Preparation of Fosaprepitant Dimeglumine

Abstract

The invention relates to a synthetic method for preparing fosaprepitant diester, specifically comprising the following steps: (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine is subjected to a condensation reaction with (3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)phosphonate under the action of a catalyst and a ligand to prepare fosaprepitant diester.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis and relates to a method for preparing fosaprepitant. Background Art

[0002] Fosaprepitant dimeglumine is a NK-1 selective, high-affinity receptor antagonist. It is an antiemetic drug recommended by domestic and international guidelines for highly and moderately emetogenic chemotherapy regimens (HEC / MEC). It mainly works by blocking the brain's nausea and vomiting signal mechanism, and is used to prevent chemotherapy-related nausea and vomiting. It can be used in combination with 5-HT3 receptor antagonists to improve the antiemetic effect. As an injectable dosage form, the drug can meet the clinical needs of patients who cannot take it orally, have difficulty swallowing, or have poor digestive function, and can benefit a wider range of people. Clinical studies have shown that fosaprepitant (trade name: Tenan) can effectively prevent chemotherapy-related nausea and vomiting, and has good clinical application safety. Tenan's single-day single injection has the characteristics of accurate dosage, rapid onset, and convenience. This drug is a neurokinin-1 (NK-1) receptor antagonist and a prodrug of aprepitant. It is clinically used to prevent nausea and vomiting caused by chemotherapy drugs. This product is a powder injection for intravenous injection, which is highly safe and widely used in clinical practice. Compared to oral aprepitant, injectable administration provides greater flexibility and convenience for some patients who have disease-related nausea and cannot tolerate oral administration. The product has become a must-have antiemetic in prescription combinations for the treatment of tumors.

[0003] As a prodrug of aprepitant, fosaprepitant dimeglumine has the same clinical efficacy as aprepitant. The US FDA and European EMA approved the marketing application of fosaprepitant in January 2008 as an adjuvant drug for chemotherapy to prevent nausea and vomiting caused by chemotherapy. According to patents and literature reports, a synthetic route of fosaprepitant is to start from (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine hydrochloride, first react with 2-(2-chloro-1-ethylidene)hydrazide formic acid methyl ester to undergo nucleophilic substitution reaction, and then close the ring to obtain aprepitant. Then aprepitant reacts with tetrabenzyl pyrophosphate to prepare fosaprepitant dimeglumine, and fosaprepitant dimeglumine is prepared by hydrogenation to remove the benzyl protection and the obtained free base and dimeglumine are salified to prepare fosaprepitant dimeglumine. In addition, patents and literature (WO01 / 94324; JACS, 2003, 2129-2135 etc.) also reported another route for preparing aprepitant from (2R, 3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine hydrochloride, specifically involving the condensation of the hydrochloride and 5-chloromethyl-2,4-dihydro[1,2,4]triazol-3-one. The structures of aprepitant and fosaprepitant dimeglumine and the above-mentioned synthetic route are as follows:

[0004]

[0005] Patent CN104650143 reports the synthesis of fosaprepitant dibenzyl ester. The synthesis involves the reaction of (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine hydrochloride and (3-(chloromethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonic acid dibenzyl ester to prepare fosaprepitant dibenzyl ester. The relevant synthesis route is as follows:

[0006]

[0007] The above-mentioned synthetic routes for synthesizing fosaprepitant dimeglumine all involve the intermediate fosaprepitant dibenzyl ester, and the synthetic routes for synthesizing fosaprepitant dibenzyl ester all involve related chloromethyl compounds. Since chloromethyl compounds belong to genotoxic compounds and potential genotoxic compounds, and since fosaprepitant dimeglumine is an injection variety, the residual requirements for genotoxic compounds and potential genotoxic compounds are high (based on the TTC method and the daily dosage of fosaprepitant dimeglumine, the residual amount of these genotoxic impurities and potential genotoxic impurities should be less than 130ppm), therefore, the use and removal of these genotoxic impurities, genotoxic compounds and potential genotoxic compounds is a huge challenge for the industrialization of fosaprepitant dimeglumine. The structures of the genotoxic compounds and potential genotoxic compounds used in the above-mentioned synthetic routes are as follows:

[0008] Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a new synthetic method for preparing fosaprepitant diester, which can avoid the use of chloromethyl genotoxic compounds.

[0010] The study found that (2R, 3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine (compound formula II) reacts with (3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonate (compound formula I) under the action of a catalyst and a ligand to prepare fosaprepitant diester (compound formula III). The specific reaction formula is as follows:

[0011]

[0012] The catalyst used in the reaction is [Ru(p-cymene)Cl2]2 (dichlorobis(4-methylisopropylbenzene)ruthenium(II));

[0013] The ligand used in the reaction is a bisphosphine ligand selected from bis(2-diphenylphosphinophenyl) ether, 1,1'-bis(diphenylphosphino)ferrocene, [1,1'-binaphthyl]-2,2'-bisdiphenylphosphine, 1,4-bis(diphenylphosphino)butane, bisdiphenylphosphinoethane, 1,4-bis(diphenylphosphino)alkane;

[0014] The solvents used in the reaction are toluene, acetonitrile, and xylene;

[0015] In the compound of formula I, R is H, Me;

[0016] In the compound of formula III, R is H, Me;

[0017] Since this route does not involve the use of chloromethyl compounds to prepare fosaprepitant dimeglumine, it avoids the use of genotoxic compounds and potential genotoxic compounds, which is of great significance for improving the quality of the final product, fosaprepitant dimeglumine. DETAILED DESCRIPTION

[0018] The present invention can be more specifically understood through the following examples, which are intended to illustrate rather than limit the scope of the present invention.

[0019] Example

[0020] 1. Preparation of Fosaprepitant Diester (Compound Formula III, R=H)

[0021] A 200 mL reaction bottle was equipped with a magnetic stirrer and a reflux device. Under nitrogen protection, catalyst [Ru(p-cymene)Cl2]2 (400 mg, 0.653 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (700 mg, 1.263 mmol) were added in sequence. Then, (3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonate (compound formula I, R=H) (18.77 g, 50.01 mmol), (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine (compound formula II) (21.88 g, 50.03 mmol) and anhydrous toluene (70 mL) were added under nitrogen protection. After the addition was completed, the system was replaced with nitrogen three times again. Subsequently, the reaction system was slowly heated to reflux for 24 hours. The reaction system was cooled to room temperature, and the solvent was removed under reduced pressure by a rotary evaporator. The residue was purified by column chromatography to obtain fosaprepitant diester (compound formula III, R=H) (36.56 g, 92%). 1 H NMR (600MHz, DMSO): δ (ppm): 12.02 (s, 1H), 7.85 (s, 1H), 7.49 (s, 2H), 7.32~7.37 (m, 12H),7.06(t,J=6.0Hz,2H),5.12~5.19(m,4H),4.95(q,J=6.0Hz,1H),4.33(d,J=3. 0Hz,1H),4.11(td,J=12.0,1.2Hz,1H),3.63(dd,J=10.8,1.2Hz,1H),3.51(d,J=2.4 Hz, 1H), 3.37 (s, 1H), 2.79 ~ 2.81 (m, 2H), 2.40 (td, J = 11.4, 3.0Hz, 1H), 1.36 (s, 3H).

[0022] 2. Preparation of Fosaprepitant Diester (Compound Formula III, R = Me)

[0023] In a 25 mL reaction bottle, catalyst [Ru(p-cymene)Cl2]2 (80 mg, 0.131 mmol) and [1,1'-binaphthyl]-2,2'-bisdiphenylphosphine (160 mg, 0.257 mmol), (3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonate (compound formula I, R = Me) (4.05 g, 10.04 mmol), (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine (compound formula II) (4.40 g, 10.06 mmol) and anhydrous xylene (12 mL) were added in sequence under nitrogen protection. After the addition was completed, the system was replaced with nitrogen three times again. Subsequently, the reaction system was slowly heated to 110±5°C for 24 hours. The reaction system was cooled to room temperature, and the solvent was removed under reduced pressure by a rotary evaporator. The residue was purified by column chromatography to obtain fosaprepitant diester (compound formula III, R=Me) (6.99 g, 84.6%).

[0024] 3. Preparation of Fosaprepitant Dimeglumine

[0025]

[0026] The 100mL high pressure reaction bottle was sequentially added with the prepared fosaprepitant diester (compound formula III, R = H) (5.0g, 6.29mmol), meglumine (2.8g, 14.47mmol), methanol (30.0g) and palladium carbon (0.5g, containing 10% palladium) in Example 1, stirred evenly, and the system was replaced with nitrogen three times, and then replaced with hydrogen three times. The reaction system was then kept at 25 ± 5 ° C and the hydrogen pressure was 0.2-0.3MPa and stirred for 24h. The reaction solution was filtered, the system was rotary evaporator to remove the solvent under reduced pressure, methanol (50.0g) was added to the residue to dissolve, acetone (200.0g) was slowly added dropwise, and the solid was precipitated, filtered and dried to obtain fosaprepitant meglumine (5.14g, 81.3%).

Claims

1. A synthetic method for preparing fosaprepitant diester, specifically (2R, 3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine (compound formula II) undergoes a condensation reaction with (3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonate (compound formula I) under the action of a catalyst and a ligand to prepare fosaprepitant diester (compound formula III), and the specific reaction formula is as follows: The catalyst used in the reaction is [Ru(p-cymene)Cl2]2 (dichlorobis(4-methylisopropylbenzene)ruthenium(II)); The ligand used in the reaction was 1,1'-bis(diphenylphosphino)ferrocene; The solvent used in the reaction is toluene; In the compound represented by formula I, R is H; The molar ratio of catalyst, ligand, compound of formula I, and compound of formula II is 0.653:1.263:50.01:50.03; The usage ratio of compound formula I to the solvent is 50.01 mmol:70 mL.

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