Helmut Vorbrüggen

A simple synthesis of Δ2-oxazines, Δ2-oxazines, Δ2-thiazolines and 2-substituted benzoxazoles

Abstract Carboxylic acids react readily at O°→+24°C with amino alcohols, amino mercaptans and o-aminophenols in the presence of triphenylphosphine- or tributylphosphine dichloride (generated in situ from the reaction of the phosphines with hexachloroethane or CCl4) and triethylamine in acetonitrile to form the corresponding Δ2-oxazolines, Δ2-oxazines, Δ2-thiazolines and 2-substituted benzoxazoles in one reaction step in yields of up to 80%.

A simple synthesis of Δ2-oxazolines, Δ2-oxazines, Δ2-thiazolines and Δ2-imidazolines

Abstract Carboxylic acids react with amino alcohols, amino mercaptans or diamines in the presence of triphenylphosphine, CCl4 and tert. bases to afford in 50–75% yield the corresponding Δ2-oxazolines, Δ2-oxazines, Δ2-thiazolines and Δ2-imidazolines.

Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat.

A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro- 6a- carbaprostaglandin-I2 (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-mimetics with a potency equal or even superior to PGI2. The 3-oxa-analogue was found to be stabilized against beta-oxidation, a main metabolic degradation step also for chemically stable PGI2-analogues. The compound is orally available and displays a long duration of 4.5-48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC50 of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED20 being 0.1-0.2 micrograms/kg after injection and less than or equal to 0.05 micrograms/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC50 of 0.037 micrograms/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5-12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects. The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI2) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI2 and Iloprost have already been shown to be therapeutically useful principles.

The introduction of nitrile-groups into heterocycles and conversion of carboxylic groups into their corresponding nitriles with chlorosulfonylisocyanate and triethylamine

Abstract Addition of chlorosulfonylisocyanate (CSI) to heterocycles such as thiophene ( 4 ) or indole ( 15 ) and unsaturated systems such as dihydropyran ( 7 ) gives N-chlorosulfonylamides RCONHSO 2 Cl, which can be converted by equivalent amounts of triethylamine to their corresponding nitriles. Since carboxylic acids react with CSI to N-chlorosulfonylamides, subsequent treatment with triethylamine affords the corresponding nitriles, but no isocyanates as claimed by other authors. The mechanisms of the conversion of the intermediate N-chlorosulfonylamides into the corresponding nitriles are discussed.

A facile conversion of primary or secondary alcohols with n-perfluorobutane-sulfonyl fluoride/1,8-diazabicyclo[5.4.0]undec-7-ene into their corresponding fluorides

The combination of n-perfluorobutanesulfonyl fluoride (2) with 1,8-diazabicyclo-[5.4.0]undec-7-ene efficiently converts primary and secondary alcohols in unpolar solvents into their corresponding fluorides.

Stable 9ß- or 11α-halogen-15-cyclohexyl-prostaglandins with high affinity to the PGD2-receptor

Various chemically stable prostaglandin analogues were studied for their affinity towards the PGD2-receptor in human platelet membranes in order to define the requirements for specific ligand binding to this receptor. On replacing the 11- or 9-hydroxyl groups of PGF2 alpha by an 11 alpha- or 9 beta-chloro- or fluoro atom, stable prostaglandin analogues were obtained, which showed high affinity towards the PGD2-receptor. The lower side chain consisted of a 15-cyclohexyl group or of the natural 15-n-pentyl group, other substitutents decreased the affinity substantially. The highest PGD2-mimetic activity with a relative affinity of 0.5 to the PGD2-receptor was found in 9-deoxy-9 beta-chloro-16,17,18,19,20-pentanor-15-cyclohexyl-PGF2 alpha (ZK 110 841, compound 16 in Table 1). ZK 110 841 is a chemically stable crystalline substance, which is orally active and which might thus turn out to be an interesting tool for the study of PGD2-receptor interactions. Some other prostaglandin as well as prostacyclin analogues with a 15-cyclohexyl or 15-n-pentyl group exhibited in addition to their known high affinity to the PGE2-receptor of human uterine membranes or the PGI2-receptor of human platelets also affinities to the PGD2-receptor. Generally, the receptor affinities correlate with the activities as stimulators of adenylate cyclase and inhibitors of thrombin induced elevation of cytoplasmic free calcium as well as their ability to inhibit ADP-induced platelet aggregation. The PGI2-character regarding the effector systems prevails in compounds with affinity to both the PGI2- and PGD2-receptor. Compounds which bind to the PGE2- and PGD2-receptor show a flat dose response curve regarding platelet activation suggesting a mixture of pro- and antiaggregatory properties within these molecules.

Advances in amination of nitrogen heterocycles

Publisher Summary This chapter discusses primarily the advances made in the amination of nitrogen heterocycles. Furthermore, because of the vast number of recent publications and patents describing the standard technology of conversion of hydroxy-N-heterocycles into the corresponding chloro derivatives, only the general problems connected with this method as well as some pertinent applications of this standard methodology are analyzed. The rate of attack of amines on nitrogen heterocycles containing a leaving group X, followed by subsequent elimination of X, is dependent on the nature of (a) the heterocycle, (b) the amine, (c) the solvent, and (d) the leaving group. The structure of AE intermediates in heteroaromatic as well as aromatic nucleophilic substitution is examined, and evidence is presented for single-electron transfer in some cases. The reactivity factors in aminations include reactivity of different nitrogen heterocycles, reactivity of different amines, influence of solvents, and the effect of the leaving group. The chapter also discusses the comparison of several amination methods.

E- or Z-selective Horner-Wittig reactions of substituted bicyclo[3.3.0]octane-3-ones with chiral phosphonoacetates

The Horner-Wittig reaction of substituted bicyclo[3.3.0]octane-3-ones with chiral phosphonoacetates 2 gave the corresponding unsaturated esters in E/Z-ratios of up to 91 : 9.

Conversion of heterocyclic n-oxides into α-alkylated heterocycles trimethylsilanol as leaving group — IV

Abstract Aromatic heterocyclic N-oxides are readily converted into α-alkylated heterocycles by allyl- or benzyltrimethylsilane and fluoride ion.

Chemistry of Stable Prostacyclin Analogues: Synthesis of Iloprost

The discovery of prostacyclin (PGI2) and its potent inhibitory action on platelet aggregation in 1976 by S. Moncada, R. Gryglewski, S. Bunting and J.R. Vane [1], has not only revolutionized concepts in cardiovascular research but has also made this important molecule a target for intensive biological and chemical research.