The synthesis of indinavir

Indinavir was a formidable synthetic target. It was probably the most complex compound ever made in quantity by organic synthesis and the 3g per day dose meant that huge quantities were required. The complexity largely arises from the stereochemistry. As with all chiral new drugs, it is a single enantiomer: there are five stereogenic centres, marked with coloured circles on the diagram below, and their disposition means that three separate pieces of asymmetric synthesis must be devised.

The challenge with indinavir, as with any drug, is to make it efficiently: high yields, few steps. 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 28, and they all correspond to reliable reactions. These disconnections split the molecule into five manageable fragments, three of which contain stereogenic centres and will have to be made as single enantiomers. One of the orange stereogenic centres would have to be made in the enolate alkylation step, so this step will need to be diastereoselective. Let’s take the three chiral fragments in turn. First, the simplest one: the central epoxide. The reagent we need here will carry a leaving group, such as a tosylate, to allow it to alkylate the piperazine to the left, and it can easily be made from an epoxyalcohol. This gives a very good way of making this compound as a single enantiomer—a Sharpless asymmetric epoxidation of allyl alcohol.

Next, the piperazine fragment. This has two nucleophilic nitrogen atoms and they will both need protecting with different protecting groups to allow them to be revealed one at a time. It will also need to be made as a single enantiomer. In an early route to indinavir, this was done by resolution, but enantioselective hydrogenation provides a better alternative. Starting from a pyrazine derivative, a normal hydrogenation over palladium on charcoal could be stopped at the tetrahydropyrazine stage. The two nitrogens in this compound have different reactivities because one is conjugated with the amide while one is not (the curly arrows in the margin show this). The more nucleophilic nitrogen—the one not conjugated with the amide— was protected with benzyl chloroformate to give the Cbz derivative. Now the less reactive nitrogen can be protected with a Boc group, using DMAP as a base.

You met asymmetric hydrogenation using BINAP complexes of rhodiumas a method for the synthesis of amino acids. The substrate and catalyst are slightly different here, but the principle is the same: the chiral ligand, BINAP, directs addition of hydrogen across one of the enantiotopic faces of the double bond with almost perfect enantioselectivity and in very high yield. A further hydrogenation step allowed selective removal of the Cbz group, preparing one of the two nitrogen atoms for alkylation.

The remaining chiral fragment is a compound whose synthesis was discussed. It can be made on a reasonably large scale (600 kg) in one reaction vessel, starting from indene. First, the double bond is epoxidized, not with m-CPBA but with the cheaper hydro gen peroxide in an acetonitrile/methanol mixture, which generates a peroxyimidic acid (the C=N analogue of a peracid) as the active oxidant. Acid-catalysed opening of the epoxide leads to a cation, which takes part in a reversible Ritter reaction with the acetonitrile solvent, leading to a single diastereoisomer of a heterocyclic intermediate, which is hydrolysed to the amino-alcohol.

The product is, of course, racemic but, as it is an amine, resolution with an acid should be straightforward. Crystallization of its tartrate salt, for example, leads to the required single enantiomer in 99.9% ee. With such cheap starting materials, resolution is just about acceptable, even though it wastes half the material. It would be better to oxidize the indene enantio selectively, and the solution here , is to use a Jacobsen epoxidation, which gives the epoxide in 79% yield and 84% ee.

Only one, orange, stereogenic centre remains, and its stereoselective formation turns out to be the most remarkable reaction of the whole synthesis. The centre is the one created in the planned enolate alkylation step, shown in the margin. The obvious way to make this centre is to make Y a chiral auxiliary, which would direct a diastereoselective alkylation before being removed and replaced with the amino-alcohol portion. But the Merck chemists noticed that amino alcohol itself, certainly once protected, has a remarkable similarity to Evans’ oxazolidinone auxiliaries anyway, and it turns out that this amino alcohol will function very successfully as a chiral auxiliary, which does not need to be removed, avoiding waste and saving steps! The amino alcohol was acylated with the acyl chloride, and the amide was protected as the nitrogen analogue of an acetonide by treating with 2-methoxypropene (the methyl enol ether of acetone) and an acid catalyst. The enolate of this amide reacts highly diastereoselectively with alkylating agents, including, for example, allyl bromide.

The reason for the stereoselectivity is not altogether clear, but we would expect the bulky nitrogen substituents to favour formation of the cis enolate. With the amino-alcohol portion arranged as shown, the top face is more open to attack by electrophiles. The enolate also reacts diastereoselectively with the epoxy-tosylate prepared earlier. The epoxide, being more electro philic than the tosylate, is opened first, giving an alkoxide, which closes again to give a new epoxide. The absolute configuration at the stereogenic centre within the epoxide was, of course, already fixed (by the earlier enantioselective Sharpless epoxidation).

Three of the fi ve fragments have now been assembled, and only the two amine alkylations remain. The fi rst alkylation makes use of the epoxide to introduce the required 1,2-amino alcohol functionality. The protected enantiomerically pure piperazine reacted with the epoxide, and the product was treated with acid to deprotect both the second piperazine nitrogen and the gem-dimethyl group left over from the earlier chiral auxiliary step. The newly liberated secondary amine was alkylated with the reactive electrophile 3-chloromethyl pyridine, and the final product was crystallized as its sulfate salt.

اخر الاخبار

اخبار العتبة العباسية المقدسة

المجمع العلمي: نحو 300 ألف مستفيد من مشروع القراءة الصحيحة في كربلاء وباقي المحافظات

صحفيون: استحداث المركز الإعلامي لزيارة الأربعين أسهم في تسهيل عمل الإعلاميين وتوفير بيئة مهنية لإنجاز مهماتهم

موكب عميد بني هاشم (عليه السلام) يقدم 4500 وجبة طعام يوميًّا لزائري الأربعين

بمشاركة زائري الأربعين.. إقامة صلاة الجماعة عند مرقد أبي الفضل العباس (عليه السلام)

المزيد

الآخبار الصحية

حجم جزء محدد من الجسم يعكس الصحة العامة ومخاطر الأمراض

تفشي عدوى بكتيرية بفرنسا يحتمل ارتباطها بنوع من الجبن الطري

دراسة حديثة تكشف ما تفعله الشاشات بـ"قلوب الأطفال" !

متلازمة المبنى المريض.. هكذا يتحول تكييف الهواء إلى خطر صحي ؟؟

المزيد

الآخبار التكنلوجية

كيف تتعامل مع حرارة الطقس أثناء القيادة؟

لماذا يجب عليك إيقاف تكييف السيارة قبل إطفاء المحرك؟

دراسة تكشف سببا محتملا وراء زيادة خطر إصابة الأطفال بالتوحد

تشيلي.. العثور على متحجرة حيوان ثديي صغير من زمن الديناصورات

المزيد

مواضيع ذات صلة

The future of organic chemistry

The synthesis of oseltamivir

Chemistry vs viruses

Terpenes are volatile constituents of plants

Aromatic polyketides

Fatty acids and other polyketides are made from acetyl CoA

Benzyl isoquinoline alkaloids are made from tyrosine

Pyrrolidine alkaloids are made from the amino acid ornithine

Alkaloids are made by amino acid metabolism

The shikimic acid pathway

Phosphoenolpyruvate

Nature’s enolate equivalents: lysine enamines and coenzyme A