Cinchona alkaloids extraction

Schuur B, Winkelmam JGM, Heeres HJ. Equilibrium studies on enantioselective liquid-liquid amino acid extraction using a cinchona alkaloid extractant. Ind. Eng. Chem. Res. 2008 47 10027-10033. 

Following the reaction, simple extraction provided access to both the hemiester prodnct and the alkaloid withont chromatography and the recovered cinchona alkaloid conld be reused with no deterioration in the ee or yield. This method has found use in the synthesis of P-amino alcohols and in natural product synthesis [198-201] and has recently been reported as an Organic Syntheses method [202],... 

Other Cinchona Alkaloids Dissolve about 2.5 g of sample in 60 mL of water contained in a separator, add 10 mL of 6 A ammonium hydroxide, extract the mixture successively with 30 mL and 20 mL of chloroform, and evaporate the combined chloroform extracts to dryness on a steam bath. Dissolve 1.5 g of the residue in 25 mL of alcohol dilute the solution with 50 mL of hot water add 1 A sulfuric acid (about 5 mL) until the solution is acid, using 2 drops of methyl red TS as the indicator and neutralize the excess acid with 1 A sodium hydroxide. Evaporate the solution to dryness on a steam bath,... 

Figure 1.1 Quinine and other cinchona alkaloids are extracted from the barkofthe cinchona tree [2], which is mainly cultivated in Africa, Latin America, and Indonesia. Approximately 700 metric tons of cinchona alkaloids is harvested annually.

In the same period, Deng and coworkers also reported that the racemic 5-alkyl l,3-dioxolane-2,4-diones 51 undergo kinetic resolution in the presence of alcohols (ethanol or allyl alcohol) and dimeric cinchona alkaloids such as (DHQD)2AQN (11, 10mol%) [42]. A range of 5-alkyl dioxolanes 51 were highly enantioselectively converted to the (R)-esters (R)-52 (selectivity factors up to 133) (Scheme 11.27). The hydrolysis of the reaction mixture converts the remaining (S)-53 to the (S)-acid (s)-53 that can be easily separated from the (R)-ester 52 by extraction (Scheme 11.27). 

Due to the high number of steps, challenging stereocontrol, and low overall yield, the known total synthesis of cinchona alkaloids cannot compete with the extraction of the natural products from readily available cinchona bark and any subsequent semisynthetic modifications. 

Enantia polycarpa Engl, et Diels and E. pilosa Exell. (2, 3), which principally afford protoberberine alkaloids. Furthermore, cinchonidine and other Cinchona alkaloids have been extracted from the leaves of Olea europaea L (4). 

Of the various pharmaceuticals derived from plants, the Cinchona alkaloids are probably, by volume the largest market, with an estimated production of 300-500 metric tons a year of pure quinine (32) and quinidine (33). These alkaloids are extracted from the bark of Cinchona trees, which require about 10 years to mature before harvesting. Furthermore most of the plantations are in areas not easily accessible, often threatened by infections with Phytophthora cinnamomi. This leads to many uncertainties in planning of the production, and as a result alternative sources for the alkaloids are of interest. Various synthetic aproaches have been used (552) but are not of industrial interest. Therefore, interest in biotechnological approaches is large. Patents related to the production of quinoline alkaloids by means of plant cell cultures are summarized in Table XXVIII. 

With a year production of 300-500 tons (26), the Cinchona alkaloids (quinine 1 and quinidine 2) probably form one of the largest markets of fine chemicals derived from higher plants. They are extracted from stem and rootbark of Cinchona trees, containing 5-18Z of alkaloid, with an average of about 8X (27). Because of the high demand a number of attempts have been made to develop a commercial synthesis (28 and references cited therein) of the quinoline alkaloids. Although successful syntheses have been reported they could not be commercialized. 

Although Cinchona alkaloids are easily separated from products by acid-base extractions and recycled, immobilisation of the catalyst on polymers was investigated by Oda. In parallel with new catalyst synthesis, their immobilisation to various solid supports was also studied. Immobilised catalysts are easily isolated by filtration and reused several times, although their initial enantioselectivity is slightly lower compared with homogeneous catalysis. 

In addition, in 2(X)4 Mamoka and co-workers [72] synthesized a recyclable fluorous chiral phase-transfer catalyst which was successfully applied for the catalytic asymmetric alkylation of a glycine-imine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent. Later, in 2010 Itsuno and co-workers [73] published a new type of polymer-supported quarternary ammonium catalysts based on either cinchona alkaloids or Maruoka s-type catalyst bound via ionic bonds to the polymeric sulfonates. 

The highest demand for quinine (and to a lesser extent for other Cinchona alkaloids) has been observed in the nineteenth and in the first half of the twentieth century when quinine remained the only antimalarial drug available. In more recent times, introduction of the other alternative antimalarials resulted in the reduced but relatively stable annual production of quinine at the level of 500-7001 (perhaps the only alkaloid produced in a multiton scale ). Due to their relatively high abundance in the plant resources (Cinchona bark) and the well-developed isolation and purification technologies based on the extraction and crystallization, they are inexpensive natural products (ca. 200 per 1 kg of quinine) with a high potential to be even more extensively explored in the future as green, sustainable, and chiral substrate. 

Extract of Cinchona, B.P.C. 1954. A soft extract made with strong alcohol and containing 10 per cent of total cinchona alkaloids. 

The two Cinchona alkaloid selectors will be used to really get into a particular chiral recognition mechanism. Quinine is a natural alkaloid extracted from the bark of the South American Cinchona tree of the Rubiaceae family and used as an anti malaria drug (Fig. 6). Its 8 and 9 positions are, respectively, substituted in the S and R configuration. By chance, quinidine is the mirror image form of quinine, also found in the Cinchona bark with the 8R and 9S configuration. These two alkaloid enantiomers... 

Cinchona alkaloids are well-known natural products with a fascinating medicinal history and an intriguing molecular structure that is responsible for their use in chemistry [1, 2]. The natural cinchona alkaloids are obtained from the bark extract of the Cinchona tree and consist of quinine, quinidine, cinchonine, and cinchoni-dine with the structures shown in Figure 6.1. 

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