Fundamentals of Medicinal Chemistry

COCl

H 2 NCH 2 CH 2 N(C 2 H 5 ) 2

O 2 N

O 2 N

CONHCH 2 CH 2 N(C 2 H 5 )

H 2 N CONHCH 2 CH 2 N(C 2 H 5 ) 2

H 2 / Raney Ni

OH

C1CH 2 CH 2 N(CH 3 ) 2

N Ph

CH 3

NaNH 2

N Ph

CH 3

OCH 2 CH 2 N(CH 3 ) 2

N Ph

CH 3

O− Na+

1-Phenyl-1-(2-pyridyl)ethanol

Doxylamine (antihistimimic, hypnotic)

O-Alkylation

H 2 NSO 2 NH 2 H 2 NSO 2

BrCH 2 COOH (1 mole)

NaHCO 3 / C 2 H 5 OCH 2 CH 2 OH

100 
C / 32 hours

NHCH 2 COOH

Dapsone (antibacterial leprostatic) Acediasulphone (antibacterial)

N-Alkylation

O-Acylation

Metronidazole (antiprotozoal) Metronidazole 4-(morpholinylmethyl)benzoate (antiprotozoal)

NO 2

CH 3

N−CH 2 CH 2 OH

N

NO 2

CH 3

N−CH 2 CH 2 OCO

N

CH 2 −N O

C

O

Cl

CH 2 −N O

N-Acylation

Chloramphenicol (antibacterial)

O 2 N CHCH O 2 N

OH CH 2 OH

NHCOCHCl 2

CHCH

CO

CO

O

OH

(ii) NaOH NHCOCHCl

2

(i)

CH 2 OCOCH 2 CH 2 COONa

Chloramphenicol sodium succinate (antibacterial)

Succinylsulphathioazole (antibacterial)

4-Nitrobenzoyl chloride Procainamide

Sulphathioazole (antibacterial)

N

S

NHSO 2 NH 2

CO

CO

O

CH 3 CH 2 OH

N

S

NHSO 2 NHCOCH 2 CH 2 COOH

ACID and BASIC GROUPS

Figure 3.6 Examples of water solubilizing structures and the routes used to introduce them into

the lead structures. O-alkylation, N-alkylation, O-acylation and N-acylation reactions are used to

introduce both acidic and basic groups. Acetylation methods use both the appropriate acid

chloride and anhydride.

68 AN INTRODUCTION TO DRUG DISCOVERY