A process for the preparation of zolmitriptan

Abstract

The application discloses a preparation method of zolmitriptan, relates to the technical field of drug synthesis, and comprises the following steps: adding compound 1 and reagent 1 into solvent 1 to perform a first reaction to obtain compound 2; adding the compound 2, reagent 2 and reagent 3 into solvent 2 to perform a second reaction to obtain compound 3 and the like. Compared with the prior art, the application provides a novel synthetic route for preparing zolmitriptan, the route uses L-4-bromophenylalanine as a starting material, and new synthetic steps are adopted, such as using reagent 5, such as a t-butyl alcohol metal salt and sodium hydride, to construct the oxazolidinone structure in zolmitriptan and using a coupling reaction to construct the indole ring in zolmitriptan, so that the yield of the obtained target product is significantly improved, the use of high-toxicity and high-risk reagents in the existing synthetic route is effectively avoided, and a mild, efficient, green and environmentally-friendly synthetic route for preparing zolmitriptan is provided.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing zolmitriptan. Background Technology

[0002] Zolmitriptan, developed by GlaxoWellcome in the UK, is a highly selective 5-HT1B / 1D receptor agonist used to treat acute attacks of various migraines. Its mechanism of action involves direct stimulation of 5-HT1B / 1D receptors in the intracranial vascular system, causing vasoconstriction of abnormally dilated blood vessels in the brain and dura mater. It may also act on the caudal nucleus of trigeminal nerve cells and the synapses of the trigeminal nerve, inhibiting the release of inflammatory neurotransmitters. The chemical structure of zolmitriptan is shown below:

[0003] .

[0004] Currently, numerous patents and publications both domestically and internationally report methods for synthesizing zolmitriptan. There are several existing synthetic routes for zolmitriptan, such as the synthetic route used in prior art 1. Figure 1 As shown. However, the existing synthetic routes for zolmitriptan have drawbacks such as low product yield and purity, and the use of highly toxic and dangerous reagents such as phosgene (or triphosgene) and stannous chloride, which require further improvement. Summary of the Invention

[0005] To address the above problems, this invention provides a method for preparing zolmitriptan.

[0006] This invention provides a method for preparing zolmitriptan, comprising the following steps:

[0007] Compound 1 and reagent 1 were added to solvent 1 to carry out the first reaction, yielding compound 2;

[0008] Compound 2, reagent 2 and reagent 3 were added to solvent 2 to carry out a second reaction to obtain compound 3;

[0009] Compound 3 and reagent 4 were added to solvent 3 to carry out a third reaction, yielding compound 4;

[0010] Compound 4 and reagent 5 were added to solvent 4 to carry out a fourth reaction, yielding compound 5.

[0011] Compound 5 was added to solvent 5, and then reagents 6, 7 and 8 were added to carry out the fifth reaction to obtain compound 6.

[0012] Compound 6 was added to solvent 6, followed by reagent 9 to carry out a sixth reaction, yielding compound 7; then reagent 10 was added to the reaction system to carry out a seventh reaction, yielding zolmitriptan.

[0013] The structural formula of compound 1 is as follows: ;

[0014] The reagent 1 includes at least one of thionyl chloride, concentrated sulfuric acid, hydrogen chloride, and p-toluenesulfonic acid;

[0015] The structural formula of compound 2 is: ;

[0016] Reagent 2 is an amino protecting agent;

[0017] The reagent 3 includes at least one of carbonates and organic bases;

[0018] The structural formula of compound 3 is: ;

[0019] The reagent 4 includes at least one of sodium borohydride, lithium aluminum hydride, boron dimethyl sulfide complex, and boron tetrahydrofuran complex.

[0020] The structural formula of compound 4 is: ;

[0021] The reagent 5 includes at least one of tert-butanol metal salt and sodium hydride;

[0022] The structural formula of compound 5 is: ;

[0023] The structural formula of reagent 6 is: ;

[0024] The reagent 7 includes cuprous salt;

[0025] The reagent 8 includes at least one of L-proline, 4-hydroxy-L-proline and pyridinecarboxylic acid;

[0026] The structural formula of compound 6 is: ;

[0027] The reagent 9 includes at least one of trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, and scandium trifluoromethanesulfonate;

[0028] The structural formula of compound 7 is: ;

[0029] The structural formula of reagent 10 is: .

[0030] Further, the amino protecting agent includes di-tert-butyl dicarbonate, the carbonate includes at least one of sodium carbonate and sodium bicarbonate, the organic base includes at least one of triethylamine and N,N-diisopropylethylamine, the tert-butanol metal salt includes at least one of sodium tert-butoxide and potassium tert-butoxide, and the cuprous salt includes cuprous iodide.

[0031] Further, the conditions and parameters of the first reaction include: the molar ratio of compound 1 to reagent 1 is 1:(3~10), the temperature is 0~20℃, and the time is 1~10 hours;

[0032] And / or, the solvent 1 includes an alcohol solvent, the alcohol solvent including at least one of methanol and ethanol, and the mass ratio of the compound 1 to the solvent 1 is 1:(3~20).

[0033] Further, the conditions and parameters of the second reaction include: the molar ratio of compound 2 to reagent 2 is 1:(0.95~2.0), the molar ratio of compound 2 to reagent 3 is 1:(1.2~2.0), the temperature is 20~50℃, and the time is 1~10 hours;

[0034] And / or, the solvent 2 includes at least one of tetrahydrofuran, acetonitrile, dichloromethane and 1,4-dioxane, and the mass ratio of the compound 2 to the solvent 2 is 1:(3~10).

[0035] Furthermore, the conditions for the third reaction include: the molar ratio of compound 3 to reagent 4 is 1:(1.0~5.0), the temperature is 20~70℃, and the time is 1~10 hours;

[0036] And / or, the solvent 3 includes at least one of methanol, ethanol, isopropanol and acetonitrile, and the mass ratio of the compound 3 to the solvent 3 is 1:(3~10).

[0037] Furthermore, the conditions and parameters of the fourth reaction include: the molar ratio of compound 4 to reagent 5 is 1:(1.0~4.0), the temperature is 20~50℃, and the time is 1~10 hours;

[0038] And / or, the solvent 4 includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and 1,4-dioxane, and the mass ratio of the compound 4 to the solvent 4 is 1:(3~20).

[0039] Further, the conditions and parameters of the fifth reaction include: the molar ratio of compound 5 to reagent 6 is 1:(2.0~5.0), the molar ratio of compound 5 to reagent 7 is 1:(0.1~1.0), the molar ratio of compound 5 to reagent 8 is 1:(0.1~1.0), the temperature is 40~80℃, and the time is 10~20 hours;

[0040] And / or, the solvent 5 includes at least one of dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and methyl tert-butyl ether, and the mass ratio of the compound 5 to the solvent 5 is 1:(8~20).

[0041] Furthermore, the conditions and parameters of the sixth reaction include: the molar ratio of compound 6 to reagent 9 is 1:(5~20), the temperature is 20~50℃, and the time is 2~10 hours;

[0042] And / or, the solvent 6 includes at least one of methanol, ethanol, water, acetonitrile, tetrahydrofuran and dichloromethane, and the mass ratio of the compound 6 to the solvent 6 is 1:(3~15).

[0043] Furthermore, the conditions for the seventh reaction include: the molar ratio of compound 7 to reagent 10 is 1:(0.9~2.0), the temperature is 65~100℃, and the time is 3~15 hours;

[0044] And / or, the solvent 7 includes at least one of methanol, ethanol, water, acetonitrile and tetrahydrofuran, and the mass ratio of the compound 7 to the solvent 7 is 1:(3~15).

[0045] Further, the conditions and parameters of the first reaction include: the molar ratio of compound 1 to reagent 1 is 1:(4~5), the temperature is 0~20℃, and the time is 6~8 hours;

[0046] The solvent 1 includes an alcohol solvent, which includes at least one of methanol and ethanol, and the mass ratio of the compound 1 to the solvent 1 is 1:(5~10).

[0047] The conditions and parameters for the second reaction include: the molar ratio of compound 2 to reagent 2 is 1:(1.0~1.2), the molar ratio of compound 2 to reagent 3 is 1:(1.2~2.0), the temperature is 20~30℃, and the time is 2~4 hours;

[0048] The solvent 2 includes at least one of tetrahydrofuran, acetonitrile, dichloromethane and 1,4-dioxane, and the mass ratio of the compound 2 to the solvent 2 is 1:(5~7).

[0049] The conditions for the third reaction include: the molar ratio of compound 3 to reagent 4 is 1:(1.0~2.0), the temperature is 45~55℃, and the time is 2~3 hours;

[0050] The solvent 3 includes at least one of methanol, ethanol, isopropanol and acetonitrile, and the mass ratio of the compound 3 to the solvent 3 is 1:(4~6).

[0051] The conditions for the fourth reaction include: the molar ratio of compound 4 to reagent 5 is 1:(1.5~2.0), the temperature is 20~40℃, and the time is 2~4 hours;

[0052] The solvent 4 includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and 1,4-dioxane, and the mass ratio of the compound 4 to the solvent 4 is 1:(6~8).

[0053] The conditions and parameters of the fifth reaction include: the molar ratio of compound 5 to reagent 6 is 1:(2.0~3.0), the molar ratio of compound 5 to reagent 7 is 1:(0.1~0.2), the molar ratio of compound 5 to reagent 8 is 1:(0.1~0.2), the temperature is 50~60℃, and the time is 10~20 hours;

[0054] The solvent 5 includes at least one of dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and methyl tert-butyl ether, and the mass ratio of the compound 5 to the solvent 5 is 1:(10~12).

[0055] The conditions and parameters for the sixth reaction include: the molar ratio of compound 6 to reagent 9 is 1:(8~10), the temperature is 20~40℃, and the time is 4~6 hours;

[0056] The solvent 6 includes at least one of methanol, ethanol, water, acetonitrile, tetrahydrofuran, and dichloromethane, and the mass ratio of the compound 6 to the solvent 6 is 1:(6~8).

[0057] The conditions for the seventh reaction include: the molar ratio of compound 7 to reagent 10 is 1:(0.9~1.5), the temperature is 80~100℃, and the time is 6~9 hours;

[0058] The solvent 7 includes at least one of methanol, ethanol, water, acetonitrile and tetrahydrofuran, and the mass ratio of the compound 7 to the solvent 7 is 1:(8~10).

[0059] The technical solutions provided in the embodiments of the present invention have at least the following advantages compared with the prior art:

[0060] This invention provides a method for preparing zolmitriptan. Compared with existing technologies, this invention offers a novel synthetic route for preparing zolmitriptan. This route uses L-4-bromophenylalanine as the starting material and employs novel synthetic steps such as using tert-butanol metal salts and sodium hydride to construct the oxazolidinone structure of zolmitriptan and using coupling reactions to construct the indole ring of zolmitriptan. These novel steps significantly improve the yield of the target product and effectively avoid the use of highly toxic and hazardous reagents in existing synthetic routes, providing a mild, efficient, and environmentally friendly synthetic route for the preparation of zolmitriptan. Specifically:

[0061] 1) The key steps in the existing synthetic route, which rely on diazotization, highly toxic phosgene (or triphosgene), and the heavy metal reagent stannous chloride, are replaced with a mild, safe, and efficient reaction. This transformation brings several significant advantages:

[0062] A qualitative leap has been achieved in operational safety and environmental friendliness: The process has completely eliminated diazotizing intermediates with high explosion risks, highly toxic and corrosive phosgene reagents, and environmentally unfriendly heavy metal salts such as stannous chloride. This not only fundamentally eliminates major safety hazards but also ensures that the entire production process conforms to green chemistry principles, preventing the generation and treatment of heavy metal pollutants at the source, and significantly reducing environmental pressure and production costs.

[0063] Simplified process and reduced costs: The new synthetic route features concise steps, mild reaction conditions, and eliminates the need for complex phosgene protection, exhaust gas treatment, and heavy metal waste recovery systems. This simplified process leads to a significant reduction in equipment and maintenance costs and energy consumption, while greatly improving process robustness and production efficiency, making it highly valuable for industrial applications.

[0064] 2) Improved product quality and purity: This invention avoids the diazotization side reaction and the chlorine-containing impurities that may be introduced by phosgene. This results in higher purity and more stable quality of the final product, significantly enhancing its competitiveness. Attached Figure Description

[0065] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0066] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0067] Figure 1 A roadmap for the synthesis of zolmitriptan using existing technology 1;

[0068] Figure 2 The NMR spectrum of intermediate compound 6 in the embodiments of the present invention;

[0069] Figure 3 The image shows the NMR spectrum of the target product zolmitriptan in this embodiment of the invention. Detailed Implementation

[0070] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0071] Unless otherwise specified, all raw materials, reagents, instruments, and equipment used in this invention can be purchased commercially or prepared using existing methods. Furthermore, unless otherwise specified or detailed, the steps and parameters involved can be performed using existing high-performance liquid chromatography (HPLC) methods or directly using existing equipment; these will not be elaborated upon further in this invention document.

[0072] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed according to national standards. If no corresponding national standard exists, then generally accepted international standards, conventional conditions, or conditions recommended by the manufacturer are followed.

[0073] Example 1

[0074] This example provides a method for preparing zolmitriptan, which includes the following steps:

[0075] Step (1): Cool solvent 1 (specifically methanol, with a mass ratio of compound 1 to solvent 1 of 1:4) to below 0°C and add reagent 1 (specifically thionyl chloride, with a molar ratio of compound 1 to reagent 1 of 1:4); maintain the temperature at around 0°C and stir for 30 minutes, then add 50.00g of compound 1 (i.e., L-4-bromophenylalanine) to carry out the first reaction (specific reaction temperature is 0°C, time is 8 hours); after the reaction is completed, concentrate the reaction solution under reduced pressure at 50°C, add 150ml of water and 200ml of EA (ethyl acetate), adjust the pH of the aqueous phase to 9-10 with saturated sodium bicarbonate, separate the layers, extract the aqueous phase again with 200ml of EA, combine the organic phases, wash with 150ml×2 saturated sodium chloride solution, combine the organic layers and concentrate under reduced pressure to dryness to obtain 50.22g of compound 2, yield 92%.

[0076] Step (2): 50.00 g of compound 2 was added to solvent 2 (specifically tetrahydrofuran, with a mass ratio of compound 2 to solvent 2 of 1:5) and the pH was adjusted to 8 using reagent 3 (specifically triethylamine, with a molar ratio of compound 2 to reagent 3 of 1:2); then reagent 2 (specifically ditert-butyl dicarbonate, with a molar ratio of compound 2 to reagent 2 of 1:1.05) was added to carry out the second reaction (specific reaction temperature was 25℃, and the time was 3 hours); after the reaction was completed, 400 ml of water and 1200 ml of ethyl acetate were added, the mixture was extracted, the organic phases were combined and concentrated under reduced pressure at 45℃ to obtain 66.63 g of compound 3, with a yield of 91%.

[0077] Step (3): Add 50.00g of compound 3 to solvent 3 (specifically anhydrous methanol, with a mass ratio of compound 3 to solvent 3 of 1:5), cool to 0℃ and add reagent 4 (specifically sodium borohydride, with a molar ratio of compound 3 to reagent 4 of 1:2) to carry out the third reaction for 1h; then heat to 50℃ and continue the third reaction for 3h; after the reaction is completed, add 500ml of water, cool to 10℃ to crystallize for 5h, filter, and vacuum dry at 50℃ to obtain 41.50g of compound 4, with a yield of 87%.

[0078] Step (4): 40.00g of compound 4 was added to solvent 4 (specifically tetrahydrofuran, with a mass ratio of compound 4 to solvent 4 of 1:8), followed by the addition of reagent 5 (specifically sodium tert-butoxide, with a molar ratio of compound 4 to reagent 5 of 1:3) to carry out the fourth reaction (specific reaction temperature of 30℃ and reaction time of 4h); after the reaction was completed, 300ml of water was added, and then extracted with 600ml of ethyl acetate. The organic phases were combined and concentrated under reduced pressure at 45℃ to obtain 28.50g of compound 5, with a yield of 90%.

[0079] Step (5): Mix 30.00g of compound 5, solvent 5 (specifically dimethyl sulfoxide, with a mass ratio of compound 5 to solvent 5 of 1:10), reagent 7 (specifically cuprous iodide, with a molar ratio of compound 5 to reagent 7 of 1:0.3), reagent 8 (4-hydroxy-L-proline, with a molar ratio of compound 5 to reagent 8 of 1:0.3), and 60.00g of cesium carbonate, and then add reagent 6 (specifically tert-butyl hydrazinoate). The fifth reaction was carried out with a molar ratio of compound 5 to reagent 6 of 1:1 (specific temperature 60℃, time 15h). After the reaction was completed, the reaction solution was cooled and 600ml of water and 600ml of ethyl acetate were added at 30℃. The mixture was separated, and the aqueous phase was extracted with 1200ml of ethyl acetate. The organic phases were combined and washed with 900ml of water. The organic phase was concentrated under reduced pressure at 45℃ to obtain 31.70g of compound 6, with a yield of 80%.

[0080] Step (6): Add 50.00g of compound 6 to solvent 6 (specifically, 6300ml of ethanol and 100ml of water), then add reagent 9 (specifically, hydrochloric acid, with a molar ratio of compound 6 to reagent 9 of 1:3.0) to carry out the sixth reaction (specifically, at 25℃ for 4 hours) to obtain a solution of compound 7; adjust the pH of the system to 3 with sodium hydroxide, and then add reagent 10 to the reaction system ( The seventh reaction was carried out with the molar ratio of compound 6 and reagent 10 being 1:1.3 (specifically, at 80℃ for 12 hours). After the reaction was completed, the mixture was concentrated under reduced pressure, 200 ml of water was added, the pH was adjusted to 9.5 with sodium hydroxide, 200 ml of ethyl acetate was added, and the mixture was cooled to 5℃ to crystallize. The solid was filtered, and the solid was then dissolved in 500 ml of ethyl acetate by heating. The mixture was cooled to 0℃ and kept at that temperature for 8 hours to crystallize. The solid was then filtered and dried at 50℃ to obtain 21.07 g of compound 8 (i.e., the target product - zolmitriptan), with a yield of 45%.

[0081] The NMR spectrum of intermediate compound 6 in this embodiment is as follows: Figure 2 The NMR spectrum of the target product zolmitriptan is shown in the figure. Figure 3 As shown; furthermore, the purity of the target product obtained in this embodiment, zolmitriptan, is 99.552%.

[0082] Example 2

[0083] This example provides a method for preparing zolmitriptan, which differs from Example 1 only in that:

[0084] (1) The conditions and parameters of the first reaction in step (1) include: the molar ratio of compound 1 to reagent 1 is 1:3, the temperature is 0°C, the time is 10 hours, the mass ratio of compound 1 to solvent 1 is 1:5; the yield of the obtained product compound 2 is 84%;

[0085] (2) The conditions and parameters of the second reaction in step (2) include: the molar ratio of compound 2 to reagent 2 is 1:1.0, the molar ratio of compound 2 to reagent 3 (specifically sodium carbonate) is 1:2.0, the temperature is 20°C, and the time is 10 hours; the mass ratio of compound 2 to solvent 2 is 1:3; and the yield of the obtained product compound 3 is 83%.

[0086] (3) The conditions and parameters of the third reaction in step (3) include: the molar ratio of compound 3 to reagent 4 is 1:1.0, the temperature is 20°C, and the time is 10 hours; the solvent 3 is ethanol, and the mass ratio of compound 3 to solvent 3 is 1:3; the yield of the obtained product compound 4 is 80%;

[0087] (4) The conditions and parameters of the fourth reaction in step (4) include: the molar ratio of compound 4 to reagent 5 is 1:1.0, the temperature is 20°C, and the time is 10 hours; the solvent 4 is tetrahydrofuran, and the mass ratio of compound 4 to solvent 4 is 1:5; the yield of the obtained product compound 5 is 65%;

[0088] (5) The conditions and parameters of the fifth reaction in step (5) include: the molar ratio of compound 5 to reagent 6 is 1:2.0, the molar ratio of compound 5 to reagent 7 is 1:0.1, the molar ratio of compound 5 to reagent 8 is 1:0.1, the temperature is 40°C, and the time is 20 hours; the solvent 5 is N,N-dimethylformamide, and the mass ratio of compound 5 to solvent 5 is 1:8; the yield of the obtained product compound 5 is 70%;

[0089] (6) The conditions for the sixth reaction in step (6) include: the molar ratio of compound 6 to reagent 9 is 1:5, the temperature is 20°C, and the time is 10 hours; the mass ratio of compound 6 to solvent 6 is 1:3; and the conditions for the seventh reaction include: the molar ratio of compound 7 to reagent 10 is 1:0.9, the temperature is 65°C, and the time is 15 hours; the mass ratio of compound 7 to solvent 7 is 1:3; the yield of the target product zolmitriptyline is 32%, and the purity is 98.752%.

[0090] Example 3

[0091] This example provides a method for preparing zolmitriptan, which differs from Example 1 only in that:

[0092] (1) The conditions and parameters of the first reaction in step (1) include: the molar ratio of compound 1 to reagent 1 is 1:10, the temperature is 20°C, the time is 1 hour, the mass ratio of compound 1 to solvent 1 is 1:30; the yield of the obtained product compound 2 is 90%;

[0093] (2) The conditions and parameters of the second reaction in step (2) include: the molar ratio of compound 2 to reagent 2 is 1:2.0, the molar ratio of compound 2 to reagent 3 (specifically sodium carbonate) is 1:1.2, the temperature is 50°C, and the time is 1 hour; the mass ratio of compound 2 to solvent 2 is 1:10; and the yield of the obtained product compound 3 is 88%.

[0094] (3) The conditions and parameters of the third reaction in step (3) include: the molar ratio of compound 3 to reagent 4 is 1:5.0, the temperature is 70°C, and the time is 1 hour; the solvent 3 is ethanol, and the mass ratio of compound 3 to solvent 3 is 1:10; the yield of the obtained product compound 4 is 85%;

[0095] (4) The conditions and parameters of the fourth reaction in step (4) include: the molar ratio of compound 4 to reagent 5 is 1:4.0, the temperature is 50°C, and the time is 1 hour; the solvent 4 is tetrahydrofuran, and the mass ratio of compound 4 to solvent 4 is 1:20; the yield of the obtained product compound 5 is 75%;

[0096] (5) The conditions and parameters of the fifth reaction in step (5) include: the molar ratio of compound 5 to reagent 6 is 1:5.0, the molar ratio of compound 5 to reagent 7 is 1:1.0, the molar ratio of compound 5 to reagent 8 is 1:1.0, the temperature is 80°C, and the time is 10 hours; the solvent 5 is N,N-dimethylformamide, and the mass ratio of compound 5 to solvent 5 is 1:20; the yield of the obtained product compound 5 is 62%;

[0097] (6) The conditions for the sixth reaction in step (6) include: the molar ratio of compound 6 to reagent 9 is 1:20, the temperature is 50°C, and the time is 2 hours; the mass ratio of compound 6 to solvent 6 is 1:15; and the conditions for the seventh reaction include: the molar ratio of compound 7 to reagent 10 is 1:2.0, the temperature is 100°C, and the time is 3 hours; the mass ratio of compound 7 to solvent 7 is 1:15; the yield of the target product zolmitriptyline is 29%, and the purity is 98.652%.

[0098] Example 4

[0099] This example provides a method for preparing zolmitriptan, which differs from Example 1 only in that:

[0100] (1) The conditions and parameters of the first reaction in step (1) include: the molar ratio of compound 1 to reagent 1 is 1:4.5, the temperature is 10°C, the time is 7 hours, the mass ratio of compound 1 to solvent 1 is 1:8; the yield of the obtained product compound 2 is 97%;

[0101] (2) The conditions and parameters of the second reaction in step (2) include: the molar ratio of compound 2 to reagent 2 is 1:1.1, the molar ratio of compound 2 to reagent 3 (specifically sodium carbonate) is 1:1.5, the temperature is 25°C, and the time is 3 hours; the mass ratio of compound 2 to solvent 2 is 1:1.7; and the yield of the obtained product compound 3 is 95%.

[0102] (3) The conditions and parameters of the third reaction in step (3) include: the molar ratio of compound 3 to reagent 4 is 1:1.5, the temperature is 50°C, and the time is 2.5 hours; the solvent 3 is ethanol, and the mass ratio of compound 3 to solvent 3 is 1:5; the yield of the obtained product compound 4 is 93%;

[0103] (4) The conditions and parameters of the fourth reaction in step (4) include: the molar ratio of compound 4 to reagent 5 is 1:1.8, the temperature is 30°C, and the time is 3 hours; the solvent 4 is tetrahydrofuran, and the mass ratio of compound 4 to solvent 4 is 1:7; the yield of the obtained product compound 5 is 92%;

[0104] (5) The conditions and parameters of the fifth reaction in step (5) include: the molar ratio of compound 5 to reagent 6 is 1:2.5, the molar ratio of compound 5 to reagent 7 is 1:0.1, the molar ratio of compound 5 to reagent 8 is 1:0.1, the temperature is 55°C, and the time is 15 hours; the solvent 5 is N,N-dimethylformamide, and the mass ratio of compound 5 to solvent 5 is 1:11; the yield of the obtained product compound 5 is 85%;

[0105] (6) The conditions for the sixth reaction in step (6) include: the molar ratio of compound 6 to reagent 9 is 1:9, the temperature is 30°C, and the time is 5 hours; the mass ratio of compound 6 to solvent 6 is 1:7; and the conditions for the seventh reaction include: the molar ratio of compound 7 to reagent 10 is 1:1.2, the temperature is 90°C, and the time is 8 hours; the mass ratio of compound 7 to solvent 7 is 1:9; the total yield of the target product zolmitriptyline is 52%, and the purity is 99.952%.

[0106] Comparative Example 1

[0107] This example provides a prior art method for preparing zolmitriptan, such as... Figure 1 As shown, the specific conditions and parameters for each step are in accordance with the existing technical document US5466699; the yield of the target product zolmitriptyline is 18% and the purity is 98.697%.

[0108] Table 1 summarizes the yields of the target product zolmitriptyline obtained from the above embodiments and comparative examples.

[0109] Table 1

[0110]

[0111] As shown in Table 1, compared with the prior art, the preparation method of zolmitriptan provided in this embodiment of the invention yields a better product.

[0112] In summary, the embodiments of the present invention provide a method for preparing zolmitriptan. Compared with the prior art, the present invention provides a novel synthetic route for preparing zolmitriptan. This route uses L-4-bromophenylalanine as the starting material and employs novel synthetic steps such as using tert-butanol metal salts and sodium hydride to construct the oxazolidinone structure in zolmitriptan and using coupling reactions to construct the indole ring in zolmitriptan. These novel synthetic steps significantly improve the yield of the target product and effectively avoid the use of highly toxic and dangerous reagents in existing synthetic routes. This provides a mild, efficient, green and environmentally friendly synthetic route for the preparation of zolmitriptan.

[0113] Various embodiments of the present invention may exist in the form of a range; it should be understood that the description in the form of a range is merely for convenience and brevity and should not be construed as a hard limitation on the scope of the invention; therefore, it should be considered that the range description has specifically disclosed all possible subranges and single numerical values ​​within that range. For example, it should be considered that the range description from 1 to 6 has specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and single numbers within the range, such as 1, 2, 3, 4, 5, and 6, regardless of the range. Furthermore, whenever a numerical range is referred to herein, it means including any referenced number (fraction or integer) within the range referred to.

[0114] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A method for preparing zolmitriptan, characterized in that, Includes the following steps: Compound 1 and reagent 1 were added to solvent 1 to carry out the first reaction, yielding compound 2; Compound 2, reagent 2 and reagent 3 were added to solvent 2 to carry out a second reaction to obtain compound 3; Compound 3 and reagent 4 were added to solvent 3 to carry out a third reaction, yielding compound 4; Compound 4 and reagent 5 were added to solvent 4 to carry out a fourth reaction, yielding compound 5. Compound 5 was added to solvent 5, and then reagents 6, 7 and 8 were added to carry out the fifth reaction to obtain compound 6. Compound 6 was added to solvent 6, followed by reagent 9 to carry out a sixth reaction, yielding compound 7; then reagent 10 was added to the reaction system to carry out a seventh reaction, yielding zolmitriptan. The structural formula of compound 1 is as follows: ; The reagent 1 includes at least one of thionyl chloride, concentrated sulfuric acid, hydrogen chloride, and p-toluenesulfonic acid; The structural formula of compound 2 is: ; The reagent 2 is an amino protecting agent, and the amino protecting agent is ditert-butyl dicarbonate; The reagent 3 includes at least one of carbonates and organic bases; The structural formula of compound 3 is: ; The reagent 4 includes at least one of sodium borohydride, lithium aluminum hydride, boron dimethyl sulfide complex, and boron tetrahydrofuran complex. The structural formula of compound 4 is: ; The reagent 5 includes at least one of tert-butanol metal salt and sodium hydride; The structural formula of compound 5 is: ; The structural formula of reagent 6 is: ; The reagent 7 includes cuprous salt; The reagent 8 includes at least one of L-proline, 4-hydroxy-L-proline and pyridinecarboxylic acid; The structural formula of compound 6 is: ; The reagent 9 includes at least one of trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, and scandium trifluoromethanesulfonate; The structural formula of compound 7 is: ; The structural formula of reagent 10 is: ; Solvent 1 is methanol.

2. The method for preparing zolmitriptan according to claim 1, characterized in that, The carbonate includes at least one of sodium carbonate and sodium bicarbonate, the organic base includes at least one of triethylamine and N,N-diisopropylethylamine, the tert-butanol metal salt includes at least one of sodium tert-butoxide and potassium tert-butoxide, and the cuprous salt includes cuprous iodide.

3. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions and parameters for the first reaction include: the molar ratio of compound 1 to reagent 1 is 1:(3~10), the temperature is 0~20℃, and the time is 1~10 hours; And / or, the mass ratio of compound 1 to solvent 1 is 1:(3~20).

4. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions and parameters for the second reaction include: the molar ratio of compound 2 to reagent 2 is 1:(0.95~2.0), the molar ratio of compound 2 to reagent 3 is 1:(1.2~2.0), the temperature is 20~50℃, and the time is 1~10 hours; And / or, the solvent 2 includes at least one of tetrahydrofuran, acetonitrile, dichloromethane and 1,4-dioxane, and the mass ratio of the compound 2 to the solvent 2 is 1:(3~10).

5. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions for the third reaction include: the molar ratio of compound 3 to reagent 4 is 1:(1.0~5.0), the temperature is 20~70℃, and the time is 1~10 hours; And / or, the solvent 3 includes at least one of methanol, ethanol, isopropanol and acetonitrile, and the mass ratio of the compound 3 to the solvent 3 is 1:(3~10).

6. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions for the fourth reaction include: the molar ratio of compound 4 to reagent 5 is 1:(1.0~4.0), the temperature is 20~50℃, and the time is 1~10 hours; And / or, the solvent 4 includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and 1,4-dioxane, and the mass ratio of the compound 4 to the solvent 4 is 1:(3~20).

7. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions and parameters of the fifth reaction include: the molar ratio of compound 5 to reagent 6 is 1:(2.0~5.0), the molar ratio of compound 5 to reagent 7 is 1:(0.1~1.0), the molar ratio of compound 5 to reagent 8 is 1:(0.1~1.0), the temperature is 40~80℃, and the time is 10~20 hours; And / or, the solvent 5 includes at least one of dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and methyl tert-butyl ether, and the mass ratio of the compound 5 to the solvent 5 is 1:(8~20).

8. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions and parameters for the sixth reaction include: the molar ratio of compound 6 to reagent 9 is 1:(5~20), the temperature is 20~50℃, and the time is 2~10 hours; And / or, the solvent 6 includes at least one of methanol, ethanol, water, acetonitrile, tetrahydrofuran and dichloromethane, and the mass ratio of the compound 6 to the solvent 6 is 1:(3~15).

9. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions for the seventh reaction include: the molar ratio of compound 7 to reagent 10 is 1:(0.9~2.0), the temperature is 65~100℃, and the time is 3~15 hours.

10. The method for preparing zolmitriptan according to claim 1, characterized in that, The conditions and parameters for the first reaction include: the molar ratio of compound 1 to reagent 1 is 1:(4~5), the temperature is 0~20℃, and the time is 6~8 hours; The mass ratio of compound 1 to solvent 1 is 1:(5~10). The conditions and parameters for the second reaction include: the molar ratio of compound 2 to reagent 2 is 1:(1.0~1.2), the molar ratio of compound 2 to reagent 3 is 1:(1.2~2.0), the temperature is 20~30℃, and the time is 2~4 hours; The solvent 2 includes at least one of tetrahydrofuran, acetonitrile, dichloromethane and 1,4-dioxane, and the mass ratio of the compound 2 to the solvent 2 is 1:(5~7). The conditions for the third reaction include: the molar ratio of compound 3 to reagent 4 is 1:(1.0~2.0), the temperature is 45~55℃, and the time is 2~3 hours; The solvent 3 includes at least one of methanol, ethanol, isopropanol and acetonitrile, and the mass ratio of the compound 3 to the solvent 3 is 1:(4~6). The conditions for the fourth reaction include: the molar ratio of compound 4 to reagent 5 is 1:(1.5~2.0), the temperature is 20~40℃, and the time is 2~4 hours; The solvent 4 includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and 1,4-dioxane, and the mass ratio of the compound 4 to the solvent 4 is 1:(6~8). The conditions and parameters of the fifth reaction include: the molar ratio of compound 5 to reagent 6 is 1:(2.0~3.0), the molar ratio of compound 5 to reagent 7 is 1:(0.1~0.2), the molar ratio of compound 5 to reagent 8 is 1:(0.1~0.2), the temperature is 50~60℃, and the time is 10~20 hours; The solvent 5 includes at least one of dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and methyl tert-butyl ether, and the mass ratio of the compound 5 to the solvent 5 is 1:(10~12). The conditions and parameters for the sixth reaction include: the molar ratio of compound 6 to reagent 9 is 1:(8~10), the temperature is 20~40℃, and the time is 4~6 hours; The solvent 6 includes at least one of methanol, ethanol, water, acetonitrile, tetrahydrofuran, and dichloromethane, and the mass ratio of the compound 6 to the solvent 6 is 1:(6~8). The conditions for the seventh reaction include: the molar ratio of compound 7 to reagent 10 is 1:(0.9~1.5), the temperature is 80~100℃, and the time is 6~9 hours.

Images