Robinson

Chapter 3. Analgesics and Narcotic Antagonists Franklin M. Robinson 

Merck Sharp. Dohme Research Laboratories, West Point, Pa. 19h36 

Literature reports over the last year indicate some decrease in the amount of chemical effort devoted to new analgesic structures, but a continued increase in investigation of biochemical mechanisms of analgesia and dependence. Interest in narcotic antagonists for the treatment and prevention of narcotic abuse has stimulated much current research on new compounds. In neither area was there evidence of a significant advance during the year. 

An extensive review of the literature on narcotic antagonists and analgesics from July, I966 to April, I97O appeared.  

New Clinical Studies - No clinical studies on new compounds were reported, but new studies on dlviminol, tilldlne, and bezitramide continue to indicate that these are orally effective analgesics in the codeine-morphine potency range which do not produce tolerance. 

All the ring transform packages in LHASA employ binary search techniques. This means that all structural questions are to be answered with a yes or a no. Preparation of the sequence of questions relating to straightforward chemical situations poses no real problems. It is the identification and resolution of the extraordinary cases that are difficult. For example, in a Robinson disconnection for the sequence below, the geminal dimethyl substitution is a formidable problem. 

It is up to the chemist designing the tables to first perceive that this situation might occur. Second, decide whether he wishes to have the tables salvage the difficult situation and if he does, he has to manually determine what kind of chemistry should be attempted. 

The above example is a clear black or white situation. Unless the dimethyl substituent is removed, the transform just cannot proceed. The grey areas cause just as much of a dilemma for the chemist, In Marshall s synthesis of isonootkatone two possible stereoisomers could have resulted. 

ACS Symposium Series American Chemical Society Washington, DC, 1977. 

As we have been adding to the data base at Du Pont (to the one and two group tables), the question has often been raised how much detail should we go into in the qualifiers This is somewhat of a dilemma, many of the industrial reactions we are dealing with have only been considered for a limited number of substrates. It is not clear whether qualifiers should be incorporated that restrict the transforms to only those cases where it is known to work or whether only those which are known to fail should be specifically excluded. Both ways take an immense amount of literature work to do consistently. 

An unusually large proportion of the research reported during I966 concerned mechanisms of action of compounds previously reported to be clinically effective. A number of new chemical structures exhibiting hypotensive or antihypertensive activity in animals were discovered and preliminary data in humans reported for some but potentially major, new advances in the trsatinent of hypertension were not evident. 

Several reviews of antihypertensives and clinical comparisons of the newer confounds appeared. 

New clinical studies have confirmed previous reports of effective antihypertensive action with a low incidence of side effects aivi no impairment of renal hemodynamicsIn cases of poor control with ST 155 alone, combination with methyldopa or guanethidine gave good results without orthostatic or renal problems J  

Methvldopa - Strong evidence for a central mechanism of action was reported Pretreatment with RO-4-4602, (N -DL-seryl-N-2,3,4-trihydroxybenzyihydrazine) a central and peripheral decarboxylase inhibitor, conpletely inhibited the 

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Hydrocarbon mixtures are most often modeled by the equations of state of Soave, Peng Robinson, or Lee and Kesler. 

A quite different approach was adopted by Robinson and Stokes [8], who emphasized, as above, that if the solute dissociated into ions, and a total of h molecules of water are required to solvate these ions, then the real concentration of the ions should be corrected to reflect only the bulk solvent. Robinson and Stokes derive, with these ideas, the following expression for the activity coefficient ... 

Robinson R A and Stokes R H 1959 Electrolyte Solutions (London ButtenA/orth)... 

Robinson P J and Fioibrook K A 1972 Unimolecular Reactions (London Wiiey)... 

Zhu S-B, Lee J, Robinson G W and Lin S H 1988 A microscopic form of the extended Kramers equation. A simple friction model for cis-trans isomerization reactions Chem. Phys. Lett. 148 164-8... 

Zhu S-B, Lee J, Robinson G Wand Lin S H 1989 Theoretical study of memory kernel and velocity correlation function for condensed phase isomerization. I. Memory kernel J. Chem. Phys. 90 6335-9... 

Singh S, Krishnan R and Robinson G W 1990 Theory of activated rate processes with space-dependent friction Chem. 

Eyring H 1935 The activated complex in chemical reactions J. Chem. Phys. 3 107-15 Hofacker L 1963 Quantentheorie chemischer Reaktionen Z. Naturf. A 18 607-19 Robinson P J and Holbrook K A 1972 Unimolecular Reactions (New York Wiley)... 

Richmond G L, Robinson J M and Shannon V L 1988 Second harmonic generation studies of interfacial structure and dynamics Prog. Surf. Sc/. 28 1-70... 

Crowfoot D, Bunn C W, Rogers-Low B W and Turner-Jones A 1949 The X-ray orystallographio investigation of the struoture of penioiiiin Chemistry of Penicillin ed H T Ciarke, J R Johnson and R Robinson (Prinoeton, NJ Prinoeton University Press) pp 310-66... 

Greet R, Peat R, Peter L M, Pletcher D and Robinson J 1993 Instrumental Methods in Electrochemistry (Chichester Southampton Electrochemistry Group/Ellis Horwood)... 

France M R, Buchanan J W, Robinson J C, Pullins S FI, Tucker J T, King R B and Duncan M A 1997 Antimony and bismuth oxide clusters growth and decomposition of new magic number clusters J. Phys. Chem. A 101 6214... 

Klimov V, Smilowitz L, Wang H, Grigorova M, Robinson J M, Koskelo A, Mattes B R, WudI F and Me Braneh D W 1997 Femtoseeond to nanoseeond dynamies in fullerenes implieations for exoited-state optioal nonlinearities Res. Chem. Intermed. 23 587-600... 

Monroe C, Swann W, Robinson H and Wieman C 1990 Very oold trapped atoms in a vapor oell Phys.Rev.Lett. 65 1571-4... 

Robinson J S 1979 Corrosion inhibitors—Recent Deveiopments (Park Ridge, NJ Noyes) Sastri V S 1998 Corrosion inhibitors (Chichester Wiley)... 

Dunn C M, Robinson B FI and Leng F J 1990 Photon-correlation spectroscopy applied to the size characterization of water-in-oil microemulstion systems stabilized by aerosol-OT effect of change in the counterion Spectrochim. Acta. A 46 1017... 

Takens, F. Motion under the influence of a strong constraining force. In Global Theory of Dynamical Systems, Evanston 1979 (Z. Nitecki and C. Robinson, eds.). Springer-Verlag, Berlin, Heidelberg, New York (1980)... 

The 20th century brought important advances in the field of organic chemistry. In the first decades of the century, the syntheses of inaeasingly complex molecules were accomplished. Some notable compounds synthesized during that time were a-terpinol (WH. Perkin, 1904), camphor (G. Komppa, 1903), and tropinone (R. Robinson, 1917 Figure 10.3-28). 

Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

Assistance with the illustrations for the second edition was provided by Drs R Groot, S McGrother and V Milman. Many of the figures from the first edition are also included here and so 1 would like to thank again Dr S E Greasley, Dr M M Harm, Dr H Jhoti, Dr S N Jordan, Professor G R Luckhurst, Dr P M McMeekin, Dr A Nicholls, Dr P Popelier, Dr A Robinson and Dr T E Klein. 

For the mechanism of this reaction, see Robinson and Robinson,1918, H3i 639 1924, 145, 827.) The reaction is of wide application for example, the use of methyl-phenyl-hydrazine, CsH5(CHj)> -iN H, in the above reaction gives i-methyl-2-phenylindole, whereas pyruvic acid, CH CO COOH, when converted to its phenylhydrazone and then indolised, gives indole-2-carboxylic... 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

It turned out that the dodecylsulfate surfactants Co(DS)i Ni(DS)2, Cu(DS)2 and Zn(DS)2 containing catalytically active counterions are extremely potent catalysts for the Diels-Alder reaction between 5.1 and 5.2 (see Scheme 5.1). The physical properties of these micelles have been described in the literature and a small number of catalytic studies have been reported. The influence of Cu(DS)2 micelles on the kinetics of quenching of a photoexcited species has been investigated. Interestingly, Kobayashi recently employed surfactants in scandium triflate catalysed aldol reactions". Robinson et al. have demonshuted that the interaction between metal ions and ligand at the surface of dodecylsulfate micelles can be extremely efficient. ... 

Chemistry as it was realized substantially derives from the interae-tion of electrons. The electronic theory of chemistry, particularly of organic chemistry, emerged, explaining the great richness of chemical observations and transformation, as expressed by Ingold, Robinson, Hammett, and many others following in their footsteps. 

No mechanistic aspects of organic chemistry (or, for this reason, any reaction intermediates) were ever mentioned by Zemplen in his lectures or writings, nor did he consider or accept their existence. I never heard him mention the names of Meerwein, Ingold, Robinson, or any other pioneers of the mechanistic electronic theory of organic chemistry. The possible role of organic ions was similarly never mentioned. He was. 

Review Problem 1 In 1936, Robinson carried out this reaction, hoping to get the alcohol A ... 

Analysis the obvious disconnection takes us back to the halide used by Robinson, the one we synthesised in fi ame 27 ... 

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