Fosaprepitant dimeglumine and preparation method of intermediate of fosaprepitant dimeglumine

Abstract

The invention relates to fosaprepitant dimeglumine and an intermediate preparation method thereof, which is characterized in that on the basis of a four-step synthetic route of fosaprepitant dimeglumine, ethyl acetate is not required to refine an intermediate I in a condensation reaction. The method has the beneficial effects that the yield of the fosaprepitant dimeglumine intermediate I without introducing impurities exceeding the limit in the condensation reaction step is increased by about 10%.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a preparation method of fosaprepitant dimeglumine and an intermediate thereof. Background Art

[0002] The four-step synthesis of fosaprepitant dimeglumine (referred to as the four-step method) involves condensing 3-chloromethyl-1,2,4-triazolin-5-one (SM1) and (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride (SM2) as starting materials to produce intermediate I. Intermediate I then undergoes phosphonylation with tetrabenzyl pyrophosphate (SM3) and debenzylation to produce intermediate II. Intermediate II is then debenzylated and salted using palladium on carbon and meglumine (SM4) to yield the crude product. The crude product is then purified to obtain the finished product. This synthetic route utilizes readily available starting materials, avoids the use of hazardous reagents, and reduces the complexity and operational complexity of purification.

[0003] In the condensation reaction of the aforementioned synthetic route, intermediate I needs to be purified with ethyl acetate. However, the use of ethyl acetate for purification will significantly reduce the yield of intermediate I. Failure to use ethyl acetate for purification will result in fosaprepitant dimeglumine containing impurities from the condensation reaction step (impurity H, impurity I, impurity J, impurity K, impurity L, impurity M, impurity N, impurity O, impurity P, and impurity Q) exceeding the limit. Since fosaprepitant dimeglumine is heat-sensitive and degrades upon heating and reflux, these impurities cannot be purified and removed by recrystallization. Therefore, once introduced, it will be difficult to remove these impurities. Summary of the Invention

[0004] In order to solve the above technical problems, the present invention provides a preparation method of fosaprepitant dimeglumine, which uses 3-chloromethyl-1,2,4-triazolin-5-one (SM1) and (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride (SM2) as starting materials, and generates intermediate I through condensation reaction; intermediate I undergoes phosphonylation reaction with tetrabenzyl pyrophosphate (SM3) and debenzylation to generate intermediate II; intermediate II is sequentially debenzylated and salified by palladium carbon and meglumine (SM4) to generate a crude product; the crude product is refined to generate a finished product, wherein,

[0005] The conditions for generating intermediate I are:

[0006] The molar ratio of 3-chloromethyl-1,2,4-triazolin-5-one (SM1), (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride (SM2), and N,N-diisopropylethylamine (DIEA) is 1:0.97-0.99:1.9-2.1; preferably, the molar ratio is 1:0.98:2.0;

[0007] The weight-to-volume ratio of 3-chloromethyl-1,2,4-triazolin-5-one (SM1), pulping purified water, and condensation reaction washing purified water is 1:32:48:24;

[0008] The conditions for generating crude product are:

[0009] The molar ratio of intermediate II and meglumine (SM4) is 1:2.0;

[0010] The weight-to-volume ratio of intermediate II, 10% palladium on carbon, tributylphosphine, methanol, and anhydrous ethanol is 1:0.05:0.01:6.5:12;

[0011] The conditions for generating finished products are:

[0012] The weight-to-volume ratio of the crude product, methanol, anhydrous ethanol, and acetone is 1:4:32:6.

[0013] The present invention also provides a method for preparing an intermediate of fosaprepitant dimeglumine, wherein the intermediate is intermediate I generated by the aforementioned method for preparing fosaprepitant dimeglumine.

[0014] The beneficial effects of the present invention are that the yield of the fosaprepitant dimeglumine intermediate I is increased by about 10%, and the finished fosaprepitant dimeglumine product does not introduce impurities (impurity H, impurity I, impurity J, impurity K, impurity L, impurity M, impurity N, impurity O, impurity P, impurity Q) in the condensation reaction step exceeding the limit, that is, the yield of the fosaprepitant dimeglumine intermediate I that does not introduce impurities (impurity H, impurity I, impurity J, impurity K, impurity L, impurity M, impurity N, impurity O, impurity P, impurity Q) in the condensation reaction step exceeding the limit is increased by about 10%. DETAILED DESCRIPTION

[0015] The following examples further illustrate the present invention, but should not be construed as limiting the present invention. Without departing from the spirit and substance of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention are within the scope of the present invention.

[0016] Explanation of terms:

[0017] Trituration is a purification method between washing and recrystallization, which uses the difference in solubility of the product and impurities in a single solvent (or mixed solvent) for purification.

[0018] Quenching refers to the necessary step to terminate the reaction by adding specific reagents or taking certain operations after the reaction is completed.

[0019] eq indicates the amount of base used is the molar multiple of the substrate.

[0020] The contract route of the embodiment of the present invention is:

[0021]

[0022] The abbreviations or abbreviations of the substances in the examples of the present invention are shown in Table 1:

[0023] Table 1: List of abbreviations or acronyms

[0024]

[0025]

[0026] The impurities in the step of generating intermediate I (condensation reaction step) of the embodiment of the present invention are shown in Table 2:

[0027] Table 2: Impurities in the Condensation Reaction Step

[0028]

[0029]

[0030] Example 1 Synthesis of Intermediate Ⅰ

[0031] Table 3: List of materials used in the synthesis of intermediate I

[0032]

[0033] To a 150-L glass reactor, add 5.22 kg of SM2, 36.0 L of DMF, and 2.9 kg of N,N-diisopropylethylamine. Then slowly add a DMF solution of SM1 (1.5 kg of SM1 dissolved in 12.0 L of DMF). After the addition is complete, control the temperature to 20 ± 10 °C and stir the reaction for 2 to 3 h. Monitor the reaction progress by TLC.

[0034] After the reaction is completed, 72.0 L of purified water is added to the reaction solution, the temperature is controlled to 20±10°C, stirred and crystallized for 1 h, filtered, and the filter cake is washed with purified water (12.0 L×3). The filter cake is collected and dried under reduced pressure at 80±10°C for 8-12 h to obtain intermediate I.

[0035] ①TLC monitoring method:

[0036] Developing solvent: ethyl acetate-petroleum ether (2:1);

[0037] Detection wavelength: UV254nm;

[0038] End point indication: No SM1 UV spot on the TLC plate.

[0039] ②Quality control indicators are shown in Table 4 below:

[0040] Table 4 Quality control indicators

[0041]

[0042]

[0043] The results of Example 1 are shown in Tables 5 and 6.

[0044] Table 5: Results of investigation of intermediate I

[0045]

[0046] Table 6: Results of investigation of intermediate I

[0047]

[0048] Result analysis: (1) In the condensation reaction of the method of Example 1, there is no need to purify the intermediate I with ethyl acetate. The yield of the intermediate I of fosaprepitant dimeglumine is increased by about 10% compared with the yield of the intermediate I (83.5-87.6%) of the process route of the prior art. (2)

[0049] The condensation reaction impurities (impurity H, impurity I, impurity J, impurity K, impurity L, impurity M, impurity N, impurity O, impurity P, and impurity Q) in Example 1 are all less than 0.1%. Therefore, the finished product of sapitant dimeglumine does not introduce impurities from the condensation reaction step exceeding the limit.

[0050] Example 2 Synthesis of Intermediate II

[0051] The reaction uses 6-14 times tetrahydrofuran (water content ≤0.05%) as solvent, 1.3-1.5 eq of SM3, and 2-2.5 eq of sodium hexamethyldisilazane. The reaction is carried out at 5±10°C for 2-4 hours. After extraction and washing, the oil is concentrated into an oil. 6-14 times methanol is added, and the oil is reacted at 45±5°C. The temperature is lowered to 10-30°C, stirred and crystallized for 1 hour, and filtered to obtain a crude product. The crude product is stirred with tetrahydrofuran / methanol (4:8) for 2 hours, filtered, and the filter cake is dried under reduced pressure at 40-45°C for 5-8 hours to obtain intermediate II.

[0052] ① Yield range: 50% to 70%.

[0053] ②TLC monitoring method 1:

[0054] Developing solvent: dichloromethane-methanol (10:1);

[0055] Detection wavelength: UV254nm;

[0056] End point indication: no UV spot of intermediate I on the TLC plate.

[0057] ③TLC monitoring method 2:

[0058] Developing solvent: dichloromethane-methanol (10:1);

[0059] Detection wavelength: UV254nm;

[0060] End point indication: no intermediate UV spot (fosaprepitant dibenzyl ester) on the TLC plate.

[0061] Example 3 Synthesis of crude product

[0062] Table 7: List of materials used in the synthesis of crude products

[0063]

[0064] To a 100 L autoclave, add 4.03 kg of intermediate II, 2.25 kg of meglumine (SM4), 26.2 L of methanol, and 0.20 kg of 10% palladium on carbon. Stir and react for 8 to 12 h at a temperature of 20 ± 10 ° C and a hydrogen pressure of 1.0 ± 0.5 MPa. During the reaction, add hydrogen in time until the pressure in the autoclave no longer decreases.

[0065] After the reaction is completed, filter and wash the filter cake with a small amount of methanol. The filtrate is transferred to a 50L double-layer glass reactor, 40ml of tributylphosphine is added, and stirred at room temperature for 4h under nitrogen protection. Then, it is concentrated under reduced pressure below 35°C to about 3 times the volume (based on the amount of intermediate II), and then slowly added to 48.4L of anhydrous ethanol.

[0066] After the addition, stir at 0±10°C for 1 hour to allow crystallization, filter under nitrogen, collect the filter cake, and dry under reduced pressure at 35±5°C for 12 hours to obtain crude fosaprepitant dimeglumine. Yield range: 80% to 90%.

[0067] Example 4 Preparation of finished product

[0068] Table 8: List of materials used in the preparation of finished products

[0069]

[0070]

[0071] Add 4.77 kg of crude fosaprepitant dimeglumine and 19.1 L of methanol to a 50 L double-layer glass reactor, stir to dissolve, then slowly add to 152.6 L of anhydrous ethanol. After addition, stir and crystallize at 0 ± 10 ° C for 1 h. Filter under nitrogen protection, wash the filter cake with 28.6 L of acetone, collect the filter cake, and dry it under reduced pressure at 35 ± 5 ° C for 24 h to obtain the finished product fosaprepitant dimeglumine.

[0072] Table 9: Finished product inspection results

[0073]

[0074] Table 10: Finished product inspection results

[0075]

[0076] Comparative Example 1

[0077] "Optimization and scale-up of the synthetic process of fosaprepitant dimeglumine, a chemotherapy adjuvant drug," Xiupeng Liu, Shandong University.

[0078] 1. Synthesis of Intermediate I

[0079] Weigh 172g of raw material 1 and add it to a 5L four-necked flask, add 860mL of DMF and stir to dissolve, add 116.3g of DIEA, and dropwise add a solution of 61.4g of raw material 2 in 340mL of DMF into the flask. The temperature is controlled at 20±5°C. After the addition is complete, continue stirring for 2-3h. After stirring for 2h, take a small amount of the reaction liquid for HPLC monitoring. When the content of raw material 1 is less than 0.5%, the reaction is considered complete. 3L of water is added dropwise, the temperature is controlled at 20±5°C, and stirring is continued for 30min after the addition is complete. Filter and wash the solid with 300mL of water three times. The obtained solid is placed in a vacuum drying oven (vacuum degree>0.09MPa, 50±5°C) and dried for 10-14h to obtain about 180g of solid.

[0080] The dried solid was added to a 2L four-necked flask, and 360mL of ethyl acetate was added, followed by stirring and heating to reflux. After reflux for 1 hour, the temperature naturally dropped to room temperature, and then the temperature was cooled to -5±5°C and continued to stir for 2 hours. The filter cake was placed in a vacuum drying oven and vacuum dried (vacuum degree >0.09MPa, 50±5°C) for 6 to 7 hours to obtain about 172g of a white solid. The reaction yield range was 80 to 90%.

[0081] 2. Synthesis of Intermediate II

[0082] After replacing the atmosphere in a 5 L four-necked flask with nitrogen twice, 150 g of intermediate I, 226 g of raw material 3 and 1.5 L of tetrahydrofuran (dried overnight with 225 g of type 4A molecular sieves) were added. A thermometer, a 250 mL constant pressure dropping funnel and a nitrogen bag were installed. The atmosphere in the flask was replaced with nitrogen twice again and the temperature was lowered to -10 to -5°C. Under nitrogen protection, 0.7L 1.OM sodium hexamethyldisilazide tetrahydrofuran solution was transferred to a 1L constant pressure dropping funnel and slowly added dropwise, controlling the temperature within the range of -5 to -5°C. After the addition was complete, cooling was stopped and the reaction solution was naturally heated and continued to stir for 1 to 2 hours. After stirring for 1 hour, the reaction was monitored by HPLC. When the content of intermediate I was less than 5%, the reaction solution was poured into a 20L separator containing a stirred mixed solution of 4.4L saturated sodium bicarbonate aqueous solution and 4.4L methyl tert-butyl ether. After stirring for 10 minutes, the mixture was allowed to stand and separate. The organic layer was separated and then washed with 4.4L saturated sodium bicarbonate aqueous solution, 2.2L Wash with 10% sodium bisulfate solution, 2.2 L of water, and 2.2 L of saturated brine. Dry the resulting organic phase over 1.4 kg of anhydrous sodium sulfate for 12-14 hours, then filter. Concentrate the filtrate to dryness under vacuum at 25°C. Dissolve the residue in 1.2 L of methanol and heat to 40-50°C in a 3 L four-necked flask, stirring for 18-20 hours. After stirring for 18 hours, remove a small amount of the reaction solution for HPLC monitoring. The reaction is complete when the content of Intermediate II-A is less than 5%.

[0083] Stop heating, lower the temperature to 25±5°C, continue stirring for 1 hour, filter, and place the obtained solid in a vacuum drying oven for vacuum drying (vacuum degree >0.09 MPa, 45±5°C, 3-4 hours) to obtain about 115 g of solid.

[0084] The dried solid was added to a 2L four-necked flask, 230mL of tetrahydrofuran was added to dissolve it, 550L of anhydrous methanol was added dropwise, and the mixture was stirred for 30min and filtered. The filter cake was dried in a vacuum drying oven (vacuum degree >0.09MPa, 45±5°C) for 5-6h to obtain about 104g of a white solid. The reaction yield range was 50-60%.

[0085] 3. Synthesis of crude product:

[0086] To a 500mL hydrogenation kettle were added, in sequence, 12.2g of 10% wet palladium-carbon (59% water content), 300mL of anhydrous methanol, 54.7g of starting material 4, and 100g of intermediate II. This mixture was catalytically hydrogenated at 25±5°C and a hydrogen pressure of 0.2-0.3MPa for 3-4h. After 3h, a small amount of the reaction liquid was sampled for HPLC monitoring. The reaction was complete when the intermediate II content was less than 0.1%. The reaction liquid was filtered, poured into a filter press, and filtered again through a 0.45μm microporous membrane. Under nitrogen, a mixture of 10L of anhydrous ethanol and 3L of acetonitrile was added dropwise to the 10L reaction flask with stirring, maintaining the temperature between 0 and 10°C. After the additions were complete, the mixture was stirred at this temperature for 0.5h. The precipitate was allowed to settle, and most of the supernatant was decanted. The remaining mixture was stirred evenly and filtered under nitrogen atmosphere. The solid was placed in a vacuum drying oven and vacuum dried (vacuum degree > 0.09 MPa, 20 ± 5 ° C) for 8 to 9 hours to obtain about 122 g of a white solid with a yield range of 80 to 90%.

[0087] 4. Refining:

[0088] Add 118.2 g of crude fosaprepitant dimeglumine to 236 mL of anhydrous methanol and stir until the solids are completely dissolved. Then, add 1.5 mL of tributylphosphine and stir under nitrogen at 25±5°C for 14-16 hours. Then, transfer the system to a filter press and filter through a 0.45 μm microporous membrane. The filtrate is added dropwise to a 10 L reaction flask containing a stirred mixture of 2.4 L of anhydrous ethanol and 2.4 L of acetonitrile under nitrogen. Maintain the temperature at 0-10°C. Stir for 0.5 hour after addition and allow to settle. Most of the supernatant was decanted, and the remaining mixture was stirred evenly and filtered under a nitrogen atmosphere. The filter cake was transferred to a 2L three-necked flask, 600mL of acetone was added and slurried for 4 hours, and then filtered under a nitrogen atmosphere. The solid was washed with 100L of acetone and then placed in a vacuum drying oven (vacuum degree >0.09MPa, 20±5°C) and vacuum dried for 9 hours to obtain about 104g of a white solid with a yield range of 80-90%.

[0089] The results of comparative example 1 are shown in Tables 11, 12, 13 and 14.

[0090] Table 11: Investigation results of intermediate I of comparative example 1

[0091]

[0092] Table 12: Investigation results of intermediate I of comparative example 1

[0093]

[0094] Table 13: Comparative Example 1 Finished Product Inspection Results

[0095]

[0096] Table 14: Finished product inspection results of Comparative Example 1

[0097]

[0098] Analysis of the results: In the condensation reaction of intermediate I in Comparative Example 1, ethyl acetate is required to purify intermediate I. Although the condensation reaction impurities (impurity H is less than 0.15%, impurity I, impurity J, impurity K, impurity L, impurity M, impurity N, impurity O, impurity P, and impurity Q are all less than 0.1%) meet the limit requirements, the yield of intermediate I in Comparative Example 1 is only 83.0%; and the finished product of sapitant dimeglumine does not introduce impurities from the condensation reaction step that exceed the limit.

[0099] Comparative Example 2

[0100] The difference from Comparative Example 1 is that Comparative Example 2 does not have the step of refining the intermediate I with ethyl acetate.

[0101] The results of comparative example 2 are shown in Tables 15, 16, 17 and 18.

[0102] Table 15: Investigation results of intermediate I of comparative example 2

[0103]

[0104] Table 16: Investigation results of intermediate I of comparative example 2

[0105]

[0106] Table 17: Comparative Example 2 Finished Product Inspection Results

[0107]

[0108] Table 18: Comparative Example 2 Finished Product Inspection Results

[0109]

[0110]

[0111] Analysis of the results: In the condensation reaction of the method in Comparative Example 2, there is no need to use ethyl acetate to purify the intermediate I. Although the yield reaches 90.8%, the impurities in the condensation reaction, impurity K, impurity L, and impurity M all exceed 0.1%, and impurity H is 2.69%, all exceeding the impurity limit, resulting in the introduction of impurities H, impurity K, impurity L, and impurity M in the condensation reaction step exceeding the limit into the finished product of sapitant dimeglumine.

[0112] Comparative Example 3

[0113] CN1305475A (2001.7.25) patent.

[0114] Experimental Procedure: A solution of SM1 (3.18 g) in DMF (30 ml) was added to a slurry of SM2 (15 g) and potassium carbonate (7.7 1) in DMF (100 ml) at 22° C. over 1 hour. The reaction mixture was allowed to stand at 22° C. for 20 minutes, then water (400 ml) was added over 30 minutes. The crystallization mixture was cooled in an ice bath, allowed to stand for 30 minutes, and the product was collected by filtration. The solid was washed with water (400 ml), air-dried, and dried in vacuo at 45-50° C.

[0115] The results of comparative example 3 are shown in Tables 19 and 20.

[0116] Table 19: Comparative Example 3 Investigation Results

[0117]

[0118] Table 20: Comparative Example 3 Investigation Results

[0119]

[0120] Result analysis: In the condensation reaction of the method in Comparative Example 3, there is no need to use ethyl acetate to purify the intermediate I. Although the yield reaches 91.3%, the impurities in the condensation reaction, impurity K, impurity L, and impurity M all exceed 0.1%, and impurity H is 2.55%, all exceeding the impurity limit.

[0121] Experimental Example 1 Evaluation of Single Factor Parameters in the Process of Generating Intermediate I

[0122] The key process parameters of the step of forming intermediate I (condensation reaction step) in Example 1 of the present invention were evaluated. The key process parameters refer to the process parameters that contribute to high yield and compliance with the limit requirements of condensation reaction impurities (see Example 1).

[0123] When evaluating each process parameter, the starting materials were SM1 and SM2. For other process conditions not listed, see Example 1.

[0124] 1. Type of alkali

[0125] Table 21: Condensation reaction step process parameter evaluation (1)

[0126]

[0127]

[0128] 2. Reaction temperature and time

[0129] Table 22: Process Parameter Evaluation of Step 1 Condensation Reaction (2)

[0130]

[0131] 3. SM2 dosage

[0132] Table 23: Step 1 Condensation Reaction Process Parameter Evaluation (3)

[0133]

[0134] 4. Alkali dosage

[0135] Table 24: Step 1 Condensation Reaction Process Parameter Evaluation (4)

[0136]

[0137] 5. Crystallization solvent ratio (DMF: water)

[0138] Table 25: Step 1 Condensation Reaction Process Parameter Evaluation (5)

[0139]

[0140] 6. Crystallization temperature and time

[0141] Table 26: Step 1 Condensation Reaction Process Parameter Evaluation (6)

[0142]

[0143] 7. Drying temperature and time

[0144] Table 27: Step 1 Condensation Reaction Process Parameter Evaluation (7)

[0145]

[0146] Discussion: The results of the single factor investigation of Experimental Example 1 show that the optimal single factor key process parameters are when the base type is DIEA, the base dosage is 2.0eq, the reaction temperature and time are 10℃~50℃ (2~3h), the SM2 dosage is 0.67~0.77eq, the crystallization solvent ratio (DMF: water) is 1:2.5 or 1:3, the crystallization temperature and time are -10~30℃ (1h), and the drying temperature and time are 50℃~90℃ (8~12h).

[0147] Experimental Example 2 Evaluation of Multi-factor Process Parameters in Intermediate I Production Step

[0148] Based on the experimental results of Experimental Example 1, the optimal single-factor process parameters were selected as the control group. The key process parameters of the control group were: DIEA as the base type, 2.0 eq of base, 25°C (2.5 h) of reaction temperature and time, 0.77 eq of SM2, 1:2.5 ratio of crystallization solvent (DMF:water), 25°C (1 h) of crystallization temperature and time, and 50°C (12 h) of drying temperature and time. The remaining process conditions were the same as those in Example 1. The experimental group differed from the control group in at least two process parameters, and the remaining process conditions were the same.

[0149] The evaluation indicators are impurity H, impurity I, impurity J, impurity K, impurity L, impurity M, impurity N, impurity O, impurity P, impurity Q and yield.

[0150] Table 28: Multi-factor process parameter evaluation of intermediate I step

[0151]

[0152]

[0153] Discussion: The differences between experimental groups 7 to 9 and the control group lie in the amount of SM2, the ratio of crystallization solvent, drying temperature and time. The yields of the two groups are not much different, but the condensation reaction impurities in the former all meet the impurity limits, indicating that the amount of SM2, the ratio of crystallization solvent, drying temperature and time, and the amount of DIEA determined according to Experimental Example 1 are the key process parameters that work synergistically.

[0154] The difference between Experimental Groups 4 to 6 and Experimental Groups 7 to 9 is that at least one of the process parameters, namely, the amount of SM2, the ratio of crystallization solvent, the drying temperature and time, is different. The yields of the two are not much different, but at least one of the condensation reaction impurities in the former exceeds the impurity limit, which proves that the amount of SM2, the ratio of crystallization solvent, the drying temperature and time, and the amount of DIEA determined according to Experimental Example 1 are the key process parameters that work synergistically.

[0155] The difference between the corresponding two groups of experimental groups 1 to 3 and experimental groups 4 to 6 (for example, experimental group 1 and experimental group 4) is that at least one process parameter is different, namely, the amount of SM2, the ratio of crystallization solvent, drying temperature and time. The yields of the two groups are not much different, but the condensation reaction impurities in the former exceed the impurity limit to a greater extent, which proves that the amount of SM2, the ratio of crystallization solvent, drying temperature and time, and the amount of DIEA determined according to Experimental Example 1 are key process parameters that work synergistically and have a greater impact on the effect than other process indicators.

[0156] Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. A method for preparing fosaprepitant dimeglumine, comprising: using 3-chloromethyl-1,2,4-triazolin-5-one (SM1) and (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride (SM2) as starting materials, and subjecting intermediate I to a condensation reaction; phosphonylating intermediate I with tetrabenzyl pyrophosphate (SM3) and debenzylating intermediate II; and sequentially subjecting intermediate II to palladium-carbon catalysis and meglumine (SM4) for debenzylation and salt formation to produce a crude product; and refining the crude product to produce a finished product, characterized in that: The conditions for generating intermediate I are: The molar ratio of 3-chloromethyl-1,2,4-triazolin-5-one (SM1), (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride (SM2), and N,N-diisopropylethylamine (DIEA) is 1:0.97-0.99:1.9-2.1; preferably, the molar ratio is 1:0.98:2.0; The weight-to-volume ratio of 3-chloromethyl-1,2,4-triazolin-5-one (SM1), pulping purified water, and condensation reaction washing purified water is 1:32:48:24; The conditions for generating crude product are: The molar ratio of intermediate II and meglumine (SM4) is 1:2.0; The weight-to-volume ratio of intermediate II, 10% palladium on carbon, tributylphosphine, methanol, and anhydrous ethanol is 1:0.05:0.01:6.5:12; The conditions for generating finished products are: The weight-to-volume ratio of the crude product, methanol, anhydrous ethanol, and acetone is 1:4:32:

6.

2. The method according to claim 1, wherein: The conditions for generating intermediate I also include: The crystallization solvent system is DMF and purified water, and the ratio of DMF to purified water is 1:1.5; The crystallization temperature is 20±10℃ and the crystallization time is 1h; The reduced pressure drying temperature is 70-90°C and the reduced pressure drying time is 8-12 hours; The condensation reaction temperature is 10-30°C, and the condensation reaction time is 2-3h.

3. The method according to any one of claims 1 to 2, characterized in that: The conditions for generating intermediate I are: The condensation reaction uses DMF as solvent, 0.98 eq of SM2 and 2.0 eq of N,N-diisopropylethylamine (DIEA). SM1 is added, and the reaction is stirred at 10-30°C for 2-3 h. 1.5 times the amount of purified water based on DMF is added, and crystallization is carried out at 10-30°C for 1 h. The mixture is filtered, and the filter cake is dried under reduced pressure at 70-90°C for 8-12 h to obtain intermediate I.

4. The method according to claim 3, wherein: The conditions for generating intermediate II are: The molar ratio of intermediate I, tetrabenzyl pyrophosphate (SM3), and sodium hexamethyldisilazane (NaHMDS) is 1:1.3-1.5:2-2.5; The weight-to-volume ratio of intermediate I, anhydrous tetrahydrofuran, methyl tert-butyl ether, saturated NaHCO3 solution, 10% NaHSO4 solution, purified water for phosphonylation reaction, methanol, and anhydrous sodium sulfate is 1:6-14:20:40:20:20:6-14:

2.

5. The method according to claim 1, wherein: The conditions for generating crude product are: The crystallization solvent is anhydrous ethanol, and the weight ratio of intermediate II to anhydrous ethanol is 1:12; The crystallization temperature is 0±10℃ and the crystallization time is 1h; The drying temperature is 35±5℃ and the drying time is 12h.

6. The method according to claim 5, wherein: The conditions for generating crude product are: The reaction uses methanol as a solvent and palladium carbon in an amount of 5%. Intermediate II is stirred at a temperature of 20±10°C and a hydrogen pressure of 1.0±0.5 MPa for 8 to 12 hours, filtered, and tributylphosphine is added to the filtrate and stirred for 4 hours. The reaction mixture is then added to 12 times anhydrous ethanol, stirred and crystallized at 0±10°C for 1 hour, filtered, and dried under reduced pressure at 35±5°C for 12 hours to obtain a crude product of fosapitant dimeglumine.

7. The method according to claim 1, wherein: The conditions for generating finished products are: The crystallization solvent was anhydrous ethanol, and the weight ratio of anhydrous ethanol to methanol was 8:1; The crystallization temperature is 0±10℃ and the crystallization time is 1h; The washing solvent was acetone.

8. The method according to claim 7, wherein: The conditions for generating finished products are: The crude product was dissolved in 4 times methanol, then slowly added to 8 times (based on methanol) anhydrous ethanol, cooled to 0±10°C, stirred and crystallized for 1 hour, filtered, washed with acetone, and the filter cake was dried under reduced pressure at 35±5°C for 24 hours to obtain the finished product.

9. The method according to claim 1, wherein: The impurities and impurity limits of the intermediate I are: The impurities and impurity limits of the finished product are: 。 10. A method for preparing an intermediate of fosaprepitant dimeglumine, characterized in that: The intermediate is intermediate I produced by the method for preparing fosaprepitant dimeglumine according to any one of claims 1 to 9.

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