Method for synthesizing aprepitant intermediate through hydrogenation
By using microchannel reactors and specific process in aprepitane intermediate synthesis, the problems of increased by-products and decreased yields in the prior art are solved, and efficient and high-purity aprepitane intermediate synthesis is achieved, which is suitable for laboratory and industrial production.
Patent Information
- Application Number
- CN202510046864.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-13
- Publication Date
- 2025-05-30
AI Technical Summary
When the prior art amplifies and synthesizes key intermediates of aprepitane, the by-products increase and the yield decreases, resulting in unfavorable industrial production.
The microchannel reactor is combined with a specific process, and hydrogenation is carried out through the process routes from steps S1 to S4, including dropping the tetrahydrofuran solution of 4-fluorophenylmagnesium bromide in the range of 5 to 15°C to form an intermediate reaction solution, and then mixed with a palladium carbon catalyst, a mixed gel solution of p-toluenesulfonic acid and methanol in the microchannel reactor, hydrogen gas is used for catalytic hydrogenation reaction, and finally obtain aprepitant intermediate through post-treatment.
It significantly reduces the occurrence of side reactions, improves the yield and purity of the product, and achieves a yield of 92.7% to 93.2% and 99.9% purity under laboratory and industrial scale, with good industrial application prospects.
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Figure CN120058632A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of aprepitant drug synthesis, and particularly relates to a method for hydrogenating and synthesizing an aprepitant intermediate. Background Art
[0002] Aprepitant was first approved by the US Food and Drug Administration (FDA) for marketing by Merck & Co., Inc. on March 26, 2003, under the trade name Eend. Its Chemical Abstracts Service (CAS) registry number is 170729-80-3, and its structural formula is as Figure 1 shown.
[0003] Aprepitant is a high-affinity NK-1 receptor inhibitor and a new type of antiemetic drug. It is used to prevent acute and delayed nausea and vomiting caused by chemotherapy. It can cross the blood-brain barrier and occupy the NK-1 receptors in the brain, with high selectivity and affinity. Since its affinity for NK-2 and NK-3 receptors is relatively low, its effect of reducing nausea and vomiting is significantly better than that of other drugs. Therefore, this drug has a good market prospect.
[0004] (2R,3S)-2-[(IR)-1-[3,5-Bis(difluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine hydrochloride is a key intermediate for the preparation of aprepitant, and its structural formula is as Figure 2 shown.
[0005] Currently, there are many routes for synthesizing this aprepitant intermediate. Among them, the preparation method reported in Organic Process Research & Development 2006, 10, 109-117 has relatively high feasibility, and the process route is as Figure 3 shown.
[0006] In this method, a tetrahydrofuran solution of phenylmagnesium bromide fluoride is dropped into a tetrahydrofuran solution of compound I. After the reaction is completed, a methanol solution of p-toluenesulfonic acid is added for quenching, and then palladium on carbon is added for catalytic hydrogenation. After the reaction solution is extracted and concentrated, the residue is salted with hydrochloric acid and then crystallized in methyl isobutyl ketone, and the target compound III is obtained by filtration and drying. Summary of the Invention
[0007] In the implementation process of the present invention, it is found that when using the method reported in the literature, good product purity and yield can be obtained in the small-scale test stage. However, after scaling up to the pilot scale, the by-products increase and the yield decreases. Further comparative studies show that the system is still in an unstable state after quenching with a methanol solution of p-toluenesulfonic acid, and the extended operation time due to scaling up leads to more side reactions, which is not conducive to industrial production scale-up.
[0008] In view of the problem that the increase in by-products in the prior art during the amplification synthesis of the key intermediate of aprepitant leads to a decrease in purity and yield, the present invention provides a new method for the hydrogenation synthesis of the intermediate of aprepitant.
[0009] The key intermediate of aprepitant is (2R,3S)-2-[(IR)-1-[3,5-bis(difluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine hydrochloride, abbreviated as aprepitant intermediate III. The process route for preparing the aprepitant intermediate in the present invention is as Figure 4 shown.
[0010] The method for the hydrogenation synthesis of the aprepitant intermediate provided by the present invention includes the following steps: Step S1: Dissolve (2R)-4-benzyl-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]morpholin-3-one in tetrahydrofuran, cool down to the range of 5-15 °C, and dropwise add a tetrahydrofuran solution of 4-fluorophenylmagnesium bromide to obtain an intermediate reaction solution; Step S2: Mix palladium-carbon catalyst, p-toluenesulfonic acid and methanol evenly to form a mixed colloidal solution; Step S3: Mix the intermediate reaction solution prepared in Step S1 with the mixed colloidal solution prepared in Step S2 in a microchannel reactor, introduce hydrogen, and keep the reaction temperature in the range of 15-30 °C to carry out catalytic hydrogenation reaction; Step S4: The reaction product obtained in Step S3 is post-treated to obtain the aprepitant intermediate.
[0011] As a further optimized scheme for the synthesis method of the aprepitant intermediate, in Step S1, the molar ratio of the starting material (2R)-4-benzyl-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]morpholin-3-one to 4-fluorophenylmagnesium bromide is 1:1 to 1:2.
[0012] As a further optimized scheme for the synthesis method of the aprepitant intermediate, in Step S2, the dosage of the palladium-carbon catalyst in the mixed colloidal solution is controlled to be 0.5%-1% of the mass of the starting material (2R)-4-benzyl-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]morpholin-3-one; the weight percentage of p-toluenesulfonic acid in the mixed colloidal solution is 20-30%.
[0013] As a further optimized scheme for the synthesis method of the aprepitant intermediate, in Step S3, the flow rate ratio of the intermediate reaction solution to the mixed colloidal solution is 1:1 to 2:1.
[0014] As a further optimized scheme for the synthesis method of the aprepitant intermediate, in Step S3, the pressure of hydrogen is 0.5-5 MPa.
[0015] As a further optimization scheme for the synthesis method of aprepitant intermediate, in step S3, adjust the flow rate ratio of the intermediate reaction solution to hydrogen so that the molar ratio of the intermediate compound in the intermediate reaction solution to hydrogen is 1:2 - 1:4.
[0016] As a further optimization scheme for the synthesis method of aprepitant intermediate, in step S3, the reaction residence time of the material in the microchannel is 5 - 8 min.
[0017] As a further optimization scheme for the synthesis method of aprepitant intermediate, in step S3, the palladium-carbon catalyst is 5% Pd / C, and the p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate.
[0018] As a further optimization scheme for the synthesis method of aprepitant intermediate, in step S4, filter the reaction solution obtained in step S3, concentrate the filtrate, add methyl isobutyl ketone, sodium bicarbonate and water for liquid separation, take the organic phase, add hydrochloric acid, cool down to 0 ± 5 °C for crystallization, filter, and dry to obtain the aprepitant intermediate.
[0019] As a further optimization scheme for the synthesis method of aprepitant intermediate, in step S4, the hydrochloric acid is 30% concentrated hydrochloric acid; the crystallization time is 2 - 3 h.
[0020] Beneficial effects By using a microchannel reactor in combination with a specific process to synthesize the key intermediate of aprepitant, the present invention can significantly reduce the occurrence of side reactions, and significantly improve the yield and purity of the product. The experimental results show that at the laboratory scale and industrial scale-up, the method of the present invention can obtain a yield of 92.7% to 93.2% and a purity of 99.9%. Especially in industrial scale-up production, the present invention has significant superiority compared with the existing schemes, providing a new, efficient and highly selective solution for the large-scale industrial production of the key intermediate of aprepitant. Description of the drawings
[0021] Figure 1 It is the molecular structure diagram of aprepitant.
[0022] Figure 2 It is the molecular structure diagram of the key intermediate of aprepitant.
[0023] Figure 3 It is the process route diagram of the preparation of aprepitant intermediate reported in the literature.
[0024] Figure 4 It is the process route diagram of the preparation of aprepitant intermediate of the present invention.
[0025] Figure 5 It is the liquid chromatogram of the analysis of the aprepitant intermediate product in Example 1.
[0026] Figure 6 For Figure 5 Statistical chart of retention time and peak area of each component in
[0027] Figure 7 Is the liquid chromatogram of aprepitant intermediate product analyzed in Example 2.
[0028] Figure 8 For Figure 7 Statistical chart of retention time and peak area of each component in
[0029] Figure 9 Is the 1H NMR spectrum of aprepitant intermediate product in Example 2.
[0030] Figure 10 Is the mass spectrum of aprepitant intermediate product in Example 2.
[0031] Figure 11 Is the liquid chromatogram of aprepitant intermediate product analyzed in Comparative Example 1.
[0032] Figure 12 For Figure 11 Statistical chart of retention time and peak area of each component in Detailed implementation manners
[0033] The present invention will be further illustrated by specific examples below. These examples are exemplary and are intended to illustrate and explain the present invention, rather than being a limitation.
[0034] Example 1 Add 50 g of starting material I and 60 ml of tetrahydrofuran to a 500 ml three-necked flask, stir well and cool down to 5 - 15 °C, dropwise add 151 ml of 1 mol / L 4-fluorophenylmagnesium bromide tetrahydrofuran solution, and keep the temperature at 20 °C - 25 °C for 1 h after the addition is completed.
[0035] 5.0 g of 5% Pd / C, 42.6 g of p-toluenesulfonic acid monohydrate and 160 ml of methanol were stirred well to form a homogeneous colloidal solution. The temperature of the microchannel reactor was maintained at 20 ± 5 °C. The intermediate reaction solution was used as liquid A, and the colloidal solution of palladium carbon and p-toluenesulfonic acid in methanol was used as liquid B. The flow rate ratio of liquid A to liquid B was adjusted to 1.2 / 1, and the pressure of hydrogen gas introduced was 2 MPa to form a gas-liquid mixing system in the pipeline reactor. The residence time of the feed liquid in the pipeline reactor was 6 - 7 min. The liquid flowing out of the pipeline reactor was directly filtered, and the filter cake was washed with 150 ml of methanol. The filtrate was concentrated to dryness, 350 ml of methyl isobutyl ketone, 35 g of sodium bicarbonate and 500 ml of water were added thereto, and after stirring well, the mixture was allowed to stand for liquid separation. 15 g of 30% concentrated hydrochloric acid was added to the organic phase, and the temperature was slowly lowered to 0 ± 5 °C for crystallization for 2 - 3 h, followed by filtration, and the filter cake was washed once with 50 ml of pre-cooled methyl isobutyl ketone and dried to obtain 49 g of white solid aprepitant intermediate III, with a yield of 92.7% and a purity of 99.9%. The product purity was obtained by quantitative analysis of liquid chromatography, and the obtained liquid chromatogram was as shown in Figure 5 shown, and the retention time and peak area of each component were as shown in Figure 6 shown.
[0036] Example 2 150 kg of starting material I and 160 kg of tetrahydrofuran were added to a 1000 L reactor A, stirred well and cooled to 5 - 15 °C, and a 450 kg solution of 1 mol / L 4-fluorophenylmagnesium bromide in tetrahydrofuran was added dropwise. After the addition was completed, the temperature was maintained at 20 °C - 25 °C for reaction for 1 h.
[0037] 15 kg of 5% Pd / C, 128 kg of p-toluenesulfonic acid monohydrate and 380 kg of methanol were pre-added to a 1000 L reactor B, the internal temperature was adjusted to 20 - 25 °C and kept stirring for 1 h. The flow rate ratio of the liquid from reactor A and reactor B entering the microchannel reactor was adjusted to 1.2 / 1, the pressure of hydrogen gas introduced was 2 MPa, and the residence time of the feed liquid in the pipeline reactor was 6 - 7 min. The liquid flowing out of the pipeline reactor directly entered the filter, and the microchannel pipeline and the filter cake were washed with 355 kg of methanol. The filtrate was transferred to a 2000 L reactor, and the pressure was reduced to distill at 40 - 50 °C until the distillate liquid was in drops. 840 kg of methyl isobutyl ketone, 105 kg of sodium bicarbonate and 1500 kg of water were added to the 2000 L reactor. After stirring well, the upper organic phase was separated by liquid separation, and the lower aqueous phase was discarded. 45 kg of 30% concentrated hydrochloric acid was slowly added dropwise to the 2000 L reactor, and the temperature was slowly lowered to 0 ± 5 °C for crystallization for 2 - 3 h, followed by centrifugation, and the centrifuged filter cake was rinsed with 120 kg of pre-cooled methyl isobutyl ketone and dried to obtain 148 kg of white solid aprepitant intermediate III, with a yield of 93.2% and a purity of 99.9%. The product purity was obtained by quantitative analysis of liquid chromatography, and the obtained liquid chromatogram was as shown in Figure 7as shown, where the retention time and peak area of each component are as Figure 8 shown.
[0038] The 1H NMR spectrum of the product aprepitant intermediate is as Figure 9 shown, 1H-NMR 400M, DMSO δ 7.89 s, 1H, 7.52 q, J = 4 Hz, 2H, 7.48 s, 2H, 7.21 t, J = 4 Hz, 2H, 5.02 q, J = 4 Hz, 1H, 4.73 d, J = 4 Hz, 1H, 4.61 s, 1H, 4.17 m, 1H, 3.86 d, J = 8 Hz, 1H, 3.34 d, J = 4 Hz, 1H, 1.45 d, J = 4 Hz, 3H. The mass spectrum of the product aprepitant intermediate is as Figure 10 shown, MS ESI: m / z 438 M+1. Both the 1H NMR spectrum and the mass spectrum verified the successful synthesis and high purity of the product aprepitant intermediate.
[0039] Comparative Example 1 Add 50 g of starting material I and 60 ml of tetrahydrofuran to a 500 ml three-necked flask, stir well and cool to 5 - 15 °C, add dropwise 151 ml of 1 mol / L 4-fluorophenylmagnesium bromide tetrahydrofuran solution. After the addition is complete, maintain the temperature at 20 - 25 °C and react for 1 h, then cool to 0 - 10 °C, slowly add 100 ml of methanol to quench, and then slowly dropwise add a solution containing 42.6 g of p-toluenesulfonic acid monohydrate and 60 ml of methanol solution, and let it stand at 0 - 10 °C for 2 h. Then add 5.0 g of 5% Pd / C, maintain at 20 - 25 °C, introduce hydrogen, maintain the pressure at 2 ± 0.2 MPa, hydrogenate for 2 - 8 h until the in-process inspection is complete, filter, wash with 150 ml of methanol, concentrate the filtrate to dryness, add 350 ml of methyl isobutyl ketone, 35 g of sodium bicarbonate and 500 ml of water thereto, stir well and let it stand for liquid separation. Add 15 g of 30% concentrated hydrochloric acid to the organic phase, start to slowly cool to 0 ± 5 °C for crystallization for 2 - 3 h, filter, wash once with 50 ml of pre-cooled methyl isobutyl ketone, and dry to obtain 39.6 g of a white solid aprepitant intermediate III, with a yield of 74.9% and a purity of 98.9%. The product purity was obtained by quantitative analysis of liquid chromatography, and the obtained liquid chromatogram is as Figure 11 shown, where the retention time and peak area of each component are as Figure 12 shown.
[0040] It can be seen that Example 1 and Example 2 were carried out on a laboratory scale and an industrial scale-up respectively, and finally aprepitant intermediate III with high yields of 92.7% and 93.2% and high purity of 99.9% was obtained. Comparative Example 1 used a traditional process for the hydrogenation reaction, with a yield of 74.9% and a purity of 98.9%, which were significantly lower than those of Example 1 and Example 2. Therefore, compared with the traditional batch process, using a microchannel reactor combined with a specific process for the hydrogenation reaction significantly reduced the operation time between quenching and catalytic hydrogenation, significantly reduced the occurrence of side reactions, and improved the reaction yield and the purity of the product. Moreover, the experimental results also showed that the preparation process of the present invention had good feasibility on both the laboratory scale and the industrial scale-up, especially had significant superiority in large-scale production, could achieve both high yield and high purity, and had good industrial application prospects.
[0041] The above embodiments are exemplary, and their purpose is to illustrate the technical concept and characteristics of the present invention, so that those skilled in this field can understand the content of the present invention and implement it accordingly, and it should not be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.
Claims
1. A method for synthesizing an aprepitant intermediate by hydrogenation, characterized in that: The following steps are involved: Step S1: dissolving (2R)-4-benzyl-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]morpholin-3-one in tetrahydrofuran, cooling the temperature to 5 to 15° C., and adding dropwise a tetrahydrofuran solution of 4-fluorophenylmagnesium bromide to react to obtain an intermediate reaction liquid; Step S2: mixing the palladium carbon catalyst, p-toluenesulfonic acid and methanol evenly to form a mixed glue solution; Step S3: mixing the intermediate reaction liquid obtained in step S1 and the mixed glue solution obtained in step S2 in a microchannel reactor, introducing hydrogen, maintaining the reaction temperature in the range of 15 to 30° C., and performing a catalytic hydrogenation reaction; Step S4: The reaction product obtained in step S3 is post-treated to obtain an aprepitant intermediate.
2. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 1, characterized in that: In step S1, the molar ratio of the starting material (2R)-4-benzyl-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]morpholin-3-one to 4-fluorophenylmagnesium bromide is 1:1 to 1:
2.
3. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 1, characterized in that: In step S2, the amount of palladium-carbon catalyst in the mixed colloid is controlled to be 0.5%-1% of the mass of the starting material (2R)-4-benzyl-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]morpholine-3-one; the weight percentage of p-toluenesulfonic acid in the mixed colloid is 20-30%.
4. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 3, characterized in that: In step S3, the flow ratio of the intermediate reaction liquid to the mixed glue liquid is 1:1-2:
1.
5. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 1, characterized in that: In step S3, the pressure of hydrogen is 0.5-5 MPa.
6. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 5, characterized in that: In step S3, the flow ratio of the intermediate reaction liquid and the hydrogen is adjusted so that the molar ratio of the intermediate compound in the intermediate reaction liquid to the hydrogen is 1:2-1:
4.
7. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 1, characterized in that: In step S3, the reaction residence time of the material in the microchannel is 5 to 8 minutes.
8. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 1, characterized in that: In step S3, the palladium-carbon catalyst is 5% Pd / C, and the p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate.
9. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 1, characterized in that: In step S4, the reaction solution obtained in step S3 is filtered, the filtrate is concentrated, methyl isobutyl ketone, sodium bicarbonate and water are added for liquid separation, the organic phase is taken, hydrochloric acid is added, the temperature is lowered to 0±5° C. for crystallization, filtered and dried to obtain an aprepitant intermediate.
10. The method for synthesizing an aprepitant intermediate by hydrogenation according to claim 9, characterized in that: In step S4, the hydrochloric acid is 30% concentrated hydrochloric acid; and the crystallization time is 2 to 3 hours.