265121-04-8

Basic information

• Product Name: Fosaprepitant dimeglumine
• Synonyms: Phosphonic acid, (3-(((2R,3S)-2-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)-, compd. with 1-deoxy-1-(methylamino)-D-glucitol (1:2);Unii-D35fm8T64x;[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoroMethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-Morpholinyl]Methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate 1-Deoxy-1-(MethylaMino)-D-glucitol;1-Deoxy-1-(MethylaMino)-D-glucitol [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoroMethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-Morpholinyl]Methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate;1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL [[(2R,3S]-2-[(1R)-1-[3,5-BIS (TRIFLUOROMETHYL)PHENYL] PHENYL]ETHOXY]-(4-FLUOROPHENYL);Fosaprepitant diMegluMine salt;3-[2(R)-[1(R)-[3,5-Bis(trifluoroMethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)Morpholin-4-ylMethyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-phosphinic acid bis(N-Methyl-D-glucaMine) salt;Fosaprepitant dimeglumine, >=99%
• CAS NO: 265121-04-8
• Molecular Formula: C60H78F14N10O20P2
• Molecular Weight: 1587.2414868
• EINECS: 1592732-453-0
• Product Categories: Other APIs;Inhibitors
• Mol File: 265121-04-8.mol

Chemical Properties

• Boiling Point: 588.9 °C at 760 mmHg
• Flash Point: 310 °C
• Appearance: /
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: ≥50.24 mg/mL in DMSO; insoluble in EtOH; ≥13.16 mg/mL in H2O with ultrasonic
• CAS DataBase Reference: Fosaprepitant dimeglumine(CAS DataBase Reference)
• NIST Chemistry Reference: Fosaprepitant dimeglumine(265121-04-8)
• EPA Substance Registry System: Fosaprepitant dimeglumine(265121-04-8)

Safety Data

• Hazardous Substances Data: 265121-04-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Fosaprepitant dimeglumine is used as an antiemetic drug for the treatment of postoperative or chemotherapy-induced nausea and vomiting. As a prodrug of Aprepitant, it rapidly converts to Aprepitant when administered intravenously, providing relief from these symptoms.
Used in Research and Development:
Fosaprepitant-d4 Dimeglumine, a labeled analogue of Fosaprepitant Dimeglumine, is used in research and development for studying the mechanisms of action and potential applications of NK-1 receptor antagonists in various conditions, including nausea and vomiting.
Brand Name:
The brand name for Fosaprepitant dimeglumine is IvEmend.

Originator

Merck (United States)

Indications

Fosaprepitant dimeglumine is a new drug indicated to prevent nausea and vomiting associated with highly emetogenic cisplatin-based and moderately emetogenic cancer chemotherapy in adults.

Biological Activity

Fosaprepitant dimeglumine acts as a therapeutic agent to treat chemotherapy-induced nausea and vomiting. It also acts as a weak inhibitor of cytochrome P450 3A4 (CYP3A4).Fosaprepitant dimeglumine is a Substance P/neurokinin-1 (NK1) receptor antagonist. It is a water soluble prodrug of the antiemetic drug aprepitant.Fosaprepitant dimeglumine is a water-soluble prodrug form of the neurokinin-1 receptor antagonist aprepitant. Formulations containing fosaprepitant dimeglumine have been used to prevent chemotherapy-induced nausea and vomiting.

Side effects

Most common adverse reactions in adults (≥2%) are: fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity.Adverse reactions in pediatrics are similar to adults.

Mode of action

Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors.Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies have shown that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Clinical claims and research

One of the most debilitating side effects of cancer treatment is CINV. Although concomitant anti-emetic agents have been prevalent for the past two decades, 50 60% of patients are still plagued by CINV. To meet this need, fosaprepitant dimeglumine has been launched as a water-soluble, phosphoryl pro-drug of aprepitant for intravenous applications. This pro-drug is rapidly converted to aprepitant in vivo, which has a high affinity for the NK-1 receptor (IC50= 90 50 pM for the displacement of [125I]-substance P from hNK-1 expressed in CHO cells); antagonism 606 Shridhar Hegde and Michelle Schmidt of NK-1 prevents binding of the endogenous substance P that is known to induce vomiting. Fosaprepitant is prepared by the regioselective phosphorylation of aprepitant with dibenzylphosphoryl chloride followed by catalytic hydrogenolysis in the presence of N-methyl-Dglucamine. It is approved for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic cancer chemotherapy.

InChI:InChI=1/C23H22F7N4O6P.2C7H17NO5/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)40-20-19(13-2-4-17(24)5-3-13)33(6-7-39-20)11-18-31-21(35)34(32-18)41(36,37)38;2*1-8-2-4(10)6(12)7(13)5(11)3-9/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H,31,32,35)(H2,36,37,38);2*4-13H,2-3H2,1H3/t12-,19+,20-;2*4-,5+,6+,7+/m100/s1

Upstream product

• 6284-40-8 1-deoxy-1-(methylamino)-D-glucitol 
• 265121-01-5 [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid bis(phenylmethyl)ester 
• 170729-80-3 aprepitant 
• 97780-33-1 N-methyl-D-glucamine 
• 889852-02-2 benzyloxy (3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phosphinic acid 
• 97780-33-1 (2S,3S,4S,5R)-6-(methylamino)hexane-1,2,3,4,5-pentaol 
• 6284-40-8 6-methylamino-hexane-1,2,3,4,5-pentaol 

Relevant articles and documents

Preparation method of medicine for preventing chemotherapy-related nausea and vomiting

The invention discloses a preparation method of a medicine for preventing chemotherapy-related nausea and vomiting. The preparation method comprises the following steps: dissolving aprepitant and tetrabenzyl pyrophosphate in a tetrahydrofuran solvent, adding sodium bis(trimethylsilyl)amide, adding meglumine, carrying out Pd/C catalytic reaction by taking ammonium formate as a hydrogen source reagent, adding triphenylphosphine and 1,2-propane diamine to remove palladium after the reaction is finished, and performing temperature-controlled crystallization in an ethanol-acetonitrile-acetone mixed solvent for 2 hours so as to finish preparation of fosaprepitant dimeglumine is in a one-pot manner. According to the invention, time is saved, yield is improved, and ammonium formate is used for replacing hydrogen, so safety is higher. According to the method, a process is good in palladium removal effect and high in purity, the three solvents are mixed for crystallization, and the obtained product is not sticky after being dried.

Preparation method of NK-1 receptor antagonist

The invention provides a preparation method of fosaprepitant dimeglumine. The preparation method is characterized by comprising the following steps: step 1) catalyzing aprepitant dibenzyl phosphate under the action of a borane pyridine complex to prepare fosaprepitant; and 2) reacting fosaprepitant with N-methyl- D-glucosamine to generate fosaprepitant dimeglumine. The borane-pyridine complex is used as a catalyst, aprepitant dibenzyl phosphate can directly generate fosaprepitant, then the fosaprepitant dibenzyl phosphate reacts with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine, the reaction is mild, and conversion of raw materials can be completed quickly at the temperature of about room temperature only by using a small amount of the catalyst. The catalytic efficiency ishigh, the reaction conditions are mild and the yield is high. The high-purity and high-yield fosaprepitant can be obtained by recrystallizing the reaction crude product with deionized water, the post-treatment is extremely simple, and the fosaprepitant dimeglumine is generated by reacting the reaction crude product with N-methyl-D-glucosamine, so that the purity and the yield are high.

Application of borane-pyridine complex in preparation of NK-1 receptor antagonist

The invention provides an application of a borane-pyridine complex in preparation of an NK-1 receptor antagonist fosaprepitant dimeglumine. The application is characterized by comprising the followingsteps: step 1) catalyzing aprepitant dibenzyl phosphate

Synthesis method of fosaprepitant dimeglumine (by machine translation)

The invention discloses a synthesis method of fosaprepitant dimeglumine, and belongs to the technical field of medicines. The synthesis method mainly comprises the following steps: reaction of tetra-benzyl pyrophosphate, adsorption of impurities, carbon hydrogenation of palladium mesoporous carbon, refining and the like. The method comprises the following steps: firstly, carrying out quenching reaction by adding sodium carbonate, adding mesoporous carbon to adsorb impurities and tar, avoiding deactivation of the palladium carbon catalyst, directly using a tetrahydrofuran system for reaction. (by machine translation)

A luck sha pitan preparation method of dimethyl Meglumine

The invention provides a preparation method of fosaprepitant dimeglumine. The preparation method comprises the following steps: by taking aprepitant as a raw material, carrying out phosphorylation on the raw material under an alkaline condition to obtain a dibenzyl ester intermediate; further hydrolyzing the intermediate to obtain fosaprepitant; and further reacting with N-methyl-D-glucosamine to obtain the fosaprepitant dimeglumine. The method provided by the invention is simple to operate and mild in reaction condition, and avoids pressurization and v, so that the method is safe and effective and suitable for industrial production on a large scale.

A PROCESS FOR PREPARATION OF FOSAPREPITANT DIMEGLUMINE AND AN INTERMEDIATE THEREOF

The present invention relates to a novel process for the preparation of intermediate of fosaprepitant dimeglumine. The present invention particularly relates to a process for the preparation of fosaprepitant dibenzyl ester, an intermediate of fosaprepitant dimeglumine, which is simple, easy to handle on commercial scale and efficient.

luck Sha Pitan preparation method of dimethyl Meglumine

The invention relates to a preparation method of fosaprepitant dimeglumine. Fosaprepitant dimeglumine is a compound shown in the formula I. The preparation method is characterized in that a compound shown in the formula II reacts with tetrabenzyl pyrophos

A PROCESS OF MAKING FOSAPREPITANT DIMEGLUMINE

A process of effectively reducing palladium content in fosaprepitant dimeglumine to below 0.3 ppm which is the detection limit using the current analytical method.

A process for preparing luck Sha Pitan b a Meglumine method

The invention discloses a fosaprepitant dimeglumine preparation method, fosaprepitant dimeglumine has a structure shown as the formula I, and the route of synthesis of the method comprises the following two steps: (1) reacting compound di(benzhydryl) phosphoryl chloride (shown as the formula III) with aprepitant (shown as the formula II) under the action of a steric hindrance strong alkali to produce a new phosphorylation product intermediate (shown as the IV); (2) removing protecting group diphenylmethane of the new compound by catalytic reduction to obtain fosaprepitant and simultaneously to obtain a target product by salifying with N-methyl-D - glucosamine. A phosphorylation reagent used by the method has two higher steric hindrance protecting groups, due to the space steric hindrance effect, the regional selectivity and intermediate stability of the first step reaction can be enhanced, the intermediate stability can be enhanced, and the reaction yield can be improved.

A kind of preparation method of dimethyl luck Sha Pitan cyclophosphadenosine

The invention relates to a method for preparing fosaprepitant. The fosaprepitant is shown as a formula (I). The method comprises steps 1, 2, 3 and 4, finally, a compound shown as the formula (I) is obtained through hydrogenation reduction; in the step 1, a compound in a formula (II) reacts with a Grignard reagent to generate a compound shown as a formula (III) in the presence of palladium carbon and ammonium formate. The method for preparing is simple in production step, has high reaction yield and less side products, is easy in control of the reaction conditions and is suitable for medical industrial production.