Synthesis, chiral HPLC resolution and configuration assignment of 1‐phenylglyceryl trinitrate stereomers

Abstract

As an introductory study of in vitro vasodilating activity, the access to the four stereomers of 1-phenylglyceryl trinitrate is described using achiral and chiral chromatography. For semi-preparative separation of the enantiomers, a Chiralcel OD (250 3 10 mm, 10 lm) was used. Catalytic reduction leading to the corresponding stereomers of 1-phenylglycerol allowed absolute configuration assignments. The same methods were used for the separation and configuration assignment of the enantiomers of 3-phenylpropane-1,2-diyl dinitrate. The organic esters of nitric acid, the nitrates, are a heterogeneous class of products widely used for the treatment of a number of cardiovascular diseases, including congestive heart failure and coronary heart disease. 1These products act through a common mechanism which implies the activation of the soluble guanylate cyclase (sGC), with consequent increase of intracellular cGMP. This increase in the vascular smooth muscle results in vasodilation. The prototype of nitrates is glyceryl trinitrate (GTN, nitroglycerin). It was introduced in therapy for relief of angina pectoris pain in 1876.2 The major limit in the practical application of this drug is an early development of the tolerance. In this article, we describe the synthesis, isolation, and configuration assignment of the four stereomers of the new nitrate 3 (Ph-GTN) obtained by introducing a phenyl ring on the terminal methylene group of achiral GTN. The related nitrate 5 formally obtained from 3 by elimination of one nitrooxy groups is also described (Scheme 1).The overall Energy Release Potential (ERP), a parameter that evaluates the explosive hazard of a compound, calculated using the ASTM Program CHEAT AH 7.2, was found to be high for compound 3, as well as for the other nitric esters studied in the present work. Consequently, we always treated only small amounts of these substances with a great caution, although we never observed violent decomposition induced by thermal and mechanical shock. MATERIAL AND METHODS GeneralAll compounds were routinely checked by IR (Shimadzu FT-IR 8101 M). 1 H and 13 C-NMR spectra were recorded on a Bruker Avance 300 at 300 and 75 MHz, respectively, using Si(CH 3 ) 4 as an internal standard. The following abbreviations were used to indicate the peak multiplicity: s ¼ singlet, d ¼ doublet, and m ¼ multiplet. Low-resolution mass spectra were recorded with a Finnigan-Mat TSQ-700. Mass spectra in Desorption Chemical Ionization (DCI) of the derivatives 3a, 3b were obtained with a Finnigan-Mat 8400 spectrometer using iso-butane as reacting gas. Accurate molecular mass of 5 was determined by peak matching using perfluorokerosene (PFK) as an internal standard on a Finnigan-Mat 8400 spectrometer. Melting points were determined with a capillary apparatus (Büchi 540) and are uncorrected. Flash column chromatography was performed on silica gel (Merck Kieselgel 60, 230-400 mesh ASTM) using the indicated eluents. Petroleum ether 40-608C (PE) was used as coeluent. The progress of the reactions was follow...

Synthesis, chiral separation, and absolute configuration of bis‐(N‐aryl) atropisomeric triads: 1,2‐Bis‐[4‐methyl‐2‐(thi)oxo‐2,3‐dihydrothiazol‐3‐yl]‐benzene

“…In such a case, the use of chromatography on chiral support with polarimetric detection is an excellent option. [56][57][58] Having determined the chromatographic conditions and sign of first and second eluted enantiomers for each pair in rac-1, rac-2, and rac-3, it was quite easy to select the right chromatographic system to show that starting from enantiopure (1)aS,aS-1, (1)-2 and (1)-3 were obtained (Scheme 4). Chiralcel OB-H was the only column able to separate the enantiomers of the Compounds 1, 2, and 3 in the same run.…”

Synthesis of Some Novel Organic Nitrates and Comparative in Vitro Study of Their Vasodilator Profile

“…Analysis (C, H, N) of the new compounds dried at 20 °C, pressure < 10 mmHg for 24 h, were performed at the University of Geneva, and the results are within ±0.4% of the theoretical values. Structures 1 , 2 , 3a , 8 , and 9 were synthesized according to published methods. Compound 3b was obtained by the same procedure used to obtain 3a starting from trans -but-2-en-1,4-diol, and its spectral characteristics correspond to those published …”

“…Compounds (+) 2 , (−) 2 , (+) 5a , (−) 5a , (+) 5b , (−) 5b , (+) 7 , (−) 7 , 8 , and 9 were dissolved in DMSO. The solution of compounds (+) 1a , (−) 1a , (+) 1b , and (−) 1b obtained after chiral separation were concentrated without completely removing the solvent to reduce the hazard of explosion and used after determination of their concentrations (HPLC) for the vasodilator experiments. Addition of the drug vehicle had no appreciable effect on contraction level.…”

“…5 In light of the importance of nitrates in medicine, it is of undoubted interest to make new products available both as potential drugs which may increase the effectiveness of those employed in therapy and for use as probes to examine further the mode of action of drugs of this class. In a previous work, 6 we described synthesis and configuration assignment of 1-phenylpropane-1,2,3-triyl trinitrate stereomers (+)1a, (-)1a, (+)1b, (-)1b, and of 3-phenylpropane-1,2-diyl dinitrate stereomers (+)2, (-)2 (Chart 1). In this paper, we report synthesis and chiral HPLC resolution of the related butyl derivatives (+)5a, (-)5a, (+)5b, (-)5b, (+)7, and (-)7 (Chart 1).…”