Stereochemistry and conformation in solution of diltiazem hydrochloride, a 1,5-benzothiazepine coronary vasodilator

Robert Glaser, Benjamin Sklarz

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Major and minor species have been observed in a ca. 12:1 ratio in the ambient-temperature 1H n.m.r. spectrum of crystalline (+)-(M,2S,3S)-diltiazem hydrochloride (1) dissolved in (CD3) 2SO, CDCl3, or CD2Cl2. The two solution species were characterized by 1H and 13C n.m.r. spectroscopy, including various 2D-n.m.r. techniques. The 1H n.m.r. spectroscopic parameters of the major solution species are fully consistent with the (M,2S,3S)-twist-boat 1,5-benzothiazepine ring conformation noted in the solid state in which the methoxyphenyl and acetoxy moieties are, respectively, axially, and equatorially oriented. Dissolution of crystalline diltiazem hydrochloride (+)-(1) results in a diastereoisomerization to form a minor species the stereochemistry of which appears to be the 1,5-benzothiazepine ring-inverted (P,2S,3S)-boat (twist-boat) analogue. The heptagonal-ring- inversion process [(M,S,S) ⇆ (P,S,S)] converts axial and equatorial substituent orientations. In molecular-mechanics calculated models for both (P,S,S)-twist-boat and boat conformations, the (C=O)CH3 methyl protons are located almost directly above the benzo ring centre as a result of the axial-like acetoxy orientation. This is consistent with the finding that (C=O)CH3 protons suffer a Δδ 0.49 ppm upfield shift in the minor solution (P,S,S) -species. Variable-temperature 1H n.m.r. [300 MHz; (CD3)2SO] experiments showed dynamic behaviour. The ΔG‡ for the diastereoisomerization process was measured to be 17.2(1) kcal mol-1 by line-shape analysis on variable-temperature spectra.

Original languageEnglish
Pages (from-to)1031-1036
Number of pages6
JournalJournal of the Chemical Society. Perkin Transactions 2
Issue number8
DOIs
StatePublished - 1 Jan 1989

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