Synthesis of heterocyclic compounds

Tapio Nevalainen Drug synthesis II 2010

http://www.scripps.edu/chem/baran/heterocycles/

Pyrrole synthesis

Knorr pyrrole synthesis: Condensation of -aminoketone and synthesis:

ketoester

PaalPaal-Knorr Pyrrole-Synthesis: condensation amine and 1,4-ketone Pyrrole1,4

Example: Example: Synthesis of atorvastatin (Lipitor) Lipitor)

Pyrrole synthesis

Hantzsch pyrrole synthesis: from -holomethyl ketones, -keto

esters and ammonia or amines

Huisgen Pyrrole Synthesis

From Amino acids and alkynes Example: atorvastatin

A. Hantzsch, Ber. 23, 1474 (1890)

Thiophenes

Hinsberg Synthesis of Thiophene Derivatives

Paal Knorr

Gewald reaction

Furans

Paal Knorr

FeistFeist-Benary

Pyrazoles

Pyrazoles can be synthesized from 1,3-dicarbonyls with 1,3hydrazine

Pyrazoles are made also by 1,3-dipolar cycloaddition of 1,3diazomethane and acetylene.

Example of pyrazole synthesis:

Rimonabant

Pyrazoles: The synthesis of sildenafil (Viagra)

Retrosynthesis

Pyrazoles: Pyrazoles: The synthesis of sildenafil (Viagra) Viagra)

Bioorg. Bioorg. Med. Chem. Lett. 6, pp. 1819, 1996 Lett.

Pyrazoles: Pyrazoles: The synthesis of sildenafil (Viagra) Viagra)

O OEt O Cl + H2N H2N CH3 O EtO ClSO2OH HN N CH3 CH3 N N HN N O S O Cl CH3 O S O N N CH3 O CH3 N N pyridine H2N EtO HN O OEt EtO HN N CH3 CH3 N N O NaOH EtO HN N CH3 O CH3 N N CH3 CH3 N N

Bioorg. Med. Chem. Lett. 6, pp. 1819, 1996

Isoxazoles

Oximation of 1,3-Dicarbonyl Compounds or -Ketoesters 1,3O R1 R2 O R1 R2 O OEt + HO NH2 H2O/M OH O/MeOH O R3 + HO NH2 H2O/MeOH O N R1 R2 O NH R1 R2 O R1 R2 HN O O R3

NaOH

NaOH

Isoxazoles

Cycloaddition of Nitrile Oxides to Unsaturated Compounds

Chimichi, S.; Cosimelli, B.; Synth. Commun., 1992, 22, 2909-2920

Nitrile oxides can be prepared by the -elimination of chlorooximes or the dehydration of nitroalkanes

Azoles

Oxazoles and thiazoles can be obtained by the RobinsonRobinson-Gabriel synthesis from 2-acylamino2-acylaminoketones.

Imidazoles
N HN Cl Histamine Hi t i Cl NH2 N H N N H HN N Cimetidine Ci tidi CH3 S H N N H N CH3 CH3 H3C CH3 CH3 N Xylometazoline X l t li CH3 H N CN Clonidine Cl idi

Synthesis of 1,2,5-trisubstituted imidazoles from 1,2,5N-monosubstituted amidines and 2-halo-3-alkoxy2-halo- alkoxy2-propenals

J. Org Chem. 1997, 62, 8449

Imidazoles

Cimetidine
O O O Cl O 2 H2N H N O+ H HN H H O O Bredereck reaction* O N H O+ H N H H N N CN O O O

O LiAlH4 HN N O HN N

HS OH

NH2 HN N H N S NH2

HN N

H N N CN

cimetidine * Bredereck, H.; Theilig, G., Chemische Berichte-Recueil 1953, 86, 88-96. http://www.chem.yale.edu/~wood/Theses/thesisstu.pdf

Imidazoles

2-Butyl-4-chloro-5-hydroxymethyl-1HButyl- chloro- hydroxymethyl-1Himidazole

Dihydroimidazoles
Clonidine (anti-hypertensive agent) anti- yp agent) g

Oxymetazoline (topical decongestant)

H2N CN H2N 235C, N2 CH3 CH3 CH3 CH3 N Oxymetazoline HO CH3 H N

HO

CH3 CH2O/HCl

HO

CH3 Cl KCN

HO

CH3

Imidazoles from isocyanides

The reaction of aldehydes, primary amines and aldehydes, toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,51,4,5trisubstituted imidazoles (A M van Le sen, J Wildeman, O H (A. M. an Leusen J. Wildeman, O. H. Leusen,
Oldenziel, Org. Chem. 1977, 42, Oldenziel, J. Org. Chem. 1977, 42, 1153.
R3 O R1 NH2 + H R2 R3 N N R1 Ts Base H R2 - H2O R1 N N C R2 R3 R2 + H3C O S O TOSMIC Base N N R1 O S

CH3

C N

R3 Ts

N R H 2 R1 OH

http://www.organic-chemistry.org/Highlights/2005/05May.shtm

Imidazoles from isocyanides

Substituted tosylmethyl isocyanides (TosMICs) are synthesized from (TosMICs) tosylmethyl formamides and p-methylphenylsulphinic acid. acid.

Synthesis of the GSK p38 kinase inhibitor

Thiazoles

Most important method for syntesis of thiazoles is from thioamides and -halocarbonyl compounds

Example: Example: synthesis of nizatidine

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Oxazoles

Robinson-Gabriel synthesis: cyclodehydration of -acylaminocarbonyl compounds

BlmleinBlmlein-Lewy Synthesis: heating an haloketone with amide Synthesis:

1,41,4-Dihydropyridines
Hantzsch Dihydropyridine (Pyridine) Synthesis
4-Aryl-1,4-dihydropyridines (e.g. nifedipine) are calcium channel modulators for the treatment of cardiovascular diseases such as hypertension, cardiac arrhythmias, or angina.

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Glutarimides

Thalidomide

Aminoglutethimide A i l t thi id

Pyrimidines

Pinner pyrimidine sythesis: from 1,3-dicarbonyl compounds and amidines

Instead of amidines, pyrimidines are obtained also by using guanidine, urea and thiourea
R4 O N R1 R2 R1 NH2 N R1 R2 N R3 H2N NH2 NH R2 H2N N R3 H2N R4 NH O O R3 S NH2 R1 R2 N S NH R3 H2N O NH2 R1 R2 N NH R3

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Pyrimidines

Example: trimethoprim (bacteriostatic antibiotic)

NH2 N N NH2 MeO H MeO OMe MeO OMe
O O EtO O OEt 1. NaH 2. ArCH2Br MeO MeO OMe OH O OEt H2N MeO MeO MeO OMe MeO OMe MeO OMe NH2 NH2 NH N N OH 1. POCl3 2. NH3 MeO N EtO O OEt NaCl DMSO MeO OMe NH2 N NH2 O OEt MeO HCO2Et EtO

NH2 H2N O NH

guanidine EtO FGI NH2

O OEt EtO

O OEt Br

MeO MeO MeO OMe MeO OMe

MeO

Pyrimidines

Biginelli Reaction: acid-catalyzed, reaction between an aldehyde, Reaction: acid-catalyzed, aldehyde,

a,a,-ketoester and urea constitutes a rapid and facile synthesis of tetrahydropyrimidones. tetrahydropyrimidones.

Synthesis of rac-Monastrol (Mitosis blocker by kinase Eg5

inhibition)

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Tetrazoles

Carboxylic acid isostere Synthesis

Synthesis of Losartan (antihypertensive)

Indoles

The conversion of aryl hydrazones to indoles; requires elevated temperatures and the addition of Brnsted or Lewis acids

Fischer Indole Synthesis:

Synthesis of Sumatriptan

(Daniel Lednicer: Strategies for Organic Drug Synthesis and Design)

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Quinolines

Quinoline nucleus is usually formed in one of two ways

SkraupSkraup-reaction

Mechanism:

OH HO OH

H+

H2C H [O]

NH2 N H

CHO

N H

Quinolines

,-unsaturated ketone or aldehyde can be used instead of glycerol

Saturated aldehyde can aldolcondensate to -unsaturated aldehyde to form a quinoline (Doebner-Miller reaction) Doebnerreaction)

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Quinolines

ConradConrad-Limpach reaction: Synthesis of 4oxyquinolines by condensation of esters of beta-keto acids with aromatic amines Skraup-reaction SkraupCH3 < 100 C CO2Et + NH2 O CH3 D - EtOH N CO2Et 260 C N H CH3 - H2O N H O O H
+

CH3 - H2O

N H O

CH3 - EtOH

Quinolines

FriedlnderFriedlnder-quinoline synthesis
CHO + NH2 H3C O CH3 pH 12 N CH3

Mechanism:

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Isoquinolines

The general synthetic routes to isoquinolines involve the following skeletal types: g yp

Isoquinolines

BischlerBischler-Napieralski Reaction:
-Phenylethylamine is acylated then cyclodehydrated using phosphoryl chloride, phosphorous pentoxide or other lewis acids. This gives the dihydroisoquinoline, which can be aromatised by dehydrogenation with palladium. E.g. in the synthesis of papaverine

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Isoquinolines

PictetPictet-Spengler synthesis: -Arylethylamine is heated in the presence of an aldehyde and acid. acid. A special case of the Mannich reaction. reaction.

Synthesis of Tadalafil y

Isoquinolines

PomeranzPomeranzFritsch Reaction

EtO O R

OEt - H2O N R

OEt OEt H3O+ N R

+
H2N

C. Pomeranz, M C P Monatsh. 14 116 (1893) t h 14, P. Fritsch, Ber. 26, 419 (1893) OH - H2O N R R N

SchlittlerSchlittlerMller Reaction

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Quinolones

Retrosynthesis

Synthesis

Thiadiazoles

Synthesis of Timolol (-blocker) blocker)

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Benzodiazepines
The retrosynthesis of diazepam

The synthesis of diazepam (Sternbach et al, 1961).

O CH3 NH Ac2O Cl Cl CH3 O N NH3 Cl N Cl CH3 O N O O Cl Cl Cl O N O Ph C Cl CH3 Cl AlCl3 N CH3 O NaOH, H2O Cl CH3 N H O

Diazepam

Benzodiazepines

Ugi Reaction (Ugi, I., et. al. Angew. Chem.

1959, 71, 386)

Concise synthesis of benzodiazepines with Ugi Reaction (Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021)

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