- A practical synthesis of multitargeted antifolate LY231514
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A concise and scalable synthesis of LY231514 (1), a new pyrrolo[2,3-d]pyrimidine-based antitumor agent, is presented. Reaction of 2-bromo-4-arylbutanal 9 with 2,4-diamino-6-hydroxypyrimidinc (10) regioselectively provided pyrrolo[2,3-d]pyrimidine 11, representing the core structure of the drug, in good yield. Assimilation of the glutamic acid residue by conventional means completed the synthesis. Development of the optimized synthetic route emphasized avoiding isolation of the relatively unstable aldehyde and bromoaldehyde intermediates.
- Barnett, Charles J.,Wilson, Thomas M.,Kobierski, Michael E.
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- Synthesis and antiviral study of novel 4-(2-(6-amino-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyrimidin-3-yl)ethyl)benzamide derivatives
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A series of ten new compounds (7a–j) has been synthesized by absolutely replacing the glutamic acid part of Pemetrexed drug, chemically known as N-{4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-l-glutamic acid, with primary, secondary, and aryl amines in high yields using diethylphosphorocyanidate (DEPC) as a peptide coupling agent. All the synthesized compounds are characterized by 1H and 13C NMR, LCMS, and FT-IR spectral techniques. All the synthesized novel non-glutamate 4-(2-(6-amino-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyrimidin-3-yl)ethyl)benzamide derivatives showed 4- to 7-folds higher antiviral activity than its structurally similar commercial drug Pemetrexed against Newcastle disease virus, an avian paramyxovirus. Among the lot, compounds possessing carboxamide synthesized using five-membered heteroaryl amines (7i and 7j) exhibited the highest antiviral activity. [Figure not available: see fulltext.].
- Balaraman, Selvakumar,Nayak, Nagaraj,Subbiah, Madhuri,Elango, Kuppanagounder P.
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- An Efficient Synthesis of Pemetrexed Disodium
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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.
- Qi,Wen,Li,Bai,Chen,Wang
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- PdII-Catalyzed Site-selective β- and γ-C(sp3)-H Arylation of Primary Aldehydes Controlled by Transient Directing Groups
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Pd(II)-catalyzed site-selective β- and γ-C(sp3)-H arylation of primary aldehydes is developed by rational design of L,X-type transient directing groups (TDG). External 2-pyridone ligands are identified to be crucial for the observed reactivity. By minimizing the loading of acid additives, the ligand effect is enhanced to achieve high reactivities of the challenging primary aldehyde substrates. Site selectivity can be switched from the proximate to the relatively remote position by changing the bite angle of TDG to match the desired palladacycle size. Experimental and computational investigations support this rationale for designing TDG to potentially achieve remote site-selective C(sp3)-H functionalizations.
- Li, Yi-Hao,Ouyang, Yuxin,Chekshin, Nikita,Yu, Jin-Quan
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p. 4727 - 4733
(2022/04/07)
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- Multi-arm polymeric prodrug conjugates of pemetrexed-based compounds
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Among other aspects, provided herein are multi-arm polymeric prodrug conjugates of pemetrexed-based compounds. Methods of preparing such conjugates as well as methods of administering the conjugates are also provided. Upon administration to a patient, release of the pemetrexed-based compound is achieved.
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- Carbonylative Transformation of Allylarenes with CO Surrogates: Tunable Synthesis of 4-Arylbutanoic Acids, 2-Arylbutanoic Acids, and 4-Arylbutanals
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In this Communication, procedures for the selective synthesis of 4-arylbutanoic acids, 2-arylbutanoic acids, and 4-arylbutanals from the same allylbenzenes have been developed. With formic acid or TFBen as the CO surrogate, reactions proceed selectively and effectively under carbon monoxide gas-free conditions.
- Wu, Fu-Peng,Li, Da,Peng, Jin-Bao,Wu, Xiao-Feng
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p. 5699 - 5703
(2019/08/01)
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- Synthetic pemedolac preparation process
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The invention discloses a synthetic pemedolac preparation method, which specifically comprises: carrying out a Heck reaction by using methyl p-bromobenzoate and 3-butene-1-ol as starting raw materialsto obtain crude aldehyde, and directly carrying out a bromination reaction, a cyclization reaction and a hydrolysis reaction through a one-pot method to obtain pemedolac. According to the present invention, the method has characteristics of mild reaction conditions, easy control, simple and safe process operation, good product yield and high product purity.
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Paragraph 0051-0052; 0054-0055; 0057-0058; 0060-0061; 0063
(2019/07/04)
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- Method for preparing pemetrexed disodium key intermediate
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The invention discloses a method for preparing a pemetrexed disodium key intermediate (I). The method comprises the following steps: carrying out classical Friedenylation and esterification reactionson raw materials comprising toluene and succinic anhydride to obtain methyl 3-(4-methylphenyl)-4-oxobutanoate, carrying out oxygen or air oxidation on the methyl 3-(4-methylphenyl)-4-oxobutanoate under the catalysis of N-hydroxyphthalimide (NHPI) and cobalt acetate to obtain 4-(methoxy-4-oxobutylcarbonyl)benzoic acid, and carrying out selective reduction, selective oxidation, esterification and bromination reactions on the obtained oxidation product to prepare methyl 4-(3-bromo-4-oxobutyl)benzoate. The method has the advantages of cheap and easily available raw materials, mild reaction conditions, simplicity in treatment, good yield and good purity of the product, and suitableness for industrial production.
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- INHIBITORS OF HISTONE LYSINE SPECIFIC DEMETHYLASE (LSD1) AND HISTONE DEACETYLASES (HDACS)
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A series of phenelzine analogs comprising a phenelzine scaffold linked to an aromatic moiety and their use as inhibitors of lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs) is provided. The presently disclosed phenelzine analogs exhibit potency and selectivity for LSD1 versus MAO and LSD2 enzymes and exhibit bulk, as well as, gene specific histone methylation changes, anti-proliferative activity in several cancer cell lines, and neuroprotection in response to oxidative stress. Accordingly, the presently disclosed phenelzine analogs can be used to treat diseases, conditions, or disorders related to LSD1 and/or HDACs, including, but not limited to, cancers and neurodegenerative diseases.
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- PROCESS FOR THE PREPARATION OF PEMETREXED AND LYSIN SALT THEREOF
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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.
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Page/Page column 15
(2014/03/21)
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- A short and efficient synthetic protocol for the synthesis of 5-substituted-4,6-dioxo-pyrrolo[2,3-d]pyrimidines
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A short and efficient synthesis for 5-substituted-4,6-dioxo-pyrrolo[2,3-d] pyrimidines has been developed by the cyclocondensation of α,α- dibromoaldehydes with 2,4-diamino-6-hydroxypyrimidine under mild basic conditions in good yields. Application of this protocol has been demonstrated in the synthesis of a metabolite of Pemetrexed disodium, a novel multi-targeted antifolate.
- Sekhar,Acharyulu, Palle V.R.,Anjaneyulu, Yerramilli
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scheme or table
p. 4140 - 4144
(2011/09/19)
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- PROCESSES FOR PREPARING PEMETREXED DISODIUM AND ITS INTERMEDIATE,4-(4-CARBOMETHOXYPHENYL)BUTANAL
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The present invention provides a process for preparing pemetrexed disodium and its intermediate, 4-(4-carbomethoxyphenyl)butanal. The process for preparing the intermediate comprises the following steps: condensing methyl 4-bromobenzoate with 3-buten-1-ol; extracting with an organic solvent during the work-up; adding silica gel to decolorize; and evaporating the organic solvent to give 4-(4-carbomethoxyphenyl)butanal. The product obtained by the present process, with a yield of higher than 80%, and a purity measured by GC of higher than 95%, may be directly used in the next bromination reaction for synthesizing pemetrexed disodium without purification. The present process is suitable for industrial production, as the operation is simple and the reagents used are cheap and readily available.
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Page/Page column 5
(2011/04/24)
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- Process for Preparing Pemetrexed Disodium and Its Intermediate, 4-(4-Carbomethoxyphenyl) Butanal
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The present invention provides a process for preparing pemetrexed disodium and its intermediate, 4-(4-carbomethoxyphenyl)butanal. The process for preparing the intermediate comprises the following steps: condensing methyl 4-bromobenzoate with 3-buten-1-ol; extracting with an organic solvent during the work-up; adding silica gel to decolorize; and evaporating the organic solvent to give 4-(4-carbomethoxyphenyl)butanal. The product obtained by the present process, with a yield of higher than 80%, and a purity measured by GC of higher than 95%, may be directly used in the next bromination reaction for synthesizing pemetrexed disodium without purification. The present process is suitable for industrial production, as the operation is simple and the reagents used are cheap and readily available.
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Page/Page column 3
(2011/06/19)
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- Structural determinants for histamine H1 affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs
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In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H1 binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H1 assays.
- Aslanian, Robert,Piwinski, John J.,Zhu, Xiaohong,Priestley, Tony,Sorota, Steve,Du, Xiao-Yi,Zhang, Xue-Song,McLeod, Robbie L.,West, Robert E.,Williams, Shirley M.,Hey, John A.
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supporting information; experimental part
p. 5043 - 5047
(2010/03/31)
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- Samarium(II)-promoted radical spirocyclization onto an aromatic ring
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Samarium(II)-mediated spirocyclization onto an aromatic ring was achieved by the reaction of methyl 4-(4-oxoalkyl)benzoates with SmI2 in the presence of i-PrOH and HMPA, yielding methyl 1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields. Utilizing this chemistry, spiro[3.5] and -[5.5] systems, and sterically congested spiro[4.5] systems, were easily synthesized. For the successful conversion, appropriate activation of the aromatic ring has proven to be extremely important: while an ester or amide functionality on the aromatic ring can promote the spirocyclization, a sulfonamide substituent causes ortho cyclization.
- Ohno, Hiroaki,Okumura, Mitsuaki,Maeda, Shin-Ichiro,Iwasaki, Hiroki,Wakayama, Ryutaro,Tanaka, Tetsuaki
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p. 7722 - 7732
(2007/10/03)
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- 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
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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.
- Taylor, Edward C.,Liu, Bin
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p. 9938 - 9947
(2007/10/03)
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- Process for the preparation of pyrrolo[2,3-d]pyrimidines
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4(3H)-X-7H-Pyrrolo[2,3-d]pyrimidines in which X is =O or =NH are prepared by treating a 6-amino-4(3H)-X-pyrimidine with a unsubstituted or substituted 1-nitroalk-1-ene to yield a 6-amino-4(3H)-X-pyrimidine which is substituted in the 5-position by a 1-nitroalk-2-yl group; (ii) converting the 5-(1-nitroalk-2-yl)-6-amino-4(3H)-X-pyrimidine to the corresponding 5-(1-oxoalk-2-yl)-6-amino-4(3H)-X-pyr-imidine; and (iii) removing the elements of water from the 5-(1-oxoalk-2-yl)-6-amino-4(3H)-X-pyrimidine to effect cyclization. A typical embodiment involves treating 2,6-diamino-4(3H)-pyrimidone with 1-nitro-4-(4-ethoxycarbonylphenyl)-1-butene to yield 1 -nitro-2-(2,6-diamino-4(3H)-oxopyrimidin-5-yl)-4-(4-ethoxy-carbonylphenyl)butane which is then treated sequentially with base and acid, without isolation of the intermediate aldehyde, to form 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, a valuable known chemical intermediate for the preparation of N-[4-{2-(2-hydroxy-4-amino-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl}benzoyl]glutamic acid.
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- Processes and intermediates useful to make antifolates
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The present application relates to a series of novel sulfonic acid metal cation salts of the formula STR1 which are useful intermediates to prepare antifolate 5-substituted pyrrolo[2,3-d]pyrimidines. The present invention also relates to a novel process for preparing the sulfonic acid metal cation salts and to a novel process for preparing aldehydes of the formula STR2 from the corresponding sulfonic acid metal cation salts.
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- Process for the preparation of fused pyridine compounds
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Pyrido[2,3-d]pyrimidine compounds are prepared through the reaction of 2,4-diamino-6(1H)-pyrimidone and an activated derivative of a dialdehyde. A typical embodiment utilizes the dinitrile.
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