A method for efficiently synthesizing N-benzyltropine, an intermediate of maraviroc

Abstract

A method for efficiently synthesizing N-benzyltropine, an intermediate of maraviroc, belongs to the technical field of pharmaceutical intermediates. By using an Rh660 catalyst in the ketoxime reduction reaction to replace the traditional reduction conditions with metallic sodium, the reaction scheme is optimized, significantly improving the reaction yield while reducing the risk of the reaction. Recycling the reaction catalyst does not increase production costs. Because of the increased reaction conversion rate, separation and purification of the intermediates in each step are no longer necessary; simply controlling the order of addition allows the reaction to proceed directly. This improves the generation of pollutants during the reaction and reduces environmental pollution. The optimized reaction scheme improves yield, reduces costs, and is environmentally friendly, meeting the requirements of green and modern production.

Description

Technical Field

[0001] The present invention relates to a method for developing an efficient synthesis method of a maraviroc intermediate N-benzyltropine, belonging to the technical field of pharmaceutical intermediates. Background Art

[0002] N-Benzyltropine is a pharmaceutical intermediate primarily used in the synthesis of maraviroc. Maraviroc is an anti-HIV drug. It is a CCR5 receptor antagonist, a necessary pathway for HIV infection. Therefore, it can be used as a broad-spectrum anti-HIV drug. Therefore, maraviroc has a promising market prospect.

[0003] However, traditional processes present several challenges, particularly in the synthesis of N-benzyltropine. The use of metallic sodium for reduction significantly impacts the reaction environment, resulting in low safety, long reaction times, high temperatures, and poor yields. Furthermore, these processes generate large amounts of waste water and organic solvents, creating significant environmental hazards. Furthermore, the reaction exhibits poor selectivity and makes purification of the final product difficult, increasing costs and bringing unavoidable harm to both humans and the environment. Therefore, improvements and optimization are needed to address these steps. Summary of the Invention

[0004] To address the problems existing in the prior art, the present invention provides a method for efficiently synthesizing N-benzyltropine, an intermediate of maraviroc; the purpose is to use Rh660 ((-)-1,2-bis((2R,5R)-2,5-diethylphosphonate)benzene(1,5-cyclooctadiene)rhodium tetrafluoroborate (I)) catalyst during the reduction of ketoxime, so that the reduction can be carried out under a hydrogen atmosphere at room temperature and low pressure, thereby increasing the reaction yield of this step to over 95%. At the same time, the catalyst does not show a significant decrease in catalytic activity after 20 cycles. This can avoid the increase in production costs caused by the use of the catalyst, and the process reduces environmental pollution and the difficulty of post-processing; it is also easy to operate and simple to handle. The use of this optimized synthetic route has many advantages, such as significantly increased yield, reduced cost, improved safety, and energy savings, and meets the requirements of modern chemical production for green reactions.

[0005] Catalyst name details Rh660 ((-)-1,2-bis((2R,5R)-2,5-diethylphosphonate)benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate) CAS: 228121-39-9.

[0006] The technical solution adopted by the present invention is: a method for synthesizing the maravirol intermediate N-benzyltropine, the structural formula of the maravirol intermediate N-benzyltropine is as follows:

[0007]

[0008] The method comprises the following steps:

[0009]

[0010] 2,5-Dimethoxytetrahydrofuran and dilute hydrochloric acid were sequentially added to the reaction flask and heated for reaction. After the reaction, the reaction solution was cooled to 0°C, and acetone dicarboxylic acid, concentrated hydrochloric acid, sodium acetate, and benzylamine were sequentially added. The temperature was then raised to room temperature and kept warm for 10-14 hours. The solution was filtered and the filtrate was adjusted to neutral with sodium hydroxide, extracted twice with ethyl acetate, and concentrated to obtain N-benzyltropinone.

[0011] The concentration of the dilute hydrochloric acid is 0.5-2M; the dosage ratio of the 2,5-dimethoxytetrahydrofuran: dilute hydrochloric acid is (6-28) g: 100 mL;

[0012] The molar ratio of acetone dicarboxylic acid: sodium acetate: benzylamine is (1.1-1.2): (1.1-1.2): 1;

[0013]

[0014] Add N-benzyltropinone, methanol, hydroxylamine hydrochloride and sodium bicarbonate to the reaction flask in sequence, heat and reflux for 3 to 5 hours, concentrate the reaction solution until there is no fraction, add water to the reaction kettle, stir at 20 to 25°C, filter and dry to obtain N-benzyltropinone oxime;

[0015] The molar ratio of N-benzyltropinone:hydroxylamine hydrochloride:sodium bicarbonate is 1:(1.05-1.1):(1.05-1.1);

[0016]

[0017] N-benzyltropine oxime, ethanol, and catalyst Rh660 were added to a reaction flask, and the atmosphere was replaced with nitrogen and then with hydrogen. The reaction was carried out at 20-25° C. and a hydrogen pressure of 0.5-1.0 MPa for 4-6 hours. After the reaction was completed, the reaction solution was filtered and concentrated until there was no fraction to obtain N-benzyltropine amine.

[0018] The amount of the catalyst Rh660 used is 0.2%-0.4% by weight of N-benzyltropine oxime. Further, the method comprises the following steps:

[0019] (1) 2,5-Dimethoxytetrahydrofuran and 1N HCl were added to a three-necked flask in sequence. The reaction solution was heated to 70°C and kept warm for 1 hour. The reaction solution was cooled to 0°C and acetone dicarboxylic acid, concentrated hydrochloric acid, sodium acetate and benzylamine were added in sequence. The temperature was then raised to room temperature and kept warm for 12 hours. The solution was filtered and the filtrate was adjusted to neutral with sodium hydroxide. The solution was extracted twice with ethyl acetate and concentrated to obtain crude N-benzyltropine.

[0020] (2) Add N-benzyltropine, methanol, hydroxylamine hydrochloride and sodium bicarbonate to the reaction flask in sequence, heat to reflux for 3 to 5 hours, concentrate the reaction solution until there is no fraction, add water to the reactor, stir at 20 to 25°C for 2 hours, filter and dry to obtain N-benzyltropine oxime.

[0021] (3) Add N-benzyltropine oxime, ethanol, and Rh660 to a reaction flask, replace the atmosphere with nitrogen three times, and replace the atmosphere with hydrogen three times. The reaction is carried out at 20-25° C. and a hydrogen pressure of 0.5-1.0 MPa for 4-6 hours. After the reaction is completed, the reaction solution is filtered and concentrated until there is no fraction to obtain N-benzyltropine amine.

[0022] The present invention has the following beneficial effects: Maraviroc, a very important pharmaceutical product with significant medical applications, is in high demand. The catalyst Rh660 is used in the reduction of N-benzyltropine ketone oxime to produce N-benzyltropine amine, directly and selectively reducing the ketone oxime to N-benzyltropine amine, reducing isomer formation and significantly improving product yield. This preparation process is inexpensive, operates under mild reaction conditions, minimizes environmental pollution, and offers a high safety factor. The yield of this step can be increased to over 98% at room temperature. This process replaces the traditional method of reducing N-benzyltropine ketone with metallic sodium, reducing reaction risk, increasing reaction conversion, simplifying the process, and lowering equipment requirements. Furthermore, after 20 cycles of Rh660, the catalyst activity does not significantly decrease. Furthermore, after this modified reaction, the final product does not require purification, significantly simplifying the production process and reducing environmental pollution caused by the organic solvent used for purification, resulting in a very high purity final product. This process reduces environmental pollution and post-processing difficulties, and is easy to operate and handle. The optimized synthesis route has many advantages, such as greatly improved yield, reduced cost, improved safety, and energy saving, and meets the modern chemical production requirements of green reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the liquid phase diagram of N-benzyltropine. DETAILED DESCRIPTION

[0024] The present invention will be further described below by way of examples for the purpose of providing a better understanding of the present invention. Therefore, the examples given do not limit the scope of protection of the present invention.

[0025] Example 1: N-Benzyltropine

[0026]

[0027] 2,5-Dimethoxytetrahydrofuran (132.16 g 1.0 mol) was dissolved in 1N HCl (1000 mL) and heated to 70°C for 1 hour. The reaction mixture was cooled to 0°C and acetone dicarboxylic acid (160.71 g, 1.1 mol), 110 ml of concentrated hydrochloric acid, sodium acetate (90.2 g, 1.1 mol) and benzylamine (107.16 g, 1.0 mol) were added in sequence. The mixture was then heated to room temperature and kept warm for 12 hours. The mixture was filtered and the filter cake was rinsed with 200 mL of water. The filtrate was adjusted to neutral with solid sodium hydroxide and extracted twice with 500 mL of ethyl acetate. The organic layer was washed twice with 200 mL of water and concentrated to give 215.3 g of crude N-benzyltropinone with a purity of 98.5% and a yield of 100%.

[0028] Example 2: N-Benzyltropine oxime

[0029]

[0030] 215.3 g (1.0 mol) of N-benzyltropine, methanol (600 mL), hydroxylamine hydrochloride (73.0 g, 1.05 eq.) and sodium bicarbonate (88.2 g, 1.05 eq.) were added to the reaction flask in sequence and heated to reflux for 3 to 5 hours. After the reaction was completed, the reaction solution was concentrated until there was no fraction. Water (800 mL) was added dropwise to the reactor, and the temperature was lowered to 20 to 25° C., stirred for 2 h, filtered, and dried to obtain 216.3 g of N-benzyltropine oxime with a purity of 99.2% and a yield of 93.9%.

[0031] Example 3: N-Benzyltropine

[0032]

[0033] 216.3 g (0.939 mol) of N-benzyltropine oxime, 600 mL of ethanol, and 0.648 g of catalyst (0.3% of the amount of N-benzyltropine oxime) were added to a reaction flask, and the atmosphere was replaced with nitrogen three times and hydrogen three times. The reaction was carried out at 20-25° C. and a hydrogen pressure of 0.5-1.0 MPa for 4-6 hours. After the reaction was completed, the reaction solution was filtered, the catalyst was recovered and reused, and the reaction solution was concentrated until there was no fraction to obtain 199.1 g of N-benzyltropine amine with a purity of 99.8% and a yield of 98.0%. The liquid phase spectrum was shown in FIG. Figure 1 shown.

[0034] Table 1 Comparison of catalytic effects of Rh660 after 20 cycles

[0035]

[0036] Example 4: Comparison of yield and cost between the new process and the traditional process

[0037] Table 2 Yield balance between new process and traditional process

[0038]

[0039] As shown in Table 2 above, the total yield of N-benzyltropine amine in the traditional process was 59.3%, while the new process achieved a total yield of 92.0%, increasing the yield from 128.2 g to 199.1 g. This not only reduced costs but also increased yield, boosting factory revenue and profits. The purity of the final product also increased, meeting pharmaceutical requirements. The improved process significantly enhances safety and environmental performance, making post-processing relatively easy and environmentally friendly.

Claims

1. A method for synthesizing the maraviroc intermediate N-benzyltropine, characterized in that: The method comprises the following steps: 2,5-Dimethoxytetrahydrofuran and dilute hydrochloric acid were sequentially added to the reaction flask and heated for reaction. After the reaction, the reaction solution was cooled to 0°C, and acetone dicarboxylic acid, concentrated hydrochloric acid, sodium acetate, and benzylamine were sequentially added. The temperature was then raised to room temperature and kept warm for 10-14 hours. The solution was filtered and the filtrate was adjusted to neutral with sodium hydroxide, extracted twice with ethyl acetate, and concentrated to obtain N-benzyltropinone. The concentration of the dilute hydrochloric acid is 0.5-2M; the dosage ratio of the 2,5-dimethoxytetrahydrofuran: dilute hydrochloric acid is (6-28) g: 100 mL; The molar ratio of acetone dicarboxylic acid: sodium acetate: benzylamine is (1.1-1.2): (1.1-1.2): 1; Add N-benzyltropinone, methanol, hydroxylamine hydrochloride and sodium bicarbonate to the reaction flask in sequence, heat and reflux for 3 to 5 hours, concentrate the reaction solution until there is no fraction, add water to the reaction kettle, stir at 20 to 25°C, filter and dry to obtain N-benzyltropinone oxime; The molar ratio of N-benzyltropinone:hydroxylamine hydrochloride:sodium bicarbonate is 1:(1.05-1.1):(1.05-1.1); N-benzyltropine oxime, ethanol, and catalyst Rh660 were added to a reaction flask, and the atmosphere was replaced with nitrogen and then with hydrogen. The reaction was carried out at 20-25° C. and a hydrogen pressure of 0.5-1.0 MPa for 4-6 hours. After the reaction was completed, the reaction solution was filtered and concentrated until there was no fraction to obtain N-benzyltropine amine. The amount of the catalyst Rh660 is 0.2%-0.4% by weight of N-benzyltropine oxime; The catalyst Rh660 is (-)-1,2-bis((2R,5R)-2,5-diethylphosphonate)benzene(1,5-cyclooctadiene)rhodium tetrafluoroborate(I).

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