Process for making N-sulfonated-amino acid derivatives
View Patent ↗This invention relates to a process for preparing optically active α-amino acid substrates which are used to make potent lethal factor (LF) inhibitors for the treatment of anthrax. This invention further relates to a process for synthesis of potent LF-inhibitors for the treatment of anthrax. Specifically, the invention concerns a novel, high-yielding and highly enantioselective asymmetric hydrogenation reaction of a tetrasubstituted ene-sulfonamide acid or ester.
1. A process for making a compound of formula III or Formula IIIa:
a pharmaceutically acceptable salt or mixture thereof, wherein:
R 3 represents (CH 2 ) n C 6-10 aryl, said aryl substituted with 2 groups of R a ;
R a represents C 1-6 alkyl and halogen;
Z represents S(O) 2 ;
Y represents NHOH; and
n is 0;
said process comprising:
(1) reacting a compound of formula IV:
wherein R 4a represents H, C 1-4 alkyl, magnesium, lithium or sodium, with a compound of formula V:
in the presence of an acid selected from the group consisting of methanesulfonic acid, pTsOH, CSA, PhSO 3 H, phosphoric acids, TFA, AcOH, H 2 SO 4 , HCl and POCl 3 ;
(2) heating to a temperature of about 100° C. to about 125° C., for about one to about 30 hours, to produce a compound of formula VI:
(3) asymmetrically hydrogenating a compound of formula VI in the presence of a metal catalyst and ligand to produce a compound of formula III or IIIa.
2. A process for making a compound of Formula III, Formula IIIa or mixture thereof:
a pharmaceutically acceptable salt or mixture thereof, wherein:
R 3 represents (CH 2 ) n C 6-10 aryl, said aryl substituted with 2 groups of R a ;
R a represents C 1-6 alkyl and halogen;
Z represents S(O) 2 ;
Y represents NHOH; and
n is 0;
said process comprising:
(1) asymmetric hydrogenation of a compound of formula IX:
in the presence of a rhodium or ruthenium catalyst/ligand complex to produce a compound of formula IXa, IXb or a mixture thereof:
(2) hydrogenolysis of a compound of formula IXa, IXb or a mixture thereof in the presence of a palladium catalyst to produce a compound of formula VIII, VIIIa, a pharmaceutically acceptable salt or mixture thereof:
wherein P* is an acid and R 4a represents H, C 1-4 alkyl, magnesium, lithium or sodium;
(3) coupling the compound of formula VIII or VIIIa or mixture thereof with compound of formula X:
in the presence of a base selected from the group consisting of triethylamine, diisopropylethylamine, tri-n-butylamine, NaOH, LiOH, KOH, NaHCO 3 , Na 2 CO 3 ;
(4) hydrolyzing and purifying the coupled compound to produce a compound of formula III or IIIa.
3. A process according to claim 2 , wherein the acid is selected from the group consisting of HCl, acetic acid, HI, HBr, TFA, PTSA, and HBF 4 .
4. The process according to claim 1 , wherein the compound of Formula III or Formula IIIa is (2R)-2-{[(4-Fluoro-3-methylphenyl)sulfonyl]amino}-N-hydroxy-2(tetrahydro-2H-pyran-4-yl)acetamide.