Verlukast

Chemical Properties

Dark Yellow Solid

Originator

Verlukast,Merck Frosst (Merck and Co.)

Uses

A receptor antagonist for the treatment of respiratory diseases.

Manufacturing Process

5-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6- dithiaoctanoic acid was prepared in 7 steps:
Step 1: Preparation of 2-bromomethyl-7-chloroquinoline:
A solution of 7-chloroquinaldine (177 g, 1 mole) N-bromosuccinimide (178 g, 1 mole), benzoylperoxide (1 g) in 2 L CCl 4 were heated at reflux for 2 days under a sun lamp. The reaction mixture was cooled, and passed through a plug of SiO 2 (approx. 1 Kg) using toluene as eluent. Chromatography on 2 x 1 kg SiO 2 columns using toluene as eluent afforded 110-120 g of the title compound, MP: 112°C.
Step 2: Preparation of (7-chloroquinolin-2-yl)-methyltriphenylphosphonium bromide:
To a suspension of 2-bromomethyl-7-chloroquinoline (120 g, 0.5 mol) in 800 ml of CH 3 CN at 60°C was added triphenylphosphine (183 g). The reaction mixture was heated overnight at 60°C, cooled and 400 ml ether was added. The solid was filtered and dried to yield 170 g phosphonium salt.
Step 3: Preparation of dimethyl 5-(3-formylphenyl)-4,6-dithianonanedioate:
To a solution of isophthalaldehyde (40 g, 0.3 mol.) in chloroform (400 ml) and methyl 3-mercaptopropanoate (68 ml, 0.6 mol) was added dropwise trimethylsilyl chloride (48 ml, 0.38 mol) over 30 min. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with 25% aq. NH 4 OAc, extracted with ethyl acetate, dried and evaporated. Flash chromatography of the residue afforded 50 g of the title compound.
Step 4: Preparation of dimethyl 5-(3-(2-(7-chloroquinolin-2- yl)ethenyl)phenyl)-4,6-dithianonanedioate:
To a suspension of 190 g phosphonium salt from Step 2 (0.36 mol.) in THF (2 L) at -78°C were added 1.6 M BuLi (220 ml) dropwise over 1.5 hrs. The resulting brown suspension was stirred 30 min at -78°C. To the suspension was added the aldehyde (Step 3) (11.7 g, 0.32 mol.) in THF (400 ml) dropwise over 1.5 hrs. The reaction mixture was allowed to warm to room temperature and quenched with pH 7 buffer (approx. 2 L). Ethyl acetate (1 L) was added. The organic phase was separated, dried and evaporated. Flash chromatography of the residue using 30% ethyl acetate hexane; followed by crystallization with 3:1 hexane/ether afforded 135 g of the title compound as a white solid. MP: 53°C.
Step 5: Preparation of methyl 5-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate:
A solution of the aluminum reagent was prepared by adding dropwise 150 ml of 2 M trimethylaluminum in hexane at -20°C to a solution of 2 M dimethylamine in toluene (300 ml). The solution was allowed to warm to room temperature. To the diester (step 4) (95 g) in CH 2 Cl 2 (1 L) was added dropwise 150 ml of the aluminum reagent. The reaction was stirred 7-8 hrs at room temperature. The reaction was carefully quenched at 0°C with 2 N HCl (until the vigorous reaction subsided); then pH 7 buffer (25% NH 4 OAc in H 2 O) (1 L) and CH 2 Cl 2 (1 L) were added. The organic phase was separated, dried and evaporated. Flash chromatography of the residue using first 50% ethyl acetate hexane followed by ethyl acetate afforded 38 g recovered di-ester and 38 g desired amide. The recovered di-ester was recycled through the sequence to give 18 g di-ester and 14 g desired amide. Total yield: 52 g of amide.
Step 6: Preparation of 5-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-8- dimethylcarbamyl-4,6-dithiaoctanoic acid:
To the amide (30 g) in 800 ml 1,2-dimethoxyethane (DME) was added 1.5 eq 1 N LiOH (75 ml). The reaction mixture was stirred one hour under N 2 . The DME was evaporated. The residue was partitioned between H 2 O (500 ml) and ethyl acetate (1 L). The aqueous phase was reextracted with ethyl acetate (500 ml). The aqueous phase was acidified with AcOH and a little 2 N HCl to pH 4 and extracted with ethyl acetate (2 x 600 ml). The organic phase was dried and evaporated. The residue was co-evaporated with toluene (300 ml) and triturated with cold ethyl acetate to give 18 g of the acid. MP: 153-155°C. Recrystallization from 2-butanone gave MP: 157-158°C.

Therapeutic Function

Anti-asthmatic, Antiallergic