Study of the Factors that Control the Ratio of the Products between 5-Fluorouracil, Uracil, and Tetrahydrobenzoxazepine O,O-Acetals Bearing Electron-Withdrawing Groups on the Nitrogen Atom

Abstract

(RS)-1-(2-Nitrobenzenesulfonyl)- and (RS)-1-(4-nitrobenzenesulfonyl)-3-methoxy-1,2,3,5-tetrahydro-4,1-benzoxazepines are better substrates than 1-acyl-3-methoxy-1,2,3,5-tetrahydro-4,1-benzoxazepine derivatives for the Lewis acid mediated condensation reaction with pyrimidine bases to give O,N-acetals. Acetonitrile, stannic chloride, 50 degrees C, and a reaction time higher than 48 h are the optimum conditions for such condensation reactions. Under these conditions, 5-fluorouracil preferably links to the aminalic carbon through its N-1" position, while the attachment of the uracil fragment is through N-3" or N-1" of the cyclic or acyclic products, respectively. The causes that influence the course of the reactions are analyzed and discussed. Examination of the (1)H NMR spectra revealed the presence of a single form for the secondary amine 11 and of two conformers for the tertiary sulfonamides 7a,b, 9a,b, and 10b and for the amides 7d and 13, with the following distribution: 7a, 59/41; 7b, 53/47; 9a, 52/48; 9b, 59/41; 10b, 56/44; 7d, 50/50; 13, 80/20. On increasing the temperature, the (1)H NMR spectrum (DMSO-d(6)) of 7b showed coalescence at 110 degrees C. The torsional barrier determined [DeltaG(c)++ value of 19.0 +/- 0.2 kcal.mol(-1) (79.1 +/- 1.0 kJ.mol(-1))] proved to be the highest ever observed for sulfonamide moieties.

Bozepinib: A Promising Selective Derivative Targeting Breast Cancer Stem Cells

“…The preparation of the O,N-acetals 1 and 2 was achieved by the microwaveassisted Vorbrüggen one-pot condensation of the cyclic acetals 3a and 3b [27] and the commercially available purine base 2,6-dichloropurine, using trimethylsilyl chloride (TMSCl), 1,1,1,3,3,3-hexamethyldisilazane (HMDS) and tin(IV) chloride as the Lewis acid in anhydrous acetonitrile. The reaction mixture was microwaveirradiated at a temperature of 140°C for 5 min (Figure 6).…”

“…Compounds 11 and 12 were obtained along with the cyclic 2,6-dichloropurine O,N-acetals (1 and 2, bozepinib) and the acyclic one 13 (when starting from 3b) in the reaction of purines with 3a and 3b, respectively. The mechanism of the reaction of these compounds is important as none of them were previously isolated in the corresponding reactions with uracil or 5-FU [27]. We have previously explained the mechanism of the reaction leading to the benzo-fused derivatives 1, 2, 11 and 12 [28].…”

Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

“…The imides were first converted to the corresponding carboxylic acids through the reactions of 1,8-naphthalic or phthalic anhydride with relevant amino acids [21], then the imide moiety was linked to 5-Fu via an (acyloxy)methylene group, known to be easily removable [3,8]. All structures were verified by 1 H-NMR, 13 C-NMR, MS and elemental analysis. …”

“…Recently, the concept of mutual prodrugs in which two different antineoplastic agents are coupled directly or by means of a spacer has become well accepted [8][9][10][11][12][13][14][15][16][17]. This technique can be used to overcome many problems including poor solubility or absorption, patient acceptability, drug instability and toxicity, and especially drug resistance [11].…”

Synthesis and Biological Evaluation of New 4β-5-Fu-substituted 4'-Demethylepipodophyllotoxin Derivatives

“…To tackle these problems, numerous modifications of the 5-FU structure have also been performed. The N-1 or/and N-3 substituted derivatives, in particular, have exhibited improved pharmacological and pharmacokinetic properties, including increased bioactivity, selectivity, metabolic stability, absorption and lower toxicity [17][18][19][20][21][22].…”