catalyst is selected from aluminum isopropoxide and isopropyl alcohol; In step S1, the solvent is selected from ethanol, ether, and an alkaline solution, and the alkaline solution is a pyridine solution or a sodium hydroxide solution; In step S2, the reaction environment is an alkaline environment, and in step S2, one of triethylamine or N,N-diisopropylethylamine is added to the alkaline environment; In step S2, the solvent is one of ethanol, ether, or water; 2. The synthesis process of propranolol according to claim 1, wherein: In step S2, the reaction temperature is 30-45°C; 3. The synthesis process of propranolol according to claim 2, wherein: After the reaction in step S2 is completed, the temperature is lowered to 0-10°C for crystallization; 4. The synthesis process of propranolol according to claim 3, characterized in that: In step S3, the reaction solvent is selected from methanol or a mixed solvent of anhydrous ethanol and dimethylformamide.

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