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Química Medicinal · Metabolism and drug synthesis

Síntese de fármacos comuns

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O que você vai aprender

  • Draw the acyl substitutions that build drug amides and esters (paracetamol, lidocaine, procaine, captopril) and explain which nucleophile reacts and why.
  • Follow the Boots and BHC syntheses of ibuprofen step by step and compare them by atom economy and waste.
  • Plan protecting-group sequences for sulfanilamide and explain the chemistry of phenytoin, from its Biltz synthesis to its sodium salt and the fosphenytoin prodrug.
  • Draw the key steps toward salbutamol and fluoxetine (α-bromination, amine alkylation, borohydride reduction, Mannich reaction, SNAr ether formation) and predict their stereochemical outcome.
  • Calculate yields (including limiting reagents), ionised fractions and enantiomeric excess for drug preparations.

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Acyl transfer makes most drug amides and esters

Paracetamol, lidocaine, procaine and captopril all contain a C(=O)–N or C(=O)–O bond made by nucleophilic acyl substitution: the nucleophile adds to the carbonyl carbon, the tetrahedral intermediate expels the best leaving group, and a base removes the last proton. Reactivity follows leaving-group ability: acid chloride > anhydride > ester > amide. When a molecule has two nucleophiles, the more nucleophilic one wins. 4-Aminophenol reacts with acetic anhydride at nitrogen because a neutral amine is a much better nucleophile than a neutral phenol, giving paracetamol (drawn left). Industrially, paracetamol is also made from 4-hydroxyacetophenone: its (E)-oxime undergoes a Beckmann rearrangement in which the aryl group anti to the oxime OH migrates to nitrogen, giving the N-aryl acetamide directly. 4-Aminophenol itself is made by hydrogenating nitrobenzene in dilute sulfuric acid: the intermediate N-phenylhydroxylamine is protonated, loses water to a cation with positive charge on the ortho and para ring carbons, and water adds mainly at the para carbon (Bamberger rearrangement). Nitrating phenol instead gives a mixture of 2- and 4-nitrophenol that must be separated. In any preparation, compare moles of the reactants to find the limiting reagent before calculating the theoretical yield. With excess anhydride and pyridine the phenol is acetylated too, but brief treatment with dilute base removes that phenyl ester and leaves the amide. Lidocaine (drawn right) is made in two steps: 2,6-dimethylaniline is acylated at the acid chloride carbon of chloroacetyl chloride, then diethylamine displaces the remaining chloride by SN2.

Local anaesthetics: esters versus amides

Benzocaine (ethyl 4-aminobenzoate) and procaine are esters of 4-aminobenzoic acid. Benzocaine is made from 4-nitrotoluene by oxidising the methyl group, esterifying, and only then reducing the nitro group, because an amine would not survive the oxidation. Procaine can be made from benzocaine by base-catalysed transesterification with 2-(diethylamino)ethanol, driven by distilling off ethanol, or from 4-nitrobenzoyl chloride and the same amino alcohol followed by nitro reduction. Lidocaine is an amide. Plasma esterases cleave ester anaesthetics quickly, while lidocaine's amide is less reactive and is shielded by its two ortho methyl groups, so it acts longer. The tertiary amine (lidocaine pKa about 7.9) matters too: only the neutral base crosses the nerve membrane, and at pH 7.4 about a quarter of lidocaine is neutral.

Ibuprofen: the Boots route and the BHC route

Both routes start with Friedel–Crafts acylation of isobutylbenzene para to the isobutyl group. The Boots route (six steps) uses acetyl chloride with a full equivalent of AlCl₃, then a Darzens condensation with ethyl chloroacetate to a glycidic ester, hydrolysis and decarboxylation to an aldehyde, conversion to the oxime, dehydration to the nitrile with acetic anhydride, and hydrolysis to the acid. The BHC route (three catalytic steps) acylates with acetic anhydride in HF, which is recovered and reused, hydrogenates the ketone to the alcohol over Raney nickel, and carbonylates the alcohol with CO and a palladium catalyst. Atom economy is the mass of the wanted product divided by the mass of all reactants: about 40% for Boots and about 77% for BHC, rising to about 99% if the acetic acid by-product is recovered and used.

Sulfanilamide and phenytoin

Sulfanilamide is made from aniline in four operations: acetylate the amine, chlorosulfonate the ring para to the acetamido group with chlorosulfonic acid, convert the sulfonyl chloride to the sulfonamide with ammonia, and remove the acetyl group with hot aqueous acid. The acetyl group stops the amine from being protonated or attacking the sulfonyl chloride, and the bulky acetamido group directs para. Acid then cleaves the carboxamide while the sulfonamide survives. Sulfanilamide mimics 4-aminobenzoic acid and blocks bacterial folate synthesis. Phenytoin (5,5-diphenylimidazolidine-2,4-dione) is made by the Biltz synthesis: benzil, urea and KOH, in which a phenyl group shifts to the neighbouring carbon so that both phenyls end on one carbon. The N–H between the two carbonyls is acidic (pKa about 8.3). Phenytoin sodium is therefore soluble only at high pH, and the water-soluble prodrug fosphenytoin is built on that nitrogen through an N-hydroxymethyl group.

Salbutamol and fluoxetine

A classic salbutamol route brominates the methyl ketone of methyl 5-acetylsalicylate through its enol under acid catalysis, displaces bromide with N-benzyl-tert-butylamine, reduces the carbonyl groups, and removes the benzyl group by hydrogenolysis. The benzyl group prevents a second alkylation of nitrogen. Hydride adds to either face of the planar ketone, so the product is racemic; the (R)-enantiomer (levalbuterol) carries the bronchodilator activity. Fluoxetine is built from acetophenone: a Mannich reaction with formaldehyde and dimethylamine gives the β-amino ketone, reduction gives the alcohol, and the aryl ether is formed by SNAr. The Mannich base carries two N-methyl groups and fluoxetine only one, so one methyl is removed, for example by ethyl chloroformate (an SN2 attack of chloride on an N-methyl group of the acylammonium ion) followed by hydrolysis of the carbamate. Sodium hydride turns the alcohol into an alkoxide, which displaces chloride from 1-chloro-4-(trifluoromethyl)benzene; the para CF₃ group stabilises the anionic intermediate. No bond to the stereocentre is broken, so an enantiopure alcohol gives fluoxetine with the same configuration.

Captopril: a protected thiol on L-proline

Captopril, the first orally active ACE inhibitor, binds the zinc ion of the enzyme through a free thiol. A thiol would be acylated by an acid chloride and is easily oxidised to a disulfide, so it is carried through the synthesis as an S-acetyl thioester. 3-(Acetylsulfanyl)-2-methylpropanoyl chloride acylates the ring nitrogen of L-proline under Schotten–Baumann conditions (aqueous base), and ammonia then removes the acetyl group: a thioester is far more reactive toward amines than the tertiary amide. If the acid chloride is racemic, coupling with enantiopure L-proline gives two diastereomers, which differ in solubility and can be separated by crystallisation. Captopril is the (2S,2S) isomer.

What to carry forward

Drug syntheses are built from a small set of reactions: acyl substitution at the most reactive carbonyl by the most nucleophilic atom, SN2 at activated carbons, electrophilic and nucleophilic aromatic substitution, enol and enolate chemistry, and hydride reduction. Protecting groups (acetamide, S-acetyl, N-benzyl) control which atom reacts, and the order of steps is chosen so that each group survives the reagents that follow. Greener routes such as BHC ibuprofen replace stoichiometric reagents with recoverable catalysts.

Problemas de prática (40)

Praticar é grátis com uma conta.

Desenhe o mecanismo 18

Salbutamol, fluoxetine and captopril

  • Captopril route: acylation of L-proline under Schotten–Baumann conditionsDraw the acylation of the secondary amine of L-proline by an S-acetyl-protected acid chloride and the deprotonation that gives the tertiary amide, keeping both stereocentres unchanged.
  • Captopril: ammonia removes the S-acetyl protecting groupDraw the aminolysis of the S-acetyl thioester by ammonia that frees the thiol of captopril, and explain why the amide bond to proline survives.
  • Fluoxetine route: removing one N-methyl group with ethyl chloroformateDraw how ethyl chloroformate acylates a tertiary amine and how chloride then removes a methyl group by SN2, converting the N,N-dimethylamine into the N-methyl carbamate that is hydrolysed to fluoxetine.
  • Fluoxetine route: Mannich reaction of acetophenoneDraw the formation of the dimethyliminium ion from dimethylamine and formaldehyde, the acid-catalysed enolisation of acetophenone, and the C–C bond formation that gives the β-amino ketone (Mannich base) used to make fluoxetine.
  • Fluoxetine: SNAr ether formation with a CF₃-activated aryl chlorideDraw the deprotonation of the amino alcohol by sodium hydride and the addition–elimination substitution at the CF₃-activated aryl chloride that forms the aryl ether of fluoxetine with retention of configuration.
  • Salbutamol route: acid-catalysed α-bromination of methyl 5-acetylsalicylateDraw the acid-catalysed enolisation of an aryl methyl ketone and the attack of the enol on bromine that gives the α-bromo ketone used to build salbutamol.
  • Salbutamol route: N-benzyl-tert-butylamine displaces bromideDraw the SN2 displacement of bromide from an α-bromo ketone by N-benzyl-tert-butylamine and the proton transfer that gives the tertiary amino ketone.
  • Salbutamol: borohydride reduction of the amino ketoneDraw hydride transfer from borohydride to the ketone that precedes salbutamol and the protonation of the alkoxide by methanol, and explain why the product is racemic.

Analgesics: paracetamol and ibuprofen

  • Boots ibuprofen route: Darzens condensation of 4-isobutylacetophenoneDraw the Darzens condensation of 4-isobutylacetophenone with ethyl chloroacetate: enolate formation, addition to the ketone, and intramolecular SN2 ring closure to the glycidic (epoxy) ester.
  • Boots ibuprofen route: the aldoxime becomes a nitrileDraw the O-acetylation of an aldoxime by acetic anhydride and the elimination of acetic acid that turns the C=N–OAc group into a nitrile.
  • Paracetamol from 4-aminophenol and acetic anhydrideDraw the acetylation of the amino group of 4-aminophenol by acetic anhydride and explain why the phenol oxygen is left untouched.

Local anaesthetics: benzocaine, procaine, lidocaine

  • Lidocaine step 1: chloroacetylation of 2,6-dimethylanilineDraw the acylation of 2,6-dimethylaniline at the acid chloride carbon of chloroacetyl chloride, giving the α-chloroamide used in the lidocaine synthesis.
  • Lidocaine step 2: SN2 displacement by diethylamineDraw the SN2 reaction of diethylamine with the α-chloroamide and the proton transfer to a second diethylamine that gives lidocaine.
  • Einhorn procaine route: 4-nitrobenzoyl chloride and 2-(diethylamino)ethanolDraw the esterification of 2-(diethylamino)ethanol by 4-nitrobenzoyl chloride, with the molecule's own tertiary amine taking up the HCl, and explain why the nitrogen is not acylated.
  • Procaine from benzocaine by transesterificationDraw the ethoxide-catalysed exchange of the ethyl ester of benzocaine for a 2-(diethylamino)ethyl ester, and explain how the equilibrium is driven toward procaine.

Sulfonamides and phenytoin

  • Toward fosphenytoin: N3-hydroxymethylation of phenytoinDraw the addition of the phenytoin N3 anion to formaldehyde and the protonation that gives 3-(hydroxymethyl)phenytoin, the precursor of fosphenytoin.
  • Phenytoin sodium: deprotonating the imide N–HDraw the deprotonation of phenytoin at the nitrogen between its two carbonyl groups and the resonance that spreads the negative charge onto oxygen.
  • Sulfanilamide: acid hydrolysis removes the acetyl protecting groupDraw the acid-catalysed hydrolysis of the acetamide in 4-acetamidobenzenesulfonamide using only hydronium and water, and explain why the sulfonamide survives.

Preveja o produto 3

Sulfonamides and phenytoin

  • Chlorosulfonation of acetanilidePredict the position and form of the sulfonyl group introduced into acetanilide by excess chlorosulfonic acid.

Analgesics: paracetamol and ibuprofen

  • Paracetamol by a Beckmann rearrangementPredict which group migrates in the Beckmann rearrangement of 4-hydroxyacetophenone oxime and identify the drug formed.
  • Excess anhydride on 4-aminophenolPredict the diacetylated product formed when 4-aminophenol is treated with excess acetic anhydride and pyridine.

Classificar 1

  • Spot the amide-type local anaestheticClassify local anaesthetics as amide-type or ester-type from the linkage between the aromatic ring and the rest of the molecule.

Comparar 4

Local anaesthetics: benzocaine, procaine, lidocaine

  • Rank acylating agents toward 2,6-dimethylanilineRank acetic acid derivatives by their reactivity toward an aryl amine from the stability of the leaving group.

Analgesics: paracetamol and ibuprofen

  • Two routes to 4-aminophenolCompare phenol nitration with the Bamberger rearrangement as routes to 4-aminophenol and explain the para selectivity of the rearrangement.

Salbutamol, fluoxetine and captopril

  • Which aryl chloride gives the fluoxetine ether?Compare aryl chlorides as SNAr partners for an alkoxide and identify the one activated by a para electron-withdrawing group.

Sulfonamides and phenytoin

  • What sulfanilamide imitatesIdentify the bacterial folate-pathway substrate whose shape and functional groups sulfanilamide mimics.

Calcular 5

Salbutamol, fluoxetine and captopril

  • Enantiomeric excess of a levalbuterol batchCalculate enantiomeric excess from the percentages of two enantiomers in a drug sample.

Local anaesthetics: benzocaine, procaine, lidocaine

  • How much lidocaine is neutral at pH 7.4?Calculate the percentage of an amine drug present as the neutral base at physiological pH from its pKa.

Analgesics: paracetamol and ibuprofen

  • Which reagent limits a paracetamol preparation?Find the limiting reagent in a paracetamol preparation from a mass and a liquid volume, and calculate the theoretical yield.
  • Percent yield of a paracetamol preparationCalculate the percent yield of paracetamol from the mass of 4-aminophenol used, converting through moles.

Sulfonamides and phenytoin

  • Overall yield of the four-step sulfanilamide synthesisCalculate the overall yield of a linear multistep drug synthesis from the yield of each step.

Encontre o erro 1

  • A lidocaine run that stalls at half conversionDiagnose why an amine alkylation that releases HCl stops at about 50% conversion when only one equivalent of amine is used.

Trabalhe de trás para frente 1

  • Which diketone gives phenytoin?Work backwards from phenytoin to the 1,2-diketone that condenses with urea in the Biltz synthesis.

Planeje uma síntese 3

Local anaesthetics: benzocaine, procaine, lidocaine

  • Plan a benzocaine synthesisOrder oxidation, esterification and nitro reduction so that each functional group survives the later steps in a benzocaine synthesis.

Analgesics: paracetamol and ibuprofen

  • Rescuing an over-acetylated batchChoose conditions that cleave an aryl ester selectively in the presence of an amide.

Sulfonamides and phenytoin

  • Put the sulfanilamide synthesis in orderOrder the protection, chlorosulfonation, amination and deprotection steps of the sulfanilamide synthesis from aniline.

Explique por quê 4

Salbutamol, fluoxetine and captopril

  • Separating isomers in a captopril synthesisExplain how coupling a racemic acid chloride to enantiopure L-proline allows the captopril stereoisomer to be separated.

Local anaesthetics: benzocaine, procaine, lidocaine

  • Why lidocaine outlasts procaineExplain the longer duration of lidocaine compared with procaine from the stability of its amide linkage.

Sulfonamides and phenytoin

  • How both phenyls reach one carbonExplain the 1,2-phenyl shift that converts the benzil skeleton into the 5,5-diphenyl substitution pattern of phenytoin.
  • Why acetylate aniline before chlorosulfonation?Explain how converting aniline into acetanilide makes chlorosulfonation selective and prevents self-reaction.

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