A kind of preparation method of high-purity arecoline hydrobromide

Abstract

The invention provides a method for preparing high-purity arecoline hydrobromide, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: (1) using methanol as a solvent, methyl acrylate A and methylamine aqueous solution B are subjected to addition reaction to obtain product C; (2) using toluene as a solvent, product C and sodium methoxide are subjected to ring-closing reaction to obtain product D; (3) using methanol as a solvent, product D and sodium borohydride are subjected to reduction reaction to obtain product E; (4) using toluene as a solvent, product E is dehydrated under acidic conditions to obtain arecoline hydrobromide; the preparation method uses methyl acrylate as a starting material, sequentially undergoes methylamine addition, sodium methoxide ring closure, sodium borohydride reduction, and dehydration under acidic conditions, and purifies the salt to obtain arecoline hydrobromide. The method is simple, and the final product has a yield of more than 70% and a purity of more than 99%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing high-purity arecoline hydrobromide. Background Art

[0002] Arecoline is an organic compound with the chemical formula C8H 13 NO2, oily liquid in nature. Arecoline hydrobromide is a colorless crystal with a bitter taste, soluble in water and ethanol. Arecoline is used in medicine to treat glaucoma and can paralyze tapeworms, so it is also used as an anthelmintic, which is more effective than pumpkin seeds. It is clinically used to treat postpartum uterine bleeding, poor uterine involution, menorrhagia, etc. It is a cholinergic drug that can shrink the pupil and reduce intraocular pressure, and is suitable for relieving the symptoms of acute cataracts.

[0003] There are three main methods for preparing arecoline hydrobromide:

[0004] First, patent CN101029019A discloses a new process for large-scale extraction and separation of arecoline, which represents a plant extraction method. The main process is to crush the stems, leaves, flowers, fruits and seeds of plants containing arecoline, soak them in extracts, enrich them with macroporous resins, elute and concentrate them, and purify them into salts. The disadvantages are high yield, low cost and high energy consumption.

[0005] Secondly, patent CN1990472A discloses a method for preparing arecoline or its analogs, which represents the preparation method of nicotinic acid, which is methylated by methyl iodide to form an ester, reduced by borohydride, and purified to form a salt. The disadvantage is that the yield is low, the reduced intermediate has a dienophilic structure, and side reactions are very likely to occur, resulting in a low yield.

[0006] Thirdly, patent CN112694436A discloses that methyl 3-bromopropionate is used as a starting material, and arecoline is obtained by sequentially undergoing sodium methoxide Claisen ester condensation, methylamine ring closure, sodium borohydride reduction and dehydration under alkaline conditions.

[0007] Although it is an improvement over the previous two methods, it is still not cost-effective enough.

[0008]

[0009] Since the known methods cannot fully meet the requirements in the industrial and biomedical fields in terms of selectivity, cost, yield, etc., there is still a need for a method for efficiently preparing arecoline that is suitable for industrial scale-up. Summary of the invention

[0010] Based on the deficiencies in the prior art, the present invention aims to provide a method for preparing high-purity arecoline hydrobromide. The preparation method uses methyl acrylate as a starting material, sequentially undergoes methylamine addition, sodium methoxide ring closure, sodium borohydride reduction, and dehydration under acidic conditions to purify the salt to obtain arecoline hydrobromide.

[0011] A method for preparing high-purity arecoline hydrobromide comprises the following steps:

[0012] (1) With methanol as solvent, methyl acrylate A and methylamine aqueous solution B undergo addition reaction to obtain product C;

[0013] (2) Using toluene as solvent, product C undergoes a ring-closing reaction with sodium methoxide to obtain product D;

[0014] (3) Using methanol as solvent, product D is reduced with sodium borohydride to obtain product E;

[0015] (4) Using toluene as solvent, product E is dehydrated under acidic conditions to obtain arecoline hydrobromide.

[0016] The reaction route is:

[0017]

[0018] The molar ratio of methyl acrylate to methylamine in the above step (1) is 2-2.5:1-1.5; preferably 2-2.5:1-1.2; more preferably 2-2.5:1.

[0019] The mass volume ratio of methyl acrylate and methanol in the above step (1) is 1-1.5:1.0-2, g / mL; preferably 1-1.5:1.1-1.5, g / mL; more preferably 1-1.5:1.15, g / mL.

[0020] The mass fraction of the methylamine aqueous solution in the above step (1) is 20-30%, preferably 25%.

[0021] The methylamine aqueous solution in the above step (1) is added to methyl acrylate under ice bath conditions, and reacted at room temperature for 1-50 hours, preferably 24 hours; or, the methylamine aqueous solution is added to methyl acrylate at 0-5°C, and reacted at 0-5°C for 1-50 hours, preferably 40 hours.

[0022] The above step (1) needs to be carried out under sealed conditions, and the reaction product can be directly used in the next step without purification.

[0023] The product C described in the above step (2) needs to be dissolved in toluene, heated to remove water, cooled to room temperature, and then sodium methoxide is added to react.

[0024] The mass volume ratio of the product C described in the above step (2) to toluene is 1-1.5:2.5-10, g / mL.

[0025] The heating temperature is 110-130°C, preferably 120°C.

[0026] The molar ratio of the product C to sodium methoxide in the above step (2) is 1-1.1:1.1-3.

[0027] The reaction temperature in the above step (2) is 80-100°C and the reaction time is 4-5h.

[0028] The mass volume ratio of the product D described in the above step (3) to methanol is 1-1.5:5-30, g / mL.

[0029] The mass ratio of the product D in the above step (3) to sodium borohydride is 1-1.1:0.1-2; preferably 1:0.5.

[0030] The sodium borohydride described in step (3) above is added to the product D under ice bath conditions, and reacted at room temperature for 1-3 hours, preferably 2 hours; or, the sodium borohydride described in step (3) above is added to the product D under 0-5°C conditions, and reacted at 0-5°C for 1-30 hours, preferably 24 hours.

[0031] The mass volume ratio of the product E described in the above step (4) to toluene is 1-1.5:5-30, g / mL.

[0032] The reagent used for dehydration is thionyl chloride or methanesulfonyl chloride; the mass volume ratio of the product E to thionyl chloride is 1-1.1:0.5-5, g / mL; the mass volume ratio of the product E to methanesulfonyl chloride is 2-2.5:1-1.5, g / mL.

[0033] The reaction temperature of the above step (4) is 80-100°C and the reaction time is 2h.

[0034] As a preferred embodiment, the method for preparing high-purity arecoline hydrobromide comprises the following steps:

[0035] S1. Using methanol as solvent, methyl acrylate A and methylamine aqueous solution B are subjected to addition reaction for 1-50 hours to obtain product C. The reaction product can be directly used in the next step reaction without purification;

[0036] S2, using toluene as solvent, heating the product C to remove water and cooling to room temperature, and then reacting with sodium methoxide at 80-100°C for 4-5h to obtain the product D after post-treatment;

[0037] S3, using methanol as solvent, sodium borohydride was added to product D in batches for reduction reaction, and product E was obtained after post-treatment;

[0038] S4. Using toluene as solvent, slowly add a dehydrating agent to the product E. Under nitrogen protection, react at 80-100°C for 2h. After post-treatment, arecoline hydrobromide is obtained.

[0039] The post-treatment described in the above step S2 is: quenching the reaction with hydrochloric acid, separating the liquids, washing the toluene phase with a small amount of hydrochloric acid, combining the aqueous phases, adjusting the pH to alkaline with sodium bicarbonate, extracting twice with DCM (dichloromethane), combining and concentrating, and obtaining product D.

[0040] The post-treatment described in the above step S3 is: quenching with aqueous ammonium chloride solution, concentrating to remove methanol, and extracting and concentrating with DCM to obtain product E.

[0041] The post-treatment described in the above step S4 is: after the reaction solution is concentrated, it is dissolved with EA (ethyl acrylate), the pH is adjusted to neutral with sodium bicarbonate, filtered, the filter cake is washed with EA, the EA phase is stirred and slowly added with hydrobromic acid and acetic acid solution until crystals are precipitated, the temperature is controlled at 0-5°C in an ice bath to crystallize for 2h, filtered and collected, and dried to obtain arecoline hydrobromide.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] (1) The preparation method uses methyl acrylate as the starting material, and sequentially undergoes methylamine addition, sodium methoxide ring closure, sodium borohydride reduction, and dehydration under acidic conditions to purify the salt to obtain arecoline hydrobromide.

[0044] (2) The preparation method is simple, and the final product yield is greater than 55% and the purity is greater than 99%. DETAILED DESCRIPTION

[0045] The present invention is further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

[0046] The reaction route is:

[0047]

[0048] Example 1

[0049] (1) Synthesis of product C:

[0050]

[0051] Methyl acrylate A (481 g, 5.6 mol) was dissolved in methanol (500 mL), and 25% methylamine aqueous solution B (347 mL, 2.8 mol) was added dropwise to the system under ice bath. The reaction was allowed to proceed overnight at room temperature. TLC (iodine dye) detected that the reaction was complete. The product C was concentrated to obtain 411 g, with a yield of 72% and a purity of 95%. The product was directly used in the next step without purification.

[0052] (2) Synthesis of product D:

[0053]

[0054] Raw material C (411 g, 2.0 mol) was dissolved in toluene (1 L), heated to 120 ° C to remove water, cooled to room temperature, added with sodium methoxide (112 g, 3.0 mol) and reacted at 100 ° C for 4 h. TLC iodine color development showed that the reaction was complete. The mixture was cooled to room temperature and quenched with 1N hydrochloric acid (500 mL × 2). The liquids were separated, and the toluene phase was washed with an appropriate amount of 1N hydrochloric acid. The liquids were separated, the aqueous phases were combined, the pH was adjusted to alkaline with sodium bicarbonate, and the product D was extracted twice with DCM and concentrated to obtain 220 g of product D with a yield of 70% and a purity of 95%.

[0055] (3) Synthesis of Product E:

[0056]

[0057] Product D (36 g, 209 mmol) was dissolved in methanol (360 mL), and sodium borohydride (4.0 g, 104 mmol) was added to the system in batches under an ice bath. The reaction was carried out at room temperature for 2 h. TLC showed that the raw material disappeared. The product was quenched with aqueous ammonium chloride solution, and the methanol was concentrated. The product E was extracted and concentrated with DCM to obtain about 22 g of product E, with a yield of 67% and a purity greater than 95%.

[0058] (4) Synthesis of Arecoline Hydrobromide

[0059]

[0060] The raw material E (22 g, crude product) was dissolved in toluene (100 mL), and dichlorothionyl (15 mL) was slowly added. Under nitrogen protection, the reaction was heated at 100 ° C for 2 h. The sample was taken and the neutralization plate was taken. It showed that the raw material disappeared and a relatively pure product was generated. The product was concentrated and dissolved with EA (200 mL). The pH was adjusted to neutral with sodium bicarbonate. The product was filtered and the filter cake was washed with an appropriate amount of EA. The EA phase was stirred and hydrobromic acid acetic acid solution (20 mL, 114 mmol) was slowly added to crystals precipitate. The crystals were crystallized at 0-5 ° C in an ice bath for 2 h. The product was collected by filtration and dried to obtain 12.8 g of arecoline hydrobromide with a yield of 58%. The purity was 99.6% as measured by HPLC.

[0061] Example 2

[0062] (1) Synthesis of product C:

[0063]

[0064] Methyl acrylate A (860.4 g, 10.0 mol) was dissolved in methanol (1000 mL), and the temperature was controlled at 0-5 degrees in a low-temperature reactor. 25% methylamine aqueous solution B (608 mL, 4.9 mol) was added dropwise to the system, and the system was sealed with a balloon. The reaction was carried out at 0-5 degrees for 40 hours. The reaction was complete after TLC detection. The system was concentrated and the unreacted raw materials and solvent were dried by rotary evaporation to obtain 995 g of product C with a purity of 98.5% and a yield of 100%. The product was directly used in the next step without purification.

[0065] (2) Synthesis of product D:

[0066]

[0067] Raw material C (812 g, 4.0 M) was dissolved in toluene (2 L), heated to 120 ° C to remove water, cooled to room temperature, added with sodium methoxide (158 g, 4.1 M) and reacted at 80 ° C for 5 h. The reaction was complete by TLC iodine color development. The reaction was cooled to room temperature, quenched with 1N hydrochloric acid (1000 mL × 2), separated, and the toluene phase was washed with a small amount of 1N hydrochloric acid. The aqueous phases were combined, the pH was adjusted to alkaline with sodium bicarbonate, and the product D was extracted twice with DCM and concentrated to obtain 680 g of product D with a yield of 96%. The purity was 98% as measured by HPLC.

[0068] (3) Synthesis of Product E:

[0069]

[0070] Product D (108 g, 0.62 M) was dissolved in methanol (1000 mL) and the temperature was controlled at 0-5°C in a low-temperature reactor. Acetic acid (15 mL) was added, and solid sodium borohydride (12.0 g, 0.31 M) was weighed and added to the system in batches at 0-5°C. The reaction was carried out at 0-5°C overnight. TLC showed that the raw material disappeared. The mixture was quenched with aqueous ammonium chloride solution (50 mL), the methanol was concentrated, and the product E was extracted and concentrated with DCM to obtain about 100 g of product E with a yield of 93% and a purity of 97.5%.

[0071] (4) Synthesis of Arecoline Hydrobromide

[0072]

[0073] The raw material E (100 g) was dissolved in toluene (500 mL), and methanesulfonyl chloride (45 mL) was slowly added at room temperature under nitrogen protection. After the addition was completed, the mixture was stirred for 0.5 h, and then heated to 80 ° C for 2 h. The sample was taken and the neutralization plate was checked. It showed that the raw material disappeared and a pure product was generated. The mixture was concentrated and dissolved with EA (800 mL). The pH was adjusted to neutral with an appropriate amount of sodium bicarbonate. The mixture was filtered and the filter cake was washed with an appropriate amount of EA. The EA phase was stirred and slowly dripped with hydrobromic acid acetic acid solution (95 mL, 0.54 M) to precipitate crystals. The mixture was crystallized by controlling the temperature at 0-5 ° C in an ice bath for 2 h. The filter cake was collected by filtration and washed with an appropriate amount of EA. It was dried to obtain 125 g of arecoline hydrobromide with a yield of 92%. The purity was 99.9% as measured by HPLC.

[0074] Comparative Example 1

[0075] The condensation conditions of methyl acrylate and methylamine in WO02088080A2 were used to obtain C

[0076] Add dimethyl acrylate (17.7 g) and 20 mL of methanol into a 100 mL sealed tube reactor, add methylamine aqueous solution (12.7 mL), seal the tube, place in a 100 °C oil bath to react for 8 h, cool to room temperature, release the pressure and take a sample. TLC shows that the target product is produced, but the system is messy and needs to be purified by column chromatography.

[0077] Comparative Example 2

[0078] Arecoline is obtained by removing the hydroxyl group under the conditions in CN112694436A:

[0079] E (2 g), 10 mL of methanol and crushed sodium hydroxide (0.44 g) were added to the reaction flask and refluxed for 3 h. The TLC plate showed that the starting material disappeared, the system was chaotic, and there was no obvious target product point. The repeated experiment failed.

[0080] Comparative Example 3

[0081] Using CN1990472, nicotinate methyl salt is reduced to obtain arecoline:

[0082] Add nicotinate methylonium salt (2 g) and 10 mL of acetic acid to the reaction bottle, add an appropriate amount of sodium borohydride, and react at room temperature for 3 hours. The TLC on the central control plate shows that the raw material has not reacted completely. Overnight, TLC shows that the target product spots are generated, but they are messy and difficult to purify.

[0083] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing high-purity arecoline hydrobromide, characterized in that: The steps include: S1. Using methanol as solvent, methyl acrylate A and methylamine aqueous solution B are subjected to addition reaction to obtain product C, which can be directly used in the next step reaction without purification; the molar ratio of methyl acrylate to methylamine is 2-2.5:1-1.5; the mass fraction of the methylamine aqueous solution is 20-30%; S2, using toluene as solvent, heating the product C to remove water and cooling to room temperature, and then reacting with sodium methoxide at 80-100° C. for 4-5 hours to obtain the product D after post-treatment; the molar ratio of the product C to the sodium methoxide is 1-1.1:1.1-3; S3, using methanol as solvent, sodium borohydride was added to product D in batches for reduction reaction, and product E was obtained after post-treatment; the mass ratio of product D to sodium borohydride was 1-1.1:0.1-2; S4, using toluene as solvent, slowly adding dehydrating agent methanesulfonyl chloride to product E, reacting at 80-100°C for 2h under nitrogen protection, and obtaining arecoline hydrobromide after post-treatment; The post-treatment described in step S4 is as follows: after the reaction solution is concentrated, it is dissolved with EA, the pH is adjusted to neutral with sodium bicarbonate, filtered, the filter cake is washed with EA, the EA phase is stirred and slowly added with hydrobromic acid and acetic acid solution until crystals are precipitated, the temperature is controlled at 0-5° C. in an ice bath to crystallize for 2h, filtered and collected, and dried to obtain arecoline hydrobromide; The mass volume ratio of the product E to methanesulfonyl chloride is 2-2.5:1-1.5, g / mL; The reaction route is: 。 2. The preparation method according to claim 1, characterized in that: The post-treatment in step S2 is as follows: quenching the reaction with hydrochloric acid, separating the liquids, washing the toluene phase with a small amount of hydrochloric acid, combining the aqueous phases, adjusting the pH to alkaline with sodium bicarbonate, extracting twice with DCM, combining and concentrating, and obtaining product D; The post-treatment described in step S3 is: quenching with aqueous ammonium chloride solution, concentrating to remove methanol, and extracting and concentrating with DCM to obtain product E.

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