Tropic acid

When heated with acids or alkalis, hyoscyamine undergoes hydrolysis into tropine and dZ-tropic acid probably via conversion into atropine, and it is this alkaloid which is hydrolysed. According to Gadamer, when hyoscyamine is hydrolysed with cold water the products are inactive tropine and Z-tropie acid. Amenomiya has shown that Ladenburg and Hundt s partially synthetic d- and Z-atropines were probably mixtures of atropine with d- and Z-hyoscyamines. He resolved dZ-tropic acid into the d- and Z- forms, esterified these with tropine in 5 per cent, hydrochloric acid, and so obtained d- and Z-hyoscyamines, the latter identical with the natural alkaloid, d- and Z-Hyoscyamines have also been obtained by Barroweliff and Tutin by the resolution of atropine by means of d-camphorsulphonic acid. 

Tropic Acid. The constitution of both tropic and atropic acids is known from syntheses by Ladenburg et al. from acetophenone. The ketone (I) by treatment with phosphorus pentachloride was converted into a-dichloroethylbenzene (II), and this, by the action of potassium cyanide in alcohol, into ethoxycyanoethylbenzene (III), which on hydrolysis yielded ethylatrolactic acid (TV). The latter was converted by strong... 

Other syntheses of tropic acid have been accomplished by Spiegel, Miiller, Wislicenus and Bilhiiber, Chambon and Natarajan and Swamina. ( > Of these, the most interesting is the reduction of ethyl formylphenylacetate (VIII) CHO. CHPh. COOC Hj in moist ethereal solution by aluminium amalgam to ethyl tropate, from which the acid (IX) HO. CHj. CHPh. COOH, is obtainable by hydrolysis with baryta. 

Mackenzie and Wood obtained low yields by this method, which is the basis of both the Muller and Wislicenus processes, and recommended instead the hydrolysis of acetophenonecyanohydrin (X) into atrolaetie acid (XI), conversion of the latter by distillation under reduced pressure into atropic acid (XII), which was then treated in ethereal solution with hydrochloric acid and the halogen in the resulting, 8-chlorohydratropie acid replaced by hydroxyl, by boiling the acid with aqueous sodium carbonate solution, giving tropic acid (XIII), thus ... 

Tropic acid crystallises in prisms and melts at 117°. It contains an asymmetric carbon atom and can be resolved into d- and Z-forms, which, according to King, melt at 128-9°, and have [ajj, + 81-6° and — 81-2° (HjO) respectively. 

This synthetic tropidine was converted into bromodihydrotropidine by hydrogen bromide in aeetie aeid, and the solution heated with 10 per cent, sulphurie acid at 200-10°, when it passed into -tropine,and, sinee this may be partially converted into tropine by oxidation to tropinone and reduction of the latter by zinc dust and hydriodic acid, this series of reactions affords a complete synthesis of tropine and of the tropeines. Combining the formula given above for tropine with that of tropic acid, atropine and hyoscyamine are represented as follows ... 

When warmed with barium hydroxide, dilute alkalis or acids, hyoscin is hydrolysed, yielding tropic acid and a new base, CgHjsOjN, oscine o scopoline. Depending on the conditions of experiment, the tropic aci obtained may be either the pure Z-form or the partially racemised acid but the oscine obtained is invariably inactive. 

Homatropine (mandelyltropine) being a useful mydriatic it is surprising that of nine esters of mandelic acid tried, none showed mydriatic activity though three were local anaesthetics, two of them being described as good. Only one of the tropic acid esters tried showed local anaesthetic action and that was poor. ... 

Tritopine. See Laudanidine. Tropacocaine, 62, 64, 79, 100 pharmacological action, 106 Tropane, 87, 108 Tropane group alkaloids, 64, 776 pharmacological action, 105 Tropeines, 73, 79, 81 Tropehone, 80 Tropic acid, 72... 

The hyoscine system occurs alone in certain northern Duboisia myo-poroides, and forms scopine, -tropine, dihydroxytropane and, in Datura meieloides, teloidine. Of these amino-alcohols, all the scopine is esterified by tropic acid and the minor bases by tiglic, methylbutyric or isovaleric acid, which contain the isoprene skeleton and are presumed to arise from that source. 

The hyoscyamine system is found alone in some adult Duboisia Leichhardtii and possibly in some southern D. myoporoides. It produces tropine and nortropine only, which are esterified with tropic acid, or as in ajooatropine found in belladonna, with atropic acid, and to a small extent with the isoprene acids referred to above. Some tropine or nortropine may occur as such. Scopine, -tropine and dihydroxytropane are absent. 

Upon adding concentrated ammonia in excess, the condensation product separates and is taken up in chloroform. The chloroform solution is dried and distilled, the tropic acid N-ethyl-N-(7-picolyl)-amide being thereby obtained in the form of a thick oil, which crystallizes after prolonged time and which then melts at 96° to 97°C. 

A CSP based on the adsorption of a chiral anthrylamine on porous graphitic carbon successfully resolved the enantiomers of tropic acid derivatives and anti-inflammatory agents in SFC [65]. The carbon-based CSP produced superior results when compared to an analogous silica-based CSP. Occasional washing of the column was necessary to remove highly retained substances. 

Photographic fixer. Kodak tropical acid hardening-fixing bath F5 or equivalent. 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

Aiming at the feasibility study of such type of asymmetric decarboxylation, we screened microorganisms which are able to grow on the medium containing tropic acid as the sole source of carbon. It is expected that at least one of the major metabolic pathway of tropic acid is the oxidation of the hydroxyl group followed by decarboxylation and further oxidation of the resulting aldehyde (Fig. 20). If... 

Figure 20 Possible metabolic path of tropic acid.

Fortunately, some soil microorganisms were found to grow utilizing tropic acid as the sole source of carbon. Among them, a bacterium identified as Rhodococ-cus sp. was also active to the methyl derivative. The isolated product was R)-a-phenylproionate as shown in Fig. 20. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Several pathways are used for the aerobic degradation of aromatic compounds with an oxygenated C2 or C3 side chain. These include acetophenones and reduced compounds that may be oxidized to acetophenones, and compounds including tropic acid, styrene, and phenylethylamine that can be metabolized to phenylacetate, which has already been discussed. 

A strain of Pseudomonas sp. ATS degraded tropic acid, which has a -CH-(CH20H)-COjH side chain to phenylacetate (Long et al. 1997). 

Long MT, BA Bartholomew, Ml Smith, PW Trudgill, DJ Hopper (1997) Enzymology of oxidation of tropic acid to phenylacetic acid in metabolism of atropine by Pseudomonas sp. strain AT3. J Bacteriol 179 1044-1050. 

The (S)-tropic acid, the acid moiety found in hyoscyamine (27) and scopolamine (89), is formed from phenylalanine by an intramolecular 2,3-carbonyl shift (5,124). Feeding of the four possible stereoisomers of [l-14C,3-3H]phenylalanine to Datura innoxia and D. stramonium was used to prove that during the 2,3-carbonyl shift a 3,2-hydrogen shift takes place as well (725)(Scheme 23). With D. innoxia, the 2,3-carbonyl shift was shown to... 

Scheme 31. McLafferty rearrangement of tropic acid derivatives.

The fact that the EP wants to replace old TEC methods with more selective, efficient, and sensitive separation methods provides the chance for the introduction of more CE methods. The continuous development of analytical methods is reflected in the national and international pharmacopoeias. This might be demonstrated for atropine sulfate. Whereas the Deutsches Arzneibuch, 7th Edition (DAB 7) only limits the tropic acid by extraction and titration with NaOH and phenolphthalein indication, the 4th edition of the EP looked for foreign alkaloids and decomposition products by means of TEC with a potassium iodobismuthate for detection. By intensity comparison of the obtained spots, it was possible to limit these impurities to 0.5%. The EP 5 utilizes an ion-pair HPLC method that is able to limit most of the impurities to less than 0.2%. To make the method more robust, an HPLC method using a polar embedded was applied, which might be the next step for the EP. However, recently the same authors have reported on a MEEKC method being as robust and precise as the latter HPLC method (see Eigure 6) but far more sensitive and, therefore, a future perspective for the EP. 

The tropane alkaloids (—)-hyoscyamine and (—)-hyoscine are found in the toxic plants deadly nightshade (Atropa belladonna) and thornapple (Datura stramonium) and are widely used in medicine. Hyoscyamine, usually in the form of its racemate atropine, is used to dilate the pupil of the eye, and hyoscine is employed to control motion sickness. Both alkaloids are esters of (—)-tropic acid. 

---