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SynthesisSynthesis of of heterocyclicheterocycliccompoundscompounds

Tapio NevalainenTapio Nevalainen

DrugDrug synthesissynthesis IIII

20102010

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

KnorrKnorr pyrrolepyrrole synthesissynthesis:: CondensationCondensation ofof --aminoketoneaminoketone and and --ketoesterketoester

Pyrrole synthesisPyrrole synthesis

PaalPaal--KnorrKnorr PyrrolePyrrole--SynthesisSynthesis: : condensationcondensation amineamine and 1,4and 1,4--ketone ketone

ExampleExample: : SynthesisSynthesis of of atorvastatinatorvastatin ((LipitorLipitor))

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PyrrolePyrrole synthesissynthesis Hantzsch Hantzsch pyrrolepyrrole synthesis:synthesis: from α-holomethyl ketones, β-keto

esters and ammonia or amines

A. Hantzsch, Ber. 23, 1474 (1890) Huisgen Huisgen PyrrolePyrrole SynthesisSynthesis

From Amino acids and alkynesExample: atorvastatinExample: atorvastatin

Thiophenes Thiophenes Hinsberg Synthesis of Thiophene Derivatives Hinsberg Synthesis of Thiophene Derivatives

Paal KnorrPaal Knorr

Gewald reactionGewald reaction Gewald reactionGewald reaction

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FuransFurans

Paal KnorrPaal Knorr

FeistFeist--BenaryBenary

PyrazolesPyrazoles

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

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

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Example of pyrazole synthesis: Example of pyrazole synthesis: RimonabantRimonabant

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

RetrosynthesisRetrosynthesis

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PyrazolesPyrazoles: The : The synthesissynthesis of of sildenafilsildenafil ((ViagraViagra))

BioorgBioorg. Med. Chem. . Med. Chem. LettLett. 6, pp. 1819, 1996. 6, pp. 1819, 1996

PyrazolesPyrazoles: The : The synthesissynthesis of of sildenafilsildenafil ((ViagraViagra))

H2NN

N

O CH3

Cl

Opyridine

H2NN

N

O CH3

HN

HNN

N

O CH3

NaOHOEt

EtO

EtO

CH3

H2NCl +

CH3

HN

OEt

OCH3

N

HNN

N

O CH3

CH3

N

SO O

HN

NCH3

N

HNN

N

O CH3

CH3

N

SO

ClSO2OH

EtO EtO

EtO

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

ClN

NCH3

O

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IsoxazolesIsoxazoles

OximationOximation of 1,3of 1,3--Dicarbonyl Dicarbonyl CompoundsCompounds oror ββ--KetoestersKetoesters

O N

R3R1

R2

R1

O O

R2

R3HO NH2

H2O/MeOH

NaOH

+

R1

O O

R

OEt

O NH

OR1HO NH2

H O/M OH

NaOH

+

HN O

OR1

RR2 R2H2O/MeOH R2

IsoxazolesIsoxazoles CycloadditionCycloaddition of of NitrileNitrile OxidesOxides to to UnsaturatedUnsaturated

CompoundsCompounds

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

NitrileNitrile oxidesoxides cancan bebe preparedprepared byby the the --eliminationelimination of of chlorooximeschlorooximesoror the the dehydrationdehydration of of nitroalkanesnitroalkanes

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AzolesAzoles OxazolesOxazoles and and thiazolesthiazoles can be obtained by the can be obtained by the

RobinsonRobinson--Gabriel synthesis from 2Gabriel synthesis from 2--acylaminoacylamino--ketones.ketones.

ImidazolesImidazolesN

NH

NH

Cl

Cl

X l t li

HN

N

CH3

CH3

CH3

H3C

CH3HN

NNH2

Hi t i

N

HN

CH3

S

HN

N

HN

CH3

CN

Ci tidiCl idi

SynthesisSynthesis of 1,2,5of 1,2,5--trisubstitutedtrisubstituted imidazoles fromfromNN--monosubstitutedmonosubstituted amidinesamidines and 2and 2--halohalo--33--alkoxyalkoxy--22--propenals propenals

XylometazolineHistamine CimetidineClonidine

J. Org Chem. 1997, 62, 8449

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ImidazolesImidazoles CimetidineCimetidine

OH2N

O

HO

NO

O

2

NHN S

NH2

NHN OH

HSNH2

NHN O

O

Cl

OOBredereckreaction*

H2N H

HN O

H

N

O+ H

O

H

N O

H

N

O+H

H

N

HN

CN

S

2

LiAlH4

NHN S

HN

N

HN

CNcimetidine

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

ImidazolesImidazoles

22--ButylButyl--44--chlorochloro--55--hydroxymethylhydroxymethyl--1H1H--imidazoleimidazoleimidazoleimidazole

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DihydroimidazolesDihydroimidazoles

ClonidineClonidine ((antianti--hypertensivehypertensive agentagent))(( ypyp gg ))

Oxymetazoline (topical decongestant) Oxymetazoline (topical decongestant)

Oxymetazoline

HN

N

CH3

CH3

HOCH3

CH3

HOCN

CH3

CH3

HOCl

CH3

CH3

HO

CH2O/HCl H2N

H2N

235°C, N2

KCN

ImidazolesImidazoles fromfrom isocyanidesisocyanides The The reactionreaction of of aldehydesaldehydes, , primaryprimary aminesamines and and

toluenesulphonylmethyltoluenesulphonylmethyl isocyanideisocyanide (TOSMIC) (TOSMIC) yieldyield 1,4,51,4,5--trisubstitutedtrisubstituted imidazolesimidazoles (A M an(A M an Le senLe sen JJ WildemanWildeman O HO Htrisubstituted trisubstituted imidazolesimidazoles (A. M. van (A. M. van LeusenLeusen, J. , J. WildemanWildeman, O. H. , O. H. OldenzielOldenziel, , J. J. OrgOrg. . ChemChem.. 19771977, , 4242, 1153. , 1153.

R1NH2 +

R1 N R2

CH3

S

O

ON

R3

N R2

R3

TOSMIC- H2O

Base

CH

O

R2

N TsC

H

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

2

R1

N

NTsR3

R1

N R2

NR3

+

H3C

S

O

OH

BaseR1

Base

H

R2

H

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ImidazolesImidazoles fromfrom isocyanidesisocyanides Substituted Substituted tosylmethyltosylmethyl isocyanides (isocyanides (TosMICsTosMICs) are synthesized from ) are synthesized from

tosylmethyltosylmethyl formamidesformamides and and pp--methylphenylsulphinicmethylphenylsulphinic acidacid..

Synthesis of the GSK p38 Synthesis of the GSK p38 kinasekinase inhibitor inhibitor

ThiazolesThiazoles Most important method for syntesis of thiazoles is Most important method for syntesis of thiazoles is

from thioamides and from thioamides and --halocarbonyl compoundshalocarbonyl compounds

ExampleExample: : synthesissynthesis of of nizatidinenizatidine

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OxazolesOxazoles Robinson-Gabriel synthesis: cyclodehydration of -acylaminocarbonyl

compounds

BlümleinBlümlein--LewyLewy SynthesisSynthesis: : heatingheating an an haloketonehaloketone withwith amideamide

1,41,4--DihydropyridinesDihydropyridinesHantzsch Dihydropyridine (Pyridine) Synthesis• 4-Aryl-1,4-dihydropyridines (e.g. nifedipine) are calcium channel

modulators for the treatment of cardiovascular diseases such as modulators for the treatment of cardiovascular diseases such as hypertension, cardiac arrhythmias, or angina.

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GlutarimidesGlutarimides TThalidomide

A i l t thi idA i l t thi id AminoglutethimideAminoglutethimide

PyrimidinesPyrimidines Pinner pyrimidine sythesis: from 1,3-dicarbonyl

compounds and amidines

NHH2N

R4NN

R4

R1 R3

NHN

O

R1 R3NH2H2N

O

Instead of amidines, pyrimidines are obtained also by using guanidine, urea and thiourea

R2

O

R3

OR2

R1

R2

NN

NH2

R1 R3

R2

R2

NHN

S

R1 R3

NHH2N

NH2

NH2H2N

S

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PyrimidinesPyrimidines Example: trimethoprim (bacteriostatic antibiotic)

NN

NH

NH2

NHH2N

NH2guanidine

FGI

OO

OEt

OO

OEtEtO EtO

OMe

NH2

OMe

NH2

OO

H

FGI

OMe

OMe

BrMeO

MeO MeO

MeO

MeO

MeO

MeO

MeO

OO

OEtOO

OEt

1. NaH

2. ArCH2BrNaCl

DMSO

O

OEtHCO2Et

EtO

MeO MeOEtO

EtO

OMe

NN

NH2

NH2

NHH2N

NH2

OMe OMe

EtO

OMe

O

OEt

OH

OMe

NN

OH

NH2

1. POCl3

2. NH3

MeO MeO

MeO

MeO

MeO

MeO

MeO

MeO

Pyrimidines Pyrimidines BiginelliBiginelli ReactionReaction: : acidacid--catalyzedcatalyzed, , reactionreaction betweenbetween an an aldehydealdehyde, ,

a,ßa,ß--ketoesterketoester and urea and urea constitutesconstitutes a a rapidrapid and and facilefacile synthesissynthesis of of

tetrahydropyrimidonestetrahydropyrimidones..

Synthesis of rac-Monastrol (Mitosis blocker by kinase Eg5 inhibition)inhibition)

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TetrazolesTetrazoles Carboxylic acid isostereCarboxylic acid isostere

SynthesisSynthesis

Synthesis of Losartan (antihypertensive)Synthesis of Losartan (antihypertensive)

IndolesIndoles Fischer Indole Synthesis:

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

Synthesis of Sumatriptan Synthesis of Sumatriptan

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

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QuinolinesQuinolines Quinoline nucleus is usually formed in one of Quinoline nucleus is usually formed in one of

two waystwo ways

SkraupSkraup--reactionreaction

MechanismMechanism:: OH

OH

HO

OH2C

H

NH2

NH

CHO

NH N

[O]

H+

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

SaturatedSaturated aldehydealdehyde cancan aldolcondensatealdolcondensate to to --unsaturatedunsaturated aldehydealdehyde to to formforma a quinolinequinoline ((DoebnerDoebner--MillerMiller ––reactionreaction))

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QuinolinesQuinolines ConradConrad--Limpach reaction: Limpach reaction: Synthesis of 4-

oxyquinolines by condensation of esters of beta-keto acids with aromatic amines SkraupSkraup--reactionreaction

NH CH+

NH

CH3

ONH

O

CH3

O< 100 °C

- H2OH+

- H2OCO2Et

NH2 CH3O

NH

O

CH3

260 °C

N CH3

D

- EtOH - EtOH

CO2Et

QuinolinesQuinolines

FriedländerFriedländer--quinoline synthesisquinoline synthesis

Mechanism:Mechanism:

CH3

O

H3CNH2

CHO

N CH3

+pH 12

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IsoquinolinesIsoquinolines

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

IsoquinolinesIsoquinolines BischlerBischler--Napieralski Reaction:Napieralski Reaction:

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

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IsoquinolinesIsoquinolines PictetPictet--Spengler synthesis:Spengler synthesis: ββ--ArylethylamineArylethylamine is is heatedheated in the in the presencepresence

of an of an aldehydealdehyde and and acidacid..

A A specialspecial case of the case of the MannichMannich reactionreaction. .

Synthesis of TadalafilSynthesis of Tadalafilyy

IsoquinolinesIsoquinolines PomeranzPomeranz--

Fritsch Fritsch ReactionReaction

NH2

EtO OEt

R

ON

OEt

OEt

R

N

O

R

C P M t h 14 116 (1893)

+- H2O H3O

+

R

N

R

N

OH

- H2O

C. Pomeranz, Monatsh. 14, 116 (1893)P. Fritsch, Ber. 26, 419 (1893)

SchlittlerSchlittler--MüllerMüllerMüller Müller ReactionReaction

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QuinolonesQuinolones

Retrosynthesis

Synthesis

ThiadiazolesThiadiazoles SynthesisSynthesis of of TimololTimolol ((--blockerblocker))

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BenzodiazepinesBenzodiazepines The retrosynthesis of diazepamThe retrosynthesis of diazepam

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

Cl

NH

CH3

N

O

CH3

C

O

ClPh

AlCl3Cl

N

O

CH3

ONaOH, H2O

Cl

NH

O

CH3

Ac2O

Cl Cl

ClO

Cl

Cl

N

O

CH3O

ClNH3

Cl N

NO

CH3

Diazepam

BenzodiazepinesBenzodiazepines 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)