- Method for preparing pemetrexed disodium at high yield
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The invention relates to a preparation method of pemetrexed disodium. The preparation method is characterized in that an alkali-modified microporous/mesoporous molecular sieve catalyst is used as a catalyst to replace NaOH as a reaction catalyst, so favorable yield and product purity are obtained under the condition of enlarged reaction scale.
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Page/Page column 9; 11-13
(2021/01/12)
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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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- Preparation method of pemetrexed acid
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Belonging to the technical field of organic compound synthesis, the invention in particular relates to a preparation method of pemetrexed acid. The method is characterized by utilizing methyl p-formylbenzoate and malonic acid as the starting materials to synthesize the target product. Compared with the methods for synthesis of the compound reported in previous literatures, the method provided by the invention has the advantages of easily available raw materials, low price and no pollution, greatly reduces the production cost, and is suitable for large-scale industrial production. The method isa brand new synthetic route for the compound.
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Paragraph 0057-0059
(2019/05/16)
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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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- 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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p. 2538 - 2546
(2018/11/10)
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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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p. 1565 - 1569
(2015/10/06)
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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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- 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
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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.
- Mitchell-Ryan, Shermaine,Wang, Yiqiang,Raghavan, Sudhir,Ravindra, Manasa Punaha,Hales, Eric,Orr, Steven,Cherian, Christina,Hou, Zhanjun,Matherly, Larry H.,Gangjee, Aleem
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p. 10016 - 10032
(2014/01/17)
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- DRUG DERIVATIVES
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The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
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Paragraph 0425; 0434
(2013/09/12)
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- DRUG DERIVATIVES
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The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
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Page/Page column 116-117
(2012/05/31)
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- A NEW CRYSTALLINE FORM OF PEMETREXED DISODIUM
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The present invention relates to a new polymorphic or crystalline form of Pemetrexed Disodium, processes for its preparation and its use, in particular for the preparation of medicaments.
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- Determination of the source of the N-methyl impurity in the synthesis of pemetrexed disodium heptahydrate
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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.
- Kjell, Douglas P.,Hallberg, Dallas W.,Kalbfleisch, J. Michael,McCurry, Cynthia K.,Semo, Michael J.,Sheldon, Edward M.,Spitler, Jeremy T.,Wang, Ming
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p. 738 - 742
(2012/12/26)
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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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- 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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p. 184 - 188
(2013/09/08)
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- A simple and concise synthesis of LY231514 (MTA)
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The pyrrolo[2,3-d]pyrimidine anticancer agent LY231514 (MTA, 1) has been prepared utilizing, as a key sequence, Michael condensation of 2,6-diamino- 4(3H)-pyrimidinone (as the donor) with the nitro olefin 8, followed by a Nef reaction that leads to the annulated pyrrole ring of 1.
- Taylor, Edward C.,Liu, Bin
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p. 4023 - 4026
(2007/10/03)
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- Process for preparing 5-substituted pyrrolo-[2,3-d]pyrimidines
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Processes for preparing 5-substituted pyrrolo[2,3-d]pyrimidines which are useful as intermediates for the preparation of pyrrolo[2,3-d]pyrimidine antineoplastic agents or as antineoplastic agents themselves are provided.
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- A Novel Synthetic Approach to Pyrrolopyrimidine Antifolates
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A novel and efficient synthetic method for the synthesis of pyrrolopyrimidine antifolates is described.The key reaction of this method is the photo-initiated free radical addition of bromomalononitrile or ethyl bromocyanoacetate to an enol ether to afford the backbone skeleton of the targeted antifolate molecule.The key intermediates 3 or 4 are smoothly converted to the pyrrolopyrimidine antifolates 1 or 2 in three steps and in high overall yield.
- Miwa, Tetsuo,Hitaka, Takenori,Akimoto, Hiroshi
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p. 1696 - 1701
(2007/10/02)
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