Glaxo synthesis

Fig. 4. Glaxo synthesis of and where ]>TsCl = -toluenesulfonyl chloride and Py = pyridine (24).

The Glaxo synthesis of zanamivir (2) started with the esterification of commercially available A-acetyl-neuraminic acid (88) with methanolic HCl to give the methyl ester as shown in Scheme 7.14 (Chandler and Weir, 1993 Chandler et ah, 1995 Patel, 1994 Weir et al., 1994). Global acetylation of all the hydroxyl groups with acetic anhydride in pyridine with catalysis by 4-(dimethylamino)pyridine (DMAP) led to the penta-acetoxy compound 89. Treatment of 89 with trimethylsilyl triflate in ethyl acetate at 52°C introduced the oxazoline as well as the 2,3-double bond to provide 86. Addition of trimethysilyl azide to the activated allylic oxazoline group led to the stereoselective introduction of azide at the C-4 position to afford 83 as in Scheme 7.13. 

In a Glaxo synthesis of vitamin A from cyclohexanone, one step involved dehydration of the alcohol (2), or elimination of acetic acid from the corresponding acetate (4), to produce the eneyne (5). This transformation proved to be surprisingly... 

Imitrex (Sumatriptan) 82 is the first selective 5-HTid agonist developed by Glaxo for the treatment of migraine. The synthesis of Imitrex has been carried out by several different routes all of which involved a Fischer indolization reaction as the key step. Outlined below is one of the synthetic routes. 

Scheme 14. Glaxo s formal asymmetric synthesis of camptothecin (55).

The medical success of these drugs gave new emphasis to the pharmaceutical industry, which was boosted further by the commencement of industrial-scale penicillin manufacture in the early 1940s. Around this time, many of the current leading pharmaceutical companies (or their forerunners) were founded. Examples include Ciba Geigy, Eli Lilly, Wellcome, Glaxo and Roche. Over the next two to three decades, these companies developed drugs such as tetracyclines, corticosteroids, oral contraceptives, antidepressants and many more. Most of these pharmaceutical substances are manufactured by direct chemical synthesis. 

Other useful nucleophiles for this type of substitution include azide and thiolacetic acid. Glaxo researchers utilized such a strategy in their synthesis of the neuraminic acid analogue 346 (Scheme 8.109). ° Itzstein and co-workers used a similar strategy to synthesize a thio analogue of neuraminic acid 347 °" and reported that thiolacetic acid was also a suitable nucleophile. ° ... 

An alternative synthesis from the Glaxo patents involves Fnedel-Crafts acylation of the 3-position of the indole intermediate 22 (Scheme 5) Reaction of hydrazine 10 with (phenylthio)acetaldehyde gave hydrazone 20, which was subjected to the Fischer indole reaction to give 3-thiophenylindole 21. It is noteworthy that this Fischer cyclization took place at room temperature because most require heat. Reductive desulfurization of 21 using Raney nickel provided indole 22. Acylation of the 3-position... 

Zolmitriptan (2, BW-311C90) was discovered by Wellcome in the United Kingdom and then transferred to AstraZeneca upon the acquisition of Wellcome by Glaxo (now GlaxoSmithKline). The synthesis began with 4-nitro-L-phenylalanine (29), which was converted to the methyl ester and then reduced with NaBHj to give the amino alcohol (Scheme 8). ° Oxazolidinone 30 was formed by treating the amino alcohol... 

Dr. Roy By wood no doubt made many contributions to Glaxo s Evans Medical Division before this unit s research effort was shut down. We were fortunate to engage Roy Bywood. His persnickety, quantitative approach to organic synthesis contributed... 

Research teams at Glaxo then undertook the synthesis of derivatives of betamethasone that might afford superior local anti-inflammatory and anti-allergic effectiveness. Using McKenzie and Stoughton s [21] new human-based pharmacologic test that could identify with ease the relative topical potency of steroid inflammatory compounds, a series of 17-esters of betamethasone prepared by Elks [22] was evaluated. This resulted in compounds with new standards of topical potency such as triamcinolone acetonide and fluocinolone acetonide. It was then discovered, that potency peaked with betamethasone-17-valerate and betamethasone-17,21-dipropionate, which were between four- and ten-fold more potent than the standard. 

Chemists at Glaxo exploited this reactivity sequence in their synthesis of the anti-asthma drug, salmefamol (sister of the best seller salbutamol, which will be discussed in Chapter 25). Three reducing agents are used in the sequence sodium borohydride (NaBH lithium aluminium hydride (LiAlH4) and hydrogen gas over a palladium catalyst. 

Thyroxine has two aromatic rings, and you should be prepared to draw upon what you learned about aromatic chemistry in Chapters 22 and 23. It is also an amino acid and, in order to make the synthesis as cheap as possible, the chemists at Glaxo who developed the method used the amino acid tyrosine as a starting material. Nitration of tyrosine puts two nitro groups ortho to the OH group in an electrophilic aromatic substitution (make sure that you understand why ). 

For the synthesis of the Glaxo anti-HIV drug abacavir (ziagen) a chiral cyclo-pentene derivative was needed. At Glaxo the application of savinase, a cheap en-... 

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