- A novel and convenient route for the construction of 5-((1H-1,2,4-triazol- 1-yl)methyl)-1H-indoles and its application in the synthesis of Rizatriptan
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In this study, a novel and convenient route for the construction of 5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indoles (8) is presented starting from (1H-1,2,4-triazol-1-yl)methanol (5) and indolines (6) under 98% H 2SO4 at room temperature for 4-24 h, followed by deacetylation and dehydrogenation. Based on this finding, a novel route to synthesize Rizatriptan starting from tryptamine was designed and accomplished with 48.5% overall yield in 6 steps. Compared with operational art, the new route afforded higher yield and more pure products requiring no chromatographic purification, which may further be applied in industrialization.
- He, Yi,Li, Xiaolong,Li, Jue,Li, Xiaocen,Guo, Li,Hai, Li,Wu, Yong
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- Synthesis of the 5-HT1D receptor agonist MK-0462 via a Pd-catalyzed coupling reaction
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Application of a palladium-catalyzed coupling between 3 and 5a to the synthesis of the novel 5-HT1D receptor agonist MK-0462 (1), a potential anti-migraine drug, is described.
- Chen, Cheng-Yi,Lieberman, David R.,Larsen, Robert D.,Reamer, Robert A.,Verhoeven, Thomas R.,Reider, Paul J.,Cottrell, Ian F.,Houghton, Peter G.
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Read Online
- Rizatriptan preparation method
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The invention discloses a rizatriptan preparation method, wherein 5-methyltryptamine is used as a raw material, and five steps of amino methylation, bromination, Boc amino protection, triazole substitution and Boc deprotection are performed to obtain rizatriptan. According to the present invention, the existing indole synthesis method is avoided by using 5-methyltryptamine as the starting raw material, the used reagent is environmentally friendly, and the preparation method has characteristics of simpleness, mild condition and simple post-treatment, is suitable for industrial promotion, and isthe completely-new rizatriptan preparation method.
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- Method for preparing the advantage grips Qu Tan a benzoic acid
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The invention discloses a novel preparation method for rizatriptan benzoate. The preparation method uses indoline as a starting material, and performs five-step reaction of triazole methylation, dehydrogenation, side chain formation, reduction and salt formation so as to obtain the rizatriptan benzoate. The innovative point of the method is that a brand-new method for forming an indole ring is adopted, and the defects caused by a fisher indole synthesis method adopted in a conventional course that the impurity content of the product is high, and the purification is difficult. The method has the advantages that the operation is simple and convenient, the reaction condition is mild, no expensive reagent is used, and the product purity is high.
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Paragraph 0041-0043
(2017/02/09)
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- the advantage grips Qu Tan a method of preparing benzoic acid
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The invention discloses a novel method for preparing rizatriptan benzoate. According to the method, high-purity rizatriptan benzoate is prepared by performing seven steps of reaction of N,N-methylation, reduction, protection, triazole methylation, deprotection, dehydrogenation and salifying on tryptamine as an initial raw material. The method is characterized in that indole rings are established by using a novel method, and the defects that the product impurity content is high and purification is difficult because of a fisher indole synthesis method used in the conventional process are avoided. The method has the advantages that the operation is simple and convenient, the reaction condition is gentle, no expensive reagents is used, column chromatography purification is not needed, and the product purity is high.
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Paragraph 0052; 0053; 0054; 0055
(2016/10/07)
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- Aqueous Titanium Trichloride Promoted Reductive Cyclization of o-Nitrostyrenes to Indoles: Development and Application to the Synthesis of Rizatriptan and Aspidospermidine
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Treatment of o-nitrostyrenes with aqueous TiCl3 solution at room temperature afforded indoles through a formal reductive C(sp2)-H amination process. A range of functions such as halides (Cl, Br), carbonyl (ester, carbamate), cyano, hydroxy, and amino groups were tolerated. From β,β-disubstituted o-nitrostyrenes, 2,3-disubstituted indoles were formed by a domino reduction/cyclization/migration process. Mild conditions, simple experimental procedure, ready accessibility of the starting materials and good to excellent yields characterize the present transformation. The methodology was used as a key step in a concise synthesis of rizatriptan and a formal total synthesis of aspidospermidine. Mild and efficient treatment of o-nitrostyrenes with aqueous TiCl3 solution at room temperature afforded indoles through a formal reductive C(sp2)-Hamination process. A concise synthesis of a marketed drug (rizatriptan) and a formal total synthesis of aspidospermidine featuring this novel N-heterocyclization process are reported.
- Tong, Shuo,Xu, Zhengren,Mamboury, Mathias,Wang, Qian,Zhu, Jieping
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supporting information
p. 11809 - 11812
(2015/10/05)
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- NOVEL PROCESS
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The present invention relates to a novel process for the preparation of rizatriptan and its pharmaceutically acceptable salts. It provides a novel process for the preparation of highly pure rizatriptan, which can be easily adopted for commercial production with a high degree of consistency in purity and yield. Subsequently the rizatriptan base prepared can be converted into any suitable pharmaceutically acceptable salt, such as the oxalate, succinate or benzoate salt, for dosage form preparation. The present invention also provides a composition comprising rizatriptan useful for the manufacture of a medicament for the treatment or prevention of migraine.
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Page/Page column 6-7
(2010/10/19)
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- NOVEL PROCESS
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The present invention relates to a novel process for the preparation of rizatriptan and its pharmaceutically acceptable salts. It provides a novel process for the preparation of highly pure rizatriptan, which can be easily adopted for commercial production with a high degree of consistency in purity and yield. Subsequently the rizatriptan base preparedcan be converted into any suitable pharmaceutically acceptable salt, such as the oxalate, succinate or benzoate salt,for dosage form preparation. The present invention also provides a composition comprising rizatriptan useful for the manufacture of a medicament for the treatment or prevention of migraine.
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Page/Page column 13
(2009/01/24)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF RIZATRIPTAN
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The present invention relates to an improved process for preparing N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine of Formula I and its pharmaceutically acceptable salts.
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Page/Page column 11-12
(2008/12/06)
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- A new synthesis of rizatriptan based on radical cyclization
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A new methodology useful for preparation of indole derivatives bearing a 2-(dialkylamino)-ethyl substituent at the 3-position has been developed. Application of this methodology to the synthesis of N,N-dimethyl-2-{5-[(1H-1,2, 4-triazol-1-yl)methyl]-1H-indol-3-yl}ethan-1-amine (rizatriptan; 3) is described. The key reaction step is based on the radical cyclization of N-[4-(dimethylamino)but-2-yn-1-yl]-N-(2-iodo-4-[(1H-1,2,4-triazol-1-yl)methyl] phenyl}-acetamide (21), easily available by the Mannich reaction, and subsequent isomerization of the primarily formed methylidene derivative 22.
- Radl, Stanislav,Klecan, Ondrej,Klvana, Robert,Havlicek, Jaroslav
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p. 116 - 126
(2008/09/21)
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- PROCESS FOR THE LARGE SCALE PRODUCTION OF RIZATRIPTAN BENZOATE
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The present invention provides a method for preparing pure Rizatriptan benzoate having purity more than 99.5% and dimer impurity less than 0.1% comprises, i) Condensation of 1,2,4-Triazole with 4-Nitro benzyl bromide to yield l-(4-nitrophenyl) methyl-1,2,4- triazole ii) Reducing the l-(4-nitrophenyl) methyl-1,2,4-triazole to give l-(4- aminophenyl) methyl-1,2,4-triazole iii) Converting l-(4-aminophenyl) methyl-1,2,4-triazole to l-(4-hydrazinophenyl) methyl-1,2,4-triazole hydrochloride iv) Condensing the hydrazine derivative with 4-(Dimethylamino) butanal diethylacetal to get Rizatriptan and v) Salification of Rizatriptan to Rizatriptan benzoate.
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Page/Page column 5; 9
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF RIZATRIPTAN BENZOATE
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Present invention discloses an improved and commercially viable process for the preparation of rizatriptan benzoate of formula (I). According to the present process the hydrazone intermediate derived from the phenylhydrazine of formula- (III) and 4- dimethylaminobutyraldehyde diethyl acetal is gradually heated to 60-70 °C in aqueous sulfuric acid medium and maintained for 3-4hr to get rizatriptan with less dimeric impurity of formula (X). The resultant rizatriptan is isolated and converted into the pharmaceutically acceptable benzoate salt. Present process produces less percentage of dimeric (less than 3 %) or polymeric impurities compared to the prior art process and more yield of rizatriptan. Rizatriptan benzoate produced according to the present process has more than 99.5 % purity with less than 0.1% dimeric impurity of formula (X) by HPLC. Rizatriptan benzoate is useful for the treatment of migraine.
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- RIZATRIPTAN PROCESS
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Rizatriptan is prepared by reacting 4-hydrazinophenylmethyl-1,2,4-triazole dihydrochloride with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of hydrochloric acid.
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Page/Page column 10-11; 12
(2008/06/13)
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- SYNTHESIS METHODS AND INTERMEDIATES FOR THE MANUFACTURE OF RIZATRIPTAN
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The invention relates to a process for the manufacture of an 1,2,4-triazol-1-yl compound of the formula [A], or a salt thereof, wherein each of R3 and R4 is hydrogen or lower alkyl, said process comprising reacting a hydrazine compound of the formula [B] wherein R is hydrogen or acyl, R2 is hydrogen or a protecting group, are hydrogen or lower alkyl, and R6 is hydrogen or COOR7, or a salt thereof, with a 1,2,4-triazolyl forming reagent. In addition, novel intermediates for the synthesis of the anti-migraine agent Rizatriptan and methods for their synthesis are presented.
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Page/Page column 50-51
(2010/02/13)
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- PROCESS FOR PREPARING RIZATRIPTAN
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In particular, rizatriptan or a pharmaceutically acceptable salt thereof, which includes a) Preparation of the diazonium salt of the aniline hydrochloride (II); followed by reduction and acidification to give the hydrazine (III); b) reaction in situ of the hydrazine hydrochloride (III) with α-keto-δ-valerolactone, to give the hydrazone (IV); c) Fischer indole reaction of the hydrazone (IV), to give the pyranoindolone (V), optionally followed by a hydrolysis reaction to give (VI); d) Transesterification of (V) or esterification of its hydrolysis product (VI), to give (VII), where R means straight or branched C1-C4 alkyl chain; e) Conversion of the hydroxyl group of (VII) into dimethylamino, to give the indolecarboxylate (VIII), where R has the meaning defined above; f) Saponification of the 2-carboalkoxy group of (VIII) to give indolecarboxylic acid (IX); and g) Decarboxylation of the indolecarboxylic acid (IX) to give rizatriptan and, eventually, to obtain a pharmaceutically acceptable salt thereof. The invention also relates to synthesis intermediates to obtain rizatriptan.
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- PALLADIUM CATALYZED INDOLIZATION
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We have found that 2-unsubstituted indoles of structural formula (IV) can be cost-effectively synthesized in high yield by the palladium-catalyzed coupling/ring closure of a 2-halo or 2-trifluoromethylsulfonyloxy aniline (I) and an acyl silane derivative (II), followed by deprotection of the silyl protecting groups. The process of the present invention is particularly useful to form indoles containing acid-labile substituents such as triazole, acetyl, ketal, cyano, and carbamate, or indoles having a good leaving group in the benzyl position. The advantages of the present process are that it does not require the use of triphenyl phosphine or tetrabutyl ammonium chloride or lithium chloride. When applied to 5-triazolyl substituted indoles, the present process also eliminates the tendency of triazolyl polymerization in the Fischer indole synthesis. Still further, the present invention is also directed to the novel intermediates of structural formulae (V) and (VI).
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- Process for preparing indole derivatives containing a 1,2,4-triazol-1-yl substituent
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A process for preparing tryptamine derivatives and related compounds having a 1,2,4-triazol-1-yl moiety within the molecule comprises reacting 4-amino-1,2,4-triazol with a nitrobenzene derivative containing a readily displaceable group; deaminating the aminotriazolium salt thereby obtained by treatment with nitrous acid followed by neutralisation; reducing the triazolyl-nitrobenzene derivative thereby obtained by transfer hydrogenation; treating the triazolyl-aniline derivative thereby obtained with nitrous acid and then with an alkali metal sulphate, followed by acidification; and subsequently reacting the triazolyl-hydrazine derivative thereby obtained in situ with a suitable carbonyl compound, to obtain the required triazolyl-indole derivative.
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- Sulphate salt of a substituted triazole, pharmaceutical compositions thereof, and their use in therapy
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The sulphate salt of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine is a selective agonist of 5-HT 1 -like receptors and is therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated.
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- Palladium catalyzed ring closure of triazolyltryptamine
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A new process is described for the synthesis of the triazolyl tryptamine: STR1 and related compounds. The process involves a palladium-catalyzed ring closure between a substituted ortho-iodoaniline and a protected 1-alkynol. The process is carded out at high temperature, e.g. 100° C., in a dry inert solvent, e.g., DMF and in the presence of a proton acceptor, e.g., Na2 CO3 or a trialkylamine. The triazolyl tryptamine, as well as acid addition salts thereof, is a 5 HT1 D receptor agonist having anti-migraine properties.
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- Synthesis and serotonergic activity of N,N-dimethyl-2-[5-(1,2,4-triazol- 1-ylmethyl)-1H-indol-3-yl]ethylamine and analogues: Potent agonists for 5- HT(1D) receptors
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The synthesis and the 5-HT receptor activity of a novel series of N,N- dimethyltryptamines substituted in the 5-position with an imidazole, triazole, or tetrazole ring are described. The objective of this work was to identify potent and selective 5-HT(1D) receptor agonists with high oral bioavailability and low central nervous system penetration. Compounds have been prepared in which the azole ring is attached through either nitrogen or carbon to the indole. Conjugated and methylene-bridged derivatives have been studied (n = 0 or 1). Substitution of the azole ring has been explored either α or β to the point of attachment to indole. In a series of N-linked azoles (X = N), simple unsubstituted compounds have high affinity and selectivity for 5-HT(1D) receptors. It is proposed that for good affinity and selectivity a hydrogen bond acceptor interaction with the 5-HT(1D) receptor, through a β-nitrogen in the azole ring, is required. In a series of C-linked triazoles and tetrazoles (X = C), optimal affinity and selectivity for the 5-HT(1D) receptor was observed when the azole ring is substituted at the 1-position with a methyl or ethyl group. This study has led to the discovery of the 1,2,4-triazole 10a (MK-462) as a potent and selective 5-HT(1D) receptor agonist which has high oral bioavailability and rapid oral absorption. The in vitro activity and the preliminary pharmacokinetics of compounds in this series are presented.
- Street,Baker,Davey,Guiblin,Jelley,Reeve,Routledge,Sternfeld,Watt,Beer,Middlemiss,Noble,Stanton,Scholey,Hargreaves,Sohal,Graham,Matassa
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p. 1799 - 1810
(2007/10/02)
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- Triazole containing indole derivatives
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A class of substituted imidazole, triazole and tetrazole derivatives are selective agonists of 5-HT 1 -like receptors and are therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated.
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