Chemical Properties
N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt is Off-White Solid
Uses
Pemetrexed is used in the treatment of malignant pleural mesothelioma (MPM) and erectile dysfunction therapy.
Definition
ChEBI: Pemetrexed is an N-acylglutamic acid in which the N-acyl group is specified as 4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl. Inhibits thymidylate synthase (TS), 421 dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). It has a role as an antineoplastic agent, an antimetabolite, an EC 2.1.1.45 (thymidylate synthase) inhibitor, an EC 1.5.1.3 (dihydrofolate reductase) inhibitor and an EC 2.1.2.2 (phosphoribosylglycinamide formyltransferase) inhibitor. It is a pyrrolopyrimidine and a N-acyl-L-glutamic acid. It is a conjugate acid of a pemetrexed(2-).
brand name
Alimta (Lilly).
Side effects
The most common side effects for pemetrexed include fatigue, nausea, vomiting, anorexia, mucositis, myelosuppression ± infection, bleeding, rash, diarrhea and ↑ LFTs.
Severe myelosuppression is often dose-limiting for pemetrexed. Sepsis, in some cases fatal, have occurred in approximately 1% of patients in clinical trials. Prophylactic folic acid and intramuscular vitamin B12 supplements are necessary to reduce hematologic or non-hematologic toxicities.
Pemetrexed may cause serious and in some cases fatal dermatologic toxicities. Rarely, StevensJohnson syndrome and toxic epidermal necrolysis have been reported.
Synthesis
The general procedure for the synthesis of pemetrexed disodium salt from (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic acid diethyl ester 4-methylbenzenesulfonate is as follows:
1. Preparation of pemetrexedic acid (Eq. 2):
a. Add 1 L of a 1N aqueous NaOH solution to the reactor and cool to 5-15°C.
b. To the cooled NaOH solution, slowly add 143 g of the compound of Formula 3 prepared in Example 1, maintaining the temperature at 5-15°C.
c. The reaction mixture was stirred at 5-15°C for 2 hours, followed by filtration (HPLC purity: 99.8%).
d. 2L of EtOH was added to the filtrate followed by slow dropwise addition of 2N HCl aqueous solution at 5-15°C to adjust the pH to 3.0.
e. The crystalline mixture formed was stirred at 40-50°C for 1 hr and then filtered at 40°C.
f. The filtered product was washed with 2 L of pure water followed by 1 L of EtOH.
g. Dissolve the washed product in 4L of EtOH/pure water (1:1, v/v) and stir at 40-50°C for 1 hour.
h. Cool to room temperature and filter, wash with 2L of pure water and then with 1L of EtOH.
i. The product was dried under vacuum at 40-45 °C for 16 h to give 88 g of pemetrexedic acid as a white solid (yield: 95%, HPLC purity: 99.9%, individual impurity content: not mentioned). ii.
Mode of action
Pemetrexed is a pyrrolopyrimidine antifolate that exerts its antineoplastic activity by inhibiting thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT) and dihydrofolate reductase (DHFR), which are involved in folate metabolism and DNA synthesis, resulting in inhibition of purine and thymidine nucleotide synthesis.
References
[1] Patent: US2016/214987, 2016, A1. Location in patent: Paragraph 0081
[2] Patent: US2008/45711, 2008, A1. Location in patent: Page/Page column 11
![N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid 1,5-diethyl ester 4-methylbenzenesulfonate](/CAS/GIF/165049-28-5.gif)
