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Synthesis of Azadirachtin

Azadirachtin

11141-17-6  cas no

Azadirachtin, a chemical compound belonging to the limonoid group, is asecondary metabolite present in neem seeds. It is a highly oxidizedtetranortriterpenoid which boasts a plethora of oxygen functionality, comprising an enol ether, acetal, hemiacetal, and tetra-substituted oxirane as well as a variety of carboxylic esters.

This compound is a tetraterpenoid characteristic of the Meliaceae family but particularly from the Neem tree (A. indica), indigenous to India. The compound is found in bark, leaves and fruits of the tree but seeds have the highest concentration. This compound has not yet been synthesized in the laboratory, but when isolated and tested pure the results have been less than when extracts are used.  In the extract 18 compounds have been identified among which salanine, meliantrol and azadiractin are most prominent, the latter being in the highest concentration. Azadirachtin shows antifeedant activity, is a growth regulator, inhibits oviposition and is also a sterilizing compound. Today, commercial formulations of neem may be found with names like Neem Gold, Neemazal, Econeem, Neemark, Neemcure and Azatin among others, in many countries including the United States, India, Germany and several Latin American countries.

Azadirachtin has a complex molecular structure, and as a result the first synthesis was not published for over 22 years after the compound’s discovery. The first total synthesis was completed by Steven Ley in 2007.[1][2] Both secondary and tertiary hydroxyl groups and tetrahydrofuran ether are present and the molecular structure reveals 16 stereogenic centres, 7 of which are tetrasubstituted. These characteristics explain the great difficulty encountered when trying to produce it by a synthetic approach. The described synthesis was actually a relay approach, with the heavily functionalized decalin being made by total synthesis in a small scale but also being derived from the natural product itself for the purpose of obtaining gram amounts of the material to complete the synthesis.

Azadirachtin

“I would rank this as being one of the very toughest syntheses so far reported.”
– Steven Ley, University of Cambridge, UK, 1 G E Veitch et al, Angewandte Chemie, 2007, DOIs: 10.1002/anie.200703027 and 10.1002/anie.200703028
2 M L Maddess et al, Angewandte Chemie, 2006, 46, 591 (DOI: 10.1002/anie.200604053)

 

IT TOOK 22 YEARS and the efforts of more than 40 chemists, but Steven V. Ley‘s group has finally managed to complete a 64-step synthesis of azadirachtin, a naturally occurring insecticide (Angew. Chem. Int. Ed., DOI:10.1002/anie.200703027 and 10.1002/anie.200703028).

Isolated from the Indian neem tree Azadirachta indica, azadirachtin possesses a small but densely functionalized architecture. It has 16 stereogenic centers, seven of which are tetrasubstituted, and a diverse array of oxygenated functionalities.

“This has been a tough project from start to finish, as the molecule is so prone to rearrangement under acidic, basic, or photolytic conditions,” says Ley, a chemistry professor at England’s Cambridge University. “It has forced us to be inventive.”

Of the many hurdles the researchers had to overcome, Ley reckons the most challenging was coupling the molecule’s two main fragments. After years of attempts at this convergent approach, the group was finally able to marry these two fragments by means of a propargylic enol ether Claisen reaction. The next step, a radical-induced cyclization, elegantly constructed one sterically dense portion of the molecule.

“Making a molecule such as this is not an Everest-climbing exercise; it’s about what you learn from the experience,” Ley says. “We can be proud of the new methods and solutions to the tough problems we have encountered, and now we have the tools and procedures to really work out how this molecule functions biologically.”

Amos B. Smith III, a chemistry professor at the University of Pennsylvania, calls the work “an outstanding achievement, further demonstrating Ley and colleagues as superb tacticians in the art of complex-molecule total synthesis.”

Smith adds: “More important than the actual conquest is the exciting new chemistry that has emanated over the past 22 years from the Ley and other laboratories who have participated in this monumental challenge. Clearly, the science of synthesis is the winner.”

It was initially found to be active as a feeding inhibitor towards the desert locust(Schistocerca gregaria),[3] it is now known to affect over 200 species of insect, by acting mainly as an antifeedant and growth disruptor, and as such it possesses considerable toxicity toward insects (LD50(S. littoralis): 15 μg/g). It fulfills many of the criteria needed for a natural insecticide if it is to replace synthetic compounds. Azadirachtin is biodegradable (it degrades within 100 hours when exposed to light and water) and shows very low toxicity to mammals(the LD50 in rats is > 3,540 mg/kg making it practically non-toxic).

This compound is found in the seeds (0.2 to 0.8 percent by weight) of the neemtree, Azadirachta indica (hence the prefix aza does not imply an aza compound, but refers to the scientific species name). Many more compounds, related to azadirachtin, are present in the seeds as well as in the leaves and the bark of the neem tree which also show strong biological activities among various pest insects [4][5] Effects of these preparations on beneficial arthropods are generally considered to be minimal. Some laboratory and field studies have found neem extracts to be compatible with biological control. Because pure neem oil contains other insecticidal and fungicidal compounds in additional to azadirachtin, it is generally mixed at a rate of 1 ounce per gallon (7.8 ml/l) of water when used as a pesticide.

Azadirachtin is formed via an elaborate biosynthetic pathway, but is believed that the steroid tirucallol is the precursor to the neem triterpenoid secondary metabolites. Tirucallol is formed from two units of farnesyl diphosphate (FPP) to form a C30 triterpene, but then loses three methyl groups to become a C27steroid. Tirucallol undergoes an allylic isomerization to form butyrospermol, which is then oxidized. The oxidized butyrospermol subsequently rearranges via a Wagner-Meerwein 1,2-methyl shift to form apotirucallol.

Apotirucallol becomes a tetranortriterpenoid when the four terminal carbons from the side chain are cleaved off. The remaining carbons on the side chain cyclize to form a furan ring and the molecule is oxidized further to form azadirone and azadiradione. The third ring is then opened and oxidized to form the C-seco-limonoids such as nimbinnimbidinin and salannin, which has been esterified with a molecule of tiglic acid, which is derived from L-isoleucine. It is currently proposed that the target molecule is arrived at by biosynthetically converting azadirone into salanin, which is then heavily oxidized and cyclized to reach azadirachtin.


Azadirachtin ball and stick view

  1.  Veitch GE, Beckmann E, Burke BJ, Boyer A, Maslen SL, Ley SV (2007). “Synthesis of azadirachtin: a long but successful journey”. Angew. Chem. Int. Ed. Engl. 46 (40): 7629–32.doi:10.1002/anie.200703027PMID 17665403.
  2.  Sanderson K (August 2007). “Chemists synthesize a natural-born killer”. Nature 448 (7154): 630–1. doi:10.1038/448630a.PMID 17687288.
  3.  Butterworth, J; Morgan, E (1968). “Isolation of a Substance that suppresses Feeding in Locusts”. Chemical Communications (London) (1): 23.doi:10.1039/C19680000023.
  4.  Senthil-Nathan, S., Kalaivani, K., Murugan, K., Chung, G. (2005). “The toxicity and physiological effect of neem limonoids on Cnaphalocrocis medinalis (Guenée) the rice leaffolder”.Pesticide Biochemistry and Physiology 81 (2): 113.doi:10.1016/j.pestbp.2004.10.004.
  5. Senthil-Nathan, S., Kalaivani, K., Murugan, K., Chung, P.G. (2005). “Effects of neem limonoids on malarial vector Anopheles stephensi Liston (Diptera: Culicidae)”. Acta Tropica96 (1): 47. doi:10.1016/j.actatropica.2005.07.002.PMID 16112073.

File:Azadirachtin model.png

Extracts of the neem tree (Azadirachta indica) , the chinaberry tree (Melia azedarach) , and other plants in the family Meliaceae (e.g. Azadirachta excelsa) have long been known to have insectici al activity (Natural Pesticides from the Neem Tree, Proc. 1st Int’l Neem Conf. 1980 [H. Schmutterer et al. eds. 1982]; Natural Pesticides from the Neem Tree and Other Tropical Plants, Proc. 2nd Int’l Neem Conf. 1983 [H. Schmutterer and K.R.S. Asher eds. 1984]; Natural Pesticides from the Neem Tree and Other Tropical Plants, Proc. 3rd Int’l Neem Conf. 1986 [H. Schmutterer and K.R.S. Asher eds. 1987]). Azadirachtin, a major active ingredient in many of these extracts, is a limonoid of the tetranortriterpenoid type. Azadirachtin has been shown to be a potent insect growth regulator and feeding deterrent with value as an active ingredient in commercial insecticides (R.B. Yamasaki et al. (1987) J. Agric. Food Che . 3_5:467-471) .

The use of azadirachtin in commercial insecticides requires that the compound be extracted from the plant material and concentrated in a convenient form. Suitableazadirachtin concentrates are solid in form, have high levels of azadirachtin

(typically greater than 1-3% by weight) , and contain little or no plant oils and water. These characteristics facilitate handling, storage, distribution, and formulation.

Various methods of extracting azadirachtin from neem seeds are known in the art. J.H. Butterworth and E.D. Morgan, (1971) J. Insect. Physiol. Y]_ 969-911, describe the extraction of azadirachtin and neem oil from neem seeds using ethanol, a common solvent for azadirachtin isolation. Further separation steps (including filtration, partition of the soluble portion between light petroleum and methanol, and chromatography of the methanol extract on Floridin earth) are used to concentrate the azadirachtin to obtain a solid. Larson (U.S. Patent No. 4,556,562) discloses a similar method whereby neem seeds are first reduced in size to that of a regular grind of coffee. Azadirachtin is then extracted at elevated temperatures, again using ethanol. No further concentration steps are used, however, and the final extract is a liquid containing only 0.5-1% azadirachtin. Walter (U.S. Patent No. 4,946,681) describes a related process for extractingazadirachtin from ground de-oiled neem seeds with aprotic solvents or alcohols. The liquid extract is further treated with molecular sieves to remove water. Carter et al. (U.S. Patent No. 5,001,146) describes a two-step extraction process comprising a “cleanup” extraction with a non- polar aprotic solvent to remove the neem oil from the seeds, followed by a second extraction of the defatted neem seeds using a more polar, azadirachtin-soluble solvent. The final extract from this process is a solution containing about 4.5 g/1 azadirachtin. Kleeberg (WO 92/16109) also describes a multi-step procedure whereby the azadirachtin is first extracted from neem oil and plant material using water. The aqueous fraction is then extracted with an organic solvent to remove the azadirachtin from the water. A solid azadirachtin concentrate is ultimately obtained using a slow and inefficient phase separation followed by concentration of the organic phase and crystallization.

Inefficiencies and limitations associated with the processes described above illustrate the need for more practical and versatile methods for obtainingazadirachtin concentrates. Specifically, current methods that produce extracts containing suitably high azadirachtin content (>l-3% by weight) all involve expensive steps to remove neem oil, water, and other impurities. Such steps include decantation, phase separation, chromatography, crystallization, treatment with molecular sieves, and other purification steps. None of the known methods provides a suitably efficient, economical, or practical means for recoveringazadirachtin in a concentrated solid form that contains little or no neem oil or water.

It is known that the seeds and other parts of the neem tree [Azaderachta indicia and related species) contain natural pesticidal compositions. The main active pesticidal composition is azadirachtin which is a tetranortriterpenoid that causes feeding inhibition and growth inhibition in a variety of organisms including insects, mites and nematodes. It is possible that there are a number of similar insecticidal compounds present in neem extracts that partition with the azadirachtin. As used in this specification, the term azadirachtin is taken to include all insecticidal terpenoids present in neem extracts that partition with azadirachtin. In recoveringazadirachtin from neem seeds it is necessary to separate the active constituent from other materials including the other triterpenes, the oil. fibre and other insoluble materials, and water soluble constituents such as sugars and water soluble proteins. These separation procedures are complicated by the fact thatazadirachtin is susceptible to hydrolysis in water and to heat degradation.

One conventional method for extracting azadirachtin from neem seeds involves the use of three organic solvents and two liquid/liquid partition steps. Firstly, the neem seeds are pressed to remove the majority of the neem oil. The resulting expeller cake is then extracted with methanol. The methanol extracts a wide range of substances including azadirachtin and the other triterpenes, diterpenes. the residual oil, and some polysaccharides and proteins. To produce a powder from the methanolic supernatant, the extract must undergo a number of clean-up steps.

In the first clean-up step, the supernatant is concentrated and partitioned against hexane, or a similar non-polar solvent, to remove the oils and diterpenes. The hexane is then driven off in a still and the resulting oil is collected. The second clean-up step involves taking the de-oiled supernatant and driving off the methanol. The resulting tar is then resolved in ethyl acetate, or a similar solvent, and partitioned against water to remove the polysaccharides and water soluble proteins. The ethyl acetate which contains the azadirachtin and other triterpenes is then evaporated to produce an azadirachtin rich powder.

There are a number of problems associated with this conventional method, with the major problem being cross-contamination of the solvents used in the process and the resulting variation in product quality. While good quality azadirachtinpowder can be produced when first using the process with fresh solvents, after a number of cycles problems with cross- contamination do arise. While hexane and methanol are normally considered essentially immiscible, in a multi-component system, such as is created during the extraction of azadirachtin described above, the hexane and methanol do demonstrate some miscibility. The change in the polarity of the solvents allows oils to be carried through the hexane partition and so creates difficulties in producing a non-oily or flowable powder. A more serious problem is any occurrence of cross-contamination between the methanol and ethyl acetate. If the methanol is not removed in the drying step after the hexane partition, cross-contamination with ethyl acetate occurs. This contamination of the ethyl acetate with methanol causes azadirachtin to be carried over into the water in the ethyl acetate/water partition or in the worst case prevents a partition forming at all. A further problem with the conventional method for extractingazadirachtin is the production of waste water with a high biological oxygen demand (BOD). In many countries, the release of waste water with high BOD is not permitted and requires the installation of a relatively expensive water treatment facility. An alternative azadirachtin extraction process is described in Australian patent no 661482 to Trifolio-M GmbH, Herstellung Und Vertrieb Hochreiner Biosubstanzen. In this alternative process, the neem seed is pressed or crushed to remove the majority of the oil and the expeller cake is extracted with warm water. The warm water extraction removes the azadirachtin. some of the more polar triterpenes. the majority of the polysaccharides and water soluble proteins, and a slight amount of the more polar oily compounds. The aqueous supernatant is partitioned against a solvent of intermediate polarity, such as ethyl acetate or dichloro me thane. with the azadirachtin partitioning into the organic layer. The organic layer can then be concentrated under vacuum and theazadirachtin precipitated through the addition of a non-polar solvent, such as hexane or petroleum ether. While high yields of azadirachtin powder are produced using this alternative process, the process still results in the discharge of an aqueous solution loaded with polysaccharides and proteins which, in some countries, will require treatment to meet environmental standards. Further, the precipitation step where a non-polar solvent is added to the concentrated supernatant results in cross-contamination with its attendant problems and expense of requiring purification of the solvents prior to their re-use in the extraction process.

 

G. E. Veitch, E. Beckmann, B. J. Burke, A. Boyer, S. L. Maslen, S. V. Ley*
University of Cambridge, UK
Synthesis of Azadirachtin: A Long but Successful Journey
Angew. Chem. Int. Ed.  2007,  46:  7629-7632

Azadirachtin is an insect antifeedant. A major challenge in this 22-year odyssey was the construction of 16 contiguous stereogenic centers seven of which are quaternary. The excerpt depicted here focuses on the Claisen rearrangment used to construct the congested C8-C14 bond.

Compounds A and G were obtained by total synthesis and by degradation of azadirachtin. The degradation route enabled exploration of the difficult closing stages of the synthesis. Note the harsh conditions required to effect the difficult epoxidation F→G.

 

………………………………..

azadirachtin2.gif

The basic skeleton of the decalin fragment, intramolecularDiels-Alder reaction and aldol type cyclization and is building well using. Together is important for the selectivity of the Diels-Alder reaction, a silyl group in the after Tamao-Fleming oxidationhas become a stepping stone for introducing a hydroxyl group by.

azadirachtin3.gif

 Subsequently, a fragment coupling. An attempt was made to make the binding by alkylation, but what has been obtained, It was a compound the reaction is going on in the oxygen atom of the enol.

Anyway Since make a bond between the fragments, was a stepping stone to this Claisen rearrangement by carbon – and is trying to build a carbon bond. Reaction seems to have gone even heat, but has been developed by Toste et al (I) catalyst Au Claisen rearrangement using that seems to have been effective. 
 Conversion fairly high hurdle is followed thereafter. Barton-McCombie conditions and it has succeeded in building carbon skeleton of the right half be subjected to a radical cyclization reaction by. At a position that is crowded Then epoxidation and we have been. Becomes the conditions investigated thoroughly that (7 days) radical scavenger addition temperature (100 ℃ or more) time, it’s easy to imagine that even just one step here, consider mind-boggling are stacked . Same compound obtained in Degradation Studies This is obtained, advances the synthesized according to the reverse route later, we have completed the synthesis of azadirachtin.

azadirachtin4.gif

 Total synthesis route of the 64 steps that have been achieved 

 

azadirachtin.gif

Synthesis of Azadirachtin: A Long but Successful Journey Veitch, GE; Beckmann, E.; Burke, BJ; Boyer, A.; Maslen, SL; Ley, SV …. Angew Chem Int Ed 2007 , 46 ., 7629 DOI:10.1002/Anie.200703027
A Relay Route for the Synthesis of Azadirachtin Veitch, GE; Beckmann, E.; Burke, B. j;. Boyer, A.; Ayats, C.; Ley, SV … Angew Chem Int Ed. 2007 , 46 ., 7633 DOI: 10.1002/Anie.200703027\

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ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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Sweet Poison, Star fruit neurotoxin identified, caramboxin

 

 

Star fruit neurotoxin identified

Neurotoxin from Star Fruit

Patients with kidney disease have to watch what they eat: bananas, oranges, tomatoes, nuts, broccoli, and beans are all off-limits. Putting star fruit or carambola on the menu would be downright dangerous. This fruit contains a substance that is a deadly neurotoxin for people with kidney disease. Brazilian researchers have now isolated and identified this neurotoxin. As they report in the journal Angewandte Chemie, it is an amino acid similar to phenylalanine.

Caramboxin: Patients suffering from chronic kidney disease are frequently intoxicated after ingesting star fruit. The main symptoms of this intoxication are named in the picture. Bioguided chemical procedures resulted in the discovery of caramboxin, which is a new phenylalanine-like molecule that is responsible for intoxication. Functional experiments in vivo and in vitro point towards the glutamatergic ionotropic molecular actions of caramboxin, which explains its convulsant and neurodegenerative properties.

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Sweet Poison

http://www.chemistryviews.org/details/ezine/5542471/Sweet_Poison.html

star fruit (Averrhoa carambola) or carambola has been cultivated in Malaysia, Southern China, Taiwan, India and Brazil. It is rather popular in the Philippines and Queensland, Australia and moderately so in some of the South Pacific Islands, particularly Tahiti, New Caledonia and Netherlands New Guinea, Guam and in Hawaii and south Florida. There are some subspecies in the Caribbean Islands, in Central America and in tropical West Africa. The fruits are also available in many European countries and Canada. Range of soluble oxalate salts concentrations obtained from many cultivars varies from 80 to 730 mg/100 g of the fruit

Structural Elucidation and Spectroscopic Data of Caramboxin (1)
Most 1H and 13C NMR data from the isolated compound were easily assigned due to the relationship
of this compound with well-known aromatic amino acids such as phenylalanine. The side chain is
identical to phenylalanine as attributed in the NMR data below. The tetra-substituted pattern of the aromatic ring was also easily recognized by the only two signals for aromatic protons at δ 6.42 and6.37 with a coupling constant (2.0 Hz) typical of aromatic meta coupling. The positioning of
substituents in the aromatic ring were attributed due to the 13C chemical shifts and confirmed by
HMBC experiment. In this way acetyl group was placed at C-6 due to the low chemical shift (104.1ppm) of this aromatic carbon; methoxyl was placed at C-3 due to its highest chemical shift (165.2ppm) among aromatic protons, which was confirmed by HMBC experiment; finally the hydroxyl group was placed at the remaining C-5. Comparison of the observed accurate mass measurement with theoretically calculated formulae for the signal at m/z 256.0823 allows only a few reasonable [MH]+ ion formulae within a standard deviation of 50 ppm. The ion formula [C11H13NO6 + H]+ had the best mass accuracy (0.7 ppm error) and correlation with the NMR spectra. The MS/MS spectrum of m/z 256 shows an intense ion at m/z 192 in addition to neutral elimination of H2O (m/z 238) and CO2 (m/z 212) from the carboxylic acid group. In source dissociation followed by MS/MS analysis revealed that m/z 192 was only obtained from m/z 238, due to the elimination of CH2O2 (46 massunits) as a neutral molecule by 1,2 elimination. The same mechanism was also observed for the m/z166 formation from the ion at m/z 212. Finally, 2D NMR data from HMQC and HMBC confirmed the entire spectral assignment

Caramboxin: 1H-NMR (400 MHz, D2O) δ 6.42 (d, J = 2.0 Hz, 1H, H-4), 6.37 (d, J = 2.0 Hz, 1H, H-2), 4.25 (dd, J = 5.5, 8.0 Hz, 1H, H-8), 3.80 (s, 3H, H-11), 3.66 (dd, J = 14.0, 5.5 Hz, 1H, H-7A),3.18 (dd, J = 14.0, 8.0 Hz, 1H, H-7B);

 

13C-NMR (100 MHz, DMSO-d6) δ 172.8 (C, C-9), 171.2 (C,C-10), 165.2 (C, C-5), 162.2 (C, C-3), 138.8 (C, C-1), 110.0 (CH, C-2), 104.1 (C, C-6), 100.5 (CH,C-4), 55.4 (CH3, C-11), 53.5 (CH, C-8), 35.9 (CH2, C-7); 15N-NMR (50 MHz, DMSO-d6) δ -268(nitromethane as internal reference).

HMBC (500 MHz, DMSO-d6): H-2 → C-3, C-4, C-7; H-4 →C-2, C-3, C-5; H-7 → C-1, C-2, C-8, C-9; H-8 → C-1, C-7, C-9; H-11 → C-3;

 

HRMS (m/z): [MH]+calcd for C11H14NO6, 256.0816; found: 256.0818

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Pregabalin

 

PREGABALIN
LEARN ABOUT SPECTRAL DATA AT
Pregabalin (INN/prɨˈɡæbəlɨn/ is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults.[1] It has also been found effective for generalized anxiety disorder and is (as of 2007) approved for this use in the European Union and Russia. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade nameLyrica. Pfizer described in an SEC filing that the drug could be used to treat epilepsy, post-herpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia. Sales reached a record $3.063 billion in 2010. In Bangladesh Pregabalin is sold under the brand of Nervalin by Beximco Pharma It is effective at treating some causes of chronic pain such as fibromyalgia but not others. It is considered to have a low potential for abuse, and a limited dependence liability if misused, but is classified as a Schedule V drug in the U.S.
Lyrica is one of four drugs which a subsidiary of Pfizer in 2009 pleaded guilty to misbranding “with the intent to defraud or mislead”. Pfizer agreed to pay $2.3 billion (£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer illegally promoted the drugs and caused false claims to be submitted to government healthcare programs for uses that were not approved by the U.S. Food and Drug Administration (FDA

In the United States, the Food and Drug Administration (FDA) has approved pregabalin for adjunctive therapy for adults with partial onset seizures, management of postherpetic neuralgia andneuropathic pain associated with spinal cord injury and diabetic peripheral neuropathy, and the treatment of fibromyalgia. Pregabalin has also been approved in the European Union and Russia(but not in US) for treatment of generalized anxiety disorder.

A package of 150 mg pregabalin (Finland)

READ AT ……………http://www.rsc.org/chemistryworld/News/2008/July/09070801.asp

  • (S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,

    Figure imgb0001

    is also known as γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin, marketed under the name LYRICA®, has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain’s major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.

  • [0003]
    Several processes for the synthesis of (S)-Pregabalin are known. For example, see DRUGS OF THE FUTURE, 24 (8), 862-870 (1999). One such process is illustrated in scheme 1.

    Figure imgb0002
  • [0004]
    In Scheme 1, 3-isobutyl glutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with refluxing acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 4, which is resolved with (R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 5. Combining the salt with an acid liberates the R enantiomer, compound 6. Finally, a Hoffmann degradation with Br2/NaOH provides (S)-Pregabalin. A disadvantage of this method is that it requires separating the two enantiomers, thereby resulting in the loss of half the product, such that the process cost is high.
  • [0005]
    Several stereoselective processes for the synthesis of (S)-Pregabalin have been disclosed. For example, U.S. Patent No. 5,599,973 discloses the preparation of (S)-Pregabalin using stoichiometric (+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. In general, however, that route is of limited use for scale-up, principally due to the low temperature required for the reactions, the use of pyrophoric reagent, such as, butyl lithium, to side reactions, and due to a low overall yield.
  • [0006]
    Another process is disclosed inU.S. Patent Application Publication No. 2003/0212290 , which discloses asymmetric hydrogenation of a cyano-substituted olefin, compound 7, to produce a cyano precursor of (S)-3-(aminomethyl)-5-methyl hexanoic acid, compound 8, as seen in scheme 2.

    Figure imgb0003
  • [0007]
    Subsequent reduction of the nitrile in compound 8 by catalytic hydrogenation produces (S)-Pregabalin. The cyano hexenoate starting material, compound 7, is prepared from 2-methyl propanal and acrylonitrile (Yamamoto et al, Bull. Chem. Soc. Jap., 58, 3397 (1985)). However, the disclosed method requires carbon monoxide under high pressure, raising serious problems in adapting this scheme for production scale processes.
  • [0008]
    A process published by G.M. Sammis, et al., J. Am. Chem. Soc., 125(15), 4442-43 (2003), takes advantage of the asymmetric catalysis of cyanide conjugate addition reactions. The method discloses the application of aluminum salen catalysts to the conjugate addition of hydrogen cyanide to α,β-unsaturated imides as shown in scheme 3. Reportedly, TMSCN is a useful source of cyanide that can be used in the place of HCN. Although the reaction is highly selective, this process is not practicable for large scale production due to the use of highly poisonous reagents. Moreover, the last reductive step requires high pressure hydrogen, which only adds to the difficulties required for adapting this scheme for a production scale process.

    Figure imgb0004
  • [0009]
    In 1989, Silverman reported a convenient synthesis of 3-alkyl-4-amino acids compounds in SYNTHESIS, Vol. 12, 953-944 (1989). Using 2-alkenoic esters as a substrate, a series of GABA analogs were produced by Michael addition of nitromethane to α,β-unsaturated compounds, followed by hydrogenation at atmospheric pressure of the nitro compound to amine moiety as depicted in scheme 4.

    Figure imgb0005
  • [0010]
    Further resolution of compound 14 may be employed to resolve Pregabalin. This, of course, results in the loss of 50 percent of the product, a serious disadvantage. However, the disclosed methodology reveals that the nitro compound can serve as an intermediate for the synthesis of 3-alkyl-4-amino acids.
  • [0011]
    Recent studies have indicated that cinchona alkaloids are broadly effective in chiral organic chemistry. A range of nitroalkenes were reportedly treated with dimethyl or diethyl malonate in THF in the presence of cinchona alkaloids to provide high enantiomeric selectivity of compound 15,

    Figure imgb0006

    and its analogues. For example, see H. Li, et al., J. Am. Chem. Soc, 126(32), 9906-07 (2004). These catalysts are easily accessible from either quinine or quinidine, and are reportedly highly efficient for a synthetically C-C bond forming asymmetric conjugate addition as shown in scheme 5.

    Figure imgb0007
  • [0012]
    R3 represents several alkyl and aryl groups. The scope of the reaction has been extended to other nitroolefins and applied to prepare ABT-546 employing bis(oxazoline)Mg(OTf)2. See, for example, D.M. Barnes, et al., J. Am. Chem. Soc., 124(44), 13097-13105 (2002).
  • [0013]
    Other groups have investigated a new class of bifunctional catalysts bearing a thiourea moiety and an amino group on a chiral scaffold. SeeT. Okino, et al., J. Am. Chem. Soc., 127(1), 119-125 (2005). On the basis of a catalytic Michael addition to the nitroolefin with enantiomeric selectivity, they were able to prepare a series of analogues of compound 15.
  • [0014]
    Thus, there is a need in the art for new processes for the preparation of (S)-Pregabalin that does not suffer from the disadvantages mentioned above. Chemical Abstracts, database accession no. 2005:236589 refers to a process for the synthesis of pregabalin using methyl cyanoacetate, by condensation, addition, cyclization, aminolysis, Hoffmann rearrangement and resolution with (S)-mandelic acid.
    Karenewsky, D. S., et al., J. Org. Chem., 1991, 56, 3744-3747, discloses reaction of a glutaric acid anhydride with (S)-1-phenyethylamine to prepare the corresponding amide, which is subsequently used to prepare β-ketophosphonate derivatives.
    Verma, R., et al., J. Chem. Soc. Perkin Trans. I, 1999, 257-264, discloses desymmetrization of prochiral anhydrides with Evans’ oxazolidinones to prepare homochiral glutaric and adipic acid derivatives.
    Shintani, R. et al., Angew. Chem. Int. Ed. 2002, 41 (6), 1057-1059, discloses the desymmetrization of various glutaric acid anhydrides using Grignard reagents in the presence of (-)-sparteine
Yu H.-J, Shao C, Cui Z, Feng C.-G, * Lin G.-Q. * Shanghai Institute of Organic Chemistry, P. R. of China
Highly Enantioselective Alkenylation of Cyclic α,β-Unsaturated Carbonyl Compounds as Catalyzed by a Rhodium–Diene Complex: Application to the Synthesis of (S)-Pregabalin and (–)-α-Kainic Acid.Chem. Eur. J. 2012;18: 13274-13278

Pregabalin (Lyrica®) is a lipophilic GABA analogue that is prescribed for the treatment of epilepsy. This short, small-scale synthesis of pregabalin features a highly enantioselective asymmetric conjugate addition of the alkenyl tri­fluoroborate B to the α,β-unsaturated lactam A catalyzed by a rhodium complex incorporating the chiral bicyclo[3.3.0]octa-2,5-diene ligand L.
A further 17 examples of this new variant of the Hayashi–Miyaura asymmetric conjugate addition reaction are reported using six α,β-un­saturated carbonyl substrates and ten alkenyl tri­fluoroborates. The asymmetric conjugate addition was also applied to the synthesis of the potent neuroexcitatory agent α-kainic acid (seven steps, 40% overall yield).

fruits from Rosaceae family (Genus: Prunus). The collected fruits are peach (Prunus persica), Himalayan wild cherry (Prunus avium), Red Indian plum (Prunusdomestica), Himalayan plum (Prunus americana), apricot (Prunus armeniaca) and shakarpara (white apricot, a hybrid cultivar of normal apricot found in Nepal and India). All the six newly found HNLs are R-selective, i.e., they yield R-mandelonitrile from benzaldehyde bySi-facial attack of the cyanide anion. The enantioselectivity obtained for the formation of mandelonitriles by all the six HNLs are in the range of 60-93%. The best results are obtained with PavHNL and ParsHNL (both provide 93% ee), where as PpHNL is the least enantioselective (provides 60% ee for R-mandelonitrile formation). The main object of the project proposal will be the development of efficient biocatalytic route for various value added products such as Pregablin, Baclofen and Pril drugs


http://www.google.com/patents/EP2053040A1

http://www.google.com/patents/EP2170813A2

http://www.google.com/patents/EP2170813A2

– See more at: http://worlddrugtracker.blogspot.in/#sthash.AUeFbwD7.dpuf

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Whisky lactone

Whisky Lactone

Whisky lactone, also known as β-methyl-γ-octalactone or quercus lactone (from the Latin for oak treeQuercus alba), is a flavouring found in American bourbon whiskies, and is also found in all types of oak. The flavour gets into the whisky when it’s matured in oak barrels. The pure molecule has a fierce, strong, and sweet smell and can be dissolved in alcohol in any proportion.

6

http://www.sciencedirect.com/science/article/pii/S0957416698000809

5-butyl-4-methyloxolan-2-one | CAS Registry Number: 39212-23-2
Synonyms: Whiskey lactone, Oaklactone, 3-Methyl-4-octanolide, cis-3-Methyl-4-octanolide, beta-Methyl-gamma-octalactone, W380318_ALDRICH, FEMA No. 3803, EINECS 254-357-4, 5-Butyl-4-methyldihydro-2(3H)-furanone, 5-Butyldihydro-4-methyl-2(3H)-furanone, cis-.beta.-Methyl-.gamma.-Octalactone, 2(3H)-Furanone, 5-butyldihydro-4-methyl-, 4-Hydroxy-3-methyloctanoic acid lactone, 5-Butyldihydro-4-methylfuran-2(3H)-one, 5-Butyl-4-methyl-dihydro-2(3H)-furanone, ()-5-Butyl-4-methyldihydro-2(3H)-furanone, 2(3H)-Furanone, 5-butyldihydro-4-methyl-, cis-, 39212-23-2

The cis isomer is the chemical extracted from oak wood that gives whiskey a coconut-like aroma. But not all isomers of this molecule are quite this tasty. The trans isomers of 3-methyl-4-octanolide is by contrast, used as an insect repellent.

 

 

  • Whiskey lactone (3-methyl-4-octanolide) is one of perfume components of whiskey and wine.
  •  
    There are stereoisomers in the natural whiskey lactone, which are of the trans-type or cis-type in accordance with the configuration of methyl group at 3-position thereof and butyl group at 4-position thereof.
    As compared to trans-whiskey lactone
    [(3S,4R)-3-methyl-4-octanolide] (D), generally, a less amount of cis-whiskey lactone
    [(3S,4S)-3-methyl-4-octanolide] (A) is contained, for example, in whiskey and wine. However, cis-whiskey lactone (A) is superior in the characteristic of perfume.

    Figure imgb0001


    However, means for selectively synthesizing natural type cis-whiskey lactone (A) having superior properties than those of trans-type isomer (D) as described above has not been known.

  •  
    Liebigs Annalen der Chemie, No. 12, 1986, pages 2112 – 2122, disclose a method, how all four stereoisomers of 3-methyl-4-octanolide can be produced. It is taught to separate a racemic cis/trans octanolide into the two cis- and the two trans-isomers chromatographically. Furthermore, it is disclosed how to hydrolyse a lactone ring with potassium hydroxide and to protect the carboxy group subsequently yielding the isopropyl carboxylic ester. Diastereomeric pairs of the acid-protected gamma-hydroxyacid are formed by reaction with an optically active carboxylic acid, and are separated from each other by liquid chromatography. It is disclosed how to perform the hydrolysis of the diastereomers and the relactonization to obain the four stereoisomers of whiskey-lactone. No reaction at the 4-hydroxy group is suggested to invert the configuration of the chiral centre
  • Synthesis, No. 1, 1981, pages 1-28, discloses the use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. However, there is no indication for a combination of these documents. Furthermore, it is well-known that the Mitsunobu reaction proceeds according to Sn2 reaction mechanism. In the case of 3,4-trans compound (III) which is a substrate of the method of the present invention, the steric hindrance to the 4-methyl group is large because of the influence from the methyl group at a 3-position.

 

Physical data of the obtained cis-whiskey lactone are
Boiling Point : 124 – 126°C/(17 mmHg) 2266 Pa
¹H-NMR(CDCl₃) : δ 0.92(3H, t, J = 7.0 Hz), 1.02(3H, d, J = 6.9 Hz), 1.20 – 1.75(6H, m), 2.20(1H, dd, J = 3.8 and 16.8 Hz), 2.51 – 2.64(1H, m), 2.70(1H, dd, J = 7.8 and 16.8 Hz), 4.40 – 4.48(1H, m) (ppm units)

 

 

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Amide Hydrogenation in Flow Reactor

thumbnail image: Amide Hydrogenation in Flow Reactor

http://www.chemistryviews.org/details/ezine/5392681/Amide_Hydrogenation_in_Flow_Reactor.html

Amide Hydrogenation in Flow Reactor (wiley)

Amines are produced by amide hydrogenation over a bimetallic platinum–rhenium catalyst in a high-throughput vertical flow reactor

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Teaching Old Drugs New Tricks

A library of novel 5-nitroimidazole antibiotics displayed broad-spectrum activity

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Transition-metal-catalyzed C–C bond formation through the fixation ofcarbon dioxide

Graphical abstract: Transition-metal-catalyzed C–C bond formation through the fixation of carbon dioxide

Carbon dioxide is an important carbon source in the atmosphere and is “problematic” toward the activities of human beings. Although carbon dioxide is a cheap, abundant and relatively nontoxic C1 source, its chemical transformations have not been widely developed so far and are still far from synthetic applications, especially in the construction of the C–C bond. This critical review summarizes the recent advances on transition-metal-catalyzed C–C bond formation through the fixation of carbon dioxide and their synthetic applications (124 references).

http://pubs.rsc.org/en/content/articlelanding/2011/cs/c0cs00129e#!divAbstract

Transition-metal-catalyzed C–C bond formation through the fixation ofcarbon dioxide

*

Corresponding authors

aBeijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Chem. Soc. Rev., 2011,40, 2435-2452

DOI: 10.1039/C0CS00129E

 

 

 

 

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Green N-Methylation of Electron Deficient Pyrroles with Dimethylcarbonate

Abstract Image

The N-methylation of electron-deficient pyrroles was affected using dimethyl carbonate in the presence of DMF and catalytic DABCO. This alkylation methodology has proven useful for the alkylation of a variety of pyrroles in 72−98% yields and is considered to be greenchemistry relative to the more common use of methyl halides or dimethyl sulfate.

Eli Lilly and Company, Chemical Product Research and Development Division, Indianapolis, Indiana 46285, U.S.A
Org. Process Res. Dev., 2009, 13 (6), pp 1199–1201
DOI: 10.1021/op900256t
Publication Date (Web): October 26, 2009
Herein, the N-methylation of compound 1 along with a number of commercially available pyrrole derivatives using DMC, DMF and catalytic 1,4-diazabicyclo[2.2.2]octane (DABCO) are described.
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Article On Alternative Solvents:  Shades of Green

Abstract Image

The use of alternative reaction solvents is reviewed in terms of life cycle. Supercritical CO2, ionic liquids, fluorous solvents, water, and renewable organics are compared on the basis of their solvency, ease of use, reusability, health and safety, environmental impact, and economic cost.

James H. Clark * and Stewart J. Tavener
Green Chemistry Centre, Department of Chemistry, University of York, Heslington, York, U.K. YO10 5DD
Org. Process Res. Dev., 2007, 11 (1), pp 149–155
DOI: 10.1021/op060160g
Publication Date (Web): November 4, 2006

http://pubs.acs.org/doi/full/10.1021/op060160g?prevSearch=GREEN%2BSOLVENTS&searchHistoryKey=

This article  critically reviewS the use of alternative solvents in chemistry. Rather than follow the well-trodden path of discussing in turn the reactions that have been performed in each major type of alternative solvent, we will instead structure our article in terms of what we consider to be the fundamental issues:  life cycle analysis (so as to establish the “green” and sustainability aspects from the outset), solvency (so as to consider what is needed in the application and how the alternatives manage to meet these needs), and application (to consider practical issues in both process and product).

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