Merck procedure

The biomimetic approach to the core skeleton of C-nor-D-homosteroid was first developed by the Merck research group (Scheme 2.1) [16]. In the Merck procedure,... 

In the original Merck procedure commercial 30% formalin was used as the source of formaldehyde, and in the case of cortisol (1) it was observed that the 1 lyS-hydroxyl group reacted in part to give the 1 l 8-methoxymethylene ether (2), ascribable to the presence of methanol in the formalin. Syntex workers circumvented this side... 

Preparation (2%) [1, 1030, after citation of ref. 4], Blomquist et al.4a used the Merck procedure, but noted that it is not necessary to use a flame to initiate the reaction if the sodium is cut with scissors and added directly to the mercury. 

Compound 151 was then transformed into the ( ) PS-5 carbapenem following the Merck procedure. The same authors reported the synthesis of ( ) PS-6 by using an analogous methodology. 

The synthesis of PS-5 was achieved by treatment of silylimine of 0-protected (S) lactic aldehyde with the lithium enolate of /-butyl butanoate. The reaction is highly diastereoselective affording almost completely the trans a2etidinone with the natural configuration at C3. This azetidinone was converted, by sequential Jones and Baeyer-Villiger oxidation of hydroxyethyl side chain to the 4-acetoxy doivative that represents a most useful chiral building block fcv the synthesis of final carbapenem PS-5 via the Merck procedure (Scheme 8). 

Condensation of silylimine of (5)-lactic aldehyde with lithium enolate of t-butyl isovalerate affords the -lactam in 80% chemical yield and in a 97 3 diastereomeric ratio. The mixture was desilylated and treated with lead tetracetate to give, in one step, through a radical fragmentation reaction, the 4-acetoxy derivative as a 1 1 4(R) 4(S) imeric mixture. The lack oi stereospecificity is not easy to rationalize expecially if one considers that the analogous lead tetraacetate induced oxidative decarboxylation is completely trans stereoselective. Both reactions should have the same radical intermediate. However, this lack of stereospecificity is not important for the success of the synthesis since the mixture of diastereoisomers exclusively affords the trans 4-substituted azetidinone by the subsequent Merck procedure (Scheme 9). 

The choice of which reactions to include is not an easy one. First there are the well known "Name Reactions", that have appeared in various monographs or in the old Merck index. Some of these are so obvious mechanistically to the modern organic chemistry practitioner that we have in fact omitted them for instance esterification of alcohols with acid chlorides - the Schotten-Baumann procedure. Others are so important and so well entrenched by name, like the Baeyer-Villiger ketone oxidation, that it is impossible to ignore them. In general we have kept older name reactions that are not obvious at first glance. 

Oicyclopentadiene, obtained from the Aldrich Chemical Company, Inc. (or E. Merck, Darmstadt, FRG), was cracked just prior to use according to the procedure of Fieser and Williamson, to give the monomer, bp 40-42°C. 

Acknowledgment The authors wish to express their gratitude to Dr. J. Edwards of Syntex Research who provided the experimental procedure utilizing silver carbonate on Celite. We are also indebted to the Synthetic Chemical Research Department of Merck Sharp Dohme Research Laboratories for providing time to complete this review and also to Miss Joanna Mohr for her patience and care in preparing the manuscript. 

All reactions and manipulations were carried out under an inert atmosphere (N2 or Ar gas) using the Schlenk technique. Solvents were freshly distilled under an Ar atmosphere using the standard procedures (Na/BC/benzophenone or CaH2). Chromatography was performed on alumina (aluminum oxide, activity Il-IV(Merck art 1097). The H- and C-NMR spectra were recorded on a Bruker AC-200 spectrometer ( H, 200 MHz) and Nippon... 

As previously described, Eq. 6 contains two constants characteristic of the system and the sample, feo and S, which can be determined by two chromatographic mns differing only in tc. These two values allow to calculate log fe using Eq. 4. However, because there is no empirical solution, values of log few and S have to be computed by iteration. Such procedures are included in several commercially available LC software packages, such as Drylab (Rheodyne, CA, USA), Chromsword (Merck, Darmstadt, Germany), ACD/LC simulator (Advanced Chemical Development, Toronto, Canada) or Osiris (Datalys, Grenoble, Erance). This approach was comprehensively described and successfully applied for accurate log P determination of several solutes with diverse chemical structures [9, 12, 43, 50]. 

Apovincaminic acid ethylester was supplied by Richter Gedeon Co., (-)-dihydroapovincaminic acid ethyl ester was prepared according to the procedure described in (11). fSj-a, -diphcnyl-2-py rro 1 idincmethanol was synthesised as described (12). 2-benzylidene-l-benzosuberone was prepared as described in (13). Isophorone was supplied by Merck. Cinchonidine was purchased from Fluka. 

The reagent was generated in situ by sequential addition of 1.63 mL of triethylamine trishydrofiuoride (obtained from Riedel deHaen, Merck, or Aldrich Chemical Company, Inc.) and 2.80 mL of triethylamine to the solution of 2. The procedure reported in reference 4 provides a reagent with an approximate stoichiometry of NEt3-2HF that can also be used for the purpose described.5... 

The parent NH4ZSM-5 (Zeolyst, Si A 1=15) was treated with a 0.1 M Co(N03)2 at room temperature. The ion exchange procedure was repeated three times and then the precipitate was washed with water and dried at 380 K. The cobalt content corresponded to Co/Al = 0.18. We used also MgZSM-5 (Mg/Al = 0.10) obtained by the treatment of NH4ZSM-5 with Mg(N03)2 solution. Propene (MERCK 99 %), as well as carbon monoxide, and nitrogen monoxide (Linde Gas Polska 99.95%, and 99.5% resp.) were used as adsorbates. 

A comparative study [12] of the reactivity of the oxalimide 16 in a variety of solvents (xylene, chlorobenzene, toluene) and of methylphosphinite 17 was performed with the focused microwave Synthewave 402 reactor (Merck Eurolab, div. Prolabo, France), using different conditions of power and exposure time (Scheme 8.8). In all experiments yields were better than those of previous procedures with classical heating (Tab. 8.2), and the authors wrote it is dear that microwave technique is applicable to highly functionalized compounds containing stereogenic centers without appreciable modification of these centers . 

The synthesis of Merck s glycine NMDA receptor or antagonist L-701,324 is illustrative, it can be prepared in one step by use of this procedure the reported synthetic procedure comprises several reaction steps. 

Another route to the synthesis of the furanone-containing compounds (e.g., 84, Scheme 18) is via magnesium-mediated carbometallation of propar-gyl alcohols, as described by Forgione et al. [67]. Scheme 20 demonstrates this procedure as a feasible means of producing the Merck anti-inflammatory drug Vioxx, 85. 

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

Zinc powder, obtainable from Mallinckrodt Chemical Works, St. Louis, Missouri, and Merck and Co., Rahway, New Jersey, is placed in a beaker and is washed consecutively and rapidly ( 10 seconds) with three 100-ml. portions of 3% hydrochloric acid, two 100-ml. portions of water, two 200-ml. portions of 2% aqueous copper sulfate (until blue color disappears), two 200-ml. portions of water, two 100-ml. portions of acetone, two 100-ml. portions of dimethylformamide, and is washed into the reaction vessel with dimethylformamide. This procedure is a modification of one described by Hennion and Sheehan.3... 

Due to the very time consuming of the above procedure, the latter was modified as follows (synthesis B) equal volumes of silicate and Al-Pr4N+-H2SO, solutions were added at the same rate to an aqueous solution of NaCl (Merck, anal, grade). The gel which is formed (pH 3.5), is stirred for 2 h before its pH is adjusted to about 9-9.5 by further adding of the remaining excess of Na silicate solution. The so obtained gel is stirred for 3 h before heating. 

Enzymatic assay techniques have been developed for several additives by Merck. BIOQUANT kits are available for aspartame (intense sweetener) and nitrate (preservative). Gromes et al. (1995) applied the Bioquant kit to determination of aspartame in yoghurt, quark and confectionery. For low concentrations of aspartame a blank correction procedure was necessary. Recoveries of aspartame were in the range 93-102%. 

The RQ flex test kit (Merck) which uses specific test strips is useful for the semi-quantitative determination of several analytes. D(+) ascorbic acid can be determined in fortified food products with an accuracy of 85-115% (unpublished data), however the procedure cannot be applied to coloured food products. Added iron salts may be extracted from food products with dilute sulphuric acid and adjusted to pH2 with NaOH solution. Fe3+ is reduced to Fe2+ with ascorbic acid. Fe2+ reacts with Ferrospectral to form a red-violet complex. An internal calibration is provided on a barcode which is read by the RQ-flex reflectometer prior to any measurements. This avoids the need to calibrate the instrument with standard solutions. 

This procedure utilises a glass column (130mmx5mn) wet packed with approximately 2gm of Silica Gel (Merck 7754 BDH Chemicals) prepared by heating to 500°C 20°C for two hours, cooled and deactivated to 1.0% w/w water. Solvents are n-pentane (glass distilled, Rathbum Chemicals Ltd) and diethyl ether (Distol, Fisons). 

Methylacrylate and ethylenediamine were obtained from the Merck. Jeffamine T-3000 was purchased from Texaco Chemical Company. Other chemicals were used as obtained from the Fluka without further purification unless otherwise noted. Solvents were dried and distilled according to literature procedures prior to use. Reactions were controlled by thin layer chromatography (TLC) on silica gel 60 F254 and spots were detected either by UV-visible light or by charging with vapor. 

Over the counter precursors are sometimes psychoactive and need no further treatment once extracted from the inert material. It would be impractical for me to give specific details on how to remove every drug or precursor from every different type of inert material that each different company is using. So, I will give you a few examples and explicit directions on how to use the Merck Index to get the physicd properties of these substances and use this information to extract the goodies. Once you understand this procedure, you will be able to use it on any substances that you may run into. 

Reagents and Materials. All the chemicals used were of high grade purity and were obtained from E. Merck (Darmstadt, Germany). The standard reference material for Li was L-SVEC in Li2C03 form. The ion exchangers, both anion and cation types, were prepared in our laboratory as described elsewhere. Pure and Na-free SiOj gels were prepared in our laboratory by refinement of the procedure reported in the literature. ... 

This procedure can be used to synthesize the key intermediate 34 of Merck s HIV protease inhibitor Crixivan 35 (Fig. 5) [25]. This reaction is done using dichloroacetaldehyde 26 instead of chloroacetaldehyde, forming the classical Ugi product 30. This intermediate is then treated with triethylamine to obtain the corresponding vinylchloride 31. Cyclization with KO Bu followed by stereoselective hydrogenation using the chiral catalyst Rh-BINAP afforded the Crixivan intermediate 34. (Scheme 5) The classical way to make this intermediate requires five steps, and thus makes the MCR route more attractive [25]. 

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