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))
1
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
2
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.
3
Example of pyrazole synthesis: Rimonabant
Pyrazoles: The synthesis of sildenafil (Viagra) Retrosynthesis
4
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
6
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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