Continuous-flow multistep synthesis of , , 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

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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 Nol,*[a, b] andVolker Hessel*[a]

Cinnarizine, cyclizine, buclizine, and belong to excellent waytosynthesize intermediates to be used in drug afamily of 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 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. Nol, 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.Nol 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 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 acid was used with 15 min as aresidencetime.[33] For solid compounds such as dodecanol, cyclohexanol, naptha- The results of the initial screening at 1208Care shown in lenemethanol, diphenyl methanol, and cinnamyl alcohol, atolu- Table 1. Already,88% of 1-chlorobutane was obtained in ene/acetone (2:1) solventcombination was used to afford solu- tions of 2.2m.

Table 1. Resultsofthe initial screening of the synthesis of primary chlor- ides and the optimization of benzyl chloride synthesis.[a] Utilization of benzylchloride

Entry Substrate Residence time HCl GC yield[b] Microflow technologyallows the connectionofsubsequent re- [min] [equiv.] [%] actions to afford truly continuous operation with aminimum [34,35] 11-butanol 15 3 88 of manual handling. To see the potential in the application 21-butanol 30 3 77 of continuous chloride synthesis, we connected the product 31-hexanol 15 3 46 stream of thebenzyl chloride forming reactiontoasecond re- 41-hexanol 30 3 82 actor in which another nucleophilic substitution would take 5benzyl alcohol 15 3 100 6benzyl alcohol 15 2 97[c] place.The connectionrelied on continuous inline liquid–liquid 7benzyl alcohol 30 2 98[c] separation, which occurred in aTeflon-membrane-based sepa- rator.Similarseparators have been used previously in multistep [a] The experiments wereperformedat120 Cinthe microcapillary-based 8 [36–38] setup (Scheme 1) with aqueousHCl (36 wt%). [b] The yieldswere calcu- continuous syntheses. The designand operation of this lated based on the GC–FID response with respect to 1,3-dimethoxyben- separator is described in the Supporting Information. For zene as an internal standard.Calibrations wereperformed with corre- acomplete separation, the correct pressure differenceshould spondingchloridespurchased from Sigma–Aldrich. [c] The presence of be appliedoverthe membrane to allow permeate to pass unconverted alcohol and dibenzyl etherwas detected. through the membrane without causing abreakthrough of the retained phase,oralternatively, without carrying the permeate within the retentate. The use of a5psi (1 psi= 6.89 kPa) back- 15 min residence time. The extension of the residence time to pressure regulator at the aqueous outlet afforded perfect sepa- 30 min increased the formationofdibutyl ether and resulted ration with no loss of benzyl chloride. Aloopofalarger in adecrease in the yield to 77%. For hexanol,the reaction volume(35 mL) filled with hydrochloric acid wasused in this was slower,and longer residence times improved the yield. two-step synthesis to allow alonger uninterrupted operation. As the benzylmoiety is widely used in API synthesis, our After three volumes of the reaction mixture passed through target compound was benzyl chloride. Under the same condi- the reactor,separated benzyl chloride was collected in an Er- tions, 100 %yield of benzyl chloride wasobtainedwithoutthe lenmeyer flask (10 mL). The flow rate of benzylchloride at the 1 formation of dibenzyl ether,and no any other byproducts organic outlet of the liquid–liquid separatorwas 40 mLminÀ 1 were observed in the GC chromatogram with 15 min residence (21 mmolhÀ ). Acollection time of 2hwas allowedbefore the time. We speculated that the partial solubility of benzyl alcohol product was pumped into asecond reactor by using another in water minimizes the mass transfer limitations. Moreover, as HPLC pump (Scheme 2). benzylchloride has alower solubility in water than benzyl al- We chose nitrogen-containing substrates as nucleophiles for cohol, the equilibrium of the reaction shifts to the product the subsequentreactionbecause of their presenceinAPI side. Adecrease of the amountofhydrochloric acid with an in- structures. Thus , n-methyl piperazine, morpholine,

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Scheme1.Top: Schematic representation of the setup used for the current investigation. Bottom:Chlorides synthesized with 3equivalents of HCl (aq) at 1208Cwith 15 minresidence time. Yields are determined by 1HNMR spectroscopy with respect to 1,3-dimethoxybenzeneasanexternal standard.

Scheme2.Schematicrepresentation of the two-stepsynthesis. The synthesis of benzyl chloride is connected to its separation from the aqueous phase, which takes place in aliquid–liquid-membrane-based separator.The separated neat benzyl chloride is mixed with secondaryamines to undergoanother nucleophil- ic substitution. The collectedand isolated products are shownalong with the corresponding yield values. and ethyl isonipecotate were used as nucleophiles. In combi- was increased to 1608Cand residence time to 30 minwith nation with benzyl chloride, piperazine wasthe only insoluble 1.5 equivalents of n-methyl piperazine. More detailsonthe op- substrate. The other substrates, even though miscible at first, timization are given in the Supporting Information. The isolat- resultedinprecipitate at the end of the reaction. Relatively ed yields obtained under these conditions are given in high volumes of ethanol dissolved the products,which indicat- Scheme2. ed the need for larger amounts of solventand lower concen- trations. Diethyleneglycol monomethyl ether (methyl carbitol) Applications in API synthesis afforded homogeneousreaction mixtures with relativelyhigh concentrations of products (1.1 m). For piperazine, the addition The diphenylmethyl moiety is found widely in antiemetic, anti- of water (methyl carbitol/water 2:1) was needed to keep the , and drugs. The diphenyl piperazine product dissolved. The homogeneity of the reactant and prod- substrateisakey constituent of cyclizine,cinnarizine,mecli- uct mixtures allowed the translation of batch to continuous zine, , , buclizine, , and other conditions. The reactionofbenzyl chlorideand n-methyl piper- drugs of the same family.The ease to connect the synthesis of azine (1.2equivalents) at 1208Cwith 15 min residence time re- the chloride with asubsequent reaction motivated us to sulted in an 81%conversion of benzyl chloride and 100%se- expand the scope to commerciallyavailable APIs,such as cycli- lectivity.The conversion increased to > 99%ifthe temperature zine, cinnarizine, and 1-diphenylmethyl-4-,

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quired for the completion of the reaction. At 1008Cand 10 min, the full conversion of diphenyl methanol was reached. The evaporation of acetoneupon collection resulted in 97% isolatedyield of diphenylmethyl chloride. To perform asecond nucleophilic substitution to synthesize cyclizine, we pumped neat piperazine into the product stream and quenched with NaOH solution. However,this resulted in clogging, thuswediluted n-methyl piperazine with methyl car- bitol. As aresult, the substantial formation of bisdiphenyl methylether was observedbecause of the presence of water. Amaximum selectivity of 80%towards cyclizine was reached at full conversion from the screening of awiderange of oper- ating conditions. Alternatively, as in the case of benzyl chloride, Scheme3.Generic APIs based on diphenylmethyl piperazine used to treat we connected the product stream of diphenylmethyl chloride nausea,vomiting, cerebralapoplexy,and dizziness. to aliquid–liquid separator.The application of 5psi to the aqueous outlet resulted in the breakthrough of retentate at the permeate outlet.The application of apressure of 2psi by which resemble meclizine and buclizine (Scheme3). Therefore, using an ultra-low-volume adjustable breakthrough pressure the synthesis and inline separation of diphenyl methyl chloride regulator (BPR) on the aqueous outlet with the attachment of was optimized to pave away to these final compounds. tubing (20 cm, 250 mminternal diameter) to the organic side outlet gave aperfect qualitative separation. Acontinuousrun 1 on a7mmolhÀ scale was performed over 8hand resulted in Synthesis of cyclizine the loss of 0.2%oforganic phase into the aqueous phase. Karl Cyclizine is an antihistamine used in the treatment of nausea, Fischer titration indicated the presence 1.78%ofwater in the vomiting, and dizziness associated with motion sickness, verti- separated product. go, and consequences of anesthesia and the use of opioids.Its Subsequently,the product was pumpedinto aT-mixer,in chemicalname is 1-diphenylmethyl-4-methyl piperazine andit which it was mixed with n-methyl piperazine (1.5 equivalents) is constructed by the nucleophilic substitution of diphenyl- in methylcarbitol to give afinal concentration of 1.5m of di- methyl chloride with n-methyl piperazine. The two-stepsetup phenylmethyl chloride. At high temperatures, the partial hy- shown in Scheme 2was used to connectthe formation of drolysis of diphenylmethyl chloride was observed because of chlorodiphenylmethane to the stream of N-methyl piperazine the presence of water.Therefore, we decreased the tempera- to form cyclizine (Scheme 4). The solubility of diphenyl metha- ture to 1008Cand increased the residence time to 45 min to reach full conversion. Transparent crystals precipitated upon cooling. The first crop resulted in 92%yield of cyclizine with high purity (>99%GC–MS). The evaporation of acetone and extraction of the restofthe mother liquor afforded 2% more cyclizine. Impurities detected in the motherliquor were diphe- nylmethanol and bisdiphenyl methyl ether.

Synthesis of meclizine and buclizinederivatives Scheme4.Synthesis of cyclizine in continuous flow from diphenylmethanol. Meclizine and buclizineare alike in terms of their chemical structures and are built from 1-chloro-4-phenylmethyl ben- zene, piperazine, andbenzyl moieties. 1-Chloro-4-phenylmeth- nol was re-evaluated, and acetoneproved to be abetter sol- yl benzene resembles adiphenyl methyl moiety,therefore, we vent, which resulted in ahigh concentration of 3.1m.High decidedtobuild 1-diphenylmethyl-4-benzylpiperazine as concentrations are desired to minimizethe use of solvent. acommon derivative. Aschematic representation of the over- However,upon mixing the streamofdiphenylmethanol in ace- all synthesis is shown in Scheme 5. More detailsonthe assem- tone with hydrochloric acid, diphenylmethanol precipitated in bly of the setup and its operation are provided in the Support- the T-mixer because of the change in solution composition. ing Information. The synthesis and separation of diphenyl The relatively low meltingpoint (69 8C) of diphenylmethanol methyl and benzylchlorides was performed as described allowed us to circumvent clogging by immersing the T-mixer above.Westartedthe synthesis of 1-(diphenylmethyl)piper- in an oil bath. As aresult of the highvolatility of acetone, azine with the conditions we used for benzylchloride (methyl alower temperature of 1008Cwas set as the reaction tempera- carbitol/water 2:1). However,atthe full conversionofchlorodi- ture. As aresult of the miscibility of acetone with water,the phenylmethane, only aminor formation of 1-(diphenylmethyl)- mass transfer barrier between diphenylmethanol and hydro- piperazine (< 15%yield) was formed,and the major products chloric acid was minimized, which led to ashorter time re- were {[2-(2-methoxyethoxy)ethoxy] methylene} dibenzeneand

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Scheme5.Schematicrepresentation of the four-stepsynthesis with tabulated conditions. The synthesis and separation of chlorides are connected to the sub- sequentreactions. The two stepsofthe buclizine derivative and cinnarizine were the same. To differentiate the rest of the sequence cinnarizine reagents are highlighted in dashed rectangles.

diphenylmethanol. Similarresultswere obtainedifethanol and quired theoretically to 250 psi. As aresult less precipitation methanol were used as solvents. We concluded that because was observed. The fact that the crystals formed towards the of the higher steric hindrance of diphenylmethyl chloride than end of the reactor led us to believe that it might be piperazine that of benzylchloride, nucleophilic substitution by smaller hydrochloride or 1-(diphenylmethyl)piperazine hydrochloride. molecules, such as water or alkoxides,was faster.Alternative We mixed water into the product stream to dissolve the un- organic solvents such as toluene,heptane, DMF,acetonitrile, reactedreactant to allow the optimization of the reaction. If dimethoxyethane, methyltetrahydrofuran, 4-methylpentanone, the conversion was incomplete, diphenyl methanolwas acetone, dichloromethane, and various combinationscould formed upon mixing with water at theoutlet. As aresult of not dissolve piperazine. Acombination of dichloromethane alower concentration and the use of anonpolar solvent, the and acetone (4:1) dissolved piperazine with amaximum con- reactionwas slower.Full conversionwith92% selectivity to- centrationof1.26m.However,the mixture was metastable and wards 1-(diphenylmethyl)piperazine was observed at 1508C led to the precipitation of piperazine if it was pumped through with 45 min of residence time and 1.5 equivalents of pipera- the reactor tubing. Therefore, we switched to THF,which dis- zine. Finally,noprecipitation was observedifwater addition solved piperazine with concentrationsonly up to 0.5m.Never- stoppedafter two volumes of the reactants had passed. theless, precipitation within the reactor was still observed. We Subsequently,tosynthesize buclizine and the meclizine de- switched to atubularreactor with alarger internal diameter of rivative, 1-(diphenylmethyl)piperazine needed to react with the 1.58 mm to allow the visual observation of the precipitate for- synthesized and separated benzyl chloride. Before the flow ex- mation. We stopped the reactionand pushed out the precipi- periments, batch investigationsshowed the precipitation of tate to see that it was unreacted piperazine. One of the causes the product from the reaction mixture. Methanol, used in an for the precipitation could be bubble formationwithin the re- equivolumetric amount with respect to the product mixture, actor followed by adecrease of available solventbecause of was sufficient to afford homogeneity.Thus, methanol along evaporation, which would cause the precipitation of piper- with 2.0 equivalents of benzyl chloride were injected into azine. Thus, we increased the pressure from the 100 psi re- aproduct stream of 1-(diphenylmethyl)piperazine through

ChemSusChem 2016, 9,67–74 www.chemsuschem.org 71 2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Papers across (Scheme 5). At 100 8Cand 15 min residence time, 67% designed and integrated in the reactor network. This allowed yield wasobserved. This yield could be furtherincreased to the separation of intermediate chlorides and their consump- 71%ifthe temperature was increased to 1208C. An increaseof tion in the construction of the target molecules. Overall four the temperature to 1508Cresulted in the full conversion of 1- steps were realized in 90 min with good yields at aproduction 1 (diphenylmethyl)piperazine, and ayield of 89%based on di- rate of 2mmolhÀ of final products. phenylmethanolwas obtained. Benzylpiperazine, dibenzylpi- As aresult of its corrosive nature, hydrochloric acidhas to , benzyl alcohol, and benzyl methyl ether were formed be isolatedfrom the pumps and was delivered through aloop, as byproducts in the final product mixture.Isolated yield ex- which has to be refilled while the continuous operation of periments were performed withoutthe addition of the internal chlorination steps is paused. Therefore, the greatest limitation standard. To separate the product, all volatile solvents were re- of this methodisthe supply of hydrochloric acid.AHCl gas moved from the collected sample. Water wasadded to the supply could revolutionize the synthesis, however, its supply product, and the pH was adjusted to < 3. Ethyl acetate was into amicroflow environmenthas not yet been developed. then used to extract the excessofbenzylchloride and formed The methodology demonstrated herein allows an easy and ac- benzylmethyl ether.Subsequently,the pH of the aqueous cessibleroute to chlorides. phase was adjusted to 4with acetic acid/sodium acetate trihy- drate buffer.Atthis point, secondary amineswere extracted into the aqueous phase. The evaporation of ethyl acetate fol- lowed by the recrystallization of 1-diphenylmethyl-4-benzylpi- Experimental Section perazinefrom EtOH afforded 87%isolated yield. Operating platform:The working setup used in the current inves- tigation was built from acid-resistant HPLC pumps, fluorinated eth- Synthesis of cinnarizine ylene propylene (FEP) tubing, and inline BPRs. The use of the HPLC pump for hydrochloric acid resulted in amalfunction of the pump. To synthesizecinnarizine, 1-diphenylmethyl piperazine needed After ashort operation time, the pump would stop delivering the to react with the synthesized and separated cinnamyl chloride. acid to the reactor.Upon purging the pump, gas slugs were ob- The optimal conditions for benzyl chloride synthesiswere not served, which led to the conclusion that the pump malfunctioned optimal for the synthesis of cinnamyl chloride. Lower tempera- because of the accumulation of hydrogen chloride gas within the tures, 608C, gave ahigher selectivity and amaximum yield of pump head. Thus, HCl loops of 6mLand later of 35 mL (Scheme 1, 95%yield at 5.0m concentrationintoluene. Batch investiga- top) filled with concentrated hydrochloric acid (36 wt%) were used as the HCl source. Alcohols were pumped in their neat form and tions showedthat homogeneous conditions were afforded if mixed with HCl within apolytetrafluoroethylene (PTFE) T-mixer. the final reactionwas performed in asolutionofequal vol- Areactor with an inner diameter of 762 mmand volume of 2.2 mL umes of acetone and 25 wt%NaOH in water.Therefore, the was used. The volume could be increased by using more tubing, solution and 2.0 equivalents of cinnamyl chloride were injected however,tominimize the use of chemicals, we kept it average. Fi- into aproduct streamof1-(diphenylmethyl)piperazine through nally,because we started investigations at 1208C(superheated across without its intermediate separation. At 1008Cand with conditions), aBPR was added to avoid boiling within the reactor.A 15 min residence time, a77% yield was observed, and an in- stream of NaOH (25 wt %) was introduced before the BPR to avoid crease of the time to 30 min led to the full conversion of 1-(di- its corrosion. More information regarding the setup is provided in the Supporting Information. phenylmethyl)piperazine and an 85 %yield of cinnarizine based on diphenyl methanol. Isolatedyield experiments were Synthesis of alkyl chlorides:All of the pumps were purged with performed without the addition of an internal standard in isopropanol. BPRs with cartridges of 1000 psi were attached imme- asimilar manner to the synthesis of 1-diphenylmethyl-4-ben- diately after the pressure sensors of the HPLC pumps to ensure zylpiperazine. MeOH was used for the recrystallization of cin- aconstant flow at lower flow rates. Neat alcohol substrates were narizine to afford an 82%isolated yield. used as received from asupplier.Pumps were purged with sub- strate, water,and 25 wt %NaOH, respectively.The HCl loop was filled with HCl from asyringe with aluer adapter.With the syringe Conclusions still attached to one end, another was connected to the T-mixer, and the first end was connected to aunion. Water was pumped We have demonstrated asimplification and acceleration of into the loop to deliver HCl to the reactor through aT-mixer.Sub- chemicalreactions with the help of microflow technology. Bulk sequently,the pumps were set to the required flow rates and the alcohols were used in asequence of nucleophilicsubstitution entire setup (tubing) was filled with the fluid. The BPR was at- reactions to build meclizine, abuclizine derivative, and com- tached, and the capillary reactor was immersed into aheating bath merciallyavailable cyclizine and cinnarizine. Our continuous- (IKA) at the operating temperature. The residence time was varied flow protocol delivered an excellent yield of benzylchloride in by adjusting the flow rates while the reactor volume was kept the same (2.2 mL). Flow rates were recalculated for each substrate 15 min residence time under superheated conditions of 1208C based on their molecular weight and density.For benzyl alcohol and 100 psi using hydrochloric acid as the chlorinating agent. with 15 min residence time, benzyl alcohol, HCl, and NaOH solu- The same conditions were applied to awidevariety of aliphat- 1 tion were pumped at 40, 110, and 410 mLminÀ ,respectively.The ic and aromatic alcohols. HCl loop was refilled after 80 %ofthe initial volume has been To connect chlorodehydroxylation reactions to asubsequent used. Before the refill, the capillary reactor was cooled to RT,and reactionstep, amembrane-basedliquid–liquid separatorwas the nut of the union was unscrewed to refill the loop.

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NOTE:Dodecanol, cyclohexanol, napthalenemethanol, diphenyl connected to BPRs of 100 psi, which were connected to two methanol, and cinnamyl alcohol are solids under atmospheric con- liquid–liquid separators. The adjustable BPR (M-410) was connected ditions and, therefore, needed addition of toluene/acetone (2:1) to to the aqueous outlet of the diphenylmethyl chloride separator to be able to be delivered into aflow setup. The maximum common apply 2psi, and the product was collected on the organic outlet concentration was 2.2m. through atubing of 20 cm with 250 mmID. Meanwhile, the BPR with a5psi cartridge was connected to the aqueous outlet of the benzyl chloride separator.Both reactors were then immersed in Utilization of benzyl chloride and two-step synthesis:All five heating baths, and after 30 min of operation diphenylmethyl chlo- pumps were purged with isopropanol. The 35 mL HCl loop was ride was collected, whereas benzyl chloride was collected after filled with HCl from asyringe with aluer adapter.Water was 45 min. After 2hof operation, the inlet tubing for the fifth pump pumped into the loop to deliver the HCl. Thymol Blue was added was immersed in the collection flask of diphenylmethyl chloride, to 25 wt%NaOH solution to assess the separation efficiency at the 1 and the flow rate was set to 1mLminÀ for 3min to fill the inlet liquid–liquid separator visually.The outlet of the reactor BPR was tubing (1.5 m, 1/16“ ID, 1/8” OD). Pump 6was purged with 0.5m of connected directly to the liquid–liquid separator. piperazine solution. Next, the flow rate of the fifth pump was set 1 1 The separator was based on two ethylene tetrafluoroethylene in- to 0.013 mLminÀ ,and pump 6was set to 0.12 mLminÀ .Pump 7 1 serts. Both inserts had an identical channel in the shape of an el- was set to 0.15 mLminÀ to pump MeOH into the cross, and the lipse with 1mmdepth. The upper insert had two ports, one for inlet tubing of pump 8was filled with collected benzyl chloride 1 the inlet of amixture and another for the outlet of aqueous phase. and set to 0.01 mLminÀ .The reactor tubing for both reactors (6 The lower insert had only one port for the outlet of the organic and 4.4 mL) was filled with THF with asyringe, and the reactors phase. Extra space was created next to the operating channel to were connected to across. Asecond reactor of 4.4 mL was con- detect leakage caused by the overpressure of the unit. The upper nected to the 250 psi BPR at another end. Both reactors were then limit of the unit was 250 psi. AZefluor membrane, available from immersed into one heating bath. The product was collected after Pall Corporation, was squeezed between the inserts. Twostainless- 150 min from the start of the heating of the reactors. The collected steel holders were used to create ashell for the separator.Apic- product was separated from all volatile solvents by using arotary ture and atechnical drawing of the device are given in the Sup- evaporator.Water (5 volumes) and ethyl acetate (5 volumes) were porting Information. Pressure over the membrane was applied by added to the collected sample and the pH was decreased to 3by connecting BPRs to the outlets of the separator.ABPR with 5psi the addition of HCl. Ethyl acetate was then used to extract the cartridge was connected to the aqueous outlet and resulted in excess of benzyl chloride and formed benzyl methyl ether.Subse- aperfect separation with no loss of benzyl chloride, confirmed by quently,the pH of the aqueous phase was adjusted to 4with collected volumes of the permeate and retentate. acetic acid/sodium acetate trihydrate buffer.Atthis point, the sec- ondary amines were extracted into an aqueous phase. The evapo- After three volumes of the reaction mixture had passed through ration of ethyl acetate followed by the recrystallization of 1-diphe- the reactor,the separated benzyl chloride was collected in an Er- nylmethyl-4-benzylpiperazine from EtOH afforded an 87%isolated lenmeyer flask (10 mL). Afeed tube for the other pump was im- yield. mersed into the flask in which the benzyl chloride was collected. The pump delivered separated benzyl chloride to aT-mixer in which it was mixed with methyl piperazine in methyl carbitol Acknowledgements (1.5m). Optimization consisted of screening the effects of tempera- ture, residence time, and the amount and concentration of methyl We would like to thank Nico Erdmann, Mark Graus, Slavisa Jovic, piperazine. 1,3,5-Trimethoxybenzene was used as internal standard and was added to the methyl piperazine solution. The yield was Erik van Herk, and Bert Mettenfor their help during different calculated based on the internal standard from aGCwith flame stagesofour investigation. Fundingfrom the Advanced Europe- ionization detection (FID) response. Atemperature of 1608C, an Research Council Grant “Novel Process Windows—Boosted 30 min, and 1.5 equivalents of methyl piperazine were optimum Micro Process Technology” (Grantnumber:267443) is gratefully and resulted in an isolated yield of 97%. acknowledged.

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