Novel preparation method of isoprenaline hydrochloride

Abstract

The invention discloses a novel preparation method of isoprenaline hydrochloride, which comprises the following steps: taking 2-chloro-3 ', 4'-dihydroxyacetophenone as a starting material, and carrying out epoxy protection, amination, reduction and deprotection salification to obtain the isoprenaline hydrochloride. According to the synthesis method disclosed by the invention, the hydroboron is used as a reducing agent to reduce the epoxy-protected isoproterenolone, so that a hydrogenation Pd / C reduction process with high production cost and low safety coefficient is avoided, and the isoproterenol obtained by reduction is subjected to epoxy protection, is stable under an alkaline condition, is insoluble in water and is easy to extract. The use amount of hydroboron is greatly reduced, and the safety and the pollution are small. The preparation method is simple and convenient to operate, the obtained product is high in purity, the preparation method is suitable for industrial production of isoprenaline hydrochloride raw material medicine, meanwhile, high-risk reagents such as Pd / C and benzylate are avoided, the preparation process is safe and simple, environmental pollution is small, the yield of the target product is high, and the industrial production requirement is met. And # imgabs0 #.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing isoproterenol hydrochloride. Background Art

[0002] Bronchial asthma is a common disease that seriously endangers people's health. In recent years, with the deepening of understanding of the pathogenesis of bronchial asthma, the drug treatment and research of asthma have made important progress.

[0003] Isoproterenol hydrochloride [3,4-dihydroxy-α-(isopropylaminomethyl)-benzyl alcohol hydrochloride] is a vasoactive drug and a β-receptor agonist. It is used for bronchial asthma, cardiogenic or septic shock, complete atrioventricular block, and cardiac arrest. It is currently widely used in clinical practice.

[0004] As a non-selective β-receptor agonist, the earliest dosage form of isoproterenol hydrochloride was a metered-dose aerosol, which was first approved for marketing in Canada in December 1954 and sold by Sanofi. In December 1957, isoproterenol hydrochloride aerosol was approved by PMDA for marketing in Japan; in 1981, isoproterenol hydrochloride was approved by NMPA to enter the domestic market.

[0005] According to the literature, the synthesis methods of isoproterenol can be divided into two categories based on the reduction method:

[0006] (1) Reduction with borohydride

[0007]

[0008] In the reaction of route 1, the phenolic hydroxyl group of the starting material is not protected. After the borohydride reduction, if it is quenched with water, the quenching solution is strongly alkaline, and the isoproterenol obtained by reduction becomes an organic salt and dissolves in water. If it is quenched with hydrochloric acid water, the quenching solution is acidic, and the isoproterenol obtained by reduction becomes a hydrochloride and dissolves in water. Both are difficult to extract with organic solvents, resulting in a low extraction yield in the reduction step; (2) The phenolic hydroxyl group of the starting material is not protected and is easily oxidized by the oxidant, especially under alkaline conditions, and it is more likely to deteriorate when dissolved in water, producing oxidized impurities; (3) In the hydroboration reaction, unprotected adrenoceptor has poor solubility in low-boiling point solvents such as alcohols and acetonitrile, which is not conducive to hydroboration reduction. The use of high-boiling point polar solvents such as N,N-dimethylformamide and water is not conducive to concentrated extraction, and the risk of inorganic salt residue after salt formation may be relatively large.

[0009] (2) Hydrogenation and pressure reduction using Pd / C catalyst

[0010]

[0011] In the reaction of route 2, the phenolic hydroxyl group of the starting material is not protected, and the generation of oxidative impurities cannot be ruled out. At the same time, route 2 uses Pd / C hydrogenation reduction. Although the operation is simple, it increases the risk of heavy metal pollution, increases production costs, and greatly increases production risks. Summary of the invention

[0012] Based on the technical problems existing in the background technology, the present invention proposes a method for synthesizing isoproterenol hydrochloride. The present invention avoids the use of heavy metal Pd / C reagents, performs epoxy protection on the phenolic hydroxyl group, reduces the risk of oxidation of the phenolic hydroxyl group, and improves the yield of hydroboration reduction. In addition, the process steps are short, the equipment requirements are low, the operation is simple, and the environmental pollution is small.

[0013] This novel method for synthesizing isoproterenol hydrochloride comprises the following steps:

[0014] (1) The compound of formula 1, 2-chloro-3',4'-dihydroxyacetophenone, and 2,2-dimethoxypropane are catalyzed in an organic solvent to obtain the compound of formula 2, 2-chloro-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone.

[0015] (2) The compound of formula 2, 2-chloro-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone, is subjected to amination with isopropylamine in an organic solvent to obtain the compound of formula 3, 2-isopropylamino-1-((2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone.

[0016] (3) The compound of formula 3, 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone, is reduced with borohydride in an organic solvent to obtain the compound of formula 4, 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanol.

[0017] (4) The compound of formula 4, 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanol, is deprotected by adding hydrochloric acid and salified to obtain crude isoproterenol hydrochloride.

[0018] (5) The crude adrenaline hydrochloride is purified by recrystallization with an organic solvent to obtain isoproterenol hydrochloride.

[0019] The above synthesis steps are further performed,

[0020] The organic solvent selected in step (1) is dichloromethane, toluene, 1,4-dioxane, N,N-dimethylformamide, preferably toluene, and the volume of the selected solvent is 3 times the weight of the compound of formula 1.

[0021] The catalyst used in step (1) is p-toluenesulfonic acid, acetic acid, sulfuric acid, preferably p-toluenesulfonic acid, and the amount of the selected catalyst is 3%-5% by weight of the compound of formula 1.

[0022] The reaction temperature selected in step (1) is controlled at 0-150°C, preferably the temperature for dropwise addition of 2,2-dimethoxypropane is 20-30°C, and the reaction temperature is 110-120°C.

[0023] The amount of 2,2-dimethoxypropane used in step (1) is 1-2 times the molar amount of the compound of formula 1, and preferably the amount of 2,2-dimethoxypropane used is 1.5 times the molar amount of the compound of formula 1.

[0024] The organic solvent selected in step (2) is acetonitrile, anhydrous ethanol, ethyl acetate, preferably acetonitrile, and the volume of the selected solvent is 5 times the weight of the compound of formula 2.

[0025] In step (2), the amount of isopropylamine used is 2-3 times the molar amount of the compound of formula 2, preferably 2.5 times the molar amount of the compound of formula 2.

[0026] The reaction temperature selected in step (2) is controlled at 0-100°C, preferably the temperature for adding isopropylamine is 0-10°C, and the reaction temperature is 75-80°C, the reflux temperature of acetonitrile.

[0027] The organic solvent selected in step (3) is methanol, ethanol, isopropanol, preferably ethanol, and the volume of the organic solvent is 5 times the weight of the compound of formula 3.

[0028] The borohydride selected in step (3) is sodium borohydride or potassium borohydride, preferably potassium borohydride, and the amount of the borohydride used is 0.25 times the molar amount of the compound of formula 3.

[0029] In step (3), the reaction temperature is controlled at 0-10°C when the reducing agent is added, and then the temperature is controlled at 0-30°C for reaction. Preferably, the temperature is 0-10°C when the reducing agent is added, and the reaction temperature is 20-30°C.

[0030] The reagents used in step (4) are ethanolic hydrogen chloride solution, isopropanol hydrogen chloride solution, ethyl hydrogen chloride solution and acetone hydrogen chloride solution, preferably ethanol hydrogen chloride solution, and the volume of the reagent is twice the weight of the compound of formula 4.

[0031] The organic solvent selected in step (4) is the hydrogen chloride solution according to claim 12, preferably ethanol as the solvent, and the volume of the solvent is 8 times the weight of the compound of formula 4.

[0032] In step (4), when the organic solvent hydrogen chloride solution is added dropwise, the temperature is controlled at 0-10°C, and then the temperature is controlled at 0-90°C for reaction, and the crystallization temperature is controlled at 0-10°C, preferably the dropping temperature is 0-10°C, the reaction temperature is 75-80°C, the ethanol reflux temperature, and the crystallization temperature is 0-10°C.

[0033] The organic solvent selected in step (5) is methanol, ethanol, isopropanol, preferably ethanol, and the volume of the organic solvent is 20 times the weight of the compound of formula 5.

[0034] The reflux temperature of the purification in step (5) is 50-100°C, and the crystallization temperature is controlled at 0-10°C. Preferably, the reflux temperature is 75-80°C, which is the ethanol reflux temperature, and the crystallization temperature is 0-10°C.

[0035] The invention has the advantages of: epoxy protecting the phenolic hydroxyl group in the whole reaction process to avoid oxidation, reducing the generation of oxidative impurities, avoiding the use of heavy metal reagents, reducing environmental pollution, low equipment requirements, simple operation, mild reaction conditions, short steps, low cost, and being suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is the HPLC purity analysis chart of isoproterenol hydrochloride. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is described in detail below through specific embodiments. The following description of the embodiments of the present invention by those skilled in the art based on the present disclosure is only exemplary and is not intended to limit the solution of the present invention.

[0038] Example 1

[0039] Synthesis of 2-chloro-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone

[0040] 50.00 g of 2-chloro-3',4'-dihydroxyacetophenone and 2.50 g of a catalytic amount of p-toluenesulfonic acid were added to a 500 mL three-necked flask, and then 100 mL of toluene was added and stirred to dissolve to a brown solution. A mixed solution formed by 41.86 g of 2,2-dimethoxypropane and 50 mL of toluene was slowly added dropwise to the reaction solution at 20-30° C. After the addition was completed, the temperature was raised to 110-120° C. and refluxed, and stirring was continued until the reaction was complete. A saturated sodium bicarbonate solution was added to the reaction solution to adjust the reaction system to weak alkalinity, and the reaction solution was allowed to stand for stratification. The organic layer was separated, and the organic phase was washed with a saturated sodium chloride aqueous solution and water, respectively, and then dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, concentrated, and concentrated under reduced pressure to obtain a light yellow oily liquid, which was recrystallized by adding 80% ethanol, and dried in vacuo to obtain 74.52 g of a light gray-brown solid with a yield of 81.5%.

[0041] 1 H-NMR (400Mz, CDCl3) δ: 1.710 (s, 6H); 5.004 (s, 2H); 6.828~6.848 (m, 1H); 7.358~7.402 (m, 2H);

[0042] ESI-HRMS showed molecular ion peak m / z = 227.0473 [M+H] + The corresponding molecular weight is consistent with the theoretical calculated value of the structural formula (227.0470), and the absolute error is within the error range of high-resolution mass spectrometry.

[0043] Example 2

[0044] Synthesis of 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone

[0045] 70.00 g of 2-chloro-1-((2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone was added to a 1L three-necked flask, dissolved in 350 ml of acetonitrile, and 45.64 g of isopropylamine was added at 0-10°C. After the addition was completed, the temperature was raised to 75-80°C and refluxed for 4-5 hours until the reaction was complete. After cooling to room temperature, the mixture was concentrated in vacuo to obtain a brown oily substance. Water was added and the mixture was extracted with dichloromethane. The organic phase was washed with sodium chloride solution and water, and then dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the mixture was concentrated under reduced pressure to obtain 68.45 g of a yellow oily liquid with a yield of 90.0%.

[0046] 1 H-NMR (400Mz, CDCl3) δ: 1.281~1.298 (d, 6H); 1.625 (s, 6H); 2.050 (s, 1H); 2. 495~2.512((m, 1H); 4.577(s, 2H); 6.923~6.943(m, 1H); 7.436~7.471(m, 2H);

[0047] ESI-HRMS showed molecular ion peak m / z = 250.1440 [M+H] + The corresponding molecular weight is consistent with the theoretical calculated value of the structural formula (250.1438), and the absolute error is within the error range of high-resolution mass spectrometry.

[0048] Example 3

[0049] Synthesis of 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanol

[0050] 65.00 g of 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone was added to a 1L three-necked flask, 325 ml of anhydrous ethanol was added to dissolve, 3.43 g of potassium borohydride was added in batches at 0-10°C, and the reaction was completed at room temperature for 1-2 hours. The ethanol was evaporated under reduced pressure, water was added and extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride solution and water until neutral, dried over anhydrous sodium sulfate, sodium sulfate was filtered, and vacuum concentrated to obtain 60.52 g of light yellow oily liquid with a yield of 92.4%.

[0051] 1 H-NMR(400Mz, CDCl3)δ: 1.275~1.288(d, 6H); 1.585(s, 6H); 2.150(s, 1H); 2.500~2.515((m, 1H); 4.580(s, 2H); 4.870((m, 1H); 5.890((s, 1H); 6.920~6.941(m, 1H); 7.450~7.481(m, 2H);

[0052] ESI-HRMS showed that the molecular ion peak m / z = 252.1590 [M+H] +, and the corresponding molecular weight was consistent with the theoretical calculated value of the provided structural formula (252.1594), and the absolute error was within the error range of high-resolution mass spectrometry.

[0053] Example 4

[0054] Synthesis of Isoproterenol Hydrochloride

[0055] 50.00 g of 2-isopropylamino-1-((2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanol and 400 mL of anhydrous ethanol were added to a 1L three-necked flask and stirred to form a yellow clear liquid. The system was cooled to 0-10°C and maintained at this temperature. 100 mL of HCl / ethanol solution (33% mass fraction) was added dropwise to the system. After the addition was completed, the temperature was raised to reflux and stirred for 1-2 hours, and the temperature was lowered to 0-10°C for crystallization. The filter cake was washed with 50 mL of cold anhydrous ethanol and dried in vacuo to obtain 44.50 g of crude isoproterenol hydrochloride as a white solid with a yield of 90.3%.

[0056] Add 40.00 g of crude isoproterenol hydrochloride and 800 mL of anhydrous ethanol into a 1 L three-necked flask, stir and heat to reflux to dissolve, keep warm for 0.5-1 hour, cool to 0-10°C for crystallization, filter, wash the filter cake with 80 mL of cold anhydrous ethanol, and vacuum dry to obtain 28.00 g of isoproterenol hydrochloride as a white crystalline powder with a yield of 70.0%.

[0057] 1H-NMR (400Mz, d-DMSO) δ: 1.24~1.27(m,6H); 2.88~2.94(m,2H); 3.31(m,1H); 4.83(m,1H); 5.92(d,1H) ); 6.64(dd,1H); 6.75(d,1H); 6.82(d,1H); 8.57(s,br,1H); 8.96(s,1H); 8.99(s,1H); 9.23(s,br,1H).

[0058] ESI-HRMS showed molecular ion peak m / z = 212.1275 [M+H] + The corresponding molecular weight is consistent with the theoretical calculated value of the structural formula (212.1281), and the absolute error is within the error range of high-resolution mass spectrometry.

[0059] HPLC purity is 99.86%, as Figure 1 .

[0060] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A novel method for synthesizing isoproterenol hydrochloride, comprising the following steps: (1) The compound of formula 1, 2-chloro-3',4'-dihydroxyacetophenone, and 2,2-dimethoxypropane are catalyzed in an organic solvent to obtain the compound of formula 2, 2-chloro-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone. (2) The compound of formula 2, 2-chloro-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone, is subjected to amination with isopropylamine in an organic solvent to obtain the compound of formula 3, 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone. (3) The compound of formula 3, 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanone, is reduced with borohydride in an organic solvent to obtain the compound of formula 4, 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanol. (4) The compound of formula 4, 2-isopropylamino-1-(2,2-dimethylbenzo[d][1,3]dihydroxy-5-yl)ethanol, is deprotected by adding hydrochloric acid and salified to obtain crude isoproterenol hydrochloride. (5) The crude adrenaline hydrochloride is purified by recrystallization with an organic solvent to obtain isoproterenol hydrochloride.

2. The method according to claim 1, characterized in that The organic solvent selected in step (1) is any one of dichloromethane, toluene, 1,4-dioxane, and N,N-dimethylformamide, and the volume of the selected solvent is 2-5 times the weight of the compound of formula 1.

3. The method according to claim 1-2, characterized in that: The catalyst selected in step (1) is any one of p-toluenesulfonic acid, acetic acid and sulfuric acid. The amount of the selected catalyst is 1%-10% by weight of the compound of formula 1.

4. The method according to claims 1 to 3, characterized in that: The reaction temperature selected in step (1) is controlled at 20-150°C.

5. The method according to claims 1 to 4, characterized in that The amount of 2,2-dimethoxypropane used in step (1) is 1-2 times the molar amount of the compound of formula 1.

6. The method according to claim 1, characterized in that The organic solvent selected in step (2) is any one of acetonitrile, anhydrous ethanol and ethyl acetate, and the volume of the selected solvent is 2-5 times the weight of the compound of formula 2.

7. The method according to claims 1 and 6, characterized in that In step (2), the amount of isopropylamine used is 2-3 times the molar amount of the compound of formula 2.

8. The method according to claims 1 and 6-7, characterized in that The reaction temperature selected in step (2) is controlled at 0-100°C.

9. The method according to claim 1, characterized in that The organic solvent selected in step (3) is any one of methanol, ethanol and isopropanol. The volume of the organic solvent is 2-5 times the weight of the compound of formula 3.

10. The method according to claims 1 and 9, characterized in that The borohydride selected in step (3) is any one of sodium borohydride and potassium borohydride, and the amount of the borohydride used is 0.25-0.5 times the molar amount of the compound of formula 3.

11. The method according to claims 1 and 9-10, characterized in that In step (3), the reaction temperature is controlled at 0-10°C when the reducing agent is added, and then the reaction temperature is controlled at 0-30°C.

12. The method according to claim 1, characterized in that The reagent selected in step (4) is any one of hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, hydrogen chloride ethyl acetate solution and hydrogen chloride acetone solution, and the volume of the reagent is 1-2 times the weight of the compound of formula 4.

13. The method according to claims 1 and 12, characterized in that The organic solvent selected in step (4) is any one of the hydrogen chloride solutions described in claim 12, and the volume of the solvent is 5-8 times the weight of the compound of formula 4.

14. The method according to claims 1 and 12-13, characterized in that In step (4), when the hydrogen chloride solution of the organic solvent is added dropwise, the temperature is controlled at 0-10°C, and then the temperature is controlled at 0-90°C for reaction, and the crystallization temperature is controlled at 0-10°C.

15. The method according to claim 1, wherein: The organic solvent selected in step (5) is any one of methanol, ethanol and isopropanol. The volume of the organic solvent is 10-20 times the weight of the compound of formula 5.

16. The method according to claims 1 and 15, characterized in that The reflux temperature of the refining in step (5) is 50-100°C, and the crystallization temperature is controlled at 0-10°C.

Images