53230-10-7

Usage

Uses

Used in Pharmaceutical Industry:
Mefloquine is used as an antimalarial agent for treating and preventing chloroquine-resistant forms of malaria caused by P. falciparum. It is particularly effective against blood schizontosides P. vivax and P. falciparum.
Used in Travel Medicine:
Mefloquine is used as a prophylactic agent for short-term travelers to areas where malaria is prevalent. It helps protect against the risk of contracting malaria during their stay.
Used in Drug Metabolism Research:
Mefloquine is used in research to study the metabolism of drugs through CYP3A4 oxidation. Its metabolism to its major inactive metabolite, carboxymefloquine, can be influenced by the coadministration of CYP3A4 inhibitors, such as ketoconazole.
Chemical Properties:
Mefloquine is an off-white solid and is available under the brand name Lariam (Roche).

Pharmacology and mechanism of action

Mefloquine is a quinolinemethanol derivative which is structurally related to quinine. It was synthesized and tested by the United States army in the 1960s. The available mefloquine preparation is a racemate with two enantiomers in equal proportions [1]. It was introduced for the treatment of multiresistant P. falciparum in the mid-1980s [2]. In Africa, there are only occasional reports of therapeutic failures, but there has been a rapid development of resistance in the 1990s in parts of Southeast Asia, particularly in Thailand [3]. Cross-resistance with quinine and halofantrine has also been reported [4, 5]. The mechanism of action is not well established. Mefloquine is a schizontocidal drug active against the erythrocytic stages of all species of malaria parasites. It is inactive against exoerythrocytic forms and thus cannot prevent relapse of P. vivax and P. ovale infections [6].

Indications

Treatment and prophylaxis against chloroquine resistant P. falciparum malaria.

Indications

Mefloquine (Lariam) is a 4-quinolinemethanol derivative used both prophylactically and acutely against resistant P. falciparum malaria. It is ineffective against the liver stage of P. vivax malaria. While its detailed mechanism of action is unknown, it is an effective blood schizonticide; that is, it acts against the form of the parasite responsible for clinical symptoms. Orally administered mefloquine is well absorbed and has an absorption half-life of about 2 hours; the elimination half-life is 2 to 3 weeks. Among its side effects are vertigo, visual alterations, vomiting, and such CNS disturbances as psychosis, hallucinations, confusion, anxiety, and depression. It should not be used concurrently with compounds known to alter cardiac conduction or prophylactically in patients operating dangerous machinery. It should not used to treat severe malaria, as there is no intravenous formulation.

Contraindications

There is little experience in children under 2 years, and mefloquine is therefore not recommended in this group unless other alternatives are ineffective . Mefloquine should not be used by persons involved in activities requiring fine co-ordination and spatial performance such as air crews or by persons with a history of epilepsy or psychiatric disorders . People taking cardioactive drugs like digoxin, quinidine, beta-blockers, or calcium channel blockers should avoid mefloquine . Those on mefloquine prophylaxis or given mefloquine treatment should only be given quinine under close medical supervision because of the risk of additive neurological and cardiological toxicity [3].

Side effects

The severity and frequency of side effects during treatment are dose-related. In early clinical trials (a total of 436 patients), the most frequent adverse reactions were nausea (18%), diarrhoea (15%), dizziness (15%), vomiting (13%), sinus bradycardia (9%), abdominal pain (8%), skin itching or rash (1%) and behaviour disorders with paranoid ideas and hallucinations (1%) [7]. Early vomiting within 1 hour after drug administration reduced the mefloquine concentrations in patients with P. falciparum malaria. This indicates that vomiting within 1 hour requires a repeated dose [8]. The most important side effects of mefloquine are neuropsychiatric reactions. In 7 volunteers given 15 mg mefloquine/kg, all experienced some neurological symptoms (concentration difficulties, dizziness, vertigo) within 6 hours after administration of the drug [9]. Serious neuropsychiatric adverse reactions, in particular general convulsions, confusion, and hallucinations, have been reported after therapeutic use of mefloquine [10,11]. The incidence may be as high as 1% and the onset usually occurs within 4 days of intake [12]. Neurological and psychiatric reactions seem to be dose-dependent . All neuropsychiatric reactions are reversible once the drug administration is discontinued. No fatalities have been reported [13]. Less frequent adverse effects mainly associated with curative doses are anorexia, asthenia, irregular heart rate, pulse irregularities, constipation, insomnia, diarrhoea, arthralgia, and hearing disturbances [14]. Single case reports of Stevens-Johnson syndrome, severe facial rash, and agranulocytosis have been filed [15]. During prophylaxis, the frequency of reported symptoms among 2780 travellers using mefloquine was similar to that of chloroquine and only one possible serious reaction (depression) was reported [16]. In 1991, the recommended prophylactic dose of mefloquine for adults was increased to 250 mg once weekly during the whole period. The experience with this dose is still limited, but it was well tolerated in a trial in US peace corps volunteers in West Africa [17]. There are no large, double-blind, prospective, randomized studies that compare the risk for adverse reactions between different antimalarial drugs used for prophylaxis. Large retrospective studies in US Peace Corps volunteers and European travellers found no major difference in the incidence of side effects in mefloquine compared to chloroquine users . Until May 1991, a total of 59 serious neuropsychiatric adverse reactions (26 convulsions, 12 depressions, 20 psychotic episodes, and one toxic encephalopathy) have been reported to Roche after prophylaxis The majority (80%) of all neuropsychiatric reactions appeared within 3 weeks of onset of prophylaxis[18]. In Germany, the risk of moderate to severe neuropsychiatric reactions during prophylaxis was calculated to be one in 13,000 users [19].

Side effects

At prophylactic doses risks of serious toxicity are about 1 in 10 000, similar to chloroquine. Doses used in therapy are more commonly associated with nausea, dizziness, fatigue, mental confusion and sleep loss. Psychosis, encephalopathy and convulsions are seen in about 1 in 1200–1700 patients. Mefloquine(+), the enantiomer with potential lower toxicity, is currently in development.

Preparations

Available as mefloquine hydrochloride: 274 mg hydrochloride is equal to 250 mg base. ? Lariam? (Roche) (or Laricum in some countries). Tablets 250 mg base (228 mg base in the US). ? Mephaquin? (Mepha). Tablets 250 mg base.

References

1. Sweeney T (1981). The present status of malaria chemotherapy: mefloquine, a novel antimalarial. Med Res Rev, 1, 281–301. 2. Practical Chemotherapy of Malaria. Technical report series No. 805 (1990). (Geneva: World Health Organization). 3. International Travel and Health (1994). (Geneva: World Health Organization). 4. Rojas-Rivero L, Gay F, Bustos MDG, Ciceron L, Pichet C, Danis M, Gentilini M (1992). Mefloquine-halofantrine cross-resistance in Plasmodium falciparum induced by intermittant mefloquine pressure. Am J Trop Med Hyg, 47, 372–377. 5. Brasseur P, Kouamouo J, Druilhe P (1991). Mefloquine-resistant malaria induced by inappropriate quinine regimens. J Infect Dis, 164, 625–626. 6. Black RH, Canfield CJ, Clyde DF, Peters W, Wernsdorfer WH (1986). Mefloquine. In: Chemotherapy of Malaria, 2nd edn, edited by L.Bruce-Chwatt. (Geneva: World Health Organization 1986). 7. Advances in Malaria Chemotherapy. Technical Report Series No. 711 (1984). (Geneva: World Health Organization). 8. Karbwang J, Na Bangchang K, Bunnag D, Harinasuta T (1991). Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute falciparum malaria. Bull World Health Organ, 69, 207–212. 9. Patchen LC, Campell CC, Williams SB (1989). Neurological reactions after a therapeutic dose of mefloquine. N Engl J Med, 321, 1415. 10. Rouveix B, Bricaire F, Michon C, Franssen G, Le Bras J, Bernard J, Ajana F, Vienne JL (1989). Mefloquine and an acute brain syndrome. Ann Intern Med, 110, 577–578. 11. Stuvier PC, Ligthelm RJ, Goud Th JLM (1989). Acute psychosis after mefloquine. Lancet, ii, 282. 12. World Health Organization. Review of central nervous system adverse events related to antimalarial drug, mefloquine (1985–1990) (WHO/MAL911063). (Geneva: World Health Organization). 13. Bem JL, Kerr L, Stürchler D (1992). Mefloquine prophylaxis: an overview of spontaneous reports of severe psychiatric reactions and convulsions. J Trop Med Hyg, 95, 167–179. 14. Mefloquine. Therapeutic Drugs, edited by Sir Colin Dollery (1991) (London: Churchill Livingstone), pp. M35–M39. 15. Martindale: The Extra Pharmacopoeia, 30th edn, (1993) (London: Pharmaceutical Press), pp. 402–403. 16. Steffen R, Heusser R, M?chler R, Bruppacher R, Naef U, Chen D, Hofmann AM, Somaini B (1990). Malaria chemoprophylaxis among European tourists in tropical Africa: use, adverse reactions and efficacy. Bull World Health Organ, 68, 313–322. 17. Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC (1993). Long-term prophylaxis with weekly mefloquine. Lancet, 341, 848–851. 18. Stürchler D, Handschin J, Kaiser D, Kerr L, Mittelholzer M-L, Reber R, Fernex M (1990). Neuropsychiatrie side effects of mefloquine. N Engl J Med, 322, 1752–1753. 19. Weinke T, Trautmann M, Held T, Weber G, Eichenlaub D, Fleischer K, Kern W, Pohle HD (1991). Neuropsychiatrie side effects after the use of mefloquine. Am J Trop Med Hyg, 45, 86–91.

Originator

Lariam,Roche Pharmaceuticals,Switz.

Manufacturing Process

The first method of synthesis of 2,8-bis(trifluoromethyl)-4-quinolinyl-2- pyridinylmethanoneN-Methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4-carboxamide was prepared using synthetic methodology reported by Thiesen et al (J. Org. Chem. 1988, 53, 2374). To a suspension of 12.5 g (40.4 mmol) 2,8- bis(trifluoromethyl)quinoline-4-carboxylic acid (was prepared by the method of Hickmann et al. (U.S. Patent No. 4,327,215)) in 200 ml CH2Cl2 was added 1,1'-carbonyldiimidazole (7.3 g, 45 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.25 g, 45 mmol). The resulting deep red solution was stirred overnight, then poured into dilute hydrochloric acid (0.25 M, 200 ml). The organic phase was separated, and washed with dilute sodium hydroxide and brine, and dried (MgSO4). The solvents was evaporated to leave a viscous brown oil, which was filtered through a pad of silica gel using ethyl acetatehexane (1:1) as eluent to give N-methoxy-N-methyl-2,8-bis(trifluoromethyl)- quinoline-4-carboxamide as a yellowish oil, 14.3 g (98%), which solidified on standing. This material was broken up under hexane to afford the product as a solid, melting point 93-95°C. Analysis of this material by HPLC showed it to be >99.8% pure.To a solution of the N-methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4- carboxamide amide (10 g, 28.4 mmol) in anhydrous ether (100 ml) was added a solution of 2-pyridyl lithium (Pinder et al (J. Med. Chem. 1968, 11, 267)) [formed by addition of 2-bromopyridine (3.3 ml, 34.6 mmol) to a solution of butyl lithium (29.7 ml of a commercial 1.6 M solution, diluted with an equal quantity of ether) at -78°C] at -78°C. Analysis of the reaction by TLC after 10 min showed that no starting material remained. The reaction was allowed to warm to room temperature, then poured into aqueous ammonium acetate, and extracted with ether, the combined organic layers washed with brine and dried (MgSO4). Filtration through a pad of silica gel using ethyl acetate-hexane (1:1) afforded 9.0 g (84%) of the crude 2,8- bis(trifluoromethyl)-4-quinolinyl-2-pyridinylmethanone. This was recrystallised from isopropyl alcohol to give the product as colourless needles, identical to that described in the literature (Hickmann et al.; Pinder et al.; Ohnmacht et al.; and Adam et al. (Tetrahedron 1991, 36, 7609)).The second method of synthesis of 2,8-bis(trifluoromethyl)-4-quinolinyl-2- pyridinylmethanoneIn a round bottom flask (100 ml) were placed 4-chloro-2,8- bis(trifluoromethyl)quinoline (0.0385 mole, 11.52 g), 2-pyridylacetonitrile (0.0423 mole, 5.0 g), benzyltriethylammonium chloride (0.26 g, 3 mole %), THF (35 ml) and aq NaOH (20 N, 9.63 ml, 0.192 moles). On stirring the colour of the solution became cherry red. The reaction temperature was increased to 5-0°C and stirred for further 1 hour. Monitoring of the reaction mixture by thin layer chromatography (TLC) or gas liquid chromatography (GLC) indicated complete consumption of 4-chloroquinoline to give nitrile. The reaction temperature was lowered to 20-25°C followed by addition of 30% H2O2 (13 ml, 0.1154 moles). TLC and GLC monitoring indicated complete conversion of nitrile compound to 2,8-bis(trifluoromethyl)-4-quinolinyl-2- pyridinylmethanone. Reaction mixture was cooled to 0-5°C and neutralized by ortho-phosphoric acid (85% aq, 4.5 ml). THF was distilled off, followed by addition of water (30 ml) and extraction with toluene. The crude product was crystallized from isopropanol to obtain 2,8-bis(trifluoromethyl)-4-quinolinyl]-2- pyridinylmethanone. Yield = 13.17 g (92%), melting point 123°C.

Therapeutic Function

Antimalarial

World Health Organization (WHO)

Mefloquine was developed in response to proliferation of multidrug resistant strains of Plasmodium falciparum, and has been widely used since the early 1980s. Provided the drug is used appropriately, the risks associated with its prophylactic use are clearly outweighed by the benefits. Mefloquine is listed in the WHO Model List of Essential Drugs.

Antimicrobial activity

Mefloquine is a lipophilic drug with a high affinity to membranes. A concentration of 10–40 nm has rapid dose-related activity against erythrocytic stages of Plasmodium spp., including strains resistant to chloroquine, sulfonamides and pyrimethamine. The C-11 (hydroxy) enantiomers have equal antimalarial activity. It also exhibits activity against bacteria (including methicillin-resistant Staphylococcus aureus), and some fungi and helminths.

Acquired resistance

Resistance in P. falciparum is widespread in South East Asia where high-grade resistance was found in 15% of patients and low-grade resistance in about 50%. There is cross-resistance with quinine and halofantrine, and an inverse relationship with chloroquine resistance has been reported. The molecular basis of resistance remains unclear but polymorphisms of the pfmdr1 gene, associated with chloroquine resistance, led to increased sensitivity to mefloquine. Resistant strains of P. falciparum appeared in Africa before the drug was used in that continent, perhaps because of quinine abuse or intrinsic resistance. In South East Asia, declining response rates to combination therapy with mefloquine and artesunate are reported.

Pharmaceutical Applications

A synthetic 4-quinolinemethanol, formulated as the hydrochloride for oral administration. It is slightly soluble in water.

Pharmacokinetics

Oral absorption: 70–80% Cmax 1 g oral: 1 mg/L after 2–12 h Plasma half-life: 20 days Volume of distribution: 16–25 L/kg Plasma protein binding: 98% Mefloquine is concentrated two- to five-fold in erythrocytes. The major metabolites do not have antimalarial activity. Pregnant women require larger doses than non-pregnant women to achieve comparable blood levels. It is predominantly excreted in the bile. Less than 10% is excreted in urine.

Clinical Use

Antimalarial prophylaxis in areas of chloroquine resistance Treatment of uncomplicated multidrug-resistant malaria A mefloquine–artesunate co-formulation is available. Mefloquine has been used for the treatment of cutaneous leishmaniasis in South America.

Synthesis

Mefloquine, D,L-erythro-α-2-piperidyl-2,8-bis-(trifluoromethyl)-4-quinolinmethanol (37.1.1.53), is made in various ways from 2-trifluoromethylaniline. According to the first method, heterocyclization of the reaction product 2-trifluoromethylaniline with trifluoroacetoacetic ester gives 2,8-bis-(trifluoromethyl)-4-hydroxyquinoline (37.1.1.48). Reacting the product with phosphorus tribromide replaces the hydroxyl group in the fourth position of the quinoline ring with a bromine atom, giving 2,8-bis-(trifluoromethyl)-4-bromoquinoline (37.1.1.49). Reaction of the last with butyllithium gives a organolithium derivative—2,8- bis-(trifluoromethyl)-4-lithiumquinoline (37.1.1.50). Reacting this with carbon dioxide makes 2,8-bis-(trifluoromethyl)-4-quinolincarboxylic acid (37.1.1.51). Interaction of the resulting acid with 2-lithiumpyridine gives the ketone (37.1.1.52). Reducing both the keto group and the pyridine ring with hydrogen using a platinum catalyst gives the desired mefloquine. The second way of making mefloquine is from 2,8-bis-(trifluoromethyl)-4-lithiumquiniline described above (37.1.1.50), which is reacted with 2-formylpyridine to make α-2-pyridyl-2,8-bis-(trifluoromethyl)-4-methanolquinoline (37.1.1.54). The pyridiyl group in MEFLOQUINE is also reduced as described above, resulting in the formation of the desired mefloquine. Finally, the third way of making mefloquine also begins with 2-trifluoromethylaniline, except in this case it is reacted with chloralhydrate and hydroxylamine to make isonitrosoacetyl(2-trifluoromethyl)anilide (37.1.1.55), which when heated in the presence of sulfuric acid cyclizes to 7-trifluoromethylisatine (37.1.1.56) (Sandmeyer reaction). The resulting 7-trifluoromethylisatine (37.1.1.56) is then reacted with 1,1,1-trifluoroacetone in the presence of a base in a Friedlaender reaction conditions to make 2,8-bis-(trifluoromethyl)-4-quinoline carboxylic acid described above (37.1.1.51). Reacting this with lithium hydroxide turns it into a lithium salt, which is reacted with a Grignard reagent, 2-magnesiumbromopyridine (made from 2-bromopyridine and magnesium). The resulting ketone (37.1.1.52) is again reduced with a platinum catalyst to make the desired mefloquine.

InChI:InChI=1/C17H16F6N2O/c18-16(19,20)11-5-3-4-9-10(15(26)12-6-1-2-7-24-12)8-13(17(21,22)23)25-14(9)11/h3-5,8,12,15,24,26H,1-2,6-7H2/t12-,15+/m0/s1

Upstream product

• 1309854-87-2 tert-butyl (S)-2-((R)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate 
• 1309854-88-3 (S)-tert-butyl 2-((R)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carboxylate 
• 705291-21-0 (+)-(11S,12R)-erythro-mefloquine, O,O-(-)-di-p-toluoyl-L-tartrate 
• 35853-41-9 2,8-bis(trifluoromethyl)quinolin-4-ol 
• 821-41-0 5-Hexen-1-ol 
• 35853-45-3 (2,8-bis-trifluoromethyl)-4-bromoquinoline 
• 52898-33-6 N-(5-hexenyl)phthalimide 
• 51773-92-3 mefloquine hydrochloride 

Downstream Products

• 68682-28-0 (2,8-bis-trifluoromethyl-quinolin-4-yl)-piperidin-2-yl-methanol; hydrochloride 
• 1443837-22-6 (+)-(11S,12R)-erythro-mefloquine-(R)-mosher amide 
• 68682-28-0 (R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidin-1-ium chloride 
• 936089-21-3 (R)-tert-butyl 2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carboxylate 

Relevant academic research and scientific papers

Chiral Vicinal Diamines Derived from Mefloquine

Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino-Cinchona alkaloids. Most effectively, 11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo-11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that erythro-11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing epi-aminoquinine in terms of selectivity.

Attrition-Enhanced Deracemization of the Antimalaria Drug Mefloquine

Mefloquine is an important drug for prevention and treatment of malaria. It is commercially available as a racemic mixture, wherein only one enantiomer is active against malaria, while the other one causes severe psychotropic effects. By converting the drug into a compound that crystallizes as a racemizable racemic conglomerate, the deracemization of mefloquine into the desired enantiomer was achieved.

A Robust, Recyclable Resin for Decagram Scale Resolution of (±)-Mefloquine and Other Chiral N-Heterocycles

Decagram quantities of enantiopure (+)-mefloquine have been produced via kinetic resolution of racemic mefloquine using a ROMP-gel supported chiral acyl hydroxamic acid resolving agent. The requisite monomer was prepared in a few synthetic steps without chromatography and polymerization was safely performed on a >30 gram scale under ambient conditions. The reagent was readily regenerated and reused multiple times for the resolution of 150 grams of (±)-mefloquine and other chiral N-heterocylces.

A Concise and Highly Enantioselective Total Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

A concise asymmetric (>99:1 e.r.) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless-derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)-anti- and (-)-syn-mefloquine, respectively. The synthetic (+)-anti- and (-)-syn-mefloquine samples were derivatized with (S)-(+)-mandelic acid tert-butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X-ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)-anti- as well as (-)-syn-mefloquine.

Absolute configuration and antimalarial activity of erythro-mefloquine enantiomers

Mefloquine (MQ), an antimalarial drug, is used as a racemate of (-)- and (+)-enantiomers, which display biological differences. The question concerning their exact configuration remains a matter of debate. The absolute configuration of the two MQ enantiomers as well as their biological activity has been established, thus confirming the importance of the stereochemistry in the design of MQ analogues that have fewer adverse side effects (see figure). Copyright

Trapped in misbelief for almost 40 years: Selective synthesis of the four stereoisomers of mefloquine

Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti-malaria drug that is applied as a racemate of the erythro form. However, the (-)-isomer induces psychosis, while the (+)-enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira-6π- electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers. Five to four: A total synthesis that yields all four stereoisomers of the important antimalarial drug mefloquine (Lariam) has been developed. This five-step approach with a domino Sonogashira-6π- electrocyclisation as key step has confirmed synthetically the correct absolute configuration of all four isomers (see scheme).

Asymmetric total synthesis of the antimalarial drug (+)-mefloquine hydrochloride via chiral N-amino cyclic carbamate hydrazones

Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral α-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.

RESOLUTION OF MEFLOQUINE WITH O,O-DI-P-AROYLTARTARIC ACID

A process for increasing the optical purity of a mixture of enantiomers of mefloquine, used a substantially single enantiomer of a O, O-di-p-aroyltartaric acid as a resolving agent.