Synthesis Synthesis of heterocyclic heterocyclic compounds

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Paal-Knorr Pyrrole-Synthesis. Synthesis: condensation condensation amine and 1,4-ketone. ▫ Example: Synthesis. Synthesis of atorvastatin atorvastatin (Lipitor)  ...

Synthesis of heterocyclic compounds Tapio Nevalainen Drug synthesis II 2010 http://www.scripps.edu/chem/baran/heterocycles/

Pyrrole synthesis 

Knorr pyrrole synthesis: synthesis: Condensation of -aminoketone and ketoester



Paal--Knorr PyrrolePaal Pyrrole-Synthesis: condensation amine and 1,4 1,4--ketone 

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

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Pyrrole synthesis Hantzsch pyrrole synthesis: from α-holomethyl ketones, β-keto



esters and ammonia or amines

Huisgen Pyrrole Synthesis



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

From Amino acids and alkynes Example: atorvastatin

Thiophenes Hinsberg Synthesis of Thiophene Derivatives







Paal Knorr

Gewald reaction

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Furans 



Paal Knorr

Feist--Benary Feist

Pyrazoles 



Pyrazoles can be synthesized from 1,31,3-dicarbonyls with hydrazine

Pyrazoles are made also by 1,31,3-dipolar cycloaddition of diazomethane and acetylene.

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Example of pyrazole synthesis: Rimonabant

Pyrazoles: The synthesis of sildenafil (Viagra) Retrosynthesis

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

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

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

H2N Cl +

O CH3 N N pyridine

H2N

CH3 N N

H2N EtO

O EtO

HN

ClSO2OH

CH3

CH3 N N

CH3 O

HN

HN

CH3 N N

N N

O S O Cl

CH3

EtO

N

HN N

OEt

CH3 N N

EtO

NaOH

HN O

CH3

O

CH3

CH3

O S O N N

CH3

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

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Isoxazoles 

Oximation of 1,3 1,3--Dicarbonyl Compounds or β-Ketoesters O

O

R3

R1

HO NH2

+

O

R2

R2

+

HO NH2

HN O

O NH

NaOH OEt

R1

R3

R1 H2O/MeOH

R2 O

O N

NaOH

O

R1 H2O/MeOH O/M OH

O

R1

R2

R2

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

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Azoles 

Oxazoles and thiazoles can be obtained by the Robinson--Gabriel synthesis from 22--acylamino Robinson acylamino-ketones.

Imidazoles N

Cl NH2

HN Cl Hi t i Histamine



CH3

N

N H

Cl idi Clonidine

N H

S

HN N

H N

H N N

Ci tidi Cimetidine

CH3

CH3

CH3 H3C

CN

CH3

H N

CH3 N X l Xylometazoline t li

Synthesis of 1,2,5 1,2,5--trisubstituted imidazoles from N-monosubstituted amidines and 22-halo halo--3-alkoxy alkoxy-2-propenals

J. Org Chem. 1997, 62, 8449

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Imidazoles 

Cimetidine O

O O

O O

O Cl

2 H2N

N

Bredereck reaction*

O+ H

O

N

HN H

N

H O+ H

H

OH

HN

N

O O

HS

LiAlH4 O

HN

O

H

O H H N

S

NH2

N

NH2

S

HN

N

CN

N

S

HN

H N

N

H N N

cimetidine

CN

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

Imidazoles 

2-ButylButyl-4-chlorochloro-5-hydroxymethyl hydroxymethyl--1H1Himidazole

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

Oxymetazoline (topical decongestant)

HO

CH3

HO

CH3

HO Cl

CH2O/HCl

H2N

CH3 CN

KCN

HO

CH3

H2N

H N

235°C, N2 CH3

CH3

CH3 N

CH3

Oxymetazoline

Imidazoles from isocyanides 

The reaction of aldehydes, aldehydes, primary amines and toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5 1,4,5-trisubstituted imidazoles (A. (A M M. van an Leusen Le sen, J. Leusen, J Wildeman Wildeman,, O. O H H. Oldenziel,, J. Org Oldenziel Org.. Chem Chem.. 1977 1977,, 42 42,, 1153. R3 N

O R1

NH2

+ H

R2

- H2O

R1

C R2

N

O S O

CH3

TOSMIC

C N

R3 N R1

Ts Base H R2

N N R1

R3 R2

O S

+

Ts

N R H 2 R1

Base N

R3

OH

H3C

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

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Imidazoles from isocyanides 



Substituted tosylmethyl isocyanides ((TosMICs TosMICs)) are synthesized from 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:: synthesis of nizatidine Example

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Oxazoles 



Robinson-Gabriel synthesis: cyclodehydration of -acylaminocarbonyl compounds

Blümlein--Lewy Synthesis: Blümlein Synthesis: heating an haloketone with amide

1,4--Dihydropyridines 1,4 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



A i Aminoglutethimide 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

R4

N

N

R3

R1

O NH

H2N

R2

NH2

N

N

H2N R3

R1 R2

NH

R3 R2

O R3

R1 NH2

NH2 R1

H2N

O

NH

N

R2

S

S H2N

NH

N

NH2

R3

R1 R2

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Pyrimidines 

Example: trimethoprim (bacteriostatic antibiotic) NH2 N

NH2

N NH2

O

guanidine

MeO

Br

MeO

MeO

NH2

H

MeO

MeO

MeO

OEt

EtO

OEt

EtO FGI

O

O

O

O

O

NH

H2N

OMe

MeO

OMe

OMe

MeO OMe O

O O

O

2. ArCH2Br

OEt

EtO

O OEt NaCl

EtO

1. NaH MeO

OEt HCO2Et

MeO

DMSO MeO

EtO MeO

OMe

OMe NH2

NH2

OH O

NH2

OEt H2N

N

NH

N

N OH

MeO MeO

2. NH3

N NH2

1. POCl3 MeO

MeO OMe

MeO

MeO OMe

OMe

Pyrimidines 

Biginelli Reaction: Reaction: acid acid--catalyzed catalyzed,, reaction between an aldehyde, aldehyde, a,ß--ketoester and urea constitutes a rapid and facile synthesis of a,ß 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 



Fischer Indole Synthesis:

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

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



Skraup--reaction Skraup





Mechanism:

OH HO

H+ OH

O

H2C

CHO

NH2

H

N H

[O] N H

N

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





Saturated aldehyde can aldolcondensate to  --unsaturated aldehyde to form a quinoline (Doebner Doebner--Miller –reaction reaction))

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Quinolines 

Conrad--Limpach reaction: Synthesis of 4Conrad oxyquinolines by condensation of esters of beta-keto acids with aromatic amines Skraup Skraup--reaction CH3 < 100 °C CO2Et + NH2

O

CH3

O

+

H

- H2O N H

O

- H2O

N H

CH3

O

O CO2Et

D - EtOH

N

260 °C

CH3 - EtOH

N H

CH3

Quinolines 

Friedländer--quinoline synthesis Friedländer CHO + NH2

O H3C

pH 12 CH3

N

CH3

Mechanism:

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Isoquinolines 

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

Isoquinolines  

Bischler--Napieralski Reaction: Bischler -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 



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

Synthesis y of Tadalafil

Isoquinolines 

PomeranzPomeranzFritsch Reaction

EtO O R

+

OEt

OEt - H2O

O

OEt

H3O+ N

N

H2N

R

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

OH - H2O N R



N R

SchlittlerSchlittlerMüller 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

O N

N

O Ph C Cl CH3 Cl AlCl3

CH3 O

CH3 N H NaOH, H2O

O

Cl

Cl CH3 O N

CH3 O N NH3

Cl

N

Cl

O

O Cl

Cl

Cl

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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