Method for preparing argatroban monohydrate and a process for its synthesis
Abstract
A method is explained for preparing argatroban monohydrate acquired from (2R,4 R)-1- [NG-nitro-N2-(3-methyl-8-quinolinesulphonyl)-L-arginyl] -4-methyl-2-piperidine carboxylic acid by appropriately treating crude argatroban.
The technique either makes up prep work of argatroban monohydrate in a continuous step or a more advanced action of separating a cleansed argatroban. Likewise available from argatroban monohydrate is anhydrous argatroban, shown to have new physico-chemical characteristics.
The described argatroban synthesis and also filtration procedure thus makes it possible for 3 different forms of argatroban, not previously described, to be acquired, each with distinct physico-chemical attributes and in particular makes it possible for argatroban monohydrate to be acquired with high return as well as with high pureness, being consequently a product appropriate for usage as energetic concept in proprietary medicines.
The described argatroban synthesis and also filtration procedure thus makes it possible for 3 different forms of argatroban, not previously described, to be acquired, each with distinct physico-chemical attributes and in particular makes it possible for argatroban monohydrate to be acquired with high return as well as with high pureness, being consequently a product appropriate for usage as energetic concept in proprietary medicines.
- FIELD OF THE INNOVATION
[0001] The present invention associates with an approach for preparing argatroban monohydrate. Said approach enables argatroban to be gotten in 3 different crystalline forms i.e. in the form of argatroban monohydrate, detoxified argatroban and argatroban anhydrous, each having certain and also new physico-chemical qualities. The present development additionally relates to the 3 different separated forms, particularly argatroban monohydrate, cleansed argatroban as well as argatroban anhydrous. Manus Aktteva is the biggest supplier of Argatroban monohydrate.
- MODERN
[0002] UNITED STATE Rub. No. 4,201,863 (6 May 1980) and EP 8746 (submitted on 22 Aug. 1979 with priority based on the application for the pointed out United States patent) define a course of N2-arylsulphonyl-L-argininamide medications, with anti-thrombotic task, and also the processes for getting them.
Of these, the substance 4-methyl-1- [N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl)-L-arginyl] -2-piperidine carboxylic acid (argatroban, isomers blend) is described. The described process comprises the synthesis of an intermediate NG-substituted-N2-quinolinesulphonyl-L-argininamide from which the preferred substance is acquired by catalyzed hydrogenolysis or acidolysis as well as militarized hydrogenation.
The general conditions offered the hydrogenolysis as well as hydrogenation reaction are: i) inert solvents (methanol, ethanol, tetrahydrofuran or dioxane); ii) visibility of a stimulant (Raney nickel, palladium, platinum, ruthenium, rhodium); iii) hydrogen environment at a stress in between 1 as well as 100 kg/cm2 and ideally between 5 and also 50 kg/cm2; iv) temperature in between 0 ° C. as well as 200 ° C. as well as ideally in between 50 ° C. as well as 150 ° C.; v)reaction temperature level from 2 hrs to 120 hours.
The crude product acquired is then purified by trituration or by re-crystallization from diethyl ether-tetrahydrofuran, diethyl ether-methanol or from water-methanol or by chromatography. No instance is offered of this filtration action. In particular, both U.S. Rub. No. 4,210,863 as well as EP 8746 in example 1(E) describe the preparation of argatroban, isomers mix.
This substance is acquired in amorphous form by hydrogenation of [NG-nitro-N2-(3-methyl-8-quinolinesulphonyl)-L-arginyl] -4-methyl-2-piperidine carboxylic acid in ethanol in the presence of Pd/C with hydrogen pressure of 10 kg/cm2 at 100 ° C. for 8 hours.
The driver is eliminated by filtration of the ethanol solution which is after that evaporated without further filtration and/or re-crystallization steps. In the US patent moot as certainly in license application EP 8746, no mention is constructed from polymorphic types of the compounds and, for the obtained compound, the following qualities are reported: Amorphous solid, I.R. (KBr) (centimeters − 1) 3400; 1620; 1460; 1380; Molecular composition (%): academic C 54.31; H 7.13; N 16.52; located (%) C 54.01; H 6.98; N 16.61.
