Aprepitant CAS 170729-80-3

Introduction：Basic information about Aprepitant CAS 170729-80-3, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Aprepitant Basic information

• Product Name: Aprepitant
• Synonyms: CS-274;Aprepitant (MK-0869, L-754030);5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one;Emend;MK-0869;5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,;5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, Emend;Aprepitant(MK-0869)
• CAS: 170729-80-3
• MF: C23H21F7N4O3
• MW: 534.43
• EINECS: 677-636-6
• Product Categories: Inhibitors;Aprepitant;Pharmaceutical intermediate;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;API;170729-80-3
• Mol File: 170729-80-3.mol

Aprepitant Chemical Properties

• Melting point: 244-246°C
• alpha: D25 +69° (c = 1.00 in methanol)
• density: 1.51±0.1 g/cm3(Predicted)
• storage temp.: Sealed in dry,2-8°C
• solubility: Soluble in DMSO (>25 mg/ml)
• pka: 8.06±0.20(Predicted)
• form: powder
• color: white to beige
• Optical Rotation: [α]/D +61 to +71°, c = 1.0 in methanol
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• InChIKey: ATALOFNDEOCMKK-OITMNORJSA-N
• SMILES: N1C(CN2CCO[C@H](O[C@@H](C3=CC(C(F)(F)F)=CC(C(F)(F)F)=C3)C)[C@@H]2C2=CC=C(F)C=C2)=NC(=O)N1
• CAS DataBase Reference: 170729-80-3(CAS DataBase Reference)

Safety Information

• WGK Germany: WGK 3
• HS Code: 2934990002
• Storage Class: 11 - Combustible Solids

Aprepitant Usage And Synthesis

Anti-Vomiting drug during chemotherapy

Aprepitant is a neurokinin-1 (NK-1) receptor antagonist and belongs to the treating agents of vomiting during chemotherapy of cancer. It was first successfully developed by Merck Company (German). In March 2003, the US Food and Drug Administration approved it for being used in the treatment of chemotherapy vomiting. This product has a high selective affinity to human beings while has a low affinity to serotonin, dopamine and glucocorticoid receptor affinity. Aprepitant, when combined with 5-HT3 receptor inhibitors (such as ondansetron hydrochloride) and the corticosteroid dexamethasone, can further alleviate the cisplatin-induced acute and (or) delayed emesis. Applying this drug alone can have some preventive effect.
Substance P, a kind of tachykinin (neurokinin), is mainly distributed in the neurons of central and peripheral nervous system. It is related with a lot of features such as vomiting, depression, inflammatory pain and other inflammatory diseases. The role of substance P is mediated by NK-1 receptor which is a kind of G protein receptor coupled with phosphoinositide signaling pathway. The drug has blocking effect on the NK-1 receptor through direct binding to this receptor, thus further obtaining the treatment of substance P-mediated diseases.
Aprepitant can selectively prevent the binding of substance P with NK-1 receptor in the central nervous system to take antiemetic effect. Therefore, it can be used for treating the nausea and vomiting caused by the moderately and highly emetogenic chemotherapy.

Dose and usage

When being used for treating the chemotherapy-induced nausea and vomiting, aprepitant is often used in combination with ondansetron (only at the first day of administration) and dexamethasone. Detailed as follows:
At 30 min before chemotherapy, intravenously inject 32 mg of ondansetron, taking 12 mg of dexamethasone; at the morning of 2~4d, take 8 mg of dexamethasone again.
For nausea and vomiting induced by chemotherapy, use a initial dose of 125mg at the first day, administer at 1 hour before chemotherapy; the first 2~3d, daily 80mg; administer at 1 h before chemotherapy; for treating severe depression (with anxiety) administer 300mg each time, qd. However, the efficacy is still not clear. The above instruction doesn’t need dose adjustment for different gender or races. For patients of renal insufficiency, there is no need for dose adjustment; for mild to moderate liver dysfunction, there is no need to adjust the dose as well; we are currently still lack of pharmacokinetic data when severe liver damage happens. It is also not necessary for the elderly to adjust the dose. There is also no need for dose adjustment to patients who are undergoing hemodialysis due to advanced renal disease.
The above information is edited by the chemicalbook of Dai Xiongfeng.

Side effects

Gastrointestinal reaction: when used for the prevention of chemotherapy-induced emesis, aprepitant may cause diarrhea, but clear relationship is still lacking.
Central nervous system: the drug can cause drowsiness and weakness (or lack thereof), but statistical significance was not obvious.
Genitourinary system: when aprepitant is applied for the treatment of severe depression, sexual dysfunction can occur.
Respiratory system: the drug is used for the prevention of chemotherapy-induced emesis, can also cause hiccups. But the clinical significance is not clear.
Skin: occasionally History-Johnson syndrome, urticaria and angioedema can occur.
Liver: when aprepitant is used for the prevention of chemotherapy-induced emesis, it can cause the increase of serum aminotransferase, but the clinical significance is unclear. No cases of liver toxicity had been reported.

Uses

Antineoplastic drug.

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.

Chemical Properties

Off-White to Light Yellow Cyrstalline Solid

Originator

Merck (US)

Uses

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.

Uses

anticholinergic

Definition

ChEBI: A morpholine-based antiemetic, which is or the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/eurokinin 1 (NK1) receptors.

Brand name

Emend (Merck).

Clinical Use

Aprepitant, a substance P (neurokinin-1 [NK-1]) receptor antagonist used for thetreatment 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 havinga trisubstituted morpholine with three chiral centers. Two syntheses have beendescribed. 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 stepsutilizing a chiral induction strategy to set the new centers based upon the chiral 2-oxomorpholine intermediate. SAR efforts leading to aprepitant included engineeringin potency for NK-1, decreasing affinity for L-type calcium ion channels, mostimportantly by decreasing the basicity of the core heterocycle. In vitro, it binds withvery high affinity (90 pM) to the hNK1 in transfected CHO cells. It is described as aninverse 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 effectis enhanced with the dosing of dexamethasone and it is effective against both theacute and delayed phase of cisplatin-induced emesis. Cisplatin-induced emesis clinicalstudies showed that aprepitant (125 mg p.o.) in combination with ondansetron (32 mgi.v.) and dexamethasone (20 mg p.o.) therapeutically followed by repeat dosing (days2–5) of aprepitant (80 mg) dexamethasone (20 mg) provided acute (8 h) and delayedphase (days 2–7) no vomiting rates of 83 and 70%, respectively. L-758298, a prodrugof aprepitant, was not as effective as ondansetron (32 mg i.v.) in reducing acute phasevomiting, but was superior in reducing vomiting in the delayed phase. The terminalhalf-life range of aprepitant is 9–13 h and the bioavailability is about 65%. It ishighly protein bound (95%) and has a Vdss of 70 L. It is a moderate CYP3A4inhibitor, thus several drugs cleared by CYP3A4 should not be used concurrently. It isalso an inducer of CYP2C9 thus potentially modulating the PK of drugs cleared byCYP2C9. Most side effects were mild to moderate, with fatigue, asthenia, diarrhea,and hiccups.

Synthesis

Severalvariations to the synthesis of aprepitant (II) have beenpublished by the Merck group. The latest optimizedsynthesis utilizing a novel crystallization-induceddiastereoselective synthesis of aprepitant is highlighted in theScheme. The synthetic approach entailed (1) thesynthesis and coupling of the key pieces, N-benzyl lactamlactol 13 and sec-phenethyl alcohol 7, to provide lactamacetal 14, (2) stereoselective elaboration to the keyintermediate 14, and (3) conversion to the final compoundvia either intramolecular cyclization or intermolecularcoupling with triazolinone chloride 24. The intermediate secphenethylalcohol 7 was synthesized in 97% yield and 95%e.e. (improved to 99% e.e. after recrystallization) via theenantioselective borane reduction of ketone 6 in the presenceof 2 mol % of (S)-oxazaborolidine catalyst 8. The optimizedconditions involved the slow addition of ketone 6 to a solution containing catalyst 8 and BH3?¤PhNEt2 complex inMTBE at ¨C10 to 0??C. The synthesis of lactam 12 was doneby reacting N-benzylethanolamine (9) with slight excess ofaqueous glyoxylic acid (10, 2.3 equivalent of 50% aqueoussolution) in refluxing THF. Adjustment of the solventcomposition from predominantly THF to predominantlywater resulted in the crystallization of lactam 12 directlyfrom 11 in the reaction mixture in 76% yield. Lactam 12was treated with trifluoroacetic anhydride (1 equiv) to givetrifluoroacetate 13, which was reacted in situ with chiralalcohol 7 in the presence of BF3?¤OEt2 to give, after workup,a 55:45 mixture of the acetals 14 and 15 in 95-98% overallyield. To obtain the desired diastereomer from the 55:45mixture of 14 and 15, an optimized crystallization sequencewas developed. To a solution of the crude mixture inheptane, 3,7-dimethyl-3-octanol (17) (0.9 equiv) was added,cooled to ¨C10 to ¨C5??C and, after seeding the mixture withpure 14, potassium salt of 3,7-dimethyl-3-octanol (16) (0.3equiv) was added to initiate the crystallization-inducedepimerization of 15 to 14. After 5 hr, the mixture wastransformed into a 96:4 mixture from which 14 was isolatedin 83-85% yield and ￡?99% e.e. Under an optimizedcondition, the lactam 1 4 was reacted with 4-fluorophenylmagnesium bromide (18) (1.3 equiv) in THF atambient temperature followed by methanol quench andaddition of p-toluenesulfonic acid (1.8-2.2 equiv).Immediate hydrogenation of this mixture in the presence of5% Pd/C gave the addition product 19, which was isolatedas hydrochloride salt in 91% yield. Under these conditions,no cleavage of the benzylic ether group was seen, even afterextended hydrogenation periods. Elaboration to aprepitant(II) was done by the initial alkylation of 19 in the presenceof a base with amidrazone chloride 20, which was preparedfrom chloroacetonitrile, to give the intermediate 21.Thermolysis of 21 in toluene provided aprepitant (II) in85% overall yield. Alternatively, the hydrochloride salt 19has also been alkylated directly with the triazolinonechloride 24 to give aprepitant (II).

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.

Metabolism

Aprepitant undergoes extensive metabolism. Following a single IV 100mg dose of [14C]fosaprepitant, a prodrug for aprepitant, aprepitant accounts for approximately 19% of the radioactivity in plasma over 72 hours. 12 metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant, primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19, occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active.
Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine (57%) and via biliary excretion in faeces (45%).

storage

Store at -20°C

References

Curran, Monique P., and D. M. Robinson. "Aprepitant."Drugs69.13(2009):1853-1878.
Sant P. Chawla M.D. † ‡, et al. "Establishing the dose of the oral NK 1, antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting." Cancer 97.9(2003):2290-2300.
Warr, D. G., et al. "Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy." Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology23.12(2005):2822-30.
https://en.wikipedia.org/wiki/Aprepitant

Aprepitant Preparation Products And Raw materials

• Raw materials: Aprepitant Impurity 9