Merck group

The use of protecting groups other than ketals appears to have been rather limited. The Merck group introduced the use of semicarbazones. 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

In search of a replacement of the C-terminal carboxylic acid, the IRBM/ Merck group discovered that a phenethylamide group extends into the... 

No Other work has appeared from the Merck group for a number of years and oxytocin receptor antagonism appears to be no longer an active research area for the company. 

A neolignan isolated by the Merck group from the plant Piperfutokadsurae, was the first natural product discovered as a potent inhibitor of the binding of [3H ]PAF to rabbit platelet membrane preparation with an IC50 close to 0.1 /iM [268]. Named kadsurenone (26), it was also shown to be a specific and potent inhibitor of PAF-induced rabbit platelet aggregation with an IC50 value of 0.99 juM. 

This redox activity, coupled with the lipophilicity and 7r-electron character (which was felt to mimic the arachidonic acid chain), led a Merck group to develop a series of substituted phenothiazinones as selective 5-LO inhibitors [227]. The lead compound, L-651,392 (87) was potent in cRBL, a puri-... 

It is inconvenient to have to specify two measures, i.e., recall and precision, to quantify the effectiveness of a search. The Merck group have made extensive use of the enrichment factor, i.e., the number of actives retrieved relative to the number that would have been retrieved if compounds had been picked from the database at random (12). Thus, using the notation of Table 1, the enrichment factor at some point, n, in the ranking resulting from a similarity search is given by... 

Enantiomerically pure epoxides and diols, readily available through the asymmetric epoxidation and asymmetric dihydroxylation reactions, are ideal precursors to prepare cis-amino alcohols via the Ritter reaction. " " A Merck group has shown that indene oxide 175a can be converted effectively to c/i-l-amino-2-indanol, a key fragment of the HlV-protease inhibitor Indinavir via the cis-... 

Alkylation Alkylation of the phenylindanone 31 with catalyst 3a by the Merck group demonstrates the reward that can accompany a careful and systematic study of a particular phase-transfer reaction (Scheme 10.3) [5d,5f,9,36], The numerous reaction variables were optimized and the kinetics and mechanism of the reaction were studied in detail. It has been proposed that the chiral induction step involves an ion-pair in which the enolate anion fits on top of the catalyst and is positioned by electrostatic and hydrogen-bonding effects as well as 71—71 stacking interactions between the aromatic rings in the catalyst and the enolate. The electrophile then preferentially approaches the ion-pair from the top (front) face, because the catalyst effectively shields the bottom-face approach. A crystal structure of the catalyst as well as calculations of the catalyst-enolate complex support this interpretation [9a,91]. Alkylations of related active methine compounds, such as 33 to 34 (Scheme 10.3), have also appeared [10,11]. 

The avermectin biosynthetic genes encompass a region of approximately 85 kb of the S. avermitilis genome which have been cloned and sequenced by us, by the Merck group [10], and by the Kitasato group [11], The DNA sequence of the avermectin biosynthetic region was recently published [11]. The avermec-... 

The notorious propensity for terminal olefins to undergo non-selective epoxidation has been overcome in one case by the stepwise formation of the epoxide. Thus, a Merck group capitalized on the chiral environment of oxazolidine 40 by first carrying out a diastereoselective iodohydration using N-iodo succinimide (NIS) under a carefully chosen set... 

This synthesis requires the separation of the diastereoisomers of 92 (obtained from D-penicillamine). An attempt to control the stereochemistry was developed by the Merck group in 1974, in a total synthesis based on the [2+2] cycloaddition of the ketene derived from azidoacetyl chloride and the chiral thiazoline 94. The reaction only gives the /ra .r-pcnam derivative 95, which could be epimerized via the Schiff base 96 (cisltrans ratio = 2 1) (Scheme 51). The separated tyr-isomcr has been transformed into synthetic penicillin G <1974JOC437>. 

In the past decade many new examples have been described, mostly for amino acid derivatives using (substituted) benzaldehyde as a racemization catalyst. In Scheme 7.7 an application of this procedure on multi-kilogram scale from Merck Co is described for the asymmetric transformation of a benzodiazepinone in the synthesis of the CCK antagonist, L-364,718 (10),36 More recently, the Merck group also applied this method to other bendiazepinones.37... 

The 4-ary 1-2,4-diketobutanoic acid class of IN inhibitors (also known as 1,3-diketo acids, or DKAs) was discovered independently by researchers from Merck and Shionogi, with patents from both groups published in the same year.13 From a random screen of > 250,000 compounds, the Merck group identified DKAs as the most active IN inhibitors. Compound 7 was the most potent compound found in this screen (Table 1), completely inhibiting HIV-1 infection in a cell-based assay at a concentration of 10 pM.10... 

The Merck group s efforts to find a more stable substitute for the DKA pharmacophore resulted in the design of 8-hydroxy-[l,6]naphthyridines such as compound 10,19 wherein the keto-enol-acid triad was replaced with a 1,6-naphthyridine ketone bearing a phenolic hydroxyl group. Further refinement of compound 10—replacement of the naphthyridine phenyl ketone with a 4-fluorobenzyl carboxamide and addition of a six-membered sulfonamide at the 5-position of the naphthyridine core—resulted in compound 11, the second IN inhibitor to reach the clinic.20 The discovery of liver toxicity in long-term safety studies of compound 11 in dogs led to the suspension of clinical development21 of this compound. 

The Merck group has applied the electrophilic amination using lithium terf-butyl N-(tosyloxy)carbamate 9a to the chiral amide derived from (lS,2/ )-cw-amino-indanol [10] (Scheme 4). Treatment of 10 with n-Buli in THF at -78 °C gave the lithium enolate which was reacted with CuCN. The resulting amide cuprate was allowed to react with 9a. The authors found that a single diastereomer of a-Boc-protected amino amide 11 was formed. The sense of asymmetric induction observed was consistent with preferential approach of 9a from the least hindered face of the enolate. The removal of the chiral auxiliary with refluxing 6N HC1 afforded a-amino acids 12 in good yields and optical purities. 

Subsequent to the synthesis of 5-carba-5-deaza- and 1-carba-1-deazariboflavin, the Merck group synthesized 1,5-dideazari-boflavin, XIV, with both redox-active nitrogens replaced by carbon (22). Some expected patterns of reactivity are observed. The reduction potential for two-electron reduction to the dihydro form, XV, has been estimated at —370 mV, an essentially additive effect from the two deazaflavins previously noted. This low value puts XIV out of the... 

Since the first publication by the Merck group disclosing a novel series of... 

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