Merck studies

Alcohols can be converted electrochemically into the corresponding carboxylic acids in very good yields if Ni oxide anodes are used in alkaline electrolytes. This reaction was studied intensively in industry for the electrochemical oxidation of diacetone-L-sorbose to diacetone-2-ketogulonic acid (intermediates of the vitamin C synthesis). On the basis of Sowjet work 282 284) (initially Pt anodes and NaBr—NaCl—NiCl2— NaOH electrolytes subsequently Ni oxide anodes), Roche and Merck studied the synthesis on the laboratory and pilot scale. In cooperation with the ETH Zurich 285-286 a special cell 287 288) was developed for this reaction. 

Merck studied the use of iron oxide anodes 289) for this reaction (yields up to 91 %). The rapid loss of electrode activity can be suppressed by adding alkali-resistant solvents, such as anisole or xylene 290). 

BBT solution on unmodified sorbents of different nature was studied. Silica gel Merck 60 (SG) was chosen for further investigations. BBT immobilization on SG was realized by adsoi ption from chloroform-hexane solution (1 10) in batch mode. The isotherm of BBT adsoi ption can be referred to H3-type. Interaction of Co(II), Cu(II), Cd(II), Ni(II), Zn(II) ions with immobilized BBT has been studied in batch mode as a function of pH of solution, time of phase contact and concentration of metals in solution. In the presence of sodium citrate absorbance (at X = 620 nm) of immobilized BBT grows with the increase of Cd(II) concentration in solution. No interference was observed from Zn(II), Pb(II), Cu(II), Ni(II), Co(II) and macrocomponents of natural waters. This was assumed as a basis of soi ption-spectroscopic and visual test determination of Cd(II). Heavy metals eluted from BBT-SG easily and quantitatively with a small volume of HNO -ethanol mixture. This became a basis of soi ption-atomic-absoi ption determination of the total concentration of heavy metals in natural objects. 

MK-677, an orally active spiroindoline-based growth hormone secretagogue (GHS) agonist, discovered by Merck and currently in Phase II clinical studies, was synthesized with a Fischer indolization as a key step. The synthesis of this agonist involved a Fischer indole/reduction process and was achieved in 48% overall yield from the relatively cheap starting material, isonipecotic acid 72. ... 

A precursor in the synthesis of a promising calcium sensitizing agent from E. Merck [33], a chiral thiadiazin-2-one EMD 53986, 3,6-Dihydro-5-[l,2,3,4-tetrahy-dro-6-quinolyl]-6-methyl-2H-l,3,4-thiadiazin-2-one [26]. The study was performed using Celluspher , a CSP prepared from cellulose tri(p-methylbenzoate) according to a patent from Ciba-Geigy [34]. The spherical particles had a mean particle diameter of 20 3 pm and the mobile phase was pure methanol. 

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. 

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

The PAMIR study predicts fine chemicals as one of the first fields where commercialization of micro-reactor technology will start [241, 337]. The small quantities, sometimes only in the kilogram range, and the large margins make the substitution of existing processes by micro reactors attractive. Currently, we can see the first signs of this, e.g. the work of Merck, Siemens-Axiva, Clariant and others. 

Another PDF inhibitor series derived from comparisons with known metalloprotease inhibitor classes has been reported by Merck [68]. Their study investigated a small set of peptide aldehyde inhibitors, postulating that the aldehyde might bind to the metal centre in the form of a hydrate,... 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

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 . 

In the early 1990s, FTIR was being evaluated at Merck for the in situ monitoring of reactions. This new technology was expected to provide a powerful means to study a reaction as well as a method for analytical control in production [28]. Both silyl imidate formation and the reaction with DDQ could be conveniently monitored by FTIR, as shown in Figure 3.13. Silyl imidate formation was indicated by the appearance of an absorbance at 1667.5 cm4 with concomitant disappearance of the absorbance corresponding to BSTFA at 1324.0cm-1. A new absorbance... 

Xanthans from several different sources were used in this study Xanthan samples A, B and C were kindly provided as freeze dried powder of ultrasonic degraded xanthan by Dr. B. Tinland, CERMAV, Grenoble, France. The molecular weights of these samples were determined experimentally in dilute solution by Dr. B. Tinland. Xanthan D was kindly provided as pasteurized, ultrafiltrated fermentation broth by Dr. G. Chauveteau, Institut Francais du Petrole, France. Xanthan E was kindly provided as a freeze dried sample from Dr. I. W. Sutherland, Edinburgh, Scotland. Xanthan F was obtained as a commercial, powdered material (Kelzan, Kelco Inc., a Division of Merck, San Diego CA.). Xanthan G was obtained as a commercial concentrated suspension (Flocon 4800, Pfizer, New York, NY)... 

Promising results have also been obtained in cycling ability studies performed in model coin-type cells with this same amorphous cathode material. Moreover, it has been found that either thermally treated or even initial amorphous manganese oxide exhibit satisfactory results. Cyclic voltammetric studies have been carried out with the LP-30 electrolyte (Merck). Cathode materials have been prepared from amorphous manganese oxide in question (80wt%) mixed with a conductive additive (10wt%) and a... 

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 . 

Widespread medicinal use of colloidal bismuth subcitrate (CBS) has prompted extensive studies of bismuth compounds involving the citrate anion. Bismuth citrate is essentially insoluble in water, but a dramatic increase in solubility with increasing pH has been exploited as a bio-ready source of soluble bismuth, a material referred to as CBS. Formulation of these solutions is complicated by the variability of the bismuth anion stoichiometry, the presence of potassium and/ or ammonium cations, the susceptibility of bismuth to oxygenation to Bi=0, and the incorporation of water in isolated solids. Consequently, a variety of formulas are classified in the literature as CBS. Solids isolated from various, often ill-defined combinations of bismuth citrate, citric acid, potassium hydroxide, or ammonium hydroxide have been assigned formulas on the basis of elemental analysis data or by determination of water and ammonia content, but are of low significance in the absence of complementary data other than thermal analysis (163), infrared spectroscopy (163), or NMR spectroscopy (164). In this context, the Merck index lists the chemical formula of CBS as KgfNHJaBieOafOHMCeHsCbh in the 11th edition (165), but in the most recent edition provides a less precise name, tripotassium dicitrato bismuthate (166). 

Further hydrogenations of a variety of C=C substrates depicted in Figure 37.22 range from a pilot process to several feasibility studies. Of special interest are PhanePhos, originally reported by Merck, an unsymmetrically substituted phos-pholane developed by Pfizer, and the rare case of an Ir-diphosphine complex active for the hydrogenation of a C=C bond. Nevertheless, the catalyst performances of most processes summarized in Figure 37.22 are probably not (yet) sufficient for manufacturing purposes. Indeed, several of the reports explicitly mention that further development was stopped, either because another route proved to be superior or because the compound was abandoned. 

Besides Ir-diphosphines, two more catalyst systems have shown promise for industrial application. As mentioned in Section 37.5.2, the Rh-Josiphos-cata-lyzed hydrogenation of unprotected /1-dehydro amino acid derivatives by Merck actually involves the hydrogenation of a C=N and not a C=C bond (see Fig. 37.10) [3, 51]. Noyori s Ru-PP-NN catalyst system seems also suitable for C=N hydrogenation [129], and was successfully applied in a feasibility study by Dow/Chirotech for the hydrogenation of a sulfonyl amidine [130]. Avecia also showed the viability of its CATHy catalyst for the transfer hydrogenation of phosphinyl imines [115] (see Fig. 37.34). 

Gaboxadol (9) is a selective extrasynaptic GABA receptor agonist in late-stage investigation for the treatment of insomnia. The action of this compound was extensively reviewed in Chebib et al. [13] and updated in Wafford et al. [23]. Nevertheless, the sponsor companies Merck Co., Inc., and H. Lundbeck A/S announced in March 2007 that the results from recently completed clinical studies do not support further development and announced the discontinuation of their joint development program for gaboxadol. 

Samples from the same study averaged over a typical 8-hour workshift for the area around the backhoe showed average levels of 3.06 mg/m3 (1.10 ppmv). Even higher levels (perhaps in excess of 10,000 ppmv) are possible around large spills of -hexane at such elevated concentrations, as with many components of gasoline-type hydrocarbons, there could be considerable danger from explosions, which are possible when the -hexane levels exceed approximately 1.2% of the volume of air (Merck 1989). Since 0.1% by volume is equivalent to 1,000 ppmv, this flash-point level for -hexane would be at a level of 12,000 ppmv or higher. 

The use of the enzyme system then known as invertin, which was extracted from beer yeast with water and precipitated from the aqueous solution, was available to Fischer when he began his classical studies of the enzymic hydrolysis of glucosides reported in 1894. The stage was also set by another enzyme known as emulsin, which Fischer purchased from E. Merck, Darmstadt, and which was known to hydrolyze several natural aromatic glucosides such as salicin, coniferin, arbutin, and the synthetic phenyl glucoside. These aryl glucosides were already known to not be cleaved by invertin. 

The FDA approved this selective cyclooxigenase (COX)-2 inhibitor (Vioxx) for the treatment of pain and inflammation in 1999. This NSAID demonstrated to have a lower risk of side effects such as gastrointestinal ulcers and bleeding than nonse-lective COX inhibitors, for example, ibuprofen. In 2004, a long-term study of Vioxx in patients at increased risk of colon polyps was halted because of an increased cardiovascular risk (heart attack, stroke) in the rofecoxib group. Subsequently, Merck withdrew the drug from the world market at the end of September 2004 [46]. 

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