Merck process

The batch containing 1% starting material was resubjected to the dehydrogenation reaction using a reduced charge of DDQ and the batch was saved. This story has been told many times and has become legend in Merck Process Research. There are clearly some important lessons here that every process chemist should learn-and best not the hard way. We later showed that methyl acetoacetate could be used as a quench, eliminating the potential for reduction. 

This method was later adapted for the large-scale preparation of the LTD4 antagonist 64 by another Merck Process Research group (Figure 3.11) [21], Conversion of a methyl benzoate to the corresponding acetophenone was required. Formation of the tertiary alcohol was again minimized with the addition of H M DS and excellent reaction performance was achieved. 

The author would like to thank the SERM team members in Merck Process Research, who were the coauthors for the original publications reviewed in this chapter, for their original contributions to the work. 

Scheme 9.4. The Merck process synthesis of losartan potassium (1).

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

The oxidation of an alcohol to the aldehyde or ketone on large scale would ideally be carried out with an inexpensive, easily handled reagent at ambient temperature. Scott Hoermer of Merck Process, Rahway, NJ reports (Organic Lett. 5 285, 2003) that stoichiometric iodine in the... 

The Merck process group in Rahway has developed two syntheses of rizatriptan (4) utilizing palladium catalyzed indolization reactions (Schemes 19 and 20). Both routes start from the iodoaniline 51, which was prepared by reaction of 47 with iodine monochloride in the presence of CaCOa. " Palladium catalyzed coupling of iodoaniline 51 with bis-triethylsilyl protected butynol in the presence of NaaCOa provided a mixture of indoles 52a and 52b. This mixture was desilylated with aqueous HCl in MeOH to furnish the tryptophol 53 in 75% yield from 51. Protection of the alkyne prevented coupling at the terminal carbon of the alkyne and tnethylsilyl (TES) was found to be optimal because it offered the correct balance between reactivity (rate of coupling) and... 

The sitagliptin project helped rewrite the way that small-molecule pharmaceuticals are developed at Merck Process Research and set the foundations to realizing new ways for different groups to work together as a team in pursuit of a common goal. Dr. Rich D. Tillyer led the Process Research Department during this time of transformation, and we are thankful for his vision and for his support of innovation as the best way to develop new pharmaceutical compounds. 

Merck process research group developed a short and efficient synthesis of 3-(2,2,2-trifluoroethyl)-hexahydro-2//-l,4-diazepin-2-one 85 as part of an ongoing research program to identify peptidase inhibitors <07S2779>. 

A concise and efficient synthesis of the potent reverse transcriptase inhibitor Elfavirenz [Scheme 3.130] by the DuPbnt-Merck process development groups entailed the removal of an A O-acetal under basic conditions.252 Oxidation of the N-p-methoxybenzy derivative 130.1 with DDQ at 0 °C generated the NtO-acetal 130.2 in quantitative yield. Treatment of 130,2 with sodium hydroxide in... 

This method has been applied by other researchers as well. The recent total syndiesis of (-)-FK 506 by the Merck Process Group employed A -methoxy-lV-methylamide functionality as a mild route to complex aldehydes (equation 9). ... 

Perchloric acid is manufactured by the Merck process through electrolysis of chlorine dissolved in cold (ca. 0°C) perchloric acid ... 

Keith was selected for many awards in recent years, including an A.P. Sloan Fellowship, an Eli Lilly Granteeship, Amgen Young Investigator Award, AstraZeneca Award, Merck Process Research Award, University of Ottawa Researcher of the Year, and most recently the OMCOS Award. He was the only Canadian to be so honored and the list of prior winners (Kobayashi, Camera, Fu, Ma, Hartwig, and Nozaki) is a Who s Who of the field of catalysis. At the time of his death, he held the position University of Ottawa Research Chair in Novel Catalytic Transformations. ... 

Merck process chemists showed that an acid-regulated, one-pot transformation of a cephalosporin derivative to the antibiotic cefoxitin was complex (Weinstock, 1986). Not only did it entail eight discrete chemical reactions at least, but some of them had to occur synchronously to maximize the antibiotic yield. Moreover, the concentration of hydrochloric acid reached an optimum at 0.004 molar. The rates of some of the eight reactions were proportional to this concentration and others to its square. 

The Merck process research group found that Xantphos was the best ligand for the palladium-catalyzed cross-coupling of aminoheterocycles and aryl bromides, or halopyridines.69 Depending upon the reaction partners, CS2CO3, Na2C03, K3PO4, or NaO/-Bu was used as the base. 

The Merck process group was able to use the Buchwald-Hartwig amination as a means to resolve rac-4,12-dibromo[2.2]paracyclophane 41.86 They report that (5)-[2.2]Phanephos was able to perform a catalytic, asymmetric amination of rac-4,12-dibromo[2.2]paracyclophane 41. This kinetic resolution selectively aminated (42), de-... 

The theory and experiment of direct crystallization of enantiomers is quite well understood at present [10]. There are a number of variables which affect the resolution by direct crystallization in practice. Several technological schemes based on this principle are realized on the commercial scale. These are, for example, the Merck process used for the production of antihypertensive drug methyldopa [11], a process developed by Harman and Reimer for (-)-menthol, which is separated as an ester [12], the process patented by Industria Chimica Profarmaco for the resolution of naproxen enantiomers as the ethylamine salt [13], the production of L-glutamic acid by the Japanese company Ajinomoto on a scale in excess of 10000 tons annually as early as the 1960s [14], etc. In general, it seems that spontaneous crystallization is a very useful technique for the enantioseparation of the naturally occurring a-amino acids. All of them may be resolved either directly or as derivatives [10]. 

For some diazo transfer reactions, a more lipophilic azide than mesyl or 4-toluenesulfonyl azide, is preferred. This is the case, for instance, in the Merck process for the synthesis of the )ff-lactam antibiotic thienamycin (Lx)racarbef), in which benzenesulfonyl azide with an dodecyl substitutent on the benzene ring is used (Salzmann et al., 1980 Reider and Grabowski, 1982 Bodurow et al., 1989 Reider, 1993). We will discuss the chemistry of the Merck process in Section 8.7. 

The Merck Process Group has developed a new method for indole synthesis involving a Pd-catalyzed annulation between o-iodoanilines 55 and ketones 56 <97JOC2676>. The reaction presumably involves formation of the enamine 57 followed by an intramolecular Heck reaction in the presence of a non-oxidizable amine base such as DABCO. The reaction is especially effective for cyclic ketones and tolerates a variety of functional groups in the product indole 58. 

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