DesignandsynthesisofCalciumAntagonist---oneoftheDihydropyridineDerivativesExperimentalmedicinalchemistryPurpose:1.TolearnthemethodstosynthesizetheDihydropyridineDerivativesbasedonHantzschpyridinesynthesis

2.Tocomprehendthenitrationreaction,thecharacteristicsandoperatingconditions.3.Tomasterhowtodesignasynthesisofcompound.Principles1.synthesisofm-nitrobenzaldehyde+H2SO4Principle

2.Synthesisof1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylatedimethylesterThe

Hantzschpyridinesynthesis

or

Hantzschdihydropyridinesynthesis

isa

multi-component

organicreaction

betweenan

aldehyde

suchas

formaldehyde,2equivalentsofa

β-ketoester

suchas

ethylacetoacetate

andanitrogendonorsuchas

ammonium

acetate

or

ammonia.Theinitialreactionproductisadihydropyridinewhichcanbe

oxidized

inasubsequentsteptoa

pyridine.Thedrivingforceforthissecondreactionstepis

aromatization.Thisreactionwasreportedin1881by

ArthurRudolfHantzsch.Hantzschpyridinesynthesis1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylatedimethylesterm-nitrobenzaldehydeethylacetoacetateprincipleR1:-OCH2CH3R2：Materials1.instruments:reflux

condenser,three-neck

flask

,dropper,beaker,filtrationapparatus,mortar,oilbathslot,thermometer,reducedistillationapparatus2:chemicals:chemicalsarelistedinthetablefollowingtheprocedureProcedure

1.synthesisofm-nitrobenzaldehydeA.In

a250mlthreeneckflaskequippedwithrefluxcondenser,thermometer

and

dropping

funnel,

add

in

accurately

weighed

11g

potassium

nitrate

,

dissolve

with

40ml

concentrated

sulfuric

acid.

B.Then

the

three-neckflaskisplacedin

ice

bath,maintainingthe

temperature

below

0℃.Stir

strongly

and

slowly

add

benzaldehyde

10ml(use

about

60-90min

to

finish

this

step),

the

temperature

of

the

whole

procedure

shouldbecontrolledin0~5℃.Letthereactiongoingforanother90minandthetemperatureiscontrolledas

before.

C.Then

slowly

pour

the

reaction

mixture

into

200ml

ice

water

with

stirring.

There

is

yellow

solid

exhalation

by

vacuum

filtration.D.Thefilterresidueismovedtothemortar,porphyrizing.Add5%sodiumcarbonate20ml,thengrindingfor5min.Filterandwash7-8timesbyicewater.Presstogetm-nitrobenzaldehydeandletdrynaturally.Weightheproductandcalculatethepercentageyield.materialamountmmolratiopotassium

nitrate11g80benzaldehyde11ml100concentrated

sulfuric

acid40ml5%NaCO320mlIcewater5%NaCO3:dissolve1gramNaCO3in20mlwater2.Synthesisof1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylatedimethylesterA:Weighm-nitrobenzaldehyde7.6g,ethylacetoacetate13.0g,andammoniumbicarbonate7.9g.Addthemtoa100mlthreeneckflaskequippedwitharefluxcondenserandthermometer,andaddboilingstones.B.Heatthemixtureat70℃for30min.AfteraccomplishingthereactionmonitoredbyTLC,coolthemixturetoroomtemperature.materialAmountusedmmolMoleratiom-nitrobenzaldehyde7.6g501ethylacetoacetate13.0g1002ammoniumbicarbonate7.9g1002magnesiumsulfate95%ethanol20mlC.Pour30mlwaterintothemixture,andstirvigorouslyfor10minutes.Discardthewaterlayer.Theresidueisdissolvedbyethylacetate.Usemagnesiumsulfatetodrythemixture.Thedryerisremovedbyvacuumfiltration.D.Thecrudedrugisobtainedbydistillationunderreducepressure(thesolventisremovedinthisstep).Thecrudedrugispurifiedbyrecrystallizationinhot95%ethanol(20ml).Thepurifiedsolidisachievedbyfiltration.Weightheproductandcalculatethepercentageyield.Note1.Thetemperatureshouldbecontrolledatornearzeroforthefirstsynthesisstep.2.Becarefultouseconcentratedacid,avoidingtotouchskin.Besides,addbenzaldehyedropwise.3.Tomindwhetherthesolidorfiltratewegetisusefulofuseless.4.Avoidanysolventinthesynthesisofdihydropyridine.advantages1.thereactiontimeislargelyreducedandthepercentageyieldofdihydropyridinederivativesissatisfactory.2.theprocedureissimpleandeconomiccomparedwithothersand.Thinking:WhywechooseNH4HCO3?(safe,reducedcontamination)Whyreactat70℃for30min?Reference:[1]CaiXiaohua,ZhuangGuolin,One-potSynthesisofDihydropyridinesunderSolvent-freeCondition,ChineseJournalofOrganicChemistry,vol.25,No.8,pag.930-933,in2005[2]JinlongSuetal,newmethodtosynthesize1,4-dihydropyridinecompounds,ChemicalEnginee