Synthesis process of 5-methoxyl laudanidin tartrate

Abstract

The invention discloses a synthesis process of 5-methoxy laudanin tartrate, which is characterized in that 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is added for catalytic reaction, 3, 4, 5-trimethoxy phenylacetic acid and 3, 4-dimethoxy phenylethylamine react in dichloromethane at 25 DEG C to obtain a condensation product, the reaction temperature is greatly reduced, and the reaction time is greatly shortened. In the ring closing reaction, purification and crystallization are carried out in a methanol and water system, and a product is obtained after direct filtration, so that the reaction yield is improved, and the operation is simplified; according to the method, acetic acid and formaldehyde are added for reaction, then sodium borohydride is used for reduction, so that the reaction can be well carried out, relatively pure 5-methoxylavatianin is obtained, and then the 5-methoxylavatianin and tartaric acid are salified to form a solid which can be stably stored.

Description

Technical Field

[0001] The invention relates to the preparation of a pharmaceutical intermediate 5-methoxylabdanine tartrate and process development suitable for industrialized scale-up production, and in particular to the process development of 5-methoxylabdanine tartrate. Background Art

[0002] The synthesis method of 5-methoxylaudanine tartrate reported in the literature is mainly to reflux 3,4,5-trimethoxyphenylacetic acid and 3,4-dimethoxyphenylethylamine in xylene at 140°C to separate water to obtain a condensation product, then react with phosphorus oxychloride to obtain a ring-closure product, and then react with sodium borohydride and formaldehyde to obtain a methylated product.

[0003] The first step of the condensation reaction under these conditions has a high reaction temperature and a long reaction time, and it takes more than 20 hours for the reaction to be complete, which is not conducive to large-scale production. When sodium borohydride and formaldehyde are used to form methyl groups, only a small amount of the target product is obtained, and column chromatography is required to obtain a pure product. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a synthesis process of 5-methoxylabdanine tartrate and a synthesis method of 5-methoxylabdanine tartrate, so that the synthesized product has good quality, high yield, low energy consumption, mild reaction conditions, low production cost and is easy to industrialize.

[0005] To achieve the above purpose, the present invention provides the following technical solutions A synthesis process of 5-methoxylabdanine tartrate comprises the following steps: , where A is ; B is ; C is ; D is ; E is .

[0006] As a further solution of the present invention, 3,4,5-trimethoxyphenylacetic acid, 3,4-dimethoxyphenylethylamine and dichloromethane are added to the reaction flask and stirred to dissolve, and the condensation agent is continuously added and stirred at room temperature overnight. After the reaction is complete, water is added for washing, and the liquid is separated. The organic phase is continuously washed with saturated brine, and the organic phase is separated, anhydrous sodium sulfate is added for drying, and the filtrate is filtered. The filtrate is concentrated, and n-heptane is added dropwise for crystallization, and the solid B is obtained by filtering and drying.

[0007] As a further solution of the present invention, solid B is added to a reaction bottle, toluene is stirred, phosphorus oxychloride is continuously added and the temperature is raised to 65-85°C to react until the raw material disappears, the temperature is lowered, the system is concentrated to dryness, the purification system is added and stirred until completely dissolved, 10N sodium hydroxide aqueous solution is added dropwise to adjust the pH of the system to 10-13, the temperature is lowered to 0-20°C, filtered, and dried to obtain solid C.

[0008] As a further solution of the present invention, solid C is added to a reaction flask, methanol is stirred, sodium borohydride is added in batches, the temperature is raised to 20-45°C, and the reaction is carried out until the raw material disappears, the temperature is lowered, water, saturated brine, and dichloromethane are added, stirred, and the liquids are separated, the aqueous phase is continuously extracted with dichloromethane, the organic phases are combined, washed once with saturated brine, the organic phase is separated, and concentrated to obtain an oily substance D.

[0009] As a further scheme of the present invention, dioxane is added to the reaction bottle, the oil D is stirred to dissolve, and the formaldehyde aqueous solution is continued to be added, and the acetic acid is reacted at room temperature for 0-2 hours, sodium borohydride is added in batches, and the reaction temperature is controlled. After the addition is completed, the stirring is continued for 10-40 minutes at a temperature of 10N, water is added, and a 10N sodium hydroxide aqueous solution is added dropwise to adjust the pH of the system to 10-13, and methyl tert-butyl ether is added for extraction, and the liquids are separated. The organic phase is continued to be washed with saturated brine, and the liquids are separated. After the organic phase is dried over anhydrous sodium sulfate, it is concentrated to obtain an oil E, and the reaction temperature is -10-100°C, preferably 0-20°C.

[0010] As a further solution of the present invention, the oily substance E is added to the reaction bottle, the solvent is stirred to dissolve, L-tartaric acid is added, the temperature is raised to 60-95°C, and the reaction is refluxed for 2 hours, the temperature is lowered to 0-20°C, the temperature is kept for crystallization for 0-1 hour, and the filter cake is rinsed with methyl tert-butyl ether and dried to obtain solid 5-methoxylabdanine tartrate.

[0011] As a further embodiment of the present invention, the condensation agent is one of EDCI, DCC, HATU, DIC, HBTU, and HOBt.

[0012] As a further embodiment of the present invention, the purification system is one of methanol and water, ethanol and water, isopropanol and water, ethyl acetate and water, ethanol and ethyl acetate, methanol and ethyl acetate, and methanol and methyl tert-butyl ether.

[0013] As a further embodiment of the present invention, the solvent is at least one of ethyl acetate, methanol, ethanol, tetrahydrofuran, dioxane, and n-heptane.

[0014] The present invention has the following beneficial effects: The present invention adds 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride to catalyze the reaction, so that 3,4,5-trimethoxyphenylacetic acid and 3,4-dimethoxyphenylethylamine react in dichloromethane at 25°C to obtain a condensation product, which greatly reduces the reaction temperature and reaction time. The ring-closing reaction is purified and crystallized in a methanol and water system, and the product is obtained after direct filtration, which improves the reaction yield and simplifies the operation. Acetic acid and formaldehyde are added to react, and then sodium borohydride is used for reduction so that the reaction can proceed well, thereby obtaining relatively pure 5-methoxylaudanine, and then tartaric acid is salified to form a solid that can be stably stored. DETAILED DESCRIPTION

[0015] The synthesis method of the existing 5-methoxylabdanin tartrate reported in the literature is mainly to reflux 3,4,5-trimethoxyphenylacetic acid and 3,4-dimethoxyphenylethylamine in xylene at 140°C to obtain a condensation product, then react with phosphorus oxychloride to obtain a ring-closing product, and then react with sodium borohydride and formaldehyde to obtain a methylated product. Under this condition, the reaction temperature is very high and the reaction time is very long during the first step of the condensation reaction. It takes more than 20 hours to complete the reaction, which is not conducive to large-scale production. When sodium borohydride and formaldehyde are used to methylate, only a small amount of the target product is obtained, and column chromatography is required; the existing preparation process is complex, energy-intensive, and has a low yield.

[0016] The invention provides a method for synthesizing 5-methoxylabdanine tartrate, so that the synthesized product has good quality, high yield, low energy consumption, mild reaction conditions, low production cost and is convenient for industrial production.

[0017] Specifically, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is added to catalyze the reaction, so that 3,4,5-trimethoxyphenylacetic acid and 3,4-dimethoxyphenylethylamine react in dichloromethane at 25°C to obtain a condensation product, which greatly reduces the reaction temperature and reaction time. The ring-closing reaction is purified and crystallized in a methanol and water system, and the product is obtained by direct filtration, which improves the reaction yield and simplifies the operation.

[0018] By adding acetic acid and formaldehyde to react, and then reducing with sodium borohydride to make the reaction proceed well, relatively pure 5-methoxy-laudanine is obtained, and then salted with tartaric acid to form a solid that can be stably stored. Through the innovative optimization of process conditions, a process route suitable for industrial scale-up production, simple operation, low cost, and economical and efficient was explored. The purity of the product can reach more than 98%, and the total yield is increased to more than 65%. The following provides specific embodiments Example 1

[0019] A synthesis process of 5-methoxylabdanine tartrate comprises the following steps:

[0020] For ease of explanation, letters will be used instead, as follows , Where A is ; B is ; C is ; D is ; E is

[0021] The specific synthesis of B, C, D and E in the above is as follows: Synthesis of B: Add 3,4,5-trimethoxyphenylacetic acid, 3,4-dimethoxyphenylethylamine and dichloromethane to the reaction flask, stir until dissolved, continue to add EDCI, stir at room temperature overnight, and react completely. Add water for washing, separate the liquids, and continue to wash the organic phase with saturated brine. Separate the organic phase, add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate to a residual volume of about 1.5 volume. Add n-heptane dropwise for crystallization, filter, and dry to obtain solid B.

[0022] Synthesis of C: Add B to the reaction flask, stir with toluene, continue to add phosphorus oxychloride, heat up to 75-80°C and react until the raw material disappears, cool down, concentrate the system to dryness, add methanol, stir with water until completely dissolved, dropwise add 10N sodium hydroxide aqueous solution to adjust the pH of the system to 11-12, cool down to 0-10°C, filter and dry to obtain solid C.

[0023] Synthesis of D: Add C to the reaction flask, stir with methanol, add sodium borohydride in batches, heat to 30-35°C and react until the raw material disappears, cool down, add water, saturated brine, and dichloromethane, stir, separate, and extract the aqueous phase once with dichloromethane. Combine the organic phases, wash once with saturated brine, separate the organic phase, and concentrate to obtain oil D.

[0024] Synthesis of E: Add dioxane to the reaction flask, stir until D dissolves, continue to add 37% formaldehyde aqueous solution, react with acetic acid at room temperature for 1 hour, add sodium borohydride in batches, control the temperature at 0-10°C, after the addition is completed, continue to keep warm and stir for 30 minutes, add water, add 10N sodium hydroxide aqueous solution dropwise to adjust the pH of the system to 11-12, add methyl tert-butyl ether for extraction, separate the liquids, continue to wash the organic phase with saturated brine, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain oily substance E.

[0025] Synthesis of 5-methoxylaudanine tartrate: Add E to the reaction flask, stir with ethyl acetate to dissolve, continue to add L-tartaric acid, heat to 80-85°C, reflux for reaction for 2 hours, cool to 0-10°C, keep warm for crystallization for 1 hour, filter, rinse the filter cake with methyl tert-butyl ether, and dry to obtain solid 5-methoxylabdanine tartrate.

[0026] Example 2 A synthesis process of 5-methoxylabdanine tartrate comprises the following steps: , For ease of explanation, letters will be used instead, as follows , where A is ; B is ; C is ; D is ; E is

[0027] The specific synthesis of B, C, D and E in the above is as follows: Synthesis of B: Add 3,4,5-trimethoxyphenylacetic acid (10-20g), 3,4-dimethoxyphenylethylamine (10-30g) and dichloromethane (50-120ml) to the reaction flask, stir to dissolve, continue to add EDCI (10-30g), stir at room temperature overnight, react completely, add water (20-80ml) for washing, separate the liquids, continue to wash the organic phase with saturated brine (20-60ml), separate the organic phase, add anhydrous sodium sulfate to dry, filter, concentrate the filtrate to a remaining volume of about 60-100ml, add n-heptane (80-140ml) dropwise for crystallization, filter, and dry to obtain solid B.

[0028] Synthesis of C: Add B (10-30g) and toluene (60-100ml) to the reaction flask and stir. Continue to add phosphorus oxychloride (10-35g) and heat to 75-80℃ to react until the raw material disappears. Cool down and concentrate the system to dryness. Add methanol (20-60ml) and water (10-30ml) and stir until completely dissolved. Add 10N sodium hydroxide aqueous solution dropwise to adjust the pH of the system to 11-12. Cool down to 0-10℃, filter and dry to obtain solid C.

[0029] Synthesis of D: Add C (5-20g) and methanol (10-40ml) to the reaction flask and stir. Add sodium borohydride (0.05-0.7g) in batches and heat to 30-35℃ to react until the raw material disappears. Cool down, add water (10-40ml), saturated brine (10-30ml), and dichloromethane (20-60ml) and stir. Separate the liquids, and continue to extract the aqueous phase with dichloromethane (10-40ml) once. Combine the organic phases and wash them once with saturated brine (10-40ml). Separate the organic phase and concentrate to obtain oil D.

[0030] Synthesis of E: Add dioxane (50-200 ml) and D (5-20 g) to the reaction flask, stir to dissolve, continue to add 37% formaldehyde aqueous solution (10-40 ml) and acetic acid (10-30 ml) and react at room temperature for 1 hour, add sodium borohydride (0.01-0.5 g) in batches, control the temperature to 0-10°C, after the addition is completed, continue to keep warm and stir for 30 minutes, add water (10-30 ml), add 10N sodium hydroxide aqueous solution dropwise to adjust the pH of the system to 11-12, add methyl tert-butyl ether (20-70 ml) for extraction, separate the liquids, and continue to wash the organic phase with saturated brine (10-50 ml), separate the liquids, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain oily substance E.

[0031] Synthesis of 5-methoxylaudanine tartrate: Add E (5-20 g) and ethyl acetate (50-200 ml) to the reaction flask, stir to dissolve, continue to add L-tartaric acid (1-10 g), raise the temperature to 80-85 ° C, reflux for 2 hours, cool to 0-10 ° C, keep warm for 1 hour for crystallization, filter, rinse the filter cake with methyl tert-butyl ether, and dry to obtain solid 5-methoxylabdanine tartrate.

[0032] The present invention adds 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride to catalyze the reaction, so that 3,4,5-trimethoxyphenylacetic acid and 3,4-dimethoxyphenylethylamine react in dichloromethane at 25°C to obtain a condensation product, which greatly reduces the reaction temperature and reaction time. The ring-closing reaction is purified and crystallized in a methanol and water system, and the product is obtained after direct filtration, which improves the reaction yield and simplifies the operation. Acetic acid and formaldehyde are added to react, and then sodium borohydride is used for reduction so that the reaction can proceed well, thereby obtaining relatively pure 5-methoxylaudanine, and then tartaric acid is salified to form a solid that can be stably stored.

[0033] The present invention explores a process route suitable for industrialized scale-up production, which is simple to operate, low-cost, and economical and efficient through innovative optimization of process conditions. The reaction conditions are mild, the purity of the product can reach more than 98%, and the total yield is increased to more than 65%.

[0034] The technical principle of the present invention is described above in combination with the specific embodiments, which are only preferred implementations of the present invention. The protection scope of the present invention is not limited to the above embodiments, and all technical solutions under the idea of ​​the present invention belong to the protection scope of the present invention. Those skilled in the art can think of other specific implementations of the present invention without creative work, and these methods will fall within the protection scope of the present invention.

Claims

1. A synthesis process of 5-methoxylabdanine tartrate, characterized in that: The following steps are involved: , where A is ; B is ; C is ; D is ; E is .

2. A process for synthesizing 5-methoxylabdanine tartrate according to claim 1, characterized in that: Add 3,4,5-trimethoxyphenylacetic acid, 3,4-dimethoxyphenylethylamine and dichloromethane to the reaction flask, stir to dissolve, continue to add condensation agent, stir at room temperature overnight, react completely, add water to wash, separate the liquids, continue to wash the organic phase with saturated brine, separate the organic phase, add anhydrous sodium sulfate to dry, filter, concentrate the filtrate, add n-heptane dropwise to crystallize, filter, and dry to obtain solid B.

3. A process for synthesizing 5-methoxylabdanine tartrate according to claim 2, characterized in that: Add solid B to the reaction flask, stir with toluene, continue to add phosphorus oxychloride and heat the reaction until the raw material disappears, cool down, concentrate the system to dryness, add to the purification system and stir until completely dissolved, add 10N sodium hydroxide aqueous solution dropwise to adjust the pH of the system, cool down, filter, and dry to obtain solid C.

4. A process for synthesizing 5-methoxylabdanine tartrate according to claim 3, characterized in that: Add solid C to the reaction flask, stir with methanol, add sodium borohydride in batches, heat up and react until the raw material disappears, cool down, add water, saturated brine, and dichloromethane, stir, separate the liquids, continue to extract the aqueous phase with dichloromethane, combine the organic phases, wash once with saturated brine, separate the organic phase, and concentrate to obtain oil D.

5. A process for synthesizing 5-methoxylabdanine tartrate according to claim 4, characterized in that: Add dioxane to the reaction flask, stir the oily substance D to dissolve, continue to add formaldehyde aqueous solution, react with acetic acid at room temperature, add sodium borohydride in batches, control the reaction temperature, and continue to keep warm and stir after the addition is completed. Add water, dropwise add 10N sodium hydroxide aqueous solution to adjust the pH of the system, add methyl tert-butyl ether to extract, separate the liquids, continue to wash the organic phase with saturated brine, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain oily substance E. The reaction temperature is -10-100°C.

6. A process for synthesizing 5-methoxylabdanine tartrate according to claim 5, characterized in that: Add oily substance E to the reaction flask, stir the solvent to dissolve, continue to add L-tartaric acid, heat up and reflux to react, cool down, keep warm for crystallization for 1 hour, filter, rinse the filter cake with methyl tert-butyl ether, and dry to obtain solid 5-methoxylabdanine tartrate.

7. A process for synthesizing 5-methoxylabdanine tartrate according to claim 2, characterized in that: The condensation agent is one of EDCI, DCC, HATU, DIC, HBTU and HOBt.

8. A process for synthesizing 5-methoxylabdanine tartrate according to claim 3, characterized in that: The purification system is one of methanol and water, ethanol and water, isopropanol and water, ethyl acetate and water, ethanol and ethyl acetate, methanol and ethyl acetate, and methanol and methyl tert-butyl ether.

9. A process for synthesizing 5-methoxylabdanine tartrate according to claim 6, characterized in that: The solvent is at least one of ethyl acetate, methanol, ethanol, tetrahydrofuran, dioxane and n-heptane.

Images