Synthesis of deuterium labeled NMDA receptor inhibitor - 20-Oxo-5β-[9,12,12-(2)H(3)]pregnan-3α-yl-L-glutamyl 1-ester.
20-Oxo-5β-[9,12,12-(2)H(3)]pregnan-3α-yl-l-glutamyl 1-ester 11 was synthesized as an internal standard for quantification of a neuroprotective NMDA receptor ligand, 20-oxo-5β-pregnan-3α-yl-l-glutamyl 1-ester 18 and its metabolites, in plasma and tissue. 11α-Hydroxy-progesterone (1) was reduced under basic conditions to yield the corresponding 5β-steroid. Protection of the 3- and 20-oxo groups and oxidation of the 11α-hydroxy group was then followed by a deuterium exchange, conducted under basic conditions using deuterated methanol. Next, the carbonyl moiety at C-11 was reduced and the 11α-hydroxyl group removed through utilization of the Barton-McCombie reaction. Subsequent deprotection of the 3- and 20-acetals and stereoselective reduction of the 3-oxo group gave the desired trideuterated pregnanolone (8). This was coupled with protected glutamic acid, which was then deprotected to yield [9,12,12-(2)H(3)]-pregnanolone glutamate (11) with >99% isotopic purity.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, Czech Republic.
Vojtech
V
Kapras
Alena
A
Slavickova
Eva
E
Stastna
Ladislav
L
Vyklicky
Karel
K
Vales
Hana
H
Chodounska
D002855:Chromatography, Thin Layer; D003903:Deuterium / Q000737:chemistry*; D005971:Glutamates / Q000737:chemistry*; D006908:Hydroxyprogesterones / Q000737:chemistry; D007553:Isotope Labeling / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012997:Solvents / Q000737:chemistry
C571988:20-oxo-5-pregnan-3-yl-glutamyl 1-ester; D005971:Glutamates; D006908:Hydroxyprogesterones; D016194:Receptors, N-Methyl-D-Aspartate; D012997:Solvents; C030228:11-hydroxyprogesterone; D003903:Deuterium; D011280:Pregnanolone