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  • Continuous-flow multistep synthesis of cinnarizine,cyclizine, and a buclizine derivative from bulk alcoholsBorukhova, S.; Nol, T.; Hessel, V.

    Published in:ChemSusChem


    Published: 09/12/2015

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  • Continuous-Flow Multistep Synthesis of Cinnarizine,Cyclizine, and a Buclizine Derivative from Bulk AlcoholsSvetlana Borukhova,[a] Timothy Nol,*[a, b] and Volker Hessel*[a]


    Functional group interconversion is one of the most used tech-

    niques in drug synthesis.[1] The conversion of hydroxyl groups

    to their corresponding halides is arguably one of the most ver-satile transformations, which is often followed by a nucleophilic

    substitution. Therefore, this is one of the key research areas inthe synthesis of active pharmaceutical ingredients (APIs).[2]

    Chlorides are very interesting because of their abundance innature and their low molecular weight. The synthesis of chlo-

    ride derivatives from alcohols usually requires the use of chlori-

    nating agents such as thionyl chloride,[3] phosphorus chlor-ides,[4] pivaloyl chloride,[5] Vilsmeier reagent,[6] tosyl chloride,[7]

    2,4,6-trichloro-[1,3,5]triazine with DMF,[8] oxalyl chloride,[9] andphosgene.[10] Unfortunately, these chlorinating agents have

    high toxicities.[11] Moreover, as only a part of the chlorinatingagent molecule is used in the reaction, waste is generated instoichiometric amounts, which leads to a process that is not

    atom efficient or green.[12]

    The ideal process to convert primary alcohols to the corre-sponding chlorides is based on the reaction of neat alcoholwith hydrogen chloride. This will maximize atom efficiency and

    result in water as the sole by product. Although possible, thehandling of hydrogen chloride gas is challenging, especially on

    a large scale. Hydrochloric acid can be used as an alternative.However, low to average temperatures need to be maintainedto keep the solubility of hydrogen chloride in water sufficiently

    high.[13] Thus, reaction rates can only be increased to a limited

    extent in batch reactors. In contrast to batch reactors, micro-

    flow technology offers an excellent platform to enable this sortof processes.[1417] The absence of headspace and safe pressuri-

    zation within microchannels helps to keep hydrogen chloridedissolved at high reaction temperatures. Multiple examples of

    reaction rate acceleration in microreactors under high temper-ature and pressure exist.[1821] In addition, the modularity of

    continuous-flow reactors allows the construction of reaction

    networks to deliver natural products[22, 23] and APIs[2429] ina safe, quick, and efficient way.

    Several milestones have been reached in the conversion ofalcohols to chlorides, that is, chlorodehydroxylation. Tundo

    et al. have described a solvent-free synthetic method, that is,gas-liquid phase-transfer catalysis (GL-PTC), in which a gaseous

    reagents flow through a molten phase-transfer catalyst sup-

    ported on a solid.[30, 31] Microwave heating technology showedhigh efficiency in the field of chlorodehydroxylations.[32] Reidet al. combined the microwave heating of ionic liquids andaqueous hydrochloric acid for a range of alcohols with and

    without added catalysts.[32] Short-chain alcohols have beenconverted in high yields and selectivity within 10 min under

    pressurized microwave conditions. The reaction rates weremeasured to be in the order of 100 times faster than nonmi-crowave high-temperature chlorodehydroxylations. Kappe

    et al. have extended the microwave heating technology withhydrochloric acid to a continuously operating microchip-based

    flow setup.[33] The full conversion of n-butanol was obtainedwith three equivalents of hydrochloric acid, within 15 min resi-

    dence time at 160 8C and 20 bar. If the optimal conditionswere applied to n-hexanol and n-decanol, the reactivity de-creased with the increased chain length.

    In this study, we convert bulk alcohols into the correspond-ing chlorides, which are subsequently consumed in the contin-

    uous multistep synthesis of antiemetic agents and antihista-mines, such as cyclizine, meclizine, a buclizine derivative, and

    Cinnarizine, cyclizine, buclizine, and meclizine belong toa family of antihistamines that resemble each other in terms of

    a 1-diphenylmethylpiperazine moiety. We present the develop-

    ment of a four-step continuous process to generate the finalantihistamines from bulk alcohols as the starting compounds.

    HCl is used to synthesize the intermediate chlorides in a shortreaction time and excellent yields. This methodology offers an

    excellent way to synthesize intermediates to be used in drugsynthesis. Inline separation allows the collection of pure prod-

    ucts and their immediate consumption in the following steps.

    Overall isolated yields for cinnarizine, cyclizine, and a buclizinederivative are 82, 94, and 87 %, respectively. The total residence

    time for the four steps is 90 min with a productivity of2 mmol h1.

    [a] S. Borukhova, Dr. T. Nol, Prof. Dr. V. HesselDepartment of Chemical Engineering and ChemistryTechnische Universiteit EindhovenDen Dolech 2, 5600 MB Eindhoven (Netherlands)E-mail :

    [b] Dr. T. NolDepartment of Organic ChemistryGhent UniversityKrijgslaan 281 (S4), 9000 Ghent (Belgium)

    Supporting Information for this article is available on the WWW under

    ChemSusChem 2016, 9, 67 74 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim67

    Full PapersDOI: 10.1002/cssc.201501367

  • cinnarizine. We extend the progress in the field of chlorodehy-droxylation by applying milder conditions on a wide scope of

    substrates in the capillary reactor. This offers a robust andmore accessible alternative to microchips, as well as greater

    versatility with regard to the production volume and rate. Asa result of the high abundance of the benzyl moiety in APIs,

    we started by optimizing the conversion of benzyl alcohol tobenzyl chloride. The integration of an inline liquidliquid sepa-

    rator with the reactor afforded pure benzyl chloride, which

    was used readily in subsequent reactions. Finally, we demon-strate a step-by-step procedure to perform a four-step continu-

    ous synthesis to prepare relevant APIs, such as cinnarizine, cy-clizine, and a buclizine derivative.

    Results and Discussion

    Synthesis of alkyl chlorides

    The synthesis of chlorides started from similar conditions to

    those applied by Kappe et al. , in which three equivalents ofhydrochloric acid was used with 15 min as a residence time.[33]

    The results of the initial screening at 120 8C are shown inTable 1. Already, 88 % of 1-chlorobutane was obtained in

    15 min residence time. The extension of the residence time to

    30 min increased the formation of dibutyl ether and resultedin a decrease in the yield to 77 %. For hexanol, the reaction

    was slower, and longer residence times improved the yield.As the benzyl moiety is widely used in API synthesis, our

    target compound was benzyl chloride. Under the same condi-tions, 100 % yield of benzyl chloride was obtained without theformation of dibenzyl ether, and no any other byproducts

    were observed in the GC chromatogram with 15 min residencetime. We speculated that the partial solubility of benzyl alcoholin water minimizes the mass transfer limitations. Moreover, asbenzyl chloride has a lower solubility in water than benzyl al-cohol, the equilibrium of the reaction shifts to the productside. A decrease of the amount of hydrochloric acid with an in-

    crease of the residence time leads to incomplete conversionalong with the formation of dibenzyl ether.

    Subsequently, the optimal conditions found for the reactionwith

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