Drug synthesis disconnection

When workers at GlaxoSmithKline wanted to make 107 as an intermediate in the synthesis of a drug for the treatment of osteoporosis, they chose the double disconnection 107 because they already had a way of making single enantiomers of the diacid 108. 

We conclude this chapter with the synthesis of Novartis PKI 166 121, a new anti-cancer drug of great promise.16 It has fused pyrrole and pyrimidine rings and the reaction we have just discussed allows disconnection of the amine from the pyrimidine ring 121. Now we can use standard C-N disconnections on the two rings in turn 122 and 123 to reveal a much simpler starting material 124. 

This compound was an intermediate in the synthesis of the potential anti-obesity drug ICI-D7114 you met at the beginning of the chapter. You can spot that, with two ethers and an amine functional group, it requires several disconnections to take it back to simple compounds. The question is which do we do first One way to solve the problem is to write down all the possibilities and see which looks best. Here there are four reasonable disconnections one at each of the ether groups (a and b) or on either side of the amine (c and d),... 

Moxnidazole is,an antiparasitic drug, and our next target molecule is an important intermediate in its synthesis, The obvious first disconnection is of the carbamate group, revealing two 1,2 relationships. A 1,2-diX disconnection gives an epoxide that can be made by alkylation of morpholine with epiehlorohydrin,... 

The challenge with Crixivan, as with any drug, is to make it efficiently—high yields few steps. It has five stereogenic centres, so the chemists developing the synthesis needed to address the issue of diastereoselectivity. And it is a single enantiomer, so an asymmetric synthesis was required. We can start by looking at some likely disconnections, summarized in the scheme above. They are all disconnections of the sorts you met in Chapter 30, and they all correspond to reliable reactions. 

Under more equilibrating conditions such as alkoxide bases in alcohol solution or amide bases in liquid ammonia, enolisation occurs to give the extended enolate 83 which is then alkylated in the a-position by alkyl halides. At first this seems the most difficult combination to achieve thermodynamic enolisation followed by kinetically controlled addition of an electrophile, but it is in fact a common result achieved with a variety of bases. Examples include the synthesis of pentethylcyclanone 100, an anti-tussive drug, by alkylation of the enone 103, the aldol dimer of cyclopentanone. Disconnection at the branchpoint to the available alkyl halide 102 X = Cl requires a-alkylation of the extended enolate 101 derived from the cyclopentanone aldol dimer27 103. This is easily achieved by sodium amide in toluene.28... 

These drugs are clearly peptide mimics having a genuine amide portion to the right as drawn, a hydroxamic acid to the left and a core that binds zinc and acts as a transition state mimic for the peptide cleavage. They have a C-C bond instead of the amide linkage in the natural substrate so that the drug cannot be hydrolysed by the metallopeptidase. This is easily seen if we disconnect 71a to show the amino acid tert-leucine 73 and a derivative of succinic acid (butanedioic acid) as the core 72. A similar core is present in trocade 70. We shall discuss the asymmetric synthesis of both core succinates. 

The synthesis of Fenfluramine (21), a drug acting on the central nervous system, illustrates two amine disconnections. The ethyl group can be removed by the amide method leaving the branched chain primary amine (22) available from the ketone (23) by the oxime method. 

Total reduction of a benzene to a cyclohexane ring requires pressure and active catalysts and is more easily done industrially than in the lab. The antispasmodic drug Dicyclomine (20) can be made this way" and this synthesis illustrates that six-membered rings can be made by methods other than the three presented in this chapter. Disconnection of the ester reveals acid (21) with one ring that could have been aromatic (22). Note that this is FGA logic (Chapters 24 and 28). Acid (22) can be made by simple alkylation, using cyanide (23) cf. Chapter 35). 

In fact, the overall perspective and conception of a synthesis commences with a careful logical dissection of the tai et-drug-molecular skeleton into S3mthons. However, the disconnection of a bond within a monocyclic system shall be a retro-synthetic ring-opening phenomenon, otherwise termed as the retro-synthetic approach. Likewise, the disconnection of a bond caused in a bridged-structure would ultimately produce either a mono- or a di- substituted monocyclic structure. Sometimes, it may also be possible to accomplish two-bond disconnections taking place almost simultaneously. 

The synthesis of a drug to control blood clotting gives us the opportunity to review both methods. This compound also has a central piperazine ring and disconnection of the right-hand side chain reveals an amine that could be functionalized by alkylation with a suitable benzylic halide or reductive amination. 

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