Direct crystallization

NEW METHOD FOR DETERMINATION OF DRY RESIDUE IN NATURAL WATER BY MEANS OF DIRECTED CRYSTALLIZATION... 

In striking contrast to the above observations is the finding that both reduction and reductive methylation of the tetrahydropyranyl ether of 17a-ace-toxypregnenolone (71) afford the expected products (72a, b) in 85-88 % yields by direct crystallization of the crude reaction products. Clearly, the complications in the reduction of the 16-en-20-one system are attributable primarily to reactions of the carbon-carbon double bond rather than to the a-carbanion (73), which is the final intermediate in both the reduction of the 16-dehydro compounds and the 17-acetoxy ketones. 

Androst-4-ene-3,17-dione. Testosterone (0.58 g, 2 mmoles) is dissolved in a solution prepared from 3 ml of benzene, 3 ml of dimethyl sulfoxide, 0.16 ml (2 mmoles) of pyridine and 0.08 ml (1 mmole) of trifluoroacetic acid. After addition of 1.24 g (6 mmoles) of dicyclohexylcarbodiimide, the sealed reaction flask is kept overnight at room temperature. Ether (50 ml) is added followed by a solution of 0.54 g (6 mmoles) of oxalic acid in 5 ml of methanol. After gas evolution has ceased ( 30 min) 50 ml of water is added and the insoluble dicyclohexylurea is removed by filtration. The organic phase is then extracted twice with 5 % sodium bicarbonate and once with water, dried over sodium sulfate and evaporated to a crystalline residue (0.80 g) which still contains a little dicyclohexylurea. Direct crystallization from 5 ml of ethanol gives androst-4-ene-3,17-dione (0.53 g, 92%) in two crops, mp 169-170°. 

Note 2. Under conditions described in Note 1 VPC analysis of the crude material indicated 90.2% of 6j6, 19-ether and only 6.5% of ketone. In this case direct crystallization from ether-hexane affords pure 6j6, 19-ether. 

M. Yao, D. H. Matthiesen, A. Chait. Numerical simulation of heat transport and fluid flow in directional crystal growth of GaAs. Numer Heat Transf A 30 685, 1996. 

The diastereoselectivity is observed in the Henry reaction using optical active niti o compounds or a-heteroatom substituted aldehydes. Lor example, the reaction of O-benzyl-D-lactal-dehyde with methyl 3-niti opropionate in the presence of neubal alumina leads to a mixture of three niti o-aldol products from which D-ribo isomer is isolated by direct crystallization. D-Ribo... 

However, pMBCl 42 has a thermal stability issue and is expensive (Aldrich price 25 g for 69.90 the largest bottle). On the other hand, pMBOH 43 is stable and economically viable (Aldrich price 500 g for 84.90 the largest bottle). It was found that mono-N-alkylation of 36 proceeded well by slow addition (over 3 h) of 43 to a solution of 36 in acetonitrile in the presence of a catalytic amount of acid (p-TsOH) at 70 °C, as shown in Scheme 1.16. Slow addition of alcohol 43 minimized the self-condensation of 43 to form symmetrical ether 44, which was an equally effective alkylating agent. The product 41 was then directly crystallized from the reaction mixture by addition of water and was isolated in 90% yield and in >99% purity. A toluene solution of 41 can be used for the next reaction without isolation but the yield and optical purity of the asymmetric addition product were more robust if isolated 41 was used. In general, the more complex the reaction, the purer the starting materials the better. 

In order to overcome these two issues, we reversed the order of the reaction sequence, as summarized in Scheme 1.20. We took advantage of the alcohol functional group in 50. Oxidation ofpMB of 50 with DDQ proceeded smoothly to form cyclic aminal 52 (as a mixture of a and P = 11.5 1) in toluene at 0-10 °C. The resulting DDQH, which is insoluble in toluene, was filtered off, and isolated DDQH could be recycled as we demonstrated in the Proscar process (see p. 92) [32]. Thus, this process minimizes the impact to the environment from an oxidizing reagent. Cyclic aminal 52 was solvolyzed with NaOH in MeOH at 40 °C. The resulted anisaldehyde was reduced in situ to pMBOH 43 by addition of NaBH4 and the desired amino alcohol 53 was isolated by direct crystallization from the reaction mixture, upon neutralization with acetic acid, in 94% yield and >99.9% ee after crystallization from toluene-heptane. 

Preparation of ligand 31 Originally, chiral ligand 31 was prepared from (1R,2R)-1,2-diaminocydohexane 33 based on the racemic synthesis reported by Barnes et al. in 1978 [15], where picolinic acid 34 was activated with P(OPh)3 and then coupled with trans-l,2-diaminocyclohexane. The reported isolated yield in the case of racemate was only 47%. We optimized the preparation as shown in Scheme 2.8 [16]. Picolinic acid 34 was activated with CDI in THF. After confirmation of activation, chiral diamine 33 was added to the solution. When complete, the reaction was quenched via the addition of a small amount of water (to quench excess CDI). The reaction solvent was then switched from THF to EtOH, when the desired ligand 31 directly crystallized out. Ligand 31 was isolated in 87% yield by simple filtration of the reaction mixture in high purity. With a 22 litter flask, 1.25 kg of 31 was prepared in a single batch. 

The ratio of 8Z to HE is slightly better in the presence of DABCO in THF (Table 6.2 entry 9) than in pure methanol (Table 6.2 entry 7). Since the DABCO must be removed prior to the thermal rearrangement and the minimal impact on overall yield, we decided to run the Michael addition in methanol to afford a mixture of Z- and -adducts 8 in quantitative yield. The resulting solution of adducts 8 was solvent-switched to xylenes and heated at 125 °C for 2h, and at 135 °C for 4h to give a 62% assay yield of desired product 3. The reaction mixture was concentrated and hydroxypyrimidinone 3 was directly crystallized in 54% isolated yield as a white crystalline solid. 

Crystal structures are best viewed as three-dimensional computer images that can be rotated and viewed from any direction. Crystal structures can be displayed, and downloadable programs for graphical presentation of crystal structures can be found at the EPSRC s Chemical Database Service at Daresbury. This can be accessed at http //cds.dl.ac.uk/ cds. See also ... 

The submitters found that purification of the oil by direct crystallization gives only a small amount of the pure product. Attempted purification by distillation did not give satisfactory results. 

The commercially available form of Aspartame is hemihydrate Form II, which transforms into hemihydrate Form I when milled, and a 2.5-hydrate species is also known [57,58]. XRPD has been used to study the desolvation and ultimate decomposition of the various hydrates. When heated to 150°C, both hemihydrate forms dehydrate into the same anhydrous phase, which then cyclizes into 3-(carboxymethyl)-6-benzyl-2, 5-dioxopiperazine if heated to 200°C. The 2.5-hydrate was shown to dehydrate into hemihydrate Form II when heated to 70°C, and this product was then shown to undergo the same decomposition sequence as directly crystallized hemihydrate Form II. 

Fig. 4 Schematic representation of control over block copolymer thin film orientation by directional eutectic solidification. The scheme shows control of polystyrene-b-polyethylene (PS-b-PE) block copolymer microdomain orientation through directional crystallization of benzoic acid (BA), (taken from [95])...

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