An Antimalarial Alkaloid From Hydrangea. Xvii. Some 5-Substituted Derivatives

Abstract

Substitution of a group such as chloro or methyl on the 5-position of the 4quinazolone moiety of the Hydrangea alkaloid has been found to have a favorable effect on the activity and the chemotherapeutic index (1, 2). In order to exploit this lead the fluoro, iodo, ethyl, propyl, trifluoromethyl, nitro, acetamino, methylthio, and methylsulfonyl groups were introduced into the 5-position.The fluoro derivative had an index and activity1 about the same as the 5-C1, whereas the iodo had a very low activity and index. When the methyl group was replaced by the larger ethyl or propyl groups the activity decreased in that order. These data indicate that a large group has an unfavorable action. However, trifluoromethyl had the highest index, 15, yet observed in analogs of the alkaloid, although the quinine coefficient was decreased to 35.These compounds were all prepared by condensation of the appropriately substituted 4-quinazolone with the blocked side chain, l-carbethoxy-2-(7-bromoacetonyl)-3-methoxypiperidine, followed by two-stage hydrolysis of the blocking groups as previously described (3).Six of the requisite 4-quinazolones were synthesized from the known 5-nitro-4quinazolone (4) via the readily available 6-nitroanthranilic acid (I) (5). 6-Iodo-2-nitrobenzoic acid (IV) was obtained in good yield from I, but all attempts to reduce this compound chemically or catalytically to 6-iodoanthranilic acid (VII)were unsuccessful. The steps were then reversed by reduction of 6-nitro-2formylaminobenzoic acid (VI) to VIII. Attempted replacements of the amino group with iodo through the diazonium salt were unsuccessful. The diazonium salt from I when treated with potassium ethyl xanthate gave 2-nitro-6-methylthiobenzoic acid (V) in low yield after methylation. All of the above difficulties were surmounted by the use of the diazonium salt from 5-amino-4-quinazolone (III). The 5-iodo derivative, IX, was obtained in 59% yield by treatment with potassium iodide. The 5-methylthio derivative (XI) was obtained with sodium methyl mercaptide in 71% yield and was oxidized to the sulfone, XII, with permanganate in dilute acetic acid. The use of sodium thiophenoxide gave XIII, but the procedure could not always be duplicated. The 5-fluoro derivative offered some difficulty since the diazonium fluoroborate was water-soluble. However, the diazonium fluoroborate could be isolated when the diazotization was carried out in 42% fluoroboric acid (6) to give an over-all yield of 56% of IX after pyrolysis in xylene.3-Nitrophthalic acid appeared attractive as a starting material for 5-ethyl-(XXIII) and 5-propyl-4-quinazolone (XXXIII). -Methyl hydrogen

Synthesis of oxo analogs of Lamotrigine and some related compounds

“…The diazonium salt 7, when treated with potassium iodide, gave 5-(5,6-dichlorophenyl-2-iodo)-6-azauracil (11). Diazotation in sulfuric acid solution with subsequent boiling yielded 5-(2,3-dichloro-6-hydroxyphenyl)-6-azauracil (12). …”

“…The formed white solid was filtered off, washed with water and dried yielding the white solid 9 (199 mg, 81.9%); mp 335-337 °C (ethanol). IR (KBr): ṽ 3057 (C-H arom ), 1699 cm -1 (CO); (12). Triazine 3 (150 mg, 0.6 mmol) was dissolved in NaOH (10%, 5 mL) with heating.…”

Counter-Current chromatography separation of isatin derivatives using the sandmeyer methodology

“…17 Anthranilic acids have a wide application in organic synthesis, especially in the synthesis of polycyclic aromatic hydrocarbons. [18][19][20] The development of a simple, fast and economic chromatographic technique for the separation of these isomers is, therefore, of great relevance. The traditional separation of these reaction products on silica gel column chromatography demands a large amount of solvent and time.…”

Highly Enantioselective Rhodium‐Catalyzed Hydrogenation of 2‐(2‐Methoxy‐2‐oxoethyl)acrylic Acid − A Convenient Access of Enantiomerically Pure Isoprenoid Building Blocks

“…(b) The known mono ester 5 [19] appeared a particularly well suited starting material as it is crystalline and available in excellent yield by simple acid-catalyzed esterification. We were not able to meet our objectives with L1, however a simple change to the potentially hemilabile ligand L2 in conjunction with optimization of the solvent were successful.…”