Merck Process Group

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 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... 

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). ... 

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 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. 

The molybdenum and tungsten complexes catalyze reactions of soft nucleophiles, such as malonates, related 1,3-dicarbonyl compoimds, and nitroalkanes. Azlactones are also soft carbanions, and Trost has shown that complexes formed from molybdenum and the bis(pyridine) ligands catalyze enantioselective and diastereoselective allylation of azlactones with allylic phosphates to form quaternary amino acids (Equation 20.40). In these reactions, the nucleophile adds to the more substituted position of the allylic electrophile, and a stereocenter is formed at both the allyl carbon and the azlactone carbon. One route to the protease inhibitor tipranavir by the molybdenum-catalyzed allylation with 1,3-dicarbonyl compounds was demonstrated by Trost (Equation 20.41), and the Merck process group used related allylation chemistry with Trost s bis(pyridine) ligand to prepare the cyclopentanone precursor to various analogs of tipranavir (Equation 20.42). 

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 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. 

The rhodium(II)-induced tandem cyclization-cycloaddition process has also been applied with notable success to the core structure of zaragozic acid by the Merck research group <94TL9185>. Zaragozic acid A (20) was discovered as a metabolite from an unidentified... 

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... 

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. 

Using a different approach, in 2005, Merck Process Research labs reported the synthesis of benzo[b]furans via a Cul-catalyzed intramolecular arylation of 2-haloaryl ketones (Scheme 2.25) [122]. The reaction was performed in DMF at 105°C, and was tolerant of a variety of functional groups affording the benzofurans in 72-99% yields. The mechanism was studied, and it appeared to involve enolization of the ketone, followed by an S j l mechanism on a Cu-arene-enolate intermediate, resulting in O-arylation. 

A strategy employing intramolecular amidation can also be exploited to access benzimidazolones (Scheme 24.12). The use of N,N -disubstituted ureas such as 27 was described by a process group working at Merck [60]. A palladium-based catalyst system promoted the intramolecular arylation and generated the desired heterocycles in excellent yields. Copper-catalyzed variants have also been reported [61,62]. The second reaction shown in Scheme 24.12, described by Barbero et al. illustrates such a variation where water is used as the solvent [63]. 

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