Fosdenopterin

Fosdenopterin is a synthetic cyclic pyranopyrimidine (cPMP or Precursor Z) that is an important intermediate in the biosynthesis of molybdenum-binding cyclic pyranopterin (Moco). Moco is an essential cofactor that catalyzes a variety of enzymatic reactions. Patients with MoCD are unable to convert GTP to cPMP due to mutations in the MOCS1 gene, resulting in a blockage in the synthesis of Moco. Clinical trials of fosdenopterin have shown that patients with MoCD type A who receive cPMP/synthetic fosdenopterin replacement therapy have a reduced risk of death, increased survival, and reduced levels of sulfosuccinimide (SSC) in the urine compared to untreated patients. Elevated levels of SSC are known to cause irreversible neurological damage.

Nulibry is a cyclic pyranopterin monophosphate (cPMP) used for treatment of molybdenum cofactor deficiency type A.

ChEBI: Precursor Z hydrate is a linear-fused organic heterotetracyclic compound consisting of a [1,3,2]dioxaphosphinane fused to a pyran ring which is in turn fused to a pteridine ring system. Molybdenum cofactor biosynthesis intermediate. Dehydrated derivative known as precursor Z. It has a role as an Escherichia coli metabolite. It is an organic heterotetracyclic compound, an oxacycle, an organonitrogen heterocyclic compound and a ketone hydrate.

Fosdenopterin (Nulibry), a drug developed by Alexion Pharmaceuticals, is approved by the USFDA to reduce the risk of death in patients with molybdenum cofactor deficiency (MoCD) type A, a rare genetic disease that causes neurodegeneration and early death.

Fosdenopterin is synthesized from D-galactose in a two-step reaction:
Step 1: Preparation of the nucleus (11.5) of fosdenopterin: D-galactose (11.1, Fig. 1) is treated to obtain galactose phenylhydrazine 11.2, which is in equilibrium with its tautomer 11.3. This key starting material is used to react with 2,5,6-triamino-3,4-dihydropyrimidone 11.4 in methanol/water by heating (110°C) to rapidly synthesize the nucleus structure 11.5 as a single isomer (yield 36%). It is noteworthy that in this reaction process, the conversion of 11.2 to 11.3 is believed to be initially achieved through the Amadori rearrangement of phenylhydrazone, followed by regioselective condensation with the most basic amino group (5-NH2) in 11.4, and further through intramolecular addition reaction of the C5 hydroxyl group in galactose and the formation of pyran.

Step 2: Synthesis of Fosdenopterin hydrochloride: To avoid oxidation of the advanced intermediate 11.5 to its corresponding aromatic pteridine derivative, a method of protecting N10 was adopted (Fig. 2). Therefore, 11.5 was reacted with an excess of Boc anhydride (9 equivalents) and DMAP in THF to obtain a series of products containing different degrees of Boc protection, including intermediates 11.6 and 11.7 (seven-fold and six-fold Boc protection, respectively). However, 11.6 was found to have limited stability, and 11.6 was simply treated with silica gel to obtain the six-fold protected intermediate 11.7. Based on this, 11.6 and 11.7 can be converted to the triply Boc-amine protected intermediate 11.8 by adding a precisely controlled amount of sodium methoxide in MeOH, followed by post-treatment with acidic Dowex resin. Treatment of 11.8 with methyl dichlorophosphate and pyridine in DCM gave the desired phosphate ester 11.9. The final steps of the synthesis involved Swern oxidation of the secondary alcohol, hydrate formation from the resulting ketone, and subsequent overall deprotection. Since the hydrate was unstable after workup, this crude intermediate was immediately treated with trimethylsilyl bromide in aqueous acetone to complete the deprotection of the amine and phosphate and afford 11 by crystallization. 11 was recrystallized from aqueous hydrobromic acid/isopropanol to afford fosdenopterin monobromide dihydrate with a purity of 95%.