Ephedrine synthesis

This whole-cell biotransformation is still a subject of research for several reasons Besides fhe desired product (1 )-PAC, several by-products are formed through enzymatic reduction of fhe product or fhe substrate benzaldehyde, resulting in the formation of l-phenylpropan-2,3-diol and benzylalcohol, respectively. Further byproducts are acetoin, butane-2,3-dione, l-phenyl-propane-2,3-dione, benzoic acid and 2-hydroxypropiophenone, leading to a reduced yield of the desired product and difficult product isolation. To circumvent fhis problem strain improvement and reaction engineering have been used [15, 16]. Application of an isolated enzyme in a two-phase system resulted in improved space-time yield and high product purity [17]. 

The problems encountered with the bakers yeast whole cell process may be overcome by the appUcation of isolated enzymes. Pohls group applied site-directed mutagenesis strategies to tailor PDC for fhe synfhesis of (P)-PAC. They 

Although the first industrial process using biocatalysts was estabhshed 70 years ago, based on enzymatic C-C bond formation, fhis type of catalysis has only recently been taken up for ofher transformations (cf. Section 4.2.7). 

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In 1925 Spath and Roller described a new ephedrine synthesis. a-Phenylpropylene was reacted with bromine to l-phenyl-l,2-dibromo-propane. One bromine was then substituted by methoxyl, the other by NH CHa. On hydrolysis with fuming hydrobromic acid, racemic -ephedrine was formed. (Compare also Spath and Bretschneider, 261.)... 

The ephedrine synthesis described by Manske and Johnson (74) and by Skita and Keil (77) in 1929 is founded on a different reaction. If a mixture of o -phenylpropane-a,/S-dione and methylamine, in absolute alcohol is hydrogenated catalytically in the presence of platinum oxide (Manske) or colloidal platinum (Skita), dl-ephedrine, with a little dJr -ephedrine is obtained. The reaction has been further elaborated by Coles, Manske, and Johnson (76), by Skita, Keil and coworkers (78, 79, 262, 263) and by Couturier (265). Manske and Johnson (75) synthesized some ephedrine homologs and resolved racemic ephedrine by means of d-and f-mandelic acid. The pure I form of this acid is prepared easily with the aid of natural ephedrine, as confirmed by Jarowski and Hartung (268). 

Chloronaphthalene Hydrogen sulfide Tri-m-cresyl phosphate Tri-p-tolyl phosphate EPDM peroxide-cured modifier 1,2-Polybutadiene Vinyl butadiene ephedrine synthesis Ethyl phenyl ketone epilepsy management Boron... 

Microbiological conversions, microbiological iranrformaiions conversions of materials occurring in one or more stages, and catalysed by microorganisms. M.c. are the result of microbiological enzyme action, and often have no importance for the microbial cell. Several M.c. are important in the pharmaceutical industry. Examples are the stereospecific conversions of steroids, oxidation of sorbitol to sorbose by Acetobacter suboxydans (in the production of vitamin C), and the addition of acetaldehyde to benzalde-hyde by Saccharomyces cerevisiae. The product of this last reaction is phenylacetylcarbinol, a precursor for D-ephedrine synthesis. 

FIGURE 4.32 Ephedrine synthesis of phenyl-acetyl carbinol. 

The production of (i )-phenylacetyl carbinol by fermenting yeast was one of the first industrial biotransformations and continues to be used as a first step in L-ephedrine synthesis. 

The first product in the Spath and Gohring synthesis is d/-i/i-ephedrine, m.p. 118-9°, which was resolved, by crystallisation of the d-tartrate and Z-tartrate in succession, into Z- and [Pg.641]

A Cp2ZrCl2-catalyzed addition of Bu2AlH to terminal alkynes has been applied in the synthesis of (E)-vinyl phosphonates [84]. 1-Hexyne and 1-octyne were hydroalu-minated at 0°C and the resulting vinylalanes transformed into the respective alumi-nate complexes by treatment with methyllithium. Subsequent addition of oxaza-phospholidinone 79, derived from (-)-ephedrine, lead to the homochiral vinyl phosphonates in yields of ca. 75% (Scheme 2-23). 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Effenberger, F. and Eichhorn, J. (1997) Stereoselective synthesis of thienyl and furyl analogues of ephedrine. 

The asymmetric synthesis of 2-aryl(alkyl)-l,3,2-oxazaphospholidines 52 was based on the reaction of achiral organophosphonous diamides 51 with L-ephedrine (42) (Scheme 19) [44], The diastereomeric excess ranges from 0% (R=Ph) to 95%... 

Taapken, T. and Biechert, S., Stereoselective synthesis of homochiral (E)-vinyl phosphonates derived from (-)-ephedrine, Tetrahedron Lett., 36, 6659, 1995. 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Starting from the Pt-cinchona modified system, more recently an interesting concept has been developed by Feast and coworkers [144], A chiral acidic zeolite was created by loading one molecule of iM,3-dithianc-l-oxide per supercage of zeolite Y, either during or after the zeolite synthesis. Other chiral zeolites were formed by adsorbing ephedrine as a modifier on zeolites X and Y for the Norrish-Yang reaction [145],... 

Despite the high sensitivity of the methods for chiral resolution described in Section IV.D.4, more direct methods are afforded by NMR spectroscopy, especially for the products of synthesis. Ephedrine (179), pseudoephedrine (180a) and its Me ether (180b) yield stable epimeric N — BH3 adducts on treatment with borane. The configuration of the nitrogen moiety was established by NMR, taking into account the conformational analysis of the molecule392. 

The effect of temperature on the reduction of nitro-alkanes has been extensively exploited in the synthesis of cp-ephedrine analogues [i5,21,22] starting from 1-aryl-2-nitropropenes which are easily converted to the substrates 2. Reduction of these nitrocompounds below 20° C affords the hydroxylamine. The amine is formed above 55° C. Neutralisation of either reaction mixture causes rapid intramolecular migration of the acetyl group from oxygen to nitrogen, a reaction which implies a... 

In the alkaloid synthesis, L-phenylalanine (Figure 30) provides to alkaloid the phenyl or phenylpropyl nucleus. These kinds of nuclei occur in cathionine, cathine, ephedrine, pseudoephedrine and norpseudoephedrine. Such alkaloids are found especially in many species of Ephedra. Natural alkaloid molecules from these plants have similar properties to synthetic compounds used as narcotics (e.g., amphetamine). 

Ephedrine is the main alkaloid produced in the roots of Ephedra sinica, preparations of which have found medical application in China for at least 5000 years. It was first purified from its natural source in 1887, and its chemical synthesis was achieved in 1927. It was initially used in cardiovascular medicine, but subsequently found wider application in the treatment of mild hayfever and asthma. It is also used as a nasal decongestant and cough suppressant. 

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