Removal of ruthenium by-product by supercritical fluid processing

A process for removing ruthenium or ruthenium-containing compound from a mixture comprising:

• (i) a compound of the following formula (I):
• wherein
• RA is a leaving group or a group of formula II
• W is CH or N,
• L0 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R23)2,
• wherein each R23 is independently H, C1-6 alkyl or C3-6 cycloalkyl;
• L1, L2 are each independently H, halogen, C1-4alkyl, —O—C1-4alkyl, or —S—C1-4alkyl (the sulfur being in any oxidized state);
• or
• L0 and L1 or
• L0 and L2 may be covalently bonded to form together with the two C-atoms to which they are linked a 4-, 5- or 6-membered carbocyclic ring wherein one or two (in the case of a 5- or 6-membered ring) —CH2— groups not being directly bonded to each other, may be replaced each independently by —O— or NRa wherein Ra is H or C1-4alkyl, and wherein said ring is optionally mono- or di-substituted with C1-4 alkyl;
• R22 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or C10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur;
• said cycloalkyl, aryl or Het being substituted with R24,
• wherein R24 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R25)2, NH—C(O)—R25;
• or NH—C(O)—NH—R25, wherein each R25 is independently:
• H, C1-6 alkyl or C3-6 cycloalkyl;
• or R24 is NH—C(O)—OR26 wherein R26 is C1-6 alkyl or C3-6 cycloalkyl;
• R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or 10 aryl, heteroaryl, —C(O)—R20, —C(O)—NHR20 or —C(O)—OR20, wherein R20 is C1-6 alkyl or C3-6 cycloalkyl;
• D is a 5 to 10 atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from:
• O, S or N—R27, wherein R27 is H, C1-6alkyl, C3-6cycloalkyl or C(O)R28, wherein R28 is C1-6alkyl, C3-6cycloalkyl or C6 or 10 aryl;
• R4 is H, or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of:
• C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl;
• and
• A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of:
• C1-8 alkyl, C3-6 cycloalkyl, C6 or 10 aryl, C7-16 aralkyl, or SO2R5A wherein R5A is C1-8 alkyl, C3-7 cycloalkyl or C1-6 alkyl-C3-7 cycloalkyl;
• or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof;
• (ii) an organic solvent;
• and
• (iii) ruthenium or ruthenium-containing compound;
• said process comprising:
• (1) exposing said mixture to a sufficient quantity of pressurized gaseous fluid to form a fluid solution in which the compound of formula (I) and organic solvent are substantially soluble but said ruthenium or ruthenium-containing compound is substantially insoluble such that particles of the ruthenium or ruthenium-containing compound precipitate out of said solution;
• (2) introducing the fluid solution into a lower pressure region to expel at least some of said gaseous fluid from the fluid solution and obtain an organic solvent solution comprising the compound of formula (I) and the organic solvent;
• (3) optionally repeating steps (1) and (2) one or more times using the organic solvent solution obtained in step (2) as the mixture to be exposed in step (1) to said pressurized gaseous fluid;
• and
• (4) optionally recovering the compound of formula (I) from the organic solvent solution.