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Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols

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Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols Continuous-flow multistep synthesis of cinnarizine, cyclizine, and a buclizine derivative from bulk alcohols Citation for published version (APA): Borukhova, S., Noël, T., & Hessel, V. (2015). Continuous-flow multistep synthesis of cinnarizine, cyclizine, and a buclizine derivative from bulk alcohols. ChemSusChem, 9(1), 67-74. https://doi.org/10.1002/cssc.201501367 DOI: 10.1002/cssc.201501367 Document status and date: Published: 09/12/2015 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 25. Sep. 2021 DOI:10.1002/cssc.201501367 Full Papers Continuous-Flow Multistep SynthesisofCinnarizine, Cyclizine, and aBuclizine Derivative from Bulk Alcohols Svetlana Borukhova,[a] Timothy Nol,*[a, b] andVolker Hessel*[a] Cinnarizine, cyclizine, buclizine, and meclizine belong to excellent waytosynthesize intermediates to be used in drug afamily of antihistamines that resemble each other in terms of synthesis. Inline separation allows the collection of pure prod- a1-diphenylmethylpiperazinemoiety.Wepresent the develop- ucts and their immediate consumption in the following steps. ment of afour-step continuous process to generate the final Overallisolated yields for cinnarizine, cyclizine, and abuclizine antihistamines from bulk alcohols as the starting compounds. derivativeare 82, 94, and 87%, respectively. The total residence HCl is used to synthesizethe intermediate chlorides in ashort time for the four steps is 90 min with aproductivity of 1 reactiontime and excellent yields. This methodology offers an 2mmolhÀ . Introduction Functional group interconversion is one of the most used tech- high.[13] Thus, reaction rates can only be increased to alimited niques in drug synthesis.[1] The conversion of hydroxyl groups extentinbatch reactors. In contrast to batch reactors, micro- to their corresponding halidesisarguably one of the most ver- flow technology offers an excellent platform to enable this sort satile transformations,whichisoften followed by anucleophilic of processes.[14–17] The absence of headspace and safe pressuri- substitution. Therefore, this is one of the key research areasin zation within microchannels helps to keep hydrogen chloride the synthesis of activepharmaceutical ingredients (APIs).[2] dissolved at high reactiontemperatures. Multiple examples of Chlorides are very interesting because of their abundance in reactionrate acceleration in microreactors under high temper- nature and their low molecular weight. The synthesisofchlo- ature and pressure exist.[18–21] In addition, the modularity of ride derivatives from alcohols usually requires the use of chlori- continuous-flow reactors allowsthe construction of reaction nating agents such as thionylchloride,[3] phosphorus chlor- networks todeliver natural products[22,23] and APIs[24–29] in ides,[4] pivaloyl chloride,[5] Vilsmeier reagent,[6] tosyl chloride,[7] asafe, quick, and efficient way. 2,4,6-trichloro-[1,3,5]triazine with DMF,[8] oxalyl chloride,[9] and Several milestones have been reachedinthe conversionof phosgene.[10] Unfortunately,these chlorinating agents have alcohols to chlorides, that is, chlorodehydroxylation. Tundo high toxicities.[11] Moreover,asonly apart of the chlorinating et al. have described asolvent-free synthetic method, that is, agent molecule is used in the reaction, waste is generated in gas-liquid phase-transfer catalysis (GL-PTC), in which agaseous stoichiometric amounts, which leads to aprocess that is not reagents flow through amolten phase-transfer catalyst sup- atom efficient or green.[12] ported on asolid.[30,31] Microwave heating technology showed The ideal process to convert primary alcohols to the corre- high efficiency in the field of chlorodehydroxylations.[32] Reid sponding chlorides is based on the reactionofneat alcohol et al. combined the microwaveheatingofionic liquidsand with hydrogen chloride. This will maximize atom efficiency and aqueous hydrochloric acid for arange of alcohols with and result in water as the sole by product. Although possible, the withoutadded catalysts.[32] Short-chain alcohols have been handling of hydrogen chloride gas is challenging, especially on converted in highyields and selectivitywithin 10 min under alarge scale. Hydrochloric acid can be used as an alternative. pressurized microwaveconditions. The reaction rates were However,low to average temperatures need to be maintained measured to be in the order of 100 times faster than nonmi- to keep the solubility of hydrogen chloride in water sufficiently crowavehigh-temperature chlorodehydroxylations. Kappe et al. have extended the microwave heatingtechnology with [a] S. Borukhova,Dr. T. Nol, Prof. Dr.V.Hessel hydrochloric acid to acontinuouslyoperating microchip-based Department of Chemical Engineering and Chemistry flow setup.[33] The full conversion of n-butanol was obtained Technische UniversiteitEindhoven Den Dolech 2, 5600 MB Eindhoven (Netherlands) with three equivalents of hydrochloric acid, within 15 min resi- E-mail:[email protected] dence time at 160 8Cand 20 bar.Ifthe optimal conditions [email protected] were applied to n-hexanol and n-decanol,the reactivity de- [b] Dr.T.Nol creasedwith the increasedchain length. Department of Organic Chemistry In this study,weconvert bulk alcohols into the correspond- Ghent University Krijgslaan 281 (S4), 9000 Ghent(Belgium) ing chlorides, whichare subsequently consumed in the contin- Supporting Information for this article is available on the WWW under uous multistep synthesis of antiemetic agents and antihista- http://dx.doi.org/10.1002/cssc.201501367. mines, such as cyclizine, meclizine, abuclizine derivative, and ChemSusChem 2016, 9,67–74 67 2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Papers cinnarizine. We extend the progress in the field of chlorodehy- crease of the residence time leads to incomplete conversion droxylation by applying milderconditions on awide scope of along with the formation of dibenzyl ether. substrates in the capillary reactor.This offers arobust and Subsequently,the optimal conditions found for the reaction more accessible alternative to microchips, as well as greater with benzyl alcohol were applied to other alcohols. The chlor- versatility with regard to the production volumeand rate. As ides synthesized at 120 8Cwithin 15 min residence time along aresult of the high abundance of the benzylmoiety in APIs, with their yields are shown in Scheme 1. The chloride deriva- we startedbyoptimizing the conversion of benzylalcoholto tives of alcohols are usually volatile because of the presence of benzylchloride. The integration of an inline liquid–liquidsepa- weak intermolecular forces, therefore, the products werecol- rator with the reactor afforded pure benzyl chloride, which lected into asealed vial with deuterated chloroform that con- was used readily in subsequentreactions. Finally,wedemon- tained an external standard (1,3-dimethoxybenzene) and later strate astep-by-step procedure to perform afour-step continu- analyzed as such. In the case of the terminal alkyne 4-pentyn- ous synthesis to prepare relevant APIs, such as cinnarizine, cy- 1-ol, the formation of dark viscousagglomerates with alow clizine,and abuclizine derivative. yield of the chloride was observed. The reaction with tetrahy- drofurfuryl alcohol resulted in the partial cleavageofether and gave amixture of mono- and disubstitutedchloropentanes. If Results and Discussion the same conditions were applied to 1,5-pentanediol, full con- version was observedand a19% yield of dichloropentane was Synthesis of alkyl chlorides formed. Aromaticcompounds included in the scope differed in The synthesis of chlorides started from similar conditions to their solubility in the aqueous phase, which can explain the those applied by Kappe et al.,inwhich three equivalents of differences in yields in the substitution at the benzylic position. hydrochloric
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