- Method of resolving argatroban starting material isomer impurities
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The invention provides a method of resolving argatroban starting material isomer impurities. The method includes: with ethyl 4-methyl-2-piperidinecarboxylate racemate as a raw material and L-(-)-dibenzoyltartaric acid as a resolving agent, salifying to obtain ethyl (2R,4S)-4-methyl-2-piperidinecarboxylate-L-(-)-dibenzoyltartrate shown as a compound I, freeing the compound I under alkaline conditions to obtain ethyl (2R,4S)-4-methyl-2-piperidinecarboxylate shown as a compound II. The method provided herein is simple to perform, and has total resolving yield of 45.2% and post-resolving chiral purity of 99.2%.
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Paragraph 0029; 0036-0040; 0056-0058; 0062
(2019/05/22)
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- Method for splitting isomer impurity of agathiban starting material
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The invention provides a method for splitting the isomer impurity of an argatroban starting material. The method comprises the following steps: performing salt formation by taking 4-methyl-2-piperidinecarboxylate racemate as a raw material and taking D-(+
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Paragraph 0030; 0037-0040; 0041; 0047-0051; 0054; 0056; 0060
(2019/06/05)
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- Method for splitting argatroban isomer impurity
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The invention provides a method for splitting an argatroban isomer impurity. The method comprises the following steps: performing salt formation by taking 4-methyl-2-piperidinecarboxylate racemate asa raw material and taking D-tartaric acid as a splitting agent to obtain (2S,4S)-4-methyl-2-piperidinecarboxylate-D-tartrate shown by a compound I; dissociating the compound I under an alkaline condition to obtain (2S,4S)-4-methyl-2-piperidinecarboxylate shown by a compound II. The splitting method provided by the invention is easy and convenient to operate, the total yield of splitting reaches 46.5 percent, and the chiral purity after splitting can reach 99.2 percent.
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Paragraph 0028-0046
(2019/06/05)
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- Synthesis method of argatroban intermediate (2R,4R)-4-methyl piperidine-2-ethyl formate
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The invention relates to a synthesis method of an argatroban intermediate (2R,4R)-4-methyl piperidine-2-ethyl formate compound. The synthesis method comprises the following steps: (1) under the action of a rhodium catalyst and ferric oxalate, carrying out catalytic hydrogenation on (2R)-4-methyl-1-((S)-1-phenethyl)-1,2,3,6-tetrahydropyridine-2-ethyl formate, so that (2R,4R)-4-methyl-1-((S)-1-phenethyl)-2-pyridine ethyl formate is obtained; and (2) under the action of a palladium catalyst and ferric oxalate, removing benzyl, so that the (2R,4R)-4-methyl piperidine-2-ethyl formate is obtained. The synthesis method provided by the invention has the advantages that the ferric oxalate is introduced into a reaction system, two-step reaction yield is increased, especially the efficiency is the highest when the ferric oxalate and a rhodium-silicon dioxide catalyst are used together, and the cost is effectively reduced, so that the synthesis method is applicable to industrial production.
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Paragraph 0029; 0030; 0031; 0032-0034; 0039-0044; 0046; 0048
(2017/09/01)
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- Preparation method of argatroban intermediate esterified substance 4-methyl-2-ethyl piperidinecarboxylate
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The invention relates to a preparation method of an argatroban intermediate esterified substance 4-methyl-2-ethyl piperidinecarboxylate. The preparation method comprises the following steps: adding a solvent, namely ethanol into a reaction kettle, putting a reactant, namely 4-methyl-2-piperidinecarboxylicacid hydrochloride into the reaction kettle, stirring to cool to (-5)-0 DEG C, maintaining the temperature, adding a catalyst, namely thionyl chloride, stirring to completely react until disappearance of raw material points is detected by virtue of a thin-layer chromatography, and carrying out vacuum reduced pressure concentration at 60 DEG C, so as to remove the solvent; and cooling the room temperature, adding dichloromethane, neutralizing reaction liquid by virtue of a 10% Na2CO3 solution, carrying out layered extraction, drying an organic solvent, and carrying out vacuum reduced pressure concentration at 50 DEG C on the organic solvent to remove the solvent, so as to obtain the esterified substance 4-methyl-2-ethyl piperidinecarboxylate. Mixed solvents including glacial acetic acid, ethanol and chloroform are replaced with single ethanol in a synthetic process, the reaction pressure is reduced, the catalyst thionyl chloride is low in cost, the operation is simple and convenient, the yield is substantially increased, and reaction solvents can be recycled, so that the preparation method is relatively beneficial to large-scale industrial production.
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Paragraph 0023; 0024; 0025; 0026; 0027; 0028; 0029-0040
(2017/10/07)
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- Preparation method for argatroban intermediate
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The invention belongs to the technical field of medicine synthesis, and relates to a preparation method for argatroban intermediate, namely, 4-methyl-2-piperidinecarboxylate. The argatroban intermediate is generated through catalysis of ethyl alcohol in an atmosphere of carbon monoxide. According to the preparation method, reaction steps are reduced; the reaction yield is improved generally; a product is more stable and purer; raw materials which are liable to produce poison, and highly acidic and corrosive raw materials are not used, so that the environmental protection pressure is lightened; the used solvent, ethyl alcohol, is easy to recycle and utilize; reaction conditions are mild; an economic and feasible process route is provided for large-scale industrial production.
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Paragraph 0027; 0028; 0029; 0030; 0037; 0038-0049
(2017/07/19)
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- PROCESS INTERMEDIATES AND METHODS FOR THE PREPARATION OF PROCESS INTERMEDIATES FOR THE SYNTHESIS OF ARGATROBAN MONOHYDRATE
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Methods are provided for the synthesis of key intermediates for the synthesis of Argatroban monohydrate, ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl. Such intermediates are also provided.
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- METHOD FOR THE PREPARATION OF PROCESS INTERMEDIATES FOR THE SYNTHESIS OF ARGATROBAN MONOHYDRATE
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Object of the present invention is a method for the synthesis of a key intermediate for the synthesis of Argatroban monohydrate, ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4- methylpiperidine-2-carboxylate compounded with HCl.
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Page/Page column 30-31
(2012/10/18)
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- Diastereoselective synthesis of an argatroban intermediate, ethyl (2R,4R)-4-methylpipecolate, by means of a Mandyphos/rhodium complex-catalyzed hydrogenation
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The synthetic antithrombotic argatroban is a dipeptide between the nonproteogenic (2R,4R)-4-methyl-2-piperidine carboxylic acid and l-arginine, in turn bonded to a methyltetrahydroquinoline sulfonyl group. An extensive screening of transition metal-based complexes with different ligands was performed in order to identify the best catalyst for the diastereoselective hydrogenation of a suitable 4,5-dehydropiperidine precursor aimed toward a synthesis of the (2R,4R)-4-methyl piperidine moiety. Copyright
- Ferraboschi, Patrizia,Mieri, Maria De,Grisenti, Paride,Lotz, Matthias,Nettekoven, Ulrike
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p. 1626 - 1631
(2012/01/03)
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- Direct diastereoselective synthesis of (±)-cis- and (±)-trans-4-methylpipecolic acid and derivatives
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(±)-cis- or (±)-trans-4-Methylpipecolic acid and ester derivatives can be obtained directly by addition of electrophiles to α-lithiated N-Boc 4-methylpiperidine.
- Cossy, Janine,Belotti, Damien
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p. 2119 - 2120
(2007/10/03)
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- Scavenger assisted combinatorial process for preparing libraries of amides, carbamates and sulfonamides
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This invention relates to a novel solution phase process for the preparation of amide, carbamate, and sulfonamide combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
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- ANTITHROMBOTIC AMIDINOTETRAHYDROPYRIDYLALANINE DERIVATIVES
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This invention is directed to compounds of formula (I), STR1 pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of either entity, wherein Y is optionally monounsaturated C 3-C 5 alkylene optionally substituted with C. sub.1-C 4 alkyl or methylene; R 1 is H; C 1-C 4 alkyl optionally substituted with C 1-C 4 alkoxy, OH, NR 5 R 6, CONR 5 R 6, C 3-C 6 cycloalkyl or aryl; or C 3-C 6 alkenyl; R 2 is H; C 1-C 4 alkyl optionally substituted with C 1-C 4 alkoxy, OH, NR 5 R 6, CONR 5 R 6, C 3-C 6 cycloalkyl or aryl; or CONR 5 R 6 ; R. sup.3 and R 4 are each independently selected from H; C 1-C. sub. 4 alkyl optionally substituted with NR 5 R 6 ; C 1-C. sub.4 alkoxy; halo; CONR 5 R 6 and aryl; aryl is phenyl optionally substituted with one, two or three substituents independently selected from C 1-C 4 alkyl, C 1-C 4 alkoxy, OH, halo and CF 3 ; R 5 and R 6 are each independently selected from H and C 1-C 4 alkyl; and m and n are each independently 1, 2 or 3; which are potent and selective thrombin inhibitors useful in the treatment of inter alia, deep vein thrombosis; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; restenosis and occlusion following angioplasty; or neurodegenerative disorders.
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- HETEROCYCLIC THROMBIN INHIBITORS
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Heterocyclic thrombin inhibitors are provided which have the structure STR1 wherein n, R, R 1, R 2, R 3, G, G x, R. sup.6', Ra, Xa, R 6, Rb, R 3, p, Q, A and R 4 are as defined herein.
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- HETEROAROMATIC AMINE THROMBIN INHIBITORS
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Sulfonamide thrombin inhibitors are provided which have the structure STR1 including all stereoisomers thereof, wherein n is 1, 2 or 3; m is 0, 1 or 2; R 1 and R 2 are independently H, lower alkyl, cycloalkyl, aryl, heteroaryl or heteroaryl-alkyl, or R 1 and R. sup.2 can be taken together with the N atom to which they are attached to form a 4-to 8-membered ring; R 3 is monocyclic heteroaryl; and R 4 is alkyl, cycloalkyl, aryl, heteroaryl, quinolinyl or tetrahydroquinolinyl, and pharmaceutically acceptable salts thereof.
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- Enantio- and Diastereo-selective Synthesis of Pipecolic Acid Derivatives using the Aza-Diels-Alder Reaction of Imines with Dienes
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Optically active pipecolic acid derivatives can be prepared by the aza-Diels-Alder reaction of simple dienes with the imine derived from ethyl glyoxylate and chiral 1-phenylethylamine; the cycloadditions are regiospecific, highly diastereoselective within the heterocyclic ring (>92percent exo with cyclic dienes, and 100percent endo with acyclic dienes), and lead to high asymmetric induction in most cases (average d.e. = 72percent).
- Bailey, Patrick D.,Wilson, Robert D.,Brown, George R.
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p. 1337 - 1340
(2007/10/02)
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- Asymmetric Synthesis of Pipecolic Acid Derivatives Using the Aza-Diels-Alder Reaction
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Imines of the type R-N=CHCO2Et can be coerced into undergoing a (4+2) cycloaddition with substituted dienes if the reaction is carried out in DMF in the presence of both water and acid; these reactions show extremely high regio- and diastereoselectivity.U
- Bailey, Patrick D.,Brown, George R.,Korber, Fritjof,Reed, Amanda,Wilson, Robert D.
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p. 1263 - 1282
(2007/10/02)
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- N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
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N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
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- N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
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N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
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- N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
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N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
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- N2 -arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof
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N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
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- N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
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N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
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- N2 -arylsulfonyl-argininamides and the pharmaceutically acceptable salts thereof
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N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
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- N2 alkoxynaphthylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
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N2 -alkoxynaphthylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
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