Medicinal chemistry conversion

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

Rice, K.C. (1977) A Rapid, High-Yield Conversion ofCodeineto Morphine. Journal of Medicinal Chemistry, 20, 164-165. 

With a common intermediate from the Medicinal Chemistry synthesis now in hand in enantiomerically upgraded form, optimization of the conversion to the amine was addressed, with particular emphasis on safety evaluation of the azide displacement step (Scheme 9.7). Hence, alcohol 6 was reacted with methanesul-fonyl chloride in the presence of triethylamine to afford a 95% yield of the desired mesylate as an oil. Displacement of the mesylate using sodium azide in DMF afforded azide 7 in around 85% assay yield. However, a major by-product of the reaction was found to be alkene 17, formed from an elimination pathway with concomitant formation of the hazardous hydrazoic acid. To evaluate this potential safety hazard for process scale-up, online FTIR was used to monitor the presence of hydrazoic acid in the head-space, confirming that this was indeed formed during the reaction [7]. It was also observed that the amount of hydrazoic acid in the headspace could be completely suppressed by the addition of an organic base such as diisopropylethylamine to the reaction, with the use of inorganic bases such as... 

This process (also known as the Ferrier II Reaction ) has proved to be of considerable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex compounds of interest in biological and medicinal chemistry. ... 

Ornithine decarboxylase catalyzes the conversion of ornithine into putrescine. Like other polyamines, the latter is involved in the regulation of cell development. Inhibition of this enzyme has been an important goal in medicinal chemistry. In this context, difluoroornithine has been shown to be an excellent inhibitor... 

As cyclic amines are at the heart of medicinal chemistry, there is always interest in new methods for their preparation. Marco Ciufoiini of the Universitc Claude Bernard in Lyon reports (Organic. Lett. 5 4943, 2003) the preparation of a series of dihydro indole derivatives, exemplified here by 3, 6, and 9, by free radical cyclization of an N-O precursor. The N-O precursor can be prepared from the corresponding bromide, as illustrated by the conversion of 1 to 2 and of 4 to 5. Alternatively, a radical precursor such as 8 can be prepared separately. The generated radical is then trapped by 7 to make a new radical, that cyclizcs to 9. 

In addition, the conversion of a compound collection of drug-like heterocycles as might be used in a medicinal chemistry program was investigated. An equimolar mixture of 20 pyrazole acids, synthesized by a split-and-mix approach, was treated with methyl resin 10 (Ri = CH3, 5 equiv.) for 6 h to yield the respective pyrazole esters. All 20 pyrazole acids in the starting reaction mixture and all their corresponding 20 pyrazole methyl esters in the product mixture could be identified by FT-ICR MS coupled to micro-HPLC with a relative mass error <2.2 ppm. 

The Uppsala team then turned their attention to the development of a fast and efficient procedure that allowed conversion of aryl halides to benzoni-triles and aryl tetrazoles by microwave heating. The aryl bromide 11 was subjected to the optimized reaction conditions, which delivered the bis-tetrazole 15 in a two-step yield of 82% (Scheme 8, Kt = 0.56 nM), demonstrating the potential of the method for medicinal chemistry [61]. The tetrazole functionality is one of the most utilized carboxylic acid bioisosteres. 

Burger. A.. Burger s Medicinal Chemistry, 4th ed., Wolff, M. E Ed.. John Wiley. Sons, New York, 1980-1981, parts II and III. Gall, M Kamdar, B. V., Lipton, M. F., Chi-destcr, C. G and DuCamp, D. J.. Mannich reactioas of heterocycles with di-mcthyl(methylene)ammonium chloride a high yield, one-step conversion of estazolam to adinazolam, J. HeteriKjcl. Chem., 25. 1649, 1988. 

As previously mentioned, nitropyrazole 5 is one of the regulatory starting materials for sildenafil citrate, so not surprisingly the compound has attracted the attention of fine chemical companies and within Pfizer. The optimization of the condensation reaction to make intermediate 1 has been previously reported. In the medicinal chemistry synthesis, conversion of 1 to compound 3 was accomplished via reaction with hydrazine followed by a methylation reaction. Clearly a more efficient way of making this transformation is to use a regioselective condensation reaction with methylbydrazine. " " ... 

A special attention is given to stereochemistry, as some compounds are published without proper chirality representation even though the information is available, for example, for natural compounds and their derivatives. Furthermore, as illustrated in Fig. 13.2-8, compounds published in medicinal chemistry literature are often depicted in a human-readable format that is, structures are drawn in a format that chemists can interpret to reconstruct proper chirality. However, this format is not machine-readable , that is, cheminformatics software for 3D structural conversion, or for automatically generating IUPAC (International Union of Pure and Applied Chemistry) nomenclature, cannot perceive the stereo centers correctly... 

The original medicinal chemistry route used a dimethyltitanocene-mediated olefmation of resulting ester 2. Although examples of this reagent in the conversion of esters to vinyl ethers had been reported, this reagent had never been produced on a multi-kilogram scale. Therefore, a significant amount of fundamental research was performed that resulted in an improved preparation, mechanistic elucidation, titration method for... 

The tetrazole functional group is of particular interest in medicinal chemistry, because of its potential role as a bioisostere of the carboxyl group. In this context, Schulz et al. have demonstrated the synthetic utility of the cyano group of arylni-trile boronates as a source of tetrazole derivatives under microwave conditions. The reaction is conducted with azidotrimethylsilane and dibutyltin oxide as catalyst to provide aryltetrazole boronates in yields ranging from 60 to 93% [56]. In the same manner, microwaves may assist successful conversion of sterically hindered nitriles into tetrazoles [57]. 

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