Argatroban synthesis

Yield:74863-84-6 93%

Reaction Conditions:

with hydrogen;5%-palladium/activated carbon in methanol;acetic acid at 85; under 6375.64 Torr; for 8 h;Product distribution / selectivity;

Steps:

3

Example 2: treatment of the crude argatroban with NaOH and crystallization from normal propanolA one-litre glass autoclave was fed with 50 g of (2f?,4/^:?)-1 -[N^G-nitro-N²-(3-methyl- 8-quinolinesulphonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid, 375 ml of methanol, 95 ml of acetic acid and 16.4 g of palladium on 5% carbon (60% wetted).The mixture thus obtained was treated, under vigorous stirring, at 85^QC in a 8.5 bar hydrogen atmosphere for 8 hours. The mass was then cooled to room temperature and the catalyst removed by filtration. The obtained solution was concentrated to a residue under reduced pressure.570 ml of methylene chloride was added to the oily residue obtained and the solution divided into two parts. Half of the obtained solution was fed into a jacketed 1 -litre glass reactor and to it 120 ml of water were added. The acetic acid residue was then neutralized by addition of a 30% sodium hydroxide solution until pH=7.5 was achieved. In order to obtain a net separation between the organic phase and aqueous phase 12 ml of methanol were then added. The mixture was maintained under stirring for 1 hour, then the aqueous phase was removed and the organic phase washed twice with 120 ml of water, adding each time the necessary quantity of methanol to achieve a good separation.The solution in methylene chloride thus obtained was then percolated into a 500 ml jacketed reactor containing 140 ml of 1 -propanol. The mass was then heated to 55^QC to distil off the dichloromethane present. The solution was then cooled to 0^QC over a period of 2 hours and maintained at this temperature for 2 hours.The solid obtained by crystallization was filtered off and dried at 50^QC under vacuum for 16 hours, giving 17.0 g of purified (2fl,4fl)-4-methyl-1 -[N²-[(1 ,2,3,4- tetrahydro-3-methyl-8- quinolylsulphonyl]-L-arginyl]pipecolic acid (IV). Yield = 73%. Example 3: treatment of crude argatroban without neutralization and with crystallization from isopropanolHalf of the compound (III) solution in dichloromethane obtained in example 2 was extracted twice with a mixture of 120 ml of water and 12 ml of methanol. The solution in methylene chloride thus obtained was then percolated into a 500 ml jacketed reactor containing 140 ml of 2-propanol, the mass obtained was concentrated by distillation.When the distillation was complete the temperature was brought to 90^QC, the mass left under agitation for 1 hour, cooled to 20^QC and finally to 0^QC where it was maintained for 2 hours.The solid obtained by crystallization was filtered off and dried at 50^QC under vacuum for 16 hours to give 21.5 g of purified (2fl,4fl)-4-methyl-1 -[N²-[(1 ,2,3,4- tetrahydro-3-methyl-8-quinolylsulphonyl]-L-arginyl]pipecolic acid (IV). Yield = 93%.

References:

WO2009/124906,2009,A2 Location in patent:Page/Page column 20-21