146943-43-3

Basic information

• Product Name: 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
• Synonyms: (S)-Diethyl 2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanedioate;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;PeMetrexed diethyl ester (L-GlutaMic acid, N-[4-[2-(2-aMino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyriMidin-5-yl)ethyl]benzoyl]-, 1,5-diethyl ester );PeMetrexed Diethyl Ester
• CAS NO: 146943-43-3
• Molecular Formula: C₂₄H₂₉N₅O₆
• Molecular Weight: 483.52
• Mol File: 146943-43-3.mol

Chemical Properties

• Melting Point: 84-86 ºC
• Appearance: /
• Density: 1.38
• Storage Temp.: Refrigerator
• Solubility: DMSO, Methanol (Slightly)
• CAS DataBase Reference: 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(CAS DataBase Reference)
• NIST Chemistry Reference: 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(146943-43-3)
• EPA Substance Registry System: 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(146943-43-3)

Safety Data

• Hazardous Substances Data: 146943-43-3(Hazardous Substances Data)

Usage

Uses

Pemetrexed Diethyl Ester is an protected intermediate in the synthesis of Pemetrexed (P219500), an multitargeted antifolate that inhibits thymidylate synthase as well as other folate dependent enzymes.

Upstream product

• 126931-32-6 tert-Butyl 4-(3-hydroxy-1-propyl)benzoate 
• 134372-99-9 3-(4-<2,2-dimethylethyl>carboxyphenyl)-1-propanal 
• 126931-31-5 methyl 3-<4-(tert-butoxycarbonyl)phenyl>propanoate 
• 3140-73-6 2-chloro-4,6-dimethoxy-1 ,3,5-triazine 
• 1118-89-4 diethyl-L-glutamate hydrochloride 
• 137281-39-1 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid 
• 137281-39-1 C₁₅H₁₄N₄O₃ 
• 109-02-4 4-methyl-morpholine 
• 619-44-3 methyl 4-iodobenzoate 
• 151864-75-4 ethyl 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl)benzoate 
• 927897-33-4 ethyl 4-(3-bromo-4-oxobutyl)benzoate 
• 72313-37-2 ethyl 4-(3-formylpropyl)benzoate 
• 1209465-70-2 C₂₀H₁₉N₇O₅ 
• 123910-88-3 methyl 4-(4-hydroxybut-1-yl)benzoate 

Relevant articles and documents

A pemetrexed disodium preparation method

The invention discloses a preparation method of pemetrexed disodium, which comprises the following steps: preparing 4-(4,4-dialkoxy-1-butenyl)benzoate 6 and 4-(3-formyl-3-halo-1-propenyl)benzoate 7, carrying out ring-closing reaction on the compound 7 and 2,4-diamido-6-hydroxypyrimidine under the action of an alkali to obtain a compound 9; carrying saponification on the compound 9, and acidifying to obtain a compound 10; carrying out condensation reaction on the compound 10 and diethyl L-glutamate to obtain a compound 11; carrying out catalytic hydrogenation reaction on the compound 11 under the action of a catalyst to obtain a compound 12; and carrying out hydrolysis reaction on the compound 12 under the action of an alkali to obtain the target product pemetrexed disodium 1. The method has the advantages of accessible raw materials, wide sources, low preparation cost and low price, is suitable for industrial production, and solves the problems of high preparation cost and difficulty for industrial production in the prior art.

An Efficient Synthesis of Pemetrexed Disodium

An efficient synthetic method for the pemetrexed disodium has been developed using methyl 4-iodobenzoate and 3-buten-1-ol as starting materials via six steps. The developed process avoided some tedious workup procedures and unfriendly reagents compared with the reported synthetic routes. In addition, two impurities generated in the process were isolated and characterized by 1H NMR, 13C NMR, and HRMS. The mechanisms of the two impurities were also discussed, and the impurities could be easily removed by suitable workup procedures. The overall yield of pemetrexed disodium was increased from 12.8% (literature) to 34.9%. Therefore, this cost-effective, environmental friendly, and high-yielding process is more suitable for scale-up production of pemetrexed disodium.

PROCESS FOR THE PREPARATION OF PEMETREXED AND LYSIN SALT THEREOF

The present invention refers to a process for the synthesis of pemetrexed and salts thereof, in particular to a lysine salt thereof, to said salt as such and to pharmaceutical compositions that comprise the same. Furthermore, the present disclosure also relates to a crystalline form of the synthesis intermediate pemetrexed diethyl ether and a crystalline form of the pemetrexed lysine salt.

Discovery of 5-substituted pyrrolo[2,3- d ]pyrimidine antifolates as dual-acting inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis: Implications of inhibiting 5-aminoimidazole-4- carboxamide ribonucleotide formyltransferase to AMPK activation and antitumor activity

We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5-10) with one-to-six bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analogue and potently inhibited proliferation of folate receptor (FR) α-expressing Chinese hamster ovary and KB human tumor cells. Growth inhibition was reversed completely or in part by excess folic acid, indicating that FRα is involved in cellular uptake, and resulted in S-phase accumulation and apoptosis. Antiproliferative effects of compound 8 toward KB cells were protected by excess adenosine but not thymidine, establishing de novo purine nucleotide biosynthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both AICA ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase). Inhibition of GARFTase and AICARFTase by compound 8 was confirmed by cellular metabolic assays and resulted in ATP pool depletion. To our knowledge, this is the first example of an antifolate that acts as a dual inhibitor of GARFTase and AICARFTase as its principal mechanism of action.

PROCESS FOR PREPARATION OF HIGHLY PURE DIALKYL PEMETREXED

The invention discloses a process for preparation of highly pure dialkyl pemetrexed by reacting a 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)ethylbenzoic acid with a glutamatic acid diester or its salt in presence of a safe, mild, inexpensive, non-oxidative and easy to handle reagent such as substituted triphenyl phosphate. The invention further discloses purification of dialkyl pemetrexed by crystallization or trituration and conversion of purified dialkyl pemetrexed to pemetrexed or its disodium salt.

A novel process for the synthesis of pemetrexed disodium salt

The present invention relates to a novel process for the preparation of pemetrexed diethyl ester 2 which comprises the step of purifying the mixture obtainable by reacting compounds 1 and 1a in the presence of a chemical agent capable of promoting the for

NOVEL PROCESS FOR THE SYNTHESIS OF PEMETREXED DISODIUM SALT

The present invention relates to a novel process for the preparation of pemetrexed diethyl ester 2 by purifying the mixture obtainable by reacting compounds 1 and 1a in the presence of a chemical agent capable of promoting the formation of a peptide bond

Determination of the source of the N-methyl impurity in the synthesis of pemetrexed disodium heptahydrate

The synthesis of Pemetrexed Disodium Heptahydrate has consistently resulted in a very low level (ca. 0.02%) unknown impurity. To ensure long-term control, the identity and source of the impurity were desired. Isolation and characterization identified the impurity as the N-methyl derivative. The source was identified as the methyl groups on the peptide coupling agent, 2,6-Dimethoxy-1,3,5-triazine (CDMT). Further work assured the current conditions provide adequate control.

A New and Efficient Synthesis of Pyrrolo[2,3-d]pyrimidine Anticancer Agents: Alimta (LY231514, MTA), Homo-Alimta, TNP-351, and Some Aryl 5-Substituted Pyrrolo[2,3-d]pyrimidines

Alimta, as well as homo-Alimta, a nonbridged analogue of Alimta, and TNP-351 have been prepared by a new method that involves Michael addition of the appropriate 1-nitroalkene with 2,6-diamino-3H-pyrimidin-4-one or 2,4,6-triaminopyrimidine, followed by a Nef reaction of the resulting primary nitro Michael adduct. Spontaneous intramolecular cyclization of the resulting aldehyde with the pyrimidine 6-amino group yields the corresponding pyrrolo[2,3-d]pyrimidine. A series of previously unknown 5-arylpyrrolo[2,3-d]pyrimidines was prepared by the same methodology from the above pyrimidines and nitrostyrenes. It has been found that the intermediate primary nitro Michael adduct can be prepared in a single step by sonication of a mixture of an arylaldehyde, nitromethane, and the 6-aminopyrimidine in acetic acid containing ammonium acetate.

A new route to 7-substituted derivatives of N-{4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) -ethyl]benzoyl}-L-glutamic acid [ALIMTA (LY231514, MTA)]

Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylation with methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate induced radical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to the thiolactams 6 and guanidine cyclization then gave a series of 2-amino-3,4-dihydro-4-oxo-5-vinyl-7-substituted pyrrolo[2,3-d]pyrimidines (7). Palladium-catalyzed C-C coupling with diethyl 4-iodobenzoylglutamate led in one step via an unexpected redox reaction to the diethyl esters 9 of a series of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues 10 were readily prepared by saponification. Attempted deprotection at position 7 was successful in only one case (9d, R = CH2C6H3(OMe)2 (-3′,4′), which resulted in a known pentultimate precursor (9, R = H) of ALIMTA. The 7-substituted derivatives 10 proved to be inactive in vitro as inhibitors of cell division.