Methodforpreparingargatroban

monohydrateandaprocessforitssynthesis
Abstract

A method is explained for preparing argatroban monohydrate acquired from

(2R,4R)1[NGnitroN2(3methyl8quinolinesulphonyl)Larginyl] 4methyl
2piperidinecarboxylicacidbyappropriatelytreatingcrudeargatroban.

The technique either makes up prep work of argatroban monohydrate in a

continuoussteporamoreadvancedactionofseparatingacleansedargatroban.
Likewise available from argatroban monohydrate is anhydrous argatroban,
shown to
have new physicochemical characteristics.

Thedescribedargatrobansynthesisandalsofiltrationprocedurethusmakesit
possible for 3 different forms of argatroban, not previously described, to be
acquired, each with distinct physicochemical attributes and in particular
makesitpossibleforargatrobanmonohydratetobeacquiredwithhighreturn
aswellas withhighpureness,being consequently aproduct appropriatefor
usageasenergeticconceptinproprietarymedicines.

FIELDOFTHEINNOVATION


[0001] The present invention associates with an approach for preparing
argatrobanmonohydrate.Saidapproachenablesargatrobantobegottenin3
different crystalline forms i.e. in the form of argatroban monohydrate,
detoxifiedargatrobanandargatrobananhydrous,eachhavingcertainandalso
newphysicochemicalqualities.Thepresentdevelopmentadditionallyrelatesto
the3differentseparatedforms,particularlyargatrobanmonohydrate,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 N2arylsulphonylL
argininamidemedications,withantithrombotictask,andalsotheprocessesfor
gettingthem.

Of these, the substance 4methyl1 [N2(3methyl1,2,3,4tetrahydro8

quinolinesulphonyl)Larginyl] 2piperidine carboxylic acid (argatroban,
isomersblend)isdescribed.Thedescribedprocesscomprisesthesynthesisofan
intermediate NGsubstitutedN2quinolinesulphonylLargininamide from
which the preferred substance is acquired by catalyzed hydrogenolysis or
acidolysisaswellasmilitarizedhydrogenation.

The general conditions offered the hydrogenolysis as well as hydrogenation

reactionare:i)inertsolvents(methanol,ethanol,tetrahydrofuranordioxane);
ii) visibility of a stimulant (Raney nickel, palladium, platinum, ruthenium,
rhodium);iii)hydrogenenvironmentatastressinbetween1aswellas100
kg/cm2andideallybetween5andalso50kg/cm2;iv)temperatureinbetween0
C.aswellas200C.aswellasideallyinbetween50C.aswellas150C.;
v)reactiontemperaturelevelfrom2hrsto120hours.

The crude product acquired is then purified by trituration or by re

crystallization from diethyl ethertetrahydrofuran, diethyl ethermethanol or
from watermethanol or by chromatography. No instance is offered of this
filtrationaction.Inparticular,bothU.S.Rub.No.4,210,863aswellasEP8746
inexample1(E)describethepreparationofargatroban,isomersmix.

Thissubstanceisacquiredinamorphousformbyhydrogenationof[NGnitro
N2(3methyl8quinolinesulphonyl)Larginyl]4methyl2piperidinecarboxylic
acidinethanolinthepresenceofPd/Cwithhydrogenpressureof10kg/cm2at
100C.for8hours.

Thedriveriseliminatedbyfiltrationoftheethanolsolutionwhichisafterthat
evaporatedwithoutfurtherfiltrationand/orrecrystallizationsteps.IntheUS
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)
(centimeters1)3400;1620;1460;1380;Molecularcomposition(%):academic
C54.31;H7.13;N16.52;located(%)C54.01;H6.98;N16.61.