Intermediate in a Multistep Synthesis

Goal Maximize growth to prevent excessive fines and occlusion of impurities 

Issues High slope of temperature versus solubility curve High nucleation rate results in wide PSD Seed point is difficult to define 

Crystallization of the penultimate intermediate in a multistep synthesis was required primarily for separation of the intermediate from accumulated organic impurities. The previous reaction and subsequent extraction are both run in isopropyl acetate (IPAC) and are fed to the crystallizatiorr step at a temperature (80°C) that is slightly above the saturation temperature ( 70 C) in the water-saturated IPAC solution. 

Seed addition either too soon or too late results in uncontrolled nucleation, which in this case produces excessive fines and reduced potential for growth. The issue of when to seed is often critical, and the actual saturation temperature for optimum seed addition is subject to some batch-to-batch variations because of possible changes in concentration and/or impurities from the previous reaction(s) and purification(s). 

Control of supersaturation is difficult in cooling operations when the solubihty slope is high and small temperature changes result in creation of supersaturation ratios outside the metastable region either globally or locally (i.e., at the cooling surfaces). 

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How pure do the intermediates and products need to be This might seem like another question with an obvious answer, but there are several aspects that need to be considered. It is rarely a good use of time and effort to prepare analytically pure samples of an intermediate in a multistep synthesis if that intermediate will simply be transformed into something else. If the next step in the synthesis will not be inhibited by the impurities in the crude reaction mixture, do not spend time purifying the intermediate. Instead, wait until the end of the synthesis and rigorously purify the final compound. 

As expected, the yields of catenanes by this approach are low, which is why improved methods for the preparation of such compounds have been developed. The acyloins are often only intermediate products in a multistep synthesis. For example they can be further transformed into olefins by application of the Corey-Winter fragmentation. 

Chemists from the Sankyo Co. reported the use of 6-bromopenicillanate 28, easily obtained from 6-aminopenicillanic acid, in a multistep synthesis of (3RAR)-4-acetoxy-3- (R)- -((/-hutyldimethylsilyl)oxy)ethyl]-2-azctidinonc (31)97, a pivotal intermediate for the synthesis of 1-/9-methyl carbapenem antibiotics (equation 23)98. After cleavage of the thiazolidine ring of 28 with trimethyloxonium tetralluoroborate, the intermediate 29 was subjected to a Reformatsky condensation with acetaldehyde, catalysed by diethyla-luminium chloride. The 8-(S) stereocentre in 30, formed in 50% d.e., was inverted under Mitsunobo conditions to approach the target molecule 31. 

Certain of the p-chlorophenyl-substituted carboxylic acids are related products in a multistep synthesis. A schematic outline of synthetic procedures is presented to clarify these relationships. Properties of seven new p-chlorophenyl-substituted intermediates and six new p-chlorophenyl-substituted carboxylic acids are reported. All of the 13 new compounds have been characterized by conventional criteria. Both gas-liquid chromatography and nuclear magnetic resonance are used to assess the purity of the carboxylic acids and their intermediates. 

Carboxylic acid X is an intermediate in the multistep synthesis of proparacaine, a local anesthetic. Devise a synthesis of X from phenol and any needed organic or inorganic reagents. 

In a multistep synthesis, plant productivity was limited by slow filtration and drying of a key intermediate. Analysis of the overall operation indicated that these problems resulted from the small mean particle size and bimodal PSD being obtained in the antisolvent addition step in the crystallization of the intermediate. Photomicrographs indicated some degree of agglomeration. 

In a multistep synthesis of (-)-acetomycin (31), which served to confirm its absolute configuration, the doubly-branched furanose (32) (Scheme 5), produced from D-glucose by a stereoselective Claisen rearrangement (Vol. 23, p. 150), was degraded to the intermediate (33), which was subsequently elaborated to the target (glucose carbons indicated). 5... 

Each of these syntheses of aphidicolin provides an example of the utilization of stereochemistry established in an early intermediate to control subsequent stereochemistry as the synthesis is completed. This represents the control of relative stereochemistry, and the syntheses as a whole are diastereoselective. The final products are racemic materials. Most syntheses which have been completed to date have been of racemic materials, in which control of relative stereochemistry has been sufficient. As discussed in Section 11.3, the synthesis of a substance in optically pure form requires that either a catalyst, a reagent, or one of the starting materials be optically active. Diastereoselective syntheses, such as those discussed in Schemes 11.21-11.24, can be made enantioselective if an early intermediate can be obtained in optically active form by some enantioselective process. The advantage of establishing optical purity early in a multistep synthesis is that all the material subsequently formed by diastereospecific processes will possess the desired absolute stereochemistry. A resolution or other enantioselective process introduced late in a synthetic scheme can transform only one half of the material to the desired product. 

Hydrogenation of Acetylenes. Complete hydrogenation of acetylenes to the corresponding alkanes, which maybe requited to remove acetylenic species from a mixture, or as a part of a multistep synthesis, may be accompHshed using <5 wt % palladium or platinum on alumina in a nonreactive solvent under very mild conditions, ie, <100°C, <1 MPa (10 atm). Platinum is preferred in those cases where it is desired to avoid isomeri2ation of the intermediate olefin. Silver on alumina also can be used in this appHcation as can unsupported platinum metal. 

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

The possibility of carrying out a multistep synthesis makes it possible to obtain P,B-containing derivatives from unstable intermediate a-hydroxyalkylphosphines. Thus, phenylphosphine, salicylic aldehyde, phenylboric acid anhydride, and triethylamine interact to give a bicyc-lic product—2,8,9-trioxa-1 -borata-4-phospha-6,7 -benzobicyclo [3,3,3] nonane (115) [Eq. (74)] (87IZV2118 89IZV946). In this case an aldehyde takes part in the reaction opening up new synthetic possibilities. 

The preparation of the title lactone has been described by a multistep synthesis from holarrhimine. The method described in detail above is essentially an application of the hypoiodite reaction published by Ch. Meystre and co-workers. These authors also describe the isolgition of the intermediate hemiacetal in pure form. Saturated lactones epimeric at C-20 have also been obtained by chromic acid oxidation of 18,20-dihydroxy compounds which were in turn prepared by treatment of 20-hydroxypregnanes with lead tetraacetate, acetolysis of the resulting 18,20 3-oxides, and hydrolysis. Saturated lactones of the... 

D,L-Cycloserine 26 and its 3-methyl analog, derivatives of isoxazolinone, were prepared from D,L-Ser or o.L-Thr. The transformation involved replacement of the hydroxyl group by chlorine and subsequent treatment with hydroxylamine (57HCA1531). After being transformed into its 3-chloro derivative, l-G1u was transformed in a multistep conversion into 27, an intermediate in the synthesis of an antitumoric isoxazole-5-acetic acid (81JA7357). 

Tropolone has been made from 1,2-cycloheptanedione by bromination and reduction, and by reaction with N-bromosuccinimide from cyclo-heptanone by bromination, hydrolysis, and reduction from diethyl pimelate by acyloin condensation and bromination from cyclo-heptatriene by permanganate oxidation from 3,5-dihydroxybenzoic acid by a multistep synthesis from 2,3-dimethoxybenzoic acid by a multistep synthesis from tropone by chlorination and hydrolysis, by amination with hydrazine and hydrolysis, or by photooxidation followed by reduction with thiourea from cyclopentadiene and tetra-fluoroethylene and from cyclopentadiene and dichloroketene. - The present procedure, based on the last method, is relatively simple and uses inexpensive starting materials. Step A exemplifies the 2 + 2 cycloaddition of dichloroketene to an olefin, " and the specific oycloadduot obtained has proved to be a useful intermediate in other syntheses. " Step B has been the subject of several mechanistic studies, " and its yield has been greatly improved by the isolation technique described above. This synthesis has also been extended to the preparation of various tropolone derivatives. - " ... 

As an extension of this reaction, the selective intramolecular nucleophilic addition of a hydroxy group at Cy of a ruthenium allenylidene species generated by activation of propargylic alcohol by RuCl(Cp)(PPh3)2/NH4PF6 provides a ruthenium-vinylidene intermediate. The latter compound reacts with allylic alcohol via a second nucleophilic addition (Scheme 8.13) [27]. This unprecedented tandem reaction makes possible the construction of tetrahydrofuran derivatives in good yields, and has been used in the multistep synthesis of (-)calyculin A [28]. 

As illustrated in Scheme 11.10, enone 32, prepared from D-glucal in a multistep sequence, was reacted with lithium dimethylcuprate. Clean axial attack of the reagent at C4 gave the substituted ketone 33. Subsequent Wittig methylation and reduction was used to introduce the second methyl group of 34, a key intermediate in the synthesis of a-multistriatin. The same sequence was used in the preparation of calcimycin (A23187), the 4-C-methyl synthon 33 being used to construct the two required chirons [50]. 

Cholesterol biosynthesis proceeds via the isoprenoids in a multistep pathway. The end product, cholesterol, and the intermediates of the pathway participate in diverse cellular functions. The isoprenoid units give rise to dolichol, CoQ, heme A, isopentenyl-tRNA, famesylated proteins, and vitamin D (in the presence of sunlight and 7-dehydrocholesterol). Dolichol is used in the synthesis of glycoproteins, CoQ in the mitochondrial electron transport chain, famesylation and geranylgeranylation by posttrans-lational lipid modification that is required for membrane association and function of proteins such as p2V and G-protein subunits. 

Besson and co-workers have exploited microwave-assisted Pd/C-catalyzed transfer hydrogenation conditions in the multistep synthesis of some important thiazoloquinazolinone derivatives involving the reduction of a nitro substituent in several intermediate steps [43]. Herein, thermal reactions carried out under microwave conditions have greatly favoured in reducing the overall time... 

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