Problems of the Original Route

Though the medicinal chemistry route allowed for the preparation of rizatriptan (1) in a straightforward manner, it suffered from several shortcomings that prohibited implementation of the synthesis on a kilogram scale  

1) Benzylation of sodium 1,2,4-triazole was not regjoselective and the step utilized NaH, which is not suitable for large scale preparation, for generating the sodium triazole species. 

2) The use of excess SnCl2 monohydrate as the reducing agent for the diazonium salt was not desirable because of environmental concerns and tedious separation issues. 

3) The key Fisher indole synthesis using diethyl 4-chlorobutanal (8) suffered from poor yield to make the primary tryptamine 10, which then calls for reductive amination to complete the synthesis. 

4) Multiple chromatographies coupled with several low yielding steps in the synthesis deem this route not suitable for scale-up. 

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Key problems of the original route were effectively addressed. 

After preliminary evaluation of the original route, we identified several problems in the preparation of cyclopentenone 2 ... 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

Numerous problems with the original route were identified at the beginning of the project and included ... 

The definition of a synthetic route to coenzyme B12 has been a major concern of numerous groups. The synthesis was carried out several years ago, but the problem of the origin of the corrin structure in natural systems has not been resolved in all its steps [5, 12-14]. 

One of the most efficient ways to treat this problem is to combine the ab initio MO method and the RISM theory, and this has been achieved by a slight modification of the original RISM-SCF method. Effective atomic charges in liquid water are determined such that the electronic structure and the liquid properties become self-consistent, and along the route of convergence the polarization effect can be naturally incorporated. 

The original route from p-xylene was oxidation in the presence of nitric acid. But the use of nitric acid is always problematical. There are corrosion and potential explosion problems, problems of nitrogen contamination of the product, and problems due to the requirement to run the reactions at high temperatures. Just a lot of problems that all led to the development of the liquid air phase oxidation of p-xylene. Ironically the nitrogen contamination problem was the reason that the intermediate DMT route to polyester was developed, since that was easy to purify by distillation. Subsequently, DMT has secured a firm place in the processing scheme. 

Systems (20a) and (20b) of n+B equations in n+B unknowns and Ri,... Rp, is the equivalent presentation of the original problem (16). For the single-route reaction mechanism vector R has only one element R, which is the overall reaction rate (the rate of net reaction). 

One of the most challenging vitamin D precursors to prepare is (3aJ ,4, 7a, -(Z)-ethylidene-7a-methyloctahydro-1. ff-4-indenol (88). Many possible approaches to this key intermediate were reviewed recently. Since then, ongoing work at Hoffman-LaRoche has produced an updated route starting from Hajos dione 3. One of the key problems in the original approach was the thermal instability of fert-butyl copper hydride used in the reduction of the double bond. Replacement of t-BuCu with dimethylphenylsilyl copper gave a better yield than that obtained with the former reagent. The remaining steps of the synthesis of 88 are shown below. 

A brief discussion of the synthetic routes to the [Ln(OR)x] is presented in the following sections. The reader is urged to find the original literature that detail the different efforts necessary to successfully isolate the compounds discussed. The various problems/limitations associated with these strategies are addressed below. 

The main problem with the original synthetic route to tridachiahydropyrone (9) was the Suzuki coupling step of the boronic ester 84 with the bromo-pyrone fragments 85 and 39 to form the biomimetic precursors 43 and 44 (see Sect. 1.3, Schemes 16 and 18) [1, 2]. In addition to being fairly low yielding the yields themselves were found to be inconsistent. As this occurred at such a late stage in the synthesis it was thought preferable to improve upon this reaction if possible. 

The original Medicinal Chemistry route was straightforward but, from a process chemistry point of view [20], several problems were identified at the beginning of the project and some of them were quite similar to those for the previous development candidate ... 

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