Medicinal chemistry synthesis

Scheme 3.1 The Medicinal Chemistry synthesis of A -3-keto-4-azasteroids.

Early process development and modification of the Medicinal Chemistry synthesis for the first kilogram-scale delivery of finasteride... 

Following preliminary assessment of the Medicinal Chemistry synthesis, the decision was made to modify the synthesis for scale-up to address some of the issues identified but, without a ready alternative for the double bond introduction, (PhSeO)20 would be used in the first scale-up to kilogram scale. 

Process development of the synthesis of iodoaniline 28 began with an improved synthesis of l-(4 -aminobenzyl)-l,2,4-triazole (6) (Scheme 4.7), which was prepared in the medicinal chemistry synthesis, albeit with poor regioselectivity (Scheme 4.1). We found that this aniline intermediate 6 could be readily prepared in three steps in >90% overall yield from 4-amino-l,2,4-triazole (30) and 4-nitrobenzyl bromide (4) based on a modified literature procedure [9]. The condensation of 30 and 4 in isopropyl alcohol followed by deamination gave the nitro... 

The original medicinal chemistry synthesis of ether 18 involved reaction of alcohol 10 with racemic imidate 17 in the presence of a catalytic amount of TfOH and furnished an approximately 1.1 1 mixture of 18 19 (Scheme 7.3) [1], We thought it worthwhile to reinvestigate this reaction with chiral imidate 67 in an effort to explore the diastereoselectivity of the etherification. 

Scheme 9.1 Final steps in the Medicinal Chemistry synthesis of taranabant 1.

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... 

Major advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives appeared in 1999. Solid-phase combinatorial chemistry of benzimidazoles and tiiazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. In medicinal chemistry, synthesis and structure-activity relationship (SAR) studies utilizing these core structures have been exploited heavily. The physical organic chemistry of pyrazoles and imidazoles continue. 

Scheme 1. Pfizer medicinal chemistry synthesis of sildenafil (1).

The Ghemical Development team assumed that pregabalin, like gabapentin, would be a compound with low toxicity and that large quantities of material would be required for drug safety evaluation. The initial medicinal chemistry synthesis shown in Scheme 8.1 had several issues for scale-up namely ... 

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. " " ... 

Workers at the India Orchid company have shown that the condensation of 2-pentanone with diethyl oxalate may be catalyzed by sodium methoxide which is cheaper than sodium ethoxide. After further condensation with hydrazine hydrate, the pyrazole 18 was obtained as a mixture of methyl and ethyl esters. Methylation with dimethyl sulfate was performed neat, as in the Pfizer medicinal chemistry synthesis. The mixture of the methylated pyrazoles 19 was then nitrated and subjected to ammonolysis to give the desired pyrazole intermediate 5 (Scheme 16.8). 

The medicinal chemistry synthesis produced 1300 L of waste per kilo of product, the majority of which was methylene chloride. After 4 year of chemical development, this had been reduced to 100 L/kg including a snbstantial reduction in methylene chloride use. However, a major step forward in implementing an environmentally friendly process was the introduction of a commercial route, which not only dramatically improved the yield but also set up the process for solvent recovery. In the mannfactnre of pharmaceuticals, diligent solvent recovery is very often required to fully optimize the environmental performance of a synthesis. The recovery of ethyl acetate and toluene was introdnced in 1998, the year Viagra was launched, and this was followed by the recovery of... 

As illustrated in Scheme 2, the medicinal chemistry synthesis of MK-7009 used an RCM as the key step to constmct the 20-membered macrocycle [4, 5]. Hence, vinyl isoindoline 8 was coupled with hydroxyproline 9 to form prolinol ester 11 after deprotection of the Boc group. Coupling of 11 with the ferf-leucine linker (4)... 

Scheme 2. Medicinal chemistry synthesis of PI fragment of boceprevir.

Scheme 4. Medicinal chemistry synthesis Fragment conpling and completion of...

Schone 34 Medicinal chemistry synthesis of 5-fliioro-2-(piperidin-4-yloxy)pyrimidin-4-amine... 

The development of atorvastatin 32 demonstrated the parallel approach used in chemical development. The production of the first kilos of material used modifications of the medicinal chemistry synthesis enabling the process to be carried out in the pilot plant. At the same time, process research designed, developed, and piloted a commercial process wUch was then transferred to manufacturing. 

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