Atropine resolution

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. 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

The effect of various mobile-phase modifiers on a is the result of a highly complex relationship involving the structure of the solute, as well as the structure and type of modifier, and may also involve changes in the conformation of the AGP (95). The complexity of this relationship is illustrated by the effect of various modifiers on the chiral resolution of two closely related compounds, atropine and N-methylhomatropine (Fig. 13). 

Figure 13 The effect of mobile-phase modifiers on the enantioselective resolution of atropine, methylatropine, and N-methylhomatropine.

Atropine (XXVIII) had already been prepared from ( + )-acetyltropoyl chloride and tropine (40) followed by resolution (41), using n-camphor-sulfonic acid, to obtain first the salt of dextrorotatory hyoscyamine. Recently dibenzoyltartaric acid was claimed to precipitate the salt of the ( —)-antimer first (42). Direct synthesis of hyoscyamine (XXVIII) was realized by melting S-( — )-acetyltropoyl chloride (XXXV), obtained for the first time in crystalline form, with tropine hydrochloride (XXXVI), followed by acid deacetylation of acetylhyoscyamine (XXXVII)... 

Barrowcliff, M. Tutin, F. The Configuration of Tropine and Pseudo-Tropine, and the Resolution of Atropine Journal of the Chemical Society (1909) 1966-1977... 

Since hyoscyamine is the levorotatory enantiomorph of atropine, it can therefore, be obtained by the resolution of atropine (22). 

Once atropinization had been accomplished in Dr Foroutan s Chemical Emergency Unit, casualties were evacuated to a recovery unit 100 km behind the front lines. There, he recommended that the atropine dose be reduced to a few milligrams per day, and that atropine 1 to 2 mg every 4 to 6 h be given for up to two days after the resolution of all clinical symptoms, with the dose only to be increased if bradycardia developed. 

Meteloidine (C13H21O4N) (203), occurs to the extent of 0.07% along with 1-scopolamine and atropine in Datura meteloides. This alkaloid is optically inactive and resisted all attempts at resolution (212). It is a tiglyl ester of an alkamine, teloidine, and its saponification (Ba(OH)j) may be conveniently expressed as follows ... 

D. Intermediate syndrome. Patients may develop proximal muscle weakness over a few days even after resolution of the acute cholinergic crisis. This is often first not as neck weakness, progressing to proximal limb weakness and cranial nerve palsies. Respiratory muscle weakness and respiratory arrest may occur abmptly. The intennediate syndrome is probably caused by prolonged overstimulation of the neuromuscular junction, and may be associated with inadequate oxime therapy. Atropine is not effective. 

Bhushan and Ali [25] were the first to propose the use of silica gel G layers coated with acidic L-amino acids for the resolution of racemic alkaloids such as hyoscyamine (or atropine) and colchicine. Preparation of the plates, chromatographic development, and solute detection were performed as reported previously. The slurry of silica gel G was prepared in 100 ml of water containing 0.3 g of L-aspartic acid and chromatograms were developed at 0°C for 3.5 h. Migration distance was 10 cm eluting with n-butanol/chloroform/acetic acid/water (3 6 4 1, v/v/v/v). The extremely low temperature necessary for the enantiomeric separation should be noted as no resolution was observed at 5°C. Based on the results obtained (see Table 5.9), layers impregnated with this chiral selector were suitable for the resolution of the two racemates and particularly of atropine a = 1.86). 

Resolution of racemic atropine (a = 1.88 andi s = 1-5) was observed on layers of silica gel G coated with 0.5% L-histidine solution, where pi is much lower (7.6) than those of the basic amino acids mentioned previously. This allowed to adopting pH of the slurry included between 7 and 8, so as to ensure the presence of anionic histidine and cationic atropine. Acetonitrile/methanol/water mixture (11.3 5.4 0.6, v/v/v) was used as an eluent. The best resolution of atropine enantiomers was observed at 18" C [16]. 

Bhnshan, R., Martens, J. and Arora, M., Direct resolution of (-l-)-ephedrine and atropine into their enantiomers by impregnated TLC, Biomed. Chromatogr., 15, 151-154,2001. 

---