42205-75-4

Upstream product

• 4021-08-3 4-methylpicolinic acid 
• 71-41-0 pentan-1-ol 
• 123387-50-8 4-methylpiperidine-1-carboxylic acid tert-butyl ester 
• 162167-52-4 (2R-trans)-1-[(Phenylmethoxy)carbonyl]-4-methyl-2-piperidinecarboxylic acid, ethyl ester 
• 64-17-5 ethanol 
• 134984-62-6 ethyl cis-(2S,4R)-1-<(R)-1-phenylethyl>-4-methylpipecolate 
• 134984-61-5 (6S)-1-<(R)-1-phenylethyl>-6-ethoxycarbonyl-4-methyl-3,4-didehydropiperidine 
• 78-79-5 isoprene 
• 66937-93-7 4(R)-Methylpiperidine-2(R)-carboxylic acid ethyl ester 
• 134984-62-6 (2R,4R)-4-Methyl-1-((R)-1-phenyl-ethyl)-piperidine-2-carboxylic acid ethyl ester 
• 139334-62-6 (6R)-1-<(R)-1-phenylethyl>-6-ethoxycarbonyl-4-methyl-3,4-didehydropiperidine 
• 139334-63-7 ethyl (2R)-4-methyl-1-((S)-1-phenylethyl)-1,2,3,6-tetrahydropyridine-2-carboxylate 
• 198641-56-4 ethyl (2R,4R)-4-methyl-1-((S)-1-phenylethyl)tetrahydropyridine-2-carboxylate 
• 626-58-4 4-methylpiperidin 

Downstream Products

• 74863-81-3 ethyl 1-α-(tert-butoxycarbonyl)-N^ω-nitro-L-arginyl>-4-methyl-2-piperidinecarboxylate 
• 4939-37-1 2-methylquinolizidine 
• 131278-84-7 ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate L-(+)-tartarate 
• 1401618-23-2 ethyl (2S,4S)-4-methyl-2-piperidinecarboxylate L-tartrate 
• 79199-62-5 ethyl (2S,4R)-4-methylpipecolate 
• 74874-07-0 ethyl (2R,4R)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate 
• 74874-07-0 ethyl (2R,4R)-1-[(2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate 
• 1401618-20-9 ethyl (2S,4S)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate 
• 74892-82-3 ethyl (2R-trans)-4-methylpiperidine-2-carboxylate 
• 1401618-20-9 ethyl (2S,4S)-1-[(2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate 

Relevant academic research and scientific papers

Method for splitting argatroban isomer impurity

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.

Method of resolving argatroban starting material isomer impurities

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%.

Method for splitting isomer impurity of agathiban starting material

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-(+

Preparation method of argatroban intermediate esterified substance 4-methyl-2-ethyl piperidinecarboxylate

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.

Preparation method for argatroban intermediate

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.

Synthesis method of argatroban intermediate (2R,4R)-4-methyl piperidine-2-ethyl formate

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.

PROCESS INTERMEDIATES AND METHODS FOR THE PREPARATION OF PROCESS INTERMEDIATES FOR THE SYNTHESIS OF ARGATROBAN MONOHYDRATE

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.

METHOD FOR THE PREPARATION OF PROCESS INTERMEDIATES FOR THE SYNTHESIS OF ARGATROBAN MONOHYDRATE

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.

Diastereoselective synthesis of an argatroban intermediate, ethyl (2R,4R)-4-methylpipecolate, by means of a Mandyphos/rhodium complex-catalyzed hydrogenation

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

Direct diastereoselective synthesis of (±)-cis- and (±)-trans-4-methylpipecolic acid and derivatives

(±)-cis- or (±)-trans-4-Methylpipecolic acid and ester derivatives can be obtained directly by addition of electrophiles to α-lithiated N-Boc 4-methylpiperidine.