Merck method

But mainly—at least until the last couple of years—the Merck method worked. 

The parent compounds and the metabolites have very low aqueous, solubility. They have proven difficult to extract from some matrices the current method for ivermectin involves some 41 concentration and clean-up steps preceding HPLC (8). A Merck method for recovering abamectin residues from strawberries and formation of fluorescent derivatives for HPLC analysis has 18 separate steps (9). A recently published two-step solid-phase recovery procedure for ivermectin from serum indicates that it is possible to combine an abbreviated concentration and cleanup method with a sensitive and specific detection system in this case, liquid chromatography (10). An immunoassay for avermectins that could be interfaced with simplified residue recovery protocols is a promising solution to the intensifying demands on regulatory agencies to monitor these compounds. 

An impressive example of the application of structure-based methods was the design of a inhibitor of the HIV protease by a group of scientists at DuPont Merck [Lam et al. 1994 This enzyme is crucial to the replication of the HIV virus, and inhibitors have bee shown to have therapeutic value as components of anti-AIDS treatment regimes. The star1 ing point for their work was a series of X-ray crystal structures of the enzyme with number of inhibitors boimd. Their objective was to discover potent, novel leads whid were orally available. Many of the previously reported inhibitors of this enzyme possessei substantial peptide character, and so were biologically unstable, poorly absorbed am rapidly metabolised. 

The Merck molecular force field (MMFF) is one of the more recently published force fields in the literature. It is a general-purpose method, particularly popular for organic molecules. MMFF94 was originally intended for molecular dynamics simulations, but has also seen much use for geometry optimization. It uses five valence terms, one of which is an electrostatic term, and one cross tenn. 

Bromosafrole is a great stepping stone to final product and was, in fact, the exact precursor used by Merck who was the first person to synthesize MDMA. Until very recently it was the defacto method that most underground chemists started out with (Someone-Who-Is-Not-Strike included) because, at first glance, it seems so simple and uses basic chemicals and equipment. Once someone has the bromosafrole, all one has to do is just swap out that Br with simple ammonia or methylamine and the deed is done. 

Nitroethane and 1-(3,4 methylenedioxy) 2- nitropropane This method of producing the above mentioned nitro compounds is by far the best Ritter has come across yet The problem with standard nitroethane synthesis is that the -NO2 source most commonly used is silver nitrite (a la Merck Index citing). Needless to say, this is going to be an expensive compound to make as it is not available commercially but must be synthesized from costly silver nitrate. The other methods mentioned in Vogels 5th masterpiece... 

For the industrial production of riboflavin as pharmaceuticals, the traditional methodology comprising the dkect condensation of (13) with (14) in an acidic medium with continuous optimisation of the reaction conditions is stiU used (28). A great part of riboflavin manufactured by fermentative methods is used for feeds in the form of concentrates. The present world demand of riboflavin may be about 2500 t per year. Of this amount, 60%, 25%, and 15% are used for feeds, pharmaceuticals, and foodstuffs, respectively. The main producers are Hoffmann-La Roche, BASF, Merck Co., and others. 

Merck and Maeder have patented the manufacture of arecaidine by loss of water from l-methyl-4-hydroxypiperidine-3-carboxylic acid. A method of producing the latter has been describd by Mannich and Veit and has been developed by Ugriumov for the production of arecaidine and arecoline. With the same objective, Dankova, Sidorova and Preobrachenski use what is substantially McElvain s process,but start by converting ethylene oxide, via the chlorohydrin and the cyanohydrin, into -chloropropionic acid. The ethyl ester of this with methylamine in benzene at 140° furnishes methylbis(2-carbethoxyethyl) amine (I) which on refluxing with sodium or sodium Moamyloxide in xylene yields l-methyl-3-carbethoxy-4-piperidone (II). The latter is reduced by sodium amalgam in dilute hydrochloric acid at 0° to l-methyl-3-carbethoxy-4-hydroxypiperidine (III) which on dehydration, and hydrolysis, yields arecaidine (IV R = H), convertible by methylation into arecoline (IV R = CH3). 

Apart from these methods of producing the opium alkaloids of commercial importance, processes for the minor bases have been published by Merck,Hesse, Plugge and Lohmann-Siedler. ... 

Papaverine, C20H21O4N. This alkaloid, first obtained by Merck, occurs in the mixture precipitated by ammonia from the mother liquors of opium extract from which morphine and codeine have been separated in Gregory s process, and methods for its isolation from this mixture have been published by Hesse and others. The alkaloid may be purified by conversion into the acid oxalate, B. H2C2O4, m.p. 196° or 201-5-202°, which is nearly insoluble in alcohol. 

Sabadilla Seeds. Processes for the isolation of the total alkaloids and separation of the components have been published by Wright and Luff, by Bosetti and by G. Merck. The more modem methods used by Poethke, Saito, Seiferle et al., Jacobs and Craig, and others for the alkaloids of white and green hellebores (see below) could no doubt also be used to advantage for sabadilla seed. A test for galenical preparations of sabadilla has been devised by Ramstad depending on the presence of chelidonie acid in the seed. ... 

Calculations on larger molecules have been carried out using molecular mechanics techniques and the Merck force field.- This method has proven to be suitable for the calculation of equilibrium geometries and conformational energy differences. 

To prepare a high surface area amorphous phosphate precursor AIPO4, the citrate method was used [6]. To reach an Al/P ratio fixed at 1, 0.667 mole of A1(N03)3-9H20 (Merck) and 0.667 mole of (NH4)H2P04 (Merck) were dissolved... 

All reagents and solvents were from commercial sources (Aldrich, J.T. Baker, Merck, Fluka, Mallinckrodt) and used as received. The complex 7b was synthesized following a modification of the method reported by Metz and co-woikers (13). 

Include a 3D ligand-based method. In our internal efforts across two companies, we arrived at the same conclusion as the Merck researchers [106] that a 3D similarity method appears to offer a good balance between effort expended and the number and novelty of hits generated. 

Efavirenz (1) is the second NNRTI development candidate at Merck. Prior to the development of 1, we worked on the preparation of the first NNRTI development candidate 2 [2]. During synthetic studies on 2, we discovered and optimized an unprecedented asymmetric addition of an acetylide to a carbon-nitrogen double bond. The novel asymmetric addition method for the preparation of 2 also provided the foundation for the process development of Efavirenz . Therefore, in this chapter we will first discuss chemistries for the preparation of 2 in two parts process development of large scale synthesis of 2 and new chemistries. Then, we will move into process development and its chemistries on Efavirenz . 

Scientists at DuPont Merck Pharmaceuticals [31] had also developed a new process to prepare 37, based on a modification of the Corey-Fuchs method, from cyclopropylaldehyde, prepared by thermal rearrangement of butadiene monoxide. 

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