A process for the preparation of a salt of levalbuterol

Abstract

The application discloses a preparation method of a levosalbutamol salt, relates to the field of drug synthesis, and comprises the following steps: after an intermediate N-benzyl salbutamol derivative is reacted with optically pure D-(+)-dibenzoyl tartaric acid in an organic solution to form a salt, cooling and crystallization are carried out, suction filtration is carried out, vacuum drying is carried out to obtain R-configuration N-benzyl salbutamol derivative D-(+)-dibenzoyl tartaric acid salt, and then catalytic hydrogenation and debenzylization are carried out to obtain levosalbutamol D-(+)-dibenzoyl tartaric acid salt; the levosalbutamol D-(+)-dibenzoyl tartaric acid salt is added into a salt conversion solvent, and acid is added to obtain the levosalbutamol salt. The overall production process of the levosalbutamol salt is high in stability, simple in synthesis route, can effectively reduce impurities, improve purity, and stably produce high-purity levosalbutamol meeting the requirements of inhalation preparations.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing levosabutyrate. Background Technology

[0002] L-salbutamol (R-salbutamol), chemically named (R)-4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol, is a long-acting β2-adrenergic receptor agonist with a prolonged duration of action, producing bronchodilatory effects for at least 6 hours. It has a rapid onset of action, taking effect 1–5 minutes after inhalation as an aerosol. It is used to prevent and treat bronchospasm in patients with bronchial asthma, asthmatic bronchitis, and emphysema. The chemical structure of salbutamol contains a secondary alcohol with a chiral carbon atom, and it exists in two isomers: R and S configurations. Pharmacological studies have shown that R-salbutamol has higher selectivity for β2-receptors than the S-form, and the S-form contains toxic side effects.

[0003]

[0004] The main synthetic methods for levosalbutanol reported in the literature are as follows:

[0005] 1. Racemic Resolution Method. Based on the traditional resolution technique, Chen Yang et al. improved the resolution method. Salbutamol was first acetalized in acetone to obtain 2-tert-butylamino-1-(2,2-dimethyl-4-benzo[1,3]dioxane-6-yl)ethanol, which protected its phenolic hydroxyl group. Then, it was resolved by D-(+)-dibenzoyl tartaric acid, and after alkali release, it was deprotected by hydrochloric acid and formed into salt to obtain levosabutamol hydrochloride. (Reference: Chen Yang, Liu Xiangkui, Zhang Xiaomin, et al. Preparation of levosabutamol hydrochloride [J]. China Pharmaceutical Industry Magazine, 2006, 37(6):376-377.) The disadvantage of this route is that the hydroxyl group is protected by acetone fork. This structure is sensitive to acid and temperature and is unstable. The etherification of the unprotected hydroxymethyl group under acidic conditions and the easy oxidation of the phenolic hydroxyl group make it difficult to control impurities.

[0006]

[0007] 2. Metal-catalyzed asymmetric synthesis. He Wei et al. successfully synthesized levosabutanol using a relatively simple method. Using salicylaldehyde and bromoacetyl chloride as raw materials, 5-[[(1,1-dimethylethyl)amino]acetyl]-2-hydroxybenzaldehyde hydrochloride was synthesized via Friedel-Crafts acylation and substitution reactions. Then, levosabutanol was obtained by a synergistic reduction reaction catalyzed by a chiral rhodium complex-catalyzed asymmetric hydrogen transfer reaction. Finally, levosabutanol hydrochloride was obtained by salt formation with hydrochloric acid. (Reference: He Wei, Li Xiaoye, Liu Peng, et al. Synthesis of levosabutanol hydrochloride [J]. Chinese Journal of Pharmaceutical Chemistry, 2006, 16(4):222-225.) The catalyst for this route is expensive and the process stability is poor, making it unsuitable for industrialization.

[0008]

[0009] 3. Cheng Qingfang et al. used a self-made chiral borneol-β-diketone iron complex as a catalyst to catalyze the asymmetric epoxidation of the starting material 3-acetoxymethyl-4-acetoxystyrene, obtaining (R)-3-acetoxymethyl-4-acetoxyphenyl ethylene oxide. The epoxide then underwent a ring-opening reaction with tert-butylamine, followed by salt formation with hydrochloric acid to obtain (R)-salbutamol hydrochloride. Although the catalyst is an iron complex, and although it is cheaper than other metal complexes, the raw material is not cheap and is not commonly found. (Reference: Cheng QF, Wang QF, Xu XY, et al. Enantioselective Synthesis of (R)-Salbutamol Hydrochloride. Organic Chemistry 2007, 27(12):1558-1561.)

[0010]

[0011] 4. Substrate-controlled asymmetric synthesis. Hong Yaping et al. successfully synthesized levosabutanol via enantioselective reduction using oxazaborane (oxazaborane) as a catalyst and borane as a stoichiometric reducing agent. (Reference: Hong YP, Gao Y, Nie XY, et al. Asymmetric reduction of α-ketoimines with oxazaborolidine catalysts: A novel practical approach to chiralarylethanolamines[J]. Tetrahedron Lett, 1994, 35(31): 5551-5554.) The borane dimethyl sulfide used in this route is a highly toxic compound, limiting its application, and the chiral catalyst is expensive.

[0012]

[0013] 5. Hydrolysis Kinetic Resolution. Shen Kaisheng et al. used p-hydroxybenzaldehyde as the starting material, and prepared an epoxy by chloromethylation, acetylation, and then using a sulfur ylide reagent. The resulting chiral epoxide was then obtained by hydrolysis kinetic resolution, and finally ring-opened with tert-butylamine, followed by acid hydrolysis to obtain levosabutanol hydrochloride. This route obtains chiral compounds through optical resolution, but the atom economy is poor and the production cost is high. (Reference: Shen Kaisheng, Xiong Fei, Hu Juan, et al. Application of chiral (Salen)Co-catalyzed hydrolysis kinetic resolution reaction of terminal epoxides in the synthesis of chiral drugs [J]. Organic Chemistry. 2003, 23(6): 542-545.)

[0014] Summary of the Invention

[0015] Existing methods for preparing L-salbutamol salts suffer from complex production processes, difficulty in controlling impurities, and poor process stability. To address these issues, this invention provides a method for preparing L-salbutamol salts, specifically comprising the following steps:

[0016] A method for preparing L-salbutamol salt includes the following steps:

[0017] The intermediate N-benzylsalbutamol derivative reacted with optically pure D-(+)-dibenzoyl tartrate in an organic solution to form a salt. After cooling and crystallization, the solution was filtered and dried under vacuum to obtain the R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartrate.

[0018] The structural formula of the intermediate N-benzylsalbutamol derivative is shown below:

[0019]

[0020] Preferably, a method for preparing L-salbutamol salt specifically includes the following steps:

[0021] (1) The intermediate N-benzylsalbutamol derivative reacted with optically pure D-(+)-dibenzoyl tartaric acid in an organic solution to form a salt. After cooling and crystallization, the solution was filtered and dried under vacuum to obtain the R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartaric acid salt.

[0022] (2) The R-configuration N-benzyl salbutamol derivative D-(+)-dibenzoyl tartrate was debenzylated by catalytic hydrogenation to obtain L-salbutamol D-(+)-dibenzoyl tartrate;

[0023] (3) Add L-salbutamol D-(+)-dibenzoyl tartrate to the salt conversion solvent, add acid to obtain L-salbutamol salt, filter, and vacuum dry to obtain high-purity L-salbutamol salt.

[0024] In step (1), the specific operation is to add the N-benzylsalbutamol derivative to the solvent, heat and stir to dissolve, and then add D-DBTA to the reaction system in two batches under ice bath conditions.

[0025] This invention selects the intermediate N-benzylsalbutamol derivative (ZS-D) as the starting reactant, and uses benzyl to protect the two hydroxyl and amino groups on the compound structure. After chiral resolution, the benzyl group is removed simultaneously, which reduces the occurrence of side reactions during the chiral resolution reaction and improves the purity of the product.

[0026] Preferably, the cooling crystallization temperature in step (1) is 0-20°C, and the vacuum drying temperature does not exceed 25°C.

[0027] The organic solution in step (1) is methanol or a mixture of methanol and water, wherein the ratio of methanol to water is methanol:water (v / v) = 1:2 to 5:1.

[0028] In step (2), the catalyst used for catalytic hydrogenation is Pd / C, and the amount of catalyst used is 10% of the weight of N-benzylsalbutamol DBTA salt.

[0029] Preferably, the catalytic hydrogenation debenzylation reaction in step (2) is carried out in the solvent methanol or ethanol, and the amount of solvent used is 2 to 20 times (v / m) the weight of N-benzylsalbutamol D-(+)-dibenzoyl tartrate.

[0030] Step (1) also includes recrystallizing the obtained R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartrate to improve its purity. Methanol or a mixture of methanol and water is used as the recrystallization solvent, wherein the ratio of methanol to water (v / v) is 1:2 to 5:1, the recrystallization drying temperature does not exceed 25°C, and the amount of recrystallization solvent used is 2 to 20 times (v / m) the weight of R-configuration N-benzylsalbutamol D-(+)-dibenzoyl tartrate.

[0031] Preferably, the salt transfer solvent in step (3) is ethyl acetate or acetone, and the amount used is 5 to 20 times (v / m) the weight of L-salbutamol D-(+)-dibenzoyl tartaric acid.

[0032] Preferably, the vacuum drying temperature in step (3) does not exceed 25°C.

[0033] Preferably, the acid used for salt conversion in step (3) is hydrochloric acid, and the L-salbutamol salt is L-salbutamol hydrochloride. The amount of hydrochloric acid used is hydrochloric acid: L-salbutamol D-(+)-dibenzoyl tartaric acid = 1.5:1 to 1:1 (molar ratio).

[0034] The overall synthetic route for salbutamol hydrochloride is shown below:

[0035]

[0036] The present invention has the following beneficial effects:

[0037] (1) The overall production process of the L-salbutamol salt of the present invention has high stability and simple synthesis route. It can effectively reduce impurities, improve purity, and stably produce high-purity L-salbutamol that meets the pharmaceutical requirements of inhaled preparations.

[0038] (2) This invention uses the intermediate N-benzylsalbutamol derivative (ZS-D) as the starting reactant. Simultaneously, benzyl groups are used to protect the two hydroxyl and amino groups on the compound structure. After chiral resolution, the benzyl groups are removed simultaneously, reducing side reactions during the chiral resolution reaction and improving product purity. Compared with the prior art using acetone to cross-protect the hydroxyl groups, using benzyl groups as the protecting group results in a more stable structure, avoiding the influence of acid and temperature changes on the hydroxyl groups during the reaction, and ultimately obtaining a target product with high purity and few impurities.

[0039] (3) The overall route of this invention effectively controls the reaction and reduces the occurrence of side reactions through the high selectivity of solvent and temperature. At the same time, the purity of the intermediate product is improved by recrystallizing the intermediate product R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartrate, reducing the impurities generated in the intermediate reaction and further improving the purity of the final product. Attached Figure Description

[0040] Figure 1 This is a spectral diagram showing the system suitability of levosabutanol hydrochloride related substances.

[0041] Figure 2 The liquid chromatogram of L-salbutamol hydrochloride prepared in Example 5 is shown. Specific Implementation

[0042] To make the technical problems solved by the present invention and its beneficial effects clearer, the present invention will be further described in detail below with reference to embodiments.

[0043] Example 1: Chiral resolution of N-benzylsalbutamol

[0044] N-benzylsalbutamol derivative (ZS-D) (33g) and methanol (130ml) were added to the reaction flask. Stirring was started, and the temperature was raised to 40℃. A yellow transparent solution was obtained after dissolution. D-DBTA (18g + 18g) was added to the reaction system in two separate additions under ice bath conditions. During the process, exothermic temperature rise was observed, and a light yellow transparent solution was obtained. The mixture was stirred at 10-30℃ for 1h, and a viscous solid precipitated. After cooling to 0-5℃, the mixture gradually became viscous, and a white solid precipitated. The mixture was stirred for 3h to crystallize. The solid was filtered, washed with ice-cold methanol (10ml*2), dried under vacuum at 25℃, and 60g of solid was obtained. The S-isomer content was found to be 4.6%.

[0045] The above solid (60g) was added to a reaction flask, followed by methanol (300ml). The mixture was stirred and heated to 45℃ to dissolve the solid. The reaction was maintained at this temperature for 15 minutes until the solid dissolved. The mixture was then cooled to room temperature (10-30℃) and maintained at this temperature for 30 minutes to allow crystallization. The mixture was then slowly cooled to -5 to -10℃ and stirred to allow crystallization for 2 hours. The solid was filtered, washed with 10ml of ice-cold methanol and 2 x 16ml of ethyl acetate, dried under vacuum at 25℃, and yielded 54.8g of an off-white solid with a purity of 99.8% and an enantiomeric property of 0.07%.

[0046] Example 2: Chiral resolution of N-benzylsalbutamol

[0047] N-benzylsalbutamol derivative (ZS-D) (66g), methanol (180ml), and water (360ml) were added to the reaction flask. Stirring was started, and the temperature was raised to 65℃. A yellow transparent solution was obtained by dissolving the substance. D-DBTA (38.6g + 38.6g) was added to the reaction system in two batches. During the process, an exothermic temperature rise was observed, and a light yellow transparent solution was obtained. The temperature was lowered, and the mixture was stirred at 10-20℃ for 1 hour, during which a solid precipitated. The mixture was cooled to 5℃, and stirred to crystallize for 1 hour. The solid was filtered, washed with ice-cold methanol / water (1:1) (20ml*2), dried under vacuum at 25℃ (using P2O5 as a desiccant), and 130.5g of solid was obtained. The S-isomer content was found to be 3.8%.

[0048] The above solid (130g) was added to a reaction flask, along with methanol (650ml) and water (650ml). The mixture was heated to 55℃ to dissolve, and the reaction was maintained at this temperature for 15 minutes. The solid dissolved, and the mixture was cooled to room temperature (10-30℃) to allow crystallization. The mixture was then kept at this temperature for 30 minutes to allow crystallization, followed by slow cooling to 5℃ and stirring to allow crystallization for 1 hour. The mixture was filtered, and the solid was washed with ice-cold methanol / water (1:1) (30ml*2) and ethyl acetate (25ml*2). The mixture was dried under vacuum, and the enantiomer content was found to be 0.08%. The solid was dried under vacuum below 25℃ to constant weight, yielding 118.8g of an off-white solid.

[0049] Example 3: Synthesis of L-salbutamol DBTA Salt

[0050] The separated N-benzylsalbutamol derivative DBTA salt (ZS-E) (30 g) was dissolved in 180 L of ethanol, and 10% Pd / C (2 g) was added. The air was purged with hydrogen five times, and the mixture was stirred and heated to 40–45 °C until the benzyl group was removed. After the reaction was complete, Pd / C was recovered by filtration. The filtrate was concentrated under reduced pressure until solids began to precipitate, at which point distillation was stopped, and 300 mL of ethyl acetate was added to dissolve the solids. The mixture was stirred at 0–10 °C for 1 h to crystallize.

[0051] The solid was filtered, washed with a small amount of ethyl acetate, and dried under vacuum at 25°C to obtain 25.5 g of L-salbutamol DBTA salt with a purity of 99.7% and 0.06% isomers.

[0052] Example 4: Synthesis of L-salbutamol DBTA Salt

[0053] The separated N-benzylsalbutamol derivative DBTA salt (ZS-E) (50g) was dissolved in 250ml of methanol, and 10% Pd / C (3g) was added. The air was purged with hydrogen five times, and the mixture was stirred and heated to 30-35℃ until the benzyl group was removed. After the reaction was complete, Pd / C was recovered by filtration. The filtrate was concentrated under reduced pressure until solid began to precipitate, at which point distillation was stopped, and the solution was dissolved in 450ml of ethyl acetate. Crystallization was carried out at 0-10℃ for 1 hour.

[0054] The solid was filtered, washed with a small amount of ethyl acetate, and dried under vacuum at 25°C to obtain 42.6 g of L-salbutamol DBTA salt with a purity of 99.6% and 0.05% isomers.

[0055] Example 5: Synthesis of L-salbutamol Hydrochloride

[0056] Add 170g of L-salbutamol-DBTA and 1.7L of acetone to the reaction flask, start stirring, control the temperature at -10 to -5℃, and slowly add 37.5ml of concentrated hydrochloric acid. After the addition is complete, keep the reaction at this temperature for 1 hour. Filter the solid, rinse the filter cake with 100ml of ice-cold acetone, dry it under vacuum below 35℃, and obtain 70g of L-salbutamol hydrochloride with a purity of 99.9% and 0.03% isomers.

[0057] Example 6: Synthesis of L-salbutamol Hydrochloride

[0058] Add 100g of L-salbutamol-DBTA and 2.0L of ethyl acetate to the reaction flask, start stirring, control the temperature at -15 to -10℃, and slowly add 14.6ml of concentrated hydrochloric acid. After the addition is complete, keep the reaction at this temperature for 1 hour. Filter the solid, wash the filter cake with 100ml of ethyl acetate, dry it under vacuum below 25℃, and obtain 40g of L-salbutamol hydrochloride with a purity of 99.8% and 0.05% isomers.

[0059] The levosalbutanol hydrochloride prepared by the above method was subjected to related substance testing. The related substance testing method for levosalbutanol hydrochloride is derived from the Related Substances section of the United States Pharmacopeia (USP) 43:

[0060] Method source: USP43 Related Substances section

[0061] Chromatographic column: Octadecylsilane-bonded silica gel as the packing material (Phenomenex AQUA C18 (4.6*150mm, 5μm) is recommended);

[0062] Mobile phase A: 0.1% phosphoric acid solution;

[0063] Mobile phase B: Acetonitrile-methanol-water-phosphoric acid (35:35:30:0.1)

[0064] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 30 70 30 50 28 72 50.01 0 100 55 0 100 55.01 100 0 70 100 0

[0065] Flow rate: 1.0 ml / min; column temperature: 45℃; wavelength: 220 nm; injection volume: 50 μl.

[0066] Table 1 shows the structures of common impurities in L-salbutamol hydrochloride.

[0067]

[0068]

[0069] Take appropriate amounts of standard levosalbutanol hydrochloride and impurity AI from Table 1 to prepare reference solutions. Detect the impurities using the detection conditions under the Related Substances section of USP 43. Obtain the related substances system suitability chromatogram for levosalbutanol hydrochloride. Figure 1 As shown. The levosalbutanol hydrochloride prepared in Example 5 of this invention was subjected to related substance detection under the above-described detection conditions, and the results are as follows. Figure 2 As shown, by Figure 2 Time (min) Mobile phase A (%) Mobile phase B (%) Figure 1 Figure 2 Figure 2 Time (min) Mobile phase It can be seen that the related substances in the L-salbutamol hydrochloride obtained by the present invention are significantly reduced, indicating that the production process of the present invention effectively controls impurities and the L-salbutamol hydrochloride obtained has high purity.

[0070] Three batches of levosalbutanol hydrochloride were produced using the method of this invention, namely batches 20503, 200601, and 200602. The test data of the three batches of levosalbutanol hydrochloride are summarized in Table 2 below:

[0071] Table 2: Summary Table of Multiple Batch Detection Data for Levosalbutamol Hydrochloride

[0072]

[0073]

[0074] As can be seen from Table 2, when the production process of the present invention is carried out in batch production, the overall production process is highly stable, the impurity content can be effectively controlled, and high-purity levsalbutamol that meets the pharmaceutical requirements of inhaled preparations can be stably produced.

Claims

1. A method for preparing L-salbutamol salt, characterized in that, Includes the following steps: (1) The intermediate N-benzylsalbutamol derivative reacts with optically pure D-(+)-dibenzoyl tartaric acid in an organic solution to form a salt. After cooling and crystallization, the salt is filtered and dried under vacuum to obtain the R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartaric acid salt. (2) The R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartrate was debenzylated by catalytic hydrogenation to obtain L-salbutamol D-(+)-dibenzoyl tartrate; (3) Add L-salbutamol D-(+)-dibenzoyl tartrate to the salt conversion solvent, add acid to obtain L-salbutamol salt, filter, and vacuum dry to obtain high-purity L-salbutamol salt. The structural formula of the intermediate N-benzylsalbutamol derivative is shown below: 。 2. The method for preparing L-salbutamol salt according to claim 1, characterized in that, The specific operation in step (1) is to add the N-benzylsalbutamol derivative to the solvent, heat and stir to dissolve, and then add optically pure D-(+)-dibenzoyl tartaric acid to the reaction system in two batches under ice bath conditions.

3. The method for preparing L-salbutamol salt according to claim 1, characterized in that, The catalyst used for catalytic hydrogenation in step (2) is Pd / C, and the amount of the catalyst is 10% of the weight of the R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyltartrate.

4. The method for preparing L-salbutamol salt according to claim 1, characterized in that, The step (2) catalytic hydrogenation debenzylation reaction is carried out in the solvent methanol or ethanol, and the amount of solvent used is 2 to 20 times the weight of the R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartrate, based on the bulk mass ratio v / m.

5. The method for preparing L-salbutamol salt according to claim 1, characterized in that, In the preparation method of the L-salbutamol salt, the vacuum drying temperature does not exceed 25℃.

6. The method for preparing L-salbutamol salt according to claim 1, characterized in that, Step (1) further includes a recrystallization operation of the R-configuration N-benzylsalbutamol derivative D-(+)-dibenzoyl tartrate.

7. The method for preparing L-salbutamol salt according to claim 1, characterized in that, In step (1), the organic solution or recrystallization solvent is methanol or a mixture of methanol and water, wherein the ratio of methanol to water is methanol:water = 1:2~5:1, expressed as a volume ratio v / v.

8. The method for preparing L-salbutamol salt according to claim 1, characterized in that, In step (3), the salt solvent is ethyl acetate or acetone, and the amount used is 5 to 20 times (v / m) the weight of L-salbutamol D-(+)-dibenzoyl tartaric acid.

9. The method for preparing L-salbutamol salt according to any one of claims 1-8, characterized in that, The acid in step (3) is hydrochloric acid, and the L-salbutamol salt is L-salbutamol hydrochloride.

10. The method for preparing L-salbutamol salt according to claim 9, wherein the molar ratio of hydrochloric acid to L-salbutamol D-(+)-dibenzoyl tartrate is 1.5:1 to 1:1.

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