Method for preparing S-isomer of montelukast sodium

Abstract

The invention discloses a method for preparing an S-isomer of montelukast sodium, which belongs to the technical field of chemical raw material medicines, and is characterized by comprising the following steps: dissolving a starting material montelukast sodium mother nucleus in an organic solvent, and carrying out configuration inversion under the action of an initiator and the catalysis of a composite catalyst to generate the S-isomer of the montelukast sodium mother nucleus; and adding 1-mercaptomethyl cyclopropyl acetic acid, reacting under the catalysis of a catalyst, filtering, cooling, growing crystal, carrying out suction filtration and drying to obtain the montelukast S-isomer. The preparation method has the beneficial effects that azodiisobutyronitrile is creatively used as an initiator, and under the catalysis of a composite catalyst tributylphosphine and m-chlorobenzoic acid, a montelukast mother nucleus is subjected to an isomerization reaction to obtain a montelukast mother nucleus S-isomer; and reacting with 1-mercaptomethyl cyclopropyl acetic acid under the catalysis of H < + >-montmorillonite to obtain the S-isomer of montelukast sodium.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical raw material technology, and more specifically relates to a method for preparing the S-isomer of montelukast sodium. Background Technology

[0002] Montelukast sodium (trade name: Singular) is a potent leukotriene receptor antagonist developed by Merck. It selectively binds to leukotriene receptors in the respiratory tract, blocking the action of allergy mediators, improving respiratory inflammation, and clearing the airways. It was first launched in Finland and Mexico in February 1998, followed by the UK and US in April and October of the same year, respectively, and entered the Chinese market in 2002. According to the 2008 edition of my country's "Guidelines for the Prevention and Treatment of Bronchial Asthma," leukotriene modifiers are the only long-term control medication that, besides inhaled corticosteroids, can be used alone. They can be used as an alternative treatment for mild asthma and as a combination therapy for moderate to severe asthma.

[0003] Its structural formula is as follows:

[0004] The National Pharmacopoeia clearly describes the properties and identification methods of montelukast sodium, and specifies in detail the detection methods for related substances, the S-isomer, and residual solvents. Among these, the S-isomer, as an enantiomer of montelukast sodium, may exist in the drug as a process impurity. The Pharmacopoeia explicitly requires the use of high-performance liquid chromatography (HPLC), calculated by peak area using the external standard method, to ensure that the content of the S-isomer does not exceed 0.2%, and the resolution between the S-isomer peak and the montelukast peak should be greater than 4.0. The structural formula of the S-isomer is:

[0005] According to the requirements of the Chinese Pharmacopoeia, accurate determination of the S-isomer content by high-performance liquid chromatography-external standard method requires the use of high-purity S-isomer standards with known and accurate dosage. However, there are currently no literature reports on the preparation method of montelukast sodium enantiomers. Therefore, there is an urgent need to establish a method for preparing high-purity S-isomers to meet the requirements of the Chinese and US Pharmacopoes for the detection of this impurity.

[0006] However, since montelukast and its S-isomer are enantiomers in structure, their preparation is difficult, and they may undergo isomerization under certain conditions, making it impossible to obtain stable high-purity S-isomer standards, thus making it difficult to meet the detection requirements of external standard method for quantitative analysis of impurities. Summary of the Invention

[0007] To address the aforementioned problems and overcome the shortcomings of existing technologies, this invention provides a method for preparing the S-isomer of montelukast sodium. This method effectively solves the problems that montelukast and its S-isomer are enantiomers in structure, making preparation difficult, and that the two may undergo isomerization under specific conditions, resulting in the inability to obtain stable, high-purity S-isomer standards, thus failing to meet the detection requirements of external standard methods for quantitative analysis of impurities.

[0008] The specific technical solution of the present invention to solve the above-mentioned technical problems is as follows: a method for the S-isomer of montelukast sodium, characterized by comprising the following steps: (1) The starting material sodium montelukast is dissolved in an organic solvent. Under the action of an initiator and the catalysis of a composite catalyst, a configuration inversion occurs to generate the sodium montelukast S-isomer. (2) Add 1-mercaptomethylcyclopropylacetic acid and react under the catalysis of a catalyst. After filtration and extraction, an organic phase solution of the montelukast acid isomer is obtained. (3) Add 30% sodium methoxide solution dropwise to the above organic phase solution, and obtain montelukast sodium S-isomer by filtration, cooling, crystal growth, vacuum filtration and drying.

[0009] Furthermore, the initiator is azobisisobutyronitrile.

[0010] Furthermore, the composite catalyst is a mixture of tributylphosphine and m-chlorobenzoic acid.

[0011] Furthermore, the catalyst is H+-montmorillonite.

[0012] Furthermore, in step (1): The organic solvent is toluene, acetonitrile, xylene, or a mixture of two or more of these. The mass ratio of the sodium montelukast core to the organic solvent is 1:8~12; The mass ratio of montelukast sodium core: azobisisobutyronitrile: tributylphosphine: m-chlorobenzoic acid is 1:0.04~0.06:0.05~0.07:0.04~0.06; The reaction temperature is controlled at -15 to -25℃.

[0013] Furthermore, in step (2): The mass ratio of the montelukast sodium core to 1-mercaptomethylcyclopropylacetic acid is 1:0.3~0.35; The mass ratio of the sodium montelukast core to the catalyst is 1:0.25~0.45; The reaction temperature is controlled at 55~65℃, and the reaction time is 5~10h.

[0014] Furthermore, in step (2): Filter, wash with toluene, add purified water to the toluene phase mother liquor obtained by vacuum filtration, extract at a controlled temperature of 20~30℃, add anhydrous sodium sulfate to dry, and filter to obtain an organic phase solution of montelukast acid S-isomer; the mass ratio of the montelukast sodium core to water is 1:5~8.

[0015] Furthermore, in step (3): The mass ratio of montelukast sodium core to 30% sodium methoxide solution is 1:0.25~0.30; the reaction temperature is controlled at 45~55℃; and the crystal growth temperature is -15~-25℃.

[0016] The beneficial effects of this invention are: This invention creatively uses azobisisobutyronitrile as an initiator to conduct a montelukast sodium nucleus isomerization reaction under the catalysis of the composite catalysts tributylphosphine and m-chlorobenzoic acid to obtain the montelukast sodium nucleus S-isomer, and then reacts with 1-mercaptomethylcyclopropylacetic acid under H+-montmorillonite catalysis to obtain the montelukast sodium S-isomer. This invention creatively uses azobisisobutyronitrile (AIBN) as an initiator to catalyze the isomerization reaction of montelukast sodium nucleus to obtain the montelukast sodium S-isomer under the catalysis of the composite catalysts tributylphosphine and m-chlorobenzoic acid. The applicant unexpectedly discovered that the composite catalyst of tributylphosphine and m-chlorobenzoic acid, compared with a single catalyst, can avoid the isomerization conversion of montelukast sodium, thus solving the problem of two peaks appearing in the product, namely montelukast sodium and montelukast sodium S-isomer, making it impossible to obtain a stable high-purity S-isomer standard, and thus making it difficult to meet the detection requirements of external standard method for quantitative analysis of impurities. Attached Figure Description

[0017] Appendix Figure 1 This is the high-performance liquid chromatography detection chromatogram of Example 1 of the present invention; Appendix Figure 2 This is the high-performance liquid chromatography detection chromatogram of Example 2 of the present invention; Appendix Figure 3 This is the high-performance liquid chromatography detection chromatogram of Example 3 of the present invention; Appendix Figure 4 This is the high performance liquid chromatography detection chromatogram of Comparative Example 1 of the present invention; Appendix Figure 5 This is the high performance liquid chromatography detection chromatogram of Comparative Example 2 of the present invention; Appendix Figure 6 This is the high performance liquid chromatography detection chromatogram of Comparative Example 3 of the present invention; Appendix Figure 7 This is the high performance liquid chromatography detection chromatogram of Comparative Example 4 of the present invention; Detailed Implementation Specific details in the description of this invention are merely to provide a thorough understanding of the embodiments thereof; however, those skilled in the art should understand that the implementation of this invention is not limited to these details. Furthermore, well-known structures and functions have not been described or shown in detail to avoid obscuring the key points of the embodiments of this invention. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0018] Specific embodiments of the present invention: To better understand the present invention, specific embodiments are described. It is worth emphasizing that the effects of these embodiments are not substantially different from those of various embodiments within the scope of protection of the present invention, including their respective reagents and reagent content ratios. All of them can achieve the effects described in the present invention and solve the above-mentioned problems. Other combinations are not described here. Example 1: 45.8 g (0.1 mol) of montelukast sodium core was placed in a three-necked flask. Using 500 ml of toluene as the reaction solvent, the mixture was cooled to -15 to -25 °C, and 2.0 g (12 mmol) of AIBN, 2.6 g (13 mmol) of tributylphosphine, and 2.2 g (14 mmol) of m-chlorobenzoic acid were added under stirring. After reacting for approximately 12 h, 15.0 g of 1-mercaptomethylcyclopropylacetic acid and 13.5 g of H+-montmorillonite catalyst were added sequentially. The temperature was raised to 55-65 °C, and the reaction was timed for approximately 8 h. After the reaction was complete, the mixture was filtered and washed with toluene. The mixture was cooled to 20-30 °C, and 350 ml of water was added to the filtrate. After stirring for approximately 10 min, the mixture separated into layers. The aqueous phase was discarded, and the organic phase was collected. Anhydrous sodium sulfate was added and dried for approximately 30 min. The filtrate was then filtered to obtain the mother liquor, which was directly added to the next reaction step.

[0019] Controlling the system temperature at 45-55℃, 12.4g of 30% sodium methoxide solution was added dropwise to the above-mentioned filtrate mother liquor, with the addition completed after approximately 1 hour. The reaction was stirred for about 0.5 hours. After the reaction was complete, the mixture was filtered and washed with 20ml of toluene. The filtrate was slowly cooled to -15 to -25℃, and crystallization was carried out with stirring for about 12 hours. After filtration, the mixture was washed with n-heptane and dried to obtain the montelukast sodium S-isomer with a purity of 98.37%.

[0020] Example 2: 22.9 g (50 mmol) of montelukast sodium core was placed in a three-necked flask. Using 300 ml xylene as the reaction solvent, the mixture was cooled to -15 to -25 °C, and under stirring, 1.0 g AIBN (6 mmol), 1.3 g tributylphosphine (6.5 mmol), and 1.1 g (7 mmol) m-chlorobenzoic acid were added. After reacting for approximately 12 h, 7.5 g of 1-mercaptomethylcyclopropylacetic acid and 7.0 g of H+-montmorillonite catalyst were added sequentially, followed by 4.5 g of 1-mercaptomethylcyclopropylacetic acid. The temperature was raised to 55–65 °C, and the reaction was timed for approximately 8 h. After the reaction was complete, the mixture was filtered and washed with xylene. The temperature was lowered to 20–30 °C, and 100 ml of water was added to the filtrate. After stirring for approximately 10 min, the mixture separated into layers. The aqueous phase was discarded, and the organic phase was collected. Anhydrous sodium sulfate was added and dried for approximately 30 min. The filtrate was then filtered and used directly in the next reaction step.

[0021] Controlling the system temperature at 45-55℃, 4.2g of 30% sodium methoxide solution was added dropwise to the above-mentioned filtrate mother liquor, with the addition completed after approximately 1 hour. The reaction was stirred for approximately 0.5 hours. After the reaction was complete, the mixture was filtered and washed with 10ml of xylene. The filtrate was slowly cooled to -15 to -25℃, and crystallization was carried out with stirring for approximately 12 hours. After filtration, the mixture was washed with n-heptane and dried to obtain the montelukast sodium S-isomer with a purity of 99.06%.

[0022] Example 3: 34.4 g (75 mmol) of montelukast sodium core was placed in a three-necked flask. Using 500 mL of acetonitrile as the reaction solvent, the mixture was cooled to -15 to -25 °C. Under stirring, 1.5 g of AIBN (9 mmol), 2.0 g of tributylphosphine (9.8 mmol), and 1.7 g (10.5 mmol) of m-chlorobenzoic acid were added. After reacting for approximately 12 h, 11.3 g of 1-mercaptomethylcyclopropylacetic acid and 10.5 g of H+-montmorillonite catalyst were added sequentially. 6.8 g of 1-mercaptomethylcyclopropylacetic acid was then added, and the temperature was raised to 55–65 °C. The reaction was timed for approximately 8 h. After the reaction was complete, the mixture was filtered and washed with acetonitrile. The temperature was lowered to 20–30 °C, and 700 mL of water was added to the filtrate. After stirring for approximately 10 min, the mixture separated into layers. The aqueous phase was discarded, and the organic phase was collected. Anhydrous sodium sulfate was added and dried for approximately 30 min. The filtrate was then filtered and used directly in the next reaction step.

[0023] Controlling the system temperature at 45-55℃, 6.3g of 30% sodium methoxide solution was added dropwise to the above-mentioned filtrate mother liquor, with the addition ending after approximately 1 hour. The reaction was stirred for about 0.5 hours. After the reaction was complete, the mixture was filtered and washed with 20ml of acetonitrile. The filtrate was slowly cooled to -15 to -25℃, and crystallization was carried out with stirring for about 12 hours. After filtration, the mixture was washed with n-heptane and dried to obtain the montelukast sodium S-isomer with a purity of 99.68%.

[0024] To more intuitively demonstrate the technological advantages of this invention, a comparison is made between the method used in this invention to prepare the S-isomer of montelukast sodium and a method using equivalent substitution in the same process. Comparative Example 1: The preparation method is the same as in Example 1, except that the initiator azobisisobutyronitrile was not added during the preparation of this comparative example. Comparative Example 2: The preparation method is the same as in Example 1, except that the composite catalyst is replaced with an equal amount of tributylphosphine in the preparation process of this comparative example; Comparative Example 3: The preparation method is the same as in Example 1, except that in the preparation process of this comparative example, the composite catalyst is replaced with an equal amount of m-chlorobenzoic acid; Comparative Example 4: The preparation method is the same as in Example 1, except that no composite catalyst was added during the preparation process of this comparative example. Comparative Example 5: The preparation method is the same as in Example 1, except that no catalyst H+-montmorillonite was added during the preparation of this comparative example. Comparative Example 6: The preparation method is the same as in Example 1, except that the catalyst H+-montmorillonite is replaced with 4-dimethylaminopyridine in the preparation process of this comparative example. Comparative Example 7: The preparation method is the same as in Example 1, except that: in the preparation process of this comparative example, the catalyst H+-montmorillonite is added, and 1-mercaptomethylcyclopropylacetic acid is directly replaced with sodium 1-mercaptomethylcyclopropylacetate; In the above examples and comparative examples, the detection methods for montelukast sodium and the S-isomer were carried out in accordance with the detection requirements for the "S-isomer" in the draft for comments issued by the National Pharmacopoeia Commission.

[0025] Table 1: Comparison of product indicators for montelukast sodium prepared in different examples and comparative examples

[0026] (1) A comparison of Example 1 with Comparative Examples 1 and 4 shows that: The difference between Comparative Example 1 and Example 1 is that the initiator azobisisobutyronitrile was not added; this resulted in the montelukast sodium core not being effectively converted into the montelukast sodium S-isomer, and thus the montelukast sodium S-isomer could not be obtained under the catalysis of the catalyst H+-montmorillonite. The difference between Comparative Example 4 and Example 1 is that no composite catalyst was added; this resulted in the montelukast sodium core not being effectively converted into the montelukast sodium core S-isomer, and thus the montelukast sodium S-isomer could not be obtained under the catalysis of the catalyst H+-montmorillonite. Montelukast sodium core can still be used to obtain montmorillonite sodium under the catalysis of catalyst H+-montmorillonite. There is no significant difference compared with the preparation method of montmorillonite sodium researched by our company, which does not add initiator azobisisobutyronitrile and mixed catalyst, and directly obtains montmorillonite sodium through montmorillonite sodium core under the catalysis of catalyst H+-montmorillonite. (2) A comparison between Example 1 and Comparative Examples 2-3 shows that: Comparative Examples 2-5 differ from Example 1 in that a composite catalyst was replaced with a single catalyst. As the data shows, The generated montelukast sodium S-isomer undergoes isomerization conversion, resulting in two peaks in the product: montelukast sodium and montelukast sodium S-isomer. It is impossible to obtain a stable high-purity S-isomer standard, thus making it difficult to meet the detection requirements of external standard method for quantitative analysis of impurities. (3) A comparison between Example 1 and Comparative Example 5 shows that: The difference between Comparative Example 5 and Example 1 is that the catalyst H+-montmorillonite was not added; and no peak of sodium montmorillonite or S-isomer of sodium montmorillonite was detected in Comparative Example 5. This indicates that montelukast sodium core or montelukast sodium S-isomer can only be successfully synthesized from 1-mercaptomethylcyclopropylacetic acid under the catalysis of H+-montmorillonite. (4) A comparison between Example 1 and Comparative Example 6 shows that: Comparative Example 6 differs from Example 1 in that the catalyst H+-montmorillonite is replaced with 4-dimethylaminopyridine; Among them, 4-dimethylaminopyridine and H+-montmorillonite, as widely used catalysts in the chemical field, can both catalyze this type of reaction. However, as shown in Comparative Example 2, 4-dimethylaminopyridine cannot catalyze the reaction of montelukast sodium core or montelukast sodium core S-isomer with 1-mercaptomethylcyclopropylacetic acid to synthesize montelukast sodium or montelukast sodium S-isomer. (3) A comparison between Example 1 and Comparative Example 7 shows that: The difference between Comparative Example 7 and Example 1 is that 1-mercaptomethylcyclopropylacetic acid is directly replaced with sodium 1-mercaptomethylcyclopropylacetate; Since the side chain of the finished product montelukast sodium is sodium 1-mercaptomethylcyclopropylacetate, based on the reverse thinking of chemical synthesis, those skilled in the art are motivated to use sodium 1-mercaptomethylcyclopropylacetate and related intermediates to synthesize montelukast sodium or montelukast sodium S-isomer. However, through numerous experimental attempts and studies, this application has found that sodium 1-mercaptomethylcyclopropylacetate cannot directly react to obtain sodium montmorillonite or its S-isomer in accordance with the core reaction principle disclosed in this invention, namely, the addition of the catalyst H+-montmorillonite.

[0027] In summary: This invention creatively uses azobisisobutyronitrile as an initiator to conduct a montelukast sodium nucleus isomerization reaction under the catalysis of the composite catalysts tributylphosphine and m-chlorobenzoic acid to obtain the montelukast sodium nucleus S-isomer, and then reacts with 1-mercaptomethylcyclopropylacetic acid under H+-montmorillonite catalysis to obtain the montelukast sodium S-isomer. This invention creatively uses azobisisobutyronitrile (AIBN) as an initiator to catalyze the isomerization reaction of montelukast sodium nucleus to obtain the montelukast sodium S-isomer under the catalysis of the composite catalysts tributylphosphine and m-chlorobenzoic acid. The applicant unexpectedly discovered that the composite catalyst of tributylphosphine and m-chlorobenzoic acid, compared with a single catalyst, can avoid the isomerization conversion of montelukast sodium, thus solving the problem of two peaks appearing in the product, namely montelukast sodium and montelukast sodium S-isomer, making it impossible to obtain a stable high-purity S-isomer standard, and thus making it difficult to meet the detection requirements of external standard method for quantitative analysis of impurities.

Claims

1. A method for preparing the S-isomer of montelukast sodium, characterized in that... Includes the following steps: (1) The starting material sodium montelukast is dissolved in an organic solvent. Under the action of an initiator and the catalysis of a composite catalyst, a configuration inversion occurs to generate the sodium montelukast S-isomer. (2) Add 1-mercaptomethylcyclopropylacetic acid and react under the catalysis of a catalyst. After filtration and extraction, an organic phase solution of the montelukast acid isomer is obtained. (3) Add 30% sodium methoxide solution dropwise to the above organic phase solution, and obtain montelukast sodium S-isomer by filtration, cooling, crystal growth, vacuum filtration and drying.

2. The method for preparing the S-isomer of montelukast sodium according to claim 1, characterized in that... The initiator is azobisisobutyronitrile.

3. The method for preparing the S-isomer of montelukast sodium according to claim 2, characterized in that... The composite catalyst is a mixture of tributylphosphine and m-chlorobenzoic acid.

4. The method for preparing the S-isomer of montelukast sodium according to claim 3, characterized in that... The catalyst is H+-montmorillonite.

5. The method for preparing the S-isomer of montelukast sodium according to claim 4, characterized in that... In step (1): The organic solvent is toluene, acetonitrile, xylene, or a mixture of two or more of these. The mass ratio of the sodium montelukast core to the organic solvent is 1:8~12; The mass ratio of montelukast sodium core: azobisisobutyronitrile: tributylphosphine: m-chlorobenzoic acid is 1:0.04~0.06:0.05~0.07:0.04~0.06; The reaction temperature is controlled at -15 to -25℃.

6. The method for preparing the S-isomer of montelukast sodium according to claim 5, characterized in that... In step (2): The mass ratio of the montelukast sodium core to 1-mercaptomethylcyclopropylacetic acid is 1:0.3~0.35; The mass ratio of the sodium montelukast core to the catalyst is 1:0.25~0.45; The reaction temperature is controlled at 55~65℃, and the reaction time is 5~10h.

7. The method for preparing the S-isomer of montelukast sodium according to claim 4, characterized in that... In step (2): Filter, wash with toluene, add purified water to the toluene phase mother liquor obtained by vacuum filtration, extract at a controlled temperature of 20~30℃, add anhydrous sodium sulfate to dry, and filter to obtain an organic phase solution of montelukast acid S-isomer; the mass ratio of the montelukast sodium core to water is 1:5~8.

8. The method for preparing the S-isomer of montelukast sodium according to claim 4, characterized in that... In step (3): The mass ratio of montelukast sodium core to 30% sodium methoxide solution is 1:0.25~0.30; the reaction temperature is controlled at 45~55℃; and the crystal growth temperature is -15~-25℃.

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