Fosrolapitant

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Fosrolapitant

CAS 2573694-38-7

MF C27H29F6N2O8P MW654.5 g/mol

phosphonooxymethyl (5S,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-2-oxo-8-phenyl-1,9-diazaspiro[4.5]decane-9-carboxylate

(phosphonooxy)methyl (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-2-oxo-8-phenyl-1,7-diazaspiro[4.5]decane-7-carboxylate
neurokinin 1 (NK1) receptor antagonist, HR20013, HR 20013, M5QGY92X8B

Fosrolapitant (HR20013) is a novel, intravenous, highly selective neurokinin-1 (NK-1) receptor antagonist used for the prevention of chemotherapy-induced nausea and vomiting (CINV), particularly for cisplatin-based regimens. As a prodrug, it is rapidly converted to rolapitant, offering a long half-life (~180 h). It is often combined with palonosetron and dexamethasone for high efficacy.

Fosrolapitant is a small molecule drug. The usage of the INN stem ‘-pitant’ in the name indicates that Fosrolapitant is a neurokinin NK1 (substance P) receptor antagonist. Fosrolapitant has a monoisotopic molecular weight of 654.16 Da.

Key Aspects of Fosrolapitant:

Mechanism: Acts as an NK-1 receptor antagonist to prevent nausea/vomiting.
Administration: Intravenous (IV) formula, often combined as a fixed-dose with palonosetron (HR20013).
Metabolism: Completely converted to rolapitant in the body, which has a prolonged half-life of approximately 180 hours.
Clinical Efficacy: In trials (e.g., PROFIT trial), it demonstrated high effectiveness in preventing CINV in patients receiving highly emetogenic chemotherapy.
Safety Profile: Common adverse events in trials included constipation (22.7%), increased blood pressure (18.2%), abdominal distension (13.6%), and injection site reactions (9.1%).

Fosrolapitant is designed to improve convenience and patient compliance in managing acute and delayed nausea and vomiting associated with cancer treatments.

HR20013 for Nausea and Vomiting Associated With Moderate Emetic Risk Anticancer Agents

CTID: NCT06554184

Phase: Phase 3

Status: Completed

Date: 2025-11-17

SYN

WO-2020259675-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020259675&_cid=P20-MKT4GS-85082-1

Under N2 protection, compound 3 (1.95 g, 2.543 mmol, 1 eq) dissolved in dichloromethane (40 mL) was added to a 100

_mL single-necked flask. Trifluoroacetic acid (1.45 mL, 19.52 mmol, 8 eq) was slowly added under ice water cooling. The mixture was stirred until the reaction was complete, concentrated, and 2.29 g of oil was obtained. After separation and purification, 1.39 g of white foamy solid was obtained, with a yield of 83.5%.

[0129]

¹H-NMR(400MHz，CD ₃OD):δ(ppm)7.89(s，2H)，7.86(s，1H)，7.41-7.27(m，5H)，5.66(d，J＝12Hz，1H)，5.50-5.47(m，1H)，4.60(d，J＝8Hz，1H)，4.20-3.88(m，3H)，2.51-2.10(m，5H)，1.86-1.66(m，3H)，1.44-1.31(m，4H).

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US380158929&_cid=P20-MKT480-75882-1

Example 1

STEP 1

Compound 1 (2.43 g, 4.86 mmol, 1 eq) was weighed and dissolved in dichloromethane (36 mL) in a 100 mL three-necked flask under N ₂atmosphere. Diisopropylethylamine (5 g, 38.76 mmol, 8 eq) was added and the mixture was cooled to −30° C. Trimethylchlorosilane (1.36 g, 12.52 mmol, 2.6 eq) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to −25° C. A solution of chloromethyl chloroformate (0.77 g, 6 mmol, 1.23 eq) in dichloromethane was added dropwise and the mixture was stirred under controlled temperature at −20° C.˜−5° C. until completion of the reaction. The reaction solution was poured into ice water, put to separation, and extracted with dichloromethane. Water and 1 N hydrochloric acid solution were added and put to separation. The organic layer was then successively washed with brine, saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3.0 g yellow jelly with a yield of 104%.

Compound 3 (1.95 g, 2.543 mmol, 1 eq) was added into a 100 mL single-necked flask and dissolved in dichloromethane (40 mL) under N ₂atmosphere. Trifluoroacetic acid (1.45 mL, 19.52 mmol, 8 eq) was added slowly under ice water cooling. The reaction mixture was stirred until completion of the reaction, and then concentrated to give 2.29 g oil which was then purified purified to give 1.39 g white foamy solid with a yield of 83.5%.

¹H-NMR (400 MHz, CD ₃OD): δ(ppm) 7.89 (s, 2H), 7.86 (s, 1H), 7.41-7.27 (m, 5H), 5.66 (d, J=12 Hz, 1H), 5.50-5.47 (m, 1H), 4.60 (d, J=8 Hz, 1H), 4.20-3.88 (m, 3H), 2.51-2.10 (m, 5H), 1.86-1.66 (m, 3H), 1.44-1.31 (m, 4H).

PAT