- Preparation method of raltitrexed
-
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.
- -
-
Paragraph 0062-0064
(2019/12/25)
-
- Raltitrexed synthesis of intermediates method (by machine translation)
-
The invention belongs to the field of medical technology, in particular to a method for synthesizing intermediate raltitrexed. The method adopts the 2, 5 - thiophene dicarboxylic acid compound (1) by the Curtius rearrangement as a raw material to obtain compound (2); compound (2) in the phase transfer reagent, catalyst, the presence of a base with the N - methylation reagent by the reaction of the compound (3); compound (3) in the alkali aqueous solution or organic solvent mixed solution prepared by the hydrolysis of compound (4); the compound (4) and L - glutamic acid diester hydrochloride in the condensing agent and condensation activator role in the presence of a solvent condensation to make the compound (5); the compound (5) removing the amino protecting reagent in the reaction under the effect of the compound (6). The method overcomes the technical materials are not obtained easily, the price is expensive, the cost is high, the synthetic route is complicated and lengthy, the product does not easy to be purified and the like, to obtain the high purity of the intermediate. (by machine translation)
- -
-
-
- Raltitrexed pharmaceutical composition and preparation method thereof
-
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.
- -
-
Paragraph 0085-0087
(2018/04/02)
-
- Raltitrexed related substance C as well as preparation and application thereof
-
The invention discloses a raltitrexed related substance C with inhibition activity on dihydrofolate reductase and methionine synthetase, a preparation method and application thereof as an impurity control group.
- -
-
-
- 5-((alkoxy methylene) amino) thienyl-2-formyl group)-L-glutamic acid dialkyl ester and preparation method thereof
-
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.
- -
-
Paragraph 0059-0061
(2017/08/31)
-
- Impurity A of raltitrexed, and preparation method and application thereof
-
The invention discloses a potential blood system toxic impurity A of raltitrexed, a preparation method thereof, and a use of the impurity A as an impurity reference substance.
- -
-
-
- New synthesis of thymidylate synthase inhibitor raltitrexed
-
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
-
p. 3519 - 3526
(2007/10/03)
-
- Analogues of methotrexate in rheumatoid arthritis. 2. Effects of 5- deazaaminopterin, 5,10-dideazaaminopterin, and analogues on type II collagen- induced arthritis in mice
-
Twenty-six compounds derived from the 5-deaza- and 5,10- dideazaaminopterin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-deaza series were prepared by alkylation of an appropriate N- substituted (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2- thenoyl)-L-glutamate diester with a 2,4-diamino-5-alkyl-6-(bromomethyl)-5- deazapteridine. The resultant 5-deazaaminopterin diesters were saponified to provide the target 5-deaza analogues. 5,10-Dideazaaminopterins were synthesized by similar alkylation of the carbanions of appropriate 4- carboxyphenylacetic, (5-carboxy-2-thienyl)acetic, or (5-carboxy-2- pyridyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4- deoxy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponified and then readily decarboxylated by heating in Me2SO solution to provide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Peptide coupling with diethyl L-glutamate followed by ester hydrolysis at room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position were generally quite effective as antiinflammatory agents. Thus 5-propyl-5-deazaaminopterin, 5-methyl-10- propargyl-5-deazaaminopterin, 5-methyl-10-allyl-5-deazaaminopterin, 5-ethyl- 5-deazamethotrexate, and 2,5-disubstituted thiophene analogue of 5-methyl-5- deazaaminopterin showed potencies greater than methotrexate by intraperitoneal or oral administration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideazaaminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C-10 was generally detrimental to antiinflammatory activity in this series.
- Piper, James R.,DeGraw, Joseph I.,Colwell, William T.,Johnson, Cheryl A.,Smith, R. Lane,Waud, William R.,Sirotnak, Francis M.
-
p. 377 - 384
(2007/10/03)
-
- Antiinflammatory and antineoplastic 5-deazaaminopterins and 5,10-dideazaaminopterins
-
Antiinflammatory and antineoplastic 5-deazaaminopterins and 5,10-dideazaaminopterins and their 5 and 10 alkyl analogs. A method for the treatment and prevention of inflammatory disease, such as rheumatoid arthritis, and for suppression and prevention of neoplastic growth in tumors and in blood forming tissues. A process for preparation of 10-deazaaminopterins.
- -
-
-
- Quinazoline Antifolate Thymidylate Synthase Inhibitors: Heterocyclic Benzoyl Ring Modifications
-
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.
-
p. 1594 - 1605
(2007/10/02)
-