- New synthesis of thymidylate synthase inhibitor raltitrexed
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The quinazoline-based inhibitor of thymidylate synthase, Raltitrexed, was synthesized from 2,5-thiophenedicarboxylic acid via monocoupling with diethyl L-glutamate, modified Curtius reaction, N-methylation, removal of Boc-protecting group, condensation with (bromomethyl)quinazolinone and saponification in 18.2% overall yield.
- Cao, Sheng-Li,Wan, Rong,Feng, Yu-Ping
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- Preparation method of raltitrexed
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The invention belongs to the field of drug synthesis, and in particular, relates to a preparation method of raltitrexed. With an N-methylation reaction in the preparation method, the problems of longreaction time, more by-products and inconvenient post-treatment in a conventional method are overcome, and provided is new intermediate compounds represented by the formula IIIa and IVa. The N-methylation intermediate (compound represented by the formula IVa) and raltitrexed are rapidly prepared with high yield, high purity and fastness; the preparation method is simple in reaction operation and post-treatment, short in production cycle, good in reproducibility, mild in conditions, and suitable for industrial production.
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- Raltitrexed pharmaceutical composition and preparation method thereof
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The invention relates to a raltitrexed pharmaceutical composition which is high in safety and a preparation method thereof. The raltitrexed pharmaceutical composition comprises raltitrexed and thiophene related substances, wherein the content of the thiophene related substances is not higher than 0.3%. The raltitrexed pharmaceutical composition is good in safety, effectiveness and stability and can relieve the blood toxicity of the raltitrexed to a certain degree.
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- 5-((alkoxy methylene) amino) thienyl-2-formyl group)-L-glutamic acid dialkyl ester and preparation method thereof
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The invention belongs to the field of medicine synthesis, and discloses a compound of formula 4 as shown in the specification, a preparation method and application of the compound. The compound can be used as an intermediate to synthesize an anti-cancer medicine of formula 1 as shown in the specification, has the advantages of low cost, high purity, gentle reaction and simple and convenient posttreatment, and is applicable to industrially enlarged production.
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- Anti-tumour agents
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A quinazoline of the formula: STR1 wherein R1 is alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, aryloxy, arylalkyl, halogeno, hydroxy, mercapto, pyridylthio, pyrimidinylthio, or substituted alkyl or alkoxy; wherein R2 is hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl or alkanoyl; wherein Ar is phenylene, naphthylene or heterocyclene which is unsubstituted or bears one or more substituents and wherein R3 is such that R3 --NH2 is an amino acid; or a pharmaceutically-acceptable salt or ester thereof. The compounds possess anti-tumour activity.
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- Quinazoline Antifolate Thymidylate Synthase Inhibitors: Heterocyclic Benzoyl Ring Modifications
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The synthesis is described of a series of C2-methyl-N10-alkylquinazoline-based antifolates in which the p-aminobenzoate ring is replaced by the heterocycles thiophene, thiazole, thiadiazole, pyridine, and pyrimidine.These were generally elaborated by the reaction of (bromomethyl)quinazoline 18 or its N3--protected derivative 36 with suitable heterocyclic amines although each heterocyclic system required its own particular synthetic approach.The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS).Theywere also examined for their inhibition of the growth of L1210 cells in culture.The thiophene system 7 and its related thiazole 8 gave analogues that were considerably more potent than the parent benzene series 2 as inhibitors of L1210 cell growth although in general these heterocycles were somewhat poorer inhibitors of the isolated TS enzyme.The enhanced cytotoxicities of the thiophene and thiazole analogues result, at least in part, from their efficient transport into the cells via the reduced folate carrier mechanism and very good substrate activity for folypolyglutamate synthetase.The replacement of the C2-methyl group by C2-(fluoromethyl) and C2-(hydroxymethyl) substituents in the thiophene and thiazole series gave derivatives that were only slightly less potent inhibitors of the TS enzyme but which were considerably less cytotoxic.
- Marsham, Peter R.,Hughes, Leslie R.,Jackman, Ann L.,Hayter, Anthony J.,Oldfield, John,et al.
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p. 1594 - 1605
(2007/10/02)
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