Synthesis crystallisation

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

A variety of strategies have been devised to obtain chiral separations. Although the focus of this article is on chromatographicaHy based chiral separations, other methods include crystallisation and stereospecific ensymatic-catalysed synthesis or degradation. In crystallisation methods, racemic chiral ions are typically resolved by the addition of an optically pure counterion, thus forming diastereomeric complexes. 

Nitrates. Iron(II) nitrate hexahydrate [14013-86-6], Fe(N03)2 6H20, is a green crystalline material prepared by dissolving iron in cold nitric acid that has a specific gravity of less than 1.034 g/cm. Use of denser, more concentrated acid leads to oxidation to iron(III). An alternative method of preparation is the reaction of iron(II) sulfate and barium or lead nitrate. The compound is very soluble in water. Crystallisation at temperatures below — 12°C affords an nonahydrate. Iron(II) nitrate is a useful reagent for the synthesis of other iron-containing compounds and is used as a catalyst for reduction reactions. 

Ak2o has been iastmmental ia developiag a new process for the stereospecific synthesis of 1,4-cyclohexane diisocyanate [7517-76-2] (21). This process, based on the conversion of poly(ethylene terephthalate) [25038-59-9] circumvents the elaborate fractional crystallisation procedures required for the existing -phenylenediamine [108-45-2] approaches. The synthesis starts with poly(ethylene terephthalate) (PET) (32) or phthaUc acid, which is converted to the dimethyl ester and hydrogenated to yield the cyclohexane-based diester (33). Subsequent reaction of the ester with ammonia provides the desired bisamide (34). The synthesis of the amide is the key... 

The tetrahydronicotyrine produced by these methods is identical with dZ-nicotine, and this, by crystallisation of the d-ditartrate, was separated into d- and Z-nicotine. The salient steps in Pictet s original synthesis may be represented as follows —... 

The close relationship of eegonine to tropine is brought out by its Oxidation products, which when chromic anhydride in acetic acid is the agent used are tropinone, CgHijON (p. 74), tropinic acid, CgHi304N (P- 75) and ecgoninic acid, C HnOgN. The latter crystallises from benzene in colourless needles, m.p. 93°, and has been shown by Willstatter and Bode to W-methylpyrrolidone-2-acetic acid, and this was confirmed by Willstatter and Hollander s synthesis of the acid. 

This formula was confirmed hy Haworth and Perkin s synthesis of a-flZZocryptopine from herherine, the first application of a process, of which examples have heen given already in the syntheses of cryptopine (p. 298) and protopine (p. 301) hy the same authors. Anhydrotetrahydromethyl-herherine (I cf. hase (a), p. 346) in dry chloroform was added to a solution of perhenzoic acid in ether cooled helow 5°. The amine oxide, C21H23O5N (II), separated as an oil, which after shaking with sodium hydroxide solution, solidified and was crystallised from water in slender prisms, m.p. 135°. It was dissolved in acetic acid, hydrochloric acid added, the mixture heated in boiling water for an hour and the hase precipitated hy addition of potassium hydroxide. The precipitate was dissolved in methyl alcohol, ether added, the alcohol washed out with water and the ethereal... 

The first product in the Spath and Gohring synthesis is d/-i/i-ephedrine, m.p. 118-9°, which was resolved, by crystallisation of the d-tartrate and Z-tartrate in succession, into Z- and [Pg.641]

The unwanted erythro isomer of (11) crystallised out at this point, so the synthesis continues with the mother liquors. We must now protect the NH2 and both OH groups during the nitration - this also allows purification of crystalline threo (12). 

The use of ultrasound in both the synthesis and crystallisation of a broad array of both organic and inorganic materials has been intensively researched and is well documented [61-64]. An application of ultrasound that has received relatively less attention however, is in the dissolution of colloidal particles. Prakash and Ghosh [65] reported on the dissolution of silver colloids under 1 MHz ultrasound irradiation, proposing that the silver is oxidised by sonochemically produced hydroxyl radicals. Sostaric et al. [66] investigated the dissolution of MnC>2 colloids in the presence of aliphatic alcohols at a lower frequency of 20 kHz. They found that... 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

With these solid supports in hand, we turned our attention to a new route to the synthesis of our target molecule 23 (Scheme 8). The tricky reductive amination should be replaced by an N-alkylation. To that end, bromoacetic acid is attached to 24c using DIC and Hiinig s base followed by the nucleophilic substitution with the corresponding benzy-lamine in DMSO/toluene (1 1), which can be easily monitored by the Beilstein test, followed by sulfonamide formation in DCM using N-methylmorpholine as base. For the final cleavage, 2% TFA in DCM is used and the resulting solution is filtered in a saturated NaHCC>3 solution to neutralise the acid before evaporation of the solvent. The crude product was then crystallised from ethyl acetate/heptane to yield the desired product in 27% yield overall and 99A% HPLC purity (see Table 4). 

This stereospecific oxidation does not occur for all dioximes, probably due to isomerisation of the dioxime during the reaction or to different reaction mechanisms involved in the use of different oxidants. When the lipophilic-hydrophilic balance of the two furoxan isomers is appropriate, they are easily separated by chromatography or fractional crystallisation. For example, the synthesis of 4-hydroxymethyl-3-furoxancarboxamide (CAS 1609), one of the most promising furoxancarboxamide vasodilators (see later), passes through the intermediate formation of a mixture of the two isomeric methyl hydroxymethylfuroxancarboxylic esters, which can easily be separated by recrystallisation from isopropyl acetate [18]. 

Experiment. E. Fischer s Indole Synthesis.—Mix 2 g. of phenylhydrazine with 2 c.c. of acetone in a test tube. Water is eliminated and a turbidity appears. Suspend the tube in the boiling water bath for forty-five minutes, then add 6 g. of dry zinc chloride and heat the mixture for a few minutes with stirring in an oil bath at 180°. Now wash the dark-coloured melt into a small round-bottomed flask with four volumes of dilute hydrochloric acid and separate the resultant a-methylindole by distillation with steam. The substance collects as an oil which soon solidifies. After drying crystallise it from a little petrol ether. Melting point 59°. 

A synthesis of acetylalanine, from which alanine can be obtained by hydrolysis, was described in 1900 by de Jong. Pyruvic acid was neutralised with ammonium carbonate there was a considerable rise in temperature, carbon dioxide was evolved and the ammonium salt of acetylalanine crystallised out The explanation of this reaction is based upon Erlenmeyer and Kunlin s synthesis of phenylalanine from phenyl-pyruvic acid and it proceeds as follows —... 

As this compound contains two asymmetric carbon atoms, four stereoisomeric forms are possible by synthesis these must occur in two inactive forms. These forms Leuchs separated by crystallisation of the copper salts, the more insoluble acid being termed (a)-7-oxy-proline, the other (b)-7-oxyproline. 

As already pointed out, recent advances in the synthesis and structural characterisation of discrete molecular alumoxanes have lately been the subject of review [8]. While developments in the crystallisation and structural... 

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