Aprepitant

Base Information

• Chemical Name: Aprepitant
• CAS No.: 170729-80-3
• Molecular Formula: C23H21F7N4O3
• Molecular Weight: 534.434
• Hs Code.: 2934990002
• Mol file: 170729-80-3.mol

Synonyms:3H-1,2,4-Triazol-3-one,5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-,[2R-[2a(R*),3a]]-;Emend;L 754030;MK 0869;MK 869;ONO7436;

Chemical Property of Aprepitant

Chemical Property:

• Appearance/Colour: off-white to light yellow cyrstalline solid
• Melting Point: 75-76°C(lit.)
• Refractive Index: 1.564
• PKA: 8.06±0.20(Predicted)
• PSA: 83.24000
• Density: 1.51 g/cm³
• LogP: 4.89000
• Storage Temp.: -20°C Freezer
• Solubility.: Soluble in DMSO (>25 mg/ml)

Purity/Quality:

99% ^*data from raw suppliers

Aprepitant ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn,Xi
• Hazard Codes: Xn,Xi

MSDS Files:

SDS file from LookChem

Useful:

• Uses: Antineoplastic drug. A novel selective neurokinin-1 (NK-1) receptor antagonist. In vitro studies using human liver microsomes indicate that Aprepitant is metabolised primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1. Antiemetic. anticholinergic
• Description: Aprepitant is an antiemetic chemical compound that belongs to “substance P” antagonists (SPA) with its effect being blocking the neurokinin 1(Nk1) receptor. It is used for the prevention of acute and delayedchemotherapy-induced nausea and vomiting(CINV) and for prevention ofpostoperative nausea and vomiting. It can also be used for the treatment of cyclic vomiting syndrome and late-stage chemotherapy induced vomiting occurring during cancer treatment. Aprepitant alleviates the case of vomiting in patients through balking the signals released by Nk1 receptors. Nk1 is a G-protein-coupled receptor with its ligand being substance P (SP). The high concentration of SP is required for the vomiting reflex. Aprepitant blocks the process of SP-NK1 signaling in activating the vomiting reflex.
• Clinical Use: Aprepitant, a substance P (neurokinin-1 [NK-1]) receptor antagonist used for the treatment of chemotherapy-induced nausea and vomiting, was launched in the US and was later approved in the European Union. It is a non-peptide analog having a trisubstituted morpholine with three chiral centers. Two syntheses have been described. In six steps p-fluorophenylacetic acid is converted to 4-benzyl-3-pfluorophenyl- 2-oxomorpholine with a resolution step setting the S-stereochemistry. This intermediate is converted in six steps to aprepitant, with two of the steps utilizing a chiral induction strategy to set the new centers based upon the chiral 2- oxomorpholine intermediate. SAR efforts leading to aprepitant included engineering in potency for NK-1, decreasing affinity for L-type calcium ion channels, most importantly by decreasing the basicity of the core heterocycle. In vitro, it binds with very high affinity (90 pM) to the hNK1 in transfected CHO cells. It is described as an inverse agonist of hNK-1 receptor, with slow dissociation rate under some conditions. In ferrets dosed orally or intravenously prior to emetogen challenge (cisplatin, apomorphine or morphine), retching and vomiting was reduced. Its antiemetic effect is enhanced with the dosing of dexamethasone and it is effective against both the acute and delayed phase of cisplatin-induced emesis. Cisplatin-induced emesis clinical studies showed that aprepitant (125 mg p.o.) in combination with ondansetron (32 mg i.v.) and dexamethasone (20 mg p.o.) therapeutically followed by repeat dosing (days 2–5) of aprepitant (80 mg) dexamethasone (20 mg) provided acute (8 h) and delayed phase (days 2–7) no vomiting rates of 83 and 70%, respectively. L-758298, a prodrug of aprepitant, was not as effective as ondansetron (32 mg i.v.) in reducing acute phase vomiting, but was superior in reducing vomiting in the delayed phase. The terminal half-life range of aprepitant is 9–13 h and the bioavailability is about 65%. It is highly protein bound (95%) and has a Vdss of 70 L. It is a moderate CYP3A4 inhibitor, thus several drugs cleared by CYP3A4 should not be used concurrently. It is also an inducer of CYP2C9 thus potentially modulating the PK of drugs cleared by CYP2C9. Most side effects were mild to moderate, with fatigue, asthenia, diarrhea, and hiccups.
• Drug interactions: Potentially hazardous interactions with other drugs Antidepressants: avoid with St John’s wort. Antipsychotics: avoid with pimozide. Avanafil: possibly increases avanafil concentration. Cytotoxics: possibly increases bosutinib concentration - avoid or reduce bosutinib dose; possibly increases ibrutinib concentration - reduce ibrutinib dose. Oestrogens and progestogens: may cause contraceptive failure. Ulipristal: possibly reduces contraceptive effect - avoid.

Technology Process of Aprepitant

There total 38 articles about Aprepitant which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 99.0%

3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one (252742-72-6) + (2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine 4-methylbenzenesulfonate (200000-59-5) → aprepitant (170729-80-3,221350-96-5)

Guidance literature:

With potassium carbonate; In water; N,N-dimethyl-formamide; at 0 ℃; for 3h;

DOI:10.1016/S0040-4039(00)01548-3

Reference yield: 98.4%

2-[2-[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]-1-iminoethyl]hydrazinecarboxylic acid methyl ester (219821-37-1) → aprepitant (170729-80-3,221350-96-5)

Guidance literature:

In 5,5-dimethyl-1,3-cyclohexadiene; for 3h; Reflux;

Reference yield: 97.9%

C3H4BrN3O + [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride (171482-05-6) → aprepitant (170729-80-3,221350-96-5)

Guidance literature:

With diethyl sulfate; triethylamine; lithium diisopropyl amide; In dimethylsulfoxide-d6; 5,5-dimethyl-1,3-cyclohexadiene; at 33 ℃; for 14h; Temperature; Inert atmosphere;

upstream raw materials:

3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one

(2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine 4-methylbenzenesulfonate

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine

[2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

Downstream raw materials:

[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

Fosaprepitant dimeglumine

Refernces

• 1、 -. "Intermediates for preparing aprepitant, and preparation method and application thereof". Paragraph 0157-0159; 0162-0165. . Retrieved 2020/02/20.
• 2、 -. "Method for preparing intermediate of the Fosaprepitant". Paragraph 0017; 0030-0039. . Retrieved 2018/05/16.