Recrystallization schemes

In a sequence of operations of the above kind the losses of the desired component A can be considerable, and the final amount of pure crystals may easily be a minute fraction of the starting mixture AB. This question of yield from recrystallization processes is of paramount importance, and many schemes have been designed with the object of increasing both yield and separation efficiency. The choice of solvent depends on the nature of the required substance A and the impurity B. Ideally, B should be very soluble in the solvent at the lowest temperature employed, and A should have a high temperature coefficient of solubility so that high yields of A can be obtained from operation within a small temperature range. Some of the factors affecting the choice of a solvent are discussed in section 3.2. 

Theoretical analyses and surveys of the factors affecting the choice of different fractional crystallization schemes have been made by Doerner and Hoskins 

Procedures for the design of industrial fractional crystallization processes for multicomponent systems, utilizing appropriate eutectic and solid solution phase diagrams, have been described by Fitch (1970, 1976), Chang and Ng (1998), Cisternas (1999), Cesar and Ng (1999) and Wibowo and Ng (2000). 

Equilibrium values from the upper Ponchon-Savarit diagram are used to construct the equilibrium curve in the lower McCabe-Thiele diagram as follows. For a given tie-line, a vertical line is drawn down from the end-point on the N-y curve on to the diagonal (x = y) in the lower diagram. A horizontal line is then drawn to the left to meet the vertical from the other end-point of the tie-line on the N-x curve. The intersection gives a point on the equilibrium curve. This procedure is repeated. 

For reflux ratio R Fmin (where R = QS /S Co) the operating line passes through Fmore steeply than the tie-line and determines the solution and crystal poles Q and W. Arbitrarily drawn lines radiating from these poles are used in 

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The reaction of (-)-ephedrine (42) with thiophosphoryl chloride was reported to give 2-chloro-l,3,2-oxazaphospholidine 2-thione as the isomeric pair 101a,b, which could be separated by chromatography over silica gel [32] or recrystallization (Scheme 29) [55],... 

Diastereomerically pure (2W,5.V)-l,3-diaza-2-(2-methylphenyl)-3-phenyl-2-phosphabicyclo[3.3.0]octane (.S )-202] was formed in the thermal reaction of (S)-2-(anilinomethyl)pyrrolidines (197a) with o-TolP(NMe2)2 and isolated in 27% yield after recrystallization (Scheme 56) [87], Its cyclopalladation with palladium diacetate followed by anion metathesis gave dimer (5,5)-203 (Scheme 56) [87],... 

The first reported synthesis of hydroxyurea (24) consists of the condensation of hy-droxylamine with potassium cyanate (Scheme 7.14) [87]. Condensation of hydroxy-lamine with ethyl carbamate also gives pure hydroxyurea in good yield after recrystallization (Scheme 7.14) [88]. Nitrogen-15 labeled hydroxyurea provides a useful tool for studying the NO-producing reactions of hydroxyurea and can be prepared by the condensation of N-15 labeled hydroxylamine with either potassium cyanate or trimethylsilyl isocyanate followed by silyl group removal (Scheme 7.14) [89, 90]. Addition of hydroxylamine to alkyl or aryl isocyanates yields alkyl or aryl N-hydroxyureas (Scheme 7.14) [91, 92]. The condensation of amines with aromatic N-hydroxy carbamates also produces N-substituted N-hydroxyureas (Scheme 7.14) [93]. 

A novd example of a catalytic enantioselective domino process1201 is the inter-intramolecular nitro-aldol reaction described by Shibasaki et al which generates substituted indanones. As catalyst a praseodym-heterobimetallic complex with binaph-thol as chiral ligand is employed. Treatment of keto-aldehyde 41 with nitromethane in the presence of the catalyst 46 at -40 °C and successive warming to room temperature affords diredly the produd 42 in an overall yield of 41 % and 96 % ee after several recrystallizations (scheme 9). As intermediates the nitromethane adduct 43 and the hemiacetal 44 can be proposed. In a second aldol reaction 44 leads to 45 which isomerizes to the thermodynamically more stable epimer 42. 

Before examining the reaction of deactivated alkenes, the phosphonium salt synthesis was applied to 1,3-dienes.21 When ( )-6-phenyl-l,3-hexadiene was treated with equimolar amounts of PPh3 and CF3S03H in the presence of RhH(PPh3)4 (2.5 mol%) in THF at 0 °C for 3 h, ( )-(6-phenyl-3-hexenyl)triphenylphosphonium salt was obtained in 89% yield after anion exchange with LiPF6 and recrystallization (Scheme 16). The addition of phosphine and hydrogen occurred at the 1- and 2-carbon atoms of the 1,3-diene, respectively. The reaction of (7)-1,3-dienes was then performed for comparison. 

The malic acid-derived auxiliary which gives good results in the ferrocene series also looks promising among the chromium complexes, and the six-membered acetal of 400 is much more easily hydrolysed than the tartrate-derived acetals of Scheme 164 . Lithiation and bromination of 400 gives, after hydrolysis of the acetal, the complex 401 in 90% ee, increasing to >99% after recrystallization (Scheme 165). 401 is an intermediate in a formal synthesis of (—)-steganone (Scheme 182, Section III.B.2.b). 

Di(p-tolyl)-1,10-phenanthroline 14 is synthesized in 70% yield from 1,10-phenanthroline 3 (1 equiv) and 4-lithiotoluene 13 (5 equiv), after hydrolysis, oxidation with Mn02 and recrystallization (Scheme 9.11). This reaction, detailed in Protocol 9, follows a literature procedure to make various poly-imines substituted by alkyl or aryl groups a to the nitrogen atoms.20... 

Two types of macrocyclic multitelluranes with hypervalent Te-O apical linkages in the main chain were prepared by the reaction of a telluronium salt 220 or a cationic ditelluroxane 221 with phthalate via [3+2] and [2+2] assembly, respectively <2001CC1428>. The generation of the telluronium salt 220 in situ by the reaction of bis(4-methylphe-nyl) telluroxide with 1 equiv of triflic anhydride in MeCN at 240 °C, followed by the addition of 1 equiv of sodium phthalate at room temperature, gave the hypervalent macrocycle 38 in 76% yield after recrystallization. Treatment of the cationic ditelluroxane 221 with the same phthalate in MeCN at room temperature produced the hypervalent macrocycle 222 in 14% yield after recrystallization (Scheme 32). 

Have purging data to show it is controlled in the recrystallization scheme. 

The reaction of TiCl4 with Li2[(CsH3)2(SiMe2)2] in toluene at room temperature affords a mixture of as- and /rmolar ratio of 1 2 after recrystallization (Scheme 164 Section 4.05.3.1.1.(iv)). 

Figure 7.6. Fractional recrystallization schemes a) diamond, b) double withdrawal. After Tipson, 1956)...

Both the Chlopin and Doemer-Hoskins relationships have been widely used to correlate the results of fractional precipitation and recrystallization schemes... 

The importance of a one-pot protocol is particularly relevant in the case of small volatile substrates, where the isolation of the azide intermediates would be both difficult and hazardous. In contrast, the corresponding amines can be isolated as their solid hydrochloride salts, which can be purified via recrystallization. For example, hydroazidation of methylenecyclobutane (75) followed by in situ reduction and acidification yielded pure cyclobutane amine hydrochloride (77) in 60% overall yield after recrystallization (Scheme 4.4). 

Reaction of 3-aminopyridine-2-ol (78) with 2b produced 79 in 75% yield after chromatographic purification and recrystallization (Scheme 24). A similar observation was made for 80a,b with 2b. Thin Layer Chromatography (TLC) analysis indicated that two equivalents of 80a,b were required to afford 81a,b in 72—76% yield (Scheme 24,05ZDN(B)999). Addition of 1-acylthiosemicarbazides 28 to 2b, resulted in an initial CTC followed by the formation of naphthothiazines 82 (Scheme 24,07AEK222). 

Lectka and coworkers took advantage of the high electrophilic reactivity of the carbon-nitrogen double bond in the AT-tosyl imino ester 340 and studied enantioselective additions of ketone-derived silyl enol ethers 220, mediated by (7 )-To1-BINAP-CuC104 (341). The loading of ligand and metal salt could be reducedto 2 mol%. Keto esters 342 were thus obtained in high chemical yields and enantiomeric excess, which could be increased to 99% ee after recrystallization (Scheme 5.92) [175]. The protocol was extended to propiophenone-derived... 

Researchers at Merck reported SAD reaction of a styrene derivative 164 for the synthesis of the substance-P inhibitor 166 [80], SAD on 164 using AD-mix a gave crude diol 165 with 87% ee optical purity, which was further upgraded to > 99% ee upon recrystallization (Scheme 9.44). Noteworthy, of the process is that the stereochemistry created in dihydroxylation reaction is responsible for the origin in installation of all the three chiral centers in the final drug substance. 

GaCh has a very strong affinity to chloride, and forms a stable gallate anion, GaCU". Onium chlorides were converted to gallate salts by treatment with GaCh, which were purified by recrystallization (Scheme 7.1) [13]. The chlorides could be regenerated by treatment with pyridine. 

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