Ephedrine chemistry

Chiral modifiers were screened in the zinc chemistry. Once again, in the case of aniline ketone 36, chichona alkaloids, binaphthol, and tartaric acid derivatives gave very poor selectivity and ephedrine derivatives provided good selectivity. The results are summarized in Table 1.8. 

Study of organic chemistry. Pioneer of pharmaceutical science of Japan. Discoverer of ephedrine... 

The little black bag of physicians did not have a whole lot of useful medicines in 1900. The role of the physician at that time was diagnosis and prognosis far more than therapy. Nonetheless, some progress in chemistry in the service of human health had been made. Quinine, morphine, salicylic acid, digitalis, antipyrine, and ephedrine were known in 1900, though their utility, and their liabilities, in treatment of human disease was not fully appreciated. ... 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

EXTENSIONS AND COMMENT ARY Here is another example of the presentation of a compound for which there has not yet been an effective level determined. Why For a very good reason. This is an example of a whole class of compounds that I have called the pseudos, or the -compounds. Pseudo- as a prefix in the literary world generally stands for false. A pseudopod is a thing that looks like a foot, but isn t one. A pseudonym is a fictitious name. But in chemistry, it has quite a different meaning. If something has a common name, and there is a second form (or isomer, or shape, or orientation) that is possible and it doesn t have a common name, it can be given the name of the first form with a pseudo- attached. Ephedrine is the erythro-isomer of N-methyl-13-hydroxyamphetamine. There is a second stereoisomer, the threo- isomer, but it has no trivial name. So it is called pseudoephedrine, or the Sudafed of sinus decongestant fame. 

Chiral [160, l70, l80]phosphomonoesters and ATPy[l60, l70, lsO] have been synthesized by Knowles and associates, who devised the procedure outlined in Fig. 19 [51-55], The procedure has been used to synthesize phenyl[160, l70, l80]phos-phate and 2-[160,170,180]phospho-D-glycerate as well as the propylene glycol ester shown. The starting cyclic adduct was prepared by reaction of (— )-ephedrine with P17OCl3, giving a separable mixture of 2-chloro-l,3,2-oxazaphospholidin-2-ones whose chemistry had been described [56], The major isomer was converted to (/ p)-l-[160, nO,180]phospho-1,2-propanediol and (Sp)-ATPy[l60, nO, lsO] by the reactions shown. The stereochemistry at each step of the synthesis was well prece-dented in the literature nevertheless, the configurations were verified by independent methods described in the next section. 

In addition to the R and S designations, compounds with two chiral centers may also be identified by stereochemical nomenclature that describes the entire system. For example, the erythro and threo nomenclature derived from carbohydrate chemistry may be employed to describe the relative positions of similar groups on each chiral carbon. Thus, the ephedrines are designated as erythro forms since the similar groups (OH and NHCH3) are on the same side of the vertical axis of the Fischer projection, and the pseudo-ephedrines are designated as threo forms since like groups are on opposite sites of the vertical axis of the projection (Fig. 10). 

The chemistry and nomenclature of these compounds are somewhat confusing, and are best understood by reference to the synthetic route used by plants to make ephedrine. All ephedra plants contain phenylalanine-derived alkaloids. Plants use phenylalanine as a precursor, but incorporate only seven of its carbon atoms. Phenylalanine is metabolized to benzoic acid, which is then acetylated and decarboxylated to form pyruvic acid. Transamination, results in the formation of forms (-)-cathinone. 

The Joint Committee" of the Pharmaceutical Society and the Society for Analytical Chemistry recommended a gas chromatographic method for the determination of ephedrine in tablets, elixir and nasal drops, using phenmetrazine as an internal standard. Ephedrine was extracted... 

This method of making crank is based on the research of Gary Small and Arlene Minnella as published in the Journal of Organic Chemistry, Volume 40, pages 3151 to 3152 (1975). The article is titled "Lithium-Ammonia Reduction of Benzyl Alcohols to Aromatic Hydrocarbons. An Improved Procedure." It results in the 100% conversion of ephedrine, pseudoephedrine or PPA in a reaction time of 10 minutes or so. 

With the modernization of Japan, science and scientific literature made rapid progress a considerable number of distinguished Japanese chemists emerged, among them Nagai, the discoverer of ephedrine (1887). However, the war years 1941-45 proved detrimental to scientific progress in Japan and, with the end of hostilities, economic conditions during the occupation often interfered with academic or industrial research. Nonetheless, considerable scientific activity, particularly in chemistry, is revealed by... 

The chemistry of ephedrines is summarized in Figure 9-9. It will be noted that the four isomers generated by the two chiral centers (22) exist as two nonsuperimposable image pairs. The two ephedrines are enantiomers. Epimerization of the a-carbon produces the other pair—the -ephedrines. Each -ephedrine is an enantiomer of the other however,... 

Figure 9-9. Chemistry of the ephedrines. Sequence rule for configuration identification. cSpecific optical rotation.

The Baeyer-Villiger oxidation of a meso-diketone was recently reported by Gonzalo and co-workers using isolated PAMO.48 Again, GDH was used as the reducing agent for NADP+. For the reaction of dione 82, conversion to 83 was 88% after 1.5 h. The authors suggested the utility of such chemistry would be to prepare ephedrine and pseudoephedrine. 

As these alkaloids are not only used in chemistry as chiral auxiliaries, starting materials, and catalysts, but also in medicine, so technical syntheses have been developed and all of these compounds are commercially available. The standard materials ( )-(l/ ,2,S )-ephedrine [(-)-3) and ( —)-(lff,25,)-norephedrine [(-)- ] are produced in a technical process on multikilogram scale by reductive amination (with methylamine or ammonia, respectively) of (—)-(f )-l -hydroxy- Tphenyl-2-acetone with a platinum catalyst1. The ketone is in turn obtained by a biotechnological procedure from cultures of selected yeast strains (Saccharomyces sp.)2. 

A revolutionary renewal of the interest on ephedrine started in 1924 with the publication of the papers of Chen and Schmidt on Ma Huang (82-86). They worked on the drug without knowledge of previous work, and recorded the similarity of the physiological action of ephedrine and adrenaline. Since then an enormous volume of literature has accumulated on the chemistry and pharmacology of ephedrine and related natural alkaloids and synthetic compounds. 

Historical The term A. was introduced by the apothecary C. F. W. Meissner in 1819 for alkali-like plant substances. The development of A. chemistry is illustrated by some dates and names morphine (1803 or 1816 Sertiimer), strychnine (1818 Pelletier and Caven-tou), solanine (1820 Desfosses), caffeine (1820 Runge), quinine (1820 Pelletier and Caventou), nicotine (1828 Posselt and Reimann), atropine (1831 Mein), codeine (1832 Robiquet), theobromine (1842 Woskresensky), cocaine (1860 Wohler), ephedrine (1887 Nagai), scopolamine (1881 Ladenburg and 1888 E. Schmidt), mescaline (1896 Heffter). The first A. synthesis was realized in 1886 by Ladenburg (coniine). In the 20th century A. chemistry is especially associated with the names Willstatter, Woodward, Schopf,... 

Ephedrine and pseudoephedrine (2-methylamino-l-phenylpropan-l-ol) are natural epimeric amino alcohols extracted from various species of the family of plants Ephedra. These plants have been used for millennia in China as stimulants and nasal decongestants. The structures of natural (—)-ephedrine and (+)-pseudoephedrine are depicted in Figure 3.3. The figure also shows norephedrine, which is the nitrogen-unsubstituted counterpart of ephedrine. These compounds are nowadays commercially available as inexpensive crystalline white solids and have been extensively used in phosphorus chemistry, as detailed in the next sections. 

The Juge-Stephan method and its variations reveal that ephedrine is an extraordinary chiral auxiliary in P-stereogenic chemistry, highlighted by the simplicity of its structure. In spite of this, there are no reasons to assume that other chiral amino alcohols or, more generally, other heterobifunctional chiral auxiliaries can not be equally good or even outperform ephedrine. In the literature, there are a few early reports on synthetic sequences resembling the Juge-Stephan method but with other auxiliaries, which are briefly described here. 

By the 19th century, organic chemistry had advanced to the stage of isolating the active principle from complex natural product extracts. Plant alkaloids such as morphine, quinine, and ephedrine were among the first to be obtained in crystalline form (Figure 2.1). Although their chemical constitution would continue to remain mysterious for some time, a crude extract was now replaceable by a pure compound. This marked a major milestone in medicinal chemistry, and we have made tremendous further strides since then. 

This phase saw continuous advances in chemistry and medicine. Organic chemistry was now capable of the synthesis of relatively complex targets by multistep sequences. The concept of systematically preparing a compound series and testing it for a biological effect became common, as exemplified in Ehrlich s quest for antisyphilitic agents. More and more pure natural products were identified and their structures elucidated. Synthetic mimics became a reahty. For example, amphetamines were inspired by the natnral prodnct lead, ephedrine. 

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