1. Synthesis of heterocyclic compounds. Tapio Nevalainen. Drug synthesis II.
2010 http://www.scripps.edu/chem/baran/heterocycles/. Heterocyclic compounds.
Synthesis of heterocyclic compounds
Tapio Nevalainen Drug synthesis II 2010
http://www.scripps.edu/chem/baran/heterocycles/
Heterocyclic compounds • Heterocycles contain one or more hereroatoms in a ring
X X Y
X Z
Y
X,Y,Z are usually N,O,S
1
Heterocycles • Aromatic five‐membered heterocycles
Heterocycles • Aromatic six‐membered heterocycles
5
7 8
5
4
6
N 1
quinoline
3
6
2
7 8
5
4 3
6
N2
7
1
isoquinoline
8
4
N
5
N3
6
2
7
1
quinazoline
8
4
N N
3 2
1
quinoxaline
2
Heterocycles • Aliphatic heterocycles
Heterocycles • Tautomerism
3
Reactions of heterocycles Five‐membered heterocycles are good nucleophiles • Reaction with bromine requires no Lewis acid and leads to substitution at all four free positions.
In Friedel–Crafts reactions the 2 the 2‐‐position is more reactive than the 3‐position the 3‐ p
Reactions of heterocycles Vilsmeier reaction (Vilsmeier‐Haack reaction) allows the formylation of heterocyclic and electron‐rich arenes. The formylating agent, y g g , chloroiminium ion, is formed in situ from N,N‐dimethylamide and POCl3
O H N H
CH3 N CH3
1. POCl3
O H
N H
2. H2O
4
Reactions of heterocycles • Aromatic heterocycles undergoes aminoalkylation (Mannich reaction) • For example N‐methylpyrrole reacts at the 2‐position . Reaction is used in the manufacture of the nonsteroidal anti‐inflammatory compound, tolmetin. compound, tolmetin. CH3 HN CH3 N H3C
CH2=O Mannich reaction
N H3C
H3C N CH 3
H3C
O
N CH3
H3C N CH 3
Tolmetin
Five Five‐‐membered heterocycles act as dienes act as dienes in Diels– in Diels–Alder reactions
Common building‐blocks for heterocyclic compounds
5
General strategies for heterocycle synthesis • ”1+4” strategy
”1+5” strategy
General strategies General strategies for for heterocycle heterocycle synthesis ”2+3” strategy ”2+3” strategy
”3+3” strategy ”3+3” strategy
Examples O X
H2N
H2N
O
HO
O
H2N
O H
X
H2N
O X X = Cl, Br, I
O O
6
Reactions used in heterocyclic ring synthesis Aldol‐‐type reactions of Aldol of enols enols or enolate anions with electrophiles. electrophiles.
Imine/enamine formation
Reactions used in heterocyclic ring synthesis •Enamine is tautomeric form of imine. If dialkylamine is used, enamine is formed used, enamine is formed
H R2
N
Enamines can function as as enolates enolates H
O
H
R3
R1 enamine
N
H
H R1 OH R3
R2
R4 R4
N
H
+
-H
+ H+
H R1
R2 R3
O
H - H2O
N
R1
R2
- H+
N
R4
H R1
R2
R3
R3
H R4
H
H
R4
7
Reactions used in heterocyclic ring synthesis •When the process leads to C‐heteroatom bond formation, then the nucleophile is an appropriate heteroatom. then the nucleophile is an appropriate heteroatom.
Furans
Paal Knorr
Feist--Benary Feist
8
Thiophenes Paal Knorr
•Hinsberg Synthesis of Thiophene Derivatives
Gewald reaction
Pyrroles •Knorr pyrrole 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))
9
Pyrroles • Hantzsch pyrrole synthesis: from α‐halomethyl ketones, β‐keto esters and ammonia or amines
Huisgen Pyrrole Synthesis
A. Hantzsch, Ber. 23, 1474 (1890)
From Amino acids and alkynes. Example: atorvastatin
1,2‐Azoles Pyrazoles can be synthesized from 1,3 1,3‐‐dicarbonyls with hydrazine
Isoxazoles can be made from 1,31,3-dicarbonyl compounds or βketoesters with hydroxylamine
10
1,2‐Azoles Example of pyrazole synthesis: Rimonabant
1,2‐Azoles The synthesis of sildenafil (Viagra)
Retrosynthesis
11
1,2‐Azoles The synthesis of sildenafil (Viagra)
Bioorg. Med. Chem. Lett. 6, pp. 1819, 1996
1,2‐Azoles The synthesis of sildenafil (Viagra) O OEt O
H2N Cl +
O C 3 CH N N pyridine
H2N
CH3 N N
H2N EtO
CH3
EtO
HN
ClSO2OH
CH3 N N
N CH3 O EtO
HN
HN
CH3 N N
N N
CH3
HN
CH3
OEt
CH3 N N
N
O S O Cl
NaOH
HN O
O
O EtO
CH3
CH3
O S O N N
CH3
Bioorg. Med. Chem. Lett. 6, pp. 1819, 1996
12
1,2‐Azoles synthesis of isoxazoles By 1,3 1,3--cycloaddition from nitrile oxides and unsaturated compounds
Nitrile oxides can be prepared by the -elimination of chlorooximes or the dehydration of nitroalkanes
1,3‐Azoles •Oxazoles and thiazoles can be obtained by the Robinson‐Gabriel synthesis from 2‐acylamino‐ketones.
2‐acylamino acylamino‐‐ketones reacts with phosphorus pentasulfide to form thiazoles pentasulfide to form thiazoles
13
1,3‐Azoles • Oxazoles can be made by Blümlein‐Lewy Synthesis: heating an haloketone with amide
Most important method for thiazoles for thiazoles is is Hantzsch Hantzsch thiazole synthesis from thioamides and a and a‐halocarbonyl compounds
1,3‐Azoles
Example:: synthesis of nizatidine Example
14
1,3‐Azoles: Synthesis of imidazoles •From amidines and hydroxy or halocarbonyl compounds
Debus‐Radziszewski imidazole synthesis Debus‐ synthesis:: diketone and ammonia form an diimine, which condenses with the aldehyde the aldehyde
For more imidazole syntheses, look: http://www.scripps.edu/chem/baran/images/grpmtgpdf/Zografos_Feb_04.pdf
1,3‐Azoles: Imidazoles from isocyanides • The reaction of aldehydes, primary amines and toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5‐ trisubstituted imidazoles (van Leusen et al. J. Org. Chem. 1977, 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
15
1,3‐Azoles: Imidazoles from isocyanides • Substituted tosylmethyl isocyanides (TosMICs) are synthesized from tosylmethyl formamides and p‐methylphenylsulphinic acid.
• Synthesis of the GSK p38 kinase inhibitor
1,3‐Azoles Synthesis of 2-Butyl-4-chloro-5-hydroxymethyl-1Himidazole
O
H N HO
CH3
HO
N
H2N OH
CH3
HN
Cl
Cl O HO
H2N + OH HN
H N
NH3, MeOH
CH3
HO
1. Me3SiCl, 2.Chlorosuccinimide 3. Zn, AcOH
H N HO
CH3 N
HN
N N N
CH3 N
Cl 2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazole
N HO
CH3 N
Cl Losartan
Synthetic Communications (1993), 23(18), 2623-30.
16
Dihydroimidazoles Clonidine (anti-hypertensive agent)
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
CH3 N Oxymetazoline
1,4‐Dihydropyridines • Hantzsch Dihydropyridine (Pyridine) Synthesis
4-Aryl-1,4-dihydropyridines (e.g. nifedipine) p ) are calcium channel modulators for the treatment of cardiovascular diseases such as hypertension, cardiac arrhythmias, or angina.
17
Pyridines •Pyridoxine, vitamin B6, has been synthesised by Guareschi ring synthesis
Glutarimides
Thalidomide
O NH2
O
O O
H2N
O
Ac2O N
N
O
O O
O CO H 2
F3C CO2H
O 2-phthalimido-D-glutaric acid
NH2 HOBt EDCCI
O O Thalidomide
O O N
O NH
O O (R)-Thalidomide
HOBt = N-hydroxybenzotriazole N N N OH EDCCl = N-(3-dimethylamino)propylN'-ethylcarbodiimide hydrochloride
Tetrahedron Letters (1999), 40(19), 3697-3698. H3C
O NH
OH
O
N
O
NH2
OH
N N C
CH3 NH+ Cl CH3
A i Aminoglutethimide l t thi id
18
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
NH
H2N
R3
R1
O
R2
R3
R1 NH2
NH2
N
N
H2N
NH
R2
S
S
NH
N
NH2
H2N
R3
R1
R3 R2
O
O
NH
N NH2 R1
H2N
R3
R1
R2
R2
Pyrimidines •Example: trimethoprim (bacteriostatic antibiotic) NH2 N
NH2
N
H2N NH2
O
O
guanidine EtO FGI
O
MeO
MeO
NH2
EtO
O OEt Br
MeO MeO OMe
OMe
OEt
MeO
MeO H
O
O
NH
MeO OMe
MeO OMe
19
Pyrimidines •Biginelli Reaction: acid‐catalyzed, reaction between an aldehyde, a,ß‐ketoester and urea constitutes a rapid and facile synthesis of tetrahydropyrimidones.
•Synthesis of rac‐Monastrol (Mitosis blocker by kinase Eg5 inhibition)
Tetrazoles
Carboxylic acid isostere Synthesis
Synthesis of Losartan (antihypertensive antihypertensive))
20
Indoles
Fischer Indole Synthesis:
The conversion of aryl hydrazones to indoles;; requires elevated temperatures indoles and the addition of Brønsted or Lewis acids
Synthesis y of Sumatriptan p
(Daniel Lednicer Lednicer::
Strategies for Organic Drug Synthesis and Design)
Quinolines
Quinoline nucleus is usually is usually formed in in one one of of two two ways
•Skraup‐reaction
O
Mechanism:
OH HO
+
H OH O
O
H2C
- 2 H2O
NH2
H
N H H
H OH [O]
N H
N H
- H2O
N H
N
21
Quinolines • Doebner‐Miller –reaction: ‐unsaturated ketone or aldehyde can be used instead of glycerol to form a quinoline
Conrad‐‐Limpach reaction: Synthesis of 4 Conrad Limpach reaction: Synthesis of 4‐‐oxyquinolines by condensation of esters of beta‐ condensation of esters of beta‐keto acids with aromatic amines
Quinolines •Friedländer‐quinoline synthesis
22
Isoquinolines
The general synthetic routes to isoquinolines involve the following g skeletal types: yp
Isoquinolines •Bischler‐Napieralski Reaction:
-Phenylethylamine is acylated then cyclodehydrated using phosphoryl chloride, phosphorous pentoxide or other lewis acids. This gives the dihydroisoquinoline, dihydroisoquinoline, which can be aromatised by dehydrogenation with palladium. E.g. in the synthesis of papaverine
23
Isoquinolines •Pictet‐Spengler synthesis: β‐Arylethylamine is heated in the presence of an aldehyde and acid. • A special case of the Mannich reaction.
Synthesis of Tadalafil
Isoquinolines • Pomeranz‐ Fritsch Reaction
EtO O R
+
OEt
OEt - H2O
O
OEt
H3O+ N
N
H2N
R
R C. Pomeranz C Pomeranz, Monatsh Monatsh. 14 14, 116 (1893) P. Fritsch, Ber. 26, 419 (1893)
OH - H2O N R
N R
SchlittlerSchlittlerMüller ü e Reaction
24
Quinolones •Retrosynthesis
Synthesis
Thiadiazoles •Synthesis of Timolol (‐blocker)
25
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
AlCl3
CH3 O
Cl
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)
26