Speciality Chemicals Magazine SEP / OCT 2024 | Page 34

PHARMACEUTICALS
Figure 3 - 1-tosyl-substituted α , β-unsaturated formamide ( left ) & Knoevenagel-type condensation product ( right )
Preparation of Knoevenageltype condensation products
The reaction of ketones or aldehydes with TosMIC and base ( e . g . t-BuOK ), at low temperatures ( -70 to -40 ° C ) in aprotic solvents ( e . g . THF ), leads to 1-tosyl-substituted α , β-unsaturated formamides . 24-27
Subsequent dehydration ( e . g . using POCl 3 and i-Pr 2
NH ) gives 1-tosyl-substituted α , β-unsaturated isocyanides , sometimes called Knoevenagel-type condensation products , which are extensively used as TosMIC homologues and as Michael acceptors for pyrrole synthesis . 4 Figure 3 shows the precursor and product .
A representative use case for this application is an improved production method , in which the intermediate α , β-unsaturated formamide compound is prepared from a ketonic precursor , for manufacturing the steroid progesterone . 28 In another recently published method for manufacturing progesterone , the intermediate Knoevenagel product compound is prepared directly from the ketonic 4-androstenedione , which was seemingly less expensive than the traditional starting material . 29
One industrial application of converting an aldehyde to a Knoevenagel product is found in some syntheses of the pharmaceutical compound papaverine . 30 For preparation of the same imidazole , reacting TosMIC with an aldehyde to get a Knoevenagel product before reacting that with an amine has given higher yields than for the corresponding direct synthesis ( mentioned previously ) via TosMIC . 25
Importance of purity
Low residual impurities in TosMIC are important in order to optimise the final product ’ s consistency , yield and quality . Every situation is different , but a use case for why low residual impurities in TosMIC are important is that p-toluenesulfinic acid ( TosH ), with pKa ≈ 1.66 , is a much stronger acid than TosMIC . 31
As such , TosH would more readily deprotonate in base , depleting the amount of base available for deprotonating TosMIC . The result would be lower yields for TosC-HNC , which , as mentioned previously , is the product of the first reaction step for all three whitepaper usage groups .
Low loss on drying ( LOD ) is important technically because LOD represents a chemical sample ’ s total moisture content . 32 TosMIC is moisturesensitive and therefore more subject to degradation in the presence of greater moisture .
Controlling the moisture content is also important in the quality preparation of pharmaceuticals , foodstuffs and plastics , among others . 33 In the case of APIs , the moisture content affects the physical and chemical properties of finished dosage forms , and is therefore important to control it by limiting the amounts introduced by reagents and / or precursors like TosMIC .
Finally , a low residue on ignition would indicate a low amount of inorganic impurities , which in TosMIC ’ s case includes heavy metals . 34 These impurities can potentially contaminate medicine or supplement products , and it would therefore be important to control and limit the amounts introduced to manufacturing processes by chemicals like TosMIC . 35
Varsal is one of the world ' s largest producers of TosMIC with capabilities for consistent , large-scale , pharma-grade production . The company ’ s proprietary manufacturing logistics processes allows it to produce consistent , stable , extremely high-purity material with low residual impurities , low LOD and low residue on ignition . ●
Don Wang
GENERAL MANAGER
VARSAL , INC . k + 1 215 957 5880 J don @ varsal . com j www . varsal . com
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34 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981