120443-16-5 Usage
Uses
Used in Pharmaceutical Industry:
Verlukast is used as a receptor antagonist for the treatment of respiratory diseases. It works by blocking the action of leukotriene receptors, which are involved in the inflammatory process of the airways. This helps to reduce inflammation and constriction in the airways, providing relief from asthma and other respiratory conditions.
Used in Respiratory Medicine:
In the field of respiratory medicine, Verlukast is used as a therapeutic agent to manage and alleviate symptoms of asthma and other respiratory diseases. Its receptor antagonist properties make it an effective treatment option for patients suffering from these conditions, improving their quality of life and reducing the frequency of asthma attacks.
Originator
Verlukast,Merck Frosst (Merck and Co.)
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
Check Digit Verification of cas no
The CAS Registry Mumber 120443-16-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,0,4,4 and 3 respectively; the second part has 2 digits, 1 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 120443-16:
(8*1)+(7*2)+(6*0)+(5*4)+(4*4)+(3*3)+(2*1)+(1*6)=75
75 % 10 = 5
So 120443-16-5 is a valid CAS Registry Number.
InChI:InChI=1/C26H27ClN2O3S2/c1-29(2)24(30)12-14-33-26(34-15-13-25(31)32)20-5-3-4-18(16-20)6-10-22-11-8-19-7-9-21(27)17-23(19)28-22/h3-11,16-17,26H,12-15H2,1-2H3,(H,31,32)/b10-6+
120443-16-5Relevant articles and documents
Aluminum-Amine Complexes for the Conversion of Carboxylic Esters to Amides. Application to the Synthesis of LTD4 Antagonist MK-0679
Sidler, Daniel R.,Lovelace, Thomas C.,McNamara, James M.,Reider, Paul J.
, p. 1231 - 1233 (1994)
The preparation and characterization of N,N-dimethylammonium dialkylaluminum chloride and the use of these complexes in the synthesis of the LTD4 antagonist MK-0679 is described.
A Practical Chemoenzymatic Synthesis Of An LTD4 Antagonist
Hughes, D. L.,Song, Z.,Smith, G. B.,Bergan, J. J.,Dezeny, G. C.,et al.
, p. 865 - 874 (2007/10/02)
Enzymatic asymmetrization of a prochiral diester having 4 bonds between the ester group and prochiral center is the comerstone of a short and efficient synthesis of an LTD4 antagonist.The enzymatic hydrolysis occurs in a heterogeneous slurry, but a kineti
Chemoenzymatic synthesis of a novel LTD4 antagonist
Shinkai, I,Bhupathy, M
, p. 127 - 130 (2007/10/02)
An efficient four-step synthesis of the novel receptor antagonist (MK-0679) of leukotriene D4 (LTD4) has been described.The key steps are enzymatic hydrolysis of prochiral diester to the ester-acid in 98percent enantiomeric excess fo
Lipase-Catalyzed Asymmetric Hydrolysis of Esters Having Remote Chiral/Prochiral Centers
Hughes, D. L.,Bergan, J. J.,Amato, J. S.,Bhupathy, M.,Leazer, J. L.,et al.
, p. 6252 - 6259 (2007/10/02)
Enzymatic hydrolysis of prochiral and racemic dithioacetal esters having up to five bonds between the prochiral/chiral center and the ester carbonyl group proceeds with selectivities up to 98 percent enantiomeric excess when commercially available lipases
ASYMMETRIC DITHIOACETALS III: THE PREPARATION OF THE ENANTIOMERS OF 3-((((3-(2-(7-CHLOROQUINOLIN-2-YL)-(E)-ETHENYL)PHENYL)-3-DIMETHYLAMINO-3-OXOPROPYLTHIO)METHYL)THIO)PROPIONIC ACID (L-660,711) (MK-571), AN ANTAGONIST OF LEUKOTRIENE D4
Young, Robert N.,Gauthier, Jacques Yves,Therien, Michel,Zamboni, Robert
, p. 967 - 978 (2007/10/02)
The application of a novel method for the preparation of chiral dithioacetals to the synthesis of the enantiomers of L-660,711, an antagonist of leukotriene D4, is described.Reaction of 3-(t-butyldiphenylsilyloxymethyl)benzaldehyde or isophthal
