Piperidine-Catalyzed Condensation of 1,3-Dicarbonyl Compounds with Ethyl ?-Ketoglutarate
GORDON N. WALKER
J. Org. Chem.[i ]1958, 23 (1), pp 34–39[/i]


Abstract
Acetylacetone, benzoylacetone, and the hydroxymethylene derivatives of phenylacetone, cyclopentanone, cyclohexanone and cycloheptanone have been condensed with ethyl-B-ketoglutarate in the presence of piperidine to give, after hydrolysis, substituted 2-hydroxyisophthalic acids, III a, b, c, d, e, and f, respectively. With the exception of IIc, a new compound, these products are the same as those obtained in the corresponding reactions carried out earlier using sodium ethoxide as the basic agent. Spectroscopic, degradative, and other data confirming the structures of the products are presented. Generally speaking, a-hydroxymethyleneketones are found to react selectively with one mole of ethylene glycol in the presence of benzenesulfonic acid, giving acetal-ketones IV.



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Synthesis of Benzo[f]quinolines and Ergolines from 5-Phenyl-6-methyl-2-pyridones
GORDON N. WALKER, BARBARA N. WEAVER
J. Org. Chem.1961, 26 (11), pp 4441–4455


Abstract
Condensation of 1-hydroxymethylene-1-phenyl-2-propanone with cyanoacetic acid derivatives and subsequent hydrolysis, gives 5-phenyl-6-methyl-2-pyridone-6-carboxylic acid, which is converted by a new process, reaction with oxalyl chloride, to exceptionally stable pyruvic acid derivatives. Cyclization with sulfuric acid, followed by transformation, first with phosphorus pentachloride and then alcohols, affords esters of 3-chlorobenzo[f]quinoline-2,6-dicarboxylic acid. These esters, and related deschloro compounds obtained by reduction with sodium borohydride to yield novel deschloro-1,4-dihydro compounds followed by rearomatization to benzo[f]quinolines, are nitrated at position 7. The nitro esters are reductively cyclized in the presence of palladium and acetic acid to corresponding lactams (aromatic ergoline derivatives), known to be intermediates in the synthesis of dihydrolysergic acid. A number of related experiments, especially those involving preparation and reactions of 5-phenyl-6-methyl-2-pyridone-3- and 4-carboxylic acids, are described, and some data presented to indicate the tautomeric states of these pyridones.

Palladium-catalyzed oxidation of terminal olefins to methyl ketones by hydrogen peroxide
Michel Roussel, Hubert Mimoun
J. Org. Chem. 1980, 45 (26), pp 5387–5390



Introduction
The use of the Wacker PdC12-CuC1, system for the oxidation
of higher terminal olefins to methyl ketones
presents major drawbacks, i.e., formation of chlorinated,
aldehydic, and internal ketones as byproducts, precipitation
of metallic palladium, and corrosion.'V2 Some improvements
have been achieved by using basic3 or alcoholic4
solvents and phase-transfer catalyst^,^ but the disadvantages
have not been completely eliminated. We have
previously described a highly selective procedure using
rhodium catalysts6 and involving molecular oxygen activation,'
but a deactivation of the catalyst system was observed.
We have also recently synthesized a new class of
stable palladium alkyl peroxidic complexes with the formula
[RCO,PdOO-t-Bu],; they undergo an oxygen transfer
to terminal olefins through a pseudocyclic peroxypalladation
mechanism

The Chemistry of Imines.
Robert W. Layer
Chem. Rev. 1963, 63 (5), pp 489–510


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The Fischer Indole Synthesis.
B. Robinson
Chem. Rev. 1963, 63 (4), pp 373–401


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Synthesis of metabolites of 3-O-t-butylmorphine
E. Mohacsi
Journal of Heterocyclic Chemistry Volume 24(2), 2009, pp.471-472



Abstract
The synthesis of 2-hydroxymethyl-2-propylmorphine (5) and 2-hydroxymethyl-2-propylnormorphine (7), the major rat urinary metabolites of 3-O-t-butylmorphine (3) are described.



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The Synthesis of Morphine
Marshall Gates, Gilg Tschudi
J. Am. Chem. Soc. 1956, 78 (7), pp 1380–1393



Abstract
The completion of the first synthesis of morphine is described.



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Determination of radioactive-labeled codeine, morphine, dihydromorphine, and their metabolites in biological materials
S. Y. Yeh, L. A. Woods
Journal of Pharmaceutical Sciences Volume 59(3), 1969 pp.380-384



Abstract
Recoveries of 14C-labeled morphine from aqueous solutions containing 1 to 500 ng. of drug (containing no ammonium ions) by extraction with three volumes of ethylene chloride containing 10, 20, or 30% of n-amyl alcohol were 82.9, 91, and 96%, respectively. Dihydromorphine was 79.1% extracted by ethylene chloride containing 30% n-amyl alcohol, and codeine, 97%, with all the above mentioned solvent mixtures. Complete hydrolysis of conjugated metabolites of morphine, codeine, or dihydromorphine was achieved by autoclaving samples in a portable autoclave at 18-20 lb. pressure for 2 hr. in a solution of 1.1 N HCl, or for 1 hr. in 2.2 N HCl, or 0.5 hr. in 3.3 N HCl. The conjugated metabolites were also completely hydrolyzed by treatment in a steam-jacketed autoclave at 20 lb. pressure for 0.5 hr. in 2.2 N HCl or 1 hr. in 1.1 N HCl. A procedure is described for the estimation of codeine and its metabolites, including morphine, in the same samples.




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An improved method for O-demethylation of codeine
J. A. Lawson, J. I. DeGraw
J. Med. Chem. 1977, 20 (1), pp 165–166



Abstract
The O-demethylation of codeine was effected by sodium propylmercaptide in dimethylformamide at 125'C to afford morphine in 80% yield. Similar treatment of thebaine was unrewarding.

Synthesis and biological evaluation of 14-alkoxymorphinans. 1. Highly potent opioid agonists in the series of (-)-14-methoxy-N-methylmorphinan-6-ones
Helmut Schmidhammer, Lislott Aeppli, Louise Atwell, Florian Fritsch, Arthur E. Jacobson, Michaela Nebuchla, Guenther Sperk
J. Med. Chem. 1984, 27 (12), pp 1575–1579


Abstract
A series of eight (-)-14-methoxymorphinan-6-ones were synthesized and biologically evaluated. The morphinones 3-7 were prepared from 3-desoxy-7,8-dihydro-14-hydroxymorphinone (1). The key step in this synthetic sequence, O-methylation in positon 14, was accomplished with dimethyl sulfate. Hydrolysis followed by reductive opening of the 4,5-oxygen bridge afforded the phenol 4, which was O-methylated to give 5. Removal of the 4-OH group yielded the aromatic unsubstituted morphinan 7. The synthesis of 9 and 10 was accomplished by starting from 14-methoxy-7,8-dihydrocodeinone and involved a similar reaction sequence. The compounds 12-15 were synthesized from oxymorphone (11) which was 3-O-benzylated, 6,14-bis-O-methylated with dimethyl sulfate, hydrolyzed, and hydrogenated to yield the oxymorphone 14-O-methyl ether 15. The derivatives 3, 4, 5, 7, 9, 10, 14 and 15 exhibited high antinociceptive potency in the hot-plate assay in mice, after both subcutaneous and oral administration. The most potent derivative in this series (15) show a potency (sc) about 400 times higher than that of morphine and about 40 times higher than its 14-OH analogue oxymorphone (11). The 14-OCH₃ series also exhibited a considerably higher affinity to opiod receptors in binding studies using [³H]naloxone as ligand when compared to their 14-OH analogues.



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Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 18.1 N-Substituted 14-Phenylpropyloxymorphinan-6-ones with Unanticipated Agonist Properties:  Extending the Scope of Common Structure?Activity Relationships
Elisabeth Greiner, Mariana Spetea, Roland Krassnig, Falko Schüllner, Mario Aceto, Louis S. Harris, John R. Traynor, James H. Woods, Andrew Coop, and Helmut Schmidhammer
J. Med. Chem. 2003, 46 (9), pp 1758–1763



Abstract
The synthesis, biological, and pharmacological evaluations of 14?-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14?-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (?, ?, ?), with the N-propyl derivative 19 displaying the highest affinity for the ?-receptor (Ki = 0.09 nM).




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Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 21.1 Novel 4-Alkoxy and 14-Phenylpropoxy Derivatives of the ? Opioid Receptor Antagonist Cyprodime
Mariana Spetea, Falko Schüllner, Radu C. Moisa, Ilona P. Berzetei-Gurske, Barbara Schraml, Cynthia Dörfler, Mario D. Aceto, Louis S. Harris, Andrew Coop, and Helmut Schmidhammer
J. Med. Chem. 2004, 47 (12), pp 3242–3247



Abstract
The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at ?, ?, and ? opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the ? opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase ? affinity in the case of benzyloxy, while a phenylpropoxy group reduces ? affinity. The ? and ? affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the ? opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at ? and ? receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [35S]GTP?S binding assay, all tested compounds were partial agonists at ? and ? receptors. Compounds 8 and 17 showed antagonism at ? receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.




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Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 20.1 14-Phenylpropoxymetopon:  An Extremely Powerful Analgesic
Johannes Schütz, Mariana Spetea, Martin Koch, Mario D. Aceto, Louis S. Harris, Andrew Coop, and Helmut Schmidhammer
J. Med. Chem. 2003, 46 (19), pp 4182–4187



Abstract
The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors (?, ?, ?), with 14-phenylpropoxymetopon (PPOM; 7) displaying the highest affinity for all three opioid receptor types. The most striking finding of this study is that the derivatives from the novel series of N-methyl-14-phenylpropoxymorphinans acted as extremely powerful antinociceptives with potencies higher than that of 14-methoxymetopon (1) and even etorphine. 14-Phenylpropoxymetopon (PPOM; 7) showed considerably increased potency in the in vivo assays in mice (25-fold in the tail-flick assay, 10-fold in the hot-plate assay, and 2.5-fold in the paraphenylquinone writhing test) when compared to etorphine, while it was equipotent to dihydroetorphine in the hot-plate assay and the paraphenylquinone writhing test and ca. twice as potent in the tail-flick assay than this reference compound. The 3-O-alkyl ethers of PPOM, compounds 6 and 8, showed less potency in in vivo assays, but partly surpassed the potency of the 3-OH analogue 14-methoxymetopon (1).


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14?-O-Cinnamoylnaltrexone and Related Dihydrocodeinones are Mu Opioid Receptor Partial Agonists with Predominant Antagonist Activity
H. Moynihan, A. R. Jales, B. M. Greedy, D. Rennison, J. H. Broadbear, L. Purington, J. R. Traynor, J. H. Woods, J. W. Lewis and S. M. Husbands
J. Med. Chem, 2009, 52 (6), pp 1553–1557




Abstract
14-O-Cinnamoyl esters of naltrexone (6) were synthesized and evaluated in isolated tissue assays in vitro and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor (MOR) antagonism, but the unsubstituted cinnamoyl derivative (6a) had partial MOR agonist activity in vitro and in vivo. When compared to the equivalent 14-cinnamoylaminomorphinones (5), the cinnamoyloxy morphinones (6) as MOR antagonists had a shorter duration of action and were less effective as pseudoirreversible antagonists. The antinociceptive activity of the cinnamoyloxycodeinones (7) was not significantly greater than that of the morphinones (6), but they exhibited no evidence of any pseudoirreversible MOR antagonism. In both respects, these profiles differed from those of the equivalent 14-cinnamoylaminocodeinones[/color]

Friedel-Crafts acylation with N-(trifluoroacetyl)-.alpha.-amino acid chlorides. Application to the preparation of .beta.-arylalkylamines and 3-substituted 1,2,3,4-tetrahydroisoquinolines
J. Eric Nordlander, Mark J. Payne, F. George Njoroge, Michael A. Balk, George D. Laikos, Vasanth M. Vishwanath
J. Org. Chem. 1984, 49 (22), pp 4107–4111


Abstract
Several N-(trifluoroacetyl)-a-amino acid chlorides have been reacted with benzene, anisole, and veratrole in the presence of AlCl3 or SnCl4 to produce the corresponding aromatic ketones in fair to high yields. The products are reducible under neutral or acidic conditions to the corresponding N-(trifluoroacetyl)-B-hydroxy-B-arylalkylamines or N-(trifluoroacetyl)-B-arylalkylamines. The latter can be readily detrifluoroacetylated by mild basic hydrolysis and thence converted to the corresponding 3-substituted 1,2,3,4-tetrahydroisoquinolines by condensation with formaldehyde.

Amines Related to 2,5-Dimethoxyphenethylamine. I
Richard Baltzly and Johannes S. Buck
J. Am. Chem. Soc. 1940, 62 (1), pp 161–164


Abstract
Preliminary pharmacological work has indicated that some amines containing the 2,5-dimethoxy-phenyl group show activity comparable with that of similar phenolic amines, and also that they probably will be active orally. It therefore became important to prepare, for pharmacological examination, as complete a series as possible of amines (as hydrochlorides) containing the 2,5-dimethoxyphenethyl grouping, the optimal C-C-N side chain being present in all cases.

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Amines Related to 2,5-Dimethoxyphenethylamine.II
Richard Baltzly and Johannes S. Buck
J. Am. Chem. Soc. 1940, 62 (1), pp 164–167



Abstract
The work described below is a continuation and completion of that described in Part I. The amines have the same structure as in the previous work but possess, in addition, a B-hydroxy group. As before, the primary, secondary, tertiary, and quaternary compounds were made. The primary amines have the formulas (structure diagram ommitted)


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Amines Related to 2,5-Dimethoxyphenethylamine. III. 2-Hydroxy and 2-Methoxy-5-methylphenylakanolamines
Alan E. Ardis, Richard Baltzly and William Schoen
J. Am. Chem. Soc. 1946, 68 (4), pp 591–595



Abstract
Pharmacological studies of the substances reported in the earlier papers of this series having shown that considerable value as pressors is exhibited by the primary and secondary B-hydroxy-B-(2,5-dimethoxy)-phenethyl and phenisopropylamines, it was of interest to compare these with the analogous susbtances in which the 5-methoxyl group was exchanged for a methyl group. At the same time the preparation of 2-hydroxy-5-methyl analogs by using the benzyl group for protection proved to be feasible although offering some experimental difficulties in the earlier part of the work.



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Amines Related to 2,5-Dimethoxyphenethylamine. IV. 2,5-Diethoxy, 2-Hydroxy-5-methoxy and 2-Hydroxy-5-ethoxyphenylalkanolamines
Walter S. Ide and Richard Baltzly
J. Am. Chem. Soc. 1948, 70 (3), pp 1084–1087



Abstract
In continuation of our studies on this interesting family of pressors, we report the preparation of the primary and secondary B-hydroxy-B-(2,5-diethoxyphenyl)-ethylamines and isopropylamines, and their analogues having hydroxyl groups in the 2-position with methoxyl or ethoxyl groups in the 5-position.



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Amines Related to 2,5-Dimethoxyphenethylamine. V. 2,5-Dihydroxy and 2-Methoxy-5-hydroxy Derivatives
Richard Baltzly, Johannes S Buck and Walter S. Ide
J. Am. Chem. Soc. 1950, 72 (1), pp 382–384


Abstract
Interest in the 2,5-dialkoxylated type of pressor was first aroused by the study of the properties of 2,5-dimethoxyphenethylmethylamine. This substance was at that time unique as being the only ring-alkoxylated pressor of considerable potency. It was also unusual as possessing considerable activity when given orally. Whereas ordinarily the hydroxy pressors are far more potent than their ethers, 2,5-dihydroxyphenethylmethylamine was of about the same potency as its dimethyl ether and its action was shorter.


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The Reactions of a-Bromo Ketones with Primary Amines
Calvin L. Stevens, Peter Blumbergs and Morton Munk
J. Org. Chem. 1963, 28 (2), pp 331–336


Abstract
The conversion of a-bromoisobutyrophenone to the corresponding a-hydroxyimines, I, II, and III has been effected in high yield by dissolution in liquid ammonia, methylamine and ethylamine, respectively. Evidence is cited to support the intramolecular nature of the oxygen migration in the transformation which suggests a reaction path proceeding via an epoxyamine (IX) as an intermediate. Apparent anomolous pathways are observed in the reaction of a-bromopropiophenone and 6-bromo-2,2,6-trimethylcyclohexanone with liquid methylamine to yield 1-phenyl-1-methylaminoacetone and 6-methylamino-2,2,6-trimethylcyclohexanone, respectively.

If Issue 9 could be downloaded as a whole, I would appreciate it.

http://www.bentham.org/ctmc/contabs/ctmc5-9.htm

NOTE.please color your whole post blue, request here. when requesting....once filled it will be deleted...this way we can tell easily what has been and what is needed.....java



The Treatment of Simple Aliphatic Amines with Nitrous Acid
Frank C. Whitmore, R. S. Thorpe
J. Am. Chem. Soc., 1941, 63 (4), pp 1118–1120



Abstract
It might be assumed that low molecular weight primary aliphatic amines would react easily with nitrous acid to form primary alcohols with liberation of nitrous oxide according to the equation:

RNH2 + HNO2 ==> ROH + N2 + H2O

This reaction takes place with n-butylamine to the extent of 25%. However, very little study has been made of the reaction of the simple amines with nitrous acid. The purpose of the present work was to study the effect of nitrous acid on methylamine, ethylamine and n-propylamine under conditions similar to those used in the succesful reaction of nitrous acid with n-butylamine.



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Notes- A Synthesis of 1-p-Methoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
Shigehiko Sugasawa, Ryuji Tachikawa
J. Org. Chem. 1959, 24 (12), pp 2043–2044






Abstract
1-Substituted 3,4,5,8-tetrahydroisoquinolines are precursors of 1,2,3,4,5,6,7,8-octahydroisoquinolines, which, when suitably substituted in the 1-position, form key intermediates for the synthesis of morphinans. Bischler-Napieralski cyclization of N-acyl-2-(1,4-cyclohexadienyl)-ethylamine to yield 1-substituted 3,4,5,8-tetrahydroisoquinolines has been described by the present authors

Practical demethylation of aryl methyl ethers using an odorless thiol reagent
Junghyun Chae
Pharmaceutical Society of KoreaVolume 31(3), 2008, pp.305-309




Abstract
A highly practical method for demethylation of aryl methyl ethers employing a long-chain thiol has been developed. Under the conditions described herein, clean and fast conversions to the desired phenolic compounds have been achieved with a broad range of substrates. Unlike other thiolate-mediated methods, this newly developed protocol features in-situ generation of sodium alkylthiolate using NaOH, and is almost free from foul smells and potentially harmful gases. It therefore provides an attractive option for the demethylation of aryl methyl ethers.

Structural determinants for high 5-HT2A receptor affinity of spiro[9,10-dihydroanthracene]-9,3?-pyrrolidine (SpAMDA)
Srinivas Peddia, Bryan L Rothb, Richard A Glennona and Richard B Westkaemper
Bioorganic & Medicinal Chemistry LettersVolume 14, Issue 9, 3 May 2004, Pages 2279-2283



Abstract
The synthesis and 5-HT2A receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3?-pyrrolidine (4), a structurally unique tetracyclic 5-HT2A receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT2A receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT2A receptor affinities. In addition, the parent compound is shown to have high 5-HT2 receptor selectivity.



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Spiro[9,10-dihydroanthracene]-9,3?-pyrrolidine—a structurally unique tetracyclic 5-HT2A receptor antagonist
Srinivas Peddia, Bryan L. Rothb, Richard A. Glennona and Richard B. Westkaemper
European Journal of Pharmacology Volume 482, Issues 1-3, 15 December 2003, Pages 335-337




Abstract
Structural elaboration of phenylethylamine to spiro[9,10-dihydroanthracene]-9,3?-pyrrolidine (SpAMDA) produces an agent with unexpectedly high affinity (Ki=4 nM) at 5-HT2A receptors. It was shown that SpAMDA acts as a 5-HT2A receptor antagonist. The structure and molecular geometry of SpAMDA are not consistent with existing pharmacophore features, and a novel 5-HT2A antagonist pharmacophore model is proposed for the binding of aminomethyl-9,10-dihydroanthracene analogs. Thus, SpAMDA may be a structurally novel parent of a new class of 5-HT2A receptor antagonists that binds to the receptor in a unique fashion that is distinct from the binding topology of existing 5-HT2A receptor antagonists.